Acalabrutinib study with Best Supportive Care Versus Best Supportive Care in Subjects Hospitalized with COVID-19. - CALAVI US

Study identifier:D822FC00003

ClinicalTrials.gov identifier:NCT04380688

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A Phase 2, Open Label, Randomized Study of the Efficacy and Safety of Acalabrutinib with Best Supportive Care Versus Best Supportive Care in Subjects Hospitalized with COVID-19

Medical condition

COVID-19

Phase

Phase 2

Healthy volunteers

Study drug

Acalabrutinib

Sex

All

Actual Enrollment

Study type

Interventional

Age

18 Years - 130 Years

Date

Study Start Date: 13 Jun 2020

Primary Completion Date: 16 Nov 2020

Study Completion Date: 16 Nov 2020

Study design

Allocation: Randomized
Endpoint Classification: -
Intervention Model: Parallel Assignment
Masking: -
Primary Purpose: Treatment

Verification:

Verified 01 Sept 2022 by AstraZeneca

Collaborators

Acerta Pharma B.V.

Inclusion and exclusion criteria

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 criteria (including positive RT-PCR nucleic acid test)
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 the time of screening due to COVID-19 pneumonia that impedes the ability to swallow pills, or in the opinion of the treating physician, the subject is likely to require mechanical ventilation within the immediate 24 hours and therefore unable to swallow pills.
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), and/or aspartate aminotransferase (AST) and/or bilirubin ≥ 3x upper limit of normal (ULN) and/or severe hepatic impairment detected during the screening period (per local lab)
Exception: AST and/or ALT ≤5 × ULN if considered due to underlying COVID-19 disease, but cannot be associated with concurrent elevated bilirubin (≤2 × ULN).
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 7 days before first dose of study drug) or inducer (within 14 days before first dose of study drug).

Location

Research Site

Buffalo, NY, United States, 14263

Location

Research Site

Hackensack, NJ, United States, 07601

Location

Research Site

Baltimore, MD, United States, 21287

Location

Research Site

Louisville, KY, United States, 40207

Location

Research Site

Washington, DC, United States, 20010

Location

Research Site

Albany, NY, United States, 12208

Location

Research Site

Philadelphia, PA, United States, 19140

Location

Research Site

Newport Beach, CA, United States, 92663

Arms	Assigned Interventions
Experimental: Arm 1 Acalabrutinib+ Best Supportive Care	Drug: Acalabrutinib Acalabrutinib administered orally
No Intervention: Arm 2 Best Supportive Care	-

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
All participants were recruited from the United States and had COVID-19 pneumonia (documented radiographically) requiring hospitalization. The first participant was randomized on 13 June 2020 and the last participant was randomized on 20 August 2020.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Screening assessments were performed within the 3 days prior to randomization. Of 70 screened participants, 62 were enrolled. Of the 8 participants that were not enrolled, 7 were screen failures (did not meet eligibility criteria) and 1 withdrew consent.

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Participant Flow: Overall Study

	Acalabrutinib + BSC	BSC alone
STARTED	31	31
COMPLETED	24	22
NOT COMPLETED	7	9
Death	2	2
Lost to Follow-up	2	4
Withdrawal by Subject	3	3

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Baseline Measures

	Acalabrutinib + BSC	BSC alone	Total
Number of Participants [units: Participants]	31	31	62
Age Continuous [units: Years] Mean ± Standard Deviation	52.5 ± 13.3	51.9 ± 14.3	52.2 ± 13.7
Age, Customized [units: Participants]
< 65 years	26	25	51
>= 65 years	5	6	11
Sex: Female, Male [units: Participants]
MALE	18	22	40
FEMALE	13	9	22
Ethnicity (NIH/OMB) [units: Participants]
HISPANIC OR LATINO	15	13	28
NOT HISPANIC OR LATINO	16	17	33
NOT REPORTED	0	0	0
MISSING	0	1	1
Race (NIH/OMB) [units: Participants]
WHITE	18	20	38
BLACK OR AFRICAN AMERICAN	7	5	12
AMERICAN INDIAN OR ALASKA NATIVE	1	0	1
ASIAN	0	0	0
NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER	0	0	0
OTHER	3	2	5
NOT REPORTED	2	3	5
MISSING	0	1	1

Outcome Measures

1. Primary Outcome Measure: 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) ]

Measure Type	Primary
Measure Name	Number of participants with Adverse Events and Serious Adverse Events
Measure Description
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)
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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 (32) is greater than the number of participants randomized to this group (31) because one participant randomized to Acalabrutinib + BSC did not receive any acalabrutinib and therefore is included in the BSC alone group for the safety analysis set.

