MANP + Sacubitril/Valsartan for Heart Failure

Overseen By Sherry Benike, RN, CCRP

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Horng Chen

Must be taking: Chronic diuretics

Disqualifiers: Diabetes, BMI > 35, others

Compensation: Varies

Number of Visits: 5

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new methods to assist people with heart failure who also experience kidney problems or difficulty breathing during exercise. Researchers are testing two treatments: Sacubitril/Valsartan, a common heart failure medication, and MANP (M-Atrial Natriuretic Peptide), an experimental treatment, to observe their effects on the body. The trial includes different groups, with some receiving the actual medications and others receiving placebo treatments (inactive substances) for comparison. Suitable candidates for this trial have heart failure with kidney issues or shortness of breath during exercise, but do not have diabetes or a body mass index (BMI) over 35. As a Phase 1, Phase 2 trial, this research aims to understand how the treatments work and measure their effectiveness in an initial group, offering participants a chance to contribute to groundbreaking medical advancements.

Will I have to stop taking my current medications?

The trial requires participants to stay on a stable dose of their current diuretic medication for at least 4 weeks before the study and throughout its duration. The protocol does not specify other medication changes, so it's best to discuss your specific medications with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that MANP is safe and well-tolerated by people with high blood pressure, effectively lowering it without major issues. A single injection of MANP proved safe and beneficial for both blood pressure and kidney function.

Sacubitril/Valsartan, already approved for certain heart conditions, has extensive safety information available. Studies have shown it is generally safe and well-tolerated, with patients often experiencing fewer hospital visits and better survival rates compared to some other treatments.

Both treatments appear safe, but participants in the trial will be closely monitored to ensure everything proceeds smoothly. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about MANP and Sacubitril/Valsartan for heart failure with preserved ejection fraction (HFpEF) because they offer unique approaches compared to current treatments like beta-blockers and diuretics. MANP is a novel peptide that targets the heart and kidneys, aiming to reduce volume overload and improve heart function, which could be a game-changer for those with chronic kidney issues. Sacubitril/Valsartan, known as an ARNI, combines two drugs to enhance heart efficiency by reducing blood pressure and volume overload. Together, these treatments could provide more comprehensive management of HFpEF, addressing symptoms at rest and during activity.

What evidence suggests that this trial's treatments could be effective for heart failure?

Research shows that Sacubitril/Valsartan effectively treats heart failure with reduced ejection fraction (HFrEF). It significantly lowers the risk of death and hospital visits, with studies indicating a 30% reduction in heart-related deaths or hospital stays. In this trial, some participants will receive Sacubitril/Valsartan alongside an injected placebo. Meanwhile, MANP has shown promise in reducing blood pressure and heart strain in heart failure models. Early findings suggest it may benefit patients with heart failure due to its ability to lower blood pressure and its safety. Other participants in this trial will receive MANP with an oral placebo. Researchers are carefully studying both treatments to understand their potential benefits for heart failure and related conditions. ^{1 2 3 6 7}

Who Is on the Research Team?

Paul M McKie

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

This trial is for adults with heart failure that still have a normal amount of blood pumped from the heart (HFpEF) and also have chronic kidney disease, but not diabetes or severe obesity. They must be on stable diuretic medication and have certain levels of kidney function and symptoms according to NYHA class.

Inclusion Criteria

I do not have diabetes and my BMI is 35 or less.

I have heart failure with moderate symptoms and am on long-term water pills.

I have been on a stable dose of a diuretic for at least 4 weeks.

Exclusion Criteria

In the opinion of the investigator, is unlikely to comply with the study protocol or is unsuitable for any reasons

Received an investigational drug within 1 month prior to dosing

I have been diagnosed with constrictive pericarditis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Diet Compliance and Medication Adjustment

Participants receive diet instructions and medication adjustments prior to the active study phase

1 week

1 visit (in-person)

Crossover Treatment

Participants undergo three crossover treatment visits with different drug/placebo combinations, each followed by a washout period

3 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• MANP
• Sacubitril/Valsartan

Trial Overview The study tests two drugs: Sacubitril/Valsartan (Entresto) and MANP, against placebos to see how they affect people with HFpEF-CKD who get short of breath during exercise without signs of fluid retention. Participants will receive either one drug or placebo through oral or injection routes.

How Is the Trial Designed?

