Acute Respiratory Distress Syndrome, Corona Virus Infection, SARS-CoV Infection
Conditions
Keywords
COVID-19, Corona Virus, SARS-COV-2
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.
Interventions
DRUGLosartan
Losartan; 50 mg daily; oral administration
OTHERPlacebo
Placebo (microcrystalline methylcellulose, gelatin capsule); oral administration
Sponsors
Bill and Melinda Gates Foundation
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in Estimated (PEEP Adjusted) P/F Ratio at 7 Days | 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
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Requiring Vasopressors for Hypotension | 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 | 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) | 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 | 28 days | Outcome reported as the number of participants who have expired at 28 days post enrollment. |
| 90-Day Mortality | 90 days | Outcome reported as the number of participants who have expired at 90 days post enrollment. |
| ICU Admission | 10 days | Outcome reported as the number of participants in each arm who require admission to the Intensive Care Unit (ICU). |
| Daily Hypotensive Episodes | 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. |
| Number of Therapeutic Oxygen-Free Days | 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 | 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 | 90 days | Outcome reported as the mean length of in-patient hospital stay (in days) for participants in each arm. |
| Disease Severity Rating | 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 | 15 days | Nasopharyngeal swabs will be collected at baseline and day 15. Viral load is measured as number of viral genetic copies per mL. |
| Number of Ventilator-Free Days | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants in this arm will receive a placebo treatment.
Placebo: Placebo (microcrystalline methylcellulose, gelatin capsule); oral administration | 104 |
| Losartan Participants in this arm will receive the study drug, Losartan.
Losartan: Losartan; 50 mg daily; oral administration | 101 |
| Total | 205 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Placebo | Losartan | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 24 Participants | 23 Participants | 47 Participants |
| Age, Categorical Between 18 and 65 years | 80 Participants | 78 Participants | 158 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 7 Participants | 9 Participants |
| Race (NIH/OMB) Black or African American | 30 Participants | 37 Participants | 67 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 24 Participants | 22 Participants | 46 Participants |
| Race (NIH/OMB) White | 47 Participants | 35 Participants | 82 Participants |
| Sex: Female, Male Female | 41 Participants | 41 Participants | 82 Participants |
| Sex: Female, Male Male | 63 Participants | 60 Participants | 123 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 11 / 104 | 11 / 101 |
| other Total, other adverse events | 90 / 104 | 101 / 101 |
| serious Total, serious adverse events | 30 / 104 | 36 / 101 |
Outcome results
Primary
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.
Time frame: 7 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Difference in Estimated (PEEP Adjusted) P/F Ratio at 7 Days | 281.4 ratio |
| Losartan | Difference in Estimated (PEEP Adjusted) P/F Ratio at 7 Days | 260.9 ratio |
Secondary
28-Day Mortality
Outcome reported as the number of participants who have expired at 28 days post enrollment.
Time frame: 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | 28-Day Mortality | 0.087 proportion of participants |
| Losartan | 28-Day Mortality | 0.11 proportion of participants |
Secondary
90-Day Mortality
Outcome reported as the number of participants who have expired at 90 days post enrollment.
Time frame: 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | 90-Day Mortality | 0.106 proportion of participants |
| Losartan | 90-Day Mortality | 0.11 proportion of participants |
Secondary
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.
Time frame: 15 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change in Viral Load by Nasopharyngeal Swab Day 15 | -4.2 log10 copies/mL |
| Losartan | Change in Viral Load by Nasopharyngeal Swab Day 15 | -4.8 log10 copies/mL |
Secondary
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.
Time frame: 10 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Daily Hypotensive Episodes | 0.048 episodes per day |
| Losartan | Daily Hypotensive Episodes | 0.119 episodes per day |
Secondary
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.
Time frame: 28 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Disease Severity Rating | 4.3 score |
| Losartan | Disease Severity Rating | 4.2 score |
Secondary
ICU Admission
Outcome reported as the number of participants in each arm who require admission to the Intensive Care Unit (ICU).
Time frame: 10 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | ICU Admission | 0.272 proportion of participants |
| Losartan | ICU Admission | 0.36 proportion of participants |
Secondary
Length of Hospital Stay
Outcome reported as the mean length of in-patient hospital stay (in days) for participants in each arm.
Time frame: 90 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Length of Hospital Stay | 5.9 days |
| Losartan | Length of Hospital Stay | 7.1 days |
Secondary
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.
Time frame: 28 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Number of Therapeutic Oxygen-Free Days | 24.6 days |
| Losartan | Number of Therapeutic Oxygen-Free Days | 23.6 days |
Secondary
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.
Time frame: 10 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Number of Vasopressor-Free Days | 9.4 days |
| Losartan | Number of Vasopressor-Free Days | 8.7 days |
Secondary
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.
Time frame: 28 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Number of Ventilator-Free Days | 18.4 days |
| Losartan | Number of Ventilator-Free Days | 18.1 days |
Secondary
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.
Time frame: 7 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Oxygen Saturation / Fractional Inhaled Oxygen (S/F) | 357.4 n/a (ratio) |
| Losartan | Oxygen Saturation / Fractional Inhaled Oxygen (S/F) | 331.5 n/a (ratio) |
Secondary
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.
Time frame: 10 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Participants Experiencing Acute Kidney Injury | 0.106 proportion of participants |
| Losartan | Proportion of Participants Experiencing Acute Kidney Injury | 0.119 proportion of participants |
Secondary
Proportion of Participants Requiring Vasopressors for Hypotension
Outcome reported as the number of participants in each arm requiring the use of vasopressors for hypotension.
Time frame: 10 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Participants Requiring Vasopressors for Hypotension | 0.106 proportion of participants |
| Losartan | Proportion of Participants Requiring Vasopressors for Hypotension | 0.198 proportion of participants |