COVID
Conditions
Keywords
COVID-19, pneumonia, 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-mechanically ventilated, hospitalized participants who require supplemental oxygen to maintain oxygen saturation (SpO2) ≥ 92% (ie, non-mechanically ventilated participants); Cohort 2 will include hospitalized participants for whom mechanical ventilation was recently initiated (ie, mechanically 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.
Interventions
DRUGmavrilimumab
anti-granulocyte-macrophage colony-stimulating factor receptor alpha (GM-CSF-Rα) monoclonal antibody (human isoform immunoglobulin G \[IgG4\])
OTHERPlacebo
matching placebo
Sponsors
Kiniksa Pharmaceuticals, Ltd.
Kiniksa Pharmaceuticals International, plc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 1, Phase 2: Percentage of Participants Alive and Free of Mechanical Ventilation at Day 29 | Day 29 | Mechanical ventilation is defined as invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). Mechanical ventilation status was evaluated based on the National Institute of Allergy and Infectious Diseases (NIAID) clinical outcome 8-point ordinal scale. Participants whose clinical outcome met a NIAID score of 2 were considered as using mechanical ventilation. The NIAID score 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, Phase 3: Percentage of Participants Alive and Free of Mechanical Ventilation at Day 29 | Day 29 | Mechanical ventilation is defined as invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). Mechanical ventilation status was evaluated based on the National Institute of Allergy and Infectious Diseases (NIAID) clinical outcome 8-point ordinal scale. Participants whose clinical outcome met a NIAID score of 2 were considered as using mechanical ventilation. The NIAID score 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, Phase 2: Percentage of Participants Who Died by Day 29 | Day 29 | Defined as the proportion of subjects with mechanical ventilation who have died by Day 29. |
| Cohort 2, Phase 3: Percentage of Participants Who Died by Day 29 | Day 29 | Defined as the proportion of subjects with mechanical ventilation who have died by Day 29. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 3, Cohort 1: Percentage of Participants Who Died at Day 29 | Day 29 | Mortality rate at day 29 is the proportion of subjects who die by day 29. 95% CI were calculated using Clopper-Pearson exact method based on the beta distribution. |
| Phase 3, Cohort 1: Ventilation-Free Survival (Time to Ventilation or Death) by Day 29 | Day 29 | Time to ventilation or death by Day 29 was defined as time (in days) from randomization to the date of death or start date of using mechanical ventilation (NIAID score ≤ 2) by Day 29. Participants who never had NIAID score ≤ 2 by Day 29 were censored at last assessment date of NIAID 8-point ordinal scale. |
| Cohort 1, Phase 2: Time to 2-point Clinical Improvement by Day 29 | Day 29 | Defined as time from randomization to a 2-point improvement on the NIAID 8-point ordinal scale, or discharge from the hospital, whichever came first. Participants who died before Day 29 were censored at Day 30. Kaplan-Meier method used to estimate the survival functions for each treatment arm. The NIAID score 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. |
| Phase 3, Cohort 2: Time to 1-point Clinical Improvement by Day 29 | Day 29 | Defined as time from randomization to the date of a 1-point improvement on the NIAID 8-point ordinal scale or discharge from the hospital, whichever occurred first, by Day 29. Participants who did not have 1-point improvement on the NIAID nor discharge from the hospital were censored at the date of the last NIAID 8-point ordinal scale assessment on/before Day 29. Participants who died were censored at Day 35. |
| Phase 3, Cohort 1: Overall Survival by Day 29 | Day 29 | Overall survival was defined as time from randomization to the date of death on/before Day 29. Participants who did not have a death record by Day 29 were censored at last date known alive on/before Day 29. |
| Phase 2, Cohort 1: Time to Return to Room Air or Discharge by Day 29 | Day 29 | Defined as time from randomization to breathing room air (NIAID score ≥ 5), or discharge from the hospital, whichever came first. Participants who died before Day 29 were censored at Day 30. |
| Phase 2, Cohort 1: Percentage of Participants Who Die by Day 29 | Day 29 | 95% CI were calculated using Clopper-Pearson exact method based on the beta distribution. |
| Phase 2, Cohort 2: Time to 1-Point Clinical Improvement by Day 29 | Day 29 | Defined as time from randomization to the date of a 1-point improvement on the NIAID score 8-point ordinal scale or discharge from the hospital, whichever occurred first, by Day 29. Participants who did not have 1-point improvement on the NIAID nor discharge from the hospital were censored at the date of the last NIAID 8-point ordinal scale assessment on/before Day 29. Participants who died were censored at Day 32. |
Countries
Brazil, Chile, Peru, South Africa, United States
Participant flow
Pre-assignment details
Participants were divided into 2 cohorts (non-mechanically ventilated and mechanically ventilated) and randomized 1:1:1 to receive a single IV infusion of mavrilimumab (10 mg/kg or 6 mg/kg) or placebo in addition to standard of care. There was a seamless transition in enrollment in both cohorts between the Phase 2 and Phase 3 portions of the study. (For each cohort, once the last participant in Phase 2 was enrolled, all subsequent participants were considered Phase 3 participants.)
Participants by arm
| Arm | Count |
|---|---|
| Phase 2: 10 mg/kg (Cohort 1) Non-mechanically ventilated participants administered mavrilimumab 10 mg/kg as a single IV infusion | 35 |
| Phase 2: 6 mg/kg (Cohort 1) Non-mechanically ventilated participants administered mavrilimumab 6 mg/kg as a single IV infusion | 40 |
| Phase 2: Placebo (Cohort 1) Non-mechanically ventilated participants administered placebo as a single IV infusion | 39 |
| Phase 2: 10 mg/kg (Cohort 2) Mechanically ventilated participants administered mavrilimumab 10 mg/kg as a single IV infusion | 15 |
| Phase 2: 6 mg/kg (Cohort 2) Mechanically ventilated participants administered mavrilimumab 6 mg/kg as a single IV infusion | 15 |
| Phase 2: Placebo (Cohort 2) Mechanically ventilated participants administered placebo as a single IV infusion | 17 |
| Phase 3: 10 mg/kg (Cohort 1) Non-mechanically ventilated participants administered mavrilimumab 10 mg/kg as a single IV infusion | 198 |
| Phase 3: 6 mg/kg (Cohort 1) Non-mechanically ventilated participants administered mavrilimumab 6 mg/kg as a single IV infusion | 192 |
| Phase 3: Placebo (Cohort 1) Non-mechanically ventilated participants administered placebo as a single IV infusion | 192 |
| Phase 3: 10 mg/kg (Cohort 2) Mechanically ventilated participants administered mavrilimumab 10 mg/kg as a single IV infusion | 20 |
| Phase 3: 6 mg/kg (Cohort 2) Mechanically ventilated participants administered mavrilimumab 6 mg/kg as a single IV infusion | 22 |
| Phase 3: Placebo (Cohort 2) Mechanically ventilated participants administered placebo as a single IV infusion | 20 |
| Total | 805 |
Baseline characteristics
| Characteristic | Phase 2: 6 mg/kg (Cohort 1) | Phase 2: Placebo (Cohort 1) | Phase 2: 10 mg/kg (Cohort 2) | Phase 2: 6 mg/kg (Cohort 2) | Phase 2: Placebo (Cohort 2) | Phase 3: 10 mg/kg (Cohort 1) | Phase 2: 10 mg/kg (Cohort 1) | Phase 3: 6 mg/kg (Cohort 1) | Phase 3: Placebo (Cohort 1) | Phase 3: 10 mg/kg (Cohort 2) | Phase 3: 6 mg/kg (Cohort 2) | Phase 3: Placebo (Cohort 2) | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 56.9 years STANDARD_DEVIATION 14.36 | 57.4 years STANDARD_DEVIATION 14.29 | 61.1 years STANDARD_DEVIATION 11.54 | 59.3 years STANDARD_DEVIATION 15.89 | 56.9 years STANDARD_DEVIATION 15.14 | 52.5 years STANDARD_DEVIATION 14.03 | 57 years STANDARD_DEVIATION 13.89 | 51.3 years STANDARD_DEVIATION 14.32 | 52.2 years STANDARD_DEVIATION 14 | 59.2 years STANDARD_DEVIATION 14.65 | 57.2 years STANDARD_DEVIATION 13.2 | 55.80 years STANDARD_DEVIATION 14.75 | 53.55 years STANDARD_DEVIATION 14.29 |
| Age, Customized < 65 years | 30 Participants | 27 Participants | 10 Participants | 9 Participants | 11 Participants | 159 Participants | 24 Participants | 157 Participants | 155 Participants | 13 Participants | 14 Participants | 14 Participants | 623 Participants |
| Age, Customized ≥ 65 years | 10 Participants | 12 Participants | 5 Participants | 6 Participants | 6 Participants | 39 Participants | 11 Participants | 35 Participants | 37 Participants | 7 Participants | 8 Participants | 6 Participants | 182 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 11 Participants | 9 Participants | 4 Participants | 8 Participants | 122 Participants | 12 Participants | 107 Participants | 118 Participants | 13 Participants | 17 Participants | 16 Participants | 447 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 20 Participants | 4 Participants | 9 Participants | 7 Participants | 38 Participants | 18 Participants | 37 Participants | 33 Participants | 2 Participants | 1 Participants | 2 Participants | 192 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants | 8 Participants | 2 Participants | 2 Participants | 2 Participants | 38 Participants | 5 Participants | 48 Participants | 41 Participants | 5 Participants | 4 Participants | 2 Participants | 166 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants | 2 Participants | 9 Participants | 4 Participants | 1 Participants | 0 Participants | 0 Participants | 22 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 4 Participants | 3 Participants | 2 Participants | 2 Participants | 15 Participants | 6 Participants | 16 Participants | 11 Participants | 0 Participants | 1 Participants | 1 Participants | 66 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 11 Participants | 2 Participants | 5 Participants | 3 Participants | 33 Participants | 8 Participants | 30 Participants | 31 Participants | 4 Participants | 8 Participants | 3 Participants | 146 Participants |
| Race (NIH/OMB) White | 25 Participants | 21 Participants | 9 Participants | 7 Participants | 11 Participants | 142 Participants | 19 Participants | 134 Participants | 143 Participants | 15 Participants | 13 Participants | 16 Participants | 555 Participants |
| Region of Enrollment Brazil | 18 Participants | 11 Participants | 10 Participants | 5 Participants | 6 Participants | 153 Participants | 14 Participants | 143 Participants | 150 Participants | 16 Participants | 19 Participants | 17 Participants | 562 Participants |
| Region of Enrollment Chile | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 11 Participants |
| Region of Enrollment Peru | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 4 Participants | 2 Participants | 8 Participants | 5 Participants | 2 Participants | 1 Participants | 0 Participants | 26 Participants |
| Region of Enrollment South Africa | 10 Participants | 12 Participants | 1 Participants | 5 Participants | 4 Participants | 13 Participants | 9 Participants | 15 Participants | 16 Participants | 1 Participants | 1 Participants | 2 Participants | 89 Participants |
| Region of Enrollment United States | 12 Participants | 15 Participants | 4 Participants | 4 Participants | 5 Participants | 25 Participants | 9 Participants | 23 Participants | 20 Participants | 0 Participants | 0 Participants | 0 Participants | 117 Participants |
| Sex: Female, Male Female | 19 Participants | 18 Participants | 3 Participants | 4 Participants | 6 Participants | 66 Participants | 12 Participants | 66 Participants | 66 Participants | 9 Participants | 5 Participants | 7 Participants | 281 Participants |
| Sex: Female, Male Male | 21 Participants | 21 Participants | 12 Participants | 11 Participants | 11 Participants | 132 Participants | 23 Participants | 126 Participants | 126 Participants | 11 Participants | 17 Participants | 13 Participants | 524 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 35 | 5 / 41 | 9 / 40 | 7 / 15 | 9 / 15 | 9 / 17 | 20 / 195 | 30 / 188 | 30 / 191 | 7 / 20 | 8 / 21 | 12 / 20 |
| other Total, other adverse events | 19 / 35 | 18 / 41 | 23 / 40 | 11 / 15 | 12 / 15 | 14 / 17 | 90 / 195 | 86 / 188 | 83 / 191 | 12 / 20 | 13 / 21 | 17 / 20 |
| serious Total, serious adverse events | 5 / 35 | 7 / 41 | 13 / 40 | 10 / 15 | 12 / 15 | 10 / 17 | 48 / 195 | 49 / 188 | 43 / 191 | 13 / 20 | 14 / 21 | 15 / 20 |
Outcome results
Primary
Cohort 1, Phase 2: Percentage of Participants 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 was evaluated based on the National Institute of Allergy and Infectious Diseases (NIAID) clinical outcome 8-point ordinal scale. Participants whose clinical outcome met a NIAID score of 2 were considered as using mechanical ventilation. The NIAID score 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.
