E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe pulmonary COVID-19 related disease |
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E.1.1.1 | Medical condition in easily understood language |
Severe coronavirus related lung disease |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053983 |
E.1.2 | Term | Corona virus infection |
E.1.2 | System Organ Class | 100000004862 |
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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 |
Part 1
To compare the efficacy of otilimab IV versus placebo.
Part 2
To compare the efficacy of otilimab IV versus placebo |
|
E.2.2 | Secondary objectives of the trial |
Part 1
To compare the efficacy of otilimab IV versus placebo.
To compare the safety and tolerability of otilimab IV versus placebo.
Part 2
To compare the efficacy of otilimab IV versus placebo
To compare the safety and tolerability of otilimab IV versus placebo |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Part 1
1. Age ≥18 years and ≤79 years at the time of obtaining informed consent.
2. Participants must:
a. have positive SARS-CoV-2 result (any validated test, e.g. RT-PCR [performed on an appropriate specimen; e.g. respiratory tract sample])
b. AND be hospitalized due to diagnosis of pneumonia (chest X-ray or computerized tomography [CT] scan consistent with COVID-19)
c. AND be developing new onset of oxygenation impairment requiring any of the following
- high-flow oxygen (≥15L/min)
- non-invasive ventilation (NIV, CPAP, BIPAP)
- mechanical ventilation ≤48h prior to dose
d. AND have increased biological markers of systemic inflammation (either CRP >ULN or serum ferritin >ULN).
3. No gender restriction.
4. Female participants must meet and agree to abide by the contraceptive criteria detailed in the protocol.
5. Capable of giving written informed consent. If participants are not capable of giving written informed consent, alternative consent procedures will be followed.
Part 2
1. Age 70 years or above at the time of obtaining informed consent.
2. Participants must:
a. have positive SARS-CoV-2 result (any validated test, e.g. RT-PCR [performed on an appropriate specimen; e.g. respiratory tract sample])
b. AND be hospitalized due to diagnosis of pneumonia (chest X-ray or computerized tomography [CT] scan consistent with COVID-19)
c. AND be developing new onset of oxygenation impairment requiring any of the following
- high-flow oxygen (≥15L/min)
- non-invasive ventilation (NIV, CPAP, BIPAP)
- mechanical ventilation ≤48h prior to dose
d. AND have increased biological markers of systemic inflammation (either CRP >ULN or serum ferritin >ULN).
3. No gender restriction
4. Capable of giving written informed consent. If participants are not capable of giving written informed consent, alternative consent procedures will be followed. |
|
E.4 | Principal exclusion criteria |
Part 1
1. Progression to death is imminent and inevitable within the next 48 hours, irrespective of the provision of treatments, in the opinion of the investigator.
2. Multiple organ failure according to the investigator’s judgement or a Sequential Organ Failure assessment (SOFA score) >10 if in the ICU.
3. Extracorporeal membrane oxygenation (ECMO) haemofiltration/dialysis, or high-dose (>0.15 μg/kg/min) noradrenaline (or equivalent) or more than one vasopressor.
4. Current serious or uncontrolled medical condition (e.g. significant pulmonary disease [such as severe COPD or pulmonary fibrosis], heart failure [NYHA class III or higher], significant renal dysfunction, acute myocardial infarction or acute cerebrovascular accident within the last 3 months) or abnormality of clinical laboratory tests that, in the investigator's judgment, precludes the participant's safe participation in and completion of the study.
5. Untreated systemic bacterial, fungal, viral, or other infection (other than SARS-CoV-2).
6. Known active tuberculosis (TB), history of untreated or incompletely treated active or latent TB, suspected or known extrapulmonary TB.
7. Known HIV regardless of immunological status.
8. Known HBsAg and/or anti-HCV positive.
9. Currently receiving radiotherapy, chemotherapy or immunotherapy for malignancy.
10. Received monoclonal antibody therapy (e.g. tocilizumab, sarilumab) within the past 3 months prior to randomization, including intravenous immunoglobulin or planned to be received during the study.
11. Received immunosuppressant therapy including but not limited to cyclosporin, azathioprine, tacrolimus, mycophenolate, JAK inhibitors (e.g. baricitinib, tofacitinib, upadacitinib) within the last 3 months prior to randomization or planned to be received during the study.
