Sacubitril/Valsartan for Coronavirus

(PARACOR-19 Trial)

Overseen By Stephen Greene, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Duke University

Must not be taking: ACE inhibitors, ARBs

Disqualifiers: Fever, Low ejection fraction, Pregnancy, others

Compensation: Varies

Number of Visits: 2

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether the drug sacubitril/valsartan (an oral tablet known as Entresto) can improve heart health in individuals who have recovered from COVID-19. Participants will receive either this drug or a placebo (a pill with no active medicine) to assess its effects on heart injury and function. It is suitable for those who had COVID-19, have a systolic blood pressure of at least 100 mmHg, and have conditions like diabetes or a history of certain heart problems. The researchers aim to determine if this medication can protect the heart after a COVID-19 infection. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications like ACE inhibitors, ARBs, aliskiren, or sacubitril/valsartan before participating. If you are on these medications, you would need to discontinue them to join the study.

Is there any evidence suggesting that sacubitril/valsartan is likely to be safe for humans?

Research has shown that the treatment under study, sacubitril/valsartan, is usually well-tolerated by most patients. Common side effects include low blood pressure, dizziness, and cough. Some individuals might also experience high potassium levels, and less frequently, kidney issues.

The FDA has already approved this treatment for heart failure, indicating its safety when used correctly. However, like any medication, it can have side effects, so monitoring for these is important for trial participants. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for the cardiac consequences of COVID-19 focus on managing symptoms and stabilizing heart function. However, sacubitril/valsartan, commonly known as Entresto, stands out because it combines two active ingredients that work together to enhance heart efficiency and reduce strain. This combination targets the heart's ability to pump blood by inhibiting certain enzymes that contribute to heart stress and damage. Researchers are excited about sacubitril/valsartan because it not only addresses symptoms but also targets underlying mechanisms, potentially offering enhanced protection for heart health in COVID-19 patients.

What evidence suggests that sacubitril/valsartan might be an effective treatment for cardiac injury after COVID-19?

Research has shown that sacubitril/valsartan, which participants in this trial may receive, effectively treats heart failure with reduced ejection fraction. In earlier studies, patients taking sacubitril/valsartan experienced fewer hospital visits for heart problems compared to those using other common heart medications. Higher doses of sacubitril/valsartan proved even more successful in reducing these hospitalizations. While these results specifically address heart failure, they suggest that sacubitril/valsartan might also aid in heart issues during COVID-19 recovery. This treatment relaxes blood vessels and improves blood flow, potentially protecting the heart. ^{6 7 8 9 10}

Who Is on the Research Team?

Stephen J Greene, MD

Principal Investigator

Duke University

G. Michael Felker, MD, MHS

Principal Investigator

Duke University

Are You a Good Fit for This Trial?

Inclusion Criteria

Patient with a history of laboratory proven-diagnosis of COVID-19 who is 4-16 weeks from their last positive COVID-19 test

Systolic blood pressure ≥100 mmHg at screening

Successful collection of baseline serum biomarkers

Exclusion Criteria

Fever within the past 96 hours of >100.3 degrees Fahrenheit

Actively receiving therapy with an angiotensin-converting enzyme inhibitor (ACEI), angiotensin II receptor blocker (ARB), aliskiren, or sacubitril/valsartan

Last known left ventricular ejection fraction of ≤40%

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive sacubitril/valsartan or placebo, with dose titration based on blood pressure

12 weeks

2 visits (in-person) for dose titration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Sacubitril / Valsartan Oral Tablet [Entresto]

How Is the Trial Designed?

Group I: Sacubitril/valsartan Experimental Treatment 1 Intervention

Initial dose for patients randomized to sacubitril/valsartan (LCZ696) will be determined by the blood pressure at the time of randomization. Study treatment will be titrated to the next highest dose (dose level 2 or 3) based on blood pressure at the time of visit 2/titration visit. Dose adjustments are only allowed if indicated per protocol defined criteria and per investigator judgement of safety and tolerability. Sacubitril/valsartan (LCZ696) tablet with minimum dose 24/26 mg, maximum dose 97/103 mg twice daily administered orally. Other Name: LCZ696

Group II: Placebo Placebo Group 1 Intervention

Initial dose for patients randomized to sacubitril/valsartan matching placebo will be determined by the blood pressure at the time of randomization. Study treatment will be titrated to the next highest dose (dose level 2 or 3) based on blood pressure at the time of visit 2/titration visit. Dose adjustments are only allowed if indicated per protocol defined criteria and per investigator judgement of safety and tolerability. Sacubitril/valsartan matching placebo with minimum dose matching the 24/26 mg dose, maximum dose matching the 97/103 mg dose, administered twice daily orally.

Who Is Running the Clinical Trial?

Duke University

Lead Sponsor

Trials

2,495

Recruited

5,912,000+

Novartis Pharmaceuticals

Industry Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

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/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 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 2018, 1043 patients in Ireland were prescribed Entresto, showing a steady increase in its use since reimbursement approval, with a total expenditure of €1.2 million, which was lower than expected.

Patients in Ireland using Entresto were generally older and more symptomatic than those in the pivotal PARADIGM-HF trial, and starting treatment with Entresto led to a reduction in the use of other heart failure medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/valsartan (Entresto) utilisation and prescribing patterns in the context of a reimbursement application system. Kennedy, C., Smith, A., Doran, S., et al.[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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39888167/

Real-world comparative effectiveness of sacubitril ... Among patients with de novo HFrEF, sacubitril/valsartan (compared with that of ACEi/ARB) was associated with fewer all-cause, CV and HF hospitalizations.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10018087/

Efficacy and safety of low‐dose sacubitril/valsartan in heart ... Compared with low‐dose sacubitril/valsartan, high‐dose sacubitril/valsartan significantly reduced the risk of HF hospitalization (OR: 0.4, 95% ...

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

Clinical Trial and Biomarker Data Clinical outcomes when utilizing sacubitril/valsartan vs. ACEi/ARB in patients with HF and ejection fractions spanning from reduced to preserved—a ...

4. 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).

5. 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 ...

6. mayoclinic.org mayoclinic.org/drugs-supplements/sacubitril-and-valsartan-oral-route/description/drg-20150920

Sacubitril and valsartan (oral route) - Side effects & dosage Side Effects ; More common. Blurred vision; confusion ; Less common. Bloody urine; decreased frequency or amount of urine ; Incidence not known.

7. goodrx.com goodrx.com/entresto/entresto-side-effects-you-should-know-about?srsltid=AfmBOooxakqXr0sceA104iLNy5ysAEFYtRS4aPewuGqATzh6t3xn7xGJ

5 Entresto Side Effects to Know and How to Manage Them The most common Entresto side effect is low blood pressure, which can cause dizziness. Other possible side effects include cough and increased potassium levels.

8. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK507904/

Sacubitril-Valsartan - StatPearls - NCBI Bookshelf Adverse effects include hypotension, hyperkalemia, renal failure, cough, and angioedema. In the PARADIGM-HF trial comparing sacubitril-valsartan to enalapril 10 ...

9. webmd.com webmd.com/drugs/2/drug-169241/entresto-oral/details

Entresto (sacubitril/valsartan) - Uses, Side Effects, and More What are the most common side effects of Entresto? · Decreased blood pressure (see below) · High potassium level (see below) · Cough · Dizziness.

10. medsafe.govt.nz medsafe.govt.nz/consumers/cmi/e/entresto.pdf

Entresto® Common side effects include: dizziness, fainting, light-headedness, cough, headache, diarrhoea, feeling sick, stomach pain, tiredness, weakness. Serious side ...