LCZ696 for Heart Failure

Overseen By Lynne W. Stevenson, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Vanderbilt University Medical Center

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

46 Participants Needed

Trial Summary

What is the purpose of this trial?

LCZ696, a molecular complex of the angiotensin receptor blocker (ARB) valsartan with an inhibitor of neprilysin (NEP, neutral endopeptidase-24.11) sacubitril improved mortality compared to enalapril in patients with heart failure (HF), reduced ejection fraction (EF), and increased brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) in the PARADIGM-HF trial.1 The PIONEER-HF study demonstrated the efficacy of LCZ696 in preventing rehospitalization in patients with acutely decompensated HF.2 LCZ696 has been underutilized in heart failure, in part due to concerns about hypotension. NEP degrades several vasodilator peptides including bradykinin, substance P and brain-type natriuretic peptide. Decreased degradation of endogenous bradykinin could contribute to hypotension at initiation of LCZ696 through vasodilation or through increased natriuresis and diuresis. Inhibition of the bradykinin B2 receptor using icatibant would be expected to prevent this effect. Objectives The main objectives of this mechanistic randomized, double-blind, crossover-design study are: * The primary objective is to test the hypothesis that endogenous bradykinin contributes to effects of ARB/NEP inhibition on blood pressure, natriuresis, and diuresis at initiation. * The secondary objective is to test the hypothesis endogenous bradykinin contributes to effects of ARB/NEP inhibition on blood pressure, natriuresis, and diuresis after up-titration. Eighty (80) subjects with stable heart failure who meet all inclusion/exclusion criteria will be enrolled. Subjects who qualify will collect their urine for 24 hours before each study day for measurement of volume, sodium and potassium. At the start of the study, they will stop their regular angiotensin-converting enzyme (ACE) inhibitor or ARB. After a 48-hour washout, they will undergo a study day in which they are given a single dose of 50 mg LCZ696. They will also receive either the bradykinin B2 receptor antagonist icatibant or placebo vehicle in random order (double-blind). After a 96-hour washout, they will repeat the study day and receive a single dose of 50 mg LCZ696 and the opposite study drug (icatibant or placebo). After completion of the two acute study days, subjects will take LCZ696 50 mg bid for two weeks, followed by LCZ696 100 mg bid for three weeks, and then LCZ696 200 mg bid, following the conservative up-titration protocol from the TITRATION study.3 Criteria for continuing up-titration appear in the full study protocol. On the 7th and 10th day of the 200 mg bid or highest tolerated dose, subjects will again undergo two more study days three days apart in which they are randomized to receive either icatibant or vehicle.

Will I have to stop taking my current medications?

Yes, you will need to stop taking your regular angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) before starting the trial. There is a 48-hour period without these medications before you begin the study.

Will I have to stop taking my current medications?

Yes, you will need to stop taking your regular angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) before starting the trial. There is a 48-hour period without these medications before you begin the study.

What data supports the effectiveness of the drug LCZ696 (Sacubitril/Valsartan) for heart failure?

Research shows that LCZ696 (Sacubitril/Valsartan) is effective in treating heart failure with reduced ejection fraction, as it significantly reduces the risk of death from heart-related causes and hospitalizations compared to another heart failure drug, enalapril. It also helps in controlling blood pressure in patients with heart failure. ^{1 2 3 4 5}

What data supports the effectiveness of the drug LCZ696 (Sacubitril/Valsartan) for heart failure?

Research shows that LCZ696 (Sacubitril/Valsartan) is effective in treating heart failure with reduced ejection fraction, as it significantly reduces the risk of death from heart-related causes and hospitalizations compared to another heart failure drug, enalapril. It also helps in controlling blood pressure in patients with hypertension. ^{1 2 3 4 5}

What makes the drug LCZ696 unique for treating heart failure?

