Study of Open Label Losartan in COVID-19

• ClinicalTrials.gov Identifier: NCT04335123
• Recruitment Status: Completed
• First Posted: April 6, 2020
• Last Update Posted: November 3, 2020
• Sponsor: University of Kansas Medical Center
• Information provided by (Responsible Party): Matthias Salathe, MD, University of Kansas Medical Center

Tracking Information

• First Submitted Date: March 31, 2020
• First Posted Date: April 6, 2020
• Last Update Posted Date: November 3, 2020
• Actual Study Start Date: April 4, 2020
• Actual Primary Completion Date: June 21, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 2, 2020)

Number of participants with treatment-related adverse events as assessed by protocol definition of AE [ Time Frame: 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 2, 2020)

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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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, 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

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.

• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention 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)
Primary Purpose: Treatment

• Condition: COVID-19

Intervention

Drug: Losartan

25 mg QD from day 0 to day 3. Dose escalation to 50 mg QD until study completion

Other Name: Cozaar

Study Arms

Experimental: Open Label Losartan

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.

Intervention: Drug: Losartan

• Publications *: Smolander J, Bruchfeld A. [COVID-19 and kidney disease]. Lakartidningen. 2020 Jul 13;117. pii: 20110. Swedish.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 2, 2020): 34
• Original Estimated Enrollment (submitted: April 2, 2020): 50
• Actual Study Completion Date: August 17, 2020
• Actual Primary Completion Date: June 21, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

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: NCT04335123
• Other Study ID Numbers: STUDY00145514
• 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

• Responsible Party: Matthias Salathe, MD, University of Kansas Medical Center
• Study Sponsor: University of Kansas Medical Center
• Collaborators: Not Provided

Investigators

• Principal Investigator: Matthias Salathe; University of Kansas Medical Center

• PRS Account: University of Kansas Medical Center
• Verification Date: November 2020