Acalabrutinib Study With Best Supportive Care Versus Best Supportive Care in Subjects Hospitalized With COVID-19. (CALAVI US)

• ClinicalTrials.gov Identifier: NCT04380688
• Recruitment Status: Completed
• First Posted: May 8, 2020
• Results First Posted: September 13, 2021
• Last Update Posted: September 13, 2021
• Sponsor: AstraZeneca
• Collaborator: Acerta Pharma BV
• Information provided by (Responsible Party): AstraZeneca

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: COVID-19
• Intervention: Drug: Acalabrutinib
• Enrollment: 62

Participant Flow

Recruitment Details	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	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.

Arm/Group Title	Acalabrutinib + BSC	BSC Alone
Arm/Group Description	Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.
Period Title: Overall Study
Started	31	31
Completed	24	22
Not Completed	7	9
Reason Not Completed
Death	2	2
Lost to Follow-up	2	4
Withdrawal by Subject	3	3

Baseline Characteristics

Arm/Group Title		Acalabrutinib + BSC	BSC Alone	Total
Arm/Group Description		Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.	Total of all reporting groups
Overall Number of Baseline Participants		31	31	62
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	31 participants	31 participants	62 participants
		52.5 (13.3)	51.9 (14.3)	52.2 (13.7)
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	31 participants	31 participants	62 participants
< 65 years		26	25	51
>= 65 years		5	6	11
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	31 participants	31 participants	62 participants
	Female	13 41.9%	9 29.0%	22 35.5%
	Male	18 58.1%	22 71.0%	40 64.5%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	31 participants	31 participants	62 participants
HISPANIC OR LATINO		15	13	28
NOT HISPANIC OR LATINO		16	17	33
NOT REPORTED		0	0	0
MISSING		0	1	1
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	31 participants	31 participants	62 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

Title	Number of Participants With Adverse Events and Serious Adverse Events
Description	[Not Specified]
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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Acalabrutinib + BSC	BSC Alone
Arm/Group Description:	Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.
Overall Number of Participants Analyzed	30	32
Measure Type: Count of Participants; Unit of Measure: Participants
Any Adverse Event	17 56.7%	15 46.9%
Any Serious Adverse Event	4 13.3%	6 18.8%

2. Primary Outcome

Title	Percentage of Participants Alive and Free of Respiratory Failure at Day 28
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

Outcome Measure Data

Analysis Population Description

Full analysis set (as randomized).

Arm/Group Title	Acalabrutinib + BSC	BSC Alone
Arm/Group Description:	Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.
Overall Number of Participants Analyzed	31	31
Measure Type: Number; Number (90% Confidence Interval); Unit of Measure: Percentage of participants
	80.6; (67.4 to 93.9)	83.9; (71.4 to 96.3)

3. Secondary Outcome

Title	Percentage of Participants Alive and Free of Respiratory Failure at Day 14
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

Outcome Measure Data

Analysis Population Description

Full analysis set (as randomized).

Arm/Group Title	Acalabrutinib + BSC	BSC Alone
Arm/Group Description:	Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.
Overall Number of Participants Analyzed	31	31
Measure Type: Number; Number (90% Confidence Interval); Unit of Measure: Percentage of participants
	80.6; (67.4 to 93.9)	87.1; (75.6 to 98.6)

4. Secondary Outcome

Title	Percent Change From Baseline in C-reactive Protein.
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

Outcome Measure Data

Analysis Population Description

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/Group Title		Acalabrutinib + BSC	BSC Alone
Arm/Group Description:		Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.
Overall Number of Participants Analyzed		31	31
Mean (Standard Deviation); Unit of Measure: Percent change
Day 3	Number Analyzed	27 participants	24 participants
		-41.08 (71.27)	-26.74 (69.02)
Day 5	Number Analyzed	18 participants	18 participants
		-72.05 (26.29)	-49.55 (54.97)
Day 7	Number Analyzed	11 participants	12 participants
		-75.72 (29.48)	-40.53 (75.99)
Day 10/ Discharge (last post-baseline assessment if discharged from hospital prior to Day 10)	Number Analyzed	30 participants	29 participants
		-73.85 (27.92)	9.23 (354.21)
Day 10	Number Analyzed	5 participants	7 participants
		-73.23 (29.34)	212.22 (710.39)
Day 14	Number Analyzed	21 participants	19 participants
		-56.62 (97.54)	-56.61 (59.19)
Day 28	Number Analyzed	19 participants	14 participants
		-66.89 (73.45)	-39.63 (161.97)

5. Secondary Outcome

Title	Percent Change From Baseline in Ferritin
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

Outcome Measure Data

Analysis Population Description

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/Group Title		Acalabrutinib + BSC	BSC Alone
Arm/Group Description:		Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.
Overall Number of Participants Analyzed		31	31
Mean (Standard Deviation); Unit of Measure: Percent change
Day 3	Number Analyzed	25 participants	19 participants
		-15.25 (21.87)	-7.38 (31.17)
Day 5	Number Analyzed	14 participants	12 participants
		-29.67 (25.79)	-17.93 (36.74)
Day 7	Number Analyzed	10 participants	8 participants
		-36.59 (22.78)	-9.67 (45.84)
Day 10/ Discharge (last post-baseline assessment if discharged from hospital prior to Day 10)	Number Analyzed	29 participants	25 participants
		-24.48 (31.30)	-20.38 (28.00)
Day 10	Number Analyzed	4 participants	7 participants
		-47.58 (31.60)	-1.24 (34.52)
Day 14	Number Analyzed	19 participants	18 participants
		-45.25 (23.09)	-40.20 (26.81)
Day 28	Number Analyzed	18 participants	15 participants
		-62.28 (37.27)	-63.69 (16.43)

6. Secondary Outcome

Title	Percent Change From Baseline in Absolute Lymphocyte Count
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

Outcome Measure Data

Analysis Population Description

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/Group Title		Acalabrutinib + BSC	BSC Alone
Arm/Group Description:		Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.
Overall Number of Participants Analyzed		31	31
Mean (Standard Deviation); Unit of Measure: Percent change
Day 3	Number Analyzed	17 participants	17 participants
		54.75 (92.83)	34.66 (61.47)
Day 5	Number Analyzed	9 participants	12 participants
		28.18 (64.35)	76.86 (63.02)
Day 7	Number Analyzed	6 participants	9 participants
		46.22 (72.11)	102.80 (107.71)
Day 10/ Discharge (last post-baseline assessment if discharged from hospital prior to Day 10)	Number Analyzed	19 participants	20 participants
		100.79 (142.10)	97.45 (92.75)
Day 10	Number Analyzed	3 participants	6 participants
		67.41 (73.04)	118.26 (66.81)
Day 14	Number Analyzed	14 participants	13 participants
		108.55 (110.73)	106.85 (103.52)
Day 28	Number Analyzed	11 participants	11 participants
		135.30 (88.00)	127.09 (136.57)

7. Secondary Outcome

Title	Overall Survival
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.

Outcome Measure Data

Analysis Population Description

Full analysis set (as randomized).

Arm/Group Title	Acalabrutinib + BSC	BSC Alone
Arm/Group Description:	Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.
Overall Number of Participants Analyzed	31	31
Median (90% Confidence Interval); Unit of Measure: Days
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

The median and lower and upper limit of the 95% confidence interval (CI) could not be calculated as there were an insufficient number of participants with events.

8. Secondary Outcome

Title	Percentage of Participants Alive and Discharged From ICU
Description	[Not Specified]
Time Frame	At Day 14 and at Day 28

Outcome Measure Data

Analysis Population Description

Full analysis set (as randomized).

Arm/Group Title	Acalabrutinib + BSC	BSC Alone
Arm/Group Description:	Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.
Overall Number of Participants Analyzed	31	31
Measure Type: Number; Unit of Measure: Percentage of participants
At Day 14	83.9	87.1
At Day 28	83.9	87.1

9. Secondary Outcome

Title	Time From Randomization to First Occurrence of Respiratory Failure or Death on Study Due to Any Cause
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.