LCZ696 (sacubitril/valsartan) is unique because it combines two actions: it blocks the angiotensin receptor, which helps relax blood vessels, and inhibits neprilysin, an enzyme that breaks down natural substances that open blood vessels. This dual action makes it more effective in reducing blood pressure and improving heart function compared to traditional treatments. ^{2 3 5 6 7}

What makes the drug LCZ696 unique for treating heart failure?

LCZ696 (sacubitril/valsartan) is unique because it combines two actions: it blocks a hormone that narrows blood vessels and breaks down a protein that helps widen them, making it effective for heart failure with both preserved and reduced ejection fraction. ^{2 3 5 6 7}

Research Team

Nancy J. Brown, M.D.

Principal Investigator

Vanderbilt University Medical Center

Eligibility Criteria

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.

Inclusion Criteria

I have been on a stable dose of ACEi or ARB and a beta blocker for at least 4 weeks.

I am a woman who is either postmenopausal, sterilized, or if able to have children, I use birth control and agree to regular pregnancy tests.

I have heart failure and have been on a stable heart medication for 4 weeks, unless it was not suitable for my kidney function or potassium levels.

Exclusion Criteria

I understand the details and risks of the study.

I have had severe heart failure in the last 3 months.

I have low blood pressure or symptoms of it.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Washout and Initial Dosing

Participants undergo a 48-hour washout period, followed by a study day with a single dose of 50 mg LCZ696 and either icatibant or placebo.

1 week

2 visits (in-person)

Crossover Dosing

After a 96-hour washout, participants repeat the study day with a single dose of 50 mg LCZ696 and the opposite study drug (icatibant or placebo).

1 week

2 visits (in-person)

Up-titration

Participants undergo up-titration of LCZ696 over seven weeks, starting with 50 mg bid for two weeks, followed by 100 mg bid for three weeks, and then 200 mg bid.

7 weeks

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including measurements of mean arterial pressure, urine sodium excretion, and other parameters.

4 weeks

Treatment Details

Interventions

• Icatibant
• LCZ 696
• Placebo

Trial Overview 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.

Participant Groups

Group I: placebo, icatibant, placebo, icatibant Experimental Treatment 5 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, placebo Experimental Treatment 5 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 icatibant and placebo, respectively.

Group III: icatibant, placebo, placebo, icatibant Experimental Treatment 5 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 placebo Experimental Treatment 5 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 icatibant and placebo, respectively.

LCZ 696 is already approved in United States, European Union for the following indications:

Approved in United States as Entresto for:

• Heart failure with reduced ejection fraction (NYHA Class II-IV)

Approved in European Union as Entresto for:

• Heart failure with reduced ejection fraction (NYHA Class II-IV)

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Findings from Research

In the PARADIGM-HF trial, sacubitril/valsartan significantly reduced the risk of death from cardiovascular causes or hospitalization for worsening heart failure compared to the ACE inhibitor enalapril, demonstrating its efficacy in treating chronic heart failure with reduced ejection fraction (HFrEF).

Sacubitril/valsartan was generally well tolerated, with no increase in life-threatening adverse events, although it did have a higher incidence of symptomatic hypotension compared to enalapril, indicating it is a safer and more effective alternative for managing HFrEF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/Valsartan: A Review in Chronic Heart Failure with Reduced Ejection Fraction. McCormack, PL.[2021]

Sacubitril/valsartan (Entresto) is a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi) that has shown efficacy in treating heart failure in patients with both preserved (HFpEF) and reduced ejection fraction (HFrEF).

Recent studies have further supported the effectiveness of this combination drug in managing heart failure, highlighting its potential as a significant treatment option for patients with varying types of heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin receptor-neprilysin inhibitor (ARNi): Clinical studies on a new class of drugs. Gori, M., Volterrani, M., Piepoli, M., et al.[2021]

LCZ696 (sacubitril/valsartan) significantly reduces both systolic and diastolic blood pressure in patients with hypertension, with a total of 6,064 participants analyzed across 12 randomized controlled trials.

