This file contains full details on each clinical trial selected for download. Where multi-state trials have been downloaded full information for each of the member states/countries involved in the trial are included separately. Summary EudraCT Number: 2013-002396-17 Sponsor's Protocol Code Number: NA National Competent Authority: UK - MHRA Clinical Trial Type: EEA CTA Trial Status: Prematurely Ended Date on which this record was first entered in the EudraCT database: 2013-08-02 Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-002396-17/GB/ A. Protocol Information A.1 Member State Concerned: UK - MHRA A.2 EudraCT number: 2013-002396-17 A.3 Full title of the trial: The effect of Pramipexole on recovery from chronic post-stroke aphasia A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: Does the drug Pramipexole improve the verbal communication ability of stroke patients with impaired language function? A.3.2 Name or abbreviated title of the trial where available: Pramipexole in aphasia A.4.1 Sponsor's protocol code number: NA A.7 Trial is part of a Paediatric Investigation Plan: No A.8 EMA Decision number of Paediatric Investigation Plan: B. Sponsor Information Sponsor 1 B.1.1 Name of Sponsor: Birmingham Community Healthcare NHS Trust B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: Birmingham Community Healthcare NHS Trust B.4.2 Country: United Kingdom B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: Birmingham Community Healthcare NHS Trust B.5.2 Functional name of contact point: Dr. Clive Thursfield B.5.3 Address B.5.3.1 Street Address: West Midlands Rehabilitation Centre, 91 Oak Tree Lane B.5.3.2 Town/ city: Birmingham B.5.3.3 Post code: B29 6JA B.5.3.4 Country: United Kingdom B.5.4 Telephone number: 01214663042 B.5.6 E-mail: Clive.thursfield@bhamcommunity.nhs.uk D. IMP Identification D.IMP: 1 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: Yes D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Pramipexole D.3.4 Pharmaceutical form: Tablet D.3.4.1 Specific paediatric formulation: No D.3.7 Routes of administration for this IMP: Oral use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: pramipexole D.3.9.4 EV Substance Code: AS1 D.3.10 Strength D.3.10.1 Concentration unit: µg microgram(s) D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): No D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: No D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: No D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.8 Information on Placebo D.8 Placebo: 1 D.8.1 Is a Placebo used in this Trial? Yes D.8.3 Pharmaceutical form of the placebo: Tablet D.8.4 Route of administration of the placebo: Oral use E. General Information on the Trial E.1 Medical condition or disease under investigation E.1.1 Medical condition(s) being investigated: Post-stroke aphasia E.1.1.1 Medical condition in easily understood language: Post-stroke language impairment E.1.1.2 Therapeutic area: Diseases [C] - Nervous System Diseases [C10] MedDRA Classification E.1.3 Condition being studied is a rare disease: No E.2 Objective of the trial E.2.1 Main objective of the trial: Does Pramipexole when combined with standard speech and language therapy improve the clinical outcomes better than standard speech and language therapy alone in chronic post-stroke aphasia? E.2.2 Secondary objectives of the trial: NA E.2.3 Trial contains a sub-study: No E.3 Principal inclusion criteria: First-ever stroke at least 6 months prior to the start of the study and resulting in severe or moderately severe predominantly expressive aphasia. E.4 Principal exclusion criteria: Parkinson’s disease Major depressive illness Significant cognitive impairment Severe renal impairment Known hypersensitivity to dopamine agonists, pregnancy, breast feeding or psychosis Patients for whom English is not the first language will also be excluded because of concerns about the validity and reliability of the translated versions of the Western Aphasia Battery. E.5 End points E.5.1 Primary end point(s): Change in language function as measured with the Western Aphasia Battery E.5.1.1 Timepoint(s) of evaluation of this end point: Completition of treatment and follow up - end of week 8 of study. E.5.2 Secondary end point(s): NA E.5.2.1 Timepoint(s) of evaluation of this end point: NA E.6 and E.7 Scope of the trial E.6 Scope of the Trial E.6.1 Diagnosis: No E.6.2 Prophylaxis: No E.6.3 Therapy: Yes E.6.4 Safety: No E.6.5 Efficacy: Yes E.6.6 Pharmacokinetic: No E.6.7 Pharmacodynamic: No E.6.8 Bioequivalence: No E.6.9 Dose response: No E.6.10 Pharmacogenetic: No E.6.11 Pharmacogenomic: No E.6.12 Pharmacoeconomic: No E.6.13 Others: No E.7 Trial type and phase E.7.1 Human pharmacology (Phase I): No E.7.1.1 First administration to humans: No E.7.1.2 Bioequivalence study: No E.7.1.3 Other: No E.7.1.3.1 Other trial type description: E.7.2 Therapeutic exploratory (Phase II): Yes E.7.3 Therapeutic confirmatory (Phase III): No E.7.4 Therapeutic use (Phase IV): No E.8 Design of the trial E.8.1 Controlled: Yes E.8.1.1 Randomised: Yes E.8.1.2 Open: No E.8.1.3 Single blind: No E.8.1.4 Double blind: Yes E.8.1.5 Parallel group: No E.8.1.6 Cross over: No E.8.1.7 Other: No E.8.2 Comparator of controlled trial E.8.2.1 Other medicinal product(s): No E.8.2.2 Placebo: Yes E.8.2.3 Other: No E.8.2.4 Number of treatment arms in the trial: 4 E.8.3 The trial involves single site in the Member State concerned: Yes E.8.4 The trial involves multiple sites in the Member State concerned: No E.8.5 The trial involves multiple Member States: No E.8.6 Trial involving sites outside the EEA E.8.6.1 Trial being conducted both within and outside the EEA: No E.8.6.2 Trial being conducted completely outside of the EEA: No E.8.7 Trial has a data monitoring committee: No E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: LVLS E.8.9 Initial estimate of the duration of the trial E.8.9.1 In the Member State concerned years: 0 E.8.9.1 In the Member State concerned months: 7 E.8.9.1 In the Member State concerned days: 28 E.8.9.2 In all countries concerned by the trial years: 0 E.8.9.2 In all countries concerned by the trial months: 0 E.8.9.2 In all countries concerned by the trial days: 0 F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18: No F.1.1 Number of subjects for this age range: 0 F.1.1.1 In Utero: No F.1.1.1.1 Number of subjects for this age range: 0 F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No F.1.1.2.1 Number of subjects for this age range: 0 F.1.1.3 Newborns (0-27 days): No F.1.1.3.1 Number of subjects for this age range: 0 F.1.1.4 Infants and toddlers (28 days-23 months): No F.1.1.4.1 Number of subjects for this age range: 0 F.1.1.5 Children (2-11years): No F.1.1.5.1 Number of subjects for this age range: 0 F.1.1.6 Adolescents (12-17 years): No F.1.1.6.1 Number of subjects for this age range: 0 F.1.2 Adults (18-64 years): Yes F.1.2.1 Number of subjects for this age range: 10 F.1.3 Elderly (>=65 years): Yes F.1.3.1 Number of subjects for this age range: 30 F.2 Gender F.2.1 Female: Yes F.2.2 Male: Yes F.3 Group of trial subjects F.3.1 Healthy volunteers: No F.3.2 Patients: Yes F.3.3 Specific vulnerable populations: No F.3.3.1 Women of childbearing potential not using contraception : No F.3.3.2 Women of child-bearing potential using contraception: No F.3.3.3 Pregnant women: No F.3.3.4 Nursing women: No F.3.3.5 Emergency situation: No F.3.3.6 Subjects incapable of giving consent personally: No F.3.3.7 Others: No F.4 Planned number of subjects to be included F.4.1 In the member state: 40 F.4.2 For a multinational trial F.4.2.1 In the EEA: 0 F.4.2.2 In the whole clinical trial: 0 F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): None G. Investigator Networks to be involved in the Trial G.4 Investigator Network to be involved in the Trial: 1 G.4.1 Name of Organisation: Birmingham & the Black Country Comprehensive Local Research Network G.4.3.4 Network Country: United Kingdom N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision: Authorised N. Date of Competent Authority Decision: 2013-09-30 N. Ethics Committee Opinion of the trial application: Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion: N. Date of Ethics Committee Opinion: 2013-12-04 P. End of Trial P. End of Trial Status: Prematurely Ended P. Date of the global end of the trial: 2013-12-04 Summary EudraCT Number: 2014-002348-42 Sponsor's Protocol Code Number: RG_13-151 National Competent Authority: UK - MHRA Clinical Trial Type: EEA CTA Trial Status: Completed Date on which this record was first entered in the EudraCT database: 2014-10-21 Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002348-42/GB/ A. Protocol Information A.1 Member State Concerned: UK - MHRA A.2 EudraCT number: 2014-002348-42 A.3 Full title of the trial: Effectiveness of progesterone to prevent miscarriage in women with early pregnancy bleeding: A randomised placebo-controlled trial (PRISM Trial: PRogesterone In Spontaneous Miscarriage Trial) A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: Effectiveness of progesterone to prevent miscarriage in women with early pregnancy bleeding: A randomised placebo-controlled trial (PRISM Trial: PRogesterone In Spontaneous Miscarriage Trial) A.3.2 Name or abbreviated title of the trial where available: PRISM: PRogesterone In Spontaneous Miscarriage A.4.1 Sponsor's protocol code number: RG_13-151 A.7 Trial is part of a Paediatric Investigation Plan: No A.8 EMA Decision number of Paediatric Investigation Plan: B. Sponsor Information Sponsor 1 B.1.1 Name of Sponsor: University of Birmingham B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: National Institute for Health Research B.4.2 Country: United Kingdom B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: University of Birmingham B.5.2 Functional name of contact point: Professor Arri Coomarasamy B.5.3 Address B.5.3.1 Street Address: c/o Academic Unit, 3rd Floor, Birmingham Women's Hospital Foundation Trust, Mindelsohn Way B.5.3.2 Town/ city: Edgbaston, Birmingham B.5.3.3 Post code: B152TT B.5.3.4 Country: United Kingdom B.5.4 Telephone number: 01216272775 B.5.6 E-mail: a.coomarasamy@bham.ac.uk D. IMP Identification D.IMP: 1 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: Yes D.2.1.1.1 Trade name: Utrogestan 200mg capsules D.2.1.1.2 Name of the Marketing Authorisation holder: Laboratoire Besins International D.2.1.2 Country which granted the Marketing Authorisation: France D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Progesterone 200mg capsules D.3.4 Pharmaceutical form: Capsule D.3.4.1 Specific paediatric formulation: No D.3.7 Routes of administration for this IMP: Vaginal use Rectal use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: Each capsule contains 200 mg micronised progesterone (INN) D.3.9.1 CAS number: 57-83-0 D.3.9.4 EV Substance Code: AS1 D.3.10 Strength D.3.10.1 Concentration unit: mg milligram(s) D.3.10.2 Concentration type: equal D.3.10.3 Concentration number: 200 D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): No D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: No D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: No D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.8 Information on Placebo D.8 Placebo: 1 D.8.1 Is a Placebo used in this Trial? Yes D.8.3 Pharmaceutical form of the placebo: Capsule D.8.4 Route of administration of the placebo: Vaginal use E. General Information on the Trial E.1 Medical condition or disease under investigation E.1.1 Medical condition(s) being investigated: Vaginal bleeding in the first 12 weeks of pregnancy. E.1.1.1 Medical condition in easily understood language: Vaginal bleeding in the first 12 weeks of pregnancy. E.1.1.2 Therapeutic area: Body processes [G] - Reproductive physiologi cal processes [G08] MedDRA Classification E.1.3 Condition being studied is a rare disease: No E.2 Objective of the trial E.2.1 Main objective of the trial: To test the hypothesis that in women presenting with vaginal bleeding in the first trimester, progesterone (vaginal capsules 400mg twice daily), started as soon as possible after a scan has demonstrated a visible intrauterine gestation sac and continued to 16 completed weeks of gestation, compared with placebo, increases maternities with live births beyond 34 completed weeks by at least 5%. E.2.2 Secondary objectives of the trial: To test the hypothesis that progesterone improves other pregnancy and neonatal outcomes such as gestation at delivery, viable pregnancy at 12 weeks, and survival at 28 days of neonatal life. To test the hypothesis that progesterone is not associated with serious adverse effects to the mother or the neonate, including chromosomal and congenital abnormalities. To explore the effects of progesterone in prognostic subgroups, including age, fetal heart activity, gestation at presentation, amount of bleeding and body mass index. To explore the effect of progesterone on the use of healthcare resources such as antenatal, outpatient or emergency visits and inpatient admissions (nights in hospital, maternal admissions to high dependancy unit or intensive care unit, and neonatal admissions to special care baby unit or neonatal unit). E.2.3 Trial contains a sub-study: No E.3 Principal inclusion criteria: Women presenting with vaginal bleeding in the first 12 weeks of pregnancy with an intrauterine gestation sac visible on ultrasonography. E.4 Principal exclusion criteria: Women of age less than 18 years or ≥40; women with life-threatening bleeding; women already taking progesterone supplementation therapy; women with contraindications to progesterone use. E.5 End points E.5.1 Primary end point(s): Live births beyond 34 completed weeks of gestation, as a proportion of all women randomised. E.5.2 Secondary end point(s): Gestation at delivery; ongoing pregnancy at 12 weeks (range 11 – 13 weeks) gestation, miscarriage rate, survival at 28 days of neonatal life, chromosomal and congenital abnormalities, and adverse events. E.6 and E.7 Scope of the trial E.6 Scope of the Trial E.6.1 Diagnosis: No E.6.2 Prophylaxis: No E.6.3 Therapy: Yes E.6.4 Safety: Yes E.6.5 Efficacy: Yes E.6.6 Pharmacokinetic: No E.6.7 Pharmacodynamic: No E.6.8 Bioequivalence: No E.6.9 Dose response: No E.6.10 Pharmacogenetic: No E.6.11 Pharmacogenomic: No E.6.12 Pharmacoeconomic: No E.6.13 Others: No E.7 Trial type and phase E.7.1 Human pharmacology (Phase I): No E.7.1.1 First administration to humans: No E.7.1.2 Bioequivalence study: No E.7.1.3 Other: No E.7.1.3.1 Other trial type description: E.7.2 Therapeutic exploratory (Phase II): No E.7.3 Therapeutic confirmatory (Phase III): Yes E.7.4 Therapeutic use (Phase IV): No E.8 Design of the trial E.8.1 Controlled: Yes E.8.1.1 Randomised: Yes E.8.1.2 Open: No E.8.1.3 Single blind: No E.8.1.4 Double blind: Yes E.8.1.5 Parallel group: No E.8.1.6 Cross over: No E.8.1.7 Other: No E.8.2 Comparator of controlled trial E.8.2.1 Other medicinal product(s): No E.8.2.2 Placebo: Yes E.8.2.3 Other: No E.8.2.4 Number of treatment arms in the trial: 2 E.8.3 The trial involves single site in the Member State concerned: No E.8.4 The trial involves multiple sites in the Member State concerned: Yes E.8.4.1 Number of sites anticipated in Member State concerned: 23 E.8.5 The trial involves multiple Member States: No E.8.6 Trial involving sites outside the EEA E.8.6.1 Trial being conducted both within and outside the EEA: No E.8.6.2 Trial being conducted completely outside of the EEA: No E.8.7 Trial has a data monitoring committee: No E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: The interventional phase of the trial will end when the last participant recruited has completed her last dose of trial treatment. The observational phase of the trial will cease when the 28-day follow-up has been completed for the baby of the last participant recruited. E.8.9 Initial estimate of the duration of the trial E.8.9.1 In the Member State concerned years: 2 E.8.9.1 In the Member State concerned months: 11 E.8.9.1 In the Member State concerned days: 30 E.8.9.2 In all countries concerned by the trial years: 2 E.8.9.2 In all countries concerned by the trial months: 11 E.8.9.2 In all countries concerned by the trial days: 30 F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18: No F.1.1 Number of subjects for this age range: 0 F.1.1.1 In Utero: No F.1.1.1.1 Number of subjects for this age range: 0 F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No F.1.1.2.1 Number of subjects for this age range: 0 F.1.1.3 Newborns (0-27 days): No F.1.1.3.1 Number of subjects for this age range: 0 F.1.1.4 Infants and toddlers (28 days-23 months): No F.1.1.4.1 Number of subjects for this age range: 0 F.1.1.5 Children (2-11years): No F.1.1.5.1 Number of subjects for this age range: 0 F.1.1.6 Adolescents (12-17 years): No F.1.1.6.1 Number of subjects for this age range: 0 F.1.2 Adults (18-64 years): Yes F.1.2.1 Number of subjects for this age range: 4150 F.1.3 Elderly (>=65 years): No F.1.3.1 Number of subjects for this age range: 0 F.2 Gender F.2.1 Female: Yes F.2.2 Male: No F.3 Group of trial subjects F.3.1 Healthy volunteers: No F.3.2 Patients: Yes F.3.3 Specific vulnerable populations: No F.3.3.1 Women of childbearing potential not using contraception : No F.3.3.2 Women of child-bearing potential using contraception: No F.3.3.3 Pregnant women: No F.3.3.4 Nursing women: No F.3.3.5 Emergency situation: No F.3.3.6 Subjects incapable of giving consent personally: No F.3.3.7 Others: No F.4 Planned number of subjects to be included F.4.1 In the member state: 4150 F.4.2 For a multinational trial F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): Study participants will be given either progesterone or placebo (inactive) capsules, at a dose of 400mg, to insert vaginally twice a day. The treatment will be given up to 16 weeks of pregnancy. After 16 weeks of gestation, no further treatment will be given, and the participants will revert to routine antenatal care. There is no requirement for continued provision of the study drug beyond the sixteenth week of gestation. G. Investigator Networks to be involved in the Trial G.4 Investigator Network to be involved in the Trial: 1 G.4.1 Name of Organisation: BBC (Birmingham and Black Country) CLRN N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision: Authorised N. Date of Competent Authority Decision: 2014-12-10 N. Ethics Committee Opinion of the trial application: Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion: N. Date of Ethics Committee Opinion: 2014-11-26 P. End of Trial P. End of Trial Status: Completed P. Date of the global end of the trial: 2018-04-15 Summary EudraCT Number: 2014-000179-18 Sponsor's Protocol Code Number: RG_13-322 National Competent Authority: UK - MHRA Clinical Trial Type: EEA CTA Trial Status: Completed Date on which this record was first entered in the EudraCT database: 2015-03-10 Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-000179-18/GB/ A. Protocol Information A.1 Member State Concerned: UK - MHRA A.2 EudraCT number: 2014-000179-18 A.3 Full title of the trial: Local Oestrogen Treatment in Postmenopausal Women Undergoing Pelvic Organ Prolapse Surgery (LOTUS) - Feasibility Study A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: Local Oestrogen Treatment in Postmenopausal Women Undergoing Pelvic Organ Prolapse Surgery (LOTUS) A.3.2 Name or abbreviated title of the trial where available: LOTUS A.4.1 Sponsor's protocol code number: RG_13-322 A.7 Trial is part of a Paediatric Investigation Plan: No A.8 EMA Decision number of Paediatric Investigation Plan: B. Sponsor Information Sponsor 1 B.1.1 Name of Sponsor: University of Birmingham B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: NIHR RfPB grant B.4.2 Country: United Kingdom B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: University of Birmingham B.5.2 Functional name of contact point: Dr Tina Verghese B.5.3 Address B.5.3.1 Street Address: Birmingham Women's Hospital B.5.3.2 Town/ city: Birmingham B.5.3.3 Post code: B15 2Tg B.5.3.4 Country: United Kingdom B.5.4 Telephone number: 07903545731 B.5.6 E-mail: t.s.verghese@bham.ac.uk Sponsor 2 B.1.1 Name of Sponsor: Birmingham Women's Hospital B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: NIHR RfPB Grant B.4.2 Country: United Kingdom B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: Birmingham Women's NHS Foundation Trust B.5.2 Functional name of contact point: Kelly Hard B.5.3 Address B.5.3.1 Street Address: Metchley Park Road B.5.3.2 Town/ city: Edgbaston, Birmingham B.5.3.3 Post code: B15 2TG B.5.3.4 Country: United Kingdom B.5.6 E-mail: kelly.hard@bwnft.nhs.uk D. IMP Identification D.IMP: 1 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: Yes D.2.1.1.1 Trade name: Vagifem 10 micrograms vaginal tablets D.2.1.1.2 Name of the Marketing Authorisation holder: Novo-Nordisk D.2.1.2 Country which granted the Marketing Authorisation: United Kingdom D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Vagifem 10 micrograms vaginal tablets D.3.4 Pharmaceutical form: Vaginal tablet D.3.4.1 Specific paediatric formulation: No D.3.7 Routes of administration for this IMP: Vaginal use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: Estradiol hemihydrate D.3.9.1 CAS number: 35380-71-3 D.3.9.2 Current sponsor code: ZK 5018 D.3.9.3 Other descriptive name: b-Estradiol hemihydrate D.3.9.4 EV Substance Code: AS1 D.3.10 Strength D.3.10.1 Concentration unit: µg microgram(s) D.3.10.2 Concentration type: equal D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): No D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: No D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: No D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.8 Information on Placebo D.8 Placebo: 1 D.8.1 Is a Placebo used in this Trial? Yes D.8.3 Pharmaceutical form of the placebo: Vaginal tablet D.8.4 Route of administration of the placebo: Vaginal use E. General Information on the Trial E.1 Medical condition or disease under investigation E.1.1 Medical condition(s) being investigated: Pelvic organ prolapse E.1.1.1 Medical condition in easily understood language: Prolapse of womb or vagina E.1.1.2 Therapeutic area: Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] MedDRA Classification E.1.3 Condition being studied is a rare disease: No E.2 Objective of the trial E.2.1 Main objective of the trial: Study Aim The aim of the feasibility study is to find out if an appropriately powered randomised controlled trial can be realistically undertaken. The feasibility study will also allow the research team to identify any barriers to recruitment and compliance, and fine tune study procedures such as data collection and prescription of the study treatments. The aim of the definitive study would be to test the hypothesis that vaginal oestrogen treatment of postmenopausal women undergoing pelvic floor repair surgery leads to improved patient reported outcomes in relation to urinary, bowel, sexual function and prolapse related quality of life (QoL). Feasibility study specific objectives: 1.To obtain estimates for important aspects of the protocol to allow development of a definitive trial 2.To derive real- time data on the design aspects of the study I.Proportion of eligible women of those screened II.Proportion of eligible women randomised III.Attrition rates IV.Compliance with tr E.2.2 Secondary objectives of the trial: Secondary Objectives of the definitive trial: 1.Improvement sexual function related quality of life (QoL) at 12 months with the use of PISQ 12. 2.Reduction of intraoperative complications like tearing or button holing of the vagina and blood loss. 3.Reduction in the incidence of surgical wound infection and urinary tract infection postoperatively. 