Group I: HFpEF-EI with Sacbitril/Valsartan with an injected placebo Experimental Treatment 2 Interventions

Subjects with with HFpEF with exercise induced dyspnea (difficult or labored breathing) without clinical symptoms at rest (e.g. peripheral edema, weight gain, and abdominal distention) will receive study drug Sacbitril/Valsartan and an injected placebo followed by a 1 week washout period.

Group II: HFpEF-EI with MANP and oral placebo Experimental Treatment 2 Interventions

Subjects with with HFpEF with exercise induced dyspnea (difficult or labored breathing) without clinical symptoms at rest (e.g. peripheral edema, weight gain, and abdominal distention) will receive study drug MANP and an oral placebo followed by a 1 week washout period.

Group III: HFpEF-CKD with Sacbitril/Valsartan with an injected placebo Experimental Treatment 2 Interventions

Subjects with with HFpEF volume overload in the presence of chronic kidney diseases and clinical symptoms at rest (e.g. peripheral edema, weight gain, and abdominal distention) will receive study drug Sacbitril/Valsartan and an injected placebo followed by a 1 week washout period.

Group IV: HFpEF-CKD with MANP and oral placebo Experimental Treatment 2 Interventions

Subjects with with HFpEF volume overload in the presence of chronic kidney diseases and clinical symptoms at rest (e.g. peripheral edema, weight gain, and abdominal distention) will receive study drug MANP and an oral placebo followed by a 1 week washout period.

Group V: HFpEF-EI with an oral and injected placebo Placebo Group 2 Interventions

Subjects with with HFpEF with exercise induced dyspnea (difficult or labored breathing) without clinical symptoms at rest (e.g. peripheral edema, weight gain, and abdominal distention) will receive an oral and injected placebo followed by a 1 week washout period.

Group VI: HFpEF-CKD with an oral and injected placebo Placebo Group 2 Interventions

Subjects with with HFpEF volume overload in the presence of chronic kidney diseases and clinical symptoms at rest (e.g. peripheral edema, weight gain, and abdominal distention) will receive an oral and injected placebo followed by a 1 week washout period.

Who Is Running the Clinical Trial?

Horng Chen

Lead Sponsor

Trials

4

Recruited

170+

Published Research Related to This Trial

In a study of 30 patients with chronic heart failure, treatment with sacubitril/valsartan for 12 months led to a significant improvement in left ventricular ejection fraction, increasing from a median of 26.3% to 36.3%.

The study also monitored NT-proBNP levels and glomerular filtration rates, indicating that sacubitril/valsartan not only improves heart function but may also positively impact other cardiovascular health markers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring the dynamics of clinical and laboratory markers of chronic heart failure during 12 months of sacubitril/valsartan treatment. Čepelová, J., Malý, M., Daněk, J., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7754892/

Efficacy of exogenous atrial natriuretic peptide in patients ... Exogenous atrial natriuretic peptide (ANP) may be a logical treatment for heart failure (HF) patients with ANP deficiency.

2. jacc.org jacc.org/doi/10.1016/j.jacbts.2023.08.011

MANP in Hypertension With Metabolic Syndrome: Proof-of- ... A single subcutaneous injection of M-atrial natriuretic peptide was safe, well-tolerated, and exerted pleiotropic properties including blood pressure–lowering, ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8916975/

MANP (M-Atrial Natriuretic Peptide) Reduces Blood ... In an experimental model of hypertensive heart failure (HF), MANP lowered cardiac filling pressures and BP similar to the soluble (cytosolic) ...

4. ahajournals.org ahajournals.org/doi/10.1161/HYPERTENSIONAHA.121.17159

First-in-Human Study of MANP: A Novel ANP (Atrial ... Thus, M-atrial natriuretic peptide has a favorable safety profile and produced expected pharmacological effects in human hypertensive subjects ...

5. academic.oup.com academic.oup.com/cardiovascres/article/118/18/3416/6675294

Natriuretic peptide pathways in heart failure - Oxford Academic Research has established the production of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) from the heart.

6. sciencedirect.com sciencedirect.com/science/article/pii/S2452302X23004163

MANP in Hypertension With Metabolic Syndrome: Proof-of- ... In this proof-of-concept human study, we investigated the safety, tolerability, pharmacokinetics, pharmacodynamics, and cardiovascular and metabolic properties ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9897690/

Natriuretic peptide pathways in heart failure - PubMed Central This section will focus on the data emphasizing their beneficial effects in the heart and microcirculation. 3.1. ANP counter-regulates the adverse ...