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 randomized 1:1 to daily losartan or placebo for 10 days or treatment failure (hospital admission).
Interventions
DRUGLosartan
Losartan; 25 mg daily; oral administration
OTHERPlacebo
Placebo (microcrystalline methylcellulose, gelatin capsule); oral administration
Sponsors
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
* Positive laboratory test for COVID-19 based on local laboratory standard * Age greater than or equal to 18 years of age * One of the following: Upper respiratory symptoms (cough, rhinorrhea) or fever (\>101.5) or loss of taste / smell
Exclusion criteria
* Randomization \> 72 hours of meeting inclusion criteria * Randomization \> 7 days of symptom onset * 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 women * Females able to have children 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, condom use or abstinence during the study. All participants of child bearing potential enrolled in this fashion will be informed of the teratogenic risks. * 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 (must be have been measured within 1 month of enrollment) 4. Other kidney disease that in the opinion of the investigator, would affect losartan clearance * Patient reported dehydration and significantly decreased urine output in the past 72 hours * Most recent systolic blood pressure prior to enrollment \<110 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. Other liver disease that in the opinion of the investigator, would affect losartan clearance 4. Documented AST or ALT \> 3 times the upper limit of normal within 3 months of randomization (if available in electronic medical record) * Potassium \>5.0 mmol/L (must have been measured within 1 month) of enrollment * Concurrent treatment with aliskiren * Inability to obtain informed consent * Enrollment in another blinded randomized clinical trial for COVID
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Admitted to the Hospital | 15 days | Outcome reported as the percentage of participants per arm admitted to inpatient hospital care due to COVID-19-related disease within 15 days of randomization. Currently, there is a pre-planned pooled analysis with a national trial network under development. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in SF-12 Physical Composite Score | 10 days | The SF-12 is a self-reported validated outcome measure assessing the impact of health on an individual's everyday life. Patients fill out a 12 question survey which is then scored by a clinician or researcher. Physical score is computed using the scores of twelve questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health. The 33-item Severity bank assesses the severity of difficulty breathing during various specific activities (the same 33 activities assessed in Dyspnea Functional Limitations). Each activity is rated in terms of degree of dyspnea (0 = no shortness of breath, 1 = mildly short of breath, 2 = moderately short of breath, 3 = severely short of breath) while engaging in the activity over the past 7 days. Total scores range from 0 to 99 with higher scores reflecting greater levels of dyspnea during daily activity. |
| Change in SF-12 Mental Composite Score | 10 days | The SF-12 is a self-reported validated outcome measure assessing the impact of health on an individual's everyday life. Patients fill out a 12 question survey which is then scored by a clinician or researcher. Mental composite score is computed using the scores of twelve questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health. |
| Daily Maximum Temperature | 10 days | Participants will report their maximum daily oral temperature to the study team. Outcome is reported as the mean maximum daily body temperature (in degrees Celsius) over 10 days. |
| Count of Participants With an Emergency Department or Clinic Presentation | 28 days | Outcome is reported as the mean number of emergency department and clinic presentations combined per participant in each arm. |
| Change in PROMIS Dyspnea Scale | 10 days | The PROMIS dyspnea scale consists of 4 subscales. 3 (1. general shortness of breath, 2. intensity, and 3. Frequency) are scored from 0 (no symptoms) to 10 (most severe). The 4th subscale is scored from 0-4 in response to the question I've been short of breath with 0 representing none and 4 the most severe, for a total range of 0-34. Results are difference between enrollment and day 10. There are no units. |
| Change in Viral Load by Nasopharyngeal Swab at Day 9 | 9 days | Viral load is measured as number of viral genetic copies per mL. |
| Change in Viral Load by Nasopharyngeal Swab at Day 15 | 15 days | Viral load is measured as number of viral genetic copies per mL. |
| Percentage of Patients Admitted to the Intensive Care Unit Within 15 Days | 15 days | Outcome reported as the percent of participants in each arm who require ICU admission by day 15 following randomization. |
| Need for Oxygen Therapy at 15 Days | 15 days | Outcome reported as the percent of participants in each arm who require oxygen therapy by day 15 following randomization. |
| Disease Severity Rating Day 15 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Losartan Participants in this arm will receive the study drug, Losartan.
Losartan: Losartan; 25 mg daily; oral administration | 58 |
| Placebo Participants in this arm will receive a placebo treatment.
Placebo: Placebo (microcrystalline methylcellulose, gelatin capsule); oral administration | 59 |
| Total | 117 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Physician Decision | 4 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Losartan | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 0 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 55 Participants | 59 Participants | 114 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 5 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 4 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 10 Participants | 18 Participants |
| Race (NIH/OMB) White | 45 Participants | 40 Participants | 85 Participants |
| Sex: Female, Male Female | 33 Participants | 25 Participants | 58 Participants |
| Sex: Female, Male Male | 25 Participants | 34 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 58 | 0 / 59 |
| other Total, other adverse events | 43 / 58 | 56 / 59 |
| serious Total, serious adverse events | 3 / 58 | 1 / 59 |
Outcome results
Primary
Percentage of Participants Admitted to the Hospital
Outcome reported as the percentage of participants per arm admitted to inpatient hospital care due to COVID-19-related disease within 15 days of randomization. Currently, there is a pre-planned pooled analysis with a national trial network under development.
