Sacubitril-Valsartan for Heart Failure in HIV

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Massachusetts General Hospital

Must not be taking: RAAS pathway, Steroids, Diuretics, others

Disqualifiers: Heart failure, Recent stroke, Diabetes, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing a medication called sacubitril/valsartan in people with HIV who show early signs of heart changes. The medication aims to block a harmful hormone and increase a protective one to prevent heart problems. The study will see if this treatment can improve heart health in these patients.

Will I have to stop taking my current medications?

You may need to stop taking certain medications, especially those that affect the RAAS pathway (like ACE inhibitors, ARBs, or MR blockers), potassium supplements, or diuretics, as they are not allowed in this trial.

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

Research shows that Sacubitril-Valsartan significantly improves heart health and quality of life in patients with heart failure and reduced ejection fraction, which means the heart pumps less blood with each beat. This suggests it could be beneficial for heart failure in HIV patients as well. ^{1 2 3 4 5}

Is Sacubitril-Valsartan generally safe for humans?

Sacubitril-Valsartan has been studied for heart failure and is generally considered safe, but some patients may stop using it due to side effects, and a small percentage may experience serious outcomes. ^{4 6 7 8 9}

How is the drug Sacubitril-Valsartan unique for treating heart failure in HIV patients?

Sacubitril-Valsartan is unique because it combines two actions: it blocks a hormone that narrows blood vessels and inhibits an enzyme that breaks down beneficial proteins, which helps improve heart function. This dual action is different from many other heart failure treatments that typically focus on just one mechanism. ^{1 4 5 10 11}

Research Team

Eligibility Criteria

This trial is for people with HIV who've been on antiretroviral therapy for over a year, have controlled viral loads, and show early signs of heart issues but no recent severe cardiac events or uncontrolled diabetes. They shouldn't be pregnant, seeking pregnancy, breastfeeding, or using certain hormones and must not have liver disease or be on medications that affect the same pathways as the study drugs.

Inclusion Criteria

Your heart's ability to squeeze and relax is less than 18%.

Your heart is too big for your body size.

Your left atrium is too big for this study.

Exclusion Criteria

My kidney function is reduced with creatinine over 1.5 mg/dL and GFR under 60.

Your blood pressure is less than 100 mmHg.

Your blood potassium level is higher than 5.5 milliequivalents per liter.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline Assessment

Baseline cardiac imaging and blood tests to assess heart structure and function

1 week

1 visit (in-person)

Treatment

Participants receive sacubitril/valsartan or placebo for 6 months with lifestyle modification counseling

6 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Placebo oral tablet (Drug)
• Sacubitril-Valsartan 49-51Mg Oral Tablet (Angiotensin Receptor-Neprilysin Inhibitor)

Trial Overview The ENCHANTMENT HIV Study tests if Sacubitril/Valsartan can help prevent heart failure in those with HIV by blocking harmful hormones and improving heart function. Participants will either receive this medication or a placebo without knowing which one they're taking to compare effects fairly.

Participant Groups

Group I: Sacubitril/Valsartan Experimental Treatment 1 Intervention

Sacubitril/Valsartan 49-51mg twice daily along with lifestyle modification (counseling regarding diet and healthy activity) for 6 months

Group II: Placebo Placebo Group 1 Intervention

Placebo twice daily along with lifestyle modification (counseling regarding diet and healthy activity) for 6 months

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Dr. William Curry

Massachusetts General Hospital

Chief Medical Officer

MD from Harvard Medical School

Dr. Anne Klibanski

Massachusetts General Hospital

Chief Executive Officer since 2019

MD from Harvard Medical School

Findings from Research

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]

In a retrospective study of 132 heart failure patients with reduced ejection fraction, those treated with sacubitril/valsartan showed significant improvements in both left ventricular ejection fraction (LVEF) and global left ventricular longitudinal strain (GLS) over an average of 14 months, indicating enhanced heart function.

Unlike the control group receiving conventional therapy, which only improved LVEF, the sacubitril/valsartan group demonstrated a notable increase in GLS, suggesting that this medication may offer additional benefits in heart remodeling beyond just improving ejection fraction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/valsartan improves left ventricular longitudinal deformation in heart failure patients with reduced ejection fraction. De Vecchis, R., Paccone, A., Di Maio, M.[2023]

In a study using a rabbit model of acute myocardial infarction, sacubitril/valsartan (SAC/VAL) significantly reduced infarct size and preserved left ventricular ejection fraction (LVEF) compared to placebo, demonstrating its acute infarct-sparing benefits.

SAC/VAL not only improved LVEF over time in heart failure treatment protocols but also significantly reduced left ventricular scar size after myocardial infarction, indicating its superior long-term protective effects compared to valsartan alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/Valsartan Averts Adverse Post-Infarction Ventricular Remodeling and Preserves Systolic Function in Rabbits. Torrado, J., Cain, C., Mauro, AG., et al.[2021]

In a study involving 498 heart failure patients, initiating and uptitrating sacubitril/valsartan from 50 to 200 mg twice daily over 3 to 6 weeks showed a tolerability profile similar to other heart failure treatments, with low rates of adverse effects like hypotension and renal dysfunction.

