Study of Open Label Losartan in COVID-19

Phase 1

Completed

Conditions: COVID-19

Interventions: Drug: Losartan

Registration Number: NCT04335123

Lead Sponsor: University of Kansas Medical Center

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 34

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Open Label Losartan	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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
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 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 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
Hospital Length of Stay (Days)	from enrollment through hospital discharge	Hospital length of stay (days)
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 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