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.

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 (32) is greater than the number of participants randomized to this group (31) because one participant randomized to Acalabrutinib + BSC did not receive any acalabrutinib and therefore is included in the BSC alone group for the safety analysis set.

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Measured Values

	Acalabrutinib + BSC	BSC alone
Number of Participants Analyzed [units:participants]	30	32
Number of participants with Adverse Events and Serious Adverse Events [units: Participants]
Any Adverse Event	17	15
Any Serious Adverse Event	4	6

No statistical analysis provided for Number of participants with Adverse Events and Serious Adverse Events

2. Primary Outcome Measure: Percentage of participants alive and free of respiratory failure at Day 28 [ Time Frame: At Day 28 ]

Measure Type	Primary
Measure Name	Percentage of participants alive and free of respiratory failure at Day 28
Measure Description	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) Noninvasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation
Time Frame	At Day 28
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set (as randomized).

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Measured Values

	Acalabrutinib + BSC	BSC alone
Number of Participants Analyzed [units:participants]	31	31
Percentage of participants alive and free of respiratory failure at Day 28 [units: Percentage of participants] Number (90% Confidence Interval)	80.6 (67.4 to 93.9)	83.9 (71.4 to 96.3)

No statistical analysis provided for Percentage of participants alive and free of respiratory failure at Day 28

3. Secondary Outcome Measure: Percentage of participants alive and free of respiratory failure at Day 14 [ Time Frame: At Day 14 ]

Measure Type	Secondary
Measure Name	Percentage of participants alive and free of respiratory failure at Day 14
Measure Description	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) Noninvasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation
Time Frame	At Day 14
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set (as randomized).

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Measured Values

	Acalabrutinib + BSC	BSC alone
Number of Participants Analyzed [units:participants]	31	31
Percentage of participants alive and free of respiratory failure at Day 14 [units: Percentage of participants] Number (90% Confidence Interval)	80.6 (67.4 to 93.9)	87.1 (75.6 to 98.6)

No statistical analysis provided for Percentage of participants alive and free of respiratory failure at Day 14

4. Secondary Outcome Measure: Percent change from baseline in C-reactive protein. [ Time Frame: Days 3, 5, 7, 10, 14, 28 ]

Measure Type	Secondary
Measure Name	Percent change from baseline in C-reactive protein.
Measure Description	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
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Measured Values

	Acalabrutinib + BSC	BSC alone
Number of Participants Analyzed [units:participants]	31	31
Percent change from baseline in C-reactive protein. [units: Percent change] Mean (Standard Deviation)
Day 3	-41.08 (71.27)	-26.74 (69.02)
Day 5	-72.05 (26.29)	-49.55 (54.97)
Day 7	-75.72 (29.48)	-40.53 (75.99)
Day 10/ Discharge (last post-baseline assessment if discharged from hospital prior to Day 10)	-73.85 (27.92)	9.23 (354.21)
Day 10	-73.23 (29.34)	212.22 (710.39)
Day 14	-56.62 (97.54)	-56.61 (59.19)
Day 28	-66.89 (73.45)	-39.63 (161.97)

No statistical analysis provided for Percent change from baseline in C-reactive protein.

5. Secondary Outcome Measure: Percent change from baseline in ferritin [ Time Frame: Days 3, 5, 7, 10, 14, 28 ]

Measure Type	Secondary
Measure Name	Percent change from baseline in ferritin
Measure Description	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
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Measured Values

	Acalabrutinib + BSC	BSC alone
Number of Participants Analyzed [units:participants]	31	31
Percent change from baseline in ferritin [units: Percent change] Mean (Standard Deviation)
Day 3	-15.25 (21.87)	-7.38 (31.17)
Day 5	-29.67 (25.79)	-17.93 (36.74)
Day 7	-36.59 (22.78)	-9.67 (45.84)
Day 10/ Discharge (last post-baseline assessment if discharged from hospital prior to Day 10)	-24.48 (31.30)	-20.38 (28.00)
Day 10	-47.58 (31.60)	-1.24 (34.52)
Day 14	-45.25 (23.09)	-40.20 (26.81)
Day 28	-62.28 (37.27)	-63.69 (16.43)

