E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
COVID-19 associated cytokine storm |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 [ICU] care) of ruxolitinib + standard-of-care (SoC) therapy compared with placebo + SoC therapy, for the treatment of COVID-19 by Day 29 |
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E.2.2 | Secondary objectives of the trial |
evaluate efficacy (as measured by clinical status using a 9-point ordinal scale) of ruxolitinib + SoC therapy compared with placebo + SoC therapy, for treatment of COVID-19.
evaluate efficacy of ruxolitinib + standard-of-care (SoC) therapy compared with placebo + SoC therapy, on in-hospital outcomes in patients with COVID-19.
evaluate efficacy of ruxolitinib + SoC therapy, compared with placebo + SoC therapy, in change in the National Early Warning Score (NEWS2) score in patients with COVID-19.
evaluate efficacy of ruxolitinib + SoC therapy, compared with placebo + SoC therapy, in change in SpO2/FiO2 ratio in patients with COVID-19.
evaluate efficacy of ruxolitinib + SoC therapy, compared with placebo + SoC therapy, in proportion of patients with no oxygen therapy (defined as oxygen saturation ≥ 94% on room air) in patients with COVID-19.
evaluate safety of ruxolitinib + standard-of-care (SoC) therapy compared with placebo + SoC therapy, in treatment of patients with COVID-19.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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).
Additional inclusion criteria as per main section in the protocol may apply. |
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E.4 | Principal 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.
Additional exclusion criteria as per main section in the protocol may apply. |
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E.5 End points |
E.5.1 | Primary end point(s) |
composite endpoint defined as proportion of patients who
- die OR
- develop respiratory failure (require mechanical ventilation) OR
- require intensive care unit (ICU) care |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. 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 (noninvasive ventilation or highflow 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.
2. Percentage of patients with at least two-point improvement from baseline in clinical status on the 9-point ordinal scale.
3. Percentage of patients with at least one-point improvement from baseline in clinical status on the 9-point ordinal scale.
4. Percentage of patients with at least one-point deterioration from baseline in clinical status on the 9-point ordinal scale.
5. Time to improvement from baseline category to one less severe category of the 9-point ordinal scale.
6. Mean change from baseline in clinical status on the 9-point ordinal scale
7. Mortality rate
8. Proportion of patients requiring mechanical ventilation
9. Duration of hospitalization.
10. The time to discharge or to a NEWS2 score of ≤2 and maintained for 24 hours whichever comes first.
11. Change from baseline in NEWS2 score.
12. Change from baseline in SpO2/FiO2 ratio.
13. Proportion of patients with no oxygen therapy (no oxygen therapy is required if oxygen saturation ≥ 94% on room air) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Day 15, Day 29 2. Baseline, Day 15, Day 29
3. Baseline, Day 15, Day 29
4. Baseline, Day 15, Day 29
5. 29 days
6. Baseline, Day 15, Day 29
7. Day 15, Day 29 8. 29 days
9. 29 days
10. 29 days
11. Baseline, Days 3, 5, 8, 11, 15, and 29
12. Baseline, Day 15, Day 29
13. Day 15, Day 29 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
France |
Germany |
Italy |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 8 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 8 |