Losartan for Patients With COVID-19 Requiring Hospitalization

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Respiratory Distress Syndrome; Corona Virus Infection; SARS-CoV Infection
• Intervention / Treatment: Drug: Losartan; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 205
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32611
      • University of Florida Health Gainesville
    • Jacksonville, Florida, United States, 32209
      • University of Florida Health Jacksonville
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Grady Memorial Hospital
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Minnesota
    • Burnsville, Minnesota, United States, 55337
      • M Health Fairview Ridges Hospital
    • Edina, Minnesota, United States, 55435
      • M Health Fairview Southdale Hospital
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • M Health Fairview University of Minnesota Medical Center
    • Robbinsdale, Minnesota, United States, 55422
      • North Memorial Health Hospital
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • Cooper University Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Medical Center

Participation Criteria

Eligibility Criteria

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

Description

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:

  1. Any history of dialysis
  2. History of chronic kidney disease stage IV
  3. 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:

  1. Cirrhosis
  2. History of hepatitis B or C
  3. 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

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: Losartan; Participants in this arm will receive the study drug, Losartan.	Drug: Losartan; Losartan; 50 mg daily; oral administration; Other Names: Cozaar
Placebo Comparator: Placebo; Participants in this arm will receive a placebo treatment.	Other: Placebo; Placebo (microcrystalline methylcellulose, gelatin capsule); oral administration

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Minnesota
• Collaborators: Bill and Melinda Gates Foundation

Publications and helpful links

General Publications

• Puskarich MA, Ingraham NE, Merck LH, Driver BE, Wacker DA, Black LP, Jones AE, Fletcher CV, South AM, Murray TA, Lewandowski C, Farhat J, Benoit JL, Biros MH, Cherabuddi K, Chipman JG, Schacker TW, Guirgis FW, Voelker HT, Koopmeiners JS, Tignanelli CJ; Angiotensin Receptor Blocker Based Lung Protective Strategies for Inpatients With COVID-19 (ALPS-IP) Investigators. Efficacy of Losartan in Hospitalized Patients With COVID-19-Induced Lung Injury: A Randomized Clinical Trial. JAMA Netw Open. 2022 Mar 1;5(3):e222735. doi: 10.1001/jamanetworkopen.2022.2735. Erratum In: JAMA Netw Open. 2022 May 2;5(5):e2215958.
• Smolander J, Bruchfeld A. [COVID-19 and kidney disease]. Lakartidningen. 2020 Jul 13;117:20110. Swedish.

Study record dates

Study Major Dates

• Study Start (Actual): April 13, 2020
• Primary Completion (Actual): February 1, 2021
• Study Completion (Actual): February 1, 2021

Study Registration Dates

• First Submitted: March 13, 2020
• First Submitted That Met QC Criteria: March 13, 2020
• First Posted (Actual): March 17, 2020

Study Record Updates

• Last Update Posted (Actual): June 29, 2022
• Last Update Submitted That Met QC Criteria: June 27, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: COVID-19; SARS-COV-2; Corona Virus
• Additional Relevant MeSH Terms: Pathologic Processes; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease Attributes; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; COVID-19; Coronavirus Infections; Infections; Communicable Diseases; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Losartan
• Other Study ID Numbers: SURG-2020-28675; INV-017069 (Other Grant/Funding Number: Bill and Melinda Gates Foundation)

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
• product manufactured in and exported from the U.S.: No