Activin Ligand-Trap + Exercise for Heart Failure

(EXAMINE-HFC Trial)

Overseen By Gregory D. Lewis, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Must not be taking: GLP-1 agonists, SGLT2 inhibitors

Disqualifiers: Primary cardiomyopathy, Pregnancy, Severe anemia, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a new drug, activin ligand-trap biological therapy, combined with exercise, can help individuals with heart failure with preserved ejection fraction (a condition where the heart pumps normally but is stiff when relaxed) improve their exercise capacity and cognitive function. Researchers aim to determine if this treatment eases breathing during exercise and enhances cognitive abilities. The trial compares the effects of the actual drug to a placebo, a substance resembling the drug but without an active ingredient. It is suitable for individuals over 40 with heart failure with preserved ejection fraction who struggle to stay active. As a Phase 2 trial, it measures the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to significant research.

Do I have to stop taking my current medications for the trial?

The trial requires that you have been on a stable dose of your current medications for at least 30 days before screening, meaning no new medications or significant changes in dosage. It doesn't specify that you need to stop taking your current medications.

Is there any evidence suggesting that activin ligand-trap biological therapy is likely to be safe for humans?

In earlier studies, KER-012, an activin ligand-trap treatment, was generally well tolerated at doses up to 5 mg/kg, meaning most participants did not experience serious side effects at these doses. Lab studies have tested KER-012 for its potential to reduce heart-related problems before large-scale human trials.

Although this trial is in an early stage, with safety information still being collected, earlier studies suggest that KER-012 could be safe for humans. While researchers continue to gather more safety data, the results so far are encouraging. As with any trial, researchers closely monitor participants to ensure their safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for heart failure?

Most treatments for heart failure focus on managing symptoms and improving heart function, often using medications like ACE inhibitors, beta-blockers, or diuretics. However, the activin ligand-trap therapy (KER-012) is unique because it targets a different pathway by acting as a biological trap for activin, a protein involved in inflammation and fibrosis. This novel mechanism aims to directly influence heart tissue remodeling and reduce heart stress. Researchers are excited about this therapy because it could potentially improve heart health in a new way, offering hope for better outcomes for heart failure patients.

What evidence suggests that activin ligand-trap biological therapy might be an effective treatment for heart failure with preserved ejection fraction?

In this trial, participants will receive either the Activin ligand-trap biological therapy (KER-012) or a placebo, both alongside an individualized physical activity program. Research has shown that treatments like KER-012 might benefit the heart by reducing scarring and improving its pumping efficiency. Previous studies found that these treatments can decrease muscle loss and enhance heart function, particularly in conditions stressing the heart and lungs. Early evidence suggests that KER-012 can benefit heart and lung tissues, supporting its potential to aid individuals with heart problems. While more research is needed, these findings suggest it could improve exercise capacity and possibly mental function for those with heart failure with preserved ejection fraction (HFpEF). ^{2 6 7 8 9}

Who Is on the Research Team?

Gregory D. Lewis, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

This trial is for individuals with heart failure where the heart muscle pumps normally (HFpEF). Participants should be able to perform exercise and undergo cognitive function tests. Specific eligibility criteria are not provided, but typically include age range, disease severity, and no conflicting medications or conditions.

Inclusion Criteria

Body mass index ≥ 27 kg/m2

Achievement of a respiratory exchange ratio (RER) at baseline CPET of ≥ 1.05

My heart pumps well and I have mild to moderate heart symptoms.

Exclusion Criteria

Conditions anticipated to independently impact exercise capacity or clinical stability during the trial period

Lactating, pregnant, or planning to become pregnant

I have a heart condition with reduced function or inflammation.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Baseline measurements including CPET, actigraphy, blood studies, DEXA scan, KCCQ, NIHTB-CB, and RAVLT are conducted

1 week

Treatment Phase 1

Participants receive either activin ligand-trap biological therapy or placebo combined with physical activity for 12 weeks

12 weeks

3 visits (in-person) for subcutaneous injections

Crossover Treatment Phase

Participants crossover to receive the alternate treatment (activin ligand-trap biological therapy or placebo) combined with physical activity for an additional 12 weeks

12 weeks

3 visits (in-person) for subcutaneous injections

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Activin ligand-trap biological therapy

Trial Overview The EXAMINE-HFC trial is testing whether a new drug called activin ligand-trap biological therapy can improve how much oxygen your body uses during peak exercise (peak VO2) and brain function in patients with HFpEF when combined with exercise training. It's compared to a placebo made of normal saline.

How Is the Trial Designed?

Group I: Activin ligand-trap biological therapy (KER-012) subcutaneously (SC) 1.5mg/kg every 4 weeks X 3 Active Control 1 Intervention

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

Group II: Normal Saline subcutaneous injection every 4 weeks X 3 Placebo Group 1 Intervention

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

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

American Heart Association

Collaborator

Trials

352

Recruited

6,196,000+

University of Michigan

Collaborator

Trials

1,891

Recruited

6,458,000+

Oakland University

Collaborator

Trials

15

Recruited

3,300+

Citations

1. ir.kerostx.com ir.kerostx.com/news-releases/news-release-details/keros-therapeutics-presents-preclinical-and-clinical-data-its

Keros Therapeutics Presents Preclinical and Clinical Data ... These data demonstrate that RKER-012 lessened the severity of cardiac fibrosis and remodeling, leading to an improvement in left ventricular ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7124007/

Activin type II receptor signaling in cardiac aging and heart ... Activin type II receptor (ActRII) ligands have been implicated in muscle wasting in aging and disease. However, the role of these ligands ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06658522

A Prospective Single Arm Open Label Phase 4 Study to ... These results suggest that cardiac work is reduced and cardiac efficiency is improved in patients being treated with sotatercept, in contrast with ...

4. ir.kerostx.com ir.kerostx.com/static-files/b53ad76f-59c7-4597-b253-48c36b18d2b4

RKER-012, a Novel Activin Receptor Type IIB (ActRIIB) Ligand ... These results provide early evidence that KER-012 has the potential to benefit lung and heart tissues in PAH, and support continued clinical development in ...

5. publications.ersnet.org publications.ersnet.org/content/erj/65/5/25e6505

ERJ Podcast May 2025: Efficacy and safety of the activin ... Chief Editor James Chalmers interviews Associate Editor Marius Hoeper about the efficacy and safety of the activin signalling inhibitor sotatercept.

6. academic.oup.com academic.oup.com/eurheartj/article/44/Supplement_2/ehad655.2011/7391945

Development of KER-012, a modified ActRIIB ligand trap, for ... Safety, PK and biomarkers of activin target engagement were assessed. Results. KER-012 was generally well tolerated at dose levels up to 5 mg/kg ...

7. anzctr.org.au anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12623001290684

ANZCTR - Registration A Phase 2, Open-label, Single-arm Study to Evaluate the Tolerability, Safety, and Pharmacodynamic Effects of KER-012 in Participants with Chronic Heart Failure.

8. atsjournals.org atsjournals.org/doi/pdf/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A1187?download=true

Administration of KER-012, a Modified Activin Receptor IIB ... Preclinical data in rodent models of PAH and cardiovascular disease demonstrated that. RKER-012 (a research form of KER-012) prevented increases in pulmonary ...

9. academic.oup.com academic.oup.com/eurheartj/article/45/Supplement_1/ehae666.3360/7838132

RKER-012, a novel modified ActRIIB ligand trap, attenuated ... RKER-012, a research version of KER-012, is an investigational modified activin receptor type IIB (ActRIIB) ligand trap designed to specifically bind and ...