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Angiotensin Receptor Blocker/Neprilysin Inhibitor

LCZ696 for Heart Failure

Phase 4

Recruiting

Led By Nancy J. Brown, M.D.

Research Sponsored by Vanderbilt University Medical Center

Eligibility Criteria Checklist

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

Must have

Stable patients with a reduced ejection fraction (EF) ≤40%

History of symptoms of New York Heart Association (NYHA) class I, II, or III heart failure (HF)

Must not have

Mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study

Symptomatic hypotension and/or a systolic blood pressure (SBP)<100 mmHg at screening or <95 mmHg during the study

Timeline

Screening 3 weeks

Treatment Varies

Follow Up over six hours on each of four study days

Awards & highlights

Drug Has Already Been Approved

Pivotal Trial

Summary

This trial is testing the hypothesis that the effects of LCZ696 on blood pressure, natriuresis, and diuresis at initiation are due to the inhibition of neprilysin, which degrades endogenous bradykinin. The study will enroll 80 subjects with stable heart failure who will be given LCZ696 50 mg and either the bradykinin B2 receptor antagonist icatibant or placebo vehicle in random order (double-blind).

Who is the study for?

This trial is for stable heart failure patients with reduced ejection fraction (EF ≤40%), not hospitalized in the last six months, and on a stable dose of ACEi or ARB and beta blocker. It includes both men and women who are either postmenopausal, surgically sterilized, or using reliable birth control if of childbearing potential.

What is being tested?

The study tests LCZ696's effects on blood pressure, natriuresis (sodium excretion), and diuresis (urine production) in heart failure patients. It involves stopping current ACEi/ARB medication, taking LCZ696 with placebo or icatibant (a bradykinin B2 receptor antagonist), followed by an up-titration protocol to assess changes.

What are the potential side effects?

Potential side effects may include hypotension due to vasodilation from increased bradykinin levels when starting LCZ696. Other risks involve reactions to contrast agents used during testing, as well as general drug-related allergies or sensitivities.

Eligibility Criteria

Inclusion Criteria

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

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My heart pumps less blood than normal but my condition is stable.

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I have experienced symptoms of heart failure but can still perform daily activities.

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I haven't been hospitalized in the last 6 months.

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I am not currently taking LCZ696.

Exclusion Criteria

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

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I understand the details and risks of the study.

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I have low blood pressure or symptoms of it.

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I have not taken long-term steroid pills in the past year.

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I am currently taking lithium.

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I have had fainting spells due to irregular heartbeats.

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I have a significant blockage in the heart's outflow tract.

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I have a slow heartbeat or heart block without a pacemaker.

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I might need heart or neck artery surgery within the next 6 months.

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My type 2 diabetes is not well-managed, with a HgbA1c over 9%.

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I am not allergic to the study drugs or similar medications.

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I have had pancreatitis or have known pancreatic lesions.

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I have a history of immune or blood disorders.

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I use my asthma inhaler more than once a week.

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I have had a serious brain condition like a stroke or seizure.

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I have a history of cancer, except for non-dangerous skin cancer.

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I have Type 1 diabetes.

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My liver tests (AST or ALT) are more than three times the normal range.

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My kidney function is significantly reduced.

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I have a digestive issue that affects how my body absorbs medication.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ over six hours on each of four study days

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~over six hours on each of four study days

This trial's timeline: 3 weeks for screening, Varies for treatment, and over six hours on each of four study days for reporting.

Treatment Details

Study Objectives

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

Primary study objectives

Urine sodium excretion

mean arterial pressure

Secondary study objectives

Glomerular filtration rate

Heart rate

Renal plasma flow

+2 more

Awards & Highlights

Drug Has Already Been Approved

The FDA has already approved this drug, and is just seeking more data.

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

4Treatment groups

Experimental Treatment

Group I: placebo, icatibant, placebo, icatibantExperimental Treatment5 Interventions

After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and icatibant. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive placebo and icatibant, respectively.

Group II: placebo, icatibant, icatibant, placeboExperimental Treatment5 Interventions

Group III: icatibant, placebo, placebo, icatibantExperimental Treatment5 Interventions

After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and icatibant. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive placebo and icatibant, respectively.

Group IV: icatibant, placebo, icatibant placeboExperimental Treatment5 Interventions

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

placebo

2010

Completed Phase 4

~6580

LCZ 696

2018

N/A