Registrational Study With Omecamtiv Mecarbil (AMG 423) to Treat Chronic Heart Failure With Reduced Ejection Fraction

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine if treatment with omecamtiv mecarbil when added to standard of care is well tolerated and superior to placebo in reducing the risk of cardiovascular death or heart failure events in adults with chronic heart failure with reduced ejection fraction (HFrEF).

Detailed Description
-----------------
This study was conducted by Amgen as the IND holder, with Cytokinetics as a collaborator. Due to the termination of the collaboration agreement between Amgen and Cytokinetics in May 2021 and subsequent transfer of the omecamtiv mecarbil IND from Amgen to Cytokinetics, Cytokinetics is now listed as the sponsor.

Official Title
-----------------
A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Assess the Efficacy and Safety of Omecamtiv Mecarbil on Mortality and Morbidity in Subjects With Chronic Heart Failure With Reduced Ejection Fraction (GALACTIC-HF)

Conditions
-----------------
Heart Failure

Intervention / Treatment
-----------------
* Drug: Omecamtiv Mecarbil
* Drug: Placebo
* Drug: Standard of Care


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Subject has provided informed consent Male or female, ≥ 18 to ≤ 85 years History of chronic heart failure (HF), defined as requiring treatment for HF for a minimum of 30 days before randomization Left ventricle ejection fraction (LVEF) ≤ 35%, per subjects most recent medical record, within 12 months prior to screening. New York Heart Association (NYHA) class II to IV at most recent screening assessment. Managed with HF standard of care (SoC) therapies consistent with regional clinical practice guidelines according to investigator judgment of subject's clinical status Current hospitalization with primary reason of HF OR one of the following events within 1 year of screening: hospitalization with primary reason of HF; urgent visit to emergency department (ED) with primary reason of HF. Elevated B-type natriuretic peptide (BNP) or n-terminal-prohormone brain natriuretic peptide (NT-proBNP) Other Inclusion Criteria May apply Key Exclusion Criteria: Currently receiving treatment in another investigational device or drug study, or < 30 days since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded. Malignancy within 5 years prior to randomization with the following exceptions: localized basal or squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, stage 1 prostate carcinoma, breast ductal carcinoma in situ. Subject has known sensitivity to any of the products or components to be administered during testing Other Exclusion Criteria May apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Omecamtiv Mecarbil<br>Participants received oral omecamtiv mecarbil (OM) twice daily in addition to standard heart failure therapy. The starting dose of OM was 25 mg; At week 4, participants with week 2 OM predose plasma concentrations < 200 ng/mL had their dose increased to 50 mg BID; participants with week 2 predose plasma concentrations ≥ 200 and < 300 ng/mL had their dose increased to 37.5 mg BID and participants with week 2 predose plasma concentrations ≥ 300 ng/mL and < 1000 ng/mL maintained a 25 mg BID dosing regimen. | Drug: Omecamtiv Mecarbil<br>* Omecamtiv mecarbil tablets for oral administration<br>* Other names: AMG 423;Drug: Standard of Care<br>* Participants were required to be optimally managed with standard of care therapies for chronic HF (eg, beta blockers, renin angiotensin aldosterone system inhibitors), consistent with regional clinical practice guidelines, unless contraindicated.<br>|
| Placebo Comparator: Placebo<br>Participants received matching placebo tablets twice a day in addition to standard heart failure therapy. | Drug: Placebo<br>* Matching placebo tablets<br>Drug: Standard of Care<br>* Participants were required to be optimally managed with standard of care therapies for chronic HF (eg, beta blockers, renin angiotensin aldosterone system inhibitors), consistent with regional clinical practice guidelines, unless contraindicated.