Study of Open Label Losartan in COVID-19

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

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.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Drug: Losartan

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
• Enrollment (Actual): 34
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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.

Drug: Losartan; 25 mg QD from day 0 to day 3. Dose escalation to 50 mg QD until study completion; Other Names: Cozaar

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Kansas Medical Center
• Investigators: Principal Investigator: Matthias Salathe, University of Kansas Medical Center

Publications and helpful links

General Publications

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

Study record dates

Study Major Dates

• Study Start (Actual): April 4, 2020
• Primary Completion (Actual): June 21, 2020
• Study Completion (Actual): August 17, 2020

Study Registration Dates

• First Submitted: March 31, 2020
• First Submitted That Met QC Criteria: April 2, 2020
• First Posted (Actual): April 6, 2020

Study Record Updates

• Last Update Posted (Actual): May 10, 2021
• Last Update Submitted That Met QC Criteria: May 6, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: SARS-CoV-2; COVID-19; respiratory failure; losartan
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Losartan
• Other Study ID Numbers: STUDY00145514

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices)
• IPD Sharing Time Frame: Beginning 3 months and ending 5 years following article publication
• IPD Sharing Access Criteria: Proposals should be directed to msalathe@kumc.edu. To gain access, data requestors will need to sign a data access agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Analytic Code

Drug and device information, study documents

• 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