COVID-19
Conditions
Keywords
2019 novel coronavirus disease, Acalabrutinib, Btk inhibitor
Brief summary
CALAVI will investigate the safety, efficacy and pharmacokinetics of acalabrutinib together with Best Supportive Care in the treatment of COVID-19.
Interventions
DRUGAcalabrutinib
Acalabrutinib- administered orally
Sponsors
Acerta Pharma BV
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Study will consist of two arms Arm 1 is acalabrutinib + best supportive care or Arm 2 is best supportive care alone
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent or have a legal representative provide consent and authorization to use protected health information (in accordance with national and local patient privacy regulations) 2. Men and women ≥18 years of age at the time of signing the informed consent form 3. Confirmed infection with SARS-CoV-2 confirmed per World Health Organization (WHO) criteria (including positive RT-PCR nucleic acid test of any specimen \[eg, respiratory, blood, urine, stool, or other bodily fluid\]) within 4 days of randomization 4. COVID-19 pneumonia (documented radiographically) requiring hospitalization and oxygen saturation \<94% on room air or requires supplemental oxygen 5. Able to swallow pills 6. Willing to follow contraception guidelines
Exclusion criteria
1. Respiratory failure at time of screening due to COVID-19 2. Known medical resuscitation within 14 days of randomization 3. Pregnant or breast feeding 4. Suspected uncontrolled active bacterial, fungal, viral, or other infection (besides infection with SARS-CoV-2) 5. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or bilirubin ≥ 3x upper limit of normal (ULN) and/or severe hepatic impairment detected within 24 hours at screening (per local lab) 6. Uncontrolled or untreated symptomatic arrhythmias, myocardial infarction within the last 6 weeks, or congestive heart failure (NYHA Grade 3 or 4). Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll 7. Treatment with a strong cytochrome P450 (CYP)3A inhibitor (within 14 days before first dose of study drug) or inducer (within 7 days before first dose of study drug). 8. Requires treatment with proton-pump inhibitors (PPIs; eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving PPIs who switch to H2-receptor antagonists or antacids are eligible for enrollment in this study 9. Received oral antirejection or immunomodulatory drugs (eg, anticytokines, Btk inhibitors, JAK inhibitors, PI3K inhibitors) within 30 days before randomization on study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Alive and Free of Respiratory Failure at Day 14 | At Day 14 | Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates \>20 L/min with fraction of delivered oxygen ≥0.5) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events and Serious Adverse Events | Screening to 28 (+3) days after last dose of acalabrutinib (for acalabrutinib + BSC participants) or to 38 (+3) days after randomization (for BSC alone participants) | — |
| Percentage of Participants Alive and Free of Respiratory Failure at Day 28 | At Day 28 | Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) Oxygen delivered by highflow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates \>20 L/min with fraction of delivered oxygen ≥0.5) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation |
| Percent Change From Baseline in C-reactive Protein. | Days 3, 5, 7, 10, 14, 28 | Baseline is defined as the result obtained on the date of randomization. If no result was obtained on the date of randomization, the last result prior to the date of randomization is used. Percent change from baseline at Day X is calculated by multiplying the following result by 100%: (Day X value - Baseline value)/Baseline value. The mean of this result for all analyzed patients is taken to get the mean percent change from baseline. |
| Percent Change From Baseline in Ferritin | Days 3, 5, 7, 10, 14, 28 | Baseline is defined as the result obtained on the date of randomization. If no result was obtained on the date of randomization, the last result prior to the date of randomization is used. Percent change from baseline at Day X is calculated by multiplying the following result by 100%: (Day X value - Baseline value)/Baseline value. The mean of this result for all analyzed patients is taken to get the mean percent change from baseline. |
| Percent Change From Baseline in Absolute Lymphocyte Count | Days 3, 5, 7, 10, 14, 28 | Baseline is defined as the result obtained on the date of randomization. If no result was obtained on the date of randomization, the last result prior to the date of randomization is used. Percent change from baseline at Day X is calculated by multiplying the following result by 100%: (Day X value - Baseline value)/Baseline value. The mean of this result for all analyzed patients is taken to get the mean percent change from baseline. |
| Overall Survival | From randomization until 90 days after randomization. Safety Issue: | Median overall survival, calculated using the Kaplan-Meier technique. Confidence interval for median overall survival (days) is derived based on Brookmeyer-Crowley method with log-log transformation. |
| Percentage of Participants Alive and Discharged From ICU | At Day 14 and at Day 28 | — |
| Time From Randomization to First Occurrence of Respiratory Failure or Death on Study Due to Any Cause | From randomization to 28 days after randomization. | Median time to first occurrence of respiratory failure or death, calculated using the Kaplan-Meier technique. Confidence interval for median overall survival (days) is derived based on Brookmeyer-Crowley method with log-log transformation. |
| Number of Days Alive and Free of Respiratory Failure | From randomization to 28 days after randomization. | Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) Oxygen delivered by highflow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates \>20 L/min with fraction of delivered oxygen ≥0.5) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation |
| Number of Days With Respiratory Failure | From randomization to 28 days after randomization. | Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates \>20 L/min with fraction of delivered oxygen ≥0.5) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation For participants who die (due to any cause) prior to Day 28, days from death to Day 28 are counted as days with respiratory failure. For participants in hospital and experiencing respiratory failure at the time they withdraw from the study, days from last known status to Day 28 are counted as days with respiratory failure. |
| Number of Days Hospitalized | From randomization to 28 days after randomization. | For this summary, the hospitalization must be considered clinically indicated to count as a day hospitalized. For participants who die (due to any cause) prior to Day 28, days from death to Day 28 are counted as days hospitalized. For participants in hospital at the time they withdraw from the study, days from last known status to Day 28 are counted as days hospitalized. |
| Number of Days in ICU | From randomization to 90 days after randomization. | For this summary, the ICU stay must be considered clinically indicated to count as a day in ICU. For participants who die (due to any cause) prior to Day 90, days from death to Day 90 are counted as days in ICU. |
| Number of Days Alive Outside of Hospital | From randomization to 28 days after randomization. | — |
| Percent Change From Baseline in Oxygenation Index | Days 3, 5, 7, 10, 14, 28 | Baseline is defined as the result obtained on the date of randomization. Percent change from baseline at Day X is calculated by multiplying the following result by 100%: (Day X value - Baseline value)/Baseline value. The mean of this result for all analyzed patients is taken to get the mean percent change from baseline. |
| Time From Randomization to Clinical Improvement of at Least 2 Points on a 9-point Category Ordinal Scale | From randomization to 28 days after randomization. | 9-point category ordinal scale: 0. \* Uninfected, no clinical or virological evidence of infection 1. Ambulatory, no limitation of activities 2. Ambulatory, limitation of activities 3. Hospitalized - mild disease, no oxygen therapy 4. Hospitalized - mild disease, oxygen by mask or nasal prongs 5. Hospitalized - severe disease, non-invasive ventilation or high flow oxygen 6. Hospitalised - severe disease, intubation and mechanical ventilation 7. Hospitalized - severe disease, ventilation and additional organ support, such as pressors, renal replacement therapy, extracorporeal membrane oxygenation 8. Death Median time to first occurrence of respiratory failure or death, calculated using the Kaplan-Meier technique. Confidence interval for median overall survival (days) is derived based on Brookmeyer-Crowley method with log-log transformation. |
| Pharmacokinetics of Acalabrutinib | Day 3 and Day 7 | Summary of plasma concentrations (ng/mL) of acalabrutinib |
| Pharmacokinetics of ACP-5862 | Day 3 and Day 7 | Summary of plasma concentrations (ng/mL) of ACP-5862 |
Countries
Argentina, Brazil, Chile, France, Germany, India, Italy, Japan, Mexico, Peru, Poland, Russia, South Africa, Turkey (Türkiye)
Participant flow
Recruitment details
All participants had COVID-19 pneumonia (documented radiographically) requiring hospitalization and were recruited from the following countries: South Africa; India; Turkey; Japan; Russian Federation; France; Italy; Brazil; Argentina; Peru; Mexico; Chile. The first participant was randomized on 15 June 2020 and the last participant was randomized on 17 August 2020.
Pre-assignment details
Screening assessments were performed within the 3 days prior to randomization. Of 236 screened participants, 177 were enrolled. Of the 59 participants that were screened but not enrolled, 54 were screen failures (did not meet eligibility criteria), 1 died, 1 was withdrawn by physician decision and 3 withdrew consent.
