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

Tracking Information

• First Submitted Date: March 13, 2020
• First Posted Date: March 17, 2020
• Results First Submitted Date: March 15, 2022
• Results First Posted Date: June 29, 2022
• Last Update Posted Date: June 29, 2022
• Actual Study Start Date: April 13, 2020
• Actual Primary Completion Date: February 1, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 15, 2022)

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.

Original Primary Outcome Measures (submitted: March 13, 2020)

Sequential Organ Failure Assessment (SOFA) Respiratory Score [ Time Frame: 28 days ]

The SOFA assessment is used to track a person's risk status during stay in the Intensive Care Unit (ICU). The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems. Each organ system is assigned a point value from 0 (normal) to 4 (high degree of dysfunction/failure). Outcome is reported as only the respiratory component score. Respiratory scores range from 0-4, with higher scores indicating greater chance of mortality due to respiratory failure.

Current Secondary Outcome Measures (submitted: June 27, 2022)

• 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.
• 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.
• 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.
• 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.
• 28-Day Mortality [ Time Frame: 28 days ]
  Outcome reported as the number of participants who have expired at 28 days post enrollment.
• 90-Day Mortality [ Time Frame: 90 days ]
  Outcome reported as the number of participants who have expired at 90 days post enrollment.
• 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).
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Original Secondary Outcome Measures (submitted: March 13, 2020)

• 28-Day Mortality [ Time Frame: 28 days ]
  Outcome reported as the number of participants who have expired at 28 days post enrollment.
• 90-Day Mortality [ Time Frame: 90 days ]
  Outcome reported as the number of participants who have expired at 90 days post enrollment.
• Respiratory Failure Requiring Mechanical Ventilation [ Time Frame: 7 days ]
  Outcome reported as the number of participants receiving in-patient hospital care requiring mechanical ventilation due to respiratory failure.
• Number of 28-Day 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.
• Length of Hospital Stay [ Time Frame: approximately 28 days ]
  Outcome reported as the mean length of in-patient hospital stay (in days) for participants in each arm.
• ICU Admission [ Time Frame: approximately 28 days ]
  Outcome reported as the number of participants in each arm who require admission to the Intensive Care Unit (ICU).
• ICU Length of Stay [ Time Frame: approximately 28 days ]
  Outcome reported as the mean length of stay (in days) in the Intensive Care Unit (ICU) for participants in each arm.
• Acute Kidney Injury [ Time Frame: approximately 28 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:

  1. Increase in serum creatinine by 0.3mg/dL or more within 48 hours OR
  2. Increase in serum creatinine to 1.5 times baseline or more within the last 7 days OR
  3. Urine output less than 0.5 mL/kg/h for 6 hours.
• Hypotension Requiring Vasopressors [ Time Frame: approximately 28 days ]
  Outcome reported as the number of participants in each arm requiring the use of vasopressors for hypotension.
• Sequential Organ Failure Assessment (SOFA) Total Score [ Time Frame: approximately 14 days ]
  The SOFA assessment is used to track a person's risk status during stay in the Intensive Care Unit (ICU). The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems. Each organ system is assigned a point value from 0 (normal) to 4 (high degree of dysfunction/failure). Total score is calculated by entering patient data into a SOFA calculator, a widely-available software. Total scores range from 0-24, with higher scores indicating greater chance of mortality.
• Severity Assessment [ Time Frame: 15 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.
• Incidence of Respiratory Failure [ Time Frame: approximately 28 days ]
  Outcome reported as the number of participants requiring BiPAP OR high flow nasal cannula OR mechanical ventilation OR extracorporeal membranous oxygenation (ECMO) utilization during in-patient hospital care in each arm.
• Oxygen Saturation / Fractional Inhaled Oxygen (F/S) [ Time Frame: 72 hours ]
  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 F/S ratio is unitless.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Losartan for Patients With COVID-19 Requiring Hospitalization
• Official Title: Randomized Controlled Trial of Losartan for Patients With COVID-19 Requiring Hospitalization
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

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

Intervention

• Drug: Losartan
  Losartan; 50 mg daily; oral administration
  Other Name: Cozaar
• Other: Placebo
  Placebo (microcrystalline methylcellulose, gelatin capsule); oral administration

Study Arms

• Experimental: Losartan
  Participants in this arm will receive the study drug, Losartan.
  Intervention: Drug: Losartan
• Placebo Comparator: Placebo
  Participants in this arm will receive a placebo treatment.
  Intervention: Other: Placebo

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 16, 2021): 205
• Original Estimated Enrollment (submitted: March 13, 2020): 200
• Actual Study Completion Date: February 1, 2021
• Actual Primary Completion Date: February 1, 2021 (Final data collection date for primary outcome measure)

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:

  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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04312009
• Other Study ID Numbers: SURG-2020-28675; INV-017069 ( Other Grant/Funding Number: Bill and Melinda Gates Foundation )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University of Minnesota
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Minnesota
• Original Study Sponsor: Same as current
• Collaborators: Bill and Melinda Gates Foundation

Investigators

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

• PRS Account: University of Minnesota
• Verification Date: June 2022