E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 1 diabetes mellitus |
Type 1 diabetes mellitus |
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E.1.1.1 | Medical condition in easily understood language |
Juvenile diabetes |
Suikerziekte (ontstaan op jonge leeftijd) |
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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 | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10063623 |
E.1.2 | Term | Type I diabetes mellitus inadequate control |
E.1.2 | System Organ Class | 100000004861 |
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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 in a double-blind randomized, placebo controlled trial whether three years treatment with metformin 1000 mg bd added to titrated insulin therapy (towards target HbA1c 7.0%/ 53 mmol/mol) reduces atherosclerosis, as measured by progression of carotid Intima Media Thickness (IMT), in adults with confirmed type 1 diabete mellitus aged 40 years and over at increased risk for CVD.
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In een dubbelblind gerandomiseerde, placebo gecontroleerde studie zal onderzocht worden of behandeling met metformine 1000mg 2dd toegevoegd aan (getitreerde) insuline therapie (doel HbA1c 7.0%/ 53 mmol/mol) voor een periode van 3 jaar zal leiden tot een reductie in atherosclerose, gemeten als intima media dikte (IMT), in volwassen patienten (> 40 jaar) met type 1 diabetes mellitus en een verhoogd risico op het ontwikkelen van hart- en vaatziekten.
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E.2.2 | Secondary objectives of the trial |
To examine over this period the effect of metformin on other markers of diabetic micro- and macrovascular complications and intermediate disease- related biomarkers (HbA1c, LDL-cholesterol, micro-albuminuria, retinopathy stage, weight, insulin dose, endothelial function). The composite secondary endpoint will provide clinically meaningful information on the potential of metformin to influence clinical practice in this condition. |
De effecten van metformine op andere markers van diabetische micro- en macrovasculaire complicaties en intermediaire, ziekte-gerelateerde biomarkers (HbA1c, LDL-cholesterol, micro-albuminurie, retinopathie stadium, gewicht, insuline dosis, endotheelfunctie). Dit samengestelde secundaire eindpunt zal klinisch relevante informatie opleveren of metformine in staat is de dagelijkse klinische praktijk te beinvloeden. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Type 1 diabetes for five years or more*; age ≥ 40 years; 7.0 ≤ HbA1c < 10.0% (53-86 mmol/mol)
AND three or more of the following ten CVD risk factors: (i) BMI ≥ 27 kg/m2 (ii) current HbA1c > 8.0% (64 mmol/mol) (iii) known CVD/ peripheral vascular disease (iv) current smoker (v) eGFR < 90 ml/ min/ 1.73 m2 (vi) micro- (or macro-) albuminuria [according to local assays and reference ranges] (vii) hypertension (BP¬≥140/ 90 mmHg; or established on antihypertensive treatment) (viii) dyslipidaemia [total cholesterol≥5.0 mmol/L (200 mg/dL); or HDL cholesterol<1.20 mmol/L (46 mg/dL) [men] HDL cholesterol<1.30 mmol/L (50 mg/dL) [women]; or fasting triglycerides≥1.7 mmol/L (150 mg/dL); or established on lipid-lowering treatment (ix) strong family history of CVD (at least one parent, sibling or aunt/uncle with myocardial infarction, CABG or stroke aged < 60 years) (x) duration of diabetes > 20 years.
* Type 1 diabetes is defined as diagnosis below age 40 years AND insulin use within 1 year of diagnosis |
Diabetes mellitus type 1 langer dan 5 jaar*; leeftijd ≥ 40 jaar; 7.0 ≤ HbA1c < 10.0% (53-86 mmol/mol)
EN drie of meer van de volgende tien cardiovasculaire risicofactoren: (i) BMI ≥ 27 kg/m2 (ii) huidig HbA1c > 8.0% (64 mmol/mol) (iii) cardiovasculaire ziekte/perifeer vaatlijden in de voorgeschiedenis (iv) huidig roker (v) geschatte klaring < 90 ml/ min/ 1.73 m2 (vi) micro- (of macro-) albuminurie [volgens lokale bepalingen en referentiewaarden] (vii) hypertensie (bloeddruk ≥140/ 90 mmHg, of behandeling met antihypertensiva) (viii) dyslipidemie [totaal cholesterol 5.0 mmol/L (200 mg/dL); of HDL cholesterol<1.20 mmol/L (46 mg/dL) [mannen] HDL cholesterol<1.30 mmol/L (50 mg/dL) [vrouwen]; of nuchter triglyceriden≥1.7 mmol/L (150 mg/dL); of behandeling met lipideverlagende medicatie (ix) sterk positieve familie-anamnese (tenminste een ouder, broer/zus of oom/tante met myocardinfarct, CABG of beroerte voor 60e levensjaar) (x) diabetesduur > 20 jaar
* Diabetes mellitus type 1 is gedefinieerd als diagnose < 40 jaar EN gebruik van insuline binnen een jaar na stellen van diagnose |
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E.4 | Principal exclusion criteria |