4.Validate Patient Global Impression of Improvement (PGI-I) in relation to the POP surgery, PFDI SF20 and PFIQ-7. E.2.3 Trial contains a sub-study: No E.3 Principal inclusion criteria: Inclusion criteria: 1.Postmenopausal women 2.Consented to undergo surgical intervention for pelvic organ prolapse 3.Have not received HRT in the last 12 months 4.Willing to be randomised 5.Give written informed consent E.4 Principal exclusion criteria: Exclusion criteria: 1. Previous breast or uterine malignancy or other hormone- dependent neoplasms 2. Genital bleeding of unknown origin 3. Previous thrombo-embolic episodes in relation to oestrogen therapy 4. Women who cannot understand speak or write in English 5. Women known to be allergic to any of the components of vaginal oestrogens 6. Two or more episodes of culture positive UTI in the last 6 months 7. Previous POP surgery 8. Voiding dysfunction(PVR>150ml) 9. Current or previous POP surgery involving mesh E.5 End points E.5.1 Primary end point(s): As a feasibility study, the objectives is to obtain estimates for important aspects of the protocol to allow development of a definitive trial. A primary outcome measure is not defined. The primary clinical outcome of a definitive trial would be improvement in prolapse related QoL at 12 months as assessed by PFDI SF20. E.5.1.1 Timepoint(s) of evaluation of this end point: The evaluation of this endpoint will occur after 12 month follow-up. E.5.2 Secondary end point(s): As a feasibility study, the objectives is to obtain estimates for important aspects of the protocol to allow development of a definitive trial. Secondary outcome measures are not defined. The secondary clinical outcomes of a definitive trial would be: 1. Sexual function related quality of life (QoL) at 12 months with the use of PISQ 12 2. Intraoperative complications like tearing or button holing of the vagina and blood loss. 3. Incidence of surgical wound infection and urinary tract infection postoperatively. E.5.2.1 Timepoint(s) of evaluation of this end point: Secondary outcomes would be collected at 6 weeks, 6 and 12 months. E.6 and E.7 Scope of the trial E.6 Scope of the Trial E.6.1 Diagnosis: No E.6.2 Prophylaxis: No E.6.3 Therapy: Yes E.6.4 Safety: No E.6.5 Efficacy: No E.6.6 Pharmacokinetic: No E.6.7 Pharmacodynamic: No E.6.8 Bioequivalence: No E.6.9 Dose response: No E.6.10 Pharmacogenetic: No E.6.11 Pharmacogenomic: No E.6.12 Pharmacoeconomic: No E.6.13 Others: Yes E.6.13.1 Other scope of the trial description: Feasibility E.7 Trial type and phase E.7.1 Human pharmacology (Phase I): No E.7.1.1 First administration to humans: No E.7.1.2 Bioequivalence study: No E.7.1.3 Other: No E.7.1.3.1 Other trial type description: E.7.2 Therapeutic exploratory (Phase II): No E.7.3 Therapeutic confirmatory (Phase III): No E.7.4 Therapeutic use (Phase IV): Yes E.8 Design of the trial E.8.1 Controlled: Yes E.8.1.1 Randomised: Yes E.8.1.2 Open: Yes E.8.1.3 Single blind: No E.8.1.4 Double blind: No E.8.1.5 Parallel group: No E.8.1.6 Cross over: No E.8.1.7 Other: No E.8.2 Comparator of controlled trial E.8.2.1 Other medicinal product(s): No E.8.2.2 Placebo: No E.8.2.3 Other: Yes E.8.2.3.1 Comparator description: No treatment E.8.2.4 Number of treatment arms in the trial: 2 E.8.3 The trial involves single site in the Member State concerned: No E.8.4 The trial involves multiple sites in the Member State concerned: Yes E.8.4.1 Number of sites anticipated in Member State concerned: 4 E.8.5 The trial involves multiple Member States: No E.8.6 Trial involving sites outside the EEA E.8.6.1 Trial being conducted both within and outside the EEA: No E.8.6.2 Trial being conducted completely outside of the EEA: No E.8.7 Trial has a data monitoring committee: No E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: The definition of the end of the interventional phase of the trial will be when the last participant has completed her final course of pessaries, and for the observation phase, when she has completed 12 month follow-up. E.8.9 Initial estimate of the duration of the trial E.8.9.1 In the Member State concerned years: 2 E.8.9.1 In the Member State concerned months: 0 E.8.9.1 In the Member State concerned days: 1 E.8.9.2 In all countries concerned by the trial years: 2 E.8.9.2 In all countries concerned by the trial months: 0 E.8.9.2 In all countries concerned by the trial days: 1 F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18: Information not present in EudraCT F.1.1 Number of subjects for this age range: 0 F.1.1.1 In Utero: No F.1.1.1.1 Number of subjects for this age range: 0 F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No F.1.1.2.1 Number of subjects for this age range: 0 F.1.1.3 Newborns (0-27 days): No F.1.1.3.1 Number of subjects for this age range: 0 F.1.1.4 Infants and toddlers (28 days-23 months): No F.1.1.4.1 Number of subjects for this age range: 0 F.1.1.5 Children (2-11years): No F.1.1.5.1 Number of subjects for this age range: 0 F.1.1.6 Adolescents (12-17 years): No F.1.1.6.1 Number of subjects for this age range: 0 F.1.2 Adults (18-64 years): Yes F.1.2.1 Number of subjects for this age range: 50 F.1.3 Elderly (>=65 years): Yes F.1.3.1 Number of subjects for this age range: 50 F.2 Gender F.2.1 Female: Yes F.2.2 Male: No F.3 Group of trial subjects F.3.1 Healthy volunteers: No F.3.2 Patients: Yes F.3.3 Specific vulnerable populations: No F.3.3.1 Women of childbearing potential not using contraception : No F.3.3.2 Women of child-bearing potential using contraception: No F.3.3.3 Pregnant women: No F.3.3.4 Nursing women: No F.3.3.5 Emergency situation: No F.3.3.6 Subjects incapable of giving consent personally: No F.3.3.7 Others: No F.4 Planned number of subjects to be included F.4.1 In the member state: 100 F.4.2 For a multinational trial F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): Not applicable. G. Investigator Networks to be involved in the Trial G.4 Investigator Network to be involved in the Trial: 1 N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision: Authorised N. Date of Competent Authority Decision: 2015-03-13 N. Ethics Committee Opinion of the trial application: Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion: N. Date of Ethics Committee Opinion: 2015-04-28 P. End of Trial P. End of Trial Status: Completed P. Date of the global end of the trial: 2017-09-01 Summary EudraCT Number: 2016-004250-15 Sponsor's Protocol Code Number: National Competent Authority: UK - MHRA Clinical Trial Type: EEA CTA Trial Status: Ongoing Date on which this record was first entered in the EudraCT database: 2018-03-27 Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-004250-15/GB/ A. Protocol Information A.1 Member State Concerned: UK - MHRA A.2 EudraCT number: 2016-004250-15 A.3 Full title of the trial: A prospective, phase II, single centre, cross-sectional, randomised trial investigating Dehydroepiandrosterone and it's Pharmacokinetics in Trauma A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: Establishing a dose of hormone supplementation in trauma patients that will increase hormone levels in the body A.3.2 Name or abbreviated title of the trial where available: A Dehydroepiandrosterone and Pharmacokinetics in Trauma study (ADaPT) A.4.1 Sponsor's protocol code number: A.5.4 Other Identifiers: CAS Number XX2004 A.7 Trial is part of a Paediatric Investigation Plan: No A.8 EMA Decision number of Paediatric Investigation Plan: B. Sponsor Information Sponsor 1 B.1.1 Name of Sponsor: University Hospitals Birmingham B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: AO-UK B.4.2 Country: United Kingdom B.4.1 Name of organisation providing support: Queen Elizabeth Hospital Birmingham Charity B.4.2 Country: United Kingdom B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: Queen Elizabeth Hospital, Birmingham B.5.2 Functional name of contact point: Lt Col Mark Foster B.5.3 Address B.5.3.1 Street Address: Mindolsohn Way B.5.3.2 Town/ city: Edgbaston B.5.3.3 Post code: B15 2TT B.5.3.4 Country: United Kingdom B.5.6 E-mail: m.foster@bham.ac.uk D. IMP Identification D.IMP: 1 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: No D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Dehydroepiandrosterone filmcoat tablet D.3.4 Pharmaceutical form: Coated tablet D.3.4.1 Specific paediatric formulation: No D.3.7 Routes of administration for this IMP: Nasogastric use (Noncurrent) Oral use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: Dehydroepiandrosterone Oral Tablets D.3.9.1 CAS number: 53-43-0 D.3.9.4 EV Substance Code: AS2 D.3.10 Strength D.3.10.1 Concentration unit: mg milligram(s) D.3.10.2 Concentration type: equal D.3.10.3 Concentration number: 50 D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): No D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: No D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: No D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.IMP: 2 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: No D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Dehydroepiandrosterone sublingual tablets D.3.4 Pharmaceutical form: Sublingual tablet D.3.4.1 Specific paediatric formulation: No D.3.7 Routes of administration for this IMP: Sublingual use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: Dehydroepiandrosterone Sublingual Tablets D.3.9.1 CAS number: 53-43-0 D.3.9.4 EV Substance Code: AS3 D.3.10 Strength D.3.10.1 Concentration unit: mg milligram(s) D.3.10.2 Concentration type: equal D.3.10.3 Concentration number: 50 D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): No D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: No D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: No D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.8 Information on Placebo D.8 Placebo: 1 D.8.1 Is a Placebo used in this Trial? Yes E. General Information on the Trial E.1 Medical condition or disease under investigation E.1.1 Medical condition(s) being investigated: DHEA depletion in trauma and hip fracture patients. E.1.1.1 Medical condition in easily understood language: Low hormone levels in patients who have been severely injured in accidents or have a hip fracture. E.1.1.2 Therapeutic area: Body processes [G] - Metabolic Phenomena [G03] MedDRA Classification E.1.2 Medical condition or disease under investigation: E.1.2 Version: 20.0 E.1.2 Level: PT E.1.2 Classification code: 10056629 E.1.2 Term: Dehydroepiandrosterone decreased E.1.2 System Organ Class: 10022891 - Investigations E.1.3 Condition being studied is a rare disease: No E.2 Objective of the trial E.2.1 Main objective of the trial: To establish a dose of supplemental Dehydroepiandrosterone (DHEA) sufficient to raise circulating DHEA levels in severely injured trauma and hip fracture patients, after up to 3 days of supplementation, to levels observed in healthy young male adults. E.2.2 Secondary objectives of the trial: To review the effect of a single and multiple dose of DHEA on circulating DHEA and DHEAS levels and related hormones. To assess if DHEA supplementation has any effect on neutrophil function, metabolic and cytokine profiles of severely injured trauma and female hip fracture patients. To identify what route of DHEA administration is more efficient at raising DHEA levels sufficiently. E.2.3 Trial contains a sub-study: No E.3 Principal inclusion criteria: The inclusion criteria is split into trauma patients and hip fracture patient cohorts. TRAUMA PATIENTS INCLUSION CRITERIA (males and females) - 16 - 50 years of age - Severely injured trauma patient (Injury severity score (ISS) ≥16 and ≤50) - Admitted to University Hospital Birmingham within 6 days of trauma - Anticipated to be an inpatient for the 11 day trial period HIP FRACTURE PATIENTS INCLUSION CRITERIA (females only) - 50 years of age and older. - Female. - Neck of Femur fracture. - Admitted to University Hospital Birmingham within 6 days of fracture. - Anticipated to be an inpatient for the 11 day trial period. E.4 Principal exclusion criteria: The exclusion criteria is split into trauma patients and hip fracture patient cohorts. TRAUMA PATIENTS EXCLUSION CRITERIA 1. Ages <16 or >51 years of age. 2. ISS <16 or >50 3. Isolated brain injury. 4. Unlikely to survive the study period (11 days). 5. Previous or known hormone sensitive malignancy. 6. Known Prostatic hypertrophy (M) 7. Intake of adrenal medication prior to admission to hospital. 8. Female patients taking Hormone Replacement Therapy medication. 9. Intake of any drugs that is likely to influence the metabolism of steroids, in particular inducers and inhibitors of the drug-metabolising enzyme CYP3A4 in the last 3 months. 10. Previous documented liver failure. 11. Current malignancy with ongoing active treatment. 12. Prescribed antipsychotic medication. 13. Pregnant and/or breast-feeding females HIP FRACTURE PATIENTS EXCLUSION CRITERIA 1. <50 years of age. 2. Unlikely to survive the study period (11 days). 3. Previous or known hormone sensitive malignancy. 4. Intake of any drugs that is likely to influence the metabolism of steroids, in particular inducers and inhibitors of the drug-metabolising enzyme CYP3A4 in the last 3 months. 5. Previous documented liver failure. 6. Current malignancy with ongoing active treatment. 7. Prescribed antipsychotic medication. 8. Pregnant and/or breast-feeding females E.5 End points E.5.1 Primary end point(s): To establish a dose of supplemental Dehydroepiandrosterone (DHEA) sufficient to raise circulating DHEA levels in injured trauma and hip fracture patients, after 3 days of supplementation, to levels observed in healthy young male adults. E.5.1.1 Timepoint(s) of evaluation of this end point: Blood samples once daily on day 7,8,9,10,11. E.5.2 Secondary end point(s): To establish an optimal dose of DHEA to enhance immune function through the assessment of neutrophil function and cytokine profiles. To assess if DHEA supplementation via sublingual administration is more effective than an oral administration of the same dose. E.5.2.1 Timepoint(s) of evaluation of this end point: Blood samples once daily on day 7,8,9,10,11. E.6 and E.7 Scope of the trial E.6 Scope of the Trial E.6.1 Diagnosis: No E.6.2 Prophylaxis: No E.6.3 Therapy: No E.6.4 Safety: No E.6.5 Efficacy: Yes E.6.6 Pharmacokinetic: Yes E.6.7 Pharmacodynamic: No E.6.8 Bioequivalence: No E.6.9 Dose response: Yes E.6.10 Pharmacogenetic: No E.6.11 Pharmacogenomic: No E.6.12 Pharmacoeconomic: No E.6.13 Others: No E.7 Trial type and phase E.7.1 Human pharmacology (Phase I): No E.7.1.1 First administration to humans: No E.7.1.2 Bioequivalence study: No E.7.1.3 Other: No E.7.1.3.1 Other trial type description: E.7.2 Therapeutic exploratory (Phase II): Yes E.7.3 Therapeutic confirmatory (Phase III): No E.7.4 Therapeutic use (Phase IV): No E.8 Design of the trial E.8.1 Controlled: No E.8.1.1 Randomised: No E.8.1.2 Open: No E.8.1.3 Single blind: No E.8.1.4 Double blind: No E.8.1.5 Parallel group: No E.8.1.6 Cross over: No E.8.1.7 Other: No E.8.2 Comparator of controlled trial E.8.2.1 Other medicinal product(s): Information not present in EudraCT E.8.2.2 Placebo: Information not present in EudraCT E.8.2.3 Other: Information not present in EudraCT E.8.2.4 Number of treatment arms in the trial: 2 E.8.3 The trial involves single site in the Member State concerned: Yes E.8.4 The trial involves multiple sites in the Member State concerned: No E.8.4.1 Number of sites anticipated in Member State concerned: 1 E.8.5 The trial involves multiple Member States: No E.8.6 Trial involving sites outside the EEA E.8.6.1 Trial being conducted both within and outside the EEA: No E.8.6.2 Trial being conducted completely outside of the EEA: No E.8.7 Trial has a data monitoring committee: Yes E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: The end of trial will be the last patient last visit from the male trauma or female hip fracture groups. The female trauma group will only be recruiting until the other two patient groups are complete. This is due to low admissions of females with a traumatic injury and based on admission data it could take up to 4 years to recruit 90 patients. We envisage that this trial will take 18 months to complete recruitment. E.8.9 Initial estimate of the duration of the trial E.8.9.1 In the Member State concerned years: 1 E.8.9.1 In the Member State concerned months: 6 E.8.9.1 In the Member State concerned days: 1 E.8.9.2 In all countries concerned by the trial years: 1 E.8.9.2 In all countries concerned by the trial months: 6 E.8.9.2 In all countries concerned by the trial days: 1 F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18: Yes F.1.1 Number of subjects for this age range: 10 F.1.1.1 In Utero: No F.1.1.1.1 Number of subjects for this age range: 0 F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No F.1.1.2.1 Number of subjects for this age range: 0 F.1.1.3 Newborns (0-27 days): No F.1.1.3.1 Number of subjects for this age range: 0 F.1.1.4 Infants and toddlers (28 days-23 months): No F.1.1.4.1 Number of subjects for this age range: 0 F.1.1.5 Children (2-11years): No F.1.1.5.1 Number of subjects for this age range: 0 F.1.1.6 Adolescents (12-17 years): Yes F.1.1.6.1 Number of subjects for this age range: 10 F.1.2 Adults (18-64 years): Yes F.1.2.1 Number of subjects for this age range: 200 F.1.3 Elderly (>=65 years): Yes F.1.3.1 Number of subjects for this age range: 60 F.2 Gender F.2.1 Female: Yes F.2.2 Male: Yes F.3 Group of trial subjects F.3.1 Healthy volunteers: No F.3.2 Patients: Yes F.3.3 Specific vulnerable populations: Yes F.3.3.1 Women of childbearing potential not using contraception (For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2018-03-27) : Yes F.3.3.2 Women of child-bearing potential using contraception: Yes F.3.3.3 Pregnant women: No F.3.3.4 Nursing women: No F.3.3.5 Emergency situation: Yes F.3.3.6 Subjects incapable of giving consent personally: Yes F.3.3.6.1 Details of subjects incapable of giving consent: Patients post traumatic injury and elderly patients with hip fractures F.3.3.7 Others: No F.4 Planned number of subjects to be included F.4.1 In the member state: 270 F.4.2 For a multinational trial F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): Once the trial is complete, patients will continue to receive standard of care. G. Investigator Networks to be involved in the Trial G.4 Investigator Network to be involved in the Trial: 1 G.4.1 Name of Organisation: Queen Elizabeth Hospital, Birmingham G.4.3.4 Network Country: United Kingdom N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision: Authorised N. Date of Competent Authority Decision: 2018-05-21 N. Ethics Committee Opinion of the trial application: Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion: N. Date of Ethics Committee Opinion: 2018-06-08 P. End of Trial P. End of Trial Status: Ongoing Summary EudraCT Number: 2004-004835-72 Sponsor's Protocol Code Number: UB-MedSci-001/2004 National Competent Authority: UK - MHRA Clinical Trial Type: EEA CTA Trial Status: Prematurely Ended Date on which this record was first entered in the EudraCT database: 2005-02-17 Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2004-004835-72/GB/ A. Protocol Information A.1 Member State Concerned: UK - MHRA A.2 EudraCT number: 2004-004835-72 A.3 Full title of the trial: A study to determine the effects of growth hormone (GH) replacement therapy on quality of life and cardiovascualr risk in GH deficient adults A.3.2 Name or abbreviated title of the trial where available: Growth Hormone and Quality of Life (GroH-QoL) A.4.1 Sponsor's protocol code number: UB-MedSci-001/2004 A.7 Trial is part of a Paediatric Investigation Plan: Information not present in EudraCT A.8 EMA Decision number of Paediatric Investigation Plan: B. Sponsor Information Sponsor 1 B.1.1 Name of Sponsor: University of Birmingham B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: B.4.2 Country: B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: B.5.2 Functional name of contact point: Sponsor 2 B.1.1 Name of Sponsor: University Hospital Birmingham Foundation NHS Trust B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: B.4.2 Country: B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: B.5.2 Functional name of contact point: D. IMP Identification D.IMP: 1 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: Information not present in EudraCT D.2.1.1.1 Trade name: Norditropin SimpleXx 5mg/1.5ml D.2.1.1.2 Name of the Marketing Authorisation holder: Novo Nordisk A/S D.2.1.2 Country which granted the Marketing Authorisation: United Kingdom D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Norditropin SimpleXx 5mg/1.5ml D.3.4 Pharmaceutical form: Solution for injection D.3.4.1 Specific paediatric formulation: Information not present in EudraCT D.3.7 Routes of administration for this IMP: Subcutaneous use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: Somatropin D.3.9.3 Other descriptive name: Growth Hormone, GH D.3.10 Strength D.3.10.1 Concentration unit: mg/ml milligram(s)/millilitre D.3.10.2 Concentration type: equal D.3.10.3 Concentration number: 3.33 D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: No D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): Yes D.3.11.3 Advanced Therapy IMP (ATIMP): Information not present in EudraCT D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: Information not present in EudraCT D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): Information not present in EudraCT D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: Information not present in EudraCT D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: Information not present in EudraCT D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: Information not present in EudraCT D.3.11.8 Extractive medicinal product: Information not present in EudraCT D.3.11.9 Recombinant medicinal product: Information not present in EudraCT D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.8 Information on Placebo D.8 Placebo: 1 D.8.1 Is a Placebo used in this Trial? Yes D.8.3 Pharmaceutical form of the placebo: Solution for injection D.8.4 Route of administration of the placebo: Subcutaneous use E. General Information on the Trial E.1 Medical condition or disease under investigation E.1.1 Medical condition(s) being investigated: Growth hormone deficiency in adult life MedDRA Classification E.1.3 Condition being studied is a rare disease: No E.2 Objective of the trial E.2.1 Main objective of the trial: To determine the impact of growth hormone replacement therapy on quality of Life in adults with severe growth hormone deficiency E.2.2 Secondary objectives of the trial: To determine the impact of growth hormone replacement therapy on markers of cardiovascualr risk and bone density in adults with severe growth hormone deficiency E.2.3 Trial contains a sub-study: Information not present in EudraCT E.3 Principal inclusion criteria: Aged over 18 Able to provide informed consent Severe GH deficiency in adult life No GH replacement for six months Other hormone therapy stable over preceding six months Life expectancy > 15 months E.4 Principal exclusion criteria: Active malignant disease Active Cushing's disease or active acromegaly Pregnancy Breast feeding Proliferative diabetic retinopathy Sensitivity to GH or it preservative E.5 End points E.5.1 Primary end point(s): Quality of life determined using the Quality of Life Adult Growth Hormone Deficiency Assessment (QoL-AGHDA) E.6 and E.7 Scope of the trial E.6 Scope of the Trial E.6.1 Diagnosis: No E.6.2 Prophylaxis: No E.6.3 Therapy: Yes E.6.4 Safety: Yes E.6.5 Efficacy: Yes E.6.6 Pharmacokinetic: No E.6.7 Pharmacodynamic: No E.6.8 Bioequivalence: No E.6.9 Dose response: No E.6.10 Pharmacogenetic: Information not present in EudraCT E.6.11 Pharmacogenomic: No E.6.12 Pharmacoeconomic: No E.6.13 Others: No E.7 Trial type and phase E.7.1 Human pharmacology (Phase I): No E.7.1.1 First administration to humans: No E.7.1.2 Bioequivalence study: No E.7.1.3 Other: No E.7.1.3.1 Other trial type description: E.7.2 Therapeutic exploratory (Phase II): No E.7.3 Therapeutic confirmatory (Phase III): No E.7.4 Therapeutic use (Phase IV): Yes E.8 Design of the trial E.8.1 Controlled: Yes E.8.1.1 Randomised: Yes E.8.1.2 Open: No E.8.1.3 Single blind: No E.8.1.4 Double blind: Yes E.8.1.5 Parallel group: No E.8.1.6 Cross over: No E.8.1.7 Other: No E.8.2 Comparator of controlled trial E.8.2.1 Other medicinal product(s): No E.8.2.2 Placebo: Yes E.8.2.3 Other: No E.8.3 The trial involves single site in the Member State concerned: Yes E.8.4 The trial involves multiple sites in the Member State concerned: No E.8.5 The trial involves multiple Member States: No E.8.6 Trial involving sites outside the EEA E.8.6.1 Trial being conducted both within and outside the EEA: No E.8.6.2 Trial being conducted completely outside of the EEA: Information not present in EudraCT E.8.7 Trial has a data monitoring committee: Information not present in EudraCT E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: Last visit of the last subject E.8.9 Initial estimate of the duration of the trial E.8.9.1 In the Member State concerned years: 4 E.8.9.1 In the Member State concerned months: E.8.9.1 In the Member State concerned days: E.8.9.2 In all countries concerned by the trial years: 4 F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18: No F.1.1.1 In Utero: No F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No F.1.1.3 Newborns (0-27 days): No F.1.1.4 Infants and toddlers (28 days-23 months): No F.1.1.5 Children (2-11years): No F.1.1.6 Adolescents (12-17 years): No F.1.2 Adults (18-64 years): Yes F.1.3 Elderly (>=65 years): Yes F.2 Gender F.2.1 Female: Yes F.2.2 Male: Yes F.3 Group of trial subjects F.3.1 Healthy volunteers: No F.3.2 Patients: Yes F.3.3 Specific vulnerable populations: Information not present in EudraCT F.3.3.1 Women of childbearing potential not using contraception (For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2005-02-17) : Yes F.3.3.2 Women of child-bearing potential using contraception: Information not present in EudraCT F.3.3.3 Pregnant women: No F.3.3.4 Nursing women: No F.3.3.5 Emergency situation: No F.3.3.6 Subjects incapable of giving consent personally: No F.3.3.7 Others: No F.4 Planned number of subjects to be included F.4.1 In the member state: 200 F.4.2 For a multinational trial F.4.2.1 In the EEA: 200 F.4.2.2 In the whole clinical trial: 200 G. Investigator Networks to be involved in the Trial N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision: Authorised N. Date of Competent Authority Decision: 2005-01-12 N. Ethics Committee Opinion of the trial application: Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion: N. Date of Ethics Committee Opinion: 2004-06-28 P. End of Trial P. End of Trial Status: Prematurely Ended P. Date of the global end of the trial: 2013-10-23 Summary EudraCT Number: 2011-004199-12 Sponsor's Protocol Code Number: RG_11-139vitd National Competent Authority: UK - MHRA Clinical Trial Type: EEA CTA Trial Status: Completed Date on which this record was first entered in the EudraCT database: 2011-11-25 Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-004199-12/GB/ A. Protocol Information A.1 Member State Concerned: UK - MHRA A.2 EudraCT number: 2011-004199-12 A.3 Full title of the trial: An open label dose ranging study to optimise vitamin D levels prior to oesophagectomy A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: what dose of vitamin D is the right one trial A.3.2 Name or abbreviated title of the trial where available: vitamin d open label replacement oesophagectomy. A.4.1 Sponsor's protocol code number: RG_11-139vitd A.5.1 ISRCTN (International Standard Randomised Controlled Trial) number: ISRCTN66719785 A.7 Trial is part of a Paediatric Investigation Plan: No A.8 EMA Decision number of Paediatric Investigation Plan: B. Sponsor Information Sponsor 1 B.1.1 Name of Sponsor: University of Birmingham B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: Medical Research Council UK B.4.2 Country: United Kingdom B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: University of Birmingham B.5.2 Functional name of contact point: Dr David Thickett B.5.3 Address B.5.3.1 Street Address: Edgbaston B.5.3.2 Town/ city: birmingham B.5.3.3 Post code: b15 2tt B.5.6 E-mail: d.thickett@bham.ac.uk D. IMP Identification D.IMP: 1 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: Yes D.2.1.1.1 Trade name: Vigantol oil D.2.1.1.2 Name of the Marketing Authorisation holder: merck D.2.1.2 Country which granted the Marketing Authorisation: Germany D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: vigantol oil (cholecalciferol) D.3.2 Product code: NA D.3.4 Pharmaceutical form: Oral liquid D.3.4.1 Specific paediatric formulation: No D.3.7 Routes of administration for this IMP: Oral use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: cholecalciferol (vitamin D) D.3.9.1 CAS number: 67-97-0 D.3.9.3 Other descriptive name: vigantol oil D.3.9.4 EV Substance Code: AS1 D.3.10 Strength D.3.10.1 Concentration unit: mg/ml milligram(s)/millilitre D.3.10.2 Concentration type: equal D.3.10.3 Concentration number: 0.5mg/ml D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): No D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: No D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: No D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.8 Information on Placebo D.8 Placebo: 1 D.8.1 Is a Placebo used in this Trial? Yes E. General Information on the Trial E.1 Medical condition or disease under investigation E.1.1 Medical condition(s) being investigated: perioperative inflammation in patients undergoing oesophagectomy. E.1.1.1 Medical condition in easily understood language: inflammation following surgery for oesophgeal cancer. E.1.1.2 Therapeutic area: Diseases [C] - Cancer [C04] MedDRA Classification E.1.3 Condition being studied is a rare disease: No E.2 Objective of the trial E.2.1 Main objective of the trial: The aim of this study is to determine the minimum dose that will effectively replace vitamin D cases in all patients undergoing oesophagectomy. It is important to test the dosing as our patients are very deficient and have defective oesophageal motility. Our dosing escalation study will therefore cover a dose range from 100,000 to 300,000 IU in starting at 100,000 units. Our primary endpoint is restoration of plasma vitamin D levels to above 75nmol/l in all treated cases. E.2.2 Secondary objectives of the trial: Secondary outcomes are safety and tolerability data- blood biochemistry, medication related side effects. 2) Plasma vitamin D (25D3) levels over the 14 days after dosing. 3) plasma LL-37 (a downstream vitamin D target) at baseline and on the day of operation. 4) Change in Plasma 1, 25 D3 (the biologically active hormone) from baseline on the day of operation E.2.3 Trial contains a sub-study: No E.3 Principal inclusion criteria: • Planned transthoracic oesophagectomy for oesophageal carcinoma at a participating centre. • Aged over 16 years on day of first dose of IMP • Ability to give written informed consent to participate in the study. E.4 Principal exclusion criteria: • known intolerance of vitamin D • known sarcoidosis, hyperparathyroidism, or nephrolithiasis • taking more than 1000iu/day vitamin D supplementation in the month preceding enrolment • baseline serum corrected calcium >2.65 mmol/L • undergoing haemodialysis • Pregnant or breastfeeding. • Taking cardiac glycoside, carbamazepine, phenobarbital, phenytoin, primidone or long-term immunosuppressant therapy. • Taking oral preparation containing > 10 micrograms vitamin D/day up to 2 months before first dose of IMP. • Diagnosis of COPD with an FEV1 less than 50% predicted or resting oxygen saturations of less 92%. E.5 End points E.5.1 Primary end point(s): Plasma vitamin 25D3 level upon the day of oesophagectomy E.5.1.1 Timepoint(s) of evaluation of this end point: preoperative plasma taken at the start of the operation. E.5.2 Secondary end point(s): 1) Safety and tolerability data – blood biochemistry, medication related side effects.2) Plasma 25D3 levels at 7, 10 and 14 days post dose. 3) plasma LL-37 (a downstream vitamin D target) at baseline and on the day of operation. 4) Change in Plasma 1,25 D3 (the biologically active hormone) from baseline on the day of operation E.5.2.1 Timepoint(s) of evaluation of this end point: at enrollment, preoperative plasma. E.6 and E.7 Scope of the trial E.6 Scope of the Trial E.6.1 Diagnosis: No E.6.2 Prophylaxis: Yes E.6.3 Therapy: No E.6.4 Safety: Yes E.6.5 Efficacy: No E.6.6 Pharmacokinetic: No E.6.7 Pharmacodynamic: No E.6.8 Bioequivalence: No E.6.9 Dose response: Yes E.6.10 Pharmacogenetic: No E.6.11 Pharmacogenomic: No E.6.12 Pharmacoeconomic: No E.6.13 Others: No E.7 Trial type and phase E.7.1 Human pharmacology (Phase I): No E.7.1.1 First administration to humans: No E.7.1.2 Bioequivalence study: No E.7.1.3 Other: No E.7.1.3.1 Other trial type description: E.7.2 Therapeutic exploratory (Phase II): Yes E.7.3 Therapeutic confirmatory (Phase III): No E.7.4 Therapeutic use (Phase IV): No E.8 Design of the trial E.8.1 Controlled: No E.8.1.1 Randomised: No E.8.1.2 Open: No E.8.1.3 Single blind: No E.8.1.4 Double blind: No E.8.1.5 Parallel group: No E.8.1.6 Cross over: No E.8.1.7 Other: No E.8.2 Comparator of controlled trial E.8.2.1 Other medicinal product(s): No E.8.2.2 Placebo: No E.8.2.3 Other: No E.8.3 The trial involves single site in the Member State concerned: No E.8.4 The trial involves multiple sites in the Member State concerned: Yes E.8.4.1 Number of sites anticipated in Member State concerned: 2 E.8.5 The trial involves multiple Member States: No E.8.6 Trial involving sites outside the EEA E.8.6.1 Trial being conducted both within and outside the EEA: No E.8.6.2 Trial being conducted completely outside of the EEA: No E.8.7 Trial has a data monitoring committee: No E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: The end of the study will be defined as the date of the final day of the final participant undergoing follow-up. E.8.9 Initial estimate of the duration of the trial E.8.9.1 In the Member State concerned years: 1 E.8.9.1 In the Member State concerned months: 0 E.8.9.1 In the Member State concerned days: 0 E.8.9.2 In all countries concerned by the trial years: 0 E.8.9.2 In all countries concerned by the trial months: 9 E.8.9.2 In all countries concerned by the trial days: 0 F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18: No F.1.1 Number of subjects for this age range: 0 F.1.1.1 In Utero: No F.1.1.1.1 Number of subjects for this age range: 0 F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No F.1.1.2.1 Number of subjects for this age range: 0 F.1.1.3 Newborns (0-27 days): No F.1.1.3.1 Number of subjects for this age range: 0 F.1.1.4 Infants and toddlers (28 days-23 months): No F.1.1.4.1 Number of subjects for this age range: 0 F.1.1.5 Children (2-11years): No F.1.1.5.1 Number of subjects for this age range: 0 F.1.1.6 Adolescents (12-17 years): No F.1.1.6.1 Number of subjects for this age range: 0 F.1.2 Adults (18-64 years): Yes F.1.2.1 Number of subjects for this age range: 9 F.1.3 Elderly (>=65 years): Yes F.1.3.1 Number of subjects for this age range: 9 F.2 Gender F.2.1 Female: Yes F.2.2 Male: Yes F.3 Group of trial subjects F.3.1 Healthy volunteers: No F.3.2 Patients: Yes F.3.3 Specific vulnerable populations: No F.3.3.1 Women of childbearing potential not using contraception : No F.3.3.2 Women of child-bearing potential using contraception: No F.3.3.3 Pregnant women: No F.3.3.4 Nursing women: No F.3.3.5 Emergency situation: No F.3.3.6 Subjects incapable of giving consent personally: No F.3.3.7 Others: No F.4 Planned number of subjects to be included F.4.1 In the member state: 18 F.4.2 For a multinational trial F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): The patients vitamin D status will be communicated to the GP so that the patient can discuss lifestyle changes and or supplementation of vitamin D in the future. G. Investigator Networks to be involved in the Trial G.4 Investigator Network to be involved in the Trial: 1 N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision: Authorised N. Date of Competent Authority Decision: 2012-01-04 N. Ethics Committee Opinion of the trial application: Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion: N. Date of Ethics Committee Opinion: 2011-11-04 P. End of Trial P. End of Trial Status: Completed P. Date of the global end of the trial: 2014-04-09 Summary EudraCT Number: 2011-005134-19 Sponsor's Protocol Code Number: RG_11-171 National Competent Authority: UK - MHRA Clinical Trial Type: EEA CTA Trial Status: Completed Date on which this record was first entered in the EudraCT database: 2012-01-05 Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-005134-19/GB/ A. Protocol Information A.1 Member State Concerned: UK - MHRA A.2 EudraCT number: 2011-005134-19 A.3 Full title of the trial: An open label pragmatic randomised controlled trial of nicotine patch preloading for smoking cessation. A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: Preloading Trial A.3.2 Name or abbreviated title of the trial where available: Preloading Trial A.4.1 Sponsor's protocol code number: RG_11-171 A.7 Trial is part of a Paediatric Investigation Plan: No A.8 EMA Decision number of Paediatric Investigation Plan: B. Sponsor Information Sponsor 1 B.1.1 Name of Sponsor: University of Birmingham B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: National Institute for Health Research B.4.2 Country: United Kingdom B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: University of Birmingham B.5.2 Functional name of contact point: Nicola Lindson B.5.3 Address B.5.3.1 Street Address: Primary Care Clinical Sciences, University of Birmingham B.5.3.2 Town/ city: Birmingham B.5.3.3 Post code: B15 2TT B.5.3.4 Country: United Kingdom B.5.4 Telephone number: 01214142657 B.5.6 E-mail: n.lindson@bham.ac.uk D. IMP Identification D.IMP: 1 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: Yes D.2.1.1.1 Trade name: NiQuitin CQ 21 mg Patch D.2.1.1.2 Name of the Marketing Authorisation holder: Beecham Group PLC D.2.1.2 Country which granted the Marketing Authorisation: United Kingdom D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: NiQuitin clear 21mg (Niquitin clear 14mg where indicated) D.3.4 Pharmaceutical form: Transdermal patch D.3.4.1 Specific paediatric formulation: No D.3.7 Routes of administration for this IMP: Transdermal use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: Nicotine D.3.9.1 CAS number: 54-11-5 D.3.9.4 EV Substance Code: AS1 D.3.10 Strength D.3.10.1 Concentration unit: mg milligram(s) D.3.10.2 Concentration type: equal D.3.10.3 Concentration number: 114 per patch D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: No D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): Yes D.3.11.3 Advanced Therapy IMP (ATIMP): No D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: No D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: No D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: Yes D.3.11.13.1 Other medicinal product type: The product is primarily intended for use as a smoking cessation aid. D.8 Information on Placebo D.8 Placebo: 1 D.8.1 Is a Placebo used in this Trial? Yes E. General Information on the Trial E.1 Medical condition or disease under investigation E.1.1 Medical condition(s) being investigated: The IMP will assist smoking cessation in smokers wishing to stop. E.1.1.1 Medical condition in easily understood language: Smoking cessation E.1.1.2 Therapeutic area: Psychiatry and Psychology [F] - Behavioral Disciplines and Activities [F04] MedDRA Classification E.1.3 Condition being studied is a rare disease: No E.2 Objective of the trial E.2.1 Main objective of the trial: To assess six month prolonged abstinence from smoking in all participants, measured by the Russell standard criteria ('abstinence' is defined as smoking fewer than 5 cigarettes following a quit date and biochemically confirmed by an exhaled CO of <10 parts per million). E.2.2 Secondary objectives of the trial: To assess the no. of participants smoking at four weeks and 12 months after quit day using self report only, not biologically confirmed. To assess no. of participants at 4 weeks, 6 and 12 months who have not been smoking for the previous 7 days. To collect data on the side-effects of NRT patch use and symptoms of nicotine overdose (such as nausea, excessive salivation) at each contact. E.2.3 Trial contains a sub-study: No E.3 Principal inclusion criteria: • Smokers aged ≥ 18 years of age (assessed on telephone screening) • Smokers who, in the judgement of the clinician, would be suitable for preloading (assessed on telephone screening and in clinic). • Those seeking NHS support to stop smoking (assessed on telephone screening) and willing to quit in 4 weeks • Those able and willing to comply with study procedures (assessed on telephone screening). E.4 Principal exclusion criteria: • Those who are pregnant or breastfeeding (assessed on telephone screening) • Those with extensive dermatitis/other skin disorder that precludes patch use (assessed on telephone and clinic screening) • Those with acute coronary syndrome or stroke within the past three weeks (assessed on telephone screening) • Those with active phaeocromocytoma and uncontrolled hyperthyroidism (assessed on telephone screening) E.5 End points E.5.1 Primary end point(s): Six month prolonged abstinence, measured by the Russell standard criteria i.e. a grace period of 2 weeks, followed by smoking fewer than 5 cigarettes thereafter and biochemically confirmed by an exhaled Carbon monoxide (CO) reading of less than 10 parts per million. E.5.1.1 Timepoint(s) of evaluation of this end point: 6 months after quit day. E.5.2 Secondary end point(s): Four week and 12 month abstinence and 7-day point prevalence biochemically confirmed abstinence at 4 weeks, 6 and 12 months according to the Russell Standard (validated CO must be less than 10 parts per million). E.5.2.1 Timepoint(s) of evaluation of this end point: 4 weeks, 6 and 12 months after quit day. E.6 and E.7 Scope of the trial E.6 Scope of the Trial E.6.1 Diagnosis: No E.6.2 Prophylaxis: No E.6.3 Therapy: Yes E.6.4 Safety: Yes E.6.5 Efficacy: Yes E.6.6 Pharmacokinetic: No E.6.7 Pharmacodynamic: No E.6.8 Bioequivalence: No E.6.9 Dose response: No E.6.10 Pharmacogenetic: No E.6.11 Pharmacogenomic: No E.6.12 Pharmacoeconomic: No E.6.13 Others: No E.7 Trial type and phase E.7.1 Human pharmacology (Phase I): No E.7.1.1 First administration to humans: No E.7.1.2 Bioequivalence study: No E.7.1.3 Other: No E.7.1.3.1 Other trial type description: E.7.2 Therapeutic exploratory (Phase II): No E.7.3 Therapeutic confirmatory (Phase III): No E.7.4 Therapeutic use (Phase IV): Yes E.8 Design of the trial E.8.1 Controlled: Yes E.8.1.1 Randomised: Yes E.8.1.2 Open: Yes E.8.1.3 Single blind: No E.8.1.4 Double blind: No E.8.1.5 Parallel group: No E.8.1.6 Cross over: No E.8.1.7 Other: No E.8.2 Comparator of controlled trial E.8.2.1 Other medicinal product(s): No E.8.2.2 Placebo: No E.8.2.3 Other: Yes E.8.2.3.1 Comparator description: There is no placebo. The comparator will be standard care. E.8.2.4 Number of treatment arms in the trial: 2 E.8.3 The trial involves single site in the Member State concerned: No E.8.4 The trial involves multiple sites in the Member State concerned: Yes E.8.4.1 Number of sites anticipated in Member State concerned: 6 E.8.5 The trial involves multiple Member States: No E.8.6 Trial involving sites outside the EEA E.8.6.1 Trial being conducted both within and outside the EEA: No E.8.6.2 Trial being conducted completely outside of the EEA: No E.8.7 Trial has a data monitoring committee: No E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: The end of the trial is defined shortly after the date of last follow up, once all data has been collected and as soon as database lock has taken place. E.8.9 Initial estimate of the duration of the trial E.8.9.1 In the Member State concerned years: 3 E.8.9.1 In the Member State concerned months: 5 E.8.9.1 In the Member State concerned days: 30 E.8.9.2 In all countries concerned by the trial years: 3 E.8.9.2 In all countries concerned by the trial months: 5 E.8.9.2 In all countries concerned by the trial days: 30 F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18: No F.1.1 Number of subjects for this age range: 0 F.1.1.1 In Utero: No F.1.1.1.1 Number of subjects for this age range: 0 F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No F.1.1.2.1 Number of subjects for this age range: 0 F.1.1.3 Newborns (0-27 days): No F.1.1.3.1 Number of subjects for this age range: 0 F.1.1.4 Infants and toddlers (28 days-23 months): No F.1.1.4.1 Number of subjects for this age range: 0 F.1.1.5 Children (2-11years): No F.1.1.5.1 Number of subjects for this age range: 0 F.1.1.6 Adolescents (12-17 years): No F.1.1.6.1 Number of subjects for this age range: 0 F.1.2 Adults (18-64 years): Yes F.1.2.1 Number of subjects for this age range: 1429 F.1.3 Elderly (>=65 years): Yes F.1.3.1 Number of subjects for this age range: 357 F.2 Gender F.2.1 Female: Yes F.2.2 Male: Yes F.3 Group of trial subjects F.3.1 Healthy volunteers: No F.3.2 Patients: Yes F.3.3 Specific vulnerable populations: No F.3.3.1 Women of childbearing potential not using contraception : No F.3.3.2 Women of child-bearing potential using contraception: No F.3.3.3 Pregnant women: No F.3.3.4 Nursing women: No F.3.3.5 Emergency situation: No F.3.3.6 Subjects incapable of giving consent personally: No F.3.3.7 Others: No F.4 Planned number of subjects to be included F.4.1 In the member state: 1786 F.4.2 For a multinational trial F.4.2.1 In the EEA: 1786 F.4.2.2 In the whole clinical trial: 1786 F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): NRT can be prescribed in standard NHS practice, following participants' quit day. Following quit day, all participants will receive standard NHS cessation support, which may include a continuation of the patches similar or indentical to those used in the study. G. Investigator Networks to be involved in the Trial G.4 Investigator Network to be involved in the Trial: 1 G.4.1 Name of Organisation: Birmingham and Black Country Comprehensive Clinical Research Network G.4.3.4 Network Country: United Kingdom N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision: Authorised N. Date of Competent Authority Decision: 2011-12-29 N. Ethics Committee Opinion of the trial application: Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion: N. Date of Ethics Committee Opinion: 2012-01-31 P. End of Trial P. End of Trial Status: Completed P. Date of the global end of the trial: 2016-04-14 Summary EudraCT Number: 2011-006049-14 Sponsor's Protocol Code Number: RG11_1128 National Competent Authority: UK - MHRA Clinical Trial Type: EEA CTA Trial Status: Prematurely Ended Date on which this record was first entered in the EudraCT database: 2012-02-22 Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-006049-14/GB/ A. Protocol Information A.1 Member State Concerned: UK - MHRA A.2 EudraCT number: 2011-006049-14 A.3 Full title of the trial: Vildalgliptin and Glucose Variability in Type 2 Diabetes A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: Vildalgliptin use in Type 2 Diabetes A.3.2 Name or abbreviated title of the trial where available: Vildalgliptin study A.4.1 Sponsor's protocol code number: RG11_1128 A.7 Trial is part of a Paediatric Investigation Plan: No A.8 EMA Decision number of Paediatric Investigation Plan: B. Sponsor Information Sponsor 1 B.1.1 Name of Sponsor: The University of Birmingham B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: Novartis Ltd B.4.2 Country: United Kingdom B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: The University of Birmingham B.5.2 Functional name of contact point: Kiran Dubb B.5.3 Address B.5.3.1 Street Address: IBR 2nd Floor B.5.3.2 Town/ city: Edgbaston, Birmingham B.5.3.3 Post code: B15 2TT B.5.3.4 Country: United Kingdom B.5.4 Telephone number: 4401214143718 B.5.5 Fax number: 4401214146919 B.5.6 E-mail: k.dubb@bham.ac.uk Sponsor 2 B.1.1 Name of Sponsor: Heart of England NHS Foundation Trust B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: Novartis Ltd B.4.2 Country: United Kingdom B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: The University of Birmingham B.5.2 Functional name of contact point: Kiran Dubb B.5.3 Address B.5.3.1 Street Address: IBR 2nd Floor B.5.3.2 Town/ city: Edgbaston, Birmingham B.5.3.3 Post code: B15 2TT B.5.3.4 Country: United Kingdom B.5.4 Telephone number: 4401214143718 B.5.5 Fax number: 4401214146919 B.5.6 E-mail: k.dubb@bham.ac.uk D. IMP Identification D.IMP: 1 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: Yes D.2.1.1.1 Trade name: Vildalgliptin Galvus D.2.1.1.2 Name of the Marketing Authorisation holder: Novartis Europharm Ltd. D.2.1.2 Country which granted the Marketing Authorisation: United Kingdom D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Vildalgliptin D.3.4 Pharmaceutical form: Tablet D.3.4.1 Specific paediatric formulation: No D.3.7 Routes of administration for this IMP: Oral use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: metformin hydrochloride D.3.9.1 CAS number: 657-24-9 D.3.10 Strength D.3.10.1 Concentration unit: mg milligram(s) D.3.10.2 Concentration type: range D.3.10.3 Concentration number: 1000 to 1350 D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): No D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: No D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: No D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.IMP: 2 D.1.2 and D.1.3 IMP Role: Comparator D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: Yes D.2.1.1.1 Trade name: Glucopahge D.2.1.1.2 Name of the Marketing Authorisation holder: Merck Serono Limited D.2.1.2 Country which granted the Marketing Authorisation: United Kingdom D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: glucophage D.3.4 Pharmaceutical form: Tablet D.3.4.1 Specific paediatric formulation: No D.3.7 Routes of administration for this IMP: Oral use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.9.1 CAS number: 274901-16-5 D.3.9.3 Other descriptive name: galvus D.3.10 Strength D.3.10.1 Concentration unit: mg milligram(s) D.3.10.2 Concentration type: range D.3.10.3 Concentration number: 50 to 100 D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): No D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: No D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: No D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.8 Information on Placebo E. General Information on the Trial E.1 Medical condition or disease under investigation E.1.1 Medical condition(s) being investigated: Diabetes and Cardiac risk benefit in South Asians. E.1.1.1 Medical condition in easily understood language: Diabetes E.1.1.2 Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18] MedDRA Classification E.1.2 Medical condition or disease under investigation: E.1.2 Version: 14.1 E.1.2 Level: LLT E.1.2 Classification code: 10063624 E.1.2 Term: Type II diabetes mellitus inadequate control E.1.2 System Organ Class: 10027433 - Metabolism and nutrition disorders E.1.3 Condition being studied is a rare disease: No E.2 Objective of the trial E.2.1 Main objective of the trial: Patients will be given Vildagliptin 50mg daily and metformin or continue with their sulphonylurea and metformin algorithm to determine if Vildagliptin is effective in reducing cardiac risk profiles in South Asians. Patients diagnosed with Type II diabetes will be recruited into a 12-week, open labeled, randomized, case-controlled clinical study E.2.2 Secondary objectives of the trial: The secondary outcome exploratory endpoints include cardiac autonomic function and continuous glucose monitoring testing and standardized quality of life measures. Safety measures will include glycosolated haemaglobin, lipid profiles, thyroid function tests, fasting glucose, liver function tests and full blood count. Further secondary measures include oxidative stress measurements. E.2.3 Trial contains a sub-study: No E.3 Principal inclusion criteria: 1. Type 2 diabetes of at least 6 months duration; HbA1c should be 7-9%. 2. Established on metformin and sulphonylurea combination therapy for at least 3 months 3. Body mass index from 25 kg/m2 to 45 kg/m2 4. Stable body weight (<10% variation for the 3 months prior to screening 5. Age between 18 and 75 years: 6. Women of childbearing potential must be using contraception to prevent pregnancy E.4 Principal exclusion criteria: 1. Nursing mothers, pregnant women (excluded by a negative pregnancy test). 2. Patients with a history of drug/alcohol abuse 3. Abnormal liver function tests 4. Severe chronic renal failure (GFR<50 ml/min) or diabetic nephropathy 5. previous/ known hypersensivity to Vildalgliptin or any other substance in the study medic ation. 