Clinical trial NCT04382586
Conditions: COVID-19 Pulmonary Complications COVID-19
Keywords: Corona Virus COVID-19
Sponsor: BeiGene
Start date: 2020-07-06; Completion date: 2021-02-01
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study was to evaluate if the addition of zanubrutinib to supportive care increases the respiratory failure-free survival rate at Day 28 in participants hospitalized for Corona Virus Disease 2019 (COVID-19) and pulmonary distress not receiving mechanical ventilation.

Detailed description:

Arms: arm 1: Participants received zanubrutinib plus supportive care arm 2: Participants received placebo plus supportive care alone
Interventions: intervention 1: Zanubrutinib intervention 2: Supportive Care intervention 3: Placebo
Intervention descriptions: intervention 1: 320 mg (4 x 80 mg) capsules administered orally once daily intervention 2: Supportive care treatment was selected and administered as deemed appropriate by the study investigator intervention 3: Placebo to match zanubrutinib

Protocol documents:
Prot_000.pdf: 
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CLINICAL RESEARCH PROTOCOL
Protocol Title: 
A Phase 2, Randomized, Double Blind, Placebo-Controlled 
Study of Zanubrutinib Treatment in Patients Hospitalized 
for COVID-19 Infection and Pulmonary Distress
Protocol Identifier:
BGB-3111-219
Phase:
2
Investigational Product:
Zanubrutinib (BGB-3111)
Indication:
COVID-19 Pulmonary Complications
Sponsor:
BeiGene, Ltd.
c/o BeiGene USA, Inc.  
2955 Campus Drive, Suite 200
San Mateo, CA 94403 
USA
Sponsor Medical Monitor
Telephone: 
Email: 
Original Protocol (Version 0.0):
13 April 2020
Amendment 1.0:
06 May 2020
Amendment 2.0:
22 July 2020 
Amendment 3.0:
16 October 2020
Amendment 4.0:
08 January 2021
Confidentiality Statement
This confidential information in this document is provided to you as an investigator or consultant for 
review by you, your staff, and the applicable Institutional Review Board/Independent Ethics 
Committee.  Your acceptance of this document constitutes agreement that you will not disclose the 
information contained herein to others without written authorization from the sponsor.
1&7


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FINAL PROTOCOL APPROVAL SHEET
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of Zanubrutinib Treatment in 
Patients Hospitalized for COVID-19 Infection and Pulmonary Distress
BeiGene, Ltd. Approval:
____________
___________________________________
Date


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SYNOPSIS
Name of Sponsor/Company: BeiGene, Ltd.
Investigational Product: Zanubrutinib (BGB-3111)
Title of Study: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of Zanubrutinib 
Treatment in Patients Hospitalized for COVID-19 Infection and Pulmonary Distress
Protocol Identifier: BGB-3111-219
Phase of Development: 2
Number of Patients: Approximately 73
Study Centers: Multicenter
Study Objectives:
Primary Objectives (Cohort 1)
x
To evaluate if the addition of zanubrutinib to supportive care increases the respiratory failure-free
survival rate at Day 28
x
To evaluate if the addition of zanubrutinib to supportive care reduces the time to breathing room air
Secondary Objectives (Cohort 1)
x
To compare the efficacy of zanubrutinib plus supportive care versus best supportive care as
measured by secondary endpoints
x
To compare the safety of zanubrutinib plus supportive care versus best supportive care
Exploratory
x
x
x
Study Design:
This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter study of zanubrutinib plus 
supportive care versus placebo plus supportive care in approximately 63 patients (Cohort 1) with 
confirmed COVID-19 by reverse transcription polymerase chain reaction (RT-PCR) from swabs, who 
require hospitalization and have been on supplemental oxygen for a duration of ≤96 hours for 
pulmonary distress related to COVID-19.  Randomization will be stratified by age (< 65 years or
≥65 years) and use of antiviral therapy (yes or no). The first dose of study drug should be given 
≤12 hours after randomization.  Study drug (zanubrutinib 320 mg once daily or placebo 4 capsules 
once daily) will be administered for up to 28 days.  Approximately 63 patients will be enrolled in 
Cohort 1.


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The primary endpoints for this study are the respiratory failure-free survival rate at Day 28 and the 
time to breathing room air, both in the randomized cohort.  Secondary endpoints include:
x
Proportion of patients experiencing respiratory failure or death
x
All-cause mortality
x
Proportion of patients discharged alive
x
Proportion of patients discharged from the ICU alive
x
Median reduction in days spent on supplemental oxygen
x
Mechanical ventilation-free survival
x
Days on mechanical ventilation
x
Duration of hospitalization
x
Time to discharge
x
Change in WHO 8-point scale from baseline
x
PAO2:FIO2 and/or oxygenation index, for patients on mechanical ventilation
x
Safety and tolerability of zanubrutinib as an adjuvant therapy to standard of care as
assessed by treatment-emergent adverse events (TEAEs), serious adverse events (SAEs),
related adverse events (AEs), TEAEs by grade, and abnormal laboratory findings
x
Clinical status assessed using an ordinal scale at a pre-specified timepoint
x
Time to objective measure of recovery
Study Assessments:
Efficacy will be assessed by the number of patients who are respiratory failure free at Day 28 and the 
time to breathing room air.  The assessments will include level of oxygenation, amount of supplemental 
O2, functional status, and mechanical ventilation status.
Secondary efficacy assessments will explore days on mechanical ventilation if required and the number 
of days of oxygen, all-cause mortality, duration of hospitalization, and change in WHO 8-point scale 
from baseline.
Assessments of safety will include TEAEs, SAEs, and changes from baseline in selected laboratory 
analytes, physical findings, electrocardiograms, and vital signs.
Efficacy will be assessed through 28 days after first dose of study drug.  Safety will be followed 
through 56 days after last dose of study drug.


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Main Eligibility Criteria:
To participate in this study, patients must be ≥18 years of age, have a confirmed diagnosis of Severe 
Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, and have been on supplemental 
O2 for ≤96 hours.  A smaller cohort of patients requiring mechanical ventilation at study entry will be 
accrued.
Test Product, Dose, and Mode of Administration: 
Cohort 1: Zanubrutinib (320 mg once daily) or placebo administered orally for 28 days.
Statistical Methods:
Analysis Sets:
The Safety Analysis Set includes all patients who received any dose of study drug.  The Safety 
Analysis Set will be the primary analysis set for all safety analyses.  The intent-to-treat analysis (ITT) 
set will be the primary analysis set for all efficacy analyses.  The Safety Analysis Set will also be used 
for selected efficacy analyses.
Analysis of Primary Endpoints:
The coprimary endpoints for this study are the respiratory failure-free survival rate at Day 28 and the 
time to breathing room air, both in Cohort 1.  The respiratory failure-free survival rate will be 
compared between the two treatment arms by Fisher's exact test. The time to breathing room air will be 
compared between the two arms using a Cox model with the stratification factors in the randomization 
and the WHO 8-point scale at baseline as covariates. Two analyses (interim and final) will be 
performed for the coprimary endpoints in Cohort 1, with the interim analysis performed when the first 
42 patients complete 28 days of treatment.  The type 1 error increase owing to these the interim and 
final analyses will be controlled by the O’Brien Fleming alpha spending function for each test.  The 
boundary for efficacy stop will be based on the p-value controlled from the Fisher’s exact test for 
respiratory failure-free survival at Day 28 and the p-value from the Cox model for time to breathing 
room air. 
Analysis of Secondary Endpoints:
The secondary endpoints include 
Efficacy:
x 
Median reduction in days spent on supplemental oxygen, with time on supplemental oxygen 
imputed to the maximum number of days on supplemental oxygen observed in the study + 1 for all 
points following the death of a patient
x 
All-cause mortality at Study Days 7, 14, 21, and 28
x 
Proportion of patients discharged alive at Days 7, 14, 21, and 28
x 
Proportion of patients discharged from the ICU alive at Days 7, 14, 21 and 28
x 
Change from baseline in the WHO 8-point ordinal scale
x 
Proportion of patients experiencing respiratory failure or death on Study Days 7, 14, 21, and 28
x 
Mechanical ventilation-free survival
x 
Days on mechanical ventilation


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x 
Duration of hospitalization
x 
Time to discharge
x 
PaO2:FiO2 and/or oxygenation index
x 
Clinical status assessed using an ordinal scale at a pre-specified timepoint
x 
Time to objective measure of recovery (eg, return to baseline oxygen requirement, as appropriate
x 
Proportion of patients discharged alive 
.
Safety and Tolerability:
x 
TEAEs and SAEs, frequency, seriousness and relatedness of TEAEs will be analyzed according to 
the Medical Dictionary for Regulatory Activities (MedDRA). Laboratory abnormalities will be 
analyzed according to National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) v5.0.
Safety Analysis:
Adverse event verbatim descriptions (as recorded by the investigator) will be coded to standardized 
medical terminology using MedDRA and graded according to the NCI-CTCAE v5.0. All TEAEs will 
be summarized.  SAEs, deaths, TEAEs ≥Grade 3, and TEAEs that led to treatment discontinuation, 
dose reduction, or treatment interruption, will be summarized.
Clinical laboratory data with values outside of the normal range will be identified.  Select laboratory 
data will be summarized by visit and grade.
Exploratory Pharmacokinetic Analysis:
x 
Sample Size:
The study will enroll approximately 67 to 73 patients with 63 patients in Cohort 1 randomized to either 
zanubrutinib and supportive care (Arm A) or placebo plus supportive care (Arm B).  Assuming 10% 
dropout, unrelated to efficacy, 42 patients total in Cohort 1 will provide approximately 81% of power 
to detect the increase in the respiratory failure-free rate of 25% (70% vs 95%) under a z-test at 1-sided 
level of 0.1. Sixty-three patients will provide 81% power to detect and increase in the respiratory 
failure-free survival rate from 70% to 91%. Fifty-nine of 63 patients breathing room air will provide 
80% power to detect a hazard ratio of 0.57 (an event is breathing room air).


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TABLE OF CONTENTS
CLINICAL RESEARCH PROTOCOL...........................................................................................1 
FINAL PROTOCOL APPROVAL SHEET....................................................................................2 
SYNOPSIS3 
1.
INTRODUCTION ......................................................................................................14
1.1. 
Study Disease(s) .........................................................................................................14 
1.2. 
Investigational New Drug...........................................................................................14 
1.3. 
Rationale.....................................................................................................................14 
1.4. 
Zanubrutinib ...............................................................................................................22 
2.
STUDY OBJECTIVES ..............................................................................................23 
2.1. 
Primary Objectives (Cohort 1)....................................................................................23 
2.2. 
Secondary Objectives (Cohort 1)................................................................................23 
2.3. 
Exploratory Objectives ...............................................................................................23 
3.
STUDY DESIGN .......................................................................................................25 
3.1. 
Summary of Study Design..........................................................................................25 
3.2. 
Study Schema .............................................................................................................26 
4.
ELIGIBILITY CRITERIA .........................................................................................27 
4.1. 
Inclusion Criteria ........................................................................................................27 
4.2. 
Exclusion Criteria.......................................................................................................28 
5.
ENROLLMENT AND STUDY PROCEDURES ......................................................30 
5.1. 
Visit Windows ............................................................................................................30 
5.2. 
Screening ....................................................................................................................30 
5.2.1. 
Informed Consent .......................................................................................................30 
5.2.2. 
Females of Childbearing Potential and Contraception ...............................................30 
5.2.3. 
Patient Numbering......................................................................................................31 
5.2.4. 
Medical History ..........................................................................................................31 
5.2.5. 
Confirmation of Eligibility .........................................................................................32 
5.3. 
Randomization............................................................................................................32 
5.4. 
Study Drug Dispensation............................................................................................32 
5.5. 
Safety Assessments.....................................................................................................33 
5.5.1. 
Physical Examination and Vital Signs........................................................................33 
5.5.2. 
Electrocardiogram.......................................................................................................33 


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5.5.3. 
Adverse Events Review..............................................................................................33 
5.6. 
Efficacy Assessments .................................................................................................33 
5.6.1. 
Oxygenation................................................................................................................33 
5.6.2. 
Radiographic Evaluation ............................................................................................34 
5.7. 
Laboratory Assessments .............................................................................................34 
5.7.1. 
Hematology.................................................................................................................34 
5.7.2. 
Serum chemistries.......................................................................................................34 
5.7.3. 
Inflammatory and Cardiac Markers............................................................................34 
5.7.4. 
SARS-CoV-2 Testing.................................................................................................34 
5.7.5. 
Coagulation.................................................................................................................34 
5.7.6. 
Hepatitis B and C testing............................................................................................35 
5.7.7. 
Pregnancy Test............................................................................................................36 
5.8. 
..................................................................................................................36 
5.8.1. 
....................................................................................................37 
5.9. 
..........................................................................................................37 
5.10. 
Hospital Discharge......................................................................................................37 
5.11. 
Outpatient Visits.........................................................................................................38 
5.12. 
Unscheduled Visits .....................................................................................................38 
5.13. 
End of Treatment Period.............................................................................................38 
5.14. 
Safety Follow-up ........................................................................................................38 
5.15. 
End of Study ...............................................................................................................38 
5.16. 
Lost to Follow-up .......................................................................................................39 
6. 
STUDY TREATMENT..............................................................................................40 
6.1. 
Study Treatment Preparation and Dispensation .........................................................40 
6.1.1. 
Packaging and Labeling..............................................................................................40 
6.1.2. 
Handling and Storage .................................................................................................40 
6.1.3. 
Compliance and Accountability .................................................................................40 
6.1.4. 
Disposal and Destruction............................................................................................40 
6.2. 
Dosage and Administration ........................................................................................41 
6.2.1. 
Study Drug..................................................................................................................41 
6.2.2. 
Dispensation for Outpatient Administration...............................................................41 
6.3. 
Overdose.....................................................................................................................41 


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6.3.1. 
Minor Surgical Procedures .........................................................................................41 
6.3.2. 
Elective Major Surgical Procedures ...........................................................................42 
6.3.3. 
Emergency Major Surgical Procedures ......................................................................42 
6.4. 
Dose Modifications.....................................................................................................42 
6.5. 
Discontinuation from Study Treatment ......................................................................42 
6.5.1. 
Discontinuation for Adverse Events...........................................................................42 
6.5.2. 
Discontinuation for Clinical Benefit...........................................................................43 
6.6. 
Blinding ......................................................................................................................43 
6.6.1. 
Emergency Unblinding...............................................................................................44 
6.6.2. 
Inadvertent Unblinding...............................................................................................44 
7. 
CONCOMITANT THERAPY ...................................................................................45 
7.1. 
Concomitant Therapy .................................................................................................45 
7.1.1. 
Permitted Medications................................................................................................45 
7.1.2. 
Prohibited Medications...............................................................................................45 
7.2. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications.................................................................................................................46 
7.2.1. 
Effects of Cytochrome P450 (CYP)-Inhibiting/Inducing Drugs on Exposure 
of Zanubrutinib ...........................................................................................................46 
7.2.2. 
Effects of zanubrutinib on exposure of other concomitant medications ....................46 
8. 
SAFETY MONITORING AND REPORTING .........................................................48 
8.1. 
Adverse Events ...........................................................................................................48 
8.1.1. 
Definitions and Reporting...........................................................................................48 
8.1.1.1. 
Assessment of Severity...............................................................................................48 
8.1.1.2. 
Assessment of Causality.............................................................................................49 
8.1.1.3. 
Follow-up of Adverse Events and Serious Adverse Events .......................................50 
8.1.2. 
Laboratory Test Abnormalities...................................................................................50 
8.1.3. 
Lack of Efficacy .........................................................................................................51 
8.2. 
Serious Adverse Events ..............................................................................................51 
8.2.1. 
Definitions ..................................................................................................................51 
8.3. 
Suspected Unexpected Serious Adverse Reaction .....................................................52 
8.4. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................52 
8.4.1. 
Adverse Event Reporting Period ................................................................................52 


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8.4.2. 
Prompt Reporting of Serious Adverse Events............................................................52 
8.4.2.1. 
Timeframes for Reporting Serious Adverse Events...................................................52 
8.4.2.2. 
Completion and Transmission of the Serious Adverse Event Report ........................52 
8.4.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................53 
8.4.3. 
Eliciting Adverse Events ............................................................................................53 
8.4.4. 
Death...........................................................................................................................53 
8.5. 
Pregnancy Reporting ..................................................................................................53 
8.6. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees................................................54 
8.7. 
Safety Monitoring Committee....................................................................................54 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION.................55 
9.1. 
Randomization Methods.............................................................................................55 
9.2. 
Study Endpoints..........................................................................................................55 
9.3. 
Sample Size, Accrual Rate and Study Duration .........................................................58 
9.3.1. 
Statistical Considerations for the Mechanical Ventilation Cohort .............................60 
9.3.2. 
Update to the Statistical Considerations for Cohort 1 ................................................60 
10. 
STUDY COMMUNICATION ...................................................................................62 
10.1. 
Provision of Study Results and Information to Investigators.....................................62 
11. 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS ..........................63 
11.1. 
Regulatory Authority Approval..................................................................................63 
11.2. 
Investigator Responsibilities.......................................................................................63 
11.2.1. 
Good Clinical Practice................................................................................................63 
11.2.2. 
Ethical Conduct of the Study and Ethics Approval....................................................63 
11.2.2.1. 
Protocol Amendments ................................................................................................63 
11.2.3. 
Informed Consent .......................................................................................................64 
11.2.4. 
Investigator Reporting Requirements.........................................................................64 
11.2.5. 
Confidentiality............................................................................................................64 
11.2.6. 
Data Collection ...........................................................................................................65 
11.2.7. 
Data Management/Coding..........................................................................................66 
11.2.8. 
Drug Accountability ...................................................................................................66 
11.2.9. 
Inspections, Audits, and Monitoring Visits ................................................................66 
11.2.10. 
Protocol Adherence ....................................................................................................67 
11.2.11. 
Financial Disclosure ...................................................................................................67 


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11.3. 
Study Report and Publications....................................................................................67 
11.4. 
Study and Study Center Closure.................................................................................68 
11.5. 
Records Retention and Study Files.............................................................................68 
11.6. 
Information Disclosure and Inventions ......................................................................70 
11.7. 
Joint Investigator/Sponsor Responsibilities................................................................70 
11.7.1. 
Access to Information for Monitoring........................................................................70 
11.7.2. 
Access to Information for Auditing or Inspections ....................................................71 
12. 
REFERENCES ...........................................................................................................72 
LIST OF TABLES
Table 1: 
Summary of Pro-Inflammatory and Chemoattractant Cytokine Patterns in 
Patients Infected With SARS-CoV-1 and SARS-CoV-2 (highlighted in red),
and Following Ibrutinib Treatment in Patients With CLL, WM, and cGVHD 
(highlighted in green) .................................................................................................18 
Table 2: 
Active Hepatitis B or Hepatitis C Infection (Detected Positive by 
Polymerase Chain Reaction).......................................................................................36 
Table 3: 
Study Drug Dose Reduction Levels ...........................................................................42 
Table 4: 
Dose Modification for Study Drug when Co-Administered with 
Strong/Moderate CYP3A Inhibitors or Inducers........................................................46 
Table 5: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................52 
Table 6: 
Ordinal Scale for Clinical Improvement.....................................................................57 
Table 7: 
Respiratory Failure and Death in the Standard Care Arm of Lopinavir-
Ritonavir Study...........................................................................................................58 
Table 8: 
Highest Level of Respiratory Support in Kaiser Permanente Study ..........................59 
Table 9: 
Power for the Primary Endpoint of Respiratory Failure-Free Survival at 
Day 28.........................................................................................................................59 
Table 10: 
...................................................60 
Table 11: Power, Sample Size, and Type 1 Error for the Interim Analysis Plan .......................61 
LIST OF FIGURES
Figure 1: 
A Model for the Immunopathogenesis of SARS Based on SARS-CoV-1
Model..........................................................................................................................15 
Figure 2: 
Summary of the Main Macrophage Polarization States of Activated 
Macrophages...............................................................................................................16 


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Figure 3: 
Pulmonary Findings for Mice Treated With PBS or Ibrutinib Following 
Lethal Intranasal Challenge With Mouse Adapted H1N1 Influenza..........................19 
Figure 4: 
Survival and Body Weight Loss for Mice Treated With PBS or Ibrutinib 
Following Lethal Intranasal Challenge With Mouse Adapted H1N1 
Influenza .....................................................................................................................20 
Figure 5: 
Inflammatory Cells Observed in BAL Fluids, and Cytokine Levels From 
Lung Homogenates in Mice Treated With PBS or Ibrutinib Following Lethal 
Intranasal Challenge With Mouse-Adapted H1N1 Influenza.....................................21 
Figure 6: 
Study Schema .............................................................................................................26 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
ACE2
angiotensin-converting enzyme 2
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATII
alveolar type II
BTK
Bruton tyrosine kinase
Cmax
maximum concentration 
COVID-19
coronavirus disease 2019
CRF
case report form
CYP
cytochrome P450
ECG
electrocardiogram
eCRF
electronic case report form
GCP
Good Clinical Practice
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCK
hematopoietic cell kinase
HCV
hepatitis C virus
IC50
50% maximum inhibitory concentration
ICF
informed consent form
IEC
Independent Ethics Committee
IRB
Institutional Review Board
MedDRA
Medical Dictionary for Regulatory Activities
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
PCR
polymerase chain reaction
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SMC
Safety Monitoring Committee
TEAE
treatment-emergent adverse event
TLR
Toll-like receptors
ULN
upper limit of normal
WHO
World Health Organization


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1.
INTRODUCTION
1.1.
Study Disease(s)
Patients with confirmed coronavirus disease 2019 (COVID-19) by reverse transcription 
polymerase chain reaction (RT-PCR) from swabs, and who require hospitalization, have been on 
supplemental oxygen for a duration of ≤96 hours, and have pulmonary distress related to 
COVID-19, are eligible for this study.  An additional pilot cohort of 4 to 10 patients, who have 
been on mechanical ventilation for ≤ 24 hours, will be treated on the protocol.
1.2.
Investigational New Drug
Zanubrutinib (also known as BGB-3111) is an irreversible inhibitor of Bruton tyrosine kinase 
(BTK) that is approved by the United States Food and Drug Administration (FDA) for the 
treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one 
prior therapy.  Accelerated approval was granted for this indication based on overall response 
rate. Continued approval for this indication may be contingent upon verification and description 
of clinical benefit in a confirmatory trial.
1.3.
Rationale
COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) (Guan et al 2020). Pulmonary failure is the main cause of mortality related to 
COVID-19 (Bhatraju et al 2020; Wang et al 2020). Up to 80% of patients who require 
hospitalization for COVID-19 require supplemental oxygenation for an average of 13 days (Cao 
et al 2020). Furthermore 30% to 40% of those hospitalized for pulmonary distress may require 
mechanical ventilation (Wang et al 2020; Wu et al 2020). Therapies that block COVID-19-
related lung injury and improve pulmonary function are, therefore, urgently needed.
SARS-CoV-2 binds via the angiotensin-converting enzyme 2 (ACE2) receptor that is highly 
expressed on alveolar type II (ATII) cells in the lung (Du et al 2009; Hoffman et al 2020). ATII 
cells constitute 5% to 15% of the lung epithelium.  While alveolar type I cells are highly adapted 
for gas exchange, ATII cells have a specialized role in innate immune response (Fujino et al 
2011).  ATII cells express Toll-like receptors (TLRs) and can trigger inflammatory cytokines and 
chemoattractants in response to viral and bacterial pathogens that recruit and activate other 
immune cells, including macrophages and neutrophils (Pechkovsky et al 2005; Wang et al 2009;
Thorley et al 2010; Chuquimia et al 2013; Werner and Steele 2014).  Highly relevant to 
coronavirus infection, expression of pro-inflammatory and chemoattractant cytokines IL1-B, 
IL-6, IP-10/CXCL-10, MCP-1, and TNF-α were identified in the ACE2-positive cells from 
autopsy tissue of SARS-CoV-1 infected patients, that appeared causally related to the acute lung 
injury and pathogenesis observed with SARS-CoV-1 (Figure 1, He et al 2006). A similar profile 
of elevated cytokine levels of IL-6, IL-8, IP-10/CXCL-10 and MCP-1 was also reported in the 
plasma of SARS-CoV-1 patients during the progressive and end stage of infection (Jiang et al 
2005), a profile more consistent with M1-polarized macrophage response (Figure 2, Ley 2017;
Atri et al 2018).


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Figure 1:
A Model for the Immunopathogenesis of SARS Based on SARS-CoV-1
Model
Source: Figure and notes taken from He et al 2006.
Abbreviations: ACE2, angiotensin‐converting enzyme 2; ALI, acute lung injury; ARDS, acute respiratory distress 
syndrome; MΦ, macrophages; PICs, pro‐inflammatory cytokines; SARS-CoV, severe acute respiratory syndrome 
coronavirus.
Notes: SARS‐CoV in droplets enters into the lung, where the virus binds via its S protein to ACE2 on the alveolar or 
bronchial epithelial cells. The virus replicates in these cells, from which new virions are released into the blood.
The infected cells under the stimulation of SARS‐CoV and some uninfected cells induced by viral antigens or PIC‐
regulatory factors produce high levels of PICs to mediate inflammatory responses for combating the virus.
However, these PICs also damage the host cells. Some of the PICs, eg monocyte chemoattractant protein‐1 
(MCP-1), attract monocytes in blood to migrate to the alveolar cavities, where the monocytes are stimulated by other 
PICs to become proliferative and/or activated macrophages (MΦ). The activated macrophages can produce more 
PICs and may transmit SARS‐CoV to other sites. Some of the PICs, including TGF‐β1 and TNF‐α, may induce 
apoptotic death of the epithelial cells, pneumocytes, and lymphocytes, or mediate pulmonary fibronosis, resulting in 
ALI and ARDS. The cell‐free and MΦ‐associated SARS‐CoV in the blood can be transmitted from the lung to other 
organs to infect the ACE2‐expressing cells in the local sites. More PICs are produced and the level of PICs in the 
blood is rapidly elevated, leading to multi‐organ dysfunction.


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Figure 2:
Summary of the Main Macrophage Polarization States of Activated 
Macrophages
Source: Figure and notes taken from Atri et al 2018.
Abbreviations: IFNγ, interferon gamma; iNOS, inducible nitric oxide synthase; IL, interleukin; LPS, 
lipopolysaccharide; MCP, monocyte chemoattractant protein; MCSF, macrophage colony stimulating-factor; MHC,
major histocompatibility complex; MR, mannose receptor; ROS, reactive oxygen species; TGF, transforming 
growth factor; TNF, tumor necrosis factor.
Notes: Summary of the main macrophage polarization states of activated macrophages.  Different stimuli and 
signaling pathways have been described as inducers of M1-like or M2-like activation states, of which the most 
widely referenced ones are summarized here.  M1-like or M2-like polarization has been reported in humans as being 
related to distinct defensive or healing schemas.  Many roles have been ascribed to the polarization status, of which 
pro- and anti-inflammatory macrophage potentiation has for a long time been classically associated to the M1-
like/M2-like-like dichotomy.
SARS-CoV-1 shares 86% homology and has a similar pathogenetic mechanism to SARS-CoV-2
(Chan et al 2020; Heurich et al 2014). Similar to SARS-CoV-1 patients, SARS-CoV-2 patients 
that required intensive care showed elevated plasma levels of inflammatory cytokines and 
chemoattractants such as IL-2, IL-6, IL-7, IL-10, G-CSF, IP-10/CXCL-10, MCP-1/CCL2, 
MIP-1a/CCL3, and TNF-α (Huang et al 2020). The importance of inflammatory cytokines to 
lung injury in SARS-CoV-2 infected patients has been suggested by reports of benefit with IL-6
and IL-6-receptor-blocking antibodies, and clinical trials to examine their use have been initiated 
(ClinicalTrials.gov IDs: NCT04317092, NCT04306705, NCT04315298).


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Studies have shown an important role for the TEC family member BTK, and its upstream 
activator, hematopoietic cell kinase (HCK), an SRC family member that triggers TLR-mediated 
signaling (Jeffries et al 2003; Yang et al 2013; Yang et al 2016). Both BTK and HCK can be 
triggered by MYD88, a TLR-adaptor protein that signals for all TLRs except TLR3 in response 
to viral and bacterial pathogens, including coronaviruses (Wang and Liu 2016). ATII cells 
express TLRs, as do alveolar macrophages that coordinate inflammatory responses with ATII 
cells (Pechkovsky et al 2005; Wang et al 2009; Thorley et al 2010; Chuquimia et al 2013;
Werner and Steele 2014). As components of TLR/MYD88 signaling, BTK and HCK can drive 
inflammatory cytokine production through ERK1/2 (Chen et al 2018).
In a transgenic mouse model, overexpression of activated HCK promoted extensive pulmonary 
inflammation and enhanced innate immune response characterized by extensive eosinophilic and 
mononuclear cell infiltration within the lung parenchyma, alveolar air spaces, and around blood 
vessels, as well as marked epithelial mucus metaplasia in conducting airways (Ernst et al 2002).
Lungs from these mice show areas of emphysema and pulmonary fibrosis, which together with 
inflammation resulted in altered lung function and respiratory distress, particularly in aging mice 
(Ernst et al 2002). Elevated levels of TNF-α were also identified in the bronchoalveolar lavage 
fluids of these mice following LPS challenge. The pulmonary pathology findings from these 
mice show great overlap with those described in the lungs of patients with COVID-19 infection 
which showed serous and fibrin exudation with alveolar infiltration consisting majorly of 
macrophages and monocytes. The blood vessels of alveolar septum were also congested, 
edematous and widened, with modest infiltration of monocytes and lymphocytes (Tian et al 
2020; Yao et al 2020).
Ibrutinib is a highly potent, covalent inhibitor of BTK (biochemical 50% maximum inhibitory 
concentration [IC50] 0.5 nM). Ibrutinib is also a potent reversible inhibitor of HCK (IC50 49
nM) (Yang et al 2016, Harvard Medical School LINCS Project 2020). The IC50 levels for BTK 
and HCK are well within the pharmacologically attainable dosimetry of orally administered 
ibrutinib, although HCK inhibition has not yet been demonstrated in patients under ibrutinib 
therapy, possibly due to the rapid clearance (Byrd et al 2013). Serially collected blood samples 
from patients with chronic lymphocytic leukemia, Waldenström macroglobulinemia, and chronic 
graft versus host disease on ibrutinib monotherapy showed marked reductions in 
proinflammatory and chemoattractant cytokines that greatly overlapped with those reported 
elevated in the plasma of SARS-CoV-1 and SARS-CoV-2 patients, and in ACE2-positive cells 
from lung tissue of SARS-CoV-1 patients (Table 1, He et al 2006; Jiang et al 2005; Huang et al 
2020; Niemann et al 2016; Vos et al 2017; Miklos et al 2017). In the iLLUMINATE randomized 
study, chronic lymphocytic leukemia patients treated with ibrutinib immediately prior to infusion 
with obinutuzumab also showed significantly decreased levels of inflammatory cytokines 
associated with infusion-related reactions (a cytokine release syndrome) (Greil et al 2019). 


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Table 1:
Summary of Pro-Inflammatory and Chemoattractant Cytokine Patterns in 
Patients Infected With SARS-CoV-1 and SARS-CoV-2 (highlighted in red),
and Following Ibrutinib Treatment in Patients With CLL, WM, and cGVHD
(highlighted in green)
He et al 
2006
Jiang et al 
2005
Huang et 
al 2020
Niemann 
et al 2016
Greil et al 
2019
Vos et al 
2017
Miklos et
al 2017
Patients
CoV-1
CoV-1
CoV-2
CLL on 
ibrutinib
CLL on 
ibrutinib
WM on 
ibrutinib
cGVHD 
on 
ibrutinib
Tissue
ACE2+ 
cells
Plasma
Plasma
Plasma
Plasma
Plasma
Plasma
GMCSF
↑
↓
IL1B
↑
IL2
↑
↓ (IL2RA)
IL6
↑
↑
↓
↓
↓
IL7
↑
IL8
↑
↓
↓
↓
↓
IL10
↑
↓
↓
Variable
IP10/CXCL10
↑
↑
↓
↓
↓
MCP-1/CCL2
↑
↑
↑
↓
↓
↓
MIP-1A/CCL3
↑
↓
↓
MIP1B/CCL4
↑
↓
↓
↓
TNFA
↑
↓
↓
↓
↓
Abbreviations: ACE2, angiotensin‐converting enzyme 2; CCL, C-C motif chemokine ligand; cGVHD, chronic graft 
versus host disease; CLL, chronic lymphocytic leukemia; CXCL10, C-X-C motif chemokine 10; GMCSF, 
granulocyte-macrophage colony-stimulating factor; IL, interleukin; IP-10, interferon gamma-induced protein 10;
MCP-1, monocyte chemoattractant protein-1; MIP, macrophage inflammatory protein; TNFA, tumor necrosis factor 
alpha; WM, Waldenström macroglobulinemia.
The potential for ibrutinib to abrogate lung injury and death was demonstrated in an 
experimental model wherein mice challenged with a lethal intranasal inoculum of a mouse 
adapted strain of H1N1 influenza virus were protected against lung injury. Control mice that 
received phosphate buffered saline (PBS) developed respiratory failure, along with histological 
and CT findings consistent with lung injury in sharp contrast to the mice that received ibrutinib 
(Figure 3, Florence et al 2018). Mice treated with PBS also lost weight and died, whereas those 
treated with ibrutinib recovered their weight after a brief loss and all survived (Figure 4, Florence
et al 2018). Notably, mice treated with ibrutinib also showed decreased inflammatory cell 
infiltration as well as proinflammatory cytokines in lung tissues that included pro-inflammatory 
and chemoattractant cytokines such as IL-1β, IL-6, KC/CXCL1, TNFα, and MCP-1 observed in 
SARS-CoV-1 and SARS-CoV-2 patients (Figure 5, Florence et al 2018).


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Figure 3:
Pulmonary Findings for Mice Treated With PBS or Ibrutinib Following 
Lethal Intranasal Challenge With Mouse Adapted H1N1 Influenza
Source: Figures and notes taken from Florence et al 2018.
Abbreviations: Btk Inh, Bruton tyrosine kinase inhibitor; Flu, influenza A virus; PBS, phosphate buffered saline; 
PMN, polymorphonuclear leukocyte.
A: representative hematoxylin-eosin-stained lung sections (left and middle) and CT images (right) from mice 7 days 
after influenza A virus (Flu) infection [n = 10 and 5 mice for PBS- and Btk inhibitor (Inh)-treated groups, 
respectively].
B: representative images of Bruton tyrosine kinase (Btk) in lungs of influenza A virus-infected mice. Tissue sections 
were analyzed by immunofluorescent staining for Btk and a PMN marker (Ly6G 1A8). White arrows indicate 
Ly6G/Btk double-positive cells; note differences in Btk staining between PBS- and Btk inhibitor-treated groups.
Figure
C: lung volume derived from CT data (n = 10 and 5 mice for PBS- and Btk inhibitor-treated groups, respectively). 
Values are means ± SD; n = 3 mice in each group. *P < 0.05 (by Mann-Whitney rank sum test).
D: average intensity of Btk staining expressed as fold change over control. Values are means ± SD; n = 3 mice in 
each group.


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Figure 4:
Survival and Body Weight Loss for Mice Treated With PBS or Ibrutinib 
Following Lethal Intranasal Challenge With Mouse Adapted H1N1 Influenza
Source; Figures and legend taken from Florence et al 2018.
Abbreviations: Btk Inh, Bruton tyrosine kinase inhibitor; PBS, phosphate buffered saline.
Notes: Survival (A) and weight loss (B) of C57BL/6 mice infected intranasally with influenza A virus (A/PR/8/34). 
Starting 3 days after infection, mice were treated daily with PBS (n = 7) or Bruton tyrosine kinase (Btk) inhibitor 
(Inh, n = 10) administered intranasally. Animals were monitored until death (4 mice) or weight loss of >30%, at 
which point they were euthanized and counted as dead (3 mice). Values for weight loss are means ± SE. Statistical 
significance of weight loss for days 4–9 of PBS-treated mice (n = 7) and Btk inhibitor-treated mice (n = 10) was 
determined by 2-way repeated-measures ANOVA with post hoc Bonferroni’s t-test: **P < 0.01.


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Figure 5:
Inflammatory Cells Observed in BAL Fluids, and Cytokine Levels From 
Lung Homogenates in Mice Treated With PBS or Ibrutinib Following Lethal 
Intranasal Challenge With Mouse-Adapted H1N1 Influenza
Source: Figures and legend taken from Florence et al 2018.
Abbreviations: BAL, bronchoalveolar lavage; Btk Inh, Bruton tyrosine kinase inhibitor; Flu, influenza A virus; IL, 
interleukin; KC, keratinocyte chemoattractant; PBS, phosphate buffered saline; TNFα, tumor necrosis factor alpha;
MCP-1, monocyte chemoattractant protein‐1; WBC, white blood cell.
A: bronchoalveolar lavage (BAL) protein concentration, total white blood cell (WBC) count, and number of 
neutrophils in BAL fluids at 7 days after influenza A virus (Flu) infection. Values are means ± SD; n = 10 and 4 
mice for PBS- and Bruton tyrosine kinase (Btk) inhibitor (Inh)-treated groups, respectively, for BAL protein 
concentration and 10 and 5 mice for PBS- and Btk inhibitor-treated groups, respectively, for cell counts. **P < 0.01 
(by Mann-Whitney rank sum test); ***P < 0.001 (by Student’s t-test).
B: inflammatory cytokine/chemokine concentrations in lung homogenates from mice at 7 days after influenza A 
virus infection. Values are means ± SD; n = 10 and 5 mice for PBS- and Btk inhibitor-treated groups, respectively. 
*P < 0.001 (by Student’s t-test).
The above findings support the rationale that an exaggerated cytokine response triggered by 
ATII cells and resident macrophages in response to SARS-CoV-2 is etiological for the 
pulmonary injury and respiratory failure associated with COVID-19.  The importance of 
inflammatory cytokines to lung injury in SARS-CoV-2 infected patients has been suggested by 
reports of benefit with IL-6 and IL-6-receptor-blocking antibodies, and clinical trials to examine 
their use have been initiated (ClinicalTrials.gov IDs: NCT04317092, NCT04306705, 


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NCT04315298).  The ability to block inflammatory cytokine production to limit pulmonary 
injury has been observed in patients with severe COVID-19 who received treatment with the IL-
6 blocking antibody tocilizumab.
Ibrutinib blocks TLR signaling, and cytokines associated with SARS-CoV-2, including those 
found in ATII cells. Importantly, in a relevant experimental mouse model, ibrutinib protected 
mice subjected to lethal intranasal inoculums of mouse adapted H1N1 influenza and suppressed 
inflammatory cell recruitment and pathological cytokines that overlapped with many of those 
observed in SARS-CoV-2 infected patients. Ibrutinib and the BTK inhibitor class may therefore 
protect against lung injury in patients with COVID-19 related pulmonary distress.
1.4.
Zanubrutinib
Zanubrutinib is a potent, specific, and irreversible BTK inhibitor that was designed to be more 
specific than ibrutinib; similar to ibrutinib, zanubrutinib potently inhibited BTK kinase in 
biochemical assays, with an IC50 of 0.3 nM, and in vitro cellular assays also show that 
zanubrutinib inhibited BTK signaling and cellular growth in several mantle cell lymphoma cell 
lines.
Zanubrutinib is more selective than ibrutinib for the inhibition of kinase activity of BTK versus 
EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, and TEC. Cellular assays also confirmed 
that zanubrutinib is significantly less active than ibrutinib in inhibiting ITK (10-fold) and EGFR 
(> 6-fold).  Zanubrutinib was shown to be at least 10-fold weaker than ibrutinib in inhibiting 
rituximab-induced antibody‐dependent cell‐mediated cytotoxicity.  In a randomized clinical trial 
comparing zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia, fewer 
adverse events (AEs) were noted in the zanubrutinib arm.  Adverse events > Grade 3 occurred in 
58.4% of patients in the zanubrutinib arm and 63.3% of patients in the ibrutinib arm of the study. 
Four percent of zanubrutinib-treated patients discontinued therapy because of AEs, and 1% had a 
Grade 5 event; 9.2% of ibrutinib-treated patients discontinued because of an AE, and 4.1% had 
Grade 5 events.  For zanubrutinib and ibrutinib, respectively, the rates of all-grade atrial 
fibrillation/flutter were 2% and 15.3%, of minor bleeding were 48.5% and 59.2%, of major 
hemorrhage were 5.9% and 9.2%, and of diarrhea were 20.8% and 31.6%.  Neutropenia was 
more common with zanubrutinib (29.7%) than with ibrutinib (13.3%) (Tam et al 2020).


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2.
STUDY OBJECTIVES
2.1.
Primary Objectives (Cohort 1)
x To compare the efficacy of zanubrutinib plus supportive care versus placebo plus 
supportive care as measured by respiratory failure-free survival rate at Day 28
x To evaluate if the addition of zanubrutinib to supportive care reduces time to 
breathing room air
2.2.
Secondary Objectives (Cohort 1)
x To compare the efficacy of zanubrutinib plus supportive care versus placebo plus best 
supportive care as measured by:
 Proportion of patients experiencing respiratory failure or death;
 All-cause mortality;
 Proportion of patients discharged alive;
 Proportion of patients discharged from the ICU alive;
 Median reduction in days spent on supplemental oxygen;
 Mechanical ventilation-free survival;
 Days on mechanical ventilation;
 Duration of hospitalization;
 Time to discharge;
 Change in World Health Organization (WHO) 8-point scale from baseline;
 PAO2:FIO2 and/or oxygenation index, for patients on mechanical ventilation;
 Safety and tolerability of zanubrutinib as an adjuvant therapy to standard of care 
as assessed by treatment-emergent adverse events (TEAEs), serious adverse 
events (SAEs), related AEs, TEAEs by grade, and abnormal laboratory findings;
 Clinical status assessed using an ordinal scale at a pre-specified timepoint;
 Time to objective measure of recovery.
x To compare the safety of zanubrutinib plus supportive care versus placebo plus best 
supportive care
2.3.
Exploratory Objectives
x 
x 


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x 


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3.
STUDY DESIGN
3.1.
Summary of Study Design
There is currently no standard of care for hospitalized patients experiencing COVID-19 beyond 
supportive care.  Numerous studies examining various study interventions are underway.  
Discovering/providing treatment options for patients with moderate or severe COVID-19 is a 
high priority, particularly for those with respiratory distress.  Exaggerated cytokine response 
triggered by ATII cells and resident macrophages in response to SARS-CoV-2 appears 
etiological for the pulmonary injury and respiratory failure associated with COVID-19.  The 
BTK inhibitor, ibrutinib, blocks TLR signaling and cytokines associated with SARS-CoV-2,
including those found in ATII cells.  Importantly, in a relevant experimental mouse model, 
ibrutinib protected mice subjected to lethal intranasal inoculums of mouse adapted H1N1 
influenza and suppressed inflammatory cell recruitment and pathological cytokines that 
overlapped with many of those observed in SARS-CoV-2 infected patients.  Based on this, it is 
hypothesized that inhibitors of BTK may potentially provide protection against lung injury.
Zanubrutinib is an oral BTK inhibitor approved by the FDA for the treatment of adult patients 
with mantle cell lymphoma  who have received at least one prior therapy.  Accelerated approval 
was granted for this indication based on overall response rate.
This study will enroll patients who meet inclusion/exclusion criteria and sign an associated 
consent form.  Patients will be enrolled 
 based on mechanical ventilation 
requirements at screening:
x Cohort 1 - no mechanical ventilation (N = 63)
x 
Patients not requiring mechanical ventilation (Cohort 1) will be randomized 1:1 to receive 
zanubrutinib plus supportive care or placebo plus supportive care.  Patients will be stratified by 
age (< 65 years or ≥65 years) and use of antiviral therapy (yes or no) on the date of
randomization.  The first dose of study drug should be given ≤12 hours after randomization.  
Study drug (zanubrutinib 320 mg once daily or placebo 4 capsules once daily) will be 
administered for up to 28 days.  Approximately 63 patients will be enrolled in Cohort 1.
The coprimary endpoints for this study are the respiratory failure-free survival rate at Day 28 and 
the time to breathing room air.  The respiratory failure-free survival rate at Day 28 can also be 
described as the proportion of patients who have not had respiratory failure nor died any time
≤28 days from randomization.
Participating clinical trial sites must have the capability of implementing appropriate infection 
control measures to prevent infection of study staff and others who share the clinical site space.


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3.2.
Study Schema
Figure 6:
Study Schema
Abbreviation: MV, mechanical ventilation.


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4.
ELIGIBILITY CRITERIA
4.1.
Inclusion Criteria
Each patient eligible to participate in this study must meet all of the following criteria:
1. Age ≥ 18 years
2. Willing and able to provide consent prior to study therapy, including by virtual 
consenting per hospital policy
3. Patient requires hospitalization for COVID-19
4. Patient has SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR)
Documented SARS-CoV-2 infection confirmed by PCR within 10 days prior to screening 
is acceptable
5. For Cohort 1, patient requires supplemental oxygen, but not mechanical ventilation, for 
pulmonary distress related to COVID-19, and has been on supplemental oxygen for no 
more than 96 hours from time of screening.  
6. C-reactive protein ≥ 8.0 mg/L at time of screening
7. Adequate hematologic function defined as:
a. Absolute neutrophil count > 750 cells/mm3 (0.75 x 109/L)
b. Platelet count > 50,000 cells/mm3 (50 x 109/L)
8. Adequate hepatic and renal function defined as:
a. Estimated Creatinine Clearance ≥ 30 mL/min (Cockcroft-Gault)
b. Bilirubin ≤ 2.0 x upper limit of normal (ULN) unless bilirubin rise is due to Gilbert’s 
syndrome or of non-hepatic origin.
c. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN
9. Female patients of childbearing potential must practice highly effective methods 
(Section 5.2.2) of contraception initiated before first dose of study drug, for the duration 
of the study, and for ≥ 90 days after the last dose of study drug
10. Male patients are eligible if vasectomized; otherwise they must agree to the use of barrier 
contraception combined with other highly effective methods described in Section 5.2.2
during the study treatment period and for ≥ 90 days after the last dose of study drug
11. Prothrombin time/International normalized ratio < 1.5 x ULN and activated partial 
thromboplastin time < 1.5 x ULN


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4.2.
Exclusion Criteria
Each patient eligible to participate in this study must not meet any of the following exclusion 
criteria prior to initiation of study drug:
1. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or 
resection of the stomach or small bowel, symptomatic inflammatory bowel disease or 
ulcerative colitis, or partial or complete bowel obstruction
2. Patient has a “Do Not Intubate” order at time of screening
3. On a BTK inhibitor
4. Planned or concurrent use of host modifiers/immune-based therapies.  Treatment with 
intravenous immunoglobulin or convalescent plasma is allowed.  See Appendix 7 for 
guidance.
5. Prior therapy or planned on-study treatment with an anti-CD20 monoclonal antibody 
treatment (eg, rituximab, obinutuzumab, ofatumumab), and/or an immune checkpoint 
inhibitor (eg, pembrolizumab, nivolumab)
6. Current use of therapeutic anticoagulation or combined use of an anti-platelet agent with 
an anticoagulant.  Anticoagulation to prevent thrombosis is allowed
7. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia)
8. Major surgery ≤4 weeks before first dose of study drug
9. Patients in whom surgery is anticipated to be necessary within 72 hours.
10. History of stroke or intracranial hemorrhage ≤6 months before first dose of study drug
11. Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus 
(HCV) or hepatitis B virus (HBV).  Patients who are positive for hepatitis B core 
antibody (HBcAb), hepatitis B surface antigen (HBsAg), or HCV antibody must have a 
negative PCR result before enrollment.  Those who are PCR positive will be excluded.
12. Currently active, clinically significant cardiovascular disease, such as uncontrolled 
arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart 
Association Functional Classification; or a history of myocardial infarction, unstable 
angina, or acute coronary syndrome within 6 months prior to randomization.
13. Asymptomatic arrythmias (eg, nonsustained ventricular tachycardia , bradycardia heart 
rate < 50 bpm, or atrioventricular block, or any other atrial or ventricular arrythmia) 
and/or known history ejection fraction < 40%.
14. Patients receiving a strong cytochrome P450 (CYP) 3A4 inhibitor with the exception of 
those receiving anti-fungal therapy/prophylaxis or antiviral therapy (Appendix 3).
15. Patients with chronic liver disease and hepatic impairment meeting Child-Pugh Class C.
16. Female patients who are pregnant, or breastfeeding, or planning to become pregnant 
while enrolled in this study or within 3 months of last dose of study drug.  Male patients 
who plan to father a child while enrolled in this study or within 3 months after the last 
dose of study drug.


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17. Underlying medical conditions that, in the investigator’s opinion, will render the 
administration of study drug hazardous or obscure the interpretation of toxicity or AEs.
18. Unwilling or unable to participate in all required study evaluations and procedures
19. Unable to understand the purpose and risks of the study and to provide a signed and dated 
informed consent form (ICF) and authorization to use protected health information (in 
accordance with national and local patient privacy regulations), except to the extent that 
surrogate consents and assents are obtained in accordance with national and local laws 
and regulations. For clarity, the surrogate consents and assents may include, but are not 
limited to, the following: court-appointed guardians, healthcare proxies, durable powers 
of attorney, or family members/next-of-kin.
20. Vaccinated with a live, attenuated vaccine ≤4 weeks before first dose of study drug
21. Hypersensitivity to zanubrutinib or its formulation excipients
22. Uncontrolled hypertension (systolic blood pressure > 150 mmHg and diastolic blood 
pressure ≥90 mmHg)
23. History of interstitial lung disease
24. Prior or current hematologic malignancy, or solid tumor malignancy with treatment 
consisting of chemotherapy, immunotherapy, and/or radiation therapy within 6 months 
prior to study entry or planned use of any of these treatments in the next 3 months 


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5.
ENROLLMENT AND STUDY PROCEDURES
Study enrollment and procedures are summarized in the following subsections.  The timing of all 
study procedures is provided in the Schedule of Assessments (Appendix 5).
5.1.
Visit Windows
Study visits are daily for patients that are admitted.  A ± 1-day window for outpatient visits on 
Days 7, 14, and 21 is permitted (Appendix 6).  There is a ± 3-day window for the End of 
Treatment visit and ± 7-day window for each of the follow-up visits.
5.2.
Screening
5.2.1.
Informed Consent
Study site personnel must explain to potential study participants all aspects of the study, 
including all scheduled visits and activities.  A copy of the ICF will be given to the patient to 
read, and the patient must have adequate time to understand the content and ask questions.
Study site personnel must obtain signed informed consent before any study specific assessments 
or procedures are conducted unless part of routine standard of care.  The informed consent 
process must be documented in the patient’s clinical record.  Consent must be obtained using the 
most current version of the form approved by the Independent Review Board (IRB)/Independent 
Ethics Committee (IEC).
All screening procedures must be completed within 14 days before the first dose of study drug.  
Repeating screening procedures or tests are allowed once within the protocol-specified screening 
window if the patient did not previously meet the inclusion and exclusion criteria or if needed to 
have a documented acceptable result. Screening procedures performed within 2 days before date 
of first dose need not be repeated on Day 1.
For patients who provide informed consent and subsequently do not meet eligibility criteria or 
withdraw consent before initiation of study drug, study site personnel should document the 
screen failure in the patient’s source documents. Patients may be rescreened once.
5.2.2.
Females of Childbearing Potential and Contraception
A woman is considered of childbearing potential (ie, fertile) after menarche and until becoming 
postmenopausal unless surgically sterilized.  Surgical sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
Contraception methods include the following:
x Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation
 Oral, intravaginal, or transdermal
x Progestogen-only hormonal contraception associated with the inhibition of ovulation
 Oral, injectable, or implantable
x An intrauterine device


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x Intrauterine hormone-releasing system
x Bilateral tubal occlusion
x Vasectomized partner (provided that the vasectomized partner is the sole sexual 
partner of the woman of childbearing potential study participant and that the 
vasectomized partner has received medical assessment of surgical success)
x Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatment, starting the day before first 
dose of study drug, for the duration of the study, and for ≥ 90 days after the last dose 
of study drug).
Total sexual abstinence should only be used as a contraceptive method if it is in line 
with the patients’ usual and preferred lifestyle.  Periodic abstinence (eg, calendar, 
ovulation, symptothermal, postovulation methods), declaration of abstinence for the 
duration of exposure to investigational medicinal product, and withdrawal are not 
acceptable methods of contraception.
Of note, barrier contraception (including male and female condoms with or without spermicide) 
is not considered a highly effective method of contraception, and, if used, this method must be 
used in combination with another acceptable method listed above.
If a woman of childbearing potential is using hormonal contraceptives such as birth control pills 
or devices, a second barrier method of contraception (eg, condoms) must also be used.
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause.  A high follicle-stimulating hormone level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy.  However, in the absence of 12 months of amenorrhea, a single 
follicle-stimulating hormone measurement is insufficient.
5.2.3.
Patient Numbering
After obtaining informed consent, study site personnel will record in Interactive Response 
Technology (IRT) and a unique patient number will be assigned to the potential study 
participant. Patient number will be assigned in chronological order by site starting with the 
lowest number.  Once a patient number has been assigned to a patient, it cannot be re-assigned to 
any other patient.
5.2.4.
Medical History
After obtaining informed consent, a review of the medical history will be conducted, most 
notably the onset of signs and symptoms related to COVID-19.  Clinically significant medical 
history (ie, previous diagnoses, diseases, or surgeries) that does not pertain to the study 
indication, will be captured in the electronic case report form (eCRF).  “Clinically significant” is 
defined as any event, diagnosis, or laboratory value requiring treatment or follow-up or the 
presence of signs or symptoms that require medical intervention.  Concurrent medical signs and 
symptoms must be documented to establish baseline severities.  All medical conditions ongoing 
at the time of first study drug dose and all relevant conditions that may have resolved prior to the 


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first dose of study drug should be recorded.  The reason for current hospitalization will be 
recorded.
Other background information to be collected include prior medications/significant nondrug 
therapies and demographic data (gender, year of birth [or age], and race/ethnicity) will also be 
collected.
New onset SAEs that occur during the Screening period will be reported on the AE eCRF.  Any 
new or continuing non-SAEs during Screening will be recorded on the medical history eCRF.
5.2.5.
Confirmation of Eligibility 
The investigator will assess and confirm the eligibility of each patient.  Should the investigator 
have any concerns while determining if a patient is eligible, the investigator or designee can 
discuss with the medical monitor.
5.3.
Randomization
For patients in Cohort 1, site personnel will access the IRT system to randomize to treatment 
assignment (Arm A or Arm B).  Study drug should be administered ≤12 hours after 
randomization/treatment assignment. Randomization will be stratified by age (< 65 years or 
≥65 years) and use of antiviral therapy (yes or no).  
5.4.
Study Drug Dispensation
For hospitalized patients, study drug will be administered by qualified staff. For patients 
discharged from the hospital, study drug will be self-administered, and participants will be 
instructed to write in a diary daily, documenting that the drug was taken, and AEs were 
experienced.  Patients should be instructed to take the study drug with a glass of water at 
approximately the same time each day.  Patients taking study drug at home will be instructed on 
how to complete the diary by study staff prior to discharge.  If a dose is not taken at the 
scheduled time, it can be taken as soon as possible on the same day with a return to the normal 
schedule the following day.  The patient should not take extra capsules to make up a missed 
dose.  The patient will be instructed to document missed study drug doses in the study diary.  
Furthermore, they will be instructed to call their provider, the principal investigator, or research 
nurse if vomiting occurs or they have recurrence of their COVID-19 symptoms or any other AEs
consistent with the product label.  If the pills are vomited, this should be noted on the patient 
diary, but a replacement dose should not be taken that day.  All dosages prescribed and dispensed 
to the patient, and all dose changes during the study should be recorded.  Diaries will be 
collected at the end of the treatment period.  In the event of circumstances that prevent a 
discharged patient from returning to clinic, a telehealth visit is permitted.  Study staff will collect 
or coordinate with patient in the event of a telehealth visit for the return of any unused drug and 
the study diary.  Unused drug will be counted and returned to the pharmacy to be destroyed.  A 
prescription for dispensing study drug for at home use, as detailed above, will be filled by the 
study pharmacy.  Medication labels will comply with U.S. legal requirements and be printed in 
English.  The storage conditions for study drug will be described on the medication label.  Study 
drug (zanubrutinib or placebo) will be provided by BeiGene, Ltd.  Zanubrutinib is formulated as 
capsules for oral administration and will be available for this study in 80-mg capsules.  Placebo 


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is formulated as capsules with the same appearance as zanubrutinib 80-mg capsules for this 
study.
5.5.
Safety Assessments
5.5.1.
Physical Examination and Vital Signs
Physical examination and vital signs (blood pressure, heart rate, body temperature, and weight), 
will be performed daily while hospitalized as well at the end of treatment and follow up visits.  
Height (cm) is determined at Screening only.
A complete physical examination includes an assessment of organ systems per standard of care 
at the study site and as clinically indicated for evaluation of new onset signs or symptoms.
5.5.2.
Electrocardiogram
A 12-lead electrocardiogram (ECG) will be performed at Screening for all patients. During the 
study, an ECG will be conducted on Days 1 through 3, Day 7, and then weekly if patient remains 
hospitalized (Appendix 5).
5.5.3.
Adverse Events Review
Record all new or worsening, non-SAEs from the time of first dose of study drug through the 
Safety Follow-up Visit.  Information on all SAEs will be collected from the time of informed 
consent through screen failure or safety follow-up.  The AE reporting period is defined in 
Section 8.4.1.
Data related to any new infection will be reported in the AE case report form (CRF).
Information related to the infection such as infecting agent, site of infection, and source of 
culture will also be collected on the CRF.
All TEAEs and SAEs will be followed until resolution or stabilization.  The regulatory definition 
for an AE is provided in Section 8.1, and the definition of an SAE is provided in Section 8.2.1.
Important additional requirements for reporting SAEs are explained in Section 8.
5.6.
Efficacy Assessments
5.6.1.
Oxygenation
Oxygen saturation and documentation of supplemental oxygen (if any) will be assessed daily 
while in the hospital, and at the end of treatment and follow up visits as specified per the 
Schedule of Assessments (Appendix 5).
Data related to delivery techniques and modes of mechanical ventilation including the clinical 
decisions to implement or discontinue mechanical ventilation will be documented in the CRF, 
including changes in goals of care, and impacts due to changes in allocation of resources.


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5.6.2.
Radiographic Evaluation
A chest computed tomography or similar radiographic studies will be performed at Screening.  A 
similar modality of study may be used for follow-up as clinically indicated.  All imaging studies 
will be reviewed locally at each respective study site as part of the assessments.
5.7.
Laboratory Assessments
Laboratory studies will be assessed in a local laboratory unless otherwise indicated.  Laboratory 
assessments will be performed at the timepoints specified in the Schedule of Assessments 
(Appendix 5) and may also be performed at other timepoints as medically necessary.
5.7.1.
Hematology
Complete blood count including hemoglobin, hematocrit, platelet count, red blood cell count, 
and white blood cell count with differential (neutrophil, lymphocyte, monocyte, eosinophil, and 
basophil) will be performed at timepoints specified in the Schedule of Assessments. Patients 
who develop marked and persistent lymphocytosis should have an analysis (ie, flow cytometry) 
to rule out an underlying hematologic malignancy disorder.
5.7.2.
Serum chemistries
Serum chemistries including sodium, potassium, glucose, blood urea nitrogen, creatinine, 
calcium, total bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, and LDH will 
be performed at the timepoints specified in the Schedule of Assessments (Appendix 5).
5.7.3.
Inflammatory and Cardiac Markers
C-reactive protein, serum ferritin, and cardiac troponin will be drawn at Screening and 
timepoints noted in Schedule of Assessments (Appendix 5).
5.7.4.
SARS-CoV-2 Testing
Based on Emergency Use Authorization by the FDA, only qualitative PCR is feasible for 
nasopharyngeal sampling.  Blood and stool sampling has not been validated given its unknown 
clinical utility.  In a study by Wang et al (Wang et al 2020), viremia related to SARS-CoV-2 was 
only observed in 3 of 307 (1%) patients. Stool samples also had a low (44/153; 29%) rate of 
positivity.  Serial follow-up after discharge may also be complicated due to limited testing 
resources, and potential of exposure of uninfected individuals.  We also note anecdotal reports of 
detectable virus by RT-PCR in the absence of symptoms after patient discharge, which may be 
due to remnant virus.  These limitations in the current landscape of viral load determination have 
prompted us to limit qualitative SARS-CoV-2 testing to baseline assessment.
Clinical samples for SARS-CoV-2 diagnostic testing will be obtained according to WHO 
guidelines.  For each patient, a sampling strategy will be implemented in which samples are 
obtained at screening.  Samples will be tested for viral load using a qualitative RT-PCR assay.
5.7.5.
Coagulation
The coagulation profile includes prothrombin time/international normalized ratio, activated 
partial thromboplastin time, and D-dimer.  With the exception of D-dimer, the coagulation 


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profile will be performed at Screening and only as clinically indicated thereafter (see 
Appendix 5).
5.7.6.
Hepatitis B and C testing
Viral hepatitis B and C  serologic markers and/or viral load will be tested at Screening.  HBV 
and HCV testing will be performed in a local laboratory.  The HBV panel includes HBsAg, 
HBcAb, and hepatitis B surface antibody (HBsAb), as well as quantitative HBV DNA by PCR, if 
the patient is negative for HBsAg but HBcAb positive (regardless of HBsAb status).  The HCV 
panel includes HCV antibody as well as quantitative HCV RNA by PCR if the patient is HCV 
antibody positive.
Patients positive for HBsAg and/or with detectable levels of HBV DNA are not eligible for the 
study.
Patients who are HBsAg negative, HBcAb positive, and HBV DNA negative must undergo at 
least monthly HBV DNA screening by PCR.  These patients should be considered for 
prophylactic antiviral treatment in consultation with a local HBV expert.  If a patient is receiving 
prophylactic antiviral treatment, HBV DNA screening by PCR must be done at least every 
90 days.
HBV DNA values between 20 and 100 IU/mL should be rechecked within 2 weeks.  Study drug 
should be interrupted, and antiviral therapy initiated if, on repeat testing, this level of HBV DNA 
is confirmed.  If the HBV DNA level is 100 IU/mL or higher, study drug should be interrupted,
and antiviral therapy initiated or continued.  Resumption of study drug in patients whose HBV 
reactivation resolves should be discussed with, and approved by, the medical monitor and 
physicians with expertise in managing chronic HBV infection.
Patients positive for HCV antibody, but negative for HCV RNA, must undergo monthly HCV 
RNA screening.  Patients with HCV RNA ≥ 15 IU/mL should stop study drug and antiviral 
therapy should be initiated.  Resumption of study drug in patients whose HCV reactivation 
resolves should be discussed with, and approved by, the medical monitor and physicians with 
expertise in managing HCV infection.
All patients with a history of hepatitis B and C viral infection and baseline negative PCR that 
develop elevations in liver function tests should be evaluated for viral hepatitis reactivation.
The medical monitor should be informed of any suspected HBV or HCV reactivation.  Table 2
describes how the results for HBV and HCV testing at Screening relate to study eligibility.


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Table 2:
Active Hepatitis B or Hepatitis C Infection (Detected Positive by Polymerase 
Chain Reaction)
Screening 
assessment
Meets inclusion criteria
To be excluded
HBV
HBsAg (-) and HBcAb (-)
HBsAg (+)
HBsAg (-) and HBcAb (+) and
HBV DNA “Not detected”
Perform monthly monitoring of HBV DNA
HBsAg (-) and HBcAb (+) and
HBV DNA detected
HCV
Antibody (-)
Antibody (+) and
HCV RNA detected
Antibody (+) and 
HCV RNA “Not detected”
Perform monthly monitoring of HCV RNA
Abbreviations: HBcAb, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; HBV, viral hepatitis B; 
HCV, viral hepatitis C.
5.7.7.
Pregnancy Test
Any female patient who is pregnant is not eligible for the study.  In women of childbearing 
potential, a serum pregnancy test will be performed within 7 days before first dose of study drug.  
Additional β-HCG testing will be performed as described in Appendix 5 and Appendix 6. A
patient who has a positive pregnancy test result at any time after the first administration of study 
drug will immediately discontinue study treatment and withdraw from the study.
5.8.


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5.8.1.
5.9.
5.10.
Hospital Discharge
Patients may be discharged from the hospital prior to completion of the full 28-day treatment 
course.  Discharge may be considered if:
x Patient is clinically stable on room air with an O2 saturation ≥94%
x Patient is NOT receiving oxygen therapy
x Patient is afebrile (body temperature ≤38.0ºC)


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x Patient is not on receiving intravenous antibiotics, excluding antibiotics for a central 
venous catheter infection
5.11.
Outpatient Visits
In the event a patient is discharged from the hospital prior to Day 28, outpatient visits should be 
conducted at Days 7, 14, 21, and 28 as described in Appendix 6.  A safety follow-up visit should 
be conducted 30 ± 7 days and 56 ± 7 days after last dose for all patients who discontinue the
study drug, as described in Appendix 5 and Appendix 6.  A telehealth visit with coordinated 
diary collection and/or return of zanubrutinib is permitted after discharge from hospital if 
circumstances prevent a clinic visit.  Lab draws and other assessments that may be clinically 
indicated should be performed through outpatient laboratory or radiology services unless it is not 
medically safe.
5.12.
Unscheduled Visits
Unscheduled visits may be performed at any time as necessary for evaluation of treatment or
disease-related complications.  If an unscheduled visit is necessary to assess toxicity or for 
suspected worsening of pulmonary function, diagnostic tests may be performed as directed by 
the investigator, and the results of the assessments should be entered on the unscheduled visit 
eCRF.
5.13.
End of Treatment Period
The treatment period starts with the first day of study treatment and ends 30 days after the date of 
permanent study drug discontinuation.
Patients may discontinue study drug for any of the reasons listed in Section 6.5.
Patients may voluntarily withdraw consent for treatment at any time.
5.14.
Safety Follow-up
All patients who permanently discontinue study drug will have Safety Follow-up Visits
30 ± 7 days and 56 ± 7 days after the last dose of study drug.  Refer to the Schedule of 
Assessments (Appendix 5) for the assessments to be performed at the Safety Follow-up Visits.
5.15.
End of Study
Reasons for withdrawal from the study may include the following:
x Patient withdrew consent
x Death 
x Lost to follow-up
x Investigator decision
x Study termination by sponsor
x Other (specify)


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5.16.
Lost to Follow-up
Every reasonable effort should be made to contact any patient lost to follow-up during the study 
to complete study related assessments, record outstanding data, and retrieve study drug.
After unsuccessful telephone contact, an effort to contact the patient by mail using a method that 
provides proof of receipt should be attempted.  Alternate contacts are permissible if the patient is 
not reachable (eg, primary care providers, referring physician, relatives).  Such efforts should be 
documented in the patient’s source documents.
If all efforts to establish contact with the patient fail, the patient will be considered lost to 
follow-up, which will be documented in the patient's source documents and CRF.


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6.
STUDY TREATMENT
6.1.
Study Treatment Preparation and Dispensation
6.1.1.
Packaging and Labeling 
Study drug (either zanubrutinib 80-mg capsules or placebo capsules) will be provided in a 
child-resistant, high-density polyethylene bottle with induction seal and bottle label.
The contents of the label will be in accordance with all applicable local regulatory requirements.
Study drug (either zanubrutinib 80-mg capsules or placebo capsules) is formulated as hard 
gelatin capsules with the same appearance.
6.1.2.
Handling and Storage
The study drug will be dispatched to a study center only after receipt of the required documents 
in accordance with applicable regulatory requirements and the sponsor’s procedures.  The 
investigator or pharmacist/designated personnel is responsible for maintaining the drug supply 
inventory and acknowledging receipt of all study drug shipments.  All study drug must be stored 
in a secure area, with access limited to the investigator and authorized study center personnel and 
kept under physical conditions that are consistent with study drug-specific requirements.  The 
study drug must be kept at the temperature condition as specified on the labels.
Study drug bottles must be stored at room temperature 15ºC to 30ºC (59ºF to 86ºF).
Study drug must be dispensed or administered according to procedures described herein.  Only 
patients enrolled in the study may receive study drug, in accordance with all applicable 
regulatory requirements.  Only sponsor authorized study center personnel may supply or 
administer study drug.
6.1.3.
Compliance and Accountability
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or guardian.
The investigator and/or study personnel will keep accurate records of the quantities of study drug 
dispensed and used by each patient.  This information must be captured in the source document 
at each patient visit.  The investigator is responsible for study drug accountability, reconciliation, 
and record maintenance.  In accordance with all applicable regulatory requirements, the 
investigator or designated study center personnel must maintain study drug accountability 
records throughout the course of the study.  This person will document the amount of study drug 
received from the sponsor, the amount supplied, and/or the amount administered to and returned 
by patients, if applicable.
6.1.4.
Disposal and Destruction
After completion of the study and after final drug inventory reconciliation by the monitor, the 
study site, upon sponsor’s election, will destroy or return all unused study drug supplies to 
sponsor.  The inventoried supplies can be destroyed on site or at the depot according to 
institutional policies after receiving prior written sponsor approval.


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6.2.
Dosage and Administration
6.2.1.
Study Drug
Study drug for this study is zanubrutinib or placebo administered orally once daily.  The capsules 
are to be taken around the same time each day with a glass of water.  Study drug can be taken 
with or without food.  The capsules should be swallowed intact and patients should not attempt 
to open capsules or dissolve them in water.  For patients who require nasogastric or feeding tube
placement while on study, study drug may be administered by qualified site staff by opening the 
capsules, mixing with the recommended dosing solution, and flushing down the nasogastric or 
feeding tube (see guidance for nasogastric/feeding tube administration in Appendix 2).  Though 
the use of strong CYP3A inhibitors/inducers (see Appendix 3) and grapefruit and Seville oranges 
should be avoided for the duration of treatment, treatment with antifungal prophylaxis (eg, 
voriconazole, posaconazole) and antiviral therapy is permitted; however, dose reductions of 
study drug are necessary (see Table 4).  If a dose is not taken at the scheduled time, it can be 
taken as soon as possible on the same day with a return to the normal schedule the following day.  
Extra capsules to make up the missed dose should not be dispensed.
Dose reductions for toxicity will be permitted (Section 6.4).
Patients should be instructed that if a dose of the study drug is not taken at the scheduled time, 
they should skip the dose if the time to next dose is ≤ 8 hours and return to normal dosing 
intervals with the next dose thereafter.  If a patient vomits after a dose of study drug, that dose 
should not be repeated.
6.2.2.
Dispensation for Outpatient Administration
Study drug will be dispensed to patients who, upon discharge (see Section 5.10), do not meet the 
criteria for study drug discontinuation for clinical benefit described in Section 6.5.2.
6.3.
Overdose
Any dose of study drug in excess of that specified in this protocol is considered to be an 
overdose.  AEs associated with an overdose or incorrect administration of study drug will be 
recorded on the AE eCRF.  Any SAEs associated with an overdose or incorrect administration 
are required to be reported within 24 hours via the SAE reporting process as described in 
Section 8.4.2.1.  There is no specific antidote for an overdose of zanubrutinib.  In the event of an 
overdose, patients should be closely monitored and given appropriate supportive treatment.
6.3.1.
Minor Surgical Procedures
For minor procedures (eg, central venous catheter, arterial line placement) that are urgently 
needed and could result in bleeding, immediately stop study drug and consider transfusion with 
platelets just prior to procedure.  Study drug should be held for 24 hours after procedure.  If there 
is ongoing bleeding after the procedure, additional platelet transfusions can be administered, and 
study drug held to 24 hours after bleeding stops.  No drug hold or platelet transfusions are 
needed for routine venipunctures or peripheral IV placement.


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6.3.2.
Elective Major Surgical Procedures
For any elective surgery or invasive procedure requiring sutures or staples for closure, study drug 
should be held at least 3 to 7 days prior to the intervention (except for emergency procedures) 
and should be held at least 3 to7 days after the procedure and restarted at the discretion of the 
treating physician when the surgical site is reasonably healed without serosanguineous drainage 
or the need for drainage tubes.  For less than 7 days hold prior to the procedure, consider a 
transfusion of platelets just prior to the procedure to decrease risk of bleeding.
6.3.3.
Emergency Major Surgical Procedures
For emergency procedures that could result in bleeding and require sutures or staples for closure, 
transfusion with platelets prior to the procedure should be given and study drug held after the 
procedure for at least 3 days after the surgical procedure.  Consider additional platelet 
transfusions peri- and post-operatively to reduce bleeding risk or active bleeding.
6.4.
Dose Modifications
The guidelines below (Table 3) should be followed for modification of study drug dosing for 
non-COVID-19 hematologic and nonhematologic toxicities (other than hypertension adequately 
controlled with oral medication or asymptomatic laboratory events).  Laboratory events 
indicating liver or renal dysfunction will not be considered asymptomatic laboratory events and 
should compel adherence to dose modification guidelines provided below.
Lymphocytosis is considered as an expected manifestation of treatment with zanubrutinib and 
therefore may not be an AE; clinical correlates should be present if reporting lymphocytosis as 
an AE.
Table 3:
Study Drug Dose Reduction Levels
Toxicity occurrence
Dose level
Study drug dose
First
-1 dose level
Restart at 160 mg once daily
Second
-2 dose level
Restart at 80 mg once daily
Third
Discontinue study drug
Discontinue study drug
Any patient experiencing a ≥Grade 3 hematologic or nonhematologic toxicity should have their 
dose held.  The dose hold should start on the day that the above occurrence is noted.  Study drug 
may be restarted at the next lower dose level upon resolution of toxicity if interrupted for up to 
7 consecutive days, per the investigator’s discretion.  A maximum of 2 dose reductions will be 
allowed before study drug is allowed.
6.5.
Discontinuation from Study Treatment
6.5.1.
Discontinuation for Adverse Events
Any 1 or more of the following will require permanent discontinuation of study drug:
x All study drug-related Grade 4 AEs (hematologic and/or nonhematologic)


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x The following changes in liver function tests:
 ALT or AST > 8 x ULN
 ALT or AST > 5 x ULN for more than 2 weeks
 ALT or AST > 3 x ULN and (total bilirubin > 2 x ULN or international 
normalized ratio > 1.5)
 ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%)
x Hemorrhage/bleeding AEs meeting the following criteria:
 Any ≥Grade 3 hemorrhagic/bleeding AE, regardless of underlying condition
 Any grade serious bleeding AE
 Any grade intracranial hemorrhage/hematoma
x ≥Grade 3 atrial fibrillation
x Any patient with a baseline history of mild and/or moderate chronic hepatic 
impairment should discontinue study drug for worsening liver disease (eg, 
progression from Class A to Class B or C, etc).
x Withdrawal of consent for further study participation (see Section 5.15)
x Pregnancy
x The investigator or sponsor determines it is in the best interest of the patient
x Intercurrent illness that compromises the patient’s ability to participate in the study
x Need for prohibited concomitant medication
x Study drug interruption > 7 days 
x Significant, persistent, or recurrent AEs
x For all patients discontinuing therapy, the reason for discontinuation should be 
recorded in the medical record.
All patients that discontinue study treatment for an AE should be followed through resolution 
and study completion.
6.5.2.
Discontinuation for Clinical Benefit
Patients who are discharged and are clinically stable on room air for ≥24 hours with an O2
saturation ≥94% should discontinue the use of study drug.
6.6.
Blinding
Patients in Cohort 1 will be randomized to receive zanubrutinib or matched placebo in a 
double-blind fashion in Arm A and Arm B (Figure 6). It is imperative to maintain the blind such 
that neither the investigator, nor the patient, nor medical or ancillary medical staff will know 


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which drug is being administered in addition to supportive care. Due to the ongoing need to 
assess safety, the sponsor staff will not be blinded to patient treatment assignment.
Every effort should be made to avoid unblinding the patient’s treatment assignment in Cohort 1 
unless necessary.  Unblinding may be indicated and permissible only in specific situations as 
described below and, if necessary, for the patient’s welfare.
6.6.1.
Emergency Unblinding
In case of an emergency, such as when a patient has an AE suspected to be related to the 
investigational drug product and for which management of the AE with one or more drug 
products with substantial toxicity or invasive procedures is being considered, unblinding can 
occur in Cohort 1. The investigator has the sole responsibility for determining if unblinding of a 
patient’s treatment assignment is warranted.  Patient safety must always be the first consideration 
in making such a determination.  If the investigator decides that unblinding is warranted, the 
investigator should make every effort to inform the medical monitor of their intent before 
unblinding a patient’s treatment assignment unless this could delay emergency treatment of the 
patient.  If a patient’s treatment assignment is unblinded, the sponsor must be notified 
immediately.
The investigator performs the emergency unblinding for AEs through an IRT System as per the 
instructions in the IRT site user manual.  Unblinded patients may remain on study treatment at 
the discretion of the investigator in consultation with the medical monitor and only as 
permissible per definitions in the study protocol.
6.6.2.
Inadvertent Unblinding
Every effort will be made to blind both the patient and the investigator to the identity of the 
treatment assignment in Cohort 1 (ie, zanubrutinib or placebo), but the inadvertent unblinding of 
a patient may occur.  If an investigator, site personnel (eg, those performing assessments), or 
patient is unblinded, the unblinding will not be sufficient cause (in and of itself) for that patient 
to be discontinued from study therapy or excluded from any safety or efficacy analyses.
Additionally, there may be ethical reasons to have the patient remain on the study treatment.  For 
patients to continue study treatment in the event of unblinding, the investigator must obtain 
specific approval from the medical monitor.


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7.
CONCOMITANT THERAPY
7.1.
Concomitant Therapy
All concomitant medications and herbal supplements taken during the study will be recorded in 
the eCRF, including indications and dates of administration.
7.1.1.
Permitted Medications
The following treatments are allowed (per institutional standards of care):
x Blood product transfusions and growth factor support 
x Myeloid growth factors to manage neutropenia 
x Therapy to reduce symptoms 
x Infection prophylaxis 
x Antiviral treatment
x Dexamethasone
x Intravenous immunoglobulin
x Convalescent plasma
x Anticoagulation to prevent thrombosis
In patients with a high risk for opportunistic infections, including Pneumocystic jirovecii 
pneumonia , prophylaxis should be considered as per institutional standards.
7.1.2.
Prohibited Medications
In all arms, the concomitant use of the following agents is prohibited during the study:
x BTK inhibitors
x Host modifiers or immune-based therapies (see Appendix 7)
x Therapy with anti-CD20 monoclonal antibody treatment (eg, rituximab, 
obinutuzumab, ofatumumab), and/or immune checkpoint inhibitor (eg, 
pembrolizumab, nivolumab)
x Therapeutic anticoagulation including warfarin
x Combined use of antiplatelet + anticoagulation (low molecular weight heparin or 
direct-acting oral anticoagulants)


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7.2.
Potential Interactions Between the Study Drugs and Concomitant 
Medications
7.2.1.
Effects of Cytochrome P450 (CYP)-Inhibiting/Inducing Drugs on Exposure of 
Zanubrutinib
Administration of study drug with strong/moderate CYP3A inhibitors or inducers (refer to 
Appendix 3 for a list of these medications), grapefruit juice, or Seville oranges should be done
with caution because they may affect the metabolism of zanubrutinib.  If at all possible, patients 
are encouraged not to administer concurrent strong/moderate CYP3A inhibitors and inducers and 
consider using alternative agents.  If these agents will be used, follow the dose modification table 
instructions in Table 4.  The medical monitor should be consulted in these situations.  Please 
refer to http://medicine.iupui.edu/clinpharm/ddis/main-table/ for a more complete list.  A list of 
potential agents used for the management of COVID-19 and potential dose modifications is 
shown in Appendix 4.
Table 4:
Dose Modification for Study Drug when Co-Administered with 
Strong/Moderate CYP3A Inhibitors or Inducers
CYP3A
Co-administered Drug
Recommended use
Inhibition
Strong CYP3A inhibitor (eg, 
ketoconazole, conivaptan, clarithromycin, 
indinavir, itraconazole, lopinavir, 
ritonavir, telaprevir, posaconazole, 
voriconazole)
80 mg once daily
Moderate CYP3A inhibitor (eg, 
erythromycin, ciprofloxacin, diltiazem, 
dronedarone, fluconazole, verapamil, 
aprepitant, imatinib, grapefruit products)
160 mg once daily
Induction
Strong CYP3A inducer (eg, 
carbamazepine, phenytoin, rifampin, 
St. John’s wort)
Avoid concomitant use; consider 
alternative agents with less induction 
potential.
Moderate CYP3A inducer (eg, bosentan, 
efavirenz, etravirine, modafinil, nafcillin)
320 mg once daily, use with caution; 
monitor for potential lack of efficacy.
Abbreviations: CYP3A, cytochrome P450, family 3, subfamily A.
7.2.2.
Effects of zanubrutinib on exposure of other concomitant medications
A clinical drug-drug interaction study (Study BGB-3111-108) indicated that zanubrutinib is a 
mild inducer of CYP3A4 and CYP2C19.  Narrow therapeutic index drugs that are metabolized 
by CYP3A4 (alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus and tacrolimus), and CYP2C19 (eg, S-mephenytoin) should be used with 
caution, as zanubrutinib may decrease the plasma exposures of these drugs.
Because ethinylestradiol (a key ingredient in a variety of combined oral contraceptives) is partly 
metabolized by CYP3A4, patients using hormonal contraceptives (eg, birth control pills or 
devices) must use a barrier method of contraception (eg, condoms) as well (Section 5.2.2).


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Repeated dosing of zanubrutinib increased exposure of digoxin (P-gp substrate) with a mean 
increase of 11% for AUC0-t and 34% for Cmax.  The coadministration of oral P-gp substrates with 
a narrow therapeutic index (eg, digoxin) should be used with caution as zanubrutinib may 
increase their concentrations.


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8.
SAFETY MONITORING AND REPORTING
The investigator is responsible for the detection and documentation of events meeting the 
definition of an AE or SAE as provided in this protocol.  In addition, a separate Safety 
Monitoring Committee (Section 8.7) will be formed to monitor the safety (including lack of 
efficacy) of the study on a periodic basis.
8.1.
Adverse Events
8.1.1.
Definitions and Reporting
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study 
drug, whether considered related to study drug or not.
Examples of AEs include the following:
x Worsening of a chronic or intermittent pre-existing condition, including an increase in 
severity, frequency, duration, and/or has an association with a significantly worse 
outcome
x New conditions detected or diagnosed after study drug administration even though it 
may have been present before the start of the study
x Signs, symptoms, or the clinical sequelae of a suspected interaction
x Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug
or a concurrent medication (overdose per se should not be reported as an AE or SAE)
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory results, and diagnostics reports) relative to 
the AE or SAE.  The investigator will then record all relevant information regarding an AE or 
SAE in the eCRF.  However, there may be instances when copies of medical records for certain 
cases are requested by the sponsor.  In these instances, all patient identifiers will be blinded on 
the copies of the medical records before submission to the sponsor.  When a new infection is 
reported, the site of infection and the diagnostic test used to make the diagnosis will be recorded.
8.1.1.1.
Assessment of Severity
The investigator will assess the severity for each AE and SAE reported during the study.  AEs 
and SAEs should be assessed and graded based upon the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 5.0 (NCI-CTCAE v5.0).
Toxicities that are not specified in the NCI-CTCAE v5.0 will be defined as follows:
x Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated
x Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
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x Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living
x Grade 4: Life-threatening consequences; urgent intervention indicated
x Grade 5: Death related to AE
Note: The terms “severe” and “serious” are not synonymous.  Severity is a measure of intensity 
(eg, grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 3], or 
life-threatening [Grade 4]), whereas seriousness is classified by the criteria based on the 
regulatory definitions.  Seriousness serves as the guide for defining regulatory reporting 
obligations from the sponsor to applicable regulatory authorities as described in Section 8.2.
8.1.1.2.
Assessment of Causality
The investigator is obligated to assess the relationship between the study drug and the occurrence 
of each AE or SAE, using best clinical judgement.  Alternative causes, such as natural history of 
the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of 
the AE or SAE to the study drug should be considered and investigated.  The investigator should 
consult the IB in the determination of his/her assessment.
There may be situations when an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the sponsor.  However, it is very important that the 
investigator assesses causality for every SAE before transmission of the SAE report to the 
sponsor because the causality assessment is one of the criteria used when determining regulatory 
reporting requirements.  The investigator may change his/her opinion of causality in light of 
follow-up information and amend the SAE report accordingly.
The causality of each AE should be assessed and classified by the investigator as “related” or 
“not related.”  An AE is considered related if there is “a reasonable possibility” that the AE may 
have been caused by the study drug (ie, there are facts, evidence, or arguments to suggest 
possible causation).  A number of factors should be considered in making this assessment, 
including the following:
x Temporal relationship of the AE to the administration of study treatment/study 
procedure
x Whether an alternative etiology has been identified
x Mechanism of action of the study drug
x Biological plausibility
An AE should be considered “related” to study drug if any of the following criteria are met, 
otherwise the event should be assessed as not related:
x There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out.
x There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely.


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x There is some evidence to suggest a causal relationship (eg, the AE occurred within a 
reasonable time after administration of the study drug).  However, the influence of 
other factors may have contributed to the AE (eg, the patient’s clinical condition or 
other concomitant AEs).
8.1.1.3.
Follow-up of Adverse Events and Serious Adverse Events
After the initial AE or SAE report, the investigator is required to proactively follow each patient 
and provide further information to the sponsor on the patient’s condition.
All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be 
reviewed at subsequent visits/contacts.
All AEs and SAEs will be followed until resolution, the condition stabilizes or is considered 
chronic, the AE or SAE is otherwise explained, the patient is lost to follow-up, or the patient 
withdraws consent.  The investigator will ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE.  
This may include additional laboratory tests or investigations, histopathological examinations, 
radiographic imaging, or consultation with other health care professionals.
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of 
the AE or SAE.  The investigator is obligated to assist.  If a patient dies during participation in 
the study or during a recognized follow-up period, the sponsor will be provided with a copy of 
any postmortem findings, including histopathology.
New or updated information should be reported to the sponsor according to the SAE instructions 
provided by the sponsor within the time frames outlined in Section 8.4.2.1.
8.1.2.
Laboratory Test Abnormalities
Abnormal laboratory findings (eg, clinical chemistry, complete blood count, coagulation, or 
urinalysis) or other abnormal assessments (eg, ECGs, X-rays, or vital signs) that are judged by 
the investigator as clinically significant will be recorded as AEs or SAEs.  This includes 
clinically significant abnormal laboratory findings or other abnormal assessments that are present 
at baseline and significantly worsen during the study.  The definition of clinically significant is 
left to the judgment of the investigator; in general, these are laboratory test abnormalities that are 
associated with clinical signs or symptoms, require active medical intervention, or lead to dose 
interruption or discontinuation, require close observation, more frequent follow-up assessments, 
or further diagnostic investigation.
Lymphocytosis is considered as an expected manifestation of treatment with zanubrutinib and 
therefore may not be an AE; clinical correlates should be present if reporting lymphocytosis as 
an AE. Patients who develop marked and persistent lymphocytosis should have an analysis (ie, 
flow cytometry) to rule out an underlying hematologic malignancy disorder.
For information on procedures for the monitoring and prevention of hepatitis B and hepatitis C, 
see Section 5.7.6.


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8.1.3.
Lack of Efficacy
Lack of efficacy will not be reported as an AE.  The signs and symptoms or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfill the AE or SAE definition (including 
clarifications).  
8.2.
Serious Adverse Events
8.2.1.
Definitions
An SAE is any untoward medical occurrence that, at any dose:
x Results in death
x Is life-threatening
Note: the term “life-threatening” in the definition of “serious” refers to an AE in 
which the patient was at risk of death at the time of the AE.  It does not refer to an 
AE, which hypothetically might have caused death, if it was more severe.
x Requires hospitalization or prolongation of existing hospitalization
Note: In general, hospitalization signifies that the patient was admitted (usually 
involving at least an overnight stay) to the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting.
x Results in disability/incapacity
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance, such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle), which may 
interfere or prevent everyday life functions, but do not constitute a substantial 
disruption.
x Is a congenital anomaly/birth defect
x Is considered a significant medical AE by the investigator based on medical judgment 
(eg, may jeopardize the patient or may require medical/surgical intervention to 
prevent one of the outcomes listed above)
The following are NOT considered SAEs:
x Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline
x Hospitalization for social/convenience considerations
x Scheduled therapy for the target disease of the study, including admissions for 
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8.3.
Suspected Unexpected Serious Adverse Reaction
A suspected unexpected serious adverse reaction is a serious adverse reaction that is both 
unexpected (ie, not present in the product’s Reference Safety Information) and meets the 
definition of a serious adverse drug reaction, the specificity or severity of which is not consistent 
with those noted in the IB.
8.4.
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events
8.4.1.
Adverse Event Reporting Period
After informed consent has been signed but prior to the administration of the study drug, only 
SAEs should be reported.
After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, will be 
reported until 56 days after the last dose of study drug.  The investigator should report any SAEs 
that are assessed as related to study-drug treatment, at any time after treatment discontinuation.
8.4.2.
Prompt Reporting of Serious Adverse Events
8.4.2.1.
Timeframes for Reporting Serious Adverse Events
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the 
event must be reported promptly (within 24 hours) to the sponsor or designee as described in 
Table 5.
Table 5:
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee
Timeframe for 
Making Initial 
Report
Documentation 
Method
Timeframe for 
Making Follow-up
Report
Documentation 
Method
Reporting 
Method
All 
SAEs
Within 24 hours of 
first knowledge of 
the AE
SAE Report
As expeditiously as 
possible
SAE Report
Email or fax 
SAE form 
Abbreviations: AE, adverse event; SAE, serious adverse event.
8.4.2.2.
Completion and Transmission of the Serious Adverse Event Report
Once an investigator becomes aware that an SAE has occurred in a patient, he/she is to report the 
information to the sponsor within 24 hours as outlined above in Section 8.4.2.1.  The SAE report 
will always be completed as thoroughly as possible with all available details of the event and 
forwarded to the sponsor or designee within the designated time frames.
If the investigator does not have all information regarding an SAE, he/she is not to wait to 
receive additional information before notifying the sponsor or designee of the SAE and 
completing the form.  The form will be updated when additional information is received.
The investigator must always provide an assessment of causality at the time of the initial report 
as described in Section 8.1.1.2.


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The sponsor will provide contact information for SAE report submission.
8.4.2.3.
Regulatory Reporting Requirements for Serious Adverse Events
The investigator will report all SAEs to the sponsor in accordance with the procedures detailed in 
Section 8.4.2.1.  The sponsor has a legal responsibility to notify, as appropriate, both the local 
regulatory authority and other regulatory agencies about the safety of a product under clinical 
investigation.
The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities 
and the IRB/IEC.
All suspected unexpected serious adverse reaction (as defined in Section 8.3) will be submitted 
to all applicable regulatory authorities and investigators for zanubrutinib studies.
When a study center receives an initial or follow-up safety report or other safety information (eg, 
revised IB) from the sponsor, the investigator or designated responsible person is required to 
promptly notify his/her IRB or IEC.  The investigator should place copies of safety reports from 
the sponsor in the Investigator Site File.
8.4.3.
Eliciting Adverse Events
The investigator or designee will ask about AEs by asking the following standard questions:
x How are you feeling?
x Have you had any medical problems since your last visit?
x Have you taken any new medicines since your last visit?
8.4.4.
Death
Death is an outcome and not usually considered an event.  If the only information available is 
death and the cause of death is unknown, then the death is reported as an event (eg, “death,” 
“death of unknown cause,” or “death unexplained”).
8.5.
Pregnancy Reporting
If a female patient or the partner of a male patient becomes pregnant while receiving 
investigational therapy or within 90 days after the last dose of study drug, a pregnancy report 
form is required to be completed and expeditiously submitted to the sponsor to facilitate outcome 
follow-up.  Information on the status of the mother and child will be forwarded to the sponsor.  
Generally, follow-up will be no longer than 6 to 8 weeks after the estimated delivery date.  Any 
premature termination of the pregnancy will be reported.
While pregnancy itself is not considered to be an AE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE.
An abortion, whether accidental, therapeutic, or spontaneous, should always be reported as an 
SAE.  Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the 
study drug should be recorded and reported as an SAE.


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8.6.
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Independent Ethics Committees
The sponsor will promptly assess all SAEs against cumulative study drug experience to identify 
and expeditiously communicate new safety findings to regulatory authorities, investigators, 
IRBs, and IECs based on applicable legislation.  To determine the reporting requirements for 
individual SAEs, the sponsor will assess the expectedness of the SAEs using the Zanubrutinib
Investigator’s Brochure.
8.7.
Safety Monitoring Committee
Due to the critically ill nature of these patients and the potential impact of blunting an immune 
response during an active infection, a Safety Monitoring Committee (SMC) will be established.  
An SMC will review and monitor toxicity and accrual data from this study on an ongoing basis, 
.  The committee will meet at 
least weekly until the study is fully accrued and all patients have completed at least 28 days of 
treatment.  All active patients will be reviewed at least weekly until the final patient has 
completed active therapy.  Thereafter, the SMC will continue at a frequency that is dependent 
upon the patterns that have been seen to date.  All deaths will be reviewed and patterns of SAEs 
will be discussed at the weekly meeting.  A decision will be made to continue as planned, modify 
the protocol for safety reasons or discontinue the protocol if significant safety concerns are 
identified.  The SMC will consist of at least the following: 3 physician consultants, the medical 
monitor, an internal medical chair, a biostatistician, and a safety representative from BeiGene.
The SMC may have access to unblinded information to assess safety and efficacy on an ongoing 
basis.


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9.
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock.  This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.  Any deviations in the planned analysis as stated in 
the protocol will be delineated in the SAP.  Any deviations from the SAP will be reported in the 
clinical study report.  A data review will be conducted prior to database lock.  This review will 
assess the accuracy and completeness of the study database, participant evaluability, and 
appropriateness of the planned statistical methods.
9.1.
Randomization Methods
As discussed in Section 5.3, patients in Cohort 1 will be randomized 1:1 to zanubrutinib plus 
supportive care (Arm A) versus placebo plus supportive care (Arm B).  Patients will be stratified 
by age (< 65 years or ≥65 years) and the use of antiviral therapy (yes or no).  As no standard for 
treatment in patients with COVID-19 in pulmonary distress currently exists and new treatment 
options are urgently needed, this study will be exploratory in nature, and following the
assessment of efficacy and safety results from the first 42 patients the study may continue to 
enroll based on review of the trial outcomes by study amendment.
9.2.
Study Endpoints
The coprimary endpoints for this study are the respiratory failure-free survival rate at 28 days
and the time to breathing room air, both in Cohort 1.
Respiratory failure-free survival is defined as the time to the first occurrence of either respiratory 
failure or death.  The rate of respiratory failure-free survival at 28 days is the proportion of 
patients who have not had respiratory failure nor died at any time ≤28 days after randomization.
Respiratory failure is defined by a clinical diagnosis of respiratory failure and initiation of one of 
the following therapies:
1. Endotracheal intubation and mechanical ventilation,
2. Extracorporeal membrane oxygenation,
3. Clinical diagnosis of respiratory failure with initiation of none of these measures only
when clinical decision-making driven is driven solely by resource limitation or change in 
goals of therapy (these events will be formally collected in the CRF and flagged, for 
purposes of sensitivity analyses).
Time to breathing room air is defined as the time from randomization to the earliest time when
the patient is stable on room air. If a patient is on room air for several hours and subsequently
receives oxygen, the patient is not considered stable on room air and will not be considered back 
to room air for purposes of calculating the endpoint.
If a patient dies before breathing room air, time to breathing room air will be treated as censored 
at Day 28 in the analysis. If a patient is lost to follow-up before breathing room air, they will be 


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censored at the time they are lost to follow-up. All patients who take longer than 28 days to 
breathe room air will be censored at Day 28.
The respiratory failure-free survival rate at Day 28 will be compared between the two arms using 
simple proportions.  The proportions will be compared by Fisher's exact test.  If the 1-sided
p-value is less than 0.10, the addition of zanubrutinib to best supportive care will be considered 
to increase the respiratory failure-free survival rate at 28 days. 
The impact of adding zanubrutinib to best supportive care on the time to breathing room air will 
be described by the “hazard ratio” from a Cox model with treatment as an explanatory variable.  
The Cox model will include the stratification factors as explanatory variables as well as the
WHO 8-point score at baseline. The p-value for testing the effect of zanubrutinib will come from 
the Wald test on the treatment parameter in the model. 
Because testing will be carried out at the 0.10 one-sided level of significance for both of the 
coprimary endpoints instead of the traditional 0.05 two-sided level, a positive result will not be 
considered definitive evidence of zanubrutinib’s effectiveness. Two analyses (interim and final) 
will be performed for the coprimary endpoints in Cohort 1, with the interim analysis performed 
when the first 42 randomized patients complete 28 days of follow-up.  The type 1 error increase 
due to the interim and final analyses will be controlled by the O’Brien Fleming alpha spending 
function. The boundary for efficacy stop will be based on the p-value controlled from the 
Fisher’s exact test for the respiratory failure-free survival rate at Day 28 and the p-value from the 
Cox model for the time to breathing room air.
The respiratory failure-free survival rate will also be assessed on an exploratory basis using a 
Cox proportional hazards regression approach, treating the occurrence of respiratory failure or 
death as an event.  The stratification variables of age category (< 65 or ≥65), and use of
antivirals (yes or no), as well as a time-dependent variable for the amount the dose was reduced 
compared to the full dose during their treatment course will be added to the Cox proportional 
hazards model as explanatory variables.
Secondary endpoints will include:
x Proportion of patients experiencing respiratory failure or death on Study Days 7, 14 
and 21
x All-cause mortality at Study Days 7, 14, 21, and 28
x Proportion of patients discharged alive at Days 7, 14, 21, and 28
x Proportion of patients discharged from the ICU alive at Days 7, 14, 21 and 28
x Median reduction in days spent on supplemental oxygen, with time on supplemental 
oxygen imputed to the maximum number of days on oxygen observed in the study 
+ 1 for patients who died.  Testing to compare the two groups will be done with the 
Wilcoxon rank sum test.
x Mechanical ventilation-free survival
x Days on mechanical ventilation. Death will be assigned the maximum value observed 
in the trial + 1 and comparison between the two arms will be done using the 
Wilcoxon rank sum test.


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x Duration of hospitalization.  Death will be assigned the maximum value observed in 
the trial + 1 and comparison between the two arms will be done using the Wilcoxon 
rank sum test.
x Time to discharge. Death will be assigned the maximum value observed in the trial 
+ 1 and comparison between the two arms will be done using the Wilcoxon rank sum 
test.
x Proportion of patients discharged alive 
x Change in WHO 8-point scale from baseline. Comparison between the two arms will 
be done using the Wilcoxon rank sum test. The WHO 8-point scale is defined as in 
Table 6.
Table 6:
Ordinal Scale for Clinical Improvement
Patient State
Descriptor
Score
Uninfected
No clinical or virologic evidence of disease
0
Ambulatory
No limitation of activity
1
Limitation of activities
2
Hospitalized, Mild disease
Hospitalized, no oxygen therapy
3
Oxygen by mask or nasal prongs
4
Hospitalized, Severe Disease
Non-invasive ventilation or high-flow oxygen
5
Intubation and mechanical ventilation
6
Ventilation + additional organ support-pressors, RRT, ECMO
7
Dead
Death
8
Abbreviations: ECMO, extracorporeal membrane oxygenation; RRT, registered respiratory therapist.
x PAO2:FIO2 and/or oxygenation index, for patients on mechanical ventilation.  Death 
will be assigned the maximum value observed in the trial + 1 and comparison 
between the two arms will be done using the Wilcoxon rank sum test.
x Clinical status assessed using an ordinal scale at a pre-specified timepoint
x Time to objective measure of recovery (eg, return to baseline oxygen requirement, as 
appropriate)
x Safety and tolerability of zanubrutinib as an adjuvant therapy to standard of care as 
assessed by TEAEs, SAEs, related AEs, TEAEs by grade, and abnormal laboratory 
findings.  Frequency, seriousness and relatedness of TEAEs will be analyzed 
according to Medical Dictionary for Regulatory Activities (MedDRA).  Laboratory 
abnormalities will be analyzed according to NCI CTCAE v5.0.
Time to event data will be assessed using survival curves, and the Cox proportional hazard 
model may be utilized to determine predictors of response and to control for patient variability.  
Time will be measured starting from the randomization date.  For patients who were randomized 
and not treated, time to an event will be measured from the day of randomization.


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Demographic and baseline disease characteristics will be assessed by randomization group to 
identify any factors in which there was an imbalance between the treatment groups.  Should an 
imbalance exist in spite of randomization, the variable in which an imbalance is noted, may be 
added as an explanatory variable to adjust for the imbalance in the efficacy interpretation.
Sensitivity analyses that include age, gender, and other demographic and baseline characteristics 
will be conducted to assess robustness of the trial results.
9.3.
Sample Size, Accrual Rate and Study Duration
The study will enroll approximately 67 to 73 patients with 63 patients in Cohort 1 randomized to 
either zanubrutinib and supportive care (Arm A) or placebo and supportive care (Arm B).  
Enrollment is anticipated to be complete within 3 to 6 months.  The study is expected to be 
complete within 6 to 9 months after activation.
The standard of care for treating COVID-19 patients with respiratory distress is changing rapidly 
and as a result the rate of respiratory failure or death anticipated in the sample size calculations 
below may be higher than what will actually be seen in the study.  If the rate of respiratory 
failure or death in Cohort 1 is substantially less than what was anticipated for the trial per advice 
from the SMC, the sample size for the study may be increased to ensure there is adequate power 
for the primary endpoints.  Further, the change in standard of care may make a small study with 
respiratory failure-free survival at Day 28 as a primary endpoint not feasible because of a low 
rate of such events. 
From the standard of care arm of the lopinavir-ritonavir study (n = 100) (Cao et al 2020), we 
have the following statistics regarding respiratory failure and death (Table 7).
Table 7:
Respiratory Failure and Death in the Standard Care Arm of Lopinavir-
Ritonavir Study
Time point
Respiratory 
failure
Death
Respiratory 
failure or 
death
n (%)
n (%)
n (%)
Baseline
16 (16)
16 (16)
Day 7
25 (25)
7 (7)
32 (32)
Day 14
11 (11)
17 (17)
28 (28)
Day 28
25(25)
NA
Abbreviation: NA, not available.
The maximum observed rate of respiratory failure or death is 32%.  In Cohort 1 of the current 
study under consideration, patients in respiratory failure are not enrolled.  However, in the study 
by Cao et al, there were patients in respiratory failure at baseline.  Removing patients in the Cao 
et al study in respiratory failure at baseline from our estimate of the respiratory failure--free 
survival rate at Day 28, we estimate the respiratory failure or death rate to be 16% on Day 28 for 
the population in Cohort 1 of this study, or an 84% respiratory failure-free rate.


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Myers et al (Myers et al 2020) identified of 377 patients treated for COVID-19 as inpatients at
Kaiser Permanente Northern California.  The following statistics on the highest level of 
respiratory support were presented.
Table 8:
Highest Level of Respiratory Support in Kaiser Permanente Study
Respiratory support
n (%)
Nasal cannula/face mask 
150
(39.8)
High-flow oxygen 
12
(3.2)
Noninvasive ventilation 
8
(2.1)
Invasive ventilation 
110
(29.2)
Forty-six percent, (110 + 8 + 12) / (110 + 8 + 12 + 150), of patients who received some sort of 
respiratory support were in what the current protocol defines as respiratory failure. 
Unfortunately, we cannot decipher how many were in respiratory failure when they were 
admitted to the hospital.  Thus, the maximum respiratory failure rate expected in this study is 
46%.  If we assume the same baseline rate that was observed in the Lopinavir-Ritonavir trial, 
(Cao et al 2020), then we would come up with a respiratory failure rate of 46% - 16% = 30%.
Assuming a 10% dropout prior to Day 28, unrelated to efficacy, 42 patients total in Cohort 1will 
provide approximately 81% power to detect an increase in the respiratory failure-free survival 
rate from 70 to 95% under a z-test for proportions with type 1 error of 0.10 1-sided (see 
Section 9.3.2 for the update to these sample size considerations). It will also provide 77% power 
for detecting an increase from 80 to 99% and 64% power for detecting an increase from 85 to 
99% both with type 1 error of 0.10 one sided.
Table 9:
Power for the Primary Endpoint of Respiratory Failure-Free Survival at 
Day 28
Respiratory Failure-Free Survival Rate
Control
Zanubrutinib
Power
Alpha = 0.10 one-sided
n = 19 per group
0.85
0.90
0.208
0.85
0.95
0.405
0.85
0.99
0.642
0.80
0.90
0.341
0.80
0.95
0.561
0.80
0.99
0.767
0.70
0.80
0.286
0.70
0.90
0.622
0.70
0.98
0.897


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Respiratory Failure-Free Survival Rate
Control
Zanubrutinib
Power
Alpha = 0.10 one-sided
n = 19 per group
0.70
0.95
0.807
9.3.1.
Table 10:
9.3.2.
Update to the Statistical Considerations for Cohort 1
During the execution of this study, the RECOVERY study (RECOVERY Collaborative Group et 
al 2020) reported that the use of dexamethasone reduced the percentage of patients who died by a 
factor of 0.82 in those patients who received oxygen but not mechanical ventilation. The 
original analysis plan for Cohort 1 and the data that were used to determine the size of Cohort 1
did not reflect these published data. As a result, the sample size for Cohort 1 will be increased 
by a factor of 1/0.82**2, which represents an approximately 50% increase in the size of 
Cohort 1.


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The incidence of respiratory failure is similarly assumed to be reduced by a factor of 0.82. In 
addition, an interim/futility analysis will be performed in Cohort 1 at the point when the final 
analysis for Cohort 1 was previously planned to occur, specifically when 42 patients reach an 
event of respiratory failure or complete 28 days of treatment, whichever occurs later. Table 11
summarizes the planned interim and final analyses for Cohort 1 that will preserve the overall 
type 1 error at the 0.10, 1-sided level and provide 81% power to detect an increase in respiratory 
failure-free survival at Day 28 from 70% to 91%.  The study was initially designed to detect an 
increase in the respiratory failure-free survival rate from 70% to 95%.
Table 11:
Power, Sample Size, and Type 1 Error for the Interim Analysis Plan
Parameter
Interim analysis
Final analysis
Total number of patients
42
63
p-value boundary for efficacy (reject the null)
0.044
0.087
p-value boundary for futility (reject the alternative)
0.15 favoring 
control
0.087
Cumulative power
0.53
0.807
Cumulative type 1 error (1-sided)
0.044
0.100
Cumulative probability of stopping for futility 
(alternative)
0.002
0.193
Cumulative probability of stopping for futility (null)
0.15
0.90
There is 81% power overall to detect the treatment benefit described above.  There is a 53%
chance that the study will stop at the interim analysis for efficacy. If the study drug is not 
effective, the study has a 15% chance to stop for futility at the interim analysis, where futility is 
defined as a p-value of 0.15 favoring control.
If the respiratory failure-free survival rate at Day 28 is ≤0.547 on zanubrutinib compared with 
0.700 on control, then the study will be stopped for futility (per an approximation using the 
z-test).
In Amendment 4.0, time to breathing room air has been made a coprimary endpoint. From the 
first stage of the Adaptive Covid-19 trial (ACTT-1) which investigated the use of remdesivir,
patients on oxygen who received remdesivir took a median of 7 days to recover. Assuming that 
the treatment effect of zanubrutinib corresponds to hazard ratio of 0.50 (the event is breathing 
room air), then 38 events will provide 80% power with a type 1 error of 0.10 one-sided. A hazard 
ratio of 0.57 will require 59 events for 80% power with a type 1 error of 0.10 one-sided.


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10.
STUDY COMMUNICATION
10.1.
Provision of Study Results and Information to Investigators
When the clinical study report is completed, the sponsor will provide the major findings of the 
study to the investigator.
In addition, details of the study drug assignment will be provided to the investigator to enable 
him/her to review the data to determine the outcome of the study for his/her patient(s).
The sponsor will not routinely inform the investigator or patient of the test results, because the 
information generated from this study will be preliminary in nature, and the significance and 
scientific validity of the results would be undetermined at such an early stage of research.


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11.
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS
11.1.
Regulatory Authority Approval
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country specific regulatory requirements or file the protocol to 
an appropriate regulatory agency before the study is initiated at a study center in that country.
11.2.
Investigator Responsibilities
11.2.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” International Council on Harmonisation guidelines and that the basic 
principles of “Good Clinical Practice,” as adopted by and outlined in 21 Code of Federal 
Regulations 312, Subpart D, “Responsibilities of Sponsors and Investigators,” 21 Code of 
Federal Regulations, Part 50, and 21 Code of Federal Regulations, Part 56, are adhered to.
11.2.2.
Ethical Conduct of the Study and Ethics Approval
This study will be conducted by the investigator and the study center in accordance with GCP 
and all applicable regulatory requirements, including, where applicable, the current version of 
the Declaration of Helsinki.
The sponsor’s sample ICF will be provided to each investigator who shall adapt it, subject to 
sponsor’s approval, for use at his/her site.  The investigator (or sponsor, where applicable) is 
responsible for ensuring that: 1) this protocol, 2) the study center’s ICF, and 3) any other 
information or forms that will be presented to potential patients (eg, advertisements, Health 
Insurance Portability and Accountability Act of 1996 authorization, or information that supports 
or supplements the informed consent) are reviewed and approved by the appropriate Independent 
Ethics Committee/Institutional Review Board (IEC/IRB).  The IEC/IRB must be constituted in 
accordance with all applicable regulatory requirements.  The sponsor will provide the 
investigator with relevant document(s)/data that are needed for IEC/IRB review and approval of 
the study.  Before the study drug(s) can be shipped to the study center, the sponsor or its 
authorized representative must receive copies of the IEC/IRB approval, the approved ICF, and 
any other information that the IEC/IRB has approved for presentation to potential patients.
11.2.2.1.
Protocol Amendments
Protocol modifications, except those intended to reduce immediate risk to study patients, may be 
initiated only by BeiGene, Ltd.  All protocol modifications must be submitted by the investigator 
(or sponsor, where applicable) to competent authorities according to local requirements and to 
the IRB/IEC together with, if applicable, a revised model ICF in accordance with local 
requirements.  Written documentation from competent authorities (according to local 
requirements) and from the IRB/IEC and required site approval must be obtained – before 
changes can be implemented.


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Information on any change in risk and/or change in scope must be provided to patients already 
actively participating in the study, and they must read, understand, and sign each revised ICF, 
confirming willingness to remain in the trial.
If the protocol, the ICF, or any other information that the IRB/IEC has approved for presentation 
to potential patients is amended during the study, the investigator (or sponsor, where applicable) 
is responsible for ensuring the IRB/IEC reviews and approves, where applicable, these amended 
documents.  The investigator must follow all applicable regulatory requirements pertaining to the 
use of an amended ICF including obtaining IRB/IEC approval of the amended form before new 
patients can consent to take part in the study using this version of the form.  Copies of the 
IRB/IEC approval of the amended ICF/other information and the approved amended ICF/other 
information must be forwarded to the sponsor promptly.
11.2.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after an adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures.  The 
investigator must utilize an IRB/IEC-approved ICF for documenting written informed consent.  
Each ICF will be appropriately signed and dated by the patient or the patient’s legally authorized 
representative and the person obtaining consent.  
Informed consent must be obtained before the patient can participate in the study.  Virtual 
consenting will be allowed per hospital policy.  The contents and process of obtaining informed 
consent will be in accordance with all applicable regulatory requirements.
In the event that the ICF or other form signed by the patient is amended during their participation 
in the study, patients must be reconsented to the most current version of the ICFs or form.  For 
any updated or revised ICFs or forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was reobtained using 
the updated/revised ICFs for continued participation in the study.  
A copy of each signed ICF must be provided to the patient or the patient’s legally authorized 
representative.  All signed and dated ICFs must remain in each patient’s study file or in the site 
master study file and must be available for verification by study monitors at any time.
11.2.4.
Investigator Reporting Requirements
As indicated in Section 8.4.1, the investigator (or sponsor, where applicable) is responsible for 
reporting SAEs to the IRB/IEC, in accordance with all applicable regulations.  Furthermore, the 
investigator may be required to provide periodic safety updates on the conduct of the study at 
his/her study center and notification of study closure to the IRB/IEC.  Such periodic safety 
updates and notifications are the responsibility of the investigator and not of the sponsor.
11.2.5.
Confidentiality
The investigator and sponsor will maintain confidentiality and privacy standards by following 
applicable data privacy laws covering the collection, storage, transmission, and processing of 
patients’ personal and medical information.  


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Patient medical information obtained during this study is confidential and may be disclosed only 
to third parties as permitted by the signed ICF (or a separate authorization for the use and 
disclosure of personal health information that has been signed by the patient), unless permitted or 
required by law.
In the event of a breach of the confidentiality of a patient’s personal and medical information, the 
investigator and sponsor, as appropriate, shall fulfill all mediation steps and reporting obligations 
under applicable data privacy laws.
Information on maintaining patient confidentiality in accordance with individual local and 
national patient privacy regulations must be provided to each patient as part of the ICF process, 
either as part of the ICF or as a separate signed document (for example, in the United States, a 
site specific Health Insurance Portability and Accountability Act of 1996 consent may be used).
The investigator must assure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties.  The investigator shall code the medical 
information obtained during the study with a unique patient identification number assigned to 
each patient enrolled in the study.  This approach ensures that patients’ identifiable information 
is not included in any data set transmitted to any sponsor location.  Only date of independent 
central review and an identification code (ie, not names) should be recorded on any form or 
biological sample submitted to the sponsor, IRB, or laboratory.  The investigator must keep a 
screening log showing codes, names, and addresses for all patients screened and for all patients 
enrolled in the trial.
The investigator agrees that all information received from the sponsor, its affiliates, or
representatives, including but not limited to the IB, this protocol, eCRFs, the investigational 
drug, and any other study information, remain the sole and exclusive property of the sponsor
during the conduct of the study and thereafter.  This information is not to be disclosed to any 
third party (except employees or agents directly involved in the conduct of the study or as 
required by law) without prior written consent from sponsor.  The investigator further agrees to 
take all reasonable precautions to prevent the disclosure by any employee or agent of the study 
site to any third party or otherwise into the public domain.
If the written contract for the conduct of the study includes confidentiality provisions regarding 
sponsor’s confidential information inconsistent with this section, that contract’s provisions shall 
apply to the extent they are inconsistent with this section.
11.2.6.
Data Collection
Data required by the protocol should be entered into the electronic data capture (EDC) system 
promptly, unless otherwise indicated in the written contract for the conduct of the study. Data 
collection in the CRF should follow the instructions described in the eCRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF.  The investigator or designee as identified on Statement of 
Investigator Form must sign the completed casebooks to attest to its accuracy, authenticity, and 
completeness.
Data contained in the eCRFs are the sole property of sponsor and should not be made available 
in any form to third parties without prior written permission from sponsor, except for authorized 
representatives of BeiGene or appropriate regulatory authorities.


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11.2.7.
Data Management/Coding
All final patient data, both eCRF and external data (eg, laboratory data), collected according to 
the protocol, will be stored at sponsor at the end of the study.  
Standard procedures (including following data review guidelines, computerized validation to 
produce queries, and maintenance of an audit file which includes all database modifications) will 
be followed to support accurate data collection.  Data will be reviewed for outliers, logic, data 
inconsistencies, and completeness.
During the course of the study, a study monitor (clinical research associate) will make site visits 
to review protocol compliance, compare eCRFs against individual patient’s medical records, and 
ensure that the study is being conducted according to pertinent regulatory requirements.
Electronic CRF entries will be verified with source documentation.  The review of medical 
records will be performed in a manner to ensure that patient confidentiality is maintained.  
Checking the eCRFs for completeness, clarity, and cross-checking with source documents is 
required to monitor the progress of the study.  Direct access to source data is also required for 
inspections and audits and will be carried out giving due consideration to data protection and 
medical confidentiality.
Adverse events will be coded using the MedDRA.  Concomitant medications will be coded using 
the WHO Drug Dictionary.  Concomitant diseases/medical history will be coded using the 
MedDRA.
11.2.8.
Drug Accountability
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug.  This includes acknowledgment of receipt of each shipment of 
study product (quantity and condition), patient drug dispensation records, and returned or 
destroyed study product.  Dispensing records will document quantities received from sponsor, 
quantities dispensed to patients, and quantities destroyed or returned to sponsor, including lot 
number, date dispensed, patient identifier number, and the initials of the person dispensing the 
medication.
At study initiation, sites should have an appropriate standard operating procedure for study drug 
disposal/destruction.  At the end of the study, after final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused study drug supplies, including 
empty containers, according to these procedures and applicable law, including that regarding 
disposal of hazardous waste.  If the site cannot meet BeiGene’s requirements for disposal, 
arrangements will be made between the site and BeiGene or its representative for destruction or 
return of unused study drug supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
11.2.9.
Inspections, Audits, and Monitoring Visits
The investigator must ensure the facilities used for this trial and all the source documents for this 
trial should be made available to appropriately qualified personnel from BeiGene or its 
representatives, to IRBs/IECs, or to regulatory authority or health authority inspectors.


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11.2.10.
Protocol Adherence
The investigator is responsible for ensuring that the study is conducted in strict accordance with 
the procedures and evaluations described in this protocol.  Investigators assert that they will 
apply due diligence to avoid protocol deviations.
The investigator is to document and explain any deviations from the approved protocol.  The 
investigator must promptly report any major deviations that might impact patient safety and/or 
data integrity to the sponsor and, if applicable, to the IRB/IEC, in accordance with established 
IRB/IEC policies and procedures.
11.2.11.
Financial Disclosure 
Investigators and Sub-investigators (as designated on the Form FDA1572) are required to 
provide the sponsor with sufficient, accurate financial information in accordance with regulations 
to allow the sponsor to submit complete disclosure or certification to the absence of certain 
financial interest of clinical investigators and/or disclose those financial interests, as required by 
the appropriate health authorities.  This is intended to ensure financial interests and arrangements 
of clinical investigators with BeiGene that could affect reliability of data submitted to health 
authorities are identified and disclosed by the sponsor.  Investigators and Sub-investigators are 
responsible for providing information about their financial interests before participation in the 
study, and to update this information if any relevant changes occur during the study and for 
1 year after completion of the study (ie, last patient, last visit).
11.3.
Study Report and Publications
A clinical study report will be prepared and provided to the regulatory agency(ies).  Sponsor will 
ensure that the report meets the standards set out in the International Conference on 
Harmonisation Guideline for Structure and Content of Clinical Study Reports (International 
Conference on Harmonisation E3).  Note that an abbreviated report may be prepared in certain 
cases.
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry, and 
regulatory guidance, and the need to protect the intellectual property of BeiGene (sponsor), 
regardless of the outcome of the trial.  The data generated in this clinical trial are the exclusive 
property of the sponsor and are confidential.  As this is a multicenter study, the first publication 
or disclosure of study results shall be a complete, joint multicenter publication or disclosure 
coordinated by the sponsor.  Thereafter, any secondary publications will reference the original 
publication(s).  Authorship will be determined by mutual agreement, and all authors must meet 
the criteria for authorship established by the International Committee of Medical Journal Editors 
Uniform Requirements for Manuscripts or stricter local criteria (International Committee of 
Medical Journal Editors, 2019).
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor for review before submission or presentation 
in accordance with the clinical study agreement.  This allows the sponsor to protect proprietary 
information, to provide comments based on information from other studies that may not yet be 
available to the investigator, and to ensure scientific and clinical accuracy.  The details of the 


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processes of producing and reviewing reports, manuscripts, and presentations based on the data 
from this trial will be presented in the clinical study agreement.  Each investigator agrees that, in 
accordance with the terms of the clinical study agreement, a further delay of the 
publication/presentation may be requested by the sponsor to allow for patent filings in advance 
of the publication/presentation.
11.4.
Study and Study Center Closure
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the investigator or study center personnel, as appropriate:
x Return of all study data to the sponsor
x Resolve and close all data queries
x Accountability, reconciliation, and arrangements for unused study drug(s)
x Review of study records for completeness
In addition, the sponsor reserves the right to suspend or prematurely discontinue this study either 
at a single study center or at all study centers at any time for any reason; some reasons include, 
but are not limited to, safety or ethical issues or noncompliance with this protocol, GCP, sponsor 
written instructions, the clinical study agreement, or applicable laws and regulations.  If the 
sponsor determines such action is needed, the sponsor will discuss this with the investigator 
(including the reasons for taking such action) at that time.  When feasible, the sponsor will 
provide advance notification to the investigator of the impending action before it takes effect.
The sponsor will promptly inform all other investigators and/or institutions conducting the study 
if the study is suspended or terminated for safety reasons and will also inform the regulatory 
authorities of the suspension or termination of the study and the reason(s) for the action.  If 
required by applicable regulations, the investigator must inform the IRB/IEC promptly and 
provide the reason for the suspension or termination.
If the study is prematurely discontinued, all study data must still be provided to the sponsor.  In 
addition, arrangements will be made for all unused study drug(s) in accordance with the 
applicable sponsor procedures for the study.
Financial compensation to investigators and/or institutions will be in accordance with the clinical 
study agreement established between the investigator and/or institutions and the sponsor.
11.5.
Records Retention and Study Files
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents should 
be classified into at least the following 2 categories: (1) investigator’s study file and (2) patient 
clinical source documents.
The investigator’s study file will contain the protocol/amendments, eCRF and queries within the 
EDC System, IRB/IEC, and governmental approval with correspondence, informed consent, 
drug records, staff curriculum vitae and authorization forms, and other appropriate documents 
and correspondence.


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Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include (although not be limited to) 
the following: 
x Patient hospital/clinic records
x Physician’s and nurse’s notes
x Appointment book
x Original laboratory reports
x ECG
x Electroencephalogram
x Imaging assessments
x Pathology
x Special assessment reports
x Consultant letters
x Screening and enrollment log
After closure of the study, the investigator must maintain all study records in a safe and secure 
location.  The records must be maintained to allow easy and timely retrieval when needed (eg, 
audit or inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and personnel.  Where permitted 
by local laws/regulations or institutional policy, some or all of these records can be maintained in 
a format other than hard copy (eg, microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken.  The investigator must assure that all reproductions are 
legible, are a true and accurate copy of the original, and meet accessibility and retrieval 
standards, including re-generating a hard copy, if required.  Furthermore, the investigator must 
ensure there is an acceptable back up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.
The sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements.  The minimum retention time will meet the longer of 
the strictest standard applicable to that study center for the study, as dictated by local laws or 
regulations or the sponsor’s standards/procedures; otherwise, or 15 years.
The investigator must notify the sponsor of any changes in the archival arrangements, including, 
but not limited to, the following: archival at an off-site facility, transfer of ownership of or 
responsibility for the records in the event the investigator leaves the study center.
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and BeiGene to 
store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit.  When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage outside of the site.


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Biological samples remaining after this study may be retained in storage by the sponsor for the 
shorter of a period of up to 20 years or as allowed by the IRB/IEC.  A longer storage period may 
apply in the event that patients consent to BeiGene retaining remaining samples for future 
research.
11.6.
Information Disclosure and Inventions
All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) are the sole property of the 
sponsor.
All rights, title, and interests in any inventions, know-how or other intellectual or industrial 
property rights, whether or not patentable, which are conceived or reduced to practice by the 
study center personnel during the course of or because of the study are the sole property of the 
sponsor, and are hereby assigned to the sponsor.
If a written contract for the conduct of the study that includes ownership provisions inconsistent 
with this statement is executed between the sponsor and the study center and/or investigator, that 
contract’s ownership provisions shall apply rather than this statement.
All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) will be kept confidential by the 
investigator and other study center personnel.  This information and data will not be used by the 
investigator or other study center personnel for any purpose other than conducting the study and 
as allowed herein for publications and presentations.  
These restrictions do not apply to the following:
x Information that becomes publicly available through no fault of the investigator or 
study center personnel
x Information that is necessary to disclose in confidence to an IRB/IEC solely for the 
evaluation of the study
x Information that is necessary to disclose to provide appropriate medical care to a 
patient
x Study results that may be published as described in Section 11.3.
If a written contract for the conduct of the study which includes provisions inconsistent with this 
Section 11.6 is executed, that contract’s provisions shall apply rather than this statement. 
11.7.
Joint Investigator/Sponsor Responsibilities
11.7.1.
Access to Information for Monitoring
In accordance with International Conference on Harmonisation GCP guidelines, the study 
monitor must have direct access to the investigator’s source documentation to verify the data 
recorded in the eCRFs for consistency.
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 


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data being entered on them.  The monitor should have access to any patient records needed to 
verify the entries on the eCRFs.  The investigator agrees to cooperate with the monitor to ensure 
that any problems detected or queries raised in the course of these monitoring visits are resolved.
11.7.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of sponsor may conduct inspections or audits any 
time during or after completion of this clinical study.  If the investigator is notified of an 
inspection by a regulatory authority, the investigator agrees to notify the sponsor or its designee 
immediately.  The investigator agrees to cooperate with representatives of a regulatory agency 
and sponsor and to provide them access to records, facilities, and personnel for the effective 
conduct of any inspection or audit.


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12.
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Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N 
Engl J Med. 2020;382(18):1708‐20. 


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Harvard Medical School LINCS Project 2020. 
https://lincs.hms.harvard.edu/db/datasets/20222/results?page=1. Accessed 29 December 2020. 
He L, Ding Y, Zhang Q, et al. Expression of elevated levels of pro-inflammatory cytokines in 
SARS-CoV-infected ACE2+ cells in SARS patients: relation to acute lung injury and 
pathogenesis of SARS. J Pathol. 2006;210(3):288‐97. 
Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, et al. TMPSSR2 and ADAM17 cleave 
ACE2 differentially and only proteolysis by TMPSSR2 augments entry driven by the severe 
acute respiratory syndrome coronavirus spike protein. J Virol. 2014;88(2):1293‐1307. 
Hoffman M, Kleine-Weber H, Schroeder S et al.  SARS-CoV-2 Cell Entry Depends on ACE2 
and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271‐
80.e8. 
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus 
in Wuhan, China. Lancet. 2020;395(10223):497‐506. 
International Committee of Medical Journal Editors (ICMJE). Recommendations for
the conduct, reporting, editing, and publication of scholarly work in medical journals. Updated 
December 2019. Available at: http://www.icmje.org
Jeffries CA, Doyle S, Brunner C, et al. Bruton's tyrosine kinase is a Toll/interleukin-1 receptor 
domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 
4. J Biol Chem. 2003;278(28):26258‐64. 
Jiang Y, Xu J, Zhou C, et al. Characterization of cytokine/chemokine profiles of severe acute 
respiratory syndrome. Am J Respir Crit Care Med. 2005;171(8):850‐57. 
Keskin DB, Anandappa AJ, Sun J, et al. Neoantigen vaccine generates intratumoral T cell 
responses in phase Ib glioblastoma trial. Nature. 2019;565(7738):234‐39. 
Ley K. M1 means Kill; M2 means Heal. J Immunol. 2017;199(7):2191‐93. 
Li G, Chen X, Xu A, et al. Profile of specific antibodies to the SARS-Associated coronavirus. N 
Engl J Med. 2003;349(5):508‐9. 
Li S, Sun J, Allesoe R, et al. RNase H-dependent PCR-enabled T-cell receptor sequencing for 
highly specific and efficient targeted sequencing of T-cell receptor mRNA for single-cell and 
repertoire analysis. Nat Protoc. 2019;14(8):2571‐94. 
Miklos D, Cutler CS, Arora M, et al. Ibrutinib for chronic graft-versus-host disease after failure 
of prior therapy. Blood. 2017;130(21):2243‐50. 
Myers LC, Parodi SM, Escobar GJ, et al. Characteristics of hospitalized adults with COVID-19
in an integrated health care system in California. JAMA. 2020;323(21):2195‐98. 


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National Cancer Institute (NCI). National Cancer Institute (NCI). Common Toxicity Criteria 
Version 5.0. Cancer Therapy Evaluation Program.  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
CTCAE_v5_Quick_Reference_8.5x11.pdf. Accessed 3 January 2021
Niemann CU, Herman SE, Maric I, et al. Disruption of in vivo Chronic Lymphocytic Leukemia 
Tumor–Microenvironment Interactions by Ibrutinib – Findings from an Investigator-Initiated 
Phase II Study. Clin Cancer Res. 2016;22(7):1572‐82. 
Pechkovsky D, Goldmann T, Ludwig C, et al. CCR2 and CXCR3 chemokines are differentially 
expressed and regulated in human alveolar epithelial cells type II. Respir Res. 2005;6(1):75.
RECOVERY Collaborative Group, Peter Horby, Wei Shen Lim, et al. Dexamethasone in 
Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med. 2020:
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Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and 
outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 
2020;323(20):2052‐59. 
Simon R. Optimal two-stage designs for Phase II clinical trial. Controlled Clinical Trials. Control 
Clin Trials. 1989;10(1):1‐10. 
Tam CSL, Opat S, D'Sa S, et al. ASPEN: Results of a phase III randomized trial of zanubrutinib 
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peripheral human lung-role of alveolar epithelial TLR expression and signaling. PLoS One. 
2011;6(7):e21827. 
Tian S, Hu W, Niu L, et al. Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus 
(COVID-19) Pneumonia in Two Patients With Lung Cancer. J Thoracic Oncol. 2020;15(5):700‐
4.
Vos JM, Tsakmaklis N, Patterson CJ, et al. CXCL13 levels are elevated in patients with 
Waldenström macroglobulinemia, and are predictive of major response to ibrutinib. 
Haematologica. 2017;102(11):e452‐e455. 
Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 
Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA 2020; 323(11):1061-69.
Wang J, Oberley-Deegan R, Wang S, et al. Differentiated human alveolar type II cells secrete
antiviral IL-29 in response to influenza A infection. J Immunol. 2009;182(3):1296‐1304. 
Wang Y and Liu L. The Membrane Protein of Severe Acute Respiratory Syndrome Coronavirus 
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Interferon Induction via a Toll-Like-Receptor-Related TRAF3-Independent Mechanism. mBio. 
2016;7(1):e01872-15.
Werner JL and Steele C. Innate receptors and cellular defense against pulmonary infections. J 
Immunol. 2014;193(8):3842‐50.
Wu C, Chen X, Cai Y, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome 
and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA 
Intern Med. 2020;e200994. doi:10.1001/jamainternmed.2020.0994
Yang G, Buhrlage SJ, Tan L, et al. HCK is a survival determinant transactivated by mutated 
MYD88, and a direct target of zanubrutinib. Blood. 2016;127(25):3237‐52.
Yang G, Zhou Y, Liu X, et al. A mutation in MYD88 (L265P) supports the survival of 
lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström 
macroglobulinemia. Blood. 2013;122(7):1222‐32.
Yao XH, Li TY, He ZC, et al. A pathological report of three COVID-19 cases by minimally 
invasive autopsies. Zhonghua Bing Li Xue Za Zhi. 2020;49(5):411‐17. 


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APPENDIX 1.
SIGNATURE OF INVESTIGATOR
PROTOCOL TITLE:
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of 
Zanubrutinib Treatment in Patients Hospitalized for COVID-19 Infection and Pulmonary 
Distress
PROTOCOL NO:
BGB-3111-219
This protocol is a confidential communication of BeiGene, Ltd. and its subsidiaries.  I confirm 
that I have read this protocol, I understand it, and I will work according to this protocol and the 
terms of the clinical study agreement governing the study.  I will also work consistently with the 
ethical principles that have their origin in the Declaration of Helsinki and that are consistent with 
good clinical practices and the applicable laws and regulations.  Acceptance of this document 
constitutes my agreement that no unpublished information contained herein will be published or 
disclosed without prior written approval from BeiGene, Ltd. or one of its subsidiaries.
Instructions to the investigator: Please SIGN and DATE this signature page prior to 
implementation of this sponsor-approved protocol. PRINT your name, title, and the name of 
the center in which the study will be conducted. 
I have read this protocol in its entirety and agree to conduct the study accordingly:
Signature of Investigator:
_______________________________   Date: _____________
Printed Name:
_______________________________
Investigator Title:
_______________________________
Name/Address of Center:
_______________________________
_______________________________
_______________________________
_______________________________


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APPENDIX 2.
NASOGASTRIC/FEEDING TUBE ADMINISTRATION
FOR ZANUBRUTINIB
For patients who require nasogastric (NG) or feeding tube placement while on study, 
zanubrutinib/placebo may be administered by opening the capsules, mixing with the
recommended dosing solution, and flushing the suspension down the NG or feeding tube.
Additional guidance regarding preparation of zanubrutinib/placebo suspension is detailed in the 
Pharmacy Manual. The zanubrutinib/placebo capsule(s) should be gently squeezed/massaged to 
break cakes before opening the capsules.  The zanubrutinib/placebo suspension should be drawn 
into a syringe and administered via the NG or feeding tube.
If your local site’s practices are to formulate the zanubrutinib/placebo suspension within the 
Pharmacy, please consider for all patients (regardless of Cohort or Arm assignment) 
retaining all study drug bottles at the Pharmacy for daily dispensation in lieu of dispensing 
both bottles to the patient for self-administration. 


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APPENDIX 3.
CYP3A INHIBITORS AND INDUCERS
Note: The list of drugs in this table is not exhaustive.  Please refer to the prescribing information 
and Summary of Product Characteristics to check for CYP3A inhibition or induction risks or 
contact the medical monitor of the protocol.
Strong CYP3A Inhibitors
Antibiotics:  clarithromycin, telithromycin, troleandomycin
Antifungals:  itraconazole, ketoconazole, posaconazole, voriconazole
Antivirals:  boceprevir, telaprevir
Other:  cobicistat, conivaptan, elvitegravir, mibefradil, nefazodone, idelalisib
Protease inhibitors:  indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir
Moderate CYP3A Inhibitors
CYP3A4, CYP3A5, CYP3A7
Antibiotics:  ciprofloxacin, erythromycin
Antifungals: fluconazole, clotrimazole
Protease inhibitors: amprenavir, atazanavir, darunavir/ritonavir, fosamprenavir
Calcium channel blockers:  diltiazem, verapamil
Tyrosine kinase inhibitors (anticancer):  imatinib, crizotinib
Food products:  grapefruit juice (citrus paradisi juice), Seville oranges
Herbal medications:  Schisandra sphenanthera
Others:  amiodarone, aprepitant, casopitant, cimetidine, cyclosporine, dronedarone, tofisopam 
Strong/Moderate CYP3A Inducers
Avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St. 
John’s wort (hypericum perforatum), enzalutamide, mitotane, bosentan, efavirenz, etravirine, modafinil
Abbreviations: CYP3A, cytochrome P450, family 3, subfamily A.
Source:  Food and Drug Administration Drug Development and Drug Interactions:  Table of Substrates, Drug 
Development and Drug Interactions and Inducers: https://www.fda.gov/drugs/drug-interactions-labeling/drug-
development-and-drug-interactions-table-substrates-inhibitors-and-inducers
For a more complete list, please refer to the Flockhart Table: http://medicine.iupui.edu/clinpharm/ddis/main-table


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APPENDIX 4.
GUIDANCE ON POSSIBLE DRUG INTERACTIONS FOR
ZANUBRUTINIB AND MEDICATIONS THAT MAY BE
IN USE TO TREAT COVID-19
Drug name
Interaction
Recommended study drug dose
Antivirals
Atazanavir
Potent CYP450 3A4 Inhibitor
80 mg once daily
Cobistat
Potent CYP450 3A4 Inhibitor
80 mg once daily
Darunavir
Moderate CYP450 3A4 Inhibitor
160 mg once daily
Lopinavir/Ritonavir (Kaletra)
Potent CYP450 3A4 Inhibitor
80 mg once daily
Remdesivir
None
No dose adjustment necessary
Blood product
Immune globulin-IV
None
No dose adjustment necessary
Statins
Atorvastatin
None
No dose adjustment necessary
Pitavastatin
None
No dose adjustment necessary
Pravastatin
None
No dose adjustment necessary
Rosuvastatin
None
No dose adjustment necessary
Abbreviation: CYP450 3A, cytochrome P450, family 3, subfamily A. 


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APPENDIX 5.
SCHEDULE OF ASSESSMENTS
Baseline
(Screening)
Day 1 
(Predose)
Treatment Period
Days 1 to 28
Study Drug
End of Treatment
(0 ± 3 days after 
the last dose)
Follow-up Visit
(30 days ± 7 days after 
the last dose)
Follow-up Visit
(56 days ± 7 days after 
the last dose)
Informed consent
X
Demographics
X
Medical history including 
onset of COVID-19
symptoms
X
Concurrent Medicationsa
X
X
X
X
X
Physical Exam including 
vitalsa
X
Daily while in 
hospital; weight if 
feasible
X
X
X
O2 saturation and 
documentation of 
supplemental O2a
X
Daily while in hospital
X
As clinically indicated
As clinically indicated
CBC with differentiala,b
X
Weekly and as 
clinically indicated
X
As clinically indicated
As clinically indicated
Serum Chemistries, BUN, 
Cr, LDHa
X
Weekly and as 
clinically indicated
X
As clinically indicated
As clinically indicated
PT/aPTT
X
C-reactive protein, ferritin, 
D-dimer
X
X (Day 2, Day 7)
Cardiac troponin
X
X (Day 2, Day 7)
Viral RNA (SARS-CoV-2)
X
X


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Baseline
(Screening)
Day 1 
(Predose)
Treatment Period
Days 1 to 28
Study Drug
End of Treatment
(0 ± 3 days after 
the last dose)
Follow-up Visit
(30 days ± 7 days after 
the last dose)
Follow-up Visit
(56 days ± 7 days after 
the last dose)
X
ECGe
X
X
As clinically 
indicated
As clinically indicated
As clinically indicated
β-HCGf
X
X
X
Hepatitis serologiesg
X
Radiological evaluationh
X
As clinically indicated
As clinically 
indicated
As clinically indicated
As clinically indicated
Survivala
X
X
X
X
X
Adverse events related or 
possibly related to study 
druga
X
X
X
X
Randomization
X
Study drug dispensation
X
Study drug administrationi
X
Abbreviations: aPTT, activated partial thromboplastin time; β-HCG, beta-human chorionic gonadotropin; BUN, blood urea nitrogen; CBC, complete blood 
count; Cr, creatinine; CT, computed tomography; ECG, electrocardiogram; EDTA, ethylenediamine tetra acetic acid; FT, feeding tube; HBcAb, hepatitis B core 
antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; LDH, lactate dehydrogenase; MTM, molecular transport medium; NG, nasogastric; PCR, 
polymerase chain reaction; PK, pharmacokinetic; PT, prothrombin time; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2.
Note: Screening procedures performed within 2 days before date of first dose need not be repeated on Day 1.
a A telehealth visit with coordinated diary collection and/or return of study drug at end of study is permitted if circumstances prevent a clinic visit.  Laboratory
draws and other studies that may be clinically indicated will be performed through outpatient laboratory or radiology services or other accessible facilities 
determined by the treating physician or study team unless it is not medically safe.
b Patients who develop marked and persistent lymphocytosis should have an analysis (ie, flow cytometry) to rule out an underlying hematologic malignancy 
disorder.
c Unless patient is unstable or blood draw is not possible, blood samples for serology (1 x 10 mL, red top) will be collected at screening, Day 2, Day 7, Day 28, 
and at the first follow-up visit.  Additionally, if possible, blood samples for the following assessments will be collected at screening, Day 2, and Day 7: blood 
(1 x 10 mL) for the assessment of cytokines in EDTA tubes, blood (2 x 2.5 mL) for the NanoString transcriptome analysis, and blood (4 x 10 mL, heparin) for 
single cell RNA analysis (Section 5.8).  Additionally, a swab will be collected on Day 1 in an MTM tube for the confirmation of SARS-CoV-2.  For details for 
the correct procedures for collection, labelling and shipment of all samples, please refer to the study Laboratory Manual.


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d
e An ECG will be performed daily for Days 1 through 3, Day 7, and then weekly thereafter while the patient is hospitalized.
f β-HCG should be performed in all women of child-bearing potential at screening, Week 2, Week 4, and the End-of-Treatment Visit.
g Patients who are HBsAg negative, HBcAb positive, and HBV DNA negative must undergo at least monthly HBV DNA screening by PCR.  If a patient is 
receiving prophylactic antiviral treatment, HBV DNA screening by PCR must be done at least every 90 days.
h Chest CT or radiographic studies will be performed at screening.  A similar modality of study may be used for follow-up unless medical resources are limited.
i The first dose of study drug should be given ≤12 hours after randomization.


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APPENDIX 6.
SCHEDULE OF ASSESSMENTS - OUTPATIENT VISITS (DISCHARGE PRIOR TO
DAY 28)
Day 7 (± 1 day)
Day 14 (± 1 day)
Day 21 (± 1 day)
End of 
Treatment
(0 ± 3 days after 
the last dose)
Follow-up Visit
(30 days ± 7 days
after the last dose)
Follow-up Visit
(56 days ± 7 days
after the last dose)
Concurrent medicationsa
X
X
X
X
X
CBC with differentiala,b
X
X
X
As clinically indicated
As clinically indicated
Serum chemistries, BUN, Cr, 
LDHa
X
X
X
As clinically indicated
As clinically indicated
C-reactive protein, ferritin, D-
dimera
X
Cardiac troponina
X
β-HCGd
X
X
Radiological evaluationa,e
As clinically 
indicated
As clinically 
indicated
X
As clinically indicated
As clinically indicated
Survivala
X
X
X
X
X
Adverse events related or 
possibly related to study druga
X
X
X
X
X
Study drug administration
Daily until Day 28 or until 
discontinuation for clinical benefit 
criteria are met (Section 6.5.2)
Abbreviations: β-HCG, beta-human chorionic gonadotropin; BUN, blood urea nitrogen; CBC, complete blood count; Cr, creatinine; EDTA, ethylenediamine 
tetra acetic acid; LDH, lactate dehydrogenase.
Note: Unless otherwise specified the visit window for outpatient visits is ± 1 day of the nominal visit date.
a A telehealth visit with coordinated diary collection and/or return of study drug at end of study is permitted if circumstances prevent a clinic visit. Laboratory
draws and other studies that may be clinically indicated will be performed through outpatient laboratory or radiology services or other accessible facilities 
determined by the treating physician or study team unless it is not medically safe.
b Patients who develop marked and persistent lymphocytosis should have an analysis (ie, flow cytometry) to rule out an underlying hematologic malignancy 
disorder.


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08 January 2021
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Page 84
c Unless patient is unstable or blood draw is not possible, blood samples for serology (1 x 10 mL, red top) will be collected on Day 7, Day 28, and at the first 
follow-up visit.  Additionally, if possible, blood samples for the following assessments will be collected on Day 7: blood (1 x 10 mL) for the assessment of 
cytokines in EDTA tubes, blood (2 x 2.5 mL) for the NanoString transcriptome analysis, and blood (4 x 10 mL, heparin) for single cell RNA analysis 
(Section 5.8).  For details for the correct procedures for collection, labelling and shipment of all samples, please refer to the study Laboratory Manual.
d β-HCG should be performed in all women of child-bearing potential at screening, Week 2, Week 4, and the End-of-Treatment Visit.
e Chest CT or radiographic studies will be performed at screening. A similar modality of study may be used for follow-up unless medical resources are limited.


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Page 85
APPENDIX 7.
PROHIBITED HOST MODIFIERS/IMMUNE-BASED 
THERAPIES
Planned or concurrent use of the following host-based modifiers and immune-based therapies are 
prohibited during the study:
x Allogeneic HB-adMSCs (stem cell therapy)
x Anti-CCR5 (T-cell therapy)
x CD24Fc (checkpoint inhibitor)
x Colchicine
x Estrogen used as therapy to treat COVID-19
x FT516 (NK cell product)
x Anti-GM-CSF
x Hydroxychloroquine
 Hydroxyquinone plus antibiotic (eg, azithromycin)
x INO-4800 (vaccine)
x Interferons (eg, interferon-α, interferon-β)
 Peg-interferon-λ 1a
x Interleukin-1 inhibitors (eg, anakinra)
x Interleukin-6 inhibitors (eg, sarilumab, siltuximab, tocilizumab)
x Interleukin-8 inhibitors
x Jason kinase inhibitors (eg, baricitinib)
x Leflunomide
x Immunomodulation with naltrexone/ketamine
x Progesterone used as therapy to treat COVID-19
x Sirolimus
x Anti-TNF therapy
x Umbilical stem cell therapy
x Low dose whole body XRT
Adapted from: https://covid19treatmentguidelines.nih.gov/therapeutic-options-under-
investigation/host-modifiers-immunotherapy/

SAP_001.pdf: 
Beigene USA, Inc  
BGB-3111-219
 Statistical Analysis Plan
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
BGB-3111-219 
Study Protocol 
Title: 
A Phase 2, Randomized, Double Blind, Placebo-Controlled Study of 
Zanubrutinib Treatment in Patients Hospitalized for COVID-19 
Infection and Pulmonary Distress 
Date: 
Mar 3, 2021  
Version: 
3.1 
1&7


Beigene USA, Inc                                                                                                             
BGB-3111-219
                                                                                                                                  Statistical Analysis Plan
  
SIGNATURE PAGE 
Approval 
Date: ________________ 
Date: ________________ 
Date: ________________ 
Date: ________________ 


 
Beigene USA, Inc                                                                                                             
BGB-3111-219
                                                                                                                                  Statistical Analysis Plan
  
 
 
 
 
 
Date: ________________ 
 
 
 
 
 
 
 
 
 
 


 
Beigene USA, Inc                                                                                                             
BGB-3111-219
                                                                                                                                  Statistical Analysis Plan
  
 
 
 
 
 
TABLE OF CONTENTS 
 
1 
INTRODUCTION 
8 
2 
STUDY OVERVIEW 
8 
3 
STUDY OBJECTIVES 
10 
3.1 
Primary 
10 
3.2 
Secondary 
10 
3.3 
Exploratory 
11 
4 
STUDY ENDPOINTS 
12 
4.1 
Primary Endpoint 
12 
4.2 
Secondary Endpoints 
13 
4.3 
Exploratory 
15 
5 
SAMPLE SIZE CONSIDERATION 
15 
5.1 
Sample size consideration for Cohort 1 
16 
5.2 
Sample size consideration for 
 
19 
5.3 
Modification to the sample size for Cohort 1 
19 
6 
STATISTICAL METHODS 
21 
6.1 
Analysis Sets 
21 
6.2 
Data Analysis General Considerations 
22 
6.2.1 
Definitions and Computations 
22 
6.2.2 
Handling of Missing Data 
23 
6.2.3 
Adjustment for Covariates 
23 
6.2.4 
Multiplicity Adjustment 
24 
6.2.5 
Data Integrity 
24 
6.3 
Subject Characteristics 
24 
6.3.1 
Subject Disposition 
24 
6.3.2 
Demographics and Other Baseline Characteristics 
24 


 
Beigene USA, Inc                                                                                                             
BGB-3111-219
                                                                                                                                  Statistical Analysis Plan
  
 
 
 
 
 
6.3.3 
Clinical Characteristics at Baseline 
25 
6.3.4 
Prior and Concomitant Therapy 
25 
6.4 
Efficacy Analysis 
25 
6.4.1 
Primary Efficacy Endpoint Analysis 
25 
6.4.2 
Secondary Efficacy Endpoints Analysis 
31 
6.4.2.1 
Comparisons of rates 
32 
6.4.2.2 
Comparisons of continuous measurements 
33 
6.4.2.3 
Comparisons of the time to an event 
34 
6.4.2.4 
Other Secondary Efficacy Endpoints 
34 
6.4.3 
Exploratory Efficacy Analysis 
35 
6.4.4 
Sensitivity Analysis 
35 
6.4.5 
 
36 
6.5 
Safety Analyses 
36 
6.5.1 
Extent of Exposure 
36 
6.5.2 
Adverse Events 
37 
6.5.2.1 
 
38 
6.5.3 
Laboratory Analyses 
38 
6.5.4 
Vital Signs 
39 
6.5.5 
Electrocardiogram 
39 
7 
INTERIM ANALYSIS 
39 
7.1 
Interim Analysis for Cohort 1 
39 
7.2 
Interim analysis for 
 
40 
7.3 
Final Analysis 
40 
8 
DEVIATIONS FROM THE PROTOCOL 
40 
9 
REFERENCES 
45 
APPENDIX A: 
ADVERSE EVENTS OF SPECIAL INTEREST 
46 
 
 
 


 
Beigene USA, Inc                                                                                                             
BGB-3111-219
                                                                                                                                  Statistical Analysis Plan
  
 
 
 
 
 
 LIST OF TABLES  
Table 1:  
List of abbreviations and definitions of terms 
7 
Table 2: 
WHO 8 point ordinal scale for clinical improvement 
14 
Table 3: 
Respiratory failure and death in the standard care arm of Lopinavir-
Ritonavir study 
16 
Table 4: 
Highest level of respiratory support in Kaiser Permanente Study 
17 
Table 5: 
Power for the primary endpoint of respiratory failure-free survival rate at 
Day 28 
18 
Table 6:  
Properties of a proposed Simon two stage design 
19 
Table 7: 
Power, sample size, and type 1 error for the interim analysis plan 
21 
Table 8: 
Rules for determining respiratory failure-free survival rate at Day 28 
25 
Table 9: 
Censoring rules for the respiratory failure-free survival analysis 
26 
Table 10: 
Censoring rules for survival analysis of the time to breathing room air 
27 
Table 11:  
Table of difference between this SAP and the protocol 
40 
Table 12:  
Properties of a proposed Simon two stage design from the protocol 
43 
Table 13:  
Properties of a proposed Simon two stage design from the SAP 
44 
 
 LIST OF FIGURES  
Figure 1: 
Study Diagram 
10 
 
 


 
Beigene USA, Inc                                                                                                             
BGB-3111-219
                                                                                                                                  Statistical Analysis Plan
  
 
 
 
 
 
Table 1:  
List of abbreviations and definitions of terms 
Abbreviation 
Term 
AEs 
Adverse events 
BMI 
Body mass index 
CI 
Confidence interval 
CSR 
Clinical study report 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute Common Toxicity Criteria for Adverse Events 
 
  
PT 
Preferred term 
Q1, Q3 
First quartile, third quartile 
SAEs 
Serious adverse events 
SAP 
Statistical analysis plan 
SOC 
System organ class 
SD 
Standard deviation 
TEAE 
Treatment-emergent adverse event  
WHO 
World Health Organization 


 
Beigene USA, Inc                                                                                                             
BGB-3111-219
                                                                                                                                  Statistical Analysis Plan
  
 
 
 
 
 
1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the detailed plan for analysis of data in evaluation of 
safety and efficacy for study BGB-3111-219.  This document is based on protocol amendment 4.0 
dated 08Jan2021. The analysis plan for the 
 
analyses are not included in this SAP.   
 
2 
STUDY OVERVIEW  
Those patients whose health care providers feel that they qualify to participate in this study, who 
meet inclusion/exclusion criteria and sign an associated informed consent form will be enrolled 
into the study. These patients will have been hospitalized for COVID-19 infection and associated 
respiratory distress. Patients who have been on supplemental O2  96 hours and have pulmonary 
distress related to COVID-19 infection will be assigned to Cohort 1 and randomized to receive 
either zanubrutinib plus best supportive care or placebo plus best supportive care. The dose of 
zanubrutinib will be 320 mg once daily for a maximum of 28 days. Sixty-three patients will be 
enrolled in this double blind randomized part (Cohort 1) of the study. 
 
 
 
   
The coprimary endpoints for this study are i) the respiratory failure-free survival rate at Day 28 in 
Cohort 1 and ii) the time to breathing room air in Cohort 1. 
Respiratory failure-free survival at Day 28 is defined as not having died or gone into respiratory 
failure on or prior to Day 28.  Respiratory failure is defined by a clinical diagnosis of respiratory 
failure and initiation of one of the following therapies: 
1. Endotracheal intubation and mechanical ventilation, 


 
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2. Extracorporeal membrane oxygenation, 
3. Clinical diagnosis of respiratory failure with initiation of none of these measures only when 
clinical decision-making driven is driven solely by resource limitation or changes in goals 
of therapy (these events will be formally collected in the CRF and flagged, for purposes of 
sensitivity analyses). 
Time to breathing room air is defined as the time from randomization to the earliest time where 
the patient is stable on room air without any supplemental O2 therapy. If a patient is on room air 
for several hours and subsequently receives O2 therapy, the patient is not considered stable on 
room air and will not be considered to have returned to breathing room air for purpose of 
calculating this endpoint. If a patient dies before returning to breathing room air, time to room air 
will be treated as censored at Day 28 in the analysis. If a patient is lost to follow-up on or before 
Day 28 without returning to breathing room air, they will be censored at the time they are lost to 
follow-up. All the patients who do not return to breathing room air on or before Day 28 will be 
censored at Day 28.  
Subjects will be randomized in a 1:1 ratio to zanubrutinib plus best supportive care or placebo plus 
best supportive care. Randomization will be stratified by Age (> 65 vs <65) and use of anti-viral 
therapy (Yes vs No). Below is a diagram describing the study. 
 


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Figure 1:
Study Diagram
3
STUDY OBJECTIVES
3.1
PRIMARY
To compare the efficacy of zanubrutinib plus supportive care versus placebo plus 
supportive care as measured by respiratory failure-free survival rate at Day 28 and time 
to breathing room air (Cohort 1)
3.2
SECONDARY
To compare the efficacy of zanubrutinib plus supportive care versus placebo plus best
supportive care (Cohort 1) as measured by:


 
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 Proportion of patients experiencing respiratory failure or death 
 All-cause mortality 
 Proportion of patients discharged alive 
 Proportion of patients discharged from the ICU alive 
 Days spent on supplemental O2 
 Mechanical ventilation-free survival 
 Days on mechanical ventilation 
 Duration of hospitalization/Time to Discharge 
 Change in WHO 8-point scale from baseline 
 PAO2:FIO2 and/or oxygenation index, for patients on mechanical ventilation 
 Clinical status as assessed using the WHO 8 point ordinal scale at Days 7, 14, 21, 
and 28 
 To compare the safety of zanubrutinib plus supportive care versus placebo plus best 
supportive care (Cohort 1) as measured by TEAEs, SAEs, TEAEs by grade, and 
abnormal laboratory findings. 
3.3 
EXPLORATORY 
 
 
 
  
 
 
 
 


 
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4 
STUDY ENDPOINTS 
 
 
4.1 
PRIMARY ENDPOINT 
The coprimary endpoints for this study are i) the respiratory failure-free survival rate at Day 28 in 
Cohort 1 and ii) the time to breathing room air in Cohort 1. 
Respiratory failure-free survival is defined as the time to the first occurrence of either respiratory 
failure or death. 
Respiratory failure is defined by a clinical diagnosis of respiratory failure and initiation of one of 
the following therapies: 
1. Endotracheal intubation and mechanical ventilation, 
2. Extracorporeal membrane oxygenation, 
3. Clinical diagnosis of respiratory failure with initiation of none of these measures only 
when clinical decision-making driven is driven solely by resource limitation or change in 
goals of therapy (these events will be formally collected in the CRF and flagged, for 
purposes of sensitivity analyses). 


 
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Time to breathing room air is defined as the time from randomization to the earliest time where 
the patient is stable on room air without any supplemental O2 therapy. If a patient is on room air 
for several hours and subsequently receives O2 therapy, the patient is not considered stable on 
room air and will not be considered to have returned to breathing room air for purpose of 
calculating this endpoint. If a patient dies before returning to breathing room air on or before Day 
28, time to room air will be treated as censored at Day 28 in the analysis. If a patient is lost to 
follow-up on or before Day 28 without returning to breathing room air, they will be censored at the 
time they are lost to follow-up. All the patients who do not return to breathing room air on or 
before Day 28 will be censored at Day 28.  
 
4.2 
SECONDARY ENDPOINTS 
Secondary endpoints for Cohort 1 will include: 
 Proportion of patients experiencing respiratory failure or death on Study Days 7, 14 
and 21 
 All-cause mortality at Study Days 7, 14, 21, and 28 
 Proportion of patients discharged alive at Study Days 7, 14, 21, and 28 
 Proportion of patients discharged from the ICU alive at Study Days 7, 14, 21 and 28 
 Days spent on supplemental O2 
 Mechanical ventilation-free survival 
 Days on mechanical ventilation.  


 
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 Duration of hospitalization/Time to discharge. Death will be assigned the maximum 
value observed in the trial + 1 and comparison between the two arms will be done using 
the Wilcoxon rank sum test. 
 Change in WHO 8-point scale from baseline. Comparison between the two arms will 
be done using the Wilcoxon rank sum test. The WHO 8-point scale is defined as in 
Table 2.  
 Proportion of patients whose WHO 8-point scale changed from 
 at baseline to 
at Study Days 7, 14, 21 and 28  
 
Table 2: 
WHO 8 point ordinal scale for clinical improvement 
Patient State 
Descriptor 
Score
Uninfected 
No clinical or virologic evidence of disease 
0 
Ambulatory 
No limitation of activity 
1 
Limitation of activities 
2 
Hospitalized, Mild disease 
Hospitalized, no oxygen therapy 
3 
Oxygen by mask or nasal prongs 
4 
Hospitalized, Severe Disease 
Non-invasive ventilation or high-flow oxygen 
5 
Intubation and mechanical ventilation 
6 
Ventilation + additional organ support-pressors, RRT, ECMO 
7 
Dead 
Death 
8 
Abbreviations: RRT, registered respiratory therapist; ECMO, extracorporeal membrane oxygenation. 
 
 
 PAO2:FIO2 and/or oxygenation index, for patients on mechanical ventilation.   
 Safety and tolerability of zanubrutinib as an adjuvant therapy to standard of care as 
assessed by TEAEs, SAEs, TEAEs by grade, and abnormal laboratory findings.  


 
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Frequency, seriousness and relatedness of TEAEs will be analyzed according to 
MedDRA.  Laboratory abnormalities will be analyzed according to NCI-CTCAE v5.0. 
4.3 
EXPLORATORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 
SAMPLE SIZE CONSIDERATION 
The study will enroll approximately 67 to 73 patients with 63 patients in Cohort 1 randomized to 
either zanubrutinib and supportive care (Arm A) or placebo and supportive care (Arm B).  
 
  


 
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Enrollment was anticipated to be complete within 3 to 6 months.  The study was expected to be 
complete within 6 to 9 months after activation. 
Below we present the original rational for the size of Cohort 1 
. At the end of this 
section we provide a justification for a 50 % increase in the size of Cohort 1. 
5.1 
SAMPLE SIZE CONSIDERATION FOR COHORT 1 
From the SOC arm of the lopinavir-ritonavir study (n = 100) (Cao et al, 2020), we have the 
following statistics regarding respiratory failure and death (Table 3). 
 
Table 3: 
Respiratory failure and death in the standard care arm of Lopinavir-Ritonavir 
study 
Time point 
Respiratory failure 
n (%) 
Death 
n (%) 
Respiratory failure or death 
n (%) 
Baseline 
16 (16) 
 
16 (16) 
Day 7 
25 (25) 
7 (7) 
32 (32) 
Day 14 
11 (11) 
17 (17) 
28 (28) 
Day 28 
 
25(25) 
NA 
Abbreviation: NA, not available. 
 
The maximum observed rate of respiratory failure or death is 32%. In Cohort 1 of the current study 
under consideration, patients in respiratory failure are not enrolled.  However in this study by Cao 
et al, there were patients in respiratory failure at baseline.  Removing patients in the Cao et al study 


 
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in respiratory failure at baseline from our estimate of the respiratory failure-free survival rate at 
Day 28 we estimate the respiratory failure or death rate to be 16% at Day 28 for the population in 
Cohort 1 of this study or a 84% respiratory failure-free rate. 
Myers and others (Myers et al, 2020) identified of 377 patients treated for COVID-19 as inpatients 
at Kaiser Permanente Northern California.  The following statistics on the highest level of 
respiratory support were presented. 
 
Table 4: 
Highest level of respiratory support in Kaiser Permanente Study 
Respiratory support 
n (%) 
Nasal cannula/face mask 
150 (39.8) 
High-flow oxygen 
12 (3.2) 
Noninvasive ventilation 
8 (2.1) 
Invasive Ventilation 
110 (29.2) 
 
Forty-six percent, (110 + 8 + 12) / (110 + 8 + 12 + 150), of patients who received some sort of 
respiratory support were in what the current protocol defines as respiratory failure.  Unfortunately, 
we cannot decipher how many were in respiratory failure when they were admitted to the hospital.  
So all we can say from this study by Meyers et al is that the maximum that the respiratory failure 
rate could be in the study we are considering in this protocol with this information in hand is 46 
percent.  However, if we assume further that the baseline rate of respiratory failure in the study by 
Meyers et al is the same as the baseline rate that was observed in the Lopinavir-Ritonavir trial, 


 
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Cao et al NEJM March 18 2020, then we would come up with a Respiratory failure rate of 
46% - 16% = 30%. 
From above, both 70% and 84% were assumed as the respiratory failure-free survival rate for the 
control arm (Arm B). 
Assuming a 10% dropout prior to Day 28, unrelated to efficacy, 38 patients total will provide 
approximately 81% power to detect an increase in the respiratory failure-free survival rate from 
70 to 95% under a z-test for proportions with type 1 error of 0.10 1-sided. It will also provide 77% 
power for detecting an increase from 80 to 99% and 64% power for detecting an increase from 85 
to 99% both with type 1 error of 0.10 one sided. 
 
Table 5: 
Power for the primary endpoint of respiratory failure-free survival rate at Day 28 
Respiratory Failure-Free Survival Rate 
Power 
(Alpha = 0.10, one-sided, n = 19 per group) 
Control 
Zanubrutinib 
0.85 
0.90 
0.208 
0.85 
0.95 
0.405 
0.85 
0.99 
0.642 
0.80 
0.90 
0.341 
0.80 
0.95 
0.561 
0.80 
0.99 
0.767 
0.70 
0.80 
0.286 
0.70 
0.90 
0.622 
0.70 
0.98 
0.897 
0.70 
0.95 
0.807 
 


 
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5.2 
SAMPLE SIZE CONSIDERATION FOR 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


 
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5.3 
MODIFICATION TO THE SAMPLE SIZE FOR COHORT 1 
During the execution of this study, the RECOVERY study (RECOVERY Collaborative Group et 
al 2020) reported that the use of dexamethasone reduced the percentage of patients who died by a 
factor of 0.82 in those patients who received O2 but not mechanical ventilation.  We will assume 
that the incidence of respiratory failure and death is reduced by a factor of 0.82 since respiratory 
failure is a precursor event of death. The original analysis plan for Cohort 1 and the data that were 
used to determine the size of Cohort 1 did not reflect these published data.  As a result, the sample 
size for Cohort 1 will be increased by a factor of 1/0.82**2, which represents an approximately 
50% increase in the size of Cohort 1. 
 
Increasing the sample size by 1/0.82**2 accounts for a change in the difference in proportions in 
the denominator above due to the introduction of dexamethasone.  To be conservative, we did not 
adjust the sample size for the change in the variance component of the sample size formula above.  
In addition, an interim/futility analysis will be performed in Cohort 1 at the point when the final 
analysis for Cohort 1 was previously planned to occur, specifically 28 days after the 42nd 
randomized 
first dose date. Table 7 summarizes the planned interim and final analyses 
for Cohort 1 that will preserve the overall type 1 error at the 0.10, 1-sided level and provide 81% 
power to detect an increase in respiratory failure-free survival rate at Day 28 from 70% to 91%. 
The efficacy boundary is determined by the Obrien Fleming spending function. This permits 
flexibility in the number and timing of interim analyses for this study. The study was initially 
designed to detect an increase in the respiratory failure-free survival rate from 70% to 95%. 


 
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Table 7: 
Power, sample size, and type 1 error for the interim analysis plan 
Parameter 
Interim analysis 
Final analysis 
Number of subjects total 
42 
63 
p-value boundary for efficacy (reject the null) 
0.044 
0.087 
p-value boundary for futility (reject the alternative) 
0.15 favoring 
control 
0.087 
Cumulative power 
0.53 
0.807 
Cumulative type 1 error (1-sided) 
0.044 
0.100 
Cumulative prob. of stopping for futility (alternative) 
0.002 
0.193 
Cumulative prob. of stopping for futility (null) 
0.15 
0.90 
 
There is 81% power overall to detect the treatment benefit described above.  There is a 53% chance 
that the study will stop at the interim analysis for efficacy.  If the study drug is not effective, the 
study has a 15% chance to stop for futility at the interim analysis, where futility is defined as a p-
value of 0.15 favoring control. 
If the respiratory failure-free surviv
 0.547 on zanubrutinib compared with 
0.700 on control, then the study will be stopped for futility (per an approximation using the z-test). 
In the protocol amendment 4, the endpoint time to breathing room air has been made a coprimary 
endpoint. From the first stage of the Adaptive Covid-19 trial (ACTT-1) which investigated the use 
of remdesivir, patients on O2 therapy who received remdesivir took a median of 7 days to 
recover. Assuming that the treatment effect of Zanubrutinib corresponds to hazard ratio of 0.50 
(the event is back to room air), then 38 events will provide 80% power with a type 1 error of 0.10 
one sided. A hazard ratio of 0.57 will require 59 events for 80% power with a type 1 error of 0.10 
one sided. 


 
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6 
STATISTICAL METHODS 
6.1 
ANALYSIS SETS 
The Intent-to-Treat (ITT) Analysis Set includes all randomized patients in Cohort 1.  The ITT 
Analysis Set will be the primary population for efficacy analyses in Cohort 1.  Subjects will be 
analyzed according to their randomized treatment assignment.  
 
 
The Safety Analysis Set includes all patients who received any dose of study drug. Patients will 
be included in the treatment group corresponding to the actual treatment received. The Safety 
Analysis Set will be used for all safety analyses.  
The Per-Protocol Analysis Set includes patients who received any dose of study medication in 
Cohort 1 and may exclude those with critical protocol deviations. Criteria for exclusion from the 
Per-Protocol Analysis Set will be determined and documented before the database lock for the 
primary analysis.   
 
 
6.2 
DATA ANALYSIS GENERAL CONSIDERATIONS 
Descriptive statistics include n, mean, standard deviation (SD), median, first quartile (Q1), third 
quartile (Q3), minimum (min), and maximum (max) for continuous variables and n (%) for 
categorical variables.  
All calculations and analyses will be conducted using SAS version 9.2 or higher or R version 3.6.0 
or higher. 


 
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6.2.1 Definitions and Computations 
Study treatment (study drug): Study drug for this study is zanubrutinib or placebo. 
Study Day (Day): Study day will be calculated relative to the date of the first dose of study 
treatment (Study Day 1).  For subjects not dosed, the randomization date will be used instead of 
the first dose date.  For assessments conducted on or after Study Day 1, Study Day will be 
calculated as (assessment date  Study Day 1 + 1).  For assessments conducted before the Study 
Day 1, Study Day is calculated as (assessment date  Study Day 1).  There is no Study Day 0.   
In the situation where the event date is partial or missing, the date will appear partial or missing in 
the listings. Study Day and any corresponding durations will be presented based on the imputations 
specified in Analysis Details Specification document. 
Treatment duration: The treatment duration will be calculated as (date of last dose of study 
treatment  Study Day 1 + 1). 
Baseline: Unless otherwise specified, a baseline value is defined as the last non-missing value 
collected before Study Day 1.  Note that assessments that occur on the first day of dosing but prior 
to the time of the first dose can qualify to be a baseline value. 
6.2.2 Handling of Missing Data  
Missing data will not be imputed unless otherwise specified.  Missing dates or partially missing 
dates 
will 
be 
imputed 
conservatively 
for 
adverse 
events 
and 
prior/concomitant 
medications/procedures.  
When summarizing categorical variables, subjects with missing data are generally included in the 
denominator to calculate percentages unless otherwise specified. When needed, the category of 
s created and the number of subjects with missing data is presented.   
When summarizing continuous variables, subjects with missing data are not included in 
calculations unless otherwise specified. 


 
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No imputation of AE grades will be performed. TEAEs with missing CTCAE grade will only be 
summarized in the all-grades column. 
If the assessment of the relationship of an AE to study treatments is missing, then the AE is 
assumed to be related to the study treatment in the safety analysis summary.  No imputation will 
be done in the AE listings. 
6.2.3 Adjustment for Covariates 
Covariate adjusted analysis will be performed to adjust for important baseline covariates for the 
primary and some secondary endpoints.  These important baseline covariates could be the 
stratification factors in the randomization as well as important prognostic factors that are 
imbalanced between the arm. 
6.2.4 Multiplicity Adjustment 
The level of the primary hypothesis for this phase 2 study is 1-sided 0.1. There are no planned 
adjustments for multiplicity. 
6.2.5 Data Integrity 
Before pre-specified statistical analysis begins, the integrity of the data should be reviewed to 
assure fit-for-purpose. The data set for analysis should be an accurate and complete representation 
of the subjects  relevant outcomes from the clinical database. All essential data should be complete 
and reviewed up to a pre-specified cutoff date. Critical consistency checks and appropriate source 
data verification should be completed according to the final data extraction plan. 
6.3 
SUBJECT CHARACTERISTICS 
6.3.1 Subject Disposition 
The number of patients screened, randomized, treated, prematurely discontinued from study drug 
(defined as those who discontinued study drug due to any reason except for being discharged and 


 
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clinically stable on 
 48 hours with an O2 
 94%) with reasons, completed 
study treatment, and remained on study treatment will be summarized. In addition the number of 
patients discontinued from study with reasons and completed study will be counted.  
6.3.2 Demographics and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized using the ITT Analysis Set 
(Cohort 1) 
 using descriptive statistics. Continuous variables 
include age, weight, height, BMI; categorical variables include sex, age group, race, ethnicity, 
obesity. A listing of demographic and baseline characteristics will be also provided. 
6.3.3 Clinical Characteristics at Baseline 
A wide range of clinical characteristics at baseline will be summarized with descriptive statistics, 
primarily counts and proportions. These clinical characteristics include medical history, vital signs, 
selected laboratory test result, coexisting conditions, symptoms and the WHO 8 point ordinal scale. 
6.3.4 Prior and Concomitant Therapy 
Prior and concomitant medications will be coded using the WHO Drug Dictionary and the 
Anatomical Therapeutic Chemical Classification. Prior medications will be defined as medications 
that stopped before the first dose of study drug. Concomitant medications will be defined as 
medications that (1) started before the first dose of study drug and were continuing at the time of 
the first dose of study drug, or (2) started on or after the date of the first dose of study drug up to 
 
6.4 
EFFICACY ANALYSIS 
6.4.1 Primary Efficacy Endpoint Analysis 
The primary efficacy analyses for this study involve two comparisons. First a comparison of the 
respiratory failure-free survival rate at Day 28 between the zanubrutinib plus best supportive care 


 
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arm and the placebo plus best supportive care arm and second a comparison of the time to breathing 
room air for the same two arms in Cohort 1. 
Table 8 provides rules for determining respiratory failure-free survival rate at Day 28 as a simple 
proportion. The rate of respiratory failure-free survival at Days 7, 14 and 21 will be determined 
similarly. Analyses of respiratory failure-free survival rate is restricted to the time period up to 
Day 28. 
 
Table 8: 
Rules for determining respiratory failure-free survival rate at Day 28 
Condition 
Rules for determining respiratory failure-free 
survival rate at Day 28 
Completed Day 28 assessment without any event 
(death or respiratory failure) 
No failure 
Death at any time on or before Day 28 
Failure 
Respiratory failure at any time on or before Day 
28 
Failure 
Discharged from the hospital and lost to follow-up 
with no record of death nor readmission to the 
hospital on or before Day 28 
No failure   
Not discharged from the hospital but lost to 
follow-up with no record of death or respiratory 
failure at any time on or before Day 28 
If the last measured post-baseline O2 use 
measured in liters is less than baseline, treat as no 
failure. Otherwise, treat as a failure. 
Randomized and not treated, discharged or went 
back to room air before lost to follow-up with no 
record of death nor readmission to the hospital on 
or before Day 28  
No failure  
 
Table 9 provides censoring rules for the respiratory failure-free survival analysis. 


 
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Table 9: 
Censoring rules for the respiratory failure-free survival analysis 
Condition 
Censoring rules for the respiratory failure-free 
survival analysis 
Completed Day 28 assessment without any event 
(death or respiratory failure) at any time on or 
before Day 28 
Censored at Day 28 
Death at any time on or before Day 28 
Failure on death date 
Respiratory failure at any time on or before Day 
28 
Failure on respiratory failure date  
Discharged from the hospital and lost to follow-up 
with no record of death nor readmission to the 
hospital on or before Day 28 
Censored at Day 28 
Not discharged from the hospital but lost to 
follow-up with no record of death or respiratory 
failure at any time on or before Day 28 
Censored on the minimum of Day 28 and the lost 
to follow-up date 
Randomized and not treated, discharged with no 
record of death nor readmission to the hospital on 
or before Day 28  
Censored on the minimum of Day 28 and the lost 
to follow-up date 
 
Note in Table 8 that patients who are discharged from the hospital and who are lost to follow-up 
will be treated as no failure at Day 28. The rational for this is that having been discharged from 
the hospital, it is very likely that they will be without respiratory failure at Day 28.   
Further note that patients who are not discharged but lost to follow-up and their last assessment 
showed improvement in O2 use from baseline will be treated as no failure at Day 28. This situation 
is very unlikely but may occur in 1 or 2 cases. 


 
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Assuming that patients who are alive without respiratory failure at their last assessment prior to 
being lost to follow-up have experienced respiratory failure or death at Day 28 seems hard to 
justify. Further assuming that patients who are alive without respiratory failure at their last 
assessment prior to being lost to follow-up are still alive without respiratory failure at Day 28 
seems hard to justify as well from the analysis perspective because we will be assuming a good 
outcome for treatment which is what we are trying to prove. Thus we took an intermediate path 
and based the imputation of response at Day 28 on the change in O2 use from baseline. Note that 
these cases where subjects are lost to follow-up without being discharged from the hospital should 
be very few in number.  
Table 10 provides censoring rules for survival analysis of the time to breathing room air. 
 
Table 10: 
Censoring rules for survival analysis of the time to breathing room air 
Condition 
Censoring rules for survival analysis of the 
time to breathing room air 
Returned to breathing room air on or before Day 
28 
Event on the date returned to breathing room air 
Completed Day 28 assessment without returning 
to breathing room air at any time on or before Day 
28 
Censored at Day 28 
Death before returning to breathing room air at 
any time on or before Day 28 
Censored at Day 28 
Discharged from the hospital and lost to follow-up 
with no record of returning to breathing room air 
on or before Day 28 
Censored at lost to follow-up date 
Not discharged from the hospital but lost to 
follow-up with no record of returning to breathing 
room air on or before Day 28 
Censored at lost to follow-up date 


 
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Randomized and not treated, discharged with no 
record of returning to breathing room air on or 
before Day 28 
Censored at hospital discharge date 
 
The null and alternative hypotheses for formally testing the superiority of zanubrutinib over 
placebo for the endpoint respiratory failure-free survival rate at Day 28 are as follows: 
H0:  
 
Ha: 
 
where p denotes the rate of respiratory failure free survival at Day 28, that is the proportion of 
patients who have not experienced respiratory failure or death at any time on or before Day 28. 
The primary inference regarding this hypothesis will be based on unstratified 
 
with a type 1 error rate of 0.10 1-sided. The associated odds ratio and its 2-sided 95% CI will also 
be presented.  If the 1-sided p-value is less than 0.10, the addition of zanubrutinib to best supportive 
care will be considered to increase the respiratory failure-free survival rate at Day 28. Because 
testing will be carried out at the 0.10 1-sided level of significance instead of the traditional 0.05 
two-sided 
effectiveness.  
The null and alternative hypotheses for formally testing the superiority of zanubrutinib over 
placebo for the endpoint time to breathing room air are as follows: 
H0:  
 
Ha: 
 
where 
 represents the hazard ratio of the event return to breathing room air 
between zanubrutinib (hazard 
) and placebo (hazard 
) arms. The impact of 
adding zanubrutinib to best supportive care on the time to breathing room air will be formally 


 
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tested using the hazard ratio from a Cox model with treatment as an explanatory variable. P-value 
will be calculated from the 2-sided log-rank test. For exploratory analysis purpose, the 
stratification variables of age category (< 
 65) and use of antivirals (yes or no) may be 
included as additional explanatory variables in the Cox model.  
Two analyses (interim and final) will be performed for the coprimary endpoints in Cohort 1. The 
interim analysis will summarize Day 28 follow-up of the first 42 randomized patients and will be 
performed no sooner than 28 days after the 42nd randomized patient
first dose date. The final 
analysis will be a complete summary of the efficacy and safety data for all patients randomized to 
the study and will take place no sooner than 84 days (28 days of treatment and 56 days of safety 
follow-up) after the last 
te. The type 1 error increase due to these 
efficacy stop will be based on two p-values, one from 
 for the respiratory 
failure-free survival rate at Day 28 and the other from Cox model for time to breathing room air. 
Potential intercurrent events that can affect the estimates of the rates of respiratory failure-free 
survival at Day 28 include treatment discontinuation due to an adverse event and lost to follow-up 
after hospital discharge. Regarding treatment discontinuation there will be no adjustments for this 
intercurrent event since the intention is to estimate the effect of zanubrutinib in this clinical setting 
and that includes outcomes for patients who experience an adverse event and as a result have to 
stop taking zanubrutinib. Thus the outcome for these patients will depend on further follow-up for 
respiratory failure or death. 
Regarding subjects who are lost to follow-up following hospital discharge, we will treat these 
subjects as alive and without respiratory failure up to Day 28 unless they die or are re-hospitalized 
with respiratory failure. However subjects who are lost to follow-up without hospital discharge 
and without respiratory failure or death will be censored at the point where they are lost to follow-
up for purposes of survival analyses. For purposes of determining the respiratory failure-free 


 
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survival rate as a simple proportion these patients will be handled as indicated in Table 8 depending 
on the change in their O2 support from baseline. As supportive analyses, we intend to utilize 
survival analysis techniques that incorporate methods for censoring to adjust estimates of 
respiratory failure-free survival at Days, 7, 14, 21 and 28 for subjects who are lost to follow-up if 
there are any. Testing based on survival analysis techniques would then rely on Kaplan Meier 
mula for the variance of these estimates. 
It should be noted that death is an expected intercurrent event for time to breathing room air since 
it does not numerically incorporate death. It is our intention to use time to breathing room air to 
somehow. As noted for the formal comparison of the two arms of the trial with this endpoint, a 
Cox model is used where patients who have died without returning to breathing room air are 
censored at Day 28.  
The impact of treatment on respiratory failure-free survival will also be assessed with an exact 
conditional logistic regression model. Because we only expect to have 10 of 63 subjects with 
respiratory failure, these analyses will be exploratory in nature.  
The impact of treatment on respiratory failure-free survival will be also compared between the two 
arms using a Cox proportional hazards regression approach, treating the occurrence of respiratory 
failure or death as an event. Time to an event will be measured starting from the randomization 
date up to Day 28. For exploratory analysis purpose, the stratification variables of age category 
(< 
 65) and use of antivirals (yes or no) may be included as explanatory variables. These 
analyses will be exploratory in nature since we only expect to have around 10 of 63 subjects with 
respiratory failure or death.  
Demographic and baseline disease characteristics will be assessed by randomization group to 
identify any prognostic factors in which there was an imbalance between the treatment groups.  


 
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Should an imbalance exist in spite of randomization, the variable in which an imbalance is noted, 
may be added as an explanatory variable to adjust for the imbalance in the efficacy interpretation.  
6.4.2 Secondary Efficacy Endpoints Analysis 
The types of secondary efficacy endpoints fall into three general categories. Comparisons of rates, 
comparisons of continuous measurements and comparisons of times to an event. 
6.4.2.1 Comparisons of rates 
The following secondary endpoints fall into the general category of comparisons of rates. 
 Proportion of patients experiencing respiratory failure or death on Study Days 7, 14 and 21 
 All-cause mortality at Study Days 7, 14, 21, and 28 
 Proportion of patients discharged alive at Days 7, 14, 21, and 28 
 Proportion of patients discharged from the ICU alive at Days 7, 14, 21 and 28 
For these endpoints, the number and percent of subjects with an event will be presented. An 
unstratified 1-sided 
test will be used to compare the two groups on these endpoints 
and the associated odds ratio and 95% CI will be provided. Note that for the proportion of patients 
discharged alive from the ICU, the denominator will be the cumulative number of patients admitted 
to the ICU on or before Days 7, 14, 21, and 28 respectively. The denominator will be presented 
along with the cumulative number of patients discharged alive from the ICU. Because this endpoint 
is based on a subset of the randomized population any differences observed between the arms 
should be interpreted cautiously. 
Possible intercurrent events that can affect the estimate of these endpoints are discontinuation of 
study drug due to adverse events, and lost to follow-up after being discharged from the hospital 
for the endpoints respiratory failure or death, and all cause mortality. Regarding discontinuation 
of study drug due to adverse events, the intention is to estimate the effect of zanubrutinib in this 


 
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clinical setting and that includes outcomes for patients who experience adverse events and can no 
longer take zanubrutinib. Consequently, this intercurrent event will not lead to adjustments in the 
estimates of the rates of these endpoints.  As far as lost to follow-up following hospital discharge 
is concerned, the intention is to estimate the respiratory failure-free survival and all cause mortality 
for all subjects. Subjects who are discharged alive and are lost to follow-up will be treated as alive 
in these analyses at all later timepoint. Similarly for subjects who are discharged without 
respiratory failure up to that point and lost to follow-up without observing the endpoint following 
hospital discharge, survival analysis techniques may be used to adjust the estimate of these 
endpoints. Such subjects will be censored at the point where they are lost to follow-up. In the 
situation where subjects are discharged from the hospital, they will be assumed alive and 
respiratory failure-free at all later time points unless data is collected to the contrary. Comparison 
of the Kaplan Meier estimates in the two arms at Days 7, 14, 21 and 28 will be made with the 
. 
6.4.2.2 Comparisons of continuous measurements 
The following endpoint analyses are based on comparisons of continuous measurements.  
 Days on mechanical ventilation  
 Duration of hospitalization/Time to discharge 
It should be noted that death is an expected intercurrent event for these endpoints since they do not 
numerically incorporate death. It is our intention to use these endpoints to compare zanubrutinib s 
effectiveness with placebo. Therefore we must account for deaths somehow. For the formal 
comparison of the two arms of the trial with these endpoints, a Wilcoxon rank sum test will be 
used where patients who have died without an event are assigned a value equal to 1 plus the 
maximum value observed in Cohort 1. That is deaths will be assigned to the highest/lowest rank 
which represents the worst patient outcome. The actual observed values of these endpoints will be 
further summarized with descriptive statistics by treatment arm. In addition to the rank-based 


 
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Wilcoxon test, we will apply a test of the hypothesis that the medians are the same developed by 
Mood (Mood et al, 1954). This test involves creating a 2x2 table of treatment by subjects who are 
above vs equal to or below the overall median and testing with a chi-square test. Note that we 
anticipate the death rate in Cohort 1 to be less than 50%. If this is the case then assigning patients 
who died the worst rank will allow us to estimate a true median value for these endpoints and 
Moods test on the medians will allow us to assess if any differences we observe in the medians are 
statistically significant. 
Other intercurrent events that could affect these endpoints are stopping treatment due to an adverse 
event. Our intention is to describe the impact of zanubrutinib in this clinical setting and stopping 
treatment due to an adverse event is part of the clinical setting. So no adjustment for this will be 
required. 
6.4.2.3 Comparisons of the time to an event 
The following endpoints are based on comparisons of time to an event.  
 Respiratory failure-free survival 
 Mechanical ventilation-free survival  
Both respiratory failure-free survival and mechanical ventilation-free survival are endpoints that 
will be evaluated using traditional survival analysis techniques. Subjects will be censored as in 
Table 9 if they have not had an event prior to the data cutoff or if they are lost to follow-up. The 
number of patients with respiratory failure/mechanical ventilation, and death as well as the total 
follow-up time will be summarized.  Simple estimates of the hazard (total number of events/total 
follow-up time) and the hazard ratio (95% CI) from a Cox model with treatment as the sole 
explanatory variable will be provided. P-value will be calculated from the 2-sided log-rank test. 
6.4.2.4 
Other Secondary Efficacy Endpoints 
6.4.2.4.1 WHO 8  ordinal scale for clinical improvement 


 
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The actual values and the change from baseline in WHO 8-point scale will be summarized by 
descriptive statistics. Comparison of the change from baseline between the two arms will be done 
using the Wilcoxon rank sum test. The WHO 8-point scale is defined as in Table 6 in the protocol. 
In addition shift tables will be created for comparing baseline with Days 7, 14, 21 and 28. 
Proportion of patients whose WHO 8-
 
at Study 
Days 7, 14, 21 and 28 will be compared between two arms using unstratified 1-
test and the associated odds ratio and 95% CI will be provided.  
6.4.2.4.2 PAO2:FIO2/Oxygenation Index 
For patients in Cohort 1 who started mechanical ventilation, PAO2:FIO2/Oxygenation index 
appropriately standardized will be calculated and listed. 
6.4.2.4.3 
  
 
 
 
6.4.3 Exploratory Efficacy Analysis 
 
 
 
6.4.4 Sensitivity Analysis 
For the coprimary endpoint of the respiratory failure-free survival rate at Day 28, a logistic 
regression analysis will be undertaken as a complement to the unstratified primary analysis. The 
explanatory variables will be those incorporated in the randomization, age (>= 65 vs < 65) and use 
of antivitral therapy (yes vs no). In addition, baseline factors that are associated with respiratory 


 
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failure-free survival and are imbalanced between the treatment arms may be included in the logistic 
regression analyses to see how they impact the estimate of the treatment effect.  
Similar sensitivity analyses may be undertaken for secondary endpoints that involve the 
comparison of rates at specific time points. 
For coprimary efficacy endpoints, a Per-Protocol Analysis may be undertaken to assess the 
robustness of the result obtained from the ITT analysis. 
6.4.5 
 
 
 
6.5 
SAFETY ANALYSES 
Safety will be assessed by monitoring and recording of all AEs graded by NCI-CTCAE v5.0. 
Laboratory values (CBC, serum chemistry and coagulation), vital signs, physical exams and ECG 
findings will also be used in assessing safety.  Descriptive statistics will be used to analyze all 
safety data by treatment group. 
6.5.1 Extent of Exposure 
Extent of exposure to study drug will be summarized descriptively as the duration of exposure 
(days), cumulative total dose received per patient (mg), dose intensity (mg/day) and relative dose 
intensity (%). 
The number of patients with dose reductions will be summarized with simple proportions. The 
number of dose reductions per patient will be summarized by numerical category (e.g. 1, 2, 3, or 
). Doses missed will be summarized by counts as well as by descriptive statistics. 
Patient data listings will be provided for all dosing records and for calculated summary statistics. 


 
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6.5.2 Adverse Events 
The AE verbatim descriptions (as recorded by the investigator on the eCRF) will be classified into 
standardized medical terminology using Medical Dictionary for Regulatory Activities 
(MedDRA®).  Adverse events will be coded to MedDRA (Version 23.0) lower level term closest 
to the verbatim term. The linked MedDRA preferred term and primary system organ class will 
also be captured in the database. 
A treatment-emergent AE (TEAE) is defined as an AE that had an onset date on or after the first 
dose date (Day 1) of study drug (zanubrutinib or placebo) up to 56 days following the last dose 
date.   
 The incidence of TEAEs will be reported as the number and percentage of patients with 
TEAEs by System Organ Class (SOC) and Preferred Term (PT).  A patient will be counted 
only once by the highest severity grade according to NCI-CTCAE v5.0 within a system 
organ class and preferred term, even if the patient experienced more than 1 TEAEs.  An 
overall summary of TEAEs will be presented by treatment groups for the number of 
patients with (1) any TEAE, (2) any Grade 3 or higher TEAE, (3) any serious TEAE, (4) 
any treatment-related TEAE, (5) any TEAE leading to dose modification (interruption and 
reduction), (6) any TEAE leading to study treatment discontinuation, (7) any TEAE leading 
to death. A general summary of TEAEs by SOC and PT will be provided with the number 
and percent of patients who experienced the following types of events by treatment groups: 
 Any TEAE  
 Any Grade 3 or higher TEAE 
 Any serious TEAE 
 Any treatment-related TEAE 
 Any TEAE leading to dose modification 


 
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 Any TEAE leading to study treatment discontinuation 
 Any TEAE leading to death 
 Any TEAE of special interest 
Data listing for all adverse events will be provided. 
6.5.2.1 
 
, i.e. adverse events that are generally related to the drugs mechanism of 
action, will be summarized
A. 
6.5.3 Laboratory Analyses 
CBC and serum chemistry values will be evaluated for each laboratory parameter by treatment 
group. Abnormal laboratory values will be flagged and identified as those outside (above or below) 
the normal range. Reference (normal) ranges for laboratory parameters will be included in the 
CSR. Descriptive summary statistics for laboratory parameters and their changes from baseline 
will be calculated.  Laboratory values will be summarized by visit and by worst post-baseline visit. 
Laboratory parameters that are graded in NCI-CTCAE v5.0 will be summarized by CTCAE grade.  
In the summary of laboratory parameters by CTCAE grade, parameters with CTCAE grading in 
both high and low directions (e.g. calcium, glucose, magnesium, potassium, sodium) will be 
summarized separately. 
Laboratory measurements that are collected without units will not be included in the summary 
tables described above. Instead these lab assessments will be identified in a listing of labs with 
missing units. 


 
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6.5.4 Vital Signs 
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure, heart rate, 
body temperature, and weight) and changes from baseline will be presented by visit and treatment 
group for all visits.   
6.5.5 Electrocardiogram 
Descriptive statistics for ECG assessments and changes from baseline will be presented by visit 
and treatment group for all visits. 
 
7 
INTERIM ANALYSIS 
7.1 
INTERIM ANALYSIS FOR COHORT 1 
When 42 subjects are randomized, an interim analysis will take place 28 days after the 42nd 
randomized 
first dose date. For the interim analysis in Cohort 1, only the first 42 
randomized patients will be included. 
Type 1 
maximum information is 63 subjects. A futility analysis will be undertaken at that time as well. If 
the p-value for a test of respiratory failure-free survival favors control with a p-value of 0.15, then 
the futility boundary will have been crossed. These boundaries for the interim analysis are guides 
to help the SMC in their decision making.  
7.2 
INTERIM ANALYSIS FOR 
 
 
 
 


 
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7.3 
FINAL ANALYSIS 
The final analysis will take place 84 days after the last randomized 
first dose date. The 
analysis of the coprimary endpoint will be based on Day 28 follow-up for each randomized patient 
in Cohort 1. 
The study will be frequently monitored by a Safety Monitoring Committee on a every 1 to 2 week 
basis for the purpose of monitoring safety. 
 
8 
DEVIATIONS FROM THE PROTOCOL 
The following table identifies items where this SAP differs from the protocol. 
 
Table 11:  
Table of difference between this SAP and the protocol 
Protocol 
SAP 
Rationale 
Duration of Hospitalization and 
Time to Discharge are two 
separate secondary objectives 
Duration of Hospitalization and 
Time to Discharge are combined 
into 1 secondary objective 
These are two terms describing 
the same quantity 
Safety as assessed by related 
 
In cohort 1 there is a 
randomized control so the 
investigator assessment of 
relatedness is not as informative 
as in a single arm trial. 
Secondary Objective: Clinical 
Stats assessed using an ordinal 
Secondary Objective: Replaced 
with Clinical Status as assessed 
More specific 


 
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scale at a pre-specified 
timepoint 
using the WHO 8 point ordinal 
scale at Days 7, 14, and 28 
Objective: Time to objective 
measure of recovery 
Deleted 
Redundant. Time to return to 
breathing room air was intended 
 
The protocol describes the use 
of a time dependent covariate 
for dosing in a model of 
Respiratory failure-free survival 
as an important supportive 
analysis in support of the 
primary endpoint 
The SAP describes the use of 
this time dependent covariate for 
dosing as an exploratory 
analysis. A cox model with just 
the stratification factors is the 
main supportive analysis for the 
primary endpoint 
It is not appropriate to adjust a 
main analysis of treatment effect 
with information post baseline. 
The post baseline information 
can inappropriately alter the 
estimate of the treatment effect. 
Includes related AEs as a 
secondary safety endpoint in 
cohort 1 
Cohort 1 has a randomized 
control arm. 
Endpoint: Clinical Stats 
assessed using an ordinal scale 
at a pre-specified timepoint 
Endpoint: Replaced with 
Clinical Status as assessed using 
the WHO 8 point ordinal scale 
at Days 7, 14, and 28 
More specific 
Endpoint: Time to objective 
measure of recovery 
Deleted 
Redundant. Time to return to 
breathing room air was intended 
measure of reco
 


 
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Covariate adjusted analysis will 
be performed to adjust for 
important baseline covariates for 
the primary and some secondary 
endpoints.   
Covariate adjusted analysis will 
be performed to adjust for 
important baseline covariates for 
the primary and some secondary 
endpoints.  These important 
baseline covariates could be the 
stratification factors in the 
randomization as well as 
important prognostic factors that 
are imbalanced between the 
arms. 
Added text to describe what 
could be used as independent 
variables in the model. 
Nothing on intercurrent events 
for the efficacy endpoints. 
Added test for intercurrent 
events and describe the use of 
Moods test along with the 
difference in medians as another 
test to be performed in addition 
to the Wilcoxon rank sum test. 
To respond to FDA comments 
on the protocol 
The number (percentage) of 
patients with TEAEs will also 
be summarized by relationship 
to study drug 
This will be done just for arm 1 
 
ECOG performance status will 
be summarized at each visit, etc. 
Deleted 
we are not collecting ECOG 
performance status 


 
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Text indicated death assumes 
the maximum value observed in 
the trial plus 1 
Changed to death assumes the 
minimum value observed in the 
trial  1 for PAO2/FIO2 
Low values for PAO2:FIO2 
represent a worse outcome. 
One of the secondary endpoint 
Median reduction in days 
spent on supplemental oxygen  
pent on 
supplemental oxygen  
The original intention was to 
present the nominal days, not 
the median reduction. 
 
 
 
 
 
Protocol 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAP 


 
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9 
REFERENCES 
Cao B, Wang Y, Wen D, et al. (2020) A trial of Lopinavir-Ritonavir in adults hospitalized with 
severe Covid-19. N. Engl. J. Med., 382:1787-1799. 
Myers L, Paorodi S, Escobar G et al. (2020) Characteristics of hospitalized adults with COVID-
19 in an integrated health care system in California. JAMA, 323 (21): 2195-2198. 
Richardson S, Hirsch J, Narasimhan M, et al. (2020) Presenting characteristics, comorbidities and 
outcomes among 5700 patients hospitalized with Covid-19 in the New York city area. JAMA, 323 
(20): 2052-2059. 
Mood, A. M.  (1954) On the asymptotic efficiency of certain non-parametric two sample tests. 
Ann. Math. Statist., 25 (3): 514-522. 
Simon R. (1989) Optimal two-stage designs for phase II clinical trials. Controlled Clinical Trials, 
10 (1):1-10. 
 
 
 
 


 
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APPENDIX A: 
ADVERSE EVENTS OF SPECIAL INTEREST 
Adverse Event of Clinical Interest Category 
Search Criteria 
Hemorrhage 
Haemorrhage terms (excl laboratory terms) 
(SMQ) Narrow 
Major hemorrhage 
Major hemorrhage = All Haemorrhage PT if AE 
SOC is 'Nervous system disorders' or serious or 
grade 3 and above Haemorrhage PT if AESOC is 
not 'Nervous system disorders' 
Atrial fibrillation and flutter 
Atrial fibrillation PT, Atrial flutter PT 
Hypertension 
Hypertension (SMQ) Narrow 
Second primary malignancies 
Malignant Tumours (SMQ) Narrow 
Tumor lysis syndrome 
Tumour lysis syndrome (SMQ) Narrow 
Infections 
Opportunistic infections 
Infections: Infections and Infestations SOC 
Subcategory - Opportunistic infections: 
Opportunistic infections (CMQ) 
Neutropenia 
Neutropenia PT, Neutrophil count decreased PT, 
Febrile neutropenia PT, Agranulocytosis PT, 
Neutropenic infection PT, Neutropenic sepsis PT 
Thrombocytopenia 
Thrombocytopenia PT, Platelet count decreased 
PT 
Anemia 
Anaemia PT, Haemoglobin decreased PT