Acute Respiratory Distress Syndrome, Ards, Coronavirus, Coronavirus Infection, COVID, Covid-19, Sars-CoV2, Severe Acute Respiratory Syndrome, Severe Acute Respiratory Syndrome Coronavirus 2
Conditions
Brief summary
The purpose of this study is to evaluate the safety and effectiveness of APL-9 in adults with mild to moderate ARDS (acute respiratory distress syndrome) caused by COVID-19 who are hospitalized and require supplemental oxygen therapy with or without mechanical ventilation. It is thought that COVID-19 activates the complement system, part of the immune system that responds to infection or tissue damage, and increases inflammation in the lungs. APL-9 has been designed to inhibit or block activation of part of the complement pathway, and potentially reduce inflammation in the lungs. Part 1 of the study is open-label to evaluate safety; all participants will receive APL-9 plus standard of care. Part 2 of the study is double-blind, randomized; participants will receive either APL-9 or the vehicle-control plus standard of care.
Interventions
DRUGAPL-9
Complement (C3) Inhibitor
OTHERVehicle Control
Normal saline of equal volume to active arm
Sponsors
Apellis Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Be at least 18 years of age at time of informed consent * Diagnosis of active SARS CoV 2 infection using viral RNA or viral antigen within 7 days of screening * Respiratory failure requiring oxygen supplementation or either invasive or noninvasive mechanical ventilation with PaO2/FiO2 ratio \>100 mm Hg. Respiratory failure cannot be fully explained by cardiac failure or fluid overload.
Exclusion criteria
* Treatment with immune checkpoint inhibitors, or other immunomodulators within 3 months prior to study enrollment (however, treatment with convalescent plasma, steroids, IL-6 inhibitors, and antiviral agents is NOT excluded) * Active bacterial, fungal, or parasitic infection * History of neuromuscular degenerative disease (eg, amyotrophic lateral sclerosis, Duchenne muscular dystrophy, or multiple sclerosis) * Current participation in an interventional clincial trial * Subjects who have, at screening, been on mechanical ventilation for \>7 days Have evidence of kidney and liver failure at screening * Have a hereditary complement deficiency * Pregnancy or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Experienced Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | From the first dose of study drug and up to 30 (+7) days after the last dose of study drug. Part 1: Day 1 up to Day 44; Part 2: Day 1 up to Day 58 | TEAEs were defined as those adverse events that developed or worsened in severity after initiation of the first dose of study drug and up to 30 (+7) days beyond the last dose of study drug. A serious TEAE was any TEAE or suspected adverse reaction that, in the view of either the Investigator or Sponsor, resulted in any of the following outcomes: death; is life threatening; inpatient hospitalization or prolongation of existing hospitalization; a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; or a congenital anomaly/birth defect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Part 2: Day 1 up to Day 58 (until the safety follow-up assessment 30 days after last study treatment [+7 days]) | Overall survival was defined as randomization date to death of any cause, censored at the last day known to be alive. Median overall survival was estimated using the Kaplan-Meier method. |
| Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score Over Time | Part 2: Baseline (Day 1) and Days 3, 5, 7, 11, 15 and end of treatment (EOT) visit (up to Day 21) | The SOFA score is an aggregate score based on objective measures of 6 organ systems: respiratory, coagulation, hepatic, cardiovascular, neurologic, and renal. The minimum value is 0 and maximum value is 24. Higher scores indicate worse outcomes. A subject with a SOFA score of zero was defined as being free of organ failure. |
| Total Duration of Mechanical Ventilation | Part 2: Day 1 up to Day 58 | Total duration of mechanical ventilation was calculated from the randomization date and was defined as days on mechanical ventilation during the study participation. For subjects with death of any cause (or withdrawal of study participation), total duration of mechanical ventilation was imputed with the longest duration observed in the study. Any subject who was not on mechanical ventilation at the randomization date was excluded. Median total duration of mechanical ventilation was estimated using the Kaplan-Meier method. |
| Total Duration of Oxygen Therapy | Part 2: Day 1 up to Day 58 | Total duration of oxygen therapy was calculated from randomization date and was defined as days on mechanical ventilation or supplemental oxygen during the study participation. For subjects with death of any cause (or withdrawal of study participation), total duration of oxygen therapy was imputed with the longest duration observed in the study. Any subject who was not on mechanical ventilation or supplemental oxygen at the randomization date was excluded. Median total duration of oxygen therapy was estimated using the Kaplan-Meier method. |
| Serum Concentration of APL-9 Over Time | Part 1: Day 1 (pre- and post-dose) and Days 3, 5 and 7 (including EOT visit); Part 2: Day 1 (pre- and post-dose) and Days 3, 5, 7, 11, 15 and EOT visit (up to Day 21) | To evaluate pharmacokinetics (PK), blood samples were collected at pre-specified timepoints and serum concentrations of APL-9 were determined. Blood was collected 3 times on Day 1: prior to the initial infusion, as soon as possible following the initial infusion (within 5-10 minutes) prior to the continuous infusion, and at 2 hours after the beginning of the continuous infusion. Blood was then collected once daily between 1-2 hours after the first dose on Days 3, 5, 7, 11 (if treatment was ongoing), Day 15 (if treatment was ongoing) and at the EOT visit. |
| Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3 and C4 | Part 1: Baseline (Day 1) and EOT visit (up to Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) | To evaluate pharmacodynamic (PD) parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for complement biomarkers C3 and C4. |
| Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3a, C4a, C5a and Terminal Complement Complex (TCC) | Part 1: Baseline (Day 1) and EOT visit (up to Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) | To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for complement biomarkers C3a, C4a, C5a and TCC. |
| Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Complement Bb | Part 1: Baseline (Day 1) and EOT visit (up to Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) | To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for complement biomarker Bb, a marker of alternative pathway activation. |
| Hospital Length of Stay | Part 2: Day 1 up to Day 58 | Hospital length of stay was defined as randomization date to hospital discharge. For subjects with death of any cause or withdrawal of study participation, hospital length of stay was imputed with the longest hospital length of stay observed in the study. Median hospital length of stay was estimated using the Kaplan-Meier method. |
| Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Reticulocytes | Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) | To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the coagulation biomarker reticulocytes. Percentage (%) of reticulocytes was calculated as (Number of Reticulocytes / Number of Red Blood Cells) X 100. |
| Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Schistocytes | Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) | To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the coagulation biomarker schistocytes. |
| Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Lactate Dehydrogenase | Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) | To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the coagulation biomarker lactate dehydrogenase. |
| Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: D-Dimer and Ferritin | Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) | To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the coagulation biomarkers D-dimer and ferritin. |
| Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Haptoglobin and Fibrinogen | Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) | To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the coagulation biomarkers haptoglobin and fibrinogen. |
| Change From Baseline at EOT Visit in Biomarkers of Inflammation: C-reactive Protein (CRP) | Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) | To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the inflammatory cytokine CRP. |
| Change From Baseline at EOT Visit in Biomarkers of Inflammation: Tumor Necrosis Factor Alpha (TNFα), Interleukin-1-beta (IL-1β) and Interleukin-6 (IL-6) | Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) | To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the inflammatory cytokines TNFα, IL-1β and IL-6. |
| Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Alternative Complement Pathway Hemolytic Activity (AH50) | Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) | To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for complement biomarker AH50. |
Countries
Brazil, United States
Participant flow
Recruitment details
This was a randomized, double-blind, vehicle-controlled, multicenter, parallel-group Phase 1/2 study (with an initial open-label period) evaluating the safety and efficacy of APL-9 versus (vs) vehicle control as an add-on therapy to standard of care (SoC) in subjects who had respiratory failure, including mild to moderate acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19).