No statistical analysis provided for Percent change from baseline in ferritin

6. Secondary Outcome Measure: Percent change from baseline in absolute lymphocyte count [ Time Frame: Days 3, 5, 7, 10, 14, 28 ]

Measure Type	Secondary
Measure Name	Percent change from baseline in absolute lymphocyte count
Measure Description	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
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Measured Values

	Acalabrutinib + BSC	BSC alone
Number of Participants Analyzed [units:participants]	31	31
Percent change from baseline in absolute lymphocyte count [units: Percent change] Mean (Standard Deviation)
Day 3	54.75 (92.83)	34.66 (61.47)
Day 5	28.18 (64.35)	76.86 (63.02)
Day 7	46.22 (72.11)	102.80 (107.71)
Day 10/ Discharge (last post-baseline assessment if discharged from hospital prior to Day 10)	100.79 (142.10)	97.45 (92.75)
Day 10	67.41 (73.04)	118.26 (66.81)
Day 14	108.55 (110.73)	106.85 (103.52)
Day 28	135.30 (88.00)	127.09 (136.57)

No statistical analysis provided for Percent change from baseline in absolute lymphocyte count

7. Secondary Outcome Measure: Overall Survival [ Time Frame: From randomization until 90 days after randomization. ]

Measure Type	Secondary
Measure Name	Overall Survival
Measure Description	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 Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set (as randomized).

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Measured Values

	Acalabrutinib + BSC	BSC alone
Number of Participants Analyzed [units:participants]	31	31
Overall Survival [units: Days] Median (90% Confidence Interval)	NA (NA to NA) ^[1]	NA (NA to NA) ^[1]

No statistical analysis provided for Overall Survival

8. Secondary Outcome Measure: Percentage of participants alive and discharged from ICU [ Time Frame: At Day 14 and at Day 28 ]

Measure Type	Secondary
Measure Name	Percentage of participants alive and discharged from ICU
Measure Description
Time Frame	At Day 14 and at Day 28
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set (as randomized).

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Measured Values

	Acalabrutinib + BSC	BSC alone
Number of Participants Analyzed [units:participants]	31	31
Percentage of participants alive and discharged from ICU [units: Percentage of participants]
At Day 14	83.9	87.1
At Day 28	83.9	87.1

No statistical analysis provided for Percentage of participants alive and discharged from ICU

9. Secondary Outcome Measure: Time from randomization to first occurrence of respiratory failure or death on study due to any cause [ Time Frame: From randomization to 28 days after randomization. ]

Measure Type	Secondary
Measure Name	Time from randomization to first occurrence of respiratory failure or death on study due to any cause
Measure Description	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.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set (as randomized).

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Measured Values

	Acalabrutinib + BSC	BSC alone
Number of Participants Analyzed [units:participants]	31	31
Time from randomization to first occurrence of respiratory failure or death on study due to any cause [units: Days] Median (90% Confidence Interval)	NA (NA to NA) ^[1]	NA (NA to NA) ^[1]

Statistical Analysis 1 for Time from randomization to first occurrence of respiratory failure or death on study due to any cause

Groups^[1]	All groups
Method^[3]	Regression, Cox
Hazard Ratio (HR)^[5]	0.553
90% Confidence Interval	( 0.145 to 1.952 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Adjusting for age (<65 vs >=65 years) and comorbidities (present vs absent). Ties handled by Efron approach. HR CI using profile likelihood approach.
[5]	Other relevant estimation information:
	No text entered.

10. Secondary Outcome Measure: Number of days alive and free of respiratory failure [ Time Frame: From randomization to 28 days after randomization. ]

Measure Type	Secondary
Measure Name	Number of days alive and free of respiratory failure
Measure Description	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) Noninvasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation
Time Frame	From randomization to 28 days after randomization.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set (as randomized).

