Study to Assess the Effect of Omecamtiv Mecarbil on Exercise Capacity in Subjects With Heart Failure (METEORIC-HF)

A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Assess the Effect of Omecamtiv Mecarbil on Exercise Capacity in Subjects With Heart Failure With Reduced Ejection Fraction and Decreased Exercise Tolerance

The purpose of this study is to evaluate the effect of treatment with omecamtiv mecarbil compared with placebo on exercise capacity as determined by cardiopulmonary exercise testing following 20 weeks of treatment with omecamtiv mecarbil or placebo

Study Overview

• Status: Completed
• Conditions: Heart Failure With Reduced Ejection Fraction
• Intervention / Treatment: Drug: Omecamtiv Mecarbil; Drug: Placebo

Detailed Description

Oversight Authorities:

United States: Food and Drug Administration Canada: Health Canada France: National Agency for the Safety of Medicine and Health Products Germany: Federal Institute for Drugs and Medical Devices Hungary: National Institute of Pharmacy and Nutrition Italy: Italian Medicines Agency Netherlands: Medicines Evaluation Board Poland: Chief Pharmaceutical Inspectorate Sweden: Medical Products Agency

• Study Type: Interventional
• Enrollment (Actual): 276
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • Foothills Medical Centre
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • London Health Sciences Centre - University Hospital
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Ecogene-21
    • Montreal, Quebec, Canada, H1Y 3N1
      • Universite de Montreal Institut de Cardiologie de Montreal ICM Montreal Heart Institute MHI
    • Montreal, Quebec, Canada, H3P1E1
      • Mcgill University Health Centre (MUHC)-The Montreal General Hospital (MGH)
• France
  • Bayonne cedex, France, 64109
    • Centre Hospitalier de la Côte Basque
  • Grenoble, France, 38028
    • Groupe Hospitalier Mutualiste de Grenoble
  • La Tronche, France, 38700
    • Centre Hospitalier Universitaire de Grenoble-Hopital Albert Michallon
  • Nantes CEDEX 1, France, 44093
    • Universite De Nantes - L'Institut Du Thorax
  • Paris, France, 75010
    • Assistance Publique - Hopitaux de Paris (AP-HP) - Hopital Lariboisiere
  • Rouen Cedex, France, 76031
    • Chu de Rouen Hopital Charles Nicolle
  • Toulouse Cedex 9, France, 31059
    • Centre Hospitalier Universitaire (CHU) de Toulouse - Hopital Rangueil
• Germany
  • Bad Nauheim, Germany, 61231
    • Kerckhoff-Klinik- Bad Nauheim
  • Dresden, Germany, 01099
    • Praxisklinik Dresden
  • Homburg, Germany, 66421
    • Universitaetsklinikum Des Saarlandes Und Medizinische Fakultaet Der Universitaet Des Saarlandes
  • Baden-wurttemberg
    • Heidelberg, Baden-wurttemberg, Germany, 69120
      • Universitaetsklinik Heidelberg
  • Saxony-Anhalt
    • Magdeburg, Saxony-Anhalt, Germany, 39120
      • Universitätsklinikum Magdeburg
  • Thueringen
    • Jena, Thueringen, Germany, 07747
      • Universitaetsklinikum Jena
• Hungary
  • Balatonfured, Hungary, 8230
    • Balatonfüredi Állami Szívkórház
  • Budapest, Hungary, 1122
    • Semmelweis University Heart and Vascular Center
  • Pecs, Hungary, 7624
    • Pecsi Tudomanyegyetem (PTE) Altalanos Orvostudomanyi Kar (AOK) (University of Pecs Medical School)
• Italy
  • Napoli, Italy, 80131
    • Divisione di Cardiologia con Utic ed Emodinamica
  • Napoli, Italy, 80131
    • Ospedale Monaldi
  • Apulia
    • Foggia, Apulia, Italy, 71100
      • Ospedali Riuniti Foggia
  • Lombardia
    • Milano, Lombardia, Italy, 20138
      • Centro Cardiologico Monzino IRCCS
  • Province Of Bologna
    • Bologna, Province Of Bologna, Italy, 40138
      • Azienda Ospedaliera S.Orsola Malpighi
  • Province Of Brescia
    • Brescia, Province Of Brescia, Italy, 25123
      • Azienda Ospedaliera Spedali Civili Di Brescia-Universita Degli Studi Di Brescia
  • Rome
    • Roma, Rome, Italy, 00163
      • Insituto Di Ricovero E Cura A Carattere Scientifico San Raffaele Pisana
• Netherlands
  • 'S-Hertogenbosch, Netherlands, 5223 GZ
    • Jeroen Bosch ziekenhuis
  • Amsterdam, Netherlands, 1061 AE
    • Onze Lieve Vrouwe Gasthuis (OLVG) Locatie West
  • Groningen, Netherlands, 9713 GZ
    • University Medical Center Groningen
  • Leiden, Netherlands, 2300RC
    • Leids Universitair Medisch Centrum (LUMC)
  • Nijmegen, Netherlands, 6500 HB
    • Radboud Universiteit - Radboud Universitair Medisch Centrum (Radboudumc)
  • Utrecht, Netherlands, 3584 CX
    • Universitair Medisch Centrum Utrecht - Wilhelmina Kinderziekenhuis
  • Veldhoven, Netherlands, 5504 DB
    • Maxima Medisch Centrum Veldhoven
  • South Holland
    • Rotterdam, South Holland, Netherlands, 3000 CA
      • Erasmus MC - Universitair Medisch Centrum Rotterdam
• Poland
  • Bialystok, Poland, 15-276
    • Uniwersytecki Szpital Kliniczny w Bialymstoku
  • Gdansk, Poland, 80-952
    • Uniwersyteckie Centrum Kliniczne Kliniczne Centrum Kardiologii
  • Krakow, Poland, 31- 202
    • Oddzial Kliniczny Choroby Wiencowej i Niewydolnosci Serca z Pododdzialem Intensywnego Nadzoru Kardiologicznego
  • Lodz, Poland, 93-513
    • Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika, Oddzial Kardiologiczny
  • Warsaw, Poland, 04-628
    • Instytut Kardiologii Heart Failure Clinic
  • Wroclaw, Poland, 50556
    • Centrum Chorob Serca, Uniwersytecki Szpital Kllniczny im. Jana Mikulicza Radeckiego we Wrociawiu
  • Podkarpackie
    • Rzeszow, Podkarpackie, Poland, 35-055
      • Centrum Medyczne Medyk Sp z o.o. Sp. k.
• Sweden
  • Göteborg, Sweden, 413 45
    • Sahlgrenska Universitetssjukhuset
  • Lund, Sweden, 22242
    • Enhet Klinisk forskning, hjartmedicin, Skanes Universitet Sjukhus
• United States
  • Alaska
    • Anchorage, Alaska, United States, 99508
      • Alaska Heart and Vascular Institute
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Cardiology Clinic
  • California
    • Torrance, California, United States, 90509
      • Harbor-UCLA Medical Center
  • Colorado
    • Littleton, Colorado, United States, 80120
      • South Denver Cardiology Associates, PC
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Hartford Hospital-University of Connecticut School of Medicine
  • Florida
    • Fort Lauderdale, Florida, United States, 33308-4603
      • Holy Cross Hospital - Fort Lauderdale
    • Pembroke Pines, Florida, United States, 33024
      • Broward Research Center - Pembroke Pines
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Indiana
    • Indianapolis, Indiana, United States, 46227
      • Community Hospital South, Inc.
    • Indianapolis, Indiana, United States, 46260
      • Saint Vincent Medical Group Inc.
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
  • Massachusetts
    • Boston, Massachusetts, United States, 02114-2621
      • Massachusetts General Hospital (MGH) - Cardiac Unit Associates
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Heart & Vascular Institute
    • Petoskey, Michigan, United States, 49770
      • McLaren Health Care Corporation
    • Ypsilanti, Michigan, United States, 48197
      • Michigan Heart
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Health System
  • Montana
    • Kalispell, Montana, United States, 59901
      • Glacier View Research Institute, Cardiology
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University Of Nebraska Medical Center
  • New Jersey
    • Elmer, New Jersey, United States, 08318
      • Cardiovascular Associates Of The Delaware Valley (Cadv), P.A. - Elmer Physicians Care Center - Elmer
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
  • New York
    • New York, New York, United States, 10016
      • NYU Langone Medical Center
    • Rosedale, New York, United States, 11422
      • Queens Heart Institute
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Raleigh, North Carolina, United States, 27610
      • Wake Med Health and Hospital
    • Winston-Salem, North Carolina, United States, 27101
      • Wake Forest University School of Medicine
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74104
      • St. John Clinical Research Institute
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health
  • Pennsylvania
    • Camp Hill, Pennsylvania, United States, 17011
      • Capital Area Research, LLC
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Children's Hospital
    • Lancaster, Pennsylvania, United States, 17603
      • Lancaster Heart and Stroke Foundation
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Greenville Health System
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas - Southwestern Medical Center
    • Dallas, Texas, United States, 75246
      • Baylor Scott and White Heart and Vascular Hospital
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Inova Heart and Vascular Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

