Protecting With ARNI Against Cardiac Consequences of Coronavirus Disease 2019

(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

42 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a heart medication called sacubitril/valsartan on people who have recovered from COVID-19. The goal is to see if it can help improve their heart health by making it easier for blood to flow and reducing stress on the heart. Sacubitril/valsartan has been shown to reduce the risk of cardiovascular death or heart failure hospitalization and improve symptoms in chronic heart failure with reduced ejection fraction.

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.

What safety data exists for sacubitril/valsartan (Entresto)?

Sacubitril/valsartan (Entresto) is generally used for heart failure and can cause side effects like low blood pressure, swelling (angioedema), kidney problems, and high potassium levels. There have been rare reports of liver injury and low sodium levels in the blood. It should not be used during pregnancy, breastfeeding, or with certain other medications in people with diabetes. ^{1 2 3 4 5}

How is the drug Sacubitril/Valsartan (Entresto) unique in treating heart failure?

Sacubitril/Valsartan (Entresto) is unique because it combines two actions: it blocks a protein called neprilysin, which helps control blood pressure, and it also blocks angiotensin II receptors, which relaxes blood vessels. This dual action makes it more effective than some older treatments like enalapril in reducing the risk of death and hospitalization for heart failure. ^{1 3 4 6 7}

Research Team

Stephen J Greene, MD

Principal Investigator

Duke University

G. Michael Felker, MD, MHS

Principal Investigator

Duke University

Eligibility Criteria

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

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

Treatment Details

Interventions

• Placebo
• Sacubitril / Valsartan Oral Tablet [Entresto]

Participant Groups

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

Findings from Research

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]

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 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]

References

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

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

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

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

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

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

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

▼ Sacubitril valsartan for heart failure. [2021]

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

Adverse events with sacubitril/valsartan in the real world: emerging signals to target preventive strategies from the FDA adverse event reporting system. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

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

7. England pubmed.ncbi.nlm.nih.gov

Sacubitril/valsartan (Entresto) utilisation and prescribing patterns in the context of a reimbursement application system. [2021]