A Study of the Effect of IW-1973 on the Exercise Capacity of Patients With Heart Failure With Preserved Ejection Fraction (HFpEF) (CAPACITY-HFpEF)

A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 2 Study Evaluating the Safety and Efficacy of Different Doses of IW-1973 Over 12 Weeks in Patients With Heart Failure With Preserved Ejection Fraction

The objective of the CAPACITY-HFpEF study is to evaluate the safety and efficacy of IW-1973 compared with placebo when administered daily for approximately 12 weeks to patients with HFpEF. The study will evaluate the effect of oral IW-1973 on peak exercise capacity in patients with HFpEF, with or without permanent or persistent atrial fibrillation.

Study Overview

• Status: Completed
• Conditions: Heart Failure With Preserved Ejection Fraction
• Intervention / Treatment: Drug: IW-1973; Drug: Placebo Oral Tablet

• Study Type: Interventional
• Enrollment (Actual): 196
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Québec, Canada, G1V 4G5
    • Institut Universitaire De Cardiologie Et De Pneumologie De Québec
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • London Health Sciences Centre
    • Toronto, Ontario, Canada, M5G 1X5
      • Mount Sinai Hospital
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Ecogene-21
    • Sherbrooke, Quebec, Canada, J1G 2E8
      • CIUSSS de l'Estrie - CHUS
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Arizona Arrhythmia Research Center
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • Arkansas
    • Little Rock, Arkansas, United States, 72204
      • Cardiology and Medicine Clinic
  • California
    • La Mesa, California, United States, 91941
      • JEHM
    • Los Angeles, California, United States, 90036
      • Axis Clinical Trials
    • National City, California, United States, 91950
      • JEHM
    • Northridge, California, United States, 91325
      • Valley Clinical Trials
    • Palo Alto, California, United States, 94305
      • Stanford University
    • Torrance, California, United States, 90509
      • Harbor Ucla Medical Center
  • Colorado
    • Denver, Colorado, United States, 80218
      • Aurora Denver Cardiology
    • Littleton, Colorado, United States, 80120
      • South Denver Cardiology Associates
  • Florida
    • Fort Lauderdale, Florida, United States, 33308
      • Holy Cross Hospital
    • Hialeah, Florida, United States, 33016
      • New Generation of Medical Research
    • Jacksonville, Florida, United States, 32216
      • East Coast Institute for Research
    • Miami, Florida, United States, 33126
      • PCRS Network, LLC
    • Pembroke Pines, Florida, United States, 33024
      • Broward Research Center
    • Port Orange, Florida, United States, 32127
      • Progressive Medical Research
  • Idaho
    • Boise, Idaho, United States, 83712
      • St. Luke's Regional Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Peoria, Illinois, United States, 61602
      • Unity Point Health - Methodist Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46237
      • Franciscan Physician Network - Indiana Heart Physicians
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Louisiana
    • Bogalusa, Louisiana, United States, 70427
      • Lousiana Heart Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02118
      • Boston University School Of Medicine
    • Burlington, Massachusetts, United States, 01805
      • Lahey Clinic
  • Michigan
    • Ypsilanti, Michigan, United States, 48197
      • Michigan Heart
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
    • Saint Louis, Missouri, United States, 63106
      • VA Healthcare John Cochran Medical Center
  • New Jersey
    • Ridgewood, New Jersey, United States, 07450
      • The Valley Hospital
  • New York
    • New York, New York, United States, 10025
      • Mount Sinai School of Medicine
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Medical Center (OSUMC)
    • Toledo, Ohio, United States, 43606
      • ProMedica Toledo Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73135
      • South Oklahoma Heart Research
    • Oklahoma City, Oklahoma, United States, 73159
      • Newton Clinical Research
    • Tulsa, Oklahoma, United States, 74104
      • Oklahoma Heart Institute
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University (OHSU)
    • Springfield, Oregon, United States, 97477
      • PeaceHealth, Sacred Heart Physicians
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17602
      • Research Institute of Lancaster General Health
    • Philadelphia, Pennsylvania, United States, 19102
      • Drexel University College of Medicine
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Dallas, Texas, United States, 75235
      • Southwest Family Medicine Associates
    • Dallas, Texas, United States, 75069
      • North Dallas Research Associates
    • Dallas, Texas, United States, 75231
      • Texas Health Research and Education Insitute
    • San Antonio, Texas, United States, 78229
      • Schnitzler Cardiovascular Consultants
  • Vermont
    • Burlington, Vermont, United States, 05401
      • University of Vermont Medical Center
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University Medical College of Virginia
  • Washington
    • Tacoma, Washington, United States, 98431
      • Madigan Army Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin - Madison
    • Madison, Wisconsin, United States, 53713
      • Unity Point Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patient is an ambulatory male or female ≥45 years old at the Screening Visit
2. Patient has heart failure with ejection fraction (EF) of ≥40%
3. Patient has a peak VO2 measuring <80% of age- and sex-adjusted normal values