• Male or female, greater than or equal to 18 to lesser than or equal to 85 years of age
• History of chronic HF, defined as requiring continuous treatment with medications for HF for a minimum of 3 months before screening
• New York Heart Association (NYHA) class II or III at screening
• Left ventricular ejection fraction less than or equal to 35%
• On maximally tolerated HF standard of care (SoC) therapies consistent with regional clinical practice guidelines, if not contraindicated and according to investigator judgment of the subject's clinical status. Beta blocker dose must be stable for 30 days prior to randomization.
• N-terminal (NT)-proBNP level greater than or equal to 200 pg/mL
• Peak VO2 less than or equal to 75% of the predicted normal value with respiratory exchange ratio (RER) greater than or equal to 1.05 on a screening CPET, confirmed by a CPET core laboratory

Exclusion Criteria

• Severe uncorrected valvular heart disease
• Paroxysmal atrial fibrillation or flutter documented within the previous 6 months, direct-current (DC) cardioversion or ablation procedure for atrial fibrillation within 6 months, or plan to attempt to restore sinus rhythm within 6 months of randomization. Subjects with persistent atrial fibrillation and no sinus rhythm documented in the prior 6 months are permitted.
• Symptomatic bradycardia, second-degree Mobitz type II, or third-degree heart block without a pacemaker.
• History of gastrointestinal bleeding requiring hospitalization, urgent procedure or transfusion in the prior year, or received intravenous (IV) iron, blood transfusion, or an erythropoiesis-stimulating agent (ESA) within 3 months prior to screening, or planned blood transfusion or ESA use during the study screening or treatment period. Chronic, stable use of oral iron is permitted.
• Ongoing or planned enrollment in cardiac rehabilitation.
• Requires assistance to walk or use of mobility assistive devices such as motorized devices, wheelchairs, or walkers. The use of canes for stability while ambulating is acceptable if the subject is deemed capable of performing CPET.
• Major medical event or procedure within 3 months prior to randomization, including: hospitalization, surgery, renal replacement therapy or cardiac procedure. This includes episodes of decompensated HF that require IV HF treatment.
• At screening: Resting systolic BP greater than 140 mmHg or less than 85 mmHg, or diastolic BP greater than 90 mmHg (mean of triplicate readings); Resting heart rate greater than 90 beats per minute, or less than 50 beats per minute (mean of triplicate readings); Estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73m2 (by the modified Modification of Diet in Renal Disease equation); Hepatic impairment defined by a total bilirubin (TBL) greater than or equal to 2 times the upper limit of normal (ULN), or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than or equal to 3 times ULN. Patients with documented Gilbert syndrome and TBL greater than or equal to 2 times ULN due to unconjugated hyperbilirubinemia, without other hepatic impairment, are permitted.
• Room air oxygen saturation under 90% at screening
• Hemoglobin less than 10.0 g/dL at screening
• Significant adverse finding (e.g., exercise-induced early ischemic changes, abnormal decrease in BP [systolic BP falls by more than 10 mmHg], unexpected arrhythmia or other serious finding) during CPET at screening that precludes safe participation in the study, per investigator
• Chronotropic incompetence (including inadequate pacemaker rate response) during CPET at screening, defined as a maximum heart rate <60% of the maximum predicted heart rate

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Omecamtiv Mecarbil; Omecamtiv mecarbil was administered as an oral modified-release tablet twice daily for up to 20 weeks. Participants randomized to this arm started at an omecamtiv mecarbil dose of 25 mg twice daily. The dose could be increased based on plasma concentrations at Weeks 2 and 6.	Drug: Omecamtiv Mecarbil; Oral omecamtiv mecarbil twice daily for up to 20 weeks with dose level determined by periodic blood testing; Other Names: CK-1827452; AMG-423
Placebo Comparator: Placebo; Participants randomized this arm received placebo tablets (matching the appearance of the omecamtiv mecarbil tablets) twice daily for up to 20 weeks.	Drug: Placebo; Oral placebo twice daily for up to 20 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Peak Oxygen Uptake on Cardiopulmonary Exercise Testing From Baseline to Week 20	The effect of treatment on exercise capacity, as assessed by peak oxygen uptake, was assessed during cardiopulmonary exercise testing (CPET) with gas-exchange analysis. Cycle ergometry was the preferred modality for exercise testing; treadmill exercise testing was an acceptable alternative. Participants were to use the same testing modality for all exercise tests during the study. Whenever possible, CPET was administered by the same study personnel using the same equipment throughout the study.	Baseline and Week 20

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Total Workload During Cardiopulmonary Exercise Testing From Baseline to Week 20	Total workload was measured during CPET (cycle ergometry [preferred] or treadmill exercise testing) and represents the maximum load to which a participant was subjected during CPET in order to produce work.	Baseline and Week 20
Change in Ventilatory Efficiency During Cardiopulmonary Exercise Testing From Baseline to Week 20	Ventilatory efficiency (ventilation [VE]/volume of exhaled carbon dioxide [VCO2]) was measured through CPET with gas exchange analysis.	Baseline and Week 20
Change in the Average Daily Activity Units Measured Over a 2-week Period From Baseline (Week -2 to Day 1) to Weeks 18-20	The effect of treatment on daily activity, as assessed by average daily activity units, was evaluated by actigraphy. Actigraphy was collected during 4 sessions throughout the study for 2 week intervals.	Baseline (Week -2 to Day 1) to Weeks 18-20

Collaborators and Investigators

• Sponsor: Cytokinetics
• Investigators: Study Director: Cytokinetics, MD, Cytokinetics

Publications and helpful links

General Publications

• Lewis GD, Voors AA, Cohen-Solal A, Metra M, Whellan DJ, Ezekowitz JA, Bohm M, Teerlink JR, Docherty KF, Lopes RD, Divanji PH, Heitner SB, Kupfer S, Malik FI, Meng L, Wohltman A, Felker GM. Effect of Omecamtiv Mecarbil on Exercise Capacity in Chronic Heart Failure With Reduced Ejection Fraction: The METEORIC-HF Randomized Clinical Trial. JAMA. 2022 Jul 19;328(3):259-269. doi: 10.1001/jama.2022.11016.
• Lewis GD, Docherty KF, Voors AA, Cohen-Solal A, Metra M, Whellan DJ, Ezekowitz JA, Ponikowski P, Bohm M, Teerlink JR, Heitner SB, Kupfer S, Malik FI, Meng L, Felker GM. Developments in Exercise Capacity Assessment in Heart Failure Clinical Trials and the Rationale for the Design of METEORIC-HF. Circ Heart Fail. 2022 May;15(5):e008970. doi: 10.1161/CIRCHEARTFAILURE.121.008970. Epub 2022 Mar 3.

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2019
• Primary Completion (Actual): November 8, 2021
• Study Completion (Actual): January 6, 2022

Study Registration Dates

• First Submitted: November 15, 2018
• First Submitted That Met QC Criteria: November 28, 2018
• First Posted (Actual): November 30, 2018

Study Record Updates

• Last Update Posted (Estimate): March 7, 2023
• Last Update Submitted That Met QC Criteria: February 11, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: CY 1031; 2018-001233-40 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
• IPD Sharing Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• IPD Sharing Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No