| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| left-ventricular dysfunction after myocardial infarction |
|
| E.1.1.1 | Medical condition in easily understood language |
| left-ventricular dysfunction after myocardial infarction |
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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 | PT |
| E.1.2 | Classification code | 10049694 |
| E.1.2 | Term | Left ventricular dysfunction |
| E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
|
| 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 | 10028598 |
| E.1.2 | Term | Myocardial infarction old |
| E.1.2 | System Organ Class | 10007541 - Cardiac 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 |
| The primary objective of this pilot study is to investigate the safety and tolerability after multiple oral doses of BAY 1142524 administered BID (using 3 dose groups) or OD (using a 4th dose group) as combinations of 5 and 50 mg IR tablets for 14 days in 12 patients with left-ventricular dysfunction after myocardial infarction (9 verum and 3 placebo) per dose group in comparison to placebo in a randomized, single blind group-comparison design. |
|
| E.2.2 | Secondary objectives of the trial |
| An additional objective is to assess the pharmacokinetics of BAY 1142524 in plasma after multiple doses and to explore the effects of BAY 1142524 on neuro-hormonal and immunological biomarkers in stable patients with LVD |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Clinically stable patients with left-ventricular dysfunction (LVEF ≤ 45%) after myocardial infarction, whereby the MI occurred 6 or more months before randomization.
2. NYHA class I-II.
3. Left-ventricular ejection fraction ≤ 45%, confirmed by any imaging technique within the last 3 months prior to screening visit will be accepted for screening purposes. If no data are available, an echocardiography has to be performed at screening for inclusion.
4. Treatment with evidence-based therapy for left-ventricular dysfunction post MI for at least 4 weeks prior to screening visit. This therapy has to include at least an ACE inhibitor or an ARB. Beta-blockers, diuretics, MRAs, antiplatelet therapy, statins, and aspirin are to be used if indicated. Treatment with stable doses of ACE inhibitors or ARBs using at least half of the recommended target dose (as defined in the ESC guidelines, see appendix 16.4) ≥ 4 weeks prior to the screening visit is mandatory.
5. No planned changes to post MI drug therapy during the active treatment phase of the study.
6. Men or confirmed postmenopausal women (defined as exhibiting spontaneous amenorrhea for at least 12 months before screening or as exhibiting spontaneous amenorrhea for 6 months before screening with documented serum FSH levels > 40 mIU/mL) or women without childbearing potential based on surgical treatment 6 weeks before screening such as bilateral tubal ligation, bilateral oophorectomy with or without hysterectomy (documented by medical report verification).
Men of reproductive potential must agree to use 2 reliable and acceptable methods for contraception simultaneously when sexually active and not to act as sperm donor. This applies for the time period between signing of the informed consent form and 12 weeks after the last administration of study drug.
Acceptable methods of contraception include, but are not limited to, (i) condoms (male or female) with or without a spermicidal agent; (ii) diaphragm or cervical cap with spermicide; (iii) intra-uterine device; (iv) hormone-based contraception.
7. Age: 40 to 79 years (inclusive) at the screening visit.
8. Race: Caucasian
9. Ability to understand and follow study-related instructions.
10. Written informed consent. The informed consent must be signed before any study specific tests or procedures are done.
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| E.4 | Principal exclusion criteria |
Medical and surgical history
1. Non-ischemic causes for cardiomyopathy will be excluded (including, but not limited to: primary cardiomyopathy, constrictive, restrictive or hypertrophic cardiomyopathy, acute myocarditis, cardiomyopathy secondary to cardiotoxic chemotherapeutic agents).
2. Hospitalization for decompensated heart failure within the last 3 months prior to randomization.
3. Coronary revascularization within 6 weeks prior to randomization or if revascularization is anticipated or needed during the study duration.
4. Clinically relevant, (i.e. requiring revascularization [such as coronary artery bypass grafting or percutaneous coronary intervention]) cardiac ischemia in a stress test within 3 months before screening.
