| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 | 10015488 |
| E.1.2 | Term | Essential hypertension |
|
| 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 |
| Compare effects of aliskiren, ramipril and the combination following 12-week treatment on venous angiotensin II levels in patients with decompensated systolic heart failure (SHF) and left ventricular ejection fraction ≤40%. |
|
| E.2.2 | Secondary objectives of the trial |
• Compare effects of aliskiren, ramipril and the combination during and following 12-week treatment on transcardiac angiotensin II and other renin system biomarkers (coronary sinus-arterial angiotensin II concentration gradient) in patients with decompensated chronic SHF and left ventricular ejection fraction ≤40%.
• Characterize steady state pharmacokinetics of aliskiren using population PK approach in patients with decompensated chronic SHF and left ventricular ejection fraction ≤40%.
• Assess the safety and tolerability of aliskiren, ramipril and the combination during and following a 12-week treatment period in patients with decompensated SHF and left ventricular ejection fraction ≤40%.
Exploratory objective:
• Explore effects of aliskiren, ramipril and the combination during and following a 12-week treatment period on other biomarkers (e.g. UACR, cystatin C) in patients with decompensated SHF and left ventricular ejection fraction ≤40%. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female patients, aged 18 years and above, with a history of chronic heart failure who could be hypertensive with a controlled blood pressure (BP ≤160/95 mmHg). The use of beta blockers (BB) is allowed.
2. Patients must have a history of chronic heart failure (≥12 months) and meet all the following criteria:
• Systolic left ventricular dysfunction (SLVD) defined as left ventricular ejection fraction (LVEF) ≤40% confirmed by echocardiography within 2 months of screening.
• An episode of acute decompensated heart failure requiring hospitalization within 3 months prior to screening. At the time of hospitalization patients must have had NYHA functional class II to IV symptoms including dyspnea, paroxysmal nocturnal dyspnea, orthopnea, fatigue on exertion.
• Brain natriuretic peptide (BNP) level ≥ 100 pg/mL at screening and on Day -1.
• At the beginning of the treatment period (Day 29), patients must be clinically euvolemic (within 2 kg of optimal weight, without signs of peripheral edema) by clinical examination by appropriate adjustment of diuretic doses and be on a stable diuretic dose for at least 1 week prior to randomization.
• The dose of diuretics and other concomitant medications during the 12-week study treatment period should only be changed if required by a change in the clinical status of the patient. Any change in concomitant medications must be documented in the CRF.
3. At Screening and on Day -1, vital signs must be within the following ranges:
Oral body temperature between 35.0-37.5 °C
MSSBP ≤160 mmHg
MSDBP ≤95 mmHg
Pulse rate, 50 - 90 bpm
4. Female subjects must be of non-childbearing potential. Postmenopausal females must have had no regular menstrual bleeding for at least one (1) year prior to screening. Menopause will be confirmed by a plasma FSH level that meets the local laboratory´s postmenopausal range at screening.
Female subjects who report surgical sterilization must have had the procedure at least six months prior to initial dosing. Surgical sterilization procedures should be supported with clinical documentation made available to the sponsor and noted in the Relevant Medical History / Current Medical Conditions section of the CRF.
5. At screening, subjects must weigh at least 50 kg to participate in the study, and must have a body mass index (BMI) within the range of 19 to 35 kg/m2.
6. Able to communicate well with the investigator, to understand and comply with the requirements of the study. Understand and sign the written informed consent. |
|
| E.4 | Principal exclusion criteria |
For full list, please refer to the protocol.
1. Use of other ACEis or ARBs following initiation of the run-in period with ramipril or history of requirement of both ACE and ARB inhibitor treatment.
2. Pregnancy or lactating females.
3. Acute heart failure secondary to acute myocardial infarction, acute coronary syndrome, myocarditis, or new tachyarrhythmia (within last 3 months).
4. Occurrence of unstable angina or myocardial infarction within 12 weeks prior to screening.
5. Significant illness other than decompensated heart failure (e.g. severe pneumonia requiring hospitalization) within two weeks prior to screening.
6. History of acute or chronic bronchospastic disease including asthma and chronic obstructive pulmonary disease.
7. Pericardial disease or severe chronic lung disease with cor pulmonale, as the cause of symptoms and signs of heart failure.
8. History of metastatic cancer or evidence of recurrence in the 2 years prior to screening (other than resected cutaneous basal or squamous cell carcinoma).
9. History of clinically significant drug allergy or history of atopic allergy (asthma, urticaria, eczematous dermatitis). A known reaction to the study drugs like coughing due to ACE use or history of angioedema.
10. History of hypertensive encephalopathy or stroke within 12 months prior to screening. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary focus of this study is to assess changes in RAAS and other biomarkers both in peripheral and coronary sinus blood. |
|
| 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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 | 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
| |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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