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COMMUNITY: Study of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalized Patients

Sponsor
Amgen (Industry)
Overall Status
Completed
CT.gov ID
NCT04590586
Collaborator
(none)
515
Enrollment
59
Locations
6
Arms
8.3
Actual Duration (Months)
8.7
Patients Per Site
1.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objective of this study is to evaluate the time to confirmed clinical recovery in participants hospitalized with COVID-19. Candidate agents will be evaluated frequently for efficacy and safety, with candidate agents being added to and/or removed from the study on an ongoing basis, depending on the results of their evaluation.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

This adaptive, randomized, placebo-controlled platform study is designed to rapidly assess multiple candidate agents as treatments for COVID-19 in hospitalized patients. Candidate agents will be evaluated frequently (through ongoing monitoring) for futility and safety, with candidate agents being added to and/or removed from the study on an ongoing basis, depending on the results of their evaluation.

For inclusion, participants will need to be hospitalized with a clinical status of Grade 2 to

Grade 5, as defined by the following Clinical Severity Status 8-Point Ordinal Scale:

  1. Death

  2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)

  3. Hospitalized, on noninvasive 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

Participants will be randomized equally to either the candidate agent plus standard of care (SoC) or placebo plus SoC in a double-blind fashion. Participants who are randomized to placebo plus SoC will subsequently be randomized equally to a matching placebo corresponding to an available agent whose sub-protocol the patient qualified for (ie, a 2-stage randomization). Each participant in the placebo plus SoC group will only receive one type of placebo. Randomization will be stratified by baseline clinical severity of 2 on the 8-point ordinal scale (yes/no) and remdesivir use at baseline (yes/no).

The study will evaluate each candidate agent separately as an add-on to the SoC to assess safety and efficacy. The comparator group for a candidate agent will include participants randomized to the placebo arm of any sub-protocol according to the following conditions:

  • Apremilast sub-protocol: participants who were enrolled concurrently to apremilast and who would have been eligible for the apremilast sub-protocol.

  • Lanadelumab sub-protocol: at a site where at least one participant was randomized to either lanadelumab active or placebo arms.

  • Zilucoplan sub-protocol: at a site where at least one participant was randomized to either the zilucoplan active or placebo arms.

Study Design

Study Type:
Interventional
Actual Enrollment :
515 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
Industry Alliance Platform Trial to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalized Patients
Actual Study Start Date :
Nov 24, 2020
Actual Primary Completion Date :
Aug 3, 2021
Actual Study Completion Date :
Aug 3, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Apremilast + Standard of Care

Participants will be randomized to receive 30 mg apremilast orally twice a day (BID) in addition to standard of care treatment for 14 days or until hospital discharge, death, or discontinuation of investigational product, whichever occurred first.

Drug: Standard of care
Standard of care (SoC) treatment for COVID-19 infection in line with institutional practice. The SoC may change as new information becomes available about treating COVID-19.

Drug: Apremilast
Apremilast administered orally as a tablet.
Other Names:
  • Otezla

    		•
    Placebo Comparator: Apremilast Placebo + Standard of Care

    Participants will be randomized to receive matching placebo to apremilast orally twice a day in addition to standard of care treatment for 14 days or until hospital discharge, death, or discontinuation of investigational product, whichever occurred first.

    Drug: Standard of care
    Standard of care (SoC) treatment for COVID-19 infection in line with institutional practice. The SoC may change as new information becomes available about treating COVID-19.

    Drug: Apremilast placebo
    Matching apremilast placebo administered orally as a tablet.
    Experimental: Lanadelumab + Standard of Care

    Participants will be randomized to receive lanadelumab 300 mg by intravenous infusion on Day 1, and a second dose administered on Day 4 in addition to standard of care.

    Drug: Standard of care
    Standard of care (SoC) treatment for COVID-19 infection in line with institutional practice. The SoC may change as new information becomes available about treating COVID-19.

    Drug: Lanadelumab
    Lanadelumab administered as an intravenous (IV) infusion.
    Other Names:
  • TAKHZYRO™
  • TAK-743

    		•
    Placebo Comparator: Lanadelumab Placebo + Standard of Care

    Participants will be randomized to receive placebo to lanadelumab by intravenous infusion on Day 1, and a second dose administered on Day 4 in addition to standard of care.

    Drug: Standard of care
    Standard of care (SoC) treatment for COVID-19 infection in line with institutional practice. The SoC may change as new information becomes available about treating COVID-19.

    Drug: Lanadelumab placebo
    Matching lanadelumab placebo (normal saline) administered as an intravenous (IV) infusion.
    Experimental: Zilucoplan + Standard of Care

    Participants will be randomized to receive 32.4 mg zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment in addition to standard of care.

    Drug: Standard of care
    Standard of care (SoC) treatment for COVID-19 infection in line with institutional practice. The SoC may change as new information becomes available about treating COVID-19.

    Drug: Zilucoplan
    Zilucoplan administered as a subcutaneous (sc) injection in the abdomen, thigh, or upper arm.
    Placebo Comparator: Zilucoplan Placebo + Standard of Care

    Participants will be randomized to receive placebo to zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment in addition to standard of care.

    Drug: Standard of care
    Standard of care (SoC) treatment for COVID-19 infection in line with institutional practice. The SoC may change as new information becomes available about treating COVID-19.

    Drug: Zilucoplan placebo
    Matching zilucoplan placebo administered as a subcutaneous (sc) injection in the abdomen, thigh, or upper arm.

    Outcome Measures

    Primary Outcome Measures

    1. Lanadelumab Sub-protocol: Time to Confirmed Clinical Recovery Without Rehospitalization Through Day 29 [Day 1 (the day of the first dose of study drug for randomized participants who received at least one dose of study drug or the day of randomization for randomized participants who did not receive any study drug) to Day 29]

      Confirmed clinical recovery means the participant is fit for discharge from hospital, defined by achieving a score of 6 (hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care), 7 (not hospitalized, limitation on activities and/or requiring home oxygen), or 8 (not hospitalized, no limitations on activities) on the clinical severity status 8-point ordinal scale, without being re-hospitalized prior to Day 29. The Kaplan-Meier estimate of the time to confirmed clinical recovery through Day 29, without re-hospitalization through Day 29, was calculated from Study Day 1 to the earliest date on which the participant had a score of 6, 7, or 8 up to Day 29. Participants who never reached a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale before or on Day 29 were censored at Day 29. Participants who discontinued from the study before or on Day 29 were censored at time of discontinuation from study.

    2. Apremilast Sub-protocol: Time to Confirmed Clinical Recovery Without Rehospitalization Through Day 29 [Day 1 (the day of the first dose of study drug for randomized participants who received at least one dose of study drug or the day of randomization for randomized participants who did not receive any study drug) to Day 29]

      Confirmed clinical recovery means the participant is fit for discharge from hospital, defined by achieving a score of 6 (hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care), 7 (not hospitalized, limitation on activities and/or requiring home oxygen), or 8 (not hospitalized, no limitations on activities) on the clinical severity status 8-point ordinal scale, without being re-hospitalized prior to Day 29. The Kaplan-Meier estimate of the time to confirmed clinical recovery through Day 29, without re-hospitalization through Day 29, was calculated from Study Day 1 to the earliest date on which the participant had a score of 6, 7, or 8 up to Day 29. Participants who never reached a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale before or on Day 29 were censored at Day 29. Participants who discontinued from the study before or on Day 29 were censored at time of discontinuation from study.

    3. Zilucoplan Sub-protocol: Time to Confirmed Clinical Recovery Without Rehospitalization Through Day 29 [Day 1 (the day of the first dose of study drug for randomized participants who received at least one dose of study drug or the day of randomization for randomized participants who did not receive any study drug) to Day 29]

      Confirmed clinical recovery means the participant is fit for discharge from hospital, defined by achieving a score of 6 (hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care), 7 (not hospitalized, limitation on activities and/or requiring home oxygen), or 8 (not hospitalized, no limitations on activities) on the clinical severity status 8-point ordinal scale, without being re-hospitalized prior to Day 29. The Kaplan-Meier estimate of the time to confirmed clinical recovery through Day 29, without re-hospitalization through Day 29, was calculated from Study Day 1 to the earliest date on which the participant had a score of 6, 7, or 8 up to Day 29. Participants who never reached a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale before or on Day 29 were censored at Day 29. Participants who discontinued from the study before or on Day 29 were censored at time of discontinuation from study.

    Secondary Outcome Measures

    1. Lanadelumab Sub-protocol: Percentage of Participants Who Achieved Oxygen-Free Recovery at Day 29 [Day 29]

      Oxygen-free recovery at Day 29 is defined as being alive, discharged, and not receiving supplemental oxygen at Day 29. Participants who reached a score of 7 on the ordinal scale for clinical severity who were discharged to hospice care before or on Day 29 were considered as not discharged at Day 29. Participants with a missing oxygen-free recovery status at Day 29 were considered as not having an oxygen-free recovery.

    2. Lanadelumab Sub-protocol: Percentage of Participants With a ≥ 2-point Improvement From Baseline or Fit for Discharge on the Clinical Severity Status 8-Point Ordinal Scale at Day 29 [Baseline (Day 1) and Day 29]

      Fit for discharge is defined as achieving a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale. Participants with an ordinal scale score of 7 must not have been discharged to hospice care to be considered as fit for discharge. Participants with a missing clinical severity score at Day 29 were considered as not having met the event at Day 29. The clinical severity status 8-point ordinal scale scores are: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on noninvasive ventilation or high-flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities

    3. Lanadelumab Sub-protocol: Percentage of Participants Who Died Before or on Day 29 [Day 1 to Day 29]

      All-cause mortality is death due to any cause. Participants with an unknown alive/death status on Day 29 were considered alive for this analysis, with the exception of patients with a score of 7 who were discharged to hospice care before or on Day 29.

    4. Lanadelumab Sub-protocol: Clinical Severity Status 8-Point Ordinal Scale Score at Days 8, 15, and 29 [Day 8, Day 15, and Day 29]

      The clinical severity status 8-point ordinal scale scores are: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on noninvasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities Participants with a score of 7 who were discharged to hospice care are counted with participants with a score of 1 (death) for this endpoint.

    5. Lanadelumab Sub-protocol: Worst Post-Baseline Score on Clinical Severity Status 8-point Ordinal Scale From Baseline to Day 29 [Day 2 to Day 29]

      The worst post-baseline score (lower scores are worse) through Day 29 in the clinical severity status 8-point ordinal scale, derived from all scores recorded after baseline up to and including Day 29. Participants with a score of 7 discharged to hospice care are considered as having a score of 1 (death) instead of a score of 7 for this endpoint. The clinical severity status 8-point ordinal scale scores are: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities

    6. Lanadelumab Sub-protocol: Number of Intensive Care Unit (ICU) Days From Day 1 Through Day 29 [Day 1 to Day 29]

      Number of ICU days is the sum of the duration of any episode of ICU admission between Day 1 and Day 29, both inclusive. The number of ICU days of participants who died before or on Day 29 as well as of participants with a score of 7 on the clinical severity status 8-point ordinal scale who were discharged to hospice care by Day 29 was set to 30 (worst possible outcome).

    7. Lanadelumab Sub-protocol: Number of Invasive Mechanical Ventilator Days From Day 1 Through Day 29 [Day 1 to Day 29]

      Number of invasive mechanical ventilator days is the sum of the duration of any episode of invasive mechanical ventilator admission between Day 1 and Day 29, both inclusive. The number of invasive mechanical ventilator days of participants who died before or on Day 29 as well as of participants with a score of 7 on the clinical severity status 8-point ordinal scale who were discharged to hospice care by Day 29 was set to 30.

    8. Lanadelumab Sub-protocol: Percentage of Participants Who Achieved Clinical Recovery by Days 8, 15, and 29 [Day 8, Day 15, and Day 29]

      Clinical recovery is defined as being fit for discharge, i.e., the achievement of a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale. Participants with a score of 7 discharged to hospice care were not considered fit for discharge. Participants who discontinued the study on or before Days 8, 15, or 29 or with a missing clinical recovery status were considered as not having clinical recovery at each respective time point. Clinical severity status 8-point ordinal scale: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high-flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities

    9. Lanadelumab Sub-protocol: Percentage of Participants Who Achieved Sustained Clinical Recovery [Day 60]

      Sustained clinical recovery is defined as being fit for discharge (achieving a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale) by Day 29, without re-hospitalization by Day 60. Participants with a score of 7 discharged to hospice care were not considered fit for discharge. Participants who died or discontinued from study or with a missing clinical recovery status at Day 60 were not considered having sustained clinical recovery. Clinical severity status 8-point ordinal scale: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities

    10. Lanadelumab Sub-protocol: Number of Participants With Treatment-emergent Adverse Events (TEAEs) [From first dose of study drug to end of study (Day 60)]

      An adverse event (AE) is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to study treatment. A TEAE is an AE that occurs after the first dose of study drug. A Serious AE is any AE that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of hospitalization, resulted in persistent disability/incapacity, a congenital anomaly/birth defect, or an important medical event that may jeopardize the patient or require intervention to prevent an outcome listed above. The Investigator assessed the intensity of each AE according to the Common Terminology Criteria for Adverse Events (CTCAE): Grade 1 Mild; asymptomatic or mild symptoms; Grade 2 Moderate; minimal, local or noninvasive intervention indicated; Grade 3 Severe or medically significant, not immediately life-threatening; Grade 4 Life-threatening; urgent intervention indicated; Grade 5 Death due to AE.

    11. Apremilast Sub-protocol: Percentage of Participants Who Achieved Oxygen-Free Recovery at Day 29 [Day 29]

      Oxygen-free recovery at Day 29 is defined as being alive, discharged, and not receiving supplemental oxygen at Day 29. Participants who reached a score of 7 on the ordinal scale for clinical severity who were discharged to hospice care before or on Day 29 were considered as not discharged at Day 29. Participants with a missing oxygen-free recovery status at Day 29 were considered as not having an oxygen-free recovery.

    12. Apremilast Sub-protocol: Percentage of Participants With a ≥ 2-point Improvement From Baseline or Fit for Discharge on the Clinical Severity Status 8-Point Ordinal Scale at Day 29 [Baseline (Day 1) and Day 29]

      Fit for discharge is defined as achieving a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale. Participants with an ordinal scale score of 7 must not have been discharged to hospice care to be considered as fit for discharge. Participants with a missing clinical severity score at Day 29 were considered as not having met the event at Day 29. The clinical severity status 8-point ordinal scale scores are: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high-flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities

    13. Apremilast Sub-protocol: Percentage of Participants Who Died Before or on Day 29 [Day 1 to Day 29]

      All-cause mortality is death due to any cause. Participants with an unknown alive/death status on Day 29 were considered alive for this analysis, with the exception of patients with a score of 7 who were discharged to hospice care before or on Day 29.

    14. Apremilast Sub-protocol: Clinical Severity Status 8-Point Ordinal Scale Score at Days 8, 15, and 29 [Day 8, Day 15, and Day 29]

      The clinical severity status 8-point ordinal scale scores are: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on noninvasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities Participants with a score of 7 who were discharged to hospice care are counted with participants with a score of 1 (death) for this endpoint.

    15. Apremilast Sub-protocol: Worst Post-Baseline Score on Clinical Severity Status 8-Point Ordinal Scale From Baseline to Day 29 [Day 2 to Day 29]

      The worst post-baseline score (lower scores are worse) through Day 29 in the clinical severity status 8-point ordinal scale, derived from all scores recorded after baseline up to and including Day 29. Participants with a score of 7 discharged to hospice care are considered as having a score of 1 (death) instead of a score of 7 for this endpoint. The clinical severity status 8-point ordinal scale scores are: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on noninvasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities

    16. Apremilast Sub-protocol: Number of Intensive Care Unit (ICU) Days From Day 1 Through Day 29 [Day 1 to Day 29]

      Number of ICU days is the sum of the duration of any episode of ICU admission between Day 1 and Day 29, both inclusive. The number of ICU days of participants who died before or on Day 29 as well as of participants with a score of 7 on the clinical severity status 8-point ordinal scale who were discharged to hospice care by Day 29 was set to 30 (worst possible outcome).

    17. Apremilast Sub-protocol: Number of Invasive Mechanical Ventilator Days From Day 1 Through Day 29 [Day 1 to Day 29]

      Number of invasive mechanical ventilator days is the sum of the duration of any episode of invasive mechanical ventilator admission between Day 1 and Day 29, both inclusive. The number of invasive mechanical ventilator days of participants who died before or on Day 29 as well as of participants with a score of 7 on the clinical severity status 8-point ordinal scale who were discharged to hospice care by Day 29 was set to 30.

    18. Apremilast Sub-protocol: Percentage of Participants Who Achieved Clinical Recovery at Days 8, 15, and 29 [Day 8, Day 15, and Day 29]

      Clinical recovery is defined as being fit for discharge, i.e., the achievement of a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale. Participants with a score of 7 discharged to hospice care were not considered fit for discharge. Participants who discontinued the study on or before Days 8, 15, or 29 or with a missing clinical recovery status were considered as not having clinical recovery at each respective time point. Clinical severity status 8-point ordinal scale: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high-flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities

    19. Apremilast Sub-protocol: Percentage of Participants Who Achieved Sustained Clinical Recovery [Day 60]

      Sustained clinical recovery is defined as being fit for discharge (achieving a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale) by Day 29, without re-hospitalization by Day 60. Participants with a score of 7 discharged to hospice care were not considered fit for discharge. Participants who died or discontinued from study or with a missing clinical recovery status at Day 60 were not considered having sustained clinical recovery. Clinical severity status 8-point ordinal scale: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities

    20. Apremilast Sub-protocol: Number of Participants With Treatment-emergent Adverse Events (TEAEs) [From first dose of study drug to end of study (Day 60)]

      An adverse event (AE) is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to study treatment. A TEAE is an AE that occurs after the first dose of study drug. A serious AE is any AE that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of hospitalization, resulted in persistent disability/incapacity, a congenital anomaly/birth defect, or an important medical event that may jeopardize the patient or require intervention to prevent an outcome listed above. The Investigator assessed the intensity of each AE according to the CTCAE grades: Grade 1 Mild; asymptomatic or mild symptoms; Grade 2 Moderate; minimal, local or noninvasive intervention indicated; Grade 3 Severe or medically significant, not immediately life-threatening; Grade 4 Life-threatening; urgent intervention indicated; Grade 5 Death due to AE.

    21. Zilucoplan Sub-protocol: Percentage of Participants Who Achieved Oxygen-Free Recovery at Day 29 [Day 29]

      Oxygen-free recovery at Day 29 is defined as being alive, discharged, and not receiving supplemental oxygen at Day 29. Participants who reached a score of 7 on the ordinal scale for clinical severity who were discharged to hospice care before or on Day 29 were considered as not discharged at Day 29. Participants with a missing oxygen-free recovery status at Day 29 were considered as not having an oxygen-free recovery.

    22. Zilucoplan Sub-protocol: Percentage of Participants With a ≥ 2-point Improvement From Baseline or Fit for Discharge on the Clinical Severity Status 8-Point Ordinal Scale at Day 29 [Baseline (Day 1) and Day 29]

      Fit for discharge is defined as achieving a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale. Participants with an ordinal scale score of 7 must not have been discharged to hospice care to be considered as fit for discharge. Participants with a missing clinical severity score at Day 29 were considered as not having met the event at Day 29. The clinical severity status 8-point ordinal scale scores are: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high-flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities

    23. Zilucoplan Sub-protocol: Percentage of Participants Who Died Before or on Day 29 [Day 1 to Day 29]

      All-cause mortality is death due to any cause. Participants with an unknown alive/death status on Day 29 were considered alive for this analysis, with the exception of patients with a score of 7 who were discharged to hospice care before or on Day 29.

    24. Zilucoplan Sub-protocol: Clinical Severity Status 8-Point Ordinal Scale Score at Days 8, 15, and 29 [Day 8, Day 15, and Day 29]

      The clinical severity status 8-point ordinal scale scores are: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities Participants with a score of 7 who were discharged to hospice care are counted with participants with a score of 1 (death) for this endpoint.

    25. Zilucoplan Sub-protocol: Worst Post-Baseline Score on Clinical Severity Status 8-Point Ordinal Scale From Baseline to Day 29 [Day 2 to Day 29]

      The worst post-baseline score (lower scores are worse) through Day 29 in the clinical severity status 8-point ordinal scale scores, derived from all scores recorded after baseline up to and including Day 29. Participants with a score of 7 discharged to hospice care were considered as having a score of 1 (death) instead of a score of 7 for this endpoint. The clinical severity status 8-point ordinal scale scores scores are: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities

    26. Zilucoplan Sub-protocol: Number of Intensive Care Unit (ICU) Days From Day 1 Through Day 29 [Day 1 to Day 29]

      Number of ICU days is the sum of the duration of any episode of ICU admission between Day 1 and Day 29, both inclusive. The number of ICU days of participants who died before or on Day 29 as well as of participants with a score of 7 on the clinical severity status 8-point ordinal scale who were discharged to hospice care by Day 29 was set to 30 (worst possible outcome).

    27. Zilucoplan Sub-protocol: Number of Invasive Mechanical Ventilator Days From Day 1 Through Day 29 [Day 1 to Day 29]

      Number of invasive mechanical ventilator days is the sum of the duration of any episode of invasive mechanical ventilator admission between Day 1 and Day 29, both inclusive. The number of invasive mechanical ventilator days of participants who died before or on Day 29 as well as of participants with a score of 7 on the clinical severity status 8-point ordinal scale who were discharged to hospice care by Day 29 was set to 30.

    28. Zilucoplan Sub-protocol: Percentage of Participants Who Achieved Clinical Recovery by Days 8, 15, and 29 [Day 8, Day 15, and Day 29]

      Clinical recovery is defined as being fit for discharge, i.e., the achievement of a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale. Participants with a score of 7 discharged to hospice care were not considered fit for discharge. Participants who discontinued the study on or before Days 8, 15, or 29 or with a missing clinical recovery status were considered as not having clinical recovery at each respective time point. Clinical severity status 8-point ordinal scale: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high-flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities

    29. Zilucoplan Sub-protocol: Percentage of Participants Who Achieved Sustained Clinical Recovery [Day 60]

      Sustained clinical recovery is defined as being fit for discharge (achieving a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale) by Day 29, without re-hospitalization by Day 60. Participants with a score of 7 discharged to hospice care were not considered fit for discharge. Participants who died or discontinued from study or with a missing clinical recovery status at Day 60 were not considered having sustained clinical recovery. Clinical severity status 8-point ordinal scale: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities

    30. Zilucoplan Sub-protocol: Number of Participants With Treatment-emergent Adverse Events [From first dose of study drug to end of study (Day 60)]

      An adverse event is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to study treatment. A TEAE is an AE that occurs after the first dose of study drug. A serious AE is any AE that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of hospitalization, resulted in persistent disability/incapacity, a congenital anomaly/birth defect, or an important medical event that may jeopardize the patient or require intervention to prevent an outcome listed above. The Investigator assessed the intensity of each AE according to the CTCAE grades: Grade 1 Mild; asymptomatic or mild symptoms; Grade 2 Moderate; minimal, local or noninvasive intervention indicated; Grade 3 Severe or medically significant, not immediately life-threatening; Grade 4 Life-threatening; urgent intervention indicated; Grade 5 Death due to AE.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Adults (≥18 years of age) with active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection confirmed by laboratory tests and/or point of care tests (eg, commercial or public health assay, which is approved for emergency use). If no diagnostic test results are available that have been obtained during the previous 72 hours, then a test should be performed as part of the screening assessment.

    • A score of Grade 2 (hospitalized, on invasive mechanical ventilation or ECMO), Grade 3 (hospitalized, on noninvasive ventilation or high-flow oxygen devices), Grade 4 (hospitalized, requiring supplemental oxygen), or Grade 5 (hospitalized, not requiring supplemental oxygen, requiring ongoing medical care [COVID-19 related or otherwise]), as defined by an 8 point ordinal scale.

    • Male participants:

    • A male participant must agree to use contraception during the treatment period and for at least 6 weeks after the last dose of study treatment and refrain from donating sperm during this period.

    • Female participants:

    • A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:

    • Not a woman of childbearing potential (WOCBP). OR

    • A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 6 weeks after the last dose of study treatment.

    • Ability to provide informed consent signed by the study participant or legally authorized representative.

    • Ability and willingness to participate in telephone/telemedicine follow-up visits if needed.

    • Zilucoplan only: Antibiotic prophylaxis: all participants must be willing to take antibiotic prophylaxis concomitantly, starting with the first dose of zilucoplan or placebo.

    Exclusion Criteria:

    • Participant has any condition for which, in the opinion of the Investigator, participation would not be in the best interest of the participant (eg, compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments (eg, participants unable to swallow study medication tablets).

    • Stage 4 severe chronic kidney disease or requiring dialysis.

    • Screening 12-lead electrocardiogram (ECG) with a measurable QTc interval according to Fridericia correction (QTcF) ≥ 500 ms.

    • Anticipated transfer to another hospital that is not a study center within 72 hours.

    • Participants who are currently pregnant or who are not willing to discontinue breastfeeding.

    • Participants participating in another clinical study of an investigational medicinal product or other unapproved (or investigational) treatment for COVID-19.

    • Active tuberculosis or a history of incompletely treated tuberculosis.

    • Active, uncontrolled systemic bacterial or fungal infection(s).

    • Apremilast only: Current treatment with apremilast, or another agent of similar mechanism of action, for any indication within 1 week prior to first dose of investigational product.

    • Apremilast only: Concurrent use at screening or randomization of cytochrome P450 (CYP)3A inducers (eg, rifampin, phenobarbital, carbamazepine) within 1 week prior to first dose of investigational product.

    • Apremilast only: Known hypersensitivity to apremilast or any excipients in formulation.

    • Lanadelumab only: Known or suspected hypersensitivity to lanadelumab or any of its excipients.

    • Lanadelumab only: Previous (within 3 months prior to baseline) or current use of immunomodulators (eg, methotrexate, azathioprine, 6-mercaptopurine, tumor necrosis factor [TNF] α inhibitor, Janus kinase [JAK] inhibitor, alpha-integrin inhibitor).

    • Lanadelumab only: Known or suspected venous thromboembolism.

    • Lanadelumab only: Previous (within 3 months [or 5 half-lives, whichever is greater] of screening) or current use of plasma kallikrein (pKal) inhibitor or bradykinin receptor blocker.

    • Zilucoplan only: Participants with unresolved or suspected infection with Neisseria meningitidis or a past history of N. meningitidis (eg, in a complement-deficient patient).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Pinnacle Research Group LLC Anniston Alabama United States 36207
    2 Good Samaritan Hospital Bakersfield California United States 93309
    3 Sharp Chula Vista Medical Center Chula Vista California United States 91910
    4 El Centro Regional Medical Center El Centro California United States 92243
    5 University of California Irvine Medical Center Orange California United States 92868
    6 Riverside Community Hospital Riverside California United States 92501-4135
    7 National Institute of Clinical Research S. El Monte California United States 91733
    8 University of California Davis Health System Sacramento California United States 95817
    9 UF Health Shands Hospital Gainesville Florida United States 32610
    10 Memorial Hospital Jacksonville Jacksonville Florida United States 32216
    11 Grady Health System Atlanta Georgia United States 30303
    12 Great Lakes Clinical Trials Chicago Illinois United States 60640
    13 The University of Iowa Iowa City Iowa United States 52242
    14 Harper University Hospital Detroit Michigan United States 48201-2018
    15 Sinai Grace Hospital Detroit Michigan United States 48235
    16 Detroit Receiving Hospital Royal Oak Michigan United States 48073
    17 University of Tennessee Health Sciences Center Memphis Tennessee United States 38103
    18 Medical City Ft. Worth Fort Worth Texas United States 76104
    19 University of Texas Health Science Center at Houston Houston Texas United States 77030
    20 Texoma Medical Center Sherman Texas United States 75090
    21 MultiCare Health System Institute for Research and Innovation Tacoma Washington United States 98405
    22 Hospital San Juan de Dios Ramos Mejia Buenos Aires Argentina 1704
    23 Hospital General de Agudos Dr. J. M. Ramos Mejia Ciudad Autonoma Buenos Aires Argentina C1221ADC
    24 Hospital General de Agudos Dr. Ignacio Pirovano Ciudad Autonoma Buenos Aires Argentina C1430BKC
    25 Clinica Adventista Belgrano Ciudad Autonoma Buenos Aires Argentina C1430EGF
    26 Hospital Italiano de Rosario Rosario Argentina 2000
    27 Chronos Pesquisa Clinica Brasília Distrito Federal Brazil 72.145-450
    28 HC-UFG - Hospital das Clínicas da Universidade Federal de Goiás Goiânia Goiás Brazil 74605-020
    29 Santa Casa de Misericórdia de Belo Horizonte Belo Horizonte Minas Gerais Brazil 30150-221
    30 Hospital de Clínicas de Porto Alegre Porto Alegre Rio Grande Do Sul Brazil 90035-903
    31 UNESP - Faculdade de Medicina da Universidade Estadual Paulista - Campus Botucatu Botucatu Sao Paulo Brazil 18618-970
    32 Praxis Pesquisa Médica Santo André Sao Paulo Brazil 09090-790
    33 Hospital Base Osorno Osorno Chile 5290000
    34 Hospital General de Tijuana Tijuana Baja California Norte Mexico 22000
    35 Hospital Civil de Guadalajara Dr. Juan I. Menchaca Guadalajara Jalisco Mexico 44340
    36 Universidad Autonoma de Nuevo Leon, Hospital Universitario Dr. Jose Eleuterio Gonzalez Monterrey Nuevo León Mexico 64460
    37 Hospital Civil de Culiacan Culiacán Sinaloa Mexico 80030
    38 TSBIH "Krasnoyarsk Interdistrict Clinical Hospital of Emergency Medical Care n.a. N.S. Karpovich Krasnoyarsk Russian Federation 660062
    39 SBIH of Moscow "Infectious Clinical Hospital # 1 of Department of Healthcare of Moscow" Moscow Russian Federation 125367
    40 SPb SBIH "Alexandrovskaya City Hospital" Saint Petersburg Russian Federation 193312
    41 St-George Hospital Saint Petersburg Russian Federation 194354
    42 SPb SBIH "Nikolaevskaya Hospital" Saint Petersburg Russian Federation 198510
    43 SPb SBIH "City Pokrovskaya Hospital" Saint Petersburg Russian Federation 199106
    44 SPb SBIH "City Hospital # 40 of Kurortnyi region" Sestroretsk Russian Federation 197706
    45 Nelson Mandela Academic Clinical Research Unit (NeMACRU) Mthatha Eastern Cape South Africa 5100
    46 Johese Clinical Research: Unitas Centurion Gauteng South Africa 0157
    47 MERC SiReN Johannesburg Gauteng South Africa 2193
    48 Drs Sarvan and Moodley Durban KwaZulu-Natal South Africa 4320
    49 Tread Research Cape Town Western Cape South Africa 7500
    50 Tiervlei Trial Centre Cape Town Western Cape South Africa 7530
    51 2 Military Hospital Internal Medicine Cape Town Western Cape South Africa 7800
    52 Dr JM Engelbrecht Trial Site Somerset West Western Cape South Africa 7130
    53 Clinical Projects Research SA (PTY) LTD Worcester Western Cape South Africa 6850
    54 Communal Noncommercial Profit "Clinical City Hospital 16 of Dnipro Regional Council" Dnipro Ukraine 49069
    55 CNE of Kharkov RC Reg Cl Infectious Hospital Kharkiv Ukraine 61096
    56 Communal Non-Commercial Medical Enterprise "O.T.Bohayevskyi Kremenchuk City Hospital #1" Kremenchuk Ukraine 39623
    57 City Clinical infectious Hospital Odesa Ukraine 65026
    58 Municipal Non-Profit Enterprise Central City Hospital Of Rivne City Council Rivne Ukraine 33017
    59 CCH #1 Vinnytsia M.I.Pyrogov NMU Ch of Infectious Diseases Vinnytsia Ukraine 21029

    Sponsors and Collaborators

    • Amgen

    Investigators

    None specified.

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Amgen
    ClinicalTrials.gov Identifier:
    NCT04590586
    Other Study ID Numbers:
    • COV-01
    First Posted:
    Oct 19, 2020
    Last Update Posted:
    Jun 29, 2022
    Last Verified:
    Jun 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Amgen
    SARS-CoV-2
    Severe acute respiratory syndrome coronavirus 2
    Additional relevant MeSH terms:
    COVID-19
    Thalidomide
    Apremilast
    Antibodies, Monoclonal

    Study Results

    Participant Flow

    Recruitment Details This adaptive platform study consisted of 3 sub-protocols, each designed to assess a candidate agent as treatment for coronavirus disease 2019 (COVID-19) in hospitalized adult patients who had severe infection with acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19. The control group for a candidate agent includes participants randomized to any matching placebo for a candidate agent if certain criteria were met (shared placebo).
    Pre-assignment Detail Participants were initially randomized to an active candidate agent or generically to placebo plus standard of care (SoC) for sub-protocols for which they met eligibility. Participants randomized to placebo plus SoC were subsequently randomized equally to a matching placebo for an available candidate agent whose sub-protocol the participant qualified for. Randomization was stratified by baseline clinical severity of 2 on the 8-point ordinal scale (yes/no) and remdesivir use at baseline (yes/no).
    Arm/Group Title Lanadelumab + Standard of Care Lanadelumab Placebo + Standard of Care Apremilast + Standard of Care Apremilast Placebo + Standard of Care Zilucoplan + Standard of Care Zilucoplan Placebo + Standard of Care
    Arm/Group Description Participants randomized to receive lanadelumab 300 mg by intravenous infusion on Day 1, and a second dose administered on Day 4, in addition to standard of care. Participants randomized to receive placebo to lanadelumab by intravenous infusion on Day 1, and a second dose administered on Day 4 in, addition to standard of care. Participants randomized to received 30 mg apremilast orally twice a day (BID) in addition to standard of care treatment for 14 days or until hospital discharge, whichever occurred first. Participants randomized to receive matching placebo to apremilast orally twice a day in addition to standard of care treatment for 14 days or until hospital discharge, whichever occurred first. Participants randomized to receive 32.4 mg zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment, in addition to standard of care. Participants randomized to receive placebo to zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment, in addition to standard of care.
    Period Title: Overall Study
    STARTED 28 1 194 184 100 8
    Received Study Drug 27 1 189 182 95 7
    Full Analysis Set 28 34 194 190 100 75
    COMPLETED 15 0 139 138 70 4
    NOT COMPLETED 13 1 55 46 30 4

    Baseline Characteristics

    Arm/Group Title Lanadelumab + Standard of Care Lanadelumab Placebo Control Apremilast + Standard of Care Apremilast Placebo Control Zilucoplan + Standard of Care Zilucoplan Placebo +Control Total
    Arm/Group Description Participants randomized to receive lanadelumab 300 mg by intravenous infusion on Day 1, and a second dose administered on Day 4, in addition to standard of care. Includes participants randomized to receive matching placebo to lanadelumab plus standard of care treatment as well as participants who were randomized to receive placebo to apremilast or placebo to zilucoplan plus standard of care treatment at a site that enrolled at least one participant in the lanadelumab sub-protocol. Participants randomized to receive 30 mg apremilast orally twice a day (BID) in addition to standard of care treatment for 14 days or until hospital discharge, whichever occurred first. Includes participants randomized to receive matching placebo to apremilast plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to zilucoplan plus standard of care treatment at a site concurrently enrolling apremilast sub-protocol participants and who would have been eligible for the apremilast sub-protocol. Participants randomized to receive 32.4 mg zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment, in addition to standard of care. Includes participants randomized to receive matching placebo to zilucoplan plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to apremilast plus standard of care treatment at a site that enrolled at least one participant in the zilucoplan sub-protocol. Total of all reporting groups
    Overall Participants 28 34 194 190 100 75 621
    Age (years) [Mean (Standard Deviation) ]
    Lanadelumab Sub-protocol
    53.4
    (15.34)
    59.6
    (13.50)
    56.8
    (14.57)
    Apremilast Sub-protocol
    57.2
    (13.84)
    55.7
    (13.37)
    56.5
    (13.61)
    Zilucoplan Sub-protocol
    53.2
    (14.13)
    58.4
    (13.62)
    55.4
    (14.11)
    Age, Customized (Count of Participants)
    ≥ 18 to ≤ 49 years
    13
    46.4%
    8
    23.5%
    21
    10.8%
    ≥ 50 to ≤ 64 years
    7
    25%
    15
    44.1%
    22
    11.3%
    ≥ 65 to ≤ 84 years
    8
    28.6%
    10
    29.4%
    18
    9.3%
    ≥ 85 years
    0
    0%
    1
    2.9%
    1
    0.5%
    ≥ 18 to ≤ 49 years
    51
    182.1%
    56
    164.7%
    107
    55.2%
    ≥ 50 to ≤ 64 years
    76
    271.4%
    81
    238.2%
    157
    80.9%
    ≥ 65 to ≤ 84 years
    64
    228.6%
    52
    152.9%
    116
    59.8%
    ≥ 85 years
    3
    10.7%
    1
    2.9%
    4
    2.1%
    ≥ 18 to ≤ 49 years
    45
    160.7%
    19
    55.9%
    64
    33%
    ≥ 50 to ≤ 64 years
    36
    128.6%
    29
    85.3%
    65
    33.5%
    ≥ 65 to ≤ 84 years
    16
    57.1%
    26
    76.5%
    42
    21.6%
    ≥ 85 years
    3
    10.7%
    1
    2.9%
    4
    2.1%
    Sex: Female, Male (Count of Participants)
    Female
    11
    39.3%
    9
    26.5%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    20
    3.2%
    Male
    17
    60.7%
    25
    73.5%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    42
    6.8%
    Female
    0
    0%
    0
    0%
    84
    43.3%
    72
    37.9%
    0
    0%
    0
    0%
    156
    25.1%
    Male
    0
    0%
    0
    0%
    110
    56.7%
    118
    62.1%
    0
    0%
    0
    0%
    228
    36.7%
    Female
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    34
    34%
    28
    37.3%
    62
    10%
    Male
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    66
    66%
    47
    62.7%
    113
    18.2%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    18
    64.3%
    19
    55.9%
    37
    19.1%
    Not Hispanic or Latino
    10
    35.7%
    15
    44.1%
    25
    12.9%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Hispanic or Latino
    75
    267.9%
    72
    211.8%
    147
    75.8%
    Not Hispanic or Latino
    108
    385.7%
    112
    329.4%
    220
    113.4%
    Unknown or Not Reported
    11
    39.3%
    6
    17.6%
    17
    8.8%
    Hispanic or Latino
    65
    232.1%
    32
    94.1%
    97
    50%
    Not Hispanic or Latino
    35
    125%
    43
    126.5%
    78
    40.2%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    1
    3.6%
    0
    0%
    3
    1.5%
    1
    0.5%
    5
    5%
    Asian
    0
    0%
    0
    0%
    3
    1.5%
    5
    2.6%
    8
    8%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    3
    10.7%
    2
    5.9%
    5
    2.6%
    5
    2.6%
    15
    15%
    White
    20
    71.4%
    28
    82.4%
    75
    38.7%
    58
    30.5%
    181
    181%
    More than one race
    2
    7.1%
    1
    2.9%
    8
    4.1%
    2
    1.1%
    13
    13%
    Unknown or Not Reported
    2
    7.1%
    3
    8.8%
    6
    3.1%
    4
    2.1%
    15
    15%
    American Indian or Alaska Native
    0
    0%
    1
    2.9%
    1
    0.5%
    Asian
    11
    39.3%
    7
    20.6%
    18
    9.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    1
    2.9%
    1
    0.5%
    Black or African American
    9
    32.1%
    9
    26.5%
    18
    9.3%
    White
    151
    539.3%
    151
    444.1%
    302
    155.7%
    More than one race
    4
    14.3%
    7
    20.6%
    11
    5.7%
    Unknown or Not Reported
    19
    67.9%
    14
    41.2%
    33
    17%
    American Indian or Alaska Native
    3
    10.7%
    1
    2.9%
    4
    2.1%
    Asian
    3
    10.7%
    5
    14.7%
    8
    4.1%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    5
    17.9%
    5
    14.7%
    10
    5.2%
    White
    75
    267.9%
    58
    170.6%
    133
    68.6%
    More than one race
    8
    28.6%
    2
    5.9%
    10
    5.2%
    Unknown or Not Reported
    6
    21.4%
    4
    11.8%
    10
    5.2%
    Region (Count of Participants)
    North America
    9
    32.1%
    9
    26.5%
    18
    9.3%
    Latin America
    18
    64.3%
    20
    58.8%
    38
    19.6%
    Eastern Europe
    0
    0%
    0
    0%
    0
    0%
    Rest of the World
    1
    3.6%
    5
    14.7%
    6
    3.1%
    North America
    53
    189.3%
    60
    176.5%
    113
    58.2%
    Latin America
    60
    214.3%
    50
    147.1%
    110
    56.7%
    Eastern Europe
    51
    182.1%
    53
    155.9%
    104
    53.6%
    Rest of the World
    30
    107.1%
    27
    79.4%
    57
    29.4%
    North America
    26
    92.9%
    10
    29.4%
    36
    18.6%
    Latin America
    65
    232.1%
    33
    97.1%
    98
    50.5%
    Eastern Europe
    6
    21.4%
    14
    41.2%
    20
    10.3%
    Rest of the World
    3
    10.7%
    18
    52.9%
    21
    10.8%
    Remdesivir Use at Baseline (Count of Participants)
    Yes
    7
    25%
    5
    14.7%
    12
    6.2%
    No
    21
    75%
    29
    85.3%
    50
    25.8%
    Yes
    45
    160.7%
    44
    129.4%
    89
    45.9%
    No
    149
    532.1%
    146
    429.4%
    295
    152.1%
    Yes
    22
    78.6%
    9
    26.5%
    31
    16%
    No
    78
    278.6%
    66
    194.1%
    144
    74.2%
    Clinical Severity Score of 2 (Count of Participants)
    Yes (Grade 2)
    3
    10.7%
    4
    11.8%
    7
    3.6%
    No (Grade 3-5)
    25
    89.3%
    30
    88.2%
    55
    28.4%
    Yes (Grade 2)
    11
    39.3%
    9
    26.5%
    20
    10.3%
    No (Grade 3-5)
    183
    653.6%
    181
    532.4%
    364
    187.6%
    Yes (Grade 2)
    8
    28.6%
    6
    17.6%
    14
    7.2%
    No (Grade 3-5)
    92
    328.6%
    69
    202.9%
    161
    83%

    Outcome Measures

    1. Primary Outcome
    Title Lanadelumab Sub-protocol: Time to Confirmed Clinical Recovery Without Rehospitalization Through Day 29
    Description Confirmed clinical recovery means the participant is fit for discharge from hospital, defined by achieving a score of 6 (hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care), 7 (not hospitalized, limitation on activities and/or requiring home oxygen), or 8 (not hospitalized, no limitations on activities) on the clinical severity status 8-point ordinal scale, without being re-hospitalized prior to Day 29. The Kaplan-Meier estimate of the time to confirmed clinical recovery through Day 29, without re-hospitalization through Day 29, was calculated from Study Day 1 to the earliest date on which the participant had a score of 6, 7, or 8 up to Day 29. Participants who never reached a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale before or on Day 29 were censored at Day 29. Participants who discontinued from the study before or on Day 29 were censored at time of discontinuation from study.
    Time Frame Day 1 (the day of the first dose of study drug for randomized participants who received at least one dose of study drug or the day of randomization for randomized participants who did not receive any study drug) to Day 29

    Outcome Measure Data

    Analysis Population Description
    The lanadelumab sub-protocol primary analysis set includes all participants who were randomized to lanadelumab as well as all participants who were randomized to any placebo arm included in the control arm for lanadelumab with a baseline clinical severity status of Grade 3 to Grade 5 on the clinical severity status 8-point ordinal scale.
    Arm/Group Title Lanadelumab + Standard of Care Lanadelumab Placebo Control
    Arm/Group Description Participants randomized to receive lanadelumab 300 mg by intravenous infusion on Day 1, and a second dose administered on Day 4, in addition to standard of care. Includes participants randomized to receive matching placebo to lanadelumab plus standard of care treatment as well as participants who were randomized to receive placebo to apremilast or placebo to zilucoplan plus standard of care treatment at a site that enrolled at least one participant in the lanadelumab sub-protocol.
    Measure Participants 25 30
    Median (95% Confidence Interval) [days]
    10.0
    15.5
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6672
    Comments
    Method Stratified log-rank test
    Comments Stratified by baseline score of 2 on the ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), and geographic region.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.17
    Confidence Interval (2-Sided) 95%
    0.59 to 2.35
    Parameter Dispersion Type:
    Value:
    Estimation Comments Hazard ratio (Lanadelumab vs. placebo) from a Cox regression model including baseline clinical severity of 2 on the ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), geographic region, and treatment arm as factors.
    2. Primary Outcome
    Title Apremilast Sub-protocol: Time to Confirmed Clinical Recovery Without Rehospitalization Through Day 29
    Description Confirmed clinical recovery means the participant is fit for discharge from hospital, defined by achieving a score of 6 (hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care), 7 (not hospitalized, limitation on activities and/or requiring home oxygen), or 8 (not hospitalized, no limitations on activities) on the clinical severity status 8-point ordinal scale, without being re-hospitalized prior to Day 29. The Kaplan-Meier estimate of the time to confirmed clinical recovery through Day 29, without re-hospitalization through Day 29, was calculated from Study Day 1 to the earliest date on which the participant had a score of 6, 7, or 8 up to Day 29. Participants who never reached a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale before or on Day 29 were censored at Day 29. Participants who discontinued from the study before or on Day 29 were censored at time of discontinuation from study.
    Time Frame Day 1 (the day of the first dose of study drug for randomized participants who received at least one dose of study drug or the day of randomization for randomized participants who did not receive any study drug) to Day 29

