Protecting With ARNI Against Cardiac Consequences of Coronavirus Disease 2019 (PARACOR-19)

The purpose of this study is to determine the effect of sacubitril/valsartan versus placebo on markers of cardiac injury, structure, and function among patients who recovered from acute COVID-19 infection.

Study Overview

• Status: Completed
• Conditions: Covid19
• Intervention / Treatment: Drug: Sacubitril / Valsartan Oral Tablet [Entresto]; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patient with a history of laboratory proven-diagnosis of COVID-19 who is 4-16 weeks from their last positive COVID-19 test
2. Systolic blood pressure ≥100 mmHg at screening
3. ≥18 years of age
4. Successful collection of baseline serum biomarkers
5. Successful completion of baseline EQ-5D questionnaire
6. Successful completion of baseline CMR study (CMR sub-study only)
7. High-sensitivity troponin T at or above the level of detection on screening labs

8. Presence of ≥1 of the following:

   1. Age ≥60
   2. History of atherosclerotic cardiovascular disease (ASCVD), including myocardial infarction, coronary artery disease, ischemic stroke/transient ischemic attack, or peripheral artery disease
   3. Diabetes mellitus (Type 1 or Type 2)
   4. Body mass index ≥35 kg/m2
   5. eGFR 30-60 ml/min/1.73m2
   6. History of atrial fibrillation/flutter

Exclusion Criteria:

1. Fever within the past 96 hours of >100.3 degrees Fahrenheit
2. Actively receiving therapy with an angiotensin-converting enzyme inhibitor (ACEI), angiotensin II receptor blocker (ARB), aliskiren, or sacubitril/valsartan
3. Last known left ventricular ejection fraction of ≤40%
4. eGFR <30 ml/min/1.73m2 on screening labs, including patients on dialysis therapy
5. Serum potassium >5.0 mEq/L on screening labs
6. Prior intolerance, allergy or angioedema to ACEI, ARB, or sacubitril/valsartan
7. Pregnant or breast-feeding
8. In women of childbearing age, unwillingness to use birth control for the duration of the study
9. History of heart transplant or durable left ventricular assist device
10. Currently implanted permanent pacemaker, defibrillator, or other device that would preclude CMR testing (CMR sub-study only)
11. Currently participating in another trial of an investigational medication or device for COVID-19.
12. Any other condition that in the judgment of the investigator would jeopardize the patient's compliance with the study protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sacubitril/valsartan; 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	Drug: Sacubitril / Valsartan Oral Tablet [Entresto]; sacubitril/valsartan (LCZ696) tablet with minimum dose 24/26 mg, maximum dose 97/103 mg twice daily administered orally.; Other Names: LCZ696
Placebo Comparator: Placebo; 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.	Drug: Placebo; sacubitril/valsartan matching placebo tablet with minimum dose 24/26 mg, maximum dose 97/103 mg twice daily administered orally.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in High-sensitivity Troponin T	An elevated level of troponin T on the high-sensitivity cardiac troponin test indicates heart muscle damage or a heart attack.	Baseline, Week 12
Change From Baseline in Soluble ST2	ST2 is a decoy receptor that inhibits beneficial cardioprotective effects of IL-33; such inhibition results in cardiac hypertrophy, myocardial fibrosis, and ventricular dysfunction. Measurement of soluble ST2 has utility for assessing heart failure severity and prognosis.	Baseline, Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in C-reactive Peptide (CRP)	CRP is a pentameric protein synthesized by the liver; its level rises in response to inflammation.	Baseline, Week 12
Change From Baseline in P1NP (Procollagen Type I N-propeptide)	Serum P1NP is designated as the reference marker of bone formation in osteoporosis. Elevated markers are associated with increased bone turnover, which increases the deterioration of bone quality and the risk of fragility fracture.	Baseline, Week 12
Change From Baseline in Galectin-3	Galectin-3 may be used as a diagnostic or prognostic biomarker for certain types of heart disease, kidney disease and cancer.	Baseline, Week 12
Change From Baseline in NT-proBNP (N-terminal Pro B-type Natriuretic Peptide)	Higher levels of NT-proBNP indicate increased heart failure.	Baseline, Week 12
Change From Baseline in GDF-15 (Growth/Differentiation Factor-15)	Highly elevated GDF-15 levels are mostly linked to pathological conditions including inflammation, myocardial ischemia, and notably cancer.	Baseline, Week 12
Change From Baseline in IL-6 (Interleukin-6)	IL-6 can be elevated with inflammation, infection, autoimmune disorders, cardiovascular diseases, and some cancers.	Baseline, Week 12
Change From Baseline in CITP (C-terminal Telopeptide of Collagen Type I)	Elevated levels of CITP indicate increased bone turnover.	Baseline, Week 12
Change From Baseline in Left Ventricular Ejection Fraction (LVEF)	LVEF is the amount of blood pumped out of the heart's left ventricle each time it contracts, represented as a percentage of the blood in the left ventricle that gets pumped out to the body. Normal = LVEF 50% to 70% (midpoint 60%) Mild dysfunction = LVEF 40% to 49% (midpoint 45%) Moderate dysfunction = LVEF 30% to 39% (midpoint 35%) Severe dysfunction = LVEF less than 30%.	Baseline, Week 12
Change From Baseline in Focal Fibrosis by Delayed-enhancement on Cardiac MRI		Baseline, Week 12
Change From Baseline in Focal Fibrosis by Percentage of Left Ventricular Myocardial Mass on Cardiac MRI		Baseline, Week 12
Change From Baseline in EuroQol-5 Dimensions (EQ-5D) Utility Score	The EQ-5D utility score is a value that represents a person's health state based on a set of weights that reflect their preferences. The score is anchored at 0, which represents a state as bad as death, and 1, which represents full health. Negative values can be assigned to health states that are considered worse than death.	Baseline, Week 12
Change From Baseline in EuroQOL-5 Dimensions (EQ-5D) Visual Analog Scale (VAS)	The EQ-5D VAS is a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).	Baseline, Week 12

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: Novartis Pharmaceuticals
• Investigators: Principal Investigator: Stephen J Greene, MD, Duke University; Principal Investigator: G. Michael Felker, MD, MHS, Duke University

Study record dates

Study Major Dates

• Study Start (Actual): August 6, 2021
• Primary Completion (Actual): June 13, 2023
• Study Completion (Actual): June 13, 2023

Study Registration Dates

• First Submitted: May 6, 2021
• First Submitted That Met QC Criteria: May 11, 2021
• First Posted (Actual): May 12, 2021

Study Record Updates

• Last Update Posted (Actual): July 3, 2024
• Last Update Submitted That Met QC Criteria: June 6, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: sacubitril/valsartan
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Valsartan; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: Pro00108314

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No