Clinical trial NCT04497948
Conditions: COVID-19
Keywords: 2019 novel coronavirus disease Acalabrutinib Btk inhibitor
Sponsor: Acerta Pharma BV
Start date: 2020-09-21; Completion date: 2020-11-18
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Study D822FC00005 will investigate the Phamacokinetics, Safety and tolerability of Acalabrutinib suspension when delivered via a nasogastric tube and co-administered with a Proton Pump Inhibitor, in the treatment of COVID-19.

Detailed description:
This study is to support the ongoing clinical development of acalabrutinib (CALQUENCE®) in hospitalized COVID-19 patients. Because many COVID-19 patients may be unable to swallow capsules due to respiratory failure (eg, they may require endotracheal intubation for ventilator support and Naso Gastric tube placement), it is important to have a clinically acceptable method to administer acalabrutinib (capsules) via NG tube. Furthermore, many hospitalized patients are placed on high doses of proton pump inhibitors (PPIs) (also commonly known as antacid medication). This study is designed to determine the Pharmaco Kinetics (effect of body/ bodily systems on the drug), safety and tolerability of acalabrutinib suspension, when coadministered with a PPI, in participants with confirmed SARS-CoV-2 infection requiring hospitalization due to respiratory failure, attributable to COVID-19 pneumonia and who have an Nasogastric (NG) tube in place.

Arms: arm 1: Single Arm
Interventions: intervention 1: Acalabrutinib
Intervention descriptions: intervention 1: Acalabrutinib (CALQUENCE®) is a covalent BTK inhibitor

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol  
Study Intervention 
Acalabrutinib 
Study Code 
D822FC00005 
Version 
3.0 
Date 
04 September 2020 
An Open-label, Multiple-dose Study to Evaluate the 
Pharmacokinetics, and Safety and Tolerability of Acalabrutinib 
Suspension Delivered via Nasogastric Tube, Coadministered With 
a Proton-pump Inhibitor, in Participants Hospitalized With 
COVID-19 
Sponsor Name:  
Acerta Pharma B.V. a member of 
AstraZeneca group of companies 
Legal Registered Address:  
Kloosterstraat 9, 5349 AB Oss,  
The Netherlands 
Regulatory Agency Identifier Number(s):  IND number 149513 
 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations. 
 
 


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Protocol Number: D822FC00005 
Amendment Number: 2 
Study Intervention: Acalabrutinib 
Study Phase: Ib 
Short Title: Study of Acalabrutinib Suspension Delivered via Nasogastric Tube With a 
Proton-pump Inhibitor in Participants Hospitalized with COVID-19 
Study Physician Name and Contact Information will be provided separately 
 
 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
 
DOCUMENT HISTORY 
Document 
Date 
Amendment 2 (Version 3.0) 
04 September 2020 
Amendment 1 (Version 2.0) 
25 June 2020 
Original Protocol (Version 1.0) 
20 May 2020 
 
Amendment 2 (04 September 2020)  
The overall rationale for the amendment was to provide clarification regarding laboratory tests 
for HBV and HCV during screening.  
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 treatment initiation. 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 BTK 
inhibitors that are available to the Sponsor. Hepatitis B virus reactivations in the setting of 
acalabrutinib treatment are infrequently reported. Among 4053 participants across all clinical 
studies investigating acalabrutinib to date, 9 participants had reactivations (1 fatal, 8 non-
serious) after a median duration of therapy of 248 days (range 43 to 582 days). Hepatitis B 
virus 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. 


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Section Number and 
Name 
Description of Change 
Brief Rationale 
Substantial/ 
Non-substantial 
1.3 Schedule of Activities 
(Table 1) 
Removed Day 1 column from 
Table 1. Made changes to “Daily 
until hospital discharge” column to 
adjust for this change. 
Clarification 
Non-substantial 
1.3 Schedule of Activities 
(Table 1), 
5.1 Inclusion Criteria 
Revised SARS-CoV-2 PCR virus 
testing Inclusion Criterion 3 in 
Section 5.1 and aligned the SoA 
(Table 1) accordingly. 
To allow flexibility 
Non-substantial 
1.3 Schedule of Activities 
(Table 1), 
8.2.5.1 Local Laboratory 
Tests, 
8.2.5.1.1 Hepatitis 
Serology Guidelines 
Added text to footnote d of Table 1 
to indicate that treatment with 
acalabrutinib can start 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 available 
at the time of the first dose. In 
addition, added hepatitis serology 
guidelines that should be followed 
(Section 8.2.5.1.1). 
See rationale 
provided above this 
table 
Substantial 
1.3 Schedule of Activities 
(Table 1), 
8.2.5.2 Central 
Laboratory Tests 
In Table 1, specified that a 
nasopharyngeal swab will be 
collected for SARS-CoV-2 viral 
load/viral shedding. In 
Section 8.2.5.2, changed 
To correct 
typographical error 
Non-substantial 
2.3.1.3 Hepatitis B and C 
Reactivation 
Added information about HCV and 
HBV reactivation with acalabrutinib 
To support hepatitis 
serology guidelines 
Substantial 
5.1 Inclusion Criteria 
Revised Inclusion Criterion 5 to 
indicate that feeding tube must 
remain in place for a minimum of 
3 days after study enrollment 
Clarification 
Non-substantial 
5.2 Exclusion Criteria 
Revised Exclusion Criterion 9 to 
align with the hepatitis serology 
guidelines 
Clarification and 
consistency 
Substantial 
Added an exception to Exclusion 
Criterion 12 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 
Substantial 


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Section Number and 
Name 
Description of Change 
Brief Rationale 
Substantial/ 
Non-substantial 
associated with 
COVID-19 (Cai et al 
2020, Guan et al 
2020a) 
Revised Exclusion Criterion 19 to 
clarify that aspirin and therapeutic/ 
high doses of low-molecular-weight 
heparin are not allowed, but that 
aspirin and prophylactic/low doses 
of low-molecular-weight heparin 
are allowed 
Clarification 
Non-substantial 
7.1 Discontinuation of 
Study Intervention, 
7.2 Participant 
Withdrawal from the 
Study 
Added that participants with 
positive HBsAg, HBV-DNA, or 
HCV-RNA test result after first 
dose administration will be 
discontinued from study 
intervention (Section 7.1) and 
withdrawn from the study 
(Section 7.2) 
To align with 
hepatitis serology 
guidelines 
Substantial 
Clinical Study Protocol 
Signature Page 
Removed 
Utilizing different 
signoff process 
Non-substantial 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; COVID-19 = coronavirus disease 2019; 
HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; PCR = polymerase chain 
reaction; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SoA = Schedule of Activities; ULN = upper 
limit of normal. 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ....................................... 3 
TABLE OF CONTENTS ........................................................................................................... 6 
1 
PROTOCOL SUMMARY .................................................................................... 11 
1.1 
Synopsis ................................................................................................................ 11 
1.2 
Schema .................................................................................................................. 15 
1.3 
Schedule of Activities ........................................................................................... 16 
2 
INTRODUCTION ................................................................................................ 21 
2.1 
Study Rationale ..................................................................................................... 21 
2.2 
Background ........................................................................................................... 21 
2.2.1 
Coronavirus Disease 2019 .................................................................................... 21 
2.2.2 
Bruton Tyrosine Kinase ........................................................................................ 22 
2.2.3 
Acalabrutinib ........................................................................................................ 23 
2.2.3.1 
Nonclinical Experience ......................................................................................... 23 
2.2.3.2 
Clinical Experience ............................................................................................... 23 
2.2.3.3 
Metabolism and Transport .................................................................................... 24 
2.2.3.4 
Effect of Raised Gastric pH on Acalabrutinib Bioavailability ............................. 24 
2.2.3.5 
Rationale for Developing an Acalabrutinib Suspension in COCA-COLA .......... 25 
2.3 
Benefit-Risk Assessment ...................................................................................... 25 
2.3.1 
Risk Assessment ................................................................................................... 26 
2.3.1.1 
Hemorrhage .......................................................................................................... 26 
2.3.1.2 
Infections .............................................................................................................. 26 
2.3.1.3 
Hepatitis B and C Reactivation............................................................................. 27 
2.3.1.4 
Progressive Multifocal Leukoencephalopathy ..................................................... 27 
2.3.1.5 
Cytopenias ............................................................................................................ 27 
2.3.1.6 
Secondary Primary Malignancies ......................................................................... 27 
2.3.1.7 
Atrial Fibrillation .................................................................................................. 28 
2.3.2 
Benefit Assessment ............................................................................................... 28 
2.3.3 
Overall Benefit: Risk Conclusion ......................................................................... 29 
3 
OBJECTIVES AND ENDPOINTS ...................................................................... 29 
4 
STUDY DESIGN ................................................................................................. 30 
4.1 
Overall Design ...................................................................................................... 30 
4.2 
Scientific Rationale for Study Design .................................................................. 31 
4.3 
Justification for Dose ............................................................................................ 32 
4.4 
End of Study Definition ........................................................................................ 32 
5 
STUDY POPULATION ....................................................................................... 32 
5.1 
Inclusion Criteria .................................................................................................. 32 
5.2 
Exclusion Criteria ................................................................................................. 33 
5.3 
Lifestyle Considerations ....................................................................................... 35 


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5.4 
Screen Failures...................................................................................................... 35 
6 
STUDY INTERVENTION ................................................................................... 36 
6.1 
Study Intervention(s) Administered ...................................................................... 36 
6.1.1 
Investigational Medicinal Products ...................................................................... 36 
6.1.2 
Dosing Instructions and Duration ......................................................................... 37 
6.1.2.1 
Dosing and Duration of Treatment ....................................................................... 37 
6.1.2.2 
Dosing of Participants Who are no Longer Intubated .......................................... 37 
6.1.2.3 
Missed Dosing Windows and Doses..................................................................... 37 
6.1.2.4 
Vomiting After Acalabrutinib Treatment .............................................................. 37 
6.1.2.5 
Discharged From Hospital Before Treatment Completion ................................... 38 
6.2 
Preparation/Handling/Storage/Accountability of Interventions ........................... 38 
6.2.1 
Preparation and Handling ..................................................................................... 38 
6.2.2 
Storage and Accountability ................................................................................... 38 
6.3 
Measures to Minimize Bias: Randomization and Blinding .................................. 38 
6.4 
Study Intervention Compliance ............................................................................ 39 
6.5 
Concomitant Therapy ........................................................................................... 39 
6.5.1 
Premedications ...................................................................................................... 39 
6.5.2 
Permitted Concomitant Therapy ........................................................................... 40 
6.5.3 
Prohibited or Restricted Concomitant Therapy .................................................... 40 
6.5.4 
Acalabrutinib 
Drug-drug 
Interaction 
Guidance 
in 
the 
Presence 
of 
Life-threatening COVID-19 Infection .................................................................. 41 
6.6 
Dose Modification ................................................................................................ 42 
6.6.1 
Acalabrutinib Dose Modifications in Special Populations ................................... 44 
6.6.1.1 
Renal Impairment ................................................................................................. 44 
6.6.1.2 
Hepatic Impairment .............................................................................................. 44 
6.7 
Intervention After the End of the Study ................................................................ 44 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................. 45 
7.1 
Discontinuation of Study Intervention ................................................................. 45 
7.2 
Participant Withdrawal from the Study ................................................................ 45 
7.3 
Lost to Follow-up ................................................................................................. 46 
8 
STUDY ASSESSMENTS AND PROCEDURES ................................................ 47 
8.1 
Efficacy and Clinical Assessments ....................................................................... 47 
8.1.1 
Efficacy Assessments ............................................................................................ 47 
8.1.1.1 
Pulmonary Assessments to Evaluate Respiratory Failure .................................... 47 
8.1.1.2 
Improvements on 9-point Category Ordinal Scale ............................................... 48 
8.1.2 
Clinical Assessments ............................................................................................ 49 
8.1.2.1 
Modified Sequential Organ Failure Assessment Scores ....................................... 49 
8.2 
Safety Assessments ............................................................................................... 49 
8.2.1 
Medical History .................................................................................................... 49 
8.2.2 
Physical Examinations and Chest Imaging........................................................... 49 
8.2.3 
Vital Signs ............................................................................................................. 50 
8.2.4 
Electrocardiograms and Echocardiograms ........................................................... 50 


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8.2.5 
Clinical Safety Laboratory Assessments .............................................................. 50 
8.2.5.1 
Local Laboratory Tests ......................................................................................... 50 
8.2.5.2 
Central Laboratory Tests ....................................................................................... 52 
8.3 
Adverse Events and Serious Adverse Events ....................................................... 52 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ................. 53 
8.3.2 
Follow-up of AEs and SAEs ................................................................................. 53 
8.3.3 
Causality Collection.............................................................................................. 54 
8.3.4 
Adverse Events Based on Signs and Symptoms .................................................. 54 
8.3.5 
Adverse Events Based on Examinations and Tests .............................................. 54 
8.3.6 
Hy’s Law ............................................................................................................... 55 
8.3.7 
Disease Progression .............................................................................................. 55 
8.3.8 
Disease Under study ............................................................................................. 55 
8.3.9 
Reporting of Serious Adverse Events ................................................................... 55 
8.3.10 
Pregnancy ............................................................................................................. 56 
8.3.10.1 
Maternal Exposure ................................................................................................ 56 
8.3.10.2 
Paternal Exposure ................................................................................................. 57 
8.3.11 
Medication Error ................................................................................................... 57 
8.3.12 
Adverse Events of Special Interest ....................................................................... 57 
8.4 
Overdose ............................................................................................................... 58 
8.5 
Human Biological Samples .................................................................................. 58 
8.5.1 
Pharmacokinetics .................................................................................................. 59 
8.5.1.1 
Determination of Drug Concentration .................................................................. 59 
8.5.2 
 ............................................................................................... 60 
8.5.3 
Immunogenicity .................................................................................................... 60 
8.6 
 ................................................................ 60 
8.6.1 
 .............................................................................................. 60 
8.6.2 
 ............................................................. 60 
8.7 
Optional Genomics Initiative Sample ................................................................... 60 
8.8 
Health Economics ................................................................................................. 60 
9 
STATISTICAL CONSIDERATIONS ................................................................... 61 
9.1 
Statistical Hypotheses ........................................................................................... 61 
9.2 
Sample Size Determination .................................................................................. 61 
9.3 
Populations for Analyses ...................................................................................... 61 
9.4 
Statistical Analyses ............................................................................................... 62 
9.4.1 
General Considerations ......................................................................................... 62 
9.4.2 
Pharmacokinetic Analysis ..................................................................................... 62 
9.4.3 
Safety Analysis ..................................................................................................... 62 
9.4.4 
Efficacy Analyses ................................................................................................. 63 
9.4.4.1 
Alive and Free of Respiratory Failure .................................................................. 63 
9.4.4.2 
Percent Change in C-reactive Protein ................................................................... 63 
9.4.4.3 
Time to Clinical Improvement on 9-point Ordinal Scale ..................................... 63 
9.4.5 
 and Exploratory Analysis ..................................................... 64 
9.5 
Interim Analyses ................................................................................................... 64 


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9.6 
Safety Review Committee .................................................................................... 64 
10 
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS ............................................................................................ 65 
11 
REFERENCES ................................................................................................... 100 
 
LIST OF FIGURES 
Figure 1 
Study Design ............................................................................................... 16 
 
LIST OF TABLES 
Table 1 
Schedule of Activities ................................................................................. 17 
Table 2 
Risks Associated with Acalabrutinib Monotherapy in Participants With 
Hematologic Malignancies (N = 1040) ....................................................... 26 
Table 3 
Objectives and Endpoints ............................................................................ 29 
Table 4 
Pharmacokinetic Sampling Relative to Start of Proton-pump Inhibitor 
Treatment .................................................................................................... 31 
Table 5 
Investigational Medicinal Products ............................................................. 36 
Table 6 
Acalabrutinib Use with Moderate CYP3A Inhibitors and Gastric 
Acid-reducing Agents ................................................................................. 41 
Table 7 
Guidelines for Acalabrutinib Dose Modification or Discontinuation ......... 42 
Table 8 
9-point Category Ordinal Scale ................................................................... 48 
Table 9 
Populations for Analysis ............................................................................. 61 
Table D10 
Hy’s Law Laboratory Kit for Central Laboratories .................................... 81 
Table E11 
CYP3A Inhibitors ........................................................................................ 83 
Table E12 
CYP3A Inducers ......................................................................................... 83 
Table E13 
Other Drugs Needing Additional Considerations ....................................... 84 
Table F14 
Highly Effective Methods of Contraception (<1% Failure Rate) ............... 87 
Table G15 
Child-Pugh Classification of Cirrhosis Severity ......................................... 88 
Table H16 
Proton-pump Inhibitor Doses Relating to Evidence Synthesis and 
Recommendations in the Original Guideline (CG17; 2004) ....................... 89 
Table H17 
Proton-pump Inhibitors Allowed in Intensive Care Unit ............................ 89 
 
LIST OF APPENDICES 
Appendix A 
Regulatory, Ethical, and Study Oversight Considerations .......................... 66 


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Appendix B 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................... 71 
Appendix C 
Handling of Human Biological Samples ..................................................... 75 
Appendix D 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law .............................................................................. 77 
Appendix E 
Examples of Coadministered Drugs That Need Additional Consideration 83 
Appendix F 
Contraception Requirements ....................................................................... 85 
Appendix G 
Child-Pugh Score ........................................................................................ 88 
Appendix H 
Proton-pump Inhibitor Equivalence Table .................................................. 89 
Appendix I 
Abbreviations .............................................................................................. 91 
Appendix J 
Protocol Amendment History ..................................................................... 94 
 


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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title  
An Open-label, Multiple-dose Study to Evaluate the Pharmacokinetics, and Safety and 
Tolerability of Acalabrutinib Suspension Delivered via Nasogastric Tube, Coadministered 
With a Proton-pump Inhibitor, in Participants Hospitalized With COVID-19 
Short Title 
Study of Acalabrutinib Suspension Delivered via Nasogastric Tube With a Proton-pump 
Inhibitor in Hospitalized COVID-19 Participants  
Rationale 
This study is being conducted to support the ongoing clinical development of acalabrutinib 
(CALQUENCE®)1 in hospitalized COVID-19 patients. Because many COVID-19 patients 
may be unable to swallow capsules due to respiratory failure (eg, they may require 
endotracheal intubation for ventilator support and NG tube placement), it is important to have 
a clinically acceptable method to administer acalabrutinib (capsules) via NG tube. 
Furthermore, due to the acute illness of COVID-19 patients, many hospitalized patients are 
placed on high doses of PPIs or continuous H2-receptor antagonists to prevent stress ulcers. 
This study is designed to determine the PK, and safety and tolerability of acalabrutinib 
suspension, when coadministered with a PPI, in participants with confirmed SARS-CoV-2 
infection requiring hospitalization due to respiratory failure (as defined in the table below) 
attributable to COVID-19 pneumonia and who have an NG tube in place. 
Objectives and Endpoints 
Objective 
Endpoint/Variable 
Primary Objectives 
Primary Endpoints/Variables 
• 
To characterize the PK of acalabrutinib and its 
active metabolite (ACP-5862) following 
administration of acalabrutinib suspension, when 
coadministered with a PPI, in participants with 
COVID-19 
• 
Primary PK parameters for acalabrutinib and 
ACP-5862 include AUC12h, AUClast, and Cmax. 
Additional PK parameters are described in the 
protocol. 
• 
To assess the safety and tolerability of 
acalabrutinib suspension in participants with 
COVID-19 when administered in the presence of 
PPIs and BSC 
• 
Type, frequency, severity, and relationship to 
study intervention of any treatment-emergent 
AEs or abnormalities of laboratory tests, SAEs, 
or AEs leading to discontinuation of study 
intervention  
 
1 CALQUENCE® is a trademark of the AstraZeneca group of companies. 


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Objective 
Endpoint/Variable 
Secondary Objective 
Secondary Endpoints/Variables 
• 
To evaluate the preliminary efficacy of adding 
acalabrutinib suspension to BSC for treatment of 
participants with COVID-19 
• 
Proportion of participants alive and free of 
respiratory failure at Days 14 and 28 
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 ≥ 0.5) 
◦ 
Noninvasive positive pressure ventilation or 
continuous positive airway pressure  
◦ 
Extracorporeal membrane oxygenation 
• 
Percent change from baseline in CRP (time 
frame: baseline, Days 3, 5, 7, 14, 28) 
• 
Time to improvement defined as time to clinical 
improvement of ≥ 2 points (from first dose date) 
on a 9-point category ordinal scale, live 
discharge from the hospital, or considered fit for 
discharge (a score of 1 or 2 on the ordinal scale), 
whichever comes first, by Day 28 
Exploratory Objectives 
Exploratory Endpoints/Variables 
 
Overall Design 
This is an open-label, multi-dose study to evaluate the PK, and safety and tolerability of 
acalabrutinib suspension, when coadministered with a PPI, in participants with confirmed 
SARS-CoV-2 infection requiring hospitalization due to respiratory failure (as defined in the 
table above) attributable to COVID-19 pneumonia and who have an NG tube in place. 
Approximately 20 participants will be included to ensure at least 16 participants are evaluable. 
Participants are considered evaluable if they have an evaluable PK profile, ie: (1) complete PK 
Visit 2 assessments; (2) receive active treatment; and (3) do not have unavailable or 


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incomplete data that may influence the PK analysis. 
In addition to receiving BSC, participants will receive acalabrutinib suspension (ie, 
acalabrutinib 100 mg suspension in COCA-COLA® delivered via NG tube) bid for 14 days (a 
maximum of 28 doses). Best supportive care is per discretion of the Investigator and 
institutional guidelines. Standard NG tubes supplied by the hospital will be used. Nasogastric 
tube placement in the stomach will be confirmed by chest x-ray.  
To assess the effect of PPIs, all participants must be receiving treatment with a PPI at the start 
of the study. Treatment with a PPI can begin at any time prior to enrollment, provided 
participants have received PPI treatment for at least 24 hours prior to the first dose of 
acalabrutinib suspension. Any PPI is permitted, provided it meets the minimum equivalent 
daily dose of 20 mg rabeprazole. Participants must be on this dosage of PPI at the start of the 
study. They may be weaned off PPIs during the study if medically appropriate. 
Blood samples for plasma PK assessment of acalabrutinib and its metabolite (ACP-5862) will 
be collected at pre-dose and 0.5, 1, 2, 4, 6, and 12 hours following treatment with 
acalabrutinib suspension as described in the table below. Note that the sample at 12 hours 
must be collected prior to the subsequent acalabrutinib dose (for trough PK sample). 
PK Visit 
Description 
Rationale 
PK Visit 1 
First PK sampling will occur on Day 1 (ie, first dosing 
day for acalabrutinib suspension) 
Allows an early assessment of 
acalabrutinib and ACP-5862 PK in 
participants receiving acalabrutinib 
suspension via NG tube 
PK Visit 2 
Second PK sampling will occur a minimum of 4 days 
after the start of PPI treatment, irrespective of the 
timing of NG tube placement and any time after 
2 doses of acalabrutinib suspension have been given 
(ie, PK sampling can begin prior to the third dose, or 
anytime thereafter) 
PK Visit 2 can occur as early as Day 2 (if participant 
has been on a PPI for ≥ 4 consecutive days prior to 
receiving the third acalabrutinib dose), and up to Day 
4 (if participant initiated PPI treatment 24 hours prior 
to receiving the first dose of acalabrutinib on Day 1) 
PPI exposure must occur for 
4 consecutive days to reach the 
maximum PPI on-target effect 
PK sample can commence at any 
point after the second dose of 
acalabrutinib suspension to ensure 
steady-state levels of the active 
metabolite and maximal 
has been reached 
PK Visit 3 
Third PK sampling will occur 3 days after PK Visit 2, 
OR on the last day the participant receives 
acalabrutinib treatment, whichever comes first 
Allows an additional opportunity 
to assess the steady-state PK of 
acalabrutinib and ACP-5862 PK 
following delivery of acalabrutinib 
suspension via NG tube 
 
Safety assessments, including AE reporting, will be performed through 28 (± 3) days after the 
last dose of the acalabrutinib suspension. 


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Disclosure Statement 
This is a single-arm, treatment study that is not blinded. 
Number of Participants 
Approximately 20 participants will be enrolled to have at least 16 evaluable participants.  
Note: “Enrolled” means a participant’s, or his/her legally acceptable representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process. Potential participants who are screened for the purpose of determining eligibility for 
the study but are not randomly assigned/assigned in the study, are considered “screen 
failures”, unless otherwise specified by the protocol.  
Intervention Groups and Duration 
Treatment with acalabrutinib suspension (ie, acalabrutinib 100 mg suspension in 
COCA-COLA delivered via NG tube) will be initiated on Day 1. All participants must have 
received PPI treatment for at least 24 hours prior to the first dose of acalabrutinib suspension. 
All participants will receive acalabrutinib suspension bid, approximately 12 hours apart, for 
14 days (a maximum of 28 doses). The acalabrutinib suspension must be prepared according 
to the Handling Instructions. 
Safety Review Committee 
An SRC will be established to conduct scheduled reviews of safety and other relevant data, 
enable early identification of safety signals in the study, and minimize the risk to participants 
during the study, in accordance with the SRC charter (see Section 9.6 for details). 
Statistical Methods 
Pharmacokinetics 
A listing of PK blood sample collection times as well as derived sampling time deviations will 
be provided. Plasma acalabrutinib and ACP-5862 concentrations and PK parameters listed 
below will be summarized using appropriate descriptive statistics. 
• 
Primary PK parameters: AUC12h, AUClast, and Cmax. 
• 
Secondary PK parameters: t1/2, tmax, and λz (acalabrutinib and ACP-5862); CL/F and Vz/F 
(acalabrutinib); and Cmax, AUClast, and AUC12h (metabolite to parent ratio). 
 
Safety 
Safety assessments will consist of monitoring and recording of AEs, SAEs, and AEs leading to 
discontinuation of study intervention; measurement of protocol-specified vital signs, ECG, 
laboratory variables and other protocol-specified safety tests or measurements. All safety 


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analyses will be performed on the Safety Analysis Set. Verbatim descriptions of AEs will be 
mapped according to the latest version of MedDRA and graded according to NCI CTCAE 
v5.0 or higher. Treatment-emergent AEs will be summarized, unless otherwise specified. 
Treatment-emergent AEs are defined as AEs starting or ongoing AEs worsening after the first 
dose of study intervention and AEs with start date up to the last dose of study intervention plus 
28 (± 3) days. 
Efficacy 
All efficacy analyses will be performed on the Efficacy Evaluable Set. For the proportion of 
participants alive and free of respiratory failure at Days 14 and 28, point estimates and their 
90% confidence intervals will be calculated. Summary statistics (n, mean, median, standard 
deviation, minimum, and maximum) will be presented for the percent change from baseline in 
CRP at the specified time points. Time to improvement defined as time to clinical 
improvement of at least 2 points (from first dose date) on a 9-point category ordinal scale, live 
discharge from the hospital, or considered fit for discharge (a score of 1 or 2 on the ordinal 
scale), whichever comes first, by Day 28 (this will also define the “responder” for the 
response rate analyses), will be analyzed using the Kaplan-Meier method. 
1.2 
Schema 
The study design is illustrated in Figure 1. 


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Figure 1 
Study Design 
 
 
a 
Blood samples for plasma PK assessment of acalabrutinib and its metabolite (ACP-5862) will be collected at pre-dose 
and 0.5, 1, 2, 4, 6, and 12 hours following treatment with acalabrutinib suspension. Note that the sample at 12 hours 
must be collected prior to the subsequent acalabrutinib dose (for trough PK sample). 
Note: PK Visit 2 can occur as early as Day 2 (if participant has been on a PPI for ≥ 4 consecutive days prior to receiving the 
third acalabrutinib dose), and up to Day 4 (if participant initiated PPI treatment 24 hours prior to receiving the first dose of 
acalabrutinib on Day 1). See Table 4 for more information. 
bid = twice daily; PK = pharmacokinetic(s); PPI = proton-pump inhibitor. 
 
1.3 
Schedule of Activities 
The SoA for the study is presented in Table 1. 
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Day
Scenario 1
PPI Start
Scenario 1 
PK Visit 1a
Acalabrutinib treatment
(100 mg bid [~12 h apart] x 14 days [a maximum of 28 doses])
-2
-3
-4
Scenario 1 
PK Visit 2a
Scenario 1 
PK Visit 3a
Scenarios of PK 
visits relative to 
PPI start
PPI Dosing Starts
(≥24 h prior to first 
acalabrutinib dose)
PK Visit 1a
(coincides with 
Day 1 of study)
PK Visit 2a
(≥4 d after start of PPI 
and any time after 2 
doses of acalabrutinib)
PK Visit 3a
(3 days after PK Visit 2 
or on last day of 
acalabrutinib treatment)
Scenario 1
(shown in figure)
Day -1
Prior to first 
acalabrutinib dose
Day 3 
(prior to fifth dose)
Day 6 
(prior to 11th dose)
Scenario 2
Day -2
Prior to first 
acalabrutinib dose
Day 2 
(prior to third dose)
Day 5
(prior to ninth dose)
Scenario 3
Day -3
Prior to first 
acalabrutinib dose
Day 2 
(prior to third dose)
Day 5
(prior to ninth dose)
Scenario 4
Day -4 or earlier
Prior to first 
acalabrutinib dose
Day 2 
(prior to third dose)
Day 5
(prior to ninth dose)


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Table 1 
Schedule of Activities 
Assessments 
Screening 
(Day -3 to  
Day -1 n) 
Daily until hospital 
discharge 
Day 14 or 
discharge f 
Day 20  
(±3 days) 
after first 
dose 
Day 28 
(±3 days) 
after first 
dose 
Safety follow-up 
28 (±3) days after 
last dose of 
acalabrutinib g,h 
Details in 
CSP 
section 
Informed consent 
X 
 
 
 
 
 
A 3 
Demography 
X 
 
 
 
 
 
5.4 
Determine eligibility 
X 
 
 
 
 
 
5.1, 5.2 
Medical history and COVID-19 
epidemiology 
X 
 
 
 
 
 
8.2.1 
Physical examination (symptom driven, 
including lung auscultation), height, 
weight 
X 
 
 
 
 
 
8.2.2 
Chest imaging 
X r 
As clinically indicated 
 
 
 
 
8.2.2 
Electrocardiogram 
X n 
As clinically indicated 
X 
 
 
 
8.2.4 
Echocardiogram 
As clinically 
indicated 
As clinically indicated 
 
 
 
 
8.2.4 
Pulmonary assessments (oxygen usage, 
ventilator parameters) 
X 
X 
X 
 
X 
 
8.1.1 
Clinical assessments (mSOFA)  
X 
Day 3, 5, 7, and 10 
X 
 
 
 
8.1.2.1 
9-point category ordinal scale 
X 
X 
X 
 
X 
 
8.1.1.2 
Vital signs (blood pressure, respiratory 
rate, pulse oximetry, heart rate, and body 
temperature) 
X s 
X 
 
X 
X 
 
8.2.3 
Arterial blood gases p 
X 
X 
X 
 
X 
 
8.1.1.1, 
8.2.3 
Local laboratory assessments: 
Urine or serum pregnancy test (for 
WOCBP only) 
X 
 
 
X 
 
X 
8.2.5.1 
Hematology b 
X 
X 
X 
X 
X 
X 
8.2.5.1 
Serum or plasma chemistry c 
X 
X 
X 
X 
X 
X 
8.2.5.1 
Hepatitis B and C testing d 
X 
As clinically indicated 
 
 
 
As clinically 
indicated 
8.2.5.1, 
8.2.5.1.1 


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Table 1 
Schedule of Activities 
Assessments 
Screening 
(Day -3 to  
Day -1 n) 
Daily until hospital 
discharge 
Day 14 or 
discharge f 
Day 20  
(±3 days) 
after first 
dose 
Day 28 
(±3 days) 
after first 
dose 
Safety follow-up 
28 (±3) days after 
last dose of 
acalabrutinib g,h 
Details in 
CSP 
section 
Fibrinogen o 
X 
qod 
 
 
 
 
8.2.5.1 
PT, aPTT, and INR o 
X 
qod 
 
 
 
 
8.2.5.1 
D-dimer o 
X 
qod 
X 
 
X 
 
8.2.5.1 
CRP 
X 
X 
X 
 
X 
 
8.2.5.1 
Cardiac troponin I o  
X 
qod 
 
 
 
 
8.2.5.1 
SARS-CoV-2 RT-PCR virus testing for 
eligibility e 
X 
 
 
 
 
 
8.2.5.1 
Central laboratory assessments: q 
Acalabrutinib PK i,k 
 
Pre-dose and 0.5, 1, 2, 4, 
6, and 12 hoursj post-dose 
(on PK Visit 1,  
PK Visit 2, and PK 
Visit 3i) 
 
 
 
 
4.1, 8.5.1 
Acalabrutinib administration 
 
bid (q12h) × 14 days 
(maximum) 
 
 
 
 
6.1.2 
Adverse events 
X 
X 
X 
X 
X 
Xh 
8.3 
Concomitant medications 
X 
X 
X 
X 
X 
Xh 
NA 
Survival status 
 
 
X 
X 
X 
Xh 
NA 


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Table 1 
Schedule of Activities 
Assessments 
Screening 
(Day -3 to  
Day -1 n) 
Daily until hospital 
discharge 
Day 14 or 
discharge f 
Day 20  
(±3 days) 
after first 
dose 
Day 28 
(±3 days) 
after first 
dose 
Safety follow-up 
28 (±3) days after 
last dose of 
acalabrutinib g,h 
Details in 
CSP 
section 
a 
Pre-dose. 
b 
Hematology: complete blood count with differential includes, but not limited to white blood cell count, hemoglobin, platelet count, absolute neutrophil count or 
percentage, red blood cell count, absolute monocyte count or percentage, and absolute lymphocyte count or percentage.  
c 
Serum or plasma chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bicarbonate, blood urea nitrogen, calcium, chloride, 
creatinine, glucose, lactate dehydrogenase, 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. Participants can be 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 first dose administration. Follow the hepatitis serology guidelines described in Section 8.2.5.1.1. 
e 
Hospitalized with coronavirus (SARS-CoV-2) infection, confirmed by PCR test or other commercial or public health assay in any specimen, as documented by either of 
the following: 1) PCR positive in sample collected < 72 hours prior to first dose; OR 2) PCR positive in sample collected ≥ 72 hours prior to first dose (but no more than 
14 days prior to first dose), documented inability to obtain a repeat sample (eg, due to lack of testing supplies, limited testing capacity, results taking > 24 hours, etc), 
AND progressive disease suggestive of ongoing SARS-CoV-2 infection. 
f 
If a participant is discharged prior to Day 14, he/she needs to visit the site for an assessment 2 to 4 days after discharge. Assessments should match those for Day 14. 
g 
All participants should have follow-up assessments for safety 28 (± 3) days after the last dose of acalabrutinib.   
h 
Telemedicine is recommended for capturing adverse events, concomitant medications, and survival status. 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. 
i 
PK Visit 1: PK sampling will occur on Day 1 (ie, first dosing day for acalabrutinib suspension). 
PK Visit 2: PK sampling can occur as early as Day 2 (if participant has been on a PPI for ≥ 4 consecutive days prior to receiving the third acalabrutinib dose), and up to 
Day 4 (if participant initiated PPI treatment 24 hours prior to receiving the first dose of acalabrutinib on Day 1). See Section 4.1 for additional details. 
PK Visit 3: PK sampling will occur 3 days after PK Visit 2, OR on the last day the participant receives acalabrutinib treatment, whichever comes first. 
j 
PK sampling will occur at pre-dose and 0.5 (± 5 min), 1 (± 5 min), 2 (± 15 min), 4 (± 15 min), 6 (± 15 min), and 12 (± 60 min) hours post-dose, 
 sampling will 
occur at pre-dose and 4 (± 15 min) and 12 (± 60 min) hours post-dose. The 12-hour post-dose PK 
 samples will be collected immediately prior to administration of 
the subsequent acalabrutinib dose. 
k 
The timing of PK 
 sample collections should be aligned as closely as possible and will be prioritized over other blood samples being collected simultaneously, 
except in the case of an adverse event for which relevant assessment/blood sample collection will be prioritized.  
l 
 
m 
 
n 
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.  
o 
Fibrinogen, PT, aPTT, INR, D-dimer, and cardiac troponin I should be performed more frequently if clinically indicated. 


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Table 1 
Schedule of Activities 
Assessments 
Screening 
(Day -3 to  
Day -1 n) 
Daily until hospital 
discharge 
Day 14 or 
discharge f 
Day 20  
(±3 days) 
after first 
dose 
Day 28 
(±3 days) 
after first 
dose 
Safety follow-up 
28 (±3) days after 
last dose of 
acalabrutinib g,h 
Details in 
CSP 
section 
p 
Arterial blood gases should be collected from participants if the sample is easily accessible and the procedure will not be painful to participants (ie, participant is in ICU or 
has arterial port). All available data from the arterial blood gases should be entered into the database. If the collection of arterial blood gases is not clinically indicated, the 
test should not be performed. 
q 
For all central laboratory assessments, sample collection windows of ± 1 day will be allowed for each of Days 4, 7, and 10. 
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 enrollment). 
s 
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 intervention should be used. 
anti-HBc = antibody to hepatitis B core antigen; aPTT = activated partial thromboplastin time, bid = twice daily; COVID-19 = coronavirus disease 2019; CRP = C-reactive 
protein; CSP = Clinical Study Protocol; CT = computed tomography; ECG = electrocardiogram; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; 
HCV = hepatitis C virus; ICU = intensive care unit; INR = international normalized ratio; mSOFA = modified Sequential Organ Failure Assessment; NA = not applicable; 
 PCR = polymerase chain reaction; 
 PK = pharmacokinetics; PPI = proton-pump inhibitor; 
PT = prothrombin time; qod = every other day; q12h = every 12 hours; 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. 
 


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2 
INTRODUCTION 
Acalabrutinib is a BTK inhibitor that is being developed for the treatment of hospitalized 
COVID-19 patients. 
2.1 
Study Rationale 
This study is being conducted to support the ongoing clinical development of acalabrutinib in 
hospitalized COVID-19 patients. Because many COVID-19 patients may be unable to 
swallow capsules due to respiratory failure (eg, they may require endotracheal intubation for 
ventilator support and NG tube placement), it is important to have a clinically acceptable 
method to administer acalabrutinib (capsules) via NG tube. Furthermore, due to the acute 
illness of COVID-19 patients, many hospitalized patients are placed on high doses of PPIs or 
continuous H2-receptor antagonists to prevent stress ulcers. This study is designed to 
determine the PK, and safety and tolerability of acalabrutinib suspension, when 
coadministered with a PPI, in participants with confirmed SARS-CoV-2 infection requiring 
hospitalization due to respiratory failure (as defined in Section 8.1.1.1) attributable to 
COVID-19 pneumonia and who have an NG tube in place. 
2.2 
Background 
2.2.1 
Coronavirus Disease 2019 
Coronavirus disease 2019 is a new pandemic disease caused by SARS-CoV-2, a novel 
coronavirus that originated from Wuhan, China. Most COVID-19 cases (~80%) are mild 
respiratory illnesses. However, moderate and severe COVID-19 cases require hospitalization 
and can progress quickly to severe acute lung injury and acute respiratory distress syndrome 
(Huang et al 2020, Zhou et al 2020), which can lead to death due to respiratory and cardiac 
failure. The death rate from COVID-19 across different populations range from 2.4% in China 
(updated data) to 7.2% in Italy (Livingston and Bucher 2020, Wu and McGoogan 2020), with 
the highest rate reported among older patients and those who are immunocompromised or 
have other comorbidities or lymphocytopenia (Guan et al 2020b, Livingston and Bucher 2020, 
Onder et al 2020, Wang et al 2020). The mortality rate in critically ill patients with COVID-19 
(ie, those requiring mechanical ventilation) is nearly 50% (Wu and McGoogan 2020). 
In patients with severe COVID-19, SARS-CoV-2-induced cytokine storm or “hyperimmune 
response” is hypothesized to cause immunopathologic damage to the lungs by modulating 
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 IL-1β, IL-6, IL-8, IL-10, TNFα, and MCP-1 (Chen et al 2020, 
Herold et al 2015, Yoshikawa et al 2009). Other risk factors for severe COVID-19 illness 
include the presence of neutrophilia, organ dysfunction (elevated lactate dehydrogenase), 
coagulation abnormalities, thrombocytopenia, and lymphocytopenia, suggesting findings 


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observed in both hemophagocytic syndrome and immune deficiency (Guan et al 2020b, Lippi 
et al 2020, Wu et al 2020). 
2.2.2 
Bruton Tyrosine Kinase 
Bruton tyrosine kinase 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 engagement of the B-cell receptor has been well established (Buggy 
and Elias 2012). Bruton tyrosine kinase is also involved in Fc gamma receptor signaling in 
myeloid cells, mast cell degranulation, osteoclast differentiation, and TLR signaling in 
neutrophils. Bruton tyrosine kinase inhibition is associated with decreased proinflammatory 
cytokines in patients with hematologic malignancies and reduced severity of anti-CD20 
antibody-induced infusion reactions (Byrd et al 2016, Lujan et al 2020).  
Substantial clinical data exist implicating BTK activation in acute pulmonary injury mediated 
by macrophages and neutrophils and subsequent acute respiratory distress syndrome. Bruton 
tyrosine kinase activation has shown to be an essential component of lung injury induced by 
infectious pathogens, sepsis, and hemorrhagic lung injury that is mediated by excessive 
inflammatory macrophages and neutrophils (Krupa et al 2013, Krupa et al 2014, Zhou et al 
2014). Genetic knock down of BTK impaired this lung injury (Krupa et al 2014, Zhou et al 
2014). This has been confirmed in subsequent pharmacologic studies with the BTK inhibitor, 
ibrutinib. In the setting of murine pneumococcal pneumonia, ibrutinib has also been shown to 
negatively affect both monocyte and neutrophil influx into the lung and also alveolar 
macrophage activation, neutrophil influx, cytokine release and plasma leakage. Antibiotic-
mediated killing of bacteria was not impaired (de Porto et al 2019). A similar study, with 
seasonal influenza A virus demonstrated that intranasal administration of ibrutinib starting 
72 hours after lethal infection with influenza A diminished weight loss and led to improved 
overall survival (Hoerauf et al 1994). Moreover, ibrutinib treatment had a dramatic effect on 
morphological changes to the lungs, including decreased alveolar hemorrhage, interstitial 
thickening, and the presence of alveolar exudate concomitant with diminished inflammatory 
mediators (TNFα, IL-1β, IL-6, KC, and MCP-1). This murine study suggests BTK inhibition 
may represent a new immunomodulating treatment for virus-induced lung damage driven by 
excess inflammation (Florence et al 2018). Ibrutinib and other BTK inhibitors, such as 
acalabrutinib, may also have an added advantage at diminishing inflammation induced by 
macrophages and monocytes as shown by both genetic and pharmacologic studies in which 
this kinase regulates TLR4-activated expression of IL-6 or other pathways involving STAT 
(Gottar-Guillier et al 2011, Guryanova et al 2011, Palmer et al 2008). 
Together, these data support BTK inhibitors, such as acalabrutinib, to diminish the lung 
pathology mediated by SARS-CoV-2 and justify application of this approach for clinical 
investigation in patients with COVID-19.  


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2.2.3 
Acalabrutinib 
Acalabrutinib is an imidazopyrazine analogue with a molecular weight of 465.5 g/mol. The 
compound has 1 stereogenic center, and acalabrutinib is the S-enantiomer. Acalabrutinib is a 
potent, highly selective covalent inhibitor of BTK (Covey 2015). Acalabrutinib is formulated 
as a capsule. For clinical testing, acalabrutinib has been manufactured and formulated 
according to current Good Manufacturing Practices. 
Acalabrutinib is currently approved in the United States for the treatment of adult patients 
with mantle cell lymphoma who have received at least 1 prior therapy, and CLL or small 
lymphocytic lymphoma (CALQUENCE 2019).  
2.2.3.1 
Nonclinical Experience 
In vitro and in vivo safety pharmacology and in vivo toxicology studies with acalabrutinib 
have demonstrated a favorable nonclinical safety profile. For detailed information on 
nonclinical safety of acalabrutinib, refer to the IB and the prescribing information 
(CALQUENCE 2019). 
2.2.3.2 
Clinical Experience 
As of 30 October 2019, acalabrutinib has been administered to more than 3300 participants in 
clinical studies, including participants with hematologic malignancies, solid tumors, or 
rheumatoid arthritis, and participants who are healthy or those with mild to moderate hepatic 
impairment. No SAEs have been reported in the hepatic impairment trial or in the healthy 
subject trials. Some participants with CLL have been receiving acalabrutinib therapy for more 
than 5 years. Acalabrutinib has been administered as monotherapy and in combination with 
other kinase inhibitors, anti-CD20 antibodies, chemoimmunotherapy (eg, 
bendamustine/rituximab), and an anti-programmed cell death-1 antibody. No dose-limiting 
toxicities have been reported with acalabrutinib monotherapy or when administered in 
combination with the aforementioned agents. Current clinical safety data support combining 
acalabrutinib with other agents. 
Based on the safety profile of acalabrutinib to date, no overt toxicities have been identified 
that would preclude acute treatment of patients with moderate to severe COVID-19 
symptoms. Patients with hematologic malignancies treated with acalabrutinib have shown a 
significant reduction in several cytokines/chemokines, including pro-inflammatory markers 
such as: TNFα (p < 0.001), IL-10 (p < 0.001), MCP-1 (p < 0.01), MIP-1 beta (p < 0.001), 
MIP-1 alpha (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 2015), 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 


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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). 
For detailed information on the clinical safety and efficacy of acalabrutinib, refer to the IB and 
the prescribing information (CALQUENCE 2019). Risks associated with acalabrutinib are 
described in Section 2.3.1 and are based on events observed in participants with cancer who 
have been treated long-term with acalabrutinib 100 mg bid. 
2.2.3.3 
Metabolism and Transport 
Based on available nonclinical and clinical data, acalabrutinib is extensively and almost 
completely metabolized by multiple CYP and non-CYP metabolic pathways. 
CYP3A-mediated oxidation is the major route of metabolism in humans. 
Based on metabolite profiles from plasma and excreta of rat, dog, and human following an 
oral dose of [14C]-acalabrutinib, 3 primary metabolic pathways were identified: amide 
hydrolysis, resulting in loss of the 2-aminopyridine group; glutathione conjugation of the 
butynamide moiety; and hydroxylation, predominantly in the pyrrolidine ring. The most 
abundant circulating metabolite in human was ACP-5862, which was formed by 
CYP3A-mediated oxidation. 
ACP-5862 was the only human metabolite in plasma that accounted for more than 10% of 
total acalabrutinib-related material. Cytochrome P450-mediated metabolism of acalabrutinib 
and ACP-5862 are catalyzed primarily by CYP3A4/5. 
For details on the metabolism of acalabrutinib, refer to the IB and prescribing information 
(CALQUENCE 2019). 
2.2.3.4 
Effect of Raised Gastric pH on Acalabrutinib Bioavailability 
Due to the basic properties of acalabrutinib, the drug solubility is pH-dependent and clinical 
evaluation of acid-reducing agents has demonstrated that increased stomach pH would lead to 
reduced exposure. When acalabrutinib 100 mg is administered following once daily dosing of 
40 mg omeprazole (a PPI), there is a 42% reduction in AUC and a 73% reduction in Cmax as 
compared to when the drug is dosed in normal acidic pH conditions (Study ACE-HV-112). 
Currently, the use of PPIs (such as, omeprazole, esomeprazole or rabeprazole) while taking 
acalabrutinib is not recommended due to a potential decrease in acalabrutinib exposure. 
Recommendations regarding coadministration with H2-receptor antagonists and antacids are 
provided in the prescribing information (CALQUENCE 2019). Due to the acuity of 
COVID-19, many patients are placed on high-dose PPIs or continuous H2-receptor 


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antagonists to prevent stress ulcers. Moreover, many COVID-19 patients may already be 
taking an acid‐reducing agent for gastroesophageal reflux disease. Proton-pump inhibitors 
inhibit acid-producing pumps in the stomach and have a prolonged 
 effect that extends 
beyond 24 hours after administration. H2-receptor antagonists also reduce acid production by 
the stomach, but their acid‐reducing effect is not as prolonged as that of PPIs unless they are 
administered continuously. The findings of the current study will support the coadministration 
of acalabrutinib (delivered via NG tube) with a PPI. 
2.2.3.5 
Rationale for Developing an Acalabrutinib Suspension in COCA-COLA 
Given its pH-dependent solubility, acalabrutinib requires an acidic medium to dissolve rapidly. 
A readily and globally available diluent was researched that could allow dissolution of 
acalabrutinib. The microenvironmental pH of acalabrutinib was measured in COCA-COLA at 
4.36 (from a starting COCA-COLA pH of 2.49). At this pH, acalabrutinib solubility is of 
1.468 mg/mL. Therefore, nearly complete dissolution of acalabrutinib is expected in 100 mL 
COCA-COLA after a limited amount of time, compatible with extemporaneous preparation 
and nasogastric administration. Furthermore, in vitro dissolution data, simulating acalabrutinib 
in a gastric environment following treatment with acid-reducing agents such as PPIs and 
100  to 240 mL of (Pepin et al 2019a, Pepin et al 2019b), the anticipated exposure to 
acalabrutinib when 100 mg acalabrutinib capsules are dosed orally with 100 mL of 
COCA-COLA in participants taking acid-reducing agents, is not significantly different from 
the values observed when 100 mg acalabrutinib capsules are dosed with water in participants 
with an acidic stomach environment. 
Overall, these results suggest that developing a formulation of acalabrutinib in COCA-COLA 
could potentially allow for the co-administration of acalabrutinib with PPIs, by overcoming 
the effect of raised gastric pH on acalabrutinib bioavailability. 
This approach has been used to manage the PPI restriction for weak basic drugs such as 
erlotinib (van Leeuwen et al 2016) where administration with COCA-COLA significantly 
improved erlotinib bioavailability during concomitant use of esomeprazole. 
2.3 
Benefit-Risk Assessment 
More detailed information about the known and expected benefits and potential risks of 
acalabrutinib may be found in the IB and prescribing information (CALQUENCE 2019). 


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2.3.1 
Risk Assessment 
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 2 summarizes the risks associated with acalabrutinib (any grade, 
≥ Grade 3, and median time to first onset) based on 1040 participants with hematologic 
malignancies who received acalabrutinib monotherapy (data on file).  
Refer to Section 6.6 for acalabrutinib dose modification and toxicity management guidance. 
Table 2 
Risks Associated with Acalabrutinib Monotherapy in Participants 
With Hematologic Malignancies (N = 1040) 
Events 
Number (%) of participants 
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 malignancies 
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. 
 
2.3.1.1 
Hemorrhage 
Bleeding events, some fatal, including central nervous system, respiratory, and gastrointestinal 
hemorrhage, have been reported in participants treated with acalabrutinib. 
2.3.1.2 
Infections 
Serious infections, including fatal events, have been reported in participants treated with 
acalabrutinib (eg, aspergillosis). Participants should be monitored for signs and symptoms of 
infection and treated as medically appropriate. 


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2.3.1.3 
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. 
Hepatitis B virus reactivations are frequently reported in the setting of acalabrutinib treatment. 
Among 4053 participants across all clinical studies investigating acalabrutinib to date, 
9 participants had HBV reactivation (1 fatal, 8 non-serious) after a median duration of therapy 
of 248 days (range, 43 to 582 days). One participant experienced a serious Grade 4 event that 
subsequently resulted in liver failure and death. Participants who are 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 participant with a rising viral load (above 
lower limit of detection) should discontinue study intervention 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 participants who 
develop HBV reactivation. 
2.3.1.4 
Progressive Multifocal Leukoencephalopathy 
Across the acalabrutinib clinical development program, 2 participants with underlying 
malignancies 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. 
2.3.1.5 
Cytopenias 
Grade 3 or 4 events of cytopenias, including anemia, neutropenia, and thrombocytopenia have 
occurred in participants with underlying malignancies treated with acalabrutinib. Monitor 
blood counts as specified in the SoA (Table 1) and as medically appropriate. 
2.3.1.6 
Secondary Primary Malignancies 
Second primary malignancies, including non-skin carcinomas solid tumors and skin cancers, 
have been reported in participants with B-cell malignancies who have been treated with 
acalabrutinib. The most frequent secondary primary malignancy was skin cancer (squamous 
basal cell carcinoma of the skin). Participants should be monitored for signs and symptoms of 
malignancy. Participants who develop a malignancy should be managed according to 
institutional guidelines with diagnostic evaluations or as clinically indicated, and it may be 
necessary for participants to permanently discontinue study intervention. Continuation of 
acalabrutinib treatment should be discussed with the Study Physician. 


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2.3.1.7 
Atrial Fibrillation 
Monitor for symptoms of atrial fibrillation and atrial flutter (eg, palpitations, dizziness, 
syncope, chest pain, dyspnea), and obtain an ECG as clinically indicated. Participants with 
atrial fibrillation should be managed per institutional guidelines with supportive care and 
diagnostic evaluations or as clinically indicated. 
More detailed information about the known and expected benefits and potential risks of 
acalabrutinib may be found in the IB and prescribing information (CALQUENCE 2019). 
2.3.2 
Benefit Assessment 
The lack of established treatments and vaccines against the novel SARS-CoV-2 virus has 
driven major medical centers to an unprecedented overload, which has undoubtedly 
contributed to the mortality observed with COVID-19. The highest mortality rate (~50%) has 
been reported in critically ill patients (Wu and McGoogan 2020). 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 ICU use are also 
needed without delay. 
Significant evidence exists that in patients with severe respiratory problems, the immune 
system and inflammation contribute to disease severity. Macrophages and neutrophils are key 
to producing cytokines driving this inflammatory process. Recently, BTK inhibition has been 
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 lung homogenates (Florence et al 2018). Consistent with 
these findings, patients with hematologic malignancies treated with acalabrutinib have shown 
statistically significant decreases in TNFα (p < 0.001), IL-10 (p < 0.001), MCP-1 (p < 0.01) 
(Byrd et al 2016), and IL-6 (p < 0.05) (data on file), suggesting that BTK inhibition may 
represent a new immunomodulatory treatment for virally-induced lung damage driven by a 
hyperimmune response in patients with COVID-19. 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). 
Overall, strong nonclinical evidence and encouraging reports suggest targeting BTK may 
effectively reduce the morbidity and mortality associated with COVID-19 illness. 


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2.3.3 
Overall Benefit: Risk Conclusion 
Considering the measures taken to minimize risk to participants and limit the number of 
participants participating in this study, the risks associated with acalabrutinib are justified by 
the anticipated benefits that may be afforded to participants with confirmed SARS-CoV-2 
infection requiring hospitalization due to respiratory failure (as defined in Section 8.1.1.1) 
attributable to COVID-19 pneumonia and who have an NG tube in place. 
3 
OBJECTIVES AND ENDPOINTS 
The objectives and endpoints are listed in Table 3. 
Table 3 
Objectives and Endpoints 
Objective 
Endpoint/Variable 
Primary Objectives 
Primary Endpoints/Variables 
• 
To characterize the PK of acalabrutinib and its 
active metabolite (ACP-5862) following 
administration of acalabrutinib suspension, when 
co-administered with a PPI, in participants with 
COVID-19 
• 
Primary PK parameters for acalabrutinib and 
ACP-5862 include AUC12h, AUClast, and Cmax. 
Additional PK parameters are described in the 
protocol. 
• 
To assess the safety and tolerability of 
acalabrutinib suspension in participants with 
COVID-19 when administered in the presence of 
PPIs and BSC 
• 
Type, frequency, severity, and relationship to 
study intervention of any treatment-emergent 
AEs or abnormalities of laboratory tests, SAEs, 
or AEs leading to discontinuation of study 
intervention  
Secondary Objective 
Secondary Endpoints/Variables 
• 
To evaluate the preliminary efficacy of adding 
acalabrutinib suspension to BSC for treatment of 
participants with COVID-19 
• 
Proportion of participants alive and free of 
respiratory failure at Days 14 and 28 
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 ≥ 0.5) 
◦ 
Noninvasive positive pressure ventilation or 
continuous positive airway pressure  
◦ 
Extracorporeal membrane oxygenation 
• 
Percent change from baseline in CRP (time 
frame: baseline, Days 3, 5, 7, 14, 28) 
• 
Time to improvement defined as time to clinical 
improvement of ≥ 2 points (from first dose date) 
on a 9-point category ordinal scale, live discharge 
from the hospital, or considered fit for discharge 
(a score of 1 or 2 on the ordinal scale), whichever 
comes first, by Day 28 


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Table 3 
Objectives and Endpoints 
Objective 
Endpoint/Variable 
Exploratory Objectives 
Exploratory Endpoint/Variable 
AE = adverse event; AUClast = area under the concentration-time curve from time 0 to last measurable time point; BSC = 
best supportive care; 
 Cmax = maximum observed concentration; COVID-19 = coronavirus 
disease 2019; CRP = C-reactive protein; 
 
 PK = pharmacokinetic(s); PPI = proton-pump inhibitor; SAE = serious adverse 
event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; 
 
 
4 
STUDY DESIGN 
4.1 
Overall Design 
This is an open-label, multi-dose study to evaluate the PK, and safety and tolerability of 
acalabrutinib suspension, when coadministered with a PPI, in participants with confirmed 
SARS-CoV-2 infection requiring hospitalization due to respiratory failure (as defined in 
Section 8.1.1.1) attributable to COVID-19 pneumonia and who have an NG tube in place. 
Approximately 20 participants will be included to ensure at least 16 participants are evaluable. 
Participants are considered evaluable if they have an evaluable PK profile, ie: (1) complete PK 
Visit 2 assessments; (2) receive active treatment; and (3) do not have unavailable or 
incomplete data that may influence the PK analysis. 
In addition to BSC, participants will receive acalabrutinib suspension (ie, acalabrutinib 
100 mg suspension in COCA-COLA delivered via NG tube) bid for 14 days (a maximum of 
28 doses). Best supportive care is per discretion of the Investigator and institutional 
guidelines. Standard NG tubes supplied by the hospital will be used. Nasogastric tube 
placement in the stomach will be confirmed by chest x-ray.  
To assess the effect of PPIs, all participants must be receiving treatment with a PPI at the start 
of the study. Treatment with a PPI can begin at any time prior to enrollment, provided 
participants have received PPI treatment for at least 24 hours prior to the first dose of 
acalabrutinib suspension (Figure 1). Any PPI is permitted, provided it meets the minimum 
equivalent daily dose of 20 mg rabeprazole (Appendix H). Participants must be on this dosage 


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of PPI at the start of the study. They may be weaned off PPIs during the study if medically 
appropriate. 
Blood samples for plasma PK assessment of acalabrutinib and its metabolite (ACP-5862) will 
be collected at pre-dose and 0.5, 1, 2, 4, 6, and 12 hours following treatment with 
acalabrutinib suspension as described in Table 4 below and illustrated in Figure 1. Note that 
the sample at 12 hours must be collected prior to the subsequent acalabrutinib dose (for trough 
PK sample). 
Table 4 
Pharmacokinetic Sampling Relative to Start of Proton-pump Inhibitor 
Treatment 
PK Visit 
Description 
Rationale 
PK Visit 1 
First PK sampling will occur on Day 1 (ie, first dosing 
day for acalabrutinib suspension) 
Allows an early assessment of 
acalabrutinib and ACP-5862 PK in 
participants receiving acalabrutinib 
suspension via NG tube 
PK Visit 2 
Second PK sampling will occur a minimum of 4 days 
after the start of PPI treatment, irrespective of the 
timing of NG tube placement and any time after 
2 doses of acalabrutinib suspension have been given 
(ie, PK sampling can begin prior to the third dose, or 
anytime thereafter) 
PK Visit 2 can occur as early as Day 2 (if participant 
has been on a PPI for ≥ 4 consecutive days prior to 
receiving the third acalabrutinib dose), and up to 
Day 4 (if participant initiated PPI treatment 24 hours 
prior to receiving the first dose of acalabrutinib on 
Day 1) 
PPI exposure must occur for 
4 consecutive days to reach the 
maximum PPI on-target effect 
PK sample can commence at any 
point after the second dose of 
acalabrutinib suspension to ensure 
steady-state levels of the active 
metabolite and maximal 
  
  has been 
reached 
PK Visit 3 
Third PK sampling will occur 3 days after PK Visit 2, 
OR on the last day the participant receives 
acalabrutinib treatment, whichever comes first 
Allows an additional opportunity 
to assess the steady state PK of 
acalabrutinib and ACP-5862 PK 
following delivery of acalabrutinib 
suspension via NG tube 
 NG = nasogastric; PK = pharmacokinetic(s); PPI = proton-pump inhibitor. 
 
Safety assessments, including AE reporting, will be performed through 28 (± 3) days after the 
last dose of the acalabrutinib suspension. 
4.2 
Scientific Rationale for Study Design 
This open-label, multiple-dose study is intended to evaluate the PK, and safety and tolerability 
of acalabrutinib suspension delivered via NG tube, when coadministered with a PPI, to inform 
supportive care in COVID-19 patients. 
Since PK and safety assessments are the primary objectives of the study, an open-label design 
was selected. The study will be conducted in participants with confirmed SARS-CoV-2 
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attributable to COVID-19 pneumonia and who have an NG tube in place. 
4.3 
Justification for Dose 
The dose and regimen of acalabrutinib in this study is 100 mg bid (approximately every 
12 hours apart), which is consistent with the recommended dosing regimen of acalabrutinib 
for clinical use (CALQUENCE 2019). The dose of 100 mg acalabrutinib to be administered in 
this study in hospitalized COVID-19+ patients requiring ventilator support is not anticipated 
to exceed the acalabrutinib exposure or Cmax reported in patients with hematologic 
malignancies. Thus, based on the results from previous clinical studies in hematologic 
malignancies, the 100-mg dose should provide sufficient plasma exposure for the PK analysis 
of acalabrutinib and its active metabolite, ACP-5862. 
The 14-day treatment duration in this study was selected based on balancing the course of the 
illness and minimizing exposure to an immunosuppressive agent. 
4.4 
End of Study Definition 
The end of the study is defined as the last expected visit/contact of the last participant in the 
study. 
A participant is considered to have completed the study if he/she has completed his/her last 
scheduled procedure shown in the SoA (Table 1).  
All participants who discontinue study intervention 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, as outlined in Section 1.3. 
The study may be stopped if, in the judgment of the Sponsor, participants are placed at undue 
risk because of clinically significant findings. 
Refer to Appendix A 5 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. 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the criteria below apply. 
1. Participant or legally authorized representative must be able to understand the purpose and 
risks of the study and provide written informed consent and authorization to use protected 
health information (in accordance with national and local patient privacy regulations). 


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2. Male or female participants at least 18 years of age at the time of signing the informed 
consent. 
3. Participants who are hospitalized with coronavirus (SARS-CoV-2) infection, confirmed by 
PCR test or other commercial or public health assay in any specimen, as documented by 
either of the following: 
a) PCR positive in sample collected < 72 hours prior to first dose, OR 
b) PCR positive in sample collected ≥ 72 hours prior to first dose (but no more than 
14 days prior to first dose), documented inability to obtain a repeat sample (eg, due to 
lack of testing supplies, limited testing capacity, results taking > 24 hours, etc), AND 
progressive disease suggestive of ongoing SARS-CoV-2 infection. 
4. Evidence of respiratory failure attributable to COVID-19 pneumonia (documented 
radiographically) before enrollment where 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. 
5. Nasogastric tube or other types of oral or percutaneous gastric feeding tube; placement 
must be radiographically confirmed and expected to remain in place, as judged by the 
Investigator, for a minimum of 3 days after study enrollment.  
6. Has received treatment with PPIs (eg, omeprazole, esomeprazole, lansoprazole, 
dexlansoprazole, rabeprazole, or pantoprazole) for a minimum of 24 hours immediately 
prior to enrollment; any PPI will be permitted, provided it meets the minimum equivalent 
daily dose of 20 mg rabeprazole. 
7. Willing to follow contraception guidelines when discharged from the hospital 
(Appendix F). 
 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the criteria below apply. 
Medical Conditions 
1. Any serious and uncorrectable medical condition or abnormality of clinical laboratory 
tests that, in the Investigator’s judgment, precludes the participant’s safe participation in 
and completion of the study. 
2. Suspected uncontrolled active bacterial, fungal, viral, or other infection (besides infection 
with SARS-CoV-2). 


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3. In the opinion of the Investigator, progression to death is imminent and inevitable within 
the next 24 hours, irrespective of the provision of treatments. 
4. Current refractory nausea and vomiting, malabsorption syndrome, disease significantly 
affecting gastrointestinal function, resection of the stomach, extensive small bowel 
resection that is likely to affect absorption, symptomatic inflammatory bowel disease, 
partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as 
gastric bypass. 
5. Pregnant or breastfeeding. 
6. Uncontrolled or untreated symptomatic arrhythmias, myocardial infarction within the last 
6 weeks, or congestive heart failure (New York Heart Association Grade 3 or 4). 
Exception: Participants with controlled, asymptomatic atrial fibrillation during screening 
are allowed to enroll on study. 
7. History of stroke or intracranial hemorrhage within 2 months of study intervention. 
8. History of primary immunodeficiency, tuberculosis, PML, aspergillus or other invasive 
mold/fungal infection, or received organ or bone marrow transplantation within 6 months 
of enrollment. 
9. 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 participant who does not meet this criterion and for whom hepatitis serology 
data are not available prior to the first dose, can start treatment, 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 PCR and HCV RNA PCR) are collected 
prior to the first dose. Refer to guidance in Section 8.2.5.1.1 on how to manage viral 
hepatitis testing. 
10. Known human immunodeficiency virus with viral load and CD4 counts < 500 cells/mm3. 
11. Participants who are unable to undergo multiple venipunctures because of poor tolerability 
or lack of easy venous access. 
 
Laboratory Assessments 
12. Alanine aminotransferase, AST and/or TBL ≥ 3 × 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). 
13. Absolute neutrophil count < 500/µL at screening (per local laboratory). 


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14. Platelet count < 50,000/µL at screening (per local laboratory). 
15. Estimated creatinine clearance of < 10 mL/min calculated using the Cockcroft-Gault 
formula [(140age) × mass (kg)/(72 × creatinine mg/dL) multiply by 0.85 if female]. 
 
Prior/Concomitant Therapy 
16. Treatment with a strong CYP3A inhibitor (within 7 days before first dose of study 
intervention) or inducer (within 14 days before first dose of study intervention).  
17. Received BTK inhibitor within 7 days before enrollment. 
18. Requires or is receiving specific anticoagulation with warfarin or equivalent vitamin K 
antagonists (eg, phenprocoumon) within 7 days prior to enrollment. Other anticoagulants 
are permitted.  
19. Participants on dual antiplatelet and therapeutic/high-dose anticoagulant therapy (eg, 
aspirin and therapeutic/high doses of low-molecular-weight heparin are not allowed; 
however, aspirin and prophylactic/low doses of low-molecular-weight heparin are 
allowed). 
20. History of hypersensitivity (ie, allergic response) to active or inactive excipients of 
acalabrutinib or other BTK inhibitors. 
21. Known cytoreductive chemotherapy treatment within 14 days of enrollment. 
 
5.3 
Lifestyle Considerations 
Participants discharged from the hospital must follow the contraception requirements outlined 
in Appendix F. 
Restrictions relating to concomitant medications are described in Section 6.5.  
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials 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 participants should be assigned the same participant number as for the 
initial screening. 


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6 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol. 
6.1 
Study Intervention(s) Administered 
6.1.1 
Investigational Medicinal Products 
Details of the investigational medicinal products are provided in Table 5. 
Table 5 
Investigational Medicinal Products 
Intervention Name 
Acalabrutinib 
Acalabrutinib 
Type  
Drug 
Drug 
Formulation 
Suspension extemporaneously 
constituted from acalabrutinib 
capsules and 100 mL flat COCA-
COLA (see Handling Instructions) 
Capsulea 
Strength/concentration 
100 mg/100 mL 
100 mg 
Dosage level 
100 mg 
100 mg 
Route of administration 
Nasogastric 
Oral 
Regimen 
bid (multiple dose) 
bid (multiple dose) 
Use 
Experimental 
Experimental 
Sourcing 
Sponsor (AstraZeneca)b 
Sponsor (AstraZeneca) 
Former name/alias 
ACP-196 
ACP-196 
a 
Acalabrutinib capsules will only be taken orally if a participant is no longer intubated and can swallow pills during the 
treatment period. 
b 
Note: COCA-COLA will be supplied locally. 
bid = twice daily. 
 
The COCA-COLA needed to constitute the acalabrutinib suspension will be supplied locally 
and must meet the criteria below: 
• 
COCA-COLA original (minimum 250 mL countenance, bottles with caps). If cans are 
used instead, 200 to 500 mL bottles with caps are needed to degas the soda to avoid 
foaming. A volume of 100 mL of flat COCA-COLA is needed for the preparation of the 
100 mg acalabrutinib suspension. 
• 
Hard plastic or glass bottles of 200 to 500 mL capacity with screw caps to constitute the 
suspensions; preferably amber glass. 
 


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6.1.2 
Dosing Instructions and Duration 
6.1.2.1 
Dosing and Duration of Treatment 
Treatment with acalabrutinib suspension (ie, acalabrutinib 100 mg suspension in 
COCA-COLA delivered via NG tube) will be initiated on Day 1. All participants must have 
received PPI treatment for ≥ 24 hours prior to the first dose of acalabrutinib suspension. All 
participants will receive acalabrutinib suspension bid, approximately 12 hours apart, for 
14 days (a maximum of 28 doses). The acalabrutinib suspension must be prepared according 
to the Handling Instructions. NOTE: COCA-COLA contains glucose (5 g per 100 mL). Blood 
glucose levels of diabetic participants must be monitored as clinically indicated and blood 
glucose-lowering medications adjusted accordingly. 
Administration of acalabrutinib suspension should not occur within a 2-hour window before 
or after feeding or delivery of other drugs. Nasogastric tubing should be flushed with water 
prior to and after acalabrutinib suspension delivery according to the Handling Instructions. 
6.1.2.2 
Dosing of Participants Who are no Longer Intubated 
If a participant is no longer intubated and can swallow pills during the treatment period, the 
participant should continue taking acalabrutinib 100 mg capsules orally bid. Capsules should 
be swallowed intact. Acalabrutinib can be taken with or without food. 
• 
If a participant remains on a PPI and switches to taking capsules orally, 100 mg 
acalabrutinib capsules should be dosed orally with at least 100 mL of COCA-COLA.  
• 
If a participant is no longer taking a PPI and switches to taking capsules orally, 
acalabrutinib capsules should be taken with water. 
 
6.1.2.3 
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 14 days (a maximum of 28 doses).  
If the 3-hour dosing window is missed, the dose must be skipped on that day. Acalabrutinib 
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 AE or for any other reason, missed doses should 
be completed so the participant receives a maximum of 28 doses of acalabrutinib, even if this 
is beyond the 14-day dosing period.  
6.1.2.4 
Vomiting After Acalabrutinib Treatment 
If vomiting occurs after taking acalabrutinib, the participant should not retake acalabrutinib 
until the next scheduled dose. 


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6.1.2.5 
Discharged From Hospital Before Treatment Completion 
Participants who are discharged from the hospital before they have completed 14 days (a 
maximum of 28 doses) of acalabrutinib therapy must complete the remaining doses at home. 
They should adhere to their established dosing schedule. These participants must complete a 
drug dosing diary to be sent electronically to the study site. 
6.2 
Preparation/Handling/Storage/Accountability of Interventions 
6.2.1 
Preparation and Handling 
Refer to the Handling Instructions for the preparation and handling of acalabrutinib 
suspension in COCA-COLA delivered via NG tube to participants. 
6.2.2 
Storage and 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 IB for additional information regarding the drug product to be 
used in this study. 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labelled 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 intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Clinical Study Agreement.  
6.3 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study and blinding is not applicable. 


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6.4 
Study Intervention Compliance 
When participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date, and time if applicable, of dose 
administered in the clinic will be recorded in the source documents and recorded in the eCRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention.  
For participants who are discharged from the hospital before they have completed 14 days (a 
maximum of 28 doses) of acalabrutinib and must complete the remaining doses (capsules) at 
home, compliance with study intervention will be assessed via a drug dosing diary that must 
be sent electronically to the study site at each visit and documented in the source documents 
and eCRF. Deviation(s) from the prescribed dosage regimen should be recorded in the eCRF.  
A record of the number of acalabrutinib suspensions or capsules dispensed to and taken by 
each participant must be maintained and reconciled with study intervention and compliance 
records. Intervention start and stop dates, including dates for intervention delays and/or dose 
reductions will also be recorded in the eCRF. 
6.5 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements or other specific categories of interest) that the participant is 
receiving at the time of enrollment or receives during the study must be recorded along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
 
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy. 
The Investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical treatment phase of the study including the 
28-day follow-up period following the last dose of study intervention.  
Best supportive care should be entered as a concomitant medication in the eCRF. 
6.5.1 
Premedications 
All participants must be receiving treatment with a PPI at the start of the study. Treatment with 
a PPI can begin at any time prior to enrollment, provided participants have received PPI 


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treatment for at least 24 hours prior to the first dose of acalabrutinib suspension. Any PPI is 
permitted, provided it meets the minimum equivalent daily dose of 20 mg rabeprazole.   
Participants in the ICU may receive higher doses of PPI, and medications more appropriate for 
NG tube delivery, such as esomeprazole or lansoprazole. Higher doses of PPIs are allowed, if 
medically necessary. Please refer  to Appendix H for equivalency charts. 
If a participant no longer requires PPIs during the course of treatment, PPIs may be stopped. 
Please refer to treatment guidelines (Section 6.1.2) in such cases. 
Any other premedication prior to treatment with acalabrutinib suspension is not necessary, but 
steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) are 
allowed. 
6.5.2 
Permitted Concomitant Therapy 
Best supportive care for COVID-19 (per Investigator discretion and institutional guidelines) is 
required for all participants 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 
The medications listed below are prohibited in the study. 
Medications Prohibited Through Day 28 
Immunomodulatory drugs: Immunomodulatory drugs, intended as treatment for COVID-19 
but not considered standard of care according to local institutional guidelines, are prohibited 
in the study through Day 28. Participants who are taking immunomodulatory drugs for other 
medical conditions (eg, tocilizumab for rheumatoid arthritis) may continue with treatment 
upon discussion with the Study Physician.  
Medications Prohibited Through Day 14 
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). 
Concomitant administration with a strong inhibitor of CYP3A has the potential to increase 


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acalabrutinib exposure. Conversely, concomitant administration with a strong inducer of 
CYP3A has the potential to decrease exposure of acalabrutinib and could reduce efficacy. 
Therefore, the concomitant use of strong inhibitors or inducers of CYP3A (see Appendix E) 
should be avoided in the study. If a participant requires a strong CYP3A inhibitor or inducer 
while on treatment with acalabrutinib, acalabrutinib treatment must be discontinued. Refer to 
Section 6.5.4 for additional information on drugs with potential drug-drug interactions. 
Other BTK inhibitors: BTK inhibitors other than acalabrutinib are prohibited. 
Certain anticoagulants: Warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) 
are prohibited in the study. Participants 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).  
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 
 
 occupancy steady-state in target B-cell and monocytic populations. Therefore, 
the Sponsor recommends that all eligible participants with COVID-19 begin dosing with 
acalabrutinib 100 mg bid. The duration of acalabrutinib therapy will be limited to 14 days (a 
maximum of 28 doses). Table 6 provides guidance for participants taking moderate CYP3A 
inhibitors and acid-reducing agents while on study. Refer to Appendix E for a list of common 
CYP3A inhibitors/inducers and gastric acid-reducing medicines. 
Table 6 
Acalabrutinib Use with Moderate CYP3A Inhibitors and Gastric 
Acid-reducing Agents 
 
Coadministered 
Medicines 
Recommended Acalabrutinib Use 
CYP3A 
Inhibitor 
Moderate CYP3A 
inhibitor  
Monitor participants closely for adverse reactions if taking 
moderate CYP3A inhibitors. For participants 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 
H2-receptor antagonists 
Take acalabrutinib 2 hours before taking a H2-receptor 
antagonist.  
Antacids  
Separate dosing by ≥ 2 hours. 
 


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Gastric Acid-reducing Medications  
Acalabrutinib solubility decreases with increasing pH. Coadministration of acalabrutinib with 
an antacid (1 g calcium carbonate) decreased acalabrutinib AUC by 53% in healthy 
participants.  
If the participant has discontinued treatment with a PPI, but 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. 
Dose modification of acalabrutinib is not necessary when coadministered with antacids or an 
H2-receptor antagonist. 
Recommendations regarding coadministration with H2-receptor antagonists and antacids are 
provided in the prescribing information (CALQUENCE 2019). 
6.6 
Dose Modification 
In general, no acalabrutinib dose modification is required if a participant experiences a 
Grade 1 or Grade 2 AE. Acalabrutinib therapy should be modified or discontinued, however, 
for the AEs described in Table 7. 
Table 7 
Guidelines for Acalabrutinib Dose Modification or Discontinuation 
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 participant for infection, and begin antibiotic 
treatment per institutional guidelines 
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 


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Table 7 
Guidelines for Acalabrutinib Dose Modification or Discontinuation 
Event 
Acalabrutinib Dose Modification/Discontinuation 
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 to 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 
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 participant 
during any AE.  
Acalabrutinib 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 AE or for any other reason, missed 


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doses should be completed so the participant receives a maximum of 28 doses of 
acalabrutinib, even if this is beyond the 14-day dosing period.  
6.6.1 
Acalabrutinib Dose Modifications in Special Populations 
6.6.1.1 
Renal Impairment 
After administration of a single 100 mg radiolabeled acalabrutinib dose in healthy 
participants, 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 participants 
with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m2, as estimated by MDRD 
equation). Acalabrutinib PK and clinical safety has not been evaluated in participants 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, metabolized, and distributed. The plasma-protein binding is 
97.5% and is noncovalent (potentially dialyzable). However, acalabrutinib covalently binds to 
the target, BTK, and will not be dialyzable. As such, it is unlikely that a clinically meaningful 
lowering of total BTK occupancy in target cell populations will be impacted. If participants 
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. 
6.6.1.2 
Hepatic Impairment 
Acalabrutinib clinical safety has not been evaluated in patients with severe hepatic 
impairment. If acalabrutinib is administered to participants with hepatic impairment, monitor 
participants carefully for AEs and follow the recommended dose modifications in Table 7. 
The PK acalabrutinib in participants with hepatic impairment has been studied. Briefly, the 
AUC of acalabrutinib increased 1.9-fold in participants with mild hepatic impairment (Child-
Pugh class A), 1.5-fold in participants with moderate hepatic impairment (Child-Pugh class 
B), and 5.3-fold in participants with severe hepatic impairment (Child-Pugh class C) 
compared with participants with normal liver function. No clinically relevant PK difference in 
ACP5862 was observed in participants with severe hepatic impairment (Child-Pugh class C) 
compared with participants with normal liver function. No clinically relevant PK differences 
in acalabrutinib and ACP5862 were observed in participants with mild or moderate hepatic 
impairment (TBL ≤ ULN and AST > ULN, or TBL > ULN and any AST) relative to 
participants with normal hepatic function (TBL and AST within ULN). 
6.7 
Intervention After the End of the Study 
There is no intervention following the end of the study. 


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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention 
Participants may discontinue study intervention for the following reasons: 
• 
Positive HBsAg, HBV-DNA, or HCV-RNA test result after the first dose 
• 
Completed treatment 
• 
Pregnancy 
• 
Adverse event 
• 
Investigator’s decision 
• 
Participant withdrawal of consent from study 
• 
Decision by the Sponsor to terminate the study 
• 
Lost to follow-up 
• 
Death 
• 
Other 
 
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study. 
A participant that decides to discontinue study intervention will always be asked about the 
reason(s) and the presence of any AEs. The date of last intake of study intervention should be 
documented in the eCRF.  
Participants should have follow-up assessments for safety 28 (± 3) days after the last dose of 
acalabrutinib (whether due to discontinuation or completion of dosing) (see Table 1).  
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 
Participant Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, 
or administrative reasons. This is expected to be uncommon. 
Participants with a positive HBsAg, HBV-DNA, or HCV-RNA test result after the first dose 
will be withdrawn from the study. 


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A participant 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). 
At the time of withdrawal from the study, if possible, an Early Study Intervention 
Discontinuation visit should be conducted. If this visit occurs prior to Day 14, the Day 14 
schedule of assessments should be followed, and if it occurs between Days 14 and 28, the 
Day 28 schedule of assessments should be followed. See SoA (Table 1) for data to be 
collected on these days and for follow-up and any further evaluations that need to be 
completed. The participant will discontinue the study intervention and be withdrawn from the 
study at that time. 
If the participant 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 participant withdraws from the study, it should be confirmed if he/she is still agreeing for 
existing samples to be used consistent with the original consent. If he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
carried in line with what was stated in the informed consent and local regulation. The 
Investigator must document the decision on use of existing samples in the site study records 
and inform the Global Study Team. 
7.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• 
Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  


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• 
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomised, including 
those who did not get study intervention. Public sources may be searched for vital status 
information. If vital status is determined as deceased, this will be documented and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information. 
 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the SoA (Table 1). Protocol waivers 
or exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA 
(Table 1), is essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• 
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA (Table 1). 
 
8.1 
Efficacy and Clinical Assessments 
8.1.1 
Efficacy Assessments 
8.1.1.1 
Pulmonary Assessments to Evaluate Respiratory Failure 
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.  


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d) Extracorporeal membrane oxygenation. 
 
Arterial blood gases, and oxygen and ventilator use data will be captured to assess respiratory 
failure as described above.  
If a participant requires oxygen supplementation, data will be recorded, including method of 
oxygen supplementation, maximum daily flow rate and FiO2. 
If a participant requires mechanical ventilation, data will be recorded regarding whether 
ventilator weaning was attempted.  
For participants 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 participants on mechanical ventilation, an arterial blood gas (pH, PaO2, partial pressure of 
carbon dioxide, and FiO2 at the time the sample was obtained) 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 blood gasses should be collected from participants if the sample is easily accessible 
and the procedure will not be painful to participants (ie, participant is in the ICU or has 
arterial port). All available data from the arterial blood gases should be entered into the 
database. If the collection of arterial blood 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. 
Respiratory data will be used to evaluate the efficacy endpoints of proportion of participants 
alive and free of respiratory failure at Days 14 and 28. 
8.1.1.2 
Improvements on 9-point Category Ordinal Scale 
For the purposes of this study, the condition of each potential participant in the study will be 
assessed using a 9-point category ordinal scale in Table 8. Assessments will be performed as 
described in the SoA (Table 1). 
Table 8 
9-point Category Ordinal Scale 
Scale 
Description 
0 a 
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 


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Table 8 
9-point Category Ordinal Scale 
Scale 
Description 
4 
Hospitalized – mild disease, oxygen by mask or nasal prongs 
5 
Hospitalized – severe disease, non-invasive ventilation or high flow oxygen 
6 
Hospitalized – 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 
a 
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 participant needs to 
show an improvement of at least 2 points (from first dose) on this scale. Time to clinical 
improvement of 2 points will be assessed as a secondary endpoint. 
8.1.2 
Clinical Assessments 
8.1.2.1 
Modified Sequential Organ Failure Assessment Scores 
A modified Sequential Organ Failure Assessment 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 oxygen saturation/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. Assessments will be performed as described 
in the SoA (Table 1). 
8.2 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Table 1). 
8.2.1 
Medical History 
Collect and record the participant’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. 
8.2.2 
Physical Examinations and Chest Imaging 
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 enrollment). Post-treatment assessment will continue as clinically indicated. 
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(Table 1). 
8.2.3 
Vital Signs 
The vital signs to be collected are blood pressure, respiratory rate, pulse oximetry, heart rate, 
and body temperature. 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 intervention should be used. The oxygen-hemoglobin 
saturation of the blood will be assessed using standard pulse oximetry or by arterial blood gas 
for those participants who have an arterial blood gas obtained. 
Vital signs will be performed at time points specified in the SoA (Table 1). 
8.2.4 
Electrocardiograms and Echocardiograms 
A single 12-lead ECG will be done during the screening period and at Day 14 or upon 
discharge from the hospital. The ECG should be collected during the treatment period, as 
clinically indicated per SoA (Table 1). For all ECGs, details of rhythm, ECG intervals, and an 
overall evaluation will be recorded. 
An echocardiogram should be collected at screening or during the treatment period, as 
clinically indicated per SoA (Table 1). 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. 
8.2.5 
Clinical Safety Laboratory Assessments 
8.2.5.1 
Local Laboratory Tests 
The following laboratory tests will be done as specified in the SoA (Table 1) using the site’s 
local laboratories: 
• 
Hematology studies must include complete blood count with differential including, but 
not limited to white blood cell count, hemoglobin, platelet count, absolute neutrophil 
count or percentage, red blood cell count, absolute monocyte count or percentage, and 
absolute lymphocyte count or percentage.  
• 
Serum or plasma chemistry will include albumin, ALP, ALT, AST, bicarbonate, blood 
urea nitrogen, calcium, chloride, creatinine, glucose, lactate dehydrogenase, magnesium, 


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phosphate, potassium, sodium, TBL (direct and indirect bilirubin, if available), total 
protein, and uric acid.   
• 
Urine or serum pregnancy testing (women of childbearing potential only; Appendix F)  
• 
C-reactive protein 
• 
Fibrinogen, D-dimer* 
• 
Prothrombin time, aPTT, 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 8.2.5.1.1) 
• 
SARS-CoV-2 reverse transcriptase-polymerase chain reaction viral test. Sites should 
report this as positive/negative. 
*These laboratory tests should be performed more frequently than described in the SoA 
(Table 1), if clinically indicated. 
NOTE: Safety and CRP laboratory tests are considered Tier 1 and should not be missed. The 
site must follow the SoA. 
NB. In case a participant shows an AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, 
refer to Appendix D for actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law’. 
8.2.5.1.1 
Hepatitis Serology Guidelines 
If feasible, hepatitis serology data should be obtained prior to administration of the first dose. 
However, if not feasible, sites should proceed as described below. 
Participants must not meet Exclusion Criterion 9 (see Section 5.2):  
• 
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. 
 
Blood samples for all HBV and HCV serology tests, and for both HBV and HCV PCR tests 
must then be collected before administration of the first dose. 
• 
If results become available before administration of the first dose, participants with 
positive HBsAg, HBV-DNA, or HCV-RNA test results will be excluded and should be 
treated per institutional guidelines. 


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− 
Participants 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.  
− 
Participants who are HCV antibody positive will need to have a negative PCR. 
• 
If results are not available at the time of first dose administration, participants can be 
started on acalabrutinib. If any of the HBsAg, HBV-DNA, or HCV-RNA test results are 
positive after the first dose, the following must occur: 
− 
Discontinue further treatment with acalabrutinib. 
− 
Withdraw the participant from the study. 
− 
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. 
 
8.2.5.2 
Central Laboratory Tests 
Samples will be collected as specified in the SoA (Table 1) and sent to a central laboratory for 
the following laboratory tests: 
• 
Plasma samples for acalabrutinib/ACP-5862 PK  
 
NOTE: PK, 
 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 is provided in Appendix C. 
8.3 
Adverse Events and Serious 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. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative).  


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The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
Adverse events will be collected from the time of signature of the ICF through 28 (± 3) days 
after the last dose of study intervention. 
Serious adverse events will be recorded from the time of signing the ICF. 
If the Investigator becomes aware of an SAE with a suspected causal relationship to the study 
intervention that occurs after the end of the clinical study in a participant treated by him or 
her, the Investigator shall, without undue delay, report the SAE to the Sponsor. 
8.3.2 
Follow-up of AEs and SAEs 
Any AEs that are unresolved at the participant’s last AE an assessment 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 
participant with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
Adverse event variables 
The following variables will be collected for each AE: 
• 
Adverse event (verbatim) 
• 
The date and time when the AE started and stopped 
• 
The CTCAE grade and grade changes, with the date they changed 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the study intervention (yes or no) 
• 
Action taken with regard to study intervention 
• 
Outcome 
 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for SAE 
• 
Date Investigator became aware of SAE 
• 
Adverse event is serious due to 
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 


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• 
Date of death 
• 
Autopsy performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment to other medication 
 
8.3.3 Causality Collection 
The Investigator should assess causal relationship between study intervention 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 study intervention?’ 
For SAEs, causal relationship should 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. 
8.3.4 Adverse Events Based on Signs and Symptoms 
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘Have you/the child 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. 
8.3.5 Adverse Events Based on Examinations and Tests 
The results from the CSP mandated laboratory tests and vital signs will be summarized in the 
CSR.  
Deterioration as compared to baseline in protocol-mandated laboratory values and vital signs 
should therefore only be reported as AEs if they fulfil any of the SAE criteria, are the reason 
for discontinuation of treatment with the study intervention or are considered to be clinically 
relevant as judged by the Investigator (which may include but not limited to consideration as 
to whether treatment or non-planned visits were required or other action was taken with the 
study intervention, eg, dose adjustment or drug interruption).  
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 


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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. 
8.3.6 Hy’s Law 
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥ 3 × ULN together with TBL ≥ 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. 
8.3.7 Disease Progression 
Disease progression can be considered as a worsening of a participant’s condition attributable 
to COVID-19 pneumonia for which the study intervention 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, acute respiratory distress syndrome, sepsis, shock, 
multiorgan failure and death. 
8.3.8 Disease Under study 
Systemic symptoms of the disease under study are those that 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 study 
intervention. 
8.3.9 
Reporting of Serious Adverse Events 
All SAEs have to be reported, whether or not considered causally related to the study 
intervention, or to the study procedure(s). All SAEs will be recorded in the eCRF. 
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate Sponsor representatives within one day ie, immediately but no later than 
24 hours of when he or she becomes aware of it. 
The designated Sponsor representative works with the Investigator to ensure that all the 


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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 
representatives of any follow-up information on a previously reported SAE within 1 calendar 
day, ie, immediately but no later than 24 hours of when he/she becomes aware of it. 
For all studies except those utilizing medical devices, Investigator safety reports must be 
prepared for SUSARs 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 IB and will notify the IRB/IEC according to local requirements, if 
appropriate. 
Refer to Appendix B for further guidance on the definition of a SAE. 
8.3.10 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to the Sponsor, with the 
exception of any pregnancy that is discovered before the participant has received any study 
intervention. 
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. 
8.3.10.1 
Maternal Exposure 
If a participant becomes pregnant during the course of the study, study intervention should be 
discontinued immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study intervention 
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 
participant was discontinued from the study. 


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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 or she becomes aware of it. 
The designated Sponsor representative works with the Investigator to ensure that all relevant 
information is provided to the Sponsor Patient Safety data entry site within 1 or 5 calendar 
days for SAEs (see Section 8.3.9) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
8.3.10.2 
Paternal Exposure  
Male participants 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 participant’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 participant’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/IRB/ethics committee prior to use. 
8.3.11 
Medication Error 
If a medication error occurs during the course of the study, the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it. 
The designated Sponsor representative works with the Investigator to ensure that all relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow up Fatal/Life-
Threatening) or 5 (other serious initial and follow up) calendar days if there is an SAE 
associated with the medication error (see Section 8.3.11) and within 30 days for all other 
medication errors. 
The definition of a Medication Error can be found in Appendix B.  
8.3.12 
Adverse Events of Special Interest 
Adverse events of special interest are events of scientific and medical interest specific to the 
further understanding of the acalabrutinib safety profile and require close monitoring and 


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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 8.3.9. 
The following events are AESIs for participants receiving acalabrutinib and must be reported 
to the Sponsor expeditiously (see Section 8.3.9 for reporting instructions), irrespective of 
regulatory seriousness criteria or causality: 
• 
Ventricular arrhythmias (eg, ventricular extrasystoles, ventricular tachycardia, 
ventricular arrhythmia, ventricular fibrillation) 
 
8.4 
Overdose 
For this study, any dose of study intervention greater than the dose that was intended to be 
given will be considered an overdose. 
• 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module. 
• 
An overdose without associated symptoms is only reported on the Overdose eCRF 
module. 
 
If an overdose on an AstraZeneca study intervention occurs in the course of the study, the 
Investigator or other site personnel inform appropriate Sponsor representatives immediately, 
but no later than 24 hours of when he or she becomes aware of it. 
The designated Sponsor representative works with the Investigator to ensure that all relevant 
information is provided to the Sponsor Patient Safety data entry site within 1 or 5 calendar 
days for overdoses associated with an SAE (see Section 8.3.9) and within 30 days for all other 
overdoses. 
8.5 
Human Biological Samples 
Instructions for the collection and handling of biological samples will be provided in the study 
specific laboratory manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. Refer to Appendix C for further details on handling of 
human biological samples. 
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated.  
• 
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization or 
six months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
consented for future analyses.  


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− 
Pharmacokinetic samples may be disposed of or anonymised by pooling. Additional 
analyses may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method. Any results from such analyses may be 
reported separately from the CSR. 
 
The timing of PK 
 sample collections should be aligned as closely as possible and will 
be prioritized over other blood samples being collected simultaneously, except in the case of 
an AE for which relevant assessment/blood sample collection will be prioritized. 
8.5.1 
Pharmacokinetics 
Blood samples will be collected for the measurement of plasma concentrations of 
acalabrutinib and its metabolite, ACP-5862, as specified in the SoA (Table 1). Briefly, blood 
samples will be collected at 3 separate study visits at pre-dose and 0.5, 1, 2, 4, 6, and 12 hours 
post-dose. The 12-hour post-dose sample will be collected immediately prior to administration 
of the subsequent dose. The PK samples will be collected as described in Table 4. 
Samples may be collected at additional time points during the study if warranted and agreed 
upon between the Investigator and the Sponsor, eg, for safety reasons. The timing of sampling 
may be altered during the course of the study based on newly available data (eg, to obtain data 
closer to the time of peak or trough matrix concentrations) to ensure appropriate monitoring.  
Samples collected for analyses of plasma concentration of acalabrutinib and ACP-5862 may 
also be used to evaluate safety or efficacy aspects related to concerns arising during or after 
the study. 
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual. 
8.5.1.1 
Determination of Drug Concentration 
Samples for determination of drug concentration in plasma will be assayed by bioanalytical 
test sites operated by or on behalf of AstraZeneca, using an appropriately validated 
bioanalytical method. Full details of the analytical method used will be described in a separate 
Bioanalytical Report. 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report. 


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8.5.2 
8.5.3 
Immunogenicity 
No antidrug antibody samples will be collected in this study. 
8.6 
 
8.7 
Optional Genomics Initiative Sample 
Optional Genomics Initiative research is not applicable to this study. 
8.8 
Health Economics 
Health economics is not applicable to this study. 


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9 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
The primary objective of the study is to characterize the PK of acalabrutinib and its active 
metabolite (ACP-5862) and assess the safety and tolerability of acalabrutinib suspension when 
coadministered with a PPI in participants with COVID-19. There is no formal hypothesis 
testing for safety and efficacy endpoints. 
9.2 
Sample Size Determination 
A sample size of 16 evaluable participants with COVID-19 was chosen based on the desire to 
gain adequate information while exposing as few participants as possible to the study 
procedures and study intervention. Given the inherent variability in the COVID-19 patient 
population, broad inclusion and exclusion criteria, and possible variability in treatment 
duration and PPI usage, approximately 20 participants will be enrolled in the study in order to 
have at least 16 evaluable participants able to complete PK Visit 2 (allowing for ~25% 
dropout rate due to disease progression).  
Note: “Enrolled” means a participant’s, or his/her legally acceptable representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process. Potential participants who are screened for the purpose of determining eligibility for 
the study but are not randomly assigned/assigned in the study, are considered “screen 
failures”, unless otherwise specified by the protocol.  
9.3 
Populations for Analyses 
The analysis populations are defined in Table 9. 
Table 9 
Populations for Analysis 
Population/Analysis set 
Description 
PK Analysis Set 
The PK Analysis Set will include all participants who received ≥ 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.  
Safety Analysis Set 
The Safety Analysis Set will include all participants who received ≥ 1 dose 
of study intervention 
Efficacy Evaluable Set 
The Efficacy Evaluable Set will include all participants who received ≥ 1 
dose of study intervention 
ITT = intent to treat; PK = pharmacokinetic; 
 PPI = proton-pump inhibitor. 
 


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9.4 
Statistical Analyses 
The SAP will be finalized prior to database lock and will include a more technical and detailed 
description of the statistical analyses described in this section. This section summarizes the 
planned statistical analyses of the most important endpoints, including primary and key 
secondary endpoints. Additional statistical analyses other than those described in this section 
may be performed if deemed appropriate. 
9.4.1 
General Considerations 
For efficacy continuous endpoints, the baseline is defined as the last observation prior to the 
first dose of acalabrutinib suspension.  
No missing data imputation will be applied for efficacy analysis. 
For safety analysis, where individual data points are missing because of dropouts or other 
reasons, the data will be summarized based on reduced denominators. 
Sensitivity analysis may be done by excluding participants with significant protocol deviations 
as appropriate. 
9.4.2 
Pharmacokinetic Analysis 
A listing of PK blood sample collection times as well as derived sampling time deviations will 
be provided. Plasma acalabrutinib and ACP-5862 concentrations and PK parameters listed 
below will be summarized using appropriate descriptive statistics, which will be fully outlined 
in the SAP. 
• 
Primary PK parameters: AUC12h, AUClast, and Cmax. 
• 
Secondary PK parameters: 
− 
Acalabrutinib and ACP-5862: t1/2, tmax, and λz. 
− 
Acalabrutinib: CL/F and Vz/F. 
− 
Metabolite to parent ratio for Cmax, AUClast, and AUC12h. 
 
No formal statistical test will be conducted for the PK parameters. 
9.4.3 
Safety Analysis 
Safety assessments will consist of monitoring and recording of all AEs, SAEs, and AEs 
leading to discontinuation of study intervention, measurement of protocol-specified vital 
signs, ECG, laboratory variables, and other protocol-specified safety tests or measurements. 
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 MedDRA terms 


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and graded per NCI CTCAE, v5.0 or higher. Extent of exposure to study intervention, all AEs, 
SAEs, any AEs leading to study intervention discontinuation, and study intervention related 
AEs will be summarized. The frequency of AEs will be summarized by system organ class 
and preferred term per MedDRA and by the worst reported NCI CTCAE grade. Treatment-
emergent AEs will be summarized, unless otherwise specified. Treatment-emergent AEs are 
defined as AEs starting or ongoing AEs worsening after the first dose of study intervention 
and AEs with start date up to the last dose of study intervention plus 28 (± 3) days. 
Laboratory abnormalities will be defined based on laboratory normal ranges (universal normal 
ranges, if central laboratory). Selected laboratory parameters may be analyzed 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. 
9.4.4 
Efficacy Analyses  
All efficacy analyses will be performed on the Efficacy Evaluable Set. 
9.4.4.1 
Alive and Free of Respiratory Failure 
The proportion of participants alive and free of respiratory failure will be assessed at Days 14 
and 28. Point estimates and their 90% confidence intervals (using Wald method with 
continuity correction) will be calculated.  
Only the participant’s survival status and respiratory failure (as defined in Section 8.1.1.1) 
status on Days 14 and 28 will be considered for this endpoint. If they experience respiratory 
failure after enrollment but recover by Days 14 or 28, per the definition of respiratory failure, 
they will be considered alive and free of respiratory failure at these time points. 
9.4.4.2 
Percent Change in C-reactive Protein 
Summary statistics (n, mean, median, standard deviation, minimum, and maximum) will be 
presented for the percent change from baseline in CRP at Days 3, 5, 7, 14, and 28. Baseline is 
defined as the last observation prior to the first dose of acalabrutinib suspension. 
9.4.4.3 
Time to Clinical Improvement on 9-point Ordinal Scale  
Time to improvement defined as time to clinical improvement of at least 2 points (from first 
dose date) on a 9-point category ordinal scale, live discharge from the hospital, or considered 
fit for discharge (a score of 1 or 2 on the ordinal scale), whichever comes first, by Day 28 (this 
will also define the “responder” for the response rate analyses), will be analyzed using 
Kaplan-Meier method with Kaplan-Meier estimates and their 90% confidence intervals. If a 


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participant did not have an improvement and did not drop out prior to Day 28, the data will be 
censored at Day 28. If a participant did not have an improvement but dropped out prior to 
Day 28, the data will be censored at the last date known that without improvement.  
9.4.5 
and Exploratory Analysis 
9.5 
Interim Analyses  
There are no formal interim futility and interim efficacy analyses in this study. 
9.6 
Safety Review Committee 
This study will have an SRC. The SRC will conduct scheduled reviews of safety and other 
relevant data. In addition, The SRC will meet to review any of the following events should 
they occur during the study: 
• 
Any death due to acalabrutinib (per Investigator) 
• 
Any Grade 4 hemorrhage due to acalabrutinib (per Investigator) 
 
The SRC will consist of the AstraZeneca Study Physician or delegate, Principal Investigator 
or equivalent delegate from active investigational sites, and Global Safety Physician or 
delegate. Other attendees may also be invited as appropriate.  
Details on the process of ongoing evaluation of safety data by the SRC and the committee 
composition is described further in the SRC charter. 


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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
 


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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 International Ethical Guidelines 
− 
Applicable ICH GCP Guidelines 
− 
Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, IB, 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 and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants. 
• 
AstraZeneca will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO but the accountability remains with the Sponsor. 
 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention 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 intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and Investigators. 
• 
For all studies except those utilizing medical devices, Investigator safety reports must be 
prepared for SUSAR according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• 
An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
 
A 2 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 


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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. 
A 3 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorized representative and answer all questions regarding the study. 
Participants or their legally authorized representative must be informed that their participation 
is voluntary, and they are free to refuse to participate and may withdraw their consent at any 
time and for any reason during the study. Participants or their legally authorized representative 
will be required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, 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 participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
Participants 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 participant or the participant’s legally authorized 
representative. 
Participants 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 participant 
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 analyzed at the time of 
the request, the Sponsor will not be obliged to destroy the results of this research. 
A 4 
Data Protection 
Each participant will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
The participant 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 and use of their 
data must also be explained to the participant in the informed consent  


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The participant 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. 
A 5 
Dissemination of Clinical Study Data 
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the study results when they are available. The clinical study and/or summary of 
study results may also be available on other websites according to the regulations of the 
countries in which the study is conducted. 
A 6 
Data Quality Assurance 
All participant data relating to the study will be recorded on 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 or electronically signing the eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the 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. 
The Sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations). 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants 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 
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. 


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A 7 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data entered in the 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. 
Definition of what constitutes source data can be found in in the Clinical Study Agreement. 
A 8 
Study and Site Start and 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. 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. 
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 participants by the Investigator 
• 
Discontinuation of further study intervention development 
 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The Investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up. 
A 9 
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 


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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 Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
B 1 
Definition of Adverse Events 
An adverse event is the development of any untoward medical occurrence in a participant or 
clinical study participant 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 (for example 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 intervention has been administered. 
B 2 
Definitions of Serious Adverse Event 
A serious adverse event 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-participant hospitalisation or prolongation of existing hospitalisation  
• 
Results in persistent or significant disability or incapacity.  
• 
Is a congenital abnormality or birth defect 
• 
Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent one of the outcomes listed above. 
 
Life Threatening 
‘Life-threatening’ means that the participant 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 
participant’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). 
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 participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study. 


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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, hospitalisation, disability or incapacity but may jeopardise the participant 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 iv 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 anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation 
• 
Development of drug dependency or drug abuse 
 
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 v5.0 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). 
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. 
B 3 
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. 


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• 
Time course. Exposure to suspect drug. Has the participant 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. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca 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 recognised 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 no available facts or arguments to suggest a 
causal relationship, 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 4 
Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study intervention that either causes harm to the 
participant or has the potential to cause harm to the participant.  


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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 participant. 
Medication error includes situations where an error.  
• 
occurred 
• 
was identified and intercepted before the participant received the drug 
• 
did not occur, but circumstances were recognised 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 participant 
• 
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  
 
Examples of events that do not require reporting as medication errors in clinical studies: 
• 
Participant accidentally missed drug dose(s) eg, forgot to take medication 
• 
Accidental overdose (will be captured as an overdose) 
• 
Participant 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 
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 
participants 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 record of receipt of arrival and onward 
shipment or disposal. 
AstraZeneca or delegated representatives 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 AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle. 
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 participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analyzed, the Sponsor is not obliged to destroy the results of this research. 
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent. 
The Investigator: 
• 
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to the Sponsor or delegate. 
• 
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented 
• 
Ensures that the participant and Sponsor are informed about the sample disposal. 
 


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AstraZeneca ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action documented and study site notified. 
C 3 
International Airline Transportation Association (IATA) 6.2 
Guidance Document 
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  
Category A pathogens are eg, Ebola, Lassa fever virus. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to UN 
2814. Infectious substances which cause disease only in animals must be assigned to UN 
2900. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, hepatitis A, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name. 
• 
UN 3373 – Biological Substance, Category B 
• 
Are to be packed in accordance with UN3373 and IATA 650 
 
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class. 
• 
Clinical study samples will fall into Category B or exempt under IATA regulations. 
• 
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf). 
• 
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content. 


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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 PHL cases and 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 participant 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 Sponsor clinical project representatives, in review 
and assessment of cases meeting PHL criteria to agree whether HL criteria are met. Hy’s Law 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than DILI caused by the study intervention.  
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 
Aspartate aminotransferase or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN at any point 
during the study following the start of study medication irrespective of an increase in ALP.  
Hy’s Law 
Aspartate aminotransferase or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other 
reason, other than the study intervention, can be found to explain the combination of 
increases, eg, elevated ALP indicating cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 


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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 participant who meets any of the following identification criteria in 
isolation or in combination: 
• 
ALT ≥ 3 × ULN 
• 
AST ≥ 3 × ULN 
• 
TBL ≥ 2 × ULN 
 
Central Laboratories Being Used 
When a participants 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 Sponsor 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 Sponsor 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 participant 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 Sponsor representative  
• 
Determine whether the participant meets PHL criteria (see Section D 2 Definitions 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 eCRF 
 
D 4 
Follow-up 
D 4.1 
Potential Hy’s Law Criteria Not Met 
If the participant does not meet PHL criteria, the Investigator will: 
• 
Inform the Sponsor representative that the participant has not met PHL criteria.  
• 
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the CSP. 
 
D 4.2 
Potential Hy’s Law Criteria Met 
If the participant does meet PHL criteria, the Investigator will: 
• 
Determine whether PHL criteria were met at any study visit prior to starting study 
intervention (See Section D 2). 
• 
Notify the Sponsor 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 participants that met PHL criteria prior to starting study intervention, the Investigator 
is not required to submit a PHL SAE unless there is a significant change# in the 
participant’s condition. 
• 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) 
and the continuous review of data. 
• 
Subsequent to this contact the Investigator will: 
− 
Monitor the participant 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 3 Liver eCRF Modules as information becomes available. 
 
#A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 


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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. 
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 
study intervention, to ensure timely analysis and reporting to health authorities within 15 
calendar days from date PHL criteria was met. The Sponsor 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 eCRF 
• 
If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE and AE eCRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the Sponsor standard processes. 
 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the study intervention: 
• 
Send updated SAE (report term ‘Hy’s Law’) according to Sponsor 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: 


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• 
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 study 
intervention and seriousness criteria is medically important, according to CSP process for 
SAE reporting. 
• 
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 
Table D10 
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 a 
IgG anti-HCV 
HCV RNA a  
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) b 
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 b 
Transferrin saturation 
a 
HCV RNA; HCV DNA are only tested when IgG anti-HCV is positive or inconclusive 
b 
CD-transferrin and Transferrin are not available in China. Study teams should amend this list accordingly 


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D 7 
REFERENCES 
Aithal et al, 2011 
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815. 
FDA Guidance for Industry, July 2009 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation 


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Appendix E Examples of Coadministered Drugs That Need Additional 
Consideration 
The lists of drugs in Table E11, Table E12, and Table E13 are not exhaustive. Any questions 
about drugs not on this list should be addressed to the Study Physician of this study. 
Table E11 
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. 
 
Table E12 
CYP3A Inducers 
Strong inducers of CYP3A 
Moderate inducers of CYP3A 
Carbamazepine 
Bosentan 


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Table E12 
CYP3A Inducers 
Strong inducers of CYP3A 
Moderate inducers of CYP3A 
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/DrugInteactionsLabeling/ucm093664.ht
m#inVivo. Accessed 23 July 2019. 
 
Table E13 
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 described below. 
F 1 
Female Participants 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 postmenopausal 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 postmenopausal 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 postmenopausal range for the institution. 
• 
Women ≥50 years of age would be considered postmenopausal 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 participants of childbearing potential who are not totally sexually abstinent (ie, 
refraining from heterosexual intercourse during the entire period of risk associated with study 
intervention), and who intend to be sexually active with a nonsterilized male partner, must use 
≥ 1 highly effective method of contraception (see Table F14) consistent with local regulations 
regarding the use of contraception for participants 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 participant 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 participant. Female participants should refrain from breastfeeding throughout this 
period. 


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F 2 
Male Participants with a Female Partner of Childbearing 
Potential 
Non-sterilized male participants (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 
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 participants 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 participants 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 participants must also use a highly 
effective method of contraception throughout this period (see Table F14). 
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 F14. 
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). 
 


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Table F14 
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, will be recorded in the eCRF as 
specified in the SoA (Table 1). 
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 G15. 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 G15 
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. 
 
REFERENCE 
Pugh et al, 1973 
Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60(8):646-9. 


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Appendix H Proton-pump Inhibitor Equivalence Table 
Table H16 shows the PPI doses relating to evidence synthesis and recommendations in the 
original NICE clinical guidelines. 
Table H16 
Proton-pump Inhibitor Doses Relating to Evidence Synthesis and 
Recommendations in the Original Guideline (CG17; 2004) 
Proton-pump inhibitor 
Full/standard dose 
Low dose (on-demand) 
Double dose 
Esomeprazole 
20 mga once daily 
Not available 
40 mgc once daily 
Lansoprazole 
30 mg once daily 
15 mg once daily 
30 mgb twice daily 
Omeprazole 
20 mg once daily 
10 mgb once daily 
40 mg once daily 
Pantoprazole 
40 mg once daily 
20 mg once daily 
40 mgb twice daily 
Rabeprazole 
20 mg once daily 
10 mg once daily 
20 mgb twice daily 
a 
Lower than the licensed starting dose for esomeprazole in GERD, which is 40 mg, but considered to be dose-
equivalent to other PPIs. When undertaking meta-analysis of dose-related effects, NICE classed esomeprazole 20 mg 
as a full-dose equivalent to omeprazole 20 mg. 
b 
Off-label dose for GERD. 
c 
40 mg is recommended as a double dose of esomeprazole because the 20-mg dose is considered equivalent to 
omeprazole 20 mg. 
GERD = gastroesophageal reflux disease; NICE = National Institute for Health and Care Excellence; PPI = proton-pump 
inhibitor. 
 
Proton-pump inhibitors listed in Table H17 may be used more frequently in the ICU setting 
and are allowed on study. 
Table H17 
Proton-pump Inhibitors Allowed in Intensive Care Unit 
Medication 
Route 
Dose in the ICU 
Esomeprazole 
PO 
NG or IV 
40 mg daily 
Lansoprazole 
PO 
NG or IV 
15 or 30 mg daily 
Omeprazole 
PO 
NG or IV 
20 to 40 mg daily 
Pantoprazole 
PO 
NG or IV 
40 mg daily 
ICU = intensive care unit; IV = intravenously; NG = nasogastric; PO = orally. 
 


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REFERENCES 
NICE Clinical Guidelines, 2015 
Gastro-oesophageal reflux disease and dyspepsia in adults: investigations and management: 
Clinical Guidelines [Internet]; 2015 [cited 2020 May 15]. Available from: 
www.nice.org.uk/guidance/cg184. 
American Society Health-System Pharmacists, 1999 
ASHP therapeutic guidelines on stress ulcer prophylaxis. ASHP Commission on Therapeutics 
and approved by the ASHP Board of Directors on November 14, 1998. Am J Health Syst 
Pharm. 1999;56(4):347-9. 
Sesler, 2007 
Sesler JM. Stress-related mucosal disease in the intensive care unit: an update on prophylaxis. 
AACN Adv Crit Care. 2007;18(2):119-26; quiz 127-28. 


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Appendix I 
Abbreviations 
Abbreviation 
or special term 
Explanation 
λz  
terminal rate constant 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
anti-HBc 
antibody to hepatitis B core antigen 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC12h 
area under the concentration-time curve from 0 to 12 hours  
AUC0-last 
area under the concentration-time curve from 0 to last measurable time point 
BCS 
Biopharmaceutical Classification System 
bid 
twice daily 
BSC 
best supportive care 
BTK 
Bruton tyrosine kinase 
CD 
cluster of differentiation 
CL/F 
apparent oral clearance 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed concentration 
CRP 
C-reactive protein 
CSP 
clinical study protocol 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
COVID-19 
coronavirus disease 2019 
CYP 
cytochrome P450 
DILI 
drug-induced liver injury 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
FDA 
Food and Drug Administration 
FiO2 
fraction of inspired oxygen 
GCP 
Good Clinical Practice 


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Abbreviation 
or special term 
Explanation 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HL 
Hy’s Law 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICU 
intensive care unit 
IFNγ 
interferon gamma 
IEC 
Independent Ethics Committee 
IL 
interleukin 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
MCP-1 
monocyte chemoattractant protein-1 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NG 
nasogastric 
PaO2 
partial pressure of oxygen 
PCR 
polymerase chain reaction 
PHL 
Potential Hy’s Law 
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 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2  
half-life 
TBL 
total bilirubin 


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Abbreviation 
or special term 
Explanation 
TLR 
Toll-like receptor 
tmax  
time to Cmax  
TNFα 
tumor necrosis factor alpha 
ULN 
upper limit of normal 
Vz/F 
apparent volume of distribution 
 
 
 


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Appendix J 
Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents. 
Amendment 1 (25 June 2020)  
The overall rationale for the amendment was to address feedback from study sites that are 
managing local challenges during the COVID-19 pandemic. 
Section number and 
name 
Description of change 
Brief rationale 
Substantial/ 
non-substantial 
1.1 Synopsis; 
1.2 Schema (Figure 1); 
4.1 Overall Design; 
6.1.2 Dosing Instructions 
and Duration; 
6.4 Study Intervention 
Compliance; 
6.5.4 Acalabrutinib Drug-
drug Interaction Guidance 
in the Presence of Life-
threatening COVID-19 
Infection 
Specified that acalabrutinib will be 
given for 14 days (a maximum of 28 
doses) instead of for 14 consecutive 
days (28 doses total). 
Clarification 
Non-substantial 
1.1 Synopsis; 
3 Objectives and 
Endpoints; 
8.1.1.2 Improvements on 
9-point Category Ordinal 
Scale; 
9.4.4.3 Time to Clinical 
Improvement on 9-point 
Ordinal Scale 
Added a footnote to Table 8 in 
Section 8.1.1.2 to indicate that a 
score of zero on 9-point category 
ordinal scale will not be evaluated 
in this study. Removed zero from 
this endpoint in Sections 1.1, 3, and 
9.4.4.3 
Clarification  
Non-substantial 
1.3 Schedule of Activities 
(Table 1) 
Changed the Screening column 
from “(Day -1 or Day 1) to “Day -3 
to Day -1)”. Added footnote n to 
indicate that screening can be 
performed within 1-3 days prior to 
dosing; also clarified that ECG can 
be collected any time during the 
screening period. 
Allow flexibility 
around timing of 
screening  
Non-substantial 
Added a separate column for Day 1. 
Moved assessment time points for 
Clarification  
Non-substantial 


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Section number and 
name 
Description of change 
Brief rationale 
Substantial/ 
non-substantial 
 from 
Screening to Day 1. 
Revised footnote l to indicate that 
Clarification 
Non-substantial 
Added footnote q to Table 1 to 
indicate that for all central 
laboratory assessments, sample 
collection windows of ± 1 day will 
be allowed for each of Days 4, 7, 
and 10. 
Clarification 
Non-substantial 
1.3 Schedule of Activities 
(Table 1); 
8.1.1.1 Pulmonary 
Assessments to Evaluate 
Respiratory Failure 
Added footnote p to Table 1 and 
text to Section 8.1.1.1 to clarify that 
arterial blood gases should be 
collected from participants if the 
sample is easily accessible and the 
procedure will not be painful to 
participants. Also stated that if 
collection of arterial blood gases is 
not clinically indicated, the test 
should not be performed. 
Patient centricity, 
since taking arterial 
blood gases is painful  
Non-substantial 
1.3 Schedule of Activities 
(Table 1); 
8.2.2 Physical 
Examinations and Chest 
Imaging 
Added footnote r in Table 1 and text 
in Section 8.2.2 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 
enrollment). 
Clarification 
Non-substantial 
1.3 Schedule of Activities 
(Table 1); 
8.2.3 Vital Signs 
Added footnote s in Table 1 and text 
in Section 8.2.3 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 
intervention should be used. 
Clarification 
Non-substantial 
1.3 Schedule of Activities 
(Table 1); 
Revised footnote d in Table 1 and 
added text to Section 8.2.5.1 to 
indicate that hepatitis serology must 
Clarification 
Non-substantial 


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Section number and 
name 
Description of change 
Brief rationale 
Substantial/ 
non-substantial 
8.2.5.1 Local Laboratory 
Tests 
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. 
Revised Table 1 to indicate that 
collection of fibrinogen, PT, aPTT, 
INR, and D-dimer to occur every 
other day while in the hospital. 
Added footnote o to Table 1 and 
text to Section 8.2.5.1 to specify 
that these laboratory tests, in 
addition to cardiac troponin I, 
should be performed more 
frequently if clinically indicated. 
Removed BNP assessment. 
Also, stated in Section 8.2.5.1 that 
“Safety and CRP 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 
2.2.3.2 Clinical 
Experience; 
2.3.2 Benefit Assessment 
Cited recent publications reporting 
activity of acalabrutinib and other 
BTK inhibitors in COVID-19.  
Clarification 
Non-substantial 
2.3.1 Risk Assessment 
Clarified the risks associated with 
acalabrutinib and added a table 
showing frequency and time to 
onset of risks associated with 
acalabrutinib. In addition, updated 
subsections for hepatitis B 
reactivation, PML, and cytopenias. 
Clarification 
Non-substantial 
5.1 Inclusion Criteria 
Inclusion Criterion 5: Removed 
“Percutaneous endoscopic 
gastrostomy tube will not be 
allowed.” Added “percutaneous” to 
this inclusion criterion as follows: 
“Nasogastric tube or other types of 
oral or percutaneous gastric 
feeding tube; …” 
Correction  
Non-substantial 
Inclusion Criterion 8: Removed the 
body mass index and weight 
restriction.  
Obesity is a 
comorbidity that has 
been associated with 
severe COVID-19 
Non-substantial 


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Section number and 
name 
Description of change 
Brief rationale 
Substantial/ 
non-substantial 
cases, which is the 
target population for 
this study 
5.2 Exclusion Criteria 
Exclusion Criterion 9: Revised 
hepatitis serology criteria. 
Clarification 
Non-substantial 
Exclusion Criterion 12: 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 17: Changed the 
BTK inhibitor washout period from 
14 to 7 days prior to enrollment. 
Based on the 
expected BTK re-
synthesis rate in 
COVID patients, a 
washout period of 7 
days is considered to 
be adequate in 
minimizing the effect 
on BTK occupancy 
of BTK inhibitors 
used prior to the 
current study 
Non-substantial 
6.1.2 Dosing Instructions 
and Duration 
Revised Section 6.1.2 and 
restructured with sub-headings for 
clarity.  
Clarification 
Non-substantial 
6.1.2.1 Dosing and 
Duration of Treatment 
Added text to indicate that COCA-
COLA® contains glucose and blood 
glucose levels of diabetic 
participants must be monitored as 
clinically indicated and blood 
glucose-lowering medications 
adjusted accordingly. 
Clarification 
Non-substantial 
6.1.2.2 Dosing of 
Participants Who are no 
Longer Intubated 
For participants who are on PPIs 
and can swallow pills, changed 
volume of COCA-COLA from 
240 mL to at least 100 mL. For 
participants not on PPIs and can 
swallow pills, removed volume 
(240 mL) of water and just stated 
that it should be taken with water. 
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/
 
Non-substantial 


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Section number and 
name 
Description of change 
Brief rationale 
Substantial/ 
non-substantial 
6.1.2.3 Missed Dosing 
Windows and Doses; 
6.6 Dose Modification 
Clarified text regarding missed 
windows and doses. 
Clarification 
Non-substantial 
6.5.2 Permitted 
Concomitant Therapy 
Clarified BSC agents that will be 
permitted in this study.  
Align with clinical 
treatment practices 
Substantial 
6.5.3 Prohibited or 
Restricted Concomitant 
Therapy 
Clarified that immunomodulatory 
drugs, intended as treatment for 
COVID-19 but not considered 
standard of care according to local 
institutional guidelines, are 
prohibited in the study through 
Day 28. Participants who are taking 
immunomodulatory drugs for other 
medical conditions (eg, tocilizumab 
for rheumatoid arthritis) may 
continue with treatment upon 
discussion with the Study Physician. 
Clarification 
Non-substantial 
Added language to indicate that 
BTK inhibitors other than 
acalabrutinib are prohibited through 
Day 14. 
Clarification  
Non-substantial 
Clarified that certain anticoagulants 
such as warfarin or equivalent 
vitamin K antagonists (eg, 
phenprocoumon) are prohibited in 
the study. Participants 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 steroid treatment 
language. 
Align with clinical 
treatment practices 
Substantial 


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Section number and 
name 
Description of change 
Brief rationale 
Substantial/ 
non-substantial 
6.5.4 Acalabrutinib Drug-
drug Interaction Guidance 
in the Presence of Life-
threatening COVID-19 
Infection; 
Appendix E Examples of 
Coadministered Drugs 
That Need Additional 
Consideration 
(Table E13) 
Removed ranitidine. 
Removed from 
market 
Non-substantial 
8.2.5.2 Central 
Laboratory Tests 
Added text to indicate that PK,
are 
considered Tier 1 and should not be 
missed. The site must follow the 
SoA. Additional minor edits were 
made to this section. 
Clarification 
Non-substantial 
8.3.7 Disease progression 
Removed “respiratory illness”. 
Clarification  
Non-substantial 
B2 Definitions of Serious 
Adverse Event 
Provided full URL for CTCAE 
v5.0. 
Correction 
Non-substantial 
anti-HBc = hepatitis B core antibody; aPTT = activated partial thromboplastin time; BNP = brain natriuretic peptide; 
BSC = best supportive care; BTK = Bruton tyrosine kinase; COVID-19 = coronavirus disease 2019; CRP = C-reactive 
protein; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = 
electrocardiogram; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; INR = international normalized ratio; 
PK = pharmacokinetics; PML = progressive 
multifocal leukoencephalopathy; PT = prothrombin time; SoA = Schedule of Activities. 
 


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11 
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Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S et al. Acalabrutinib (ACP-
196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016;374(4):323-32. 
Cai Q, Huang D, Yu H, Zhu Z, Xia Z, Su Y et al. COVID-19: Abnormal liver function tests. J 
Hepatol. 2020. 
CALQUENCE. CALQUENCE (acalabrutinib) [package insert]. Wilmington, DE: 
AstraZeneca Pharmaceuticals LP.  2019. 
Channappanavar R, Fehr AR, Vijay R, Mack M, Zhao J, Meyerholz DK et al. Dysregulated 
Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal 
Pneumonia in SARS-CoV-Infected Mice. Cell Host Microbe. 2016;19(2):181-93. 
Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H et al. Clinical and immunological features 
of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130(5):2620-9. 
Covey T, Barf T, Gulrajani M, et al. ACP-196: a novel covalent Bruton’s tyrosine kinase 
(BTK) inhibitor with improved selectivity and in vivo target coverage in chronic lymphocytic 
leukemia (CLL) patients. In: Proceedings of the 106th Annual Meeting of the American 
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SAP_001.pdf: 
Statistical Analysis Plan
Drug Substance Acalabrutinib
Study Code
D822FC00005
Version
1.0
Date
16 Jul 2020
An Open-label, Multiple-dose Study to Evaluate the Pharmacokinetics, and 
Safety and Tolerability of Acalabrutinib Suspension Delivered via 
Nasogastric Tube, Coadministered With a Proton-pump Inhibitor, in 
Participants Hospitalized With COVID-19


Statistical Analysis Plan 
AstraZeneca
Study Code D822FC00005
2(38)
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................................1
TABLE OF CONTENTS.....................................................................................................2
LIST OF ABBREVIATIONS ..............................................................................................4
AMENDMENT HISTORY..................................................................................................6
1.
STUDY DETAILS...............................................................................................7
1.1
Study Objectives..................................................................................................7
1.2
Study Design........................................................................................................8
1.3
Number of Subjects............................................................................................ 10
2.
ANALYSIS POPULATION .............................................................................. 10
2.1
Definition of Analysis Set .................................................................................. 10
2.2
Deviations.......................................................................................................... 11
3.
PRIMARY AND SECONDARY VARIABLES................................................. 11
3.1
Pharmacokinetic Variables................................................................................. 11
3.2
Safety Variables................................................................................................. 14
3.2.1
Adverse events................................................................................................... 14
3.2.2
Exposure, dose intensity and treatment compliance............................................ 14
3.2.3
Laboratory assessments...................................................................................... 15
3.2.4
Physical examination and chest imaging, electrocardiograms and 
echocardiograms ................................................................................................ 15
3.2.5
Vital signs and arterial blood gases .................................................................... 16
3.2.6
Oxygen treatment, ventilator use and mSOFA score........................................... 16
3.3
Efficacy Variables.............................................................................................. 17
3.3.1
Alive and free of respiratory failure at Day 14 (Day 28)..................................... 17
3.3.2
Percent change from baseline in C-reactive protein ............................................ 18
3.3.3
Time to 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.............................................................. 18
3.4
Exploratory 
................................... 18
3.5
Other Variables.................................................................................................. 19
3.5.1
Baseline Characteristics ..................................................................................... 19
3.5.2
Prior and Concomitant Medications and Procedures........................................... 20
4.
ANALYSIS METHODS.................................................................................... 20
4.1
General Principles.............................................................................................. 20


Statistical Analysis Plan 
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Study Code D822FC00005
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4.2
Analysis Methods for Disposition, Demographic, Baseline Characteristics, 
Prior and Concomitant Medications/Procedures ................................................. 22
4.2.1
Disposition of subjects ....................................................................................... 22
4.2.2
Protocol deviations............................................................................................. 22
4.2.3
Demographic and other baseline characteristics.................................................. 22
4.2.4
Prior and concomitant medications or procedures............................................... 23
4.3
Analysis of Pharmacokinetics ............................................................................ 23
4.4
Analysis of Efficacy........................................................................................... 24
4.4.1
Alive and free of respiratory failure at Day 14 (and 28)...................................... 24
4.4.2
Percent change from baseline in C-reactive protein ............................................ 25
4.4.3
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.............................. 25
4.5
Analysis of Safety.............................................................................................. 26
4.5.1
Adverse events................................................................................................... 26
4.5.1.1
Deaths, serious adverse events (SAEs), and other significant adverse 
events................................................................................................................. 27
4.5.2
Exposure, dose intensity and treatment compliance............................................ 28
4.5.3
Laboratory assessments...................................................................................... 28
4.5.4
Vital signs.......................................................................................................... 29
4.5.5
Physical examinations and chest imaging, electrocardiograms and 
echocardiograms ................................................................................................ 29
4.5.6
Oxygen treatment, ventilator use and mSOFA.................................................... 30
4.6
Analysis of exploratory variables 
.................................. 30
5.
INTERIM ANALYSES ..................................................................................... 31
6.
INDEPENDENT DATA MONITORING COMMITTEE .................................. 31
7.
SAFETY REVIEW COMMITTEE.................................................................... 31
8.
CHANGES OF ANALYSIS FROM PROTOCOL ............................................. 31
9.
APPENDIX ....................................................................................................... 32
9.1
AESI and ECI definitions................................................................................... 32
9.2
Fraction of Inspired Oxygen (FiO2) ................................................................... 36
9.3
Imputation rules for missing or partial AE on concomitant medication............... 37
10.
REFERENCES .................................................................................................. 38


Statistical Analysis Plan 
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Study Code D822FC00005
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LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AE
Adverse Event 
AESI
Adverse Event of Special Interest
ATC
Anatomic and Therapeutic Class
AZ
AstraZeneca
BMI
Body Mass Index
BP
Blood Pressure
BSC
Best supportive care
CI
Confidence Interval
CRP
C-reactive Protein
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for AEs
CTMS
Clinical Trial Management System
ECG
Electrocardiogram
ECHO
Echocardiogram
ECI
Events of Clinical Interest
ECMO
Extracorporeal Membrane Oxygenation
eCRF
Electronic Case Report Form
EES
Efficacy Evaluable Set
ICU
Intensive Care Unit
iDMC
Independent Data Monitoring Committee


Statistical Analysis Plan 
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Study Code D822FC00005
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IPD
Important Protocol Deviation
KM
Kaplan-Meier
MAP
Mean Arterial Pressure
MedDRA
Medical Dictionary for Regulatory Activities
mSOFA
Modified Sequential Organ Failure Assessment
NG
Nasogastric 
P/F
PaO2/FiO2
PK
Pharmacokinetic
PKS
Pharmacokinetic Analysis Set
PT
Preferred Term
SAE
Serious Adverse Event
SAS
Safety Analysis Set
SD
Standard Deviation
SOC
System Organ Class
SoA
Schedule of Activities
TEAE
Treatment Emergent Adverse Event
WHO-DD
World Health Organization-Drug Dictionary


Statistical Analysis Plan 
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Study Code D822FC00005
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AMENDMENT HISTORY
Date
Brief description of change
N/A


Statistical Analysis Plan 
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Study Code D822FC00005
7(38)
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 1 of the CSP.
This study is being conducted to support the ongoing clinical development of acalabrutinib 
(CALQUENCE®)1 in hospitalized COVID-19 patients. Because many COVID-19 patients 
may be unable to swallow capsules due to respiratory failure (eg, they may require 
endotracheal intubation for ventilator support and NG tube placement), it is important to have 
a clinically acceptable method to administer acalabrutinib (capsules) via NG tube.
Furthermore, due to the acute illness of COVID-19 patients, many hospitalized patients are 
placed on high doses of PPIs or continuous H2-receptor antagonists to prevent stress ulcers. 
This study is designed to determine the PK, and safety and tolerability of acalabrutinib 
suspension, when coadministered with a PPI, in participants with confirmed SARS-CoV-2 
infection requiring hospitalization due to respiratory failure (as defined in the table below) 
attributable to COVID-19 pneumonia and who have an NG tube in place.
1.1
Study Objectives
The objectives for this study and the corresponding endpoints/variables are shown in Table 1.
Table 1
Objectives and Endpoints
Objective
Endpoint/Variable
Primary Objectives
Primary Endpoints/Variables
•
To characterize the PK of acalabrutinib and its 
active metabolite (ACP-5862) following 
administration of acalabrutinib suspension, when 
coadministered with a PPI, in participants with 
COVID-19
•
Primary PK parameters for acalabrutinib and 
ACP-5862 include AUC12h, AUClast, andCmax.
Additional PK parameters are described in the 
protocol.
•
To assess the safety and tolerability of 
acalabrutinib suspension in participants with 
COVID-19 when administered in the presence of 
PPIs and BSC
•
Type, frequency, severity, and relationship to 
study intervention of any treatment-emergent AEs 
or abnormalities of laboratory tests, SAEs, or AEs 
leading to discontinuation of study intervention 
                                               
1 CALQUENCE® is a trademark of the AstraZeneca group of companies.


Statistical Analysis Plan 
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Study Code D822FC00005
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Objective
Endpoint/Variable
Secondary Objective
Secondary Endpoints/Variables
•
To evaluate the preliminary efficacy of adding 
acalabrutinib suspension to BSC for treatment of 
participants with COVID-19
•
Proportion of participants alive and free of 
respiratory failure at Days 14 and 28
•
Percent change from baseline in CRP (time frame: 
baseline, Days 3, 5, 7, 14, 28)
•
Time to improvement defined as time to clinical 
improvement of ≥2 points (from first dose date) 
on a 9-point category ordinal scale, live discharge 
from the hospital, or considered fit for discharge 
(a score of 0, 1, or 2 on the ordinal scale), 
whichever comes first, by Day 28
Exploratory Objectives
Exploratory Endpoints/Variables
 
 
 
 
 
 
 
 
 
 
 
1.2
Study Design
Approximately 20 participants will be included to ensure at least 16 participants are evaluable.
participants will receive acalabrutinib suspension (ie, acalabrutinib 100 mg suspension in 
COCA-COLA® delivered via NG tube) bid for 14 days (a maximum of 28 doses). In addition 
to receiving best supportive care (SOC).
To assess the effect of PPIs, all participants must be receiving treatment with a PPI at the start 
of the study. Treatment with a PPI can begin at any time prior to enrollment, provided 
participants have received PPI treatment for at least 24 hours prior to the first dose of 
acalabrutinib suspension. Any PPI is permitted, provided it meets the minimum equivalent 
daily dose of 20 mg rabeprazole. Participants must be on this dosage of PPI at the start of the 
study. They may be weaned off PPIs during the study if medically appropriate.
Blood samples for plasma PK assessment of acalabrutinib and its metabolite (ACP-5862) will 
be collected at pre-dose and 0.5, 1, 2, 4, 6, and 12 hours following treatment with 
acalabrutinib suspension as described in the table below. Note that the sample at 12 hours 
must be collected prior to the subsequent acalabrutinib dose (for trough PK sample).


Statistical Analysis Plan 
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Study Code D822FC00005
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Table 2    PK Visit and Description
PK Visit
Description
Rationale
PK Visit 1
First PK sampling will occur on Day 1 (ie, first dosing 
day for acalabrutinib suspension)
Allows an early assessment of 
acalabrutinib and ACP-5862 PK in 
participants receiving acalabrutinib 
suspension via NG tube
PK Visit 2
Second PK sampling will occur a minimum of 4 days 
after the start of PPI treatment, irrespective of the 
timing of NG tube placement and any time after 
2 doses of acalabrutinib suspension have been given 
(ie, PK sampling can begin prior to the third dose, or 
anytime thereafter)
PK Visit 2 can occur as early as Day 2 (if participant 
has been on a PPI for ≥4 consecutive days prior to 
receiving the third acalabrutinib dose), and up to Day 
4 (if participant initiated PPI treatment 24 hours prior 
to receiving the first dose of acalabrutinib on Day 1)
PPI exposure must occur for 
4 consecutive days to reach the 
maximum PPI on-target effect
PK sample can commence at any 
point after the second dose of 
acalabrutinib suspension to ensure 
steady-state levels of the active 
metabolite and
 
PK Visit 3
Third PK sampling will occur 3 days after PK Visit 2, 
OR on the last day the participant receives 
acalabrutinib treatment, whichever comes first
Allows an additional opportunity 
to assess the steady-state PK of 
acalabrutinib and ACP-5862 PK 
following delivery of acalabrutinib 
suspension via NG tube
Safety assessments, including AE reporting, will be performed through 28 (± 3) days after the 
last dose of the acalabrutinib suspension.
The study design is illustrated in Figure 1.


Statistical Analysis Plan 
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Study Code D822FC00005
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Figure 1
Study Design
a
Blood samples for plasma PK assessment of acalabrutinib and its metabolite (ACP-5862) will be collected at pre-dose 
and 0.5, 1, 2, 4, 6, and 12 hours following treatment with acalabrutinib suspension. Note that the sample at 12 hours 
must be collected prior to the subsequent acalabrutinib dose (for trough PK sample).
Note: PK Visit 2 can occur as early as Day 2 (if participant has been on a PPI for ≥4 consecutive days prior to receiving the 
third acalabrutinib dose), and up to Day 4 (if participant initiated PPI treatment 24 hours prior to receiving the first dose of 
acalabrutinib on Day 1). See table 3 for more information.
bid = twice daily; PK = pharmacokinetic(s); PPI = proton-pump inhibitor.
1.3
Number of Subjects
Approximately 20 participants will be enrolled to have at least 16 evaluable participants. No 
formal power calculation is used for sample size determination. The sample size is chosen 
based on desire to gain adequate information while exposing as few patients as possible to the 
study procedure. 
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 3.
The analysis populations are defined in Table .


Statistical Analysis Plan 
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Study Code D822FC00005
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Table 3 Populations for Analysis
Population/Analysis set
Description
PK Analysis Set (PKS)
The PK Analysis Set will include all participants who received ≥ 1 dose of 
acalabrutinib and had ≥ 1 post-dose evaluable PK data point for 
acalabrutinib. The population will be defined by AstraZeneca, the 
pharmacokinetics, and the statistician prior to any analyses being 
performed. 
Safety Analysis Set (SAS)
The Safety Analysis Set will include all participants who received ≥1 dose 
of study intervention
Efficacy Evaluable Set (EES)
The Efficacy Evaluable Set will include all participants who received ≥1 
dose of study intervention
 
PK = pharmacokinetic; 
; PPI = proton-pump inhibitor.
2.2
Deviations
Protocol deviation is defined in a separate protocol deviation list. The important protocol 
deviations will be listed and summarized. 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).
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.  
In addition to the above, other study deviations captured from the eCRF module for 
inclusion/exclusion criteria will be tabulated and listed.  Any other deviations from monitoring 
notes or reports will be reported in an appendix to the CSR.
3.
PRIMARY AND SECONDARY VARIABLES
3.1
Pharmacokinetic Variables
The PK of acalabrutinib and its active metabolite ACP-5862 in subjects with COVID-19 when 
administered with BSC is a primary endpoint and will be assessed by following PK 
parameters: 

Primary PK parameters: AUC12h, AUClast, and Cmax.

Secondary PK parameters:
◦
Acalabrutinib and ACP-5862: t1/2, tmax, and λz.
◦
Acalabrutinib: CL/F and Vz/F.
◦
Metabolite to parent ratio for Cmax, AUClast, and AUC12h.


Statistical Analysis Plan 
AstraZeneca
Study Code D822FC00005
12(38)
All PK parameters include in the protocol are listed in the Table 4 below, and are defined as 
appropriate for study design.
Table 4.
Non-Compartmental Pharmacokinetic Parameters to be Calculated
Parameter
Label in TFLs
Definition
Method of Determination
AUC0-t
AUC0-t
Area under the 
concentration-time curve 
from time 0 to the time of the 
last observed non-zero 
concentration
Calculated using the Linear 
Trapezoidal with Linear 
Interpolation Method 
AUC0-inf
AUC0-inf
Area under the 
concentration-time curve 
from time 0 extrapolated to 
infinity
AUC0-inf = AUC0-t + (Clast/Kel)
where Clast is the last observed 
non-zero concentration 
AUC%extrap
AUC%extrap
Percent of AUC0-inf 
extrapolated
%AUCextrap = (1 –
AUC0-t/AUC0-inf) x 100
Cmax
Cmax
Maximum observed 
concentration
Taken directly from 
bioanalytical data
Tmax
Tmax
Time to reach Cmax; if the 
maximum value occurs at 
more than one timepoint, 
Tmax is defined as the first 
timepoint with this value
Taken from clinical database as 
the difference in the time of the 
blood draw associated with 
Cmax and the time of study drug 
administration
Tlast
Tlast
Time of the last measurable 
non-zero concentration
Taken from the clinical 
database as the difference in the 
time of the blood draw 
associated with the last 
measurable concentration and 
the time of study drug 
administration
Kel
Kel
Apparent first order terminal 
elimination rate constant
Calculated by linear least-
squares regression analysis
from a semi-log plot of the 
plasma concentration-time 
curve, using the maximum 
number of points in the 
terminal log linear phase (e.g., 
3 or more non-zero plasma 
concentrations)
t½ 
t1/2
Apparent first order terminal 
elimination half-life
t1/2 = 0.693/Kel
CL/F
CL/F
Apparent total plasma 
clearance after oral 
(extravascular)
administration (calculated for 
acalabrutinib only)
CL/F = Dose/(AUC0-inf) 


Statistical Analysis Plan 
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Study Code D822FC00005
13(38)
Parameter
Label in TFLs
Definition
Method of Determination
Vz/F
Vz/F
Apparent volume of 
distribution during the 
terminal elimination phase 
after oral (extravascular)
administration (calculated for 
acalabrutinib only)
Vz/F = Dose/(AUC0-inf × Kel)
Pharmacokinetic concentration data will be collected as per the schedule of activities (SoA) in 
clinical study protocol (CSP). PK analysis will, where possible, be carried out using actual 
times recorded in the raw data. If actual times are missing, nominal times will be used. 
Nominal sampling times and best fit of the regression will be used for any interim PK 
parameter calculations. Plasma concentrations of study drug and its metabolite are used as 
supplied by the analytical laboratory for PK analysis. The units of concentration and resulting 
PK parameters will be presented as they are received for the analytical laboratory unless 
otherwise specified in the PK order form. 
PK parameters will be derived using non-compartmental methods with Phoenix® WinNonlin®
Version 8.1, or higher and/or SAS® Version 9.3 or higher. PK parameters will not be 
calculated for profiles with less than 3 consecutive postdose time points with quantifiable 
concentrations. The data from profiles with insufficient data to calculated the PK parameters 
will be included in the listing of concentrations but excluded from the concentration 
summaries for the affected analyte and treatment. 
For the calculation of PK parameters, plasma concentrations below the limit of quantitation 
(BLQ) prior to the first quantifiable concentration will be set to zero and plasma 
concentrations BLQ after the first quantifiable concentration will be treated as missing. 
If an entire concentration-time profile is not quantifiable, the profile will be excluded from the 
PKS.
The Cmax and tmax will be derived directly from the plasma concentration-time profiles. In the 
case where multiple peaks of equal magnitude are present, the earliest tmax will be reported.
Kel will be calculated by log-linear regression of the terminal portion of the concentration-time 
profiles for the derivation of regression-based parameters where there are sufficient data. The 
AUCs will be calculated using ‘Linear up/Log down’ method. Where appropriate, the AUClast
will be extrapolated to infinity using Kel to obtain AUCinf. The CL/F will be determined from 
the ratio of dose/AUCinf. The Vz/F will be determined from the ratio of CL/F/Kel. The MR 
parameters will be calculated after molar conversion. If t½ is estimated over less than three 
half-lives, the Kel related values will be flagged in the data listings but will be excluded from 
summary and PK statistical analysis.


Statistical Analysis Plan 
AstraZeneca
Study Code D822FC00005
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An Rsq adj value of ≥0.8 indicate good fit of the log-linear regression. Any Kel with a
Rsq_adj of <0.8 be flagged in the data listings along with the regression-based parameters and
discussed in the CSR. The Kel and related PK parameters will be excluded from summary and
PK statistical analysis.
The minimum requirement for the calculation of AUCs will be the inclusion of at least 3 
consecutive quantifiable concentrations. Where there are only 3 quantifiable concentrations at 
least one of these should follow the peak concentration. Where %AUCextrap is >10%, AUCinf
and derived parameter values will be flagged and excluded from descriptive and inferential 
statistics and discussed in the CSR.
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.
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) (using the latest or current MedDRA version) 
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. 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. The intended and actual treatment duration [days], the average daily dose (mg), 
relative dose intensity (%) and treatment compliance (%) will be reported according to table 5.
By subject exposure listing will be provided.


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Table 5 Definition of Exposure Variables
Parameters
Definition
Intended treatment duration
Date of last dose (> 0mg) - date of first dose + 1
Actual treatment duration
Intended treatment duration (days) – total duration of interruptions (days)
Average daily dose
total dose received (mg) / Actual treatment duration (days)
Relative dose intensity[RDI]
100% × d/D  where 
d is the actual cumulative dose [mg] delivered up to the actual last day of dosing 
for the drug, and
D is the total dose of the drug that would be delivered: Actual treatment duration 
[days] × 100 [mg] ×2
Treatment compliance
100 × [1- (total number of days of study drug interruption / actual treatment 
duration)].
3.2.3
Laboratory assessments
Laboratory tests will be performed as specified in the SoA in the CSP.
For the derivation of baseline and post-baseline visit values, the rules described in Section 4.1
considering definition of baseline, and how to handle multiple records will be used.
Change or percentage change from baseline in hematology and clinical chemistry variables, as 
well as ferritin and CRP 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). Physical 
examinations and chest imaging, electrocardiograms and echocardiograms
3.2.4
Physical examination and chest imaging, electrocardiograms and 
echocardiograms
Physical examinations and chest imaging, electrocardiograms and echocardiograms will be 
performed as per SoA.


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A 12-lead electrocardiogram (ECG) will be done at screening, as clinically indicated, Day 14
or discharge. Baseline is defined, after taking the average of the triplicates, as the latest non-
missing averaged triplicate prior to the first study drug.
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, oximetry, pulse, and body 
temperature, as per the SoA in the CSP.
The oxygen-haemoglobin 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 blood oxygen-haemoglobin saturation (%).  MAP will be calculated as: 
diastolic BP + 1/3 (systolic BP- diastolic BP).  
If multiple vital sign measurements are taken per day, the measurement closest to 08:00 each 
day will be used.  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 on high-flow oxygen therapy, FiO2 will be entered directly into the OXYGEN
eCRF page. For subjects not on high-flow oxygen therapy, the maximum daily flow rate will 
be entered into the OXYGEN eCRF and FiO2 will be derived as per the conversion guidelines 
in Section 9.2. Note that the conversion is different depending on whether the subject is on a 
mask or nasal cannula.
If a subject requires mechanical ventilation, data will be recorded regarding whether ventilator 
weaning was attempted. For subjects on mechanical ventilation the following ventilator 


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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. If more than one value 
is obtained for the arterial blood gases, the value closest to 08:00 will be used.
Assuming that PAO2 (the partial pressure of alveolar oxygen) is obtained from the alveolar 
gas equation:  PAO2 = (FiO2 x (760-47)) – (PaCO2/0.8) then alveolar to arterial (AA) gradient 
will be calculated as: AA gradient = PAO2 – PaO2.
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 laboratory values, the last available (if within 48 hours) will 
be used. On days when laboratory results are unavailable, values will be extrapolated from the 
previously available values.
3.3
Efficacy Variables
The efficacy of acalabrutinib in subjects with COVID-19 when administered with BSC is a 
secondary endpoint and will be assessed by following variables:
3.3.1
Alive and free of respiratory failure at Day 14 (Day 28)
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 
≥ 0.5)
◦
Noninvasive positive pressure ventilation or continuous positive airway pressure 
◦
Extracorporeal membrane oxygenation
Only the subject’s survival status and respiratory-failure status on Day 14 will be considered 
for this endpoint. If they experience respiratory failure after first dosed but recover by Day 14, 
per the definition above, they will be considered alive and free of respiratory failure at Day 
14.


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Subjects who 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.
Similar analysis will be applied for alive and free of respiratory failure at Day 28. 
3.3.2
Percent change from baseline in C-reactive protein  
This is defined as the percent change from baseline in C-reactive protein (CRP) at Day 1 to 
Day 14 and Day 28 after first dose. For this endpoint, baseline is defined as the last 
observation prior to first dose.
3.3.3
Time to 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
This is defined as the time (in days) from first dose date to the earliest date at which any of the 
following event 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 (CSP Table 8)

Live discharge from hospital

The date the subject is considered fit for discharge (a score of 0, 1 or 2 on the ordinal 
scale)
If a subject does not have an event  on or before Day 28 and does not withdraw/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/ 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 within 28 days.
If a subject does not have an event and dies before Day 28, they will be censored at Day 28.
3.4
Exploratory 
 
 


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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), defined as the following: 
o
Without respiratory failure at baseline: subjects do not require oxygen 
delivered by high-flow nasal cannula or require oxygen delivered by high-flow 
nasal cannula with flow rate ≤ 20 L/min and FiO2 < 0.5
o
With respiratory failure at baseline: subjects require oxygen delivered by high-
flow nasal cannula with 

20 L/min < flow rate <30 L/min and

0.5 ≤ FiO2 < 0.6


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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. Concomitant therapies and procedures are defined as those with 
a stop date on or after the first dose date of study treatment.
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 SAS 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.
The below mentioned general principles will be followed throughout the study:

Demography, baseline characteristics and safety data will be summarised using the 
SAS. All efficacy data will be summarised and analysed using the EES, unless 
otherwise specified. PK data will be summarized using the PKS. Exploratory 
 

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 


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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.  The SD will be 
reported to two more decimal places than the raw data.

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.  Percentages will be presented to one decimal place.

For the PK 
 summaries the reported results will be summarized using 
appropriate significant figures rather than decimal places.

Baseline will be the last assessment of the variable under consideration prior to the 
intake of the first dose of study drug.

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) × 100.

Visit windows will apply as follows:
o
Days 1-14 or discharge: no visit window. Note: if a subject is discharged prior 
to Day 14 they will visit the site for an assessment 2 to 4 days after discharge. 
Assessments should match those for Day 14.
o
Day 20: ±3 days
o
Day 28: ±3 days
o
Safety follow-up at 28 days after last dose of acalabrutinib: ±3 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 for ventilator use, the observations closest to 08:00 will be 
used as the scheduled assessment. If multiple observations are recorded per day 
for other assessments, the worst assessment reported will be used as the 
scheduled assessment.
o
For summaries 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.


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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) (Section 9.3). 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 in Section 9.3, then the earliest of these dates will be imputed.
4.2
Analysis Methods for Disposition, Demographic, Baseline
Characteristics, Prior and Concomitant Medications/Procedures
4.2.1
Disposition of subjects
The number and percentage of subjects who were enrolled to the study, received treatment, 
enrolled 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 for all subjects. 
The number and percentage of subjects in each analysis set, and in each center (using SAS) 
will also be presented.
4.2.2
Protocol deviations 
Important protocol deviations are defined in Section 2.2 and will be listed for all subjects 
received study 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 in SAS using the 
rules for summarizing continuous and categorical variables described in Section 4.1.
In addition to being summarized as continuous variables, age, weight, 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.), weight group 
(<70, ≥70 – ≤90, >90 kg) 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 will also be presented, as well as 
the number of comorbidities (e.g. the number and percentage of subjects with 1, 2, 3, etc.
comorbidities).


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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 or procedures
The following summaries will be produced for all subjects in SAS:

Summary of prior medications or procedures

Summary of concomitant medications or procedures
All concomitant and other treatment data will be listed for all subjects in the SAS.
Missing coding terms should be listed and summarised as "Not coded".
4.3
Analysis of Pharmacokinetics 
The PK analyses will be performed at AZ Research & Development.  
The plasma concentrations of acalabrutinib and ACP-5862 will be listed for all subjects and 
summarized by analyte, and nominal sample time for all subjects in the PKS. Summary 
statistics, including sample size (n), arithmetic mean (Mean), standard deviation (SD), 
coefficient of variation (CV%), standard error of the mean (SEM), minimum, median, and 
maximum will be calculated for all nominal concentration timepoints. 
Excluded subjects will be included in the concentration listings, but will be excluded from the 
summary statistics and noted as such in the tables. 
All BLQ values will be presented as “BLQ” in the concentration listings and footnoted 
accordingly. For the calculation of summary statistics, plasma acalabrutinib and ACP-5862 
concentrations BLQ will be treated as zero prior to the first quantifiable concentration and as 
missing elsewhere. 
Mean and individual concentration-time profiles for plasma acalabrutinib and ACP-5862 will 
be presented on linear and semi-log scales. Linear mean plots will be presented with and 
without SD. 
Plasma acalabrutinib and ACP-5862 PK parameters will be listed and summarized by analyte 
and treatment for all subjects in the PKS. Summary statistics (n, arithmetic mean, SD, CV%, 
SEM, minimum, median, maximum, geometric mean [Geom Mean] and geometric CV% 
[Geom CV%]) will be calculated for plasma acalabrutinib and ACP-5862 PK parameters. 
Excluded subjects will be listed in the PK parameter tables, but will be excluded from the 
summary statistics and noted as such in the tables.


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Individual plasma concentrations of acalabrutinib and ACP-5862 will be presented with the 
same level of precision as received from the bioanalytical laboratory. Individual PK
parameters will be reported to 3 significant figures for individual parameters, with the 
exception of Tmax, Tlast, and t½, which will be presented with 2 decimal places, and Cmax, 
which will be presented in the same precision as the bioanalytical data.
The level of precision for each concentration and PK parameter statistic will be as follows:

minimum/maximum with the same precision as in individual data

arithmetic mean, median and geometric mean with one more level of precision than 
minimum/maximum

SD with one more level of precision than mean/median

n will be presented as an integer 

CV% and geometric CV% will be presented to 1 decimal place.
Potential correlations of exposure with safety and efficacy outcomes or biomarker 
measurements may be explored as warranted by the data.
4.4
Analysis of Efficacy
The efficacy analyses described in this section are secondary endpoints. Formal statistical 
analysis (with generation of a p-value) will not be performed for efficacy endpoints.
4.4.1
Alive and free of respiratory failure at Day 14 (and 28)
The first efficacy endpoint is the proportion of subjects who are alive and free of respiratory 
failure at Day 14, where respiratory failure is defined in Section 3.3.1.
The point estimate and its 90% confidence interval (CI; using Wald method with continuity 
correction) will be calculated and summarized. The difference in the proportion of subjects 
who are alive and free of respiratory failure at Day 14 with its 90% Cis will be included in this 
summary. The number and percentage of subjects who experienced respiratory failure but 
were free of respiratory failure at Day 14 will also be included in above summary.
For those wo have respiratory failure, summary statistics for the number of respiratory failures 
that occurred will be summarized.
This efficacy endpoint will also be summarized (point estimate and 90% CI Wald method 
with continuity correction as above) by the following subgroups: 

age ( predefined age categories defined in Section 4.2.3)


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
sex

race 

ethnicity 

comorbidities (present vs absent) 

history of substance abuse (former/current/never)

Concomitant antiviral use (yes vs no)

Respiratory failure at baseline (with vs without, defined in Section 4.2.3)
The method for handling subjects that withdraw/ are lost to follow up prior to Day 14 is 
detailed in Section 3.3.1.
Similar analysis will be conducted for Day 28.
4.4.2
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.
Box plots of absolute value over time and percent change from baseline to each scheduled 
study assessment may be presented.
A by-subject listing will also be presented.
4.4.3
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
This efficacy endpoint will be portrayed using the KM method. Alongside summary statistics, 
a KM plot of the cumulative improvement rate over time will be presented.
The HR and its 90% CI will be estimated from a Cox Proportional Hazards model (with ties = 
Efron), The CI calculated using a profile likelihood approach. Summary statistics will include 
the lower and upper quartile and median time to clinical improvement with the 90% CI.
The method for handling subjects that withdraw/ are lost to follow up or die is detailed in 
Section 3.3.3.
Additional sensitivity analyses may be performed as appropriate.


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4.5
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. 
4.5.1
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) (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) will be presented in the summaries. 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.

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.  

A summary of the number and percentage of subjects reporting a TEAE by 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 SOC and PT.

A summary of the number and percentage of subjects reporting a TEAE by CTCAE 
grade, SOC and PT.

A summary of the number and percentage of subjects reporting a TEAE with CTCAE 
grade 3 or higher by SOC and PT.

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 


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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), by 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. 
4.5.1.1
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.

A summary of the number and percentage of subjects reporting a treatment-emergent 
SAE by 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 and PT. 

A summary of the primary cause 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 PTs are listed in Section 9.1. These events will be summarized as follows:

A summary of the number and percentage of subjects reporting an AESI by 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 SOC and PT.
A list of AESI PTs will also be provided.


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Events of clinical interest (ECIs) are provided in Section 9.1. These events will be 
summarized similarly to AESIs 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 SAEs with an outcome of death.

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 with an outcome other than death.

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.
4.5.2
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 using the definition of exposure variables in 
Table 5 in Section 3.2.3:

Intended treatment duration

Actual treatment duration

Summary statistics (n, mean, median, SD, minimum, and maximum) of RDI

The number and percentage of dose interruptions, dose increases, and reasons for dose 
interruptions and dose increases

Calculated average daily dose

Treatment compliance
4.5.3
Laboratory assessments
For the following continuous laboratory parameters, summary statistics (n, mean, median, SD, 
minimum, and maximum) of the laboratory results (conventional units and System


Statistical Analysis Plan 
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International (SI) units) and the change from baseline at each scheduled post-baseline 
assessment will be presented:

Fibrinogen

PT

aPTT

INR

D-dimer

CRP

Procalcitonin

Cardiac troponin

BNP
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) 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 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.
4.5.4
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.  
A by-subject listing of all vital sign parameters will be presented; abnormal vital signs will be 
flagged.
4.5.5
Physical examinations and chest imaging, electrocardiograms and 
echocardiograms
By-subject listings of all physical examination and weight data will be presented.


Statistical Analysis Plan 
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Study Code D822FC00005
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By-subject listings of chest imaging (when clinically indicated) findings will be presented. 
If there is a sufficient number of subjects with post-baseline assessments (≥10 subjects), 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.
By-subject listings of ECHO overall evaluation, abnormalities and LVEF will be presented.
4.5.6
Oxygen treatment, ventilator use and mSOFA
Oxygen treatment and ventilator use data will be used to assess efficacy endpoints of the 
study.
The number and percentage of subjects requiring oxygen treatment or mechanical ventilation 
at each timepoint will be presented. The method of oxygen or mechanical ventilation, as well 
as the number and percentage of subjects who go from oxygen treatment to mechanical 
ventilation, will also 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.
4.6
Analysis of exploratory variables and 
 
 
 
 
  
 
 
 
 


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Study Code D822FC00005
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5.
INTERIM ANALYSES
There are no formal interim futility and interim efficacy analyses in this study.
6.
INDEPENDENT DATA MONITORING COMMITTEE
This study will not have iDMC.
7.
SAFETY REVIEW COMMITTEE
This study will have an SRC. The SRC will conduct scheduled reviews of safety and other 
relevant data. In addition, The SRC will meet to review any of the following events should 
they occur during the study:

Any death due to acalabrutinib (per Investigator)

Any Grade 4 hemorrhage due to acalabrutinib (per Investigator)
The SRC will consist of the AstraZeneca Study Physician or delegate, Principal Investigator 
or equivalent delegate from active investigational sites, and Global Safety Physician or 
delegate. Other attendees may also be invited as appropriate. 
Details on the process of ongoing evaluation of safety data by the SRC and the committee 
composition is described further in the SRC charter.
8.
CHANGES OF ANALYSIS FROM PROTOCOL
N/A


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Study Code D822FC00005
32(38)
9.
APPENDIX
9.1
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

Suspected transmission of an infectious agent via product
Events of Clinical Interest
The Events of Clinical Interest (ECIs) have been identified based on preclinical findings, 
emerging data from clinical studies relating to acalabrutinib, and
 
The adverse events (AEs) selected for 
dedicated analysis were evaluated using Standardized MedDRA Queries (SMQs), where 
available, by System Organ Classes (SOCs), or by Sponsor-defined baskets of MedDRA 
Adverse Event Grouped Terms.
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


Statistical Analysis Plan 
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
PT Neutropenic sepsis

PT Neutrophil count decreased

PT Neutrophil percentage decreased
Other leukopenia

SMQ Haematopoietic leukopenia [narrow + 
broad] excluding PTs for neutropenia above
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 
malignancies

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 
syndrome

PT Tumour lysis syndrome
MedDRA version 23.0
HLT=High-Level Term; PT=Preferred Term; SOC=System Organ Classes; SMQ=Standardized MedDRA Queries.
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 version 23.0 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  


Statistical Analysis Plan 
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Study Code D822FC00005
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CNS Hemorrhage Preferred Terms (MedDRA Version 23.0)

Acute haemorrhagic leukoencephalitis

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


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
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 
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Study Code D822FC00005
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9.2
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 Venturi 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) × 0.04) + 0.2
Oxygen tank FLOW RATE in liters / min 
FiO2 -- Fraction of Inspired Oxygen value 
0 (no oxygen, just room air) 
0.2
1 L / min 
0.24 
2 L / min 
0.28 
3 L / min 
0.32 
4 L / min 
0.36 
5 L / min 
0.4 
6 L / min 
0.44 
For a Venturi Mask:
Oxygen tank FLOW RATE in liters / min 
FiO2 -- Fraction of Inspired Oxygen value 
< 2 L / min
0.2
2 L / min ≤ Flow Rate < 4 L / min
0.24
4 L / min ≤ Flow Rate < 6 L / min
0.28
6 L / min ≤ Flow Rate < 8 L / min
0.31
8 L / min ≤ Flow Rate < 10 L / min
0.35
10 L / min ≤ Flow Rate < 15 L / min
0.4
≥ 15 L / min
0.6


Statistical Analysis Plan 
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Study Code D822FC00005
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9.3
Imputation rules for missing or partial AE on concomitant 
medication
Imputation rules for missing or partial AE on concomitant medication dates
Form 
Imputation
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
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.
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.
End date
Missing
AE and 
CM
CM flag ongoing=  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.
Missing day and month
Impute date of last dose + 28 days + 3 days


Statistical Analysis Plan 
AstraZeneca
Study Code D822FC00005
38(38)
10.
REFERENCES


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