E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with chronic heart failure and left ventricular systolic
dysfunction |
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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] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10007648 |
E.1.2 | Term | Cardiovascular disease, unspecified |
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 evaluate the pharmacodynamics in relation to resting heart rate (HR) of two different schemes of starting doses and two step titration doses of S 38844 versus placebo in patients with moderate to severe chronic heart failure and left ventricular systolic dysfunction treated with optimal background therapy. |
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E.2.2 | Secondary objectives of the trial |
- To assess the pharmacokinetics of S 38844 and its main metabolites and the pharmacokinetic/pharmacodynamic (PK/PD) relationship with respect to resting heart rate (HR) for each tested dose of S 38844.
- To evaluate the global and cardiac safety of two different schemes of starting doses and two step titration doses of S 38844 versus placebo. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Documented sinus rhythm and mean HR ≥ 75 bpm measured on two consecutive resting 12-leads ECGs recordings one minute registration - performed at least 5 minutes apart (supine position for at least 10 minutes rest). If one of the two HR measurements is 73 or 74 bpm at the inclusion visit, the patient can be included provided that the mean of both HR measurements at the visit is ≥ 75 bpm,
- LVEF ≤ 35% as measured and documented within the previous 6 months (in stable clinical condition). For patient without known diagnosis of LVEF ≤ 35%, a LVEF will be scheduled before inclusion visit,
- Compliant to study treatment during run-in period (70-130%),
- Symptomatic CHF of New York Heart Association (NYHA) class II, III or IV for at least 3 months prior to selection,
- In stable clinical condition with regards to CHF symptoms for at least 4 weeks prior to selection,
- With optimal and unchanged CHF medications or dosages, for at least 4 weeks prior to selection. |
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E.4 | Principal exclusion criteria |
- LVEF of 35% or higher on a recently performed measurement (less than 6 months),
- Serum haemoglobin < 110 g/L,
- ALT or AST > 3 times the upper limit of normal values,
- Significant change in cardiovascular condition, since the informed consent signature, change in heart failure background therapy or dosage, or use of intravenous inotropic therapies,
- Recent (less than 3 months) myocardial infarction or coronary revascularization,
- Scheduled coronary revascularization,
- Severe aortic or mitral stenosis, or severe aortic regurgitation, or severe primary mitral regurgitation,
- Scheduled surgery for valvular heart disease,
- Cardiac Resynchronisation Therapy (CRT),
- Pacemaker carrier,
- Documented permanent atrial fibrillation or other cardiac arrhythmia that interfere with the sinus node function, or recent hospitalization for atrial fibrillation or other cardiac arrhythmia that interfere with the sinus node function within the last 3 months
- Positive blood and/or urinary pregnancy test |
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E.5 End points |
E.5.1 | Primary end point(s) |
HR change from baseline to end of each treatment period is the main endpoint to assess the pharmacodynamics effect of S 38844 (mean HR measured at trough from two 12-lead ECGs). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Safety endpoints:
- occurence of adverse events
- 24-hour Holter ECG parameters,
- Physical examination including weight, systolic and diastolic blood pressure change,
- HR on 12-lead ECG,
- Laboratory test parameters (haematology and biochemistry parameters).
Pharmacokinetic endpoints:
- Plasma pharmacokinetics parameters of the parent drug S 38844 and of its main metabolites,
- Pharmacokinetic/pharmacodynamic (PK/PD) relationship with respect to resting heart rate (HR) for each tested dose of S38844. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | Yes |
E.6.11 | Pharmacogenomic | Yes |
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.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 38 |
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 |
Belgium |
Bulgaria |
Estonia |
Hungary |
Korea, Republic of |
Latvia |
Lithuania |
Russian Federation |
Singapore |
Slovakia |
Ukraine |
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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 last participant as stated in the protocol |
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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 | 1 |
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 | 1 |
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 |