Sacubitril-Valsartan for Heart Failure

(TREAT-HF Trial)

Overseen By Massey CTO CPC Team

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Virginia Commonwealth University

Must not be taking: ACE inhibitors, ARBs, NSAIDs, lithium

Disqualifiers: Severe kidney disease, Chronic hyperkalemia, Symptomatic heart disease, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 27 months

30 Participants Needed

Trial Summary

What is the purpose of this trial?

To determine feasibility of recruitment and tolerability of treatment with sacubitril-valsartan among adult age survivors of cancer diagnosed at or before age 39 who have stage B heart failure.

Do I need to stop taking my current medications for the trial?

Yes, you will need to stop taking certain medications, such as other ACE inhibitors, ARBs, aliskiren, NSAIDs, or lithium, to participate in the trial.

What data supports the effectiveness of the drug Sacubitril-Valsartan for heart failure?

Research shows that Sacubitril-Valsartan (Entresto) is effective in reducing the risk of death and hospitalization in patients with chronic heart failure and reduced ejection fraction, performing better than the drug enalapril. It has been studied successfully in patients with both preserved and reduced ejection fraction, making it a valuable option for managing heart failure. ^{1 2 3 4 5}

Is sacubitril-valsartan safe for humans?

Sacubitril-valsartan (Entresto) is generally safe for humans, but it can cause side effects like low blood pressure, swelling (angioedema), kidney problems, and high potassium levels. It should not be used during pregnancy, breastfeeding, or with certain other medications in people with diabetes. There have been rare reports of liver injury and low sodium levels in some patients. ^{3 5 6 7 8}

How is the drug sacubitril-valsartan unique for treating heart failure?

Sacubitril-valsartan is unique because it combines two actions: it blocks a protein that narrows blood vessels (angiotensin II receptor antagonist) and inhibits an enzyme that breaks down beneficial proteins (neprilysin inhibitor). This dual action helps relax blood vessels and reduce strain on the heart, making it different from other heart failure treatments. ^{1 2 3 9 10}

Research Team

Wendy Bottinor, MD

Principal Investigator

Virginia Commonwealth University

Eligibility Criteria

Adult cancer survivors diagnosed before age 39 with stage B heart failure can join this trial. They must have had anthracycline chemo, reduced heart function but no symptoms of heart failure, and be able to perform physical activity without severe fatigue or breathlessness. Excluded are those with chronic high potassium levels, recent COVID-19 contact, certain valve issues or severe kidney disease, pregnant women, non-English/Spanish speakers who can't consent properly, and people on conflicting medications.

Inclusion Criteria

I have received anthracycline chemotherapy before.

My medical records clearly show my diagnosis and treatment plan.

I do not experience heart failure symptoms like shortness of breath or swelling.

Exclusion Criteria

My family has a history of genetic heart muscle disease.

I am not taking, or can stop taking, ACE inhibitors, ARBs, NSAIDs, aliskiren, or lithium for the study.

I have severe kidney disease.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

24 months

Treatment

Participants receive sacubitril-valsartan or valsartan orally twice daily at a maximally tolerated dose

27 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Treatment Details

Interventions

• Sacubitril-valsartan

Trial Overview The study is testing the effects of sacubitril-valsartan versus valsartan alone in treating heart dysfunction caused by cancer therapy. It aims to see if recruiting adult cancer survivors for this treatment is possible and how well they tolerate it.

Participant Groups

Group I: Arm 2: Valsartan Experimental Treatment 1 Intervention

Valsartan administered orally twice daily at a maximally tolerate dose (max dose 160mg twice daily)

Group II: Arm 1: Sacubitril-valsartan Experimental Treatment 1 Intervention

Sacubitril-valsartan administered orally twice daily at a maximally tolerate dose (max dose 97mg/103mg twice daily).

Sacubitril-valsartan is already approved in European Union, United States for the following indications:

Approved in European Union as Entresto for:

• Heart failure with reduced ejection fraction

Approved in United States as Entresto for:

• Chronic heart failure with reduced ejection fraction

Who Is Running the Clinical Trial?

Virginia Commonwealth University

Lead Sponsor

Trials

732

Recruited

22,900,000+

Findings from Research

Sacubitril valsartan (Entresto) is an oral medication approved for treating adults with symptomatic chronic heart failure and reduced ejection fraction, combining a neprilysin inhibitor and an angiotensin II receptor antagonist to enhance heart function.

The drug's mechanism of action involves inhibiting neprilysin, which helps to increase levels of beneficial peptides that promote vasodilation and reduce heart strain, making it a significant option in heart failure management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

▼ Sacubitril valsartan for heart failure. [2021]

The PANORAMA-HF study is a large, multi-center trial designed to evaluate the pharmacokinetics and efficacy of sacubitril/valsartan in pediatric heart failure patients, involving 360 participants aged from 1 month to less than 18 years.

This study will uniquely use a global rank primary endpoint to assess treatment outcomes, comparing sacubitril/valsartan to enalapril, which could provide new insights into the effectiveness of this medication in children with heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (PANORAMA-HF study). Shaddy, R., Canter, C., Halnon, N., 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 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]

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]

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]

This case report describes the first instance of severe liver injury associated with sacubitril/valsartan (Entresto) in a 90-year-old female patient, highlighting a potential risk of hepatotoxicity despite the drug's established safety profile.

After discontinuing sacubitril/valsartan, the patient's liver function improved, suggesting that while liver injury from this medication is rare, clinicians should remain vigilant for signs of hepatotoxicity during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/valsartan-induced liver injury: A case report and literature review. Zhang, T., Cai, JL., Yu, J.[2023]

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 a study involving 84 healthy male subjects, both therapeutic (400 mg) and supratherapeutic (1200 mg) doses of sacubitril/valsartan (LCZ696) did not significantly affect cardiac repolarization, as indicated by QTcF intervals remaining within safe limits.

The study confirmed the safety of LCZ696, with no significant changes in ECG parameters or increased adverse events compared to placebo, supporting its use in patients with chronic heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single therapeutic and supratherapeutic doses of sacubitril/valsartan (LCZ696) do not affect cardiac repolarization. Langenickel, TH., Jordaan, P., Petruck, J., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

▼ Sacubitril valsartan for heart failure. [2021]

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

Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (PANORAMA-HF study). [2021]

3. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

Neprilysin inhibition with sacubitril/valsartan in the treatment of heart failure: mortality bang for your buck. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

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

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

Sacubitril/Valsartan (Entresto®)-Induced Hyponatremia. [2021]

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

Sacubitril/valsartan-induced liver injury: A case report and literature review. [2023]

8. England pubmed.ncbi.nlm.nih.gov

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

9. Egypt pubmed.ncbi.nlm.nih.gov

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

10. Germany pubmed.ncbi.nlm.nih.gov

Single therapeutic and supratherapeutic doses of sacubitril/valsartan (LCZ696) do not affect cardiac repolarization. [2021]