CALAVI: 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: NCT04346199
• Collaborator: Acerta Pharma BV (Industry)
• Enrollment: 177
• Locations: 50
• Arms: 2
• Actual Duration (Months): 5.2
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

CALAVI 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: 177 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 12, 2020
• Actual Primary Completion Date: Nov 17, 2020
• Actual Study Completion Date: Nov 17, 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. Percentage of Participants Alive and Free of Respiratory Failure at Day 14 [At Day 14]

   Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen ≥0.5) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation

Secondary 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) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation

3. 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.

4. 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.

5. 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.

6. Overall Survival [From randomization until 90 days after randomization. Safety Issue:]

   Median overall survival, calculated using the Kaplan-Meier technique. Confidence interval for median overall survival (days) is derived based on Brookmeyer-Crowley method with log-log transformation.

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

8. 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.

9. Number of Days Alive and Free of Respiratory Failure [From randomization to 28 days after randomization.]

   Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) Oxygen delivered by highflow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen ≥0.5) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation

10. Number of Days With Respiratory Failure [From randomization to 28 days after randomization.]

    Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen ≥0.5) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation For participants who die (due to any cause) prior to Day 28, days from death to Day 28 are counted as days with respiratory failure. For participants in hospital and experiencing respiratory failure at the time they withdraw from the study, days from last known status to Day 28 are counted as days with respiratory failure.

11. 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.

12. 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.

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

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

15. 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.

16. 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.

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

    Summary of plasma concentrations (ng/mL) of acalabrutinib

18. 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 (WHO) criteria (including positive RT-PCR nucleic acid test of any specimen [eg, respiratory, blood, urine, stool, or other bodily fluid]) within 4 days of randomization

4. COVID-19 pneumonia (documented radiographically) requiring hospitalization and oxygen saturation <94% on room air or requires supplemental oxygen

5. Able to swallow pills

6. Willing to follow contraception guidelines

Exclusion Criteria:

1. Respiratory failure at time of screening due to COVID-19

2. Known medical resuscitation within 14 days of randomization

3. Pregnant or breast feeding

4. Suspected uncontrolled active bacterial, fungal, viral, or other infection (besides infection with SARS-CoV-2)

5. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or bilirubin ≥ 3x upper limit of normal (ULN) and/or severe hepatic impairment detected within 24 hours at screening (per local lab)

6. Uncontrolled or untreated symptomatic arrhythmias, myocardial infarction within the last 6 weeks, or congestive heart failure (NYHA Grade 3 or 4). Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll

7. Treatment with a strong cytochrome P450 (CYP)3A inhibitor (within 14 days before first dose of study drug) or inducer (within 7 days before first dose of study drug).

8. Requires treatment with proton-pump inhibitors (PPIs; eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving PPIs who switch to H2-receptor antagonists or antacids are eligible for enrollment in this study

9. Received oral antirejection or immunomodulatory drugs (eg, anticytokines, Btk inhibitors, JAK inhibitors, PI3K inhibitors) within 30 days before randomization on study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Ciudad de Buenos Aires		Argentina	1221
2	Research Site	Ciudad de Buenos Aires		Argentina	C1180AAX
3	Research Site	Monte Grande		Argentina	B1842
4	Research Site	Ramos Mejía		Argentina	B1704
5	Research Site	Botucatu		Brazil	18618-687
6	Research Site	Brasillia		Brazil	72145-450
7	Research Site	Florianópolis		Brazil	88036-800
8	Research Site	Porto Alegre		Brazil	90035-903
9	Research Site	Porto Alegre		Brazil	91350-200
10	Research Site	Ribeirão Preto		Brazil	14051-140
11	Research Site	Salvador		Brazil	40110-060
12	Research Site	Sao Bernardo do Campo		Brazil	09715090
13	Research Site	Sao Paulo		Brazil	01327-001
14	Research Site	Sao Paulo		Brazil	04004-030
15	Research Site	São Paulo		Brazil	01308-050
16	Research Site	Curico		Chile	3341643
17	Research Site	Santiago		Chile	7500692
18	Research Site	Talca		Chile	3460001
19	Research Site	Villejuif Cedex		France	94805
20	Research Site	Frankfurt		Germany	60590
21	Research Site	Gauting		Germany	82131
22	Research Site	Köln		Germany	50937
23	Research Site	Bangalore		India	560002
24	Research Site	New Delhi		India	110017
25	Research Site	Milano		Italy	20132
26	Research Site	Roma		Italy	00168
27	Research Site	Shinjuku-ku		Japan	162-8655
28	Research Site	D.F		Mexico	14050
29	Research Site	Monterrey		Mexico	64461
30	Research Site	México		Mexico	03103
31	Research Site	Lima		Peru	15324
32	Research Site	Lima		Peru	LIMA 11
33	Research Site	Lima		Peru	LIMA 1
34	Research Site	Warszawa		Poland	02-507
35	Research Site	Warszawa		Poland	04-141
36	Research Site	Moscow		Russian Federation	111539
37	Research Site	Moscow		Russian Federation	119992
38	Research Site	Moscow		Russian Federation	123182
39	Research Site	Moscow		Russian Federation	143442
40	Research Site	Murmansk		Russian Federation	183047
41	Research Site	Cape Town		South Africa	7500
42	Research Site	George		South Africa	6529
43	Research Site	Johannesburg		South Africa	1827
44	Research Site	Johannesburg		South Africa	2193
45	Research Site	Pretoria		South Africa	0157
46	Research Site	Ankara		Turkey	06800
47	Research Site	Bakirkoy		Turkey	34147
48	Research Site	Istanbul		Turkey	34214
49	Research Site	Istanbul		Turkey
50	Research Site	Umraniye		Turkey	34760

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
• Redacted CSR Synopsis
• Redacted SAP

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT04346199
• Other Study ID Numbers: D822FC00001
• First Posted: Apr 15, 2020
• Last Update Posted: Sep 17, 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 had COVID-19 pneumonia (documented radiographically) requiring hospitalization and were recruited from the following countries: South Africa; India; Turkey; Japan; Russian Federation; France; Italy; Brazil; Argentina; Peru; Mexico; Chile. The first participant was randomized on 15 June 2020 and the last participant was randomized on 17 August 2020.
Pre-assignment Detail	Screening assessments were performed within the 3 days prior to randomization. Of 236 screened participants, 177 were enrolled. Of the 59 participants that were screened but not enrolled, 54 were screen failures (did not meet eligibility criteria), 1 died, 1 was withdrawn by physician decision and 3 withdrew consent.

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	89	88
COMPLETED	74	77
NOT COMPLETED	15	11

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	89	88	177
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	56.7 (13.3)	56.7 (14.8)	56.7 (14.1)
Age, Customized (Number) [Number]
< 65 years	61 68.5%	60 68.2%	121 68.4%
>= 65 years	28 31.5%	28 31.8%	56 31.6%
Sex: Female, Male (Count of Participants)
Female	29 32.6%	24 27.3%	53 29.9%
Male	60 67.4%	64 72.7%	124 70.1%
Race/Ethnicity, Customized (Number) [Number]
HISPANIC OR LATINO	48 53.9%	47 53.4%	95 53.7%
NOT HISPANIC OR LATINO	41 46.1%	41 46.6%	82 46.3%
NOT REPORTED	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Number) [Number]
WHITE	40 44.9%	48 54.5%	88 49.7%
BLACK OR AFRICAN AMERICAN	3 3.4%	5 5.7%	8 4.5%
AMERICAN INDIAN OR ALASKA NATIVE	7 7.9%	3 3.4%	10 5.6%
ASIAN	23 25.8%	13 14.8%	36 20.3%
NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER	0 0%	0 0%	0 0%
OTHER	14 15.7%	19 21.6%	33 18.6%
NOT REPORTED	2 2.2%	0 0%	2 1.1%

Outcome Measures

1. Primary 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 high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen ≥0.5) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation
Time Frame	At Day 14

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	89	88
Number (95% Confidence Interval) [Percentage of participants]	83.1 93.4%	90.9 103.3%

2. Secondary 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 (91) is greater than the number of participants randomized to this group (88) because three participants randomized to Acalabrutinib + BSC did not receive any acalabrutinib and therefore are included in the BSC alone group for the safety analysis set.

Arm/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	86	91
Any Adverse Event	43 48.3%	37 42%
Any Serious Adverse Event	7 7.9%	2 2.3%

3. Secondary 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) Non-invasive 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	89	88
Number (95% Confidence Interval) [Percentage of participants]	84.3 94.7%	88.6 100.7%

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	89	88
Day 3	-15.06 (95.82)	-15.25 (91.61)
Day 5	-12.48 (113.38)	-41.07 (92.59)
Day 7	-45.71 (106.84)	-23.41 (223.06)
Day 10/ Discharge (last post-baseline assessment if discharged from hospital prior to Day 10)	-16.84 (194.71)	-29.32 (166.35)
Day 10	-35.53 (126.84)	-23.41 (203.02)
Day 14	-12.49 (187.37)	-17.26 (256.87)
Day 28	-30.28 (192.90)	-63.74 (75.28)

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	89	88
Day 3	9.84 (92.66)	6.49 (40.23)
Day 5	12.92 (105.09)	-12.76 (43.18)
Day 7	-8.93 (53.52)	-8.79 (36.40)
Day 10/ Discharge (last post-baseline assessment if discharged from hospital prior to Day 10)	-9.09 (58.85)	1.35 (125.95)
Day 10	-5.99 (73.71)	6.84 (178.23)
Day 14	-18.81 (67.85)	-26.80 (46.10)
Day 28	-66.82 (18.24)	-66.05 (21.67)

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	89	88
Day 3	31.74 (59.32)	36.82 (79.91)
Day 5	55.79 (101.57)	87.25 (140.37)
Day 7	51.72 (91.82)	79.33 (119.73)
Day 10/ Discharge (last post-baseline assessment if discharged from hospital prior to Day 10)	78.34 (95.88)	99.65 (149.02)
Day 10	98.55 (113.66)	83.08 (105.56)
Day 14	74.65 (124.47)	91.58 (123.63)
Day 28	89.35 (100.24)	96.62 (97.30)

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. Safety Issue:

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	89	88
Median (95% 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	89	88
At Day 14	78.7 88.4%	89.8 102%
At Day 28	83.1 93.4%	87.5 99.4%

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	89	88
Median (95% 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	0.758
	Confidence Interval	(2-Sided) 95%; 0.323 to 1.722
	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) Non-invasive 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	89	88
Mean (Standard Deviation) [Days]	24.8 (8.0)	25.3 (7.1)

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 high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen ≥0.5) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation For participants who die (due to any cause) prior to Day 28, days from death to Day 28 are counted as days with respiratory failure. For participants in hospital and experiencing respiratory failure at the time they withdraw from the study, days from last known status to Day 28 are counted as days with respiratory failure.
Time Frame	From randomization to 28 days after randomization.

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	89	88
Mean (Standard Deviation) [Days]	3.2 (8.0)	2.7 (7.1)

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	89	88
Mean (Standard Deviation) [Days]	12.2 (8.6)	10.4 (7.4)

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	89	88
Mean (Standard Deviation) [Days]	10.4 (25.5)	9.7 (25.8)

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	89	88
Mean (Standard Deviation) [Days]	15.1 (8.4)	17.0 (7.3)

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	89	88
Mean (Standard Deviation) [Days]	66.8 (28.2)	71.3 (24.5)

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	89	88
Day 3	11.65 (29.40)	12.20 (33.88)
Day 5	23.94 (41.72)	33.09 (51.50)
Day 7	30.58 (57.79)	54.51 (84.75)
Day 10/ Discharge (last post-baseline assessment if discharged from hospital prior to Day 10)	54.25 (71.71)	62.10 (80.79)
Day 10	64.44 (84.02)	80.52 (101.48)
Day 14	70.39 (77.27)	83.71 (84.96)
Day 28	80.93 (89.61)	90.68 (95.43)

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	77	83
Median (95% Confidence Interval) [Days]	10.00	10.00

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	0.967
	Confidence Interval	() 95%; 0.690 to 1.353
	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	66
Day 3, Pre-dose	15.359 (195.1)
Day 3, 0.5 hours post-dose	54.580 (139.7)
Day 3, 1 hour post-dose	56.120 (141.6)
Day 3, 2 hours post-dose	90.173 (104.3)
Day 3, 4 hours post-dose	36.841 (179.2)
Day 3, 6 hours post-dose	23.551 (205.0)
Day 7, 1 hour post-dose	117.015 (60.3)
Day 7, 4 hours post-dose	17.454 (108.6)

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	66
Day 3, Pre-dose	71.526 (94.8)
Day 3, 0.5 hours post-dose	125.332 (109.9)
Day 3, 1 hour post-dose	144.784 (95.1)
Day 3, 2 hours post-dose	213.370 (72.7)
Day 3, 4 hours post-dose	154.437 (70.3)
Day 3, 6 hours post-dose	113.769 (82.8)
Day 7, 1 hour post-dose	156.133 (68.0)
Day 7, 4 hours post-dose	95.392 (69.7)

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	7/86 (8.1%)		10/91 (11%)
Serious Adverse Events
	Acalabrutinib + BSC		BSC Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/86 (8.1%)		2/91 (2.2%)
Infections and infestations
Bacterial sepsis	1/86 (1.2%)	1	0/91 (0%)	0
Mucosal infection	1/86 (1.2%)	1	0/91 (0%)	0
Pneumonia	2/86 (2.3%)	2	0/91 (0%)	0
Septic shock	0/86 (0%)	0	1/91 (1.1%)	1
Nervous system disorders
Ischaemic stroke	0/86 (0%)	0	1/91 (1.1%)	1
Renal and urinary disorders
Acute kidney injury	1/86 (1.2%)	1	0/91 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/86 (0%)	0	1/91 (1.1%)	1
Pleural effusion	1/86 (1.2%)	1	0/91 (0%)	0
Respiratory failure	2/86 (2.3%)	2	0/91 (0%)	0
Vascular disorders
Hypotension	1/86 (1.2%)	1	0/91 (0%)	0
Other (Not Including Serious) Adverse Events
	Acalabrutinib + BSC		BSC Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/86 (11.6%)		2/91 (2.2%)
Nervous system disorders
Headache	10/86 (11.6%)	11	2/91 (2.2%)	2

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.

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.