    Outcome Measure Data

    Analysis Population Description
    The apremilast full analysis set (FAS) includes all participants who were randomized to the apremilast arm as well as all participants who were randomized to any placebo arm included in the control arm for apremilast.
    Arm/Group Title Apremilast + Standard of Care Apremilast Placebo Control
    Arm/Group Description Participants randomized to receive 30 mg apremilast orally twice a day (BID) in addition to standard of care treatment for 14 days or until hospital discharge, whichever occurred first. Includes participants randomized to receive matching placebo to apremilast plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to zilucoplan plus standard of care treatment at a site concurrently enrolling apremilast sub-protocol participants and who would have been eligible for the apremilast sub-protocol.
    Measure Participants 194 190
    Median (95% Confidence Interval) [days]
    14.0
    14.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8779
    Comments
    Method Stratified log-rank test
    Comments Stratified by baseline score of 2 on the ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), and geographic region.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.97
    Confidence Interval (2-Sided) 95%
    0.77 to 1.24
    Parameter Dispersion Type:
    Value:
    Estimation Comments Hazard ratio (apremilast vs. placebo) from a Cox regression model including baseline clinical severity of 2 on the ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), geographic region, and treatment arm as factors.
    3. Primary Outcome
    Title Zilucoplan Sub-protocol: Time to Confirmed Clinical Recovery Without Rehospitalization Through Day 29
    Description Confirmed clinical recovery means the participant is fit for discharge from hospital, defined by achieving a score of 6 (hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care), 7 (not hospitalized, limitation on activities and/or requiring home oxygen), or 8 (not hospitalized, no limitations on activities) on the clinical severity status 8-point ordinal scale, without being re-hospitalized prior to Day 29. The Kaplan-Meier estimate of the time to confirmed clinical recovery through Day 29, without re-hospitalization through Day 29, was calculated from Study Day 1 to the earliest date on which the participant had a score of 6, 7, or 8 up to Day 29. Participants who never reached a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale before or on Day 29 were censored at Day 29. Participants who discontinued from the study before or on Day 29 were censored at time of discontinuation from study.
    Time Frame Day 1 (the day of the first dose of study drug for randomized participants who received at least one dose of study drug or the day of randomization for randomized participants who did not receive any study drug) to Day 29

    Outcome Measure Data

    Analysis Population Description
    The zilucoplan full analysis set includes all participants who were randomized to the zilucoplan arm as well as all participants who were randomized to any placebo arm included in the control arm for zilucoplan.
    Arm/Group Title Zilucoplan + Standard of Care Zilucoplan Placebo Control
    Arm/Group Description Participants randomized to receive 32.4 mg zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment, in addition to standard of care. Includes participants randomized to receive matching placebo to zilucoplan plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to apremilast plus standard of care treatment at a site that enrolled at least one participant in the zilucoplan sub-protocol.
    Measure Participants 100 75
    Median (95% Confidence Interval) [days]
    14.0
    15.0
    4. Secondary Outcome
    Title Lanadelumab Sub-protocol: Percentage of Participants Who Achieved Oxygen-Free Recovery at Day 29
    Description Oxygen-free recovery at Day 29 is defined as being alive, discharged, and not receiving supplemental oxygen at Day 29. Participants who reached a score of 7 on the ordinal scale for clinical severity who were discharged to hospice care before or on Day 29 were considered as not discharged at Day 29. Participants with a missing oxygen-free recovery status at Day 29 were considered as not having an oxygen-free recovery.
    Time Frame Day 29

    Outcome Measure Data

    Analysis Population Description
    Lanadelumab sub-protocol primary analysis set
    Arm/Group Title Lanadelumab + Standard of Care Lanadelumab Placebo Control
    Arm/Group Description Participants randomized to receive lanadelumab 300 mg by intravenous infusion on Day 1, and a second dose administered on Day 4, in addition to standard of care. Includes participants randomized to receive matching placebo to lanadelumab plus standard of care treatment as well as participants who were randomized to receive placebo to apremilast or placebo to zilucoplan plus standard of care treatment at a site that enrolled at least one participant in the lanadelumab sub-protocol.
    Measure Participants 25 30
    Number (95% Confidence Interval) [percentage of participants]
    52.0
    185.7%
    56.7
    166.8%
    5. Secondary Outcome
    Title Lanadelumab Sub-protocol: Percentage of Participants With a ≥ 2-point Improvement From Baseline or Fit for Discharge on the Clinical Severity Status 8-Point Ordinal Scale at Day 29
    Description Fit for discharge is defined as achieving a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale. Participants with an ordinal scale score of 7 must not have been discharged to hospice care to be considered as fit for discharge. Participants with a missing clinical severity score at Day 29 were considered as not having met the event at Day 29. The clinical severity status 8-point ordinal scale scores are: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on noninvasive ventilation or high-flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities
    Time Frame Baseline (Day 1) and Day 29

    Outcome Measure Data

    Analysis Population Description
    Lanadelumab sub-protocol primary analysis set
    Arm/Group Title Lanadelumab + Standard of Care Lanadelumab Placebo Control
    Arm/Group Description Participants randomized to receive lanadelumab 300 mg by intravenous infusion on Day 1, and a second dose administered on Day 4, in addition to standard of care. Includes participants randomized to receive matching placebo to lanadelumab plus standard of care treatment as well as participants who were randomized to receive placebo to apremilast or placebo to zilucoplan plus standard of care treatment at a site that enrolled at least one participant in the lanadelumab sub-protocol.
    Measure Participants 25 30
    Number (95% Confidence Interval) [percentage of participants]
    72.0
    257.1%
    63.3
    186.2%
    6. Secondary Outcome
    Title Lanadelumab Sub-protocol: Percentage of Participants Who Died Before or on Day 29
    Description All-cause mortality is death due to any cause. Participants with an unknown alive/death status on Day 29 were considered alive for this analysis, with the exception of patients with a score of 7 who were discharged to hospice care before or on Day 29.
    Time Frame Day 1 to Day 29

    Outcome Measure Data

    Analysis Population Description
    Lanadelumab sub-protocol primary analysis set
    Arm/Group Title Lanadelumab + Standard of Care Lanadelumab Placebo Control
    Arm/Group Description Participants randomized to receive lanadelumab 300 mg by intravenous infusion on Day 1, and a second dose administered on Day 4, in addition to standard of care. Includes participants randomized to receive matching placebo to lanadelumab plus standard of care treatment as well as participants who were randomized to receive placebo to apremilast or placebo to zilucoplan plus standard of care treatment at a site that enrolled at least one participant in the lanadelumab sub-protocol.
    Measure Participants 25 30
    Number (95% Confidence Interval) [percentage of participants]
    32.0
    114.3%
    30.0
    88.2%
    7. Secondary Outcome
    Title Lanadelumab Sub-protocol: Clinical Severity Status 8-Point Ordinal Scale Score at Days 8, 15, and 29
    Description The clinical severity status 8-point ordinal scale scores are: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on noninvasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities Participants with a score of 7 who were discharged to hospice care are counted with participants with a score of 1 (death) for this endpoint.
    Time Frame Day 8, Day 15, and Day 29

    Outcome Measure Data

    Analysis Population Description
    Lanadelumab sub-protocol primary analysis set
    Arm/Group Title Lanadelumab + Standard of Care Lanadelumab Placebo Control
    Arm/Group Description Participants randomized to receive lanadelumab 300 mg by intravenous infusion on Day 1, and a second dose administered on Day 4, in addition to standard of care. Includes participants randomized to receive matching placebo to lanadelumab plus standard of care treatment as well as participants who were randomized to receive placebo to apremilast or placebo to zilucoplan plus standard of care treatment at a site that enrolled at least one participant in the lanadelumab sub-protocol.
    Measure Participants 25 30
    1 (Death or discharged to hospice care)
    3
    10.7%
    3
    8.8%
    2 (Hospitalized on invasive mechanical ventilation or ECMO)
    4
    14.3%
    6
    17.6%
    3 (Hospitalized on noninvasive ventilation or high-flow oxygen devices)
    3
    10.7%
    4
    11.8%
    4 (Hospitalized, requiring supplemental oxygen)
    2
    7.1%
    6
    17.6%
    5 (Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care)
    1
    3.6%
    0
    0%
    6 (Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care)
    1
    3.6%
    1
    2.9%
    7 (Not hospitalized, limitation on activities and/or requiring home oxygen)
    2
    7.1%
    3
    8.8%
    8 (Not hospitalized, no limitations on activities)
    8
    28.6%
    7
    20.6%
    Missing
    1
    3.6%
    0
    0%
    1 (Death or discharged to hospice care)
    3
    10.7%
    7
    20.6%
    2 (Hospitalized on invasive mechanical ventilation or ECMO)
    3
    10.7%
    4
    11.8%
    3 (Hospitalized on noninvasive ventilation or high-flow oxygen devices)
    1
    3.6%
    0
    0%
    4 (Hospitalized, requiring supplemental oxygen)
    0
    0%
    2
    5.9%
    5 (Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care)
    0
    0%
    0
    0%
    6 (Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care)
    0
    0%
    1
    2.9%
    7 (Not hospitalized, limitation on activities and/or requiring home oxygen)
    5
    17.9%
    3
    8.8%
    8 (Not hospitalized, no limitations on activities)
    12
    42.9%
    13
    38.2%
    Missing
    1
    3.6%
    0
    0%
    1 (Death or discharged to hospice care)
    7
    25%
    9
    26.5%
    2 (Hospitalized on invasive mechanical ventilation or ECMO)
    0
    0%
    2
    5.9%
    3 (Hospitalized on noninvasive ventilation or high-flow oxygen devices)
    0
    0%
    0
    0%
    4 (Hospitalized, requiring supplemental oxygen)
    0
    0%
    0
    0%
    5 (Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care)
    0
    0%
    0
    0%
    6 (Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care)
    0
    0%
    0
    0%
    7 (Not hospitalized, limitation on activities and/or requiring home oxygen)
    5
    17.9%
    6
    17.6%
    8 (Not hospitalized, no limitations on activities)
    12
    42.9%
    13
    38.2%
    Missing
    1
    3.6%
    0
    0%
    8. Secondary Outcome
    Title Lanadelumab Sub-protocol: Worst Post-Baseline Score on Clinical Severity Status 8-point Ordinal Scale From Baseline to Day 29
    Description The worst post-baseline score (lower scores are worse) through Day 29 in the clinical severity status 8-point ordinal scale, derived from all scores recorded after baseline up to and including Day 29. Participants with a score of 7 discharged to hospice care are considered as having a score of 1 (death) instead of a score of 7 for this endpoint. The clinical severity status 8-point ordinal scale scores are: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities
    Time Frame Day 2 to Day 29

    Outcome Measure Data

    Analysis Population Description
    Lanadelumab sub-protocol primary analysis set
    Arm/Group Title Lanadelumab + Standard of Care Lanadelumab Placebo Control
    Arm/Group Description Participants randomized to receive lanadelumab 300 mg by intravenous infusion on Day 1, and a second dose administered on Day 4, in addition to standard of care. Includes participants randomized to receive matching placebo to lanadelumab plus standard of care treatment as well as participants who were randomized to receive placebo to apremilast or placebo to zilucoplan plus standard of care treatment at a site that enrolled at least one participant in the lanadelumab sub-protocol.
    Measure Participants 25 30
    1 (Death or discharged to hospice care)
    8
    28.6%
    9
    26.5%
    2 (Hospitalized on invasive mechanical ventilation or ECMO)
    0
    0%
    4
    11.8%
    3 (Hospitalized on noninvasive ventilation or high-flow oxygen devices)
    6
    21.4%
    5
    14.7%
    4 (Hospitalized, requiring supplemental oxygen)
    8
    28.6%
    11
    32.4%
    5 (Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care)
    1
    3.6%
    0
    0%
    6 (Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care)
    0
    0%
    0
    0%
    7 (Not hospitalized, limitation on activities and/or requiring home oxygen)
    0
    0%
    0
    0%
    8 (Not hospitalized, no limitations on activities)
    1
    3.6%
    1
    2.9%
    Missing
    1
    3.6%
    0
    0%
    9. Secondary Outcome
    Title Lanadelumab Sub-protocol: Number of Intensive Care Unit (ICU) Days From Day 1 Through Day 29
    Description Number of ICU days is the sum of the duration of any episode of ICU admission between Day 1 and Day 29, both inclusive. The number of ICU days of participants who died before or on Day 29 as well as of participants with a score of 7 on the clinical severity status 8-point ordinal scale who were discharged to hospice care by Day 29 was set to 30 (worst possible outcome).
    Time Frame Day 1 to Day 29

    Outcome Measure Data

    Analysis Population Description
    Lanadelumab sub-protocol primary analysis set
    Arm/Group Title Lanadelumab + Standard of Care Lanadelumab Placebo Control
    Arm/Group Description Participants randomized to receive lanadelumab 300 mg by intravenous infusion on Day 1, and a second dose administered on Day 4, in addition to standard of care. Includes participants randomized to receive matching placebo to lanadelumab plus standard of care treatment as well as participants who were randomized to receive placebo to apremilast or placebo to zilucoplan plus standard of care treatment at a site that enrolled at least one participant in the lanadelumab sub-protocol.
    Measure Participants 25 30
    0 days
    13
    46.4%
    10
    29.4%
    1 day
    1
    3.6%
    1
    2.9%
    3 days
    0
    0%
    1
    2.9%
    5 days
    0
    0%
    1
    2.9%
    6 days
    0
    0%
    2
    5.9%
    8 days
    1
    3.6%
    3
    8.8%
    11 days
    2
    7.1%
    0
    0%
    13 days
    1
    3.6%
    1
    2.9%
    15 days
    0
    0%
    1
    2.9%
    21 days
    0
    0%
    1
    2.9%
    30 days (death or discharged to hospice care)
    7
    25%
    9
    26.5%
    10. Secondary Outcome
    Title Lanadelumab Sub-protocol: Number of Invasive Mechanical Ventilator Days From Day 1 Through Day 29
    Description Number of invasive mechanical ventilator days is the sum of the duration of any episode of invasive mechanical ventilator admission between Day 1 and Day 29, both inclusive. The number of invasive mechanical ventilator days of participants who died before or on Day 29 as well as of participants with a score of 7 on the clinical severity status 8-point ordinal scale who were discharged to hospice care by Day 29 was set to 30.
    Time Frame Day 1 to Day 29

    Outcome Measure Data

    Analysis Population Description
    Lanadelumab sub-protocol primary analysis set
    Arm/Group Title Lanadelumab + Standard of Care Lanadelumab Placebo Control
    Arm/Group Description Participants randomized to receive lanadelumab 300 mg by intravenous infusion on Day 1, and a second dose administered on Day 4, in addition to standard of care. Includes participants randomized to receive matching placebo to lanadelumab plus standard of care treatment as well as participants who were randomized to receive placebo to apremilast or placebo to zilucoplan plus standard of care treatment at a site that enrolled at least one participant in the lanadelumab sub-protocol.
    Measure Participants 25 30
    0 days
    17
    60.7%
    18
    52.9%
    6 days
    0
    0%
    1
    2.9%
    16 days
    0
    0%
    1
    2.9%
    24 days
    0
    0%
    1
    2.9%
    30 days (death or discharged to hospice care)
    8
    28.6%
    9
    26.5%
    11. Secondary Outcome
    Title Lanadelumab Sub-protocol: Percentage of Participants Who Achieved Clinical Recovery by Days 8, 15, and 29
    Description Clinical recovery is defined as being fit for discharge, i.e., the achievement of a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale. Participants with a score of 7 discharged to hospice care were not considered fit for discharge. Participants who discontinued the study on or before Days 8, 15, or 29 or with a missing clinical recovery status were considered as not having clinical recovery at each respective time point. Clinical severity status 8-point ordinal scale: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high-flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities
    Time Frame Day 8, Day 15, and Day 29

    Outcome Measure Data

    Analysis Population Description
    Lanadelumab sub-protocol primary analysis set
    Arm/Group Title Lanadelumab + Standard of Care Lanadelumab Placebo Control
    Arm/Group Description Participants randomized to receive lanadelumab 300 mg by intravenous infusion on Day 1, and a second dose administered on Day 4, in addition to standard of care. Includes participants randomized to receive matching placebo to lanadelumab plus standard of care treatment as well as participants who were randomized to receive placebo to apremilast or placebo to zilucoplan plus standard of care treatment at a site that enrolled at least one participant in the lanadelumab sub-protocol.
    Measure Participants 25 30
    Day 8
    44.0
    157.1%
    36.7
    107.9%
    Day 15
    56.0
    200%
    56.7
    166.8%
    Day 29
    60.0
    214.3%
    63.3
    186.2%
    12. Secondary Outcome
    Title Lanadelumab Sub-protocol: Percentage of Participants Who Achieved Sustained Clinical Recovery
    Description Sustained clinical recovery is defined as being fit for discharge (achieving a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale) by Day 29, without re-hospitalization by Day 60. Participants with a score of 7 discharged to hospice care were not considered fit for discharge. Participants who died or discontinued from study or with a missing clinical recovery status at Day 60 were not considered having sustained clinical recovery. Clinical severity status 8-point ordinal scale: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities
    Time Frame Day 60

