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Study of the Safety and Pharmacokinetics of BGB-3111 in Subjects With B-Cell Lymphoid Malignancies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02343120
Recruitment Status : Completed
First Posted : January 21, 2015
Results First Posted : April 27, 2022
Last Update Posted : April 28, 2022
Sponsor:
Information provided by (Responsible Party):
BeiGene

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition B-cell Malignancies
Intervention Drug: Zanubrutinib
Enrollment 385
Recruitment Details The study was conducted in 2 parts. The dose escalation part (Part 1) determined the recommended phase 2 dose (RP2D) and regimen and the dose expansion part (Part 2) further characterized the safety and efficacy at the RP2D.
Pre-assignment Details  
Arm/Group Title Part 1: 40 mg QD Part 1: 80 mg QD Part 1: 160 mg QD Part 1 and Part 2: 160 mg BID Part 1 and Part 2: 320 mg QD
Hide Arm/Group Description Participants received 40 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up Participants received 80 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up Participants received 160 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up Part 1: Participants received 160 mg of zanubrutinib twice daily (BID) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up were evaluated. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types. Part 1: Participants received 320 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up were evaluated. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Period Title: Part 1: Dose Escalation
Started 3 4 5 4 1
Completed 0 0 0 0 0
Not Completed 3 4 5 4 1
Reason Not Completed
Sponsor decision             1             2             3             2             0
Death             1             2             2             2             1
Lost to Follow-up             1             0             0             0             0
Period Title: Part 2: Expansion
Started 0 0 0 274 94
Completed 0 0 0 0 0
Not Completed 0 0 0 274 94
Reason Not Completed
Sponsor decision             0             0             0             165             67
Death             0             0             0             74             17
Withdrawal by Subject             0             0             0             28             2
Lost to Follow-up             0             0             0             5             2
Other             0             0             0             1             5
Adverse Event             0             0             0             1             1
Arm/Group Title Part 1: 40 mg QD Part 1: 80 mg QD Part 1: 160 mg QD Part 1 and Part 2: 160 mg BID Part 1 and Part 2: 320 mg QD Total
Hide Arm/Group Description Participants received 40 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up Participants received 80 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up Participants received 160 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up Part 1: Participants received 160 mg of zanubrutinib twice daily (BID) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up were evaluated. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types. Part 1: Participants received 320 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up were evaluated. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types. Total of all reporting groups
Overall Number of Baseline Participants 3 4 5 278 95 385
Hide Baseline Analysis Population Description
The Safety Analysis Set included all participants who received ≥ 1 dose of study drug
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 3 participants 4 participants 5 participants 278 participants 95 participants 385 participants
62.7  (9.45) 62.3  (14.38) 72.6  (8.88) 66.4  (11.21) 65.8  (11.24) 66.3  (11.19)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 4 participants 5 participants 278 participants 95 participants 385 participants
Female 1 1 1 86 20 109
Male 2 3 4 192 75 276
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 3 participants 4 participants 5 participants 278 participants 95 participants 385 participants
White 2 4 5 205 87 303
Asian 1 0 0 47 5 53
Black or African American 0 0 0 4 1 5
Native Hawaiians or other Pacific Islanders 0 0 0 2 0 2
Multiple 0 0 0 1 0 1
Not Reported 0 0 0 1 0 1
Other 0 0 0 18 2 20
1.Primary Outcome
Title Part 1 and Part 2: Number of Participants With Adverse Events
Hide Description Number of participants with adverse events and serious adverse events, including clinically relevant physical examinations and laboratory measurements
Time Frame Up to approximately 6 years and 7 months
Hide Outcome Measure Data
Hide Analysis Population Description
The Safety Analysis Set included all participants who received ≥ 1 dose of study drug
Arm/Group Title Part 1: 40 mg QD Part 1: 80 mg QD Part 1: 160 mg QD Parts 1 and 2: 160 mg BID Parts 1 and 2: 320 mg QD
Hide Arm/Group Description:
Participants received 40 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 80 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 160 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Part 1: Participants received 160 mg of zanubrutinib twice daily (BID) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Part 1: Participants received 320 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Overall Number of Participants Analyzed 3 4 5 278 95
Measure Type: Count of Participants
Unit of Measure: Participants
At least one treatment-emergent adverse event 3 4 5 274 94
Serious adverse events 1 2 3 157 45
2.Primary Outcome
Title Part 1: Recommended Phase 2 Dose (RP2D) for Zanubrutinib
Hide Description RP2D for zanubrutinib was the maximum tolerated dose (MTD) or less, which was determined by testing increasing doses up to 320 mg QD
Time Frame Month 9
Hide Outcome Measure Data
Hide Analysis Population Description
The Safety Analysis Set included all participants who received ≥ 1 dose of study drug
Arm/Group Title Part 1: Zanubrutinib
Hide Arm/Group Description:
Five dose regimens of zanubrutinib (40 mg QD, 80 mg QD, 160 mg QD, 160 mg BID, and 320 mg QD) were evaluated.
Overall Number of Participants Analyzed 17
Measure Type: Number
Unit of Measure: milligrams
320
3.Secondary Outcome
Title Part 1 and Part 2: Area Under the Curve From Time 0 to the Last Sampling Time Point Within the Dose Interval (AUClast) of Zanubrutinib
Hide Description [Not Specified]
Time Frame Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic (PK) analysis set included all participants for whom valid zanubrutinib PK parameters could be estimated, shown as overall number analyzed. Only participants with available data per dose were included in the analysis.
Arm/Group Title Part 1: 40 mg QD Part 1: 80 mg QD Part 1: 160 mg QD Parts 1 and 2: 160 mg BID Parts 1 and 2: 320 mg QD
Hide Arm/Group Description:
Participants received 40 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 80 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 160 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Part 1: Participants received 160 mg of zanubrutinib twice daily (BID) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Part 1: Participants received 320 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Overall Number of Participants Analyzed 3 4 5 76 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nanograms/milliliters*hour
274.7
(47.8%)
436.8
(103.5%)
1480
(53.0%)
1132
(61.1%)
2281
(60.5%)
4.Secondary Outcome
Title Part 1 and Part 2: Area Under the Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Zanubrutinib
Hide Description [Not Specified]
Time Frame Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
Hide Outcome Measure Data
Hide Analysis Population Description
The PK analysis set included all participants for whom valid zanubrutinib PK parameters could be estimated, shown as overall number analyzed. Only participants with available data per dose were included in the analysis.
Arm/Group Title Part 1: 40 mg QD Part 1: 80 mg QD Part 1: 160 mg QD Part 1 and Part 2: 160 mg BID Part 1 and Part 2: 320 mg QD
Hide Arm/Group Description:
Participants received 40 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 80 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 160 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Part 1: Participants received 160 mg of zanubrutinib twice daily (BID) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Part 1: Participants received 320 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Overall Number of Participants Analyzed 3 4 5 59 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nanograms/milliliters*hour
301.1
(51.5%)
460.0
(100.6%)
1505
(52.7%)
1253
(59.0%)
2538
(47.8%)
5.Secondary Outcome
Title Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) After Administration of Zanubrutinib
Hide Description [Not Specified]
Time Frame Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
Hide Outcome Measure Data
Hide Analysis Population Description
The PK analysis set included all participants for whom valid zanubrutinib PK parameters could be estimated, shown as overall number analyzed. Only participants with available data per dose were included in the analysis.
Arm/Group Title Part 1: 40 mg QD Part 1: 80 mg QD Part 1: 160 mg QD Part 1 and Part 2: 160 mg BID Part 1 and Part 2: 320 mg QD
Hide Arm/Group Description:
Participants received 40 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 80 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 160 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to
Part 1: Participants received 160 mg of zanubrutinib twice daily (BID) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Part 1: Participants received 320 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Overall Number of Participants Analyzed 3 4 5 76 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nanograms/milliliter
86.0
(46.6%)
125
(77.6%)
397
(76.1%)
304
(63.8%)
566
(65.6%)
6.Secondary Outcome
Title Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) After Administration of Zanubrutinib
Hide Description [Not Specified]
Time Frame Week 2 Day 1 pre-dose and 24 hours
Hide Outcome Measure Data
Hide Analysis Population Description
The PK analysis set included all participants for whom valid zanubrutinib PK parameters could be estimated, shown as overall number analyzed. Only participants with available data per dose were included in the analysis.
Arm/Group Title Part 1: 40 mg QD Part 1: 80 mg QD Part 1: 160 mg QD Part 1 and Part 2: 160 mg BID Part 1 and Part 2: 320 mg QD
Hide Arm/Group Description:
Participants received 40 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 80 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 160 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Part 1: Participants received 160 mg of zanubrutinib twice daily (BID) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Part 1: Participants received 320 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Overall Number of Participants Analyzed 3 4 5 77 72
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nanograms/milliliter
75.7
(36.2%)
169
(50.0%)
387
(60.7%)
299
(56.1%)
533
(55.0%)
7.Secondary Outcome
Title Part 1 and Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Zanubrutinib
Hide Description [Not Specified]
Time Frame Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
Hide Outcome Measure Data
Hide Analysis Population Description
The PK analysis set included all participants for whom valid zanubrutinib PK parameters could be estimated, shown as overall number analyzed. Only participants with available data per dose were included in the analysis.
Arm/Group Title Part 1: 40 mg QD Part 1: 80 mg QD Part 1: 160 mg QD Part 1 and Part 2: 160 mg BID Part 1 and Part 2: 320 mg QD
Hide Arm/Group Description:
Participants received 40 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 80 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 160 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Part 1: Participants received 160 mg of zanubrutinib twice daily (BID) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Part 1: Participants received 320 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Overall Number of Participants Analyzed 3 4 5 76 19
Median (Full Range)
Unit of Measure: Hours
1.00
(0.50 to 1.98)
2.00
(1.17 to 2.00)
1.92
(0.93 to 2.08)
2.00
(0.83 to 8.00)
2.00
(0.72 to 3.08)
8.Secondary Outcome
Title Part 1 and Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Zanubrutinib
Hide Description [Not Specified]
Time Frame Week 2 Day 1 pre-dose and 24 hours
Hide Outcome Measure Data
Hide Analysis Population Description
The PK analysis set included all participants for whom valid zanubrutinib PK parameters could be estimated, shown as overall number analyzed. Only participants with available data per dose were included in the analysis.
Arm/Group Title Part 1: 40 mg QD Part 1: 80 mg QD Part 1: 160 mg QD Part 1 and Part 2: 160 mg BID Part 1 and Part 2: 320 mg QD
Hide Arm/Group Description:
Participants received 40 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 80 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 160 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Part 1: Participants received 160 mg of zanubrutinib twice daily (BID) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Part 1: Participants received 320 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Overall Number of Participants Analyzed 3 4 5 77 72
Median (Full Range)
Unit of Measure: Hours
2.00
(2.00 to 2.00)
2.50
(1.08 to 3.00)
2.00
(1.00 to 3.17)
2.00
(0.53 to 6.00)
2.00
(0.33 to 6.00)
9.Secondary Outcome
Title Part 1 and Part 2: Apparent Terminal Half-life (t1/2) of Zanubrutinib
Hide Description [Not Specified]
Time Frame Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
Hide Outcome Measure Data
Hide Analysis Population Description
The PK analysis set included all participants for whom valid zanubrutinib PK parameters could be estimated, shown as overall number analyzed. Only participants with available data per dose were included in the analysis.
