The COvid-19 Symptom MOntelukast Trial (COSMO)

• ClinicalTrials.gov Identifier: NCT04389411
• Recruitment Status: Not yet recruiting
• First Posted: May 15, 2020
• Last Update Posted: June 2, 2020
• Sponsor: McGill University
• Collaborator: Lady Davis Institute
• Information provided by (Responsible Party): Machelle Wilchesky, McGill University

Study Description

Brief Summary:

Due to the rapidly developing nature and severity of the COVID-19 pandemic, clinical trials involving a repurposed drug approach are the best option for rapidly identifying an effective COVID-19 therapeutic. The investigators propose to evaluate the efficacy of Montelukast in attenuating cytokine storm syndrome and ARDS via a randomized, blinded, placebo-controlled clinical trial. Specifically, our primary objective is comparing the efficacy of low-dose Montelukast versus placebo in reducing the risk of acute care visits and hospital admissions among COVID-19 positive patients in the general population.

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

Detailed Description:

Background:Due to the immense humanitarian and economic toll of the COVID-19 pandemic, effective therapies are urgently required to reduce the severity, and mortality, of SARS-CoV-2 infections. A repurposed drug approach is the best option to rapidly identify a therapeutic that is effective at reducing the impact of SARS-CoV-2 and improving the clinical outcomes of severe COVID-19 patients. Two of the main complications observed in severe patients are the development of acute respiratory distress syndrome (ARDS) and a hyperinflammatory cytokine profile that is often termed a cytokine storm. NF-B (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex involved in cytokine production, among other biological processes, including control of many genes involved in innate and adaptive immune responses, and inflammation. NF-B is known to be a key player in inflammatory responses and is a rapid-acting 'first responder' to harmful stimuli, such as viral infections. Inhibition of the NF-B signaling pathway has been explored for its therapeutic potential in inflammatory diseases, with attenuation of NF-B activation often associated with a reduction in cytokine production. Montelukast, an FDA and Health Canada approved asthma drug, has been shown to inhibit the signalling of NF-B, such as interleukin-6,8,10, TNF-alpha, MCP-1, and other proinflammatory mediators. Montelukast is available as a low-cost generic and has an excellent safety profile. The investigators hypothesize that repurposing Montelukast to target suppression of NF-B activation in COVID-19 positive patients will result in a corresponding reduction of proinflammatory mediators, thereby attenuating cytokine production, and taming the cytokine storm. Additionally, the investigators are proposing that a reduction in proinflammatory mediators by Montelukast will result in a mitigation of severe COVID-19 symptoms, and serve as a therapeutic for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, thereby alleviating severe complications/symptoms of the viral infection, such as ARDS and cytokine storm syndrome.

Research Aims:The overall objective of this proposal is to determine the efficacy of Montelukast in reducing the severity of COVID-19 symptoms using a large blinded randomized controlled trial. Our primary objective is comparing the efficacy of low-dose Montelukast versus placebo in reducing the risk of acute care visits and hospital admissions among COVID-19 positive patients in the general population. Our secondary objectives are to compare the efficacy of Montelukast versus placebo in reducing: a) All cause mortality, b) Inpatient length of stay, c) Time to intensive care unit, d) Time to intubation, e) Time to complications (pneumonia, acute respiratory distress syndrome (ARDS), cardiomyopathy/arrhythmia, acute kidney injury, secondary bacterial infections), f) Symptom severity (via weekly phone, and/or online, assessments), and g) ER and hospitalization visit counts. A tertiary objective of the proposal is the development of a new COVID-19 specific symptom severity index.

Methods and Approaches: The COvid-19 Symptom Montelukast (COSMO) Trial will be a parallel assignment, phase III, quadruple blinded (i.e. participant, care provider, investigator, outcomes assessor), randomized, placebo-controlled trial of Montelukast for the treatment of SARS-CoV-2 infections. Participants will be randomized using a 1:1 allocation ratio to receive either treatment (10mg oral Montelukast) or matched placebo once daily, for 60 consecutive days following positive COVID-19 test. The study will included 600 adults aged 40+, and balanced by sex and age groups. The RCT is multi-site and will be conducted at the Integrated Health and Social Services University Network for West-Central Montreal and the Jewish General Hospital, with the utilization of the Segal Cancer Centres clinical trials infrastructure.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 600 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• 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: July 2020
• Estimated Primary Completion Date: February 2021
• Estimated Study Completion Date: June 2021

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. Emergency Room Visits and Hospitalizations [ Time Frame: 12 weeks ]
   acute care use that includes a composite outcome comprised of being hospitalized and/or having visited an emergency room during follow-up.

Secondary Outcome Measures :

1. Emergency room visit count [ Time Frame: 12 weeks ]
   The number of emergency room visits
2. Hospitalization admission count [ Time Frame: 12 weeks ]
   The number of hospitalizations
3. Time to ER Visit [ Time Frame: 12 weeks ]
4. Time to hospitalization [ Time Frame: 12 weeks ]
5. All-cause mortality [ Time Frame: 12 weeks ]
6. Inpatient Length of stay [ Time Frame: 12 weeks ]
7. Time to ICU admission [ Time Frame: 12 weeks ]
8. Time to intubation [ Time Frame: 12 weeks ]
9. 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.

Eligibility Criteria

• Ages Eligible for Study: 40 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 a positive test result to date of enrollment <1 week;
3. Time from patient reported first symptoms date of enrollment <14 days;
4. Able to complete weekly follow-up assessments and agrees to provide them on a weekly basis;
5. Agrees to use assigned medication for the 60 days prescribed; and
6. Informed consent is obtained.

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

Lady Davis Institute

Investigators

• Principal Investigator: Machelle Wilchesky, PhD; Lady Davis Institute and McGill University
• Principal Investigator: Geoffrey Tranmer, PhD; University of Manitoba

More Information

Publications:

Sanghai, N. and Tranmer, G.K. Taming the Cytokine Storm: Repurposing Montelukast for the Attenuation and Prophylaxis of Severe COVID-19 Symptoms, 2020, Submitted.

• Responsible Party: Machelle Wilchesky, Assistant Professor, McGill University
• ClinicalTrials.gov Identifier: NCT04389411
• Other Study ID Numbers: 443807
• First Posted: May 15, 2020
• Last Update Posted: June 2, 2020
• Last Verified: May 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR); Analytic Code

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

Additional relevant MeSH terms:

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