E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Heart Failure with Reduced Ejection Fraction |
|
E.1.1.1 | Medical condition in easily understood language |
Chronic Heart Failure with Reduced Ejection Fraction |
|
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 | 20.0 |
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 |
|
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 effect of ISIS 757456 weekly subcutaneous (SC) injection on plasma angiotensinogen (AGT) concentration from Baseline to Study Day 85 (Week 13) in patients with chronic heart failure (HF) with reduced ejection fraction (HFrEF) |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the effect of ISIS 757456 weekly SC injection on plasma angiotensinogen (AGT) concentration at each scheduled visit in patients with chronic HFrEF To evaluate the effect of ISIS 757456 on N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) at each scheduled visit in patients with chronic HFrEF
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Satisfy the following: Females must be non-pregnant and non-lactating and of non-childbearing potential. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential (WOCBP), she must be willing to use a highly effective contraceptive method 2. Screening NT-proBNP ≥ 600 picograms per milliliter (pg/mL) and less than (<) 8500 pg/mL. For participants in atrial fibrillation at screening the eligibility NT-proBNP value is ≥ 1200 pg/mL and < 10200 pg/mL. 3. Established diagnosis of heart failure (HF) with reduced systolic function for at least 6 months prior to the screening visit (left ventricular ejection fraction, [LVEF] ≤ 40% 4. New York Heart Association class I-III 5. Participants should receive background standard of care for HFrEF. Therapy should have been individually optimized and stable for ≥ 4 weeks before randomization and include: a. An angiotensin-converting-enzyme inhibitor (ACEi), or angiotensin II receptor blockers (ARBs) or sacubitril/valsartan (mandatory); for participants not on target dose according to local guidelines, the reason should be documented, and eligibility may be allowed in consultation with the Sponsor 's Medical Monitor. b. A beta-blocker (unless contraindicated or not tolerated). c. A mineralocorticoid receptor antagonist (MRA, unless contraindicated or not tolerated). |
|
E.4 | Principal exclusion criteria |
1. Any cause of chronic HF other than ischemic cardiomyopathy and dilated cardiomyopathy 2. Acute decompensated HF requiring intravenous (IV) diuretics, IV inotropes or IV vasodilators with discharge date within 30 days of screening or acute mechanical support (e.g., intra-aortic balloon pump, endotracheal intubation, mechanical ventilation, or any ventricular assist device) with discharge date within 90 days of screening. 3. Symptomatic hypotension or systolic blood pressure (SBP) ≤ 90 millimeters of mercury (mmHg) at screening. 4. Heart transplant, and/or Left Ventricular Assist Device (LVAD) prior to screening or anticipated heart transplant or LVAD during the study. 5. Implantation of a cardiac resynchronization therapy device (CRT) within 3 months prior screening or intent to implant a CRT within 3 months after screening. 6. Acute coronary syndrome, unstable angina, stroke, transient ischemic attack (TIA), coronary revascularization, cardiac device implantation, cardiac valve repair, carotid or other major surgery within 3 months of screening. 7. Coronary, valve or carotid artery disease likely to require surgical or percutaneous intervention within the 3 months after screening. 8. Screening laboratory results as follows, or any other clinically significant abnormalities in screening laboratory values that would render a participant unsuitable for inclusion in the opinion of the investigator. a. Estimated glomerular filtration rate (eGFR) < 40 milliliters/minute /1.73 m^2 (mL/min/1.73 meter^2) at screening. b. Serum potassium > 4.7 millimoles per liter (mmol/L) at screening. 9. Requirement of treatment with both ACEi and ARBs. 10. Previous history of intolerance to ACEi or ARBs or history of hyperkalemia. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Percent change in plasma AGT from Baseline to Study Day 85 (Week 13) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Percent change in plasma AGT from Baseline to Study Day 85 (Week 13) |
|
E.5.2 | Secondary end point(s) |
• Absolute levels and change and percent change in plasma AGT from Baseline to each scheduled, post-baseline visit • Absolute level, change, within group changes, and percent change in NT-proBNP, from Baseline to each scheduled, post-baseline visit
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
From Baseline to each scheduled, post-baseline visit |
|
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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 | 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 | No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 |
United States |
Hungary |
Poland |
|
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
|
The Primary Completion Date, defined as “the date on which the last patient in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures” is the last patient’s Day 85 study visit. The study completion date is the last patient last visit (Day 169) at the end of the Post Treatment Evaluation Period. |
|
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |