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Heart Failure With Preserved Ejection FractionPhase 2EXAMINE-HFCNCT07202000

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

A Phase 2 study testing Activin ligand-trap biological therapy in people with Heart Failure With Preserved Ejection Fraction, run by Massachusetts General Hospital at 1 site in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial 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). Read more about this study

Who is it for?
Ages 40 years and older
What is being tested?
Activin ligand-trap biological therapy
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
48 participants
Where
1 siteUnited States
Study dates
3 Jun 2026to Aug 2027
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 40 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)
  • 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);
  • 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;
Show all 12Show fewer
  • PCWP at rest > 15 mmHg (or LVEDP ≥ 18 mmHg) or ≥ 25 mmHg with exercise (or PCWP/CO ≥ 2.0 mmHg/L/min with exercise);
  • 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;
  • 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.

Who cannot join

  • 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.

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Gregory D. Lewis, MD contact

617-724-9254

glewis@partners.org

United States1 site, 1 recruiting

  • Massachusetts General Hospital

    Boston, Massachusetts, 02114

    Gregory D. Lewis, MD, 6177249254, glewis@partners.org

    Diane Cocca-Spofford, BSN, 617 726 8228, dcoccaspofford@mgh.harvard.edu

    Recruiting

Other trials in United States

About this study

Official title: Double-blind, Prospective, Randomized, Placebo-controlled Trial to Assess if Activin Ligand-trap Biological Therapy Can Improve Exercise Capacity and Cognitive Function in Heart Failure With Preserved Ejection Fraction Compared to Placebo.

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.

Read the detailed description

A double-blind, prospective, phase 2 randomized, placebo-controlled 24-week clinical trial to assess exercise tolerance after activin-ligand trap biological therapy compared to placebo in HFpEF patients with a primary endpoint of change in peak VO2.

Forty-eight participants with HFpEF who are overweight or obese will be recruited from the Cardiopulmonary Exercise Testing (CPET) Laboratory and will have a recent or scheduled clinical care CPET. These measurements will serve as baseline measures. After undergoing other baseline measurements such as actigraphy, blood studies, DEXA scan, Kansas City Cardiomyopathy Questionnaire (KCCQ), NIHTB-CB, and RAVLT, participants will be randomized (1:1) to either activin-ligand trap biological therapy combined with physical activity (n=24) or placebo combined with physical activity (n=24). Randomization will be stratified by sex and will be performed in permutated blocks of 4 to assure balanced group sizes. In order to allocate without bias and in a manner blinded to both participants and investigators, we will use random number generation at the time of randomization. After 12 weeks, patients will return for a new CPET, physical exam, urine and blood test, echocardiogram, electrocardiogram, DEXA scan, actigraphy, assessment of NYHA class, NIHTB-CB, RAVLT, KCCQ, six-minute walk test, handgrip test, and adverse events assessment. After these assessments, patients will undergo crossover at week 12 and will receive either the activin-ligand trap biological therapy combined with physical activity (n=24) or the placebo combined with physical activity (n=24) for an additional 12 weeks. At week 24, patients will return to have a repeat of the same tests that were performed at week 12.

Being tested
Activin ligand-trap biological therapy, Placebo, Normal Saline
Keywords
heart failure with preserved ejection fraction, exercise capacity, activin inhibition, cognition

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Activin ligand-trap biological therapyDrug

    Investigational therapy

  • Placebo, Normal SalineDrug

    Inactive drug

Study groups in NCT07202000
Study groupRoleWhat they receive
Activin ligand-trap biological therapy (KER-012) subcutaneously (SC) 1.5mg/kg every 4 weeks X 3Active comparatorActivin ligand-trap biological therapy subcutaneously in addition to an individualized physical activity program for 12 weeks before the crossover.
Receives: Drug: Activin ligand-trap biological therapy
Normal Saline subcutaneous injection every 4 weeks X 3Placebo comparatorPatients will receive placebo in addition to an individualized physical activity program for 12 weeks before the crossover.
Receives: Drug: Placebo, Normal Saline

What is being measured

The primary outcome is the main question the study is designed to answer.