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Measured Values

	Acalabrutinib + BSC	BSC alone
Number of Participants Analyzed [units:participants]	31	31
Number of days alive and free of respiratory failure [units: Days] Mean (Standard Deviation)	26.2 (6.7)	24.6 (7.3)

No statistical analysis provided for Number of days alive and free of respiratory failure

11. Secondary Outcome Measure: Number of days with respiratory failure [ Time Frame: From randomization to 28 days after randomization. ]

Measure Type	Secondary
Measure Name	Number of days with respiratory failure
Measure Description	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) Noninvasive 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.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set (as randomized).

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Measured Values

	Acalabrutinib + BSC	BSC alone
Number of Participants Analyzed [units:participants]	31	31
Number of days with respiratory failure [units: Days] Mean (Standard Deviation)	1.8 (6.7)	3.4 (7.3)

No statistical analysis provided for Number of days with respiratory failure

12. Secondary Outcome Measure: Number of days hospitalized [ Time Frame: From randomization to 28 days after randomization. ]

Measure Type	Secondary
Measure Name	Number of days hospitalized
Measure Description	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.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set (as randomized).

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Measured Values

	Acalabrutinib + BSC	BSC alone
Number of Participants Analyzed [units:participants]	31	31
Number of days hospitalized [units: Days] Mean (Standard Deviation)	7.6 (7.3)	9.0 (8.5)

No statistical analysis provided for Number of days hospitalized

13. Secondary Outcome Measure: Number of days in ICU [ Time Frame: From randomization to 90 days after randomization. ]

Measure Type	Secondary
Measure Name	Number of days in ICU
Measure Description	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.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set (as randomized).

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Measured Values

	Acalabrutinib + BSC	BSC alone
Number of Participants Analyzed [units:participants]	31	31
Number of days in ICU [units: Days] Mean (Standard Deviation)	4.4 (17.1)	7.0 (20.8)

No statistical analysis provided for Number of days in ICU

14. Secondary Outcome Measure: Number of days alive outside of hospital [ Time Frame: From randomization to 28 days after randomization. ]

Measure Type	Secondary
Measure Name	Number of days alive outside of hospital
Measure Description
Time Frame	From randomization to 28 days after randomization.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set (as randomized).

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Measured Values

	Acalabrutinib + BSC	BSC alone
Number of Participants Analyzed [units:participants]	31	31
Number of days alive outside of hospital [units: Days] Mean (Standard Deviation)	20.2 (7.3)	18.9 (8.6)

No statistical analysis provided for Number of days alive outside of hospital

15. Secondary Outcome Measure: Number of days alive outside of hospital [ Time Frame: From randomization to 90 days after randomization. ]

Measure Type	Secondary
Measure Name	Number of days alive outside of hospital
Measure Description
Time Frame	From randomization to 90 days after randomization.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set (as randomized).

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Measured Values

	Acalabrutinib + BSC	BSC alone
Number of Participants Analyzed [units:participants]	31	31
Number of days alive outside of hospital [units: Days] Mean (Standard Deviation)	75.3 (25.2)	72.7 (25.0)

No statistical analysis provided for Number of days alive outside of hospital

16. Secondary Outcome Measure: Percent change from baseline in oxygenation index [ Time Frame: Days 3, 5, 7, 10, 14, 28 ]

Measure Type	Secondary
Measure Name	Percent change from baseline in oxygenation index
Measure Description	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
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Measured Values

	Acalabrutinib + BSC	BSC alone
Number of Participants Analyzed [units:participants]	31	31
Percent change from baseline in oxygenation index [units: Percent change] Mean (Standard Deviation)
Day 3	14.24 (43.64)	13.51 (30.67)
Day 5	40.25 (74.37)	18.71 (32.17)
Day 7	18.41 (26.19)	28.73 (31.15)
Day 10/ Discharge (last post-baseline assessment if discharged from hospital prior to Day 10)	32.37 (66.33)	36.67 (39.33)
Day 10	-23.81 (27.53)	33.09 (50.42)
Day 14	54.87 (84.54)	59.22 (43.22)
Day 28	48.87 (51.77)	65.59 (50.76)

No statistical analysis provided for Percent change from baseline in oxygenation index

17. Secondary Outcome Measure: Time from randomization to clinical improvement of at least 2 points on a 9-point category ordinal scale [ Time Frame: From randomization to 28 days after randomization. ]

Measure Type	Secondary
Measure Name	Time from randomization to clinical improvement of at least 2 points on a 9-point category ordinal scale
Measure Description	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.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set (as randomized). Participants require a baseline and at least one post-baseline result to be included in the number analyzed.

