| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| NYHA II-III heart failure and reduced systolic function |
| NYHA II-III -luokan sydämen vajaatoiminta ja alentunut systolinen funktio |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic heart failure |
| Krooninen sydämen vajaatoiminta |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| 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 primary objective of the study is to evaluate the effects of 6 weeks of stable sacubitril/valsartan therapy, as compared with valsartan therapy, on the efficiency of cardiac work in patients with NYHA II-III heart failure (HF) and reduced systolic function using 11C-acetate and echocardiography. |
| Tämän tutkimuksen tarkoituksena on verrata kahden markkinoilla olevan valmisteen, valsartaanin ja sakubitriili/valsartaanin, vaikutuksia sydämen toimintaan positroniemissiotomgrafiaa (PET) ja sydämen ultraäänitutkimusta käyttäen. |
|
| E.2.2 | Secondary objectives of the trial |
| The exploratory objective of the study is to evaluate the effects of 6 weeks of stable sacubitril/valsartan therapy, as compared with valsartan therapy, on myocardial oxygen consumption and cardiac and systemic hemodynamics. |
| Eksploratiivisina tavoitteina tutkitaan sakubitriili/valsartaani-hoidon vaikutuksia sydämen hapenkulutukseen sekä verenkierron ja sydämen toimintaa kuvastaviin markkereihin. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Voluntary, valid written informed consent (IC) obtained before any study-related assessment is performed.
2. Sufficient command of the Finnish or Swedish language to be able to fully understand the ICF and other study information and to be able to communicate with the study personnel.
3. Male and female subjects ≥40 and ≤80 years of age.
4. Documented chronic HF with left ventricle EF 25-35% and NYHA class II-III symptoms.
5. Systolic BP 110-160 mmHg at the time of randomization.
6. Optimal standard HF therapy according to ESC guidelines, including at a minimum beta-blockers in all subjects, at a stable dose for at least 4 weeks before the first screening visit.
7. Valsartan treatment tolerated at a dose of 80 mg or 160 mg BID for at least 4 weeks during the screening/run-in period. |
|
| E.4 | Principal exclusion criteria |
1. Predicted poor compliance or inability to communicate well with the investigator or the study center personnel.
2. Current acute or subacute decompensated HF.
3. Presence of acute coronary syndrome, stroke, transient ischemic attack or other major cardiovascular event or cardiovascular procedure within 3 months before screening.
4. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within the 6 months after randomization.
5. Evidence of clinically significant renal, hepatic, hematological, gastrointestinal, pulmonary, metabolic-endocrine, neurological, urogenital or psychiatric disease that may constitute a health risk for the subject and/or would interfere with the evaluation of the results, as judged by the investigator.
6. Symptomatic hypotension that persists even after modification of concomitant medication(s), at any time during the screening/run-in period.
7. Estimated glomerular filtration rate (eGFR) < 45 ml/min at any time during the screening/run-in period that persists even after modification of concomitant medication(s).
8. Serum potassium >5.2 mmol/l at any time during the screening/run-in period that persists even after modification of concomitant medication(s).
9. Serum creatinine > 1.5 x ULN (upper limit of normal) at any time during the screening/run-in period that persists even after modification of concomitant medication(s).
10. Contraindication to neprilysin inhibitor or ARB (such as previous angioedema or known intolerance).
11. Susceptibility to severe allergic reactions or known hypersensitivity to the active substances or to any of the excipients.
12. Intake of any medication that could affect the outcome of the study, interfere with the evaluation of the results or constitute a health risk for the study subject, as judged by the investigator.
13. Positive serology to human immunodeficiency virus antibodies (HIVAgAb), hepatitis C virus antibodies (HCVAb) or hepatitis B surface antigen (HBsAg) in medical history.
14. Unwillingness to use adequate methods of contraception while participating in the study and for 3 months after the last administration of the PET tracer.
15. Participation in another clinical drug study within 3 months prior to the first study treatment administration of this study.
16. Prior participation in an investigational PET study or other medical or occupational exposure to significant doses of ionizing radiation, as judged by the investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint, change from baseline in cardiac efficiency after 6 weeks on stable sacubitril/valsartan or valsartan therapy, will be analyzed by an ANCOVA including treatment and stratification as independent factors and covariate adjustment for baseline cardiac efficiency. From this model, the within treatment group (sacubitril/valsartan-valsartan) changes will be estimated by least square means and the corresponding treatment difference between treatments will be calculated with a 95% confidence interval and p-value. In addition, treatment by stratification interaction analyses will be performed for the primary efficacy parameters in order to estimate within stratification group differences. For both the baseline visit and visit 3, the results will be also summarized using descriptive statistics, with the visit 3 results to be summarized also by dose level and treatment arm. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PET imaging and echocardiography will be performed before randomization (after a minimum of 4 weeks on stable dose of 80 or 160 mg BID of valsartan) and repeated after 6 weeks on a stable dose of either 80 or 160 mg BID of valsartan or 100 or 200 mg BID of sacubitril/valsartan. |
|
| E.5.2 | Secondary end point(s) |
| The changes in the following cardiac and systemic hemodynamics parameters will be evaluated as exploratory efficacy endpoints: EF, NT-proBNP, systemic BP, SVR, coronary vascular resistance and cardiac oxygen consumption. The change from baseline in these parameters after 6 weeks on stable sacubitril/valsartan or valsartan therapy will be analyzed by an ANCOVA including treatment and stratification as independent factors and covariate adjustment for baseline cardiac efficiency. From this model, the within treatment group (sacubitril/valsartan-valsartan) changes will be estimated by least square means and the corresponding treatment difference between treatments will be calculated with a 95% confidence interval and p-value. For both the baseline visit and visit 3, the results will be also summarized using descriptive statistics, with the visit 3 results to be summarized also by dose level and treatment arm. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Measurements for exploratory efficacy endpoints will be performed before randomization (after a minimum of 4 weeks on stable dose of 80 or 160 mg BID of valsartan) and repeated after 6 weeks on a stable dose of either 80 or 160 mg BID of valsartan or 100 or 200 mg BID of sacubitril/valsartan. |
|
| 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 | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
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