Arm/Group Title Part 1: 40 mg QD Part 1: 80 mg QD Part 1: 160 mg QD Part 1 and Part 2: 160 mg BID Part 1 and Part 2: 320 mg QD
Hide Arm/Group Description:
Participants received 40 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 80 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 160 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Part 1: Participants received 160 mg of zanubrutinib twice daily (BID) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Part 1: Participants received 320 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Overall Number of Participants Analyzed 3 4 5 59 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Hours
1.94
(28.5%)
1.97
(29.8%)
3.87
(24.9%)
2.73
(60.2%)
3.30
(61.2%)
10.Secondary Outcome
Title Part 1 and Part 2: Apparent Clearance (CL/F) of Zanubrutinib
Hide Description [Not Specified]
Time Frame Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
Hide Outcome Measure Data
Hide Analysis Population Description
The PK analysis set included all participants for whom valid zanubrutinib PK parameters could be estimated, shown as overall number analyzed. Only participants with available data per dose were included in the analysis.
Arm/Group Title Part 1: 40 mg QD Part 1: 80 mg QD Part 1: 160 mg QD Part 1 and Part 2: 160 mg BID Part 1 and Part 2: 320 mg QD
Hide Arm/Group Description:
Participants received 40 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 80 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 160 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Part 1: Participants received 160 mg of zanubrutinib twice daily (BID) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Part 1: Participants received 320 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Overall Number of Participants Analyzed 3 4 5 61 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Liters/hour
133
(51.5%)
174
(100.6%)
106
(52.7%)
128
(59.4%)
126
(47.8%)
11.Secondary Outcome
Title Part 1 and Part 2: Apparent Volume of Distribution of Zanubrutinib During the Terminal Phase (Vz/F)
Hide Description [Not Specified]
Time Frame Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
Hide Outcome Measure Data
Hide Analysis Population Description
The PK analysis set included all participants for whom valid zanubrutinib PK parameters could be estimated, shown as overall number analyzed. Only participants with available data per dose were included in the analysis.
Arm/Group Title Part 1: 40 mg QD Part 1: 80 mg QD Part 1: 160 mg QD Part 1 and Part 2: 160 mg BID Part 1 and Part 2: 320 mg QD
Hide Arm/Group Description:
Participants received 40 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 80 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 160 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Part 1: Participants received 160 mg of zanubrutinib twice daily (BID) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Part 1: Participants received 320 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Overall Number of Participants Analyzed 3 4 5 61 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Liters
371
(47.5%)
494
(78.9%)
593
(61.6%)
530
(70.0%)
600
(97.6%)
12.Secondary Outcome
Title Part 1 and Part 2: Overall Response Rate (ORR)
Hide Description ORR is defined as the percentage of participants with partial or complete response (CR), as assessed by the investigator. For CLL/SLL, ORR includes partial response (PR) with lymphocytosis (PR-L) or better (includes PR-L, PR, nodular PR or nPR and CR with incomplete marrow recovery or CRi) and for MW, ORR includes minor response or better. Efficacy results are reported for each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Richter's Transformation (RT), and Hairy cell leukemia (HCL).
Time Frame Up to 6 years and 7 months
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Evaluable Set consists of all participants who received at least one dose of zanubrutinib; for WM, participants also must have a baseline IgM (or M-protein) ≥ 5 g/L and no prior exposure to a BTK inhibitor.
Arm/Group Title Part 1 and Part 2: Overall
Hide Arm/Group Description:
The dose regimens from Part 1 (40 mg, 80 mg, 160 mg QD, 160 mg BID and 320 mg QD) and Part 2 (160 mg BID and 320 mg QD) were evaluated in different disease types. Efficacy evaluations are reported by disease type for Parts 1 and 2 combined, as pre-specified in the statistical analysis plan.
Overall Number of Participants Analyzed 378
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
CLL/SLL Number Analyzed 125 participants
95.2
(89.8 to 98.2)
WM Number Analyzed 73 participants
95.9
(88.5 to 99.1)
MCL Number Analyzed 57 participants
82.5
(70.1 to 91.3)
MZL Number Analyzed 20 participants
85.0
(62.1 to 96.8)
FL Number Analyzed 33 participants
36.4
(20.4 to 54.9)
DLBCL Number Analyzed 45 participants
42.2
(27.7 to 57.8)
RT Number Analyzed 13 participants
61.5
(31.6 to 86.1)
HCL Number Analyzed 12 participants
58.3
(27.7 to 84.8)
13.Secondary Outcome
Title Part 1 and Part 2: Complete Response Rate (CRR)
Hide Description CRR is defined as the percentage of participants who achieve a complete response, as assessed by the investigator. For CLL/SLL, CRR includes CRi or better. For WM, CRR includes very good partial response (VGPR) or better. Efficacy results are reported for each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Richter's Transformation (RT), and Hairy cell leukemia (HCL).
Time Frame Up to 6 years and 7 months
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Evaluable Set consists of all participants who received at least one dose of zanubrutinib; for WM, participants also must have a baseline IgM (or M-protein) ≥ 5 g/L and no prior exposure to a BTK inhibitor.
Arm/Group Title Part 1 and Part 2: Overall
Hide Arm/Group Description:
The dose regimens from Part 1 (40 mg, 80 mg, 160 mg QD, 160 mg BID and 320 mg QD) and Part 2 (160 mg BID and 320 mg QD) were evaluated in different disease types. Efficacy evaluations are reported by disease type for Parts 1 and 2 combined, as pre-specified in the statistical analysis plan.
Overall Number of Participants Analyzed 378
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
CLL/SLL Number Analyzed 125 participants
16.8
(10.7 to 24.5)
WM Number Analyzed 73 participants
46.6
(34.8 to 58.6)
MCL Number Analyzed 57 participants
28.1
(17.0 to 41.5)
MZL Number Analyzed 20 participants
20.0
(5.7 to 43.7)
FL Number Analyzed 33 participants
18.2
(7.0 to 35.5)
DLBCL Number Analyzed 45 participants
24.4
(12.9 to 39.5)
RT Number Analyzed 13 participants
15.4
(1.9 to 45.4)
HCL Number Analyzed 12 participants
16.7
(2.1 to 48.4)
14.Secondary Outcome
Title Part 1 and Part 2: Partial Response (PR) or Better
Hide Description PR or better is defined as the percentage of participants who achieve a partial response or better, as assessed by the investigator. For CLL/SLL, includes PR, nPR, CRi, CR and for WM includes PR, VGPR, and CR. Efficacy results are reported for the B-cell malignancy subtypes chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and Waldenström macroglobulinemia (WM).
Time Frame Up to 6 years and 7 months
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Evaluable Set consists of all participants who received at least one dose of zanubrutinib; for WM, participants also must have a baseline IgM (or M-protein) ≥ 5 g/L and no prior exposure to a BTK inhibitor.
Arm/Group Title Part 1 and Part 2: Overall
Hide Arm/Group Description:
The dose regimens from Part 1 (40 mg, 80 mg, 160 mg QD, 160 mg BID and 320 mg QD) and Part 2 (160 mg BID and 320 mg QD) were evaluated in different disease types. Efficacy evaluations are reported by disease type for Parts 1 and 2 combined, as pre-specified in the statistical analysis plan.
Overall Number of Participants Analyzed 385
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
CLL/SLL Number Analyzed 125 participants
92.0
(85.8 to 96.1)
WM Number Analyzed 73 participants
82.2
(71.5 to 90.2)
15.Secondary Outcome
Title Part 1 and Part 2: Progression-free Survival (PFS)
Hide Description PFS is defined as the time from the first dose date of study drug to the date of the earliest occurrence of progressive disease or death due to any cause, whichever occurs first. Efficacy results are reported for each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Richter's Transformation (RT), and Hairy cell leukemia (HCL).
Time Frame Up to 6 years and 7 months
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Evaluable Set consists of all participants who received at least one dose of zanubrutinib; for WM, participants also must have a baseline IgM (or M-protein) ≥ 5 g/L and no prior exposure to a BTK inhibitor.
Arm/Group Title Part 1 and Part 2: Overall
Hide Arm/Group Description:
The dose regimens from Part 1 (40 mg, 80 mg, 160 mg QD, 160 mg BID and 320 mg QD) and Part 2 (160 mg BID and 320 mg QD) were evaluated in different disease types. Efficacy evaluations are reported by disease type for Parts 1 and 2 combined, as pre-specified in the statistical analysis plan.
Overall Number of Participants Analyzed 378
Median (95% Confidence Interval)
Unit of Measure: Months
CLL/SLL Number Analyzed 125 participants
61.4 [1] 
(55.2 to NA)
WM Number Analyzed 73 participants
NA [1] 
(48.9 to NA)
MCL Number Analyzed 57 participants
27.6
(15.4 to 45.5)
MZL Number Analyzed 20 participants
NA [1] 
(17.1 to NA)
FL Number Analyzed 33 participants
10.4
(7.7 to 22.9)
DLBCL Number Analyzed 45 participants
4.1
(2.1 to 5.6)
RT Number Analyzed 13 participants
17.3 [1] 
(2.8 to NA)
HCL Number Analyzed 12 participants
NA [1] 
(28.7 to NA)
[1]
Data not estimable due to insufficient number of participants with events
16.Secondary Outcome
Title Part 1 and Part 2: Overall Survival (OS)
Hide Description OS is defined as the time from the date of the first dose to death due to any cause. Efficacy results are reported for each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Richter's Transformation (RT), and Hairy cell leukemia (HCL).
Time Frame Up to 6 years and 7 months
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Evaluable Set consists of all participants who received at least one dose of zanubrutinib; for WM, participants also must have a baseline IgM (or M-protein) ≥ 5 g/L and no prior exposure to a BTK inhibitor.
Arm/Group Title Part 1 and Part 2: Overall
Hide Arm/Group Description:
The dose regimens from Part 1 (40 mg, 80 mg, 160 mg QD, 160 mg BID and 320 mg QD) and Part 2 (160 mg BID and 320 mg QD) were evaluated in different disease types. Efficacy evaluations are reported by disease type for Parts 1 and 2 combined, as pre-specified in the statistical analysis plan.
Overall Number of Participants Analyzed 378
Median (95% Confidence Interval)
Unit of Measure: Months
CLL/SLL Number Analyzed 125 participants
NA [1] 
(NA to NA)
WM Number Analyzed 73 participants
NA [1] 
(NA to NA)
MCL Number Analyzed 57 participants
NA [1] 
(27.2 to NA)
MZL Number Analyzed 20 participants
NA [1] 
(NA to NA)
FL Number Analyzed 33 participants
NA [1] 
(37.3 to NA)
DLBCL Number Analyzed 45 participants
14.7
(5.5 to 24.8)
RT Number Analyzed 13 participants
29.3 [1] 
(4.2 to NA)
HCL Number Analyzed 12 participants
NA [1] 
(26.6 to NA)
[1]
Data not estimable due to insufficient number of participants with events
17.Secondary Outcome
Title Part 1 and Part 2: Duration of Response (DOR)
Hide Description DOR for responders is defined as time from the date of the earliest qualifying response to the date of progressive disease or death for any cause, whichever occurs earlier. Efficacy results are reported for responders (defined as PR or better, except CLL/SLL and WM) in each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; PR with lymphocytosis or better), Waldenstrom macroglobulinemia (WM; minor response or better), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Richter's Transformation (RT), and Hairy cell leukemia (HCL).
Time Frame Up to 6 years and 7 months
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Evaluable Set consists of all participants who received at least one dose of zanubrutinib; for WM, participants also must have a baseline IgM (or M-protein) ≥ 5 g/L and no prior exposure to a BTK inhibitor.
