Protecting With ARNI Against Cardiac Consequences of Coronavirus Disease 2019

Phase 1

Completed

• Conditions: Covid19
• Interventions: Drug: Placebo; Drug: Sacubitril / Valsartan Oral Tablet [Entresto]

• Registration Number: NCT04883528
• Lead Sponsor: Duke University

Brief Summary

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.

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2021-05-06
• Study First Submitted QC: 2021-05-11
• Study First Posted: 2021-05-12
• Study Start: 2021-08-06
• Primary Completion: 2023-06-13
• Study Completion: 2023-06-13
• Status Verified: 2024-06
• Results First Submitted: 2024-06-06
• Results First Submitted QC: 2024-06-06
• Last Update Submitted: 2024-06-06
• Results First Posted: 2024-07-03
• Last Update Posted: 2024-07-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 42

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	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.
Sacubitril/valsartan	Sacubitril / Valsartan Oral Tablet [Entresto]	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

Primary Outcome Measures

Name	Time	Method
Change From Baseline in High-sensitivity Troponin T	Baseline, Week 12	An elevated level of troponin T on the high-sensitivity cardiac troponin test indicates heart muscle damage or a heart attack.
Change From Baseline in Soluble ST2	Baseline, Week 12	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.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in C-reactive Peptide (CRP)	Baseline, Week 12	CRP is a pentameric protein synthesized by the liver; its level rises in response to inflammation.
Change From Baseline in P1NP (Procollagen Type I N-propeptide)	Baseline, Week 12	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.
Change From Baseline in Galectin-3	Baseline, Week 12	Galectin-3 may be used as a diagnostic or prognostic biomarker for certain types of heart disease, kidney disease and cancer.
Change From Baseline in NT-proBNP (N-terminal Pro B-type Natriuretic Peptide)	Baseline, Week 12	Higher levels of NT-proBNP indicate increased heart failure.
Change From Baseline in GDF-15 (Growth/Differentiation Factor-15)	Baseline, Week 12	Highly elevated GDF-15 levels are mostly linked to pathological conditions including inflammation, myocardial ischemia, and notably cancer.
Change From Baseline in CITP (C-terminal Telopeptide of Collagen Type I)	Baseline, Week 12	Elevated levels of CITP indicate increased bone turnover.
Change From Baseline in Left Ventricular Ejection Fraction (LVEF)	Baseline, Week 12	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%.
Change From Baseline in IL-6 (Interleukin-6)	Baseline, Week 12	IL-6 can be elevated with inflammation, infection, autoimmune disorders, cardiovascular diseases, and some cancers.
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	Baseline, Week 12	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.
Change From Baseline in EuroQOL-5 Dimensions (EQ-5D) Visual Analog Scale (VAS)	Baseline, Week 12	The EQ-5D VAS is a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).

Trial Locations

Locations (1)

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States