Pre-assignment details
The study was conducted in 2 parts: Subjects in Part 1 received open-label APL-9 from Day 1 through Day 7 or resolution of ARDS. Subjects in Part 2 were randomly assigned 1:1 to blinded treatment with either APL-9 or vehicle control from Day 1 through Day 7 or up to and including Day 21, discontinuation of respiratory support or hospital discharge, whichever occurred latest. Extended treatment beyond Day 7 in Part 2 required certain criteria to be met and was at discretion of the Investigator.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: APL-9 Subjects received an initial IV infusion of 180 mg APL-9 in 50 mL of saline once over a 10-minute period, followed within 1 hour by continuous IV infusion of 180 mg APL-9 in 250 mL saline at the rate of 15 mg/hour until Day 7 or resolution of ARDS (PaO2/FiO2 ratio \>300 mm Hg), whichever occurred earlier. In addition, subjects received institutional SoC to treat their conditions. | 6 |
| Part 2: APL-9 Subjects received an initial IV infusion of 180 mg APL-9 in 50 mL of saline once over a 10-minute period, followed within 1 hour by continuous IV infusion of 180 mg APL-9 in 250 mL saline at the rate of 15 mg/hour until Day 7 or up to and including Day 21, discontinuation of respiratory support (supplemental oxygen or mechanical ventilation), or hospital discharge, whichever occurred latest. In addition, subjects received institutional SoC to treat their conditions. | 33 |
| Part 2: Control Subjects received an initial IV infusion of 50 mL of saline once over a 10-minute period, followed within 1 hour by continuous IV infusion of 250 mL saline at the rate of 21 mL/hour until Day 7 or up to and including Day 21, discontinuation of respiratory support (supplemental oxygen or mechanical ventilation), or hospital discharge, whichever occurred latest. In addition, subjects received institutional SoC to treat their conditions. | 32 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 |
| Overall Study | Death | 1 | 12 | 7 |
| Overall Study | Other | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 |
| Overall Study | Sponsor Request | 0 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Part 1: APL-9 | Part 2: APL-9 | Part 2: Control | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 18 Participants | 14 Participants | 32 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 15 Participants | 18 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 11 Participants | 12 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 13 Participants | 14 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 9 Participants | 6 Participants | 15 Participants |
| Race/Ethnicity, Customized American Indian/Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Black/African American | 3 Participants | 3 Participants | 2 Participants | 8 Participants |
| Race/Ethnicity, Customized Native Hawaiian/Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 0 Participants | 4 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized Unspecified | 2 Participants | 4 Participants | 8 Participants | 14 Participants |
| Race/Ethnicity, Customized White | 1 Participants | 21 Participants | 18 Participants | 40 Participants |
| Sex: Female, Male Female | 3 Participants | 17 Participants | 13 Participants | 33 Participants |
| Sex: Female, Male Male | 3 Participants | 16 Participants | 19 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 6 | 13 / 33 | 8 / 32 |
| other Total, other adverse events | 3 / 6 | 20 / 33 | 20 / 32 |
| serious Total, serious adverse events | 1 / 6 | 14 / 33 | 15 / 32 |
Outcome results
Primary
Number of Subjects Who Experienced Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
TEAEs were defined as those adverse events that developed or worsened in severity after initiation of the first dose of study drug and up to 30 (+7) days beyond the last dose of study drug. A serious TEAE was any TEAE or suspected adverse reaction that, in the view of either the Investigator or Sponsor, resulted in any of the following outcomes: death; is life threatening; inpatient hospitalization or prolongation of existing hospitalization; a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; or a congenital anomaly/birth defect.
Time frame: From the first dose of study drug and up to 30 (+7) days after the last dose of study drug. Part 1: Day 1 up to Day 44; Part 2: Day 1 up to Day 58
Population: The safety set included all subjects who received at least 1 dose of study drug. Subjects were analyzed according to the actual treatment they received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: APL-9 | Number of Subjects Who Experienced Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 4 Participants |
| Part 1: APL-9 | Number of Subjects Who Experienced Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 1 Participants |
| Part 2: APL-9 | Number of Subjects Who Experienced Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 23 Participants |
| Part 2: APL-9 | Number of Subjects Who Experienced Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 14 Participants |
| Part 2: Control | Number of Subjects Who Experienced Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 22 Participants |
| Part 2: Control | Number of Subjects Who Experienced Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 15 Participants |
Secondary
Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: D-Dimer and Ferritin
To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the coagulation biomarkers D-dimer and ferritin.
Time frame: Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Population: The PD set included all subjects in the safety set with at least 1 PD evaluation. Only subjects with values at both Baseline and the EOT visit were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: D-Dimer and Ferritin | D-dimer | -783.8 ng/mL | Standard Deviation 607.57 |
| Part 1: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: D-Dimer and Ferritin | Ferritin | -133.6 ng/mL | Standard Deviation 80.8 |
| Part 2: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: D-Dimer and Ferritin | D-dimer | 217.2 ng/mL | Standard Deviation 1218.54 |
| Part 2: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: D-Dimer and Ferritin | Ferritin | -53.1 ng/mL | Standard Deviation 650.97 |
| Part 2: Control | Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: D-Dimer and Ferritin | D-dimer | 907.9 ng/mL | Standard Deviation 2986.71 |
| Part 2: Control | Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: D-Dimer and Ferritin | Ferritin | -19.3 ng/mL | Standard Deviation 694.52 |
Secondary
Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Haptoglobin and Fibrinogen
To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the coagulation biomarkers haptoglobin and fibrinogen.
