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

• ClinicalTrials.gov Identifier: NCT04447469
• Recruitment Status: Active, not recruiting
• First Posted: June 25, 2020
• Last Update Posted: January 3, 2022
• Sponsor: Kiniksa Pharmaceuticals, Ltd.
• Information provided by (Responsible Party): Kiniksa Pharmaceuticals, Ltd.

Tracking Information

• First Submitted Date: June 23, 2020
• First Posted Date: June 25, 2020
• Last Update Posted Date: January 3, 2022
• Actual Study Start Date: July 27, 2020
• Actual Primary Completion Date: November 12, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 13, 2021)

• Cohort 1: Proportion of subjects alive and free of mechanical ventilation at Day 29 [ Time Frame: 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.
• Cohort 2: Mortality rate at Day 29 [ Time Frame: Day 29 ]
  Mortality rate is defined as the proportion of subjects who have died by Day 29.

Original Primary Outcome Measures (submitted: June 24, 2020)

• Cohort 1: Proportion of Participants Alive and Without Respiratory Failure at Day 15 [ Time Frame: Day 15 ]
  Respiratory failure is defined as the need for high flow oxygen (HFO), non-invasive ventilation (NIV), invasive mechanical ventilation (IMV), or extracorporeal membrane oxygenation (ECMO).
• Cohort 2: Mortality Rate at Day 15 [ Time Frame: Day 15 ]
  Mortality rate is defined as the proportion of participants who die.

Current Secondary Outcome Measures (submitted: December 13, 2021)

• Cohort 1: Mortality rate at Day 29 [ Time Frame: By Day 29 ]
  Mortality rate is defined as the proportion of participants who die.
• Cohort 1: Ventilation-free survival by Day 29 [ Time Frame: By Day 29 ]
  Defined as time from randomization to ventilation or death; subjects still alive will be censored at Day 29.
• Cohort 1: Overall survival by Day 29 [ Time Frame: Day 29 ]
  Defined as time from randomization to death; subjects still alive will be censored at Day 29.
• Cohort 2: Time to 1-point clinical improvement by Day 29 [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: June 24, 2020)

• Cohort 1: Time to Return to Room Air by Day 15 [ Time Frame: up to Day 15 ]
  Return to room air is defined as time from the date of randomization to the start of a period of 24 hours while breathing room air (National Institute of Allergy and Infectious Diseases [NIAID] scale ≥ 5), or discharge from the hospital, whichever occurs first. 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.
• Cohort 1: Time to 2-point Clinical Improvement by Day 15 [ Time Frame: up to Day 15 ]
  Clinical Improvement, defined as time from randomization to a 2-point improvement on the NIAID scale, or discharge from the hospital, whichever comes first. 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.
• Cohort 1: Mortality Rate at Day 29 [ Time Frame: Day 29 ]
  Mortality rate is defined as the proportion of participants who die.
• Cohort 1: Time to 1-Point Clinical Improvement by Day 15 [ Time Frame: up to Day 15 ]
  Clinical improvement, defined as time from randomization to a 1-point improvement on the NIAID scale, or discharge from the hospital, whichever comes first. 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.
• Cohort 2: Mortality Rate at Day 29 [ Time Frame: Day 29 ]
  Mortality rate is defined as the proportion of participants who die.
• Cohort 2: Proportion of Participants Alive and Without Respiratory Failure at Day 15 [ Time Frame: Day 15 ]
  Respiratory failure is defined as the need for HFO, NIV, IMV, or ECMO.
• Cohorts 1 and 2: Proportion of Participants Alive and Without Respiratory Failure At Day 29 [ Time Frame: Day 29 ]
  Respiratory failure is defined as the need for HFO, NIV, IMV, or ECMO
• Cohorts 1 and 2: Time to Return to Room Air by Day 29 [ Time Frame: up to Day 29 ]
  Return to room air is defined as time from the date of randomization to the start of a period of 24 hours while breathing room air (NIAID scale ≥ 5), or discharge from the hospital, whichever occurs first. 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.
• Cohort 2: Time to 2-point Clinical Improvement by Day 15 [ Time Frame: up to Day 15 ]
  Clinical Improvement, defined as time from randomization to a 2-point improvement on the NIAID scale, or discharge from the hospital, whichever comes first. 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.
• Cohorts 1 and 2: Time to 1-point Clinical Improvement by Day 29 [ Time Frame: up to Day 29 ]
  Clinical Improvement, defined as time from randomization to a 1-point improvement on the NIAID scale, or discharge from the hospital, whichever comes first. 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.
• Cohorts 1 and 2: Time to 2-point Clinical Improvement by Day 29 [ Time Frame: up to Day 29 ]
  Clinical Improvement, defined as time from randomization to a 2-point improvement on the NIAID scale, or discharge from the hospital, whichever comes first. 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.
• Cohort 1: Respiratory Failure-Free Survival by Day 15 [ Time Frame: up to Day 15 ]
  Respiratory failure is defined as the need for HFO, NIV, IMV, or ECMO.
• Cohort 1: Respiratory Failure-Free Survival by Day 29 [ Time Frame: up to Day 29 ]
  Respiratory failure is defined as the need for HFO, NIV, IMV, or ECMO
• Cohort 1: Proportion of Participants Who Return to Room Air by Day 15 [ Time Frame: up to Day 15 ]
  Return to room air is defined as time from the date of randomization to the start of a period of 24 hours while breathing room air (NIAID scale ≥ 5), or discharge from the hospital, whichever occurs first. 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.
• Cohorts 1 and 2: Proportion of Participants Who Return to Room Air by Day 29 [ Time Frame: up to Day 29 ]
  Return to room air is defined as time from the date of randomization to the start of a period of 24 hours while breathing room air (NIAID scale ≥ 5), or discharge from the hospital, whichever occurs first. 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.
• Cohort 1: Mortality Rate at Day 15 [ Time Frame: Day 15 ]
  Mortality rate is defined as the proportion of participants who die.
• Cohorts 1 and 2: Overall Survival by Day 29 [ Time Frame: up to Day 29 ]
  Overall survival is defined as time from date of randomization to the date of death.
• Cohorts 1 and 2: Clinical Status Over Time [ Time Frame: Days 4, 8, 15, 22, and 29 ]
  Clinical status, based on the NIAID 8-point ordinal scale. 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.
• Cohorts 1 and 2: Number of Days Alive and Out of Hospital Through Day 90 [ Time Frame: through Day 90 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Mavrilimumab (KPL-301) in Participants Hospitalized With Severe Corona Virus Disease 2019 (COVID-19) Pneumonia and Hyper-inflammation
• Official Title: 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
• Brief Summary: Interventional, randomized, double-blind, placebo-controlled study encompassing 2 development phases (Phase 2 and Phase 3).
• Detailed Description: 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.
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: COVID

