EXercise and Activin Inhibition to Modulate InflammatioN Effects on Heart Failure and Cognition (EXAMINE-HFC)

NCT07202000 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 2024P001990
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to learn if therapy with activin ligand-trap biological therapy (an investigational drug) combined with exercise training can improve exercise capacity and cognitive function in heart failure with preserved ejection fraction (HFpEF). The main questions it aims to answer are:

• Does activin-ligand trap biological therapy improve exercise capacity as measured by change in peak oxygen uptake (peak VO2) from baseline to week 12?
• Does activin-ligand trap biological therapy improve cognitive function as assessed by the NIH-Toolbox Cognition Battery (NIHTB-CB) composite score and Rey Auditory Verbal Learning Test (RAVLT) from baseline to week 12? Researchers will compare activin-ligand trap biological therapy to a placebo (a look-alike substance that contains no drug) to see if activin-ligand trap therapy works to improve exercise capacity and cognitive function in patients with HFpEF.

Conditions

Heart Failure With Preserved Ejection Fraction

Keywords

heart failure with preserved ejection fraction; exercise capacity; activin inhibition; cognition

Outcome Measures

Primary Outcomes (1)

• Change in peak oxygen uptake (peak VO2) in HFpEF subjects following activin ligand-trap biological therapy or placebo.

  Peak VO2 measured by a maximal effort Cardiopulmonary Exercise Test (CPET).

  From baseline to week 12 and from week 12 to week 24

Secondary Outcomes (13)

• Change in cognitive function.

  From baseline to week 12 and from week 12 to week 24

• Change in cognitive function

  From Baseline to week 12, and from week 12- 24

• Change in body composition.

  From baseline to week 12 and week 12 to week 24

• Change in cardiac function measured by echocardiography

  From baseline to week 12 and from week 12 to 24

• Change in cardiac function measured by echocardiography

  From baseline to week 12 and from week 12 to week 24

Study Arms (2)

Activin ligand-trap biological therapy (KER-012) subcutaneously (SC) 1.5mg/kg every 4 weeks X 3

ACTIVE COMPARATOR

Activin ligand-trap biological therapy subcutaneously in addition to an individualized physical activity program for 12 weeks before the crossover.

Drug: Activin ligand-trap biological therapy

Normal Saline subcutaneous injection every 4 weeks X 3

PLACEBO COMPARATOR

Patients will receive placebo in addition to an individualized physical activity program for 12 weeks before the crossover.

Drug: Placebo, Normal Saline

Interventions

Activin ligand-trap biological therapy DRUG

Investigational therapy

Activin ligand-trap biological therapy (KER-012) subcutaneously (SC) 1.5mg/kg every 4 weeks X 3

Placebo, Normal Saline DRUG

Inactive drug

Normal Saline subcutaneous injection every 4 weeks X 3

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult ≥ 40 years of age;
• Body mass index ≥ 27 kg/m2;
• Left ventricular ejection fraction (LVEF) ≥ 0.50 with NYHA II-III;
• Established diagnosis of HFpEF based on medical history supported by at least one of the following 5 criteria (i through v, below)
• i. Documented hospitalization with HFpEF as a primary cause or other urgent outpatient visit for acute HFpEF (as primary cause) at which IV loop diuretic was provided as treatment (≥ 1 month prior to screening);
• ii. Increased left atrial (LA) size: AP dimension: ≥ 4.0 in men, \> 3.8 in women; or LA length ≥ 5.0 cm or LA volume ≥ 55 mL or LA volume index≥ 29 mL/m2;
• iii. PCWP at rest \> 15 mmHg (or LVEDP ≥ 18 mmHg) or ≥ 25 mmHg with exercise (or PCWP/CO ≥ 2.0 mmHg/L/min with exercise);
• iv. Either of the following at rest by Doppler and Tissue Dopper: a) for patients in sinus rhythm: E/e' ratio ≥ 15 at septal annulus, or E/e' ratio ≥ 13 at lateral annulus, or average E/e' ratio ≥ 14; for patients in atrial fibrillation E/e' ≥ 11 at the septal annulus;
• v. Elevated NT-proBNP ≥ 125 pg/mL (≥ 250 with chronic atrial fibrillation).
• Achievement of a respiratory exchange ratio (RER) at baseline CPET of ≥ 1.05 to ensure maximum volitional effort was provided;
• Ambulatory (not wheelchair/scooter-dependent) and able to perform CPET/6MWT/Chair stand evaluations;
• Stable dose of medications (defined as no new medication or change in existing dose of medication ≥ 50%) for at least 30 days prior to screening.

You may not qualify if:

• Conditions anticipated to independently impact exercise capacity or clinical stability during the trial period
• Current or recent (within 30 days) acute decompensated HF requiring intravenous diuretics or hospitalization;
• Initiation of treatment with GLP-1 receptor agonist or SGLT2 inhibitor within 60 days of screening;
• Planned cardiac surgery or catheter intervention during the period of trial participation;
• Entry within 30 days of screening or plans to enter a weight loss program and/or cardiac rehabilitation or initiate any new exercise program during the study.
• Primary cardiomyopathy (e.g., constrictive, restrictive, infiltrative, toxic, hypertrophic, congenital), LVEF \< 40% within the last 3 years, or active myocarditis;
• Lactating, pregnant, or planning to become pregnant;
• Non-cardiac organ system dysfunction or sufficient severity to predominate as the source of exercise intolerance in addition to the following specific criteria: pulmonary disease with chronic home daytime supplemental O2 dependence, severe anemia with hemoglobin \< 9 g/dL or chronic kidney disease (CKD) with estimated GFR \< 30 mL/min/1.73m2 based on the CKD-EPI equation.

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• American Heart Association: collaborator
• University of Michigan: collaborator
• Oakland University: collaborator

Study Sites (1)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Related Publications (7)

• Nayor M, Houstis NE, Namasivayam M, Rouvina J, Hardin C, Shah RV, Ho JE, Malhotra R, Lewis GD. Impaired Exercise Tolerance in Heart Failure With Preserved Ejection Fraction: Quantification of Multiorgan System Reserve Capacity. JACC Heart Fail. 2020 Aug;8(8):605-617. doi: 10.1016/j.jchf.2020.03.008. Epub 2020 Jun 10.

  PMID: 32535122 RESULT

• Roh JD, Hobson R, Chaudhari V, Quintero P, Yeri A, Benson M, Xiao C, Zlotoff D, Bezzerides V, Houstis N, Platt C, Damilano F, Lindman BR, Elmariah S, Biersmith M, Lee SJ, Seidman CE, Seidman JG, Gerszten RE, Lach-Trifilieff E, Glass DJ, Rosenzweig A. Activin type II receptor signaling in cardiac aging and heart failure. Sci Transl Med. 2019 Mar 6;11(482):eaau8680. doi: 10.1126/scitranslmed.aau8680.

  PMID: 30842316 RESULT

• Houstis NE, Eisman AS, Pappagianopoulos PP, Wooster L, Bailey CS, Wagner PD, Lewis GD. Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Diagnosing and Ranking Its Causes Using Personalized O2 Pathway Analysis. Circulation. 2018 Jan 9;137(2):148-161. doi: 10.1161/CIRCULATIONAHA.117.029058. Epub 2017 Oct 9.

  PMID: 28993402 RESULT

• Dhakal BP, Malhotra R, Murphy RM, Pappagianopoulos PP, Baggish AL, Weiner RB, Houstis NE, Eisman AS, Hough SS, Lewis GD. Mechanisms of exercise intolerance in heart failure with preserved ejection fraction: the role of abnormal peripheral oxygen extraction. Circ Heart Fail. 2015 Mar;8(2):286-94. doi: 10.1161/CIRCHEARTFAILURE.114.001825. Epub 2014 Oct 24.

  PMID: 25344549 RESULT

• Callaghan BC, Reynolds EL, Banerjee M, Chant E, Villegas-Umana E, Gardner TW, Votruba K, Giordani B, Pop-Busui R, Pennathur S, Feldman EL. The Prevalence and Determinants of Cognitive Deficits and Traditional Diabetic Complications in the Severely Obese. Diabetes Care. 2020 Mar;43(3):683-690. doi: 10.2337/dc19-1642. Epub 2020 Jan 13.

  PMID: 31932459 RESULT

• Hammond CA, Blades NJ, Chaudhry SI, Dodson JA, Longstreth WT Jr, Heckbert SR, Psaty BM, Arnold AM, Dublin S, Sitlani CM, Gardin JM, Thielke SM, Nanna MG, Gottesman RF, Newman AB, Thacker EL. Long-Term Cognitive Decline After Newly Diagnosed Heart Failure: Longitudinal Analysis in the CHS (Cardiovascular Health Study). Circ Heart Fail. 2018 Mar;11(3):e004476. doi: 10.1161/CIRCHEARTFAILURE.117.004476.

  PMID: 29523517 RESULT

• Ho JE, Zern EK, Wooster L, Bailey CS, Cunningham T, Eisman AS, Hardin KM, Zampierollo GA, Jarolim P, Pappagianopoulos PP, Malhotra R, Nayor M, Lewis GD. Differential Clinical Profiles, Exercise Responses, and Outcomes Associated With Existing HFpEF Definitions. Circulation. 2019 Jul 30;140(5):353-365. doi: 10.1161/CIRCULATIONAHA.118.039136. Epub 2019 May 28.

  PMID: 31132875 RESULT

MeSH Terms

Interventions

Saline Solution

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Gregory D. Lewis, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Gregory D. Lewis, MD

CONTACT

617-724-9254; glewis@partners.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Model Details: Double-blind, prospective, phase 2 randomized, placebo-controlled 24-week clinical trial with a crossover at week 12.

Study Record Dates

• First Submitted: September 8, 2025
• First Posted: October 1, 2025
• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): August 1, 2027
• Last Updated: February 19, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)