Losartan for Patients With COVID-19 Requiring Hospitalization

• ClinicalTrials.gov Identifier: NCT04312009
• Recruitment Status: Completed
• First Posted: March 17, 2020
• Results First Posted: June 29, 2022
• Last Update Posted: June 29, 2022
• Sponsor: University of Minnesota
• Collaborator: Bill and Melinda Gates Foundation
• Information provided by (Responsible Party): University of Minnesota

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Corona Virus Infection; Acute Respiratory Distress Syndrome; SARS-CoV Infection	Drug: Losartan; Other: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 205 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized Controlled Trial of Losartan for Patients With COVID-19 Requiring Hospitalization
• Actual Study Start Date: April 13, 2020
• Actual Primary Completion Date: February 1, 2021
• Actual Study Completion Date: February 1, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Difference in Estimated (PEEP Adjusted) P/F Ratio at 7 Days [ Time Frame: 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.

Secondary Outcome Measures :

1. Daily Hypotensive Episodes [ Time Frame: 10 days ]
   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.
2. Proportion of Participants Requiring Vasopressors for Hypotension [ Time Frame: 10 days ]
   Outcome reported as the number of participants in each arm requiring the use of vasopressors for hypotension.
3. Proportion of Participants Experiencing Acute Kidney Injury [ Time Frame: 10 days ]

   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.

4. Oxygen Saturation / Fractional Inhaled Oxygen (S/F) [ Time Frame: 7 days ]
   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.
5. 28-Day Mortality [ Time Frame: 28 days ]
   Outcome reported as the number of participants who have expired at 28 days post enrollment.
6. 90-Day Mortality [ Time Frame: 90 days ]
   Outcome reported as the number of participants who have expired at 90 days post enrollment.
7. ICU Admission [ Time Frame: 10 days ]
   Outcome reported as the number of participants in each arm who require admission to the Intensive Care Unit (ICU).
8. Number of Ventilator-Free Days [ Time Frame: 28 days ]
   Outcome reported as the mean number of days participants in each arm did not require mechanical ventilation during an in-patient hospital admission.
9. Number of Therapeutic Oxygen-Free Days [ Time Frame: 28 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.
10. Number of Vasopressor-Free Days [ Time Frame: 10 days ]
    Outcome reported as the mean number of days participants in each arm did not require vasopressor usage during an in-patient hospital admission.
11. Length of Hospital Stay [ Time Frame: 90 days ]
    Outcome reported as the mean length of in-patient hospital stay (in days) for participants in each arm.
12. Disease Severity Rating [ Time Frame: 28 days ]
    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.
13. Change in Viral Load by Nasopharyngeal Swab Day 15 [ Time Frame: 15 days ]
    Nasopharyngeal swabs will be collected at baseline and day 15. Viral load is measured as number of viral genetic copies per mL.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Florida

University of Florida Health Gainesville

Gainesville, Florida, United States, 32611

University of Florida Health Jacksonville

Jacksonville, Florida, United States, 32209

United States, Georgia

Grady Memorial Hospital

Atlanta, Georgia, United States, 30303

United States, Michigan

Henry Ford Hospital

Detroit, Michigan, United States, 48202

United States, Minnesota

M Health Fairview Ridges Hospital

Burnsville, Minnesota, United States, 55337

M Health Fairview Southdale Hospital

Edina, Minnesota, United States, 55435

Hennepin County Medical Center

Minneapolis, Minnesota, United States, 55415

M Health Fairview University of Minnesota Medical Center

Minneapolis, Minnesota, United States, 55455

University of Minnesota

Minneapolis, Minnesota, United States, 55455

North Memorial Health Hospital

Robbinsdale, Minnesota, United States, 55422

United States, Mississippi

University of Mississippi Medical Center

Jackson, Mississippi, United States, 39216

United States, New Jersey

Cooper University Hospital

Camden, New Jersey, United States, 08103

United States, Ohio

University of Cincinnati Medical Center

Cincinnati, Ohio, United States, 45267

Sponsors and Collaborators

University of Minnesota

Bill and Melinda Gates Foundation

Investigators

• Principal Investigator: Christopher Tignanelli, MD; University of Minnesota
• Principal Investigator: Michael Puskarich, MD, MS; University of Minnesota

  Study Documents (Full-Text)

Documents provided by University of Minnesota:

Study Protocol and Statistical Analysis Plan  [PDF] April 22, 2020

Informed Consent Form  [PDF] April 2, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: University of Minnesota
• ClinicalTrials.gov Identifier: NCT04312009
• Other Study ID Numbers: SURG-2020-28675; INV-017069 ( Other Grant/Funding Number: Bill and Melinda Gates Foundation )
• First Posted: March 17, 2020
• Results First Posted: June 29, 2022
• Last Update Posted: June 29, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by University of Minnesota:

COVID-19; Corona Virus; SARS-COV-2

Additional relevant MeSH terms:

Infections; Communicable Diseases; Coronavirus Infections; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Disease Attributes; Pathologic Processes; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Infant, Premature, Diseases; Infant, Newborn, Diseases; Lung Injury; Losartan; Anti-Arrhythmia Agents; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Molecular Mechanisms of Pharmacological Action