Study of Open Label Losartan in COVID-19

Study Overview
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Brief Summary
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This is an open label, phase 1 clinical trial to evaluate the safety of losartan in respiratory failure due to COVID-19. Briefly, 50 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 (3/25/2020) and during the study period.

Detailed Description
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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, 50 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.

Official Title
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An Open Label Phase 1 Trial of Losartan for Worsening Respiratory Illness in COVID-19

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Losartan


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: 50 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 (3/25/2020) and during the study period.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open Label Losartan<br>50 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. 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 or complete 14 days of therapy. | Drug: Losartan<br>* 25 mg QD from day 0 to day 3. Dose escalation to 50 mg QD until study completion<br>* Other names: Cozaar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 14 days of losartan treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 14 days of losartan treatment | 
| Incidence of mechanical ventilation use | Incidence of mechanical ventilation use | 14 days of losartan treatment | 
| Days on mechanical ventilation | Days on mechanical ventilation | 14 days of losartan treatment | 
| Incidence of non-invasive positive pressure ventilation or heated high flow nasal cannula use | Incidence of non-invasive positive pressure ventilation or heated high flow nasal cannula use | 14 days of losartan treatment | 
| Days on non-invasive positive pressure ventilation or high flow nasal cannula | Days on non-invasive positive pressure ventilation or high flow nasal cannula | 14 days of losartan treatment | 
| Incidence of transfer to ICU from non-ICU hospital bed | Incidence of transfer to ICU from non-ICU hospital bed | 14 days of losartan treatment | 
| ICU length of stay (days) | ICU length of stay (days) | 14 days of losartan treatment | 
| 30-day mortality rate | 30-day mortality rate | 30 days after diagnosis of COVID-19 | 
| Hospital length of stay (days) | Hospital length of stay (days) | 14 days of losartan treatment | 
| Cumulative incidence of severe adverse events | Cumulative incidence of severe adverse events | 14 days of losartan treatment | 
| Cumulative incidence of adverse events | Cumulative incidence of adverse events | 14 days of losartan treatment | 
| Change from baseline in oxygenation | Change from baseline in oxygenation | 14 days of losartan treatment | 
| Incidence of medications with possible antiviral activity (hydroxychloroquine, lopinavir/ritonavir, ribavirin or remdesivir) or adjunctive therapy use (e.g., tocilizumab) | Incidence of medications with possible antiviral activity (hydroxychloroquine, lopinavir/ritonavir, ribavirin or remdesivir) or adjunctive therapy use (e.g., tocilizumab) | 14 days of losartan treatment | 
| Incidence (and length in days) of extracorporeal membrane oxygenation use | Incidence (and length in days) of extracorporeal membrane oxygenation use | 14 days of losartan treatment | 
| Incidence (and length in days) of renal replacement therapy use | Incidence (and length in days) of renal replacement therapy use | 14 days of losartan treatment | 
| Intolerance of high dose (50mg) losartan after tolerating 25mg | Intolerance of high dose (50mg) losartan after tolerating 25mg | 14 days of losartan treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, losartan, respiratory failure, SARS-CoV-2