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

53 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of two medications, sacubitril-valsartan (a combination drug for heart failure) and valsartan, in individuals with early-stage heart failure who had cancer before age 40. The researchers aim to determine if these treatments are manageable and if enough participants can be enrolled. It targets those who underwent certain cancer treatments and now exhibit specific heart health indicators but do not experience heart failure symptoms like shortness of breath or fatigue. As a Phase 1, Phase 2 trial, this research seeks to understand how the treatment works in people and to measure its effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that sacubitril-valsartan is usually well-tolerated. Studies have found that it can lower the risk of death and hospital visits for people with heart failure. However, some side effects might include low blood pressure and kidney problems. Sacubitril-valsartan is already approved for treating heart failure, indicating its well-established safety.

The other treatment in this trial, valsartan, also has a good safety record and is often used for heart conditions. It may cause side effects like dizziness or headaches. Overall, both treatments have been studied and are used for heart issues, providing reassurance about their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about sacubitril-valsartan for heart failure because it offers a unique approach by combining two active ingredients: sacubitril, which enhances the body's natural ability to lower blood pressure, and valsartan, which blocks harmful substances that tighten blood vessels. This dual action helps the heart pump more efficiently, setting it apart from standard treatments like ACE inhibitors and beta-blockers. The sacubitril-valsartan combo has the potential to improve heart function more effectively, providing new hope for patients with heart failure.

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

Research shows that sacubitril-valsartan, which participants in this trial may receive, effectively treats heart failure with reduced ejection fraction (HFrEF). Studies have found it lowers the risk of death from heart-related issues and reduces hospital visits. Compared to enalapril, sacubitril-valsartan decreased the chances of major heart problems by 20%. In this trial, some participants will receive sacubitril-valsartan, while others will receive valsartan. Previous research comparing sacubitril-valsartan directly to valsartan found no difference in certain heart-related measures, suggesting both treatments can be helpful. However, sacubitril-valsartan has shown more overall benefits in some studies. ^{2 6 7 8 9}

Who Is on the Research Team?

Wendy Bottinor, MD

Principal Investigator

Virginia Commonwealth University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

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]

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]

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]

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]

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]

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 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]

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, 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26642078/

Sacubitril/valsartan (LCZ696) for the treatment of heart failure The PARADIGM-HF study, a large outcome trial in heart failure and reduced ejection fraction (HFrEF), has recently shown improved cardiovascular outcomes ...

2. annfammed.org annfammed.org/content/23/Supplement_1/8199

Efficacy and safety of Sacubitril/Valsartan in the treatment ... Conclusions In patients with HFrHF, Sacubitril/Valsartan reduces all-cause mortality and hospitalisations and confers an improvement in quality ...

3. ahajournals.org ahajournals.org/doi/10.1161/JAHA.121.021459

Clinical Effectiveness of Sacubitril/Valsartan Among ... Sacubitril/Valsartan has been highly efficacious in randomized trials of heart failure with reduced ejection fraction (HFrEF).

4. jamanetwork.com jamanetwork.com/journals/jamacardiology/fullarticle/2785700

Effect of Treatment With Sacubitril/Valsartan in Patients ... The results of the LIFE trial show there was no difference between sacubitril/valsartan and valsartan with respect to lowering NT-proBNP levels ...

5. archivesofmedicalscience.com archivesofmedicalscience.com/Efficacy-and-safety-of-sacubitril-valsartan-in-heart-failure-compared-to-renin-angiotensin,159113,0,2.html

Efficacy and safety of sacubitril/valsartan in heart failure ... In comparison to enalapril, sacubitril/valsartan reduced the occurrence of the primary outcome (cardiovascular death or hospitalisation for HF) by 20% and ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5076745/

Sacubitril/valsartan in heart failure: latest evidence and place ... Safety outcomes of hypotension (more in sacubitril/valsartan), renal impairment, and hyperkalemia (both more in enalapril) increased logically with age. For ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT01920711

NCT01920711 | Efficacy and Safety of LCZ696 Compared ... The purpose of this study was to evaluate the effect of LCZ696 compared to valsartan in the reduction of cardiovascular death and heart failure(HF) ...

8. entrestohcp.com entrestohcp.com/hfref/clinical-trial-biomarker-data

Clinical Trial and Biomarker Data When started in the hospital in stabilized patients, ENTRESTO reduced risk of CV death and HF readmission vs enalapril over 8 weeks.**††. ENTRESTO reduced the ...

9. hfsa.org hfsa.org/new-analysis-novartis-entrestor-data-shows-long-term-benefits-heart-failure-readmissions-and-total

New Analysis of Novartis' Entresto® Data Shows Long ... Entresto reduced the risk of first and subsequent events of heart failure hospitalizations and cardiovascular deaths following heart failure hospitalization ...