Intervention

• Drug: mavrilimumab
  anti-granulocyte-macrophage colony-stimulating factor receptor alpha (GM-CSF-Rα) monoclonal antibody (human isoform immunoglobulin G [IgG4])
  Other Name: (KPL-301; CAM3001)
• Other: Placebo
  matching placebo

Study Arms

• Active Comparator: 10 mg/kg (Cohort 1)
  Non-mechanically ventilated participants administered mavrilimumab 10 mg/kg as a single IV infusion
  Intervention: Drug: mavrilimumab
• Active Comparator: 6 mg/kg (Cohort 1)
  Non-mechanically ventilated participants administered mavrilimumab 6 mg/kg as a single IV infusion
  Intervention: Drug: mavrilimumab
• Placebo Comparator: Placebo (Cohort 1)
  Non-mechanically ventilated participants administered placebo as a single IV infusion
  Intervention: Other: Placebo
• Active Comparator: 10 mg/kg (Cohort 2)
  Mechanically ventilated participants administered mavrilimumab 10 mg/kg as a single IV infusion
  Intervention: Drug: mavrilimumab
• Active Comparator: 6 mg/kg (Cohort 2)
  Mechanically ventilated participants administered mavrilimumab 6 mg/kg as a single IV infusion
  Intervention: Drug: mavrilimumab
• Placebo Comparator: Placebo (Cohort 2)
  Mechanically ventilated participants administered placebo as a single IV infusion
  Intervention: Other: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: December 13, 2021): 815
• Original Estimated Enrollment (submitted: June 24, 2020): 573
• Estimated Study Completion Date: January 2022
• Actual Primary Completion Date: November 12, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Brazil, Chile, Peru, South Africa, United States

Administrative Information

• NCT Number: NCT04447469
• Other Study ID Numbers: KPL-301-C203
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: The Sponsor will review IPD requests proposals from qualified researchers
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Time Frame: IPD requests will be accepted after publication of the primary data manuscript
• Access Criteria: IPD access will be provided to qualified academic researchers pending the Sponsor's review of the proposed research, including scientific novelty, review of the analytical and publication plans, funding source of the proposed research, any potential conflicts of interest, and institutional capabilities to perform the planned research.

• Responsible Party: Kiniksa Pharmaceuticals, Ltd.
• Study Sponsor: Kiniksa Pharmaceuticals, Ltd.
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Kiniksa Pharmaceuticals, Ltd.
• Verification Date: December 2021