A more gradual uptitration approach was particularly beneficial for patients on low doses of ACE inhibitors or ARBs, leading to a higher percentage (84.9%) achieving the target dose without interruptions compared to a more rapid regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens. Senni, M., McMurray, JJ., Wachter, R., et al.[2022]

Sacubitril-valsartan significantly reduces the risk of all-cause and cardiovascular mortality in patients with heart failure with reduced ejection fraction (HFrEF), as shown in a meta-analysis of six trials involving 14,959 patients.

While sacubitril-valsartan is associated with a higher risk of symptomatic hypotension, it has a lower risk of worsening renal function and serious hyperkalaemia compared to traditional treatments like enalapril or valsartan.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sacubitril-valsartan in heart failure: a meta-analysis of randomized controlled trials. Zhang, H., Huang, T., Shen, W., et al.[2022]

In a study of 427 heart failure patients treated with sacubitril/valsartan (SV) over an average of 7 months, those who continued SV showed significant improvements in heart function and symptoms, while discontinuation was linked to a much higher risk of death.

SV was generally well-tolerated, with only 16.6% of patients experiencing symptomatic hypotension, indicating that it is a safe option for managing heart failure with reduced ejection fraction in everyday clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/Valsartan in Daily Clinical Practice: Data From a Prospective Registry. Vicent, L., Esteban-Fernández, A., Gómez-Bueno, M., et al.[2021]

Sacubitril-valsartan is projected to provide significant health benefits for patients with heart failure (HF) and an ejection fraction (EF) of 60% or less, adding 0.53 quality-adjusted life-years (QALYs) at an incremental cost of $40,892, resulting in an incremental cost-effectiveness ratio (ICER) of $76,852 per QALY compared to traditional renin-angiotensin system inhibitors (RASis).

The treatment is particularly cost-effective for patients with lower EFs (≤50%), with ICERs indicating high economic value, suggesting that sacubitril-valsartan could be a valuable treatment option for a broader range of HF patients, influencing clinical practice guidelines and insurance coverage decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health and Economic Evaluation of Sacubitril-Valsartan for Heart Failure Management. Bhatt, AS., Vaduganathan, M., Claggett, BL., et al.[2023]

In a meta-analysis of five cohort studies involving 8,981 patients with heart failure, sacubitril/valsartan (SV) showed similar rates of major adverse outcomes, such as all-cause mortality and heart failure hospitalizations, between men and women.

Although men had numerically higher rates of all-cause and cardiovascular mortality, these differences were not statistically significant, indicating that SV is equally safe for both sexes in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Safety of Sacubitril/Valsartan in Women and Men With Heart Failure and Reduced Ejection Fraction: A Meta-analysis. Nuechterlein, K., AlTurki, A., Ni, J., et al.[2022]

Sacubitril/valsartan is rapidly absorbed and effectively converted to its active form, sacubitrilat, which helps treat heart failure with reduced ejection fraction, showing significant increases in plasma concentrations in patients with heart failure compared to healthy subjects.

The pharmacokinetics of sacubitril/valsartan are generally unaffected by age, sex, or ethnicity, but renal impairment can significantly increase the levels of sacubitrilat, indicating the need for careful monitoring in patients with kidney issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Erratum to: Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor-Neprilysin Inhibitor. Ayalasomayajula, S., Langenickel, T., Pal, P., et al.[2019]

In a study involving 36 healthy subjects, taking sacubitril/valsartan (LCZ696) with food significantly reduced the absorption rate of sacubitril and valsartan, with Cmax values decreasing by 42-54% and ~40%, respectively.

Despite the reduced absorption rates when taken with meals, LCZ696 was found to be safe and well tolerated, indicating that while food affects its bioavailability, it does not compromise the overall safety of the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of food on the oral bioavailability of the angiotensin receptor - neprilysin inhibitor sacubitril/valsartan (LCZ696) in healthy subjects . Ayalasomayajula, S., Langenickel, TH., Chandra, P., et al.[2022]

References

1. Germany pubmed.ncbi.nlm.nih.gov

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

2. Czech Republic pubmed.ncbi.nlm.nih.gov

Monitoring the dynamics of clinical and laboratory markers of chronic heart failure during 12 months of sacubitril/valsartan treatment. [2021]

3. Italy pubmed.ncbi.nlm.nih.gov

Sacubitril/valsartan improves left ventricular longitudinal deformation in heart failure patients with reduced ejection fraction. [2023]

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

Sacubitril/Valsartan Averts Adverse Post-Infarction Ventricular Remodeling and Preserves Systolic Function in Rabbits. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sacubitril-valsartan in heart failure: a meta-analysis of randomized controlled trials. [2022]

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

Sacubitril/Valsartan in Daily Clinical Practice: Data From a Prospective Registry. [2021]

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

Health and Economic Evaluation of Sacubitril-Valsartan for Heart Failure Management. [2023]

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

Real-World Safety of Sacubitril/Valsartan in Women and Men With Heart Failure and Reduced Ejection Fraction: A Meta-analysis. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Erratum to: Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor-Neprilysin Inhibitor. [2019]

11. Germany pubmed.ncbi.nlm.nih.gov

Effect of food on the oral bioavailability of the angiotensin receptor - neprilysin inhibitor sacubitril/valsartan (LCZ696) in healthy subjects . [2022]