Clinical trial NCT04335123: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: COVID-19
Keywords: COVID-19
losartan
respiratory failure
SARS-CoV-2
Lead sponsor: University of Kansas Medical Center
Sponsor class: OTHER
First posted: 2020-04-06
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Number of Participants With Treatment-related Adverse Events as Assessed by Protocol Definition of AE
timeFrame: 14 days of losartan treatment
Secondary outcomes:
measure: Number of Days on Supplemental Oxygen in Respiratory Failure Due to COVID-19
timeFrame: 14 days of losartan treatment
measure: Number of Participants With Mechanical Ventilation Use
timeFrame: 14 days of losartan treatment
measure: Days on Mechanical Ventilation
timeFrame: 14 days of losartan treatment
measure: Number of Participants With Non-invasive Positive Pressure Ventilation or Heated High Flow Nasal Cannula Use
timeFrame: 14 days of losartan treatment
measure: Days on Non-invasive Positive Pressure Ventilation or High Flow Nasal Cannula
timeFrame: 14 days of losartan treatment
measure: Number of Participants With Transfer to ICU From Non-ICU Hospital Bed
timeFrame: 14 days of losartan treatment
measure: ICU Length of Stay (Days)
timeFrame: 14 days of losartan treatment
measure: in Hospital Mortality Rate
timeFrame: 14 days after study enrollment
measure: Hospital Length of Stay (Days)
timeFrame: from enrollment through hospital discharge
measure: Cumulative Number of Participants With of Severe Adverse Events
timeFrame: 14 days of losartan treatment
measure: Number of Participants With Increase of Supplemental Oxygen Needs From Baseline.
timeFrame: 14 days of losartan treatment
measure: Number of Participants With Medications With Possible Antiviral Activity (Hydroxychloroquine, Lopinavir/Ritonavir, Ribavirin or Remdesivir) or Adjunctive Therapy Use (e.g., Tocilizumab)
timeFrame: 14 days of losartan treatment
measure: Number of Participants With Extracorporeal Membrane Oxygenation Use
timeFrame: 14 days of losartan treatment
measure: Number of Participants With Renal Replacement Therapy Use
timeFrame: 14 days of losartan treatment
measure: Number of Participants With Intolerance to High Dose (50mg) Losartan After Tolerating 25mg
timeFrame: 14 days of losartan treatment
Other outcomes:
Locations:
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
Study officials:
affiliation: University of Kansas Medical Center
name: Matthias Salathe
role: PRINCIPAL_INVESTIGATOR
References:
citation: Smolander J, Bruchfeld A. [COVID-19 and kidney disease]. Lakartidningen. 2020 Jul 13;117:20110. Swedish.