Participants by arm
| Arm | Count |
|---|---|
| Acalabrutinib + BSC Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines. | 89 |
| BSC Alone Participants received best supportive care per the discretion of the Investigator and institutional guidelines. | 88 |
| Total | 177 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 8 | 9 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Study terminated by sponsor incorrectly entered in database - participants completed the study | 2 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 1 |
Baseline characteristics
| Characteristic | BSC Alone | Total | Acalabrutinib + BSC |
|---|---|---|---|
| Age, Continuous | 56.7 Years STANDARD_DEVIATION 14.8 | 56.7 Years STANDARD_DEVIATION 14.1 | 56.7 Years STANDARD_DEVIATION 13.3 |
| Age, Customized < 65 years | 60 Participants | 121 Participants | 61 Participants |
| Age, Customized >= 65 years | 28 Participants | 56 Participants | 28 Participants |
| Race/Ethnicity, Customized AMERICAN INDIAN OR ALASKA NATIVE | 3 Participants | 10 Participants | 7 Participants |
| Race/Ethnicity, Customized ASIAN | 13 Participants | 36 Participants | 23 Participants |
| Race/Ethnicity, Customized BLACK OR AFRICAN AMERICAN | 5 Participants | 8 Participants | 3 Participants |
| Race/Ethnicity, Customized HISPANIC OR LATINO | 47 Participants | 95 Participants | 48 Participants |
| Race/Ethnicity, Customized NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized NOT HISPANIC OR LATINO | 41 Participants | 82 Participants | 41 Participants |
| Race/Ethnicity, Customized NOT REPORTED | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized OTHER | 19 Participants | 33 Participants | 14 Participants |
| Race/Ethnicity, Customized WHITE | 48 Participants | 88 Participants | 40 Participants |
| Sex: Female, Male Female | 24 Participants | 53 Participants | 29 Participants |
| Sex: Female, Male Male | 64 Participants | 124 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 7 / 86 | 10 / 91 |
| other Total, other adverse events | 10 / 86 | 2 / 91 |
| serious Total, serious adverse events | 7 / 86 | 2 / 91 |
Outcome results
Primary
Percentage of Participants Alive and Free of Respiratory Failure at Day 14
Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates \>20 L/min with fraction of delivered oxygen ≥0.5) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation
Time frame: At Day 14
Population: Full analysis set (as randomized).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + BSC | Percentage of Participants Alive and Free of Respiratory Failure at Day 14 | 83.1 Percentage of participants |
| BSC Alone | Percentage of Participants Alive and Free of Respiratory Failure at Day 14 | 90.9 Percentage of participants |
Secondary
Number of Days Alive and Free of Respiratory Failure
Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) Oxygen delivered by highflow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates \>20 L/min with fraction of delivered oxygen ≥0.5) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation
Time frame: From randomization to 28 days after randomization.
Population: Full analysis set (as randomized).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acalabrutinib + BSC | Number of Days Alive and Free of Respiratory Failure | 24.8 Days | Standard Deviation 8 |
| BSC Alone | Number of Days Alive and Free of Respiratory Failure | 25.3 Days | Standard Deviation 7.1 |
Secondary
Number of Days Alive Outside of Hospital
Time frame: From randomization to 90 days after randomization.
Population: Full analysis set (as randomized).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acalabrutinib + BSC | Number of Days Alive Outside of Hospital | 66.8 Days | Standard Deviation 28.2 |
| BSC Alone | Number of Days Alive Outside of Hospital | 71.3 Days | Standard Deviation 24.5 |
Secondary
Number of Days Alive Outside of Hospital
Time frame: From randomization to 28 days after randomization.
Population: Full analysis set (as randomized).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acalabrutinib + BSC | Number of Days Alive Outside of Hospital | 15.1 Days | Standard Deviation 8.4 |
| BSC Alone | Number of Days Alive Outside of Hospital | 17.0 Days | Standard Deviation 7.3 |
Secondary
Number of Days Hospitalized
For this summary, the hospitalization must be considered clinically indicated to count as a day hospitalized. For participants who die (due to any cause) prior to Day 28, days from death to Day 28 are counted as days hospitalized. For participants in hospital at the time they withdraw from the study, days from last known status to Day 28 are counted as days hospitalized.
Time frame: From randomization to 28 days after randomization.