    Outcome Measure Data

    Analysis Population Description
    Lanadelumab sub-protocol primary analysis set
    Arm/Group Title Lanadelumab + Standard of Care Lanadelumab Placebo Control
    Arm/Group Description Participants randomized to receive lanadelumab 300 mg by intravenous infusion on Day 1, and a second dose administered on Day 4, in addition to standard of care. Includes participants randomized to receive matching placebo to lanadelumab plus standard of care treatment as well as participants who were randomized to receive placebo to apremilast or placebo to zilucoplan plus standard of care treatment at a site that enrolled at least one participant in the lanadelumab sub-protocol.
    Measure Participants 25 30
    Number (95% Confidence Interval) [percentage of participants]
    40.0
    142.9%
    56.7
    166.8%
    13. Secondary Outcome
    Title Lanadelumab Sub-protocol: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
    Description An adverse event (AE) is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to study treatment. A TEAE is an AE that occurs after the first dose of study drug. A Serious AE is any AE that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of hospitalization, resulted in persistent disability/incapacity, a congenital anomaly/birth defect, or an important medical event that may jeopardize the patient or require intervention to prevent an outcome listed above. The Investigator assessed the intensity of each AE according to the Common Terminology Criteria for Adverse Events (CTCAE): Grade 1 Mild; asymptomatic or mild symptoms; Grade 2 Moderate; minimal, local or noninvasive intervention indicated; Grade 3 Severe or medically significant, not immediately life-threatening; Grade 4 Life-threatening; urgent intervention indicated; Grade 5 Death due to AE.
    Time Frame From first dose of study drug to end of study (Day 60)

    Outcome Measure Data

    Analysis Population Description
    Lanadelumab safety analysis set included all participants in the lanadelumab FAS who received at least one dose of study drug.
    Arm/Group Title Lanadelumab + Standard of Care Lanadelumab Placebo Control Lanadelumab Placebo + Standard of Care
    Arm/Group Description Participants received lanadelumab 300 mg by intravenous infusion on Day 1, and a second dose administered on Day 4, in addition to standard of care. Includes participants who received matching placebo to lanadelumab plus standard of care treatment as well as participants who received placebo to apremilast or placebo to zilucoplan plus standard of care treatment at a site that enrolled at least one participant in the lanadelumab sub-protocol. Participants received placebo to lanadelumab by intravenous infusion on Day 1, and a second dose administered on Day 4 in, addition to standard of care.
    Measure Participants 27 34 1
    Any treatment-emergent adverse event (TEAE)
    17
    60.7%
    22
    64.7%
    1
    0.5%
    TEAE with a CTCAE grade ≥ 3
    11
    39.3%
    18
    52.9%
    1
    0.5%
    Serious TEAE
    11
    39.3%
    18
    52.9%
    1
    0.5%
    TEAE leading to dose modification
    2
    7.1%
    3
    8.8%
    0
    0%
    TEAE leading to discontinuation of study drug
    1
    3.6%
    5
    14.7%
    0
    0%
    14. Secondary Outcome
    Title Apremilast Sub-protocol: Percentage of Participants Who Achieved Oxygen-Free Recovery at Day 29
    Description Oxygen-free recovery at Day 29 is defined as being alive, discharged, and not receiving supplemental oxygen at Day 29. Participants who reached a score of 7 on the ordinal scale for clinical severity who were discharged to hospice care before or on Day 29 were considered as not discharged at Day 29. Participants with a missing oxygen-free recovery status at Day 29 were considered as not having an oxygen-free recovery.
    Time Frame Day 29

    Outcome Measure Data

    Analysis Population Description
    Apremilast sub-protocol full analysis set
    Arm/Group Title Apremilast + Standard of Care Apremilast Placebo Control
    Arm/Group Description Participants randomized to receive 30 mg apremilast orally twice a day in addition to standard of care treatment for 14 days or until hospital discharge, whichever occurred first. Includes participants randomized to receive matching placebo to apremilast plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to zilucoplan plus standard of care treatment at a site concurrently enrolling apremilast sub-protocol participants and who would have been eligible for the apremilast sub-protocol.
    Measure Participants 194 190
    Number [percentage of participants]
    59.8
    213.6%
    63.7
    187.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.3773
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -4.0
    Confidence Interval (2-Sided) 95%
    -12.9 to 4.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments Risk difference is from a logistic regression including the baseline clinical severity of 2 on the ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), geographic region, and treatment arm as factors.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.82
    Confidence Interval (2-Sided) 95%
    0.52 to 1.28
    Parameter Dispersion Type:
    Value:
    Estimation Comments Odds ratio (apremilast vs. placebo) is from a logistic regression including the baseline clinical severity of 2 on the ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), geographic region, and treatment arm as factors.
    15. Secondary Outcome
    Title Apremilast Sub-protocol: Percentage of Participants With a ≥ 2-point Improvement From Baseline or Fit for Discharge on the Clinical Severity Status 8-Point Ordinal Scale at Day 29
    Description Fit for discharge is defined as achieving a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale. Participants with an ordinal scale score of 7 must not have been discharged to hospice care to be considered as fit for discharge. Participants with a missing clinical severity score at Day 29 were considered as not having met the event at Day 29. The clinical severity status 8-point ordinal scale scores are: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high-flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities
    Time Frame Baseline (Day 1) and Day 29

    Outcome Measure Data

    Analysis Population Description
    Apremilast sub-protocol full analysis set
    Arm/Group Title Apremilast + Standard of Care Apremilast Placebo Control
    Arm/Group Description Participants randomized to receive 30 mg apremilast orally twice a day in addition to standard of care treatment for 14 days or until hospital discharge, whichever occurred first. Includes participants randomized to receive matching placebo to apremilast plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to zilucoplan plus standard of care treatment at a site concurrently enrolling apremilast sub-protocol participants and who would have been eligible for the apremilast sub-protocol.
    Measure Participants 194 190
    Number [percentage of participants]
    74.7
    266.8%
    77.9
    229.1%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.4846
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -2.9
    Confidence Interval (2-Sided) 95%
    -11.2 to 5.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments Risk difference is from a logistic regression including baseline clinical severity of 2 on the ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), geographic region, and treatment arm as factors.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.84
    Confidence Interval (2-Sided) 95%
    0.51 to 1.37
    Parameter Dispersion Type:
    Value:
    Estimation Comments Odds ratio (apremilast vs. placebo) is from a logistic regression including baseline clinical severity of 2 on the ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), geographic region, and treatment arm as factors.
    16. Secondary Outcome
    Title Apremilast Sub-protocol: Percentage of Participants Who Died Before or on Day 29
    Description All-cause mortality is death due to any cause. Participants with an unknown alive/death status on Day 29 were considered alive for this analysis, with the exception of patients with a score of 7 who were discharged to hospice care before or on Day 29.
    Time Frame Day 1 to Day 29

    Outcome Measure Data

    Analysis Population Description
    Apremilast sub-protocol full analysis set
    Arm/Group Title Apremilast + Standard of Care Apremilast Placebo Control
    Arm/Group Description Participants randomized to receive 30 mg apremilast orally twice a day in addition to standard of care treatment for 14 days or until hospital discharge, whichever occurred first. Includes participants randomized to receive matching placebo to apremilast plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to zilucoplan plus standard of care treatment at a site concurrently enrolling apremilast sub-protocol participants and who would have been eligible for the apremilast sub-protocol.
    Measure Participants 194 190
    Number [percentage of participants]
    17.5
    62.5%
    17.4
    51.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.9665
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 0.2
    Confidence Interval (2-Sided) 95%
    -7.3 to 7.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments Risk difference is from a logistic regression including baseline clinical severity of 2 on the ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), geographic region, and treatment arm as factors.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.01
    Confidence Interval (2-Sided) 95%
    0.59 to 1.74
    Parameter Dispersion Type:
    Value:
    Estimation Comments Odds ratio (apremilast vs. placebo) is from a logistic regression including the baseline clinical severity of 2 on the ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), geographic region, and treatment arm as factors.
    17. Secondary Outcome
    Title Apremilast Sub-protocol: Clinical Severity Status 8-Point Ordinal Scale Score at Days 8, 15, and 29
    Description The clinical severity status 8-point ordinal scale scores are: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on noninvasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities Participants with a score of 7 who were discharged to hospice care are counted with participants with a score of 1 (death) for this endpoint.
    Time Frame Day 8, Day 15, and Day 29

    Outcome Measure Data

    Analysis Population Description
    Apremilast sub-protocol full analysis set
    Arm/Group Title Apremilast + Standard of Care Apremilast Placebo Control
    Arm/Group Description Participants randomized to receive 30 mg apremilast orally twice a day in addition to standard of care treatment for 14 days or until hospital discharge, whichever occurred first. Includes participants randomized to receive matching placebo to apremilast plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to zilucoplan plus standard of care treatment at a site concurrently enrolling apremilast sub-protocol participants and who would have been eligible for the apremilast sub-protocol.
    Measure Participants 194 190
    1 (Death or discharged to hospice care)
    11
    39.3%
    8
    23.5%
    2 (Hospitalized on invasive mechanical ventilation or ECMO)
    22
    78.6%
    20
    58.8%
    3 (Hospitalized on noninvasive ventilation or high-flow oxygen devices)
    25
    89.3%
    26
    76.5%
    4 (Hospitalized, requiring supplemental oxygen)
    26
    92.9%
    26
    76.5%
    5 (Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care)
    31
    110.7%
    40
    117.6%
    6 (Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care)
    0
    0%
    1
    2.9%
    7 (Not hospitalized, limitation on activities and/or requiring home oxygen)
    36
    128.6%
    33
    97.1%
    8 (Not hospitalized, no limitations on activities)
    38
    135.7%
    34
    100%
    Missing
    5
    17.9%
    2
    5.9%
    1 (Death or discharged to hospice care)
    22
    78.6%
    24
    70.6%
    2 (Hospitalized on invasive mechanical ventilation or ECMO)
    16
    57.1%
    13
    38.2%
    3 (Hospitalized on noninvasive ventilation or high-flow oxygen devices)
    9
    32.1%
    9
    26.5%
    4 (Hospitalized, requiring supplemental oxygen)
    9
    32.1%
    8
    23.5%
    5 (Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care)
    10
    35.7%
    5
    14.7%
    6 (Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care)
    0
    0%
    2
    5.9%
    7 (Not hospitalized, limitation on activities and/or requiring home oxygen)
    46
    164.3%
    48
    141.2%
    8 (Not hospitalized, no limitations on activities)
    78
    278.6%
    79
    232.4%
    Missing
    4
    14.3%
    2
    5.9%
    1 (Death or discharged to hospice care)
    34
    121.4%
    31
    91.2%
    2 (Hospitalized on invasive mechanical ventilation or ECMO)
    6
    21.4%
    6
    17.6%
    3 (Hospitalized on noninvasive ventilation or high-flow oxygen devices)
    0
    0%
    3
    8.8%
    4 (Hospitalized, requiring supplemental oxygen)
    6
    21.4%
    1
    2.9%
    5 (Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care)
    0
    0%
    1
    2.9%
    6 (Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care)
    0
    0%
    2
    5.9%
    7 (Not hospitalized, limitation on activities and/or requiring home oxygen)
    34
    121.4%
    40
    117.6%
    8 (Not hospitalized, no limitations on activities)
    110
    392.9%
    104
    305.9%
    Missing
    4
    14.3%
    2
    5.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments Day 8
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.9119
    Comments
    Method Proportional odds model
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.02
    Confidence Interval (2-Sided) 95%
    0.71 to 1.46
    Parameter Dispersion Type:
    Value:
    Estimation Comments Odds ratio (Apremilast vs. Placebo) from a proportional odds model including the baseline clinical severity of 2 on the 8-point ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), region, and treatment arm as factors.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments Day 15
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6475
    Comments
    Method Proportional odds model
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.09
    Confidence Interval (2-Sided) 95%
    0.75 to 1.58
    Parameter Dispersion Type:
    Value:
    Estimation Comments Odds ratio (Apremilast vs. Placebo) from a proportional odds model including the baseline clinical severity of 2 on the 8-point ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), region, and treatment arm as factors.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments Day 29
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.9071
    Comments
    Method Proportional odds model
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.98
    Confidence Interval (2-Sided) 95%
    0.64 to 1.48
    Parameter Dispersion Type:
    Value:
    Estimation Comments Odds ratio (Apremilast vs. Placebo) from a proportional odds model including the baseline clinical severity of 2 on the 8-point ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), region, and treatment arm as factors.
    18. Secondary Outcome
    Title Apremilast Sub-protocol: Worst Post-Baseline Score on Clinical Severity Status 8-Point Ordinal Scale From Baseline to Day 29
    Description The worst post-baseline score (lower scores are worse) through Day 29 in the clinical severity status 8-point ordinal scale, derived from all scores recorded after baseline up to and including Day 29. Participants with a score of 7 discharged to hospice care are considered as having a score of 1 (death) instead of a score of 7 for this endpoint. The clinical severity status 8-point ordinal scale scores are: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on noninvasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities
    Time Frame Day 2 to Day 29

    Outcome Measure Data

    Analysis Population Description
    Apremilast sub-protocol full analysis set
    Arm/Group Title Apremilast + Standard of Care Apremilast Placebo Control
    Arm/Group Description Participants randomized to receive 30 mg apremilast orally twice a day in addition to standard of care treatment for 14 days or until hospital discharge, whichever occurred first. Includes participants randomized to receive matching placebo to apremilast plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to zilucoplan plus standard of care treatment at a site concurrently enrolling apremilast sub-protocol participants and who would have been eligible for the apremilast sub-protocol.
    Measure Participants 194 190
    1 (Death or discharged to hospice care)
    34
    121.4%
    31
    91.2%
    2 (Hospitalized on invasive mechanical ventilation or ECMO)
    13
    46.4%
    10
    29.4%
    3 (Hospitalized on noninvasive ventilation or high-flow oxygen devices)
    37
    132.1%
    43
    126.5%
    4 (Hospitalized, requiring supplemental oxygen)
    75
    267.9%
    62
    182.4%
    5 (Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care)
    21
    75%
    35
    102.9%
    6 (Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care)
    0
    0%
    0
    0%
    7 (Not hospitalized, limitation on activities and/or requiring home oxygen)
    5
    17.9%
    2
    5.9%
    8 (Not hospitalized, no limitations on activities)
    5
    17.9%
    5
    14.7%
    Missing
    4
    14.3%
    2
    5.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.4507
    Comments
    Method Proportional odds model
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.15
    Confidence Interval (2-Sided) 95%
    0.80 to 1.66
    Parameter Dispersion Type:
    Value:
    Estimation Comments Odds ratio (Apremilast vs. Placebo) from a proportional odds model including the baseline clinical severity of 2 on the 8-point ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), region, and treatment arm as factors.
    19. Secondary Outcome
    Title Apremilast Sub-protocol: Number of Intensive Care Unit (ICU) Days From Day 1 Through Day 29
    Description Number of ICU days is the sum of the duration of any episode of ICU admission between Day 1 and Day 29, both inclusive. The number of ICU days of participants who died before or on Day 29 as well as of participants with a score of 7 on the clinical severity status 8-point ordinal scale who were discharged to hospice care by Day 29 was set to 30 (worst possible outcome).
    Time Frame Day 1 to Day 29

    Outcome Measure Data

    Analysis Population Description
    Apremilast sub-protocol full analysis set
    Arm/Group Title Apremilast + Standard of Care Apremilast Placebo Control
    Arm/Group Description Participants randomized to receive 30 mg apremilast orally twice a day in addition to standard of care treatment for 14 days or until hospital discharge, whichever occurred first. Includes participants randomized to receive matching placebo to apremilast plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to zilucoplan plus standard of care treatment at a site concurrently enrolling apremilast sub-protocol participants and who would have been eligible for the apremilast sub-protocol.
    Measure Participants 194 190
    0 days
    124
    442.9%
    122
    358.8%
    1 day
    4
    14.3%
    2
    5.9%
    2 days
    2
    7.1%
    1
    2.9%
    3 days
    2
    7.1%
    4
    11.8%
    4 days
    0
    0%
    1
    2.9%
    5 days
    4
    14.3%
    1
    2.9%
    6 days
    2
    7.1%
    3
    8.8%
    7 days
    4
    14.3%
    2
    5.9%
    8 days
    2
    7.1%
    4
    11.8%
    9 days
    1
    3.6%
    1
    2.9%
    10 days
    1
    3.6%
    1
    2.9%
    11 days
    0
    0%
    1
    2.9%
    12 days
    1
    3.6%
    1
    2.9%
    13 days
    0
    0%
    2
    5.9%
    14 days
    2
    7.1%
    0
    0%
    15 days
    0
    0%
    1
    2.9%
    17 days
    0
    0%
    2
    5.9%
    18 days
    0
    0%
    1
    2.9%
    20 days
    0
    0%
    1
    2.9%
    21 days
    0
    0%
    2
    5.9%
    23 days
    0
    0%
    2
    5.9%
    25 days
    1
    3.6%
    0
    0%
    27 days
    1
    3.6%
    1
    2.9%
    28 days
    1
    3.6%
    0
    0%
    29 days
    8
    28.6%
    2
    5.9%
    30 days (death or discharged to hospice care)
    34
    121.4%
    32
    94.1%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.9741
    Comments
    Method Proportional odds model
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.99
    Confidence Interval (2-Sided) 95%
    0.64 to 1.53
    Parameter Dispersion Type:
    Value:
    Estimation Comments Odds ratio (Apremilast vs. Placebo) from a proportional odds model including the baseline clinical severity of 2 on the 8-point ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), region, and treatment arm as factors.
    20. Secondary Outcome
    Title Apremilast Sub-protocol: Number of Invasive Mechanical Ventilator Days From Day 1 Through Day 29
    Description Number of invasive mechanical ventilator days is the sum of the duration of any episode of invasive mechanical ventilator admission between Day 1 and Day 29, both inclusive. The number of invasive mechanical ventilator days of participants who died before or on Day 29 as well as of participants with a score of 7 on the clinical severity status 8-point ordinal scale who were discharged to hospice care by Day 29 was set to 30.
    Time Frame Day 1 to Day 29

    Outcome Measure Data

    Analysis Population Description
    Apremilast sub-protocol full analysis set
    Arm/Group Title Apremilast + Standard of Care Apremilast Placebo Control
    Arm/Group Description Participants randomized to receive 30 mg apremilast orally twice a day in addition to standard of care treatment for 14 days or until hospital discharge, whichever occurred first. Includes participants randomized to receive matching placebo to apremilast plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to zilucoplan plus standard of care treatment at a site concurrently enrolling apremilast sub-protocol participants and who would have been eligible for the apremilast sub-protocol.
    Measure Participants 194 190
    0 days
    147
    525%
    147
    432.4%
    6 days
    1
    3.6%
    1
    2.9%
    9 days
    1
    3.6%
    0
    0%
    10 days
    1
    3.6%
    0
    0%
    11 days
    1
    3.6%
    1
    2.9%
    12 days
    0
    0%
    1
    2.9%
    13 days
    2
    7.1%
    0
    0%
    16 days
    0
    0%
    2
    5.9%
    18 days
    0
    0%
    1
    2.9%
    19 days
    1
    3.6%
    0
    0%
    22 days
    1
    3.6%
    0
    0%
    23 days
    0
    0%
    1
    2.9%
    24 days
    0
    0%
    1
    2.9%
    25 days
    3
    10.7%
    1
    2.9%
    26 days
    1
    3.6%
    1
    2.9%
    29 days
    1
    3.6%
    0
    0%
    30 days (death or discharged to hospice care)
    34
    121.4%
    33
    97.1%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.8754
    Comments
    Method Proportional odds model
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.04
    Confidence Interval (2-Sided) 95%
    0.64 to 1.70
    Parameter Dispersion Type:
    Value:
    Estimation Comments Odds ratio (Apremilast vs. Placebo) from a proportional odds model including the baseline clinical severity of 2 on the 8-point ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), region, and treatment arm as factors.
    21. Secondary Outcome
    Title Apremilast Sub-protocol: Percentage of Participants Who Achieved Clinical Recovery at Days 8, 15, and 29
    Description Clinical recovery is defined as being fit for discharge, i.e., the achievement of a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale. Participants with a score of 7 discharged to hospice care were not considered fit for discharge. Participants who discontinued the study on or before Days 8, 15, or 29 or with a missing clinical recovery status were considered as not having clinical recovery at each respective time point. Clinical severity status 8-point ordinal scale: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high-flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities
    Time Frame Day 8, Day 15, and Day 29

    Outcome Measure Data

    Analysis Population Description
    Apremilast sub-protocol full analysis set
    Arm/Group Title Apremilast + Standard of Care Apremilast Placebo Control
    Arm/Group Description Participants randomized to receive 30 mg apremilast orally twice a day in addition to standard of care treatment for 14 days or until hospital discharge, whichever occurred first. Includes participants randomized to receive matching placebo to apremilast plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to zilucoplan plus standard of care treatment at a site concurrently enrolling apremilast sub-protocol participants and who would have been eligible for the apremilast sub-protocol.
    Measure Participants 194 190
    Day 8
    36.6
    130.7%
    35.8
    105.3%
    Day 15
    57.7
    206.1%
    60.0
    176.5%
    Day 29
    66.0
    235.7%
    72.1
    212.1%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments Analysis of clinical recovery on Day 8
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.9695
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 0.2
    Confidence Interval (2-Sided) 95%
    -8.7 to 9.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments Risk difference is from a logistic regression including the baseline clinical severity of 2 on the ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), geographic region, and treatment arm as factors.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments Analysis of clinical recovery on Day 8
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.01
    Confidence Interval (2-Sided) 95%
    0.64 to 1.59
    Parameter Dispersion Type:
    Value:
    Estimation Comments Odds ratio (apremilast vs. placebo) is from a logistic regression including the baseline clinical severity of 2 on the ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), geographic region, and treatment arm as factors.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments Analysis of clinical recovery on Day 15
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6236
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -2.4
    Confidence Interval (2-Sided) 95%
    -11.9 to 7.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments Risk difference is from a logistic regression including the baseline clinical severity of 2 on the ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), geographic region, and treatment arm as factors.
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments Analysis of clinical recovery on Day 15
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.90
    Confidence Interval (2-Sided) 95%
    0.59 to 1.37
    Parameter Dispersion Type:
    Value:
    Estimation Comments Odds ratio (apremilast vs. placebo) is from a logistic regression including the baseline clinical severity of 2 on the ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), geographic region, and treatment arm as factors.
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments Analysis of clinical recovery on Day 29
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.1664
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -6.2
    Confidence Interval (2-Sided) 95%
    -14.9 to 2.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments Risk difference is from a logistic regression including the baseline clinical severity of 2 on the ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), geographic region, and treatment arm as factors.
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments Analysis of clinical recovery on Day 29
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.72
    Confidence Interval (2-Sided) 95%
    0.45 to 1.15
    Parameter Dispersion Type:
    Value:
    Estimation Comments Odds ratio (apremilast vs. placebo) is from a logistic regression including the baseline clinical severity of 2 on the ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), geographic region, and treatment arm as factors.
    22. Secondary Outcome
    Title Apremilast Sub-protocol: Percentage of Participants Who Achieved Sustained Clinical Recovery
    Description Sustained clinical recovery is defined as being fit for discharge (achieving a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale) by Day 29, without re-hospitalization by Day 60. Participants with a score of 7 discharged to hospice care were not considered fit for discharge. Participants who died or discontinued from study or with a missing clinical recovery status at Day 60 were not considered having sustained clinical recovery. Clinical severity status 8-point ordinal scale: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities
    Time Frame Day 60

    Outcome Measure Data

    Analysis Population Description
    Apremilast sub-protocol full analysis set
    Arm/Group Title Apremilast + Standard of Care Apremilast Placebo Control
    Arm/Group Description Participants randomized to receive 30 mg apremilast orally twice a day in addition to standard of care treatment for 14 days or until hospital discharge, whichever occurred first. Includes participants randomized to receive matching placebo to apremilast plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to zilucoplan plus standard of care treatment at a site concurrently enrolling apremilast sub-protocol participants and who would have been eligible for the apremilast sub-protocol.
    Measure Participants 194 190
    Number [percentage of participants]
    66.0
    235.7%
    66.3
    195%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.9043
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -0.5
    Confidence Interval (2-Sided) 95%
    -9.3 to 8.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments Risk difference is from a logistic regression including the baseline clinical severity of 2 on the ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), geographic region, and treatment arm as factors.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Lanadelumab + Standard of Care, Lanadelumab Placebo Control
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.97
    Confidence Interval (2-Sided) 95%
    0.62 to 1.54
    Parameter Dispersion Type:
    Value:
    Estimation Comments Odds ratio (apremilast vs. placebo) is from a logistic regression including the baseline clinical severity of 2 on the ordinal scale for clinical severity (yes/no), remdesivir use at baseline (yes/no), geographic region, and treatment arm as factors.
    23. Secondary Outcome
    Title Apremilast Sub-protocol: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
    Description An adverse event (AE) is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to study treatment. A TEAE is an AE that occurs after the first dose of study drug. A serious AE is any AE that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of hospitalization, resulted in persistent disability/incapacity, a congenital anomaly/birth defect, or an important medical event that may jeopardize the patient or require intervention to prevent an outcome listed above. The Investigator assessed the intensity of each AE according to the CTCAE grades: Grade 1 Mild; asymptomatic or mild symptoms; Grade 2 Moderate; minimal, local or noninvasive intervention indicated; Grade 3 Severe or medically significant, not immediately life-threatening; Grade 4 Life-threatening; urgent intervention indicated; Grade 5 Death due to AE.
    Time Frame From first dose of study drug to end of study (Day 60)

    Outcome Measure Data

    Analysis Population Description
    Apremilast safety analysis set included all participants in the apremilast FAS who received at least one dose of study drug.
    Arm/Group Title Apremilast + Standard of Care Apremilast Placebo Control Apremilast Placebo + Standard of Care
    Arm/Group Description Participants received 30 mg apremilast orally twice a day in addition to standard of care treatment for 14 days or until hospital discharge, whichever occurred first. Includes participants who received matching placebo to apremilast plus standard of care treatment as well as participants who received placebo to lanadelumab or placebo to zilucoplan plus standard of care treatment at a site concurrently enrolling apremilast sub-protocol participants and who would have been eligible for the apremilast sub-protocol. Participants received matching placebo to apremilast orally twice a day in addition to standard of care treatment for 14 days or until hospital discharge, whichever occurred first.
    Measure Participants 189 187 182
    Any treatment-emergent adverse event (TEAE)
    102
    364.3%
    103
    302.9%
    100
    51.5%
    TEAE with a CTCAE grade ≥ 3
    48
    171.4%
    57
    167.6%
    54
    27.8%
    Serious TEAE
    51
    182.1%
    57
    167.6%
    55
    28.4%
    TEAE leading to dose modification
    16
    57.1%
    6
    17.6%
    6
    3.1%
    TEAE leading to discontinuation of study drug
    9
    32.1%
    12
    35.3%
    11
    5.7%
    24. Secondary Outcome
    Title Zilucoplan Sub-protocol: Percentage of Participants Who Achieved Oxygen-Free Recovery at Day 29
    Description Oxygen-free recovery at Day 29 is defined as being alive, discharged, and not receiving supplemental oxygen at Day 29. Participants who reached a score of 7 on the ordinal scale for clinical severity who were discharged to hospice care before or on Day 29 were considered as not discharged at Day 29. Participants with a missing oxygen-free recovery status at Day 29 were considered as not having an oxygen-free recovery.
    Time Frame Day 29

    Outcome Measure Data

    Analysis Population Description
    Zilucoplan sub-protocol full analysis set
    Arm/Group Title Zilucoplan + Standard of Care Zilucoplan Placebo Control
    Arm/Group Description Participants randomized to receive 32.4 mg zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment, in addition to standard of care. Includes participants randomized to receive matching placebo to zilucoplan plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to apremilast plus standard of care treatment at a site that enrolled at least one participant in the zilucoplan sub-protocol.
    Measure Participants 100 75
    Number (95% Confidence Interval) [percentage of participants]
    54.0
    192.9%
    60.0
    176.5%
    25. Secondary Outcome
    Title Zilucoplan Sub-protocol: Percentage of Participants With a ≥ 2-point Improvement From Baseline or Fit for Discharge on the Clinical Severity Status 8-Point Ordinal Scale at Day 29
    Description Fit for discharge is defined as achieving a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale. Participants with an ordinal scale score of 7 must not have been discharged to hospice care to be considered as fit for discharge. Participants with a missing clinical severity score at Day 29 were considered as not having met the event at Day 29. The clinical severity status 8-point ordinal scale scores are: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high-flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities
    Time Frame Baseline (Day 1) and Day 29

    Outcome Measure Data

    Analysis Population Description
    Zilucoplan sub-protocol full analysis set
    Arm/Group Title Zilucoplan + Standard of Care Zilucoplan Placebo Control
    Arm/Group Description Participants randomized to receive 32.4 mg zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment, in addition to standard of care. Includes participants randomized to receive matching placebo to zilucoplan plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to apremilast plus standard of care treatment at a site that enrolled at least one participant in the zilucoplan sub-protocol.
    Measure Participants 100 7
    Number (95% Confidence Interval) [percentage of participants]
    66.0
    235.7%
    69.3
    203.8%
    26. Secondary Outcome
    Title Zilucoplan Sub-protocol: Percentage of Participants Who Died Before or on Day 29
    Description All-cause mortality is death due to any cause. Participants with an unknown alive/death status on Day 29 were considered alive for this analysis, with the exception of patients with a score of 7 who were discharged to hospice care before or on Day 29.
    Time Frame Day 1 to Day 29

    Outcome Measure Data

    Analysis Population Description
    Zilucoplan sub-protocol full analysis set
    Arm/Group Title Zilucoplan + Standard of Care Zilucoplan Placebo Control
    Arm/Group Description Participants randomized to receive 32.4 mg zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment, in addition to standard of care. Includes participants randomized to receive matching placebo to zilucoplan plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to apremilast plus standard of care treatment at a site that enrolled at least one participant in the zilucoplan sub-protocol.
    Measure Participants 100 75
    Number (95% Confidence Interval) [percentage of participants]
    18.0
    64.3%
    24.0
    70.6%
    27. Secondary Outcome
    Title Zilucoplan Sub-protocol: Clinical Severity Status 8-Point Ordinal Scale Score at Days 8, 15, and 29
    Description The clinical severity status 8-point ordinal scale scores are: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities Participants with a score of 7 who were discharged to hospice care are counted with participants with a score of 1 (death) for this endpoint.
    Time Frame Day 8, Day 15, and Day 29

