E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated | |
E.1.1.1 | Medical condition in easily understood language |
Heart failure is a condition where the heart does not have enough strength to pump blood all the way round the body efficiently, and causes edema, shortness of breath and reduced physical capacity. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008908 |
E.1.2 | Term | Chronic heart failure |
E.1.2 | System Organ Class | 100000004849 |
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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 investigate in a randomized, double-blinded placebo-controlled design if metformin treatment in patients with heart failure has beneficial effects on left ventricular myocardial oxidative metabolism, efficiency, contractile function and physical performance. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Patients with chronic heart failure uptitrated to recommended or maximally tolerated dose of ACE-I/ARB (unless contraindicated) and beta-blocker (unless contraindicated). If indicated, an aldosterone receptor antagonist should be given (unless contraindicated). An ICD and/or CRT should be implanted, if indicated. Patients with a CRT device should be treated for > 3 months. - LVEF < 45% - NYHA-class II, III or IV - Relativley preserved renal function (eGFR > 30 ml/min) - Ability to understand the written patient information and to give informed consent. - Negative urine-HCG for women of childbearing potential - Patients must have insulin resistance, defined as 1 or more of the following criteria: - HbA1c 5.5 - 6.4% (37 - 47 mmol/mol) within the last 12 months prior to enrolment - Impaired fasting glucose (IFG): Fasting P-glucose 5.6 – 6.9 mmol/l within 12 months prior to enrolment (patient in stable condition) - Impaired glucose tolerance (IGT) if OGTT has been performed at any time prior to enrolment: Fasting P-glucose < 7.0 mmol/l and 2 hour P-glucose 7.8 -11.0 mmol/l |
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E.4 | Principal exclusion criteria |
- Metformin treatment within the last 3 months - Known allergy to metformin or major side effects to metformin treatment - Acute myocardial infarction, unstable angina or revascularization < 3 months at the time of randomization - Planned coronary revascularization - Significant, uncorrected cardiac valve disease - Cardiac arrest or life threatening ventricular arrhythmias within the last 3 months (unless treated with an ICD) - Atrial fibrillation with poorly controlled ventricular rate at rest (> 100 beats/min) - Hypertrophic or restrictive cardiomyopathy, infiltrative or storage myocardial disease, active myocarditis, or pericardial disease. - Listed for heart transplantation or expected to be so during the next year. - Planned major surgery - Female patients who are pregnant, nursing, or of childbearing potential while not practicing effective chemical contraceptive methods (i.e. oral, implanted, injectable, or transdermal contraceptive hormones; intrauterine device) - Age < 18 years - Current abuse of alcohol or drugs - Cancer, with a life-expectancy of less than 2 years - Stroke within the last 6 months - Liver disease with P-ALAT >3 times upper normal limit (it is possible to repeat this measurement once within a month) - Significant comorbidity or issue that makes the patient unsuitable for participation as judged by the investigator - Participation in another study involving long-term medical intervention (participation in device studies is allowed) |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 3 months of metformin treatment |
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E.5.2 | Secondary end point(s) |
Left ventricular global longitudinal strain during peak exercise Myocardial oxygen consumption Myocardial perfusion at rest LV myocardial function evaluated by LVEF and diastolic function LV mass 6 minute walking distance Maximum oxygen consumption evaluated by CPX-test Insulin resistance Minnesota living with heart failure questionnaire NT-proBNP |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After 3 months of metformin treatment |
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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 | 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 | 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
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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 | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |