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

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)

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.

Study Overview

• Status: Completed
• Conditions: Cytokine Storm (Covid-19)
• Intervention / Treatment: Drug: Ruxolitinib; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 432
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1426AAM
    • Novartis Investigative Site
  • Buenos Aires, Argentina, C1430BKC
    • Novartis Investigative Site
  • Buenos Aires
    • C A B A, Buenos Aires, Argentina, CP1405
      • Novartis Investigative Site
• Brazil
  • RJ
    • Rio de Janeiro, RJ, Brazil, 22640-000
      • Novartis Investigative Site
  • SP
    • Barretos, SP, Brazil, 14784 400
      • Novartis Investigative Site
    • Sao Paulo, SP, Brazil, 01327 001
      • Novartis Investigative Site
    • Sao Paulo, SP, Brazil, 04502 001
      • Novartis Investigative Site
    • Sorocaba, SP, Brazil
      • Novartis Investigative Site
  • Santa Catarina
    • Blumenau, Santa Catarina, Brazil, 89030101
      • Novartis Investigative Site
• Colombia
  • Barranquilla, Colombia
    • Novartis Investigative Site
  • Antioquia
    • Rionegro, Antioquia, Colombia, 054047
      • Novartis Investigative Site
  • Atlantico
    • Barranquilla, Atlantico, Colombia, 080005
      • Novartis Investigative Site
• France
  • Colombes Cedex, France, 92701
    • Novartis Investigative Site
  • Eaubonne, France, 95600
    • Novartis Investigative Site
  • Nantes Cedex 1, France, 44093
    • Novartis Investigative Site
  • Pessac, France, 33604
    • Novartis Investigative Site
  • Pierre Benite, France, 69495
    • Novartis Investigative Site
• Germany
  • Lubeck, Germany, 23538
    • Novartis Investigative Site
  • Muenchen, Germany, 81377
    • Novartis Investigative Site
  • Nuernberg, Germany, 90419
    • Novartis Investigative Site
• Mexico
  • Estado de Mexico, Mexico, 52787
    • Novartis Investigative Site
  • Distrito Federal
    • México, Distrito Federal, Mexico, 14050
      • Novartis Investigative Site
  • Mexico CP
    • Ciudad de Mexico, Mexico CP, Mexico, 14080
      • Novartis Investigative Site
• Peru
  • Lima, Peru, 10
    • Novartis Investigative Site
  • Lima, Peru, 1
    • Novartis Investigative Site
  • Lima
    • San Isidro, Lima, Peru, 27
      • Novartis Investigative Site
    • San Miguel, Lima, Peru, 32
      • Novartis Investigative Site
• Russian Federation
  • Barnaul, Russian Federation, 656045
    • Novartis Investigative Site
  • Moscow, Russian Federation, 123056
    • Novartis Investigative Site
  • Moscow, Russian Federation, 111539
    • Novartis Investigative Site
  • Ryazan, Russian Federation, 390039
    • Novartis Investigative Site
  • S-Petersburg, Russian Federation, 194354
    • Novartis Investigative Site
  • Saint Petersburg, Russian Federation, 199106
    • Novartis Investigative Site
  • Saint Petersburg, Russian Federation, 194044
    • Novartis Investigative Site
  • Sestroretsk, Russian Federation, 197706
    • Novartis Investigative Site
  • St Petersburg, Russian Federation, 193312
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28034
    • Novartis Investigative Site
  • Madrid, Spain, 28031
    • Novartis Investigative Site
  • Castilla Y Leon
    • Salamanca, Castilla Y Leon, Spain, 37007
      • Novartis Investigative Site
  • Cataluna
    • Barcelona, Cataluna, Spain, 08035
      • Novartis Investigative Site
  • Catalunya
    • Badalona, Catalunya, Spain, 08916
      • Novartis Investigative Site
• Turkey
  • Ankara, Turkey, 06100
    • Novartis Investigative Site
  • Istanbul, Turkey
    • Novartis Investigative Site
  • Yenisehir/Izmir, Turkey, 35110
    • Novartis Investigative Site
  • TUR
    • Istanbul, TUR, Turkey, 34098
      • Novartis Investigative Site
• United Kingdom
  • Harrow, United Kingdom, HA1 3UJ
    • Novartis Investigative Site
  • Leeds, United Kingdom, LS9 7TF
    • Novartis Investigative Site
  • London, United Kingdom, SE5 9RS
    • Novartis Investigative Site
  • London, United Kingdom, WC1E 6HX
    • Novartis Investigative Site
  • Manchester, United Kingdom, M13 9PL
    • Novartis Investigative Site
• United States
  • California
    • Fullerton, California, United States, 92835
      • Novartis Investigative Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Novartis Investigative Site
    • Denver, Colorado, United States, 80205
      • Novartis Investigative Site
  • Georgia
    • Atlanta, Georgia, United States, 30312
      • Novartis Investigative Site
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Novartis Investigative Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Novartis Investigative Site
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • Novartis Investigative Site
  • New York
    • Bronx, New York, United States, 10461
      • Novartis Investigative Site
  • Texas
    • Mesquite, Texas, United States, 75149
      • Novartis Investigative Site
  • Washington
    • Seattle, Washington, United States, 98104
      • Novartis Investigative Site
  • Wisconsin
    • Madison, Wisconsin, United States, 53705-3611
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Ruxolitinib 5 mg; Ruxolitinib 5 mg tablets twice daily (b.i.d.) for 14 days with possible extension of treatment to 28 days	Drug: Ruxolitinib; Ruxolitinib 5 mg tablets; Other Names: INC424
PLACEBO_COMPARATOR: Placebo; Matching-image placebo for 14 days with possible extension of treatment to 28 days	Drug: Placebo; Matching-image placebo

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Collaborators: Incyte Corporation

Publications and helpful links

General Publications

• Han MK, Antila M, Ficker JH, Gordeev I, Guerreros A, Bernus AL, Roquilly A, Sifuentes-Osornio J, Tabak F, Teijeiro R, Bandelli L, Bonagura DS, Shu X, Felser JM, Knorr B, Cao W, Langmuir P, Lehmann T, Levine M, Savic S. Ruxolitinib in addition to standard of care for the treatment of patients admitted to hospital with COVID-19 (RUXCOVID): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Rheumatol. 2022 May;4(5):e351-e361. doi: 10.1016/S2665-9913(22)00044-3. Epub 2022 Mar 29.

Helpful Links

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 2, 2020
• Primary Completion (ACTUAL): October 17, 2020
• Study Completion (ACTUAL): October 17, 2020

Study Registration Dates

• First Submitted: April 22, 2020
• First Submitted That Met QC Criteria: April 22, 2020
• First Posted (ACTUAL): April 24, 2020

Study Record Updates

• Last Update Posted (ACTUAL): October 11, 2021
• Last Update Submitted That Met QC Criteria: October 7, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: cytokine release syndrome; SARS-COV-2; ruxolitinib; COVID-19 pneumonia
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Shock; COVID-19; Cytokine Release Syndrome
• Other Study ID Numbers: CINC424J12301; INCB 18424-368 (OTHER: Incyte Study Code); 2020-001662-11 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No