Population: Full analysis set (as randomized).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acalabrutinib + BSC | Number of Days Hospitalized | 12.2 Days | Standard Deviation 8.6 |
| BSC Alone | Number of Days Hospitalized | 10.4 Days | Standard Deviation 7.4 |
Secondary
Number of Days in ICU
For this summary, the ICU stay must be considered clinically indicated to count as a day in ICU. For participants who die (due to any cause) prior to Day 90, days from death to Day 90 are counted as days in ICU.
Time frame: From randomization to 90 days after randomization.
Population: Full analysis set (as randomized).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acalabrutinib + BSC | Number of Days in ICU | 10.4 Days | Standard Deviation 25.5 |
| BSC Alone | Number of Days in ICU | 9.7 Days | Standard Deviation 25.8 |
Secondary
Number of Days With Respiratory Failure
Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates \>20 L/min with fraction of delivered oxygen ≥0.5) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation For participants who die (due to any cause) prior to Day 28, days from death to Day 28 are counted as days with respiratory failure. For participants in hospital and experiencing respiratory failure at the time they withdraw from the study, days from last known status to Day 28 are counted as days with respiratory failure.
Time frame: From randomization to 28 days after randomization.
Population: Full analysis set (as randomized).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acalabrutinib + BSC | Number of Days With Respiratory Failure | 3.2 Days | Standard Deviation 8 |
| BSC Alone | Number of Days With Respiratory Failure | 2.7 Days | Standard Deviation 7.1 |
Secondary
Number of Participants With Adverse Events and Serious Adverse Events
Time frame: Screening to 28 (+3) days after last dose of acalabrutinib (for acalabrutinib + BSC participants) or to 38 (+3) days after randomization (for BSC alone participants)
Population: Safety analysis set: If the participant receives at least 1 dose of acalabrutinib, they are summarized in the Acalabrutinib + BSC group. Otherwise, they are summarized in the BSC alone group.~The number of participants in the BSC alone group (91) is greater than the number of participants randomized to this group (88) because three participants randomized to Acalabrutinib + BSC did not receive any acalabrutinib and therefore are included in the BSC alone group for the safety analysis set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Acalabrutinib + BSC | Number of Participants With Adverse Events and Serious Adverse Events | Any Adverse Event | 43 Participants |
| Acalabrutinib + BSC | Number of Participants With Adverse Events and Serious Adverse Events | Any Serious Adverse Event | 7 Participants |
| BSC Alone | Number of Participants With Adverse Events and Serious Adverse Events | Any Adverse Event | 37 Participants |
| BSC Alone | Number of Participants With Adverse Events and Serious Adverse Events | Any Serious Adverse Event | 2 Participants |
Secondary
Overall Survival
Median overall survival, calculated using the Kaplan-Meier technique. Confidence interval for median overall survival (days) is derived based on Brookmeyer-Crowley method with log-log transformation.
Time frame: From randomization until 90 days after randomization. Safety Issue:
Population: Full analysis set (as randomized).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acalabrutinib + BSC | Overall Survival | NA Days |
| BSC Alone | Overall Survival | NA Days |
Secondary
Percentage of Participants Alive and Discharged From ICU
Time frame: At Day 14 and at Day 28
Population: Full analysis set (as randomized).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Acalabrutinib + BSC | Percentage of Participants Alive and Discharged From ICU | At Day 28 | 83.1 Percentage of participants |
| Acalabrutinib + BSC | Percentage of Participants Alive and Discharged From ICU | At Day 14 | 78.7 Percentage of participants |
| BSC Alone | Percentage of Participants Alive and Discharged From ICU | At Day 28 | 87.5 Percentage of participants |
| BSC Alone | Percentage of Participants Alive and Discharged From ICU | At Day 14 | 89.8 Percentage of participants |
Secondary
Percentage of Participants Alive and Free of Respiratory Failure at Day 28
Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) Oxygen delivered by highflow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates \>20 L/min with fraction of delivered oxygen ≥0.5) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation
Time frame: At Day 28
Population: Full analysis set (as randomized).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + BSC | Percentage of Participants Alive and Free of Respiratory Failure at Day 28 | 84.3 Percentage of participants |
| BSC Alone | Percentage of Participants Alive and Free of Respiratory Failure at Day 28 | 88.6 Percentage of participants |
Secondary
Percent Change From Baseline in Absolute Lymphocyte Count
Baseline is defined as the result obtained on the date of randomization. If no result was obtained on the date of randomization, the last result prior to the date of randomization is used. Percent change from baseline at Day X is calculated by multiplying the following result by 100%: (Day X value - Baseline value)/Baseline value. The mean of this result for all analyzed patients is taken to get the mean percent change from baseline.
Time frame: Days 3, 5, 7, 10, 14, 28
Population: Full analysis set (as randomized).~Participants require a baseline and post-baseline result at the given timepoint to be included in the number analyzed for that timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acalabrutinib + BSC | Percent Change From Baseline in Absolute Lymphocyte Count | Day 3 | 31.74 Percent change | Standard Deviation 59.32 |
| Acalabrutinib + BSC | Percent Change From Baseline in Absolute Lymphocyte Count | Day 10 | 98.55 Percent change | Standard Deviation 113.66 |
| Acalabrutinib + BSC | Percent Change From Baseline in Absolute Lymphocyte Count | Day 5 | 55.79 Percent change | Standard Deviation 101.57 |
| Acalabrutinib + BSC | Percent Change From Baseline in Absolute Lymphocyte Count | Day 14 | 74.65 Percent change | Standard Deviation 124.47 |
| Acalabrutinib + BSC | Percent Change From Baseline in Absolute Lymphocyte Count | Day 10/ Discharge (last post-baseline assessment if discharged from hospital prior to Day 10) | 78.34 Percent change | Standard Deviation 95.88 |
| Acalabrutinib + BSC | Percent Change From Baseline in Absolute Lymphocyte Count | Day 28 | 89.35 Percent change | Standard Deviation 100.24 |
| Acalabrutinib + BSC | Percent Change From Baseline in Absolute Lymphocyte Count | Day 7 | 51.72 Percent change | Standard Deviation 91.82 |
| BSC Alone | Percent Change From Baseline in Absolute Lymphocyte Count | Day 28 | 96.62 Percent change | Standard Deviation 97.3 |
| BSC Alone | Percent Change From Baseline in Absolute Lymphocyte Count | Day 3 | 36.82 Percent change | Standard Deviation 79.91 |
| BSC Alone | Percent Change From Baseline in Absolute Lymphocyte Count | Day 5 | 87.25 Percent change | Standard Deviation 140.37 |
| BSC Alone | Percent Change From Baseline in Absolute Lymphocyte Count | Day 7 | 79.33 Percent change | Standard Deviation 119.73 |
| BSC Alone | Percent Change From Baseline in Absolute Lymphocyte Count | Day 10/ Discharge (last post-baseline assessment if discharged from hospital prior to Day 10) | 99.65 Percent change | Standard Deviation 149.02 |
| BSC Alone | Percent Change From Baseline in Absolute Lymphocyte Count | Day 10 | 83.08 Percent change | Standard Deviation 105.56 |
| BSC Alone | Percent Change From Baseline in Absolute Lymphocyte Count | Day 14 | 91.58 Percent change | Standard Deviation 123.63 |
Secondary
Percent Change From Baseline in C-reactive Protein.
Baseline is defined as the result obtained on the date of randomization. If no result was obtained on the date of randomization, the last result prior to the date of randomization is used. Percent change from baseline at Day X is calculated by multiplying the following result by 100%: (Day X value - Baseline value)/Baseline value. The mean of this result for all analyzed patients is taken to get the mean percent change from baseline.
