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) (RUXCOVID)

• ClinicalTrials.gov Identifier: NCT04362137
• Recruitment Status: Completed
• First Posted: April 24, 2020
• Last Update Posted: November 12, 2020
• Sponsor: Novartis Pharmaceuticals
• Collaborator: Incyte Corporation
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: April 22, 2020
• First Posted Date: April 24, 2020
• Last Update Posted Date: November 12, 2020
• Actual Study Start Date: May 2, 2020
• Actual Primary Completion Date: October 17, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 22, 2020)

Proportion of patients who die, develop respiratory failure [require mechanical ventilation] or require intensive care unit (ICU) care [ Time Frame: 29 days ]

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 22, 2020)

• Clinical status [ Time Frame: Day 15, Day 29 ]
  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 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.
• Percentage of patients with at least two-point improvement from baseline in clinical status [ Time Frame: Baseline, Day 15, Day 29 ]
  Percentage of patients with at least two points improvement in clinical status on the 9-point ordinal scale.
• Percentage of patients with at least one-point improvement from baseline in clinical status [ Time Frame: Baseline, Day 15, Day 29 ]
  Percentage of patients with at least one point improvement in clinical status on the 9-point ordinal scale.
• Percentage of patients with at least one-point deterioration from baseline in clinical status [ Time Frame: Baseline, Day 15, Day 29 ]
  Percentage of patients with at least one point deterioration in clinical status on the 9-point ordinal scale.
• Time to improvement in clinical status [ Time Frame: 29 days ]
  Time to improvement from baseline category to one less severe category of the 9-point ordinal scale.
• Mean change from baseline in the clinical status [ Time Frame: Baseline, Day 15, Day 29 ]
  Mean change from baseline in the 9-point ordinal scale.
• Mortality rate [ Time Frame: Day 15, Day 29 ]
  Mortality rate at Day 15 and at Day 29
• Proportion of patients requiring mechanical ventilation [ Time Frame: 29 days ]
  Proportion of patients requiring mechanical ventilation
• Duration of hospitalization [ Time Frame: 29 days ]
  Duration of hospitalization
• Time to discharge or to a NEWS2 score of ≤2 [ Time Frame: 29 days ]
  The time to 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).
• Change from baseline in NEWS2 score [ Time Frame: Baseline, Days 3, 5, 8, 11, 15, and 29 ]
  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).
• Change from baseline in SpO2/FiO2 ratio. [ Time Frame: Baseline, Day 15, Day 29 ]
  Change from baseline in peripheral oxygen saturation / fraction of inspired oxygen ratio (SpO2/FiO2 ratio)
• Proportion of patients with no oxygen therapy [ Time Frame: Day 15, Day 29 ]
  No oxygen therapy is required if oxygen saturation is ≥ 94% on room air.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• Official Title: 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)
• Brief Summary: This is 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 pneumonia.

Detailed Description

This is 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 associated cytokine storm. The study will enroll patients to ruxolitinib or placebo, in addition to standard of care (SoC) per local practice. Patients who meet the inclusion/exclusion criteria will be 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 may be given, if in the opinion of the investigator, the patient's clinical signs and symptoms are not improved or worsen and the potential benefit outweighs the potential risk.

The study will include:

• Screening period of 0-2 days.
• Study period of 29 days (treatment of 14 days; an additional 14 days of study drug may be given, if in the opinion of the investigator, the patient's clinical signs and symptoms are not improved or worsen and the potential benefit outweighs the potential risk).

The primary objective is 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Cytokine Storm (Covid-19)

Intervention

• Drug: Ruxolitinib
  Ruxolitinib 5 mg tablets
  Other Name: INC424
• Drug: Placebo
  Matching-image placebo

Study Arms

• Experimental: Ruxolitinib 5 mg
  Ruxolitinib 5 mg tablets twice daily (b.i.d.) for 14 days with possible extension of treatment to 28 days
  Intervention: Drug: Ruxolitinib
• Placebo Comparator: Placebo
  Matching-image placebo for 14 days with possible extension of treatment to 28 days
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 23, 2020): 432
• Original Estimated Enrollment (submitted: April 22, 2020): 402
• Actual Study Completion Date: October 17, 2020
• Actual Primary Completion Date: October 17, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Other protocol-defined inclusion/exclusion criteria may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Brazil, Colombia, France, Germany, Mexico, Peru, Russian Federation, Spain, Turkey, United Kingdom, United States
• Removed Location Countries: Canada, Italy

Administrative Information

• NCT Number: NCT04362137
• Other Study ID Numbers: CINC424J12301; INCB 18424-368 ( Other Identifier: Incyte Study Code ); 2020-001662-11 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Study Sponsor: Novartis Pharmaceuticals
• Collaborators: Incyte Corporation

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: November 2020