  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).

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

Secondary outcomes (13)

  1. Change in cognitive function.

    Changes in cognitive function as assessed by the NIH-Toolbox Cognition Battery (NIHTB-CB) composite score standardized by age.

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

  2. Change in cognitive function

    changes in cognitive function as assessed by comparing the Rey Auditory Verbal Learning Test (RAVLT) score, standardized by age.

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

  3. Change in body composition.

    Change in body composition as measured by DEXA scan to compare the % lean muscle mass and absolute quantity of lean muscle mass

    Measured: From baseline to week 12 and week 12 to week 24

  4. Change in cardiac function measured by echocardiography

    Change in Left Atrium (LA)dimensions (cm)

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

  5. Change in cardiac function measured by echocardiography

    Change in E/e' ratio

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

  6. Change in patient-reported Quality of Life .

    Change to Quality of Life as measured by the Kansas City Cardiomyopathy Questionnaire score

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

  7. Change in New York Heart Association (NYHA) Functional Class.

    Change in New York Heart Association (NYHA) classification system which categorizes heart failure severity into four classes based on physical activity limitations and symptoms.

    Class I :No limitation of physical activity; Class II: Slight limitation of physical activity; Class III:Marked limitation of physical activity; Class IV: Unable to carry on any physical activity without discomfort; symptoms of heart failure at rest

    Measured: From baseline to week 12 and week 12 - 24

  8. Change metabolic measures such as in Hemoglobin A1C (HbA1C)

    Change in HbA1C

    Measured: From baseline to week 12, and week 12 to week 24

  9. Changes in metabolic measures such as waist to hip measurements

    Change in waist-to-hip ratio

    Measured: From baseline to week 12 and week 12 to week 24

  10. Change in six-minute walk distance

    percent change in six-minute walk distance (6MWD)

    Measured: From baseline to week 12 and week 12 -24

  11. Change in physical activity as measured by the Apple Health App

    Percent change in physical activity as measured by the Apple Health App

    Measured: From baseline to week 12 and week 12 to weeks 24

  12. Changes in cardiovascular risk biomarkers: high sensitivity c-Reactive Protein (hs-CRP)

    Change in high sensitivity c-Reactive Protein (hs-CRP) (ml/L)

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

  13. Change in cardiovascular biomarkers: N-terminal pro-B-type natriuretic peptide (NTproBNP)

    Change in N-terminal pro-B-type natriuretic peptide (NTproBNP) (pg/ml)

    Measured: from baseline to week 12 and from week 12 week 24

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Oct 2025
  2. Study start3 Jun 2026
  3. Primary completionJul 2027 (estimated)
  4. Study completionAug 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Crossover
Model description
Double-blind, prospective, phase 2 randomized, placebo-controlled 24-week clinical trial with a crossover at week 12.
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
48 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT07202000
Sponsor's protocol ID
2024P001990
Acronym
EXAMINE-HFC
Status last verified
Jul 2026
First submitted
8 Sep 2025
Last updated
9 Jul 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 32535122

  • 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.

    PubMed 30842316

  • 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.

    PubMed 28993402

  • 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.

    PubMed 25344549

  • 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.

    PubMed 31932459

  • 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.

    PubMed 29523517

  • 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.

    PubMed 31132875

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Activin ligand-trap biological therapy in people with Heart Failure With Preserved Ejection Fraction, run by Massachusetts General Hospital at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 12 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 9 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Gregory D. Lewis, MD (617-724-9254, glewis@partners.org), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in peak oxygen uptake (peak VO2) in HFpEF subjects following activin ligand-trap biological therapy or placebo. (time frame: From baseline to week 12 and from week 12 to week 24). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07202000, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jul 2026; AzTrials last refreshed its copy on 6 Nov 2026.

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