Time frame: Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Population: The PD set included all subjects in the safety set with at least 1 PD evaluation. Only subjects with values at both Baseline and the EOT visit were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Haptoglobin and Fibrinogen | Fibrinogen | -147.3 mg/dL | Standard Deviation 170.55 |
| Part 2: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Haptoglobin and Fibrinogen | Haptoglobin | -5435.4 mg/dL | Standard Deviation 7571.18 |
| Part 2: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Haptoglobin and Fibrinogen | Fibrinogen | 3995.1 mg/dL | Standard Deviation 15113.49 |
| Part 2: Control | Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Haptoglobin and Fibrinogen | Haptoglobin | -4554.0 mg/dL | Standard Deviation 7756.6 |
| Part 2: Control | Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Haptoglobin and Fibrinogen | Fibrinogen | -1348.2 mg/dL | Standard Deviation 9726.66 |
Secondary
Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Lactate Dehydrogenase
To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the coagulation biomarker lactate dehydrogenase.
Time frame: Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Population: The PD set included all subjects in the safety set with at least 1 PD evaluation. Only subjects with values at both Baseline and the EOT visit were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Lactate Dehydrogenase | -464.6 U/L | Standard Deviation 427.86 |
| Part 2: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Lactate Dehydrogenase | -135.2 U/L | Standard Deviation 186.9 |
| Part 2: Control | Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Lactate Dehydrogenase | -106.1 U/L | Standard Deviation 205.59 |
Secondary
Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Reticulocytes
To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the coagulation biomarker reticulocytes. Percentage (%) of reticulocytes was calculated as (Number of Reticulocytes / Number of Red Blood Cells) X 100.
Time frame: Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Population: The PD set included all subjects in the safety set with at least 1 PD evaluation. Only subjects with values at both Baseline and the EOT visit were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 2: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Reticulocytes | 10325.4 % of reticulocytes | Standard Deviation 20649.77 |
| Part 2: Control | Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Reticulocytes | 23929.1 % of reticulocytes | Standard Deviation 87585.96 |
Secondary
Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Schistocytes
To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the coagulation biomarker schistocytes.
Time frame: Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Population: The PD set included all subjects in the safety set with at least 1 PD evaluation. Only subjects with values at both Baseline and the EOT visit were included in the analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part 2: Control | Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Schistocytes | 0.0 10^9 cells/liter (L) |
Secondary
Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Alternative Complement Pathway Hemolytic Activity (AH50)
To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for complement biomarker AH50.
Time frame: Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Population: The PD set included all subjects in the safety set with at least 1 PD evaluation. Only subjects with values at both Baseline and the EOT visit were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Alternative Complement Pathway Hemolytic Activity (AH50) | -157.7 Units (U)/mL | Standard Deviation 26.84 |
| Part 2: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Alternative Complement Pathway Hemolytic Activity (AH50) | -84.3 Units (U)/mL | Standard Deviation 44.51 |
| Part 2: Control | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Alternative Complement Pathway Hemolytic Activity (AH50) | -2.3 Units (U)/mL | Standard Deviation 43.72 |
Secondary
Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Complement Bb
To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for complement biomarker Bb, a marker of alternative pathway activation.
Time frame: Part 1: Baseline (Day 1) and EOT visit (up to Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Population: The PD set included all subjects in the safety set with at least 1 PD evaluation. Only subjects with values at both Baseline and the EOT visit were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Complement Bb | -0.6 μg/mL | Standard Deviation 0.13 |
| Part 2: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Complement Bb | -0.9 μg/mL | Standard Deviation 0.74 |
| Part 2: Control | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Complement Bb | -0.1 μg/mL | Standard Deviation 1.56 |
Secondary
Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3a, C4a, C5a and Terminal Complement Complex (TCC)
To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for complement biomarkers C3a, C4a, C5a and TCC.
Time frame: Part 1: Baseline (Day 1) and EOT visit (up to Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Population: The PD set included all subjects in the safety set with at least 1 PD evaluation. Note: C5a was only measured in Part 2 because this biomarker was added in APL9-COV-201 Protocol Amendment 2 which was after the last subject in Part 1 finished the last study dose. Only subjects with values at both Baseline and the EOT visit were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3a, C4a, C5a and Terminal Complement Complex (TCC) | C3a | -69.6 nanograms (ng)/mL | Standard Deviation 16.35 |
| Part 1: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3a, C4a, C5a and Terminal Complement Complex (TCC) | TCC | -143.1 nanograms (ng)/mL | Standard Deviation 87.41 |
| Part 1: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3a, C4a, C5a and Terminal Complement Complex (TCC) | C4a | -337.7 nanograms (ng)/mL | Standard Deviation 371.7 |
| Part 2: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3a, C4a, C5a and Terminal Complement Complex (TCC) | C5a | -6.9 nanograms (ng)/mL | Standard Deviation 14.88 |
| Part 2: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3a, C4a, C5a and Terminal Complement Complex (TCC) | C4a | -1560.8 nanograms (ng)/mL | Standard Deviation 4821.35 |
| Part 2: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3a, C4a, C5a and Terminal Complement Complex (TCC) | C3a | -357.6 nanograms (ng)/mL | Standard Deviation 785.69 |
| Part 2: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3a, C4a, C5a and Terminal Complement Complex (TCC) | TCC | -127.4 nanograms (ng)/mL | Standard Deviation 121.9 |
| Part 2: Control | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3a, C4a, C5a and Terminal Complement Complex (TCC) | TCC | -12.2 nanograms (ng)/mL | Standard Deviation 337.02 |
| Part 2: Control | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3a, C4a, C5a and Terminal Complement Complex (TCC) | C3a | -4.0 nanograms (ng)/mL | Standard Deviation 240.7 |
| Part 2: Control | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3a, C4a, C5a and Terminal Complement Complex (TCC) | C4a | -87.0 nanograms (ng)/mL | Standard Deviation 1028.77 |
| Part 2: Control | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3a, C4a, C5a and Terminal Complement Complex (TCC) | C5a | -3.9 nanograms (ng)/mL | Standard Deviation 9.77 |
Secondary
Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3 and C4
To evaluate pharmacodynamic (PD) parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for complement biomarkers C3 and C4.
Time frame: Part 1: Baseline (Day 1) and EOT visit (up to Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Population: The PD set included all subjects in the safety set with at least 1 PD evaluation. Only subjects with values at both Baseline and the EOT visit were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3 and C4 | C3 | 38.0 mg/deciliter (dL) | Standard Deviation 11.17 |
| Part 1: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3 and C4 | C4 | 2.0 mg/deciliter (dL) | Standard Deviation 19.3 |
| Part 2: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3 and C4 | C3 | 91.4 mg/deciliter (dL) | Standard Deviation 64 |
| Part 2: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3 and C4 | C4 | -3.9 mg/deciliter (dL) | Standard Deviation 16.34 |
| Part 2: Control | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3 and C4 | C3 | 2.1 mg/deciliter (dL) | Standard Deviation 35.32 |
| Part 2: Control | Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3 and C4 | C4 | 0.2 mg/deciliter (dL) | Standard Deviation 15.4 |
Secondary
Change From Baseline at EOT Visit in Biomarkers of Inflammation: C-reactive Protein (CRP)
To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the inflammatory cytokine CRP.
Time frame: Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Population: The PD set included all subjects in the safety set with at least 1 PD evaluation. Only subjects with values at both Baseline and the EOT visit were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Inflammation: C-reactive Protein (CRP) | -7.0 mg/dL | Standard Deviation 8.67 |
| Part 2: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Inflammation: C-reactive Protein (CRP) | 6.4 mg/dL | Standard Deviation 41.21 |
| Part 2: Control | Change From Baseline at EOT Visit in Biomarkers of Inflammation: C-reactive Protein (CRP) | -3.1 mg/dL | Standard Deviation 18.52 |
Secondary
Change From Baseline at EOT Visit in Biomarkers of Inflammation: Tumor Necrosis Factor Alpha (TNFα), Interleukin-1-beta (IL-1β) and Interleukin-6 (IL-6)
To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the inflammatory cytokines TNFα, IL-1β and IL-6.
Time frame: Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Population: The PD set included all subjects in the safety set with at least 1 PD evaluation. Only subjects with values at both Baseline and the EOT visit were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 2: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Inflammation: Tumor Necrosis Factor Alpha (TNFα), Interleukin-1-beta (IL-1β) and Interleukin-6 (IL-6) | TNFα | 19.6 picograms/mL | Standard Deviation 62.24 |
| Part 2: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Inflammation: Tumor Necrosis Factor Alpha (TNFα), Interleukin-1-beta (IL-1β) and Interleukin-6 (IL-6) | IL-1β | -0.6 picograms/mL | Standard Deviation 7.15 |
| Part 2: APL-9 | Change From Baseline at EOT Visit in Biomarkers of Inflammation: Tumor Necrosis Factor Alpha (TNFα), Interleukin-1-beta (IL-1β) and Interleukin-6 (IL-6) | IL-6 | 203.6 picograms/mL | Standard Deviation 602.54 |
| Part 2: Control | Change From Baseline at EOT Visit in Biomarkers of Inflammation: Tumor Necrosis Factor Alpha (TNFα), Interleukin-1-beta (IL-1β) and Interleukin-6 (IL-6) | TNFα | 10.4 picograms/mL | Standard Deviation 73.92 |
| Part 2: Control | Change From Baseline at EOT Visit in Biomarkers of Inflammation: Tumor Necrosis Factor Alpha (TNFα), Interleukin-1-beta (IL-1β) and Interleukin-6 (IL-6) | IL-1β | -8.1 picograms/mL | Standard Deviation 22.37 |
| Part 2: Control | Change From Baseline at EOT Visit in Biomarkers of Inflammation: Tumor Necrosis Factor Alpha (TNFα), Interleukin-1-beta (IL-1β) and Interleukin-6 (IL-6) | IL-6 | 71.3 picograms/mL | Standard Deviation 499.84 |
Secondary
Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score Over Time
The SOFA score is an aggregate score based on objective measures of 6 organ systems: respiratory, coagulation, hepatic, cardiovascular, neurologic, and renal. The minimum value is 0 and maximum value is 24. Higher scores indicate worse outcomes. A subject with a SOFA score of zero was defined as being free of organ failure.
Time frame: Part 2: Baseline (Day 1) and Days 3, 5, 7, 11, 15 and end of treatment (EOT) visit (up to Day 21)
Population: The FAS included all randomized subjects who received at least 1 dose of study drug. The analyses using the FAS were based upon the actual treatment allocated. Analysis was pre-specified in Part 2 only. Only subjects with values at both Baseline and the specified visit were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: APL-9 | Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score Over Time | Change to Day 3 | 0.4 score on a scale | Standard Deviation 2.17 |
| Part 1: APL-9 | Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score Over Time | Change to Day 5 | 0.6 score on a scale | Standard Deviation 3 |
| Part 1: APL-9 | Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score Over Time | Change to Day 7 | 1.8 score on a scale | Standard Deviation 3.97 |
| Part 1: APL-9 | Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score Over Time | Change to Day 11 | 1.7 score on a scale | Standard Deviation 2.08 |
| Part 1: APL-9 | Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score Over Time | Change to Day 15 | 0.0 score on a scale | Standard Deviation 2.83 |
| Part 1: APL-9 | Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score Over Time | Change to EOT | 0.2 score on a scale | Standard Deviation 3.56 |
| Part 2: APL-9 | Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score Over Time | Change to Day 15 | -1.0 score on a scale | Standard Deviation 2.83 |
| Part 2: APL-9 | Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score Over Time | Change to Day 3 | 1.2 score on a scale | Standard Deviation 2.06 |
| Part 2: APL-9 | Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score Over Time | Change to Day 11 | 0.2 score on a scale | Standard Deviation 5.97 |
| Part 2: APL-9 | Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score Over Time | Change to Day 5 | 0.6 score on a scale | Standard Deviation 2.48 |
| Part 2: APL-9 | Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score Over Time | Change to EOT | 0.6 score on a scale | Standard Deviation 3.98 |
| Part 2: APL-9 | Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score Over Time | Change to Day 7 | 0.9 score on a scale | Standard Deviation 3.5 |
Secondary
Hospital Length of Stay
Hospital length of stay was defined as randomization date to hospital discharge. For subjects with death of any cause or withdrawal of study participation, hospital length of stay was imputed with the longest hospital length of stay observed in the study. Median hospital length of stay was estimated using the Kaplan-Meier method.
Time frame: Part 2: Day 1 up to Day 58
Population: The full analysis set (FAS) included all randomized subjects who received at least 1 dose of study drug. The analyses using the FAS were based upon the actual treatment allocated. Analysis was pre-specified in Part 2 only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: APL-9 | Hospital Length of Stay | 21.5 days |
| Part 2: APL-9 | Hospital Length of Stay | 15.5 days |
Comparison: P-value was from a 2-sided stratified Log-rank test by the randomization stratification factors (need of mechanical ventilation \[yes vs no\] and age \[\<65 years vs ≥65 years\]) at 0.1 significant level for evaluation of treatment difference. Hazard ratio was obtained from a Cox regression model with treatment and the randomization stratification factors as fixed factors and 90% confidence interval (CI) was based on the Wald method.p-value: 0.8290% CI: [0.63, 1.51]Log Rank
Secondary
Overall Survival
Overall survival was defined as randomization date to death of any cause, censored at the last day known to be alive. Median overall survival was estimated using the Kaplan-Meier method.
Time frame: Part 2: Day 1 up to Day 58 (until the safety follow-up assessment 30 days after last study treatment [+7 days])
Population: The FAS included all randomized subjects who received at least 1 dose of study treatment. The analyses using the FAS were based upon the actual treatment allocated. Analysis was pre-specified in Part 2 only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: APL-9 | Overall Survival | NA days |
| Part 2: APL-9 | Overall Survival | NA days |
Comparison: P-value was from a 2-sided stratified Log-rank test by the randomization stratification factors (need of mechanical ventilation \[yes vs no\] and age \[\<65 years vs ≥65 years\]) at 0.1 significant level for evaluation of treatment difference. Hazard ratio was obtained from a Cox regression model with treatment and the randomization stratification factors as fixed factors and 90% CI was based on the Wald method.p-value: 0.3690% CI: [0.77, 3.4]Log Rank
Secondary
Serum Concentration of APL-9 Over Time
To evaluate pharmacokinetics (PK), blood samples were collected at pre-specified timepoints and serum concentrations of APL-9 were determined. Blood was collected 3 times on Day 1: prior to the initial infusion, as soon as possible following the initial infusion (within 5-10 minutes) prior to the continuous infusion, and at 2 hours after the beginning of the continuous infusion. Blood was then collected once daily between 1-2 hours after the first dose on Days 3, 5, 7, 11 (if treatment was ongoing), Day 15 (if treatment was ongoing) and at the EOT visit.
Time frame: Part 1: Day 1 (pre- and post-dose) and Days 3, 5 and 7 (including EOT visit); Part 2: Day 1 (pre- and post-dose) and Days 3, 5, 7, 11, 15 and EOT visit (up to Day 21)
Population: The PK set included all subjects in the safety set and for whom at least 1 PK sample was evaluable.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: APL-9 | Serum Concentration of APL-9 Over Time | Day 1, Pre-dose | 0.0 micrograms (μg)/mL) | Standard Deviation 0 |
| Part 1: APL-9 | Serum Concentration of APL-9 Over Time | Day 1, 10 mins | 48.1 micrograms (μg)/mL) | Standard Deviation 14 |
| Part 1: APL-9 | Serum Concentration of APL-9 Over Time | Day 1, 2 hours | 56.2 micrograms (μg)/mL) | Standard Deviation 14.21 |
| Part 1: APL-9 | Serum Concentration of APL-9 Over Time | Day 3 | 98.0 micrograms (μg)/mL) | Standard Deviation 11.03 |
| Part 1: APL-9 | Serum Concentration of APL-9 Over Time | Day 5 | 111.5 micrograms (μg)/mL) | Standard Deviation 8.14 |
| Part 1: APL-9 | Serum Concentration of APL-9 Over Time | Day 7 | 116.0 micrograms (μg)/mL) | Standard Deviation 2.83 |
| Part 1: APL-9 | Serum Concentration of APL-9 Over Time | EOT | 114.5 micrograms (μg)/mL) | Standard Deviation 16.21 |
| Part 2: APL-9 | Serum Concentration of APL-9 Over Time | Day 15 | 133.4 micrograms (μg)/mL) | Standard Deviation 60.25 |
| Part 2: APL-9 | Serum Concentration of APL-9 Over Time | Day 3 | 87.7 micrograms (μg)/mL) | Standard Deviation 31.87 |
| Part 2: APL-9 | Serum Concentration of APL-9 Over Time | Day 5 | 103.7 micrograms (μg)/mL) | Standard Deviation 21.95 |
| Part 2: APL-9 | Serum Concentration of APL-9 Over Time | EOT | 95.0 micrograms (μg)/mL) | Standard Deviation 34.19 |
| Part 2: APL-9 | Serum Concentration of APL-9 Over Time | Day 7 | 121.6 micrograms (μg)/mL) | Standard Deviation 28.71 |
| Part 2: APL-9 | Serum Concentration of APL-9 Over Time | Day 11 | 115.3 micrograms (μg)/mL) | Standard Deviation 24.54 |
| Part 2: APL-9 | Serum Concentration of APL-9 Over Time | Day 1, Pre-dose | 3.9 micrograms (μg)/mL) | Standard Deviation 11.72 |
| Part 2: APL-9 | Serum Concentration of APL-9 Over Time | Day 1, 10 mins | 77.7 micrograms (μg)/mL) | Standard Deviation 168.78 |
| Part 2: APL-9 | Serum Concentration of APL-9 Over Time | Day 1, 2 hours | 54.1 micrograms (μg)/mL) | Standard Deviation 17.28 |
| Part 2: Control | Serum Concentration of APL-9 Over Time | Day 1, Pre-dose | 0.0 micrograms (μg)/mL) | Standard Deviation 0 |
