80 Participants Needed

Entresto + Aprepitant for Heart Failure

CM
Overseen ByChristopher Maulion, MD
Age: 18+
Sex: Any
Trial Phase: Phase 4
Sponsor: Yale University
Must be taking: ACE inhibitors, ARBs, Beta blockers, MR antagonists
No Placebo GroupAll trial participants will receive the active study treatment (no placebo)
Prior Safety DataThis treatment has passed at least one previous human trial
Approved in 2 JurisdictionsThis treatment is already approved in other countries

Trial Summary

What is the purpose of this trial?

This is a double-blind, randomized, two x two crossover (aprepitant vs placebo) during both initiation of Entresto, LCZ696, (50 mg dose) and at steady-state of Entresto (200 mg bid dose or the highest tolerated dose).

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 data supports the effectiveness of the drug Entresto (sacubitril/valsartan) for heart failure?

Research shows that Entresto, a combination of sacubitril and valsartan, is effective in reducing the risk of cardiovascular death and hospitalization in patients with chronic heart failure. It has been found to be superior to enalapril, another heart failure medication, in reducing these risks.12345

Is the combination of Entresto and Aprepitant safe for humans?

Entresto (sacubitril/valsartan) has been studied for heart failure and is generally safe, but it can cause side effects like low blood pressure, swelling, kidney problems, and high potassium levels. It should not be used during pregnancy, breastfeeding, or with certain other medications in people with diabetes. There is no specific safety data available for the combination with Aprepitant.12467

What makes the drug Entresto unique for treating heart failure?

Entresto is unique because it combines two actions: it blocks angiotensin II receptors and inhibits neprilysin, which helps reduce the risk of cardiovascular death and hospitalization in heart failure patients. This dual action makes it more effective than some traditional treatments like enalapril.13456

Research Team

NJ

Nancy J. Brown, MD

Principal Investigator

Yale University

Eligibility Criteria

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.
See 7 more

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.
See 30 more

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 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

Treatment Details

Interventions

  • Aprepitant
  • LCZ 696
  • Placebo
Trial OverviewThe 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).
Participant Groups
4Treatment groups
Experimental Treatment
Group I: placebo, aprepitant, placebo, aprepitantExperimental 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 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, placeboExperimental 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 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, aprepitantExperimental Treatment5 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, placeboExperimental Treatment5 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)

Find a Clinic Near You

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials
1,963
Recruited
3,046,000+

Findings from Research

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.
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.
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 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.
Real-Life Indications to Sacubitril/Valsartan Treatment in Patients With Chronic Systolic Heart Failure.Pinto, G., Tondi, L., Gemma, M., et al.[2021]

References

Angiotensin receptor-neprilysin inhibitor (ARNi): Clinical studies on a new class of drugs. [2021]
Effects of LCZ696 (Sacubitril/Valsartan) on Blood Pressure in Patients with Hypertension: A Meta-Analysis of Randomized Controlled Trials. [2021]
Real-Life Indications to Sacubitril/Valsartan Treatment in Patients With Chronic Systolic Heart Failure. [2021]
[Angiotensin-receptor- and neprilysin-inhibition: a new option against heart failure]. [2021]
Neprilysin inhibition with sacubitril/valsartan in the treatment of heart failure: mortality bang for your buck. [2021]
Sacubitril/Valsartan (Entresto®)-Induced Hyponatremia. [2021]
LCZ696 Therapy Reduces Ventricular Tachyarrhythmia Inducibility in a Myocardial Infarction-Induced Heart Failure Rat Model. [2022]