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Measured Values

	Acalabrutinib + BSC	BSC alone
Number of Participants Analyzed [units:participants]	31	29
Time from randomization to clinical improvement of at least 2 points on a 9-point category ordinal scale [units: Days] Median (90% Confidence Interval)	6.00 (5.00 to 7.00)	7.00 (5.00 to 11.00)

Statistical Analysis 1 for Time from randomization to clinical improvement of at least 2 points on a 9-point category ordinal scale

Groups^[1]	All groups
Method^[3]	Regression, Cox
Hazard Ratio (HR)^[5]	1.314
90% Confidence Interval	( 0.794 to 2.183 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Adjusting for age (<65 vs >=65 years) and comorbidities (present vs absent). Ties handled by Efron approach. HR CI using profile likelihood approach.
[5]	Other relevant estimation information:
	No text entered.

18. Secondary Outcome Measure: Pharmacokinetics of acalabrutinib [ Time Frame: Day 3 and Day 7 ]

Measure Type	Secondary
Measure Name	Pharmacokinetics of acalabrutinib
Measure Description	Summary of plasma concentrations (ng/mL) of acalabrutinib
Time Frame	Day 3 and Day 7
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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.

Measured Values

	Acalabrutinib + BSC
Number of Participants Analyzed [units:participants]	30
Pharmacokinetics of acalabrutinib [units: ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Day 3, Pre-dose	6.258 (248%)
Day 3, 0.5 hours post-dose	26.683 (173%)
Day 3, 1 hour post-dose	210.858 (71.5%)
Day 3, 2 hours post-dose	124.143 (89.2%)
Day 3, 4 hours post-dose	33.714 (93.4%)
Day 7, 1 hour post-dose	165.080 (NA%)^[1]
Day 7, 2 hours post-dose
Day 7, 4 hours post-dose	14.320 (NA%)^[1]

No statistical analysis provided for Pharmacokinetics of acalabrutinib

19. Secondary Outcome Measure: Pharmacokinetics of ACP-5862 [ Time Frame: Day 3 and Day 7 ]

Measure Type	Secondary
Measure Name	Pharmacokinetics of ACP-5862
Measure Description	Summary of plasma concentrations (ng/mL) of ACP-5862
Time Frame	Day 3 and Day 7
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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.

Measured Values

	Acalabrutinib + BSC
Number of Participants Analyzed [units:participants]	30
Pharmacokinetics of ACP-5862 [units: ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Day 3, Pre-dose	53.818 (140%)
Day 3, 0.5 hours post-dose	58.959 (129%)
Day 3, 1 hour post-dose	293.606 (68.1%)
Day 3, 2 hours post-dose	273.528 (50.2%)
Day 3, 4 hours post-dose	178.575 (44.2%)
Day 7, 1 hour post-dose	582.180 (NA%)^[1]
Day 7, 2 hours post-dose
Day 7, 4 hours post-dose	139.560 (NA%)^[1]

No statistical analysis provided for Pharmacokinetics of ACP-5862

Serious Adverse Events

Time Frame	Screening to 28 (+3) days after last dose of acalabrutinib (for acalabrutinib + BSC treated participants) or to 38 (+3) days after randomization (for BSC alone treated participants)
Additional Description	Population summarized is the safety analysis set (treatment actually received): All participants who received at least 1 dose of acalabrutinib were included in Acalabrutinib + BSC arm, and patients who did not receive any acalabrutinib were included in BSC alone arm.