Arm/Group Title Part 1 and Part 2: Overall
Hide Arm/Group Description:
The dose regimens from Part 1 (40 mg, 80 mg, 160 mg QD, 160 mg BID and 320 mg QD) and Part 2 (160 mg BID and 320 mg QD) were evaluated in different disease types. Efficacy evaluations are reported by disease type for Parts 1 and 2 combined, as pre-specified in the statistical analysis plan.
Overall Number of Participants Analyzed 378
Median (95% Confidence Interval)
Unit of Measure: Months
CLL/SLL Number Analyzed 125 participants
58.6 [1] 
(52.6 to NA)
WM Number Analyzed 73 participants
NA [1] 
(31.34 to NA)
MCL Number Analyzed 57 participants
28.2 [1] 
(16.2 to NA)
MZL Number Analyzed 20 participants
NA [1] 
(6.5 to NA)
FL Number Analyzed 33 participants
NA [1] 
(8.3 to NA)
DLBCL Number Analyzed 45 participants
14.2
(2.8 to 26.2)
RT Number Analyzed 13 participants
25.9 [1] 
(5.9 to NA)
HCL Number Analyzed 12 participants
NA [1] 
(NA to NA)
[1]
Data not estimable due to insufficient number of participants with events
18.Secondary Outcome
Title Number of Participants With Greater Than 75% Bruton's Tyrosine Kinase (BTK) Occupancy
Hide Description Number of participants with greater than 75% BTK occupancy of zanubrutinib in peripheral blood mononuclear cells (PBMCs)
Time Frame Week 1 Day 1 (W1D1) predose, W1D1 4 hours, W1D2 24 hours, W1D3 predose, and W2D1 predose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacodynamic analysis set consisted of participants in which PBMCs were collected and evaluable samples were obtained.
Arm/Group Title Part 1: 40 mg QD Part 1: 80 mg QD Part 1: 160 mg QD Part 1 and Part 2: 160 mg BID Part 1 and Part 2: 320 mg QD
Hide Arm/Group Description:
Participants received 40 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 80 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Participants received 160 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up
Part 1: Participants received 160 mg of zanubrutinib twice daily (BID) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up were evaluated. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Part 1: Participants received 320 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up were evaluated. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
Overall Number of Participants Analyzed 3 4 5 21 10
Measure Type: Count of Participants
Unit of Measure: Participants
3 4 5 20 9
Time Frame Up to 6 years and 7 months
Adverse Event Reporting Description One participant in the 320 mg QD group discontinued the study for Other reasons, as shown in the participant flow section, and subsequently died after study discontinuation. That participant is counted under all-cause mortality in this section.
 
Arm/Group Title Part 1: 40 mg QD Part 1: 80 mg QD Part 1: 160 mg QD Part 1 and Part 2: 160 mg BID Part 1 and Part 2: 320 mg QD
Hide Arm/Group Description Participants received 40 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up Participants received 80 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up Participants received 160 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up Part 1: Participants received 160 mg of zanubrutinib twice daily (BID) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types. Part 1: Participants received 320 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types.
All-Cause Mortality
Part 1: 40 mg QD Part 1: 80 mg QD Part 1: 160 mg QD Part 1 and Part 2: 160 mg BID Part 1 and Part 2: 320 mg QD
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/3 (33.33%)      2/4 (50.00%)      2/5 (40.00%)      76/278 (27.34%)      19/95 (20.00%)    
Hide Serious Adverse Events
Part 1: 40 mg QD Part 1: 80 mg QD Part 1: 160 mg QD Part 1 and Part 2: 160 mg BID Part 1 and Part 2: 320 mg QD
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/3 (33.33%)      2/4 (50.00%)      3/5 (60.00%)      157/278 (56.47%)      45/95 (47.37%)    
Blood and lymphatic system disorders           
Anaemia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 5/278 (1.80%)  5 2/95 (2.11%)  2
Febrile neutropenia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 7/278 (2.52%)  9 0/95 (0.00%)  0
Haemolytic anaemia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 1/95 (1.05%)  1
Hyperviscosity syndrome  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Leukocytosis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  2
Lymphocytosis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Neutropenia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 1/95 (1.05%)  1
Splenomegaly  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 1/95 (1.05%)  1
Cardiac disorders           
Acute coronary syndrome  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Acute myocardial infarction  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 3/278 (1.08%)  3 0/95 (0.00%)  0
Atrial fibrillation  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 3/278 (1.08%)  3 2/95 (2.11%)  2
Atrial flutter  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 1/95 (1.05%)  1
Atrioventricular block complete  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Bradycardia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Cardiac failure  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Cardiac failure congestive  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Coronary artery stenosis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Myocardial ischaemia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Palpitations  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Pericardial effusion  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 3/278 (1.08%)  5 0/95 (0.00%)  0
Tachycardia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Ventricular extrasystoles  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Ear and labyrinth disorders           
Deafness  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Vertigo  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 1/95 (1.05%)  1
Endocrine disorders           
Hypercalcaemia of malignancy  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Gastrointestinal disorders           
Abdominal pain  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 3/278 (1.08%)  3 0/95 (0.00%)  0
Colitis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Colitis ischaemic  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Constipation  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Diarrhoea  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 5/278 (1.80%)  5 2/95 (2.11%)  2
Dysphagia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Enteritis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Enterovesical fistula  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Gastric volvulus  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Gastrointestinal haemorrhage  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Haemorrhoids  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Hiatus hernia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Inguinal hernia strangulated  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Nausea  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Pneumatosis intestinalis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Retroperitoneal mass  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  2 0/95 (0.00%)  0
Small intestinal obstruction  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Vomiting  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
General disorders           
Chest pain  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Death  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Fatigue  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 3/278 (1.08%)  3 0/95 (0.00%)  0
Influenza like illness  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Multiple organ dysfunction syndrome  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 2/95 (2.11%)  2
Non-cardiac chest pain  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Pain  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  2 0/95 (0.00%)  0
Pyrexia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  2 9/278 (3.24%)  12 3/95 (3.16%)  3
Hepatobiliary disorders           
Bile duct stone  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Cholecystitis acute  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Immune system disorders           
