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

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04380688
• Collaborator: Acerta Pharma BV (Industry)
• Enrollment: 62
• Locations: 31
• Arms: 2
• Actual Duration (Months): 5.1
• Patients Per Site: 2
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

CALAVI US will investigate the safety, efficacy and pharmacokinetics of acalabrutinib together with Best Supportive Care in the treatment of COVID-19.

Condition or Disease	Intervention/Treatment	Phase
COVID-19	Drug: Acalabrutinib	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 62 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Study will consist of two arms Arm 1 is acalabrutinib + best supportive care or Arm 2 is best supportive care aloneStudy will consist of two arms Arm 1 is acalabrutinib + best supportive care or Arm 2 is best supportive care alone
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Jun 13, 2020
• Actual Primary Completion Date: Nov 16, 2020
• Actual Study Completion Date: Nov 16, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 Acalabrutinib+ Best Supportive Care	Drug: Acalabrutinib; Acalabrutinib administered orally
No Intervention: Arm 2 Best Supportive Care

Outcome Measures

Primary Outcome Measures

1. 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)]

2. 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) Noninvasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation

Secondary Outcome Measures

1. 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 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

2. 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.

3. 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.

4. 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.

5. Overall Survival [From randomization until 90 days after randomization.]

   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.

6. Percentage of Participants Alive and Discharged From ICU [At Day 14 and at Day 28]

7. 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.

8. 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) Noninvasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation

9. 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 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.

10. 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.

11. 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.

12. Number of Days Alive Outside of Hospital [From randomization to 28 days after randomization.]

13. Number of Days Alive Outside of Hospital [From randomization to 90 days after randomization.]

14. 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.

15. 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 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.

16. Pharmacokinetics of Acalabrutinib [Day 3 and Day 7]

    Summary of plasma concentrations (ng/mL) of acalabrutinib

17. Pharmacokinetics of ACP-5862 [Day 3 and Day 7]

    Summary of plasma concentrations (ng/mL) of ACP-5862

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 130 Years
• Sexes Eligible for Study: All
• Accepts 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 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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Anniston	Alabama	United States	36207
2	Research Site	Mobile	Alabama	United States	36604
3	Research Site	Escondido	California	United States	92029
4	Research Site	Fullerton	California	United States	92835
5	Research Site	Glendale	California	United States	91206
6	Research Site	Newport Beach	California	United States	92663
7	Research Site	New Haven	Connecticut	United States	06519
8	Research Site	Washington	District of Columbia	United States	20010
9	Research Site	Fort Lauderdale	Florida	United States	33308
10	Research Site	Jacksonville	Florida	United States	32207
11	Research Site	Jacksonville	Florida	United States	32209
12	Research Site	Loxahatchee Groves	Florida	United States	33470
13	Research Site	Fort Wayne	Indiana	United States	46804
14	Research Site	Louisville	Kentucky	United States	40207
15	Research Site	Annapolis	Maryland	United States	21401
16	Research Site	Baltimore	Maryland	United States	21287
17	Research Site	Bethesda	Maryland	United States	20889
18	Research Site	Bethesda	Maryland	United States	20892-1374
19	Research Site	Silver Spring	Maryland	United States	20910
20	Research Site	Hackensack	New Jersey	United States	07601
21	Research Site	Albany	New York	United States	12208
22	Research Site	Bronx	New York	United States	10467
23	Research Site	Buffalo	New York	United States	14263
24	Research Site	New York	New York	United States	10029
25	Research Site	Philadelphia	Pennsylvania	United States	19140
26	Research Site	Nashville	Tennessee	United States	38120
27	Research Site	Houston	Texas	United States	77030
28	Research Site	Houston	Texas	United States	77090
29	Research Site	Tyler	Texas	United States	75701
30	Research Site	Richmond	Virginia	United States	23298
31	Research Site	Renton	Washington	United States	98055

Sponsors and Collaborators

• AstraZeneca
• Acerta Pharma BV

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jul 24, 2020
• Statistical Analysis Plan - Oct 1, 2020

More Information

Additional Information:

• Redacted CSP
• Related Info
• CSR Synopsis

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT04380688
• Other Study ID Numbers: D822FC00003
• First Posted: May 8, 2020
• Last Update Posted: Sep 13, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by AstraZeneca: 2019 novel coronavirus disease; Acalabrutinib; Btk inhibitor
• Additional relevant MeSH terms: COVID-19; Acalabrutinib

Study Results

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 Detail	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

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 Participants	31	31	62
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	52.5 (13.3)	51.9 (14.3)	52.2 (13.7)
Age, Customized (Number) [Number]
< 65 years	26 83.9%	25 80.6%	51 82.3%
>= 65 years	5 16.1%	6 19.4%	11 17.7%
Sex: Female, Male (Count of Participants)
Female	13 41.9%	9 29%	22 35.5%
Male	18 58.1%	22 71%	40 64.5%
Race/Ethnicity, Customized (Number) [Number]
HISPANIC OR LATINO	15 48.4%	13 41.9%	28 45.2%
NOT HISPANIC OR LATINO	16 51.6%	17 54.8%	33 53.2%
NOT REPORTED	0 0%	0 0%	0 0%
MISSING	0 0%	1 3.2%	1 1.6%
Race/Ethnicity, Customized (Number) [Number]
WHITE	18 58.1%	20 64.5%	38 61.3%
BLACK OR AFRICAN AMERICAN	7 22.6%	5 16.1%	12 19.4%
AMERICAN INDIAN OR ALASKA NATIVE	1 3.2%	0 0%	1 1.6%
ASIAN	0 0%	0 0%	0 0%
NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER	0 0%	0 0%	0 0%
OTHER	3 9.7%	2 6.5%	5 8.1%
NOT REPORTED	2 6.5%	3 9.7%	5 8.1%
MISSING	0 0%	1 3.2%	1 1.6%

Outcome Measures

1. Primary Outcome

Title	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)

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.
Measure Participants	30	32
Any Adverse Event	17 54.8%	15 48.4%
Any Serious Adverse Event	4 12.9%	6 19.4%

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.
Measure Participants	31	31
Number (90% Confidence Interval) [Percentage of participants]	80.6 260%	83.9 270.6%

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.
Measure Participants	31	31
Number (90% Confidence Interval) [Percentage of participants]	80.6 260%	87.1 281%

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.
Measure Participants	31	31
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)

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.
Measure Participants	31	31
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)

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.
Measure Participants	31	31
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)

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.
Measure Participants	31	31
Median (90% Confidence Interval) [Days]	NA	NA

8. Secondary Outcome

Title	Percentage of Participants Alive and Discharged From ICU
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.
Measure Participants	31	31
At Day 14	83.9 270.6%	87.1 281%
At Day 28	83.9 270.6%	87.1 281%

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.
Measure Participants	31	31
Median (90% Confidence Interval) [Days]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acalabrutinib + BSC, BSC Alone
	Comments
	Type of Statistical Test	Other
	Comments	No formal hypothesis testing for this endpoint.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.553
	Confidence Interval	(2-Sided) 90%; 0.145 to 1.952
	Parameter Dispersion	Type: Value:
	Estimation Comments

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.
Measure Participants	31	31
Mean (Standard Deviation) [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.
Measure Participants	31	31
Mean (Standard Deviation) [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.
Measure Participants	31	31
Mean (Standard Deviation) [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.
Measure Participants	31	31
Mean (Standard Deviation) [Days]	4.4 (17.1)	7.0 (20.8)

14. Secondary Outcome

Title	Number of Days Alive Outside of Hospital
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.
Measure Participants	31	31
Mean (Standard Deviation) [Days]	20.2 (7.3)	18.9 (8.6)

15. Secondary Outcome

Title	Number of Days Alive Outside of Hospital
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.
Measure Participants	31	31
Mean (Standard Deviation) [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.
Measure Participants	31	31
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)

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.
Measure Participants	31	29
Median (90% Confidence Interval) [Days]	6.00	7.00

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acalabrutinib + BSC, BSC Alone
	Comments
	Type of Statistical Test	Other
	Comments	No formal hypothesis testing for this endpoint.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.314
	Confidence Interval	(2-Sided) 90%; 0.794 to 2.183
	Parameter Dispersion	Type: Value:
	Estimation Comments

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.
Measure Participants	30
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)
Day 7, 4 hours post-dose	14.320 (NA)

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.
Measure Participants	30
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)
Day 7, 4 hours post-dose	139.560 (NA)

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 (%)	# Events	Affected / at Risk (%)	# Events
Total	2/30 (6.7%)		2/32 (6.3%)
Serious Adverse Events
	Acalabrutinib + BSC		BSC Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/30 (13.3%)		6/32 (18.8%)
Gastrointestinal disorders
Rectal haemorrhage	1/30 (3.3%)	1	0/32 (0%)	0
Retroperitoneal haematoma	1/30 (3.3%)	1	0/32 (0%)	0
Hepatobiliary disorders
Hepatotoxicity	1/30 (3.3%)	1	0/32 (0%)	0
Portal vein thrombosis	0/30 (0%)	0	1/32 (3.1%)	1
Infections and infestations
Pneumonia cytomegaloviral	1/30 (3.3%)	1	0/32 (0%)	0
Staphylococcal sepsis	0/30 (0%)	0	1/32 (3.1%)	1
Urinary tract infection	0/30 (0%)	0	2/32 (6.3%)	2
Investigations
Haemoglobin decreased	0/30 (0%)	0	1/32 (3.1%)	1
Renal and urinary disorders
Chronic kidney disease	1/30 (3.3%)	1	0/32 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/30 (0%)	0	1/32 (3.1%)	1
Pulmonary embolism	0/30 (0%)	0	1/32 (3.1%)	1
Respiratory failure	0/30 (0%)	0	1/32 (3.1%)	1
Other (Not Including Serious) Adverse Events
	Acalabrutinib + BSC		BSC Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/30 (16.7%)		3/32 (9.4%)
Nervous system disorders
Headache	4/30 (13.3%)	4	0/32 (0%)	0
Psychiatric disorders
Insomnia	1/30 (3.3%)	1	3/32 (9.4%)	3

Limitations/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.

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.