Time frame: Days 3, 5, 7, 10, 14, 28
Population: Full analysis set (as randomized).~Participants require a baseline and post-baseline result at the given timepoint to be included in the number analyzed for that timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acalabrutinib + BSC | Percent Change From Baseline in C-reactive Protein. | Day 3 | -15.06 Percent change | Standard Deviation 95.82 |
| Acalabrutinib + BSC | Percent Change From Baseline in C-reactive Protein. | Day 10 | -35.53 Percent change | Standard Deviation 126.84 |
| Acalabrutinib + BSC | Percent Change From Baseline in C-reactive Protein. | Day 7 | -45.71 Percent change | Standard Deviation 106.84 |
| Acalabrutinib + BSC | Percent Change From Baseline in C-reactive Protein. | Day 14 | -12.49 Percent change | Standard Deviation 187.37 |
| Acalabrutinib + BSC | Percent Change From Baseline in C-reactive Protein. | Day 5 | -12.48 Percent change | Standard Deviation 113.38 |
| Acalabrutinib + BSC | Percent Change From Baseline in C-reactive Protein. | Day 28 | -30.28 Percent change | Standard Deviation 192.9 |
| Acalabrutinib + BSC | Percent Change From Baseline in C-reactive Protein. | Day 10/ Discharge (last post-baseline assessment if discharged from hospital prior to Day 10) | -16.84 Percent change | Standard Deviation 194.71 |
| BSC Alone | Percent Change From Baseline in C-reactive Protein. | Day 28 | -63.74 Percent change | Standard Deviation 75.28 |
| BSC Alone | Percent Change From Baseline in C-reactive Protein. | Day 5 | -41.07 Percent change | Standard Deviation 92.59 |
| BSC Alone | Percent Change From Baseline in C-reactive Protein. | Day 7 | -23.41 Percent change | Standard Deviation 223.06 |
| BSC Alone | Percent Change From Baseline in C-reactive Protein. | Day 10/ Discharge (last post-baseline assessment if discharged from hospital prior to Day 10) | -29.32 Percent change | Standard Deviation 166.35 |
| BSC Alone | Percent Change From Baseline in C-reactive Protein. | Day 10 | -23.41 Percent change | Standard Deviation 203.02 |
| BSC Alone | Percent Change From Baseline in C-reactive Protein. | Day 14 | -17.26 Percent change | Standard Deviation 256.87 |
| BSC Alone | Percent Change From Baseline in C-reactive Protein. | Day 3 | -15.25 Percent change | Standard Deviation 91.61 |
Secondary
Percent Change From Baseline in Ferritin
Baseline is defined as the result obtained on the date of randomization. If no result was obtained on the date of randomization, the last result prior to the date of randomization is used. Percent change from baseline at Day X is calculated by multiplying the following result by 100%: (Day X value - Baseline value)/Baseline value. The mean of this result for all analyzed patients is taken to get the mean percent change from baseline.
Time frame: Days 3, 5, 7, 10, 14, 28
Population: Full analysis set (as randomized).~Participants require a baseline and post-baseline result at the given timepoint to be included in the number analyzed for that timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acalabrutinib + BSC | Percent Change From Baseline in Ferritin | Day 3 | 9.84 Percent change | Standard Deviation 92.66 |
| Acalabrutinib + BSC | Percent Change From Baseline in Ferritin | Day 10 | -5.99 Percent change | Standard Deviation 73.71 |
| Acalabrutinib + BSC | Percent Change From Baseline in Ferritin | Day 7 | -8.93 Percent change | Standard Deviation 53.52 |
| Acalabrutinib + BSC | Percent Change From Baseline in Ferritin | Day 14 | -18.81 Percent change | Standard Deviation 67.85 |
| Acalabrutinib + BSC | Percent Change From Baseline in Ferritin | Day 5 | 12.92 Percent change | Standard Deviation 105.09 |
| Acalabrutinib + BSC | Percent Change From Baseline in Ferritin | Day 28 | -66.82 Percent change | Standard Deviation 18.24 |
| Acalabrutinib + BSC | Percent Change From Baseline in Ferritin | Day 10/ Discharge (last post-baseline assessment if discharged from hospital prior to Day 10) | -9.09 Percent change | Standard Deviation 58.85 |
| BSC Alone | Percent Change From Baseline in Ferritin | Day 28 | -66.05 Percent change | Standard Deviation 21.67 |
| BSC Alone | Percent Change From Baseline in Ferritin | Day 3 | 6.49 Percent change | Standard Deviation 40.23 |
| BSC Alone | Percent Change From Baseline in Ferritin | Day 5 | -12.76 Percent change | Standard Deviation 43.18 |
| BSC Alone | Percent Change From Baseline in Ferritin | Day 7 | -8.79 Percent change | Standard Deviation 36.4 |
| BSC Alone | Percent Change From Baseline in Ferritin | Day 10/ Discharge (last post-baseline assessment if discharged from hospital prior to Day 10) | 1.35 Percent change | Standard Deviation 125.95 |
| BSC Alone | Percent Change From Baseline in Ferritin | Day 10 | 6.84 Percent change | Standard Deviation 178.23 |
| BSC Alone | Percent Change From Baseline in Ferritin | Day 14 | -26.80 Percent change | Standard Deviation 46.1 |
Secondary
Percent Change From Baseline in Oxygenation Index
Baseline is defined as the result obtained on the date of randomization. Percent change from baseline at Day X is calculated by multiplying the following result by 100%: (Day X value - Baseline value)/Baseline value. The mean of this result for all analyzed patients is taken to get the mean percent change from baseline.
Time frame: Days 3, 5, 7, 10, 14, 28
Population: Full analysis set (as randomized).~Participants require a baseline and post-baseline result at the given timepoint to be included in the number analyzed for that timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acalabrutinib + BSC | Percent Change From Baseline in Oxygenation Index | Day 3 | 11.65 Percent change | Standard Deviation 29.4 |
| Acalabrutinib + BSC | Percent Change From Baseline in Oxygenation Index | Day 14 | 70.39 Percent change | Standard Deviation 77.27 |
| Acalabrutinib + BSC | Percent Change From Baseline in Oxygenation Index | Day 5 | 23.94 Percent change | Standard Deviation 41.72 |
| Acalabrutinib + BSC | Percent Change From Baseline in Oxygenation Index | Day 28 | 80.93 Percent change | Standard Deviation 89.61 |
| Acalabrutinib + BSC | Percent Change From Baseline in Oxygenation Index | Day 7 | 30.58 Percent change | Standard Deviation 57.79 |
| Acalabrutinib + BSC | Percent Change From Baseline in Oxygenation Index | Day 10/ Discharge (last post-baseline assessment if discharged from hospital prior to Day 10) | 54.25 Percent change | Standard Deviation 71.71 |
| Acalabrutinib + BSC | Percent Change From Baseline in Oxygenation Index | Day 10 | 64.44 Percent change | Standard Deviation 84.02 |
| BSC Alone | Percent Change From Baseline in Oxygenation Index | Day 10 | 80.52 Percent change | Standard Deviation 101.48 |
| BSC Alone | Percent Change From Baseline in Oxygenation Index | Day 10/ Discharge (last post-baseline assessment if discharged from hospital prior to Day 10) | 62.10 Percent change | Standard Deviation 80.79 |
| BSC Alone | Percent Change From Baseline in Oxygenation Index | Day 14 | 83.71 Percent change | Standard Deviation 84.96 |
| BSC Alone | Percent Change From Baseline in Oxygenation Index | Day 28 | 90.68 Percent change | Standard Deviation 95.43 |
| BSC Alone | Percent Change From Baseline in Oxygenation Index | Day 3 | 12.20 Percent change | Standard Deviation 33.88 |
| BSC Alone | Percent Change From Baseline in Oxygenation Index | Day 7 | 54.51 Percent change | Standard Deviation 84.75 |
| BSC Alone | Percent Change From Baseline in Oxygenation Index | Day 5 | 33.09 Percent change | Standard Deviation 51.5 |
Secondary
Pharmacokinetics of Acalabrutinib
Summary of plasma concentrations (ng/mL) of acalabrutinib
Time frame: Day 3 and Day 7
Population: PK analysis set: all participants who received at least 1 dose of acalabrutinib and had at least 1 post-dose evaluable pharmacokinetic (PK) data point for acalabrutinib or ACP-5862.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Acalabrutinib + BSC | Pharmacokinetics of Acalabrutinib | Day 3, Pre-dose | 15.359 ng/mL | Geometric Coefficient of Variation 195.1 |
| Acalabrutinib + BSC | Pharmacokinetics of Acalabrutinib | Day 3, 0.5 hours post-dose | 54.580 ng/mL | Geometric Coefficient of Variation 139.7 |
| Acalabrutinib + BSC | Pharmacokinetics of Acalabrutinib | Day 3, 1 hour post-dose | 56.120 ng/mL | Geometric Coefficient of Variation 141.6 |
| Acalabrutinib + BSC | Pharmacokinetics of Acalabrutinib | Day 3, 2 hours post-dose | 90.173 ng/mL | Geometric Coefficient of Variation 104.3 |
| Acalabrutinib + BSC | Pharmacokinetics of Acalabrutinib | Day 3, 4 hours post-dose | 36.841 ng/mL | Geometric Coefficient of Variation 179.2 |
| Acalabrutinib + BSC | Pharmacokinetics of Acalabrutinib | Day 3, 6 hours post-dose | 23.551 ng/mL | Geometric Coefficient of Variation 205 |
| Acalabrutinib + BSC | Pharmacokinetics of Acalabrutinib | Day 7, 1 hour post-dose | 117.015 ng/mL | Geometric Coefficient of Variation 60.3 |
| Acalabrutinib + BSC | Pharmacokinetics of Acalabrutinib | Day 7, 4 hours post-dose | 17.454 ng/mL | Geometric Coefficient of Variation 108.6 |
Secondary
Pharmacokinetics of ACP-5862
Summary of plasma concentrations (ng/mL) of ACP-5862
Time frame: Day 3 and Day 7
Population: PK analysis set: all participants who received at least 1 dose of acalabrutinib and had at least 1 post-dose evaluable pharmacokinetic (PK) data point for acalabrutinib or ACP-5862.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Acalabrutinib + BSC | Pharmacokinetics of ACP-5862 | Day 3, Pre-dose | 71.526 ng/mL | Geometric Coefficient of Variation 94.8 |
| Acalabrutinib + BSC | Pharmacokinetics of ACP-5862 | Day 3, 0.5 hours post-dose | 125.332 ng/mL | Geometric Coefficient of Variation 109.9 |
| Acalabrutinib + BSC | Pharmacokinetics of ACP-5862 | Day 3, 1 hour post-dose | 144.784 ng/mL | Geometric Coefficient of Variation 95.1 |
| Acalabrutinib + BSC | Pharmacokinetics of ACP-5862 | Day 3, 2 hours post-dose | 213.370 ng/mL | Geometric Coefficient of Variation 72.7 |
| Acalabrutinib + BSC | Pharmacokinetics of ACP-5862 | Day 3, 4 hours post-dose | 154.437 ng/mL | Geometric Coefficient of Variation 70.3 |
| Acalabrutinib + BSC | Pharmacokinetics of ACP-5862 | Day 3, 6 hours post-dose | 113.769 ng/mL | Geometric Coefficient of Variation 82.8 |
| Acalabrutinib + BSC | Pharmacokinetics of ACP-5862 | Day 7, 1 hour post-dose | 156.133 ng/mL | Geometric Coefficient of Variation 68 |
| Acalabrutinib + BSC | Pharmacokinetics of ACP-5862 | Day 7, 4 hours post-dose | 95.392 ng/mL | Geometric Coefficient of Variation 69.7 |
Secondary
Time From Randomization to Clinical Improvement of at Least 2 Points on a 9-point Category Ordinal Scale
9-point category ordinal scale: 0. \* Uninfected, no clinical or virological evidence of infection 1. Ambulatory, no limitation of activities 2. Ambulatory, limitation of activities 3. Hospitalized - mild disease, no oxygen therapy 4. Hospitalized - mild disease, oxygen by mask or nasal prongs 5. Hospitalized - severe disease, non-invasive ventilation or high flow oxygen 6. Hospitalised - severe disease, intubation and mechanical ventilation 7. Hospitalized - severe disease, ventilation and additional organ support, such as pressors, renal replacement therapy, extracorporeal membrane oxygenation 8. Death Median time to first occurrence of respiratory failure or death, calculated using the Kaplan-Meier technique. Confidence interval for median overall survival (days) is derived based on Brookmeyer-Crowley method with log-log transformation.
Time frame: From randomization to 28 days after randomization.
Population: Full analysis set (as randomized).~Participants require a baseline and at least one post-baseline result to be included in the number analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acalabrutinib + BSC | Time From Randomization to Clinical Improvement of at Least 2 Points on a 9-point Category Ordinal Scale | 10.00 Days |
| BSC Alone | Time From Randomization to Clinical Improvement of at Least 2 Points on a 9-point Category Ordinal Scale | 10.00 Days |
95% CI: [0.69, 1.353]Regression, Cox
Secondary
Time From Randomization to First Occurrence of Respiratory Failure or Death on Study Due to Any Cause
Median time to first occurrence of respiratory failure or death, calculated using the Kaplan-Meier technique. Confidence interval for median overall survival (days) is derived based on Brookmeyer-Crowley method with log-log transformation.
Time frame: From randomization to 28 days after randomization.
Population: Full analysis set (as randomized).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acalabrutinib + BSC | Time From Randomization to First Occurrence of Respiratory Failure or Death on Study Due to Any Cause | NA Days |
| BSC Alone | Time From Randomization to First Occurrence of Respiratory Failure or Death on Study Due to Any Cause | NA Days |
95% CI: [0.323, 1.722]Regression, Cox