Outcome Measure Data

Analysis Population Description

Full analysis set (as randomized).

Arm/Group Title	Acalabrutinib + BSC	BSC Alone
Arm/Group Description:	Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.
Overall Number of Participants Analyzed	31	31
Median (90% Confidence Interval); Unit of Measure: Days
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

The median and lower and upper limit of the 95% confidence interval (CI) could not be calculated as there were an insufficient number of participants with events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acalabrutinib + BSC, BSC Alone
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	No formal hypothesis testing for this endpoint.
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	P-value not generated.
	Method	Regression, Cox
	Comments	Adjusting for age (<65 vs >=65 years) and comorbidities (present vs absent). Ties handled by Efron approach. HR CI using profile likelihood approach.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.553
	Confidence Interval	(2-Sided) 90%; 0.145 to 1.952
	Estimation Comments	[Not Specified]

10. Secondary Outcome

Title	Number of Days Alive and Free of Respiratory Failure
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.

Outcome Measure Data

Analysis Population Description

Full analysis set (as randomized).

Arm/Group Title	Acalabrutinib + BSC	BSC Alone
Arm/Group Description:	Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.
Overall Number of Participants Analyzed	31	31
Mean (Standard Deviation); Unit of Measure: Days
	26.2 (6.7)	24.6 (7.3)

11. Secondary Outcome

Title	Number of Days With Respiratory Failure
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.

Outcome Measure Data

Analysis Population Description

Full analysis set (as randomized).

Arm/Group Title	Acalabrutinib + BSC	BSC Alone
Arm/Group Description:	Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.
Overall Number of Participants Analyzed	31	31
Mean (Standard Deviation); Unit of Measure: Days
	1.8 (6.7)	3.4 (7.3)

12. Secondary Outcome

Title	Number of Days Hospitalized
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.

Outcome Measure Data

Analysis Population Description

Full analysis set (as randomized).

Arm/Group Title	Acalabrutinib + BSC	BSC Alone
Arm/Group Description:	Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.
Overall Number of Participants Analyzed	31	31
Mean (Standard Deviation); Unit of Measure: Days
	7.6 (7.3)	9.0 (8.5)

13. Secondary Outcome

Title	Number of Days in ICU
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.

Outcome Measure Data

Analysis Population Description

Full analysis set (as randomized).

Arm/Group Title	Acalabrutinib + BSC	BSC Alone
Arm/Group Description:	Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.
Overall Number of Participants Analyzed	31	31
Mean (Standard Deviation); Unit of Measure: Days
	4.4 (17.1)	7.0 (20.8)

14. Secondary Outcome

Title	Number of Days Alive Outside of Hospital
Description	[Not Specified]
Time Frame	From randomization to 28 days after randomization.

Outcome Measure Data

Analysis Population Description

Full analysis set (as randomized).

Arm/Group Title	Acalabrutinib + BSC	BSC Alone
Arm/Group Description:	Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.
Overall Number of Participants Analyzed	31	31
Mean (Standard Deviation); Unit of Measure: Days
	20.2 (7.3)	18.9 (8.6)

15. Secondary Outcome

Title	Number of Days Alive Outside of Hospital
Description	[Not Specified]
Time Frame	From randomization to 90 days after randomization.

Outcome Measure Data

Analysis Population Description

Full analysis set (as randomized).

Arm/Group Title	Acalabrutinib + BSC	BSC Alone
Arm/Group Description:	Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.
Overall Number of Participants Analyzed	31	31
Mean (Standard Deviation); Unit of Measure: Days
	75.3 (25.2)	72.7 (25.0)

16. Secondary Outcome

Title	Percent Change From Baseline in Oxygenation Index
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

Outcome Measure Data

Analysis Population Description

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/Group Title		Acalabrutinib + BSC	BSC Alone
Arm/Group Description:		Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.
Overall Number of Participants Analyzed		31	31
Mean (Standard Deviation); Unit of Measure: Percent change
Day 3	Number Analyzed	28 participants	26 participants
		14.24 (43.64)	13.51 (30.67)
Day 5	Number Analyzed	16 participants	18 participants
		40.25 (74.37)	18.71 (32.17)
Day 7	Number Analyzed	12 participants	12 participants
		18.41 (26.19)	28.73 (31.15)
Day 10/ Discharge (last post-baseline assessment if discharged from hospital prior to Day 10)	Number Analyzed	30 participants	30 participants
		32.37 (66.33)	36.67 (39.33)
Day 10	Number Analyzed	4 participants	9 participants
		-23.81 (27.53)	33.09 (50.42)
Day 14	Number Analyzed	19 participants	18 participants
		54.87 (84.54)	59.22 (43.22)
Day 28	Number Analyzed	18 participants	18 participants
		48.87 (51.77)	65.59 (50.76)

17. Secondary Outcome

Title	Time From Randomization to Clinical Improvement of at Least 2 Points on a 9-point Category Ordinal Scale
Description	9-point category ordinal scale: 0. * Uninfected, no clinical or virological evidence of infection; Ambulatory, no limitation of activities; Ambulatory, limitation of activities; Hospitalized - mild disease, no oxygen therapy; Hospitalized - mild disease, oxygen by mask or nasal prongs; Hospitalized - severe disease, non-invasive ventilation or high flow oxygen; Hospitalised - severe disease, intubation and mechanical ventilation; Hospitalized - severe disease, ventilation and additional organ support, such as pressors, renal replacement therapy, extracorporeal membrane oxygenation; 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.

Outcome Measure Data

Analysis Population Description

Full analysis set (as randomized).

Participants require a baseline and at least one post-baseline result to be included in the number analyzed.

Arm/Group Title	Acalabrutinib + BSC	BSC Alone
Arm/Group Description:	Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.	Participants received best supportive care per the discretion of the Investigator and institutional guidelines.
Overall Number of Participants Analyzed	31	29
Median (90% Confidence Interval); Unit of Measure: Days
	6.00; (5.00 to 7.00)	7.00; (5.00 to 11.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acalabrutinib + BSC, BSC Alone
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	No formal hypothesis testing for this endpoint.
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	P-value not generated.
	Method	Regression, Cox
	Comments	Adjusting for age (<65 vs >=65 years) and comorbidities (present vs absent). Ties handled by Efron approach. HR CI using profile likelihood approach.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.314
	Confidence Interval	(2-Sided) 90%; 0.794 to 2.183
	Estimation Comments	[Not Specified]

18. Secondary Outcome

Title	Pharmacokinetics of Acalabrutinib
Description	Summary of plasma concentrations (ng/mL) of acalabrutinib
Time Frame	Day 3 and Day 7

Outcome Measure Data

Analysis Population Description

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/Group Title		Acalabrutinib + BSC
Arm/Group Description:		Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.
Overall Number of Participants Analyzed		30
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng/mL
Day 3, Pre-dose	Number Analyzed	8 participants
		6.258; (248%)
Day 3, 0.5 hours post-dose	Number Analyzed	14 participants
		26.683; (173%)
Day 3, 1 hour post-dose	Number Analyzed	10 participants
		210.858; (71.5%)
Day 3, 2 hours post-dose	Number Analyzed	18 participants
		124.143; (89.2%)
Day 3, 4 hours post-dose	Number Analyzed	10 participants
		33.714; (93.4%)
Day 7, 1 hour post-dose	Number Analyzed	1 participants
		165.080 [1]; (NA%)
Day 7, 2 hours post-dose	Number Analyzed	0 participants
Day 7, 4 hours post-dose	Number Analyzed	1 participants
		14.320 [1]; (NA%)

[1]

Only 1 participant had a result for this timepoint.

19. Secondary Outcome

Title	Pharmacokinetics of ACP-5862
Description	Summary of plasma concentrations (ng/mL) of ACP-5862
Time Frame	Day 3 and Day 7

Outcome Measure Data

Analysis Population Description

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/Group Title		Acalabrutinib + BSC
Arm/Group Description:		Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.
Overall Number of Participants Analyzed		30
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng/mL
Day 3, Pre-dose	Number Analyzed	9 participants
		53.818; (140%)
Day 3, 0.5 hours post-dose	Number Analyzed	14 participants
		58.959; (129%)
Day 3, 1 hour post-dose	Number Analyzed	10 participants
		293.606; (68.1%)
Day 3, 2 hours post-dose	Number Analyzed	18 participants
		273.528; (50.2%)
Day 3, 4 hours post-dose	Number Analyzed	10 participants
		178.575; (44.2%)
Day 7, 1 hour post-dose	Number Analyzed	1 participants
		582.180 [1]; (NA%)
Day 7, 2 hours post-dose	Number Analyzed	0 participants
Day 7, 4 hours post-dose	Number Analyzed	1 participants
		139.560 [1]; (NA%)

[1]

Only 1 participant had a result for this timepoint.

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)
Adverse Event Reporting 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.
Arm/Group Title	Acalabrutinib + BSC		BSC Alone
Arm/Group Description	Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.		Participants received best supportive care per the discretion of the Investigator and institutional guidelines.
All-Cause Mortality
	Acalabrutinib + BSC		BSC Alone
	Affected / at Risk (%)		Affected / at Risk (%)
Total	2/30 (6.67%)		2/32 (6.25%)
Serious Adverse Events
	Acalabrutinib + BSC		BSC Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/30 (13.33%)		6/32 (18.75%)
Gastrointestinal disorders
Rectal haemorrhage † 1	1/30 (3.33%)	1	0/32 (0.00%)	0
Retroperitoneal haematoma † 1	1/30 (3.33%)	1	0/32 (0.00%)	0
Hepatobiliary disorders
Hepatotoxicity † 1	1/30 (3.33%)	1	0/32 (0.00%)	0
Portal vein thrombosis † 1	0/30 (0.00%)	0	1/32 (3.13%)	1
Infections and infestations
Pneumonia cytomegaloviral † 1	1/30 (3.33%)	1	0/32 (0.00%)	0
Staphylococcal sepsis † 1	0/30 (0.00%)	0	1/32 (3.13%)	1
Urinary tract infection † 1	0/30 (0.00%)	0	2/32 (6.25%)	2
Investigations
Haemoglobin decreased † 1	0/30 (0.00%)	0	1/32 (3.13%)	1
Renal and urinary disorders
Chronic kidney disease † 1	1/30 (3.33%)	1	0/32 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease † 1	0/30 (0.00%)	0	1/32 (3.13%)	1
Pulmonary embolism † 1	0/30 (0.00%)	0	1/32 (3.13%)	1
Respiratory failure † 1	0/30 (0.00%)	0	1/32 (3.13%)	1
1 Term from vocabulary, MedDRA; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Acalabrutinib + BSC		BSC Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/30 (16.67%)		3/32 (9.38%)
Nervous system disorders
Headache † 1	4/30 (13.33%)	4	0/32 (0.00%)	0
Psychiatric disorders
Insomnia † 1	1/30 (3.33%)	1	3/32 (9.38%)	3
1 Term from vocabulary, MedDRA; † Indicates events were collected by systematic assessment

Limitations and Caveats

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.

More Information

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.

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.

Results Point of Contact

• Name/Title: Study Information Center
• Organization: AstraZeneca
• Phone: 1-877-240-9479
• EMail: information.center@astrazeneca.com

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT04380688
• Other Study ID Numbers: D822FC00003
• First Submitted: May 7, 2020
• First Posted: May 8, 2020
• Results First Submitted: August 19, 2021
• Results First Posted: September 13, 2021
• Last Update Posted: September 13, 2021