    Outcome Measure Data

    Analysis Population Description
    Zilucoplan sub-protocol full analysis set
    Arm/Group Title Zilucoplan + Standard of Care Zilucoplan Placebo Control
    Arm/Group Description Participants randomized to receive 32.4 mg zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment, in addition to standard of care. Includes participants randomized to receive matching placebo to zilucoplan plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to apremilast plus standard of care treatment at a site that enrolled at least one participant in the zilucoplan sub-protocol.
    Measure Participants 100 75
    1 (Death or discharged to hospice care)
    5
    17.9%
    5
    14.7%
    2 (Hospitalized on invasive mechanical ventilation or ECMO)
    24
    85.7%
    14
    41.2%
    3 (Hospitalized on noninvasive ventilation or high-flow oxygen devices)
    12
    42.9%
    8
    23.5%
    4 (Hospitalized, requiring supplemental oxygen)
    16
    57.1%
    14
    41.2%
    5 (Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care)
    5
    17.9%
    10
    29.4%
    6 (Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care)
    0
    0%
    1
    2.9%
    7 (Not hospitalized, limitation on activities and/or requiring home oxygen)
    22
    78.6%
    9
    26.5%
    8 (Not hospitalized, no limitations on activities)
    11
    39.3%
    12
    35.3%
    Missing
    5
    17.9%
    2
    5.9%
    1 (Death or discharged to hospice care)
    8
    28.6%
    14
    41.2%
    2 (Hospitalized on invasive mechanical ventilation or ECMO)
    16
    57.1%
    7
    20.6%
    3 (Hospitalized on noninvasive ventilation or high-flow oxygen devices)
    3
    10.7%
    3
    8.8%
    4 (Hospitalized, requiring supplemental oxygen)
    10
    35.7%
    6
    17.6%
    5 (Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care)
    2
    7.1%
    2
    5.9%
    6 (Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care)
    0
    0%
    1
    2.9%
    7 (Not hospitalized, limitation on activities and/or requiring home oxygen)
    25
    89.3%
    14
    41.2%
    8 (Not hospitalized, no limitations on activities)
    31
    110.7%
    26
    76.5%
    Missing
    5
    17.9%
    2
    5.9%
    1 (Death or discharged to hospice care)
    14
    50%
    18
    52.9%
    2 (Hospitalized on invasive mechanical ventilation or ECMO)
    10
    35.7%
    2
    5.9%
    3 (Hospitalized on noninvasive ventilation or high-flow oxygen devices)
    1
    3.6%
    1
    2.9%
    4 (Hospitalized, requiring supplemental oxygen)
    5
    17.9%
    1
    2.9%
    5 (Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care)
    1
    3.6%
    0
    0%
    6 (Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care)
    0
    0%
    2
    5.9%
    7 (Not hospitalized, limitation on activities and/or requiring home oxygen)
    20
    71.4%
    14
    41.2%
    8 (Not hospitalized, no limitations on activities)
    44
    157.1%
    35
    102.9%
    Missing
    5
    17.9%
    2
    5.9%
    28. Secondary Outcome
    Title Zilucoplan Sub-protocol: Worst Post-Baseline Score on Clinical Severity Status 8-Point Ordinal Scale From Baseline to Day 29
    Description The worst post-baseline score (lower scores are worse) through Day 29 in the clinical severity status 8-point ordinal scale scores, derived from all scores recorded after baseline up to and including Day 29. Participants with a score of 7 discharged to hospice care were considered as having a score of 1 (death) instead of a score of 7 for this endpoint. The clinical severity status 8-point ordinal scale scores scores are: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities
    Time Frame Day 2 to Day 29

    Outcome Measure Data

    Analysis Population Description
    Zilucoplan sub-protocol full analysis set
    Arm/Group Title Zilucoplan + Standard of Care Zilucoplan Placebo Control
    Arm/Group Description Participants randomized to receive 32.4 mg zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment, in addition to standard of care. Includes participants randomized to receive matching placebo to zilucoplan plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to apremilast plus standard of care treatment at a site that enrolled at least one participant in the zilucoplan sub-protocol.
    Measure Participants 100 75
    1 (Death or discharged to hospice care)
    14
    50%
    18
    52.9%
    2 (Hospitalized on invasive mechanical ventilation or ECMO)
    21
    75%
    6
    17.6%
    3 (Hospitalized on noninvasive ventilation or high-flow oxygen devices)
    24
    85.7%
    12
    35.3%
    4 (Hospitalized, requiring supplemental oxygen)
    30
    107.1%
    29
    85.3%
    5 (Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care)
    5
    17.9%
    7
    20.6%
    6 (Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care)
    0
    0%
    0
    0%
    7 (Not hospitalized, limitation on activities and/or requiring home oxygen)
    1
    3.6%
    0
    0%
    8 (Not hospitalized, no limitations on activities)
    0
    0%
    1
    2.9%
    Missing
    5
    17.9%
    2
    5.9%
    29. Secondary Outcome
    Title Zilucoplan Sub-protocol: Number of Intensive Care Unit (ICU) Days From Day 1 Through Day 29
    Description Number of ICU days is the sum of the duration of any episode of ICU admission between Day 1 and Day 29, both inclusive. The number of ICU days of participants who died before or on Day 29 as well as of participants with a score of 7 on the clinical severity status 8-point ordinal scale who were discharged to hospice care by Day 29 was set to 30 (worst possible outcome).
    Time Frame Day 1 to Day 29

    Outcome Measure Data

    Analysis Population Description
    Zilucoplan sub-protocol full analysis set
    Arm/Group Title Zilucoplan + Standard of Care Zilucoplan Placebo Control
    Arm/Group Description Participants randomized to receive 32.4 mg zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment, in addition to standard of care. Includes participants randomized to receive matching placebo to zilucoplan plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to apremilast plus standard of care treatment at a site that enrolled at least one participant in the zilucoplan sub-protocol.
    Measure Participants 100 75
    0 days
    56
    200%
    34
    100%
    1 day
    0
    0%
    2
    5.9%
    3 days
    2
    7.1%
    2
    5.9%
    4 days
    0
    0%
    1
    2.9%
    5 days
    1
    3.6%
    1
    2.9%
    6 days
    1
    3.6%
    3
    8.8%
    7 days
    4
    14.3%
    0
    0%
    8 days
    0
    0%
    4
    11.8%
    9 days
    3
    10.7%
    1
    2.9%
    10 days
    0
    0%
    1
    2.9%
    11 days
    1
    3.6%
    0
    0%
    13 days
    1
    3.6%
    2
    5.9%
    14 days
    1
    3.6%
    0
    0%
    15 days
    0
    0%
    1
    2.9%
    17 days
    1
    3.6%
    1
    2.9%
    18 days
    1
    3.6%
    0
    0%
    21 days
    0
    0%
    2
    5.9%
    22 days
    1
    3.6%
    0
    0%
    25 days
    1
    3.6%
    0
    0%
    26 days
    1
    3.6%
    0
    0%
    29 days
    8
    28.6%
    2
    5.9%
    30 days (death or discharged to hospice care)
    17
    60.7%
    18
    52.9%
    30. Secondary Outcome
    Title Zilucoplan Sub-protocol: Number of Invasive Mechanical Ventilator Days From Day 1 Through Day 29
    Description Number of invasive mechanical ventilator days is the sum of the duration of any episode of invasive mechanical ventilator admission between Day 1 and Day 29, both inclusive. The number of invasive mechanical ventilator days of participants who died before or on Day 29 as well as of participants with a score of 7 on the clinical severity status 8-point ordinal scale who were discharged to hospice care by Day 29 was set to 30.
    Time Frame Day 1 to Day 29

    Outcome Measure Data

    Analysis Population Description
    Zilucoplan sub-protocol full analysis set
    Arm/Group Title Zilucoplan + Standard of Care Zilucoplan Placebo Control
    Arm/Group Description Participants randomized to receive 32.4 mg zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment, in addition to standard of care. Includes participants randomized to receive matching placebo to zilucoplan plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to apremilast plus standard of care treatment at a site that enrolled at least one participant in the zilucoplan sub-protocol.
    Measure Participants 100 75
    0 days
    67
    239.3%
    52
    152.9%
    6 days
    0
    0%
    1
    2.9%
    7 days
    4
    14.3%
    0
    0%
    9 days
    1
    3.6%
    0
    0%
    10 days
    1
    3.6%
    0
    0%
    12 days
    0
    0%
    1
    2.9%
    13 days
    1
    3.6%
    0
    0%
    16 days
    0
    0%
    1
    2.9%
    18 days
    1
    3.6%
    0
    0%
    22 days
    1
    3.6%
    0
    0%
    24 days
    1
    3.6%
    1
    2.9%
    25 days
    1
    3.6%
    0
    0%
    26 days
    1
    3.6%
    1
    2.9%
    27 days
    1
    3.6%
    0
    0%
    28 days
    1
    3.6%
    0
    0%
    29 days
    1
    3.6%
    0
    0%
    30 days (death or discharged to hospice care)
    18
    64.3%
    18
    52.9%
    31. Secondary Outcome
    Title Zilucoplan Sub-protocol: Percentage of Participants Who Achieved Clinical Recovery by Days 8, 15, and 29
    Description Clinical recovery is defined as being fit for discharge, i.e., the achievement of a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale. Participants with a score of 7 discharged to hospice care were not considered fit for discharge. Participants who discontinued the study on or before Days 8, 15, or 29 or with a missing clinical recovery status were considered as not having clinical recovery at each respective time point. Clinical severity status 8-point ordinal scale: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high-flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities
    Time Frame Day 8, Day 15, and Day 29

    Outcome Measure Data

    Analysis Population Description
    Zilucoplan sub-protocol full analysis set
    Arm/Group Title Zilucoplan + Standard of Care Zilucoplan Placebo Control
    Arm/Group Description Participants randomized to receive 32.4 mg zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment, in addition to standard of care. Includes participants randomized to receive matching placebo to zilucoplan plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to apremilast plus standard of care treatment at a site that enrolled at least one participant in the zilucoplan sub-protocol.
    Measure Participants 100 75
    Day 8
    33.0
    117.9%
    30.7
    90.3%
    Day 15
    53.0
    189.3%
    53.3
    156.8%
    Day 29
    60.0
    214.3%
    66.7
    196.2%
    32. Secondary Outcome
    Title Zilucoplan Sub-protocol: Percentage of Participants Who Achieved Sustained Clinical Recovery
    Description Sustained clinical recovery is defined as being fit for discharge (achieving a score of 6, 7, or 8 on the clinical severity status 8-point ordinal scale) by Day 29, without re-hospitalization by Day 60. Participants with a score of 7 discharged to hospice care were not considered fit for discharge. Participants who died or discontinued from study or with a missing clinical recovery status at Day 60 were not considered having sustained clinical recovery. Clinical severity status 8-point ordinal scale: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on noninvasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities
    Time Frame Day 60

    Outcome Measure Data

    Analysis Population Description
    Zilucoplan sub-protocol full analysis set
    Arm/Group Title Zilucoplan + Standard of Care Zilucoplan Placebo Control
    Arm/Group Description Participants randomized to receive 32.4 mg zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment, in addition to standard of care. Includes participants randomized to receive matching placebo to zilucoplan plus standard of care treatment as well as participants who were randomized to receive placebo to lanadelumab or placebo to apremilast plus standard of care treatment at a site that enrolled at least one participant in the zilucoplan sub-protocol.
    Measure Participants 100 75
    Number (95% Confidence Interval) [percentage of participants]
    55.0
    196.4%
    64.0
    188.2%
    33. Secondary Outcome
    Title Zilucoplan Sub-protocol: Number of Participants With Treatment-emergent Adverse Events
    Description An adverse event is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to study treatment. A TEAE is an AE that occurs after the first dose of study drug. A serious AE is any AE that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of hospitalization, resulted in persistent disability/incapacity, a congenital anomaly/birth defect, or an important medical event that may jeopardize the patient or require intervention to prevent an outcome listed above. The Investigator assessed the intensity of each AE according to the CTCAE grades: Grade 1 Mild; asymptomatic or mild symptoms; Grade 2 Moderate; minimal, local or noninvasive intervention indicated; Grade 3 Severe or medically significant, not immediately life-threatening; Grade 4 Life-threatening; urgent intervention indicated; Grade 5 Death due to AE.
    Time Frame From first dose of study drug to end of study (Day 60)

    Outcome Measure Data

    Analysis Population Description
    Zilucoplan safety analysis set included all participants in the zilucoplan FAS who received at least one dose of study drug.
    Arm/Group Title Zilucoplan+ Standard of Care Zilucoplan Placebo Control Zilucoplan Placebo + Standard of Care
    Arm/Group Description Participants received 32.4 mg zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment, in addition to standard of care. Includes participants who received matching placebo to zilucoplan plus standard of care treatment as well as participants who received placebo to lanadelumab or placebo to apremilast plus standard of care treatment at a site that enrolled at least one participant in the zilucoplan sub-protocol. Participants received placebo to zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment, in addition to standard of care.
    Measure Participants 95 73 7
    Any treatment-emergent adverse event (TEAE)
    65
    232.1%
    47
    138.2%
    4
    2.1%
    TEAE with a CTCAE grade ≥ 3
    34
    121.4%
    29
    85.3%
    3
    1.5%
    Serious TEAE
    31
    110.7%
    29
    85.3%
    2
    1%
    TEAE leading to dose modification
    0
    0%
    5
    14.7%
    0
    0%
    TEAE leading to discontinuation of study drug
    7
    25%
    5
    14.7%
    1
    0.5%

    Adverse Events

    Time Frame From first dose of study drug to end of study (Day 60).
    Adverse Event Reporting Description All-cause mortality is reported for all randomized participants, according to randomized treatment group. Adverse events are reported for all participants who received at least one dose of study drug, according to study drug received.
    Arm/Group Title Lanadelumab + SoC Lanadelumab Placebo + SoC Apremilast + SoC Apremilast Placebo + SoC Zilucoplan + SoC Zilucoplan Placebo + SoC
    Arm/Group Description Participants received lanadelumab 300 mg by intravenous infusion on Day 1, and a second dose administered on Day 4, in addition to standard of care (SoC). Participants received placebo to lanadelumab by intravenous infusion on Day 1, and a second dose administered on Day 4 in, addition to standard of care. Participants received 30 mg apremilast orally twice a day in addition to standard of care treatment for 14 days or until hospital discharge, whichever occurred first. Participants received matching placebo to apremilast orally twice a day in addition to standard of care treatment for 14 days or until hospital discharge, whichever occurred first. Participants received 32.4 mg zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment, in addition to standard of care. Participants received placebo to zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment, in addition to standard of care.
    All Cause Mortality
    Lanadelumab + SoC Lanadelumab Placebo + SoC Apremilast + SoC Apremilast Placebo + SoC Zilucoplan + SoC Zilucoplan Placebo + SoC
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 8/28 (28.6%) 1/1 (100%) 37/194 (19.1%) 35/184 (19%) 20/100 (20%) 3/8 (37.5%)
    Serious Adverse Events
    Lanadelumab + SoC Lanadelumab Placebo + SoC Apremilast + SoC Apremilast Placebo + SoC Zilucoplan + SoC Zilucoplan Placebo + SoC
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 11/27 (40.7%) 1/1 (100%) 51/189 (27%) 55/182 (30.2%) 31/95 (32.6%) 2/7 (28.6%)
    Blood and lymphatic system disorders
    Anaemia 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Coagulopathy 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Cardiac disorders
    Acute myocardial infarction 0/27 (0%) 0/1 (0%) 0/189 (0%) 1/182 (0.5%) 2/95 (2.1%) 0/7 (0%)
    Atrial fibrillation 0/27 (0%) 0/1 (0%) 0/189 (0%) 0/182 (0%) 1/95 (1.1%) 0/7 (0%)
    Cardiac arrest 0/27 (0%) 0/1 (0%) 2/189 (1.1%) 3/182 (1.6%) 0/95 (0%) 0/7 (0%)
    Cardiac failure 0/27 (0%) 0/1 (0%) 0/189 (0%) 0/182 (0%) 1/95 (1.1%) 0/7 (0%)
    Cardio-respiratory arrest 1/27 (3.7%) 0/1 (0%) 2/189 (1.1%) 2/182 (1.1%) 2/95 (2.1%) 0/7 (0%)
    Cardiogenic shock 0/27 (0%) 0/1 (0%) 0/189 (0%) 0/182 (0%) 1/95 (1.1%) 0/7 (0%)
    Cardiopulmonary failure 0/27 (0%) 0/1 (0%) 0/189 (0%) 1/182 (0.5%) 0/95 (0%) 0/7 (0%)
    Cardiovascular insufficiency 0/27 (0%) 0/1 (0%) 0/189 (0%) 1/182 (0.5%) 0/95 (0%) 0/7 (0%)
    Right ventricular failure 0/27 (0%) 0/1 (0%) 0/189 (0%) 1/182 (0.5%) 0/95 (0%) 0/7 (0%)
    Sinus bradycardia 1/27 (3.7%) 0/1 (0%) 0/189 (0%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Supraventricular tachycardia 0/27 (0%) 0/1 (0%) 0/189 (0%) 1/182 (0.5%) 0/95 (0%) 0/7 (0%)
    Eye disorders
    Blindness unilateral 0/27 (0%) 0/1 (0%) 0/189 (0%) 1/182 (0.5%) 0/95 (0%) 0/7 (0%)
    Gastrointestinal disorders
    Constipation 0/27 (0%) 0/1 (0%) 0/189 (0%) 0/182 (0%) 1/95 (1.1%) 0/7 (0%)
    Dysphagia 0/27 (0%) 0/1 (0%) 0/189 (0%) 1/182 (0.5%) 0/95 (0%) 0/7 (0%)
    Intestinal pseudo-obstruction 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    General disorders
    Multiple organ dysfunction syndrome 0/27 (0%) 0/1 (0%) 3/189 (1.6%) 2/182 (1.1%) 2/95 (2.1%) 0/7 (0%)
    Hepatobiliary disorders
    Hepatic failure 0/27 (0%) 0/1 (0%) 0/189 (0%) 1/182 (0.5%) 0/95 (0%) 0/7 (0%)
    Infections and infestations
    Bacterial sepsis 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Bronchopulmonary aspergillosis 0/27 (0%) 0/1 (0%) 0/189 (0%) 1/182 (0.5%) 1/95 (1.1%) 0/7 (0%)
    COVID-19 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 5/182 (2.7%) 2/95 (2.1%) 0/7 (0%)
    COVID-19 pneumonia 3/27 (11.1%) 1/1 (100%) 6/189 (3.2%) 6/182 (3.3%) 2/95 (2.1%) 0/7 (0%)
    Gastroenteritis 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Klebsiella sepsis 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 0/182 (0%) 1/95 (1.1%) 0/7 (0%)
    Nosocomial infection 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Pneumonia 0/27 (0%) 0/1 (0%) 2/189 (1.1%) 4/182 (2.2%) 3/95 (3.2%) 0/7 (0%)
    Pneumonia bacterial 1/27 (3.7%) 0/1 (0%) 1/189 (0.5%) 1/182 (0.5%) 2/95 (2.1%) 0/7 (0%)
    Pneumonia staphylococcal 0/27 (0%) 0/1 (0%) 0/189 (0%) 0/182 (0%) 1/95 (1.1%) 0/7 (0%)
    Pulmonary sepsis 0/27 (0%) 0/1 (0%) 0/189 (0%) 0/182 (0%) 1/95 (1.1%) 0/7 (0%)
    Pyelonephritis 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Sepsis 1/27 (3.7%) 0/1 (0%) 3/189 (1.6%) 3/182 (1.6%) 1/95 (1.1%) 0/7 (0%)
    Septic shock 2/27 (7.4%) 0/1 (0%) 12/189 (6.3%) 10/182 (5.5%) 8/95 (8.4%) 0/7 (0%)
    Staphylococcal infection 1/27 (3.7%) 0/1 (0%) 0/189 (0%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Urinary tract infection 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Injury, poisoning and procedural complications
    Procedural pneumothorax 1/27 (3.7%) 0/1 (0%) 0/189 (0%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Procedural shock 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Investigations
    Alanine aminotransferase increased 0/27 (0%) 0/1 (0%) 0/189 (0%) 1/182 (0.5%) 0/95 (0%) 0/7 (0%)
    Hepatic enzyme abnormal 0/27 (0%) 0/1 (0%) 0/189 (0%) 0/182 (0%) 1/95 (1.1%) 0/7 (0%)
    Hepatic enzyme increased 0/27 (0%) 0/1 (0%) 0/189 (0%) 0/182 (0%) 1/95 (1.1%) 0/7 (0%)
    Oxygen saturation decreased 0/27 (0%) 0/1 (0%) 0/189 (0%) 1/182 (0.5%) 1/95 (1.1%) 0/7 (0%)
    Transaminases increased 0/27 (0%) 0/1 (0%) 0/189 (0%) 2/182 (1.1%) 0/95 (0%) 0/7 (0%)
    Metabolism and nutrition disorders
    Hyperkalaemia 0/27 (0%) 0/1 (0%) 0/189 (0%) 1/182 (0.5%) 0/95 (0%) 0/7 (0%)
    Hypokalaemia 0/27 (0%) 0/1 (0%) 0/189 (0%) 1/182 (0.5%) 0/95 (0%) 0/7 (0%)
    Hyponatraemia 0/27 (0%) 0/1 (0%) 0/189 (0%) 1/182 (0.5%) 0/95 (0%) 0/7 (0%)
    Propofol infusion syndrome 1/27 (3.7%) 0/1 (0%) 0/189 (0%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Nervous system disorders
    Cauda equina syndrome 0/27 (0%) 0/1 (0%) 0/189 (0%) 0/182 (0%) 1/95 (1.1%) 0/7 (0%)
    Cerebral haemorrhage 0/27 (0%) 0/1 (0%) 0/189 (0%) 0/182 (0%) 1/95 (1.1%) 0/7 (0%)
    Cerebrovascular accident 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 0/182 (0%) 1/95 (1.1%) 0/7 (0%)
    Coma 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Renal and urinary disorders
    Acute kidney injury 1/27 (3.7%) 0/1 (0%) 7/189 (3.7%) 4/182 (2.2%) 7/95 (7.4%) 0/7 (0%)
    Renal failure 0/27 (0%) 0/1 (0%) 2/189 (1.1%) 1/182 (0.5%) 1/95 (1.1%) 0/7 (0%)
    Renal impairment 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 1/182 (0.5%) 0/95 (0%) 0/7 (0%)
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 0/27 (0%) 0/1 (0%) 0/189 (0%) 1/182 (0.5%) 0/95 (0%) 0/7 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome 0/27 (0%) 0/1 (0%) 3/189 (1.6%) 4/182 (2.2%) 0/95 (0%) 0/7 (0%)
    Acute respiratory failure 1/27 (3.7%) 0/1 (0%) 11/189 (5.8%) 6/182 (3.3%) 5/95 (5.3%) 1/7 (14.3%)
    Bronchospasm 0/27 (0%) 0/1 (0%) 2/189 (1.1%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Dyspnoea 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 2/182 (1.1%) 1/95 (1.1%) 0/7 (0%)
    Hypoxia 0/27 (0%) 0/1 (0%) 2/189 (1.1%) 3/182 (1.6%) 2/95 (2.1%) 0/7 (0%)
    Pneumomediastinum 1/27 (3.7%) 0/1 (0%) 0/189 (0%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Pneumothorax 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 1/182 (0.5%) 1/95 (1.1%) 0/7 (0%)
    Pulmonary embolism 1/27 (3.7%) 0/1 (0%) 6/189 (3.2%) 5/182 (2.7%) 2/95 (2.1%) 0/7 (0%)
    Pulmonary oedema 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Respiratory acidosis 0/27 (0%) 0/1 (0%) 0/189 (0%) 0/182 (0%) 1/95 (1.1%) 0/7 (0%)
    Respiratory disorder 0/27 (0%) 0/1 (0%) 0/189 (0%) 0/182 (0%) 1/95 (1.1%) 0/7 (0%)
    Respiratory distress 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 1/182 (0.5%) 0/95 (0%) 0/7 (0%)
    Respiratory failure 2/27 (7.4%) 0/1 (0%) 14/189 (7.4%) 10/182 (5.5%) 8/95 (8.4%) 1/7 (14.3%)
    Skin and subcutaneous tissue disorders
    Subcutaneous emphysema 0/27 (0%) 0/1 (0%) 0/189 (0%) 1/182 (0.5%) 0/95 (0%) 0/7 (0%)
    Vascular disorders
    Deep vein thrombosis 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 0/182 (0%) 1/95 (1.1%) 0/7 (0%)
    Haemodynamic instability 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Peripheral ischaemia 0/27 (0%) 0/1 (0%) 0/189 (0%) 1/182 (0.5%) 0/95 (0%) 0/7 (0%)
    Shock 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 0/182 (0%) 1/95 (1.1%) 0/7 (0%)
    Other (Not Including Serious) Adverse Events
    Lanadelumab + SoC Lanadelumab Placebo + SoC Apremilast + SoC Apremilast Placebo + SoC Zilucoplan + SoC Zilucoplan Placebo + SoC
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 12/27 (44.4%) 1/1 (100%) 63/189 (33.3%) 50/182 (27.5%) 46/95 (48.4%) 4/7 (57.1%)
    Blood and lymphatic system disorders
    Anaemia 2/27 (7.4%) 1/1 (100%) 9/189 (4.8%) 4/182 (2.2%) 9/95 (9.5%) 0/7 (0%)
    Leukopenia 0/27 (0%) 1/1 (100%) 0/189 (0%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Cardiac disorders
    Atrial fibrillation 1/27 (3.7%) 0/1 (0%) 5/189 (2.6%) 4/182 (2.2%) 3/95 (3.2%) 1/7 (14.3%)
    Bradycardia 0/27 (0%) 1/1 (100%) 1/189 (0.5%) 3/182 (1.6%) 1/95 (1.1%) 0/7 (0%)
    Cardiac failure congestive 0/27 (0%) 1/1 (100%) 0/189 (0%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Myocardial infarction 2/27 (7.4%) 0/1 (0%) 0/189 (0%) 0/182 (0%) 0/95 (0%) 1/7 (14.3%)
    Tachycardia 1/27 (3.7%) 1/1 (100%) 3/189 (1.6%) 2/182 (1.1%) 4/95 (4.2%) 0/7 (0%)
    Gastrointestinal disorders
    Constipation 0/27 (0%) 0/1 (0%) 9/189 (4.8%) 10/182 (5.5%) 16/95 (16.8%) 1/7 (14.3%)
    Nausea 2/27 (7.4%) 0/1 (0%) 9/189 (4.8%) 5/182 (2.7%) 3/95 (3.2%) 0/7 (0%)
    General disorders
    Pyrexia 3/27 (11.1%) 0/1 (0%) 4/189 (2.1%) 6/182 (3.3%) 9/95 (9.5%) 1/7 (14.3%)
    Infections and infestations
    Bacterial infection 1/27 (3.7%) 0/1 (0%) 4/189 (2.1%) 1/182 (0.5%) 1/95 (1.1%) 1/7 (14.3%)
    Pneumonia 1/27 (3.7%) 0/1 (0%) 5/189 (2.6%) 0/182 (0%) 3/95 (3.2%) 1/7 (14.3%)
    Pneumonia klebsiella 0/27 (0%) 1/1 (100%) 0/189 (0%) 2/182 (1.1%) 2/95 (2.1%) 0/7 (0%)
    Injury, poisoning and procedural complications
    Soft tissue injury 0/27 (0%) 1/1 (100%) 0/189 (0%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Investigations
    Hepatic enzyme increased 1/27 (3.7%) 0/1 (0%) 4/189 (2.1%) 2/182 (1.1%) 5/95 (5.3%) 0/7 (0%)
    Oxygen saturation decreased 0/27 (0%) 1/1 (100%) 0/189 (0%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Procalcitonin increased 1/27 (3.7%) 0/1 (0%) 0/189 (0%) 1/182 (0.5%) 0/95 (0%) 1/7 (14.3%)
    Troponin increased 0/27 (0%) 0/1 (0%) 0/189 (0%) 4/182 (2.2%) 3/95 (3.2%) 1/7 (14.3%)
    Metabolism and nutrition disorders
    Acidosis 0/27 (0%) 1/1 (100%) 0/189 (0%) 0/182 (0%) 0/95 (0%) 0/7 (0%)
    Hyperglycaemia 0/27 (0%) 0/1 (0%) 8/189 (4.2%) 7/182 (3.8%) 3/95 (3.2%) 1/7 (14.3%)
    Hypernatraemia 2/27 (7.4%) 1/1 (100%) 4/189 (2.1%) 3/182 (1.6%) 3/95 (3.2%) 1/7 (14.3%)
    Hypertriglyceridaemia 2/27 (7.4%) 0/1 (0%) 4/189 (2.1%) 6/182 (3.3%) 5/95 (5.3%) 0/7 (0%)
    Hypoglycaemia 1/27 (3.7%) 1/1 (100%) 2/189 (1.1%) 2/182 (1.1%) 0/95 (0%) 0/7 (0%)
    Hypokalaemia 2/27 (7.4%) 0/1 (0%) 8/189 (4.2%) 3/182 (1.6%) 8/95 (8.4%) 0/7 (0%)
    Nervous system disorders
    Headache 0/27 (0%) 0/1 (0%) 10/189 (5.3%) 3/182 (1.6%) 2/95 (2.1%) 0/7 (0%)
    Psychiatric disorders
    Depression 2/27 (7.4%) 0/1 (0%) 1/189 (0.5%) 1/182 (0.5%) 0/95 (0%) 0/7 (0%)
    Insomnia 1/27 (3.7%) 0/1 (0%) 8/189 (4.2%) 5/182 (2.7%) 8/95 (8.4%) 0/7 (0%)
    Renal and urinary disorders
    Acute kidney injury 3/27 (11.1%) 1/1 (100%) 11/189 (5.8%) 5/182 (2.7%) 2/95 (2.1%) 1/7 (14.3%)
    Oliguria 1/27 (3.7%) 0/1 (0%) 1/189 (0.5%) 1/182 (0.5%) 5/95 (5.3%) 1/7 (14.3%)
    Renal impairment 0/27 (0%) 1/1 (100%) 3/189 (1.6%) 2/182 (1.1%) 0/95 (0%) 0/7 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 2/27 (7.4%) 1/1 (100%) 2/189 (1.1%) 1/182 (0.5%) 3/95 (3.2%) 1/7 (14.3%)
    Chronic obstructive pulmonary disease 0/27 (0%) 0/1 (0%) 1/189 (0.5%) 1/182 (0.5%) 0/95 (0%) 1/7 (14.3%)
    Dyspnoea 2/27 (7.4%) 0/1 (0%) 0/189 (0%) 0/182 (0%) 3/95 (3.2%) 0/7 (0%)
    Pneumomediastinum 2/27 (7.4%) 0/1 (0%) 1/189 (0.5%) 3/182 (1.6%) 0/95 (0%) 0/7 (0%)
    Pneumothorax 0/27 (0%) 0/1 (0%) 4/189 (2.1%) 4/182 (2.2%) 1/95 (1.1%) 1/7 (14.3%)
    Vascular disorders
    Hypertension 1/27 (3.7%) 0/1 (0%) 8/189 (4.2%) 7/182 (3.8%) 10/95 (10.5%) 0/7 (0%)
    Hypotension 1/27 (3.7%) 0/1 (0%) 5/189 (2.6%) 9/182 (4.9%) 13/95 (13.7%) 2/7 (28.6%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.

    Results Point of Contact

    Name/Title Study Director
    Organization Amgen Inc.
    Phone 866-572-6436
    Email medinfo@amgen.com
    Responsible Party:
    Amgen
    ClinicalTrials.gov Identifier:
    NCT04590586
    Other Study ID Numbers:
    • COV-01
    First Posted:
    Oct 19, 2020
    Last Update Posted:
    Jun 29, 2022
    Last Verified:
    Jun 1, 2022