Study of Mavrilimumab (KPL-301) in Participants Hospitalized With Severe Corona Virus Disease 2019 (COVID-19) Pneumonia and Hyper-inflammation

Study Overview
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Brief Summary
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Interventional, randomized, double-blind, placebo-controlled study encompassing 2 development phases (Phase 2 and Phase 3).

Detailed Description
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The Phase 2 portion of the study will evaluate the efficacy and safety of 2 dose levels of mavrilimumab relative to placebo (standard of care) in participants who have tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with x-ray/computed tomography (CT) evidence of bilateral pneumonia and active or recent signs of hyperinflammation (fever or clinical laboratory results indicative of hyper-inflammation). The Phase 3 portion is intended to confirm Phase 2 efficacy and safety findings. In both Phase 2 and Phase 3, participants will be enrolled into 2 cohorts: Cohort 1 will include non-intubated, hospitalized participants who require supplemental oxygen to maintain oxygen saturation (SpO2) ≥ 92% (ie, non-ventilated participants); Cohort 2 will include hospitalized participants for whom mechanical ventilation was recently initiated (ie, ventilated participants). Following Screening, enrolled participants in each cohort will be randomized 1:1:1 to receive one of 2 mavrilimumab dose levels, or placebo as a single intravenous (IV) infusion (Day 1). Participants will undergo primary study assessments through Day 29 and will be followed for safety through Day 90.

Official Title
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A Phase 2/3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Mavrilimumab (KPL-301) Treatment in Adult Subjects Hospitalized With Severe COVID-19 Pneumonia and Hyper-inflammation

Conditions
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COVID

Intervention / Treatment
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* Drug: mavrilimumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Subject (or legally authorized representative) is able and willing to provide informed consent, which includes compliance with study requirements and restrictions listed in the consent form. Consent must be performed per institutional regulations. Age of ≥ 18 years Positive SARS-CoV-2 (2019-nCoV) test within 14 days prior to randomization Hospitalized for SARS-CoV-2 (2019-nCoV) Bilateral pneumonia on chest x-ray or computed tomography Clinical laboratory results indicative of hyper-inflammation within 7 days prior to randomization Cohort 1: Receiving any form of non-invasive ventilation OR oxygenation to maintain SpO2 ≥ 92% and non-mechanically ventilated (examples include nasal cannula, face mask, venturi mask, high-flow nasal cannula, or non-invasive positive pressure ventilation) Cohort 2: Recently ventilated with mechanical ventilation beginning within 48 hours prior to randomization Key Exclusion Criteria: Onset of COVID-19 symptoms > 14 days prior to randomization Hospitalized > 7 days prior to randomization Need for invasive mechanical ventilation (Only for Cohort 1) Need for ECMO Serious prior or concomitant illness that in the opinion of the Investigator precludes the subject from enrolling in the trial Recent treatment with cell-depleting biological therapies (eg, anti-CD20) within 12 months, non-cell-depleting biological therapies (such as anti-tumor necrosis factor [TNF], anakinra, anti-IL-6 receptor [eg, tocilizumab], or abatacept) within 8 weeks (or 5 half-lives, whichever is longer), treatment with alkylating agents within 12 weeks, treatment with cyclosporine A, azathioprine, cyclophosphamide, mycophenolate mofetil (MMF), or other immunosuppressant (except for corticosteroids) within 4 weeks prior to randomization. Medications that become standard of care for COVID-19 and/or receive emergency use authorization may be allowed after discussion with the medical monitor. If subject is receiving or has received hydroxychloroquine within 3 months prior to screening visit, a corrected QT interval by Federicia method (QTcF) on Screening electrocardiogram (ECG) ≥500ms is exclusionary. If subject has a pacemaker, this criterion does not apply. Enrolled in another investigational study of a medical intervention within 30 days prior to randomization. Participation in open label trials involving investigational treatments for COVID-19 may be allowed upon approval by the Sponsor. Life expectancy less than 48 hours, in the opinion of the Investigator Known human immunodeficiency virus infection (regardless of immunological status), known hepatitis B virus surface antigen positivity and/or anti-hepatitis C virus positivity

