Clinical trial NCT04328012: COVID MED Trial - Comparison Of Therapeutics for Hospitalized Patients Infected With COVID-19
Official title: Comparison Of Therapeutics for Hospitalized Patients Infected With SARS-CoV-2 In a Pragmatic aDaptive randoMizED Clinical Trial During the COVID-19 Pandemic (COVID MED Trial)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: SARS-CoV-2 Infection
Keywords: COVID
COVID-19
coronavirus
Lead sponsor: Bassett Healthcare
Sponsor class: OTHER
Collaborators: name: Reid Health
name: Goshen Health System
First posted: 2020-03-31
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: randomized, double blind, placebo controlled clinical trial
Primary purpose: TREATMENT

Brief summary: In a randomized, double-blind, placebo-controlled, multi-center, Phase 2-like, investigator-directed trial, hospitalized adult patients with laboratory confirmed SARS-CoV-2 infection meeting inclusion and exclusion criteria, will be provided information on the trial, offered enrollment, and if informed consent provided, enrolled randomly in a 2:1 ratio to one of two groups: Group 1 standard care and losartan or Group 2 standard care and placebo. Patients will be followed for up to 60 days, with data collected to quantify the NCOSS over time (the primary objective), and for the trial's secondary objectives (see outcome measurements below).

Detailed description: Although a number of therapeutics have been utilized by clinicians to treat hospitalized patients with COVID-19, none were systematically evaluated in clinical trials at the time of the outset of this RCT (COVID MED). Since then, dexamethasone has been shown to decrease mortality and remdesivir to possibly decrease hospital LOS in the RECOVERY and ACTT-II trials and others. The initial iteration of this protocol included 4 arms, hydroxychloroquine, lopinavir/ritonavir, losartan, and placebo based on suggestive efficacy and safety and widespread empiric use. The current iteration of COVID MED includes two arms, standard of care and losartan vs. standard of care and placebo.

Hydroxychloroquine was initially included in COVID MED based on suggestive in vitro, animal preclinical, and early RCT data, and widespread empiric use in hospitalized patients with COVID-19. Lopinavir/ritonavir, an antiretroviral medication, showed equivocal and possibly positive efficacy and safety in an early pandemic Chinese RCT published in NEJM. After public release and eventual publication of the negative results for hydroxychloroquine and then lopinavir/ritonavir initially from the RECOVERY trial and then others, enrollment in COVID MED in these two arms was halted and then discontinued permanently. Data from subjects enrolled in the hydroxychloroquine arm are being incorporated into a pooled analysis of RCTs by the Trial Innovation Network.

Losartan, an angiotensin II receptor blocker (ARB), has theoretical benefit as SARSCoV-2 appears to bind to lung tissue via Angiotensin-Converting Enzyme 2 (ACE-2) receptors which might be inhibited by ARBs; other potential benefits have been hypothesized as well. Since the initial iteration of this protocol, observational studies have shown that patients already taking ACEi/ARB medications do not have adverse outcome when these drugs are continued in hospitalized COVID-19 patients. These data have reinforced continuation of the losartan vs. placebo arms of this RCT which are ongoing.

This pragmatic adaptive trial continues to compare outcome in hospitalized COVID-19 patients treated with standard of care and losartan vs. standard of care and placebo.

Eligibility criteria: Inclusion criteria

1. Hospitalized patient
2. Age \>= 18 years
3. Able to ingest oral medication or be administered medication via gastric tube or equivalent
4. Laboratory confirmation of SARS-CoV-2 infection within 1 week prior to randomization
5. Randomization within 72 hr of hospital admission
6. Negative pregnancy test for reproductive age women
7. Patient or LAR able to provide informed consent

Exclusion criteria

1. Allergy or intolerance to losartan or other ARBs
2. Already taking ACE or ARB (within 1 month)
3. Hypotension at time of enrollment (SBP \< 100 mm Hg)
4. Hyperkalemia (K \>/= 5.0 at time of screening or history of hyperkalemia)
5. Severe renal dysfunction (estimated GFR \< 30 ml/min at time of screening or history advanced renal disease)
6. Severe volume depletion or acute kidney injury (AKI) at time of enrollment
7. Known cirrhotic ascites
8. Known severe aortic or mitral valve stenosis
9. Known unstented renal artery stenosis
10. Co-administration with certain drugs due to CYP3A interactions if taken in \< 24 hr
11. Severe hepatic insufficiency (LFTs \> 5 times the upper limit of normal or known ESLD or cirrhosis)
12. Nausea/vomiting or aspiration risk precluding oral medications unless can be given by gastric tube
13. Pregnancy or breast feeding
14. Absence of dependable contraception in reproductive age women
15. Inability to obtain or declined informed consent

Primary outcomes:
measure: National Institute of Allergy and Infectious Diseases COVID-19 Ordinal Severity Scale (NCOSS)
timeFrame: 60 days
Secondary outcomes:
measure: Hospital length of stay (LOS)
timeFrame: 60 days
measure: Intensive care unit level LOS
timeFrame: 60 days
measure: Mechanical ventilation
timeFrame: 60 days
measure: survival
timeFrame: 60 days
Other outcomes:
Locations:
city: Cooperstown
country: United States
facility: Bassett Medical Center
state: New York
Study officials:
affiliation: Bassett Medical Center
name: Daniel Freilich, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.