Covid19
Conditions
Keywords
sacubitril/valsartan
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.
Interventions
sacubitril/valsartan (LCZ696) tablet with minimum dose 24/26 mg, maximum dose 97/103 mg twice daily administered orally.
DRUGPlacebo
sacubitril/valsartan matching placebo tablet with minimum dose 24/26 mg, maximum dose 97/103 mg twice daily administered orally.
Sponsors
Novartis Pharmaceuticals
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 CITP (C-terminal Telopeptide of Collagen Type I) | Baseline, Week 12 | Elevated levels of CITP indicate increased bone turnover. |
| 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 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). |
| 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 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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
Sacubitril / Valsartan Oral Tablet \[Entresto\]: sacubitril/valsartan (LCZ696) tablet with minimum dose 24/26 mg, maximum dose 97/103 mg twice daily administered orally. | 20 |
| 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.
Placebo: sacubitril/valsartan matching placebo tablet with minimum dose 24/26 mg, maximum dose 97/103 mg twice daily administered orally. | 22 |
| Total | 42 |
Baseline characteristics
| Characteristic | Sacubitril/Valsartan | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 65 years | 67 years | 69 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 41 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 38 Participants | 21 Participants |
| Region of Enrollment United States | 20 Participants | 42 Participants | 22 Participants |
| Sex: Female, Male Female | 9 Participants | 20 Participants | 11 Participants |
| Sex: Female, Male Male | 11 Participants | 22 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 22 |
| other Total, other adverse events | 0 / 20 | 0 / 22 |
| serious Total, serious adverse events | 0 / 20 | 0 / 22 |
Outcome results
Primary
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.
Time frame: Baseline, Week 12
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Sacubitril/Valsartan | Change From Baseline in High-sensitivity Troponin T | 1.12 ng/mL |
| Placebo | Change From Baseline in High-sensitivity Troponin T | 1.01 ng/mL |
p-value: 0.29Mixed Models Analysis
Primary
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.
Time frame: Baseline, Week 12
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Sacubitril/Valsartan | Change From Baseline in Soluble ST2 | 0.95 ng/mL |
| Placebo | Change From Baseline in Soluble ST2 | 0.96 ng/mL |
p-value: 0.88Mixed Models Analysis
Secondary
Change From Baseline in CITP (C-terminal Telopeptide of Collagen Type I)
Elevated levels of CITP indicate increased bone turnover.
Time frame: Baseline, Week 12
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Sacubitril/Valsartan | Change From Baseline in CITP (C-terminal Telopeptide of Collagen Type I) | 0.77 ng/mL |
| Placebo | Change From Baseline in CITP (C-terminal Telopeptide of Collagen Type I) | 1.55 ng/mL |
p-value: 0.03Mixed Models Analysis
Secondary
Change From Baseline in C-reactive Peptide (CRP)
CRP is a pentameric protein synthesized by the liver; its level rises in response to inflammation.
Time frame: Baseline, Week 12
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Sacubitril/Valsartan | Change From Baseline in C-reactive Peptide (CRP) | 0.94 mg/dL |
| Placebo | Change From Baseline in C-reactive Peptide (CRP) | 0.87 mg/dL |
p-value: 0.76Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sacubitril/Valsartan | Change From Baseline in EuroQol-5 Dimensions (EQ-5D) Utility Score | 0.01 score on a scale |
| Placebo | Change From Baseline in EuroQol-5 Dimensions (EQ-5D) Utility Score | 0.03 score on a scale |
p-value: 0.6495% CI: [-0.07, 0.04]Mixed Models Analysis
Secondary
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).
Time frame: Baseline, Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sacubitril/Valsartan | Change From Baseline in EuroQOL-5 Dimensions (EQ-5D) Visual Analog Scale (VAS) | -5.60 score on a scale |
| Placebo | Change From Baseline in EuroQOL-5 Dimensions (EQ-5D) Visual Analog Scale (VAS) | 1.95 score on a scale |
p-value: 0.0495% CI: [-14.59, 0.52]Mixed Models Analysis
Secondary
Change From Baseline in Focal Fibrosis by Delayed-enhancement on Cardiac MRI
Time frame: Baseline, Week 12
Population: Data not collected.
Secondary
Change From Baseline in Focal Fibrosis by Percentage of Left Ventricular Myocardial Mass on Cardiac MRI
Time frame: Baseline, Week 12
Population: Data not collected.
Secondary
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.
Time frame: Baseline, Week 12
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Sacubitril/Valsartan | Change From Baseline in Galectin-3 | 0.89 ng/mL |
| Placebo | Change From Baseline in Galectin-3 | 0.91 ng/mL |
p-value: 0.8Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 12
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Sacubitril/Valsartan | Change From Baseline in GDF-15 (Growth/Differentiation Factor-15) | 1.14 pg/mL |
| Placebo | Change From Baseline in GDF-15 (Growth/Differentiation Factor-15) | 1.00 pg/mL |
p-value: 0.23Mixed Models Analysis
Secondary
Change From Baseline in IL-6 (Interleukin-6)
IL-6 can be elevated with inflammation, infection, autoimmune disorders, cardiovascular diseases, and some cancers.
Time frame: Baseline, Week 12
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Sacubitril/Valsartan | Change From Baseline in IL-6 (Interleukin-6) | 1.10 pg/mL |
| Placebo | Change From Baseline in IL-6 (Interleukin-6) | 1.07 pg/mL |
p-value: 0.95Mixed Models Analysis
Secondary
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%.
Time frame: Baseline, Week 12
Population: Participants who consented to this optional substudy.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sacubitril/Valsartan | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) | 0.5 percentage of blood |
| Placebo | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) | 0.5 percentage of blood |
Secondary
Change From Baseline in NT-proBNP (N-terminal Pro B-type Natriuretic Peptide)
Higher levels of NT-proBNP indicate increased heart failure.
Time frame: Baseline, Week 12
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Sacubitril/Valsartan | Change From Baseline in NT-proBNP (N-terminal Pro B-type Natriuretic Peptide) | 0.60 pg/mL |
| Placebo | Change From Baseline in NT-proBNP (N-terminal Pro B-type Natriuretic Peptide) | 1.11 pg/mL |
p-value: 0.01Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 12
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Sacubitril/Valsartan | Change From Baseline in P1NP (Procollagen Type I N-propeptide) | 0.98 mcg/L |
| Placebo | Change From Baseline in P1NP (Procollagen Type I N-propeptide) | 0.99 mcg/L |
p-value: 0.85Mixed Models Analysis