Investigating Otilimab in Patients With Severe Pulmonary COVID-19 Related Disease
Condition: Severe Acute Respiratory Syndrome
MeSH terms: COVID-19; Severe Acute Respiratory Syndrome
Intervention: Otilimab; Placebo 1; Placebo 2; Standard of care
Intervention description: Otilimab will be administered once via IV route.; Placebo 1 will consist of sterile 0.9 percent (%) sodium chloride solution administered once via IV route.; Placebo 2 will consist of sterile 5% dextrose or 5% glucose solution administered once via IV route.; All participants will receive standard of care as per institutional protocol.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Participants will be randomized to receive either a blinded IV infusion of otilimab or placebo, in addition to standard of care.
Masking: Double (Participant, Investigator)
Masking description: This is a double-blind study.
Enrollment: 1156.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: COVID-19; Otilimab; Ordinal scale; Coronavirus; GSK3196165

Summary:

      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.
    

Eligibility criteria:

        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.