6. Failure to provide informed consent E.5 End points E.5.1 Primary end point(s): We hypothesise that the enhanced cardiac risk in South Asians with T2DM reflects in part, increased glycaemic excursions and resultant periods of hypoglycaemia interspersed with episodes of oxidative stress. We also propose that vildagliptin by reducing glycaemic variability will decrease hypoglycaemia and reduce oxidative stress in diabetes to a greater extent than that achieved using sulphonylurea therapy. Ultimately we propose that this will translate into improved cardiovascular outcomes for South Asian patients with diabetes E.5.1.1 Timepoint(s) of evaluation of this end point: 3months E.5.2 Secondary end point(s): The secondary outcome measure is the difference in MAGE in the vildagliptin and sulphonylurea treated subjects E.5.2.1 Timepoint(s) of evaluation of this end point: 3months E.6 and E.7 Scope of the trial E.6 Scope of the Trial E.6.1 Diagnosis: No E.6.2 Prophylaxis: No E.6.3 Therapy: No E.6.4 Safety: No E.6.5 Efficacy: Yes E.6.6 Pharmacokinetic: No E.6.7 Pharmacodynamic: No E.6.8 Bioequivalence: No E.6.9 Dose response: No E.6.10 Pharmacogenetic: No E.6.11 Pharmacogenomic: No E.6.12 Pharmacoeconomic: No E.6.13 Others: No E.7 Trial type and phase E.7.1 Human pharmacology (Phase I): No E.7.1.1 First administration to humans: No E.7.1.2 Bioequivalence study: No E.7.1.3 Other: No E.7.1.3.1 Other trial type description: E.7.2 Therapeutic exploratory (Phase II): No E.7.3 Therapeutic confirmatory (Phase III): No E.7.4 Therapeutic use (Phase IV): Yes E.8 Design of the trial E.8.1 Controlled: Yes E.8.1.1 Randomised: Yes E.8.1.2 Open: Yes E.8.1.3 Single blind: No E.8.1.4 Double blind: No E.8.1.5 Parallel group: No E.8.1.6 Cross over: No E.8.1.7 Other: No E.8.2 Comparator of controlled trial E.8.2.1 Other medicinal product(s): Yes E.8.2.2 Placebo: No E.8.2.3 Other: No E.8.2.4 Number of treatment arms in the trial: 2 E.8.3 The trial involves single site in the Member State concerned: Yes E.8.4 The trial involves multiple sites in the Member State concerned: No E.8.4.1 Number of sites anticipated in Member State concerned: 2 E.8.5 The trial involves multiple Member States: No E.8.6 Trial involving sites outside the EEA E.8.6.1 Trial being conducted both within and outside the EEA: No E.8.6.2 Trial being conducted completely outside of the EEA: No E.8.7 Trial has a data monitoring committee: No E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: last visit of the last subject undergoing the trial E.8.9 Initial estimate of the duration of the trial E.8.9.1 In the Member State concerned years: 1 E.8.9.1 In the Member State concerned months: 9 E.8.9.1 In the Member State concerned days: 0 E.8.9.2 In all countries concerned by the trial years: 1 E.8.9.2 In all countries concerned by the trial months: 9 E.8.9.2 In all countries concerned by the trial days: 0 F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18: No F.1.1.1 In Utero: No F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No F.1.1.3 Newborns (0-27 days): No F.1.1.4 Infants and toddlers (28 days-23 months): No F.1.1.5 Children (2-11years): No F.1.1.6 Adolescents (12-17 years): No F.1.2 Adults (18-64 years): Yes F.1.2.1 Number of subjects for this age range: 33 F.1.3 Elderly (>=65 years): Yes F.1.3.1 Number of subjects for this age range: 33 F.2 Gender F.2.1 Female: Yes F.2.2 Male: Yes F.3 Group of trial subjects F.3.1 Healthy volunteers: No F.3.2 Patients: Yes F.3.3 Specific vulnerable populations: No F.3.3.1 Women of childbearing potential not using contraception : No F.3.3.2 Women of child-bearing potential using contraception: Information not present in EudraCT F.3.3.3 Pregnant women: No F.3.3.4 Nursing women: No F.3.3.5 Emergency situation: No F.3.3.6 Subjects incapable of giving consent personally: No F.3.3.7 Others: No F.4 Planned number of subjects to be included F.4.1 In the member state: 66 F.4.2 For a multinational trial F.4.2.1 In the EEA: 66 F.4.2.2 In the whole clinical trial: 66 F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): intent-to treat subjects. participants can continue with their study regime after the study has been completed if their doctor thinks its best for their care, G. Investigator Networks to be involved in the Trial N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision: Authorised N. Date of Competent Authority Decision: 2012-03-02 N. Ethics Committee Opinion of the trial application: Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion: N. Date of Ethics Committee Opinion: 2012-05-18 P. End of Trial P. End of Trial Status: Prematurely Ended P. Date of the global end of the trial: 2014-05-19 Summary EudraCT Number: 2015-005753-12 Sponsor's Protocol Code Number: RG_15-026 National Competent Authority: UK - MHRA Clinical Trial Type: EEA CTA Trial Status: Ongoing Date on which this record was first entered in the EudraCT database: 2018-08-02 Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-005753-12/GB/ A. Protocol Information A.1 Member State Concerned: UK - MHRA A.2 EudraCT number: 2015-005753-12 A.3 Full title of the trial: Prospective, open-label, randomised pilot study to assess two possible routes of Faecal Microbiota Transplant (FMT) delivery in patients with ulcerative colitis. A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: A research study looking at faecal transplant as a treatment for ulcerative colitis, and the best way to use it in children and adults with the condition A.3.2 Name or abbreviated title of the trial where available: STOP-Colitis Pilot Trial A.4.1 Sponsor's protocol code number: RG_15-026 A.7 Trial is part of a Paediatric Investigation Plan: No A.8 EMA Decision number of Paediatric Investigation Plan: B. Sponsor Information Sponsor 1 B.1.1 Name of Sponsor: University of Birmingham B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: B.4.2 Country: B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: University of Birmingham, Institute of Applied Health Research B.5.2 Functional name of contact point: Dr Laura Magill B.5.3 Address B.5.3.1 Street Address: Public Health Building B.5.3.2 Town/ city: Edgbaston B.5.3.3 Post code: B15 2TT B.5.3.4 Country: United Kingdom B.5.4 Telephone number: 01214159105 B.5.6 E-mail: e.l.magill@bham.ac.uk D. IMP Identification D.IMP: 1 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: No D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Faecal Microbiota Transplant D.3.2 Product code: FMT D.3.4 Pharmaceutical form: Emulsion for infusion D.3.4.1 Specific paediatric formulation: No D.3.7 Routes of administration for this IMP: Nasogastric use (Noncurrent) Gastroenteral use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: faecal matter D.3.9.4 EV Substance Code: AS1 D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: No D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): Yes D.3.11.3 Advanced Therapy IMP (ATIMP): No D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: No D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: No D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.8 Information on Placebo D.8 Placebo: 1 D.8.1 Is a Placebo used in this Trial? Yes E. General Information on the Trial E.1 Medical condition or disease under investigation E.1.1 Medical condition(s) being investigated: Ulcerative colitis for at least 3 months prior to trial entry E.1.1.1 Medical condition in easily understood language: A long-term condition, where the colon and rectum becomes inflamed. E.1.1.2 Therapeutic area: Diseases [C] - Digestive System Diseases [C06] MedDRA Classification E.1.3 Condition being studied is a rare disease: No E.2 Objective of the trial E.2.1 Main objective of the trial: The aim of the pilot is to determine the most effective route for administering FMT in terms of ease of administration and patient acceptability, i.e best way of giving FMT in UC (Stop-Go guidelines will be used to decide whether to proceed to the randomised controlled trial (RCT)) and to determine if a full RCT is possible. E.2.2 Secondary objectives of the trial: To see whether FMT by the NG route helps to heal the gut in patients with active UC; To see whether FMT by the colonic route helps to heal the gut in patients with How patients tolerate FMT and how safe it is. Whether patients accept FMT given through the NG tube Whether patienst accept FMT given directly in the COLON Which route of FMT delivery (if any) is suitable to investigate in the RCT. Effect on gut bacteria (microbiome) both in the gut and the colon after FMT Effect on levels of inflammation shown in the blood test (C-Reactive Protein) from FMT Effect on the biochemistry (calprotectin levels) of the patients stool sample from FMT Whether the diet of the donors plays a role in the effects of FMT Time from stool donation to treatment E.2.3 Trial contains a sub-study: No E.3 Principal inclusion criteria: Donors: 1)Over 18 and under 50 years of age 2)regular morning bowel habits, which can be classified as Bristol stool chart type 2-5 3)normal BMI (over 18.5 and under 25) 4) presently be non-smokers (not smoked for the past 12 months) 5) provide written informed consent Patients: 1)Confirmed UC for at least 3 months from date of screening 2) Age 12-70 years 3) Partial Mayo score of between 4 and 8 despite stable 5ASA+/- thiopurine, methotrexate or no treatment 4) Rectal bleeding subscore >0 5) Written, signed informed consent and/or assent to the study. E.4 Principal exclusion criteria: Donors: GI history of: - inflammatory bowel disease - irritable bowel syndrome, idiopathic chronic constipation or chronic diarrhoea - gastrointestinal malignancy or known polyposis -celiac disease - congenital or chronic liver disease - per rectal bleeding - major gastrointestinal surgery (eg gastric bypass) AUTOIMMUNE history of systemic autoimmunity including: - Connective tissue disease - Thyroid disease - Inflammatory arthritis - Psoriasis - Alopecia ATOPIC disease inc. - Asthma - Atopic dermatitis - Eczema - Eosinophilic disorders of the gastrointestinal tract CHRONIC PAIN history inc. - Chronic fatigue syndrome - Fibromyalgia CARDIOVASCULAR history of a cardiovascular or metabolic syndrome including: - Diabetes (type 1 or type 2) - High blood pressure - High cholesterol - High fasting glucose - Heart disease (eg atherosclerosis, myocardial infarction, congestive heart failure) NEUROLOGICAL history of neurological conditions including: - Multiple Sclerosis - Parkinson’s disease - Alzheimer’s disease or dementia disorders IMMUNOSUPPRESSION history of any major immunosuppressive mechanisms including: - Calcineurin inhibitors - Exogenous glucocorticoids - Biological agents - Anti-TNF factors - Systemic chemotherapeutic anti-neoplastic agents - Transplantation (eg solid organ, bone marrow, cornea etc) MENTAL HEALTH AND WELL BEING history of having been diagnosed by a clinician with any of the following: - Depression - Bipolar disorder - Schizophrenia or delusional disorder - Eating disorder (eg anorexia and / or bulimia) INFECTIOUS DISEASES - Known to have HIV, HBV and/or HCV infection - Known to have been exposed to HIV, HBV and/or HCV in the preceding 12 months - Risk of Creutzfeldt-Jakob disease (CJD) or variant CJD - Originate from or share sexual partners or have a parent who originates from areas with high-incidence Human T-cell Lymphotropic Virus eg Caribbean, Japan, South America and Africa. - Positive microbiology testing for any of the pathogens described donor testing schedule HIGH RISK ACTIVITIES FOR BLOODBORNE INFECTIONS Engaged in any known high risk activities for blood-borne infections, including: - Sexual contact with an individual with known or suspected HIV, AIDS and/or hepatitis - Sexual contact with a man who has had sex with another man - Sex for drugs or money (both receiving and/or paying) - Use of illicit drugs including IV, oral or inhaled - Tattoo or body piercing in the preceding 6 months MEDICATIONS, PROBIOICS AND VACCINATIONS - History of proton pump inhibitor use - History of antibiotics within the preceding 3 months - History of receiving growth hormone, insulin from cows or cloting factor concentrates - History of receiving an experimental medicine or experimental vaccine - History of VSL3 probiotic food supplement or Mutaflor probiotic use - History of receiving a live vaccination within the preceding one month DIETARY, SOCIAL AND TRAVEL HISTORY - Participation in a strict vegan diet - Work or volunteering activities in which the donor comes into contact with animal or human tissues - Any previous tobacco use - Travelled outside Europe, North America or Australasia in the preceding 3 months FAMILY HISTORY - History of a first degree relative diagnosed with colon cancer under the age of 55 - History of a first degree relative having inflammatory bowel disease The following are exclusion criteria which if highlighted in the donor health questionnaire must be explored in detail with the donor. • History of any malignancy other than gastrointestinal malignancy • Use of medications not listed as absolute exclusion criteria • Other medical conditions highlighted but not listed as an absolute exclusion criteria • High risk occupation e.g. microbiology technician, health care worker, sewerage worker, vet, mortuary technician etc. • Travel abroad in the last 3 months with associated febrile illness • Travel associated risk of Zika virus infection (exclude for 1 month post return from an endemic country) • Illness other than that involving the gastrointestinal tract in the last 2 weeks Patients: 1.Partial Mayo score ≤3 2.Partial Mayo score 9 3.Rectal bleeding subscore of 0 on the partial Mayo 4.Stool positive for Clostridium difficile or infection by either PCR or ELISA 5.Positive for Hepatitis A/B/C, and/or Human Immunodeficiency Virus (HIV) infection 6.Antibiotics within last 3 months prior to screening visit 7.Systemic/topical steroids in the preceding 2 weeks prior to screening visit 8.Biologics in the preceding 3 months prior to screening visit 9.Commercial probiotics and prebiotics in the preceding 3 months prior to screening visit 10.On oral nutritional supplements or enteral/parenteral nutrition in the preceding 4 weeks prior screening visit 11.Pregnant or lactating. Spot urine testing will be performed at screening to rule out pregnancy in women of E.5 End points E.5.1 Primary end point(s): The primary outcome is a composite quantitative and qualitative assessment based on efficacy, acceptability and safety of FMT. Clinical Outcome Measures • Clinical response (primary measure of efficacy) defined as at least a 3 point reduction in the full Mayo score at week 8, and 30% reduction from randomisationand at least 1 point reduction of rectal bleeding subscore or an absolute rectal bleeding subscore of 0 or 1; • Clinical remission at week 8 (Mayo score of ≤2, with no subscore >1); • Participant’s weight; • Quality of Life (QoL) using SF36 and IBDQ in adults (16 years of age and above) • Quality of Life (QoL) using PedsQL in paediatrics (less than 16 years of age) • Paediatric Ulcerative Colitis Activity Index (PUCAI) (adults and children); E.5.1.1 Timepoint(s) of evaluation of this end point: The final analysis for the STOP-Colitis pilot study will start once the last randomised patient reaches the 12 week follow-up assessment, and data has been provided. E.5.2 Secondary end point(s): Mechanistic Outcome Measures • Faecal calprotectin; • Measures of microbiome (faecal and mucosal); • Mucosal healing; • Urinary metabolome (SCFA); • CRP; Other Outcome Measures • Time from stool donation to treatment. • Association between the donor’s dietary profile and microbiome E.6 and E.7 Scope of the trial E.6 Scope of the Trial E.6.1 Diagnosis: No E.6.2 Prophylaxis: No E.6.3 Therapy: Yes E.6.4 Safety: Yes E.6.5 Efficacy: Yes E.6.6 Pharmacokinetic: No E.6.7 Pharmacodynamic: No E.6.8 Bioequivalence: No E.6.9 Dose response: Yes E.6.10 Pharmacogenetic: No E.6.11 Pharmacogenomic: No E.6.12 Pharmacoeconomic: No E.6.13 Others: No E.7 Trial type and phase E.7.1 Human pharmacology (Phase I): No E.7.1.1 First administration to humans: No E.7.1.2 Bioequivalence study: No E.7.1.3 Other: No E.7.1.3.1 Other trial type description: E.7.2 Therapeutic exploratory (Phase II): No E.7.3 Therapeutic confirmatory (Phase III): Yes E.7.4 Therapeutic use (Phase IV): No E.8 Design of the trial E.8.1 Controlled: Yes E.8.1.1 Randomised: Yes E.8.1.2 Open: Yes E.8.1.3 Single blind: No E.8.1.4 Double blind: No E.8.1.5 Parallel group: No E.8.1.6 Cross over: No E.8.1.7 Other: No E.8.2 Comparator of controlled trial E.8.2.1 Other medicinal product(s): Yes E.8.2.2 Placebo: No E.8.2.3 Other: No E.8.2.4 Number of treatment arms in the trial: 2 E.8.3 The trial involves single site in the Member State concerned: No E.8.4 The trial involves multiple sites in the Member State concerned: Yes E.8.4.1 Number of sites anticipated in Member State concerned: 4 E.8.5 The trial involves multiple Member States: No E.8.6 Trial involving sites outside the EEA E.8.6.1 Trial being conducted both within and outside the EEA: No E.8.6.2 Trial being conducted completely outside of the EEA: No E.8.7 Trial has a data monitoring committee: No E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: LVLS E.8.9 Initial estimate of the duration of the trial E.8.9.1 In the Member State concerned years: 0 E.8.9.1 In the Member State concerned months: 6 E.8.9.1 In the Member State concerned days: 2 E.8.9.2 In all countries concerned by the trial years: 0 E.8.9.2 In all countries concerned by the trial months: 6 F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18: Yes F.1.1 Number of subjects for this age range: 2 F.1.1.1 In Utero: No F.1.1.1.1 Number of subjects for this age range: 0 F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No F.1.1.2.1 Number of subjects for this age range: 0 F.1.1.3 Newborns (0-27 days): No F.1.1.3.1 Number of subjects for this age range: 0 F.1.1.4 Infants and toddlers (28 days-23 months): No F.1.1.4.1 Number of subjects for this age range: 0 F.1.1.5 Children (2-11years): No F.1.1.5.1 Number of subjects for this age range: 0 F.1.1.6 Adolescents (12-17 years): Yes F.1.1.6.1 Number of subjects for this age range: 5 F.1.2 Adults (18-64 years): Yes F.1.2.1 Number of subjects for this age range: 20 F.1.3 Elderly (>=65 years): Yes F.1.3.1 Number of subjects for this age range: 3 F.2 Gender F.2.1 Female: Yes F.2.2 Male: Yes F.3 Group of trial subjects F.3.1 Healthy volunteers: No F.3.2 Patients: Yes F.3.3 Specific vulnerable populations: No F.3.3.1 Women of childbearing potential not using contraception : No F.3.3.2 Women of child-bearing potential using contraception: No F.3.3.3 Pregnant women: No F.3.3.4 Nursing women: No F.3.3.5 Emergency situation: No F.3.3.6 Subjects incapable of giving consent personally: No F.3.3.7 Others: No F.4 Planned number of subjects to be included F.4.1 In the member state: 30 F.4.2 For a multinational trial F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): The FMT is only given as part of this trial for UC and would not be available otherwise. FMT treatment duration is complete at 8 weeks, therefore if patients participate they would receive the full dose FMT as per treatment allocation. G. Investigator Networks to be involved in the Trial G.4 Investigator Network to be involved in the Trial: 1 G.4.1 Name of Organisation: Birmingham Clinical Trials Unit, University of Birmingham G.4.3.4 Network Country: United Kingdom N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision: Authorised N. Date of Competent Authority Decision: 2017-11-22 N. Ethics Committee Opinion of the trial application: Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion: N. Date of Ethics Committee Opinion: 2017-11-22 P. End of Trial P. End of Trial Status: Ongoing Summary EudraCT Number: 2012-000510-10 Sponsor's Protocol Code Number: RG_11-141 National Competent Authority: UK - MHRA Clinical Trial Type: EEA CTA Trial Status: Completed Date on which this record was first entered in the EudraCT database: 2012-10-08 Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-000510-10/GB/ A. Protocol Information A.1 Member State Concerned: UK - MHRA A.2 EudraCT number: 2012-000510-10 A.3 Full title of the trial: A Phase IIa trial of 177 Lutetium Dotatate in Children with Primary Refractory or Relapsed High-Risk Neuroblastoma A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: Trial investigating the activity of 177 Lutetium dotatate in children with cancer in their nervous system A.3.2 Name or abbreviated title of the trial where available: LuDo A.4.1 Sponsor's protocol code number: RG_11-141 A.7 Trial is part of a Paediatric Investigation Plan: No A.8 EMA Decision number of Paediatric Investigation Plan: B. Sponsor Information Sponsor 1 B.1.1 Name of Sponsor: University of Birmingham B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: Cancer Research UK B.4.2 Country: United Kingdom B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: University of Birmingham B.5.2 Functional name of contact point: Nicola Graham B.5.3 Address B.5.3.1 Street Address: CRCTU, School of Cancer Sciences, University of Birmingham B.5.3.2 Town/ city: Edgbaston, Birmingham B.5.3.3 Post code: B15 2TT B.5.3.4 Country: United Kingdom B.5.4 Telephone number: 01214143788 B.5.5 Fax number: 01214143700 B.5.6 E-mail: n.graham@bham.ac.uk D. IMP Identification D.IMP: 1 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: No D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Lutetium-177 DOTATATE D.3.2 Product code: n/a D.3.4 Pharmaceutical form: Radiopharmaceutical precursor, solution D.3.4.1 Specific paediatric formulation: No D.3.7 Routes of administration for this IMP: Intravenous use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: Lutetium-177 DOTATATE D.3.9.2 Current sponsor code: RG_11-141 D.3.9.4 EV Substance Code: AS1 D.3.10 Strength D.3.10.1 Concentration unit: GBq gigabecquerel(s) D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: No D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): No D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: No D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No D.3.11.5 Radiopharmaceutical medicinal product: Yes D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: No D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.8 Information on Placebo D.8 Placebo: 1 D.8.1 Is a Placebo used in this Trial? Yes E. General Information on the Trial E.1 Medical condition or disease under investigation E.1.1 Medical condition(s) being investigated: Neuroblastoma E.1.1.1 Medical condition in easily understood language: Neuroblastoma that hasn't responded to standard treatment or that has relapsed. E.1.1.2 Therapeutic area: Diseases [C] - Cancer [C04] MedDRA Classification E.1.3 Condition being studied is a rare disease: No E.2 Objective of the trial E.2.1 Main objective of the trial: The trial will evaluate how effective 177Lutetium DOTATATE is in children with high-risk relapsed or refractory neuroblastoma and determine the safety and adverse events of the treatment experienced by patients on the study. E.2.2 Secondary objectives of the trial: The trial aims to determine whether there is a relationship between the absorbed dose to the tumour and response to 177Lutetium DOTATATE. To correlate the somatostatin receptor sub-type 2 expression in the original histology specimens from primary surgery with 68Gallium DOTATATE PET/CT uptake (SUVmax values) To correlate the uptake on 68Gallium DOTATATE PET/CT by SUVmax scores with response to 177Lutetium DOTATATE therapy. E.2.3 Trial contains a sub-study: No E.3 Principal inclusion criteria: - Histologically confirmed diagnosis of neuroblastoma - Relapsed or primary refractory high risk neuroblastoma (International Neuroblastoma Staging System stage 4 or International Neuroblastoma Risk Group staging System M) - Age >18 months and <18 years of age at the time of enrolment into the study - Life expectancy of greater than 3 months - Performance Status: Karnofsky 50% or more (for patients >12 years of age) Lansky 50% or more (for patients <12 years of age) - Adequate recovery from major surgery prior to receiving study treatment - Uptake in primary tumour or metastatic tumour deposits on 68Gallium DOTATATE PET/CT at least as high as the liver uptake and performed within a month prior to trial - I-MIBG and FDG PET/CT within a month prior to trial entry - Two week washout from any prior treatment - Patients must have recovery of hematological toxicity following previous therapy - Laboratory requirements within 7 days of commencement of therapy • Haemoglobin, If Hb is <12g/dl then patient will receive a blood transfusion prior to treatment • Absolute neutrophil count > 1.0 x 10^9/L • Absolute Platelets > 100 x 10^9/L Biochemistry: • Bilirubin within normal range • ALT within 2.5 x ULN • ALP within 5 x ULN - Glomerular Filtration rate >50mL/min/1.73m2 - Before patient registration, written informed consent. - Parents or other appropriate adult to sign the local Comforters and Carers consent before patient registration. - Agreed to a follow up of 5 years. E.4 Principal exclusion criteria: - Not fit enough to undergo proposed study treatment - Concurrent treatment with any anti-tumour agents - Prior treatment with other radiolabelled somatostatin analogues - Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient or legal guardian before registration in the trial E.5 End points E.5.1 Primary end point(s): Response rate by International Neuroblastoma Response Criteria at one month after the completion of therapy. E.5.1.1 Timepoint(s) of evaluation of this end point: Evaluated at 1 month, 4 months, and then every 6 months until progression E.5.2 Secondary end point(s): ToxicityProgression free survival Overall survival Response rate by International Neuroblastoma Response criteria at four months after completion of therapy. E.5.2.1 Timepoint(s) of evaluation of this end point: Toxic effects - To be evaluated during treatment at 1 month and 4 months post therapy or until all treatment related events have resolved. Progression free survival - at point of relapse Overall survival - up to 5 years of completion of therapy. E.6 and E.7 Scope of the trial E.6 Scope of the Trial E.6.1 Diagnosis: No E.6.2 Prophylaxis: No E.6.3 Therapy: Yes E.6.4 Safety: Yes E.6.5 Efficacy: Yes E.6.6 Pharmacokinetic: No E.6.7 Pharmacodynamic: No E.6.8 Bioequivalence: No E.6.9 Dose response: Yes E.6.10 Pharmacogenetic: No E.6.11 Pharmacogenomic: No E.6.12 Pharmacoeconomic: No E.6.13 Others: No E.7 Trial type and phase E.7.1 Human pharmacology (Phase I): No E.7.1.1 First administration to humans: No E.7.1.2 Bioequivalence study: No E.7.1.3 Other: No E.7.1.3.1 Other trial type description: E.7.2 Therapeutic exploratory (Phase II): Yes E.7.3 Therapeutic confirmatory (Phase III): No E.7.4 Therapeutic use (Phase IV): No E.8 Design of the trial E.8.1 Controlled: No E.8.1.1 Randomised: No E.8.1.2 Open: No E.8.1.3 Single blind: No E.8.1.4 Double blind: No E.8.1.5 Parallel group: No E.8.1.6 Cross over: No E.8.1.7 Other: No E.8.2 Comparator of controlled trial E.8.2.1 Other medicinal product(s): No E.8.2.2 Placebo: No E.8.2.3 Other: No E.8.3 The trial involves single site in the Member State concerned: No E.8.4 The trial involves multiple sites in the Member State concerned: Yes E.8.4.1 Number of sites anticipated in Member State concerned: 1 E.8.5 The trial involves multiple Member States: No E.8.6 Trial involving sites outside the EEA E.8.6.1 Trial being conducted both within and outside the EEA: No E.8.6.2 Trial being conducted completely outside of the EEA: No E.8.7 Trial has a data monitoring committee: Yes E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: The trial end date is deemed to be 6 months after the last patient has completed study treatment. E.8.9 Initial estimate of the duration of the trial E.8.9.1 In the Member State concerned years: 2 E.8.9.1 In the Member State concerned months: 0 E.8.9.1 In the Member State concerned days: 0 E.8.9.2 In all countries concerned by the trial years: 0 E.8.9.2 In all countries concerned by the trial months: 0 E.8.9.2 In all countries concerned by the trial days: 0 F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18: Yes F.1.1 Number of subjects for this age range: 24 F.1.1.1 In Utero: No F.1.1.1.1 Number of subjects for this age range: 0 F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No F.1.1.2.1 Number of subjects for this age range: 0 F.1.1.3 Newborns (0-27 days): No F.1.1.3.1 Number of subjects for this age range: 0 F.1.1.4 Infants and toddlers (28 days-23 months): Yes F.1.1.4.1 Number of subjects for this age range: 2 F.1.1.5 Children (2-11years): Yes F.1.1.5.1 Number of subjects for this age range: 14 F.1.1.6 Adolescents (12-17 years): Yes F.1.1.6.1 Number of subjects for this age range: 7 F.1.2 Adults (18-64 years): Yes F.1.2.1 Number of subjects for this age range: 1 F.1.3 Elderly (>=65 years): No F.1.3.1 Number of subjects for this age range: 0 F.2 Gender F.2.1 Female: Yes F.2.2 Male: Yes F.3 Group of trial subjects F.3.1 Healthy volunteers: No F.3.2 Patients: Yes F.3.3 Specific vulnerable populations: Yes F.3.3.1 Women of childbearing potential not using contraception : No F.3.3.2 Women of child-bearing potential using contraception: Yes F.3.3.3 Pregnant women: No F.3.3.4 Nursing women: No F.3.3.5 Emergency situation: No F.3.3.6 Subjects incapable of giving consent personally: Yes F.3.3.6.1 Details of subjects incapable of giving consent: Children under 5 F.3.3.7 Others: No F.4 Planned number of subjects to be included F.4.1 In the member state: 24 F.4.2 For a multinational trial F.4.2.1 In the EEA: 0 F.4.2.2 In the whole clinical trial: 0 F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): In terms of follow up, weekly full blood counts will be performed at local hospitals until haematological recovery. One month after completion of therapy, I-MIBG scan, FDG PET/CT, Ga DOTATATE PET/CT and MRI or CT imaging will be performed. 