Time frame: Day 29
Population: Phase 2: Modified Intent-to-Treat (mITT) Analysis Set: All randomized participants who passed screening and received study drug (two enrolled and treated participants \[1 each in the 6 mg/kg and placebo groups\] were randomized and dosed in violation of inclusion/exclusion criteria and were thus excluded from this Set).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: 10 mg/kg (Cohort 1) | Cohort 1, Phase 2: Percentage of Participants Alive and Free of Mechanical Ventilation at Day 29 | 85.7 percentage of participants |
| Phase 2: 6 mg/kg (Cohort 1) | Cohort 1, Phase 2: Percentage of Participants Alive and Free of Mechanical Ventilation at Day 29 | 87.5 percentage of participants |
| Phase 2: Placebo (Cohort 1) | Cohort 1, Phase 2: Percentage of Participants Alive and Free of Mechanical Ventilation at Day 29 | 74.4 percentage of participants |
p-value: 0.244895% CI: [0.612, 7.144]Cochran-Mantel-Haenszel
p-value: 0.259895% CI: [0.555, 8.615]Fisher Exact
p-value: 0.16195% CI: [0.653, 9.957]Fisher Exact
p-value: 0.137895% CI: [0.756, 9.993]Cochran-Mantel-Haenszel
Primary
Cohort 1, Phase 3: Percentage of Participants 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 was evaluated based on the National Institute of Allergy and Infectious Diseases (NIAID) clinical outcome 8-point ordinal scale. Participants whose clinical outcome met a NIAID score of 2 were considered as using mechanical ventilation. The NIAID score 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.
Time frame: Day 29
Population: Phase 3: Intent-to-Treat (ITT) Analysis Set: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: 10 mg/kg (Cohort 1) | Cohort 1, Phase 3: Percentage of Participants Alive and Free of Mechanical Ventilation at Day 29 | 84.3 percentage of participants |
| Phase 2: 6 mg/kg (Cohort 1) | Cohort 1, Phase 3: Percentage of Participants Alive and Free of Mechanical Ventilation at Day 29 | 82.8 percentage of participants |
| Phase 2: Placebo (Cohort 1) | Cohort 1, Phase 3: Percentage of Participants Alive and Free of Mechanical Ventilation at Day 29 | 81.3 percentage of participants |
p-value: 0.453495% CI: [0.715, 2.12]Cochran-Mantel-Haenszel
p-value: 0.741495% CI: [0.636, 1.891]Cochran-Mantel-Haenszel
Primary
Cohort 2, Phase 2: Percentage of Participants Who Died by Day 29
Defined as the proportion of subjects with mechanical ventilation who have died by Day 29.
Time frame: Day 29
Population: Phase 2: Modified Intent-to-Treat (mITT) Analysis Set: All randomized participants who passed screening and received study drug (two enrolled and treated participants \[1 each in the 6 mg/kg and placebo groups\] were randomized and dosed in violation of inclusion/exclusion criteria and were thus excluded from this Set).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: 10 mg/kg (Cohort 1) | Cohort 2, Phase 2: Percentage of Participants Who Died by Day 29 | 46.7 percentage of participants |
| Phase 2: 6 mg/kg (Cohort 1) | Cohort 2, Phase 2: Percentage of Participants Who Died by Day 29 | 53.3 percentage of participants |
| Phase 2: Placebo (Cohort 1) | Cohort 2, Phase 2: Percentage of Participants Who Died by Day 29 | 47.1 percentage of participants |
p-value: 195% CI: [0.198, 4.884]Fisher Exact
p-value: 195% CI: [0.26, 6.417]Fisher Exact
Primary
Cohort 2, Phase 3: Percentage of Participants Who Died by Day 29
Defined as the proportion of subjects with mechanical ventilation who have died by Day 29.
Time frame: Day 29
Population: Phase 3: Intent-to-Treat (ITT) Analysis Set: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: 10 mg/kg (Cohort 1) | Cohort 2, Phase 3: Percentage of Participants Who Died by Day 29 | 40.0 percentage of participants |
| Phase 2: 6 mg/kg (Cohort 1) | Cohort 2, Phase 3: Percentage of Participants Who Died by Day 29 | 27.3 percentage of participants |
| Phase 2: Placebo (Cohort 1) | Cohort 2, Phase 3: Percentage of Participants Who Died by Day 29 | 55.0 percentage of participants |
95% CI: [-45.6, 15.6]
95% CI: [-56.4, 0.9]
Secondary
Cohort 1, Phase 2: Time to 2-point Clinical Improvement by Day 29
Defined as time from randomization to a 2-point improvement on the NIAID 8-point ordinal scale, or discharge from the hospital, whichever came first. Participants who died before Day 29 were censored at Day 30. Kaplan-Meier method used to estimate the survival functions for each treatment arm. The NIAID score 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.