(i) Women of childbearing age (i.e. continuing menstrual cycle) not using effective contraception (ii) Pregnancy and/or lactation; planning to get pregnant or not using effective contraception (iii) Patients with Acute Coronary Syndrome or Stroke/ Transient Ischaemic Attack within the last three months (iv) Symptomatic angina on mild or moderate exertion (v) Stage 3 or 4 heart failure defined according to the NYHA criteria (vi) Estimated glomerular filtration rate < 45 ml/min/1.73m2 (MDRD) (vii) Contraindications to metformin - hepatic impairment (ALT > 3.0 times ULN) - known hypersensitivity to metformin - acute illness [dehydration, severe infection, shock, acute cardiac failure] - suspected tissue hypoxia (viii) Metformin treatment for more than three months within last two years (ix) Anaemia (haemoglobin < 10.0 g/dL) (x) Ongoing treatment with oral steroids, pramlintide or GLP-1 agonist therapy (xi) Hypoglycaemia unawareness confirmed as significant by site Principal Investigator (xii) Impaired cognitive function/ unable to give informed consent (xiii) Previous carotid surgery or inability to capture adequate carotid images (xiv) Gastroparesis (on gastric emptying studies) confirmed as significant by site Principal Investigator OR more than two hospital admissions with unexplained vomiting in last year (xv) history of biochemically-confirmed acidosis (lactate > 5.0 mmol/L) (xvi) Any coexistent life-threatening condition including diagnosis of cancer within prior two years (xvii) history of alcohol problem or drug abuse (xviii) diabetes other than type 1 diabetes (e.g. secondary to pancreatitis, pancreatectomy or primary pancreatic disease) (xix) Involvement in a clinical trial involving an investigational medicinal product within the last six months |
(i) vrouw in vruchtbare levensfase zonder effectieve anticonceptie (ii) zwangerschap en/of borstvoeding (iii) acuut coronair syndroom of CVA/TIA in de laatste 3 maanden (iv) instabiele angina pectoris (v) decompensatio cordis (NYHA klasse 3-4) (vi) geschatte klaring < 45 ml/ min/ 1.73m2 (vii) contra-indicaties voor metformine - gestoorde leverfunctie (ALAT 3x boven referentiewaarde) - overgevoeligheid voor metformine - acute ziekte (dehydratie, ernstige infectie, shock, acuut hartfalen) - vermoeden van weefselhypoxie (viii) Behandeling met metformine gedurende meer dan 3 maanden in de afgelopen 2 jaar (ix) Anemie (haemoglobine < 10 g/dL) (x) Behandeling met orale steroiden, pramlintide of GLP1 agonisten (xi) hypoglycemie unawareness (beoordeeld als klinisch significant door lokale hoofdonderzoeker) (xii) gestoorde cognitieve functie / onvermogen om informed consent te geven (xiii) eerdere operatie aan de carotiden / onvermogen om de a carotis adequaat af te beelden (xiv) gastroparese, beoordeeld als klinisch significant door lokale hoofdonderzoeker OF meer dan 2 ziekenhuisopnames vanwege onverklaarbaar overgeven in het afgelopen jaar (xv) acidose (plasma lactate > 5mmol/L) in de voorgeschiedenis (xvi) elke gelijktijdig aanwezige levensbedreigende ziekte waaronder eerdere diagnose van een maligniteit binnen de afgelopen 2 jaar (xvii) alcohol- of drugsmisbruik in de voorgeschiedenis (xviii) Diabetes anders dan type 1 diabetes (bv secundair pancreatitis, pancreatectomie of primaire pancreas aandoening) (xix) Betrokkenheid bij een klinisch interventie-onderzoek met medicatie in de afgelopen 6 maanden. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Intima media thickness, measured by ultrasound at the far wall of the common carotid artery, as a surrogate for cardiovascular risk |
Intima media dikte, gemeten m.b.v. echo aan de achterwand van de arteria carotis communis, als een surrogaat voor het cardiovasculaire risico |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
at baseline (t = 0), t = 1 year, t = 2 years and at the end of the study (t = 3 years) |
bij aanvang van de studie (t = 0), t = 1 jaar, t = 2 jaar en aan het einde van de studie (t = 3 jaar) |
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E.5.2 | Secondary end point(s) |
Change in (i) HbA1c; (ii) LDL cholesterol; (iii) albuminuria and estimated glomerular filtration rate; (iv) retinopathy stage (twofield photographs); (v) weight; (vi) insulin dose; (vii) endothelial function |
Verandering in (i) HbA1c; (ii) LDL cholesterol; (iii) albuminurie en geschatte glomerulaire filtratiesnelheid; (iv) retinopathie stadium (2 field foto's); (v) gewicht; (vi) insuline dosis; (vii) endotheelfunctie |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
HbA1c, LDL cholesterol, albuminuria, estimated glomerular filtration rate, weight and insulin dose: at baseline (t = 0), t = 1 year, t = 2 years and at the end of the study (t = 3 years) Retinopathy stage: at baseline (t = 0) at the end of the study (t = 3 years) Endothelial function: at baseline (t = 0), t = 1 year and at the end of the study (t = 3 years) |
HbA1c, LDL cholesterol, albuminurie en geschatte glomerulaire filtratiesnelheid, gewicht en insuline dosis: bij aanvang van de studie (t = 0), t = 1 jaar, t = 2 jaar en aan het einde van de studie (t = 3 jaar) Retinopathie stadium: bij aanvang van de studie (t = 0) en aan het einde van de studie (t = 3 jaar) Endotheelfunctie: bij aanvang van de studie (t = 0), t = 1 jaar en aan het einde van de studie (t = 3 jaar) |
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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 | Yes |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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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
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Last visit of the last subject undergoing the trial |
Laatste bezoek van de laatste deelnemer aan het onderzoek |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
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 | 5 |
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 |