COVID-19
Conditions
Keywords
COVID-19, losartan, respiratory failure, SARS-CoV-2
Brief summary
This is an open label, phase 1 clinical trial to evaluate the safety of losartan in respiratory failure due to COVID-19. Briefly, 34 patients with COVID-19 and respiratory failure who meet eligibility criteria and agree to participation in the study will be placed on losartan 25 mg daily on study day 0. If parameters are met the dose of losartan will be increased to 50 mg once daily on study day 3. Participants will continue losartan until they experience resolution of respiratory failure (normal oxygen levels on room air), are discharged from the hospital, meet stoppage criteria (detailed below) or complete 14 days of therapy. Patients and/or surrogate decision maker who do not give consent to treatment will be asked to allow collection of data from their medical record for use as a control group. We will also collect medical information relating to safety criteria on historical controls treated at the University of Kansas Hospital in the 30 days prior to the study start date and during the study period.
Detailed description
This is an open label, phase 1 clinical trial to evaluate the safety of losartan in respiratory failure due to COVID-19. Clinical Trial setup: Detailed inclusion and exclusion criteria are listed below. Briefly, 34 patients with COVID-19 and respiratory failure who meet criteria and agree to participation in the study will be placed on losartan 25 mg daily on study day 0. If parameters are met the dose of losartan will be increased to 50 mg once daily on study day 3. Participants will continue losartan until they experience resolution of respiratory failure (normal oxygen levels on room air), are discharged from the hospital, meet stoppage criteria (detailed below) or complete 14 days of therapy. Patients and/or surrogate decision maker who do not give consent to treatment will be asked to allow collection of data from their medical record for use as a control group. Stoppage criteria for losartan * Hyperkalemia (persistent values \>5.5 mM recorded on at least 2 readings). * Worsening renal function (Cockcroft-Gault \<30 mL/min/1.73 m2) or urinary output \<20 mL/h. * Skin rashes, palpitations or other moderate or severe adverse events (interference with usual daily activities) without clear explanation should warrant immediate cessation of treatment and notification of study personnel. * Development of sustained hypotension defined as SBP \<90 mmHg, DBP \<60 mmHg recorded on at least two readings 30 min apart or use of norepinephrine \>0.1 µg/kg/min. * Any change in monitor lab parameters deemed significant and potentially related to study drug by the Investigator.
Interventions
DRUGLosartan
25 mg QD from day 0 to day 3. Dose escalation to 50 mg QD until study completion
Sponsors
University of Kansas Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
30 patients with COVID-19 and respiratory failure who meet criteria and agree to participation in the study will be placed on losartan 25 mg once daily on study day 0. If parameters are met the dose of losartan will be increased to 50 mg once daily on study day 3. Patients and/or surrogate decision maker who do not give consent to treatment will be asked to allow collection of data from their medical record for use as a control group. We will also collect medical information relating to safety criteria on historical controls treated at the University of Kansas Hospital in the 30 days prior to the study start date and during the study period.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \>18 years admitted to the University of Kansas Health System. * Confirmation of infection with SARS-CoV-2 by PCR testing. * Hypoxic respiratory failure Requiring mechanical ventilation or oxygen OR a SpO2 ≤94% on room air or a PaO2/FiO2 (P/F) ratio \<300 OR tachypnea (respiratory rate ≥24 breaths/min). Criteria to be met within 48 hours prior to Day 0. * Other concomitant medications such as antivirals and hydroxychloroquine are allowed. * Participants prescribed standard of care (SOC) losartan (25mg QD) within 48 hours of consenting may be considered for enrollment if eligibility criteria are met based on EMR data assessment, i.e. no other ARB or ACE prior to SOC medication administration. If participant is eligible and signs consent form, investigational losartan 25mg QD will be ordered to replace SOC prescription on the following scheduled dose.
Exclusion criteria
* Pregnancy. * Respiratory failure due to a process other than COVID-19. * Intolerance to ARBs. * Previous treatment with an ARB or ACE inhibitor (see exception in inclusion criteria). * Current chronic use of medication with known interactions with losartan including NSAIDs (intermittent prior use is acceptable), potassium supplementation aliskiren. * Blood pressure less than 90 mm Hg systolic or 60 mm Hg diastolic recorded on at least two readings 30 min apart. * Need for vasopressors, unless norepinephrine ≤0.1 µg/kg/min * Hyperkalemia (serum K+ \>5.5 mM). * Known cardiac failure (left ventricular ejection fraction ≤35%), renal insufficiency (Cockcroft-Gault \<30 mL/min/1.73 m2 or urinary output \<20 mL/h), hepatic failure (LFTs \> 5x normal upper limit). * Known renal artery stenosis. * Neurological, psychiatric, endocrine or neoplastic diseases that are judged to interfere with participation in the study. * On another interventional trial (including one for COVID-19) that excludes participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-related Adverse Events as Assessed by Protocol Definition of AE | 14 days of losartan treatment | Safety will be reported based on Protocol defined AEs. For the purpose of this protocol, an AE will be defined as as any untoward medical occurrence in a subject during the study listed under DMSB - Anticipated Adverse Events and Grading Scale section of this protocol as well as safety monitoring data listed on protocol table 1 as well as stoppage criteria for losartan. The event does not necessarily have a causal relationship with the treatment. AEs will be collected for both study groups, treatment and control from the time the ICF is signed until the subject completes study participation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Mechanical Ventilation Use | 14 days of losartan treatment | Number of participants with mechanical ventilation use |
| Days on Mechanical Ventilation | 14 days of losartan treatment | Days on mechanical ventilation |
| Number of Participants With Non-invasive Positive Pressure Ventilation or Heated High Flow Nasal Cannula Use | 14 days of losartan treatment | Number of participants with non-invasive positive pressure ventilation or heated high flow nasal cannula use |
| Days on Non-invasive Positive Pressure Ventilation or High Flow Nasal Cannula | 14 days of losartan treatment | Days on non-invasive positive pressure ventilation or high flow nasal cannula |
| Number of Participants With Transfer to ICU From Non-ICU Hospital Bed | 14 days of losartan treatment | Number of participants with transfer to ICU from non-ICU hospital bed |
| ICU Length of Stay (Days) | 14 days of losartan treatment | ICU length of stay (days) |
| in Hospital Mortality Rate | 14 days after study enrollment | in hospital mortality rate |
| Number of Days on Supplemental Oxygen in Respiratory Failure Due to COVID-19 | 14 days of losartan treatment | Number of days on supplemental oxygen in respiratory failure due to COVID-19 |
| Cumulative Number of Participants With of Severe Adverse Events | 14 days of losartan treatment | Cumulative number of participants with severe adverse events |
| Number of Participants With Increase of Supplemental Oxygen Needs From Baseline. | 14 days of losartan treatment | Number of participants with increase in supplemental oxygen needs from baseline. |
| Number of Participants With Medications With Possible Antiviral Activity (Hydroxychloroquine, Lopinavir/Ritonavir, Ribavirin or Remdesivir) or Adjunctive Therapy Use (e.g., Tocilizumab) | 14 days of losartan treatment | Number of participants with medications with possible antiviral activity (hydroxychloroquine, lopinavir/ritonavir, ribavirin or remdesivir) or adjunctive therapy use (e.g., tocilizumab) |
| Number of Participants With Extracorporeal Membrane Oxygenation Use | 14 days of losartan treatment | Number of participants with extracorporeal membrane oxygenation use |
| Number of Participants With Renal Replacement Therapy Use | 14 days of losartan treatment | Number of participants with renal replacement therapy use |
| Number of Participants With Intolerance to High Dose (50mg) Losartan After Tolerating 25mg | 14 days of losartan treatment | Number of participants with intolerance to high dose (50mg) losartan after tolerating 25mg |
| Hospital Length of Stay (Days) | from enrollment through hospital discharge | Hospital length of stay (days) |
Countries
United States
Participant flow
Pre-assignment details
External control group were hospitalized during study period and met enrollment criteria and were not enrolled. Participants were matched to losartan group on baseline characteristics.