5. Previous assignment to treatment during this study.
6. Any planned intervention such as: implantation of an implantable cardioverter defibrillator, implantation of cardiac resynchronization therapy devices or implantation of left ventricular assist devices, bypass operation, listing for heart transplantation or any other planned operations and medical interventions.
7. Patients carrying implantable cardioverter defibrillators, cardiac resynchronistaion therapy devices or left ventricular assist devices that had events such as ventricular tachycardias, ventricular fibrillation in the last 6 months before randomization while carrying the devices
8. Primary and uncorrected valvular disease with foreseen requirement of valve repair within the next 6 months.
9. Any stroke, TIA, any acute coronary syndrome within 6 months prior to randomization.
10. Clinically relevant hepatic dysfunction at the screening visit indicated by at least one of the following:
o hepatic insufficiency (Child-Pugh B or C) as documented in medical history
o total bilirubin > 2 times the upper limit normal (ULN) and
- alanine amino transferase (ALT) > 3 times the ULN
or
- glutamate dehydrogenase (GLDH) > 3 times the ULN
or
- gamma glutamyl transpeptidase (GT) > 5 times the ULN.
11. Known hypersensitivity to the study drugs (active substances or excipients of the preparations).
12. Patients suffering from any autoimmune disease.
13. Medical condition or history thereof that in the opinion of the investigator would impair the ability to complete the planned study procedures.
14. Anemia as evidenced by hemoglobin values of ≤ 10 mg/dl at screening.
15. Hyperthyreosis or hypothyreosis as evidenced by TSH values outside the reference range at screening.
16. Any deviation from normal laboratory values that in the opinion of the investigator would impair the ability to complete the planned study procedures or pose a potential safety risk.
Medication, drug use and special behavioral patterns
17. Use of antacids containing hydroxide salts during the study conduct. Patients using hydroxide salt containing antacid should be switched to proton pump inhibitors at least one week before treatment with study drug (day 0).
18. Consumption of grapefruit juice or St. John’s wort during the study conduct and two weeks before starting the clinical phase of the study.
19. Medication with CYP3A4 inhibitors (amiodarone, dronedarone, diltiazem, verapamil, fluvoxamine, nefazodone, clarithromycin, and antimycotics such as fluconazole, itraconazole, ketoconazole, miconazole, posaconazole, voriconazole) within 4 weeks before screening and during the study.
20. Suspicion of drug or alcohol abuse (defined as more than 24 g of pure alcohol per day for men, and 12 g for women).
21. Donation of more than 100 / 500 mL of blood within 4 weeks / 3 months prior to screening.
Electrocardiogram (ECG), blood pressure, heart rate
22. Clinically relevant findings in the ECG such as a third-degree AV block and second degree AV block (type Mobitz II), QTc > 450 msec.
23. Malignant arrhythmias or other arrhythmias that will disqualify the patient in the opinion of the investigator.
24. Systolic blood pressure below 100 or above 160 mmHg at screening
25. Diastolic blood pressure below 50 or above 105 mmHg at screening.
26. Heart rate below 50 or above 100 beats / min (ECG result) at screening.
Physical examination
27. Clinically relevant findings in the physical examination which in the opinion of the investigator preclude participation for scientific reasons or for reasons of the patient’s safety.
Laboratory examination
28. eGFR < 30 mL/min/1.73m2 using the MDRD formula at screening visit.
Other
29. Previous (last treatment of preceding study within 4 weeks prior to randomization) or concomitant participation in another clinical study with investigational medicinal product(s).
30. Criteria which in the opinion of the investigator preclude participation for scientific reasons, for reasons of compliance, or for reasons of the patient’s safety.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Safety as evidenced by the incidence and severity of adverse events and potential hemodynamic effects |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| As described in protocol 9.6 |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 8 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| 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
|
For each participating EU country, the end of the study according to the EU Clinical Trial Directive will be reached when the last visit of the last subject for all centers in the respective country has occurred.
As for this study, important data will be collected after LPLV, the end of the study as a whole will be the date when the clean database is available.
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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 | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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