The Covid-19 Outpatient Symptom Montelukast Oximetry Trial (COSMO)

• ClinicalTrials.gov Identifier: NCT04389411
• Recruitment Status: Not yet recruiting
• First Posted: May 15, 2020
• Last Update Posted: July 25, 2022
• Sponsor: McGill University
• Collaborators: Segal Cancer Centre; The McGill Practice Based Research Network; Lady Davis Institute
• Information provided by (Responsible Party): Machelle Wilchesky, Lady Davis Institute

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
COVID-19	Drug: Montelukast 10mg	Phase 2; Phase 3

Detailed Description:

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:

1. 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
2. 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

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 250 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Montelukast and placebo tablets will be over encapsulated before distribution to trial participants.
• Primary Purpose: Treatment
• Official Title: Repurposing Montelukast for the Attenuation and Prophylaxis of Severe COVID-19 Symptoms: The COvid-19 Symptom MOntelukast (COSMO) Trial
• Estimated Study Start Date: November 1, 2022
• Estimated Primary Completion Date: January 2023
• Estimated Study Completion Date: February 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Montelukast; 10mg Oral Montelukast once daily for 60 days	Drug: Montelukast 10mg; 10mg oral Montelukast will be taken daily for 60 days
Placebo Comparator: Placebo; Placebo.	Drug: Montelukast 10mg; 10mg oral Montelukast will be taken daily for 60 days

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Duration of symptoms [ Time Frame: 90 days ]
   Duration of symptoms as measured by differences in mean FluPro PLUS scores
2. Interleukin IL-6 [ Time Frame: 14 days ]
   Interleukin IL-6, a biomarker of inflammation associated with severe COVID, obtained on days 3, 6, 9, and 14 of follow-up
3. Hypoxemia incidence [ Time Frame: 30 days ]
   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.
4. Hypoxemia [ Time Frame: 30 days ]
   Differences in the means using the 2 lowest (validated) SpO2 values per patient
5. Functional Status [ Time Frame: 30 days ]
   As measured using the Post-COVID-19 Functional Status Scale
6. Time to other serious COVID-19 complications [ Time Frame: 12 weeks ]
   Complications will be defined as a composite endpoint including pneumonia, ARDS sepsis/septic shock, cardiomyopathy or arrhythmia, acute kidney injury, and secondary bacterial infections.
7. Hospitalization [ Time Frame: 6 months ]
   Hospital visits- (healthcare services use component)
8. Medications [ Time Frame: 6 months ]
   Medication use- (healthcare services use component)
9. Physician Visits [ Time Frame: 6 months ]
   Visits to primary care and specialists- (healthcare services use component)
10. Cost-Effectiveness [ Time Frame: 6 months ]
    Comparison of healthcare services use costs

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Confirmed SARS-CoV-2 infection, defined as RT-PCR provincial laboratory confirmation;
2. Time from patient reported first symptoms date of enrollment <7 days;
3. Must be experiencing at least 1 COVID-19 symptom that is either continuing or increasing in severity
4. 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
5. 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:

1. Any hospitalization for COVID-19 symptoms or complications prior to randomization;
2. Use of montelukast ≤ 30 days to screening;
3. Any contraindication to montelukast; and
4. 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.

Contacts and Locations

Contacts

Contact: Machelle Wilchesky, PhD; (514) 220-5555; machelle.wilchesky@mcgill.ca

Contact: Geoffrey Tranmer, PhD; (204) 474-8358; geoffrey.tranmer@umanitoba.ca

Sponsors and Collaborators

McGill University

Segal Cancer Centre

The McGill Practice Based Research Network

Lady Davis Institute

Investigators

• Principal Investigator: Machelle Wilchesky, PhD; Lady Davis Institute and McGill University
• Principal Investigator: Geoffrey Tranmer, PhD; University of Manitoba
• Principal Investigator: Roland Grad, MDCM MSc FCFP; Herzl Family Practice Centre and McGill University

More Information

Publications:

Sanghai N, Tranmer GK. Taming the cytokine storm: repurposing montelukast for the attenuation and prophylaxis of severe COVID-19 symptoms. Drug Discov Today. 2020 Dec;25(12):2076-2079. doi: 10.1016/j.drudis.2020.09.013. Epub 2020 Sep 16.

• Responsible Party: Machelle Wilchesky, Assistant Professor, Lady Davis Institute
• ClinicalTrials.gov Identifier: NCT04389411
• Other Study ID Numbers: 443807
• First Posted: May 15, 2020
• Last Update Posted: July 25, 2022
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: COSMO Trial Data Governance Plan: We have designed the COSMO Trial to uphold the FAIR principles such that the research data derived will be Findable, Accessible, Interoperable, and Reusable. The raw data from this study, once removed of identifiers, will be posted to a public data sharing resource to allow the data to be used and understood by the wider scientific community. The precise platforms and open access data repositories will be determined once the data is ready, but candidate platforms include github and the Google COVID-19 data sharing platform.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR); Analytic Code
• Time Frame: We will make this data available within 12 months of completion of data collection.
• Access Criteria: Undetermined.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

COVID-19; Respiratory Tract Infections; Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Montelukast; Anti-Asthmatic Agents; Respiratory System Agents; Leukotriene Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Cytochrome P-450 CYP1A2 Inducers; Cytochrome P-450 Enzyme Inducers; Molecular Mechanisms of Pharmacological Action