E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
People with type 1 diabetes with risk factors for cardiovascular disease |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
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 | 10045228 |
E.1.2 | Term | Type I diabetes mellitus |
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 |
The objective of REMOVAL is to test whether metformin tablets added in with insulin treatment in type 1 diabetes can prevent the early blood vessel complications which lead to heart attacks and strokes. |
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E.2.2 | Secondary objectives of the trial |
REMOVAL will also examine whether insulin treatment in type 1 diabetes can help to improve blood glucose and cholesterol, stabilise weight and prevent other complications. |
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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* (defined as diagnosis below age 35 AND insulin use within 1 year of diagnosis) - Age ≥ 40 years - 7.0 ≤ HbA1c < 10.0% (53-86 mmol/mol) AND three of more of the following ten CVD risk factors: - BMI greater than 27kg/m^2 - current HbA1c > 8.0% (64mmol/mol) - known CVD/peripheral vascular disease - current smoker - estimated glomerular filtration rate < 90 ml/min per 1.73 m^2 - confirmed micro- or macroalbuminuria [according to local assays and reference ranges] - hypertension (BP of 140/90mmHg or above or established on antihypertensive treatment) - dyslipidaemia [total cholesterol ≥ 5.0 mmol/L (200 mg/dL); OR HDL cholesterol <1.2 (46 mg/dL)mmol/L [men or < 1.3 mmol/L (50 mg/dL)[women]; - OR triglycerides ≥ 1.7 mmol/L (150mg/dL); or established on lipid-lowering treatment] - strong family history of CVD (at least one parent, biological aunt/uncle or sibling with myocardial infarction or stroke aged < 60 years) - duration of diabetes > 20 years * defines as diagnosis below age 40 years AND insulin use within 1 year of diagnosis |
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E.4 | Principal exclusion criteria |
- Women of child-bearing age (i.e. continuing menstrual cycle) not using effective contraception. For women of childbearing age in REMOVAL, acceptable forms of effective contraception include:* * Established use of oral, injected or implanted hormonal methods of contraception * Placement of an intrauterine device (IUD) or intrauterine system (IUS). [Consideration should be given to the type of device or system being used, as there are higher failure rates quoted for certain types, e.g. steel or copper wire] * Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) – must be combined with spermicidal foam/gel/film/cream/suppository. * Sole male partner has been sterilised with appropriate post-vasectomy documentation of the absence of sperm in ejaculate. * True abstinence: When this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
- Pregnancy and/or lactation; planning to get pregnant
- Patients with Acute Coronary Syndrome or Stroke/TIA within the last three months
- Symptomatic angina on mild or moderate exertion
- Stage 3 or 4 heart failure defined according to the NYHA criteria
- Estimated glomerular filtration rate < 45ml/min/1.73m^2
- Contraindications to metformin [hepatic impairment (ALT > 3.0 times ULN), known hypersensitivity to metformin, acute illness such as dehydration, severe infection, shock, acute cardiac failure, suspected tissue hypoxia]
- Metformin treatment for more than three months within the last two years
- Anaemia (haemoglobin <10.0 g/dL)
- Ongoing treatment with oral steroids, pramlintide or GLP-1 agonist therapy
- Hypoglycaemia unawareness confirme as significant by site Prinicipal Investigator
- Impaired cognitive function/unable to give informed consent
- Previous carotid surgery or inability to capture adequate carotid images
- Gastroparesis (on gastric emptying studies) confirmed as significant by site Principal Investigator OR more than two hospital admissions with unexplained vomiting in last year.
- History of biochemically-confirmed lactic acidosis (>5.0 mmol/L)
- Any coexistent life threatening condition including prior diagnosis of cancer within two years
- History of alcohol problem or drug abuse
- Diabetes or than Type 1 diabetes (e.g. secondary to pancreatitis, pancreatectomy or other primary pancreatic diseases)
- Involvement in a clinical trial involving an investigational medicinal product within the last six months |
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E.5 End points |
E.5.1 | Primary end point(s) |
Mixed effects regression model estimates of between-group cIMT difference over time, with 95% confidence intervals and p-values. Primary outcome regression model extended to assess whether metabolic effects could explain differences in progression of cIMT. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Carotid IMT will be measured at baseline and at years 1, 2 and 3. |
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E.5.2 | Secondary end point(s) |
Secondary endpoints: (i) HbA1c; (ii) LDL cholesterol; (iii) albuminuria & estimated glomerular filtration rate; (iv) retinopathy stage (ETDRS stage = Early Treatment Diabetic Retinopathy Study); (v) weight; (vi) insulin dose; (vii) endothelial function (in some centres).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
As for primary endpoint (baseline and annually over three years) |
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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 | 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 | 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 | Yes |
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
| 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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
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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End of trial will be defined as last patient last visit. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 5 |
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 |