Anti-neutrophil cytoplasmic antibody positive vasculitis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Infections and infestations           
Abdominal sepsis  1  1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 0/95 (0.00%)  0
Arthritis bacterial  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Asymptomatic COVID-19  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Atypical pneumonia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Bacteraemia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 3/278 (1.08%)  3 0/95 (0.00%)  0
Bronchiolitis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Bronchitis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Bronchopulmonary aspergillosis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
COVID-19  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  3 1/95 (1.05%)  1
Carbuncle  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Cellulitis  1  0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 9/278 (3.24%)  13 3/95 (3.16%)  5
Cerebral aspergillosis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Clostridium difficile colitis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Complicated appendicitis  1  1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 0/95 (0.00%)  0
Diabetic foot infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Diverticulitis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Encephalitis fungal  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Epstein-Barr viraemia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Escherichia sepsis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Gastroenteritis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 1/95 (1.05%)  1
Gastroenteritis norovirus  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Gastroenteritis viral  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
H1N1 influenza  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Haemophilus infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Haemophilus sepsis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Hepatitis viral  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Herpes simplex viraemia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Herpes zoster  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Herpes zoster disseminated  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Herpes zoster meningoencephalitis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  2
Herpes zoster oticus  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Infective exacerbation of bronchiectasis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Influenza  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 3/278 (1.08%)  3 0/95 (0.00%)  0
Kidney infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Listeria sepsis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Localised infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Lower respiratory tract infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  2 3/278 (1.08%)  3 0/95 (0.00%)  0
Lower respiratory tract infection viral  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Mastoiditis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Meningitis cryptococcal  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 3/278 (1.08%)  3 0/95 (0.00%)  0
Meningitis streptococcal  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Otitis externa  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 1/95 (1.05%)  1
Parainfluenzae virus infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Pneumonia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  8 26/278 (9.35%)  28 6/95 (6.32%)  6
Pneumonia cryptococcal  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  2 0/95 (0.00%)  0
Pneumonia influenzal  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Pneumonia staphylococcal  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Pneumonia streptococcal  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Pneumonia viral  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Postoperative wound infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Pseudomonal sepsis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Pulmonary sepsis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Pyelonephritis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Respiratory syncytial virus infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Respiratory tract infection viral  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Rhinovirus infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Scedosporium infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Scrotal infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 2/95 (2.11%)  2
Sepsis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 4/278 (1.44%)  4 1/95 (1.05%)  1
Septic shock  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 3/278 (1.08%)  3 0/95 (0.00%)  0
Sinusitis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Skin infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Staphylococcal abscess  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Streptococcal bacteraemia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Subcutaneous abscess  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Systemic viral infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Upper respiratory tract infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Urinary tract infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 12/278 (4.32%)  15 0/95 (0.00%)  0
Vestibular neuronitis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Viral infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  3 0/95 (0.00%)  0
Viral upper respiratory tract infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Wound infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 2/95 (2.11%)  3
Injury, poisoning and procedural complications           
Cervical vertebral fracture  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Contusion  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  2 0/95 (0.00%)  0
Fall  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 2/95 (2.11%)  2
Femoral neck fracture  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 1/95 (1.05%)  1
Femur fracture  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Fibula fracture  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Hip fracture  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Humerus fracture  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Joint injury  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Pelvic fracture  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Post procedural fever  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Post procedural haemorrhage  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Radius fracture  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Transfusion reaction  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Ulna fracture  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Upper limb fracture  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Investigations           
Neutrophil count decreased  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 3/278 (1.08%)  4 0/95 (0.00%)  0
Metabolism and nutrition disorders           
Diabetic ketoacidosis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Fluid overload  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Gout  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Hypercalcaemia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Hyperkalaemia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Tumour lysis syndrome  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 1/95 (1.05%)  1
Musculoskeletal and connective tissue disorders           
Arthralgia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  3 0/95 (0.00%)  0
Back pain  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 1/95 (1.05%)  1
Haemarthrosis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Intervertebral disc protrusion  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Joint effusion  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Muscular weakness  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Musculoskeletal chest pain  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Musculoskeletal pain  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Myalgia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Soft tissue necrosis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)           
Acute myeloid leukaemia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Adenocarcinoma gastric  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Basal cell carcinoma  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Breast cancer  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Chronic myeloid leukaemia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
External ear neoplasm malignant  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  4 0/95 (0.00%)  0
Intraductal papillary mucinous neoplasm  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Invasive ductal breast carcinoma  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Lentigo maligna  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/278 (0.00%)  0 0/95 (0.00%)  0
Malignant melanoma  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 1/95 (1.05%)  1
Malignant pleural effusion  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Metastases to central nervous system  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Neoplasm malignant  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Neuroendocrine carcinoma metastatic  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Prostate cancer  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 1/95 (1.05%)  1
Sarcomatoid carcinoma of the lung  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Skin squamous cell carcinoma recurrent  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  2
Squamous cell carcinoma of head and neck  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Squamous cell carcinoma of skin  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Squamous cell carcinoma of the parotid gland  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Tumour pain  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Nervous system disorders           
Central nervous system lesion  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Cerebral infarction  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Depressed level of consciousness  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Embolic stroke  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Haemorrhage intracranial  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Headache  1  1/3 (33.33%)  2 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 0/95 (0.00%)  0
Hypoglossal nerve paralysis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/278 (0.00%)  0 0/95 (0.00%)  0
Lethargy  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Sciatica  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 1/95 (1.05%)  1
Syncope  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Transient ischaemic attack  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 1/95 (1.05%)  1
Psychiatric disorders           
Anxiety  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 1/95 (1.05%)  1
Bipolar disorder  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Chronic idiopathic pain syndrome  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Delirium  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Delirium tremens  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Delusional disorder, unspecified type  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Renal and urinary disorders           
Acute kidney injury  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 4/278 (1.44%)  4 1/95 (1.05%)  1
Calculus bladder  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Cystitis haemorrhagic  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Haematuria  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 4/278 (1.44%)  4 0/95 (0.00%)  0
Hydronephrosis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Renal artery thrombosis  1  0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/278 (0.00%)  0 0/95 (0.00%)  0
Renal colic  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Subcapsular renal haematoma  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Urinary tract obstruction  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Reproductive system and breast disorders           
Pelvic pain  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Respiratory, thoracic and mediastinal disorders           
Acute pulmonary oedema  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Asthma  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Bronchiectasis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Chronic obstructive pulmonary disease  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Cough  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Dyspnoea  1  1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 3/278 (1.08%)  3 1/95 (1.05%)  1
Haemothorax  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Hypoxia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Obstructive airways disorder  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Organising pneumonia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Oropharyngeal pain  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Pleural effusion  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 5/278 (1.80%)  5 2/95 (2.11%)  2
Pleuritic pain  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Pneumonia aspiration  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Pneumonitis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  2 0/95 (0.00%)  0
Pulmonary embolism  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Respiratory failure  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Skin and subcutaneous tissue disorders           
Diabetic foot  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  1
Purpura  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Vascular disorders           
Haematoma  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Hypertension  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 0/95 (0.00%)  0
Lymphoedema  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Orthostatic hypotension  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Vasculitis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
1
Term from vocabulary, meddra 23.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 3%
Part 1: 40 mg QD Part 1: 80 mg QD Part 1: 160 mg QD Part 1 and Part 2: 160 mg BID Part 1 and Part 2: 320 mg QD
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/3 (100.00%)      4/4 (100.00%)      5/5 (100.00%)      273/278 (98.20%)      94/95 (98.95%)    
Blood and lymphatic system disorders           
Anaemia  1  0/3 (0.00%)  0 1/4 (25.00%)  1 3/5 (60.00%)  3 39/278 (14.03%)  64 8/95 (8.42%)  16
Increased tendency to bruise  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 6/278 (2.16%)  6 7/95 (7.37%)  7
Neutropenia  1  0/3 (0.00%)  0 1/4 (25.00%)  1 1/5 (20.00%)  3 44/278 (15.83%)  107 10/95 (10.53%)  29
Spontaneous haemorrhage  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/278 (0.00%)  0 1/95 (1.05%)  1
Thrombocytopenia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 25/278 (8.99%)  42 4/95 (4.21%)  6
Cardiac disorders           
Atrial fibrillation  1  1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 13/278 (4.68%)  15 3/95 (3.16%)  3
Bradycardia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 3/278 (1.08%)  3 3/95 (3.16%)  3
Cardiac failure congestive  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 1/278 (0.36%)  1 1/95 (1.05%)  1
Palpitations  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 9/278 (3.24%)  10 4/95 (4.21%)  4
Pericardial effusion  1  0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 3/278 (1.08%)  4 0/95 (0.00%)  0
Right ventricular failure  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/278 (0.00%)  0 0/95 (0.00%)  0
Ear and labyrinth disorders           
Ear pain  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 5/278 (1.80%)  6 3/95 (3.16%)  3
Tinnitus  1  1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 3/278 (1.08%)  3 2/95 (2.11%)  2
Vertigo  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 13/278 (4.68%)  14 3/95 (3.16%)  3
Eye disorders           
Blepharitis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 1/278 (0.36%)  1 1/95 (1.05%)  1
Cataract  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 5/278 (1.80%)  5 5/95 (5.26%)  5
Dry eye  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 3/278 (1.08%)  3 3/95 (3.16%)  3
Lacrimation increased  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 3/95 (3.16%)  3
Ocular rosacea  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/278 (0.00%)  0 0/95 (0.00%)  0
Periorbital oedema  1  0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 1/278 (0.36%)  2 0/95 (0.00%)  0
Vision blurred  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 3/278 (1.08%)  3 4/95 (4.21%)  5
Visual impairment  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 1/278 (0.36%)  1 0/95 (0.00%)  0
Gastrointestinal disorders           
Abdominal discomfort  1  0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 2/278 (0.72%)  2 1/95 (1.05%)  1
Abdominal distension  1  1/3 (33.33%)  1 1/4 (25.00%)  1 0/5 (0.00%)  0 5/278 (1.80%)  5 3/95 (3.16%)  3
Abdominal pain  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 21/278 (7.55%)  24 8/95 (8.42%)  11
Abdominal pain lower  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 4/95 (4.21%)  4
Abdominal pain upper  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 9/278 (3.24%)  15 4/95 (4.21%)  4
Constipation  1  1/3 (33.33%)  1 1/4 (25.00%)  1 1/5 (20.00%)  1 50/278 (17.99%)  59 23/95 (24.21%)  29
Dental caries  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 3/95 (3.16%)  3
Diarrhoea  1  2/3 (66.67%)  2 2/4 (50.00%)  6 0/5 (0.00%)  0 77/278 (27.70%)  122 23/95 (24.21%)  36
Dyspepsia  1  0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 7/278 (2.52%)  9 3/95 (3.16%)  4
Gastrooesophageal reflux disease  1  1/3 (33.33%)  1 1/4 (25.00%)  2 0/5 (0.00%)  0 24/278 (8.63%)  27 8/95 (8.42%)  9
Inguinal hernia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 3/95 (3.16%)  3
Mouth haemorrhage  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 3/95 (3.16%)  3
Mouth ulceration  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 8/278 (2.88%)  8 4/95 (4.21%)  5
Nausea  1  1/3 (33.33%)  1 2/4 (50.00%)  6 1/5 (20.00%)  1 45/278 (16.19%)  55 18/95 (18.95%)  32
Stomatitis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 10/278 (3.60%)  10 4/95 (4.21%)  5
Toothache  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 5/278 (1.80%)  5 5/95 (5.26%)  5
Vomiting  1  1/3 (33.33%)  1 2/4 (50.00%)  5 0/5 (0.00%)  0 29/278 (10.43%)  38 6/95 (6.32%)  8
General disorders           
Asthenia  1  0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 12/278 (4.32%)  20 0/95 (0.00%)  0
Fatigue  1  1/3 (33.33%)  1 1/4 (25.00%)  1 1/5 (20.00%)  1 49/278 (17.63%)  55 26/95 (27.37%)  33
Influenza like illness  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 14/278 (5.04%)  17 11/95 (11.58%)  11
Oedema peripheral  1  0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 31/278 (11.15%)  35 8/95 (8.42%)  14
Pain  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 11/278 (3.96%)  13 4/95 (4.21%)  4
Peripheral swelling  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 11/278 (3.96%)  12 6/95 (6.32%)  9
Pyrexia  1  1/3 (33.33%)  1 2/4 (50.00%)  2 0/5 (0.00%)  0 36/278 (12.95%)  85 5/95 (5.26%)  6
Sensation of foreign body  1  0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/278 (0.00%)  0 0/95 (0.00%)  0
Immune system disorders           
Hypogammaglobulinaemia  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 10/278 (3.60%)  11 1/95 (1.05%)  1
Seasonal allergy  1  1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 3/278 (1.08%)  5 1/95 (1.05%)  1
Infections and infestations           
Bronchitis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 10/278 (3.60%)  11 5/95 (5.26%)  8
Cat scratch disease  1  0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/278 (0.00%)  0 0/95 (0.00%)  0
Cellulitis  1  0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 18/278 (6.47%)  25 11/95 (11.58%)  15
Chest wall abscess  1  0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/278 (0.00%)  0 0/95 (0.00%)  0
Conjunctivitis  1  1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 14/278 (5.04%)  14 5/95 (5.26%)  6
Diverticulitis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 3/278 (1.08%)  3 3/95 (3.16%)  3
Ear infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 8/278 (2.88%)  9 3/95 (3.16%)  7
Folliculitis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 4/278 (1.44%)  4 4/95 (4.21%)  9
Gastroenteritis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 6/278 (2.16%)  9 3/95 (3.16%)  3
Helicobacter infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/278 (0.00%)  0 0/95 (0.00%)  0
Herpes simplex reactivation  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/278 (0.00%)  0 1/95 (1.05%)  1
Herpes zoster  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 13/278 (4.68%)  15 6/95 (6.32%)  6
Influenza  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 9/278 (3.24%)  9 0/95 (0.00%)  0
Localised infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 13/278 (4.68%)  21 9/95 (9.47%)  10
Lower respiratory tract infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 23/278 (8.27%)  41 8/95 (8.42%)  11
Nasal herpes  1  0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/278 (0.00%)  0 2/95 (2.11%)  2
Nasopharyngitis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 22/278 (7.91%)  32 7/95 (7.37%)  11
Onychomycosis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 3/95 (3.16%)  3
Ophthalmic herpes zoster  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/278 (0.00%)  0 0/95 (0.00%)  0
Oral candidiasis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 3/95 (3.16%)  4
Oral herpes  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  2 17/278 (6.12%)  22 4/95 (4.21%)  4
Pneumonia  1  0/3 (0.00%)  0 1/4 (25.00%)  1 1/5 (20.00%)  2 22/278 (7.91%)  24 7/95 (7.37%)  9
Pneumonia bacterial  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/278 (0.00%)  0 0/95 (0.00%)  0
Sinusitis  1  0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 34/278 (12.23%)  48 8/95 (8.42%)  14
Skin infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 13/278 (4.68%)  18 6/95 (6.32%)  7
Tinea pedis  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 1/278 (0.36%)  1 0/95 (0.00%)  0
Tooth abscess  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 4/95 (4.21%)  4
Upper respiratory tract infection  1  2/3 (66.67%)  4 2/4 (50.00%)  7 2/5 (40.00%)  10 106/278 (38.13%)  214 46/95 (48.42%)  89
Urinary tract infection  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 44/278 (15.83%)  70 18/95 (18.95%)  31
Viral upper respiratory tract infection  1  0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 5/278 (1.80%)  5 3/95 (3.16%)  4
Injury, poisoning and procedural complications           
Arthropod bite  1  1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 3/278 (1.08%)  4 1/95 (1.05%)  1
Chest injury  1  0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 1/278 (0.36%)  1 0/95 (0.00%)  0
Contusion  1  1/3 (33.33%)  1 1/4 (25.00%)  1 2/5 (40.00%)  2 97/278 (34.89%)  135 39/95 (41.05%)  57
Fall  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 28/278 (10.07%)  38 9/95 (9.47%)  13
Limb injury  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 7/278 (2.52%)  7 9/95 (9.47%)  10
Muscle strain  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/278 (0.72%)  2 4/95 (4.21%)  4
Post procedural contusion  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 4/278 (1.44%)  4 3/95 (3.16%)  3
Procedural pain  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 12/278 (4.32%)  12 5/95 (5.26%)  7
Skin laceration  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 12/278 (4.32%)  16 9/95 (9.47%)  9
Tooth fracture  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/278 (0.36%)  1 3/95 (3.16%)  3
Investigations           
Alanine aminotransferase increased  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 10/278 (3.60%)  13 4/95 (4.21%)  8
Blood creatinine increased  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 10/278 (3.60%)  11 4/95 (4.21%)  5
Gamma-glutamyltransferase increased  1  1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 0/278 (0.00%)  0 1/95 (1.05%)  2
International normalised ratio increased  1  0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/278 (0.00%)  0 0/95 (0.00%)  0
Neutrophil count decreased  1  0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 18/278 (6.47%)  93