Time frame: Day 29
Population: Phase 2: Modified Intent-to-Treat (mITT) Analysis Set: All randomized participants who passed screening and received study drug (two enrolled and treated participants \[1 each in the 6 mg/kg and placebo groups\] were randomized and dosed in violation of inclusion/exclusion criteria and were thus excluded from this Set).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: 10 mg/kg (Cohort 1) | Cohort 1, Phase 2: Time to 2-point Clinical Improvement by Day 29 | 8.0 days |
| Phase 2: 6 mg/kg (Cohort 1) | Cohort 1, Phase 2: Time to 2-point Clinical Improvement by Day 29 | 7.0 days |
| Phase 2: Placebo (Cohort 1) | Cohort 1, Phase 2: Time to 2-point Clinical Improvement by Day 29 | 11.0 days |
p-value: 0.6229Log Rank
p-value: 0.5526Log Rank
Secondary
Phase 2, Cohort 1: Percentage of Participants Who Die by Day 29
95% CI were calculated using Clopper-Pearson exact method based on the beta distribution.
Time frame: Day 29
Population: Phase 2: Modified Intent-to-Treat (mITT) Analysis Set: All randomized participants who passed screening and received study drug (two enrolled and treated participants \[1 each in the 6 mg/kg and placebo groups\] were randomized and dosed in violation of inclusion/exclusion criteria and were thus excluded from this Set).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: 10 mg/kg (Cohort 1) | Phase 2, Cohort 1: Percentage of Participants Who Die by Day 29 | 5.7 percentage of participants |
| Phase 2: 6 mg/kg (Cohort 1) | Phase 2, Cohort 1: Percentage of Participants Who Die by Day 29 | 10.0 percentage of participants |
| Phase 2: Placebo (Cohort 1) | Phase 2, Cohort 1: Percentage of Participants Who Die by Day 29 | 20.5 percentage of participants |
p-value: 0.090595% CI: [0.023, 1.328]Fisher Exact
p-value: 0.224795% CI: [0.087, 1.815]Fisher Exact
p-value: 0.062395% CI: [0.033, 1.114]Cochran-Mantel-Haenszel
p-value: 0.195795% CI: [0.085, 1.583]Cochran-Mantel-Haenszel
Secondary
Phase 2, Cohort 1: Time to Return to Room Air or Discharge by Day 29
Defined as time from randomization to breathing room air (NIAID score ≥ 5), or discharge from the hospital, whichever came first. Participants who died before Day 29 were censored at Day 30.
Time frame: Day 29
Population: Phase 2: Modified Intent-to-Treat (mITT) Analysis Set: All randomized participants who passed screening and received study drug (two enrolled and treated participants \[1 each in the 6 mg/kg and placebo groups\] were randomized and dosed in violation of inclusion/exclusion criteria and were thus excluded from this Set).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: 10 mg/kg (Cohort 1) | Phase 2, Cohort 1: Time to Return to Room Air or Discharge by Day 29 | 7.0 days |
| Phase 2: 6 mg/kg (Cohort 1) | Phase 2, Cohort 1: Time to Return to Room Air or Discharge by Day 29 | 7.0 days |
| Phase 2: Placebo (Cohort 1) | Phase 2, Cohort 1: Time to Return to Room Air or Discharge by Day 29 | 9.0 days |
p-value: 0.942680% CI: [0.71, 1.46]Log Rank
p-value: 0.683880% CI: [0.78, 1.57]Log Rank
Secondary
Phase 2, Cohort 2: Time to 1-Point Clinical Improvement by Day 29
Defined as time from randomization to the date of a 1-point improvement on the NIAID score 8-point ordinal scale or discharge from the hospital, whichever occurred first, by Day 29. Participants who did not have 1-point improvement on the NIAID nor discharge from the hospital were censored at the date of the last NIAID 8-point ordinal scale assessment on/before Day 29. Participants who died were censored at Day 32.
Time frame: Day 29
Population: Phase 2: Modified Intent-to-Treat (mITT) Analysis Set: All randomized participants who passed screening and received study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: 10 mg/kg (Cohort 1) | Phase 2, Cohort 2: Time to 1-Point Clinical Improvement by Day 29 | 28.0 days |
| Phase 2: 6 mg/kg (Cohort 1) | Phase 2, Cohort 2: Time to 1-Point Clinical Improvement by Day 29 | NA days |
| Phase 2: Placebo (Cohort 1) | Phase 2, Cohort 2: Time to 1-Point Clinical Improvement by Day 29 | NA days |
p-value: 0.376680% CI: [0.8, 3.09]Log Rank
p-value: 0.920980% CI: [0.51, 2.16]Log Rank
Secondary
Phase 3, Cohort 1: Overall Survival by Day 29
Overall survival was defined as time from randomization to the date of death on/before Day 29. Participants who did not have a death record by Day 29 were censored at last date known alive on/before Day 29.