Participants by arm
| Arm | Count |
|---|---|
| Open Label Losartan 34 patients with COVID-19 and respiratory failure participated in the study and were placed on losartan 25 mg once daily on study day 0. Losartan dose was increased to 50 mg once daily on study day 3. Participants continued losartan until they experienced resolution of respiratory failure (normal oxygen levels on room air), were discharged from the hospital, met stoppage criteria or completed 14 days of therapy.
Losartan: 25 mg QD from day 0 to day 3. Dose escalation to 50 mg QD until study completion | 30 |
| External Controls 46 external controls matched to losartan participants upon baseline characteristics. | 46 |
| Total | 76 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | External Controls | Total | Open Label Losartan |
|---|---|---|---|
| Age, Continuous | 53.8 years STANDARD_DEVIATION 15.5 | 54 years STANDARD_DEVIATION 15.3 | 54.2 years STANDARD_DEVIATION 15.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 21 Participants | 29 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 | 12 Participants | 19 Participants | 7 Participants |
| Race (NIH/OMB) White | 11 Participants | 26 Participants | 15 Participants |
| Sex: Female, Male Female | 21 Participants | 34 Participants | 13 Participants |
| Sex: Female, Male Male | 25 Participants | 42 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 30 | 3 / 46 |
| other Total, other adverse events | 24 / 30 | 44 / 46 |
| serious Total, serious adverse events | 0 / 30 | 0 / 46 |
Outcome results
Primary
Number of Participants With Treatment-related Adverse Events as Assessed by Protocol Definition of AE
Safety will be reported based on Protocol defined AEs. For the purpose of this protocol, an AE will be defined as as any untoward medical occurrence in a subject during the study listed under DMSB - Anticipated Adverse Events and Grading Scale section of this protocol as well as safety monitoring data listed on protocol table 1 as well as stoppage criteria for losartan. The event does not necessarily have a causal relationship with the treatment. AEs will be collected for both study groups, treatment and control from the time the ICF is signed until the subject completes study participation.
Time frame: 14 days of losartan treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Open Label Losartan | Number of Participants With Treatment-related Adverse Events as Assessed by Protocol Definition of AE | 24 Participants |
| External Controls | Number of Participants With Treatment-related Adverse Events as Assessed by Protocol Definition of AE | 44 Participants |
Secondary
Cumulative Number of Participants With of Severe Adverse Events
Cumulative number of participants with severe adverse events
Time frame: 14 days of losartan treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open Label Losartan | Cumulative Number of Participants With of Severe Adverse Events | 0 participants |
| External Controls | Cumulative Number of Participants With of Severe Adverse Events | 0 participants |
Secondary
Days on Mechanical Ventilation
Days on mechanical ventilation
Time frame: 14 days of losartan treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Open Label Losartan | Days on Mechanical Ventilation | 0 days |
| External Controls | Days on Mechanical Ventilation | 11 days |
Secondary
Days on Non-invasive Positive Pressure Ventilation or High Flow Nasal Cannula
Days on non-invasive positive pressure ventilation or high flow nasal cannula
Time frame: 14 days of losartan treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Open Label Losartan | Days on Non-invasive Positive Pressure Ventilation or High Flow Nasal Cannula | 0 days |
| External Controls | Days on Non-invasive Positive Pressure Ventilation or High Flow Nasal Cannula | 5 days |
Secondary
Hospital Length of Stay (Days)
Hospital length of stay (days)
Time frame: from enrollment through hospital discharge
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Open Label Losartan | Hospital Length of Stay (Days) | 9 days |
| External Controls | Hospital Length of Stay (Days) | 7 days |
Secondary
ICU Length of Stay (Days)
ICU length of stay (days)
Time frame: 14 days of losartan treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Open Label Losartan | ICU Length of Stay (Days) | 0 days |
| External Controls | ICU Length of Stay (Days) | 10 days |
Secondary
in Hospital Mortality Rate
in hospital mortality rate
Time frame: 14 days after study enrollment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Open Label Losartan | in Hospital Mortality Rate | 1 Participants |
| External Controls | in Hospital Mortality Rate | 3 Participants |
Secondary
Number of Days on Supplemental Oxygen in Respiratory Failure Due to COVID-19
Number of days on supplemental oxygen in respiratory failure due to COVID-19
Time frame: 14 days of losartan treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Open Label Losartan | Number of Days on Supplemental Oxygen in Respiratory Failure Due to COVID-19 | 4 days |
| External Controls | Number of Days on Supplemental Oxygen in Respiratory Failure Due to COVID-19 | 4 days |
Secondary
Number of Participants With Extracorporeal Membrane Oxygenation Use
Number of participants with extracorporeal membrane oxygenation use
Time frame: 14 days of losartan treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Open Label Losartan | Number of Participants With Extracorporeal Membrane Oxygenation Use | 0 Participants |
| External Controls | Number of Participants With Extracorporeal Membrane Oxygenation Use | 0 Participants |
Secondary
Number of Participants With Increase of Supplemental Oxygen Needs From Baseline.
Number of participants with increase in supplemental oxygen needs from baseline.
Time frame: 14 days of losartan treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Open Label Losartan | Number of Participants With Increase of Supplemental Oxygen Needs From Baseline. | 4 Participants |
| External Controls | Number of Participants With Increase of Supplemental Oxygen Needs From Baseline. | 12 Participants |
Secondary
Number of Participants With Intolerance to High Dose (50mg) Losartan After Tolerating 25mg
Number of participants with intolerance to high dose (50mg) losartan after tolerating 25mg
Time frame: 14 days of losartan treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Open Label Losartan | Number of Participants With Intolerance to High Dose (50mg) Losartan After Tolerating 25mg | 2 Participants |
| External Controls | Number of Participants With Intolerance to High Dose (50mg) Losartan After Tolerating 25mg | 0 Participants |
Secondary
Number of Participants With Mechanical Ventilation Use
Number of participants with mechanical ventilation use
Time frame: 14 days of losartan treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Open Label Losartan | Number of Participants With Mechanical Ventilation Use | 2 Participants |
| External Controls | Number of Participants With Mechanical Ventilation Use | 9 Participants |
Secondary
Number of Participants With Medications With Possible Antiviral Activity (Hydroxychloroquine, Lopinavir/Ritonavir, Ribavirin or Remdesivir) or Adjunctive Therapy Use (e.g., Tocilizumab)
Number of participants with medications with possible antiviral activity (hydroxychloroquine, lopinavir/ritonavir, ribavirin or remdesivir) or adjunctive therapy use (e.g., tocilizumab)
Time frame: 14 days of losartan treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Open Label Losartan | Number of Participants With Medications With Possible Antiviral Activity (Hydroxychloroquine, Lopinavir/Ritonavir, Ribavirin or Remdesivir) or Adjunctive Therapy Use (e.g., Tocilizumab) | 30 Participants |
| External Controls | Number of Participants With Medications With Possible Antiviral Activity (Hydroxychloroquine, Lopinavir/Ritonavir, Ribavirin or Remdesivir) or Adjunctive Therapy Use (e.g., Tocilizumab) | 30 Participants |
Secondary
Number of Participants With Non-invasive Positive Pressure Ventilation or Heated High Flow Nasal Cannula Use
Number of participants with non-invasive positive pressure ventilation or heated high flow nasal cannula use
Time frame: 14 days of losartan treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Open Label Losartan | Number of Participants With Non-invasive Positive Pressure Ventilation or Heated High Flow Nasal Cannula Use | 6 Participants |
| External Controls | Number of Participants With Non-invasive Positive Pressure Ventilation or Heated High Flow Nasal Cannula Use | 3 Participants |
Secondary
Number of Participants With Renal Replacement Therapy Use
Number of participants with renal replacement therapy use
Time frame: 14 days of losartan treatment
Population: This outcome was not collected for study participants, thus results are not reported
Secondary
Number of Participants With Transfer to ICU From Non-ICU Hospital Bed
Number of participants with transfer to ICU from non-ICU hospital bed
Time frame: 14 days of losartan treatment
Population: Data regarding transfer to ICU was not collected for any participants during study period and thus not reported.