The antihypertensive effect of LCZ696 is dose-dependent, with higher doses (200 mg and 400 mg) leading to greater reductions in blood pressure compared to lower doses and angiotensin receptor blockers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of LCZ696 (Sacubitril/Valsartan) on Blood Pressure in Patients with Hypertension: A Meta-Analysis of Randomized Controlled Trials. Geng, Q., Yan, R., Wang, Z., et al.[2021]

Sacubitril, a component of the heart failure treatment sacubitril/valsartan, was found to inhibit the transporters OATP1B1 and OATP1B3 in vitro, but this inhibition did not lead to significant changes in the pharmacokinetics of simvastatin in healthy subjects.

In a clinical study with 26 participants, co-administration of simvastatin with LCZ696 showed only minor decreases in the maximum concentration (Cmax) of simvastatin and its active metabolite, indicating that the combination is generally safe and well tolerated without clinically relevant interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro and clinical evaluation of OATP-mediated drug interaction potential of sacubitril/valsartan (LCZ696). Ayalasomayajula, S., Han, Y., Langenickel, T., et al.[2021]

Sacubitril/valsartan (LCZ696) has been shown to be an effective and safe treatment for hypertension, outperforming angiotensin receptor blockers (ARBs) in reducing both systolic and diastolic blood pressure across various dosages in a meta-analysis of 11 randomized controlled trials involving 6028 participants.

The study found that LCZ696 significantly reduced systolic blood pressure by up to 5.50 mm Hg and diastolic blood pressure by up to 2.51 mm Hg compared to ARBs, with no significant increase in adverse effects, indicating its potential as a superior option for managing high blood pressure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Sacubitril/Valsartan in Hypertension. Malik, AH., Aronow, WS.[2022]

In a study involving rats, LCZ696 (sacubitril/valsartan) significantly improved cardiac function and reduced myocardial injury caused by acute heart failure, indicating its potential as a protective treatment.

LCZ696 works by alleviating oxidative stress and activating the Nrf2 signaling pathway, which helps protect heart tissue from damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LCZ696 Ameliorates Isoproterenol-Induced Acute Heart Failure in Rats by Activating the Nrf2 Signaling Pathway. Hou, M., Lu, L., Wu, X., et al.[2023]

LCZ696 (sacubitril/valsartan) was found to be safe and well tolerated in a study involving 50 healthy Japanese male subjects, with single oral doses of up to 600 mg showing no significant safety concerns.

The pharmacokinetics of LCZ696 demonstrated a dose-linear increase in exposure to its active components, with food intake affecting the absorption of the drug, particularly reducing the maximum concentration (C max) of sacubitril by 72%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics After Single Ascending Dose, Food Effect, and Safety of Sacubitril/Valsartan (LCZ696), an Angiotensin Receptor and Neprilysin Inhibitor, in Healthy Japanese Subjects. Akahori, M., Ayalasomayajula, S., Langenickel, T., et al.[2022]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Sacubitril/Valsartan: A Review in Chronic Heart Failure with Reduced Ejection Fraction. [2021]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Angiotensin receptor-neprilysin inhibitor (ARNi): Clinical studies on a new class of drugs. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Effects of LCZ696 (Sacubitril/Valsartan) on Blood Pressure in Patients with Hypertension: A Meta-Analysis of Randomized Controlled Trials. [2021]

4. England pubmed.ncbi.nlm.nih.gov

In vitro and clinical evaluation of OATP-mediated drug interaction potential of sacubitril/valsartan (LCZ696). [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Efficacy of Sacubitril/Valsartan in Hypertension. [2022]

6. Egypt pubmed.ncbi.nlm.nih.gov

LCZ696 Ameliorates Isoproterenol-Induced Acute Heart Failure in Rats by Activating the Nrf2 Signaling Pathway. [2023]

7. France pubmed.ncbi.nlm.nih.gov

Pharmacokinetics After Single Ascending Dose, Food Effect, and Safety of Sacubitril/Valsartan (LCZ696), an Angiotensin Receptor and Neprilysin Inhibitor, in Healthy Japanese Subjects. [2022]