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Losartan for Patients With COVID-19 Requiring Hospitalization

Primary Purpose

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

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Losartan
Placebo
Sponsored by
University of Minnesota
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Corona Virus Infection focused on measuring COVID-19, Corona Virus, SARS-COV-2

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Florida Health Gainesville
  • University of Florida Health Jacksonville
  • Grady Memorial Hospital
  • Henry Ford Hospital
  • M Health Fairview Ridges Hospital
  • M Health Fairview Southdale Hospital
  • Hennepin County Medical Center
  • M Health Fairview University of Minnesota Medical Center
  • University of Minnesota
  • North Memorial Health Hospital
  • University of Mississippi Medical Center
  • Cooper University Hospital
  • University of Cincinnati Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Losartan

Placebo

Arm Description

Participants in this arm will receive the study drug, Losartan.

Participants in this arm will receive a placebo treatment.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
Proportion of Participants Requiring Vasopressors for Hypotension
Outcome reported as the number of participants in each arm requiring the use of vasopressors for hypotension.
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.
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.
28-Day Mortality
Outcome reported as the number of participants who have expired at 28 days post enrollment.
90-Day Mortality
Outcome reported as the number of participants who have expired at 90 days post enrollment.
ICU Admission
Outcome reported as the number of participants in each arm who require admission to the Intensive Care Unit (ICU).
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.
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.
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.
Length of Hospital Stay
Outcome reported as the mean length of in-patient hospital stay (in days) for participants in each arm.
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.
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.

Full Information

First Posted
March 13, 2020
Last Updated
June 27, 2022
Sponsor
University of Minnesota
Collaborators
Bill and Melinda Gates Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT04312009
Brief Title
Losartan for Patients With COVID-19 Requiring Hospitalization
Official Title
Randomized Controlled Trial of Losartan for Patients With COVID-19 Requiring Hospitalization
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Completed
Study Start Date
April 13, 2020 (Actual)
Primary Completion Date
February 1, 2021 (Actual)
Study Completion Date
February 1, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Minnesota
Collaborators
Bill and Melinda Gates Foundation

4. Oversight

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
Data Monitoring Committee
Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Corona Virus Infection, Acute Respiratory Distress Syndrome, SARS-CoV Infection
Keywords
COVID-19, Corona Virus, SARS-COV-2

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
205 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Losartan
Arm Type
Experimental
Arm Description
Participants in this arm will receive the study drug, Losartan.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Participants in this arm will receive a placebo treatment.
Intervention Type
Drug
Intervention Name(s)
Losartan
Other Intervention Name(s)
Cozaar
Intervention Description
Losartan; 50 mg daily; oral administration
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Placebo (microcrystalline methylcellulose, gelatin capsule); oral administration
Primary Outcome Measure Information:
Title
Difference in Estimated (PEEP Adjusted) P/F Ratio at 7 Days
Description
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.
Time Frame
7 days
Secondary Outcome Measure Information:
Title
Daily Hypotensive Episodes
Description
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.
Time Frame
10 days
Title
Proportion of Participants Requiring Vasopressors for Hypotension
Description
Outcome reported as the number of participants in each arm requiring the use of vasopressors for hypotension.
Time Frame
10 days
Title
Proportion of Participants Experiencing Acute Kidney Injury
Description
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.
Time Frame
10 days
Title
Oxygen Saturation / Fractional Inhaled Oxygen (S/F)
Description
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.
Time Frame
7 days
Title
28-Day Mortality
Description
Outcome reported as the number of participants who have expired at 28 days post enrollment.
Time Frame
28 days
Title
90-Day Mortality
Description
Outcome reported as the number of participants who have expired at 90 days post enrollment.
Time Frame
90 days
Title
ICU Admission
Description
Outcome reported as the number of participants in each arm who require admission to the Intensive Care Unit (ICU).
Time Frame
10 days
Title
Number of Ventilator-Free Days
Description
Outcome reported as the mean number of days participants in each arm did not require mechanical ventilation during an in-patient hospital admission.
Time Frame
28 days
Title
Number of Therapeutic Oxygen-Free Days
Description
Outcome reported as the mean number of days participants in each arm did not require therapeutic oxygen usage during an in-patient hospital admission.
Time Frame
28 days
Title
Number of Vasopressor-Free Days
Description
Outcome reported as the mean number of days participants in each arm did not require vasopressor usage during an in-patient hospital admission.
Time Frame
10 days
Title
Length of Hospital Stay
Description
Outcome reported as the mean length of in-patient hospital stay (in days) for participants in each arm.
Time Frame
90 days
Title
Disease Severity Rating
Description
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.
Time Frame
28 days
Title
Change in Viral Load by Nasopharyngeal Swab Day 15
Description
Nasopharyngeal swabs will be collected at baseline and day 15. Viral load is measured as number of viral genetic copies per mL.
Time Frame
15 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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: 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christopher Tignanelli, MD
Organizational Affiliation
University of Minnesota
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Michael Puskarich, MD, MS
Organizational Affiliation
University of Minnesota
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Florida Health Gainesville
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32611
Country
United States
Facility Name
University of Florida Health Jacksonville
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32209
Country
United States
Facility Name
Grady Memorial Hospital
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30303
Country
United States
Facility Name
Henry Ford Hospital
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
M Health Fairview Ridges Hospital
City
Burnsville
State/Province
Minnesota
ZIP/Postal Code
55337
Country
United States
Facility Name
M Health Fairview Southdale Hospital
City
Edina
State/Province
Minnesota
ZIP/Postal Code
55435
Country
United States
Facility Name
Hennepin County Medical Center
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55415
Country
United States
Facility Name
M Health Fairview University of Minnesota Medical Center
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
North Memorial Health Hospital
City
Robbinsdale
State/Province
Minnesota
ZIP/Postal Code
55422
Country
United States
Facility Name
University of Mississippi Medical Center
City
Jackson
State/Province
Mississippi
ZIP/Postal Code
39216
Country
United States
Facility Name
Cooper University Hospital
City
Camden
State/Province
New Jersey
ZIP/Postal Code
08103
Country
United States
Facility Name
University of Cincinnati Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45267
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
35294537
Citation
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.
Results Reference
derived
PubMed Identifier
32658300
Citation
Smolander J, Bruchfeld A. [COVID-19 and kidney disease]. Lakartidningen. 2020 Jul 13;117:20110. Swedish.
Results Reference
derived

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Losartan for Patients With COVID-19 Requiring Hospitalization

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