Time frame: Day 29
Population: Phase 3: Intent-to-Treat (ITT) Analysis Set: All randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: 10 mg/kg (Cohort 1) | Phase 3, Cohort 1: Overall Survival by Day 29 | NA days |
| Phase 2: 6 mg/kg (Cohort 1) | Phase 3, Cohort 1: Overall Survival by Day 29 | NA days |
| Phase 2: Placebo (Cohort 1) | Phase 3, Cohort 1: Overall Survival by Day 29 | NA days |
p-value: 0.133695% CI: [0.36, 1.15]Log Rank
p-value: 0.976795% CI: [0.59, 1.72]Log Rank
Secondary
Phase 3, Cohort 1: Percentage of Participants Who Died at Day 29
Mortality rate at day 29 is the proportion of subjects who die by day 29. 95% CI were calculated using Clopper-Pearson exact method based on the beta distribution.
Time frame: Day 29
Population: Phase 3: Intent-to-Treat (ITT) Analysis Set: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: 10 mg/kg (Cohort 1) | Phase 3, Cohort 1: Percentage of Participants Who Died at Day 29 | 9.6 percentage of participants |
| Phase 2: 6 mg/kg (Cohort 1) | Phase 3, Cohort 1: Percentage of Participants Who Died at Day 29 | 14.1 percentage of participants |
| Phase 2: Placebo (Cohort 1) | Phase 3, Cohort 1: Percentage of Participants Who Died at Day 29 | 14.1 percentage of participants |
p-value: 0.177295% CI: [0.34, 1.222]Cochran-Mantel-Haenszel
p-value: 0.926995% CI: [0.563, 1.881]Cochran-Mantel-Haenszel
Secondary
Phase 3, Cohort 1: Ventilation-Free Survival (Time to Ventilation or Death) by Day 29
Time to ventilation or death by Day 29 was defined as time (in days) from randomization to the date of death or start date of using mechanical ventilation (NIAID score ≤ 2) by Day 29. Participants who never had NIAID score ≤ 2 by Day 29 were censored at last assessment date of NIAID 8-point ordinal scale.
Time frame: Day 29
Population: Phase 3: Intent-to-Treat (ITT) Analysis Set: All randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: 10 mg/kg (Cohort 1) | Phase 3, Cohort 1: Ventilation-Free Survival (Time to Ventilation or Death) by Day 29 | NA days |
| Phase 2: 6 mg/kg (Cohort 1) | Phase 3, Cohort 1: Ventilation-Free Survival (Time to Ventilation or Death) by Day 29 | NA days |
| Phase 2: Placebo (Cohort 1) | Phase 3, Cohort 1: Ventilation-Free Survival (Time to Ventilation or Death) by Day 29 | NA days |
p-value: 0.957895% CI: [0.66, 1.49]Log Rank
p-value: 0.527495% CI: [0.76, 1.7]Log Rank
Secondary
Phase 3, Cohort 2: Time to 1-point Clinical Improvement by Day 29
Defined as time from randomization to the date of a 1-point improvement on the NIAID 8-point ordinal scale or discharge from the hospital, whichever occurred first, by Day 29. Participants who did not have 1-point improvement on the NIAID nor discharge from the hospital were censored at the date of the last NIAID 8-point ordinal scale assessment on/before Day 29. Participants who died were censored at Day 35.
Time frame: Day 29
Population: Phase 3: Intent-to-Treat (ITT) Analysis Set: All randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: 10 mg/kg (Cohort 1) | Phase 3, Cohort 2: Time to 1-point Clinical Improvement by Day 29 | NA days |
| Phase 2: 6 mg/kg (Cohort 1) | Phase 3, Cohort 2: Time to 1-point Clinical Improvement by Day 29 | 21.5 days |
| Phase 2: Placebo (Cohort 1) | Phase 3, Cohort 2: Time to 1-point Clinical Improvement by Day 29 | NA days |
95% CI: [0.55, 3.71]
95% CI: [0.78, 4.54]