| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| chronic heart failure (NYHA Class II - IV) |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008908 |
| E.1.2 | Term | Chronic heart failure |
| 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 co-primary objectives of this study are to test if aliskiren monotherapy is superior or at least non-inferior to enalapril monotherapy and/or to test if aliskiren/enalapril combination is superior to enalapril monotherapy in delaying time to first occurrence of either cardiovascular death or heart failure hospitalization in patients with chronic heart failure (NYHA Class II - IV). |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate whether, aliskiren monotherapy and/or the combination of aliskiren/enalapril is superior to enalapril monotherapy in reducing the BNP level from baseline to predefined timepoint.
• To evaluate whether, aliskiren monotherapy and/or the combination of aliskiren/enalapril is superior to enalapril monotherapy in improving the clinical summary score (assessed by KCCQ) from baseline to predefined timepoint. |
|
| 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 |
A multicenter, randomized, double-blind, parallel group, active-controlled sub-study to explore the relationship between seated baseline central aortic pressures and subsequent clinical outcomes in patients with chronic heart failure (NYHA Class II - IV) recruited into the ATMOSPHERE study:
The device to measure CAP will be applied at routine study visits, at Visit 4 (baseline), at Visit 8 (4 months), and at Visit 10 (1 year). The routine visit brachial BP (Blood Pressure) will be recorded as per the main study protocol. The BPro™ device will then be applied and calibrated to the study brachial BP to obtain seated pulse wave analysis The centers will be selected to represent an appropriate regional distribution (America,
Asia-Pacific, Europe) of the general ATMOSPHERE population. Participating centers
will be provided with the devices and local training for its use. The ATMOSPHERE
central aortic pressure wave-form data from participating centers will be downloaded to a central database and assessed against pre-specified quality control criteria as used previously for the CAFE studyrecordings and the corresponding central aortic BPs.
Primary Objective
To explore the relationship between seated baseline central aortic systolic pressures
(CASP) and subsequent clinical outcomes in subset of patients with CHF recruited intothe ATMOSPHERE study.
Secondary Objectives
To explore the relationship between seated baseline central aortic pulse pressures
(CAPP) and subsequent clinical outcomes in subset of patients with CHF recruited into
the ATMOSPHERE study.
Determine the relationship between seated baseline CASP and CAPP and
hemodynamics and key CHF biomarkers such as BNP
Evaluate the impact of the three therapeutic interventions (aliskiren, aliskiren/enalapril
combination, and enalapril) on seated central aortic pressures and hemodynamics in
patients with CHF.
Determine the relationship between baseline central hemodynamic parameters and
other main study endpoints such as new onset AF and symptom scores.
Explorative Objectives
Determine the relationship between change in CASP and CAPP during study with the
change in BNP and plasma renin activity (PRA).
Explore the relationship between hemodynamic parameters derived from pulse wave
analysis, such as systolic and diastolic ejection times, systolic upstroke gradient etc. and clinical outcomes. |
|
| E.3 | Principal inclusion criteria |
1. Patients ≥ 18 years of age, male or female.
2. Patients with a diagnosis of chronic heart failure (NYHA Class II – IV):
• LVEF ≤ 35% at visit 1 (local measurement, within the past 6 months assessed by echocardiography, MUGA, CT scan, MRI or ventricular angiography)
• Elevated BNP or NT-proBNP at visit 1:
BNP ≥ 150 pg/ml (or BNP ≥ 100 pg/ml and unplanned hospitalization for HF within the last 12 months prior to visit 1) (according to local measurement)
OR
NT-proBNP ≥ 600 pg/ml (or NT-proBNP ≥ 400 pg/ml and unplanned hospitalization for HF within the last 12 months prior to visit 1) (according to local measurement).
3. Patients must be treated with an ACE inhibitor at a stable dose (enalapril 10 mg daily at least or any other ACE inhibitor, e.g. ramipril, quinapril, lisinopril, fosinopril, perindopril, trandolapril; based on equivalent doses described in Table 4-1: Dose equivalence guidance table of ACEi's) for at least 4 weeks prior to visit 1.
4. Patients must be treated with a beta blocker, unless contraindicated or not tolerated, at a stable dose for at least 4 weeks prior to visit 1 (for patients not on target dose, according to local guidelines, or in absence of that medication, the reason should be documented).
5. Written informed consent to participate in the study and ability to comply with all requirements. |
|
| E.4 | Principal exclusion criteria |
For full list, please refer to the protocol.
1. History of hypersensitivity to any of the study drugs including history or allergy to ACEi’s as well as known or suspected contraindications to the study drugs or previous history of intolerance to high doses of ACEi’s during up-titration process.
2. Patients treated concomitantly with both ARB and aldosterone antagonist in addition to study drug at visit 1.
3. Current acute decompensated HF (defined as an acute exacerbation of a chronic heart failure status manifested by typical signs and symptoms of HF like dyspnea, fatigue etc, that may require IV therapy with diuretics, vasodilators and/or inotropic drugs).
4. Symptomatic hypotension and/or less than 95 mmHg SBP at visit 1 and/or less than 90 mmHg SBP at visit 4.
5. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or major vascular surgery, percutaneous coronary intervention (PCI) or carotid angioplasty, within the past 3 months prior to visit 1.
6. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within the 6 months after visit 1.
7. Right heart failure due to severe pulmonary disease.
8. Diagnosis of peripartum or chemotherapy induced cardiomyopathy within the 12 months prior to visit 1.
9. Patients with a history of heart transplant or who are on a transplant list or with LVAD (left ventricular assistance device).
10. Documented ventricular arrhythmia with syncopal episodes within past 3 months, prior to visit 1, that is untreated.
11. Documented history of ventricular tachycardia or ventricular fibrillation without ICD producing significant hemodynamic consequences or considered life-threatening within the 3 months prior to visit 1.
12. Treatment with Vaughn Williams Type Ic anti-arrhythmic agents.
13. Symptomatic bradycardia, or second or third degree heart block without a pacemaker.
14. Implantation of a CRT (cardiac resynchronization therapy) device within the prior 3 months from visit 1 or intent to implant a CRT device.
15. Presence of hemodynamically significant mitral and /or aortic valve disease, except mitral regurgitation secondary to left ventricular dilatation.
16. Presence of hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic stenosis.
17. Patients with atrial fibrillation or other significant cardiac rhythm abnormality will be excluded as this makes it difficult to acquire quality pulse waves for analysis. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable is time to first cardiovascular death or heart failure hospitalization. The primary composite endpoint will be derived based on the adjudicated events. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| morbidity and mortality trial |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| aliskiren/enalapril free combination |
|
| 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 | 433 |
| 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| 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 | 4 |
| 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 |
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