6 weeks after completion of therapy, a clinical assessment involving physical examination and documention of any continuing adverse events will be carried out to ensure recovery from any ongoing adverse events. G. Investigator Networks to be involved in the Trial G.4 Investigator Network to be involved in the Trial: 1 N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision: Authorised N. Date of Competent Authority Decision: 2012-10-08 N. Ethics Committee Opinion of the trial application: Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion: N. Date of Ethics Committee Opinion: 2012-10-09 P. End of Trial P. End of Trial Status: Completed P. Date of the global end of the trial: 2018-02-16 Summary EudraCT Number: 2017-003481-28 Sponsor's Protocol Code Number: RRK5108 National Competent Authority: UK - MHRA Clinical Trial Type: EEA CTA Trial Status: Ongoing Date on which this record was first entered in the EudraCT database: 2018-05-16 Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-003481-28/GB/ A. Protocol Information A.1 Member State Concerned: UK - MHRA A.2 EudraCT number: 2017-003481-28 A.3 Full title of the trial: A pilot randomised controlled trial to examine the efficacy and optimal dose of Acetic Acid to treat colonised burns wounds. A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: A clinical trial investigating the use of two different strengths of acetic acid in treating infected burn wounds. A.3.2 Name or abbreviated title of the trial where available: AceticA A.4.1 Sponsor's protocol code number: RRK5108 A.5.4 Other Identifiers: CRCTU CAS Number (Internal) XX2003 A.7 Trial is part of a Paediatric Investigation Plan: No A.8 EMA Decision number of Paediatric Investigation Plan: B. Sponsor Information Sponsor 1 B.1.1 Name of Sponsor: University Hospitals Birmingham NHS Foundation Trust B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: B.4.2 Country: B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: University Hospitals Birmingham NHS Foundation Trust B.5.2 Functional name of contact point: Professor Naiem Moiemen B.5.3 Address B.5.3.1 Street Address: Mindelsohn Way B.5.3.2 Town/ city: Edgbaston, Birmingham B.5.3.3 Post code: B15 2TH B.5.4 Telephone number: 01213713747 B.5.6 E-mail: naiem.moiemen@uhb.nhs.uk D. IMP Identification D.IMP: 1 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: No D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Glacial Acetic Acid 0.5% v/v 200ml D.3.2 Product code: ACE06N D.3.4 Pharmaceutical form: Concentrate for cutaneous solution D.3.4.1 Specific paediatric formulation: No D.3.7 Routes of administration for this IMP: Topical use (Noncurrent) D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: Glacial acetic acid 0.5% v/v D.3.9.1 CAS number: 64-19-7 D.3.9.3 Other descriptive name: Acetic Acid D.3.9.4 EV Substance Code: AS2 D.3.10 Strength D.3.10.1 Concentration unit: % (V/V) percent volume/volume D.3.10.2 Concentration type: equal D.3.10.3 Concentration number: 0.5 D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): No D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: No D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: No D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.IMP: 2 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: No D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Glacial Acetic Acid 2% v/v 200mL D.3.2 Product code: ACE06N D.3.4 Pharmaceutical form: Concentrate for cutaneous solution D.3.4.1 Specific paediatric formulation: No D.3.7 Routes of administration for this IMP: Topical use (Noncurrent) D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: Glacial Acetic Acid 2% v/v D.3.9.1 CAS number: 64-19-7 D.3.9.3 Other descriptive name: Acetic Acid D.3.9.4 EV Substance Code: AS3 D.3.10 Strength D.3.10.1 Concentration unit: % (V/V) percent volume/volume D.3.10.2 Concentration type: equal D.3.10.3 Concentration number: 2% D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): No D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: No D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: No D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.8 Information on Placebo D.8 Placebo: 1 D.8.1 Is a Placebo used in this Trial? Yes E. General Information on the Trial E.1 Medical condition or disease under investigation E.1.1 Medical condition(s) being investigated: Colonised burn wounds E.1.1.1 Medical condition in easily understood language: burn wounds that have identifiable bacteria E.1.1.2 Therapeutic area: Diseases [C] - Bacterial Infections and Mycoses [C01] MedDRA Classification E.1.2 Medical condition or disease under investigation: E.1.2 Version: 20.1 E.1.2 Level: PT E.1.2 Classification code: 10053615 E.1.2 Term: Thermal burn E.1.2 System Organ Class: 10022117 - Injury, poisoning and procedural complications E.1.2 Medical condition or disease under investigation: E.1.2 Version: 20.0 E.1.2 Level: PT E.1.2 Classification code: 10051548 E.1.2 Term: Burn infection E.1.2 System Organ Class: 10021881 - Infections and infestations E.1.3 Condition being studied is a rare disease: No E.2 Objective of the trial E.2.1 Main objective of the trial: To investigate the tolerability and efficacy of 0.5% and 2% acetic acid when applied to colonised burn wounds for 5 consecutive days after admittance to the Queen Elizabeth Hospital Birmingham. E.2.2 Secondary objectives of the trial: - To measure the antimicrobial activity of acetic acid by extracting fluid from removed burns dressings and assessing the minimum inhibitory concentrations (MIC) to establish if active acetic acid is still present. - To determine the percentage burn wound healing at 21 days post burn injury. - To determine the perceived treatment allocation of patients E.2.3 Trial contains a sub-study: No E.3 Principal inclusion criteria: 1. Patient to have a 1 - <10% TBSA burn injury prior to enrolment 2. Burn wound colonised with a specifically identifiable bacteria 3. Patients aged ≥18 years old 4. Patients who are anticipated to remain as inpatients for the study duration i.e. 5 days E.4 Principal exclusion criteria: 1. Patients who lack capacity to give informed consent (NB: translation services will be available for non-English speaking patients) 2. Patients who are receiving systemic antibiotics 3. Patients with burns solely to the face and/or genital area 4. Patients who have received acetic acid as part of standard therapy upon admission to inpatients for this burn injury 5. Patients deemed unsuitable to enter trial in the opinion of the investigator E.5 End points E.5.1 Primary end point(s): • Tolerability will be assessed by measuring a patient’s pain scores with a Visual Analogue Scale (VAS). • Efficacy will be assessed by measuring the bacterial load from microbiology burn wound swabs, these will be taken daily from the beginning of treatment for 5 days. E.5.1.1 Timepoint(s) of evaluation of this end point: Day 5 (after start of treatment). E.5.2 Secondary end point(s): 1. The antimicrobial activity of acetic acid will be measured by extracting fluid from removed burns dressings and assessing the minimum inhibitory concentrations (MIC) to establish if active acetic acid is still present. 2. Percentage of burn wound healed at 21 days (+/- 3 days) post burn injury 3. Perceived treatment allocation, assessed by asking patients after treatment completion which treatment they believed they received E.5.2.1 Timepoint(s) of evaluation of this end point: Day 5 post start of treatment for antimicrobial activity and perceived treatment allocation. Day 21 post burn injury for percentage of burn wound healed. E.6 and E.7 Scope of the trial E.6 Scope of the Trial E.6.1 Diagnosis: No E.6.2 Prophylaxis: No E.6.3 Therapy: No E.6.4 Safety: No E.6.5 Efficacy: Yes E.6.6 Pharmacokinetic: No E.6.7 Pharmacodynamic: No E.6.8 Bioequivalence: No E.6.9 Dose response: Yes E.6.10 Pharmacogenetic: No E.6.11 Pharmacogenomic: No E.6.12 Pharmacoeconomic: No E.6.13 Others: No E.7 Trial type and phase E.7.1 Human pharmacology (Phase I): No E.7.1.1 First administration to humans: No E.7.1.2 Bioequivalence study: No E.7.1.3 Other: No E.7.1.3.1 Other trial type description: E.7.2 Therapeutic exploratory (Phase II): Yes E.7.3 Therapeutic confirmatory (Phase III): No E.7.4 Therapeutic use (Phase IV): No E.8 Design of the trial E.8.1 Controlled: Yes E.8.1.1 Randomised: Yes E.8.1.2 Open: No E.8.1.3 Single blind: No E.8.1.4 Double blind: Yes E.8.1.5 Parallel group: No E.8.1.6 Cross over: No E.8.1.7 Other: No E.8.2 Comparator of controlled trial E.8.2.1 Other medicinal product(s): No E.8.2.2 Placebo: No E.8.2.3 Other: Yes E.8.2.3.1 Comparator description: Two doses/concentrations of the same investigational medicinal product E.8.2.4 Number of treatment arms in the trial: 2 E.8.3 The trial involves single site in the Member State concerned: Yes E.8.4 The trial involves multiple sites in the Member State concerned: No E.8.4.1 Number of sites anticipated in Member State concerned: 1 E.8.5 The trial involves multiple Member States: No E.8.6 Trial involving sites outside the EEA E.8.6.1 Trial being conducted both within and outside the EEA: No E.8.6.2 Trial being conducted completely outside of the EEA: No E.8.7 Trial has a data monitoring committee: No E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: Last Visit Last Subject. E.8.9 Initial estimate of the duration of the trial E.8.9.1 In the Member State concerned years: 1 E.8.9.1 In the Member State concerned months: 0 E.8.9.1 In the Member State concerned days: 1 E.8.9.2 In all countries concerned by the trial years: 0 E.8.9.2 In all countries concerned by the trial months: 6 E.8.9.2 In all countries concerned by the trial days: 21 F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18: No F.1.1 Number of subjects for this age range: 0 F.1.1.1 In Utero: No F.1.1.1.1 Number of subjects for this age range: 0 F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No F.1.1.2.1 Number of subjects for this age range: 0 F.1.1.3 Newborns (0-27 days): No F.1.1.3.1 Number of subjects for this age range: 0 F.1.1.4 Infants and toddlers (28 days-23 months): No F.1.1.4.1 Number of subjects for this age range: 0 F.1.1.5 Children (2-11years): No F.1.1.5.1 Number of subjects for this age range: 0 F.1.1.6 Adolescents (12-17 years): No F.1.1.6.1 Number of subjects for this age range: 0 F.1.2 Adults (18-64 years): Yes F.1.2.1 Number of subjects for this age range: 15 F.1.3 Elderly (>=65 years): Yes F.1.3.1 Number of subjects for this age range: 5 F.2 Gender F.2.1 Female: Yes F.2.2 Male: Yes F.3 Group of trial subjects F.3.1 Healthy volunteers: No F.3.2 Patients: Yes F.3.3 Specific vulnerable populations: No F.3.3.1 Women of childbearing potential not using contraception : No F.3.3.2 Women of child-bearing potential using contraception: No F.3.3.3 Pregnant women: No F.3.3.4 Nursing women: No F.3.3.5 Emergency situation: No F.3.3.6 Subjects incapable of giving consent personally: No F.3.3.7 Others: No F.4 Planned number of subjects to be included F.4.1 In the member state: 20 F.4.2 For a multinational trial F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): Once the five day treatment period has been completed patients will continue with standard of care, which may or may not be a continuation of acetic acid. The decision will be made by the burns medical and nursing staff. G. Investigator Networks to be involved in the Trial G.4 Investigator Network to be involved in the Trial: 1 G.4.1 Name of Organisation: Queen Elizabeth Hospital Birmingham G.4.3.4 Network Country: United Kingdom N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision: Authorised N. Date of Competent Authority Decision: 2017-11-22 N. Ethics Committee Opinion of the trial application: Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion: N. Date of Ethics Committee Opinion: 2017-12-21 P. End of Trial P. End of Trial Status: Ongoing Summary EudraCT Number: 2012-003756-36 Sponsor's Protocol Code Number: RRK4178 National Competent Authority: UK - MHRA Clinical Trial Type: EEA CTA Trial Status: Ongoing Date on which this record was first entered in the EudraCT database: 2013-03-14 Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-003756-36/GB/ A. Protocol Information A.1 Member State Concerned: UK - MHRA A.2 EudraCT number: 2012-003756-36 A.3 Full title of the trial: The Use of Glyceryl Trinitrate Patches in Arteriovenous Fistulas A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: The effect of GTN patches on the maturation of arteriovenous fistulas A.3.2 Name or abbreviated title of the trial where available: The Use of Glyceryl Trinitrate Patches in Arteriovenous Fistulas A.4.1 Sponsor's protocol code number: RRK4178 A.5.2 US NCT (ClinicalTrials.gov registry) number: NCT01685710 A.7 Trial is part of a Paediatric Investigation Plan: No A.8 EMA Decision number of Paediatric Investigation Plan: B. Sponsor Information Sponsor 1 B.1.1 Name of Sponsor: University Hospital Birmingham NHS Foundation B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: Queen Elizabeth Renal Surgical Charitable research fund B.4.2 Country: United Kingdom B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: B.5.2 Functional name of contact point: D. IMP Identification D.IMP: 1 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: Yes D.2.1.1.1 Trade name: Minitran (3M) 5mg patch D.2.1.1.2 Name of the Marketing Authorisation holder: Meda Pharmaceuticals Ltd D.2.1.2 Country which granted the Marketing Authorisation: United Kingdom D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Minitran 5 transdermal patch D.3.4 Pharmaceutical form: Transdermal patch D.3.4.1 Specific paediatric formulation: No D.3.7 Routes of administration for this IMP: Transdermal use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: gylceryl trinitrate D.3.9.1 CAS number: 9010-02-0 D.3.9.4 EV Substance Code: AS1 D.3.10 Strength D.3.10.1 Concentration unit: mg milligram(s) D.3.10.2 Concentration type: up to D.3.10.3 Concentration number: 5 D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): No D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: No D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: No D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.8 Information on Placebo D.8 Placebo: 1 D.8.1 Is a Placebo used in this Trial? Yes D.8.3 Pharmaceutical form of the placebo: Transdermal patch D.8.4 Route of administration of the placebo: Transdermal use E. General Information on the Trial E.1 Medical condition or disease under investigation E.1.1 Medical condition(s) being investigated: Arteriovenous fistulas for dialysis in renal failure E.1.1.1 Medical condition in easily understood language: Fistula for dialysis in kidney failure E.1.1.2 Therapeutic area: Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02] MedDRA Classification E.1.3 Condition being studied is a rare disease: No E.2 Objective of the trial E.2.1 Main objective of the trial: The principal research question is "does the application of a glyceryl trinitrate patch have a positive effect on arteriovenous fistula development and patency of the fistula" E.2.2 Secondary objectives of the trial: E.2.3 Trial contains a sub-study: No E.3 Principal inclusion criteria: - Primary arteriovenous fistula - >18 yrs old - able to consent E.4 Principal exclusion criteria: All patients undergoing complex vascular access procedures will be excluded. - Patients with cardiovascular dysfunction including hypotension, obstructive cardiomyopathy, severe aortic stenosis and confirmed myocardial infarction within the last 6 months will be excluded. - Patients with marked anaemia - Patients with a history of migraine - Patients taking sildenafil or those already taking nitrates - Patients allergic to nitrates - Patients with closed-angle glaucoma - Patients with chronically raised intra-cranial pressure - Patients with a history of thyroid disease - Patients under 18 years old - Patients unable to give valid consent - Patients who are also prisoners E.5 End points E.5.1 Primary end point(s): The primary outcome measure is change to venous diameter. E.5.1.1 Timepoint(s) of evaluation of this end point: This end point will be evaluated 6 weeks after the intervention. E.6 and E.7 Scope of the trial E.6 Scope of the Trial E.6.1 Diagnosis: No E.6.2 Prophylaxis: No E.6.3 Therapy: Yes E.6.4 Safety: No E.6.5 Efficacy: No E.6.6 Pharmacokinetic: No E.6.7 Pharmacodynamic: No E.6.8 Bioequivalence: No E.6.9 Dose response: No E.6.10 Pharmacogenetic: No E.6.11 Pharmacogenomic: No E.6.12 Pharmacoeconomic: No E.6.13 Others: No E.7 Trial type and phase E.7.1 Human pharmacology (Phase I): No E.7.1.1 First administration to humans: No E.7.1.2 Bioequivalence study: No E.7.1.3 Other: No E.7.1.3.1 Other trial type description: E.7.2 Therapeutic exploratory (Phase II): No E.7.3 Therapeutic confirmatory (Phase III): No E.7.4 Therapeutic use (Phase IV): Yes E.8 Design of the trial E.8.1 Controlled: Yes E.8.1.1 Randomised: Yes E.8.1.2 Open: No E.8.1.3 Single blind: No E.8.1.4 Double blind: Yes E.8.1.5 Parallel group: No E.8.1.6 Cross over: No E.8.1.7 Other: No E.8.2 Comparator of controlled trial E.8.2.1 Other medicinal product(s): No E.8.2.2 Placebo: Yes E.8.2.3 Other: No E.8.2.4 Number of treatment arms in the trial: 2 E.8.3 The trial involves single site in the Member State concerned: Yes E.8.4 The trial involves multiple sites in the Member State concerned: No E.8.5 The trial involves multiple Member States: No E.8.6 Trial involving sites outside the EEA E.8.6.1 Trial being conducted both within and outside the EEA: No E.8.6.2 Trial being conducted completely outside of the EEA: No E.8.7 Trial has a data monitoring committee: No E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: The trial will end with the last visit of the last recruited particpiant. E.8.9 Initial estimate of the duration of the trial E.8.9.1 In the Member State concerned years: 2 E.8.9.1 In the Member State concerned months: 0 E.8.9.1 In the Member State concerned days: 0 E.8.9.2 In all countries concerned by the trial years: 2 E.8.9.2 In all countries concerned by the trial months: 0 E.8.9.2 In all countries concerned by the trial days: 0 F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18: No F.1.1 Number of subjects for this age range: 0 F.1.1.1 In Utero: No F.1.1.1.1 Number of subjects for this age range: 0 F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No F.1.1.2.1 Number of subjects for this age range: 0 F.1.1.3 Newborns (0-27 days): No F.1.1.3.1 Number of subjects for this age range: 0 F.1.1.4 Infants and toddlers (28 days-23 months): No F.1.1.4.1 Number of subjects for this age range: 0 F.1.1.5 Children (2-11years): No F.1.1.5.1 Number of subjects for this age range: 0 F.1.1.6 Adolescents (12-17 years): No F.1.1.6.1 Number of subjects for this age range: 0 F.1.2 Adults (18-64 years): Yes F.1.2.1 Number of subjects for this age range: 150 F.1.3 Elderly (>=65 years): Yes F.1.3.1 Number of subjects for this age range: 50 F.2 Gender F.2.1 Female: Yes F.2.2 Male: Yes F.3 Group of trial subjects F.3.1 Healthy volunteers: No F.3.2 Patients: Yes F.3.3 Specific vulnerable populations: No F.3.3.1 Women of childbearing potential not using contraception : No F.3.3.2 Women of child-bearing potential using contraception: No F.3.3.3 Pregnant women: No F.3.3.4 Nursing women: No F.3.3.5 Emergency situation: No F.3.3.6 Subjects incapable of giving consent personally: No F.3.3.7 Others: No F.4 Planned number of subjects to be included F.4.1 In the member state: 200 F.4.2 For a multinational trial F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): As the trial is purely to determine the effects of the patch for the first 24hrs post fistula creation there will be no provision for continued intervention for participants. G. Investigator Networks to be involved in the Trial G.4 Investigator Network to be involved in the Trial: 1 G.4.1 Name of Organisation: Birmingham Clinical Trials Unit (BCTU) G.4.3.4 Network Country: United Kingdom N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision: Authorised N. Date of Competent Authority Decision: 2013-02-12 N. Ethics Committee Opinion of the trial application: Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion: N. Date of Ethics Committee Opinion: 2012-12-04 P. End of Trial P. End of Trial Status: Ongoing Summary EudraCT Number: 2013-004246-41 Sponsor's Protocol Code Number: RG_13-198 National Competent Authority: UK - MHRA Clinical Trial Type: EEA CTA Trial Status: Ongoing Date on which this record was first entered in the EudraCT database: 2015-07-23 Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-004246-41/GB/ A. Protocol Information A.1 Member State Concerned: UK - MHRA A.2 EudraCT number: 2013-004246-41 A.3 Full title of the trial: A phase III randomised study of folic acid supplementation in the management of menopausal symptoms in cancer survivors and healthy postmenopausal women A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: A phase III randomised study of folic acid supplementation in the management of menopausal symptoms in cancer survivors and healthy postmenopausal women (FOAM Trial) A.3.2 Name or abbreviated title of the trial where available: FOAM Trial, Version 2.0 A.4.1 Sponsor's protocol code number: RG_13-198 A.5.4 Other Identifiers: CRCTU Reference No MX3009 A.7 Trial is part of a Paediatric Investigation Plan: No A.8 EMA Decision number of Paediatric Investigation Plan: B. Sponsor Information Sponsor 1 B.1.1 Name of Sponsor: Sandwell and West Birmingham Hospitals NHS Trust B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: NIHR RfPB B.4.2 Country: United Kingdom B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: Sandwell and West Birmingham Hospitals NHS Trust B.5.2 Functional name of contact point: Jocelyn Bell B.5.3 Address B.5.3.1 Street Address: R&D Governance, Birmingham City Hospital B.5.3.2 Town/ city: Dudley Road, Birmingham B.5.3.3 Post code: B18 7QH B.5.3.4 Country: United Kingdom B.5.4 Telephone number: 01215074811 B.5.5 Fax number: 01215074945 B.5.6 E-mail: jocelyn.bell@nhs.net Sponsor 2 B.1.1 Name of Sponsor: University of Birmingham B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: NIHR RfPB B.4.2 Country: United Kingdom B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: University of Birmingham B.5.2 Functional name of contact point: Sean Jennings B.5.3 Address B.5.3.1 Street Address: Research Governance Group, Room 119, Aston Webb Building, University of Birmingham B.5.3.2 Town/ city: Birmingham B.5.3.3 Post code: B15 2TT B.5.3.4 Country: United Kingdom B.5.4 Telephone number: 01214158011 B.5.6 E-mail: researchgovernance@contacts.bham.ac.uk D. IMP Identification D.IMP: 1 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: Yes D.2.1.1.1 Trade name: Folic Acid D.2.1.1.2 Name of the Marketing Authorisation holder: TEVA UK Ltd D.2.1.2 Country which granted the Marketing Authorisation: United Kingdom D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Folic Acid (5mg) D.3.4 Pharmaceutical form: Tablet D.3.4.1 Specific paediatric formulation: No D.3.7 Routes of administration for this IMP: Oral use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: Folic acid D.3.9.1 CAS number: 59-30-3 D.3.9.3 Other descriptive name: folate, vitamin M, vitamin B9, vitamin Bc (or folacin), pteroyl-L-glutamic acid, and pteroyl-L D.3.9.4 EV Substance Code: AS1 D.3.10 Strength D.3.10.1 Concentration unit: mg milligram(s) D.3.10.2 Concentration type: equal D.3.10.3 Concentration number: 5 D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): No D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: No D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: No D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.3.11.13.1 Other medicinal product type: Vitamin supplementation D.8 Information on Placebo D.8 Placebo: 1 D.8.1 Is a Placebo used in this Trial? Yes D.8.3 Pharmaceutical form of the placebo: Tablet D.8.4 Route of administration of the placebo: Oral use E. General Information on the Trial E.1 Medical condition or disease under investigation E.1.1 Medical condition(s) being investigated: Menopause Symptoms E.1.1.1 Medical condition in easily understood language: Hot flushes E.1.1.2 Therapeutic area: Body processes [G] - Reproductive physiologi cal processes [G08] MedDRA Classification E.1.2 Medical condition or disease under investigation: E.1.2 Version: 18.0 E.1.2 Level: LLT E.1.2 Classification code: 10027311 E.1.2 Term: Menopause flushing E.1.2 System Organ Class: 100000004872 E.1.2 Medical condition or disease under investigation: E.1.2 Version: 18.0 E.1.2 Level: LLT E.1.2 Classification code: 10028812 E.1.2 Term: Natural menopause E.1.2 System Organ Class: 10041244 - Social circumstances E.1.2 Medical condition or disease under investigation: E.1.2 Version: 18.0 E.1.2 Level: PT E.1.2 Classification code: 10027308 E.1.2 Term: Menopause E.1.2 System Organ Class: 10041244 - Social circumstances E.1.2 Medical condition or disease under investigation: E.1.2 Version: 18.0 E.1.2 Level: PT E.1.2 Classification code: 10051775 E.1.2 Term: Postmenopause E.1.2 System Organ Class: 10041244 - Social circumstances E.1.3 Condition being studied is a rare disease: No E.2 Objective of the trial E.2.1 Main objective of the trial: The primary objective of this trial is to assess the efficacy of folic acid supplementation in terms of relief of the frequency and severity of vasomotor symptoms as compared to placebo E.2.2 Secondary objectives of the trial: The secondary objectives are: 1. To study the efficacy of folic acid supplementation in terms of other menopausal symptoms as compared to placebo 2. To study the efficacy of folic acid supplementation on quality of life domains as compared to placebo 3. To explore the effect of folic acid in various prognostic subgroups: • Healthy women v cancer survivors (breast or endometerial cancer survivors) • Body Mass Index (BMI): ≤30 v >30 Exploratary Translational Study Objectives: 1. To assess the effect of folic acid supplementation on the blood level of serotonin and nor-adrenaline 2. To measure the correlation between clinical improvement, serum folate levels and blood levels of serotonin and nor-adrenaline 3. To assess the effects of folic acid supplementation on urine levels of nor-adrenaline metaboloite (5-HIAA) and serotonine metabolites (MHPG) E.2.3 Trial contains a sub-study: No E.3 Principal inclusion criteria: 1. Experiencing ≥50 hot flushes per week, as quantified from daily patient Sloan Diary recordings for 7 days after consent and prior to randomisation 2. Being ≥40 and ≤70 years of age 3. Willing to participate in the trial and given informed consent E.4 Principal exclusion criteria: 1. Hormonal or non-hormonal treatment (including raloxifen) for menopausal symptoms within 8 weeks of enrolment 2. Baseline serum folic acid level which is above the normal laboratory range (3.1 to 20.0µg/L) 3. Smoking >5 cigarettes per day 4. Intestinal malabsorption e.g. celiac, tropical sprue or Crohn’s disease 5. Known chronic renal impairment or failure 6. Pernicious anaemia due to vitamin B12 deficiency 7. Taking the following drugs: • Non-steroidal anti-inflammatory drugs (NSAIDs) can interfere with folate metabolism • Cholestrol-lowering agents such as cholestryamine may decrease folic acid absorption • Chemotherapeutic agents such as fluorouracil and methotrexate can interfere with conversion of folate into tetrahydrofolate • Antibiotics such as chloramphenicol, trimethoprim and co-trimoxazole may inhibit dihydrofolic reductase • Sulfasalazine may decrease folic acid absorption • Anticonvulsants such as phenytoin, phenobarbital and primidone can interfere with absorption of anticonvulsants • Serotonin re-uptake inhibitors such as fluoxetine, venlafaxine, sertraline and paroxetine may ameliorate hot flushes • Serotonin disinhibitants such as mianserin and mirtazapine may ameliorate hot flushes • α2-adrenergic agonist such as yohimbine may aggravate hot flushes • α2-adrenergic antagonist such as clonidine may ameliorate hot flushes • Antacids containing aluminium or magnesium can interfere with folate metabolism • Preparations containing zinc such as vitamins or food supplements that may contain folic acid • Anticoagulant or thrombolytic therapy can interfere with folate assays 8. Therapies containing human anti-mouse antibodies (e.g. Trastuzumab and Bevacizumab) can interfere with folate assays 9. Alcohol consumption more than 14 units per week 10. Women with phaeochromocytoma or other medullary tumours or carcinoid syndrome 11. Known allergic reactions and/or hypersensitivity to folic acid 12. Women who are, in the opinion of the treating physician, unlikely to be able to give informed consent or successfully complete the trial intervention and procedures 13. Participation in another clinical trial within the last 4 weeks prior to enrolment E.5 End points E.5.1 Primary end point(s): Change in Hot Flush Score at 12 weeks from randomisation. A validated composite score B calculation based on frequency and severity as reported by patients in weekly Sloan Diaries E.5.1.1 Timepoint(s) of evaluation of this end point: Evaluation of the primary end point will be at the end of the treatment period. Treatment will cease at week 12. E.5.2 Secondary end point(s): 1. Change from randomisation in Hot Flush Score at weeks 4, 8 and 12 as calculated using the composite score B 2. Change from randomisation in frequency of hot flushes (mild, moderate and severe) at weeks 4, 8 and 12 as calculated using frequency score B 3. The percentage of responders at weeks 4, 8 and 12; defined as a reduction in Hot Flush Score of ≥50% from randomisation as calculated using composite score B 4. Change from randomisation in longitudinal quality of life data as measured by the Utian Quality of Life Scale at weeks 4, 8 and 12 5. Change from randomisation in other menopausal symptoms using the Greene Climacteric Scale at weeks 4, 8 and 12 6. Investigate effects in specific prognostic subgroups of: • Healthy women v cancer survivors (breast or endometrial cancer survivors) • Body Mass Index ≤30 v >30 E.5.2.1 Timepoint(s) of evaluation of this end point: Evaluation of this end point will be at the end of the treatment period. Treatment will cease at week 12. E.6 and E.7 Scope of the trial E.6 Scope of the Trial E.6.1 Diagnosis: No E.6.2 Prophylaxis: No E.6.3 Therapy: Yes E.6.4 Safety: Yes E.6.5 Efficacy: Yes E.6.6 Pharmacokinetic: No E.6.7 Pharmacodynamic: No E.6.8 Bioequivalence: No E.6.9 Dose response: No E.6.10 Pharmacogenetic: No E.6.11 Pharmacogenomic: No E.6.12 Pharmacoeconomic: No E.6.13 Others: Yes E.6.13.1 Other scope of the trial description: Compliance and Quality of Life E.7 Trial type and phase E.7.1 Human pharmacology (Phase I): No E.7.1.1 First administration to humans: No E.7.1.2 Bioequivalence study: No E.7.1.3 Other: No E.7.1.3.1 Other trial type description: E.7.2 Therapeutic exploratory (Phase II): No E.7.3 Therapeutic confirmatory (Phase III): Yes E.7.4 Therapeutic use (Phase IV): No E.8 Design of the trial E.8.1 Controlled: Yes E.8.1.1 Randomised: Yes E.8.1.2 Open: No E.8.1.3 Single blind: No E.8.1.4 Double blind: Yes E.8.1.5 Parallel group: No E.8.1.6 Cross over: No E.8.1.7 Other: No E.8.2 Comparator of controlled trial E.8.2.1 Other medicinal product(s): No E.8.2.2 Placebo: Yes E.8.2.3 Other: No E.8.2.4 Number of treatment arms in the trial: 2 E.8.3 The trial involves single site in the Member State concerned: No E.8.4 The trial involves multiple sites in the Member State concerned: Yes E.8.4.1 Number of sites anticipated in Member State concerned: 10 E.8.5 The trial involves multiple Member States: No E.8.6 Trial involving sites outside the EEA E.8.6.1 Trial being conducted both within and outside the EEA: No E.8.6.2 Trial being conducted completely outside of the EEA: No E.8.7 Trial has a data monitoring committee: Yes E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: The trial end date is deemed to be the date of last data capture. This will allow sufficient time for the completion of protocol procedures, data collection and data input. The Trial Office will notify the Medicines and Healthcare products Regulatory Agency (MHRA) and Research Ethics Committee (REC) that the trial has ended and will provide them with a summary of the clinical trial report within 12 months of the end of trial. E.8.9 Initial estimate of the duration of the trial E.8.9.1 In the Member State concerned years: 2 E.8.9.1 In the Member State concerned months: 0 E.8.9.1 In the Member State concerned days: 0 E.8.9.2 In all countries concerned by the trial years: 2 E.8.9.2 In all countries concerned by the trial months: 0 E.8.9.2 In all countries concerned by the trial days: 0 F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18: No F.1.1 Number of subjects for this age range: 0 F.1.1.1 In Utero: No F.1.1.1.1 Number of subjects for this age range: 0 F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No F.1.1.2.1 Number of subjects for this age range: 0 F.1.1.3 Newborns (0-27 days): No F.1.1.3.1 Number of subjects for this age range: 0 F.1.1.4 Infants and toddlers (28 days-23 months): No F.1.1.4.1 Number of subjects for this age range: 0 F.1.1.5 Children (2-11years): No F.1.1.5.1 Number of subjects for this age range: 0 F.1.1.6 Adolescents (12-17 years): No F.1.1.6.1 Number of subjects for this age range: 0 F.1.2 Adults (18-64 years): Yes F.1.2.1 Number of subjects for this age range: 228 F.1.3 Elderly (>=65 years): Yes F.1.3.1 Number of subjects for this age range: 8 F.2 Gender F.2.1 Female: Yes F.2.2 Male: No F.3 Group of trial subjects F.3.1 Healthy volunteers: No F.3.2 Patients: Yes F.3.3 Specific vulnerable populations: No F.3.3.1 Women of childbearing potential not using contraception : No F.3.3.2 Women of child-bearing potential using contraception: No F.3.3.3 Pregnant women: No F.3.3.4 Nursing women: No F.3.3.5 Emergency situation: No F.3.3.6 Subjects incapable of giving consent personally: No F.3.3.7 Others: No F.4 Planned number of subjects to be included F.4.1 In the member state: 236 F.4.2 For a multinational trial F.4.2.2 In the whole clinical trial: 236 F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): There will be no intervention to continue when the trial has been completed. G. Investigator Networks to be involved in the Trial G.4 Investigator Network to be involved in the Trial: 1 G.4.1 Name of Organisation: Birmingham and the Black Country CLRN G.4.3.4 Network Country: United Kingdom N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision: Authorised N. Date of Competent Authority Decision: 2015-01-26 N. Ethics Committee Opinion of the trial application: Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion: N. Date of Ethics Committee Opinion: 2014-05-06 P. End of Trial P. End of Trial Status: Ongoing Summary EudraCT Number: 2013-003107-19 Sponsor's Protocol Code Number: 13-0288 National Competent Authority: UK - MHRA Clinical Trial Type: EEA CTA Trial Status: Ongoing Date on which this record was first entered in the EudraCT database: 2014-04-11 Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-003107-19/GB/ A. Protocol Information A.1 Member State Concerned: UK - MHRA A.2 EudraCT number: 2013-003107-19 A.3 Full title of the trial: Phase II clinical trial investigating the use of epigallocatechin-3-gallate (Veregen) in the treatment of vulval intraepithelial neoplasia A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: A trial to investigate the use of Veregen ointment in the treatment of vulval intraepithelial neoplasia, a severe skin disorder that may lead to vulval cancer. A.3.2 Name or abbreviated title of the trial where available: EPIVIN trial (v 1.0) A.4.1 Sponsor's protocol code number: 13-0288 A.5.4 Other Identifiers: CRCTU CAS number VU2001 A.7 Trial is part of a Paediatric Investigation Plan: No A.8 EMA Decision number of Paediatric Investigation Plan: B. Sponsor Information Sponsor 1 B.1.1 Name of Sponsor: University of Birmingham B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: Medigene B.4.2 Country: Germany B.4.1 Name of organisation providing support: NIHR RfPB B.4.2 Country: United Kingdom B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: Cancer Research UK Clinical Trials Unit B.5.2 Functional name of contact point: Clive Stubbs B.5.3 Address B.5.3.1 Street Address: School of Cancer Sciences, University of Birmingham B.5.3.2 Town/ city: Birmingham B.5.3.3 Post code: B15 2TT B.5.3.4 Country: United Kingdom B.5.4 Telephone number: 01214147671 B.5.5 Fax number: 01214142230 B.5.6 E-mail: c.stubbs@bham.ac.uk Sponsor 2 B.1.1 Name of Sponsor: Sandwell and West Birmingham Hospitals NHS Trust B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: NIHR RfPB B.4.2 Country: United Kingdom B.4.1 Name of organisation providing support: Medigene B.4.2 Country: Germany B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: Sandwell and West Birmingham Hospitals NHS Trust B.5.2 Functional name of contact point: Jocelyn Bell B.5.3 Address B.5.3.1 Street Address: R&D Governance, City Hospital, Dudley Road, B.5.3.2 Town/ city: Birmingham B.5.3.3 Post code: B18 7QH B.5.3.4 Country: United Kingdom B.5.4 Telephone number: 01215074811 B.5.5 Fax number: 01215074945 B.5.6 E-mail: jocelyn.bell@nhs.net D. IMP Identification D.IMP: 1 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: Yes D.2.1.1.1 Trade name: Veregen D.2.1.1.2 Name of the Marketing Authorisation holder: Medigene D.2.1.2 Country which granted the Marketing Authorisation: Germany D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Veregen 10% ointment D.3.4 Pharmaceutical form: Ointment D.3.4.1 Specific paediatric formulation: No D.3.7 Routes of administration for this IMP: Cutaneous use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: Epigallocatechin gallate (EGCG) D.3.9.1 CAS number: 188265-33-0 D.3.9.3 Other descriptive name: Camellia sinensis (green leaf) D.3.9.4 EV Substance Code: AS1 D.3.10 Strength D.3.10.1 Concentration unit: mg/g milligram(s)/gram D.3.10.2 Concentration type: equal D.3.10.3 Concentration number: 10% D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: No D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): Yes D.3.11.3 Advanced Therapy IMP (ATIMP): No D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: No D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: No D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: Yes D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.8 Information on Placebo D.8 Placebo: 1 D.8.1 Is a Placebo used in this Trial? Yes D.8.3 Pharmaceutical form of the placebo: Ointment D.8.4 Route of administration of the placebo: Cutaneous use E. General Information on the Trial E.1 Medical condition or disease under investigation E.1.1 Medical condition(s) being investigated: Vulval intraepithelial neoplasia (VIN) E.1.1.1 Medical condition in easily understood language: Changes that occur in the skin cells of the vulva that cause symptoms, associated with a viral infection by HPV, that may develop into vulval cancer if untreated. E.1.1.2 Therapeutic area: Diseases [C] - Skin and Connective Tissue Diseases [C17] MedDRA Classification E.1.2 Medical condition or disease under investigation: E.1.2 Version: 16.1 E.1.2 Level: LLT E.1.2 Classification code: 10057313 E.1.2 Term: Vulval intraepithelial neoplasia grade III E.1.2 System Organ Class: 100000004864 E.1.3 Condition being studied is a rare disease: No E.2 Objective of the trial E.2.1 Main objective of the trial: The primary objective of this clinical trial is to determine whether topical application of EGCG (Veregen) can lead to histological resolution of VIN. This is done by comparing tissue biopsies taken before and after Veregen treatment. E.2.2 Secondary objectives of the trial: The secondary objectives are to evaluate in women undergoing treatment with Veregen 1. clinical responses using the RECIST criteria v1.1 2. the number of treatment withdrawals/dose reductions 3. toxicity according to NCI CTCAE v4.0 4. relief of clinical symptoms and improvement in quality of life using a validated quality of life questionnaires (DLQI) developed by the Department of Dermatology and Wound Healing, University of Cardiff. 5. the number of women requiring further treatment within 12 months of study entry E.2.3 Trial contains a sub-study: No E.3 Principal inclusion criteria: ≥ 18 years of age, histological confirmation of "usual"-type vulval intraepithelial neoplasia (VIN3)*, at least one lesion that can be accurately measured (using the RECIST 1.1 criteria) in at least one dimension with longest diameter ≥ 20 mm, using a reliable method of contraception (excluding condoms), written informed consent to participate in the trial. *All histological material generated by this study will be assessed by Specialist Consultant in Gynaecological Pathology; 10% of biopsies will be independently reviewed by a second pathologist E.4 Principal exclusion criteria: Suspected anogenital carcinoma or those considered by the attending clinician to be at high risk of developing invasive disease; pregnant, breast feeding or trying to conceive; treated for VIN within the previous four weeks; known allergy to Veregen or any of its components; patients suffering from immunosuppressive disorder or taking immunosuppressives; unable to comply with the protocol. E.5 End points E.5.1 Primary end point(s): Proportion of women with histological resolution of VIN as established by blinded pathology review. E.5.1.1 Timepoint(s) of evaluation of this end point: At Week 32 after entering the study. Treatment with active ointment or placebo will have ceased at Week 16. E.5.2 Secondary end point(s): Histological resolution at 16 weeks*; Clinical resolution (RECIST 1.1); Time to clinical resolution; Toxicity (CTC AE v4.0); Drug compliance (including ineligibility and withdrawal); Need for further treatment and time to further treatment; Patient acceptability using:(1) Pain/pruritus assessment with McGill’s questionnaires and assessment of cumulative treatment (The number of treatment withdrawals/dose reductions), and (2) Dermatology Quality of life questionnaire (DLQI). *To supplement the primary outcome the number (%) of patients with histological resolution at 32 weeks shall be contrasted against the 16 week histology results. E.5.2.1 Timepoint(s) of evaluation of this end point: Histological resolution at 16 weeks; the rest of the secondary endpoints will be assessed at the 32-week point. E.6 and E.7 Scope of the trial E.6 Scope of the Trial E.6.1 Diagnosis: No E.6.2 Prophylaxis: No E.6.3 Therapy: Yes E.6.4 Safety: Yes E.6.5 Efficacy: Yes E.6.6 Pharmacokinetic: No E.6.7 Pharmacodynamic: No E.6.8 Bioequivalence: No E.6.9 Dose response: No E.6.10 Pharmacogenetic: No E.6.11 Pharmacogenomic: No E.6.12 Pharmacoeconomic: No E.6.13 Others: Yes E.6.13.1 Other scope of the trial description: Compliance E.7 Trial type and phase E.7.1 Human pharmacology (Phase I): No E.7.1.1 First administration to humans: No E.7.1.2 Bioequivalence study: No E.7.1.3 Other: No E.7.1.3.1 Other trial type description: E.7.2 Therapeutic exploratory (Phase II): Yes E.7.3 Therapeutic confirmatory (Phase III): No E.7.4 Therapeutic use (Phase IV): No E.8 Design of the trial E.8.1 Controlled: Yes E.8.1.1 Randomised: Yes E.8.1.2 Open: No E.8.1.3 Single blind: No E.8.1.4 Double blind: Yes E.8.1.5 Parallel group: Yes E.8.1.6 Cross over: No E.8.1.7 Other: No E.8.2 Comparator of controlled trial E.8.2.1 Other medicinal product(s): No E.8.2.2 Placebo: Yes E.8.2.3 Other: No E.8.2.4 Number of treatment arms in the trial: 2 E.8.3 The trial involves single site in the Member State concerned: Yes E.8.4 The trial involves multiple sites in the Member State concerned: No E.8.5 The trial involves multiple Member States: No E.8.6 Trial involving sites outside the EEA E.8.6.1 Trial being conducted both within and outside the EEA: No E.8.6.2 Trial being conducted completely outside of the EEA: No E.8.7 Trial has a data monitoring committee: Yes E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: The end of the trial will be 3 months after the last visit of the last subject, ie, the last data capture.This will allow sufficient time for the completion of protocol procedures, data collection and data input. The Trials Office will notify the MHRA and main REC that the trial has ended and will provide them with a summary of the clinical trial report within 12 months of the end of trial. E.8.9 Initial estimate of the duration of the trial E.8.9.1 In the Member State concerned years: 3 E.8.9.1 In the Member State concerned months: 2 E.8.9.1 In the Member State concerned days: 1 E.8.9.2 In all countries concerned by the trial years: 3 E.8.9.2 In all countries concerned by the trial months: 1 E.8.9.2 In all countries concerned by the trial days: 1 F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18: No F.1.1 Number of subjects for this age range: 0 F.1.1.1 In Utero: No F.1.1.1.1 Number of subjects for this age range: 0 F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No F.1.1.2.1 Number of subjects for this age range: 0 F.1.1.3 Newborns (0-27 days): No F.1.1.3.1 Number of subjects for this age range: 0 F.1.1.4 Infants and toddlers (28 days-23 months): No F.1.1.4.1 Number of subjects for this age range: 0 F.1.1.5 Children (2-11years): No F.1.1.5.1 Number of subjects for this age range: 0 F.1.1.6 Adolescents (12-17 years): No F.1.1.6.1 Number of subjects for this age range: 0 F.1.2 Adults (18-64 years): Yes F.1.2.1 Number of subjects for this age range: 28 F.1.3 Elderly (>=65 years): Yes F.1.3.1 Number of subjects for this age range: 28 F.2 Gender F.2.1 Female: Yes F.2.2 Male: No F.3 Group of trial subjects F.3.1 Healthy volunteers: No F.3.2 Patients: Yes F.3.3 Specific vulnerable populations: Yes F.3.3.1 Women of childbearing potential not using contraception : No F.3.3.2 Women of child-bearing potential using contraception: Yes F.3.3.3 Pregnant women: No F.3.3.4 Nursing women: No F.3.3.5 Emergency situation: No F.3.3.6 Subjects incapable of giving consent personally: No F.3.3.7 Others: No F.4 Planned number of subjects to be included F.4.1 In the member state: 56 F.4.2 For a multinational trial F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): The safety and effectiveness of this treatment in genital wart cases has not been established beyond 16 weeks of use. We do not have data on the maximum use in patients with VIN, so we will use the same guidance and not recommend use continuing beyond this time. G. Investigator Networks to be involved in the Trial G.4 Investigator Network to be involved in the Trial: 1 N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision: Authorised N. Date of Competent Authority Decision: 2014-04-28 N. Ethics Committee Opinion of the trial application: Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion: N. Date of Ethics Committee Opinion: 2013-12-20 P. End of Trial P. End of Trial Status: Ongoing Summary EudraCT Number: 2004-002818-11 Sponsor's Protocol Code Number: 2003AN004 National Competent Authority: UK - MHRA Clinical Trial Type: EEA CTA Trial Status: Ongoing Date on which this record was first entered in the EudraCT database: 2005-08-31 Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2004-002818-11/GB/ A. Protocol Information A.1 Member State Concerned: UK - MHRA A.2 EudraCT number: 2004-002818-11 A.3 Full title of the trial: Magnesium Sulphate for the Prevention of Super Ventricular Dysrrhythmias following Non-Cardiac Thoracic Surgery A.3.2 Name or abbreviated title of the trial where available: MgSO for the prevention of SVD following non-cardiac thoracic surgery A.4.1 Sponsor's protocol code number: 2003AN004 A.7 Trial is part of a Paediatric Investigation Plan: Information not present in EudraCT A.8 EMA Decision number of Paediatric Investigation Plan: B. Sponsor Information Sponsor 1 B.1.1 Name of Sponsor: Heart of England NHS Foundation Trust B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: B.4.2 Country: B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: B.5.2 Functional name of contact point: D. IMP Identification D.IMP: 1 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: Information not present in EudraCT D.2.1.1.1 Trade name: Magnesium Sulphate 50% D.2.1.1.2 Name of the Marketing Authorisation holder: South Devon Healthcare,Torbay PMU, Paignton, Devon D.2.1.2 Country which granted the Marketing Authorisation: United Kingdom D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Magnesium Sulphate 50% w/v D.3.4 Pharmaceutical form: Solution for infusion D.3.4.1 Specific paediatric formulation: Information not present in EudraCT D.3.7 Routes of administration for this IMP: Intravenous use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: Magnesium Sulphate D.3.10 Strength D.3.10.1 Concentration unit: mmol/ml millimole(s)/millilitre D.3.10.2 Concentration type: equal D.3.10.3 Concentration number: 0.2 D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): Information not present in EudraCT D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: Information not present in EudraCT D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): Information not present in EudraCT D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: Information not present in EudraCT D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: Information not present in EudraCT D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: Information not present in EudraCT D.3.11.8 Extractive medicinal product: Information not present in EudraCT D.3.11.9 Recombinant medicinal product: Information not present in EudraCT D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.8 Information on Placebo D.8 Placebo: 1 D.8.1 Is a Placebo used in this Trial? Yes D.8.3 Pharmaceutical form of the placebo: Solution for infusion D.8.4 Route of administration of the placebo: Intravenous use E. General Information on the Trial E.1 Medical condition or disease under investigation E.1.1 Medical condition(s) being investigated: Post Thoracotomy Super Ventricular Dysrhythmias MedDRA Classification E.1.3 Condition being studied is a rare disease: No E.2 Objective of the trial E.2.1 Main objective of the trial: Does the peri-operative administration of IV magnesium sulphate to coorrect hypomagnesaemia decrease the incidence of postoperative super ventricular dysrhythmias? E.2.2 Secondary objectives of the trial: Does this improve mortality from thoractomy for lung resections or oesophagectomy? E.2.3 Trial contains a sub-study: Information not present in EudraCT E.3 Principal inclusion criteria: Patient having thoractomy for lobectomy, biloectomy, pneumonectomy or oesophagectomy E.4 Principal exclusion criteria: Renal impairment (creatinine >130) Pre-existing SVD Hypersensitivity to magnesium sulphate, if on antiarhythmics E.5 End points E.5.1 Primary end point(s): Incidence of post thoratomy SVD E.6 and E.7 Scope of the trial E.6 Scope of the Trial E.6.1 Diagnosis: No E.6.2 Prophylaxis: Yes E.6.3 Therapy: No E.6.4 Safety: No E.6.5 Efficacy: No E.6.6 Pharmacokinetic: No E.6.7 Pharmacodynamic: No E.6.8 Bioequivalence: No E.6.9 Dose response: No E.6.10 Pharmacogenetic: Information not present in EudraCT E.6.11 Pharmacogenomic: No E.6.12 Pharmacoeconomic: No E.6.13 Others: No E.7 Trial type and phase E.7.1 Human pharmacology (Phase I): No E.7.1.1 First administration to humans: No E.7.1.2 Bioequivalence study: No E.7.1.3 Other: No E.7.1.3.1 Other trial type description: E.7.2 Therapeutic exploratory (Phase II): No E.7.3 Therapeutic confirmatory (Phase III): No E.7.4 Therapeutic use (Phase IV): Yes E.8 Design of the trial E.8.1 Controlled: Yes E.8.1.1 Randomised: Yes E.8.1.2 Open: No E.8.1.3 Single blind: No E.8.1.4 Double blind: Yes E.8.1.5 Parallel group: No E.8.1.6 Cross over: No E.8.1.7 Other: No E.8.2 Comparator of controlled trial E.8.2.1 Other medicinal product(s): No E.8.2.2 Placebo: Yes E.8.2.3 Other: No E.8.3 The trial involves single site in the Member State concerned: Yes E.8.4 The trial involves multiple sites in the Member State concerned: No E.8.5 The trial involves multiple Member States: No E.8.6 Trial involving sites outside the EEA E.8.6.1 Trial being conducted both within and outside the EEA: No E.8.6.2 Trial being conducted completely outside of the EEA: Information not present in EudraCT E.8.7 Trial has a data monitoring committee: Information not present in EudraCT E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: E.8.9 Initial estimate of the duration of the trial E.8.9.1 In the Member State concerned years: 2 E.8.9.1 In the Member State concerned months: E.8.9.1 In the Member State concerned days: E.8.9.2 In all countries concerned by the trial years: 2 F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18: No F.1.1.1 In Utero: Information not present in EudraCT F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): Information not present in EudraCT F.1.1.3 Newborns (0-27 days): Information not present in EudraCT F.1.1.4 Infants and toddlers (28 days-23 months): Information not present in EudraCT F.1.1.5 Children (2-11years): Information not present in EudraCT F.1.1.6 Adolescents (12-17 years): Information not present in EudraCT F.1.2 Adults (18-64 years): Yes F.1.3 Elderly (>=65 years): Yes F.2 Gender F.2.1 Female: Yes F.2.2 Male: Yes F.3 Group of trial subjects F.3.1 Healthy volunteers: No F.3.2 Patients: Yes F.3.3 Specific vulnerable populations: Information not present in EudraCT F.3.3.1 Women of childbearing potential not using contraception : No F.3.3.2 Women of child-bearing potential using contraception: Information not present in EudraCT F.3.3.3 Pregnant women: No F.3.3.4 Nursing women: No F.3.3.5 Emergency situation: No F.3.3.6 Subjects incapable of giving consent personally: No F.3.3.7 Others: No F.4 Planned number of subjects to be included F.4.1 In the member state: 200 F.4.2 For a multinational trial F.4.2.1 In the EEA: 200 F.4.2.2 In the whole clinical trial: 200 F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): Normal standard treatment G. Investigator Networks to be involved in the Trial N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision: Authorised N. Date of Competent Authority Decision: 2004-12-08 N. Ethics Committee Opinion of the trial application: Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion: N. Date of Ethics Committee Opinion: 2004-12-08 P. End of Trial P. End of Trial Status: Ongoing Summary EudraCT Number: 2005-000755-15 Sponsor's Protocol Code Number: 1974 National Competent Authority: UK - MHRA Clinical Trial Type: EEA CTA Trial Status: Ongoing Date on which this record was first entered in the EudraCT database: 2005-05-27 Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2005-000755-15/GB/ A. Protocol Information A.1 Member State Concerned: UK - MHRA A.2 EudraCT number: 2005-000755-15 A.3 Full title of the trial: Perhexiline therapy in patients with Hypertrophic Cardiomyopathy A.4.1 Sponsor's protocol code number: 1974 A.7 Trial is part of a Paediatric Investigation Plan: Information not present in EudraCT A.8 EMA Decision number of Paediatric Investigation Plan: B. Sponsor Information Sponsor 1 B.1.1 Name of Sponsor: University Hospital of Birmingham Foundation Trust B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: B.4.2 Country: B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: B.5.2 Functional name of contact point: D. IMP Identification D.IMP: 1 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: Information not present in EudraCT D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Pexsig D.3.4 Pharmaceutical form: Tablet D.3.4.1 Specific paediatric formulation: Information not present in EudraCT D.3.7 Routes of administration for this IMP: Oral use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: Perxexiline D.3.9.1 CAS number: 6724-53-4 D.3.10 Strength D.3.10.1 Concentration unit: mg milligram(s) D.3.10.2 Concentration type: equal D.3.10.3 Concentration number: 100 D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): Information not present in EudraCT D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: Information not present in EudraCT D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): Information not present in EudraCT D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: Information not present in EudraCT D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: Information not present in EudraCT D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: Information not present in EudraCT D.3.11.8 Extractive medicinal product: Information not present in EudraCT D.3.11.9 Recombinant medicinal product: Information not present in EudraCT D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: Information not present in EudraCT D.8 Information on Placebo D.8 Placebo: 1 D.8.1 Is a Placebo used in this Trial? Yes D.8.3 Pharmaceutical form of the placebo: Tablet D.8.4 Route of administration of the placebo: Oral use E. General Information on the Trial E.1 Medical condition or disease under investigation E.1.1 Medical condition(s) being investigated: Hypertrophic Cardiomyopathy MedDRA Classification E.1.3 Condition being studied is a rare disease: No E.2 Objective of the trial E.2.1 Main objective of the trial: Main objective :to test whether perhexiline improve exercise capacity(peakVo2) in patients with HCM. E.2.2 Secondary objectives of the trial: Secondary objectives : symptoms,cardiac and skeletal energitics, exercise cardiac output,diastolic function and ejection fraction. E.2.3 Trial contains a sub-study: Information not present in EudraCT E.3 Principal inclusion criteria: Symptomatic non-obstructive hypertrophic cardiomyopathy patients with less than 70% of predicted peak Vo2 and in sinus rhythm E.4 Principal exclusion criteria: Abnormal liver function test, Pre-existing peripheral neuropathy, Concomitant use of amiodarone and women of childbearing potential . E.5 End points E.5.1 Primary end point(s): Peak Vo2 E.6 and E.7 Scope of the trial E.6 Scope of the Trial E.6.1 Diagnosis: No E.6.2 Prophylaxis: No E.6.3 Therapy: Yes E.6.4 Safety: No E.6.5 Efficacy: Yes E.6.6 Pharmacokinetic: Information not present in EudraCT E.6.7 Pharmacodynamic: Information not present in EudraCT E.6.8 Bioequivalence: Information not present in EudraCT E.6.9 Dose response: Information not present in EudraCT E.6.10 Pharmacogenetic: Information not present in EudraCT E.6.11 Pharmacogenomic: Information not present in EudraCT E.6.12 Pharmacoeconomic: Information not present in EudraCT E.6.13 Others: Information not present in EudraCT E.7 Trial type and phase E.7.1 Human pharmacology (Phase I): No E.7.1.1 First administration to humans: No E.7.1.2 Bioequivalence study: No E.7.1.3 Other: No E.7.1.3.1 Other trial type description: E.7.2 Therapeutic exploratory (Phase II): No E.7.3 Therapeutic confirmatory (Phase III): Yes E.7.4 Therapeutic use (Phase IV): No E.8 Design of the trial E.8.1 Controlled: Yes E.8.1.1 Randomised: Yes E.8.1.2 Open: No E.8.1.3 Single blind: No E.8.1.4 Double blind: Yes E.8.1.5 Parallel group: Yes E.8.1.6 Cross over: No E.8.1.7 Other: No E.8.2 Comparator of controlled trial E.8.2.1 Other medicinal product(s): No E.8.2.2 Placebo: Yes E.8.2.3 Other: No E.8.3 The trial involves single site in the Member State concerned: Information not present in EudraCT E.8.4 The trial involves multiple sites in the Member State concerned: Yes E.8.5 The trial involves multiple Member States: Information not present in EudraCT E.8.6 Trial involving sites outside the EEA E.8.6.1 Trial being conducted both within and outside the EEA: Information not present in EudraCT E.8.6.2 Trial being conducted completely outside of the EEA: Information not present in EudraCT E.8.7 Trial has a data monitoring committee: Information not present in EudraCT E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: Trial end by the last visit of the last subject. E.8.9 Initial estimate of the duration of the trial E.8.9.1 In the Member State concerned years: 3 E.8.9.1 In the Member State concerned months: E.8.9.1 In the Member State concerned days: F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18: No F.1.1.1 In Utero: Information not present in EudraCT F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): Information not present in EudraCT F.1.1.3 Newborns (0-27 days): Information not present in EudraCT F.1.1.4 Infants and toddlers (28 days-23 months): Information not present in EudraCT F.1.1.5 Children (2-11years): Information not present in EudraCT F.1.1.6 Adolescents (12-17 years): Information not present in EudraCT F.1.2 Adults (18-64 years): Yes F.1.3 Elderly (>=65 years): Yes F.2 Gender F.2.1 Female: Yes F.2.2 Male: Yes F.3 Group of trial subjects F.3.1 Healthy volunteers: No F.3.2 Patients: Yes F.3.3 Specific vulnerable populations: Information not present in EudraCT F.3.3.1 Women of childbearing potential not using contraception : No F.3.3.2 Women of child-bearing potential using contraception: Information not present in EudraCT F.3.3.3 Pregnant women: No F.3.3.4 Nursing women: No F.3.3.5 Emergency situation: No F.3.3.6 Subjects incapable of giving consent personally: No F.3.3.7 Others: Information not present in EudraCT F.4 Planned number of subjects to be included F.4.1 In the member state: 50 F.4.2 For a multinational trial F.4.2.1 In the EEA: 0 F.4.2.2 In the whole clinical trial: 50 F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): At the end of the study the tested Drug will be discontinued and patients will remain on the standard available treatment . However, if the patient found that it was helpful then we can arrange for the patient to be continued on Perhexiline on individual named patient basis. G. Investigator Networks to be involved in the Trial N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision: Authorised N. Date of Competent Authority Decision: 2005-08-02 N. Ethics Committee Opinion of the trial application: Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion: N. Date of Ethics Committee Opinion: 2005-10-25 P. End of Trial P. End of Trial Status: Ongoing Summary EudraCT Number: 2006-005630-21 Sponsor's Protocol Code Number: RG_06-180 National Competent Authority: UK - MHRA Clinical Trial Type: EEA CTA Trial Status: Prematurely Ended Date on which this record was first entered in the EudraCT database: 2009-04-15 Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2006-005630-21/GB/ A. Protocol Information A.1 Member State Concerned: UK - MHRA A.2 EudraCT number: 2006-005630-21 A.3 Full title of the trial: The effect of Pregabalin on Pain progressing in Painful Diabetic Neuropathy A.3.2 Name or abbreviated title of the trial where available: Pregabalin A.4.1 Sponsor's protocol code number: RG_06-180 A.7 Trial is part of a Paediatric Investigation Plan: Information not present in EudraCT A.8 EMA Decision number of Paediatric Investigation Plan: B. Sponsor Information Sponsor 1 B.1.1 Name of Sponsor: University of Birmingham B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: B.4.2 Country: B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: B.5.2 Functional name of contact point: Sponsor 2 B.1.1 Name of Sponsor: Birmingham Heartlands Hospital B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: B.4.2 Country: B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: B.5.2 Functional name of contact point: D. IMP Identification D.IMP: 1 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: Yes D.2.1.1.1 Trade name: Lyrica D.2.1.1.2 Name of the Marketing Authorisation holder: Pfizer Limited D.2.1.2 Country which granted the Marketing Authorisation: United Kingdom D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Lyrica D.3.2 Product code: pregabalin D.3.4 Pharmaceutical form: Capsule, hard D.3.4.1 Specific paediatric formulation: Information not present in EudraCT D.3.7 Routes of administration for this IMP: Oral use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: PREGABALIN D.3.9.1 CAS number: 148553508 D.3.9.2 Current sponsor code: Pregabalin D.3.9.3 Other descriptive name: Lyrica D.3.10 Strength D.3.10.1 Concentration unit: mg milligram(s) D.3.10.2 Concentration type: range D.3.10.3 Concentration number: 150 to 300 D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): Information not present in EudraCT D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: Information not present in EudraCT D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): Information not present in EudraCT D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: Information not present in EudraCT D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: Information not present in EudraCT D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: Information not present in EudraCT D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.8 Information on Placebo D.8 Placebo: 1 D.8.1 Is a Placebo used in this Trial? Yes D.8.3 Pharmaceutical form of the placebo: Capsule, hard D.8.4 Route of administration of the placebo: Oral use E. General Information on the Trial E.1 Medical condition or disease under investigation E.1.1 Medical condition(s) being investigated: Diabtes and its complications, painful neuropathy MedDRA Classification E.1.3 Condition being studied is a rare disease: No E.2 Objective of the trial E.2.1 Main objective of the trial: To determine the effect of pregabalin on cerebral pain processing and sensory perception thresholds in diabetic patients with Painful Diabetic Neuropathy. E.2.2 Secondary objectives of the trial: To determine the effect of pregabalin on pain-related brain activity at rest and during noxious thermal stimulation using blood oxygen level-dependent (BOLD) contrast functional magnetic resonance imaging (fMRI) To determine the effects of pregabalin on cerebral evoked potential (EP) response at rest and during noxious thermal stimulation E.2.3 Trial contains a sub-study: No E.3 Principal inclusion criteria: 1. Type 1 or type 2 diabetes as defined by the World Health Organization Classification. 2. Duration of diabetes of at least 5 years. 3. The HbA1c should be <9% with <1% fluctuation of HbA1c levels over the past 6 months. 4. Age between 18 and 70 years. 5. Women of childbearing potential must be using an acceptable method of contraception to prevent pregnancy when they are enrolled in the study and must agree to continue to practice an acceptable method of contraception for the duration of their participation in the study. 6. Must be meet the specified criteria for PDN (see below) and have no risk factors for other causes for neuropathy 7. Willingness to sign the Center for Research Ethics Committee (COREC) approved informed consent form E.4 Principal exclusion criteria: 1. Nursing mothers, pregnant women (excluded by a negative pregnancy test). 2. Patients with a history of drug or alcohol dependence in the last 5 years 3. Patients with severe systemic disease other than diabetes which has as a recognized complication neuropathy or severe chronic pain 4. Patients with symptoms of neuropathic pain in the upper limbs alone 5. Significant changes in skin conditions in the areas to be tested which could alter sensation. 6. Patients currently taking medications that could affect symptoms of painful DN except acetominophen (up to 3g/d) or aspirin (up to 325 mg/d). 7. Patients experiencing an increase in pain after analgesic medication washout to levels which would, in the view of the PI, require prohibited analgesic therapy within a 6 wk period. 8. Patients whose creatinine clearance is less than 70 ml/min or have significant hepatic disease (AST, ALT, γGT >2 times upper limit for normal). Patients with TSH outside normal limits 9. Patients with a history of previous kidney, pancreas or cardiac transplantation. 10. Serious or unstable medical or psychological state that may interfere with study participation. 11. Patients having taken other systemic investigational drugs (especially for neuropathy) or initiating a new or experimental insulin delivery device within 3 months of starting the study. 12.patients with a hypersensivity to pregabalin 13. Patients who refuse to sign the informed consent. E.5 End points E.5.1 Primary end point(s): A 6 week placebo-controlled, cross-over clinical study will be conducted in patients with PDN. Subjects who are eligible for the study will be randomized to one of two treatment groups: Group 1: Pregabalin (75 mg bd) (Pfizer Pharmaceutical Company), or Group 2: matched oral placebos for 2 weeks, then undergo a 2 week washout period and then cross over to the alternative therapy for 2 weeks. Weekly Activities: Subjects will complete pain diaries and sleep interference scores on a weekly basis. All subjects will be reviewed at 2 weekly intervals when compliance will be reassessed. At two weekly visits, the following procedures will be performed: Assessment of compliance; blood pressure and pulse evaluation; evaluation of current medications; collection of study drug; recording of adverse symptoms/events. Collection of data from weekly pain diaries and sleep interference scores. SF-MMPQ will be completed at each visit. At the two and six weekly visits, the following additional procedures will be performed: BOLD-contrast fMRI and somatosensory psychophysics will be performed and cerebral EP responses to thermal noxious stimulation recorded. laser doppler ans skin biopsies will also be undertaken. Clinical and Global Impression of Change questionnaires will be completed. A blood draw will include glycaemic (glucose, HbA1c) measurements. The follow-up evaluation: All patients will be contacted 4 wk after the final visit and study drug withdrawal in order to monitor response to discontinuation of treatment or regression or adverse events. E.6 and E.7 Scope of the trial E.6 Scope of the Trial E.6.1 Diagnosis: No E.6.2 Prophylaxis: Yes E.6.3 Therapy: Yes E.6.4 Safety: Yes E.6.5 Efficacy: Yes E.6.6 Pharmacokinetic: No E.6.7 Pharmacodynamic: No E.6.8 Bioequivalence: No E.6.9 Dose response: Yes E.6.10 Pharmacogenetic: No E.6.11 Pharmacogenomic: No E.6.12 Pharmacoeconomic: No E.6.13 Others: No E.7 Trial type and phase E.7.1 Human pharmacology (Phase I): No E.7.1.1 First administration to humans: No E.7.1.2 Bioequivalence study: No E.7.1.3 Other: No E.7.1.3.1 Other trial type description: E.7.2 Therapeutic exploratory (Phase II): No E.7.3 Therapeutic confirmatory (Phase III): No E.7.4 Therapeutic use (Phase IV): Yes E.8 Design of the trial E.8.1 Controlled: Yes E.8.1.1 Randomised: Yes E.8.1.2 Open: No E.8.1.3 Single blind: No E.8.1.4 Double blind: Yes E.8.1.5 Parallel group: No E.8.1.6 Cross over: Yes E.8.1.7 Other: No E.8.2 Comparator of controlled trial E.8.2.1 Other medicinal product(s): No E.8.2.2 Placebo: Yes E.8.2.3 Other: No E.8.3 The trial involves single site in the Member State concerned: No E.8.4 The trial involves multiple sites in the Member State concerned: Yes E.8.4.1 Number of sites anticipated in Member State concerned: 2 E.8.5 The trial involves multiple Member States: No E.8.6 Trial involving sites outside the EEA E.8.6.1 Trial being conducted both within and outside the EEA: No E.8.6.2 Trial being conducted completely outside of the EEA: Information not present in EudraCT E.8.7 Trial has a data monitoring committee: No E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: the last visit of the last subject undergoing the trial E.8.9 Initial estimate of the duration of the trial E.8.9.1 In the Member State concerned years: 3 E.8.9.1 In the Member State concerned months: 0 E.8.9.1 In the Member State concerned days: 0 E.8.9.2 In all countries concerned by the trial years: 0 E.8.9.2 In all countries concerned by the trial months: 0 E.8.9.2 In all countries concerned by the trial days: 0 F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18: No F.1.1.1 In Utero: No F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No F.1.1.3 Newborns (0-27 days): No F.1.1.4 Infants and toddlers (28 days-23 months): No F.1.1.5 Children (2-11years): No F.1.1.6 Adolescents (12-17 years): No F.1.2 Adults (18-64 years): Yes F.1.3 Elderly (>=65 years): Yes F.2 Gender F.2.1 Female: Yes F.2.2 Male: Yes F.3 Group of trial subjects F.3.1 Healthy volunteers: No F.3.2 Patients: Yes F.3.3 Specific vulnerable populations: No F.3.3.1 Women of childbearing potential not using contraception : No F.3.3.2 Women of child-bearing potential using contraception: No F.3.3.3 Pregnant women: No F.3.3.4 Nursing women: No F.3.3.5 Emergency situation: No F.3.3.6 Subjects incapable of giving consent personally: No F.3.3.7 Others: No F.4 Planned number of subjects to be included F.4.1 In the member state: 10 F.4.2 For a multinational trial F.4.2.2 In the whole clinical trial: 10 F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): Care of subjects after participation will be their standard care with their GP or diabetologist G. Investigator Networks to be involved in the Trial N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision: Authorised N. Date of Competent Authority Decision: 2009-04-09 N. Ethics Committee Opinion of the trial application: Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion: N. Date of Ethics Committee Opinion: 2008-10-15 P. End of Trial P. End of Trial Status: Prematurely Ended P. Date of the global end of the trial: 2014-05-19 Summary EudraCT Number: 2012-004988-42 Sponsor's Protocol Code Number: 12DIAB15 National Competent Authority: UK - MHRA Clinical Trial Type: EEA CTA Trial Status: Ongoing Date on which this record was first entered in the EudraCT database: 2013-01-04 Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-004988-42/GB/ A. Protocol Information A.1 Member State Concerned: UK - MHRA A.2 EudraCT number: 2012-004988-42 A.3 Full title of the trial: REVISE-Diabesity: Randomisation to Endoluminal intestinal liner alone Versus with Incretin analogue in SustainEd Diabesity A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: Clinical trial of patients with type 2 diabetes and obesity randomly allocated to be implanted with an intestinal liner device with or without standard diabetes liraglutide medical therapy or liraglutide alone. A.3.2 Name or abbreviated title of the trial where available: REVISE-Diabesity A.4.1 Sponsor's protocol code number: 12DIAB15 A.7 Trial is part of a Paediatric Investigation Plan: No A.8 EMA Decision number of Paediatric Investigation Plan: B. Sponsor Information Sponsor 1 B.1.1 Name of Sponsor: Sandwell and West Birmingham Hospitals NHS Trust B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: Association of British Clinical Diabetologists B.4.2 Country: United Kingdom B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: City Hospital, Birmingham B.5.2 Functional name of contact point: Dr Bob Ryder B.5.3 Address B.5.3.1 Street Address: Department of Diabetes, Dudley Road B.5.3.2 Town/ city: Birmingham B.5.3.3 Post code: B18 7QH B.5.3.4 Country: United Kingdom B.5.4 Telephone number: 01215074191 B.5.6 E-mail: bob.ryder@nhs.net D. IMP Identification D.IMP: 1 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: Yes D.2.1.1.1 Trade name: Victoza D.2.1.1.2 Name of the Marketing Authorisation holder: Novo Nordisk A/S D.2.1.2 Country which granted the Marketing Authorisation: Denmark D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Liraglutide D.3.2 Product code: n/a D.3.4 Pharmaceutical form: Solution for injection in pre-filled pen D.3.4.1 Specific paediatric formulation: No D.3.7 Routes of administration for this IMP: Subcutaneous use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: Liraglutide D.3.9.4 EV Substance Code: AS1 D.3.10 Strength D.3.10.1 Concentration unit: mg/ml milligram(s)/millilitre D.3.10.2 Concentration type: equal D.3.10.3 Concentration number: 6mg D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): No D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: No D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): No D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: No D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: No D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: No D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.8 Information on Placebo D.8 Placebo: 1 D.8.1 Is a Placebo used in this Trial? Yes E. General Information on the Trial E.1 Medical condition or disease under investigation E.1.1 Medical condition(s) being investigated: Combined Type 2 diabetes mellitus and obesity. E.1.1.1 Medical condition in easily understood language: Type 2 diabetes, a disorder of insulin resistance resulting associated with high glucose 'sugar' levels with associated short and long-term complications; Obesity. E.1.1.2 Therapeutic area: Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02] MedDRA Classification E.1.2 Medical condition or disease under investigation: E.1.2 Version: 14.1 E.1.2 Level: LLT E.1.2 Classification code: 10063624 E.1.2 Term: Type II diabetes mellitus inadequate control E.1.2 System Organ Class: 10027433 - Metabolism and nutrition disorders E.1.2 Medical condition or disease under investigation: E.1.2 Version: 14.1 E.1.2 Level: PT E.1.2 Classification code: 10029883 E.1.2 Term: Obesity E.1.2 System Organ Class: 10027433 - Metabolism and nutrition disorders E.1.3 Condition being studied is a rare disease: No E.2 Objective of the trial E.2.1 Main objective of the trial: In an NHS setting, what is the impact of Endobarrier (a device inserted into the intestine to coat its inside and prevent absorption of food where it is sited) alone versus combined Endobarrier-Liraglutide therapy (a daily injectable medication for type 2 diabetes) in patients with obesity and type 2 diabetes mellitus who have not yet met national treatment targets despite at least 6 months of Liraglutide treatment alone? E.2.2 Secondary objectives of the trial: What are the mechanisms of action by which Endobarrier exerts its effect of weight reduction and improved diabetes control? E.2.3 Trial contains a sub-study: No E.3 Principal inclusion criteria: Patients will be eligible to be included in this randomised clinical trial if they meet the following inclusion criteria: 1. participation in ABCD Nationwide Liraglutide Audit with data for at least 6 months, 2. HbA1c ≥7.5% after at least 6 months’ Liraglutide treatment, 3. BMI ≥35 Kg/m2 (≥30 Kg/m2 for Asian origin patients), 4. stable weight and HbA1c in preceding 3 months (<3 Kg reduction in weight and <0.3% reduction in HbA1c). E.4 Principal exclusion criteria: Exclusion criteria will include the following: abnormal intestinal anatomy; contraindication to oesophago-gastroduoenoscopy; previous bariatric surgery or bowel surgery; active infection or CRP >10; anticoagulation therapy; coagulopathy INR >1.3; eGFR <30; known portal hypertension; previous pancreatitis or amylase > 3 times the upper limit of normal; uncontrolled cardiovascular disease; lactating or pregnant females. Patients taking aspirin with active ischaemic heart disease or cerebrovascular disease or those in whom aspirin treatment should continue. Patients taking regular aspirin will need to discontinue it for the duration of the Endobarrier implantation if randomised to that arm and so for those in whom it is taken for primary prevention, the potential risks and benefits of deciding to discontinue aspirin will be weighed up by the clinician concerned in consultation with the patient. E.5 End points E.5.1 Primary end point(s): The primary outcome measure for the study will be participant weight and HbA1c in the two Endobarrier-treated groups at the last follow-up visit, which will be at 12 months after Endobarrier removal (equivalent to 12 months after Endobarrier implantation). E.5.1.1 Timepoint(s) of evaluation of this end point: 12 months post-explant of the Endobarrier device, which will usually be inserted for 1 year. Therefore 24 months from implant of the Endobarrier. E.5.2 Secondary end point(s): The secondary end points are: fasting insulin, glucose, c-peptide to calculate HOMA-IR and bile acids; hepatic and pancreatic triacylglycerol stores; quality of life scores; gut microbiota and faecal calprotectin changes over time in Endobarrier-treated patients. E.5.2.1 Timepoint(s) of evaluation of this end point: Insulin resistance (HOMA-IR) to be evaluated at days 2, 4 and 7 post Endobarrier placement and days 2,4 and 7 post Endobarrier removal and compared to baseline. Hepatic and pancreatic triacylglycerol stores compared at 3 months post Endobarrier placement to baseline. E.6 and E.7 Scope of the trial E.6 Scope of the Trial E.6.1 Diagnosis: No E.6.2 Prophylaxis: No E.6.3 Therapy: Yes E.6.4 Safety: No E.6.5 Efficacy: Yes E.6.6 Pharmacokinetic: No E.6.7 Pharmacodynamic: No E.6.8 Bioequivalence: No E.6.9 Dose response: No E.6.10 Pharmacogenetic: No E.6.11 Pharmacogenomic: No E.6.12 Pharmacoeconomic: No E.6.13 Others: No E.7 Trial type and phase E.7.1 Human pharmacology (Phase I): No E.7.1.1 First administration to humans: No E.7.1.2 Bioequivalence study: No E.7.1.3 Other: No E.7.1.3.1 Other trial type description: E.7.2 Therapeutic exploratory (Phase II): No E.7.3 Therapeutic confirmatory (Phase III): No E.7.4 Therapeutic use (Phase IV): Yes E.8 Design of the trial E.8.1 Controlled: Yes E.8.1.1 Randomised: Yes E.8.1.2 Open: Yes E.8.1.3 Single blind: No E.8.1.4 Double blind: No E.8.1.5 Parallel group: No E.8.1.6 Cross over: No E.8.1.7 Other: No E.8.2 Comparator of controlled trial E.8.2.1 Other medicinal product(s): Yes E.8.2.2 Placebo: No E.8.2.3 Other: Yes E.8.2.3.1 Comparator description: Endobarrier device E.8.2.4 Number of treatment arms in the trial: 3 E.8.3 The trial involves single site in the Member State concerned: No E.8.4 The trial involves multiple sites in the Member State concerned: Yes E.8.4.1 Number of sites anticipated in Member State concerned: 3 E.8.5 The trial involves multiple Member States: No E.8.6 Trial involving sites outside the EEA E.8.6.1 Trial being conducted both within and outside the EEA: No E.8.6.2 Trial being conducted completely outside of the EEA: No E.8.7 Trial has a data monitoring committee: Yes E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: LVLS E.8.9 Initial estimate of the duration of the trial E.8.9.1 In the Member State concerned years: 2 E.8.9.1 In the Member State concerned months: 6 E.8.9.1 In the Member State concerned days: 0 E.8.9.2 In all countries concerned by the trial years: 2 E.8.9.2 In all countries concerned by the trial months: 6 E.8.9.2 In all countries concerned by the trial days: 0 F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18: No F.1.1 Number of subjects for this age range: 0 F.1.1.1 In Utero: No F.1.1.1.1 Number of subjects for this age range: 0 F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No F.1.1.2.1 Number of subjects for this age range: 0 F.1.1.3 Newborns (0-27 days): No F.1.1.3.1 Number of subjects for this age range: 0 F.1.1.4 Infants and toddlers (28 days-23 months): No F.1.1.4.1 Number of subjects for this age range: 0 F.1.1.5 Children (2-11years): No F.1.1.5.1 Number of subjects for this age range: 0 F.1.1.6 Adolescents (12-17 years): No F.1.1.6.1 Number of subjects for this age range: 0 F.1.2 Adults (18-64 years): Yes F.1.2.1 Number of subjects for this age range: 65 F.1.3 Elderly (>=65 years): Yes F.1.3.1 Number of subjects for this age range: 7 F.2 Gender F.2.1 Female: Yes F.2.2 Male: Yes F.3 Group of trial subjects F.3.1 Healthy volunteers: No F.3.2 Patients: Yes F.3.3 Specific vulnerable populations: No F.3.3.1 Women of childbearing potential not using contraception : No F.3.3.2 Women of child-bearing potential using contraception: No F.3.3.3 Pregnant women: No F.3.3.4 Nursing women: No F.3.3.5 Emergency situation: No F.3.3.6 Subjects incapable of giving consent personally: No F.3.3.7 Others: No F.4 Planned number of subjects to be included F.4.1 In the member state: 72 F.4.2 For a multinational trial F.4.2.1 In the EEA: 0 F.4.2.2 In the whole clinical trial: 0 F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): By considering the inclusion criteria of participants, they will be overweight with a suboptimal HbA1c at the start of the study. The intervention will consist of either Liraglutide alone or Endobarrier (with or without Liraglutide) but the Endobarrier will be implanted for no longer than 12 months. Following the 24 month follow-up period, if the participant continues to be overweight with a suboptimal HbA1c, continued assessment will be by the local NHS Diabetologist .…. G. Investigator Networks to be involved in the Trial G.4 Investigator Network to be involved in the Trial: 1 G.4.1 Name of Organisation: Birmingham and Black Country CLRN G.4.3.4 Network Country: United Kingdom N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision: Authorised N. Date of Competent Authority Decision: 2013-02-05 N. Ethics Committee Opinion of the trial application: Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion: N. Date of Ethics Committee Opinion: 2013-01-02 P. End of Trial P. End of Trial Status: Ongoing Summary EudraCT Number: 2007-007625-43 Sponsor's Protocol Code Number: 2007PCT018 National Competent Authority: UK - MHRA Clinical Trial Type: EEA CTA Trial Status: Ongoing Date on which this record was first entered in the EudraCT database: 2008-03-26 Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-007625-43/GB/ A. Protocol Information A.1 Member State Concerned: UK - MHRA A.2 EudraCT number: 2007-007625-43 A.3 Full title of the trial: A randomised controlled trial of two analgesic techniques for the control of pain and post-operative nausea and vomiting in paediatric day-case tonsillectomy. A.3.2 Name or abbreviated title of the trial where available: RCT of two analgesic techniques for day-case tonsillectomy. A.4.1 Sponsor's protocol code number: 2007PCT018 A.7 Trial is part of a Paediatric Investigation Plan: Information not present in EudraCT A.8 EMA Decision number of Paediatric Investigation Plan: B. Sponsor Information Sponsor 1 B.1.1 Name of Sponsor: Birmingham Children’s Hospital NHS Foundation Trust B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: B.4.2 Country: B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: B.5.2 Functional name of contact point: D. IMP Identification D.IMP: 1 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: Information not present in EudraCT D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Fentanyl D.3.4 Pharmaceutical form: Injection* D.3.4.1 Specific paediatric formulation: Information not present in EudraCT D.3.7 Routes of administration for this IMP: Intravenous use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: Fentanyl D.3.10 Strength D.3.10.1 Concentration unit: µg/ml microgram(s)/millilitre D.3.10.2 Concentration type: equal D.3.10.3 Concentration number: 50 D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): Information not present in EudraCT D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: Information not present in EudraCT D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): Information not present in EudraCT D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: Information not present in EudraCT D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: Information not present in EudraCT D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: Information not present in EudraCT D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: Information not present in EudraCT D.IMP: 2 D.1.2 and D.1.3 IMP Role: Comparator D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: No D.2.1.2 Country which granted the Marketing Authorisation: United Kingdom D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Codeine Phosphate D.3.4 Pharmaceutical form: Injection* D.3.4.1 Specific paediatric formulation: Information not present in EudraCT D.3.7 Routes of administration for this IMP: Intramuscular use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: Codeine Phosphate D.3.10 Strength D.3.10.1 Concentration unit: mg/ml milligram(s)/millilitre D.3.10.2 Concentration type: equal D.3.10.3 Concentration number: 60 D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): Information not present in EudraCT D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: Information not present in EudraCT D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): Information not present in EudraCT D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: Information not present in EudraCT D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: Information not present in EudraCT D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: Information not present in EudraCT D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: Information not present in EudraCT D.IMP: 3 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: No D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Diclofenac sodium D.3.4 Pharmaceutical form: Suppository D.3.4.1 Specific paediatric formulation: Information not present in EudraCT D.3.7 Routes of administration for this IMP: Rectal use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: Diclofenac sodium D.3.10 Strength D.3.10.1 Concentration unit: mg milligram(s) D.3.10.2 Concentration type: equal D.3.10.3 Concentration number: 12.5 D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): Information not present in EudraCT D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: Information not present in EudraCT D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): Information not present in EudraCT D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: Information not present in EudraCT D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: Information not present in EudraCT D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: Information not present in EudraCT D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.IMP: 4 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: No D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Diclofenac sodium D.3.4 Pharmaceutical form: Suppository D.3.4.1 Specific paediatric formulation: Information not present in EudraCT D.3.7 Routes of administration for this IMP: Rectal use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: Diclofenac sodium D.3.10 Strength D.3.10.1 Concentration unit: mg milligram(s) D.3.10.2 Concentration type: equal D.3.10.3 Concentration number: 25 D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): Information not present in EudraCT D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: Information not present in EudraCT D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): Information not present in EudraCT D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: Information not present in EudraCT D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: Information not present in EudraCT D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: Information not present in EudraCT D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.IMP: 5 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: No D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: No D.2.5.1 Orphan drug designation number: D.3 Description of the IMP D.3.1 Product name: Diclofenac sodium D.3.4 Pharmaceutical form: Suppository D.3.4.1 Specific paediatric formulation: Information not present in EudraCT D.3.7 Routes of administration for this IMP: Rectal use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN: Diclofenac sodium D.3.10 Strength D.3.10.1 Concentration unit: mg milligram(s) D.3.10.2 Concentration type: equal D.3.10.3 Concentration number: 50 D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: Yes D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): No D.3.11.3 Advanced Therapy IMP (ATIMP): Information not present in EudraCT D.3.11.3.1 Somatic cell therapy medicinal product: No D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: Information not present in EudraCT D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): Information not present in EudraCT D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: Information not present in EudraCT D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: Information not present in EudraCT D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: Information not present in EudraCT D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.8 Information on Placebo E. General Information on the Trial E.1 Medical condition or disease under investigation E.1.1 Medical condition(s) being investigated: Tonsillectomy is one of the most common surgical procedures in children and is usually associated with moderate to severe pain which is problematic to treat because of side effects associated with the analgesics. Government targets include increasing day-case tonsillectomy We use codeine for analgesia. We wish to compare this wih the Bristol group who found a low incidence of postoperative nausea and vomiting using fentanyl. MedDRA Classification E.1.3 Condition being studied is a rare disease: No E.2 Objective of the trial E.2.1 Main objective of the trial: In children having tonsillectomy does a technique using fentanyl and diclofenac for pain relief reduce the incidence of postoperative nausea and vomiting (without compromising pain control) when compared to a technique using codeine phosphate as the pain killer? E.2.2 Secondary objectives of the trial: E.2.3 Trial contains a sub-study: No E.3 Principal inclusion criteria: All ASA I or II children aged 4 -16 years scheduled for elective tonsillectomy or adenotonsillectomy +/-grommets and suitable for day-case surgery will be invited to enter the study. E.4 Principal exclusion criteria: Children involved in other studies or who have been involved in other studies in the previous year. Sensitivity to any of the study drugs. Bleeding diathesis and renal or hepatic impairment. Children with developmental delay, behavioural problems (autism etc.) in whom pain assessment would be difficult. Children with parents that don’t speak/understand English making informed consent difficult. Children in whom obtaining informed consent is difficult for any other reason. Children requiring premedication (as this may affect the pain and sedation levels in the early postoperative period). • Children who have taken any analgesic drugs on the day of surgery. E.5 End points E.5.1 Primary end point(s): Postoperative nausea and vomiting in the first 4 hours (yes or no) E.6 and E.7 Scope of the trial E.6 Scope of the Trial E.6.1 Diagnosis: No E.6.2 Prophylaxis: No E.6.3 Therapy: Yes E.6.4 Safety: Yes E.6.5 Efficacy: Yes E.6.6 Pharmacokinetic: No E.6.7 Pharmacodynamic: No E.6.8 Bioequivalence: No E.6.9 Dose response: No E.6.10 Pharmacogenetic: No E.6.11 Pharmacogenomic: No E.6.12 Pharmacoeconomic: No E.6.13 Others: No E.7 Trial type and phase E.7.1 Human pharmacology (Phase I): No E.7.1.1 First administration to humans: No E.7.1.2 Bioequivalence study: No E.7.1.3 Other: No E.7.1.3.1 Other trial type description: E.7.2 Therapeutic exploratory (Phase II): No E.7.3 Therapeutic confirmatory (Phase III): No E.7.4 Therapeutic use (Phase IV): Yes E.8 Design of the trial E.8.1 Controlled: Yes E.8.1.1 Randomised: Yes E.8.1.2 Open: No E.8.1.3 Single blind: Yes E.8.1.4 Double blind: No E.8.1.5 Parallel group: Yes E.8.1.6 Cross over: No E.8.1.7 Other: No E.8.2 Comparator of controlled trial E.8.2.1 Other medicinal product(s): Yes E.8.2.2 Placebo: No E.8.2.3 Other: No E.8.3 The trial involves single site in the Member State concerned: Yes E.8.4 The trial involves multiple sites in the Member State concerned: No E.8.5 The trial involves multiple Member States: No E.8.6 Trial involving sites outside the EEA E.8.6.1 Trial being conducted both within and outside the EEA: No E.8.6.2 Trial being conducted completely outside of the EEA: Information not present in EudraCT E.8.7 Trial has a data monitoring committee: Yes E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: The trial will end 4 hours postoperatively (time zero = extubation point) after the research fellow has assessed the patient's suitability for discharge. E.8.9 Initial estimate of the duration of the trial E.8.9.1 In the Member State concerned years: 1 E.8.9.1 In the Member State concerned months: 0 E.8.9.1 In the Member State concerned days: 0 F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18: Yes F.1.1.1 In Utero: No F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No F.1.1.3 Newborns (0-27 days): No F.1.1.4 Infants and toddlers (28 days-23 months): No F.1.1.5 Children (2-11years): Yes F.1.1.6 Adolescents (12-17 years): Yes F.1.2 Adults (18-64 years): No F.1.3 Elderly (>=65 years): No F.2 Gender F.2.1 Female: Yes F.2.2 Male: Yes F.3 Group of trial subjects F.3.1 Healthy volunteers: No F.3.2 Patients: Yes F.3.3 Specific vulnerable populations: Yes F.3.3.1 Women of childbearing potential not using contraception : No F.3.3.2 Women of child-bearing potential using contraception: No F.3.3.3 Pregnant women: No F.3.3.4 Nursing women: No F.3.3.5 Emergency situation: No F.3.3.6 Subjects incapable of giving consent personally: Yes F.3.3.6.1 Details of subjects incapable of giving consent: Children under the age of 16 years. F.3.3.7 Others: No F.4 Planned number of subjects to be included F.4.1 In the member state: 80 F.4.2 For a multinational trial F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): N/A G. Investigator Networks to be involved in the Trial N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision: Authorised N. Date of Competent Authority Decision: 2008-03-20 N. Ethics Committee Opinion of the trial application: Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion: N. Date of Ethics Committee Opinion: 2008-04-18 P. End of Trial P. End of Trial Status: Ongoing Summary EudraCT Number: 2010-019296-30 Sponsor's Protocol Code Number: National Competent Authority: UK - MHRA Clinical Trial Type: EEA CTA Trial Status: Completed Date on which this record was first entered in the EudraCT database: 2010-04-16 Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-019296-30/GB/ A. Protocol Information A.1 Member State Concerned: UK - MHRA A.2 EudraCT number: 2010-019296-30 A.3 Full title of the trial: A pharmacokinetic and pharmacodynamic study of recombinant human IGF-I (rhIGF-I) in three boys with ALS deficiency, and insulin sensitivity and bone density in patients and heterozygous first-degree relatives. A.3.2 Name or abbreviated title of the trial where available: ALS deficiency: insulin resistance, bone strength & response to rhIGF1 A.4.1 Sponsor's protocol code number: A.5.1 ISRCTN (International Standard Randomised Controlled Trial) number: N/A A.7 Trial is part of a Paediatric Investigation Plan: Information not present in EudraCT A.8 EMA Decision number of Paediatric Investigation Plan: B. Sponsor Information Sponsor 1 B.1.1 Name of Sponsor: University Hospital Birmingham NHS Foundation Trust B.1.3.4 Country: United Kingdom B.3.1 and B.3.2 Status of the sponsor: Non-Commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support: B.4.2 Country: B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation: B.5.2 Functional name of contact point: D. IMP Identification D.IMP: 1 D.1.2 and D.1.3 IMP Role: Test D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation: Yes D.2.1.1.1 Trade name: INCRELEX D.2.1.1.2 Name of the Marketing Authorisation holder: IPSEN Biopharm D.2.1.2 Country which granted the Marketing Authorisation: European Union D.2.5 The IMP has been designated in this indication as an orphan drug in the Community: Yes D.2.5.1 Orphan drug designation number: EU/3/05/307 D.3 Description of the IMP D.3.1 Product name: Increlex D.3.4 Pharmaceutical form: Solution for injection D.3.4.1 Specific paediatric formulation: Information not present in EudraCT D.3.7 Routes of administration for this IMP: Subcutaneous use D.3.11 The IMP contains an D.3.11.1 Active substance of chemical origin: No D.3.11.2 Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP): Yes D.3.11.3 Advanced Therapy IMP (ATIMP): Information not present in EudraCT D.3.11.3.1 Somatic cell therapy medicinal product: Yes D.3.11.3.2 Gene therapy medical product: No D.3.11.3.3 Tissue Engineered Product: Information not present in EudraCT D.3.11.3.4 Combination ATIMP (i.e. one involving a medical device): Information not present in EudraCT D.3.11.3.5 Committee on Advanced therapies (CAT) has issued a classification for this product: Information not present in EudraCT D.3.11.4 Combination product that includes a device, but does not involve an Advanced Therapy: Information not present in EudraCT D.3.11.5 Radiopharmaceutical medicinal product: No D.3.11.6 Immunological medicinal product (such as vaccine, allergen, immune serum): No D.3.11.7 Plasma derived medicinal product: No D.3.11.8 Extractive medicinal product: No D.3.11.9 Recombinant medicinal product: Information not present in EudraCT D.3.11.10 Medicinal product containing genetically modified organisms: No D.3.11.11 Herbal medicinal product: No D.3.11.12 Homeopathic medicinal product: No D.3.11.13 Another type of medicinal product: No D.8 Information on Placebo D.8 Placebo: 1 D.8.1 Is a Placebo used in this Trial? Yes E. General Information on the Trial E.1 Medical condition or disease under investigation E.1.1 Medical condition(s) being investigated: ALS (acid label subunit) deficiency MedDRA Classification E.1.2 Medical condition or disease under investigation: E.1.2 Version: 12.1 E.1.2 Level: LLT E.1.2 Classification code: 10056438 E.1.2 Term: Growth Hormone Deficiency E.1.3 Condition being studied is a rare disease: Yes E.2 Objective of the trial E.2.1 Main objective of the trial: To determine the amount and duration of response in free IGF-1 after a single injection of rhIGF-1 in three patients with ALS deficiency due to an IGFALS gene mutation. E.2.2 Secondary objectives of the trial: 1) To determine the pharmacokinetic (PK) and pharmacodynamic (PD) parameters for subcutaneously injected rhIGF-I in ALS deficient individuals, including change in fasting and postprandial insulin levels. 2) To determine insulin sensitivity of the patients and heterozygous siblings and parents. 3) To determine whether bone density and bone geometric variables are abnormal the patients and their siblings and parents. 4) To assess the relation between variables of insulin sensitivity, IGF-I levels, bone strength and molecular genetic results (IGFALS gene mutation hetero- or homozygocity). 5) To assess metacarpal cortical thickness by radiography. E.2.3 Trial contains a sub-study: No E.3 Principal inclusion criteria: PK/PD study arm: Patients with confirmed IGFALS gene mutations, able to give informed consent Cross-sectional study arm: Heterozygous first-degree relatives, able to give informed consent. E.4 Principal exclusion criteria: PK/PD study arm: Patients currently receiving IncrelexTM treatment, patients allergic to Increlex, patients with cancer Cross-sectional study arm: Individuals suffering from cancer or chronic inflammatory conditions (e.g. chronic rheumatoid arthritis, inflammatory bowels disease). E.5 End points E.5.1 Primary end point(s): • Pharmacokinetic variables: Area under the curve for total and free IGF-1, half-life, IGF-1 clearance rate & production rate. • Pharmacodynamic variables: Change in serum free and total IGF-1, IGFBP-3, change in blood glucose and insulin. E.6 and E.7 Scope of the trial E.6 Scope of the Trial E.6.1 Diagnosis: No E.6.2 Prophylaxis: No E.6.3 Therapy: No E.6.4 Safety: No E.6.5 Efficacy: Yes E.6.6 Pharmacokinetic: Yes E.6.7 Pharmacodynamic: Yes E.6.8 Bioequivalence: No E.6.9 Dose response: No E.6.10 Pharmacogenetic: No E.6.11 Pharmacogenomic: No E.6.12 Pharmacoeconomic: No E.6.13 Others: No E.7 Trial type and phase E.7.1 Human pharmacology (Phase I): No E.7.1.1 First administration to humans: Information not present in EudraCT E.7.1.2 Bioequivalence study: Information not present in EudraCT E.7.1.3 Other: Information not present in EudraCT E.7.1.3.1 Other trial type description: E.7.2 Therapeutic exploratory (Phase II): No E.7.3 Therapeutic confirmatory (Phase III): No E.7.4 Therapeutic use (Phase IV): Yes E.8 Design of the trial E.8.1 Controlled: No E.8.1.1 Randomised: Information not present in EudraCT E.8.1.2 Open: Information not present in EudraCT E.8.1.3 Single blind: Information not present in EudraCT E.8.1.4 Double blind: Information not present in EudraCT E.8.1.5 Parallel group: Information not present in EudraCT E.8.1.6 Cross over: Information not present in EudraCT E.8.1.7 Other: Information not present in EudraCT E.8.2 Comparator of controlled trial E.8.2.1 Other medicinal product(s): Information not present in EudraCT E.8.2.2 Placebo: Information not present in EudraCT E.8.2.3 Other: Information not present in EudraCT E.8.3 The trial involves single site in the Member State concerned: No E.8.4 The trial involves multiple sites in the Member State concerned: Yes E.8.4.1 Number of sites anticipated in Member State concerned: 2 E.8.5 The trial involves multiple Member States: No E.8.6 Trial involving sites outside the EEA E.8.6.1 Trial being conducted both within and outside the EEA: No E.8.6.2 Trial being conducted completely outside of the EEA: Information not present in EudraCT E.8.7 Trial has a data monitoring committee: No E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial: When all investigations have been carried out E.8.9 Initial estimate of the duration of the trial E.8.9.1 In the Member State concerned years: 0 E.8.9.1 In the Member State concerned months: 2 E.8.9.1 In the Member State concerned days: 0 E.8.9.2 In all countries concerned by the trial months: 2 F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18: No F.1.1.1 In Utero: Information not present in EudraCT F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): Information not present in EudraCT F.1.1.3 Newborns (0-27 days): Information not present in EudraCT F.1.1.4 Infants and toddlers (28 days-23 months): Information not present in EudraCT F.1.1.5 Children (2-11years): Information not present in EudraCT F.1.1.6 Adolescents (12-17 years): Information not present in EudraCT F.1.2 Adults (18-64 years): Yes F.1.3 Elderly (>=65 years): No F.2 Gender F.2.1 Female: Yes F.2.2 Male: Yes F.3 Group of trial subjects F.3.1 Healthy volunteers: Yes F.3.2 Patients: Yes F.3.3 Specific vulnerable populations: No F.3.3.1 Women of childbearing potential not using contraception : Information not present in EudraCT F.3.3.2 Women of child-bearing potential using contraception: Information not present in EudraCT F.3.3.3 Pregnant women: Information not present in EudraCT F.3.3.4 Nursing women: Information not present in EudraCT F.3.3.5 Emergency situation: Information not present in EudraCT F.3.3.6 Subjects incapable of giving consent personally: Information not present in EudraCT F.3.3.7 Others: Information not present in EudraCT F.4 Planned number of subjects to be included F.4.1 In the member state: 15 F.4.2 For a multinational trial F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition): All patients are close to final height. Continuation of rhIGF-I on medical grounds for maximizing growth potential is not indicated. G. Investigator Networks to be involved in the Trial N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision: Authorised N. Date of Competent Authority Decision: 2010-05-05 N. Ethics Committee Opinion of the trial application: Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion: N. Date of Ethics Committee Opinion: 2010-05-18 P. End of Trial P. End of Trial Status: Completed P. Date of the global end of the trial: 2012-01-01