12. History of allergic reaction, including anaphylaxis to any previous treatment with an anti- GM-CSF therapy.
13. Currently receiving chronic oral corticosteroids for a non-COVID-19 related condition in a dose higher than prednisone 10 mg or equivalent per day.
14. Treatment with an investigational drug within 30 days of randomization.
15. Participating in other drug clinical trials, including for COVID-19.
16. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5x upper limit of normal (ULN)
17. Platelets <50,000/mm3
18. Hemoglobin ≤9 g/L
19. Absolute neutrophil count (ANC) <1.5 x 109/L (neutropenia ≥ Grade 2)
20. Estimated GFR ≤30 mL/min/1.73m2
21. Pregnant or breastfeeding females.
Part 2
1. Progression to death is imminent and inevitable within the next 48 hours, irrespective of the provision of treatments, in the opinion of the investigator.
2. Multiple organ failure according to the investigator’s judgement or a Sequential Organ Failure assessment (SOFA score) >10 if in the ICU.
3. Extracorporeal membrane oxygenation (ECMO) haemofiltration/dialysis, or more than one inotrope/vasopressor of any class.
4. Current serious or uncontrolled medical condition (e.g. significant pulmonary disease [such as severe COPD or pulmonary fibrosis], heart failure [NYHA class III or higher], severe renal dysfunction, acute myocardial infarction or acute cerebrovascular accident within the last 3 months), severe dementia, severe disability or abnormality of clinical laboratory tests that, in the investigator's judgment, precludes the participant's safe participation in and completion of the study.
5. Untreated systemic bacterial, fungal, viral, or other infection (other than SARS-CoV-2).
6. Known active tuberculosis (TB), history of untreated or incompletely treated active or latent TB, suspected or known extrapulmonary TB.
7. Known HIV regardless of immunological status.
8. Known HBsAg and/or anti-HCV positive.
9. Currently receiving radiotherapy, chemotherapy or immunotherapy for malignancy.
10. Received monoclonal antibody therapy (e.g. tocilizumab, sarilumab) within the past 3 months prior to randomization, including intravenous immunoglobulin or planned to be received during the study.
11. Received immunosuppressant therapy including but not limited to cyclosporin, azathioprine, tacrolimus, mycophenolate, JAK inhibitors (e.g. baricitinib, tofacitinib, upadacitinib), nintedanib, DMARDs (e.g. methotrexate) within the last 3 months prior to randomization or planned to be received during the study.
History of allergic reaction, including anaphylaxis to any previous treatment with an anti- GM-CSF therapy.
12. Received COVID-19 convalescent plasma within 48 hours of randomization.
13. Currently receiving chronic oral corticosteroids for a non-COVID-19 related condition in a dose higher than prednisone 10 mg or equivalent per day.
14. Treatment with an investigational drug within 30 days of randomization.
15. Participating in other drug clinical trials, including for COVID-19.
A complete list of Exclusion criteria for Part 2 can be found in the protocol Section 5.4 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1 and Part 2
Participants alive and free of respiratory failure |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Part 1
• All-cause mortality
• Time to last dependence on supplementary oxygen
• Participants alive and independent of supplementary oxygen
• ICU admission
• Time to final ICU discharge
• Time to final hospital discharge
• Time to all-cause mortality,
• Time to recovery from respiratory failure
• Time to last dependence on supplementary oxygen
• Occurrence of adverse events (AEs)
• Occurrence of serious adverse events (SAEs)
Part 2
• All cause mortality
• Time to all-cause mortality
• Participants alive and free of respiratory failure
• Time to recovery from respiratory failure
• Participants alive and independent of supplementary oxygen
• Time to last dependence on supplementary oxygen
• Time to final ICU discharge
• Time to first discharge from investigator site
• Time to first discharge to non-hospitalized residence
• Occurrence of adverse events (AEs)
• Occurrence of serious adverse events (SAEs)
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Various timepoints up to Day 60. |
|
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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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) | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
|
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 |
Brazil |
Canada |
Chile |
India |
Japan |
Mexico |
Peru |
Russian Federation |
South Africa |
United States |
Belgium |
France |
Netherlands |
Poland |
Spain |
United Kingdom |
Argentina |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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
|
A participant is considered to have completed the study if he/she has completed all visits of the study through to Day 60 or has died prior to Day 60. The end of the study is defined as the date of the last contact of the last participant in this additional cohort in Part 2 (or any future additional cohorts) in the study. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |