Clinical trial NCT04346199
Conditions: COVID-19
Keywords: 2019 novel coronavirus disease Acalabrutinib Btk inhibitor
Sponsor: AstraZeneca
Start date: 2020-06-12; Completion date: 2020-11-17
Enrollment: 177 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

Detailed description:

Arms: arm 1: Acalabrutinib+ Best Supportive Care arm 2: Best Supportive Care
Interventions: intervention 1: Acalabrutinib
Intervention descriptions: intervention 1: Acalabrutinib- administered orally

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol 
Drug Substance
Acalabrutinib
Study Code
ACE-ID-201 (D822FC00001)
Version
5.0
Date
24Jul2020
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
Sponsor:
Acerta Pharma B.V., a Dutch limited liability company, whose registered office is at 
Kloosterstraat 9, 5349 AB, Oss, The Netherlands, a member of the AstraZeneca group 
(“Company”)
IND# 149513
EudraCT# 2020-001644-25


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 4 (Version 5.0)
24Jul2020
Amendment 3 (Version 4.0)
23Jun2020
Amendment 2 (Version 3.0)
28Apr2020
Amendment 1 (Version 2.0)
17Apr2020 
Original Protocol (Version 1.0)
05Apr2020
Amendment 4 (24Jul2020) 
The overall rationale for the amendment was to provide clarification regarding laboratory tests 
for hepatitis B virus (HBV) and hepatitis C virus (HCV) during screening.
Coronavirus disease 2019 (COVID-19) pneumonia requiring hospitalization is an acute disease 
that requires a rapid screening evaluation to ensure prompt initiation of study treatment. The 
Sponsor is aware that at some institutions, the turnaround times for local hepatitis virus tests are 
prolonged (days rather than hours), leading to substantial delays in randomization and treatment. 
Thus, the Sponsor has reviewed the risks and benefits of initiating treatment before these test 
results are available. In the acute setting of severe COVID-19 disease, the potential benefits of 
initiating treatment in a timely manner outweigh potential risks, especially considering that 
1) HBV/HCV events are expected to be infrequent based on Sponsor data from oncology studies, 
2) the short duration of therapy is anticipated to further reduce risk, and 3) HBV/HCV events can 
be monitored and, if necessary, managed with antiviral therapies.
No reports of HCV reactivation have been received in the acalabrutinib clinical program to date, 
and there are no published reports of HCV reactivation following treatment with Bruton tyrosine 
kinase (Btk) inhibitors that are available to the Sponsor. HBV reactivations in the setting of 
acalabrutinib treatment are infrequently reported. Among 4053 subjects across all clinical studies 
investigating acalabrutinib to date, 9 subjects had reactivations (1 fatal, 8 non-serious) after a 
median duration of therapy of 248 days (range 43 to 582 days). HBV reactivations have rarely 
been reported with other Btk inhibitors, such as ibrutinib, where a larger number of patients have 
been treated to date in clinical studies and real-world settings; ibrutinib has been approved for 
use since 2014 (Hammond et al 2018). Furthermore, when HBV reactivations occur, they are 
typically observed following months to years of treatment, and are easily managed with antiviral 
therapy with good outcomes; in many cases, the Btk inhibitor is continued.
In addition to the amendment changes summarized below, a few minor errors and typos were 
corrected.


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Section number and 
name
Description of change
Brief rationale
Substantial/ 
non-substantial
1.1 Schedule of 
Activities (Table 1 and 
Table 2)
Removed Day 1 column from both 
Tables 1 and 2. Made changes to 
“Daily until hospital discharge” 
column to adjust for this change.
Clarification
Non-substantial
1.1 Schedule of 
Activities (Table 2)
Substantial
1.1 Schedule of 
Activities (Table 1 and 
Table 2),
8.1.8 Laboratory Tests,
8.1.8.1 Hepatitis 
Serology Guidelines
Added text to footnote d of Table 1 
and Table 2 to indicate that 
treatment with acalabrutinib can 
start after blood samples have been 
collected, even if the results are not 
yet available at the time of 
randomization. In addition, added 
hepatitis serology guidelines that 
should be followed 
(Section 8.1.8.1).
See rationale provided 
above this table
Substantial
1.1 Schedule of 
Activities (Table 1 and 
Table 2),
8.3 On-study 
Procedures
Added nasal swab sample 
collection for SARS-CoV-2 viral 
load/viral shedding
To clarify method of sample 
collection for SARS-CoV-2 
viral load/viral shedding
Substantial
1.1 Schedule of 
Activities (Table 1),
9.6.3 Pharmacokinetic 
and Pharmacodynamic 
Analyses
Added footnote t to Table 1 and 
text to Section 9.6.3 to indicate 
that PK assessments will be 
conducted in up to 35 evaluable 
subjects and PD assessments in up 
to 20 evaluable subjects 
randomized to Arm 1 
(acalabrutinib + BSC)
Assessment in up to 35 and 
up to 20 evaluable subjects 
are considered adequate to 
characterize the PK/active 
metabolite and PD, 
respectively, of 
acalabrutinib in the 
COVID-19 population
Non-substantial
1.2 Synopsis,
6.1.1 Dosing and 
Duration of Treatment,
6.1.3.1 Drug-drug 
Interactions,
6.5.4 Acalabrutinib 
Drug-drug Interaction 
Guidance in the 
Presence of Life-
threatening COVID-19 
Infection,
6.5.4.2 Active 
Substances That May 
Decrease Acalabrutinib 
Plasma Concentrations
For subjects not on PPIs, removed 
volume (240 mL) of water and just 
stated that it should be taken with 
water. For subjects who are on 
PPIs, changed volume of COCA-
COLA from 240 mL to “at least 
100 mL”. 
Based on in-vitro data, 
administering acalabrutinib 
100 mg oral capsules (in the 
presence of PPIs) with at 
least a 100 mL of COCA-
COLA is considered to be 
adequate for mitigating the 
effect of PPIs on 
acalabrutinib PK/PD
Non-substantial
CCI


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Section number and 
name
Description of change
Brief rationale
Substantial/ 
non-substantial
1.2 Synopsis,
4.4 Internal DMC
Replaced the planned second 
iDMC review of safety data from 
first randomized 80 subjects with 
an iDMC review of a planned 
interim efficacy analysis and 
accumulated available safety data
Added text to indicate that the 
iDMC may support any health 
authority interactions or internal 
discussions based on their review, 
and the study team will remain 
blinded to the data that the iDMC 
will review
Due to projected rapid 
enrollment and anticipated 
need for early efficacy 
information for health 
authority interaction
For transparency and to 
preserve the trial integrity
Substantial
5.2 Exclusion Criteria
Removed the cutoffs for oxygen 
flow rates from Exclusion 
Criterion 1 and indicated that 
subjects should be considered for 
eligibility in part based on their 
ability to swallow pills
Clarified which patients 
with respiratory failure are 
eligible for enrollment
Substantial
Added an exception to Exclusion 
Criterion 8 to indicate that AST 
and/or ALT can be up to 5 × ULN 
if considered due to underlying 
COVID-19, but cannot be 
associated with concurrent 
elevated bilirubin (up to 2 × ULN)
Hepatotoxicity and 
ALT/AST are not currently 
adverse drug reactions for 
acalabrutinib and there is 
evidence for ALT/AST 
increases associated with 
COVID-19 (Cai et al 2020, 
Guan et al 2020)
Substantial
Revised Exclusion Criterion 16 to 
align with the hepatitis serology 
guidelines
Clarification and 
consistency
Substantial
6.6.3 Hepatitis B and C 
Reactivation
Added information about HCV and 
HBV reactivation with 
acalabrutinib
To support hepatitis 
serology guidelines
Substantial
7.1 Discontinuation of
Treatment and Subject 
Withdrawal,
7.2 Subject Withdrawal 
from the Study
Added that subjects with positive 
HBsAg, HBV-DNA, or HCV-
RNA test result after 
randomization will be discontinued 
from study treatment (Section 7.1) 
and withdrawn from the study
(Section 7.2)
To align with hepatitis 
serology guidelines
Substantial
8.1 Screening 
Assessments,
8.1.1 Informed Consent
Moved second paragraph under 
Section 8.1.1 to Section 8.1
Paragraph relates to all 
screening visits
Non-substantial


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Section number and 
name
Description of change
Brief rationale
Substantial/ 
non-substantial
9.4 Interim Analysis 
Replaced the planned second 
iDMC review of safety data from 
first randomized 80 subjects with 
an iDMC review of a planned 
interim efficacy analysis and 
accumulated available safety data
Added multiplicity adjustment of 
the overall type I error for the 
primary efficacy to account for the 
added interim efficacy analysis
Due to projected rapid 
enrollment and anticipated 
need for early efficacy 
information for  health 
authority interaction
To preserve the statistical 
rigor
Substantial
9.6. Statistical Analyses 
Added a description of the timing 
of the primary analysis of the study 
and the updated analysis
For clarity 
Non-substantial
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BSC = best supportive care; COVID-19 = coronavirus 
disease 2019; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; iDMC = internal Data 
Monitoring Committee; PD = pharmacodynamics; PK = pharmacokinetics; PPI = proton-pump inhibitor; 
SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; ULN = upper limit of normal.


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE....................................2
TABLE OF CONTENTS......................................................................................................6
1.
PROTOCOL SUMMARY ................................................................................10
1.1
Schedule of Activities (SoA).............................................................................10
1.2
Synopsis ...........................................................................................................18
1.3
Schema .............................................................................................................23
2.
INTRODUCTION ............................................................................................24
2.1
Background and Study Rationale ......................................................................24
2.2
Benefit/Risk Assessment...................................................................................26
3.
OBJECTIVES AND ENDPOINTS...................................................................27
4.
STUDY DESIGN .............................................................................................29
4.1
Overall Design..................................................................................................29
4.2
Scientific Rationale for Study Design................................................................29
4.3
Justification for Dose ........................................................................................30
4.4
Internal DMC....................................................................................................30
4.5
End of Study Definition ....................................................................................31
5.
STUDY POPULATION ...................................................................................31
5.1
Inclusion Criteria ..............................................................................................31
5.2
Exclusion Criteria .............................................................................................32
5.3
Screen Failures .................................................................................................34
6.
STUDY TREATMENTS..................................................................................34
6.1
Treatments Administered ..................................................................................34
6.1.1
Dosing and Duration of Treatment ....................................................................34
6.1.2
Missed Dosing Windows and Doses..................................................................35
6.1.3
Special Considerations......................................................................................35
6.1.3.1
Drug-drug Interactions......................................................................................35
6.1.3.2
Subjects With Respiratory Failure and Who Can Still Swallow Pills .................36
6.1.3.3
Subjects No Longer Able to Swallow Pills........................................................36
6.1.3.4
Vomiting After Acalabrutinib Treatment...........................................................36
6.1.3.5
Discharged From Hospital Before Treatment Completion .................................36
6.2
Acalabrutinib Preparation/Handling/Storage/Accountability .............................36
6.3
Measures to Minimise Bias: Randomisation and Blinding.................................37
6.3.1
Subject Enrollment and Randomization.............................................................37
6.3.1.1
Procedures for Handling Incorrectly Enrolled or Randomized Subjects.............38
6.3.1.2
Methods for Assigning Treatment Groups.........................................................38
6.3.1.3
Methods for Ensuring Blinding .........................................................................38


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6.4
Treatment Compliance......................................................................................38
6.5
Concomitant Therapy........................................................................................39
6.5.1
Premedications..................................................................................................39
6.5.2
Permitted Concomitant Therapy........................................................................39
6.5.3
Prohibited or Restricted Concomitant Therapy..................................................39
6.5.3.1
Medications Prohibited for Subjects Treated with Acalabrutinib .......................39
6.5.3.2
Medications Prohibited for All Randomized Subjects........................................39
6.5.4
Acalabrutinib Drug-drug Interaction Guidance in the Presence of Life-threatening 
COVID-19 Infection .........................................................................................40
6.5.4.1
Active Substances That May Increase Acalabrutinib Plasma Concentrations.....41
6.5.4.2
Active Substances That May Decrease Acalabrutinib Plasma Concentrations....41
6.6
Risks Associated with Acalabrutinib.................................................................42
6.6.1
Hemorrhage ......................................................................................................42
6.6.2
Infections..........................................................................................................43
6.6.3
Hepatitis B and C Reactivation .........................................................................43
6.6.4
Progressive Multifocal Leukoencephalopathy ...................................................43
6.6.5
Cytopenias........................................................................................................43
6.6.6
Second Primary Malignancies...........................................................................44
6.6.7
Atrial Fibrillation..............................................................................................44
6.6.8
Reference Safety Information............................................................................44
6.7
Dose Modification and Toxicity Management...................................................44
6.7.1
Renal Impairment .............................................................................................46
6.7.2
Hepatic Impairment ..........................................................................................46
6.8
Treatment After the End of Study......................................................................47
7.
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL .47
7.1
Discontinuation of Study Treatment..................................................................47
7.2
Subject Withdrawal from the Study...................................................................48
7.3
Lost to Follow-Up.............................................................................................48
8.
STUDY ASSESSMENTS AND PROCEDURES..............................................49
8.1
Screening Assessments .....................................................................................49
8.1.1
Informed Consent .............................................................................................49
8.1.2
Demographics...................................................................................................49
8.1.3
Confirmation of Eligibility................................................................................50
8.1.4
Medical History ................................................................................................50
8.1.5
Physical Examinations and Chest Imaging, Electrocardiogram, and 
Echocardiogram................................................................................................50
8.1.6
Vital Signs ........................................................................................................50
8.1.7
Urine or Serum Pregnancy ................................................................................51
8.1.8
Laboratory Tests ...............................................................................................51
8.1.8.1
Hepatitis Serology Guidelines...........................................................................51
8.2
Concomitant Medications .................................................................................52
8.3
On-study Procedures.........................................................................................52
8.4
Clinical Assessments During Hospitalization ....................................................54


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8.4.1
Oxygen Treatments and Ventilator Use.............................................................54
8.4.2
Modified Sequential Organ Failure Assessment (SOFA) Scores........................54
8.4.3
Assessment of Number of Days in ICU.............................................................54
8.5
Follow Up Procedures.......................................................................................55
8.6
Collection of Adverse Events............................................................................55
8.6.1
Method of Detecting AEs and SAEs .................................................................56
8.6.2
Time Period and Frequency for Collecting AE and SAE Information................56
8.6.3
Follow-up of AEs and SAEs .............................................................................56
8.6.4
Adverse Event Data Collection .........................................................................57
8.6.5
Causality Collection..........................................................................................58
8.6.6
Adverse Events Based on Signs and Symptoms ................................................58
8.6.7
Adverse Events Based on Examinations and Tests ............................................58
8.6.8
Hy’s Law..........................................................................................................59
8.6.9
Disease Under Study.........................................................................................59
8.6.10
Disease Progression ..........................................................................................59
8.6.11
Deaths...............................................................................................................59
8.6.12
Adverse Events of Special Interest ....................................................................60
8.7
Safety Reporting and Medical Management......................................................60
8.7.1
Reporting of Serious Adverse Events................................................................60
8.7.2
Pregnancy.........................................................................................................61
8.7.2.1
Maternal Exposure............................................................................................61
8.7.2.2
Paternal Exposure .............................................................................................62
8.7.3
Overdose...........................................................................................................62
8.7.4
Medication Error...............................................................................................62
8.8
Efficacy Assessments........................................................................................63
8.8.1
Improvement on the 9-point Ordinal Scale ........................................................63
9.
STATISTICAL CONSIDERATIONS...............................................................64
9.1
Statistical Hypotheses .......................................................................................64
9.2
Sample Size Determination...............................................................................64
9.3
Populations for Analyses...................................................................................64
9.4
Interim Analysis................................................................................................65
9.5
Missing Data Handling .....................................................................................66
9.6
Statistical Analyses ...........................................................................................66
9.6.1
Safety Analyses ................................................................................................66
9.6.2
Efficacy Analyses .............................................................................................67
9.6.3
Pharmacokinetic and Pharmacodynamic Analyses ............................................68
10.
REFERENCES .................................................................................................69
LIST OF TABLES
Table 1
Schedule of Activities - Arm 1 (Acalabrutinib + BSC).............................11
Table 2
Schedule of Activities - Arm 2 (BSC Only) .............................................15


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Table 3
Protocol Objectives and Endpoints...........................................................27
Table 4
Acalabrutinib Use with Moderate CYP3A Inhibitors and Gastric Acid 
Reducing Agents......................................................................................40
Table 5
Risks Associated with Acalabrutinib Monotherapy in Subjects With 
Hematologic Malignancies (N = 1040).....................................................42
Table 6
Analysis Populations................................................................................65
Table 7
IATA Dangerous Goods Regulations Classification of Infectious 
Substances ...............................................................................................83
Table 8
CYP3A Inhibitors ....................................................................................89
Table 9
CYP3A Inducers......................................................................................90
Table 10
Other Drugs Needing Additional Considerations......................................90
Table 11
Highly Effective Methods of Contraception (<1% Failure Rate)...............92
Table 12
Child-Pugh Classification of Cirrhosis Severity .......................................93
LIST OF FIGURES
Figure 1
Study Design ...........................................................................................24
LIST OF APPENDICES
Appendix A
Regulatory, Ethical and Study Oversight Considerations..........................72
Appendix B
Adverse Event Definitions and Additional Safety Information .................77
Appendix C
Handling of Human Biological Samples ..................................................81
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ...........................................................................84
Appendix E
Examples of Coadministered Drugs That Need Additional Consideration 89
Appendix F
Contraception Requirements....................................................................91
Appendix G
Child-Pugh Score.....................................................................................93
Appendix H
Abbreviations ..........................................................................................94
Appendix I
Protocol Amendment History...................................................................97


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1.
PROTOCOL SUMMARY
1.1
Schedule of Activities (SoA)
The SoAs for Arm 1 (acalabrutinib + best supportive care [BSC]) and Arm 2 (BSC only) are
presented in Table 1 and Table 2, respectively.


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Table 1
Schedule of Activities - Arm 1 (Acalabrutinib + BSC)
Assessments
Screening
(Day -3 to 
Day -1 l)
Daily until hospital 
discharge
Day 10 or 
discharge h
Day 14
(±2 days) 
after 
randomi-
zation
Day 28
(±3 days) 
after 
randomi-
zation
Safety FU
28 (±3) days 
after last dose 
of acala-
brutinib i
Long-term 
FU 90 (±7) 
days after 
randomi-
zation i,j
CSP 
section
Informed consent
X
8.1.1
Demography
X
8.1.2
Determine eligibility
X
5.1, 5.2
Medical history and COVID-19 
epidemiology
X
8.1.4
Physical examination (symptom 
driven, including lung 
auscultation, height, weight)
X
8.1.5
Chest imaging
X r
As clinically indicated
8.1.5, 8.3
Electrocardiogram
X l
As clinically indicated
X
8.1.5, 8.3
Echocardiogram
As clinically 
indicated
As clinically indicated
8.1.5, 8.3
Vital signs (blood pressure, 
respiratory rate, oximetry, pulse 
and body temperature)
X s
X
X
X
X
8.1.6, 8.3
Local laboratory assessments:
Urine or serum pregnancy test 
(for WOCBP only)
X
X
X
8.1.7, 8.3
Hematology b
X
X
X
X
X
X
8.1.8, 8.3
Serum or plasma 
chemistry c
X
X
X
X
X
X
8.1.8, 8.3
Arterial blood gases (if 
available) n
X
X
X
X
8.1.6, 8.1.8, 
8.3, 8.4.1
Hepatitis B and C testing d
X
As clinically indicated
As clinically 
indicated
6.6.3, 8.1.8, 
8.1.8.1, 8.3
Serum ferritin m
X
qod
(starting from Day 1)
X
X
X
8.1.8, 8.3
Fibrinogen m
X
qod
8.1.8, 8.3


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Table 1
Schedule of Activities - Arm 1 (Acalabrutinib + BSC)
Assessments
Screening
(Day -3 to 
Day -1 l)
Daily until hospital 
discharge
Day 10 or 
discharge h
Day 14
(±2 days) 
after 
randomi-
zation
Day 28
(±3 days) 
after 
randomi-
zation
Safety FU
28 (±3) days 
after last dose 
of acala-
brutinib i
Long-term 
FU 90 (±7) 
days after 
randomi-
zation i,j
CSP 
section
PT, aPTT, and INR m
X
qod
8.1.8, 8.3
D-dimer m
X
qod
X
X
8.1.8, 8.3
CRP
X
X
X
X
X
8.1.8, 8.3
Procalcitonin 
(if available) m
X
qod
X
X
8.1.8, 8.3
Cardiac troponin I m
X
Day 5
X
8.1.8, 8.3
SARS-CoV-2 RT-PCR virus 
testing for eligibility e
Within 
7 days prior to 
randomization
8.1.8, 5.1
Clinical assessments
As applicable until hospital discharge
8.4
9-point ordinal scale
X
X
X
X
8.8.1
Central laboratory assessments q
Correlative samples a,o
Days 1 a, 3, and 7
X
X
X
-
8.3
Immunophenotyping a,g
Days 1 a, 3, and 7
X
X
X
8.3
Serum and nasal swab 
samples for SARS-CoV-2 
viral load/viral shedding a
Days 1 a, 3, and 7
X
X
X
8.3
Acalabrutinib PK p,t
0.5 and 2 hours
postdose on Day 3;
1 and 4 hours postdose 
on Day 7
8.3
CCI


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Table 1
Schedule of Activities - Arm 1 (Acalabrutinib + BSC)
Assessments
Screening
(Day -3 to 
Day -1 l)
Daily until hospital 
discharge
Day 10 or 
discharge h
Day 14
(±2 days) 
after 
randomi-
zation
Day 28
(±3 days) 
after 
randomi-
zation
Safety FU
28 (±3) days 
after last dose 
of acala-
brutinib i
Long-term 
FU 90 (±7) 
days after 
randomi-
zation i,j
CSP 
section
Acalabrutinib administration
The first dose of 
acalabrutinib should 
be administered 
within 6 hours of 
randomization
100 mg bid (q12h) ×
10 days (maximum)
6.1
Adverse events
X k
X
X
X
X
Xj
8.6
Concomitant medications
X
X
X
X
X
Xj
8.2
Survival status
X
X
Xj
Xj
4.5
anti-HBc = hepatitis B core antibody; aPTT = activated partial thromboplastin time, bid = twice daily; BSC = best supportive care; CD = cluster of differentiation; 
CRP = C-reactive protein; CT = computed tomography; ECG = electrocardiogram; FU = follow-up; COVID-19 = coronavirus disease 2019; CSP = Clinical Study Protocol; 
HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; ICF = Informed Consent Form; ICU = intensive care unit; INR = international normalized ratio; 
PBMC = peripheral blood mononuclear cell; PD = pharmacodynamics; PK = pharmacokinetics; PT = prothrombin time; q12h = every 12 hours; qod = every other day; 
RT-PCR = reverse transcriptase-polymerase chain reaction; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; WOCBP = women of 
childbearing potential.
a
Predose.
b
Hematology: complete blood count with differential includes, but not limited to white blood cell count, hemoglobin, platelet count, absolute neutrophil count (ANC) or 
percentage, red blood cell count, absolute monocyte count or percentage, and absolute lymphocyte count (ALC) or percentage. 
c
Serum or plasma chemistry: albumin, alkaline phosphatase, alanine transaminase (ALT), aspartate aminotransferase (AST), bicarbonate, blood urea nitrogen (BUN), 
calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphate/phosphorus, potassium, sodium, total bilirubin (direct and indirect bilirubin, if 
available), total protein and uric acid. 
d
Hepatitis serology must include, at a minimum, HBsAg, anti-HBc, and HCV antibody. If additional hepatitis serology is collected per institutional guidelines, it should be 
recorded in the database. Additional testing information is provided in Section 6.6.3 and Section 8.1.8. Subjects can be randomized and started on acalabrutinib after blood 
samples for all HBV and HCV serology tests and for both HBV and HCV PCR tests have been collected, even if the results are not yet available at the time of 
randomization. Follow the hepatitis serology guidelines described in Section 8.1.8.1.
e
COVID-19 infection must be confirmed according to the World Health Organization criteria (including positive nucleic acid test of any specimen [eg, respiratory, blood, 
urine, stool, or other bodily fluid]) within 7 days prior to randomization. If test has already been documented within 7 days prior to randomization, no need to repeat the 
testing again.
f
g
Flow cytometry testing of peripheral blood will include, but is not limited to, CD3+, CD4+, CD8+, CD14+, CD19+, and CD16+/56+ cells.
h
If a subject is discharged prior to Day 7, he/she needs to visit the site for an assessment 2 to 4 days after discharge. Assessments should match those for Day 10.
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Table 1
Schedule of Activities - Arm 1 (Acalabrutinib + BSC)
Assessments
Screening
(Day -3 to 
Day -1 l)
Daily until hospital 
discharge
Day 10 or 
discharge h
Day 14
(±2 days) 
after 
randomi-
zation
Day 28
(±3 days) 
after 
randomi-
zation
Safety FU
28 (±3) days 
after last dose 
of acala-
brutinib i
Long-term 
FU 90 (±7) 
days after 
randomi-
zation i,j
CSP 
section
i
Telemedicine is recommended for capturing adverse events concomitant medications, and survival. Safety laboratory tests can be done at the hospital or a local laboratory 
provided the results are ultimately captured in the clinical database for the study.
j
All subjects will be followed for survival for 90 (± 7) days.
k
After signing the ICF, but prior to randomization, only SAEs should be reported (see Section 8.6.2).
l
Screening can be performed within 1 to 3 days prior to dosing, depending on the local requirements for laboratory turnaround times; ECG can be collected at any time 
during this screening window.
m
Serum ferritin, fibrinogen, PT, aPTT, INR, D-dimer, procalcitonin, and cardiac troponin I should be performed more frequently if clinically indicated.
n
Arterial gases should be collected from subjects if the sample is easily accessible and the procedure will not be painful to subjects (ie, subject is in ICU or has arterial port). 
All available data from the arterial gases should be entered into the database. If the collection of arterial gases is not clinically indicated, the test should not be performed.
o
p
All blood samples for PK assessment (ie, 0.5, 1, 2, and 4 hours postdose) can also be collected during a single visit on Day 3 or after.
q
For all central laboratory assessments, sample collection windows of ± 1 day will be allowed for each of Days 3 and 7.
r
Per standard of care, chest imaging can be done by chest x-ray or CT scan with contrast, or any other appropriate means to confirm pneumonia prior to or upon 
hospitalization (within 7 days of randomization).
s
During screening, vital signs should be collected as close as possible to randomization on Day 1. If more than one value is obtained for vital signs during screening, the value 
closest to randomization should be used.
t
PK assessments will be conducted in up to 35 evaluable subjects and PD assessments in up to 20 evaluable subjects randomized to Arm 1 (acalabrutinib + BSC).
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Table 2
Schedule of Activities - Arm 2 (BSC Only)
Assessments
Screening
(Day -3 to 
Day -1 l)
Daily until hospital 
discharge
Day 10 or 
discharge h
Day 14
(±2 days) 
after 
randomi-
zation
Day 28
(±3 days) 
after 
randomi-
zation
Safety FU
38 (±3) days 
after randomi-
zation i
Long-term 
FU 90 (±7) 
days after 
randomi-
zation i,j
CSP 
section
Informed consent
X
8.1.1
Demography
X
8.1.2
Determine eligibility
X
5.1, 5.2
Medical history and COVID-19 
epidemiology
X
8.1.4
Physical examination (symptom 
driven, including lung 
auscultation, height, weight)
X
8.1.5
Chest imaging
X q
As clinically indicated
8.1.5, 8.3
Electrocardiogram
X l
As clinically indicated
X
8.1.5, 8.3
Echocardiogram
As clinically 
indicated
As clinically indicated
8.1.5, 8.3
Vital signs (blood pressure, 
respiratory rate, oximetry, pulse 
and body temperature)
X r
X
X
X
X
8.1.6, 8.3
Local laboratory assessments:
Urine or serum pregnancy test 
(for WOCBP only)
X
X
X
8.1.7, 8.3
Hematology b
X
X
X
X
X
X
8.1.8, 8.3
Serum or plasma 
chemistry c
X
X
X
X
X
X
8.1.8, 8.3
Arterial blood gases (if 
available) n
X
X
X
X
8.1.6, 8.1.8, 
8.3, 8.4.1
Hepatitis B and C testing d
X
As clinically indicated
As clinically 
indicated
6.6.3, 8.1.8, 
8.1.8.1, 8.3
Serum ferritin m
X
qod 
(starting from Day 1)
X
X
X
8.1.8, 8.3
Fibrinogen m
X
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Table 2
Schedule of Activities - Arm 2 (BSC Only)
Assessments
Screening
(Day -3 to 
Day -1 l)
Daily until hospital 
discharge
Day 10 or 
discharge h
Day 14
(±2 days) 
after 
randomi-
zation
Day 28
(±3 days) 
after 
randomi-
zation
Safety FU
38 (±3) days 
after randomi-
zation i
Long-term 
FU 90 (±7) 
days after 
randomi-
zation i,j
CSP 
section
PT, aPTT, and INR m
X
qod
8.1.8, 8.3
D-dimer m
X
qod
X
X
8.1.8, 8.3
CRP
X
X
X
X
X
8.1.8, 8.3
Procalcitonin 
(if available) m
X
qod
X
X
8.1.8, 8.3
Cardiac troponin I m
X
Day 5
X
8.1.8, 8.3
SARS-CoV-2 RT-PCR virus 
testing for 
eligibility e
Within 
7 days prior 
to randomi-
zation
8.1.8, 5.1
Clinical assessments
As applicable until hospital discharge
8.4
9-point ordinal scale
X
X
X
X
8.8.1
Central laboratory assessments p
Correlative samples a,o
Days 1 a, 3, and 7
X
X
X
-
8.3
Immunophenotyping a,g
Days 1 a, 3, and 7
X
X
X
8.3
Serum and nasal swab samples 
for SARS-CoV-2 viral 
load/viral shedding a
Days 1 a, 3, and 7
X
X
X
8.3
Adverse events
X k
X
X
X
X
Xj
8.6
Concomitant medications
X
X
X
X
X
Xj
8.2
Survival status
X
X
Xj
Xj
4.5
anti-HBc = hepatitis B core antibody; aPTT = activated partial thromboplastin time, BSC = best supportive care; CD = cluster of differentiation; CT = computed tomography; 
ECG = electrocardiogram; FU = follow-up; COVID-19 = coronavirus disease 2019; CRP = C-reactive protein; CSP = Clinical Study Protocol; HBsAg = hepatitis B surface 
antigen; HCV = hepatitis C virus; ICF = Informed Consent Form; ICU = intensive care unit; INR = international normalized ratio; PBMC = peripheral blood mononuclear cell;
PT = prothrombin time; qod = every other day; RT-PCR = reverse transcriptase-polymerase chain reaction; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory 
syndrome coronavirus 2; WOCBP = women of childbearing potential.
a
Predose.
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Table 2
Schedule of Activities - Arm 2 (BSC Only)
Assessments
Screening
(Day -3 to 
Day -1 l)
Daily until hospital 
discharge
Day 10 or 
discharge h
Day 14
(±2 days) 
after 
randomi-
zation
Day 28
(±3 days) 
after 
randomi-
zation
Safety FU
38 (±3) days 
after randomi-
zation i
Long-term 
FU 90 (±7) 
days after 
randomi-
zation i,j
CSP 
section
b
Hematology: complete blood count with differential includes, but not limited to white blood cell count, hemoglobin, platelet count, absolute neutrophil count (ANC) or 
percentage, red blood cell count, absolute monocyte count or percentage, and absolute lymphocyte count (ALC) or percentage. 
c
Serum or plasma chemistry: albumin, alkaline phosphatase, alanine transaminase (ALT), aspartate aminotransferase (AST), bicarbonate, blood urea nitrogen (BUN), 
calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphate/phosphorus, potassium, sodium, total bilirubin (direct and indirect bilirubin, if 
available), total protein and uric acid. 
d
Hepatitis serology must include, at a minimum, HBsAg, anti-HBc, and HCV antibody. If additional hepatitis serology is collected per institutional guidelines, it should be 
recorded in the database. Additional testing information is provided in Section 6.6.3 and Section 8.1.8. Subjects can be randomized and started on acalabrutinib after blood 
samples for all HBV and HCV serology tests and for both HBV and HCV PCR tests have been collected, even if the results are not yet available at the time of 
randomization. Follow the hepatitis serology guidelines described in Section 8.1.8.1.
e
COVID-19 infection must be confirmed according to the World Health Organization criteria (including positive nucleic acid test of any specimen [eg, respiratory, blood, 
urine, stool, or other bodily fluid]) within 7 days prior to randomization. If test has already been documented within 7 days prior to randomization, no need to repeat the 
testing again.
f
g
Flow cytometry testing of peripheral blood will include, but is not limited to, CD3+, CD4+, CD8+, CD14+, CD19+, and CD16+/56+ cells.
h
If a subject is discharged prior to Day 7, he/she needs to visit the site for an assessment 2 to 4 days after discharge. Assessments should match those for Day 10.
i
Telemedicine is recommended for capturing adverse events concomitant medications, and survival. Safety laboratory tests can be done at the hospital or a local laboratory 
provided the results are ultimately captured in the clinical database for the study.
j
All subjects will be followed for survival for 90 (± 7) days.
k
After signing the ICF, but prior to randomization, only SAEs should be reported (see Section 8.6.2).
l
Screening can be performed within 1 to 3 days prior to dosing, depending on the local requirements for laboratory turnaround times; ECG can be collected at any time 
during this screening window.
m
Serum ferritin, fibrinogen, PT, aPTT, INR, D-dimer, procalcitonin, and cardiac troponin I should be performed more frequently if clinically indicated.
n
Arterial gases should be collected from subjects if the sample is easily accessible and the procedure will not be painful to subjects (ie, subject is in ICU or has arterial port). 
All available data from the arterial gases should be entered into the database. If the collection of arterial gases is not clinically indicated, the test should not be performed.
o
p
For all central laboratory assessments, sample collection windows of ± 1 day will be allowed for each of Days 3 and 7.
q
Per standard of care, chest imaging can be done by chest x-ray or CT scan with contrast, or any other appropriate means to confirm pneumonia prior to or upon 
hospitalization (within 7 days of randomization).
r
During screening, vital signs should be collected as close as possible to randomization on Day 1. If more than one value is obtained for vital signs during screening, the value 
closest to randomization should be used.
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1.2
Synopsis
Protocol 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
Rationale: 
Coronavirus disease 2019 (COVID-19) is a new pandemic disease caused by the severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2). Most COVID-19 cases (~80%) are mild 
respiratory illnesses. However, some require hospitalization (mostly due to pneumonia) and 
can progress quickly to severe acute lung injury and acute respiratory distress syndrome 
(ARDS) (Huang et al 2020, Wu and McGoogan 2020, Zhou et al 2020), which is associated 
with high mortality. A viral-induced cytokine storm or “hyperimmune response” is 
hypothesized to be a major pathogenic mechanism of ARDS in these patients through 
modulation of pulmonary macrophages and dendritic cells (Channappanavar et al 2016, 
Huang et al 2005, Wong et al 2004, Yoshikawa et al 2009) and/or neutrophils (Herold et al 
2015). Putative inflammatory mediators include interleukin (IL)-1β, IL-6, IL-8, IL-10, tumor 
necrosis factor alpha (TNFα), and monocyte chemoattractant protein-1 (MCP-1) (Chen et al 
2020, Herold et al 2015, Yoshikawa et al 2009).
Bruton’s tyrosine kinase (Btk) is a Tec family non-receptor protein kinase, expressed in B 
cells, myeloid cells, osteoclasts, mast cells and platelets. The function of Btk in signaling 
pathways activated by the engagement of the B-cell receptor has been well established (Buggy 
and Elias 2012). Btk is also involved in the following biologic processes: Fc gamma receptor 
signaling in myeloid cells, mast cell degranulation, osteoclast differentiation, and signaling 
through Toll-like receptors (TLRs) in macrophages and neutrophils. Btk inhibition is 
associated with a decrease in proinflammatory cytokines in patients with hematologic 
malignancies.
Acalabrutinib is a covalent Btk inhibitor with greater selectivity and better physiochemical 
properties than ibrutinib and other Btk inhibitors currently in development. Acalabrutinib is 
currently approved in the United States for the treatment of patients with mantle cell 
lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma [Calquence® 
prescribing information]. Patients with hematologic malignancies treated with acalabrutinib 
have shown statistically significant decreases in the following cytokines: TNFα (p<0.001), 
IL-10 (p<0.001), and MCP-1 (p<0.01) (Byrd et al 2016) and IL-6 (p<0.05) (data on file). 
Decreasing these immunomodulating cytokines in patients with COVID-19 may mitigate the 
pathophysiologic response that leads to the most severe morbidity and mortality associated 
with viral infection. Recently, encouraging results were reported in a case series of patients 
hospitalized with severe COVID-19 and treated with acalabrutinib led by investigators at the 


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National Institutes of Health (Roschewski 2020). Similarly, other BTK inhibitors have shown 
promise in COVID-19 patients with hematologic malignancies (Thibaud et al 2020, Treon et 
al 2020).
The purpose of this Phase 2 study is to evaluate the preliminary efficacy and safety of adding 
acalabrutinib to BSC for subjects with life-threatening COVID-19 symptoms.
Objectives and Endpoints:
Primary Objective
Primary Endpoints/Variables
The overall objective of the study is to evaluate 
the efficacy of adding acalabrutinib to BSC for 
the treatment of COVID-19
Proportion of subjects alive and free of 
respiratory failure at Day 14
For the purpose of this study, respiratory 
failure is defined based on resource utilization 
of any of the following modalities:
o Endotracheal intubation and mechanical 
ventilation
o 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)
o Noninvasive positive pressure ventilation or 
continuous positive airway pressure 
o Extracorporeal membrane oxygenation 
Secondary Efficacy Objective
Secondary Efficacy Endpoints/Variables
To evaluate the efficacy of adding acalabrutinib 
to BSC for the treatment of COVID-19

Proportion of subjects alive and free of 
respiratory failure (defined above) at Day 28

Percent change from baseline in C-reactive 
protein (CRP; time frame: baseline, Days 3, 
5, 7, 10, 14, 28)

Change from baseline in ferritin (time frame: 
baseline, Days 3, 5, 7, 10, 14, 28)

Change from baseline in absolute 
lymphocyte counts (time frame: baseline, 
Days 3, 5, 7, 10, 14, 28)

All-cause mortality at Day 90

Proportion of subjects alive and discharged 
from the intensive care unit (ICU) at Days 14
and 28

Time from randomization to first occurrence 
of respiratory failure or death on study (up to 
28 days after randomization) due to any 
cause


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
Number of days alive and free of respiratory 
failure from randomization to 28 days after 
randomization

Number of days with respiratory failure from 
randomization to 28 days after randomization

Number of days hospitalized from 
randomization to 28 days after randomization

Number of days in ICU (length of stay) from 
randomization to 90 days after randomization

Number of days alive outside of hospital 
from randomization to 28 days after 
randomization

Number of days alive outside of hospital 
from randomization to 90 days after 
randomization

Relative change from baseline in 
oxygenation index (SpO2/FiO2) to Days 3, 5, 
7, and 10

Time to clinical improvement of at least 2 
points (from randomization) on a 9-point 
category ordinal scale through Day 28 (see 
Section 8.8.1)

Time to SpO2 > 94% on room air
Safety Objective
Safety Endpoint/Variable
To evaluate the safety of acalabrutinib in 
subjects with COVID-19 when administered 
with BSC
Type, frequency, severity, and relationship to 
study treatment of any treatment-emergent 
adverse events (TEAEs) or abnormalities of 
laboratory tests, serious adverse events (SAEs), 
or adverse events (AEs) leading to 
discontinuation of study treatment
Pharmacokinetic (PK) Objective
PK Endpoint/Variable
To assess PK of acalabrutinib and its active 
metabolite in subjects with COVID-19 when 
administered with BSC
Summarized plasma concentrations of 
acalabrutinib and ACP-5862 at specified time 
points. PK parameters (eg, area under the 
concentration-time curve [AUC] and maximum 
observed concentration [Cmax]) estimated, as 
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Exploratory Objectives
Exploratory Endpoints/Variables
Overall Design:
This is a multicenter, randomized, open-label, Phase 2 study that will evaluate acalabrutinib 
plus BSC versus BSC in subjects with COVID-19 who are hospitalized.
Subjects will be randomly assigned (1:1) to receive one of the following 2 treatments:

Arm 1: Acalabrutinib 100 mg twice daily (bid) × 10 days + BSC (n=70)

Arm 2: BSC alone (n=70)
For the purpose of this study, BSC is per discretion of the Investigator and institutional 
guidelines. However, refer to Section 5.2 and Section 6.5.3 for prohibited or restricted 
concomitant therapy. Subjects will be randomized based on the following stratification 
factors, which are considered prognostic factors for poor outcome:

Age (≥ 65 vs < 65 years)

Comorbidities (present vs absent).  “Present” is defined as having at least 1 of the 
following comorbidities: 

Cardiovascular disease, as defined by either heart failure New York Heart 
Association class ≥2 or hypertension requiring treatment

Diabetes mellitus requiring treatment

Chronic obstructive pulmonary disease or asthma requiring treatment

Current active solid tumor or hematologic malignancy
Inclusion/exclusion criteria are provided in Section 5. Assessments are provided in 
Section 1.1.
Study Period:
Estimated date of first subject enrolled Q2 2020.
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Estimated date of last subject completed is Q3 2020.
Number of Subjects:
The total number of subjects to be randomized in this study is 140.
Treatments and Treatment Duration:
Acalabrutinib treatment should be administered within 6 hours of randomization on Day 1.
Subjects will take acalabrutinib 100 mg capsules by mouth bid for 10 days (a maximum of 
20 doses). Capsules will be taken with water. The capsules should be swallowed intact and 
subjects should not attempt to open capsules or dissolve them in water.
Subjects on concomitant proton-pump inhibitors (PPIs) must take acalabrutinib with at least
100 mL of COCA-COLA® at room temperature. Other cola beverages (eg, Diet Coke®, 
COCA-COLA Zero Sugar) or juices are not permitted. The capsules should be swallowed 
intact and subjects should not attempt to open capsules or dissolve them in COCA-COLA.
NOTE: COCA-COLA contains glucose (5 g per 100 mL). Blood glucose levels of diabetic 
subjects must be monitored as clinically indicated and blood glucose-lowering medications 
adjusted accordingly.
Acalabrutinib can be taken with or without food.
Retreatment with acalabrutinib is not allowed.
BSC will be administered in both arms per Investigator’s discretion and institutional 
guidelines. 
Refer to Section 6.1 for additional information on treatments administered.
Internal Data Monitoring Committee:
An internal Data Monitoring Committee (iDMC), independent from the Sponsor’s study team, 
will be established to provide oversight of subject safety and monitoring the balance of risks 
and benefits in the study. To fulfil this, the iDMC will review unblinded safety data and a 
planned interim analysis of the primary efficacy endpoint in accordance with the iDMC 
charter (refer to Section 4.4 for details). 
Statistical Methods:
In general, continuous data will be summarized using descriptive statistics (number of 
observations, mean, standard deviation, median, minimum, and maximum). Frequencies and 
percentages will be used for summarizing categorical (discrete) data.


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For subjects randomized to Arms 1 or 2, efficacy will be summarized for the intent-to-treat 
(ITT) population, which is defined as all subjects who were randomized, to be analyzed 
according to the arm to which they are randomly assigned, following “intent-to-treat” 
principle. An estimate of the primary endpoint, the proportion of subjects who are alive and 
free of respiratory failure at Day 14 and its 95% confidence interval (CI; using Wald method 
with continuity correction) will be calculated for each treatment arm. The Cochran-Mantel-
Haenszel χ2 test stratified by age (≥ 65 vs < 65 years) and comorbidities (present vs absent) 
will be used to compare the proportion of subjects who are alive and free of respiratory failure 
at Day 14 between the two treatment arms. An unstratified analysis will also be performed. 
Finally, the difference in the proportion of subjects who are alive and free of respiratory 
failure at Day 14 will also be provided with 95% CIs.
Safety will be summarized for the treated population (Safety population) and will be based on 
the treatment they actually received. In this study, treatment is either acalabrutinib + BSC or 
BSC only. If a subject receives at least 1 dose of acalabrutinib, the subject is considered as 
acalabrutinib-treated, regardless to which arm the subject was randomized. Safety assessments 
will consist of monitoring and recording AEs, SAEs and AEs leading to discontinuation of 
study treatment; measurements of protocol-specified hematology, clinical chemistry, and other 
laboratory variables; measurement of protocol-specified vital signs; and other 
protocol-specified tests that are deemed critical to the safety evaluation of the study treatment.
Refer to Section 9 for additional details. 
1.3
Schema
The general study design is summarised in Figure 1.


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Figure 1
Study Design
bid = twice per day; BSC = best supportive care (for COVID-19 symptoms); SARS-CoV-2+ = severe acute 
respiratory syndrome coronavirus 2 positive.
2.
INTRODUCTION
2.1
Background and Study Rationale
Coronavirus disease 2019 (COVID-19) is a new pandemic disease caused by the severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2). In a retrospective study of 191 patients 
with COVID-19, sepsis was the most frequently observed complication, followed by 
respiratory failure, acute respiratory distress syndrome (ARDS), heart failure, and septic 
shock. While sepsis might be directly caused by SARS-CoV-2 infection, further research is 
needed to investigate the pathogenesis of COVID-19 illness. Most COVID-19 cases (~80%) 
are mild respiratory illnesses. 5% to 15% of these respiratory illnesses require hospitalization 
(mostly due to pneumonia) and can progress quickly to severe acute lung injury and ARDS
(Huang et al 2020, Wu and McGoogan 2020, Zhou et al 2020), which is associated with high 
mortality.  
Normally, human coronaviruses are detected and cleared by the immune system, but a subset 
of patients experience increased severity of symptoms (Channappanavar and Perlman 2017, 
Zhou et al 2020). These symptoms have been associated with the loss of control of the virally 
induced immune response (Li et al 2020). In these cases, the inflammatory response is 
hypothesized to be a major pathogenic mechanism of ARDS through modulation of 


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pulmonary macrophages and dendritic cells (Channappanavar et al 2016, Huang et al 2005, 
Wong et al 2004, Yoshikawa et al 2009) and/or neutrophils (Herold et al 2015). Putative 
inflammatory mediators include interleukin (IL)-1β, IL-6, IL-8, IL-10, tumor necrosis factor 
alpha (TNFα), and monocyte chemoattractant protein-1 (MCP-1) (Chen et al 2020, Herold et 
al 2015, Yoshikawa et al 2009). During the acute phase of coronavirus infection, T cells are 
the critical mediators of clearance of infection, while B cells generate a protective humoral 
response (Zhao et al 2009, Zhao et al 2014). Generation of antibodies against coronaviruses is 
not always protective. In a mouse model, an anti-spike immunoglobulins (specific to 
SARS-COV) could skew the inflammation-resolving response which lead to severe acute lung 
injury in mice (Liu et al 2019).
Bruton’s tyrosine kinase (Btk) is a Tec family nonreceptor protein kinase, expressed in 
B cells, myeloid cells, osteoclasts, mast cells, and platelets. The function of Btk in signaling 
pathways activated by the engagement of the B-cell receptor has been well established (Buggy 
and Elias 2012). Btk is also involved in the following biologic processes: Fc gamma receptor
signaling in myeloid cells, mast cell degranulation, and signaling through Toll-like receptors 
(TLRs) in macrophages and neutrophils. Specifically, Btk is required for TLR 7/8 signaling, 
which recognize single strand RNA viruses such as coronaviruses, signal through Btk in 
macrophages (Page et al 2018).
Recently, Btk inhibition has shown to rescue mice from lethal influenza A-virus induced acute 
lung injury by significantly decreasing lung inflammation and macrophage/monocyte 
mediated cytokines/chemokines (TNFα, IL-1β, IL-6, MCP-1, etc) in the lung homogenates. 
These results suggest that Btk inhibition may represent a new immunomodulatory treatment 
for virally induced lung damage driven by excessive inflammation (Florence et al 2018). 
Additionally, in a murine model of sepsis, acalabrutinib has shown to ameliorate the cardiac 
dysfunction by suppressing pro-inflammatory cytokines/chemokines associated with sepsis
(O'Riordan et al 2019). Patients with hematologic malignancies treated with acalabrutinib 
(Calquence®) have shown significant reduction of several cytokines/chemokines including 
pro-inflammatory markers such as: TNFα (p<0.001), IL-10 (p<0.001), MCP-1 (p<0.01), 
MIP-1β (p<0.001), MIP-1α (p<0.001), IL-16 (p<0.001), TARC (p<0.001), CXCL13 
(p<0.001), Granzyme A (p<0.001) (Byrd et al 2016, Covey 2017), and IL-6 (p<0.05) (data on 
file). Several of these cytokines/chemokines have been shown to be associated with more
severe illness in COVID-19 patients. We hypothesize that acalabrutinib treatment will inhibit 
cells that produce pro-inflammatory cytokines/chemokines, will lead to reduced inflammation 
of the lungs in patients with COVID-19, and mitigate the pathophysiologic response that leads 
to the most severe morbidity and mortality associated with viral infection. Recently, 
encouraging results were reported in a case series of patients hospitalized with severe COVID-
19 and treated with acalabrutinib led by investigators at the National Institutes of Health
(Roschewski 2020). Similarly, other BTK inhibitors have shown promise in COVID-19 
patients with hematologic malignancies (Thibaud et al 2020, Treon et al 2020).


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Together, strong scientific evidence justifies a clinical trial in this patient population. The 
purpose of this Phase 2 study is to evaluate the preliminary efficacy and safety of adding 
acalabrutinib to best supportive care (BSC) for subjects hospitalized due to COVID-19 
symptoms.
2.2
Benefit/Risk Assessment
The lack of established treatments and vaccines for the novel SARS-CoV-2 virus has driven 
major medical centers to an unprecedented overload, which has undoubtedly contributed to 
the mortality observed with this disease. While vaccines and antiviral therapies are urgently 
needed, drugs that can address the pathophysiology of the disease to decrease the morbidity 
and mortality and reduce hospital admissions and intensive care unit (ICU) use are also 
needed without delay.
Btk inhibition may serve as an important addition to the COVID-19 armamentarium by 
reducing the viral-induced hyperimmune response, which leads to lung destruction. 
Acalabrutinib is currently approved in the United States for the treatment of patients with 
mantle cell lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma. As of 
30Oct2019, acalabrutinib has been administered to over 3300 participants in clinical studies, 
including subjects with hematologic malignancies, solid tumors, or rheumatoid arthritis, and 
participants who are healthy subjects or those with mild to moderate hepatic impairment. No 
serious adverse events (SAEs) have been reported in the hepatic impairment trial or in the 
healthy volunteer trials. Some subjects with chronic lymphocytic leukemia have been 
receiving acalabrutinib therapy for more than 5 years. Acalabrutinib has been administered 
alone and in combination with other kinase inhibitors, anti-CD20 antibodies, 
chemoimmunotherapy (eg, bendamustine/rituximab), and an anti-programmed cell death 1 
(PD-1) receptor antibody. No dose-limiting toxicities (DLTs) have been identified for 
acalabrutinib monotherapy or when administered in combination with the aforementioned 
agents. Current clinical safety data supports combining acalabrutinib with other agents.
Refer to the acalabrutinib Investigator’s Brochure for the most up to date safety and efficacy 
information. Identified risks for acalabrutinib are summarized in Section 6.6 and are based on 
events observed in subjects with cancer who have been on long-term treatment with 
acalabrutinib 100 mg twice daily (bid).
Based on the safety profile of acalabrutinib to date, no overt toxicities have been identified 
that would preclude acute treatment for subjects with moderate to severe COVID-19 
symptoms.
Precautionary safety measures, in addition to regular monitoring of safety by an internal Data 
Monitoring Committee (iDMC) and the Sponsor, are included in the study design to enable 
early identification of safety signals in the study and minimize the risk to subjects.  


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3.
OBJECTIVES AND ENDPOINTS
Table 3
Protocol Objectives and Endpoints
Primary Objective
Primary Endpoints/Variables
The overall objective of the study is to evaluate 
the efficacy of adding acalabrutinib to BSC for 
the treatment of COVID-19
Proportion of subjects alive and free of 
respiratory failure at Day 14
For the purpose of this study, 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) Noninvasive positive pressure ventilation or 
continuous positive airway pressure 
(d) Extracorporeal membrane oxygenation 
Secondary Efficacy Objective
Secondary Efficacy Endpoints/Variables:
To evaluate the efficacy of adding acalabrutinib 
to BSC for the treatment of COVID-19

Proportion of subjects alive and free of 
respiratory failure (as defined above) at 
Day 28

Percent change from baseline in CRP (time 
frame: baseline, Days 3, 5, 7, 10, 14, 28)

Change from baseline in ferritin (time frame: 
baseline, Days 3, 5, 7, 10, 14, 28)

Change from baseline in absolute 
lymphocyte counts (time frame: baseline, 
Days 3, 5, 7, 10, 14, 28)

All-cause mortality at Day 90

Proportion of subjects alive and discharged 
from the ICU at Days 14 and 28

Time from randomization to first occurrence 
of respiratory failure or death on study (up to 
28 days after randomization) due to any 
cause

Number of days alive and free of respiratory 
failure from randomization to 28 days after 
randomization

Number of days with respiratory failure from 
randomization to 28 days after randomization

Number of days hospitalized from 
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
Number of days in ICU (length of stay) from 
randomization to 90 days after randomization

Number of days alive outside of hospital 
from randomization to 28 days after 
randomization

Number of days alive outside of hospital 
from randomization to 90 days after
randomization

Relative change from baseline in 
oxygenation index (SpO2/FiO2) to Days 3, 5, 
7, and 10

Time to clinical improvement of at least 2 
points (from randomization) on a 9-point 
category ordinal scale through Day 28 (see 
Section 8.8.1)

Time to SpO2 > 94% on room air
Safety Objective
Safety Endpoint/Variable
To evaluate the safety of acalabrutinib in 
subjects with COVID-19 when administered 
with BSC
Type, frequency, severity, and relationship to 
study treatment of any TEAEs or abnormalities 
of laboratory tests, SAEs, or AEs leading to 
discontinuation of study treatment
PK Objective
PK Endpoint/Variable
To assess PK of acalabrutinib and its active 
metabolite in subjects with COVID-19 when 
administered with BSC
Summarized plasma concentrations of 
acalabrutinib and ACP-5862 at specified time 
points. PK parameters (eg, AUC and Cmax) 
estimated, as appropriate.
Exploratory Objectives
Exploratory Endpoints/Variables
AE = adverse event; AUC = area under the concentration-time curve; BSC = best supportive care; 
 CL/F = apparent clearance; Cmax = maximum observed concentration; 
COVID-19 = coronavirus disease 2019; CRP = C-reactive protein; FiO2 = fraction of inspired oxygen; 
ICU = intensive care unit; 
 
 PK = pharmacokinetics; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory 
syndrome coronavirus 2; SpO2 = oxygen saturation; t1/2 = half-life; TEAE = treatment-emergent adverse 
event; tmax = time to maximum observed concentration; 
 Vdss/F = apparent 
volume of distribution at steady-state.
CCI
CCI
CCI
CCI


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4.
STUDY DESIGN
4.1
Overall Design
This is a multicenter, randomized, open-label, Phase 2 study that will evaluate acalabrutinib 
plus BSC versus BSC in subjects with COVID-19 who are hospitalized.
Subjects will be randomly assigned (1:1) to receive one of the following 2 treatments:

Arm 1:  Acalabrutinib 100 mg bid × 10 days + BSC (n=70)

Arm 2:  BSC alone (n=70)
For the purpose of this study, BSC is per discretion of the Investigator and institutional 
guidelines. However, refer to Section 5.2 and Section 6.5.3 for prohibited or restricted 
concomitant therapy. Subjects will be randomized based on the following stratification 
factors, which are considered prognostic factors for poor outcome:  

Age (≥ 65 vs < 65 years)

Comorbidities (present vs absent). “Present” is defined as having at least 1 of the 
following comorbidities: 

Cardiovascular disease, as defined by either heart failure New York Heart 
Association (NYHA) class ≥2 or hypertension requiring treatment

Diabetes mellitus requiring treatment

Chronic obstructive pulmonary disease or asthma requiring treatment

Current active solid tumor or hematologic malignancy
Inclusion/exclusion criteria are provided in Section 5. Assessments are provided in 
Section 1.1.
4.2
Scientific Rationale for Study Design
The immune system is required to clear viral infections and generate protective immunity 
from viral pathogens like SARS-CoV-2. There is significant evidence that in patients with 
severe respiratory problems, the immune system and inflammation contribute to the severity 
of the disease. Macrophages and neutrophils are key to producing cytokines driving this 
inflammation. The hypothesis being evaluated in this trial is whether Btk inhibition of the 
viral-induced macrophage and neutrophil immune response can decrease inflammation and 
reduce respiratory failure or death. Given the various covariates that contribute to these 
outcomes (eg, lack of consensus on standard of care, actively changing local treatment 
practices, and patients’ comorbid conditions), a single-arm study will likely not be informative 
as data from historical controls are changing almost daily. Hence, this will be a randomized 


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study. Subjects who are hospitalized for COVID-19 disease and meet the eligibility criteria 
will be randomized 1:1 to receive acalabrutinib plus BSC (n=70) versus BSC (n=70).
Stratification by age and comorbidities will be applied to randomization as these are expected 
to be important covariates.
4.3
Justification for Dose
Acalabrutinib 100 mg bid has been evaluated in various indications (ie, B-cell malignancies 
and solid tumours) alone and in combination with anti-CD20 antibodies, chemotherapy, a 
phosphatidylinositol-3-kinase (PI3K) inhibitor, and an anti-PD-1 antibody. No DLTs have 
been identified for acalabrutinib alone or when given in combination with these agents. For all 
of these indications, acalabrutinib was administered daily until disease progression; some 
subjects have been receiving acalabrutinib for > 5 years. The long-term safety experience of 
chronic administration of acalabrutinib 100 mg bid monotherapy and in combination with 
other agents, supports the proposed dosage of acalabrutinib is 100 mg bid for acute treatment. 
In addition, correlative studies—in subjects with chronic lymphocytic leukemia treated with 
acalabrutinib 200 mg once daily (qd) or 100 mg bid—show bid dosing maintained higher Btk 
occupancy and achieved more potent NF-kappaB pathway inhibition compared with qd dosing
(Sun et al 2020). Activation of NF-kappaB occurs in the lungs of patients with ARDS and 
may contribute to the increased expression of proinflammatory mediators (Moine et al 2000). 
Therefore, 100 mg bid dosing is proposed for this study to ensure maximum target 
engagement. 
4.4
Internal DMC
This study will have an iDMC. Details of the roles and responsibilities of the iDMC are 
provided in a charter separate from the protocol. The iDMC will be responsible for oversight 
of subject safety and monitoring the balance of risks and benefits in the study. To fulfil this, 
the iDMC will review unblinded safety data and a planned interim analysis of the primary 
efficacy endpoint. 

The first iDMC review, focusing on safety, will occur when the first 30 subjects are 
randomized into the study and have had 28 days of follow-up from randomization. 

The second iDMC review will occur when the last subject randomized has been followed 
for 14 (±2) days from randomization, and will include the primary efficacy endpoint as 
well as accumulated available safety data. See Section 9.4 for more detail about the 
interim efficacy analysis.
The 2 iDMC reviews may be combined if the study is fully enrolled at the time of the first 
iDMC review. The iDMC may support any health authority interactions or internal 
discussions based on their review. The study team will remain blinded to the data that the 
iDMC will review.


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In addition to the reviews outlined above, the iDMC will review all fatal events on an ongoing 
basis. Further details will be provided in a separate iDMC charter.
4.5
End of Study Definition
The end of study is defined as the last expected visit/contact of the last subject undergoing the 
study.
A subject is considered to have completed the study when he/she has completed his/her last 
scheduled procedure shown in the Schedule of Activities (SoA; Section 1.1). All randomized 
subjects will be followed for survival through 90 (± 7) days after randomization.
All subjects who discontinue the investigational study treatment for any reason other than 
withdrawal of consent, loss to follow-up, or death will have a safety follow up assessment 
28 (± 3) days after the last dose of acalabrutinib (Arm 1), or 38 (± 3) days after randomization 
for those subjects randomized to the BSC arm (Arm 2), as outlined in Section 1.1.
The study may be stopped if, in the judgment of the Sponsor, study subjects are placed at 
undue risk because of clinically significant findings.
See Appendix A 6 for guidelines for the dissemination of study results.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Each subject should meet all the inclusion criteria and none of the exclusion criteria for this 
study to be assigned to a study intervention. Under no circumstances can there be exceptions 
to this rule. Subjects who do not meet the entry requirements are screen failures, refer to 
Section 5.3.
5.1
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the criteria below apply.
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
(ICF).


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3.
SARS-CoV-2 confirmed per World Health Organization criteria (including positive 
nucleic acid test of any specimen [eg, respiratory, blood, urine, stool, or other bodily 
fluid]) within 7 days of randomization.
4.
COVID-19 pneumonia (documented radiographically) requiring hospitalization and 
oxygen saturation (SpO2) <94% on room air or requires supplemental oxygen.
5.
Able to swallow pills.
6.
Willing to follow contraception guidelines (refer to Appendix F).
5.2
Exclusion Criteria 
Subjects are excluded from the study if any of the criteria below apply.
COVID-19 Related Medical Conditions
1.
Respiratory failure at the time of screening (see Section 3 for definition of respiratory 
failure) 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.
Any serious medical condition or abnormality of clinical laboratory tests that, in the 
Investigator's judgment, precludes the subject’s safe participation in and completion of 
the study.
4.
Suspected uncontrolled active bacterial, fungal, viral, or other infection (besides 
infection with SARSCoV2).
5.
In the opinion of the Investigator, progression to death is imminent and inevitable within 
the next 24 hours, irrespective of the provision of treatments.
Medical Conditions
6.
Not expected to survive 28 days given their preexisting, uncorrectable medical 
condition, for example, subjects with, or suspected to have, the following conditions: 
multiorgan failure, poorly controlled neoplasms; endstage cardiac disease; cardiac arrest 
requiring cardiopulmonary resuscitation or with pulseless electrical activity or asystole 
within past 30 days; endstage lung disease; endstage liver disease; or human 
immunodeficiency virus/acquired immunodeficiency syndrome with known endstage 
process.
7.
Pregnant or breast feeding.
8.
Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or bilirubin 
≥3 × upper limit of normal (ULN) and/or severe hepatic impairment (Child-Pugh 
class C; see Appendix G) detected during the screening period (per local laboratory).
Exception: AST and/or ALT can be up to 5 × ULN if considered due to underlying 
COVID-19 disease, but cannot be associated with concurrent elevated bilirubin (up to 
2 × ULN).
9.
Absolute neutrophil count (ANC) < 500/µL at screening (per local laboratory).


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10.
Platelet count < 50,000/µL at screening (per local laboratory).
11.
Estimated creatinine clearance of <30 mL/min calculated using the Cockcroft-Gault 
formula [(140age) × mass (kg)/(72 × creatinine mg/dL) multiply by 0.85 if female].
12.
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 on study.
13.
History of chronic hypercarbia, respiratory failure in past 6 months, or use of continuous 
home oxygen in the setting of severe chronic respiratory disease.
14.
Quadriplegia.
15.
History of primary immunodeficiency, tuberculosis, progressive multifocal 
leukoencephalopathy (PML), aspergillus or other invasive mold/fungal infection, or 
received organ or bone marrow transplantation within 6 months of randomization.
16.
Known active hepatitis B or C infection as determined by active treatment, medical 
history or any routine clinical or laboratory evidence that, in the judgement of the 
Investigator, suggests chronic or active viral hepatitis.
NOTE: Any subject who does not meet this criterion and for whom hepatitis serology 
data are not available prior to randomization, can be randomized into the study, provided 
they 1) do not have a medical history of HBV or HCV infection, 2) there is no clinical or 
laboratory evidence to suggest chronic or active viral hepatitis, and 3) blood samples for 
all HBV and HCV serology and viral load tests (HBV DNA polymerase chain reaction 
[PCR] and HCV RNA PCR) are collected prior to randomization. Refer to guidance in 
Section 8.1.8.1 on how to manage viral hepatitis testing following randomization.
Prior/Concomitant Therapy
17.
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).
18.
Subjects are excluded who have already received prior immunomodulatory/
immunosuppressive treatment intended as specific treatment for COVID-19 (after 
randomization these agents may be permitted – see Section 6.5.2). Note: Steroids are 
permitted prior to randomization and on study. 
19.
Active participation in other drug clinical trials or received treatment with an 
investigational drug within 5 half-lives or 30 days (whichever is longer) of 
randomization/enrollment. 
Exception: Subjects may receive COVID-19-specific antiviral drugs (eg, remdesivir, 
hydroxychloroquine).
20.
Requires or is receiving specific anticoagulation with warfarin or equivalent vitamin K 
antagonists (eg, phenprocoumon) within 7 days of first dose of acalabrutinib. Other 
anticoagulants are permitted.


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21.
History of hypersensitivity (ie, allergic response) to active or inactive excipients of 
acalabrutinib or other Btk inhibitors.
22.
Known cytoreductive chemotherapy treatment within 14 days of randomization.
23.
Major surgery (as defined by the Investigator) within 4 weeks prior to randomization or 
still recovering from prior surgery.
5.3
Screen Failures
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently randomized. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure subjects to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAE unrelated to the disease under investigation.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened subjects should be assigned the same subject number as for the initial 
screening.
6.
STUDY TREATMENTS
Study treatment is defined as any investigational product(s) (including marketed product 
comparator and placebo) or medical device(s) intended to be administered to a study subject 
according to the study protocol. Study treatment in this study refers to acalabrutinib.
6.1
Treatments Administered
6.1.1
Dosing and Duration of Treatment
Acalabrutinib treatment should be administered within 6 hours of randomization on Day 1.
Subjects will take acalabrutinib 100 mg capsules by mouth bid for 10 days (a maximum of 
20 doses). Capsules will be taken with water. The capsules should be swallowed intact and 
subjects should not attempt to open capsules or dissolve them in water. For subjects requiring 
a proton-pump inhibitor (PPI), acalabrutinib must be administered as described in 
Section 6.1.3.1.
Acalabrutinib can be taken with or without food.
Retreatment with acalabrutinib is not allowed.
BSC will be administered in both arms per Investigator’s discretion and institutional 
guidelines.


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6.1.2
Missed Dosing Windows and Doses
The bid doses should be scheduled approximately 12 hours apart. It is recommended that 
acalabrutinib be taken as close to the scheduled time as possible (within ±1 hour). However, if 
the scheduled time is missed, it can be taken up to 3 hours after the scheduled time, with a 
return to the normal schedule upon the following dose for 10 days (a maximum of 20 doses).
If the 3-hour dosing window is missed, the dose must be skipped on that day. Study drug may 
be held for a maximum of 3 consecutive days (6 consecutive doses) from expected dose due to 
toxicity. If a dose is missed due to an adverse event (AE) or for any other reason, missed 
doses should be completed so the subject receives a maximum of 20 doses of study drug, even 
if this is beyond the 10-day dosing period.
6.1.3
Special Considerations
6.1.3.1
Drug-drug Interactions
Drug-drug interactions may occur with some of the drugs being used as BSC (eg, drugs that 
are moderate inhibitor of CYP3A, gastric acid reducing agents), and dosing of acalabrutinib 
may need to be adjusted. Please refer to Section 6.5.4 for detailed information and guidance.
Subjects on concomitant PPIs must take acalabrutinib with at least 100 mL of COCA-COLA®
at room temperature. Other cola beverages (eg, Diet Coke®, COCA-COLA Zero Sugar) or 
juices are not permitted. The capsules should be swallowed intact and subjects should not 
attempt to open capsules or dissolve them in COCA-COLA. NOTE: COCA-COLA contains 
glucose (5 g per 100 mL). Blood glucose levels of diabetic subjects must be monitored as 
clinically indicated and blood glucose-lowering medications adjusted accordingly.
Administration of acalabrutinib with COCA-COLA mitigates the effect of PPIs. Several 
acidic beverages with pH similar to COCA-COLA were assessed (eg, orange drink, lemonade, 
COCA-COLA Zero Sugar, cranberry juice, and grapefruit juice) but not found to be optimal. 
In healthy subjects, pharmacokinetic (PK) exposure following 100-mg acalabrutinib 
suspension in COCA-COLA (nasogastric delivery) is similar in the presence or absence of 
PPIs, and comparable to that of the 100-mg acalabrutinib capsule. In addition, based on a 
verified physiologically-based biopharmaceutics model (Pepin et al 2019), acalabrutinib 
exposure is predicted to be similar between the administration of 100-mg acalabrutinib 
capsule with 100 mL COCA-COLA in the presence of PPIs and the 100-mg acalabrutinib 
capsule taken with water. Overall, these data support the use of acalabrutinib in subjects who 
need to take PPIs for the management of various acid-related disorders.


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6.1.3.2
Subjects With Respiratory Failure and Who Can Still Swallow Pills
Subjects who have respiratory failure before completing the maximum of 20 doses and who 
are still able to swallow pills, will be permitted to continue treatment with acalabrutinib for 
the maximum of 20 doses, according to the Investigator’s clinical judgment.
6.1.3.3
Subjects No Longer Able to Swallow Pills
Subjects who can no longer swallow pills will not be eligible to continue acalabrutinib 
treatment.
6.1.3.4
Vomiting After Acalabrutinib Treatment
If vomiting occurs after taking acalabrutinib, the subject should not retake acalabrutinib until 
the next scheduled dose.
6.1.3.5
Discharged From Hospital Before Treatment Completion
Subjects who are discharged from the hospital before they have completed 10 days (20 doses) 
of acalabrutinib therapy will be required to complete the remaining dosing at home. They 
should adhere to their established dosing schedule and treatment guidelines, including in cases 
where subjects remain on PPIs. These subjects must complete a drug dosing diary to be faxed 
or mailed back to the study site.
6.2
Acalabrutinib Preparation/Handling/Storage/Accountability
Acalabrutinib should be stored according to the instructions on the label affixed to the 
package of the drug product.  
If a drug shipment arrives damaged or if there are any other drug complaints, a Product 
Complaint Form should be completed and emailed to the Sponsor or the Sponsor’s 
representative. Refer to the pharmacy manual and the Investigator’s Brochure for additional 
information regarding the drug product to be used in this study.
The Investigator or designee (eg, pharmacist) must confirm appropriate temperature 
conditions have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.
Only subjects enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized site staff.
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).


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Further guidance and information for the final disposition of unused study treatment are 
provided in the Clinical Study Agreement.
6.3
Measures to Minimise Bias: Randomisation and Blinding
Given the urgent nature of the COVID-19 pandemic, this will be an open-label study. 
However, the study is randomized and include stratification factors as outlined in Section 4.1.
6.3.1
Subject Enrollment and Randomization
All eligible subjects will be centrally randomized using an interactive response technology 
(IRT) that will assign the subjects to either acalabrutinib plus BSC versus BSC, stratified by 
the stratification factors defined in Section 4.1. Before the study is initiated, log-in 
information and directions for the IRT will be provided to each site. 
Investigators should keep a record (ie, the subject screening log) of subjects who entered 
screening. 
At screening, the Investigators or suitably trained delegate will:

Obtain informed consent before any study specific procedures are performed.

Obtain a unique 7-digit enrollment number (E-code), through the IRT the following 
format (ECCNNXXX: CC being the country code, NN being the center number, and 
XXX being the subject enrollment code at the center). This number is the subject’s unique 
identifier and is used to identify the subject on the electronic case report forms (eCRFs).

Determine subject eligibility (see Section 5.1 and Section 5.2).
At randomization, once the subject is confirmed to be eligible, the Investigator or suitably 
trained delegate will:

Log the E-code and stratification factors (age [≥ 65 vs < 65 years] and comorbidities 
[present vs absent]) in the IRT system and the system will sequentially randomize the 
eligible subject to 1 of the 2 treatment arms. 

If the subject is ineligible and not randomized, the IRT should be contacted to terminate 
the subject in the system. 

Subjects will begin treatment on Day 1. Treatment should start no more than 6 hours after 
being randomized. Subjects must not be randomized and treated unless all eligibility 
criteria have been met. 
If a subject withdraws from participation in the study, then his/her enrollment/randomization 
code cannot be reused. A withdrawn subject will not be replaced.


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6.3.1.1
Procedures for Handling Incorrectly Enrolled or Randomized Subjects
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication. There can be no exceptions to this rule. Subjects who are 
enrolled, but subsequently found not to meet all the eligibility criteria must not be randomized 
or initiated on treatment and must be withdrawn from the study.
Where a subject does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the study physician 
immediately, and a discussion should occur between the study physician and the Investigator 
regarding whether to continue or discontinue the subject from treatment. The study physician 
must ensure all decisions are appropriately documented and that the potential benefit:risk 
profile remains positive for the subject.
6.3.1.2
Methods for Assigning Treatment Groups
The actual treatment assigned to subjects will be determined by the randomization scheme in 
the IRT. A stratified permuted block randomization scheme will be used, with the 
stratification factors defined in Section 4.1. The randomization scheme will be produced by a 
computer software program that incorporates a standard procedure for generating 
randomization numbers. 
Randomization codes will be assigned strictly sequentially, within each stratum, as subjects 
become eligible for randomization. 
6.3.1.3
Methods for Ensuring Blinding
This is an open-label study for the personnel at study sites. Specific treatment to be taken by a 
subject will be assigned using an IRT. The site will contact the IRT prior to the start of study 
treatment administration for each subject. The site will record the treatment assignment on the 
applicable case report form, if required. To maintain the integrity of the study, the Sponsor’s 
personnel directly involved in the study conduct will, under no circumstances, view data 
aggregated by treatment arm during the course of the study.
6.4
Treatment Compliance
The study treatment should only be used as directed in this protocol. Details of treatment with 
the study treatment, including change from the dosing schedule, dose interruptions, dose 
reductions, and dose discontinuations, should be recorded in the eCRF. The investigational 
product will not be distributed to the study site until the contract is concluded between the 
study site and the Sponsor. The Investigator or designee is responsible for managing the 
investigational product from time of receipt by the study site until the destruction of all unused 
investigational product at that site. The Investigator(s) is responsible for ensuring that all 
unused investigational product is returned to the site by the subject(s).


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6.5
Concomitant Therapy
6.5.1 
Premedications
No specific premedications or supporting medications are required in conjunction with 
acalabrutinib administration.
6.5.2 
Permitted Concomitant Therapy
BSC for COVID-19 is required for all subjects in this study except as listed in Section 5.2 and 
Section 6.5.3. Given the rapid emergence of new data related to COVID-19, BSC could 
change during the duration of the study. The use of therapies such as remdesivir, therapeutic 
plasma, corticosteroids, or other immunomodulatory agents (eg, tocilizumab) is permitted if 
recommended by local authorities and part of institutional policies or guidelines. The 
concomitant administration of immunosuppressive agents with acalabrutinib may require 
additional safety monitoring as determined by the treating clinician. Investigators should 
maintain prohibitions of certain concurrent medications for other reasons as listed in 
Section 6.5.3.
6.5.3 
Prohibited or Restricted Concomitant Therapy
6.5.3.1 
Medications Prohibited for Subjects Treated with Acalabrutinib
The medications described below are prohibited for subjects treated with acalabrutinib.
Certain anticoagulants: Warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) 
are prohibited for all subjects treated with acalabrutinib. Subjects who require prophylaxis or 
therapeutic anticoagulation for thrombosis (deep vein thrombosis or pulmonary embolism) 
will be allowed to receive therapeutic anticoagulation with a non-vitamin K inhibitor class of 
anticoagulants (eg, heparin or low-molecular-weight heparin).
Strong CYP3A inhibitors or inducers: Drug-drug interactions may occur with some of the 
drugs being used as BSC (eg, drugs that are strong inducers or strong inhibitors of CYP3A). 
The concomitant use of strong inhibitors of CYP3A (see Appendix E) should be avoided. If a 
subject requires a strong CYP3A inhibitor while on treatment with acalabrutinib, discontinue 
acalabrutinib treatment. Conversely, concomitant administration of a strong inducer of 
CYP3A has the potential to decrease exposure of acalabrutinib and could reduce efficacy. 
Therefore, the concomitant use of strong CYP3A inducers should be avoided. If a subject 
requires a strong CYP3A inducer while on treatment with acalabrutinib, discontinue 
acalabrutinib. For additional information on drugs with potential drug-drug interactions, refer 
to Section 6.5.4.
6.5.3.2 
Medications Prohibited for All Randomized Subjects
Immunomodulatory drugs intended as treatment for COVID-19 but not considered standard 
of care according to local institutional guidelines are prohibited for all randomized subjects in 


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the study through Day 14. Subjects who are taking immunomodulatory drugs for other 
medical conditions (eg, tocilizumab for rheumatoid arthritis) may continue with treatment
upon discussion with the Medical Monitor. 
Refer to Section 5.2 for additional restrictions on concomitant therapy. 
6.5.4
Acalabrutinib Drug-drug Interaction Guidance in the Presence of 
Life-threatening COVID-19 Infection
Drug-drug interaction recommendations provided for acalabrutinib in this protocol are made 
with respect to the presence of life-threatening COVID-19 infection and ability to achieve 
pharmacodynamic (PD) Btk receptor occupancy steady-state in target B-cell and monocytic 
populations. Therefore, the Sponsor recommends that all eligible subjects with COVID-19 
begin dosing with acalabrutinib 100 mg bid. The duration of acalabrutinib therapy will be 
limited to 10 days (a maximum of 20 doses). Table 4 provides moderate CYP3A inhibitors
and acid reducing agent guidance for subjects with COVID-19. Refer to Appendix E for a list 
of common CYP3A inhibitors/inducers and gastric acid reducing medicines.
Table 4
Acalabrutinib Use with Moderate CYP3A Inhibitors and Gastric Acid 
Reducing Agents
Co-administered 
Medicines
Recommended Acalabrutinib Use
CYP3A 
Inhibitor
Moderate CYP3A 
inhibitor
Monitor subjects closely for adverse reactions if taking 
moderate CYP3A inhibitors. For subjects who 
experience an intolerable adverse event (ie, Grade 3-4) 
attributed to acalabrutinib therapy, reduce the dose to 
100 mg once daily.
Gastric Acid 
Reducing 
Medicines
Proton-pump inhibitors
(PPIs)
Avoid concomitant use. If PPI concomitant use cannot 
be avoided, dose modification of acalabrutinib is not 
necessary; however, acalabrutinib must be 
administered with at least 100 mL of COCA-COLA to 
improve acalabrutinib absorption (refer to 
Section 6.1.3.1). Other cola beverages are not 
permitted.
H2-receptor antagonists
Take acalabrutinib 2 hours before taking a H2-receptor 
antagonist. 
Antacids
Separate dosing by at least 2 hours.


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6.5.4.1
Active Substances That May Increase Acalabrutinib Plasma Concentrations
CYP3A Inhibitor
Co-administration with a strong CYP3A inhibitor (200 mg itraconazole qd for 5 days) 
increased acalabrutinib maximum observed concentration (Cmax) and area under the 
concentration-time curve (AUC) by 3.7- and 5.1-fold in healthy subjects (N=17), respectively.
Consider alternative therapies that do not strongly inhibit CYP3A activity. In subjects 
requiring strong CYP3A inhibitors (eg, ketoconazole, conivaptan, clarithromycin, indinavir, 
itraconazole, ritonavir, telaprevir, posaconazole, voriconazole), discontinue acalabrutinib
treatment. 
6.5.4.2
Active Substances That May Decrease Acalabrutinib Plasma Concentrations
CYP3A Inducers 
Co-administration of a strong CYP3A inducer (600 mg rifampin qd for 9 days) decreased 
acalabrutinib Cmax and AUC by 68% and 77% in healthy subjects (N=24), respectively.
Consider alternative therapies to strong inducers of CYP3A activity (eg, phenytoin, rifampin, 
carbamazepine). Avoid St. John’s wort which may unpredictably decrease acalabrutinib 
plasma concentrations. If these inducers cannot be avoided, discontinue acalabrutinib 
treatment.
Gastric Acid Reducing Medications
Acalabrutinib solubility decreases with increasing pH. Co-administration of acalabrutinib with 
an antacid (1 g calcium carbonate) decreased acalabrutinib AUC by 53% in healthy subjects. 
Co-administration with a PPI (40 mg omeprazole for 5 days), decreased acalabrutinib AUC by 
43%.
If treatment with an acid reducing agent is required, consider using an antacid (eg, calcium 
carbonate), or an H2-receptor antagonist (eg, famotidine). For use with antacids, separate 
dosing by at least 2 hours. For H2-receptor antagonists, take acalabrutinib 2 hours before 
taking the H2-receptor antagonist.
Due to the long-lasting effect of PPIs, separation of doses with PPIs may not eliminate the 
interaction with acalabrutinib. In subjects requiring treatment with PPIs (eg, omeprazole, 
esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole) during the study, 
acalabrutinib must be administered with at least 100 mL COCA-COLA at room temperature 
to improve acalabrutinib absorption (see Section 6.1.3.1). Other cola beverages are not 
permitted.


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Dose modification of acalabrutinib is not necessary when co-administered with gastric acid 
reducing medications.
6.6
Risks Associated with Acalabrutinib
The safety profile of acalabrutinib in patients with COVID-19 is not yet established. The 
COVID-19 population is distinct from patients with hematologic malignancies, the population 
for which acalabrutinib is indicated, and the duration of acalabrutinib treatment for COVID-19 
is much shorter than for the indicated population with hematologic malignancies. Therefore, 
the safety profile of acalabrutinib in the COVID-19 population may differ from that 
established in the cancer population.
The experience with chronic administration of acalabrutinib in hematologic cancer studies is 
described below. Table 5 summarizes the risks associated with acalabrutinib (any grade, 
≥Grade 3, and mean time to first onset) based on 1040 subjects with hematologic 
malignancies who received acalabrutinib monotherapy (data on file). 
For more detailed information on treatment-emergent adverse events (TEAEs), refer to the 
acalabrutinib Investigator’s Brochure. Full details regarding the clinical safety of acalabrutinib 
are presented in Sections 5 and 6 of the acalabrutinib Investigator’s Brochure.
Table 5
Risks Associated with Acalabrutinib Monotherapy in Subjects With 
Hematologic Malignancies (N = 1040)
Event category
Number (%) of subjects
Median (min, max), months
Any grade
≥Grade 3
Time to first onset
Hemorrhage
482 (46.3)
28 (2.7)
1.2 (0, 53)
Major hemorrhage
37 (3.6)
28 (2.7)
9.8 (0, 44)
Infections
694 (66.7)
183 (17.6)
3.2 (0, 45)
Anemia
144 (13.8)
81 (7.8)
0.7 (0, 41)
Neutropenia
163 (15.7)
148 (14.2)
3.1 (0, 44)
Thrombocytopenia
93 (8.9)
50 (4.8)
1.7 (0, 39)
Second primary malignancy
127 (12.2)
43 (4.1)
9.5 (0, 50)
Atrial fibrillation
46 (4.4)
13 (1.3)
17.4 (0, 43)
max = maximum; min = minimum.
6.6.1
Hemorrhage
Bleeding events, some fatal, including central nervous system, respiratory, and gastrointestinal 
hemorrhage, have been reported in subjects treated with acalabrutinib. Subjects receiving 
antiplatelet or anticoagulant therapies may be at increased risk of hemorrhage and should be 
monitored for signs of bleeding. Subjects with hemorrhage should be managed per 
institutional guidelines or as clinically indicated.


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6.6.2
Infections
Serious infections, including fatal events, have been reported in subjects treated with 
acalabrutinib (eg, aspergillosis). Subjects should be monitored for signs and symptoms of 
infection and treated as medically appropriate. Consultation with the coordinating 
Investigators or the Medical Monitor is recommended for cases of infection with invasive 
fungi including aspergillosis.
6.6.3
Hepatitis B and C Reactivation
No reports of HCV reactivation have been received in the acalabrutinib clinical program to 
date, and there are no published reports of HCV reactivation following Btk inhibitors that are 
available to the Sponsor.
HBV reactivations are frequently reported in the setting of acalabrutinib treatment. Among 
4053 subjects across all clinical studies investigating acalabrutinib to date, 9 subjects had
HBV reactivation (1 fatal, 8 non-serious) after a median duration of therapy of 248 days 
(range, 43 to 582 days). One subject experienced a serious Grade 4 event that subsequently 
resulted in liver failure and death. Subjects who are hepatitis B core antibody (anti-HBc)
positive or have a known history of HBV infection may be monitored monthly with a 
quantitative PCR test for HBV DNA, when clinically indicated. Any subject with a rising viral 
load (above lower limit of detection) should discontinue study treatment and have antiviral 
therapy instituted and a consultation with a physician with expertise in managing hepatitis B. 
Insufficient data exist regarding the safety of resuming acalabrutinib in subjects who develop 
HBV reactivation.
6.6.4
Progressive Multifocal Leukoencephalopathy 
Across the acalabrutinib clinical development program, 2 subjects had events of PML (both 
serious) after receiving acalabrutinib. Signs and symptoms of PML may include cognitive and 
behavioral changes, language disturbances, visual disturbances, sensory deficits, weakness, 
and coordination and gait difficulties. If PML is suspected, hold further treatment with 
acalabrutinib until PML is excluded. If PML is confirmed, permanently discontinue 
acalabrutinib (see Section 6.7).
6.6.5
Cytopenias
Grade 3 or 4 events of cytopenias, including anemia, neutropenia, and thrombocytopenia,
have occurred in subjects treated with acalabrutinib. Monitor blood counts as specified in the 
SoA and as medically appropriate. Please refer to Section 6.7 for study drug modification 
guidance. Subjects with cytopenias should be managed according to institutional guidelines or 
as clinically indicated.


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6.6.6
Second Primary Malignancies 
Second primary malignancies, including non-skin carcinomas solid tumors and skin cancers, 
have been reported in subjects with B-cell malignancies treated with acalabrutinib. The most 
frequent second primary malignancy was skin cancer (squamous basal cell carcinoma of the 
skin). Subjects should be monitored for signs and symptoms of malignancy. Subjects who 
develop a malignancy should be managed according to institutional guidelines with diagnostic 
evaluations or as clinically indicated, and it may be necessary for subjects to permanently 
discontinue study treatment. Continuation of acalabrutinib treatment should be discussed with 
the Medical Monitor 
6.6.7
Atrial Fibrillation 
Monitor for symptoms of atrial fibrillation and atrial flutter (eg, palpitations, dizziness, 
syncope, chest pain, dyspnea), and obtain an electrocardiogram (ECG) as clinically indicated. 
Subjects with atrial fibrillation should be managed per institutional guidelines with supportive 
care and diagnostic evaluations or as clinically indicated.
6.6.8
Reference Safety Information
See the Reference Safety Information in the acalabrutinib Investigator’s Brochure for 
assessment of expectedness of serious adverse reactions.
6.7
Dose Modification and Toxicity Management
In general, no acalabrutinib dose modification is required if a subject experiences a Grade 1 or 
Grade 2 AE. Acalabrutinib therapy should be modified or discontinued, however, for the 
following AEs:
Event
Acalabrutinib Dose 
Modification/Discontinuation
Hematological
Grade 4 neutrophil count decrease 
(ANC < 500/μL)
•
Hold acalabrutinib, and consider introducing 
growth factors (eg, G-CSF) and continue to 
monitor ANC
•
If neutropenia has improved to Grade 1 or 
baseline within 3 days of event onset, restart 
acalabrutinib
•
If neutropenia has not improved to Grade 1 or 
baseline within 3 days of event onset, 
discontinue acalabrutinib 
Any grade febrile neutropenia lasting more 
than 2 days
•
Discontinue acalabrutinib 
•
Consider introducing growth factors (eg, G-
CSF), evaluate subject for infection, and begin 
antibiotic treatment per institutional guidelines


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Event
Acalabrutinib Dose 
Modification/Discontinuation
Presence of significant bleeding events with 
or without thrombocytopenia, such as:
•
Grade 3 or 4 hemorrhage
•
Any grade serious hemorrhage event
•
Any grade intracranial hemorrhage or 
hematoma
Discontinue acalabrutinib
Grade 4 platelet count decrease
(< 25,000/mm3)  
•
Hold acalabrutinib and consider platelet 
transfusions, as clinically indicated
•
If thrombocytopenia has improved to ≤Grade 
2 within 3 days of event onset, restart 
acalabrutinib
•
If thrombocytopenia has not improved to 
≤Grade 2 within 3 days of event onset, 
discontinue acalabrutinib
Gastrointestinal/hepatic
Grade 3 or 4 nausea, vomiting, or diarrhea, if 
persistent despite optimal antiemetic and/or 
antidiarrheal therapy
Discontinue acalabrutinib
Acute hepatic toxicity or hepatic failure, 
which is of such severity that after evaluation 
by a hepatologist, would consider appropriate 
to stop all non-essential medications
Discontinue acalabrutinib 
Cardiovascular
Grade 3 or 4 hypertension, if persistent 
despite optimal antihypertensive therapy
Discontinue acalabrutinib
Grade 3 or 4 arrhythmias that are sustained or 
associated with cardiovascular instability
Discontinue acalabrutinib
Infections
Severe opportunistic infection (such as 
Pneumocystis jirovecii pneumonia, 
toxoplasmosis, disseminated Mycobacterium 
avium complex, PML)
Discontinue acalabrutinib
Grade 3 confirmed bacterial infections 
•
Hold acalabrutinib
•
If infection does not respond to appropriate 
antimicrobial therapy within 48-72 hours, 
discontinue acalabrutinib
Grade 4 confirmed bacterial infections
Discontinue acalabrutinib
Other
Any non-COVID-19-related Grade 4 AE
Discontinue acalabrutinib
Any other Grade 3 or Grade 4 toxicity that 
persists despite optimal medical management
Discontinue acalabrutinib


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Event
Acalabrutinib Dose 
Modification/Discontinuation
AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; ALP = alkaline 
phosphatase; AST = aspartate aminotransferase; G-CSF = granulocyte colony-stimulating factor; 
PML = progressive multifocal leukoencephalopathy.
Clinical judgment should be used to determine appropriate management of the subject during 
any AE. 
Acalabrutinib may be held for a maximum of 3 consecutive days (6 consecutive doses) from 
expected dose due to toxicity. Any other clinically important events where dose delays may be 
considered appropriate by the Investigator, as well as continuation of therapy after a dose is 
held beyond 3 days, must be discussed with the Medical Monitor. If a dose is missed due to an 
AE or for any other reason, missed doses should be completed so the subject receives a 
maximum of 20 doses of study drug, even if this is beyond the 10-day dosing period.
6.7.1
Renal Impairment
After administration of a single 100 mg radiolabeled acalabrutinib dose in healthy subjects, 
84% of the dose was recovered in the feces and 12% of the dose was recovered in the urine 
(2% acalabrutinib). No clinically relevant PK difference was observed in subjects with mild or 
moderate renal impairment (estimated glomerular filtration rate [eGFR] ≥30 mL/min/1.73 m2, 
as estimated by Modification of Diet in Renal Disease [MDRD] equation). Acalabrutinib PK 
and clinical safety has not been evaluated in subjects with severe renal impairment (eGFR 
<29 mL/min/1.73 m2, MDRD) or renal impairment requiring dialysis. 
The effect of dialysis on acalabrutinib plasma concentrations has not been studied. 
Acalabrutinib is rapidly absorbed, metabolised and distributed. The plasma protein binding is 
97.5% and is noncovalent (potentially dialyzable). 
 
 
 If subjects with 
COVID-19 enrolled in this study require acute hemodialysis, it is recommended to dose 
acalabrutinib 100 mg and pause hemodialysis for 2 to 4 hours after acalabrutinib 
administration to allow for absorption and distribution to target cell populations.
6.7.2
Hepatic Impairment
Acalabrutinib clinical safety has not been evaluated in patients with severe hepatic 
impairment. If acalabrutinib is administered to subjects with hepatic impairment, monitor 
subjects carefully for AEs and follow recommendation dose modifications in Section 6.7.
The PK acalabrutinib in subjects with hepatic impairment has been studied. Briefly, the AUC 
of acalabrutinib increased 1.9-fold in subjects with mild hepatic impairment (Child-Pugh 
class A), 1.5-fold in subjects with moderate hepatic impairment (Child-Pugh class B) and 
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5.3-fold in subjects with severe hepatic impairment (Child-Pugh class C) compared with 
subjects with normal liver function. No clinically relevant PK difference in ACP-5862 was 
observed in subjects with severe hepatic impairment (Child-Pugh class C) compared with 
subjects with normal liver function. No clinically relevant PK differences in acalabrutinib and 
ACP-5862 were observed in subjects with mild or moderate hepatic impairment (total 
bilirubin less and equal to ULN and AST greater than ULN, or total bilirubin greater than 
ULN and any AST) relative to subjects with normal hepatic function (total bilirubin and AST 
within ULN).
6.8
Treatment After the End of Study
Not applicable.
7.
DISCONTINUATION OF TREATMENT AND SUBJECT 
WITHDRAWAL 
7.1
Discontinuation of Study Treatment 
Subjects may discontinue study treatment for the following reasons:

Positive hepatitis B surface antigen (HBsAg), HBV-DNA, or HCV-RNA test result after 
randomization

Unable to swallow pills

Completed treatment

Pregnancy

AE

Investigator’s decision

Subject’s withdrawal of consent from study

Decision by the Sponsor to terminate the study

Lost to follow-up

Death

Other
The Investigator should instruct the subject to contact the site before or at the time if study 
treatment is stopped. A subject that decides to discontinue study treatment will always be 
asked about the reason(s) and the presence of any AEs. The date of last intake of study 
treatment should be documented in the eCRF. Refer to the guidance in Section 6.5.3.
All subjects will be followed through 90 (± 7) days after randomization.


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Subjects who receive acalabrutinib should have follow up assessments for safety 28 (± 3) days 
after the last dose of acalabrutinib (whether due to discontinuation or completion of dosing). 
Subjects who have been randomized to the BSC arm should have a follow up assessment for 
safety 38 (± 3) days after randomization. 
For the safety and survival follow-up visits, telemedicine is recommended for capturing AEs
and concomitant medications. Safety laboratory tests can be done at the hospital or a local 
laboratory provided the results are ultimately captured in the clinical database for the study.
7.2
Subject Withdrawal from the Study
A subject may withdraw from the study (eg, withdraw consent), at any time (investigational 
product and assessments) at his/her own request, without prejudice to further treatment.
Subjects (in either study arm) with a positive HBsAg, HBV-DNA, or HCV-RNA test result 
after randomization will be withdrawn from the study.
A subject who considers withdrawing from the study must be informed by the Investigator 
about modified follow-up options (eg, telephone contact, a contact with a relative or treating 
physician, or information from medical records).
If the subject withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.
If a subject withdraws from the study, he/she may request destruction of any samples taken, 
and the Investigator must document this in the site study records.  
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any AE. The Investigator will follow up subjects as medically indicated. 
7.3
Lost to Follow-Up
A subject will be considered lost to follow-up if he/she fails to return for scheduled visits or is 
unable to be contacted by the study site 
In the case a subject is lost to follow-up, every possible effort must be made by the study site 
personnel to contact the subject and determine the reason for discontinuation. Site personnel 
should check hospital records and a publicly available death registry (if available), as well as 
checking with the subject’s current physician, to obtain a current survival status. The measures 
taken to follow up must be documented (the applicable eCRF modules will be updated).
When a subject withdraws before completing the study, the reason for withdrawal must be 
documented in the eCRF and in the source documents. Subjects who withdraw consent should 


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still be encouraged to complete the SFU assessments before withdrawing consent, but these 
assessments cannot be mandated once consent is withdrawn.
Subjects who are withdrawn or removed from study treatment will not be replaced.
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the SoA in Section 1.1.
The Investigator will ensure that data are recorded on the eCRF. 
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries per the Clinical Study Agreement. The Investigator 
will sign the completed eCRF. A copy of the completed eCRF will be archived at the study 
site.
Immediate safety concerns should be discussed with the Medical Monitor upon occurrence or 
awareness to determine if the subject should continue or discontinue study treatment.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of 
all subjects screened and to confirm eligibility or record reasons for screening failure, as 
applicable.  
8.1
Screening Assessments
Procedures conducted as part of the subject’s clinical management of COVID-19 symptoms 
and obtained before signing of the ICF may be used for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within 
24 hours of signing the informed consent.
8.1.1
Informed Consent
The informed consent process must be followed per local and institutional guidelines 
(Appendix A 3).
8.1.2
Demographics
The following subject demographics will be collected: age, sex, race, ethnicity, and history of 
substance abuse (cigarettes [yes/no; if yes, specify packs per day], vaping [yes/no], 
recreational drugs [yes/no; if yes, specify name], alcohol [yes/no; if yes, specify amount]).


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8.1.3
Confirmation of Eligibility
Subject eligibility for enrollment will be assessed per Section 5.
8.1.4
Medical History
Collect and record the subject’s relevant medical history through review of medical records 
and by interview.  Concurrent medical signs and symptoms must be documented to establish 
baseline severities.  Information on COVID-19 epidemiology will also be collected.
8.1.5
Physical Examinations and Chest Imaging, Electrocardiogram, and 
Echocardiogram
The screening physical examination will be symptom-directed and include height, weight and 
lung auscultation.
Per standard of care, chest imaging can be done by chest x-ray or CT scan with contrast, or 
any other appropriate means to confirm pneumonia prior to or upon hospitalization (within 
7 days of randomization). Post treatment assessment will continue as clinically indicated.
A single 12-lead ECG and will be done during the screening period and at Day 10 or upon 
discharge from the hospital. ECG should be collected during the treatment period, as clinically 
indicated. For all ECGs, details of rhythm, ECG intervals, and an overall evaluation will be 
recorded.
An echocardiogram should be collected at baseline or during the treatment period, as 
clinically indicated per SoA. Percentage left ventricular ejection fraction should be recorded. 
If the Investigator considers an abnormal ECG or echocardiogram finding at screening or 
baseline to be clinically significant, that finding should be reported as a concurrent condition. 
Any clinically significant abnormal ECG or echocardiogram findings during the treatment 
period should be recorded in the source document and the AE section of eCRF, according to 
standard AE collection and reporting processes.
8.1.6
Vital Signs
The vital signs to be collected are blood pressure, respiratory rate, oximetry, pulse, and body 
temperature. During screening, vital signs should be collected as close as possible to 
randomization on Day 1. If more than one value is obtained for vital signs during screening, 
the value closest to randomization should be used. The oxygen-hemoglobin saturation of the 
blood will be assessed using standard pulse oximetry or by arterial blood gas for those 
subjects who have an arterial blood gas obtained.


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8.1.7
Urine or Serum Pregnancy 
Screening pregnancy testing will be done on women of childbearing potential only (refer to 
Appendix F).
8.1.8
Laboratory Tests
The screening period should occur immediately prior to randomization and dosing. Screening 
can be performed within 1 to 3 days prior to dosing, depending on the local requirements for 
laboratory turn-around times. The following laboratory tests will be done during screening as 
specified in the SoA (Section 1.1) using the sites local laboratories:

Urine or serum pregnancy test (women of childbearing potential only)

Hematology studies must include complete blood count (CBC) with differential 
including, but not limited to white blood cell count, hemoglobin, platelet count, ANC or 
percentage, red blood cell count, absolute monocyte count or percentage, and absolute 
lymphocyte count (ALC) or percentage. 

Chemistry will include albumin, alkaline phosphatase, ALT, AST, bicarbonate, blood 
urea nitrogen (BUN), calcium, chloride, creatinine, glucose, lactate dehydrogenase 
(LDH), magnesium, phosphate/phosphorus, potassium, sodium, total bilirubin (direct and 
indirect bilirubin, if available), total protein, and uric acid.  

Arterial blood gases (if available; see Section 8.4.1)

C-reactive protein (CRP)

Serum ferritin, fibrinogen, D-dimer, procalcitonin

Prothrombin time (PT), activated partial thromboplastin time (aPTT), international 
normalized ratio (INR)

Cardiac troponin I

Hepatitis serology must include, at a minimum, HBsAg, anti-HBc, and HCV antibody (if 
additional hepatitis serology is collected per institutional guidelines, it should be recorded
in the database) (see hepatitis serology guidelines in Section 8.1.8.1)

SARS-CoV-2 reverse transcriptase-polymerase chain reaction viral test. Sites should 
report this as positive/negative.
Refer to the laboratory manual for instructions on processing and shipping. Additional 
handling information provided in Appendix C.
8.1.8.1
Hepatitis Serology Guidelines
If feasible, hepatitis serology data should be obtained prior to randomization. However, if not 
feasible, sites should proceed as described below.
Subjects must not meet Exclusion Criterion 16 (see Section 5.2): 

Known active hepatitis B or C infection as determined by active treatment


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
Medical history or any routine clinical or laboratory evidence, that in the judgement of the 
Investigator, suggests chronic or active viral hepatitis.
Blood samples for all HBV and HCV serology tests, and for both HBV and HCV PCR tests
must then be collected before randomization.

If results become available before randomization, subjects with positive HBsAg or 
HBV-DNA or HCV-RNA test results will be excluded and should be treated per 
institutional guidelines.

Subjects who are anti-HBc positive and who are HBsAg negative will need to have a 
negative or undetectable hepatitis B viral load (HBV-DNA) by quantitative PCR 
result. 

Subjects who are HCV antibody positive will need to have a negative PCR.

If results are not available at the time of randomization, subjects can be randomized and 
started on acalabrutinib. If any of the HBsAg, HBV-DNA, or HCV-RNA test results are 
positive after randomization, the following must occur:

Discontinue further treatment with acalabrutinib.

Withdraw the subject from the study (applies to both study arms).

Modify BSC as clinically indicated per Investigator judgement.

Initiate a monitoring and therapeutic plan for HBV/HCV infection according to
institutional guidelines and Investigator judgement.
8.2
Concomitant Medications
Document all concomitant medications and procedures from the start of screening procedures 
through the end of participation on the study (refer to Section 1.1). Reason for treatment 
should be captured as “disease under study”.
Medications used as BSC should be captured as concomitant medications.
8.3
On-study Procedures 
Planned time points for all on-study procedures are provided in the SoA (Section 1.1). While 
the subject remains hospitalized, assessments should be performed per SoA until discharge. 
The date of admission and discharge will be collected for all subjects. If a subject is 
discharged prior to Day 10, the subject should continue to take acalabrutinib at home. If the 
subject was discharged prior to Day 7, the subject should return to the clinic 2 to 4 days after 
discharge and complete the Day 10 assessment as outlined in the SoA.
The following laboratory evaluations will be done at the local laboratories while on study:

Urine or serum pregnancy test (women of childbearing potential only)


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
Hematology studies must include complete blood count (CBC) with differential 
including, but not limited to white blood cell count, hemoglobin, platelet count, ANC or 
percentage, red blood cell count, absolute monocyte count or percentage, and absolute 
lymphocyte count (ALC) or percentage.

Chemistry will include albumin, alkaline phosphatase, ALT, AST, bicarbonate, BUN, 
calcium, chloride, creatinine, glucose, LDH, magnesium, phosphate/phosphorus, 
potassium, sodium, total bilirubin (direct and indirect bilirubin, if available), total protein, 
and uric acid.  

Arterial blood gases (if available; see Section 8.4.1)

CRP

Serum ferritin, fibrinogen, D-dimer, procalcitonin*

PT, aPTT, INR*

Cardiac troponin I*

Hepatitis B serology will be collected as clinically indicated for subjects with a known 
history of hepatitis B exposure (see Section 6.6.3)
*These laboratory tests should be performed more frequently than described in the SoA 
(Section 1.1) if clinically indicated.
Samples (peripheral blood samples for mononuclear cells, serum/plasma, and RNA) will be 
collected per the time points delineated in the SoA (Section 1.1) and sent to respective central 
laboratories for the following tests:

 

 

Immunophenotyping: Flow cytometry testing of peripheral blood will include, but is not 
limited to, CD3+, CD4+, CD8+, CD14+, CD19+ and CD16+/56+ cells

Serum and nasal swab samples for SARS-CoV-2 viral load/viral shedding 

 

Plasma samples for acalabrutinib PK (subjects on acalabrutinib arm only)

NOTE: Safety, CRP, PK, PD, and correlative laboratory tests are considered Tier 1 and 
should not be missed. The site must follow the SoA.
Refer to the laboratory manual for instructions on processing and shipping. Additional 
handling information provided in Appendix C.
Other procedures to be performed while on study include:

Chest imaging
CCI
CCI
CCI
CCI


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
ECG

Echocardiogram

Vital signs
8.4
Clinical Assessments During Hospitalization
8.4.1
Oxygen Treatments and Ventilator Use
If a subject requires oxygen supplementation, data will be recorded, including method of 
oxygen supplementation, maximum daily flow rate and fraction of inspired oxygen [FiO2].
If a subject requires mechanical ventilation, data will be recorded regarding whether ventilator 
weaning was attempted. 
For subjects on mechanical ventilation the following ventilator settings will be recorded: tidal 
volume, FiO2, peak airway pressure over the last 24 hours, plateau pressure, positive end 
expiratory pressure, and respiratory rate. The data will be recorded qd, and the worst value of 
the day will be entered
For subjects on mechanical ventilation, an arterial blood gas (pH, partial pressure of oxygen 
[PaO2], partial pressure of carbon dioxide [PaCO2], and FiO2 at the time the sample was 
obtained), if available, will be recorded qd. If more than one value is obtained for the arterial 
blood gases, the value closest to 08:00 will be used.
Arterial gasses should be collected from subjects if the sample is easily accessible and the 
procedure will not be painful to subjects (ie, subject is in the ICU or has arterial port). All 
available data from the arterial gases should be entered into the database. If the collection of 
arterial gases is not clinically indicated, the test should not be performed. 
Predicted body weight will be recorded on the ventilator eCRF for assessment of tidal volume.
8.4.2
Modified Sequential Organ Failure Assessment (SOFA) Scores
A modified SOFA score will be calculated. For each of the following routine assessments, the 
worst value of the day will be recorded in the eCRF: PaO2/FiO2 (mmHg) or SpO2/FiO2
(mmHg), platelet count, bilirubin, vasopressor use (μg/kg/min, mmHg), and creatinine ([or 
urine output]). For laboratory values, use last available (if within 48 hours). On days when 
laboratory results are unavailable, values will be extrapolated from the previously available 
values.
8.4.3
Assessment of Number of Days in ICU
Assessment of ICU length of stay will be obtained by asking the Investigator to determine if 
the subject is receiving ICU standard care (or equivalent) on each day during hospitalization 


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up to Day 90. In the event of an affirmative response, a further question will be asked to 
determine if this ICU care is considered necessary (rather than being due to logistical reasons).
Only days in the ICU (or equivalent), which the Investigator considers necessary, will be 
regarded as ICU days.
8.5
Follow Up Procedures
Follow up procedures are outlined in Section 1.1
8.6
Collection of Adverse Events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
The following are NOT considered an AE:

Pre-existing condition that has not worsened: A pre-existing condition (documented on 
the medical history eCRF) is not considered an AE unless the severity, frequency, or 
character of the event worsens during the study period.

Diagnostic testing and procedures: Testing and procedures should not be reported as 
AEs or SAEs, but rather the cause for the test or procedure should be reported. If a test or 
procedure is done to rule out a diagnosis, the sign or symptom leading to the 
test/procedure should be the event term, and the event term should only be updated to the 
diagnosis if/when the diagnosis is confirmed. Testing and procedures performed solely as 
screening measures (eg, routine screening mammography or colonoscopy) should not be 
reported as AEs or SAEs.

Abnormal laboratory results: Abnormal laboratory results are not AEs unless they are 
clinically significant. For example, a clinically significant laboratory result is one that 
requires treatment (for example a blood transfusion for low haemoglobin) or requires a 
change in study drug (eg, lowering the dose or withholding study drug while the 
laboratory finding resolves or stabilizes).

Progression of underlying disease: Progression of underlying disease unequivocally 
related to COVID-19 pneumonia (such as worsening of respiratory status or
complications associated with pneumonia) will not be reported as an AE if it is clearly 
consistent with the suspected progression of the underlying disease. Clinical symptoms of 
progression may be reported as AEs if the symptoms cannot be determined as exclusively 
due to the progression of the underlying disease, or if they do not fit the expected pattern 
of progression for the disease under study.
Symptomatic deterioration may occur in some subjects. Symptomatic deterioration is when 
progression is evident in the subject’s clinical symptoms and the Investigator may elect not to 
perform further disease assessments. 


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If there is any uncertainty about an AE being due only to the disease under study, it should be 
reported as an AE or SAE.
AE will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative).
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow up AEs see 
Section 8.6.3.
8.6.1
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.  
8.6.2
Time Period and Frequency for Collecting AE and SAE Information 
After the signing of the ICF, all SAEs must be reported. After randomization, all AEs/SAEs, 
irrespective of attribution of causality, must be reported. 
AE reporting, irrespective of seriousness, ends 28 (± 3) days after the last dose of study 
treatments(s) for those on acalabrutinib + BSC (Arm 1) and 38 (± 3) days from randomization 
for those on BSC only (Arm 2).
SAEs considered related to study treatments(s) or study procedures occurring after the end of 
the AE reporting period (as defined above) must be reported.  Information on concomitant 
medications at the time of the treatment-related SAE will also be collected.
All SAEs will be recorded and reported to the Sponsor or designee within 1 day (ie, 
immediately but no later than 24 hours from when he or she becomes aware of it), as 
indicated in Appendix B. The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available.
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for reporting SAEs are provided in Section 8.7.1.
8.6.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each subject 
at subsequent visits/contacts. All SAEs/non-SAEs/AEs of special interest (AESIs; as defined 
in Section 8.6.12), will be followed until resolution, stabilization, the event is otherwise 
explained, or the subject is lost to follow-up. 


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Any AEs that are unresolved at the subject’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the Investigator for as long as medically indicated, 
but without further recording in the eCRF. The Sponsor retains the right to request additional 
information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary.
8.6.4
Adverse Event Data Collection
The following variables will be collected for each AE:

AE diagnosis/description

The date when the AE started and stopped

Maximum Common Terminology Criteria for Adverse Events (CTCAE) grade

Whether the AE is serious or not

Investigator causality rating against the investigational product (yes or no)

Action taken regarding investigational product

Administration of treatment for the AE 

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date Investigator became aware of SAE

Seriousness criteria

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment to other medications

Description of SAE
The grading scales found in the revised NCI CTCAE Version 5.0 will be utilized for all events 
with an assigned CTCAE grading. For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria that converts mild, moderate, and severe events into 
CTCAE grades should be used. A copy of the CTCAE Version 5.0 can be downloaded from 
the Cancer Therapy Evaluation Program website 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quic
k_Reference_8.5x11.pdf).


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8.6.5
Causality Collection
The Investigator will assess causal relationship between investigational product and each AE, 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the investigational product?’
For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B of this protocol.
8.6.6
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.6.7
Adverse Events Based on Examinations and Tests
The results from the protocol-mandated laboratory tests and vital signs will be summarised in 
the Clinical Study Report. Deterioration as compared to baseline in protocol-mandated 
procedures (eg, safety laboratory tests and vital signs) should therefore only be reported as 
AEs if they fulfil any of the SAE criteria or are the reason for discontinuation of treatment 
with the investigational product.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study, see Section 8.6.9 and Section 8.6.10.


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8.6.8
Hy’s Law
Cases where a subject shows elevations in liver biochemistry may require further evaluation, 
and occurrences of AST or ALT ≥3×ULN together with total bilirubin ≥2×ULN may need to 
be reported as SAEs. Please refer to Appendix D for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s law.
8.6.9
Disease Under Study 
Systemic symptoms of the disease under study are those which might be expected to occur as 
a direct result of the clinical presentation associated with COVID-19 pneumonia and 
respiratory illness. Events which are unequivocally due to disease under study should not be 
reported as an AE during the study unless they meet SAE criteria or lead to discontinuation of 
the investigational product.
8.6.10
Disease Progression
Disease progression can be considered as a worsening of a subject’s condition attributable to 
COVID-19 pneumonia for which the investigational product is being studied. It may be an 
increase in the severity of the disease under study and/or increases in the symptoms of the 
disease. Events, which are unequivocally due to COVID-19 pneumonia, should not be 
reported as an AE or SAE during the study. Events attributable to disease progression of 
COVID-19 include pulmonary failure, ARDS, sepsis, shock, multiorgan failure and death.
8.6.11
Deaths
All deaths that occur during the study treatment period, or within the protocol-defined follow 
up period after the administration of the last dose of study treatment, must be reported as 
follows:

Death clearly resulting from disease progression should be documented in the eCRF in 
the Death page. It should not be reported as an SAE.

Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported as an SAE within 24 hours. It should also be 
documented in the Death page in the eCRF. The report should contain a comment 
regarding the co-involvement of disease progression, if appropriate, and should assign the 
main and contributory causes of death.

Deaths with an unknown cause should always be reported as an SAE and documented in 
the Death page in the eCRF, but every effort should be made to determine a cause of 
death. A post-mortem may be helpful in the assessment of the cause of death, and if 
performed, a copy of the post-mortem results should be forwarded to Sponsor Patient 
Safety or its representative within the usual time frames.
Deaths occurring after the protocol-defined follow-up period after the administration of the 
last dose of study treatment should be documented in the Death page. If the death occurred as 


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a result of an event that started after the defined follow-up period and the event is considered 
to be due to a late-onset toxicity to study treatment, then it should also be reported as an SAE.
8.6.12
Adverse Events of Special Interest
AESIs are events of scientific and medical interest specific to the further understanding of the 
acalabrutinib safety profile and require close monitoring and rapid communication by the 
Investigators to the Sponsor. An AESI can be serious or non-serious. All AESIs will be 
recorded in the eCRF. Serious AESIs will be recorded and reported as per Section 8.7.1.
The following events are AESIs for subjects receiving acalabrutinib and must be reported to 
the Sponsor expeditiously (see Section 8.7.1 for reporting instructions), irrespective of 
regulatory seriousness criteria or causality:

Ventricular arrhythmias (eg, ventricular extrasystoles, ventricular tachycardia, 
ventricular arrhythmia, ventricular fibrillation)
8.7
Safety Reporting and Medical Management
8.7.1
Reporting of Serious Adverse Events 
All SAEs have to be reported to the Sponsor, whether or not considered causally related to the 
investigational product, or to the study procedure(s). All SAEs will be recorded in the eCRF. 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a study 
treatment under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC), and Investigators.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate Sponsor representatives within 1 day (ie, immediately but no later than 
24 hours from when he or she becomes aware of it).
The designated Sponsor representative works with the Investigator to ensure that all the 
necessary information is provided to the Sponsor Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform Sponsor 


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representatives of any follow-up information on a previously reported SAE within 1 calendar 
day (ie, immediately but no later than 24 hours from when he or she becomes aware of it).
For all studies except those utilizing medical devices, Investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and Sponsor policy and forwarded to Investigators as necessary.
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and file the 
report/information with the Investigator’s Brochure and will notify the IRB/IEC according to 
local requirements, if appropriate.
For further guidance on the definition of a SAE, see Appendix B.
8.7.2
Pregnancy
All pregnancies, partner pregnancies, and outcomes of pregnancy/partner pregnancy should be 
reported to the Sponsor, with the exception of any pregnancy that is discovered before the 
subject has received any study treatment.
If a pregnancy is reported, the Investigator should inform the Sponsor within 1 day (ie, 
immediately but no later than 24 hours of when he/she becomes aware of the pregnancy).
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.7.2.1
Maternal Exposure
If a subject becomes pregnant during the course of the study, investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational
product under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented even if the 
subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate Sponsor representatives within 1 day (ie, immediately but no later 
than 24 hours of when he/she becomes aware of the pregnancy).


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The designated Sponsor representative works with the Investigator to ensure that all relevant 
information is provided to the Sponsor subject safety data entry site within either 1 day or 
5 calendar days for SAEs (see Section 8.7.1), and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
8.7.2.2
Paternal Exposure 
Male subjects should refrain from fathering a child or donating sperm during the study and for 
2 days after the last dose of acalabrutinib.
Pregnancy of a subject’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality), occurring from the date of the first dose until 2 days after the last 
dose of acalabrutinib, should, if possible, be followed up and documented in the Pregnancy 
Report Form. Consent from the partner must be obtained before the Pregnancy Report Form is 
completed.
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the Investigator must obtain the consent of the subject’s partner. The local study team should 
adopt the Master Pregnant Partner Form in line with local procedures/requirements and submit 
it to the relevant regulatory authority/institutional review board/ethics committee prior to use.
8.7.3
Overdose
Study drug overdose is the accidental or intentional use of the drug in an amount higher than 
the dose being studied. An overdose or incorrect administration of study treatment is not an 
AE unless it results in untoward medical effects. Any study treatment overdose or incorrect 
administration of study treatment should be noted on the Overdose eCRF.
All AEs associated with an overdose or incorrect administration of study treatment should be 
recorded on the Adverse Event eCRF. If the associated AE fulfils serious criteria, the event 
should be reported to the Sponsor immediately (ie, no later than 24 hours after learning of the 
event). 
For overdoses associated with a SAE, the standard reporting timelines apply; see 
Section 8.6.2. For other overdoses, reporting must occur within 30 days.
The designated Sponsor representative works with the Investigator to ensure that all relevant 
information is provided to the Sponsor Patient Safety data entry site.
8.7.4
Medication Error
If a medication error occurs in the course of the study, then the Investigator (or other site 
personnel) informs the appropriate Sponsor representatives within 1 day (ie, immediately but 


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no later than 24 hours of when the Investigator (or other site personnel) becomes aware of the 
error.
The designated Sponsor representative works with the Investigator to ensure that all relevant 
information is completed within 1 calendar day (in the event of initial fatal/life-threatening 
errors or follow-up fatal/life-threatening errors) or 5 calendar days (in the event of other 
serious initial and follow-up errors) if there is an SAE associated with the medication error 
(see Section 8.7.1), and within 30 days for all other medication errors.
The definition of a Medication Error can be found in Appendix B.
8.8
Efficacy Assessments
8.8.1
Improvement on the 9-point Ordinal Scale
For the purposes of this study, the condition of each potential subject in the study will be 
assessed using a 9-point category ordinal scale below. Assessments will be performed as 
described in the SoA.
0.*
Uninfected, no clinical or virological evidence of infection 
1. 
Ambulatory, no limitation of activities 
2. 
Ambulatory, limitation of activities 
3. 
Hospitalized – mild disease, no oxygen therapy 
4. 
Hospitalized – mild disease, oxygen by mask or nasal prongs 
5. 
Hospitalized – severe disease, non-invasive ventilation or high flow oxygen 
6. 
Hospitalised – severe disease, intubation and mechanical ventilation 
7.
Hospitalized – severe disease, ventilation and additional organ support, such 
as pressors, renal replacement therapy, extracorporeal membrane 
oxygenation 
8.
Death 
*Score of zero on 9-point category ordinal scale will not be evaluated in this study.
To be considered a “responder” to treatment with a target candidate, a subject needs to show 
an improvement of at least 2 points (from randomization) on this scale. The time to clinical 
improvement of 2 points will be assessed as a secondary endpoint.


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9.
STATISTICAL CONSIDERATIONS 
9.1
Statistical Hypotheses
Overall study design is described in Section 4.1 of the protocol. Subjects who are hospitalized 
for COVID-19 symptoms and meet the eligibility criteria will be randomized 1:1 to receive 
acalabrutinib plus BSC (Arm 1: n=70) vs BSC (Arm 2: n=70).
Stratification by age (≥65 vs <65 years) and comorbidities (present vs absent) will be applied
to randomization. 
The primary hypothesis of the study is to compare the efficacy of acalabrutinib plus BSC 
(Arm 1) vs BSC (Arm 2), as measured by the proportion of subjects who are alive and free of 
respiratory failure at Day 14:
H0: p1=p2 (there is no difference between Arms 1 and 2)
H1: p1≠p2 (there is a difference between Arms 1 and 2)
9.2
Sample Size Determination 
The planned total number of subjects in this study is 140. The sample size for this study is 
driven by the primary efficacy endpoint. 
The sample size of 140 allows for at least 85% power, with a 2-sided type 1 error of 0.05 to 
detect a difference of 20% between the 2 arms for the primary endpoint, assuming the 
proportion of subjects who are alive and free of respiratory failure at Day 14 to be 70% for 
BSC and 90% for acalabrutinib + BSC. The assumed proportion of subjects who are alive and 
free of respiratory failure at Day 14 of 70% under BSC is based on the reported rate of deaths 
and need for ICU admission (a surrogate for respiratory failure) in subjects who are 
hospitalized for COVID-19 (Arentz et al 2020, Bhatraju et al 2020, CDC 2020, Grasselli et al 
2020). 
9.3
Populations for Analyses
The analysis populations are defined as shown in Table 6.


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Table 6
Analysis Populations
Population/ Analysis set
Description
Full analysis set (ITT population)
The full analysis set will include all subjects who 
are randomized and will be used for all efficacy 
analyses. Treatment arms will be compared on the 
basis of randomized study treatment, regardless of 
the treatment actually received. Subjects who 
were randomized but did not subsequently go on 
to receive study treatment will be included in the 
analysis in the treatment arm to which they were 
randomized, following the “intent-to-treat” 
principle.
Per-protocol analysis set
The per-protocol analysis set will be a subset of 
the ITT population including only subjects 
without important detected protocol deviations 
affecting the efficacy endpoints. Subjects will be 
summarised according to the actual treatment first 
received. The primary endpoint of the study will 
also be summarized for this population.
Safety analysis set
The safety analysis set (Safety population) is 
based on the treatment subjects actually received.  
In this study, the treatment is either acalabrutinib 
+ BSC or BSC only. If a subject receives at least 1 
dose of acalabrutinib, the subject is considered as 
acalabrutinib-treated, regardless which arm the 
subject was randomized to. Subjects who are 
randomized to acalabrutinib + BSC but do not 
receive any acalabrutinib will be summarized in 
the BSC group. 
PK analysis set
The PK analysis set will include all subjects who 
receive ≥1 dose of acalabrutinib and had ≥1 post-
dose evaluable PK data point for acalabrutinib. 
The population will be defined by AstraZeneca, 
the pharmacokineticist and the statistician prior to 
any analyses being performed.
BSC = best supportive care; ITT = Intent-to-treat; PK = pharmacokinetic.
9.4
Interim Analysis
This study will use an iDMC to conduct a planned interim safety review and a planned 
efficacy interim analysis before the primary analysis of the study data. 
The first interim safety analysis will take place after the first 30 subjects have been 
randomized into the study and have had 28 days of follow-up from randomization. 
The second is a planned interim analysis of the primary efficacy point, which will take place 
when the last subject randomized has had had 14 (± 2) days of follow up after randomization. 


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At the time of the interim analysis of the primary efficacy endpoint, accumulated safety data 
will also be reviewed by the iDMC.
The primary analysis of the study will occur when all randomized subjects have been followed 
for 38 (± 3) days from randomization, and the study team will be unblinded to the results by 
treatment arm. 
To maintain the overall type I error of the study at the 2-sided 0.05 level, at the interim 
analysis of the primary efficacy endpoint, the proportion of subjects who are alive and free of 
respiratory failure at Day 14, will be tested at the 2-sided 0.0001 level. At the primary analysis 
for the study, this primary efficacy endpoint will be tested at the 2-sided 0.0499 level. 
An updated analysis for those endpoints requiring of 90-day assessments will take place after 
the last randomized subject has had 90 days of follow up from randomization.
9.5
Missing Data Handling
No imputation of values for missing data will be performed except that missing or partial start 
and end dates for AEs and concomitant medication will be imputed per prespecified, 
conservative imputation rules.  
The specification for handling death in the analysis of endpoints that do not contain mortality as a 
component will be provided in the Statistical Analysis Plan (SAP).
9.6
Statistical Analyses
A comprehensive SAP will be developed and finalized before database lock and will describe 
the subject populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. Any deviations from the SAP will be reported in the 
Clinical Study Report.
The primary analysis of the study will occur when all randomized subjects have been followed 
for 38 (± 3) days from randomization, and the study team will be unblinded to the results by 
treatment arm. 
An updated analysis for those endpoints requiring of 90-day assessments will take place after 
the last randomized subject has had 90-day follow up from randomization.
9.6.1
Safety Analyses
Safety assessments will consist of monitoring and recording AEs, SAEs and AEs leading to 
discontinuation of study treatment; measurements of protocol-specified hematology, clinical 
chemistry, and other laboratory variables; measurement of protocol-specified vital signs; and 
other protocol-specified tests that are deemed critical to the safety evaluation of the study 


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treatment. All safety analyses will be performed on the safety analysis set as defined in 
Section 9.3.
Verbatim descriptions of AEs will be mapped per the most recent version of Medical 
Dictionary for Regulatory Activities (MedDRA) thesaurus terms and graded per National 
Cancer Institute (NCI) CTCAE, v5.0 or higher. Extent of exposure to study treatment, all AEs, 
SAEs, any AEs leading to study treatment discontinuation, and study treatment related AEs 
will be summarized. The frequency of AEs will be summarized by system organ class and 
preferred terms per MedDRA by the worst reported NCI CTCAE grade. TEAEs will be 
summarized, unless otherwise specified. In this study, for Arm 1 (acalabrutinib + BSC), 
TEAEs are defined as AEs starting or ongoing AEs worsening after the first dose of study 
treatment and AEs with start date up to the last dose of study treatment plus 28 (± 3) days; for 
Arm 2 (BSC only), TEAEs are defined as AEs starting or ongoing AEs worsening after the 
date of randomization and AEs with start date up to 38 (± 3) days from randomization. 
Laboratory abnormalities will be defined based on laboratory normal ranges (universal normal 
ranges, if central lab). Selected laboratory parameters may be analysed with shift tables and 
summaries of changes from baseline to worst post-treatment value.  
Vital sign and all other safety assessments will be tabulated and summarized.
Full details of AE, laboratory assessments, vital sign assessments and all other safety 
assessments will be provided in the SAP.
9.6.2
Efficacy Analyses
Primary Endpoint
The primary endpoint is the proportion of subjects who are alive and free of respiratory failure 
at Day 14 (see Section 3 for a definition of respiratory failure). The point estimate and its 95% 
confidence interval (CI; using Wald method with continuity correction) will be calculated for 
each treatment arm. The Cochran-Mantel-Haenszel χ2 test stratified by age (≥65 vs < 65 
years) and comorbidities (present vs absent) will be used to compare the proportion of 
subjects who are alive and free of respiratory failure at Day 14 between the two treatment 
arms. An unstratified analysis will also be performed. Finally, the difference in the proportion 
of subjects who are alive and free of respiratory failure at Day 14 will also be provided with 
95% CIs. 
The primary endpoint of the study will be summarized by subgroups that include age group, 
country, sex, race, ethnicity, comorbidities, and history of substance abuse.
The primary endpoint will be summarized and analysed as per the methods above for the full 
analysis set (ITT population) as well as the per-protocol analysis set.


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Additional sensitivity analyses and subgroup analyses of the primary endpoint may be 
performed as appropriate.
Secondary Endpoints
The proportion of subjects alive and free of respiratory failure at Day 28 will be summarized 
using the full analysis set.
Summary statistics (n, mean, median, standard deviation, minimum, and maximum) will be 
presented by treatment arm for continuous secondary efficacy endpoints (refer to Section 3) .
Summary statistics for the number of days hospitalized from randomization to 28 days after 
randomization and the number of days in ICU from randomization to 90 days after 
randomization will be summarised.
Time from randomization to first occurrence of respiratory failure or death on study (up to 
28 days after randomization) due to any cause will be analysed using Kaplan-Meier method; 
hazard ratio and corresponding 95% CIs will be estimated using Cox proportional hazards 
models, stratified by randomization stratification factors.  If a subject did not have an event 
and did not drop out prior to Day 28, the data will be censored at Day 28; if a subject did not 
have an event but dropped out prior to Day 28, the data will be censored at the last date known 
to be alive and free of respiratory failure.
Similarly, time to clinical improvement of at least 2 points (from randomization) on a 9-point 
category ordinal scale through Day 28 will be analysed using Kaplan-Meier method.
The statistical analysis plan will provide the further details.
9.6.3
Pharmacokinetic and Pharmacodynamic Analyses 
PK assessments will be conducted in up to 35 evaluable subjects and PD assessments in up to 
20 evaluable subjects randomized to Arm 1 (acalabrutinib + BSC). Subjects are considered 
evaluable if they have an evaluable PK/PD profile, ie, (1) receive acalabrutinib treatment and 
(2) do not have data that are unavailable or incomplete (ie, provide data from all PK/PD visits 
indicated in the SoA).
The statistical analysis and reporting of PK and PD parameters will be provided in the SAP. 


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10.
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Appendix A
Regulatory, Ethical and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines

Applicable International Council for Harmonisation (ICH) GCP Guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator, and 
reviewed and approved by the IRB/IEC, before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects.  
The Investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations
The study will be performed in accordance with the Sponsor policy on Bioethics and Human 
Biological Samples.
A 2
Financial Disclosure
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.


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A 3
Informed Consent Process
The Investigator or his/her representative will explain the nature of the study to the subject or 
his/her legally authorised representative and answer all questions regarding the study.  
Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorised representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
center.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date and time the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF.
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative.
Subjects will be told that they are free to refuse to participate and may withdraw their consent 
at any time and for any reason during the sample storage period. If a subject withdraws 
consent to the use of donated biological samples, the samples will be disposed of/destroyed, 
and the action documented. If samples already have been analysed at the time of the request, 
the Sponsor will not be obliged to destroy the results of this research.
A 4
Data Protection
Each subject will be assigned a unique identifier by the Sponsor.  Any subject records or data 
sets transferred to the Sponsor will contain only the identifier; subject names or any 
information which would make the subject identifiable will not be transferred.  
The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject.  
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.


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A 5
Committee Structures
An iDMC will be formed.  Detailed information regarding the composition of the iDMC and 
detailed iDMC procedures will be provided in a separate charter. The iDMC will be 
responsible for reviewing the safety periodically and provide recommendations according to 
the charter.
The safety of all Sponsor clinical studies is closely monitored on an ongoing basis by Sponsor 
representatives in consultation with Patient Safety. Issues identified will be addressed; for 
example, this could involve amendments to the CSP and letters to Investigators.
A 6
Dissemination of Clinical Study Data
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the main study results when they are 
available. The clinical trial and/or summary of main study results may also be available on 
other websites according to the regulations of the countries in which the main study is 
conducted.
A 7
Data Quality Assurance
All subject data relating to the study will be recorded on printed CRF or eCRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF/eCRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF/eCRF.
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review to confirm that data entered into the 
CRF/eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 


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retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor. 
A 8
Source Documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected.  Source documents are filed at the Investigator’s site.
Data reported on the CRF/eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The Investigator 
may need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available.
Definitions of what constitutes source data can be found in the Clinical Study Agreement.
A 9
Study and Site Closure
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. The study may be stopped if, in the 
judgment of the Sponsor, trial subjects are placed at undue risk because of clinically 
significant findings that:

Meet individual stopping criteria or are otherwise considered significant 

Are assessed as causally related to study treatment, 

Are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the CRF/eCRF. All reasons for 
discontinuation of treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests.
Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has 
been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.


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Reasons for the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the Investigator

Discontinuation of further study treatment development
A 10
Publication Policy
The results of this study may be published or presented at scientific meetings once the primary 
analysis is completed and the study is unblinded. No other publications prior to that time point 
is allowed.
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data.  In this case, a 
coordinating Investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
Subsequent to the primary publication, if an Investigator plans to publish any subset of data, 
or case report, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to provide 
comments.


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Appendix B
Adverse Event Definitions and Additional Safety 
Information
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence (other than progression of the 
disease under evaluation) in a patient or clinical study subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. An AE 
can therefore be any unfavourable and unintended sign (eg, an abnormal laboratory finding), 
symptom (eg, nausea, chest pain), or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.  
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered.
B 2
Definition of Serious Adverse Events
A SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-up), 
that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability or incapacity

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardize the subject or may require medical 
treatment to prevent one of the outcomes listed above.
B 3
Life-threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred, or it is suspected that use or continued use of the product would result in the 
subject’s death. ‘Life-threatening’ does not mean that, had an AE occurred in a more severe 
form, it might have caused death (eg, hepatitis that resolved without hepatic failure).
B 4
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.


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B 5
Important Medical Event or Medical Treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the subject or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse
B 6
Intensity Rating Scale
The grading scales found in the revised NCI CTCAE v5.0 will be utilized for all events with 
an assigned CTCAE grading. For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria that converts mild, moderate and severe events into 
CTCAE grades should be used. A copy of the CTCAE can be downloaded from the Cancer 
Therapy Evaluation Program website 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quic
k_Reference_8.5x11.pdf).
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2.


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B 7
A Guide to Interpreting the Causality Question
When assessing causality consider the following factors when deciding if there is a 
‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the subject actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience. The Sponsor would not normally recommend or support a 
re-challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognized feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 8
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for a Sponsor study treatment that either causes harm to the subject or 
has the potential to cause harm to the subject.  


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A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or subject.
Medication error includes situations where an error:  

Occurred

Was identified and intercepted before the subject received the drug

Did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the subject

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed, eg, kept in the fridge when it should be at room temperature 

Wrong subject received the medication (excluding IRT errors)

Wrong drug administered to subject (excluding IRT errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT - including those which lead to one of the above 
listed events that would otherwise have been a medication error 

Subject accidentally missed drug dose(s), eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Subject failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.


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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody of Biological Samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each center keeps full traceability of collected biological samples from the 
subjects while in storage at the centre until shipment or disposal (where appropriate).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
The Sponsor will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of external 
laboratory providers.
Samples retained for further use will be stored in the Sponsor-assigned biobanks and will be 
registered by the Sponsor Biobank Team during the entire lifecycle. 
If required, the Sponsor will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
C 2
Withdrawal of Informed Consent for Donated Biological Samples
If a subject withdraws consent specifically to the subsequent use of donated biological 
samples, the samples will be disposed of/destroyed, and the action documented. If samples are 
already analyzed, the Sponsor is not obliged to destroy the results of this research. A general 
withdrawal of consent to study treatment does not imply a withdrawal of consent to 
subsequent analyses of biological samples. In case a subject withdraws the general informed 
consent and additionally wants to withdraw consent for further analyses of his/her biological 
samples, the subject is required to sign an opt-out.
As collection of the biological sample(s) is an integral part of the study, then the subject is 
withdrawn from further study participation.
The Investigator:

Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to Sponsor

Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented

Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented, 
and the signed document returned to the study site


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
Ensures that the subject and Sponsor are informed about the sample disposal.
The Sponsor ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
C 3
International Airline Transportation Association Regulations on 
Labeling and Shipment of Biological Samples
Air transportation of biological samples (including biohazardous materials and potentially 
biohazardous materials) is regulated under International Airline Transportation Association 
(IATA) Dangerous Goods Regulations (DGR; 61st edition [2020]) Division 6.2—Infectious 
Substances. The IATA DGR definition of infectious substances includes any substance that is 
known or reasonably expected to contain pathogens, ie, microorganisms (including bacteria, 
viruses, rickettsiae, parasites, fungi) or other agent, such as a proteinaceous infectious particle 
(prion), that can cause disease in humans or animals.
As Division 6.2 infectious substances, biological samples transported by air must be classified 
as Category A, Category B, or Exempt; secured in IATA-compliant packaging; and identified 
using the appropriate United Nations shipping number and label requirements corresponding 
to the species, sample type, and infectious nature of material being shipped. See Table 7 for 
details.
Under IATA regulations, subject specimens from clinical trials will fall into Category B or 
Exempt. Clinical trial samples can often be packed and transported at ambient temperature.  
However, in cases where biological samples must be refrigerated or frozen for transport (eg, 
using dry ice or liquid nitrogen), additional dangerous goods specifications will apply; refer to 
DGR Section 3.6.2.2.3.8 (e). IATA-compliant couriers and materials should be used for 
transportation and packaging, and where applicable, packing should be done by 
IATA-certified personnel. 
Transportation of biological samples by road or rail is routinely subject to local regulations 
requiring shipment in safe, appropriate packaging materials to contain any risk of infection or 
contamination at all times, in addition to the use of approved couriers. Wherever possible, 
compliance with IATA Instruction 650 standards for biological sample containment are 
encouraged for road or rail transport of subject specimens. 


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Table 7
IATA Dangerous Goods Regulations Classification of Infectious 
Substances
Category a
Description
Shipping instructions 
UN number and labeling
Category A 
infectious 
substances
Any infectious substance 
transported in a form that, 
when exposure occurs, b is 
capable of causing permanent 
disability, life threatening 
disease, or fatal disease in 
otherwise healthy humans or 
animals.  
(Examples include Ebola and 
Lassa fever virus.)
Category A pathogens must 
be: 
Packed and shipped in 
accordance with IATA 
Instruction 620 
Identified using the 
appropriate UN shipping 
number and label 
information
UN 2814
“Infectious substances 
affecting humans or both 
humans and animals”
UN 2900
“Infectious substances 
affecting animals only”
Category B 
infectious 
substances
Any infectious substance that 
does not meet the criteria for 
inclusion in Category A.  
Category B infectious 
substances are not in a form 
capable of causing permanent 
disability, life threatening 
disease, or fatal disease in 
otherwise healthy humans or 
animals when exposure 
occurs. b
(Examples include hepatitis A, B, 
C, D, and E viruses, and HIV 
types 1 and 2.)
Category B pathogens must 
be: 
Packed and shipped in 
accordance with IATA 
Instruction 650 
Identified using the 
appropriate UN shipping 
number and label 
information
UN 3373 
“Biological substance, 
Category B”
Exempt 
substances
Subject specimens for which 
there is minimal likelihood 
that pathogens are present. 
(Examples may include 
blood-based samples, tissue 
cultures, or other biological 
samples.)
Exempt substances must be: 
Packed and shipped in 
accordance with 
requirements specified in 
Division 6.2, 
Section 3.6.2.2.3.8 of the 
IATA DGR a
Identified using the 
appropriate label 
information
“Exempt human specimen”
“Exempt animal specimen”
DGR = Dangerous Goods Regulation; IATA = International Airline Transportation Association; UN = United Nations.
Note:  IATA Dangerous Goods Regulations, 61st Edition. 01 January 2020. International Air Transport Association. 
Available at: https://www.iata.org/en/programs/cargo/dgr/download/.
a
For transport purposes, the classification of infectious substances according to risk groups was removed in the DGR 
46th edition (2005).  There is no direct relationship between risk groups and Categories A and B.
b
Exposure occurs when an infectious substance is released outside of the protective packaging, resulting in physical 
contact with humans or animals.


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Appendix D
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
D 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases.  It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries. 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a subject meets 
potential PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The Investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met.  
HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
D 2
Definitions
Potential Hy’s Law
AST or ALT ≥ 3x ULN together with Total Bilirubin (TBL) ≥ 2x ULN at any point during 
the study following the start of study medication irrespective of an increase in alkaline 
phosphatase (ALP).
Hy’s Law 
AST or ALT ≥ 3x ULN together with TBL ≥ 2x ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  


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For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
D 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3xULN

AST ≥3xULN

TBL ≥ 2xULN
Central laboratories being used:
When a subject meets any of the PHL identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative). 
The Investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met, where this is the case the Investigator will:

Notify the AstraZeneca representative 

Request a repeat of the test (new blood draw) by the central laboratory without delay

Complete the appropriate unscheduled laboratory CRF module(s) with the original local 
laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:

Determine whether the subject meets PHL criteria (see Section D 2 within this Appendix 
for definition) by reviewing laboratory reports from all previous visits (including both 
central and local laboratory results)
Local laboratories being used:
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Notify the AstraZeneca representative

Determine whether the subject meets PHL criteria (see Section D 2 within this Appendix 
for definition) by reviewing laboratory reports from all previous visits


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
Promptly enter the laboratory data into the laboratory CRF
D 4
Follow-up
D 4.1
Potential Hy’s Law Criteria not met
If the subject does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the subject has not met PHL criteria.

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol.
D 4.2
Potential Hy’s Law Criteria met
If the subject does meet PHL criteria the Investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study 
treatment

Notify the AstraZeneca representative who will then inform the central Study Team 

Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE of 
Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to CSP process for SAE reporting.

For subjects that met PHL criteria prior to starting IMP, the investigator is not required to 
submit a PHL SAE unless there is a significant change# in the subject’s condition

The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up (including any further laboratory testing) and 
the continuous review of data

Subsequent to this contact the Investigator will:

Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required.

Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which the tests available 
in the Hy’s law lab kit should be used 

Complete the three Liver CRF Modules as information becomes available 
# A ‘significant’ change in the subject’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in 
isolation or in combination, or a clinically relevant change in associated symptoms.  The 
determination of whether there has been a significant change will be at the discretion of 
the Investigator; this may be in consultation with the Study Physician if there is any 
uncertainty.


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D 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from date PHL criteria was met.  The AstraZeneca Global Clinical Lead or equivalent and 
Global Safety Physician will also be involved in this review together with other subject matter 
experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF

If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE and AE CRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AZ standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:

Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to Clinical Study Protocol (CSP)
process for SAE reporting.


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
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met.  Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
D 6
Laboratory tests
Hy’s Law Laboratory Kit for Central Laboratories
Additional standard chemistry and coagulation tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNA
IgG anti-HCV
HCV RNA* 
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-transferrin)**
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
* HCV RNA is only tested when IgG anti-HCV is positive or inconclusive
** Carbohydrate deficient transferrin (CD-transferrin) is not available in China. Study teams should amend this list 
accordingly
Reference
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf.


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Appendix E
Examples of Coadministered Drugs That Need Additional 
Consideration
The lists of drugs in these tables are not exhaustive. Any questions about drugs not on this list 
should be addressed to the Medical Monitor of this study.
Table 8
CYP3A Inhibitors
Strong inhibitors of CYP3A
Moderate inhibitors of CYP3A
Boceprevir
aprepitant
clarithromycin a
cimetidine
cobicistat a
ciprofloxacin
conivaptan a
clotrimazole
danoprevir and ritonavir b
crizotinib
diltiazem a
cyclosporine
elvitegravir and ritonavir b
dronedarone a
grapefruit juice
erythromycin
Idelalisib
fluconazole
indinavir and ritonavir b
fluvoxamine
itraconazole a
imatinib
Ketoconazole
tofisopam
lopinavir and ritonavir a,b
verapamil a
Nefazodone
nelfinavir a
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir) b
Posaconazole
ritonavir a,b
saquinavir and ritonavir a,b
telaprevir a
tipranavir and ritonavir a,b
Troleandomycin
Voriconazole
a
Inhibitor of P-glycoprotein.
b
Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical practice. Caution should 
be used when extrapolating the observed effect of ritonavir alone to the effect of combination regimens on CYP3A 
activities.


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Table 9
CYP3A Inducers
Strong inducers of CYP3A
Moderate inducers of CYP3A
Carbamazepine
bosentan
Enzalutamide
efavirenz
Mitotane
etravirine
Phenytoin
modafinil
Rifampin
St. John’s wort a
a
The effect of St. John’s wort varies widely and is preparation-dependent.
Source: US FDA. Drug development and drug interactions: table of substrates, inhibitors and inducers. 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.h
tm#inVivo. Accessed 23 July 2019.
Table 10
Other Drugs Needing Additional Considerations
Proton pump inhibitors
H2-receptor antagonists
Dexlansoprazole
cimetidine
Esomeprazole
famotidine
Lansoprazole
nizatidine
Omeprazole
Rabeprazole
Pantoprazole
Source: US FDA. Established pharmacologic class text phrase. https://www.fda.gov/downloads/drugs/
guidancecomplianceregulatoryinformation/lawsactsandrules/ucm428333.pdf. Accessed 23 July 2019.  


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Appendix F
Contraception Requirements
Contraception requirements for this study are as follows.
F 1
Female Subjects of Childbearing Potential
Please note, females of childbearing potential are defined as those who are post-menarche, not 
surgically sterile (ie, bilateral salpingectomy, bilateral oophorectomy, or complete 
hysterectomy) or post-menopausal.
Women will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause.  The following age-specific requirements apply:

Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all hormonal replacement 
therapy and if they have luteinizing hormone and follicle-stimulating hormone levels in 
the post-menopausal range for the institution.

Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all hormonal replacement 
therapy, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago.
Female subjects of childbearing potential who are not totally sexually abstinent (ie, refraining 
from heterosexual intercourse during the entire period of risk associated with study 
treatments), and who intend to be sexually active with a nonsterilized male partner, must use 
at least one highly effective method of contraception (see Table 11) consistent with local 
regulations regarding the use of contraception for subjects participating in clinical trials, from 
the time of signing the ICF throughout the total duration of the drug treatment and the drug 
washout period (2 days after the last dose of acalabrutinib). 
Non-sterilized male partners of a female subject of childbearing potential must use a male 
condom plus spermicide (condom alone in countries where spermicides are not approved) 
throughout this period. Cessation of birth control after this point should be discussed with a 
responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method 
are not acceptable methods of contraception. The reliability of total sexual abstinence should 
be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle 
of the subject. Female subjects should refrain from breastfeeding throughout this period.  
F 2
Male Subjects with a Female Partner of Childbearing Potential
Non-sterilized male subjects (including males sterilized by a method other than bilateral 
orchidectomy, eg, vasectomy) who are not abstinent and intend to be sexually active with a 
female partner of childbearing potential must use a male condom plus spermicide (condom 
alone in countries where spermicides are not approved) from the time of screening throughout 


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the total duration of the drug treatment and the drug washout period (2 days after the last dose 
of acalabrutinib). Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. Male subjects should refrain from sperm donation 
throughout this period.
Vasectomized (ie, sterile) males are considered fertile and should still use a male condom plus 
spermicide as indicated above during the clinical trial.
Even if the female partner is pregnant, male subjects should still use a condom, as indicated 
above during the clinical trial, if there is a concern about damaging the developing fetus from 
drug in ejaculate.
Female partners (of childbearing potential) of male subjects must also use a highly effective 
method of contraception throughout this period (see Table 11).
F 3
Highly Effective Methods of Contraception
Highly effective methods of contraception, defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly, are described in Table 11. 
Note that some contraception methods are not considered highly effective (eg, male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non copper containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding 
Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral 
contraceptive pills).
Table 11
Highly Effective Methods of Contraception (<1% Failure Rate)
Barrier/intrauterine methods
Hormonal methods
•
Copper T intrauterine device
•
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®) a
•
Implants: Etonogestrel-releasing implants 
(eg, Implanon® or Norplant®)
•
Intravaginal devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®) 
•
Injection: Medroxyprogesterone injection 
(eg, Depo-Provera®)
•
Combined pill: Normal and low dose combined 
oral contraceptive pill
•
Patch: Norelgestromin/ethinylestradiol-releasing 
transdermal system (eg, Ortho Evra®)
•
Minipill: Progesterone based oral contraceptive 
pill using desogestrel: Cerazette® is currently the 
only highly effective progesterone-based pill
a
This is also considered a hormonal method.


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Appendix G
Child-Pugh Score
Cirrhosis severity, as determined by the Child-Pugh score (Pugh 1973), will be recorded in the 
eCRF as specified in the SoAs.
The modified Child-Pugh classification of liver disease severity according to the degree of 
ascites by clinical exam, serum concentrations of bilirubin and albumin, prothrombin time, 
and degree of encephalopathy is shown in Table 12. The severity of cirrhosis is classified as 
follows:

Child-Pugh class A (well-compensated disease): score of 5 to 6

Child-Pugh class B (significant functional compromise): score of 7 to 9

Child-Pugh class C (decompensated disease): score of 10 to 15
Table 12
Child-Pugh Classification of Cirrhosis Severity
Parameter
Points assigned
1
2
3
Ascites
Absent
Slight
Moderate
Bilirubin
<2 mg/dL
(<34.2 μmol/L)
2 to 3 mg/dL
(34.2 to 51.3 μmol/L)
>3 mg/dL
(>51.3 μmol/L)
Albumin
>3.5 g/dL
(35 g/L)
2.8 to 3.5 g/dL
(28 to 35 g/L)
<2.8 g/dL
(28 g/L)
Prothrombin time
Seconds over control
<4
4 to 6
>6
INR
<1.7
1.7 to 2.3
>2.3
Encephalopathy
None
Grade 1 to 2
Grade 3 to 4
INR = international normalized ratio.


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Appendix H
Abbreviations
Abbreviation or 
special term
Explanation
AE
Adverse event
AESI
Adverse event of special interest
ALC
Absolute lymphocyte count
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
anti-HBc
Hepatitis B core antibody
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
ARDS
Acute respiratory distress syndrome
AUC
Area under the concentration-time curve
bid
Twice daily
BSC
Best supportive care
Btk
Bruton’s tyrosine kinase
BUN
Blood urea nitrogen
CBC
Complete blood count
CI
Confidence interval
Cmax
Maximum observed concentration
COVID-19
Coronavirus disease 2019
CRF
Case report form (electronic/paper)
CRP
C-reactive protein
CSP
Clinical Study Protocol
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DGR
Dangerous Good Regulation
DILI
Drug-induced liver injury
DLT
Dose-limiting toxicity
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
FiO2
Fraction of inspired oxygen
GCP
Good Clinical Practice
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HL
Hy’s law


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Abbreviation or 
special term
Explanation
IATA
International Airline Transportation Association
ICF
Informed consent form
ICH
International Council for Harmonisation
ICU
Intensive care unit
iDMC
Internal Data Monitoring Committee
IEC
Independent Ethics Committee
IL
Interleukin
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive response technology
LDH
Lactate dehydrogenase
MCP-1
Monocyte chemoattractant protein-1
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
NCI
National Cancer Institute
NG
Nasogastric
NYHA
New York Heart Association
PaCO2
Partial pressure of carbon dioxide
PaO2
Partial pressure of oxygen
PCR
Polymerase chain reaction
PD
Pharmacodynamic(s)
PD-1
Programmed cell death 1
PHL
Potential Hy’s law
PI3K
Phosphatidylinositol-3-kinase
PK
Pharmacokinetic(s)
PML
Progressive multifocal leukoencephalopathy
PPI
Proton-pump inhibitor
PT
Prothrombin time
qd
Once daily
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SoA
Schedule of Activities
SOFA
Sequential Organ Failure Assessment
SpO2
Oxygen saturation
SUSAR
Suspected unexpected serious adverse reaction


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Abbreviation or 
special term
Explanation
TEAE
Treatment-emergent adverse event
TLR
Toll-like receptor
TNFα
Tumor necrosis factor alpha
ULN
Upper limit of normal


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Appendix I
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
Amendment 3 (23Jun2020) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
The overall rationale for the amendment was to address feedback from global study sites that 
are managing local challenges around the world during the COVID-19 pandemic.
Section number and 
name
Description of change
Brief rationale
Substantial/ 
non-substantial
1.1 Schedule of 
Activities (Table 1)
Added footnote l to indicate that 
screening can be performed within 1-3 
days prior to dosing
Allow flexibility 
around timing of 
screening 
Non-substantial
Added footnote o to indicate that 
 
 
 
Clarification
Non-substantial
Added footnote q to indicate that for 
all central laboratory assessments, 
sample collection windows of ± 1 day 
will be allowed for each of Days 3 and 
7
Clarification
Non-substantial
Added a separate column for Day 1
Clarification 
Non-substantial
Specified in title that Table 1 only 
applies to Arm 1 (acalabrutinib + 
BSC)
Clarification 
Non-substantial
1.1 Schedule of 
Activities (Table 2)
Added Table 2 for Arm 2 (BSC only) 
assessments
Clarification
Non-substantial
1.1 Schedule of 
Activities;
1.2 Synopsis;
3 Objectives and 
Endpoints;
8.8.1 Improvements on 
the 9-Point Ordinal 
Scale
Added secondary efficacy endpoint of 
time to clinical improvement of at 
least 2 points (from randomization) on 
a 9-point ordinal scale through Day 28
This is emerging as an 
important endpoint in 
the assessment of 
COVID-19. According 
to recent COVID-19-
related guidelines from 
the FDA and WHO, 
endpoints for COVID-
19 interventional 
studies should include 
Substantial
CCI


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Section number and 
name
Description of change
Brief rationale
Substantial/ 
non-substantial
a composite measure 
of clinical 
improvement and 
survival. The WHO 
9-point ordinal scale 
for clinical 
improvement, which is 
being used in many 
ongoing clinical trials 
with 
immunomodulatory 
and antiviral agents has 
been added to this 
study as a secondary 
endpoint.
1.1 Schedule of 
Activities (Table 1);
6.1 Treatments 
Administered
Revised the statement “Acalabrutinib 
must be administered within 6 hours 
of randomization” to “Acalabrutinib 
should be administered within 6 hours 
of randomization”
Patient centricity
Non-substantial
1.1 Schedule of 
Activities (Table 1);
8.1.5 Physical 
Examinations and 
Chest Imaging, 
Electrocardiogram, and 
Echocardiogram
Added footnote r in Table 1 and text 
in Section 8.1.5 to indicate that per 
standard of care, chest imaging can be 
done by chest x-ray or CT scan with 
contrast, or any other appropriate 
means to confirm pneumonia prior to 
or upon hospitalization (within 7 days 
of randomization).
Clarification
Non-substantial
1.1 Schedule of 
Activities (Table 1);
8.1.6 Vital Signs
Added footnote s in Table 1 and text 
in Section 8.1.6 to indicate that during 
screening, vital signs should be 
collected as close as possible to the 
dosing on Day 1. If more than one 
value is obtained for vital signs during 
screening, the value closest to the first 
dose of study drug should be used.
Clarification
Non-substantial
1.1 Schedule of 
Activities (Table 1);
8.1.8 Laboratory Tests
Revised footnote d in Table 1 and text 
in Section 8.1.8 to indicate that 
hepatitis serology should include, at a 
minimum, HBsAg, anti-HBc, and 
HCV antibody. Also, stated that if 
additional hepatitis serology is 
collected per institutional guidelines, 
it should be recorded in the database.
Clarification
Non-substantial


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Section number and 
name
Description of change
Brief rationale
Substantial/ 
non-substantial
1.1 Schedule of 
Activities;
8.1.8 Laboratory Tests;
8.3 On-study 
Procedures
Revised Table 1 and Sections 8.1.8 
and 8.3 so that collection of ferritin, 
D-dimer, fibrinogen, PT, aPTT, INR, 
and procalcitonin to occur every other 
day while in the hospital, and cardiac 
troponin I to be collected on Day 5 
while in the hospital. Added footnote 
m to specify that these laboratory tests 
should be collected more frequently if 
clinically indicated. Removed BNP 
assessment.
Also, stated in Section 8.3 that 
“Safety, CRP, PK, pharmacodynamic, 
and correlative laboratory tests are 
considered Tier 1 and should not be 
missed. The site must follow the 
SoA.”
Patient centricity; 
reduce amount of 
blood collection
Substantial
1.1 Schedule of 
Activities (Table 1);
8.3 On-study 
Procedures
Revised footnote h in Table 1 and text 
in Section 8.3 to indicate that if a 
subject is discharged prior to Day 7 
(+ 3 days) (instead of Day 10), he/she 
needs to visit the site for an 
assessment 2 to 4 days after discharge
Patient centricity
Non-substantial
Revised Table 1 to indicate that PK 
will be collected 0.5 and 2 hours 
postdose on Day 3, and 1 and 4 hours 
postdose on Day 7. Added footnote p 
to clarify that the these PK 
assessments can also be collected 
during a single visit on Day 3 or after. 
Patient centricity and 
understanding the 
complexities of 
multiple blood draws 
of a subject in isolation 
due to COVID-19
Non-substantial
1.1 Schedule of 
Activities (Table 1);
8.4.1 Oxygen 
Treatments and 
Ventilator Use
Added footnote n to Table 1 and text 
to Section 8.4.1 to clarify that arterial 
gases should be collected from 
subjects if the sample is easily 
accessible and the procedure will not 
be painful to subjects. Also stated that 
if collection of arterial gases is not 
clinically indicated, the test should not 
be performed.
Patient centricity, since 
taking arterial gases is 
painful 
Non-substantial
1.2 Synopsis;
2.1 Background and 
Study Rationale
Cited recent publications reporting 
activity of acalabrutinib and other Btk 
inhibitors in COVID-19 
Clarification
Non-substantial


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Section number and 
name
Description of change
Brief rationale
Substantial/ 
non-substantial
1.2 Synopsis;
3 Objectives and 
Endpoints
Reduced the number of PK parameters 
to be assessed for the PK endpoint
Given the reduced 
number of plasma 
samples for PK
Non-substantial
1.2 Synopsis;
6.1 Treatments 
administered
Revised Section 6.1 and restructured 
with sub-headers for clarity. Aligned 
Sections 1.2 and 6.1.
Clarification
Non-substantial
Added text to Section 6.1.3.1 to 
indicate that subjects on concomitant 
PPIs must take acalabrutinib with 
8 ounces (approximately 240 mL) of 
COCA-COLA at room temperature. 
Other cola beverages are not 
permitted. 
Based on new data 
generated by Sponsor 
supporting use of 
acalabrutinib with 
concomitant PPIs
Substantial
1.2 Synopsis;
9.6.2 Efficacy 
Analyses
Changed method for calculating 
confidence intervals from Blyth-Still-
Casella to Wald method with 
continuity correction
Align with comparator 
studies
Non-substantial
4.5 End of Study 
Definition;
7.1 Discontinuation of 
Study Treatment;
8.6.2 Time Period and 
Frequency for 
Collecting AE and 
SAE Information;
9.6.1 Safety Analyses
Specified that safety follow-up will 
occur 38 (± 3 days) after 
randomization for those subjects 
randomized to the BSC arm
Clarification
Non-substantial
5.1 Inclusion Criteria
Inclusion Criterion 3: Revised to 
indicate that SARS-CoV-2 infection 
must be confirmed within 7 days 
(instead of 3 days) prior to 
randomization
Patient centricity and 
given lack of RT-PCR 
resources in local 
hospitals during the 
COVID-19 pandemic
Non-substantial
5.2 Exclusion Criteria
Exclusion Criterion 8: Changed 
“within 24 hours at screening” to 
“during the screening period”
To align with revised 
screening period of 1 
to 3 days
Non-substantial
Exclusion Criterion 16: Revised 
hepatitis serology criteria
Clarification
Non-substantial
Exclusion Criterion 17: Revised 
CYP3A inhibitor and inducer washout 
periods from 14 to 7 days for 
inhibitors and from 7 to 14 days for 
inducers
Correction
Non-substantial
Exclusion Criterion 18: Removed PPI 
restriction
Based on new data 
generated by Sponsor 
Substantial


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Section number and 
name
Description of change
Brief rationale
Substantial/ 
non-substantial
supporting removal of 
exclusion
Exclusion Criterion 18: Revised 
immunomodulatory/ 
immunosuppressive treatment 
exclusion 
Clarification
Non-substantial
Exclusion Criterion 21: Removed 
steroid restriction
Align with global 
treatment practices
Substantial
Exclusion Criterion 22: Added “Other 
anticoagulants are permitted.”
Clarification
Non-substantial
6.1 Treatments 
Administered;
6.7 Dose Modification 
and Toxicity 
Management
Added text to allow subjects to make 
up missed doses 
Allow subjects to 
receive the full dosing 
of acalabrutinib (total 
of 20 doses)
Substantial
6.3.1.2 Methods for 
Assigning Treatment 
Groups
Removed the sentence, “Subjects will 
be identified to the IRT per country 
regulations.”
Not applicable as only 
year of birth and 
gender are collected in 
the IRT (no full date of 
birth or initials)
Non-substantial
6.5.2 Permitted 
Concomitant Therapy
Clarified BSC agents that will be 
permitted in this study. 
Align with global 
treatment practices
Substantial
6.5.3.1 Medications 
Prohibited for Subjects 
Treated with 
Acalabrutinib
Clarified that certain anticoagulants 
such as warfarin or equivalent vitamin 
K antagonists (eg, phenprocoumon) 
are prohibited for all subjects treated 
with acalabrutinib. Subjects who 
require prophylaxis or therapeutic 
anticoagulation for thrombosis (deep 
vein thrombosis or pulmonary 
embolism) will be allowed to receive 
therapeutic anticoagulation with a 
non-vitamin K inhibitor class of 
anticoagulants (eg, heparin or low-
molecular weight heparin)
Clarification
Non-substantial
Removed PPIs as a prohibited 
concomitant medication
Based on new data 
generated by Sponsor 
supporting removal of 
PPIs as a prohibited 
concomitant 
medication
Substantial
Removed steroid treatment language
Align with global 
treatment practices
Substantial


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Section number and 
name
Description of change
Brief rationale
Substantial/ 
non-substantial
6.5.3.2 Medications 
Prohibited for All 
Randomized Subjects
Clarified that immunomodulatory 
drugs intended as treatment for 
COVID-19 but not considered 
standard of care according to local 
institutional guidelines are prohibited 
for all randomized subjects in the 
study through Day 14. Subjects who 
are taking immunomodulatory drugs 
for other medical conditions (eg, 
tocilizumab for rheumatoid arthritis) 
may continue with treatment upon 
discussion with the Medical Monitor.
Clarification
Non-substantial
6.5.4 Acalabrutinib 
Drug-drug Interaction 
Guidance in the 
Presence of Life-
threatening COVID-19 
Infection;
6.5.4.2 Active 
Substances That May 
Decrease Acalabrutinib 
Plasma Concentrations
Added PPIs to Table 3 and specified 
that concomitant use of PPIs should 
be avoided. However, if PPI 
concomitant use cannot be avoided, 
dose modification of acalabrutinib is 
not necessary, but acalabrutinib must 
be administered with 240 mL of 
COCA-COLA to improve 
acalabrutinib absorption.
Based on new data 
generated by Sponsor 
supporting removal of 
PPIs as a prohibited 
concomitant 
medication
Substantial
6.5.4.2 Active 
Substances That May 
Decrease Acalabrutinib 
Plasma 
Concentrations;
Appendix E Examples 
of Coadministered 
Drugs That Need 
Additional 
Consideration 
(Table 8)
Removed ranitidine
Removed from market
Non-substantial
6.6 Risks Associated 
with Acalabrutinib
Clarified the risks associated with 
acalabrutinib and added a table 
showing frequency and time to onset 
of risks associated with acalabrutinib
Clarification
Non-substantial
6.7 Dose Modification 
and Toxicity 
Management
Provided more detailed guidance for 
toxicity management
Clarification
Non-substantial


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Section number and 
name
Description of change
Brief rationale
Substantial/ 
non-substantial
8.1.8 Laboratory Tests;
8.3 On-study 
Procedures
Removed wording “(at select centers 
only)” and “(at ALL centers)” for the 
exploratory samples. 
Made additional changes to these 
sections for clarity and to align with 
the SoA.
Clarification; all 
centers must collect the 
samples
Non-substantial
8.6.4 Adverse Event 
Data Collection;
B6 Intensity Rating 
Scale
Provided full URL for CTCAE V5.0
Correction
Non-substantial
9.6.2 Efficacy Analysis
Revised to indicate analysis is of 
number of days in ICU from 
randomization to 90 days (instead of 
28 days) after randomization
Correction
Non-substantial
10 References
Updated references using EndNote
Consistency with 
protocol template
Non-substantial
A7 Data Quality 
Assurance
Changed “source data verification” to
“source data review”
Correction
Non-substantial
F1 Female Subjects of 
Childbearing Potential
Removed the following text: “or 
2 months after the last dose of 
vincristine; or 6 months after the last 
dose of doxorubicin; or 12 months 
after the last dose of rituximab or 
cyclophosphamide; whichever is 
longest”
Clarification on risks 
associated with 
acalabrutinib
Non-substantial
AE = adverse event; anti-HBc = hepatitis B core antibody; aPTT = activated partial thromboplastin time; BNP = brain 
natriuretic peptide; BSC = best supportive care; COVID-19 = coronavirus disease 2019; CRP = C-reactive protein; 
CTCAE = Common Terminology Criteria for Adverse Events; CYP3A = cytochrome P450 3A; FDA = Food and Drug 
Administration; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; ICU = intensive care unit; 
INR = international normalized ratio; IRT = interactive response technology; PBMC = peripheral blood mononuclear cell; 
PK = pharmacokinetics; PPI = proton-pump inhibitor; PT = prothrombin; RT-PCR = reverse transcriptase-polymerase 
chain reaction; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SoA = Schedule of Activities; WHO = 
World Health Organization.
Amendment 2 (28Apr2020) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
The overall rationale for the amendment was to remove Part 2 of the study based on Health 
Authority feedback.


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Section # and Name
Description of Change
Brief Rationale
Title Page
Removed ACE-ID-201 and kept 
D822FC00001 as study number
D822FC00001 is the new study 
number
1.1 Schedule of Activities 
(SoA)
Revised Table 1 for clarity and 
consistency with the protocol body
and indicate that this SoA pertains to 
Arm 1 (Acalabrutinib + BSC). 
Added a separate SoA (Table 2) for 
Arm 2 (BSC Only)
Clarity and consistency
1.2 Synopsis;
2.1 Background and Study 
Rationale
Added a statement on clinical 
outcomes with Btk inhibitors for 
COVID-19 from a recent report
To further support the rationale for 
using Btk inhibitors for COVID-19
1.2 Synopsis; 
1.3 Schema;
3 Objectives and Endpoints;
4.1 Overall Design;
4.2 Scientific Rationale for 
Study Design;
4.4 Internal DMC; 
5 Study Population;
6.1 Treatments administered;
9.1 Statistical Hypotheses;
9.2 Sample Size 
Determination;
9.6.1 Safety Analyses;
9.6.2 Efficacy Analyses
Revised sections throughout protocol 
to reflect removal of Part 2 from the 
study
In response to Health Authority 
feedback
1.2 Synopsis;
3 Objectives and Endpoints
Split the safety and PK 
objectives/endpoints.
Added Days 14 and 28 to C-reactive 
protein and ferritin secondary 
endpoints and added Day 28 to the 
absolute lymphocyte counts 
secondary endpoint.
Clarity and completeness
4.5 End of Study Definition
Added that all randomized subjects 
will be followed for survival through 
90 (± 7) days after randomization
Clarity
5.1 Inclusion Criteria
Added Inclusion Criterion 5 (ability 
to swallow pills)
To align with feedback received 
from health authorities
5.2 Exclusion Criteria
Added sub-headers to group the 
different exclusion criteria. Revised 
Exclusion Criteria 1, 2, 7, 8, 17, 18, 
20, and 21
For clarity and to align with 
feedback received from healthy 
authorities
5.3 Screen Failures
Specified that the minimal set of 
screen failure information to be 
Clarity


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Section # and Name
Description of Change
Brief Rationale
collected will be unrelated to the 
disease under investigation
6 Study Treatments
Made revisions throughout this 
section. 
For clarity and to be more 
informative.
7.1 Discontinuation of Study 
Treatment
Replaced “respiratory failure” with 
“unable to swallow pills” as a reason 
for treatment discontinuation
If subjects can still swallow pills 
they should be allowed to continue 
treatment since expectation that 
benefit of treatment may still be 
possible
Removed the statement, “Subject 
who permanently discontinue 
treatment should be given locally 
available standard of care therapy, at 
the discretion of the investigator”
To avoid confusion as subjects 
already receive best supportive care
Added that all subjects will be 
followed through 90 (+ 7) days after 
randomization
Clarity
7.3 Lost to Follow-up
Added a statement to indicate that 
site personnel should check hospital 
records, public registries, and 
subject’s current physician to 
determine the reason for 
discontinuation when a subject is lost 
to follow-up
For completeness
8.1 Screening Assessments; 
8.3 On-study Procedures;
8.4 Clinical Assessments 
During Hospitalization
Revised for clarity and to align with 
the Schedule of Assessments
Clarity and consistency
8.2 Concomitant Medications
Added that the reason for treatment 
should be captured as “disease under 
study” and medications used as BSC 
should be captured as concomitant 
medications
Clarity


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CONFIDENTIAL AND PROPRIETARY
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Section # and Name
Description of Change
Brief Rationale
8.6 Collection of Adverse 
Events
For progression of underlying 
disease, specified underlying disease 
“related to COVID-19 pneumonia 
(such as worsening of respiratory 
status or complications of 
pneumonia)”
Clarity
8.6.2 Time Period and 
Frequency for Collecting AE 
and SAE Information
Revised for clarity and to align with 
the Schedule of Assessments
Clarity and consistency
8.6.4 Adverse Event Data 
Collection
Specified that grading scales found in 
the revised NCI CTCAE Version 5.0 
will be utilized for all events with an 
assigned CTCAE grading
Clarity
8.6.9 Disease Under Study;
8.6.10 Disease Progression
Specified that disease under study 
refers to “COVID-19 pneumonia and 
respiratory illness”
Clarity
9.6.1 Safety Analyses
Clarified the definition for treatment-
emergent adverse events
Clarity
10 References
Added a new reference and removed 
references not cited in the protocol
Consistency
Appendix A, Section A 10 
Publication Policy
Revised for clarity
Clarity
Appendix B, Section B 2 
Definition of Serious Adverse 
Events
Removed text regarding malignant 
tumors
Not relevant to this study population
Appendix D Actions Required 
in Cases of Increases in Liver 
Biochemistry and Elevation of 
Hy’s Law 
Revised appendix to be consistent 
with current protocol template 
language for Hy’s Law.
Consistency
Appendix G Child-Pugh Score
Added Appendix G 
To support Exclusion Criterion 8
Amendment 1 (17Apr2020) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
Changes were implemented in the protocol amendment to address the FDA comments.


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CONFIDENTIAL AND PROPRIETARY
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Section # and Name
Description of Change
Brief Rationale
Title Page;
1.2 Synopsis
Added “open-label” to the title and changed 
the IND number.
Clarity
1.1 Schedule of 
Activities
Formatted and edited the SoA for Part 1 
(Table 1) and Part 2 (Table 2) for clarity and 
consistency with changes made to the body of 
the protocol. 
Clarity and consistency
2.1 Background and 
Study Rationale;
4.2 Scientific 
Rationale for Study 
Design
Expanded the background and study rationale 
sections.
To strengthen the scientific 
rationale.
2.2 Benefit/Risk 
Assessment; 
4.4 Internal DMC;
Appendix A5 
Committee Structures
Changed from an Independent Data 
Monitoring Committee (IDMC) to an internal 
Data Monitoring Committee (iDMC) for this 
study. Removed reference to an interim 
analysis for futility.
To clarify that the Data Monitoring 
Committee will be internal.
1.2 Synopsis;
3 Objectives and 
Endpoints
Primary endpoint: Clarified the primary 
endpoint to read “proportion of subjects alive 
and free of respiratory failure” and defined 
respiratory failure according to the Agency’s 
recommendation. Also, clarified that the 
primary endpoint will be through Day 14 for 
Part 1 and through Day 28 for Part 2. 
Secondary endpoints: Added the primary 
endpoint for Part 2 as a secondary endpoint 
for Part 1 and the primary endpoint for Part 1 
as a secondary endpoint for Part 2. Added 
additional secondary endpoints for both 
Parts 1 and 2.
Safety and PK endpoints: Clarified the PK 
endpoint.
Exploratory endpoints:
 
 
 
To address FDA’s comment that 
endpoints should be meaningful for 
the target population.
CCI


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Section # and Name
Description of Change
Brief Rationale
1.2 Synopsis;
1.3 Schema;
4.1 Overall Study 
Design;
4.2 Scientific 
Rationale for Study 
Design;
4.3 Justification for 
Dose;
6.1 Treatments 
Administered;
9.2 Sample Size 
Determination;
Revised the study design so that both Parts 1 
and 2 are randomized to acalabrutinib + BSC 
or BSC and removed reference to a historical 
control for Part 2.
To address FDA’s comment that 
given the rapidly evolving 
treatment regimens and access, it is 
unlikely that a historical control 
will be an appropriate comparator 
in this setting.
Randomization for both Parts 1 and 2 to occur 
1:1 (instead of the original 2:1 randomization 
in Part 1).
To address FDA’s comment to 
randomize on 1:1 basis.
Increased treatment duration in Part 2 from 10 
to 14 days.
The duration of treatment has been 
selected based on the expected 
period of hyper-immune response 
for patients with COVID-19 
pneumonia who are moderately ill 
(Part 1) and for those who are 
severely ill (Part 2).
Removed option to cross over.
To address FDA’s comment to 
remove cross over.
Removed reference to retreatment.
To address FDA’s comment to 
remove retreatment.
Revised the sample size for Parts 1 and 2.
To reflect revised assumption for 
the primary endpoint, and the fact 
that Part 2 is now randomized.
Defined “present” in the context of 
comorbidities.
For clarity.
5.1 Inclusion Criteria 
for Part 1
Removed “(Arm 1 and Arm 2)” from the 
section header.
Revised Criterion 3 to exclude biomarkers. In 
addition, changed COVID-19 to SARS-CoV-
2 and revised this criterion to reflect that 
confirmation of SARS-CoV-2 must occur 
within 4 days of randomization (rather than 
within 3 weeks of study entry). The part of 
Criterion 3 referring to pneumonia was 
changed to a separate inclusion criterion and 
“(documented radiographically)” was added.
For clarity and to address FDA’s 
comment to exclude biomarkers.
5.2 Inclusion Criteria 
for Part 2
Removed “(ICU Cohort)” from the section 
header.
Revised Criterion 3 to be consistent with the 
definition provided in Section 5.1 (Criterion 
3).
Added an inclusion criterion (Criterion 4) for 
respiratory failure.
For clarity and consistency.


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Acalabrutinib - ACE-ID-201 (D822FC00001)
CONFIDENTIAL AND PROPRIETARY
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Section # and Name
Description of Change
Brief Rationale
5.3 Exclusion Criteria 
for Part 1and Part 2 
(All Subjects)
Removed Criterion 2 referring to “aggressive 
management”.
Given FDA’s comment that this 
may be seen as discriminatory 
against patient groups due to their 
moral or ethical beliefs regarding 
goals of care.
Added Exclusion Criteria 11, 12, and 21, and 
revised Criteria 13, 15, 16, and 17.
To ensure enrollment of subjects 
most likely to benefit from 
treatment.
5.4 Exclusion Criteria 
for Part 1 Only
Added “Only” to the section header. 
Revised Criterion 1 to be consistent with 
changes made to the inclusion criteria.
For clarity and consistency.
5.5 Exclusion Criteria 
for Part 2 Only
Added “Only” to the section header.
Added Criterion 2 to exclude subjects who 
have been receiving invasive mechanical 
ventilation (eg, endotracheal intubation and 
mechanical ventilation, or ECMO) for longer 
than 5 days prior to randomization.
For clarity.
To ensure enrollment of subjects 
who are likely to benefit.
5.6 Screen Failures
Added text to indicate that subjects may be 
rescreened.
To permit rescreening.
6.3 Measures to 
Minimise Bias: 
Randomisation and 
Blinding
Revised to be consistent with changes to the 
study design. Added sections to describe 
methods and procedures for assigning 
subjects to treatment groups, handling 
incorrectly enrolled or randomized subjects, 
and ensuring blinding.
To provide clarity regarding the 
methods and procedures for 
randomization.
6.5.3 Prohibited or 
Restricted 
Concomitant Therapy
Revised the steroids prohibition to apply to all 
subjects in the study and not just subjects 
receiving acalabrutinib. Also, specified that if 
an investigator determines that corticosteroids 
> 7.5 mg/day is required for a subject, after 
discussion with the medical monitor and both 
agree, it may be permitted.
To prevent potential imbalance 
between the treatment effects in 
the control arm versus 
acalabrutinib arm.
6.8 Toxicity 
Management
Guidelines
Changed section header from “Acalabrutinib 
Dose Modification Guidance in the Presence 
of Life-Threatening COVID-19 Infection” to 
“Toxicity Management Guidelines”.
For clarity.
7.1 Discontinuation of 
Study Treatment; 
7.3 Lost to Follow-Up
Revised text for clarification.
For clarity.
8.1 Screening 
Assessments; 
8.3 On-Study 
Procedures;
Edited the text in these sections for 
clarification. Added Section 8.4.4 
(Assessment of Number of Days in ICU) to 
describe assessment of ICU length of stay.
For clarity and consistency.


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Section # and Name
Description of Change
Brief Rationale
8.4 Clinical 
Assessments During 
Hospitalization;
8.6.2 Time Period and 
Frequency for 
Collecting AE and 
SAE Information;
8.7.2 Pregnancy
9.1 Statistical 
Hypotheses;
9.6.2 Efficacy 
Analyses
Revised to reflect the changes made to the 
study design.
For consistency and clarity.
9.3 Populations for 
Analyses
Added a table to define the analysis 
populations.
For clarity.
9.4 Interim Analyses
Revised to indicate that this study will not 
include any formal interim futility or interim
efficacy analyses.
Futility analysis removed 
following revision of sample size
9.5 Missing Data 
Handling
Specified that information on handling death 
in the analysis of endpoints that do not 
contain mortality as a component will be 
provided in the SAP.
For clarity.
9.6 Statistical Analyses
Specified that statistical analyses and 
summaries will be performed separately for 
Part 1 and Part 2.
For clarity.
9.6.2 Efficacy 
Analyses
Revised to reflect the changes made to the 
study endpoints.
For consistency.
9.6.3 Pharmacokinetic 
and Pharmacodynamic 
Analyses
Added “Pharmacodynamic” to the section 
title and specified that statistical analysis and 
reporting of pharmacodynamic parameters 
will be provided in the SAP. 
For clarity.

SAP_001.pdf: 
Statistical Analysis Plan
Drug Substance Acalabrutinib
Study Code
D822FC00001
Version
4.0
Date
01 October 2020
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


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
2(61)
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
TABLE OF CONTENTS.....................................................................................2
LIST OF ABBREVIATIONS ..............................................................................5
AMENDMENT HISTORY..................................................................................7
1.
STUDY DETAILS............................................................................................. 12
1.1
Study objectives.................................................................................................12
1.1.1
Primary objectives ............................................................................................. 12
1.1.2
Secondary objectives.......................................................................................... 12
1.1.3
Exploratory objectives ....................................................................................... 14
1.2
Study design ......................................................................................................14
1.3
Number of subjects ............................................................................................ 15
2.
ANALYSIS POPULATION .............................................................................. 15
2.1
Definition of analysis set.................................................................................... 15
2.1.1
Full analysis set (Intention-to-treat (ITT) population).........................................17
2.1.2
Per-protocol analysis set..................................................................................... 17
2.1.3
Safety analysis set.............................................................................................. 17
2.1.4
PK analysis set...................................................................................................18
2.2
Deviations..........................................................................................................18
3.
PRIMARY AND SECONDARY VARIABLES................................................. 19
3.1
Efficacy variables............................................................................................... 19
3.1.1
Alive and free of respiratory failure at Day 14.................................................... 19
3.1.2
Alive and free of respiratory failure at Day 28.................................................... 19
3.1.3
Percent change from baseline in C-reactive protein ............................................20
3.1.4
Change from baseline in ferritin.........................................................................20
3.1.5
Change from baseline in absolute lymphocyte counts.........................................20
3.1.6
All-cause mortality at Day 90............................................................................. 20
3.1.7
Alive and discharged from the ICU at Days 14 and 28 .......................................21
3.1.8
Time to first occurrence of respiratory failure or death.......................................21
3.1.9
Days alive and free of respiratory failure over the course of 28 days .................. 22
3.1.10
Days with respiratory failure over the course of 28 days.....................................23
3.1.11
Days hospitalized over the course of 28 days...................................................... 24
3.1.12
Days in ICU over the course of 90 days.............................................................. 24
3.1.13
Days alive outside of hospital over the course of 28 days ...................................25
3.1.14
Days alive outside of hospital over the course of 90 days ...................................26
3.1.15
Relative change from baseline in oxygenation index ..........................................26


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
3(61)
3.1.16
Time to clinical improvement of at least 2 points (from randomization) on 
a 9-point category ordinal scale through Day 28................................................. 26
3.1.16.1
Time to clinical improvement of at least 2 points (from randomization) on 
a 9-point category ordinal scale, live discharge from hospital, or 
considered fit for discharge, whichever comes first through Day 28 ................... 27
3.1.16.2
Time to recovery (from randomization) through Day 28.....................................28
3.1.17
Time to SpO2 > 94% on room air .......................................................................29
3.2
Safety variables..................................................................................................29
3.2.1
Adverse events...................................................................................................29
3.2.2
Exposure, dose intensity and treatment compliance............................................30
3.2.3
Laboratory assessments...................................................................................... 32
3.2.4
Physical examinations and chest imaging, electrocardiograms and 
echocardiograms ................................................................................................ 32
3.2.5
Vital signs and arterial blood gases ....................................................................33
3.2.6
Oxygen treatment, ventilator use and mSOFA score...........................................33
3.3
Pharmacokinetic variables.................................................................................. 34
3.4
Exploratory pharmacodynamic and correlative variables....................................34
3.5
Other variables...................................................................................................35
3.5.1
Baseline characteristics ...................................................................................... 35
3.5.2
Prior and concomitant medications and procedures ............................................36
4.
ANALYSIS METHODS.................................................................................... 36
4.1
General principles.............................................................................................. 36
4.2
Analysis methods............................................................................................... 40
4.2.1
Disposition of subjects ....................................................................................... 40
4.2.2
Protocol deviations............................................................................................. 41
4.2.3
Demographic and other baseline characteristics.................................................. 41
4.2.4
Prior and concomitant medications and procedures ............................................41
4.3
Analysis of efficacy ........................................................................................... 42
4.3.1
Primary endpoint................................................................................................ 42
4.3.1.1
Alive and free of respiratory failure at Day 14.................................................... 42
4.3.2
Secondary endpoints .......................................................................................... 43
4.3.2.1
Alive and free of respiratory failure at Day 28.................................................... 43
4.3.2.2
Percent change from baseline in C-reactive protein ............................................43
4.3.2.3
Change from baseline in ferritin.........................................................................44
4.3.2.4
Change from baseline in absolute lymphocyte count ..........................................44
4.3.2.5
All-cause mortality at Day 90............................................................................. 44
4.3.2.6
Alive and discharged from the ICU at Days 14 and 28 .......................................44
4.3.2.7
Time to first occurrence of respiratory failure or death.......................................45
4.3.2.8
Days alive and free of respiratory failure over the course of 28 days .................. 45
4.3.2.9
Days with respiratory failure over the course of 28 days.....................................45
4.3.2.10
Days hospitalized over the course of 28 days...................................................... 46
4.3.2.11
Days in ICU over the course of 90 days.............................................................. 46


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
4(61)
4.3.2.12
Days alive outside of hospital over the course of 28 days ...................................46
4.3.2.13
Days alive outside of hospital over the course of 90 days ...................................46
4.3.2.14
Relative change from baseline in oxygenation index ..........................................46
4.3.2.15
Time to clinical improvement of at least 2 points (from randomization) on 
a 9-point category ordinal scale through Day 28................................................. 47
4.3.2.16
Time to SpO2 > 94% on room air .......................................................................48
4.4
Analysis of safety............................................................................................... 48
4.4.1
Adverse events...................................................................................................49
4.4.1.1
Deaths, serious adverse events (SAEs), and other significant adverse 
events................................................................................................................. 50
4.4.2
Exposure, dose intensity and treatment compliance............................................51
4.4.3
Laboratory assessments...................................................................................... 51
4.4.4
Vital signs..........................................................................................................52
4.4.5
Physical examinations and chest imaging, electrocardiograms and 
echocardiograms ................................................................................................ 52
4.4.6
Oxygen treatment, ventilator use and mSOFA.................................................... 53
4.5
Analysis of pharmacokinetics............................................................................. 53
4.6
Analysis of exploratory variables and pharmacodynamics..................................53
5.
INTERIM ANALYSES ..................................................................................... 54
6.
DATA MONITORING COMMITTEE.............................................................. 54
7.
CHANGES OF ANALYSIS FROM PROTOCOL ............................................. 55
8.
APPENDIX .......................................................................................................56
8.1
AESI and ECI definitions................................................................................... 56
8.2
DMC outputs for review meeting .......................................................................60
8.3
Fraction of Inspired Oxygen (FiO2)....................................................................61
9.
REFERENCES ..................................................................................................61


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
5(61)
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AE
Adverse Event 
AESI
Adverse Event of Special Interest
ATC
Anatomic and Therapeutic Class
AZ
AstraZeneca
BID
Twice a day
BMI
Body Mass Index
BP
Blood Pressure
BSC
Best supportive care
CI
Confidence Interval
CNS
Central Nervous System
CRP
C-reactive Protein
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for AEs
CTMS
Clinical Trial Management System
DMC
Data Monitoring Committee
ECG
Electrocardiogram
ECHO
Echocardiogram
ECI
Events of Clinical Interest
ECMO
Extracorporeal Membrane Oxygenation
eCRF
Electronic Case Report Form


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
6(61)
FAS
Full Analysis Set
FiO2
Fraction of Inspired Oxygen
ICU
Intensive Care Unit
IPD
Important Protocol Deviation
IRT
Immune Response Technology
ITT
Intention-to-treat
KM
Kaplan-Meier
MAP
Mean Arterial Pressure
MedDRA
Medical Dictionary for Regulatory Activities
mSOFA
Modified Sequential Organ Failure Assessment
PID
Percentage of intended dose
PD
Pharmacodynamic
PK
Pharmacokinetic
PKAS
Pharmacokinetic Analysis Set
PPAS
Per-Protocol Analysis Set
PT
Preferred Term
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SD
Standard Deviation
SOC
System Organ Class
SpO2
Oxygen Saturation
TEAE
Treatment Emergent Adverse Event
WHO-DD
World Health Organization-Drug Dictionary


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
7(61)
AMENDMENT HISTORY
Category: 
Change 
refers to
Date
Description of change
In line 
with 
the 
CSP?
Rationale
Primary and 
secondary 
endpoints
27 July 
2020
Added secondary 
endpoints for time to 
clinical improvement and 
time to SpO2 > 94% on 
room air.
Y (v5.0)
Emerging as important 
endpoints in
the assessment of
COVID-19.
27 July 
2020
Updated formula used for 
oxygenation index.
Y (v5.0)
Clarification based on study 
assessments.
27 July 
2020
Reduced PK analyses.
Y (v5.0)
Align with reduced data 
collection in SoA.
Statistical 
analysis 
method for 
primary or 
secondary 
endpoints
27 July 
2020
Updated confidence 
interval method from 
Blyth-Still-Casella to Wald 
with continuity correction.
Y (v5.0)
Align with comparator studies.
27 July 
2020
Updated confidence 
interval from 90% to 95%.
Y (v5.0)
Typo in previous version.
27 July 
2020
Added detail on primary 
analysis and multiplicity 
adjustment of the overall 
Type I error for the 
primary analysis to 
account for the added 
interim efficacy analysis.
Y (v5.0)
For clarity and to preserve 
statistical rigor.
05 August 
2020
Removed language 
“Formal statistical analysis 
(with generation of a p-
value) will not be 
undertaken for these 
endpoints.”
NA
P-values will be generated for 
the primary and key secondary 
efficacy endpoints to support 
possible regulatory 
interactions.
28 August 
2020
Added respiratory failure 
status at baseline as a 
subgroup analysis for the 
primary endpoint
NA
Changes to eligibility criteria 
throughout CSP amendments 
mean that some patients may 
have respiratory failure at 
baseline.
Derivation 
of primary 
or secondary 
endpoint
27 July 
2020
Updated imputation rules 
for missing or partial AE 
and CM dates.
NA
Accommodate all possible 
scenarios for programming 
purposes.
27 July 
2020
Updated derivation of 
exposure variables.
NA
Accommodate limitations in 
data collection.


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
8(61)
Category: 
Change 
refers to
Date
Description of change
In line 
with 
the 
CSP?
Rationale
27 July 
2020
Updated safety follow-up 
timepoint for BSC alone 
arm to 38 (+3) days after 
randomization.
Y (v5.0)
Align more closely with 
timing of safety follow-up for 
Acalabrutinib + BSC arm.
27 July 
2020
Updated visit windows.
Y (v5.0)
Accommodate changes to the 
SoA and for clarity.
27 July 
2020
Added derivation of BSC 
from the eCRF.
NA
Clarification.
27 July 
2020
Updated the details of the 
AESI and ECI definitions.
NA
To align with study-specific 
requirements.
27 July 
2020
Added that the primary 
efficacy endpoint at Day 
14 and equivalent 
secondary endpoint at Day 
28 will be restricted to 
subjects who have had the 
opportunity for follow-up.
NA
To reduce bias and for 
clarification.
27 July 
2020
Added that proportions, 
difference and CIs for the 
primary efficacy endpoint 
at Day 14 and equivalent 
secondary endpoint at Day 
28 will also be reported in 
the FAS excluding 
subjects who have 
withdrawn or been lost to 
follow-up prior to Day 14 
and Day 28, respectively.
NA
Clarification.
30 July 
2020
Added details on the 
derivation of hospital or 
ICU stay for each endpoint 
requiring this information.
NA
Clarification.
27 August 
2020
Removed derivation of 
FiO2 for a Venturi mask 
and added the derivation of 
FiO2 for a simple mask. 
Also clarified FiO2 units 
are %.
NA
Changes in data collection 
method
27 August 
2020
Removed language on not 
including all AE entries in 
the table summaries. 
NA
Changes in data collection 
method.


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
9(61)
Category: 
Change 
refers to
Date
Description of change
In line 
with 
the 
CSP?
Rationale
28 August 
2020
Updated definition of 
baseline and visit windows 
for all variables.
NA
Previous definitions could not 
be accurately derived due to 
limited data collection.
07 
September 
2020
Added further detail on 
imputing start day and 
month for partial AE or 
CM dates.
NA
Clarification.
09 
September 
2020
Corrected rules for 
handling withdrawn of 
LTFU subjects when 
deriving the endpoint 
“Days in ICU over the 
course of 90 days”.
NA
Typo.
30 
September 
2020
Added details on 
oxygenation index formula 
and FiO2 imputation for 
subjects not on any oxygen 
or mechanical ventilation.
NA
Clarification.
Data 
presentations
27 July 
2020
Removed weight 
categories from 
demographic summary 
tables.
NA
Not required for interpretation 
(continuous summary statistics 
are sufficient).
27 July 
2020
Updated list of pre-
specified AE summaries.
NA
Clarification.
27 July 
2020
Removed percent change 
summary and added line 
graph of mean change 
from baseline for 
secondary lab and 
oxygenation index 
endpoints.
NA
Typo in previous version.
27 August 
2020
Added details on 
additional oxygen and 
mechanical ventilation 
summaries.
NA
To allow for clearer 
interpretation of the data. 
27 August 
2020
Added details on 
additional ordinal scale 
summaries.
NA
To allow for clearer 
interpretation of the data.


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
10(61)
Category: 
Change 
refers to
Date
Description of change
In line 
with 
the 
CSP?
Rationale
27 August 
2020
Added a summary of the 
proportion of subjects who 
experienced respiratory 
failure or died over the 
course of 28 days.
NA
To allow for clearer 
interpretation of the data and 
to align with DMC charter.
30 
September 
2020
Added a summary of the 
proportion of subjects who 
required invasive 
ventilation or ECMO over 
the course of 28 days.
NA
Emerging as important 
summary in the assessment of 
COVID-19.
30 
September 
2020
Updated table categories 
for days with respiratory 
failure, days hospitalized 
and days in ICU.
NA
Distinguish between subjects 
with no occurrences and those 
with at least one.
30 
September 
2020
Replaced ‘histogram’ with 
‘bar chart’ for summaries 
of days with respiratory 
failure, days in ICU and 
days hospitalized.
NA
Clarification.
Other
27 July 
2020
Reduced the list of 
important protocol 
deviations.
NA
To accommodate ongoing 
changes in BSC and 
guidelines.
27 July 
2020
Updated timings and scope 
of iDMC reviews.
Y (v5.0)
Due to projected rapid 
enrolment and for transparency 
and to preserve the trial 
integrity.
27 August 
2020
Change ‘iDMC’ to ‘DMC’ 
throughout
N (v5.0)
External members added to the
DMC (after CSP v5.0 was
released) so it is no longer 
fully internal. This change is 
aligned with the DMC 
charter v4.0.
07 
September 
2020
Updated list of outputs to 
be reviewed by the DMC.
NA
To align with the DMC 
charter v4.0.


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
11(61)
Category: 
Change 
refers to
Date
Description of change
In line 
with 
the 
CSP?
Rationale
07 
September 
2020
Added detail on total 
number of subjects 
randomized as this was 
known at the time of the 
SAP amendment.
NA
Transparency.
30 
September 
2020
Updated list of outputs to 
be reviewed by the DMC.
NA
Transparency.


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
12(61)
1.
STUDY DETAILS
This statistical analysis plan (SAP) contains a more detailed description of the analyses in the 
clinical study protocol (CSP). This SAP is based on version 5 of the CSP.
This SAP will apply to the study to determine the efficacy and safety of acalabrutinib with 
best supportive care (BSC) versus BSC in subjects hospitalized with COVID-19. The target 
population for this study is adult subjects (age ≥18 years) with confirmed infection with 
SARS-CoV-2 per World Health Organization (WHO) criteria and COVID-19 pneumonia 
requiring hospitalization. 
1.1
Study objectives
1.1.1
Primary objectives
The primary objectives for this study and the corresponding endpoints/variables are shown in  
Table 1.
Table 1
Primary objectives and endpoints
Primary Objectives
Primary Endpoints/Variables
To evaluate the efficacy of adding acalabrutinib 
to BSC for the treatment of COVID-19
Proportion of subjects alive and free of 
respiratory failure at Day 14
For the purpose of this study, respiratory 
failure is defined based on resource utilization 
of any of the following modalities:

Endotracheal intubation and mechanical 
ventilation

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 ≥50%)

Non-invasive positive pressure ventilation or 
continuous positive airway pressure 

Extracorporeal membrane oxygenation 
1.1.2
Secondary objectives
The secondary objectives for this study and the corresponding endpoints/variables are shown 
in Table 2.
Table 2
Secondary objectives and endpoints
Secondary Efficacy Objectives
Secondary Efficacy Endpoints/Variables:


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
13(61)
To evaluate the efficacy of adding acalabrutinib 
to BSC for the treatment of COVID-19

Proportion of subjects alive and free of 
respiratory failure (defined above) at Day 28

Percent change from baseline in C-reactive 
protein (CRP) (time frame: baseline, Days 3, 
5, 7, 10, 14, 28)

Change from baseline in ferritin (time frame: 
baseline, Days 3, 5, 7, 10, 14, 28)

Change from baseline in absolute 
lymphocyte counts (time frame: baseline, 
Days 3, 5, 7, 10, 14, 28)

All-cause mortality at Day 90

Proportion of subjects alive and discharged 
from the intensive care unit (ICU) at Days 14 
and 28

Time from randomization to first occurrence 
of respiratory failure or death on study (up to 
28 days after randomization) due to any 
cause

Number of days alive and free of respiratory 
failure from randomization to 28 days after 
randomization

Number of days with respiratory failure from 
randomization to 28 days after randomization

Number of days hospitalized from 
randomization to 28 days after randomization

Number of days in ICU (length of stay) from 
randomization to 90 days after randomization

Number of days alive outside of hospital 
from randomization to 28 days after 
randomization

Number of days alive outside of hospital 
from randomization to 90 days after 
randomization

Relative change from baseline in 
oxygenation index (SpO2/FiO2) (time frame:  
baseline, Days 3, 5, 7 and 10)

Time to clinical improvement of at least 2 
points (from randomization) on a 9-point 
category ordinal scale through Day 28

Time to SpO2 > 94% on room air
Safety Objective
Safety Endpoint/ Variable
To evaluate the safety of acalabrutinib in 
subjects with COVID-19 when administered 
with BSC
Type, frequency, severity, and relationship to 
study treatment of any treatment-emergent 
adverse events (TEAEs) or abnormalities of 


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
14(61)
laboratory tests, serious adverse events (SAEs), 
or adverse events (AEs) leading to 
discontinuation of study treatment
Pharmacokinetic (PK) Objectives
PK Endpoints/Variables
To assess PK of acalabrutinib and its active 
metabolite in subjects with COVID-19 when 
administered with BSC
Summarized plasma concentrations of 
acalabrutinib and ACP-5862 at specified time 
points. Pharmacokinetic parameters (e.g., AUC 
and Cmax) estimated, as appropriate.
1.1.3
Exploratory objectives
The exploratory objectives for this study and the corresponding endpoints/variables are shown 
in Table 3.
Table 3
Exploratory objectives and endpoints
Exploratory Objectives
Exploratory Endpoints/Variables
1.2
Study design
This is a multicenter, randomized, open-label, Phase 2 study that will evaluate acalabrutinib 
plus BSC versus BSC in subjects with COVID-19 who are hospitalized.
Subjects will be randomly assigned (1:1) to receive one of the following 2 treatments:

Arm 1: Acalabrutinib 100 mg twice a day (bid) x 10 days + BSC (n=70)

Arm 2: BSC alone (n=70)
For the purpose of this study, BSC is per discretion of the investigator and institutional 
guidelines.  However, refer to Section 5.2 and 6.5.3 of the CSP for prohibited or restricted 
concomitant therapy. Subjects will be randomized based on the following stratification 
factors, which are considered prognostic factors for poor outcome:  
CCI


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
15(61)
•
Age (≥ 65 vs < 65 years)
•
Comorbidities (present vs absent). “Present” is defined as having at least 1 of the 
following comorbidities:  

Cardiovascular disease, as defined by either heart failure New York Heart 
Association class ≥2 or hypertension requiring treatment

Diabetes mellitus requiring treatment

Chronic obstructive pulmonary disease or asthma requiring treatment

Current active solid tumor or hematologic malignancy
1.3
Number of subjects
The planned total number of subjects in this study is approximately 140. One hundred and 
forty (140) subjects meeting the eligibility criteria will be randomized in a 1:1 ratio to either 
Arm 1 (acalabrutinib plus BSC; n=70) or Arm 2 (BSC; n=70).
It is assumed that the proportion of subjects who are alive and free of respiratory failure at 
Day 14 is 70% under BSC. A targeted difference of 20% between two treatment arms (i.e., 
90% for acalabrutinib + BSC) is of clinical interest. With a total sample size of 140, the study 
has approximately 85% power, with a 2-sided type I error of 0.05, to detect a difference of 
20% between the 2 arms.
At the time that the SAP version 3.0 was generated (amendment of version 2.0), the study 
recruitment was complete with a total of 177 subjects randomized.
2.
ANALYSIS POPULATION
2.1
Definition of analysis set
Four analysis sets are defined in this study. A summary of the analysis sets used for each 
outcome variable in provided in Table 4.
Table 4
Summary of outcome variables and analysis populations
Outcome variable
Analysis populations
Safety data


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
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Type, frequency, severity, and relationship to study treatment 
of any TEAEs or abnormalities of laboratory tests, SAEs, or 
AEs leading to discontinuation of study treatment.
Exposure and dose intensity: actual treatment duration, 
percentage of intended dose (PID), average daily dose.
Safety analysis set
Efficacy data
Proportion of subjects alive and free of respiratory failure at 
Day 14
Full analysis set and per-protocol 
analysis set
Proportion of subjects alive and free of respiratory failure at 
Day 28
Full analysis set
Percent change from baseline in C-reactive protein
Full analysis set
Change from baseline in ferritin
Full analysis set
Change from baseline in absolute lymphocyte counts
Full analysis set
All-cause mortality at Day 90
Full analysis set
Proportion of subjects alive and discharged from the intensive 
care unit (ICU) at Days 14 and 28
Full analysis set
Time from randomization to first occurrence of respiratory 
failure or death on study due to any cause
Full analysis set
Number of days alive and free of respiratory failure from 
randomization to 28 days after randomization
Full analysis set
Number of days with respiratory failure from randomization to 
28 days after randomization
Full analysis set
Number of days hospitalized from randomization to 28 days
after randomization
Full analysis set
Number of days in ICU from randomization to 90 days after 
randomization
Full analysis set
Number of days alive outside of hospital from randomization 
to 28 days after randomization
Full analysis set
Number of days alive outside of hospital from randomization 
to 90 days after randomization
Full analysis set


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
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Relative change from baseline in oxygenation index 
(SpO2/FiO2)
Full analysis set
Time to clinical improvement of at least 2 points (from 
randomization) on a 9-point category ordinal scale through 
Day 28
Full analysis set
Time to SpO2 > 94% on room air
Full analysis set
Other data
Disposition, demography and baseline characteristics: subject 
characteristics, medical history, relevant surgical history, 
concomitant medications, oxygen therapy and ventilator 
history, history of substance abuse, SARS-CoV-2 infection 
comorbidities and risk factors/lifestyle events
Full analysis set 
PK data
PK analysis set
PD data
PK analysis set as appropriate
2.1.1
Full analysis set (Intention-to-treat (ITT) population)
The full analysis set (FAS) will include all subjects who are randomized and will be used for 
all efficacy analyses. Treatment arms will be compared on the basis of randomized study 
treatment, regardless of the treatment actually received. Subjects who were randomized but 
did not subsequently go on to receive study treatment will be included in the analysis in the 
treatment arm to which they were randomized, following the “intent-to-treat” principle.
2.1.2
Per-protocol analysis set
The per-protocol analysis set (PPAS) will be a subset of the ITT population including only 
subjects without important detected protocol deviations affecting the efficacy endpoints. 
Subjects will be summarized according to the actual treatment received. The primary efficacy 
endpoint of the study will also be summarized for this population.
2.1.3
Safety analysis set
The safety analysis set (SAF) is based on the treatment subjects actually received. In this 
study, the treatment is either acalabrutinib + BSC or BSC only. If a subject receives at least 1 
dose of acalabrutinib, the subject is considered as acalabrutinib-treated, regardless which arm 
the subject was randomized to. Subjects who do not receive any acalabrutinib will be 
summarized in the BSC group.


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
18(61)
2.1.4
PK analysis set
The PK analysis set (PKAS) will include all subjects who receive ≥1 dose of acalabrutinib and 
had ≥1 post-dose evaluable PK data point for acalabrutinib or ACP-5862. The population will 
be defined by AstraZeneca, the pharmacokineticist and the statistician prior to any analyses 
being performed.
 
2.2
Deviations
The following general categories will be considered important protocol deviations and will be 
programmatically derived from the eCRF data and entered into the Clinical Trial Management 
System (CTMS) by the monitor.  These will be listed and discussed in the Clinical Study 
Report (CSR) as appropriate:
•
Subjects randomized to the acalabrutinib + BSC arm but who did not receive any 
doses of acalabrutinib (Deviation 1)
•
Subjects who deviate from key eligibility criteria per the CSP (Deviation 2)
Inclusion criteria: 1, 3, 4 
Exclusion criteria: 1
•
Subjects developed discontinuation criteria but have not been withdrawn from 
treatment (Deviation 3):
o
Pregnancy
Subjects who receive the wrong treatment at any time will be included in the SAF as 
described in Section 2.1.  During the study, decisions on how to handle errors in treatment 
dispensing (with regard to continuation/discontinuation of study treatment or, if applicable, 
analytically) will be made on an individual basis with written instruction from the Global 
Study Lead and/or Statistician.
The important protocol deviations will be listed and summarized by randomized treatment 
group. None of the deviations will lead to subjects being excluded from the analysis sets 
described in section 2.1 (with the exception of the PK analysis set, if the deviation is 
considered to impact upon PK, and the PPAS).
The need for additional sensitivity analysis due to protocol deviations will be determined 
following review of the protocol deviations ahead of database lock and will be documented 
prior to the primary analysis being conducted.
CCI


Statistical Analysis Plan 
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3.
PRIMARY AND SECONDARY VARIABLES
3.1
Efficacy variables
3.1.1
Alive and free of respiratory failure at Day 14
The primary endpoint is the proportion of subjects who are alive and free of respiratory failure 
at Day 14. For the purpose of this study respiratory failure is defined based on resource 
utilization of any of the following modalities:
o
Endotracheal intubation and mechanical ventilation;
o
Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered 
via reinforced nasal cannula at flow rates >20L/min with fraction of delivered oxygen 
≥50%);
o
Non-invasive positive pressure ventilation or continuous positive airway pressure;
o
Extracorporeal membrane oxygenation.
Only the subject’s survival status and respiratory-failure status on Day 14 will be considered 
for this endpoint. No visit window will be used for this endpoint. If they experience 
respiratory failure after randomization but recover by Day 14, per the definition above, they 
will be considered alive and free of respiratory failure at Day 14.
For the FAS analysis, subjects who withdraw or are lost to follow up prior to Day 14, thus 
survival status and respiratory status at Day 14 cannot be assessed, will be included in the 
denominator of this analysis as though they had died or had a respiratory failure.
For the PPAS analysis, subjects who withdraw or are lost to follow up prior to Day 14, thus 
survival status and respiratory status at Day 14 cannot be assessed, will be excluded from this 
analysis, hence the percentage for each treatment group will be calculated as:
Number of subjects alive and free of respiratory failure at Day 14
Number of subjects who have died or are still in the study at Day 14 × 100%
To avoid a biased estimate of the proportion at interim analyses, the subjects included in this 
analysis (based on the FAS and PPAS definitions) will be restricted to subjects who reached 
Day 14 (or would have reached Day 14 had they not died, withdrawn or been lost to follow 
up) at the time the analysis. This will be considered the full analysis set evaluable at Day 14.
3.1.2
Alive and free of respiratory failure at Day 28  
This is defined as the proportion of subjects who are alive and free of respiratory failure at 
Day 28. Respiratory failure is defined the same as specified in Section 3.1.1 above.
Only the subject’s survival status and respiratory-failure status on Day 28 will be considered 
for this endpoint. No visit window will be used for this endpoint. If they experience 
respiratory failure after randomization but recover by Day 28, per the definition above, they 
will be considered alive and free of respiratory failure at Day 28.


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
20(61)
For the FAS analysis, subjects who are lost to follow up prior to Day 28, thus survival status 
and respiratory status at Day 28 cannot be assessed, will be included in the denominator of 
this analysis as though they had died or had a respiratory failure.
For the PPAS analysis, subjects who are lost to follow up prior to Day 28, thus survival status 
and respiratory status at Day 28 cannot be assessed, will be excluded from this analysis, hence 
the percentage for each treatment group will be calculated as:
Number of subjects alive and free of respiratory failure at Day 28
Number of subjects who have died or are still in the study at Day 28 × 100%
To avoid a biased estimate of the proportion at interim analyses, the subjects included in this 
analysis (based on the FAS and PPAS definitions) will be restricted to subjects who reached 
Day 28 (or would have reached Day 28 had they not died, withdrawn or been lost to follow 
up) at the time the analysis. This will be considered the full analysis set evaluable at Day 28.
3.1.3
Percent change from baseline in C-reactive protein  
This is defined as the percent change from baseline in C-reactive protein (CRP) at Days 3, 5, 
7, 10, 14 and 28. For this endpoint, baseline is defined as the observation on the date of 
randomization (Day 1). If no result was obtained on the date of randomization, the last result 
prior to the date of randomization will be used. Details on visit windows are provided in 
Section 4.1.
3.1.4
Change from baseline in ferritin  
This is defined as the change from baseline in ferritin at Days 3, 5, 7, 10, 14 and 28. For this 
endpoint, baseline is defined as the observation on the date of randomization (Day 1). If no 
result was obtained on the date of randomization, the last result prior to the date of 
randomization will be used. Details on visit windows are provided in Section 4.1.
The percent change from baseline at these timepoints will also be derived.
3.1.5
Change from baseline in absolute lymphocyte counts
This is defined as the change from baseline in absolute lymphocyte counts at Days 3, 5, 7, 10, 
14 and 28. For this endpoint, baseline is defined as the observation on the date of 
randomization (Day 1). If no result was obtained on the date of randomization, the last result 
prior to the date of randomization will be used. Details on visit windows are provided in 
Section 4.1.
The percent change from baseline at these timepoints will also be derived.
3.1.6
All-cause mortality at Day 90
This is defined as the proportion of subjects who have died due to any cause by Day 90.
If a subject is not known to have already died, they (or a caregiver/relative) will be contacted 
at Day 90 (± 7 days) to confirm survival status. If a subject is lost to follow-up or has 


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
21(61)
withdrawn consent to be followed-up at this timepoint, the survival status of the subject may 
be obtained by site personnel by checking publicly available resources (as applicable under 
local laws).
Subjects alive at Day 90 will be censored at Day 90 and subjects lost to follow-up (i.e. with 
unknown survival status at Day 90) will be censored at the last time known to be alive.
3.1.7
Alive and discharged from the ICU at Days 14 and 28
This is defined as the proportion of subjects alive and discharged from the ICU at Day 14 and 
the proportion of subjects alive and discharged from the ICU at Day 28.
For a subject to be considered discharged from the ICU, they must not be in ICU on Day 14 
(or Day 28), regardless of whether or not ICU-standard care is reported as not clinically 
indicated in the CHCSS eCRF. 
Only the subject’s survival status and ICU status on Day 14 (or Day 28) will be considered for 
this endpoint. No visit window will be used for this endpoint. If they are admitted to ICU after 
randomization but are discharged by Day 14 (or Day 28), they will be considered alive and 
discharged from the ICU at Day 14 (or Day 28).
For the FAS analysis, subjects who withdraw or are lost to follow up prior to Day 14 (or Day 
28), thus survival status and respiratory status at Day 14 (or Day 28) cannot be assessed, will 
be included in the denominator of this analysis as though they had died or had a respiratory 
failure.
For the PPAS analysis, subjects who withdraw or are lost to follow up prior to Day 14 (or Day 
28), thus survival status and respiratory status at Day 14 (or Day 28) cannot be assessed, will 
be excluded from this analysis, hence the percentage for each treatment group will be 
calculated as:
Number of subjects alive and free of respiratory failure at Day 14 (or Day 28)
Number of subjects who have died or are still in the study at Day 14 (or Day 28) × 100%
To avoid biased estimates of the proportions at interim analyses should they be generated, the 
subjects included in this analysis (based on the FAS and PPAS definitions) will be restricted 
to subjects who reached Day 14 (or Day 28) (or would have reached Day 14 (or Day 28) had 
they not died, withdrawn or been lost to follow up) at the time the analysis. This will be 
considered the full analysis set evaluable at Day 14 (or Day 28).
3.1.8
Time to first occurrence of respiratory failure or death
This is defined as the time (in days) from randomization to the first occurrence of respiratory 
failure or death (due to any cause) on study (up to Day 28), whichever occurs first.
If a subject does not have an event (i.e., does not experience respiratory failure or death) on or 
before Day 28 and does not withdraw or become lost to follow up from the study prior to Day 


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
22(61)
28, the data will be censored at Day 28. If a subject does not have an event but withdraws 
from the study or is lost to follow up prior to Day 28, the data will be censored at the last date 
known that the subject was alive and free of respiratory failure up to Day 28.
Subjects with respiratory failure at baseline (defined as respiratory failure on the date of 
randomization (Day 1)) will not be included in any analyses of time to first occurrence of 
respiratory failure or death.
3.1.9
Days alive and free of respiratory failure over the course of 28 days
This is defined as the total number of days alive and free of respiratory failure from 
randomization to Day 28.
For a day to count as ‘alive and free of respiratory failure’, the subject must be free of 
respiratory failure for the entire day. All days from the start date to the stop date inclusive of 
each respiratory failure will count as respiratory failure days. If a subject dies on Day 1, the 
number of days alive and free of respiratory failure is zero. If a subject is alive on Day 28 and 
has not experienced respiratory failure at any point over the 28-day period, the number of days 
alive and free of respiratory failure is 28 days.
The following rules will be applied for missing data:

If a subject has been discharged from hospital and is known to be alive at Day 28, and 
there is no evidence that respiratory failure has occurred during this period, the number 
of days from being discharged to Day 28 will be counted as days alive and free of 
respiratory failure. If a subject has been discharged from hospital but dies prior to Day 
28 and there is no evidence that respiratory failure has occurred during this period, the 
number of days from being discharged to the last date known to be alive will be 
counted as days alive and free of respiratory failure.

If a subject has been discharged from hospital but dies prior to Day 28 and there is 
evidence of respiratory failure during this period, the number of days from being 
discharged to the last date known to be free of respiratory failure will be counted as 
days alive and free of respiratory failure.

If a subject withdraws from the study or is lost to follow up prior to Day 28, the days 
with unknown survival/respiratory failure status will be considered as follow:
o
If the subject is discharged from hospital at the time they withdraw from the 
study or are lost to follow up, days from last known status to Day 28 (or date 
last known to be alive if death is known, whichever occurs first) will be 
counted as days alive and free of respiratory failure.
o
If a subject is in hospital and is not experiencing respiratory failure at the time 
they withdraw from the study, days from last known status to Day 28 (or date 


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
23(61)
last known to be alive if death is known, whichever occurs first) will be 
counted as days alive and free of respiratory failure.
o
If the subject is in hospital and is experiencing respiratory failure at the time 
they withdraw from the study, days from last known status to Day 28 will be 
assumed as experiencing respiratory failure.
3.1.10
Days with respiratory failure over the course of 28 days
This is defined as the number of days with respiratory failure from randomization to Day 28.
The number of days with respiratory failure over the course of 28 days includes all respiratory 
failures within this 28-day period. All days from the start date to the stop date inclusive of 
each respiratory failure will count as respiratory failure days.
The following rules will be applied for missing data and deaths:

Unless stated otherwise, if a subject dies (due to any cause) prior to Day 28, the 
number of days from death to Day 28 will be counted as days with respiratory failure.

If a subject has been discharged from hospital and is known to be alive at Day 28, and 
there is no evidence that respiratory failure has occurred during this period, the number 
of days from being discharged to Day 28 will be assumed free of respiratory failure.

If a subject has been discharged from hospital but dies prior to Day 28 and there is no 
evidence that respiratory failure has occurred during this period, the number of days 
from being discharged to the last date known to be alive will be assumed free of 
respiratory failure. The number of days from death to Day 28 will be counted as days 
with respiratory failure.

If a subject has been discharged from hospital but dies prior to Day 28 and there is 
evidence of respiratory failure during this period, the number of days from being 
discharged to the last date known to be free of respiratory failure will be assumed free 
of respiratory failure. The number of days from the start of respiratory failure to Day 
28 will be counted as days with respiratory failure.

If a subject withdraws from the study or is lost to follow up prior to Day 28, the days 
with unknown respiratory failure status will be considered as follow:
o
If the subject is discharged from hospital at the time they withdraw from the 
study or are lost to follow up, days from last known status to Day 28 (or date 
last known to be alive if death is known, whichever occurs first) will be 
assumed free of respiratory failure.
o
If a subject is in hospital and is not experiencing respiratory failure at the time 
they withdraw from the study, days from last known status to Day 28 (or date 


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
24(61)
last known to be alive if death is known, whichever occurs first) will be 
assumed free of respiratory failure.
o
If the subject is in hospital and is experiencing respiratory failure at the time 
they withdraw from the study, days from last known status to Day 28 will be 
counted as days with respiratory failure.
3.1.11
Days hospitalized over the course of 28 days
This is defined as the number of days hospitalized from randomization to Day 28.
For a day to be counted as a hospitalized day in this endpoint, the investigator must confirm 
that hospitalization is clinically indicated. This information is recorded in the CHCSS eCRF 
each day the subject is hospitalized. 
The number of days hospitalized over the course of 28 days includes any readmissions to 
hospital within this 28-day period. All days from the start date to the stop date inclusive of 
each hospital admission will count as hospitalized days.
The following rules will be applied for missing data and deaths:

Unless stated otherwise, if a subject dies (due to any cause) prior to Day 28, the 
number of days from death to Day 28 will be counted as days hospitalized.

If a subject withdraws from the study or is lost to follow up prior to Day 28, the days 
with hospitalization status will be considered as follow:
o
If the subject is discharged from hospital at the time they withdraw from the 
study or are lost to follow up, days from last known status to Day 28 (or date 
last known to be alive if death is known, whichever occurs first) will be 
assumed free of hospitalization.
o
If the subject is in hospital at the time they withdraw from the study, days from 
last known status to Day 28 will be counted as days hospitalized.
3.1.12
Days in ICU over the course of 90 days 
This is defined as the number of days in ICU (length of stay) from randomization to Day 90.
For a day to be counted as an ICU day in this endpoint, the investigator must confirm that the 
subject is receiving ICU-standard care (or equivalent) and that ICU is clinically indicated. 
This information is recorded in the CHCSS eCRF each day the subject is receiving ICU-
standard case. The number of days in ICU over the course of 90 days includes any 
readmissions to the ICU within this 90-day period. All days from the start date to the stop date 
inclusive of each ICU stay will count as ICU days.


Statistical Analysis Plan 
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Study Code D822FC00001
25(61)
The following rules will be applied for missing data and deaths: 

Unless stated otherwise, if a subject dies (due to any cause) prior to Day 90, the number 
of days from death to Day 90 will be counted as ICU days.

If a subject has been discharged from hospital they will be assumed free of ICU.

If a subject has been discharged from hospital but dies prior to Day 90 and there is no 
evidence of ICU admission during this period, the number of days from being 
discharged to the last date known to be alive will be assumed free of ICU. The number 
of days from death to Day 90 will be counted as ICU days.

If a subject has been discharged from hospital but dies prior to Day 90 and there is 
evidence of ICU admission during this period, the number of days from being 
discharged to the last date known to be free of ICU will be assumed free of ICU. The 
number of days from ICU admission to Day 90 will be counted as ICU days.

If a subject withdraws from the study or is lost to follow up prior to Day 90, the days 
with unknown ICU status will be considered as follow:
o
If the subject is not in ICU at the time they withdraw from the study or are lost 
to follow up, days from last known status to Day 90 (or date last known to be 
alive if death is known, whichever occurs first) will be assumed free of ICU.
o
If a subject is in ICU at the time they withdraw from the study, days from last 
known status to Day 90 (or date last known to be alive if death is known, 
whichever occurs first) will be counted as ICU days.
3.1.13
Days alive outside of hospital over the course of 28 days
This is defined as the number of days alive outside of hospital from randomization to Day 28.
For a day to be counted as outside of hospital, the subject must not be in hospital. If the 
subject is in hospital but hospitalization is recorded as not clinically indicated, this day will 
still be considered as a day in hospital and therefore will not be counted in this endpoint.
The following rules will be applied for missing data:

If a subject withdraws from the study or is lost to follow up prior to Day 28, the days 
with unknown survival/hospitalization status will be considered as follow:
o
If the subject is discharged from hospital when they withdraw from the study or 
are lost to follow up, days from last known status to Day 28 (or date last known 
to be alive if death is known, whichever occurs first) will be counted as days 
alive and outside of hospital.


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o
If a subject is in hospital at the time they withdraw from the study, days from 
last known status to Day 28 will be assumed hospitalized days.
3.1.14
Days alive outside of hospital over the course of 90 days
This is defined as the number of days alive outside of hospital from randomization to Day 90.
For a day to be counted as outside of hospital, the subject must not be in hospital. If the 
subject is in hospital but hospitalization is recorded as not clinically indicated, this day will 
still be considered as a day in hospital and therefore will not be counted in this endpoint.
The following rules will be applied for missing data:

If a subject withdraws from the study or is lost to follow up prior to Day 90, the days 
with unknown survival/hospitalization status will be considered as follow:
o
If the subject is discharged from hospital when they withdraw from the study or 
are lost to follow up, days from last known status to Day 90 (or date last known 
to be alive if death is known, whichever occurs first) will be counted as days 
alive and outside of hospital.
o
If a subject is in hospital at the time they withdraw from the study, days from 
last known status to Day 90 will be assumed hospitalized days.
3.1.15
Relative change from baseline in oxygenation index
This is defined as the percentage change from baseline in oxygenation index (SpO2/FiO2) to 
Days 3, 5, 7 and 10. For this endpoint, baseline is defined as the observation on the date of 
randomization (Day 1) only.
Oxygenation index is calculated as
SpO2 [%] / FiO2 [decimal]
It will be calculated for baseline and each post-baseline assessment using the SpO2 (oxygen 
saturation) value and the FiO2 (fraction of inspired oxygen) value collected or derived on the 
VS and OXYGEN or VENTUSE eCRF pages, respectively. Details on these variables and 
visit windows are provided in Section 3.2.6 and Section 4.1, respectively.
3.1.16
Time to clinical improvement of at least 2 points (from randomization) on a 9-
point category ordinal scale through Day 28
This is defined as the time (in days) from randomization to the date of first demonstrated 
clinical improvement of at least 2 points (i.e., a decline of two points) on the following 9-point 
category ordinal scale through Day 28:
0. *Uninfected, no clinical or virological evidence of infection 
1. Ambulatory, no limitation of activities 


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2. Ambulatory, limitation of activities 
3. Hospitalized – mild disease, no oxygen therapy 
4. Hospitalized – mild disease, oxygen by mask or nasal prongs 
5. Hospitalized – severe disease, non-invasive ventilation or high flow oxygen 
6. Hospitalised – severe disease, intubation and mechanical ventilation 
7. Hospitalized – severe disease, ventilation and additional organ support, such as 
pressors, renal replacement therapy, extracorporeal membrane oxygenation 
8. Death
*Score of zero on 9-point category ordinal scale will not be evaluated in this study.
This information will be collected in the OSCI pages in the eCRF as per the SoA in the CSP. 
Baseline ordinal scale score is defined as the result obtained on the date of randomization 
(Day 1) only.
If a subject does not have an event (i.e., does not demonstrate clinical improvement of at least 
2 points) on or before Day 28 and does not withdraw or become lost to follow up from the 
study prior to Day 28, the data will be censored at Day 28. If a subject does not have an event 
but withdraws from the study or is lost to follow up prior to Day 28, the data will be censored 
at the last date known that the subject has not demonstrated clinical improvement of at least 2 
points up to Day 28.
If a subject does not have an event and dies before Day 28, they will be censored at Day 28.
The following additional exploratory efficacy endpoints that utilise the category ordinal scale 
will be analysed:
3.1.16.1
Time to clinical improvement of at least 2 points (from randomization) on a 
9-point category ordinal scale, live discharge from hospital, or considered fit 
for discharge, whichever comes first through Day 28
This is defined as the time (in days) from randomization to the earliest date at which any of 
the following criteria are met:

First demonstrated clinical improvement of at least 2 points (i.e., a decline of two 
points) on the following 9-point category ordinal scale

Live discharge from hospital

The date the subject is considered fit for discharge (a score of 0, 1 or 2 on the ordinal 
scale)
The first demonstrated clinical improvement of at least 2 points and observing a score of 0, 1 
or 2 (i.e. the subject is considered fit for discharge) will be determined using the same ordinal 
scale described in Section 3.1.16. The date of live discharge from hospital will be captured in 
the CHCSS page in the eCRF.


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If a subject does not have an event (i.e., does not demonstrate clinical improvement of at least 
2 points or is not discharged from the hospital or is not considered fit for discharge) on or 
before Day 28 and does not withdraw or become lost to follow up from the study prior to Day 
28, the data will be censored at Day 28. If a subject does not have an event but withdraws 
from the study or is lost to follow up prior to Day 28, the data will be censored at the last date 
known that the subject did not demonstrate any of the three above criteria up to Day 28.
If a subject does not have an event and dies before Day 28, they will be censored at Day 28.
3.1.16.2
Time to recovery (from randomization) through Day 28
This is defined as the time (in days) from randomization to recovery, where the date of 
recovery is defined as the earliest date any of the categories in the following 3-point scale are 
met:
1. Hospitalized not requiring supplemental oxygen, not requiring medical care
2. Not hospitalized but limitations on activities
3. Not hospitalized and no limitations
Table 5 outlines how the 3-point scale will be derived from the information collected from the 
9-point category ordinal scale (Section 3.1.16) and hospitalization details.
Table 5
Derivation of the 3-point scale
3-point scale 
Derivation from 9-point category scale and 
hospitalization details
(1) Hospitalized not requiring supplemental 
oxygen, not requiring medical care
Hospitalized with a score of 0, 1, 2 or 3 and “Is 
hospitalization clinically indicated” answered 
No in the eCRF.
(2) Not hospitalized but limitations on activities
Discharged from hospital with a score of 2
(3) Not hospitalized and no limitations
Discharged from hospital with a score of 0 or 1
If a subject does not have an event (i.e., does not meet any of the criteria specified in the 3-
point scale) on or before Day 28 and does not withdraw or become lost to follow up from the 
study prior to Day 28, the data will be censored at Day 28. If a subject does not have an event 
but withdraws from the study or is lost to follow up prior to Day 28, the data will be censored 
at the last date known that the subject did not meet any of the criteria specified in the 3-point 
scale up to Day 28.
If a subject does not have an event and dies before Day 28, they will be censored at Day 28.


Statistical Analysis Plan 
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3.1.17
Time to SpO2 > 94% on room air
This is defined as the time (in days) from randomization to the first occurrence that SpO2 > 
94% on room air through Day 28. SpO2 will be captured on the VS module in the eCRF.
Baseline SpO2 is defined as the result obtained on the date of randomization (Day 1). Subjects 
with SpO2 > 94% on room air at baseline will not be included in any analyses of time to SpO2
> 94% on room air.
If a subject does not experience an event (i.e., does not have SpO2 > 94% on room air) on or 
before Day 28 and does not withdraw or become lost to follow up from the study prior to Day 
28, the data will be censored at Day 28. If a subject does not have an event but withdraws 
from the study or is lost to follow up prior to Day 28, the data will be censored at the last date 
known that the subject did not have SpO2 > 94% up to Day 28.
If a subject does not have an event and dies before Day 28, they will be censored at Day 28.
3.2
Safety variables
The safety of acalabrutinib in subjects with COVID-19 when administered with BSC is a 
primary endpoint and will be assessed by type, frequency, severity, and relationship to study 
treatment of any treatment-emergent adverse events (TEAEs) or abnormalities of laboratory 
tests, serious adverse events (SAEs), or adverse events leading to discontinuation of study 
treatment.
3.2.1
Adverse events
After the signing of the ICF, all SAEs must be reported.  After the first dose of study 
treatment, all AEs/SAEs, irrespective of attribution of causality, must be reported. AE 
reporting, irrespective of seriousness, ends 28 (± 3) days after the last dose of study 
treatments(s) for those on acalabrutinib + BSC (Arm 1) and 38 (± 3) days from randomization 
for those on BSC only (Arm 2).
The following are NOT considered an AE: 

Pre-existing condition that has not worsened: A pre-existing condition (documented 
on the medical history eCRF) is not considered an AE unless the severity, frequency, 
or character of the event worsens during the study period. 

Diagnostic testing and procedures: Testing and procedures should not be reported as 
AEs or SAEs, but rather the cause for the test or procedure should be reported. If a test 
or procedure is done to rule out a diagnosis, the sign or symptom leading to the 
test/procedure should be the event term, and the event term should only be updated to 
the diagnosis if/when the diagnosis is confirmed. Testing and procedures performed 
solely as screening measures (e.g., routine screening mammography or colonoscopy) 
should not be reported as AEs or SAEs. 


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
Abnormal laboratory results: Abnormal laboratory results are not AEs unless they 
are clinically significant. For example, a clinically significant laboratory result is one 
that requires treatment (for example a blood transfusion for low haemoglobin) or 
requires a change in study drug (e.g., lowering the dose or withholding study drug 
while the laboratory finding resolves or stabilizes). 

Progression of underlying disease: Progression of underlying disease unequivocally 
related to COVID-19 pneumonia (such as worsening of respiratory status or 
complications associated with pneumonia) will not be reported as an AE if it is clearly 
consistent with the suspected progression of the underlying disease. Clinical symptoms 
of progression may be reported as AEs if the symptoms cannot be determined as 
exclusively due to the progression of the underlying disease, or if they do not fit the 
expected pattern of progression for the disease under study.
Events will be defined as treatment-emergent if they onset, or worsen (by investigator report 
of a change in intensity), during the treatment period as defined in the CSP.  The Medical 
Dictionary for Regulatory Activities (MedDRA) (version 23.0) will be used to code the AEs. 
AEs will be graded according to the National Cancer Institute Common Terminology Criteria 
for AEs (CTCAE) version 5.0. The CTCAE grade will be assigned by the investigator as 
follows:

Grade 1: Mild AE

Grade 2: Moderate AE

Grade 3: Severe AE

Grade 4: Life-threatening or disabling AE

Grade 5: Death related to AE
For events with varying severity, the worst reported grade will be used.
Missing start and stop dates for AEs will be handled using the rules described in Section 4.1.
3.2.2
Exposure, dose intensity and treatment compliance
Study drug exposure and dosing information will be collected for acalabrutinib-treated 
subjects.
Intended treatment duration
Intended treatment duration [days] is defined as the number of days a subject is intended to be 
on treatment.


Statistical Analysis Plan 
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A subject is expected to receive 20 doses of acalabrutinib, with each dose taken approximately 
12 hours apart. One dose is therefore considered a duration of 0.5 days dosing. Therefore, 
depending on the timing of the subject’s first dose, they can adhere to the dosing schedule and 
receive 20 doses over two time periods:

Over the course of 10 days (bid, AM and PM), or

Over the course of 11 days (one on Day 1 (PM), bid on Day 2-10 (AM and PM), one 
on Day 11 (AM).
Since doses are approximately 12 hours (0.5 days) apart, the total intended treatment duration 
in both of the above scenarios is 10 days:

0.5 days × 2 doses × 10 days = 10 days

(0.5 days × 1 dose) + (0.5 days × 2 doses × 9 days) + (0.5 days × 1 dose) = 10 days
Hence,
Intended treatment duration (days) = 10 days
Actual treatment duration
Actual treatment duration (days) is defined as the total number of days a subject is on 
treatment. It is calculated as:
Actual treatment duration (days) = Date of last dose > 0mg – Date of first dose + 1
Dose reductions or increases are permitted, and the calculation of actual treatment duration 
makes no adjustment for any dose modifications that may have occurred. 
Average daily dose
The average daily dose (mg) is the average dose a subject received on a given day. It is 
calculated as
Average daily dose (mg) = total dose received (mg) / Actual treatment duration (days)
Percentage of Intended Dose
Percentage of intended dose (PID) is the percentage of the actual dose delivered relative to the 
intended dose. PID is calculated as:
PID= 100% * d/D, where:

d is the total dose received (mg), and

D is the total dose of the drug that would be delivered, if there were no
modifications to dose or schedule: 2000mg
If a subject overdoses, the start and stop date of the overdose and the dose received will be 
included in the above derivations of actual treatment duration, average daily dose and PID.


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3.2.3
Laboratory assessments
Laboratory tests will be performed as specified in the SoA in the CSP.
The baseline laboratory result is defined as the result obtained on the date of randomization 
(Day 1). If no result was obtained on the date of randomization, the last result prior to the date 
of randomization will be used.
Visit windows and how to handle multiple records will be described in Section 4.1.
Change or percentage change from baseline in hematology and clinical chemistry variables, as 
well as CRP, ferritin and ALC will be calculated for each post-baseline assessment recorded in 
the eCRF.
Laboratory abnormalities will be defined based on laboratory normal ranges (universal normal 
ranges for central laboratory tests), and absolute values will be classified as low (below 
range), normal (within range or limits of range), or high (above range).
Laboratory parameters will also be classified using the National Cancer Institute Common 
Terminology Criteria (CTC) version 5.0 into CTC grades.
The denominator used in laboratory abnormality summaries will include only evaluable 
subjects (i.e., those who had sufficient data to have the possibility of an abnormality). For 
example:

If an abnormality criterion involves a change from baseline, evaluable subjects would 
have both a baseline and at least 1 post-baseline value recorded

If an abnormality criterion does not consider changes from baseline to be evaluable, the 
subject need only have 1 post-baseline value recorded
3.2.4
Physical examinations and chest imaging, electrocardiograms and 
echocardiograms
Physical examinations and chest imaging, electrocardiograms and echocardiograms will be 
performed as per SoA and as described in Section 8.1.5 of the CSP.
A 12-lead electrocardiogram (ECG) will be done at screening, Day 10, and as clinically 
indicated after study entry. All ECGs will be obtained in triplicate. Each ECG will define heart 
rhythm, P wave duration, PR interval, RR interval, QRS duration, QT interval, QTc and 
overall evaluation. Baseline is defined, after taking the average of the triplicates, as the 
averaged triplicate on the date of randomization (Day 1). If no result was obtained on the date 
of randomization, the latest result prior to the date of randomization is used.


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The left ventricular ejection fraction (LVEF) will be reported when echocardiograms (ECHO) 
are conducted. The LVEF % will also be reported.
Abnormalities recorded at screening or baseline for ECG or ECHO results will be recorded as 
a concurrent condition. Abnormalities first recorded during the treatment period will be 
recorded as AEs unless unequivocally related to the disease under study.
3.2.5
Vital signs and arterial blood gases
The vital signs to be collected are blood pressure, respiratory rate, oxygen saturation [SpO2], 
pulse, and body temperature, as per the SoA in the CSP.
The oxygen saturation of the blood will be assessed using standard pulse oximetry or by 
arterial blood gas for those subjects who have an arterial blood gas obtained.
The vital sign and blood oxygen measurements are: systolic BP (mmHg), diastolic BP 
(mmHg), MAP (mmHg), pulse rate (bpm), respiratory rate (breaths/min), body temperature 
and oxygen saturation (%).  MAP will be calculated as: 
diastolic BP + 1/3 (systolic BP- diastolic BP).  
For all vital signs except oxygen saturation, baseline is defined as the result obtained on the 
date of randomization (Day 1). If no result was obtained on the date of randomization, the last 
result prior to the date of randomization will be used.
For oxygen saturation, baseline is defined as the result obtained on the date of randomization 
(Day 1) only.
Vital sign measurements taken at unscheduled visits will not be used in the summaries of vital 
signs.  However, any vital sign measurements taken at unscheduled visits that are regarded as 
abnormal or clinically significant will be presented as such.
3.2.6
Oxygen treatment, ventilator use and mSOFA score
If a subject requires oxygen supplementation, data will be recorded, including method of 
oxygen supplementation and maximum daily flow rate. Fraction of inspired oxygen [FiO2] 
will be reported or derived.
For subjects using a nasal cannula or simple mask, the maximum daily flow rate will be 
entered into the OXYGEN or VENTUSE eCRF and FiO2 will be derived as per the 
conversion guidelines in Section 8.3. Note that the conversion is different depending on 
whether the subject is on a simple mask or nasal cannula. If FiO2 is entered when a simple 
mask is selected as the method of oxygen, the value entered in the database will be used 
instead of deriving the value. For subjects on high-flow oxygen therapy or using other types of 
masks, FiO2 will be entered directly into the OXYGEN eCRF page. For subjects on high-flow 
oxygen therapy or using other types of masks, FiO2 will be entered directly into the OXYGEN 


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eCRF page. For subjects on mechanical ventilation, FiO2 will be entered directly into the 
VENTUSE eCRF page.
Since FiO2 is only collected on days that oxygen or mechanical ventilation is used, FiO2 will 
be imputed for days that no oxygen or mechanical ventilation is reported. If a subject has no 
oxygen or mechanical ventilation reported on a given day (method of oxygen (MOXDEL) is
blank in the OXYGEN form and type of assisted ventilation (ASSVENTT) is blank in the 
VENTUSE form) then FiO2 will be imputed as 21%.
If a subject requires mechanical ventilation, data will be recorded regarding whether ventilator 
weaning was attempted. For subjects on mechanical ventilation the following ventilator 
settings will be recorded: tidal volume, FiO2, peak airway pressure over the last 24 hours, 
plateau pressure, positive end expiratory pressure, and respiratory rate. Predicted body weight 
will be recorded assessment of tidal volume. The data will be recorded daily, and the worst 
value of the day will be entered in the eCRF.
For subjects on mechanical ventilation, an arterial blood gas (pH, oxygen, carbon dioxide, 
oxygen saturation and bicarbonate), if available, will be recorded daily.
For subjects admitted to ICU, the modification Sequential Organ Failure Assessment 
(mSOFA) score will be calculated. For each of the following routine assessments, the worst 
value of the day will be recorded in the eCRF: oxygen saturation by pulse oximetry 
(SpO2)/FiO2 (mmHg), platelet count, bilirubin, vasopressor use (μg/kg/min, mmHg), and 
creatinine (or urine output).
For oxygen, mechanical ventilation and mSOFA variables, baseline is defined as the result 
obtained on the date of randomization (Day 1) only.
3.3
Pharmacokinetic variables
The PK of acalabrutinib and its active metabolite (ACP-5862) in subjects with COVID-19 
when administered with BSC is a secondary endpoint. The PK will be assessed by 
summarizing the plasma concentrations for both analytes at the specified time points. 
Additionally, PK parameters for acalabrutinib and ACP-5862 (such as, maximum observed 
concentration (Cmax) and AUC) may be estimated, as considered appropriate.
Pharmacokinetic concentration data will be collected as per the SoA in the CSP. Plasma 
concentrations of study drug and/or metabolite are used as supplied by the analytical 
laboratory for PK analysis.
3.4
Exploratory pharmacodynamic and correlative variables
 
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3.5
Other variables
3.5.1
Baseline characteristics
Baseline characteristics that will be collected or derived are:

Demographics: Age (years), sex, race and ethnicity

Subject characteristics: Weight, height and body mass index (BMI), where BMI 
(kg/m2) = Weight/Height2

Medical history: Name of past and/or concomitant diseases (verbatim and coded using 
the MedDRA dictionary version 23.0), start and stop dates

Relevant surgical history: Surgical procedure (verbatim and coded using the MedDRA 
dictionary version 23.0)

Pregnancy status for applicable subjects only: test date and result (positive or negative)

History of substance abuse: cigarettes (former/current/never), vaping 
(former/current/never), recreational inhaled drugs (former/current/never), alcohol 
(former/current/never)

SARS-CoV-2 infection comorbidities: infection comorbidities prior to admission,
subcategory, comorbidity start and stop date

SARS-CoV-2 infection risk factors/lifestyle events: infection risk factor, infection risk 
factor start and stop date

SARS-CoV-2 infection signs and symptoms: infection signs or symptoms, clinical 
event start and stop date

Respiratory failure status at baseline (with vs without), as defined in Table 1, where 
baseline is defined as the result obtained on the date of randomization (Day 1)

Intensity of oxygen treatment and mechanical ventilation at baseline: most extreme 
oxygen treatment or mechanical ventilation, flow rate
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Statistical Analysis Plan 
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
Intensity of oxygen treatment and mechanical ventilation prior to baseline: most 
extreme oxygen treatment or mechanical ventilation, flow rate, duration of treatment
3.5.2
Prior and concomitant medications and procedures
All therapies (drug and non-drug), including herbal preparations, whether prescribed or over-
the-counter, that are used during the study will be recorded on the eCRF. Details include 
generic and/or brand names of the medications, World Health Organisation Drug Dictionary 
(WHO-DD) encoding (B3 format), reason for use, route, dose, dosing frequency, and start and 
end dates. Procedures performed during the study will be recorded on the eCRF and details 
include the procedure name, WHO-DD encoding (B3 format), reason for the procedure, and 
start and end dates.
Prior therapies are defined as those taken prior to study treatment with a stop date prior to the 
first dose of study treatment (acalabrutinib + BSC subjects) or prior to randomization (BSC 
only subjects). For subjects on acalabrutinib + BSC, concomitant therapies and procedures are 
defined as those with a stop date on or after the first dose date of study treatment. Start date 
may be before or after first dose. For subjects on BSC only, concomitant therapies and 
procedures are defined as those with a stop date on or after randomization. Start date may be 
before or after randomization.
Best supportive care medication will be collected as a concomitant medication with therapy 
reason as ‘disease under study’.
Missing start and stop dates for medications and procedures will be handled using the rules 
described in Section 4.1.
Medications received prior to or concomitantly will be coded using the WHO Drug Dictionary 
Anatomical Therapeutic Chemical (ATC) classification codes. Concomitant medications will 
be summarized for the FAS by ATC classification codes. Subjects with the same concomitant 
medication/procedure multiple times will be counted once per medication/procedure. A 
medication/procedure that can be classified into more than one chemical and/or therapeutic 
subgroup will be presented in each subgroup.
4.
ANALYSIS METHODS
4.1
General principles
All statistical analyses will be performed by AZ statistical programming group.  Any 
deviations from the analyses presented in this SAP will be detailed in the clinical study report.  
All outputs will be produced using SAS® version 9.4 or a later version in accordance with AZ 
standards.


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The below mentioned general principles will be followed throughout the study:

Demography and baseline characteristics data will be summarised using the FAS. 

All efficacy data will be summarised and analysed using the FAS, unless otherwise 
specified. 

Safety data will be summarized using the SAF.

PK data will be summarized using the PKAS.

 

Descriptive statistics will be used for all variables, as appropriate.

Stratification factors age (≥ 65 vs < 65 years) and comorbidities (present vs absent) as 
recorded at randomization in the IRT system will be used for any summaries or 
analyses using the FAS that are presented by stratification factor. For summaries or 
analyses by stratification factor performed using the PPAS, the true stratification 
results (captured in the eCRF) will be used.

Continuous variables will be summarised by the number of observations (n), mean, 
standard deviation (SD), median, minimum and maximum and will be based on non-
missing observations. The minimum and maximum will be reported to the same 
number of decimal places as the raw data recorded in the database. The mean and 
median will be reported to one more decimal place than the raw data recorded in the 
database.  The SD will be reported to two more decimal places than the raw data 
recorded in the database.

Categorical variables will be summarized by frequency counts and percentages and 
include the number of subjects with present data and the number of subjects with 
missing (not present) data.  Unless stated otherwise, percentages will be calculated 
based on the population total for each treatment group.  Percentages will be presented 
to one decimal place.

For the PK and PD summaries the reported results will be summarized using 
appropriate significant figures rather than decimal places.

Baseline is defined as the result obtained on the day of randomization (Day 1). If no 
result was obtained, the latest result prior to the day of randomization is used.
Applies to:
o
Baseline for all laboratory assessments
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Statistical Analysis Plan 
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o
Baseline for vital signs except oxygen saturation (SpO2)
o
Baseline ECG assessment

Baseline is defined as the result obtained on the day of randomization (Day 1) only.
Applies to:
o
Respiratory failure status at baseline
o
Baseline oxygen saturation (SpO2)
o
Baseline for all oxygen and mechanical ventilation assessments
o
Baseline ordinal scale score
o
Baseline mSOFA score

For all summaries, change from baseline variables will be calculated as the post-
baseline value minus the value at baseline. The percentage change from baseline will 
be calculated as ((post-baseline value – baseline value)/baseline value) x 100.

Unless stated otherwise, visit windows will apply as follows:
o
Day 1 (date of randomization): No window unless specified above (where 
latest result prior to date of randomization can be used)
o
Day 2-10 or discharge (whichever occurs first): no visit window. Note: if a 
subject is discharged prior to Day 7  they will visit the site for an assessment 2 
to 4 days after discharge. Assessments should match those for Day 10. 
o
Day 14: ±2 days
o
Day 28: ±3 days
o
Arm 1 Safety follow-up at 28 days after last dose of acalabrutinib: ±3 days
o
Arm 2 Safety follow-up (for AEs, concomitant medications and survival 
assessment) at 38 days after randomization: ±3 days
o
Long-term follow-up 90 days after randomization: ±7 days
o
Observations recorded on the date closest to the scheduled assessment day (as 
long as this is within the visit window) will be used as the scheduled 
assessment. Any observations recorded outside of the visit window will be 
considered unscheduled visit observations and will not be included in visit-
based summaries at a treatment-group level. If multiple observations are 
recorded per day, or observations within a visit window are equidistant from 
the target day, the worst assessment reported will be used as the scheduled 
assessment. For laboratory and vital signs assessments, this is the maximum 
reported value.


Statistical Analysis Plan 
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o
Visit-based summaries will include: Baseline (Day 1), Day 2-10, Day 14 and 
Day 28 where applicable, as per SoA.
o
For listings at a subject level, all values will be included (regardless of whether 
they appear in a corresponding visit-based summary) when deriving a patient 
level statistic such as a maximum.
No imputation of values for missing data will be performed except for missing or partial start 
and end dates for AEs and concomitant medication (CM) (Table 6). If the data cut-
off/snapshot date or the subject’s date of death is prior to the date imputed based on the rules 
outlined below, then the earliest of these dates will be imputed. 
Table 6
Imputation rules for missing or partial AE and concomitant medication 
dates
Form
Imputation
Acalabrutinib + BSC
BSC alone
Start date
Missing
AE and 
CM
AE/CM ended before first 
dose date/ randomization 
date
Impute 1st January with year being the same year as CM/AE end date
AE/CM ended after first 
dose date/ randomization 
date
Impute date of first dose
Impute date of randomization
Partial
AE and 
CM
Missing day
Impute 1st of the month unless 
AE/CM start month is the same 
month as the first dose, then 
impute date of first dose. Check 
start date is prior to end date.
Impute 1st of the month unless 
AE/CM start month is the same 
month as randomization, then 
impute date of randomization. 
Check start date is prior to end 
date.
Missing day and month
Impute 1st January unless 
AE/CM start year is the same 
year as the first dose, then 
impute date of first dose. Check 
start date is prior to end date. If
end date is now prior to start 
Impute 1st January unless AE/CM 
start year is the same year as 
randomization, then impute date 
of randomization. Check start date 
is prior to end date. If end date is 
now prior to start date, impute 1st


Statistical Analysis Plan 
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Study Code D822FC00001
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date, impute 1st January as the 
start day and month.
January as the start day and 
month.
End date
Missing
AE and 
CM
CM flag ongoing takes 
any value (yes, no or 
missing) and CM start 
date is prior, on or after 
first dose date/ 
randomization
AE stop date missing
Impute min (date of death, data cut-off/snapshot date)
Partial
CM
Missing day
Impute the last day of the month 
unless month is the same as 
month of last dose, then impute 
date of last dose.
Impute the last day of the month 
unless month is the same as month 
of randomization date + 10 days, 
then impute randomization date + 
10 days.
Missing day and month
Impute date of last dose + 28 
days + 3 days
Impute date of randomization + 
38 days + 3 days
4.2
Analysis methods  
4.2.1
Disposition of subjects
The number and percentage of subjects who were enrolled to the study, randomized, 
randomized and received treatment, randomized and did not receive treatment, completed 
treatment, discontinued prematurely from treatment, completed the study, withdrew from the 
study, and reasons for withdrawal from the study will be summarized by treatment group and 
overall for all subjects. 
The following will be presented by treatment group and as a total:

Number and percentage of subjects in each analysis set

Number and percentage of subjects in each country and center (using the FAS)

Number and percentage of subjects in each combination of the stratification factors: 
age (≥ 65 vs < 65 years) and comorbidities (present vs absent) as recorded at 
randomization in the IRT system (using the FAS)


Statistical Analysis Plan 
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The stratification factors as recorded at randomization in the IRT system will be compared to 
those entered into the clinical database and discrepancies will be summarized.
4.2.2
Protocol deviations 
Important protocol deviations are defined in Section 2.2 and will be listed by treatment group 
and summarized separately by treatment group for all subjects randomized to treatment.
The number and percentage of subjects with any IPD will be summarized for each IPD 
category. Subjects with more than one deviation in the same IPD category will be counted 
once for that IPD category. Any subjects who have deviations in more than one IPD category 
will be counted once in the overall summary.
4.2.3
Demographic and other baseline characteristics 
Demographic and other baseline characteristics will be listed for all subjects and summarized 
by treatment group and overall for the FAS using the rules for summarizing continuous and 
categorical variables described in Section 4.1.
In addition to being summarized as continuous variables, age and BMI will be summarized as 
the following categorical variable: age group (<65, ≥65 years, as well as categories of <20,  
≥20 - < 35, ≥35 - < 50,  ≥50 - <65,  ≥ 65 - <75,  ≥75 years.) and BMI group (Underweight 
[<18.5], Normal [18.5 - <25.0], Overweight [25.0 - <30.0] and Obese [>=30.0].
The number and percentage of subjects with comorbidities for each treatment group will also 
be presented, as well as the number of comorbidities (e.g. the number and percentage of 
subjects in each treatment group with 1, 2, 3, etc. comorbidities) and type.
The number and percentage of subjects with signs and symptoms at screening for each 
treatment group will be presented overall and by onset time relative to randomization.
The most extreme oxygen treatment or mechanical ventilation received at baseline will also be 
summarized (most extreme to least extreme: ECMO, invasive ventilation, non-invasive 
ventilation). If the subject’s most extreme treatment is oxygen (no mechanical ventilation was 
received), maximum oxygen flow rate will be summarized. This will be repeated for prior to 
baseline, and in addition the duration of any oxygen treatment or mechanical ventilation will 
be summarized continuously and categorically.
Medical history and surgical history are coded using MedDRA (version 23.0) and will be 
summarized by System Organ Class (SOC) and Preferred Term (PT).
4.2.4
Prior and concomitant medications and procedures
The following summaries will be produced:

Summary of prior medications

Summary of concomitant medications – including best supportive care


Statistical Analysis Plan 
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Study Code D822FC00001
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
Summary of best supportive care – past

Summary of best supportive care - current
All concomitant and other treatment data will be listed for all subjects in the FAS.
Missing coding terms should be listed and summarised as "Not coded".
4.3
Analysis of efficacy
The efficacy analyses described in this section are primary or secondary endpoints and will be 
performed for subjects in the FAS by treatment group (unless stated otherwise).
4.3.1
Primary endpoint
4.3.1.1
Alive and free of respiratory failure at Day 14
The primary endpoint is the proportion of subjects who are alive and free of respiratory failure 
at Day 14, where respiratory failure is defined in Section 3.1.1.
The point estimate and its 95% confidence interval (CI; using Wald method with continuity 
correction) will be calculated for each treatment group. The Cochran-Mantel-Haenszel χ2 test, 
stratified by age (≥ 65 vs < 65 years) and comorbidities (present vs absent), will be used to 
compare the proportion of subjects who are alive and free of respiratory failure at Day 14 
between the two treatment groups. An unstratified analysis (χ2 test) will also be performed. 
Finally, the difference in the proportion of subjects who are alive and free of respiratory 
failure at Day 14 will also be provided with 95% CIs. 
This primary endpoint will also be summarized (point estimate and 95% CI Wald method with 
continuity correction as above) by the following subgroups: 

the predefined age categories defined in Section 4.2.3

country

sex

race 

ethnicity 

comorbidities (present vs absent) 

history of substance abuse (former/current/never)

concomitant antiviral use (yes vs no)

respiratory failure status at baseline (with vs without)


Statistical Analysis Plan 
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Categories within subgroups may be combined if a category has an insufficient number of 
subjects, this will be documented in the CSR.
The number and percentage of subjects who experienced respiratory failure but were free of 
respiratory failure at Day 14 will be summarized by treatment group. This summary will also 
include summary statistics for the number of respiratory failures that occurred.
All analyses described in this section will be primarily conducted in the FAS but will be 
repeated for the PPAS.
The proportion for each group, and the difference in proportions, as well as the 95% CIs, will 
also be reported in the FAS but excluding subjects who have withdrawn or have been lost to 
follow-up on or prior to Day 14.
The method for handling subjects that withdraw or are lost to follow up prior to Day 14 is 
detailed in Section 3.1.1.
Additional sensitivity analyses and subgroup analyses (such as by concomitant medication 
usage) of the primary endpoint may be performed as appropriate.
4.3.2
Secondary endpoints
4.3.2.1
Alive and free of respiratory failure at Day 28  
The point estimate and its 95% confidence interval (CI; using Wald method with continuity 
correction) will be calculated for each treatment group. Summaries of the subgroups specified 
in Section 4.3.1.1 will also be produced. Analyses may be repeated for the PPAS, using the 
definition of the PPAS in Section 3.1.2.
The proportion for each group, and the difference in proportions, as well as the 95% CIs, will 
also be reported in the FAS but excluding subjects who have withdrawn or have been lost to 
follow-up prior to Day 28. 
The number and percentage of subjects who experienced respiratory failure but were free of 
respiratory failure at Day 28 will be summarized by treatment group. This summary will also 
include summary statistics for the number of respiratory failures that occurred.
The method for handling subjects that withdraw or are lost to follow up prior to Day 28 is 
detailed in Section 3.1.2.
4.3.2.2
Percent change from baseline in C-reactive protein  
Summary statistics (n, mean, median, SD, minimum, and maximum) and the percent change 
from baseline to each scheduled study assessment will be presented by treatment group.
Box plots of absolute value over time and a line graph of the mean change (and SD) from 
baseline to each scheduled study assessment may be presented for each treatment group.
A by-subject listing will also be presented.


Statistical Analysis Plan 
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Study Code D822FC00001
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4.3.2.3
Change from baseline in ferritin  
Summary statistics (n, mean, median, SD, minimum, and maximum) and the change and 
percent change from baseline to each scheduled study assessment will be presented by 
treatment group.
Box plots of absolute value over time and a line graph of the mean change (and SD) from 
baseline to each scheduled study assessment may be presented for each treatment group.
A by-subject listing will also be presented.
4.3.2.4
Change from baseline in absolute lymphocyte count  
Summary statistics (n, mean, median, SD, minimum, and maximum) and the change and 
percent change from baseline to each scheduled study assessment will be presented by 
treatment group.
Box plots of absolute value over time and a line graph of the mean change (and SD) from 
baseline to each scheduled study assessment may be presented for each treatment group.
A by-subject listing will also be presented.
4.3.2.5
All-cause mortality at Day 90
The number and percentage of subjects who have died (all-cause and ‘related to disease under 
investigation’ as recorded in the DEATH eCRF), those still alive, those with unknown 
survival status (lost to follow-up), those who have withdrawn consent and those censored for 
any other reason at Day 90 will be summarized by treatment group.
Kaplan-Meier (KM) plots and summary statistics will be presented for survival time by 
treatment group. The proportion of subjects alive at Day 90 will be defined as the KM 
estimate of overall survival at 90 days. This will be presented, along with its 95% CI. The 
computation of the CI will be based on a log-log transformation. 
The method for handling subjects that withdraw or are lost to follow up prior to Day 90 is 
detailed in Section 3.1.6.
Subgroup analyses on COVID-related deaths may be performed as appropriate.
4.3.2.6
Alive and discharged from the ICU at Days 14 and 28
A summary of the number and percentage of subjects alive and discharged from the ICU at 
Day 14 will be presented. This will be repeated for Day 28. Analyses may be repeated for the 
PPAS, using the definition of the PPAS in Section 3.1.7.
The method for handling subjects that withdraw or are lost to follow up prior to Day 14 (or 
Day 28) is detailed in Section 3.1.7.


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
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4.3.2.7
Time to first occurrence of respiratory failure or death
Time from randomization to first occurrence of respiratory failure or death (due to any cause) 
on study (up to Day 28), whichever occurs first, will be analyzed using the KM method by 
treatment group.
KM plots and summary statistics will be presented for time to first occurrence of respiratory 
failure or death by treatment group.
The HR and its 95% CI will be estimated from a stratified Cox Proportional Hazards model 
(with ties = Efron), stratified by age (<65 vs ≥65 years) and comorbidities (present vs absent) 
and the CI calculated using a profile likelihood approach. Summary statistics will include the 
lower and upper quartile and median survival time with 95% CI.
The method for handling subjects that withdraw or are lost to follow up is detailed in Section 
3.1.8.
4.3.2.8
Days alive and free of respiratory failure over the course of 28 days
Summary statistics (n, mean, median, SD, minimum, and maximum) of the number of days 
alive and free of respiratory failure over 28 days will be presented by treatment group. In 
addition, the number and percentage of subjects in the following categories will be presented, 
0 days, 1-6 days, 7-14 days, 15-21 days, and 22-28 days.
The method for handling subjects that withdraw or are lost to follow up prior to Day 28 is 
detailed in Section 3.1.9.
4.3.2.9
Days with respiratory failure over the course of 28 days
Summary statistics (n, mean, median, SD, minimum, and maximum) of the number of days with 
respiratory failure over 28 days will be presented by treatment group. In addition, the number 
and percentage of subjects in the following categories will be presented, 0 days, 1-6 days, 7-14 
days, 15-21 days, and 22-28 days.
A bar chart of the number of days with respiratory failure for each subject within the treatment 
group will be produced, i.e., showing graphically the distribution of the number of days with 
respiratory failure for each treatment group.
The proportion of subjects who experienced respiratory failure or died over the course of 28 
days will also be summarized by treatment group. Subjects with respiratory failure on the day 
of randomization will be excluded from this summary.
Furthermore, the proportion of subjects who required invasive ventilation or ECMO or died 
over the course of 28 days will be summarized by treatment group.
The method for handling deaths and subjects that withdraw or are lost to follow up prior to 
Day 28 is detailed in Section 3.1.10.


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
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4.3.2.10
Days hospitalized over the course of 28 days
Summary statistics (n, mean, median, SD, minimum, and maximum) of the number of days 
hospitalized over 28 days will be presented by treatment group. In addition, the number and 
percentage of subjects in the following categories will be presented, 0 days, 1-6 days, 7-14 
days, 15-21 days, and 22-28 days.
A bar chart of the number of days hospitalized for each subject within the treatment group will 
be produced, i.e., showing graphically the distribution of the number of days hospitalized for 
each treatment group.
The method for handling deaths and subjects that withdraw or are lost to follow up prior to 
Day 28 is detailed in Section 3.1.113.1.8.
4.3.2.11
Days in ICU over the course of 90 days 
Summary statistics (n, mean, SD, median, minimum and maximum) for the length of stay 
(days) in ICU over 90 days will be presented by treatment group. In addition, the number and 
percentage of subjects in the following categories will be presented, 0 days, 1-6 days, 7-14 
days, 15-21 days, 22-28 days and >28 days.
A bar chart of the number of days in ICU for each subject within the treatment group will be 
produced, i.e., showing graphically the distribution of the number of days in ICU for each 
treatment group.
The method for handling deaths and subjects that withdraw or are lost to follow up prior to 
Day 90 is detailed in Section 3.1.12.
4.3.2.12
Days alive outside of hospital over the course of 28 days
Summary statistics (n, mean, SD, median, minimum and maximum) of the days alive outside 
of hospital over 90 days will be presented by treatment group.
The method for handling subjects that withdraw or are lost to follow up prior to Day 28 is 
detailed in Section 3.1.13.
4.3.2.13
Days alive outside of hospital over the course of 90 days
Summary statistics (n, mean, SD, median, minimum and maximum) of the days alive outside 
of hospital over 90 days will be presented by treatment group.
The method for handling subjects that withdraw or are lost to follow up prior to Day 90 is 
detailed in Section 3.1.14.
4.3.2.14
Relative change from baseline in oxygenation index
Summary statistics (n, mean, median, SD, minimum, and maximum) and the percent change 
from baseline to each scheduled study assessment will be presented by treatment group.


Statistical Analysis Plan 
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Study Code D822FC00001
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Box plots of absolute value over time and a line graph of the mean change (and SD) from 
baseline to each scheduled study assessment may be presented for each treatment group.
A by-subject listing will also be presented.
4.3.2.15
Time to clinical improvement of at least 2 points (from randomization) on a 
9-point category ordinal scale through Day 28
Time from randomization to the date of first demonstrated clinical improvement of at least 2 
points on a 9-point category ordinal scale through Day 28 will be portrayed using the KM 
method by treatment group.
Alongside summary statistics, a KM plot of the cumulative improvement rate over time will 
be presented by treatment group.
The HR and its 95% CI will be estimated from a stratified Cox Proportional Hazards model 
(with ties = Efron), stratified by age (<65 vs ≥65 years) and comorbidities (present vs absent). 
The CI will be calculated using a profile likelihood approach. Summary statistics will include 
the lower and upper quartile and median time to clinical improvement with the 95% CI.
The method for handling subjects that withdraw or are lost to follow up or die is detailed in 
Section 3.1.16.
In addition to the above, for each treatment group, ordinal scale scores will be presented by 
day and the change in the score from baseline to each post-baseline assessment will be 
summarized.
Additional sensitivity analyses may be performed as appropriate.
Time to clinical improvement of at least 2 points (from randomization) on a 9-point 
category ordinal scale, live discharge from hospital, or considered fit for discharge, 
whichever comes first) through Day 28
Time from randomization to the date of first demonstrated clinical improvement of at least 2 
points on a 9-point category ordinal scale, live discharge from hospital, or considered fit for 
discharge, whichever comes first, through Day 28 will be portrayed using the KM method by 
treatment group.
Alongside summary statistics, a KM plot of the cumulative improvement rate over time will 
be presented by treatment group.
The HR and its 95% CI will be estimated from a stratified Cox Proportional Hazards model 
(with ties = Efron), stratified by age (<65 vs ≥65 years) and comorbidities (present vs absent). 
The CI will be calculated using a profile likelihood approach. Summary statistics will include 
the lower and upper quartile and median time to clinical improvement with the 95% CI.


Statistical Analysis Plan 
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Study Code D822FC00001
48(61)
The method for handling subjects that withdraw or are lost to follow up or die is detailed in 
Section 3.1.16.1.
Additional sensitivity analyses may be performed as appropriate.
Time to recovery (from randomization) through Day 28
Time from randomization to the date of recovery through Day 28 will be portrayed using the 
KM method by treatment group.
Alongside summary statistics, a KM plot of the cumulative recovery rate over time will be 
presented by treatment group.
The HR and its 95% CI will be estimated from a stratified Cox Proportional Hazards model 
(with ties = Efron), stratified by age (<65 vs ≥65 years) and comorbidities (present vs absent). 
The CI will be calculated using a profile likelihood approach. Summary statistics will include 
the lower and upper quartile and median time to clinical improvement with the 95% CI.
The method for handling subjects that withdraw or are lost to follow up or die is detailed in 
Section 3.1.16.2.
Additional sensitivity analyses may be performed as appropriate.
4.3.2.16
Time to SpO2 > 94% on room air
Time from randomization to SpO2 > 94% on room air through Day 28 will be portrayed using 
the KM method by treatment group.
Alongside summary statistics, a KM plot of the cumulative SpO2 > 94% rate over time will be 
presented by treatment group.
The HR and its 95% CI will be estimated from a stratified Cox Proportional Hazards model 
(with ties = Efron), stratified by age (<65 vs ≥65 years) and comorbidities (present vs absent). 
The CI will be calculated using a profile likelihood approach. Summary statistics will include 
the lower and upper quartile and median time to clinical improvement with the 95% CI.
The method for handling subjects that withdraw or are lost to follow up or die is detailed in 
Section 3.1.17.
Additional sensitivity analyses may be performed as appropriate.
4.4
Analysis of safety
This section describes safety analyses to be conducted. All of the analyses in this section will 
be based on the safety population and will be performed for all safety variables specified 
below.  All analyses of safety data will employ descriptive statistics. Formal statistical 
analysis (with generation of a p-value) will not be performed for these endpoints.


Statistical Analysis Plan 
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Study Code D822FC00001
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4.4.1
Adverse events
Verbatim descriptions of AEs will be mapped per version 23.0 of the MedDRA thesaurus 
terms and graded per National Cancer Institute (NCI) CTCAE, v5.0 or higher. Unless stated 
otherwise, only treatment-emergent adverse events (TEAEs) will be presented in the 
summaries. For acalabrutinib + BSC subjects, TEAEs are AEs starting or ongoing AEs 
worsening after the first dose of study treatment and AEs with start date up to the last dose of 
study treatment plus 28 (±3) days; for BSC only subjects, TEAEs are AEs starting or ongoing 
AEs worsening after date of randomization and AEs with start date up to 38 (± 3) days after 
randomization. . In the case a subject’s actual treatment received is different than their 
randomized treatment, TEAEs are AEs starting on or after the date of randomization up to the 
later of 38 (± 3) days after randomization or the last dose of study treatment plus 28 (±3) days.
When programmatically assigning the AEs as treatment emergent, the upper window will be 
used.
The following summaries will be provided:

A summary of the number and percentage of subjects reporting any TEAE, TEAEs 
with outcome of death, at least one TEAE of CTCAE grade 3 or higher, at least one 
serious TEAE, at least one TEAE possibly related to study drug, and at least one 
TEAE leading to discontinuation of study drug by treatment group.

A summary of the number of TEAEs, TEAEs with outcome of deaths, TEAEs with 
CTCAE grade 3 or higher, serious TEAEs, TEAEs possibly related to study drug, and 
TEAEs leading to discontinuation of study drug by treatment group.  

A summary of the number and percentage of subjects reporting a TEAE by treatment 
group, SOC and PT.

A summary of the number and percentage of subjects reporting the most common 
TEAEs (occurring in at least 5% of overall subjects) by treatment group , SOC and PT.

A summary of the number and percentage of subjects reporting a TEAE by treatment 
group, maximum CTCAE grade, SOC and PT. This will include a subset of grade 3 or 
higher.

A summary of the number and percentage of subjects reporting a TEAE possibly 
related to study drug by SOC and PT.

A summary of the number and percentage of subjects reporting a TEAE leading to 
discontinuation of study drug by SOC and PT.
For the most common TEAEs, all events that occur in at least 5% of subjects overall will be 
summarized by preferred term, by decreasing frequency. This cut-off may be modified after 
review of the data. When applying a cut-off (e.g., 5%), the raw percentage should be 


Statistical Analysis Plan 
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Study Code D822FC00001
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compared to the cut-off, no rounding should be applied first (i.e., an AE with frequency 4.9% 
will not appear if the cut-off is 5%).
The following by-subject listings will be provided:

A listing of all AEs (including non-treatment-emergent events and any collected but 
are not, by definition, AEs since they are related to disease under study), by treatment 
group, and including center, E-code, AE (SOC, PT, verbatim term), date of onset, date 
of resolution, duration, CTCAE grade, seriousness, action taken, outcome, relationship 
to study treatment and time from last dose to start of AE. 
4.4.1.1
Deaths, serious adverse events (SAEs), and other significant adverse events 
The following summaries will be provided:

A summary of the number and percentage of total deaths, deaths related to the disease 
under investigation (as determined by the investigator), deaths after the end of safety 
follow-up (28 (±3) days after last dose for acalabrutinib + BSC subjects, 38 (±3) days 
after randomization for BSC only subjects) by treatment group

A summary of the number and percentage of subjects reporting a treatment-emergent 
SAE by treatment group, SOC and PT.

A summary of the number of treatment-emergent SAEs by treatment group, SOC and 
PT.

A summary of the number and percentage of subjects reporting a treatment-emergent 
SAE leading to discontinuation of study drug by SOC and PT. 

A summary of the number and percentage of subjects with a treatment-emergent SAE 
with an outcome of death by treatment group and PT.
Adverse events of special interest (AESI) for acalabrutinib include ventricular arrhythmias 
(e.g., ventricular extrasystoles, ventricular tachycardia, ventricular arrhythmia, ventricular 
fibrillation). AESI preferred terms are listed in Section 8.1. These events will be summarized 
similarly as follows:

A summary of the number and percentage of subjects reporting an AESI by treatment 
group, CTCAE grade, group term and PT.

A summary of the number and percentage of subjects reporting an AESI possibly 
related to study drug by group term and PT.

A summary of the number and percentage of subjects reporting an AESI leading to 
discontinuation of study drug by group term and PT.
A list of AESI PTs will also be provided.


Statistical Analysis Plan 
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Study Code D822FC00001
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Events of clinical interest (ECIs) are provided in Section 8.1. ECIs will be reported for the 
duration of study treatment and during any protocol-specified follow-up period. These events 
will be summarized similarly to AESIs by treatment group and a list of ECI PTs will be 
provided. 
The following by-subject listings will be presented:

A by-subject listing of key information for serious adverse events (SAEs).

A by-subject listing of key information for AESIs and ECIs.

A by-subject listing of deaths, including the date of death, the primary and secondary 
cause of death, whether an autopsy was performed and whether the death was related 
to the disease under study.

A by-subject listing of key information for AEs leading to discontinuation of study 
treatment.
The following subject narratives will be provided:

Narratives of SAEs with an outcome of death.

Narratives of SAEs, possibly related to study drug.

Narratives of discontinuation of investigational product due to AEs.

Narratives of AESIs.

Narratives of any other medically-relevant AE that does not fall into the above 
categories.
No formal statistical tests will be performed to compare AE rates between treatment groups. 
4.4.2
Exposure, dose intensity and treatment compliance
Study drug exposure will be listed and summarized for acalabrutinib-treated subjects in the 
SAF. The following summaries will be produced:

Actual treatment duration

Summary statistics (n, mean, median, SD, minimum, and maximum) of PID

Calculated average daily dose
4.4.3
Laboratory assessments
For the following continuous laboratory parameters, summary statistics (n, mean, median, SD, 
minimum, and maximum) of the laboratory results (converted to SI units) and the change from 
baseline at each scheduled post-baseline assessment will be presented by treatment group:

Efficacy laboratory parameters: CRP, ALC, ferritin

Fibrinogen


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
PT

aPTT

INR

D-dimer

Procalcitonin

Cardiac troponin
Selected laboratory parameters (including categorical parameters) may be analysed with shift 
tables (defined by the normal ranges) of baseline to minimum post-baseline value (low, 
medium, high) and of baseline to maximum post-baseline value (low, normal, high) by 
treatment group may be presented. For laboratory parameters classified using CTC grades, 
shift tables for selected laboratory parameters may also be produced showing baseline CTC 
grade to maximum post-baseline CTC grade by treatment group.
By-subject listings of haematology and clinical chemistry parameters will be presented. 
Unscheduled laboratory results will not be included in the by-visit summaries but will be 
included in listings, as well as any out of range or shift tables of worst postbaseline data.
Liver function abnormality by Hy's law and frequencies of abnormal treatment emergent uric 
acid will be summarized.
4.4.4
Vital signs
Summary statistics (n, mean, median, SD, minimum, and maximum) for each of the vital signs 
and the change from baseline at each scheduled post-baseline assessment will be presented by 
treatment group.  
A by-subject listing of all vital sign parameters will be presented; abnormal vital signs will be 
flagged.
4.4.5
Physical examinations and chest imaging, electrocardiograms and 
echocardiograms
By-subject listings of all physical examination and weight data will be presented. 
If there is a sufficient number of subjects with post-baseline assessments (≥10 subjects per 
treatment group), a shift table of the number and percentage of subjects with normal or 
abnormal ECG evaluations may be presented from baseline to the most extreme post-baseline 
evaluation.
By-subject listings of all ECG parameters will be presented along with the heart rhythm and 
overall evaluation of ECGs at all visits.


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By-subject listings of ECHO overall evaluation, abnormalities and LVEF will be presented.
4.4.6
Oxygen treatment, ventilator use and mSOFA
Oxygen treatment and ventilator use data will be used to assess primary and secondary 
efficacy endpoints of the study.
The number and percentage of subjects requiring oxygen treatment or mechanical ventilation 
at each timepoint will be presented by treatment group. Oxygen flow rate and method of 
mechanical ventilation at baseline will also be presented by treatment group. Change from 
baseline in oxygen flow rate to each post-baseline flow rate and to the maximum post-baseline 
flow rate will be summarized.
For subjects requiring oxygen treatment, by-subject listings will be presented.
For subjects requiring mechanical ventilation, by-subject listings will be presented on the data 
collected, as listed in Section 3.2.6. 
By-subject listings of mSOFA scores and sub-scores may be presented.
4.5
Analysis of pharmacokinetics 
Plasma concentrations of study drug and/or metabolite will be grouped, tabulated, summarized 
and plotted, as appropriate. Plasma concentrations will be listed for each subject by nominal 
time point, as warranted by the data. Additionally, the data will also be displayed graphically, 
as appropriate.
The PK parameters for acalabrutinib and ACP-5862 (such as, AUC and Cmax) may be 
estimated using a population PK approach, if warranted by the data, and reported separately 
from the Clinical Study Report (CSR).
Potential correlations of exposure with safety and efficacy outcomes or biomarker 
measurements may be explored as warranted by the data.
4.6
Analysis of exploratory variables and pharmacodynamics 
CCI


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
54(61)
5.
INTERIM ANALYSES
A DMC will conduct a planned interim safety review and a planned efficacy interim analysis 
before the primary analysis of the study data. Details are provided in Section 6.
6.
DATA MONITORING COMMITTEE 
This study will have a DMC. The details of the roles and responsibilities of the DMC are 
provided in the DMC charter. The DMC will be responsible for oversight of participant safety 
and monitoring the balance of risks and benefits in the study. To fulfil this, the study will use 
a DMC to conduct a planned interim safety review and a planned efficacy interim analysis 
before the primary analysis of the study data. 
The first DMC review is an interim safety review which will take place after the first 30 
subjects have been randomized into the study and have had 28 days of follow-up from 
randomization. 
The second DMC review is a planned interim analysis of the primary efficacy endpoint, which 
will take place when the last subject randomized has had 14 (± 2) days of follow up after 
randomization. At the time of the interim analysis of the primary efficacy endpoint, 
accumulated safety data will also be reviewed by the DMC.
The two DMC reviews may be combined if the study is fully enrolled at the time of the first 
DMC review. The DMC may support any health authority interactions or internal discussions 
based on their review. The study team will remain blinded to the data that the DMC will 
review until database lock for the primary analysis of the study, which will occur when all 
randomized subjects have been followed for 38 (± 3) days from randomization.
In addition to the two formal reviews, the DMC will review all fatal events on an ongoing 
basis. Further details will be provided in a separate DMC charter.
To maintain the overall type I error of the study at the 2-sided 0.05 level, at the interim 
analysis, the primary efficacy endpoint (the proportion of subjects who are alive and free of 
respiratory failure at Day 14) will be tested at the 2-sided 0.0001 level. At the primary 
analysis for the study, this primary efficacy endpoint will be tested at the 2-sided 0.0499 level.
CCI


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
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An updated analysis for those endpoints requiring 90-day assessments will take place after the 
last randomized subject has had 90 days of follow up from randomization
Details on the outputs that will be provided to the DMC are listed in Section 8.2.
7.
CHANGES OF ANALYSIS FROM PROTOCOL
N/A


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
56(61)
8.
APPENDIX
8.1
AESI and ECI definitions
Adverse Event of Special Interest (AESI)
The following preferred terms for the ventricular arrhythmias AESI include:

Torsade de pointes

Ventricular arrhythmia

Ventricular extrasystoles

Ventricular fibrillation

Ventricular flutter

Ventricular tachyarrhythmia

Ventricular tachycardia
Events of Clinical Interest
The Events of Clinical Interest (ECIs) are from the acalabrutinib program with extended 
dosing of acalabrutinib in patients with haematologic malignancies.
Category
Subcategory
Definition
Cardiac events 

SOC Cardiac disorders
Atrial fibrillation

PT Atrial fibrillation 

PT Atrial flutter
Ventricular 
tachyarrhythmias

PT Torsade de pointes

PT Ventricular fibrillation

PT Ventricular flutter

PT Ventricular tachyarrhythmia

PT Ventricular tachycardia 
Cytopenias –
Anemia

SMQ Haematopoietic erythropenia [narrow + 
broad]
Cytopenias –
Leukopenia

SMQ Haematopoietic leukopenia [narrow + 
broad]
Neutropenia

PT Band Neutrophil count decreased

PT Band neutrophil percentage decreased

PT Cyclic neutropenia

PT Febrile Neutropenia

PT Idiopathic neutropenia

PT Neutropenia

PT Neutropenic infection

PT Neutropenic sepsis

PT Neutrophil count decreased

PT Neutrophil percentage decreased
Other leukopenia

SMQ Haematopoietic leukopenia [narrow + 
broad] excluding PTs for neutropenia above


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
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Cytopenias -
Thrombocytopenia

SMQ Haematopoietic thrombocytopenia [narrow 
+ broad]
Hemorrhage

SMQ Haemorrhage terms (excl. laboratory terms)
Major hemorrhage

As per Acerta definition (see below)
Hepatotoxicity

SMQ [narrow] Hepatic failure, fibrosis and 
cirrhosis and other liver damage-related 
conditions

SMQ [narrow] Hepatitis, non-infectious

SMQ [narrow] Liver related investigations signs 
Hypertension

SMQ Hypertension [narrow]
Infections 

SOC Infections and infestations
Interstitial lung 
disease/Pneumonitis

SMQ [narrow] Interstitial lung disease
Second primary 
malignanciesa

SMQ Malignant tumours (including 
Haematological malignant tumours SMQ and 
Non-haemoatological malignant tumours SMQ)

SMQ Malignant lymphomas [narrow]
SMQ Myelodysplastic syndrome [narrow]
Second primary 
malignancies 
(excluding non 
melanoma skin)

The above excluding PTs mapping to HLT Skin 
neoplasms malignant and unspecified (excluding 
melanoma) 
Tumor lysis 
syndromeb

PT Tumour lysis syndrome
MedDRA version 23.0
HLT=High-Level Term; PT=Preferred Term; SOC=System Organ Classes; SMQ=Standardized MedDRA Queries.
a Only flagged as an ECI if malignancy is reported in the subject’s medical history and is ongoing.
b Only flagged as an ECI if tumor lysis syndrome is reported in the subject’s medical history and is ongoing.
Major Hemorrhage
Major hemorrhage is defined as any hemorrhagic event that is serious, or Grade ≥ 3 in severity, or that is a CNS 
hemorrhage (any severity grade).
Search Strategy:
I.
Use standardized MedDRA query:
o
Haemorrhage terms (excluding laboratory terms) (SMQ) [20000039]
II.
Identify Major Events that are a subset of the Haemorrhage SMQ:  
o
Grade >3 AE
o
Any serious adverse event
o
All grades of CNS hemorrhage  
CNS Hemorrhage Preferred Terms (MedDRA Version 23.0)

Acute haemorrhagic leukoencephalitis


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
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
Basal ganglia haematoma

Basal ganglia haemorrhage

Basilar artery perforation

Brain contusion

Brain stem haematoma

Brain stem haemorrhage

Brain stem microhaemorrhage

Central nervous system haemorrhage

Cerebellar haematoma

Cerebellar haemorrhage

Cerebellar microhaemorrhage

Cerebral aneurysm perforation

Cerebral aneurysm ruptured syphilitic

Cerebral arteriovenous malformation haemorrhagic

Cerebral artery perforation

Cerebral cyst haemorrhage

Cerebral haematoma 

Cerebral haemorrhage

Cerebral haemorrhage foetal

Cerebral microhaemorrhage

Encephalitis haemorrhagic

Epidural haemorrhage

Extradural haematoma

Haemorrhage intracranial

Haemorrhagic cerebral infarction

Haemorrhagic stroke

Haemorrhagic transformation stroke

Intracerebral haematoma evacuation

Intracranial haematoma

Intracranial tumour haemorrhage

Intraventricular haemorrhage

Meningorrhagia

Ocular retrobulbar haemorrhage

Optic disc haemorrhage

Optic nerve sheath haemorrhage

Pituitary haemorrhage

Putamen haemorrhage

Retinal aneurysm rupture

Retinal haemorrhage

Retinopathy haemorrhagic 

Ruptured cerebral aneurysm

Spinal cord haematoma

Spinal cord haemorrhage


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
59(61)

Spinal epidural haematoma

Spinal epidural haemorrhage

Spinal subarachnoid haemorrhage

Spinal subdural haematoma

Spinal subdural haemorrhage

Subarachnoid haematoma

Subarachnoid haemorrhage

Subdural haematoma

Subdural haematoma evacuation

Subdural haemorrhage

Subgaleal haematoma

Subgaleal haemorrhage

Subretinal haematoma

Thalamus haemorrhage

Traumatic intracranial haematoma

Traumatic intracranial haemorrhage


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
60(61)
8.2
DMC outputs for review meeting
The outputs that will be produced for the DMC reviews are provided in Table 7.
Table 7
DMC review outputs
Output
Analysis set
Disposition, recruitment, stratification factors, demographic and subject 
characteristics, medical history, concomitant medications/ BSC, signs 
and symptoms at screening, duration of hospitalization, respiratory 
failure status at baseline, intensity of oxygen treatment and mechanical 
ventilation at baseline.
The above will be summarized as detailed in Section 4.2.1, 4.2.3 and 
4.2.4.
Full analysis set
Duration of exposure, average daily dose, percentage of intended dose.
The above will be summarized as detailed in Section 4.4.2.
Safety analysis set 
(acalabrutinib-treated 
subjects only)
Subjects on oxygen treatment, mechanical ventilation, or either, over the 
course of the study.
The above will be summarized as detailed in Section 4.4.6.
Safety analysis set
Adverse events: TEAEs, TEAEs leading to discontinuation of study drug, 
AEs possibly related to study drug, SAEs.
The above will be summarized as detailed in Section 4.4.1.
Safety analysis set
Listing of deaths
Full analysis set
Proportion of subjects alive and free of respiratory failure at Day 14 and 
Day 28 (summary statistics only for the first DMC interim safety review).
Stratified and unstratified analysis of the proportion of subjects alive and 
free of respiratory failure at Day 14 (testing with odds ratios and p-values 
provided for the DMC interim efficacy review).
Proportion of subjects who experienced respiratory failure of died over 
the course of 28 days.
Proportion of subjects who required invasive ventilation or ECMO or 
died over the course of 28 days.
Full analysis set


Statistical Analysis Plan 
AstraZeneca 
Study Code D822FC00001
61(61)
8.3
Fraction of Inspired Oxygen (FiO2)
For all supplemental oxygen delivery devices, the patient is not just breathing the direct 
oxygen, but rather is breathing a combination of room air plus the oxygen from the 
supplemental device. Different devices deliver to the patient more or less of a % of what is 
coming in from the tank. 
Fraction of Inspired Oxygen (FiO2) for a nasal canula and a simple mask are given in the 
tables below. For other oxygen delivery systems, such as masks, tents, there is more oxygen 
that "blows by" or is lost, therefore higher flow rate setting on the oxygen tank are needed to 
achieve the same FiO2. A tracheostomy would require different calculations as well. 
Example: with a nasal cannula, we assume that the fraction of oxygen that is inspired (above 
the normal atmospheric level or 20%) increases by 4% for every additional liter of oxygen 
flow administered. 
For a Nasal Cannula: FiO2 (%) = (Flow Rate (L/min) × 4) + 20
Oxygen tank FLOW RATE in liters / min 
FiO2 -- Fraction of Inspired Oxygen value (%)
1 L / min 
24
2 L / min 
28
3 L / min 
32
4 L / min 
36
5 L / min 
40
6 L / min 
44
For a Simple Mask:
If Flow Rate < 10 L/min: FiO2 (%) = Max[(Flow Rate (L/min) × 6) – 1, 24]
If Flow Rate ≥ 10 L/min: FiO2 (%) = Flow Rate (L/min) × 6
Oxygen tank FLOW RATE in liters / min 
FiO2 -- Fraction of Inspired Oxygen value (%)
6 L / min
35
7 L / min
41
8 L / min
47
9 L / min
53
10 L / min
60
9.
REFERENCES


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Statistical Analysis Plan Edition 4
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