LCZ696 for Heart Failure

Overseen By Lynne W. Stevenson, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Vanderbilt University Medical Center

Must be taking: Ace inhibitors, Arbs, Beta blockers

Must not be taking: Lithium, Dipeptidyl peptidase-4 inhibitors

Disqualifiers: Angioedema, Hypotension, Renal impairment, Diabetes, others

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called LCZ696 (also known as Entresto, a medication for heart failure) for individuals with stable heart failure and a reduced ejection fraction. Researchers aim to determine if adding icatibant can help manage blood pressure effects when starting LCZ696. Participants will alternate between receiving LCZ696 with either icatibant or a placebo (a substance with no therapeutic effect) to compare results. The trial seeks individuals with heart failure symptoms who have not been hospitalized in the last six months and are not currently taking LCZ696. As a Phase 4 trial, this research aims to understand how the already FDA-approved and effective treatment benefits more patients.

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 is the safety track record for these treatments?

Research has shown that LCZ696, also known as Entresto, is as safe as other heart medications like ACE inhibitors and ARBs. Studies have found it to be generally well-tolerated in people with heart failure. Some individuals might experience low blood pressure, especially when starting the treatment, but overall, the benefits outweigh the risks.

For icatibant, safety data from many patients over several years suggest it is generally well-tolerated as well. It has been used safely in various dosing situations. However, individuals with certain heart conditions, such as unstable angina (chest pain), should exercise caution.

Both treatments have undergone extensive study, providing a good understanding of their safety. Those considering joining a trial involving these treatments can find reassurance in this information. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

LCZ696, also known as sacubitril/valsartan, is unique because it combines two active ingredients that work together to treat heart failure in an innovative way. Unlike traditional treatments like ACE inhibitors or beta-blockers, LCZ696 not only blocks harmful hormones but also boosts beneficial ones, helping the heart work more efficiently. Researchers are excited about LCZ696 because it has been shown to reduce the risk of hospitalization and improve survival rates for heart failure patients more effectively than some existing treatments. This dual-action approach offers a new hope for those struggling with heart failure, potentially leading to better outcomes and improved quality of life.

What is the effectiveness track record for LCZ696 in treating heart failure?

Studies have shown that LCZ696, a combination of sacubitril and valsartan, effectively treats heart failure with reduced ejection fraction (HFrEF). In a major study, LCZ696 reduced the risk of death from heart issues or the need for hospital visits by 20% compared to enalapril, a common heart failure medication. Another study confirmed that it also lowers the chance of readmission for heart failure. The drug blocks certain enzymes, helping to keep blood vessels relaxed and improving heart function. This treatment has proven effective in clinical settings and is already approved for heart failure. In this trial, participants will receive LCZ696 combined with either icatibant or a placebo, depending on their assigned treatment arm. ^{6 7 8 9 10}

Who Is on the Research Team?

Nancy J. Brown, M.D.

Principal Investigator

Vanderbilt University Medical Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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/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]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC3467996/

An evidence-based review of the potential role of icatibant ...

Results demonstrated that icatibant was effective in the treatment of attacks. Time to 50% reduction in symptom severity was 2 hours with icatibant versus 19.8 ...

2.

clinicaltrials.gov

clinicaltrials.gov/study/NCT01034969?term=AREA%5BBasicSearch%5D(Icatibant)&rank=2

Firazyr® Patient Registry (Icatibant Outcome Survey - IOS)

Icatibant Outcome Survey (IOS) is a prospective, observational disease registry designed to document the routine clinical outcomes over time in participants ...

3.

clinicaltrials.takeda.com

clinicaltrials.takeda.com/study-detail/5f6b5fcf4db2bf003ab4684f

Firazyr® Patient Registry (Icatibant Outcome Survey - IOS)

The Icatibant Outcome Survey (IOS) is a prospective, observational disease registry designed to document the routine clinical outcomes over time in ...

4.

pei.de

pei.de/SharedDocs/Downloads/DE/awb/nis-0401-0500/0426-abschlussb.pdf?__blob=publicationFile&v=1

Icatibant Outcome Survey (IOS) Registry Study number

Stratification of the data for analysis of effectiveness included, but was not limited to, attack severity, anatomical location of the ...

5.

cda-amc.ca

cda-amc.ca/sites/default/files/cdr/clinical/SR0375_Firazyr_CL_Report.pdf

CDR Clinical Review Report for Firazyr

Two randomized, double-blind placebo-controlled studies evaluating the efficacy and safety of subcutaneous icatibant 30 mg compared with placebo ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC5434903/

Long‐term safety of icatibant treatment of patients with ...

We analyzed safety data from 3025 icatibant‐treated attacks in 557 patients (enrolled between July 2009 and February 2015). Icatibant was generally well ...

7.

firazyr.com

firazyr.com/hcp/what-is-firazyr/safety-information

FIRAZYR® Safety Profile - Healthcare Professionals Site

The safety of FIRAZYR was evaluated in 3 controlled trials that included 223 patients who received FIRAZYR 30 mg (n=113), placebo (n=75) or comparator (n=38).

8.

accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/label/2024/022150s016lbl.pdf

FIRAZYR® (icatibant) Injection, for subcutaneous use

In this trial, the safety profile of FIRAZYR in patients who self-administered FIRAZYR was similar in nature and frequency to that of patients whose therapy ...

9.

ema.europa.eu

ema.europa.eu/en/documents/product-information/firazyr-epar-product-information_en.pdf

Firazyr, INN-icatibant - EMA

Caution should therefore be observed in the administration of Firazyr to patients with acute ischemic heart disease or unstable angina pectoris (see section ...

10.

tga.gov.au

tga.gov.au/sites/default/files/auspar-icatibant-pi.pdf

AusPAR - FIRAZYR - icatibant - Shire Australia Pty Limited

The safety of icatibant has been established in 1,273 subjects treated with various doses, regimens and routes of administration during Phase I- ...