| Part 2: Control | Serum Concentration of APL-9 Over Time | Day 1, 2 hours | 2.2 micrograms (μg)/mL) | Standard Deviation 12 |
| Part 2: Control | Serum Concentration of APL-9 Over Time | Day 15 | 2.4 micrograms (μg)/mL) | Standard Deviation 3.45 |
| Part 2: Control | Serum Concentration of APL-9 Over Time | Day 7 | 2.3 micrograms (μg)/mL) | Standard Deviation 8.32 |
| Part 2: Control | Serum Concentration of APL-9 Over Time | Day 3 | 5.0 micrograms (μg)/mL) | Standard Deviation 24.8 |
| Part 2: Control | Serum Concentration of APL-9 Over Time | EOT | 0.0 micrograms (μg)/mL) | Standard Deviation 0 |
| Part 2: Control | Serum Concentration of APL-9 Over Time | Day 11 | 2.6 micrograms (μg)/mL) | Standard Deviation 5.72 |
| Part 2: Control | Serum Concentration of APL-9 Over Time | Day 5 | 2.3 micrograms (μg)/mL) | Standard Deviation 10.43 |
| Part 2: Control | Serum Concentration of APL-9 Over Time | Day 1, 10 mins | 2.6 micrograms (μg)/mL) | Standard Deviation 13.99 |
Secondary
Total Duration of Mechanical Ventilation
Total duration of mechanical ventilation was calculated from the randomization date and was defined as days on mechanical ventilation during the study participation. For subjects with death of any cause (or withdrawal of study participation), total duration of mechanical ventilation was imputed with the longest duration observed in the study. Any subject who was not on mechanical ventilation at the randomization date was excluded. Median total duration of mechanical ventilation was estimated using the Kaplan-Meier method.
Time frame: Part 2: Day 1 up to Day 58
Population: The FAS included all randomized subjects who received at least 1 dose of study drug. The analyses using the FAS were based upon the actual treatment allocated. Analysis was pre-specified in Part 2 only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: APL-9 | Total Duration of Mechanical Ventilation | 47.0 days |
| Part 2: APL-9 | Total Duration of Mechanical Ventilation | 8.5 days |
Comparison: P-value was from a 2-sided stratified Log-rank test by the randomization stratification factors (need of mechanical ventilation \[yes vs no\] and age \[\<65 years vs ≥65 years\]) at 0.1 significant level for evaluation of treatment difference. Hazard ratio was obtained from a Cox regression model with treatment and the randomization stratification factors as fixed factors and 90% CI was based on the Wald method.p-value: 0.0390% CI: [0.01, 0.51]Log Rank
Secondary
Total Duration of Oxygen Therapy
Total duration of oxygen therapy was calculated from randomization date and was defined as days on mechanical ventilation or supplemental oxygen during the study participation. For subjects with death of any cause (or withdrawal of study participation), total duration of oxygen therapy was imputed with the longest duration observed in the study. Any subject who was not on mechanical ventilation or supplemental oxygen at the randomization date was excluded. Median total duration of oxygen therapy was estimated using the Kaplan-Meier method.
Time frame: Part 2: Day 1 up to Day 58
Population: The FAS included all randomized subjects who received at least 1 dose of study treatment. The analyses using the FAS were based upon the actual treatment allocated. Analysis was pre-specified in Part 2 only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: APL-9 | Total Duration of Oxygen Therapy | 9.0 days |
| Part 2: APL-9 | Total Duration of Oxygen Therapy | 8.0 days |
Comparison: P-value was from a 2-sided stratified Log-rank test by the randomization stratification factors (need of mechanical ventilation \[yes vs no\] and age \[\<65 years vs ≥65 years\]) at 0.1 significant level for evaluation of treatment difference. Hazard ratio was obtained from a Cox regression model with treatment and the randomization stratification factors as fixed factors and 90% CI was based on the Wald method.p-value: 0.9390% CI: [0.69, 1.72]Log Rank