E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with Chronic Stable Angina |
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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 | 10049194 |
E.1.2 | Term | Stable angina pectoris |
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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 main objective of this study is to demonstrate that chronic administration of BAY 68-4986 for 28 days at doses of 1 mg, 2 mg and 4 mg, is efficacious in a patient population with chronic stable angina and documented coronary heart disease. The primary efficacy parameter will be the total exercise time. |
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E.2.2 | Secondary objectives of the trial |
The following secondary efficacy variables will be analysed descriptively by dose group for difference from baseline (ETT 2): total exercise time on Day 14 (ETT3), heart rate at rest, heart rate at trough drug concentration at comparable workload levels, heart rate during exercise at 1 mm ST-segment depression, time to 1 mm ST-segment depression, time to angina onset. The number of angina attacks and short acting nitrates usage characteristics (based on diary data) will also be analysed descriptively.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female subjects aged 35 to 75 years (if female, only if postmenopausal or permanently sterilized) 2. Stable angina of mild-moderate intensity (Canadian class II-III) with anti-anginal medication not changed for the last 5 weeks 3. ETT positive, within the previous 6 months, for myocardial ischemia (horizontal or downsloping ST segment depression of at least 1mm with respect to the isoelectric line, 80 msec after the J-point, occurring after at least 3 minutes of exercise on treadmill (according to the modified Bruce protocol) with stable ischemia threshold. 4. CAD documented by at least one of the following: • more than 70% diameter stenosis in at least one of the epicardial coronary arteries on coronary angiography • previous PTCA/CABG (> 6 months) • previous MI (> 6 months) • typical angina in male subjects aged > 55 years, who have a positive stress test result (both by the ECG and clinical criteria) 5. Subject´s written informed consent obtained at screening visit before any study-related procedures and before wash-out of pre-existing anti-anginal medication.
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E.4 | Principal exclusion criteria |
1. Inability to withdraw current anti-anginal therapy 2. Inability to withdraw any concomitant therapy that would interfere with interpretation of study results 3. More than 3 episodes of chest pain per day that require short-acting nitrates 4. Vasospastic (Prinzmetal) angina 5. Inability to perform an exercise on treadmill for least three minutes 6. Myocardial infarction or unstable angina within the last 6 months 7. PTCA or CABG performed within the last 6 months 8. Known unprotected left main coronary artery disease 9. Resting 12-lead ECG ST-segment depression greater than 0.5 mm or any other ECG findings that may interfere with interpretation of the ECG during ETT 10. Significant ST-segment elevation at rest or during ETT in non-Q-wave leads 11. Significant rhythm or conduction disorder: bradycardia on physical examination at rest (HR < 50/min) tachycardia on physical examination at rest (HR > 100/min) important or complex ventricular arrythmias (on investigators discretion) atrial fibrillation intraventricular conduction disorders sino-atrial, second degree or third degree A-V block baseline QTc > 450 msec 12. Treatment with anti-arrythmic drugs 13. Hypertension with systolic blood pressure > 180 mmHg or diastolic blood pressure > 105 mmHg 14. Postural hypotension 15. Heart failure, NYHA Class II – IV (appendix 10.3) 16. Severe cardiac valvular disease 17. Significant pulmonary disease 18. Significant peripheral vascular disease, e.g., Raynaud’s syndrome or intermittent claudication 19. Stroke or TIA in the last 6 months 20. Gross obesity (BMI > 35) 21. Failure of a major organ system or a medical disorder that would impair the subject’s ability to complete this study (in the opinion of the investigator) 22. Malignancy or disease known to markedly reduce the subjects life expectancy 23. Significant mental illness 24. History of epilepsy or other seizure disorders 25. Known hypersensitivity to BAY 68-4986 26. Concurrent use of CYP 2C9 substrates such as fluvastatin, warfarin, diclofenac, losartan, rosiglitazone, glibenclamide/glyburide, tolbutamide 27. Liver function tests (AST, ALT, LDH) >2 times the upper limit of normal at screening (see also section 4.6.4) 28. Creatine kinase (CK) levels > 3 times the upper limit of normal at screening (see section 4.6.4) 29. Hematocrit value <32% at screening 30. Blood donation within 30 days 31. Serum creatinine >2.0 mg/dl or >177 micromol/L at screening (see section 4.6.4) 32. Other abnormal laboratory parameters considered clinically significant (in the opinion of the investigator) 33. Participation in an investigational drug study during which active medication was given within the last 30 days
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable is the absolute difference in total exercise time between ETT2 (baseline) and ETT4 (day 28). ETT will be performed at trough 24 hours post-dose. Secondary efficacy objectives will be the evaluation of the effect of BAY 68-4986 on the variables listed below, with absolute differences from baseline (ETT 2) being investigated: - total exercise time on Day 14 (ETT3) - time to 1 mm ST-segment depression - heart rate at rest - heart rates at trough drug concentration at comparable workload levels - heart rate during exercise at 1 mm ST-segment depression - time to angina onset The number of angina attacks and short-acting nitrates usage characteristics (based on diary data) will also be described. In addition, BAY 68-4986 exposure in all subjects will be assessed via sparse sampling and population pharmacokinetic approaches.
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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 | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | Yes |
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 | 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 | Yes |
E.8.2.3.1 | Comparator description |
different dosage of the same drug |
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E.8.3 |
The trial involves single site in the Member State concerned
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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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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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Last visit of last patient undergoing 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 | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 10 |