4. Patient has evidence in medical history supporting clinical heart failure syndrome consisting of at least 1 of the following:

   1. Hospitalization or emergency department visit for heart failure within the past year
   2. Elevated B-type natriuretic peptide (BNP) or N-terminal pro b-type natriuretic peptide (NT-proBNP) within the past 6 months
   3. Echocardiographic evidence within the past 12 months of at least 2 of the following: left ventricular (LV) hypertrophy, left atrial (LA) enlargement, or diastolic dysfunction
   4. Hemodynamic evidence of elevated filling pressures

5. Patient meets at least 2 of the following criteria at the Screening Visit:

   1. Diagnosis of type 2 diabetes mellitus or prediabetes
   2. History of hypertension
   3. Body mass index (BMI) >30 kg/m2
   4. Age ≥70 years

Exclusion Criteria:

1. Patient has had acute coronary syndrome or percutaneous coronary intervention within 30 days before Randomization
2. Patient has had cardiac transplantation or has cardiac transplantation planned during the study
3. Patient has had cardiac artery bypass graft, cardiac mechanical support implantation, or other cardiac surgery in the 3 months before the Screening Visit or planned during the study
4. Patient has severe chronic obstructive coronary disease as defined by chronic oxygen dependence
5. Patient had had heart failure hospitalization with discharge within 30 days before the Screening Visit
6. Patient has a history of clinically significant hypersensitivity or allergies to any of the inactive ingredients contained in the active or placebo drug products
7. Patient has previously received IW-1973 in a study, or received an investigational drug during the 30 days or 5 half lives of that investigational drug (whichever is longer) before the Screening Visit, or is planning to receive another investigational drug at any time during the study
8. Patient is taking specific inhibitors of phosphodiesterase 5 (PDE5), nonspecific inhibitors of PDE5, any supplements for the treatment of erectile dysfunction, riociguat, or nitrates or nitric oxide (NO) donors in any form
9. Patient is taking strong cytochrome P450 3A (CYP3A) inhibitors
10. Women of childbearing potential must have a negative pregnancy test prior to randomization and must agree to use protocol-specified contraception from the Screening Visit through 60 days after the final dose of study drug
11. Male patients must be surgically sterile by vasectomy (conducted ≥60 days before the Screening Visit or confirmed via sperm analysis) or must agree to use protocol-specified contraception from the Screening Visit through 60 days after the final dose of study drug
12. Other exclusion criteria per protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: IW-1973 High Dose	Drug: IW-1973; Oral Tablet
PLACEBO_COMPARATOR: Placebo; Placebo to match experimental drug	Drug: Placebo Oral Tablet; Oral Tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Study Drug-related TEAEs	An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. TEAEs are defined as those adverse events (AEs) that started or worsened in severity after the administration of study drug. Causality relationship to study drug was per Investigator assessment. Number of participants with TEAEs and study drug-related TEAEs is presented.	Day 1 up to Day 113
Change From Baseline in Peak Oxygen Consumption (VO2) at Week 12	Peak VO2 was obtained from Cardiopulmonary Exercise Test (CPET), which was used to evaluate the effect of praliciguat on peak exercise capacity. Baseline is defined as the last non-missing measurement prior to the first dose of study drug. Change from Baseline was calculated by subtracting Baseline value from the Week 12 value. Data were analyzed using an analysis of covariance (ANCOVA) model with treatment group and atrial fibrillation stratification factors as categorical variable terms and Baseline peak VO2 value as a covariate. Milliliter O2 per kilogram per minute = mL O2/kg/min	Baseline and Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in 6-minute Walk Test (6MWT) Distance at Week 12	6MWT was a simple assessment of everyday functional capacity and provided a global evaluation of the organ/physiologic systems involved in exercise. 6MWT assessed the distance travelled in 6 minutes, measured at approximately the same time of day. Baseline is defined as the last non-missing measurement prior to the first dose of study drug. Change from Baseline was calculated by subtracting Baseline value from the Week 12 value. Data were analyzed using an ANCOVA model with treatment group, atrial fibrillation stratification factor and peak VO2 stratification factor as categorical variable terms and Baseline value as a covariate.	Baseline and Week 12
Change From Baseline in Ventilatory Efficiency at Week 12	Ventilatory efficiency was defined as minute ventilation/carbon dioxide (VE/VCO2) slope, production and was obtained from CPET. Baseline is defined as the last non-missing measurement prior to the first dose of study drug. Change from Baseline was calculated by subtracting Baseline value from the Week 12 value. Data were analyzed using an ANCOVA model with treatment group, atrial fibrillation stratification factor and peak VO2 stratification factor as categorical variable terms and baseline value as a covariate.	Baseline and Week 12
CPET Responders at Week 12	CPET responders were defined as participants who improved by at least 1.5 mL O2/kg/min in peak VO2 from Baseline to Week 12. Baseline is defined as the last non-missing measurement prior to the first dose of study drug.	At Week 12