Time frame: 15 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Losartan | Percentage of Participants Admitted to the Hospital | 5.2 percentage of participants |
| Placebo | Percentage of Participants Admitted to the Hospital | 1.7 percentage of participants |
Secondary
Change in PROMIS Dyspnea Scale
The PROMIS dyspnea scale consists of 4 subscales. 3 (1. general shortness of breath, 2. intensity, and 3. Frequency) are scored from 0 (no symptoms) to 10 (most severe). The 4th subscale is scored from 0-4 in response to the question I've been short of breath with 0 representing none and 4 the most severe, for a total range of 0-34. Results are difference between enrollment and day 10. There are no units.
Time frame: 10 days
Population: Only 50 patients were analyzed for this outcome measure due to loss to follow-up or refusal to complete the survey resulting in data missingness.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Losartan | Change in PROMIS Dyspnea Scale | -0.4 score on a scale | Standard Deviation 0.9 |
| Placebo | Change in PROMIS Dyspnea Scale | -0.5 score on a scale | Standard Deviation 0.7 |
Secondary
Change in SF-12 Mental Composite Score
The SF-12 is a self-reported validated outcome measure assessing the impact of health on an individual's everyday life. Patients fill out a 12 question survey which is then scored by a clinician or researcher. Mental composite score is computed using the scores of twelve questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health.
Time frame: 10 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Losartan | Change in SF-12 Mental Composite Score | -0.1 score | Standard Deviation 6.5 |
| Placebo | Change in SF-12 Mental Composite Score | -0.3 score | Standard Deviation 5.7 |
Secondary
Change in SF-12 Physical Composite Score
The SF-12 is a self-reported validated outcome measure assessing the impact of health on an individual's everyday life. Patients fill out a 12 question survey which is then scored by a clinician or researcher. Physical score is computed using the scores of twelve questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health. The 33-item Severity bank assesses the severity of difficulty breathing during various specific activities (the same 33 activities assessed in Dyspnea Functional Limitations). Each activity is rated in terms of degree of dyspnea (0 = no shortness of breath, 1 = mildly short of breath, 2 = moderately short of breath, 3 = severely short of breath) while engaging in the activity over the past 7 days. Total scores range from 0 to 99 with higher scores reflecting greater levels of dyspnea during daily activity.
Time frame: 10 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Losartan | Change in SF-12 Physical Composite Score | 1.4 score | Standard Deviation 9.1 |
| Placebo | Change in SF-12 Physical Composite Score | 0.2 score | Standard Deviation 6.5 |
Secondary
Change in Viral Load by Nasopharyngeal Swab at Day 15
Viral load is measured as number of viral genetic copies per mL.
Time frame: 15 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Losartan | Change in Viral Load by Nasopharyngeal Swab at Day 15 | -3.7 log10 copies/mL | Standard Error 0.33 |
| Placebo | Change in Viral Load by Nasopharyngeal Swab at Day 15 | -4 log10 copies/mL | Standard Error 0.29 |
Secondary
Change in Viral Load by Nasopharyngeal Swab at Day 9
Viral load is measured as number of viral genetic copies per mL.
Time frame: 9 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Losartan | Change in Viral Load by Nasopharyngeal Swab at Day 9 | -3.8 log10 copies/mL | Standard Error 0.3 |
| Placebo | Change in Viral Load by Nasopharyngeal Swab at Day 9 | -3.6 log10 copies/mL | Standard Error 0.29 |
Secondary
Count of Participants With an Emergency Department or Clinic Presentation
Outcome is reported as the mean number of emergency department and clinic presentations combined per participant in each arm.
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Losartan | Count of Participants With an Emergency Department or Clinic Presentation | 10 Participants |
| Placebo | Count of Participants With an Emergency Department or Clinic Presentation | 5 Participants |
Secondary
Daily Maximum Temperature
Participants will report their maximum daily oral temperature to the study team. Outcome is reported as the mean maximum daily body temperature (in degrees Celsius) over 10 days.
Time frame: 10 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Losartan | Daily Maximum Temperature | 97.7 degrees Farenheit | Standard Error 0.097 |
| Placebo | Daily Maximum Temperature | 97.8 degrees Farenheit | Standard Error 0.092 |
Secondary
Disease Severity Rating Day 15
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: 15 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Losartan | Disease Severity Rating Day 15 | 5.8 score | Standard Deviation 0.5 |
| Placebo | Disease Severity Rating Day 15 | 5.9 score | Standard Deviation 0.7 |
Secondary
Need for Oxygen Therapy at 15 Days
Outcome reported as the percent of participants in each arm who require oxygen therapy by day 15 following randomization.
Time frame: 15 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Losartan | Need for Oxygen Therapy at 15 Days | 1.7 percentage of participants |
| Placebo | Need for Oxygen Therapy at 15 Days | 1.7 percentage of participants |
Secondary
Percentage of Patients Admitted to the Intensive Care Unit Within 15 Days
Outcome reported as the percent of participants in each arm who require ICU admission by day 15 following randomization.
Time frame: 15 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Losartan | Percentage of Patients Admitted to the Intensive Care Unit Within 15 Days | 1.7 percentage of participants |
| Placebo | Percentage of Patients Admitted to the Intensive Care Unit Within 15 Days | 1.7 percentage of participants |