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Cardiovascular Death or First Heart Failure Event | The primary outcome was a composite of a heart-failure (HF) event or cardiovascular (CV) death, whichever occurred first, in a time-to-event analysis. A heart-failure event was defined as an urgent clinic visit, emergency department visit, or hospitalization for subjectively and objectively worsening heart failure leading to treatment intensification beyond a change in oral diuretic therapy. All deaths and HF events were adjudicated by an independent external clinical events committee (CEC) at the Duke Clinical Research Institute, using standardized definitions based on the recent American College of Cardiology/American Heart Association (ACC/AHA) standards for endpoint definitions in cardiovascular clinical trials. Time to cardiovascular death or first HF event was analyzed using Kaplan-Meier (KM) methods. Since the median was not calculated, the percentage of participants with a positively adjudicated event during the study is reported. | From randomization to up to earliest of last confirmed survival status date or analysis cut-off date (07 August 2020); the overall median duration of follow-up was 21.8 months up to a maximum of 42 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Cardiovascular Death | Cardiovascular death includes acute myocardial infarction (MI), sudden cardiac death, death due to heart failure, death due to stroke, death due to cardiovascular (CV) procedures, death due to CV hemorrhage, and death due to other CV causes. All deaths were adjudicated by an independent external clinical-events committee at the Duke Clinical Research Institute, using standardized definitions based on the recent ACC/AHA standards for endpoint definitions in cardiovascular clinical trials. Time to cardiovascular death was analyzed using Kaplan-Meier methods. Since the median was not calculated, the percentage of participants with a positively adjudicated event during the study is reported. | From randomization to up to earliest of last confirmed survival status date or analysis cut-off date (07 August 2020); the overall median duration of follow-up was 21.8 months up to a maximum of 42 months. | 
| Change From Baseline in Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ TSS) at Week 24 | The Kansas City Cardiomyopathy Questionnaire is a self-administered questionnaire with a 2-week recall period that includes 23 items that map to 7 domains: symptom frequency; symptom burden; symptom stability; physical limitations; social limitations; quality of life; and self-efficacy (the patient's understanding of how to manage their heart failure). The symptom frequency and symptom burden domains are merged into a total symptom score. Scores are represented on a 0-to-100-point scale, where lower scores represent more frequent and severe symptoms and scores of 100 indicate no symptoms. The change from baseline in KCCQ TSS was analyzed separately for each randomization setting (inpatient and outpatient). Least squares means are from the mixed model which includes baseline total symptom score value, region, baseline eGFR, scheduled visit, treatment group and interaction of treatment with scheduled visit as covariates. | Baseline and Week 24 | 
| Time to First Heart Failure Hospitalization | A HF hospitalization is defined as an event that met all of the following criteria: The participant was admitted to the hospital with a primary diagnosis of HF; The length of stay in the hospital extended for at least 24 hours; The participant exhibited documented new or worsening symptoms due to HF on presentation; The participant had objective evidence of new or worsening HF; The participant received initiation or intensification of treatment specifically for HF, including an intravenous diuretic or vasoactive agent, mechanical or surgical intervention, or mechanical fluid removal. Events were adjudicated by an independent external CEC at the Duke Clinical Research Institute using standardized definitions based on the ACC/AHA standards for endpoint definitions in CV clinical trials. Time to first HF hospitalization was analyzed using KM methods. Since the median was not calculated, the percentage of participants with a positively adjudicated event is reported. | From randomization to up to earliest of last confirmed survival status date or analysis cut-off date (07 August 2020); the overall median duration of follow-up was 21.8 months up to a maximum of 42 months. | 
| Time to All-cause Death | All events were adjudicated by an independent external clinical-events committee at the Duke Clinical Research Institute, using standardized definitions based on the recent ACC/AHA standards for endpoint definitions in cardiovascular clinical trials. Time to all-cause death was analyzed using Kaplan-Meier methods. Since the median was not calculated, the percentage of participants with an event are reported. Events that occurred up to the earliest of last confirmed survival status date or analysis cut-off date (07 August 2020) are included. | From randomization up to earliest of last confirmed survival status date or analysis cut-off date (07 August 2020); the overall median duration of follow-up was 21.8 months up to a maximum of 42 months. |