Collaborators and Investigators

• Sponsor: Akebia Therapeutics
• Collaborators: Cyclerion Therapeutics
• Investigators: Study Director: Jelena Seferovic, MD PhD, Cyclerion Therapeutics, Inc.

Publications and helpful links

General Publications

• Udelson JE, Lewis GD, Shah SJ, Zile MR, Redfield MM, Burnett J Jr, Parker J, Seferovic JP, Wilson P, Mittleman RS, Profy AT, Konstam MA. Effect of Praliciguat on Peak Rate of Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction: The CAPACITY HFpEF Randomized Clinical Trial. JAMA. 2020 Oct 20;324(15):1522-1531. doi: 10.1001/jama.2020.16641.
• Udelson JE, Lewis GD, Shah SJ, Zile MR, Redfield MM, Burnett J Jr, Mittleman RS, Profy AT, Seferovic JP, Reasner D, Konstam MA. Rationale and design for a multicenter, randomized, double-blind, placebo-controlled, phase 2 study evaluating the safety and efficacy of the soluble guanylate cyclase stimulator praliciguat over 12 weeks in patients with heart failure with preserved ejection fraction (CAPACITY HFpEF). Am Heart J. 2020 Apr;222:183-190. doi: 10.1016/j.ahj.2020.01.009. Epub 2020 Jan 21.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 7, 2017
• Primary Completion (ACTUAL): August 19, 2019
• Study Completion (ACTUAL): August 19, 2019

Study Registration Dates

• First Submitted: August 16, 2017
• First Submitted That Met QC Criteria: August 16, 2017
• First Posted (ACTUAL): August 18, 2017

Study Record Updates

• Last Update Posted (ACTUAL): September 15, 2022
• Last Update Submitted That Met QC Criteria: August 18, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Heart Failure; Cardiovascular; HF; HFpEF
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Guanylyl Cyclase C Agonists; Enzyme Activators; Praliciguat
• Other Study ID Numbers: C1973-204

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes