Entresto + Aprepitant for Heart Failure

Overseen By Christopher Maulion, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Yale University

Must be taking: ACE inhibitors, ARBs, Beta blockers, MR antagonists

Must not be taking: DPP-4 inhibitors, Lithium, Glucocorticoids

Disqualifiers: Angioedema, Heart transplant, Type 1 diabetes, Poorly controlled T2DM, 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

80 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial evaluates the effectiveness of combining two drugs, Entresto (LCZ696) and aprepitant (an anti-nausea medication), for people with heart failure. Heart failure occurs when the heart doesn't pump blood effectively, and the trial examines whether adding aprepitant to Entresto enhances treatment. Participants will receive different combinations of these drugs in a crossover setup to compare effects. Suitable candidates have been diagnosed with heart failure and have stable symptoms without recent hospital visits. 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?

The trial does not specify if you need to stop taking your current medications, but it requires that you are on a stable dose of certain heart medications like ACE inhibitors, ARBs, and beta blockers for at least four weeks. If you are taking a dipeptidyl peptidase-4 inhibitor for type 2 diabetes, you will need to stop it one month before joining the trial.

What is the safety track record for these treatments?

Research has shown that aprepitant, a medication often used to prevent nausea from chemotherapy, is generally safe. Studies indicate that people taking aprepitant do not experience more heart problems than those who do not take it. It is also considered safe for preventing nausea after surgery.

Entresto, also known as LCZ696, has been well-researched for treating heart failure. Evidence shows it reduces the risk of death and hospital visits due to heart failure compared to other common treatments, suggesting it is safe and effective for people with heart issues.

Both treatments have strong safety records. Previous studies provide confidence in their use for human health. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about combining Entresto (LCZ696) with aprepitant for heart failure because it offers a fresh approach to managing the condition. Most heart failure treatments focus on reducing fluid retention or improving heart function through well-known mechanisms like ACE inhibitors or beta-blockers. However, Entresto combines a neprilysin inhibitor with an angiotensin receptor blocker, which can enhance heart efficiency and reduce stress on the heart in a novel way. Aprepitant, typically used for preventing nausea, may offer additional benefits when paired with Entresto by potentially improving patient tolerance and outcomes. This innovative combination could lead to faster relief and better long-term management of heart failure symptoms.

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

Research has shown that Entresto, also known as LCZ696, effectively treats heart failure with reduced ejection fraction (HFrEF). It can lower the risk of death from heart-related issues and reduce hospital visits due to heart failure by about 20% compared to other treatments. Entresto also decreases the likelihood of needing to return to the hospital after experiencing heart failure. In this trial, participants will receive Entresto combined with either aprepitant or a placebo. Aprepitant is primarily used to prevent nausea after surgery or chemotherapy. While not specifically for heart failure, it is safe and effective for its intended purposes. This trial will explore the effects of combining Entresto with aprepitant or placebo in managing heart failure. ^{3 4 6 7 8}

Who Is on the Research Team?

Nancy J. Brown, MD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

This trial is for black and white men and women, aged 18 or older, with heart failure (NYHA Class I-III) and an ejection fraction (EF) ≤55%. Participants must have stable symptoms, no recent hospitalizations for heart failure, not be on LCZ696 currently, and if female and of childbearing potential, use reliable contraception. Excluded are those with allergies to study drugs or related chemicals, history of angioedema or certain cardiovascular events within the last six months.

Inclusion Criteria

My heart's pumping ability is reduced, and I've had mild to moderate heart failure symptoms.

I am a woman who is either postmenopausal, sterilized, using birth control, or willing to undergo pregnancy tests.

I have heart failure and have been on a stable heart medication for 4 weeks, unless I had bad reactions or kidney issues.

Exclusion Criteria

I have Type 1 diabetes.

I have had fainting spells due to irregular heartbeats.

You have had a heart transplant, or are on a transplant list, or have a left ventricular assistance device.

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 single dose of 50 mg LCZ696 with either aprepitant or placebo, then a 96-hour washout and repeat dosing with the opposite study drug.

1 week

2 study days (in-person)

Up-titration

Participants undergo up-titration of LCZ696 over seven weeks, starting with 50 mg bid for two weeks, then 100 mg bid for three weeks, and finally 200 mg bid or the highest tolerated dose.

7 weeks

Steady-State Evaluation

On the 7th and 10th days of the 200 mg bid or highest tolerated dose, participants undergo two more study days three days apart, receiving either aprepitant or placebo.

1 week

2 study days (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Aprepitant
• LCZ 696
• Placebo

Trial Overview The trial tests how blood pressure responds to a combination of Aprepitant vs Placebo during initiation and steady-state doses of Entresto (LCZ696). It's a double-blind study where participants randomly receive either the drug or placebo in two phases: starting dose (50 mg) and maintenance dose (200 mg bid or highest tolerated).

How Is the Trial Designed?

Group I: placebo, aprepitant, placebo, aprepitant 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 aprepitant. 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 aprepitant, respectively.

Group II: placebo, aprepitant, aprepitant, 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 aprepitant. 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 aprepitant and placebo, respectively.

Group III: aprepitant, placebo, placebo, aprepitant Experimental Treatment 5 Interventions

After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and aprepitant. 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 aprepitant, respectively.

Group IV: aprepitant, placebo, aprepitant, placebo Experimental Treatment 5 Interventions

After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and aprepitant. 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 aprepitant 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?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Published Research Related to This Trial

Sacubitril/valsartan (Entresto) significantly reduces the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure and reduced ejection fraction, outperforming enalapril in clinical studies.

While effective, sacubitril/valsartan can cause side effects such as low blood pressure, angioedema, and impaired kidney function, and it is contraindicated in pregnant or breastfeeding women and patients with severe liver impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Angiotensin-receptor- and neprilysin-inhibition: a new option against heart failure]. Bruhn, C.[2021]

In a study of 224 patients with heart failure and reduced ejection fraction, approximately 38.4% were eligible for sacubitril/valsartan treatment after being on optimized guideline-directed medical therapy.

The analysis revealed that many patients remained symptomatic despite optimal treatment, highlighting the potential need for additional therapies like sacubitril/valsartan in managing chronic heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-Life Indications to Sacubitril/Valsartan Treatment in Patients With Chronic Systolic Heart Failure. Pinto, G., Tondi, L., Gemma, M., et al.[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]

Sacubitril/valsartan (Entresto®) is the first angiotensin receptor neprilysin inhibitor (ARNI) approved for heart failure patients with reduced ejection fraction, combining a neprilysin inhibitor and an angiotensin II receptor blocker.

A case report highlighted a probable instance of ARNI-induced hyponatremia in an elderly woman, suggesting a likely association between the drug and her low sodium levels, as assessed by the Naranjo Adverse Drug Reaction Assessment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/Valsartan (Entresto®)-Induced Hyponatremia. Fuzaylova, I., Lam, C., Talreja, O., et al.[2021]

Sacubitril/valsartan (Entresto) is a newly FDA-approved medication that effectively reduces mortality and hospitalization in patients with systolic heart failure, offering a promising alternative to traditional ACE inhibitors.

Unlike previous treatments like omapatrilat, sacubitril selectively inhibits neprilysin without affecting other pathways that can cause side effects like angioedema, thus maintaining a similar safety profile while improving clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neprilysin inhibition with sacubitril/valsartan in the treatment of heart failure: mortality bang for your buck. Ansara, AJ., Kolanczyk, DM., Koehler, JM.[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]

In a study using Sprague-Dawley rats with heart failure induced by myocardial infarction, LCZ696 (valsartan/sacubitril) therapy significantly improved left ventricular ejection fraction (LVEF) and reduced the inducibility of ventricular arrhythmias compared to a vehicle treatment.

Unlike enalapril, LCZ696 therapy also upregulated the expression of key potassium channel proteins (ERG, KCNE1, and KCNE2), suggesting a beneficial effect on cardiac electrophysiology in heart failure models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LCZ696 Therapy Reduces Ventricular Tachyarrhythmia Inducibility in a Myocardial Infarction-Induced Heart Failure Rat Model. Chang, PC., Lin, SF., Chu, Y., et al.[2022]

Citations

1. frontiersin.org frontiersin.org/journals/anesthesiology/articles/10.3389/fanes.2023.1190383/full

Effects of aprepitant on post-operative nausea and ... Aprepitant, a neurokinin-1 (NK-1) receptor blocker, is safe and effective at preventing PONV resistant to standard therapies.

2. researchgate.net researchgate.net/publication/373781516_Effects_of_aprepitant_on_post-operative_nausea_and_vomiting_in_patients_with_congenital_heart_disease_undergoing_cardiac_surgery_or_catheterization_procedures_a_retrospective_study_with_subjects_as_th

(PDF) Effects of aprepitant on post-operative nausea and ... For surgical patients, there were significant decreases in PONV-related complications including delayed oral intake and delayed ambulation ( p = ...

3. ema.europa.eu ema.europa.eu/en/documents/scientific-discussion-variation/emend-h-c-527-ii-0014-epar-scientific-discussion-variation_en.pdf

Emend, INN-aprepitant - EMA A reasonable interpretation of the overall results would be that aprepitant is at least as effective as ondansetron for the prophylaxis of PONV. With ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2589537022002103

Aprepitant plus palonosetron versus dexamethasone ... our results showed the combination of aprepitant with palonosetron significantly improves antiemetic efficiency ... heart failure or acute myocardial ...

5. academic.oup.com academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djaf178/8196554

Aprepitant use during chemotherapy and association with ... Little is known about how aprepitant use could impact long-term survival outcomes in women with breast cancer. Here, we examine whether aprepitant use as an ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3335187/

Cardiovascular Events in Cancer Patients Treated with ... Aprepitant users generally did not experience higher frequencies of events compared to nonusers. Our study serves as a useful benchmark of ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6503333/

Crossover safety study of aprepitant: 2-min injection vs 30-min ... Treatment-emergent adverse events (TEAEs) were assessed at 0–30 (primary endpoint), 30–60, and >60 mins (chemotherapy administration period) ...

8. fda.gov fda.gov/files/advisory%20committees/published/Emend-%28aprepitant%29-Capsule-and-Oral-Suspension-Pediatric-Postmarketing-Pharmacovigilance-Review.pdf

Emend-(aprepitant)-Capsule-and-Oral-Suspension- ... There is no evidence from these data that there are pediatric safety concerns with aprepitant capsules or oral suspension at this time. 5 ...