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 10 mg/kg (Cohort 1)<br>Non-mechanically ventilated participants administered mavrilimumab 10 mg/kg as a single IV infusion | Drug: mavrilimumab<br>* anti-granulocyte-macrophage colony-stimulating factor receptor alpha (GM-CSF-Rα) monoclonal antibody (human isoform immunoglobulin G [IgG4])<br>* Other names: (KPL-301; CAM3001);|
| Active Comparator: 6 mg/kg (Cohort 1)<br>Non-mechanically ventilated participants administered mavrilimumab 6 mg/kg as a single IV infusion | Drug: mavrilimumab<br>* anti-granulocyte-macrophage colony-stimulating factor receptor alpha (GM-CSF-Rα) monoclonal antibody (human isoform immunoglobulin G [IgG4])<br>* Other names: (KPL-301; CAM3001);|
| Placebo Comparator: Placebo (Cohort 1)<br>Non-mechanically ventilated participants administered placebo as a single IV infusion | Other: Placebo<br>* matching placebo<br>|
| Active Comparator: 10 mg/kg (Cohort 2)<br>Mechanically ventilated participants administered mavrilimumab 10 mg/kg as a single IV infusion | Drug: mavrilimumab<br>* anti-granulocyte-macrophage colony-stimulating factor receptor alpha (GM-CSF-Rα) monoclonal antibody (human isoform immunoglobulin G [IgG4])<br>* Other names: (KPL-301; CAM3001);|
| Active Comparator: 6 mg/kg (Cohort 2)<br>Mechanically ventilated participants administered mavrilimumab 6 mg/kg as a single IV infusion | Drug: mavrilimumab<br>* anti-granulocyte-macrophage colony-stimulating factor receptor alpha (GM-CSF-Rα) monoclonal antibody (human isoform immunoglobulin G [IgG4])<br>* Other names: (KPL-301; CAM3001);|
| Placebo Comparator: Placebo (Cohort 2)<br>Mechanically ventilated participants administered placebo as a single IV infusion | Other: Placebo<br>* matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort 1: Proportion of subjects alive and free of mechanical ventilation at Day 29 | Mechanical ventilation is defined as invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). Mechanical ventilation status will be evaluated based on the National Institute of Allergy and Infectious Diseases (NIAID) clinical outcome 8-point ordinal scale. Subjects whose clinical outcome has met a NIAID score of 2 will be considered as using mechanical ventilation. The NIAID is an 8-point ordinal scale of clinical outcomes: 1=death; 2=hospitalized, on invasive mechanical ventilation or ECMO; 3=hospitalized, on non-invasive ventilation or high flow oxygen devices; 4= hospitalized, requiring supplemental oxygen; 5=hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID 19 related or otherwise); 6=hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7=not hospitalized, limitation on activities and/or requiring home oxygen; 8=not hospitalized, no limitations on activities. | Day 29 | 
| Cohort 2: Mortality rate at Day 29 | Mortality rate is defined as the proportion of subjects who have died by Day 29. | Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort 1: Mortality rate at Day 29 | Mortality rate is defined as the proportion of participants who die. | By Day 29 | 
| Cohort 1: Ventilation-free survival by Day 29 | Defined as time from randomization to ventilation or death; subjects still alive will be censored at Day 29. | By Day 29 | 
| Cohort 1: Overall survival by Day 29 | Defined as time from randomization to death; subjects still alive will be censored at Day 29. | Day 29 | 
| Cohort 2: Time to 1-point clinical improvement by Day 29 | Defined as time from randomization to a 1-point improvement on the NIAID 8-point ordinal scale, or discharge from the hospital, whichever comes first. Subjects who die before Day 29 will be censored at Day 30. | By Day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, pneumonia, hyper-inflammation