The Covid-19 Outpatient Symptom Montelukast Oximetry Trial

Study Overview
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Brief Summary
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Primary care physicians face limited availability of therapeutic options for the treatment of COVID-19 in the outpatient setting. Furthermore, monoclonal antibodies and antiviral therapies that are currently approved for use in the outpatient setting by Health Canada have excluded pregnant women and older adults from their clinical trials, are contraindicated for many patients, and most are prohibited for use by pregnant women. Identification of a safe, COVID-19 outpatient therapeutic with 20-year safety record remains urgently needed.

Detailed Description
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Objectives: Our overarching objective is to determine the efficacy of oral montelukast versus placebo in reducing the duration and severity of COVID-19 symptoms among newly infected at-risk adults in the outpatient setting using a randomized controlled trial. Our two primary objectives are to compare the efficacy of oral montelukast versus placebo in reducing: Symptom severity during the first 14 days of follow-up as measured by differences in mean FluPro PLUS scores and blood oxygen saturation SpO2 levels; and in reducing C-Reactive Protein a biomarker of inflammation associated with severe COVID, obtained on days 3, 6, 9, and 14 of follow-up. Our 7 secondary objectives of the COSMO Trial include evaluating the efficacy of Montelukast in improving: i) Duration of symptoms; ii) Interleukin IL-6; iii) Hypoxemia; iv) Symptom severity during the first 21 and 30 days of follow-up; and v) Healthcare services use in the 6 months post infection (including MD visits). Hypothesis & Preliminary Evidence: We hypothesize that repurposing Montelukast to target suppression of NF- KappaB activation in COVID-19 positive patients will result in a corresponding reduction of Pro-inflammatory mediators, thereby attenuating cytokine production, and taming the cytokine storm, improved blood oxygen saturation, a reduction in hypoxia, mitigation of severe COVID-19 symptoms, and serve as a therapeutic for SARS-CoV-2 infections. Published articles authored by Dr. Geoff Tranmer (study PI) and others provide details of this hypothesis. A retrospective analysis of 92 COVID-19 hospitalized patients conducted by our study collaborators in the USA and Belgium provides evidence that patients who had received montelukast experienced significantly fewer events of clinical deterioration compared to patients not receiving montelukast (10% vs 32%, p= 0.022). More compelling, however, is the fact that montelukast is presently being used by a growing number of clinicians around the world on a compassionate basis for their patients and is currently the standard for COVID-19 patient care in some parts of the world. Methods and Approaches: The COvid-19 Symptom Montelukast Outpatient (COSMO) Trial will be a parallel assignment, phase II, quadruple blinded, randomized, placebo-controlled trial of Montelukast for the treatment of SARS-CoV-2 infections. The study will include 250 recently infected pregnant or older adult outpatients at risk of severe disease who will be randomized to receive either treatment (20mg oral Montelukast) or matched placebo once daily, for 21 to 30 consecutive days. Patient symptoms will be monitored daily for a period of 30 days, after which follow-up will continue for an additional 60 days for outcomes such as duration of symptoms, resilience, functional status, quality of life. Healthcare services use will be evaluated at 6 months post enrollment. The study will be conducted at the Segal Cancer Center and at Quebec Primary Care Medicine Clinics with the utilization of the McGill Primary Care Practice Based Research Network and the Segal Cancer Centre clinical trials infrastructure, with recruitment directly within participating clinics. Expertise and Support: We have developed a team that possesses extensive clinical and epidemiology experience. To date, we have gained support from our participating clinics, the PRBN, the CEO of a CIUSSS Network, clinical trial infrastructure (Segal Centre), and clinical trial support (IMS). We have also received have in-kind support from Masimo (Rad-5/5V hand-held stand-alone hospital grade Pulse Oximeters valued at $40,000 CAD to be used for 3x daily symptom reporting) and $5,000USD in cash support from an independent partner. Outcomes: A therapeutic will remain necessary in the context of uncertain vaccine effectiveness, vaccine hesitancy and viral mutations. With positive results from the COSMO trial, we expect Montelukast to be recommended for COVID-19 outpatients given that it is safe, effective, and globally available

Official Title
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Repurposing Montelukast for the Attenuation and Prophylaxis of Severe COVID-19 Symptoms: The COvid-19 Symptom MOntelukast (COSMO) Trial

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Montelukast 10mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed SARS-CoV-2 infection, defined as RT-PCR provincial laboratory confirmation; Time from patient reported first symptoms date of enrollment <7 days; Must be experiencing at least 1 COVID-19 symptom that is either continuing or increasing in severity Severe disease risk factor requirements: i) Age 18-49: ≥3 risk factors ; ii) Age 50-59: ≥2 risk factors; iii) Age 60-69: ≥1 risk factor; iv) Pregnant or Age 70+: No requirements Participants must agree to: i) Use assigned medication for a maximum of 60 days or until relief of symptoms; and ii) Complete the FLU-PRO PLUS and SpO2 daily diary and other study assessments during the course of follow-up. Exclusion Criteria: Any hospitalization for COVID-19 symptoms or complications prior to randomization; Use of montelukast ≤ 30 days to screening; Any contraindication to montelukast; and Any condition (including the inability to swallow pills) which, in the opinion of the Principal Investigator, would prevent full participation in and compliance with the trial protocol, or would interfere with the evaluation of trial endpoints.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Montelukast<br>10mg Oral Montelukast once daily for 60 days | Drug: Montelukast 10mg<br>* 10mg oral Montelukast will be taken daily for 60 days<br>|
| Placebo Comparator: Placebo<br>Placebo. | Drug: Montelukast 10mg<br>* 10mg oral Montelukast will be taken daily for 60 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptom Severity | Symptom severity during the first 14 days of follow-up as measured by differences in mean FluPro PLUS scores | 14 days | 
| C-Reactive Protein | C-Reactive Protein a biomarker of inflammation associated with severe COVID, obtained on days 3, 6, 9, and 14 of follow-up | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of symptoms | Duration of symptoms as measured by differences in mean FluPro PLUS scores | 90 days | 
| Interleukin IL-6 | Interleukin IL-6, a biomarker of inflammation associated with severe COVID, obtained on days 3, 6, 9, and 14 of follow-up | 14 days | 
| Hypoxemia incidence | Each participant will be provided with a Health Canada approved Masimo Rad 5/V pulse Oximeter upon enrollment. home pulse oximetry (SpO2) recorded 3 times daily for the first 30 days of follow-up. Hypoxemia will be defied as SpO2 <92% on room air for >5 minutes. | 30 days | 
| Hypoxemia | Differences in the means using the 2 lowest (validated) SpO2 values per patient | 30 days | 
| Functional Status | As measured using the Post-COVID-19 Functional Status Scale | 30 days | 
| Time to other serious COVID-19 complications | Complications will be defined as a composite endpoint including pneumonia, ARDS sepsis/septic shock, cardiomyopathy or arrhythmia, acute kidney injury, and secondary bacterial infections. | 12 weeks | 
| Hospitalization | Hospital visits- (healthcare services use component) | 6 months | 
| Medications | Medication use- (healthcare services use component) | 6 months | 
| Physician Visits | Visits to primary care and specialists- (healthcare services use component) | 6 months | 
| Cost-Effectiveness | Comparison of healthcare services use costs | 6 months |