Investigating Otilimab in Patients With Severe Pulmonary COVID-19 Related Disease

A Randomized, Double-blind, Placebo-controlled, Study Evaluating the Efficacy and Safety of Otilimab IV in Patients With Severe Pulmonary COVID-19 Related Disease

OSCAR (Otilimab in Severe COVID-19 Related Disease) is a multi-center, double-blind, randomized, placebo-controlled trial to assess the efficacy and safety of otilimab for the treatment of severe pulmonary COVID-19 related disease. The study is being conducted in 2 parts (Part 1 and Part 2). Otilimab is a human monoclonal anti-granulocyte macrophage colony stimulating factor (GM-CSF) antibody that has not previously been tested in participants with severe pulmonary COVID-19 related disease in Part 1. The aim of this study is to evaluate the benefit-risk of a single infusion of otilimab in the treatment of hospitalized participants with severe COVID-19 related pulmonary disease with new onset hypoxia requiring significant oxygen support or requiring early invasive mechanical ventilation (less than or equal to [<=] 48 hours before dosing). Participants will be randomized to receive a single intravenous (IV) infusion of otilimab or placebo, in addition to standard of care.

Inclusion criteria for Part 1:

• Participants aged >=18 years and <=79 years at the time of obtaining informed consent.

• Participants must:

  1. have positive severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) result (any validated test, for example. reverse transcription polymerase chain reaction [RT-PCR] [performed on an appropriate specimen; for example: respiratory tract sample])

  2. and be hospitalized due to diagnosis of pneumonia (chest X-ray or computerized tomography [CT] scan consistent with COVID-19)

  3. and be developing new onset of oxygenation impairment requiring any of the following:

     1. high-flow oxygen (>=15L/min)
     2. non-invasive ventilation (for example. CPAP, BIPAP)
     3. mechanical ventilation <=48 hours prior to dose

  4. and have increased biological markers of systemic inflammation (either C-reactive protein [CRP] >upper limit of normal [ULN] or serum ferritin >ULN).

• No gender restriction.

• Female participants must meet and agree to abide by the contraceptive criteria detailed in the protocol. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

• A female participant is eligible to participate if she is not pregnant or breastfeeding or if she is using highly effective contraceptive methods. Women of non-childbearing potential can also participate. A negative highly sensitive pregnancy test at hospital admission or before the first dose of study intervention.

• Capable of giving written informed consent.

Inclusion Criteria for Part 2:

• Participants aged 70 years or above at the time of obtaining informed consent.

• Participants must:

  1. have positive SARS-CoV-2 result (any validated test, for example. RT-PCR [performed on an appropriate specimen; for example. respiratory tract sample])

  2. and be hospitalized due to diagnosis of pneumonia (chest X-ray or CT scan consistent with COVID-19).

  3. and be developing new onset of oxygenation impairment requiring any of the following:

     1. high-flow oxygen (>=15L/min)
     2. non-invasive ventilation (for example. CPAP, BiPAP)
     3. mechanical ventilation <=48 hours prior to dose

  4. and have increased biological markers of systemic inflammation (either CRP >ULN or serum ferritin >ULN.

• No gender restriction.

• Capable of giving written informed consent.

Exclusion Criteria for Part 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.
• Multiple organ failure according to the investigator's judgement or a Sequential Organ Failure assessment (SOFA score) >10 if in the ICU.
• Extracorporeal membrane oxygenation (ECMO) hemofiltration/dialysis or high-dose (>0.15 micrograms [mcg]/kilograms [kg]/min) noradrenaline (or equivalent) or more than one vasopressor.
• Current serious or uncontrolled medical condition (for example: significant pulmonary disease [such as severe chronic obstructive pulmonary disease (COPD) or pulmonary fibrosis], heart failure [New York Heart Association {NYHA} class III or higher], 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.
• Untreated systemic bacterial, fungal, viral, or other infection (other than SARS-CoV-2).
• Known active tuberculosis (TB), history of untreated or incompletely treated active or latent TB, suspected or known extrapulmonary TB.
• Known Human Immunodeficiency Virus (HIV) regardless of immunological status.
• Known hepatitis B surface antigen (HBsAg) and/or anti-hepatitis C virus (HCV) positive.
• Currently receiving radiotherapy, chemotherapy or immunotherapy for malignancy.
• Received monoclonal antibody therapy (for examplee. tocilizumab, sarilumab) within the past 3 months prior to randomization, including intravenous immunoglobulin, or planned to be received, during the study.
• Received immunosuppressant therapy including but not limited to cyclosporin, azathioprine, tacrolimus, mycophenolate, Janus Kinase (JAK) inhibitors (for examplee. baricitinib, tofacitinib, upadacitinib) 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.
• Received COVID-19 convalescent plasma within 48 hours of randomization.
• Currently receiving chronic oral corticosteroids for a non-COVID-19 related condition in a dose higher than prednisone 10 milligrams (mg) or equivalent per day.
• Treatment with an investigational drug within 30 days of randomization.
• Participating in other drug clinical trials, including for COVID-19.
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times ULN.
• Platelets <50,000/cubic millimeters (mm^3)
• Hemoglobin <=9 grams per deciliter (g/dL)
• Absolute neutrophil count (ANC) <1.5 times 10^9/L (neutropenia >= Grade 2)
• Estimated glomerular filtration rate (GFR) <=30 milliliters (mL)/min/1.73 meter square (/m^2).
• Pregnant or breastfeeding females.

Exclusion Criteria for Part 2:

• Progression to death is imminent and inevitable within the next 48 hours, irrespective of the provision of treatments, in the opinion of the investigator.
• Multiple organ failure according to the investigator's judgement or a SOFA score >10 if intubated in the ICU.
• ECMO hemofiltration/dialysis, or more than one inotrope/vasopressor of any class.
• Current serious or uncontrolled medical condition (for example. 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.
• Untreated systemic bacterial, fungal, viral, or other infection (other than SARSCoV-2).
• Known active TB, history of untreated or incompletely treated active or latent TB, suspected or known extrapulmonary TB.
• Known HIV regardless of immunological status.
• Known HBsAg and/or anti-HCV positive (participants demonstrating a sustained virologic response (SVR) are not excluded from participation).
• Currently receiving radiotherapy, chemotherapy (hormone based therapies are permitted) or immunotherapy for malignancy.
• Received monoclonal antibody therapy (for example. tocilizumab, sarilumab) within the past 3 months prior to randomization, including intravenous immunoglobulin, or planned to be received during the study.
• Received immunosuppressant therapy including but not limited to cyclosporin, azathioprine, tacrolimus, mycophenolate, JAK inhibitors (for example. baricitinib, tofacitinib, upadacitinib), nintedanib, disease modifying antirheumatic drugs (DMARDs) (for example. 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.
• Received COVID-19 convalescent plasma within 48 hours of randomization.
• Currently receiving chronic oral corticosteroids for a non-COVID-19 related condition at a dose higher than prednisone 10 mg or equivalent per day.
• Treatment with an investigational drug or substance within 30 days of randomization unless approved by the Medical Monitor.
• Participating in other drug clinical trials, including for COVID-19.
• AST or ALT >5 times ULN.
• Platelets <50,000/mm^3.
• Hemoglobin <=9 g/dL
• ANC <1.0 x 10^9/L (neutropenia >= Grade 3).
• Estimated GFR <=30 mL/min/1.73 m^2.