E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heart failure with preserved left ventricular ejection fraction |
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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 | 17.0 |
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 assess the effect of ivabradine compared to placebo on the diastolic function, the exercise capacity and the neuroendocrine activation over an 8-month treatment period. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the effects of ivabradine compared to placebo on cardiac function and structural parameters, quality of life, NYHA classification and other biomarkers;
- To evaluate the safety and tolerance profile of ivabradine compared to placebo.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Sub-study protocol on spiroergometry attached to clinical study protocol CL2-16257-101 (final version of 28th November 2012): to assess the effect of ivabradine on the cardiopulmonary exercise performance in patients with chronic heart failure and preserved left ventricular ejection fraction (HF-PEF) compared to placebo over an 8-month treatment period on exercise testing based on bicycle ergometer.
Sub-study protocol on Cardiovascular Magnetic Resonance attached to the clinical study CL2-16257-101 (final version of 5th July 2013). Effect of Ivabradine in Patients with Heart Failure with Preserved Ejection Fraction: Effect on CMR Measured, Myocardial Perfusion Reserve, Diffuse Myocardial Fibrosis and Diastolic Strain Rate.
The primary objective:
• To assess over an 8-month treatment period the effect of ivabradine compared to placebo, using CMR measured myocardial perfusion reserve (MPR) in patients with symptomatic chronic Heart Failure and Preserved left ventricular Ejection Fraction (HF-PEF).
Secondary objectives:
• To assess over an 8-month treatment period the effect of ivabradine compared to placebo on other CMR parameters including
o Diastolic Strain Rate (DSr)
o Systolic strain/strain rate (PSS/SSr)
o LV/LA volumes and function (LV mass, EDV, ESV, EF)
o Myocardial extracellular volume distribution (T1 mapping)
o Absolute Stress and Resting Myocardial Blood Flow (MBF)
o Aortic distensibility and pulse wave velocity (PWV)
• To explore the evolution all CMR parameters above from D000, M002 and M008
• To assess comparable parameters from CMR to those from echo performed in the parent study
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E.3 | Principal inclusion criteria |
- Male or female patients,
- Aged 50 years or older,
- Symptomatic Chronic Heart Failure of New York Heart Association (NYHA) class II or III 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,
- Documented sinus rhythm and HR superior or equal to 70 bpm on a resting standard 12-lead ECG at selection and inclusion,
- Left Ventricular Ejection Fraction superior or equal to 45% and E/e’ > 13 (E = early diastolic mitral flow velocity; e’ = mean of mitral annular lateral and septal proto diastolic velocities) or e’ lateral < 10 cm/s and e’ septal < 8 cm/s or LAVI > 34 mL/m² at selection,
- Documented NT-proBNP≥ 220 pg/mL or BNP ≥ 80 pg/mL at selection. |
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E.4 | Principal exclusion criteria |
- Recent (less than 3 months) myocardial infarction or coronary revascularisation,
- Scheduled coronary revascularisation,
- Large mitral calcifications,
- Severe aortic or mitral stenosis, or severe aortic regurgitation, or severe primary mitral regurgitation,
- Previous mitral valvular surgery or intervention,
- Scheduled surgery for valvular heart disease
- Congenital heart disease,
- Previous cardiac transplantation or on list for cardiac transplantation,
- 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,
- Patients able to walk more than 450 meters within 6 minutes during the selection and the inclusion visits,
- Previous treatment with ivabradine within the last 6 months before selection or current treatment with ivabradine.
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E.5 End points |
E.5.1 | Primary end point(s) |
Co-primary endpoints based on echocardiography (E/e'), neuroendocrine activation (NT-proBNP) and six-minute walk test
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Co-primary endpoints measured up to M008 |
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E.5.2 | Secondary end point(s) |
Efficacy and safety endpoints
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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 | Yes |
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 | 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 | 2 |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 89 |
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 |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Czech Republic |
France |
Germany |
Hungary |
Italy |
Netherlands |
Poland |
Portugal |
Russian Federation |
Slovenia |
Spain |
Taiwan |
United Kingdom |
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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 | 10 |
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 | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |