Study to Assess the Efficacy and Safety of Ruxolitinib in Patients With COVID-19 Associated Cytokine Storm

Study Overview
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Brief Summary
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This was a randomized, double-blind, placebo-controlled, 29-day, multicenter study to assess the efficacy and safety of ruxolitinib + standard-of-care (SoC) therapy, compared with placebo + SoC therapy, in patients aged ≥12 years with COVID-19 disease.

Detailed Description
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This was a Phase III, multicenter, double-blind, randomized, placebo-controlled study to assess the efficacy and safety of ruxolitinib in patients aged ≥12 years with COVID-19 disease. The study enrolled patients to ruxolitinib or placebo, in addition to standard of care (SoC) per local practice. Patients who meet the inclusion/exclusion criteria were randomized in a 2:1 ratio to either oral ruxolitinib 5 mg twice daily + SoC or oral matching-image placebo + SoC for a total of 14 days. An additional 14 days of study drug could be given if in the opinion of the investigator the patient's clinical signs and symptoms did not improve, or worsen, and the potential benefit outweighed the potential risk. The study included: Screening period of 0-2 days. Study period of 29 days (treatment of 14 days with possible extension of treatment to 28 days). The primary objective was to evaluate the efficacy (as measured by a composite endpoint of proportion of patients who die, develop respiratory failure [require mechanical ventilation], or require intensive care unit care) of ruxolitinib + standard-of-care (SoC) therapy compared with placebo + SoC therapy, for the treatment of COVID-19 by Day 29.

Official Title
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Phase 3 Randomized, Double-blind, Placebo-controlled Multi-center Study to Assess the Efficacy and Safety of Ruxolitinib in Patients With COVID-19 Associated Cytokine Storm (RUXCOVID)

Conditions
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Cytokine Storm (Covid-19)

Intervention / Treatment
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* Drug: Ruxolitinib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient or guardian/health proxy must provide informed consent (and assent if applicable) before any study assessment is performed. Male and female patients aged ≥ 12 years (or ≥ the lower age limit allowed by Health Authority and/or Ethics Committee/Institutional Review Board approvals). Patients with coronavirus (SARS-CoV-2) infection confirmed by polymerase chain reaction (PCR) test or another rapid test from the respiratory tract prior to randomization. Patients currently hospitalized or will be hospitalized prior to randomization. Patients, who meet at least one of the below criteria: Pulmonary infiltrates (chest X ray or chest CT scan); Respiratory frequency ≥ 30/min; Requiring supplemental oxygen; Oxygen saturation ≤ 94% on room air; Arterial oxygen partial pressure (PaO2)/ fraction of inspired oxygen (FiO2) < 300mmHg (1mmHg=0.133kPa) (corrective formulation should be used for higher altitude regions (over 1000m). Exclusion Criteria: History of hypersensitivity to any drugs or metabolites of similar chemical classes as ruxolitinib. Presence of severely impaired renal function defined by serum creatinine > 2 mg/dL (>176.8 μmol/L), or have estimated creatinine clearance < 30 ml/min measured or calculated by Cockroft Gault equation or calculated by the updated bedside Schwartz equation. Suspected uncontrolled bacterial, fungal, viral, or other infection (besides COVID-19). Currently intubated or intubated between screening and randomization. In intensive care unit (ICU) at time of randomization. Intubated or in ICU for COVID-19 disease prior to screening. Patients who are on anti-rejection, immunosuppressant or immunomodulatory drugs (i.e. tocilizumab, ruxolitinib, canakinumab, sarilumab, anakinra). Unable to ingest tablets at randomization. Pregnant or nursing (lactating) women

Ages Eligible for Study
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Minimum Age: 12 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ruxolitinib 5 mg<br>Ruxolitinib 5 mg tablets twice daily (b.i.d.) for 14 days with possible extension of treatment to 28 days | Drug: Ruxolitinib<br>* Ruxolitinib 5 mg tablets<br>* Other names: INC424;|
| Placebo Comparator: Placebo<br>Matching-image placebo for 14 days with possible extension of treatment to 28 days | Drug: Placebo<br>* Matching-image placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Who Die, Develop Respiratory Failure [Require Mechanical Ventilation] or Require Intensive Care Unit (ICU) Care | Efficacy is measured by a composite endpoint of proportion of patients who die, develop respiratory failure [require mechanical ventilation], or require intensive care unit [ICU] care for the treatment of COVID-19. Analyses are cumulative, thus analysis on Day 29 includes all events till that day. Patients who developed respiratory failure and/or required ICU at randomization are excluded from the analysis. | Day 1 - Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Status | Clinical status is measured with the 9-point ordinal scale. The scoring is: Uninfected patients have a score 0 (no clinical or virological evidence of infection). Ambulatory patients (not in hospital or in hospital and ready for discharge) can have a score 1 (no limitation of activities) or 2 (limitation of activities). Hospitalized patients with mild disease can have score 3 (no oxygen therapy defined as peripheral oxygen saturation (SpO2) ≥ 94% on room air) or 4 (oxygen by mask or nasal prongs). Hospitalized patients with severe disease can have score 5 (non-invasive ventilation or high-flow oxygen), 6 (intubation and mechanical ventilation) or 7 (ventilation + additional organ support - pressors, RRT (renal replacement therapy), ECMO (extracorporeal membrane oxygenation)). Patients who die have a score 8. | Baseline, Day 15, Day 29 | 
| Percentage of Patients With at Least Two-point Improvement From Baseline in Clinical Status | Percentage of patients with at least two points improvement in clinical status on the 9-point ordinal scale. The baseline value of clinical status is defined as the last assessment prior to first dose of double-blind treatment. Patients with missing data at Day 15 and/or Day 29 are treated as non-responders. | Baseline, Day 15, Day 29 | 
| Percentage of Patients With at Least One-point Improvement From Baseline in Clinical Status | Percentage of patients with at least one point improvement in clinical status on the 9-point ordinal scale. The baseline value of clinical status is defined as the last assessment prior to first dose of double-blind treatment. Patients with missing data at Day 15 and/or Day 29 are treated as non-responders. | Baseline, Day 15, Day 29 | 
| Percentage of Patients With at Least One-point Deterioration From Baseline in Clinical Status | Percentage of patients with at least one point deterioration in clinical status on the 9-point ordinal scale. The baseline value of clinical status is defined as the last assessment prior to first dose of double-blind treatment. Patients with missing data at Day 15 and/or Day 29 are treated as non-responders. | Baseline, Day 15, Day 29 | 
| Time to Improvement in Clinical Status | Time to improvement in clinical status from baseline category to one less severe category of the 9-point ordinal scale. The baseline value of clinical status is defined as the last assessment prior to first dose of double-blind treatment. Median time to improvement is estimated by Kaplan-Meier method, with dead patients being censored at the maximum follow-up time in the study. Patients who did not achieve improvement and did not die are censored at their last clinical status assessment date. | 29 days | 
| Mean Change From Baseline in the Clinical Status | Mean change from baseline in the 9-point ordinal scale. The baseline value of clinical status is defined as the last assessment prior to first dose of double-blind treatment. Patients with missing data at Day 15 and/or Day 29 are excluded from the analysis. A negative change from baseline in the clinical status is a favorable outcome. | Baseline, Day 15, Day 29 | 
| Mortality Rate | Mortality rate is determined as the proportion of participants who died by study Day 15 and Day 29 | Day 15, Day 29 | 
| Proportion of Patients Requiring Mechanical Ventilation | Proportion of patients requiring mechanical ventilation. Analyses are cumulative, thus analysis on Day 29 includes all events till that day. Patients who required mechanical ventilation at randomization are excluded from the analysis. | Day 1 - Day 29 | 
| Duration of Hospitalization | Duration of hospitalization is defined as time to hospital discharge. Median time to hospital discharge is estimated by Kaplan-Meier method, with dead patients being censored at the maximum follow-up time in the study. Patients who were not discharged and did not die are censored at their last assessment date. | 29 days | 
| Time to Hospital Discharge or to a NEWS2 Score of ≤2 | The time to hospital discharge or to a National Early Warning Score 2 (NEWS2) of ≤2 and maintained for 24 hours whichever comes first. The NEWS2 is based on a simple aggregate scoring system in which a score is allocated to physiological measurements, already recorded in routine practice presentation or when a patient is being monitored in hospital. The score ranges from 0 (best) to 23 (worst). Median time is estimated by Kaplan-Meier method, with dead patients being censored at the maximum follow-up time in the study. | 29 days | 
| Change From Baseline in NEWS2 Score | The National Early Warning Score 2 (NEWS2) is based on a simple aggregate scoring system in which a score is allocated to physiological measurements, already recorded in routine practice presentation or when a patient is being monitored in hospital. The score ranges from 0 (best) to 23 (worst). At each visit, only patients with a value at both baseline and the respective visit are included. A negative change from baseline in NEWS2 score is a favorable outcome. | Baseline, Days 3, 5, 8, 11, 15, and 29 | 
| Change From Baseline in SpO2/FiO2 Ratio | Change from baseline in peripheral oxygen saturation / fraction of inspired oxygen ratio (SpO2/FiO2 ratio). At each visit, only patients with a value at both baseline and the respective visit are included. A positive change from baseline in SpO2/FiO2 ratio is a favorable outcome. | Baseline, Day 15, Day 29 | 
| Proportion of Patients With no Oxygen Therapy | Proportion of patients with no oxygen therapy (defined as oxygen saturation ≥ 94% on room air) at Days 15 and 29. Analyses are cumulative, thus analysis on each day includes all events till that day. Patients with missing data at Day 15 and/or Day 29 are excluded from the analysis. | Day 15, Day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19 pneumonia, cytokine release syndrome, SARS-COV-2, ruxolitinib