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Serious Adverse Events

Acalabrutinib + BSC

BSC alone

Total, serious adverse events

# participants affected / at risk

4/30 (13.33%)

6/32 (18.75%)

Gastrointestinal disorders

Rectal haemorrhage¹,^†

# participants affected / at risk

1/30 (3.33%)

0/32 (0.00%)

# events

Gastrointestinal disorders

Retroperitoneal haematoma¹,^†

# participants affected / at risk

1/30 (3.33%)

0/32 (0.00%)

# events

Hepatobiliary disorders

Hepatotoxicity¹,^†

# participants affected / at risk

1/30 (3.33%)

0/32 (0.00%)

# events

Hepatobiliary disorders

Portal vein thrombosis¹,^†

# participants affected / at risk

0/30 (0.00%)

1/32 (3.13%)

# events

Infections and infestations

Pneumonia cytomegaloviral¹,^†

# participants affected / at risk

1/30 (3.33%)

0/32 (0.00%)

# events

Infections and infestations

Staphylococcal sepsis¹,^†

# participants affected / at risk

0/30 (0.00%)

1/32 (3.13%)

# events

Infections and infestations

Urinary tract infection¹,^†

# participants affected / at risk

0/30 (0.00%)

2/32 (6.25%)

# events

Investigations

Haemoglobin decreased¹,^†

# participants affected / at risk

0/30 (0.00%)

1/32 (3.13%)

# events

Renal and urinary disorders

Chronic kidney disease¹,^†

# participants affected / at risk

1/30 (3.33%)

0/32 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disease¹,^†

# participants affected / at risk

0/30 (0.00%)

1/32 (3.13%)

# events

Respiratory, thoracic and mediastinal disorders

Pulmonary embolism¹,^†

# participants affected / at risk

0/30 (0.00%)

1/32 (3.13%)

# events

Respiratory, thoracic and mediastinal disorders

Respiratory failure¹,^†

# participants affected / at risk

0/30 (0.00%)

1/32 (3.13%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA

Other Adverse Events

Time Frame	Screening to 28 (+3) days after last dose of acalabrutinib (for acalabrutinib + BSC treated participants) or to 38 (+3) days after randomization (for BSC alone treated participants)
Additional Description	Population summarized is the safety analysis set (treatment actually received): All participants who received at least 1 dose of acalabrutinib were included in Acalabrutinib + BSC arm, and patients who did not receive any acalabrutinib were included in BSC alone arm.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
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.
BSC alone	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

Other Adverse Events

Acalabrutinib + BSC

BSC alone

Total, other (not including serious) adverse events

# participants affected / at risk

5/30 (16.67%)

3/32 (9.38%)

Nervous system disorders

Headache¹,^†

# participants affected / at risk

4/30 (13.33%)

0/32 (0.00%)

# events

Psychiatric disorders

Insomnia¹,^†

# participants affected / at risk

1/30 (3.33%)

3/32 (9.38%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: PI shall provide copies of any materials relating to the Study, or the Developed Technologies that either intends to publish or make any presentations relating to, at least 30 days in advance of publication, submission or presentation. PI shall not include in or shall remove from any proposed publication of any Confidential Information, errors or inaccuracies; and shall withhold publication, submission for publication or presentation for 90 days from the date the Company receives the material.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data

Improvements in BSC (use of corticosteroids and antivirals) have led to a substantial reduction in mortality and morbidity in patients hospitalized with COVID-19, which, in turn, minimizes the impact that additional treatment regimens can have on patient prognosis and recovery. In addition, variability in patient population and the performance of BSC across the globe poses challenges to demonstrate benefit.

Results Point of Contact

Name/Title:	Study Information Center
Organization:	AstraZeneca
Phone	1-877-240-9479
E-mail:	[email protected]

Documents available

Redacted CSP
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CSR Synopsis
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deid_ae_aedata.csv
Download
deid_ae_saedata.csv
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deid_icoda_covar.csv
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deid_icoda_main.csv
Download
deid_coda_sub_all.csv
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deid_icoda_sub_base.csv
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deid_icoda_sub_demo.csv
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deid_icoda_ti.csv
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deid_icoda_ts.csv
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deid_mh_mhdata.csv
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Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

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CSR Synopsis

deid_ae_aedata.csv

deid_ae_saedata.csv

deid_icoda_covar.csv

deid_icoda_main.csv

deid_coda_sub_all.csv

deid_icoda_sub_base.csv

deid_icoda_sub_demo.csv

deid_icoda_ti.csv

deid_icoda_ts.csv

deid_mh_mhdata.csv

Trial Results Summaries

https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217111&parentIdentifier=D822FC00003&attachmentIdentifier=78253301-fe32-48e6-9d6a-56c0d83a543f&fileName=d822fc00003_SAP_redacted.pdf&versionIdentifier=