What side effects are associated with this type of intervention?

Common treatments for heart failure, such as Sacubatril/Valsartan (a combination of neprilysin inhibition and angiotensin II receptor blockade), can lead to side effects including hyperkalemia, hypotension, renal impairment, and angioedema. MANP, which promotes natriuresis, diuresis, and vasodilation, may cause side effects like electrolyte imbalances, dehydration, and hypotension. Both treatments aim to manage heart failure symptoms but require careful monitoring to mitigate these potential adverse effects.

What prior FDA approvals exist?

Sacubatril/Valsartan (Entresto) is a notable FDA-approved treatment for heart failure that combines neprilysin inhibition and angiotensin II receptor blockade to enhance natriuretic peptides and reduce the effects of angiotensin II, respectively. This dual mechanism helps in reducing blood pressure, promoting natriuresis, and improving heart function. Other FDA-approved drugs for heart failure include ACE inhibitors like enalapril and ARBs like valsartan, which primarily focus on blocking the renin-angiotensin system. While MANP is still under investigation, its focus on natriuresis, diuresis, and vasodilation aligns with the therapeutic goals of diuretics and vasodilators, which are commonly used in heart failure management.

What other types of research exist?

Promising novel alternatives for heart failure treatment in 2024 include SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin), which have shown benefits in heart failure patients with and without diabetes by reducing hospitalizations and improving cardiovascular outcomes. Additionally, Vericiguat, a soluble guanylate cyclase stimulator, has demonstrated efficacy in reducing heart failure-related hospitalizations and cardiovascular death in patients with worsening heart failure. These alternatives offer different mechanisms of action and can be considered based on individual patient profiles and treatment goals.

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Natriuretic Peptide System Enhancer

MANP + Sacubitril/Valsartan for Heart Failure

Phase 1 & 2

Waitlist Available

Led By Paul M McKie

Research Sponsored by Horng Chen

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Exclusion of subjects with Diabetes or BMI>35 (because endogenous natriuretic peptide levels are low in obese subjects)

Previous diagnosis of HF with New York Heart Association (NYHA) functional class II-III symptoms on chronic diuretic therapy

Must not have

Constrictive pericarditis

Sarcoidosis

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 24 hours

Summary

This trial tests two drugs, Sacubatril/Valsartan and MANP, in people with a challenging type of heart failure and kidney disease. Sacubatril/Valsartan helps relax blood vessels, while MANP may help the heart and kidneys by removing extra salt and water. The goal is to see if these treatments can improve symptoms and heart function.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Possible side effects include changes in blood pressure, kidney function alterations, electrolyte imbalances like low sodium or potassium levels, dizziness due to low blood pressure, allergic reactions if sensitive to ingredients such as iodine.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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

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

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

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

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I have moderate heart condition symptoms.

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My kidney function, measured by eGFR, is between 15-80 mL/min/1.73m^2.

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My heart pumps well and has normal pressure readings.

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I have heart failure with preserved ejection fraction and kidney disease, with an ejection fraction of 55% or higher.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have been diagnosed with constrictive pericarditis.

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I have been diagnosed with sarcoidosis.

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I have not had a stroke or significant brain blood flow issues in the last 3 months.

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I have a serious heart valve condition.

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I have a type of heart disease that thickens my heart muscle.

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I have been diagnosed with active inflammation of the heart muscle.

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I have Fabry disease.

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I was born with a serious heart condition.

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I have diabetes.

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I have been diagnosed with cardiac amyloidosis.

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I am currently pregnant or breastfeeding.

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I have high blood pressure in the lungs.

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I have not had unstable chest pain or signs of heart issues in the last 6 months.

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I have had a heart attack in the last 6 months.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 24 hours

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~24 hours

This trial's timeline: 3 weeks for screening, Varies for treatment, and 24 hours for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Change in Composite Score of cGMP, sodium excretion, GFR, and Anx-A1 Plasma cGMP, urinary cGMP, urinary sodium excretion, GFR, ANX-A1acute VE with MANP

Body Weight Changes

Secondary study objectives

Change in Plasma NT-pro BNP

Change in Plasma cGMP

Trial Design

6Treatment groups

Experimental Treatment

Placebo Group

Group I: HFpEF-EI with Sacbitril/Valsartan with an injected placeboExperimental Treatment2 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 placeboExperimental Treatment2 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 placeboExperimental Treatment2 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 placeboExperimental Treatment2 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 placeboPlacebo Group2 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 placeboPlacebo Group2 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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Injection Placebo

2020

Completed Phase 2

~250

MANP

2017

Completed Phase 1

~60

Sacubitril/Valsartan

2018

Completed Phase 4

~8060

Oral Placebo

2017

Completed Phase 4

~4590

0 / 22Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for Heart Failure (HF) like Sacubatril/Valsartan and MANP work by enhancing natriuresis, diuresis, and vasodilation. Sacubatril/Valsartan combines neprilysin inhibition, which increases natriuretic peptides, and angiotensin II receptor blockade, which prevents vasoconstriction and cardiac remodeling. MANP also promotes natriuresis, diuresis, and vasodilation. These mechanisms help reduce fluid overload, lower blood pressure, and improve cardiac function, which are essential for managing HF symptoms and reducing hospitalizations and mortality.