E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
heart failure associated with impaired glucose tolerance or type 2 diabetes mellitus |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019279 |
E.1.2 | Term | Heart failure |
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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 evaluate safety and efficacy of TRC4186 in the treatment of stable heart failure associated with HbA1c ≥ 6% or type 2 diabetes receiving oral hypoglycaemic therapy (with or without additional insulin) as an add-on to conventional treatment for heart failure (Proof of Concept) |
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E.2.2 | Secondary objectives of the trial |
To define the recommended dose level for further pivotal studies
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male and female subjects aged ≥ 45 years. Female and male subjects must be of non-childbearing or non-fertile potential, i.e. surgically sterile (bilateral oophorectomy, hysterectomy, bilateral tubal ligation, vasectomy) or post-menopausal for at least one year. Male subjects of fertile potential, must use an effective method of birth control 2. Subjects with chronic heart failure stable for last 6 weeks (NYHA class II – III) according to the criteria given in Appendix I (see section 15.1) and on stable medication for heart failure for at least 2 weeks prior to screening, with no change in drug or dose in that period. 3. Subjects with established type 2 diabetes mellitus (i.e. receiving oral therapy with or without insulin) or an impaired glucose tolerance (HbA1c should be ≥6.0% at screening) 4. Subjects with NT-proBNP (N-terminal fragment of the a brain natriuretic peptide (BNP)) ≥ 400 pg/mL (subjects with atrial fibrillation NT-proBNP ≥ 1200 pg/mL) 5. Subjects receiving a loop, thiazide or thiazide like diuretic (Metolazone, Chlorthalidon, Indapamide and Xipamide) for treating heart failure (HF) 6. Subjects able to undergo cardiopulmonary exercise testing 7. Subjects able to communicate well with the investigator and to comply with the requirements of the entire study 8. Subjects willing to give written informed consent (prior to any study-related procedures being performed) and able to adhere to the study restrictions and assessments schedule.
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E.4 | Principal exclusion criteria |
1. CHF caused by myocarditis, cor pulmonale, congenital heart disease, constrictive pericarditis, or hypertrophic or restrictive cardiomyopathy. 2. Significant important hemodynamic disease in the investigators opinion, e.g. mitral regurgitation and/or planned for surgery. 3. Acute coronary syndrome or coronary revascularization within 3 months 4. Angina as symptom limiting treadmill/bicycle exercise. 5. Evidence of myocardial ischemia which in the investigator’s opinion requires investigation by angiography with a view to coronary revascularization 6. Presence of a left ventricular (LV) aneurysm. 7. History of ventricular fibrillation or symptomatic sustained ventricular tachycardia without clear reversible precipitating cause (eg:- Severe hypokalemia [Serum potassium < 3.0 mmol/L] or acute myocardial ischemia/ infarction) in past 12 months unless treated with an implantable defibrillator. 8. Second-degree or third-degree heart block (unless treated with a pacemaker) 9. Patients scheduled for CRT or who have received CRT in past 3 months. 10. Left ventricular assist device (or an activated minute ventilation pacemaker) 11. Gross obesity (body mass index (BMI) > 40 kg/m2). 12. Pulmonary function (FEV1) less than 60 % of predicted or requiring long-term corticosteroids. 13. Type I diabetes. 14. Severe joint disease or peripheral arterial disease sufficient to impede exercise testing. 15. History of systemic and other vascular inflammatory disease. 16. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg under antihypertensive treatment). 17. Screening liver enzyme test (AST or ALT) exceeding 3 times the upper limit of normal range or hepatic impairment of Child-Pugh class C 18. Glomerular filtration rate (eGFR) < 30 ml/min. 19. Haemoglobin < 10.0 gm/dl 20. HbA1c > 10 % 21. Gastrointestinal disorder that could interfere with study drug absorption 22. Medical history of chronic hepatitis B, C 23. Medical history of HIV seropositivity 24. Pregnancy or nursing females 25. Any cancer disease, except non-invasive skin cancer (e. g. actinic keratosis or basal cell carcinoma), or any other condition that may preclude full participation in the study or that limit survival 26. Prior history of radiation and chemotherapy for malignancies 27. Known hypersensitivity to any ingredient of the study medication 28. Current participation (including prior 30 days) in any other therapeutic clinical trial 29. Unwilling or unable to comply with protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy •Physical dimension of Minnesota Living with Heart Failure Questionnaire (MLHFQ), a change of 5 points is regarded as clinically relevant •Oxygen uptake efficiency slope (OUES), a change of 10% is regarded as clinically relevant
Safety •Morbidity/hospitalization for cardiac reasons •Mortality •Glomerular filtration rate (eGFR)
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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 | No |
E.6.4 | Safety | Yes |
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 | 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
| 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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
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 | Information not present in EudraCT |
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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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 |