Losartan for Patients With COVID-19 Requiring Hospitalization

Study Overview
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Brief Summary
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This is a multi-center, double-blinded study of COVID-19 infected patients requiring inpatient hospital admission randomized 1:1 to daily Losartan or placebo for 7 days or hospital discharge.

Official Title
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Randomized Controlled Trial of Losartan for Patients With COVID-19 Requiring Hospitalization

Conditions
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Corona Virus Infection, Acute Respiratory Distress Syndrome, SARS-CoV Infection

Intervention / Treatment
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* Drug: Losartan
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Presumptive positive laboratory test for Covid-19 based on local laboratory standard Age greater than or equal to 18 years of age Admission to the hospital with a respiratory SOFA >=1 and increased oxygen requirement compared to baseline among those on home O2 Randomization within 48 hours of presentation of hospital admission or within 48 hours of a positive test result, whichever is later Exclusion Criteria: Randomization > 48 hours of admission order or positive test result, whichever is later Currently taking an angiotensin converting enzyme inhibitor (ACEi) or Angiotensin receptor blocker (ARB) Prior reaction or intolerance to an ARB or ACE inhibitor, including but not limited to angioedema Pregnant or breastfeeding Lack of negative urine or serum pregnancy test Not currently taking a protocol allowed version of contraception: intrauterine device, Depo-formulation of hormonal contraception (e.g. medroxyprogesterone acetate / Depo-Provera), subcutaneous contraceptive (e.g. Nexplanon), daily oral contraceptives with verbalized commitment to taking daily throughout the study period; use of condoms or agree to abstain from sexual intercourse during the study. All women of child bearing age enrolled in this fashion will be informed of the teratogenic risks. If enrolled under LAR, they will be informed of the risks after regaining capacity. Patient reported history or electronic medical record history of kidney disease, defined as: Any history of dialysis History of chronic kidney disease stage IV Estimated Glomerular Filtration Rate (eGFR) of < 30ml/min/1.73 m2 at the time of randomization Severe dehydration at the time of enrollment in the opinion of the investigator or bedside clinician Most recent mean arterial blood pressure prior to enrollment <65 mmHg Patient reported history or electronic medical record history of severe liver disease, defined as: Cirrhosis History of hepatitis B or C Documented AST or ALT > 3 times the upper limit of normal measured within 24 hours prior to randomization Potassium >5.0 within 24 hours prior to randomization unless a repeat value was <=5.0 Treatment with aliskiren Inability to obtain informed consent from participant or legally authorized representative Enrollment in another blinded randomized clinical trial for COVID

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Losartan<br>Participants in this arm will receive the study drug, Losartan. | Drug: Losartan<br>* Losartan; 50 mg daily; oral administration<br>* Other names: Cozaar;|
| Placebo Comparator: Placebo<br>Participants in this arm will receive a placebo treatment. | Other: Placebo<br>* Placebo (microcrystalline methylcellulose, gelatin capsule); oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Estimated (PEEP Adjusted) P/F Ratio at 7 Days | Outcome calculated from the partial pressure of oxygen or peripheral saturation of oxygen by pulse oximetry divided by the fraction of inspired oxygen (PaO2 or SaO2 : FiO2 ratio). PaO2 is preferentially used if available. A correction is applied for endotracheal intubation and/or positive end-expiratory pressure. Patients discharged prior to day 7 will have a home pulse oximeter send home for measurement of the day 7 value, and will be adjusted for home O2 use, if applicable. Patients who died will be applied a penalty with a P/F ratio of 0. | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Daily Hypotensive Episodes | Outcome reported as the mean number of daily hypotensive episodes (MAP < 65 mmHg) prompting intervention (indicated by a fluid bolus >=500 mL) per participant in each arm. | 10 days | 
| Proportion of Participants Requiring Vasopressors for Hypotension | Outcome reported as the number of participants in each arm requiring the use of vasopressors for hypotension. | 10 days | 
| Proportion of Participants Experiencing Acute Kidney Injury | Outcome reported as the number of participants in each arm who experience acute kidney injury as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines: Increase in serum creatinine by 0.3mg/dL or more within 48 hours OR Increase in serum creatinine to 1.5 times baseline or more within the last 7 days OR Urine output less than 0.5 mL/kg/h for 6 hours. | 10 days | 
| Oxygen Saturation / Fractional Inhaled Oxygen (S/F) | Oxygen saturation (percent) is measured by pulse oximeter. Fraction of inspired oxygen (FiO2) (unitless) is the volumetric fraction of oxygen to other gases in respiratory support. The S/F ratio is unitless. | 7 days | 
| 28-Day Mortality | Outcome reported as the number of participants who have expired at 28 days post enrollment. | 28 days | 
| 90-Day Mortality | Outcome reported as the number of participants who have expired at 90 days post enrollment. | 90 days | 
| ICU Admission | Outcome reported as the number of participants in each arm who require admission to the Intensive Care Unit (ICU). | 10 days | 
| Number of Ventilator-Free Days | Outcome reported as the mean number of days participants in each arm did not require mechanical ventilation during an in-patient hospital admission. | 28 days | 
| Number of Therapeutic Oxygen-Free Days | Outcome reported as the mean number of days participants in each arm did not require therapeutic oxygen usage during an in-patient hospital admission. | 28 days | 
| Number of Vasopressor-Free Days | Outcome reported as the mean number of days participants in each arm did not require vasopressor usage during an in-patient hospital admission. | 10 days | 
| Length of Hospital Stay | Outcome reported as the mean length of in-patient hospital stay (in days) for participants in each arm. | 90 days | 
| Disease Severity Rating | Outcome reported as the number of participants in each arm who fall into each of 7 categories. Lower scores indicate greater condition severity. The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities. | 28 days | 
| Change in Viral Load by Nasopharyngeal Swab Day 15 | Nasopharyngeal swabs will be collected at baseline and day 15. Viral load is measured as number of viral genetic copies per mL. | 15 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Corona Virus, SARS-COV-2