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A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumor Activity of the Oral Anaplastic Lymphoma Kinase (ALK)/Epidermal Growth Factor Receptor (EGFR) Inhibitor Brigatinib (AP26113)

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ClinicalTrials.gov Identifier: NCT01449461
Recruitment Status : Completed
First Posted : October 10, 2011
Results First Posted : June 21, 2017
Last Update Posted : August 17, 2021
Sponsor:
Information provided by (Responsible Party):
Takeda ( Ariad Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Lymphoma, Large-Cell, Anaplastic
Carcinoma, Non-Small-Cell Lung
Intervention Drug: Brigatinib
Enrollment 137
Recruitment Details Participants took part in the study at 9 investigative sites in the United States and Spain from 20 September 2011 to 18 February 2020.
Pre-assignment Details Participants with advanced malignancies, all histologies other than leukemia were enrolled in dose-escalation and participants with non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangements were enrolled in dose expansion phase. Participants received brigatinib 30 mg - 300 mg, tablets, orally once daily or twice daily.
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
Period Title: Overall Study
Started 6 18 18 32 48 15
Completed 0 0 0 0 0 0
Not Completed 6 18 18 32 48 15
Reason Not Completed
Adverse Event             0             3             2             3             4             4
Death             0             2             0             0             7             1
Physician Decision             0             1             0             4             1             0
Documented Progressive Disease             4             7             14             15             24             5
Clinical Progressive Disease             2             2             0             3             4             2
Protocol Violation             0             0             0             1             0             0
Site Terminated by Sponsor             0             1             2             3             4             1
Withdrawal by Subject             0             1             0             0             2             1
Reason not Specified             0             1             0             3             2             1
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD Total
Hide Arm/Group Description Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years). Total of all reporting groups
Overall Number of Baseline Participants 6 18 18 32 48 15 137
Hide Baseline Analysis Population Description
Safety population included all enrolled participants who received at least one dose of study drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
66.8  (9.30) 57.9  (12.93) 57.8  (10.91) 55.7  (11.41) 53.9  (11.10) 58.5  (15.60) 56.4  (12.02)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
Adults [18-64 years]
2
  33.3%
11
  61.1%
12
  66.7%
25
  78.1%
39
  81.3%
9
  60.0%
98
  71.5%
From 65 to 84 years
4
  66.7%
7
  38.9%
6
  33.3%
7
  21.9%
9
  18.8%
6
  40.0%
39
  28.5%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
Female
3
  50.0%
12
  66.7%
13
  72.2%
14
  43.8%
29
  60.4%
8
  53.3%
79
  57.7%
Male
3
  50.0%
6
  33.3%
5
  27.8%
18
  56.3%
19
  39.6%
7
  46.7%
58
  42.3%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
1
   3.1%
1
   2.1%
0
   0.0%
2
   1.5%
Asian
0
   0.0%
4
  22.2%
3
  16.7%
3
   9.4%
5
  10.4%
2
  13.3%
17
  12.4%
Black or African American
0
   0.0%
1
   5.6%
2
  11.1%
0
   0.0%
1
   2.1%
1
   6.7%
5
   3.6%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   2.1%
0
   0.0%
1
   0.7%
White
6
 100.0%
13
  72.2%
13
  72.2%
27
  84.4%
39
  81.3%
12
  80.0%
110
  80.3%
Unknown
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   2.1%
0
   0.0%
1
   0.7%
Other
0
   0.0%
0
   0.0%
0
   0.0%
1
   3.1%
0
   0.0%
0
   0.0%
1
   0.7%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
Hispanic or Latino
1
  16.7%
0
   0.0%
0
   0.0%
1
   3.1%
1
   2.1%
0
   0.0%
3
   2.2%
Not Hispanic or Latino
5
  83.3%
18
 100.0%
18
 100.0%
31
  96.9%
47
  97.9%
15
 100.0%
134
  97.8%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
United States
6
 100.0%
18
 100.0%
18
 100.0%
32
 100.0%
41
  85.4%
15
 100.0%
130
  94.9%
Spain
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
7
  14.6%
0
   0.0%
7
   5.1%
Eastern Cooperative Oncology Group (ECOG) Performance Score   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
0
0
   0.0%
3
  16.7%
3
  16.7%
13
  40.6%
13
  27.1%
2
  13.3%
34
  24.8%
1
6
 100.0%
15
  83.3%
15
  83.3%
19
  59.4%
33
  68.8%
13
  86.7%
101
  73.7%
2
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
2
   4.2%
0
   0.0%
2
   1.5%
[1]
Measure Description: ECOG assessed participant's performance status on a 5 point scale: 0 equals (=) fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, but ambulatory/able to carry out light or sedentary work; 2=ambulatory (greater than [>] 50 percentage [%] of waking hours [h]), capable of all self care, but unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair >50% of waking hours; 4= completely disabled, cannot carry on any selfcare, totally confined to bed or chair and 5=Dead.
Time Since Diagnosis of Cancer  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
2.48  (3.303) 3.33  (2.184) 2.41  (1.346) 3.19  (2.726) 2.77  (2.053) 3.27  (1.913) 2.93  (2.192)
Participants with Diagnosis of Cancer Type  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
NSCLC
3
  50.0%
16
  88.9%
18
 100.0%
31
  96.9%
45
  93.8%
15
 100.0%
128
  93.4%
Other
3
  50.0%
2
  11.1%
0
   0.0%
1
   3.1%
3
   6.3%
0
   0.0%
9
   6.6%
Number of Participants with Mutation Types  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
Anaplastic Lymphoma Kinase (ALK+)
1
  16.7%
16
  88.9%
6
  33.3%
29
  90.6%
27
  56.3%
5
  33.3%
84
  61.3%
Epidermal Growth Factor Receptor (EGFRm)
2
  33.3%
1
   5.6%
10
  55.6%
3
   9.4%
18
  37.5%
9
  60.0%
43
  31.4%
ROS Proto-oncogene 1 (ROS1+)
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
3
   6.3%
1
   6.7%
4
   2.9%
Other
3
  50.0%
1
   5.6%
2
  11.1%
0
   0.0%
0
   0.0%
0
   0.0%
6
   4.4%
Participants with Prior Chemotherapy Regimen  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
0
0
   0.0%
2
  11.1%
7
  38.9%
12
  37.5%
12
  25.0%
3
  20.0%
36
  26.3%
1
3
  50.0%
4
  22.2%
3
  16.7%
6
  18.8%
17
  35.4%
2
  13.3%
35
  25.5%
2
0
   0.0%
9
  50.0%
4
  22.2%
8
  25.0%
10
  20.8%
5
  33.3%
36
  26.3%
> 2
3
  50.0%
3
  16.7%
4
  22.2%
6
  18.8%
9
  18.8%
5
  33.3%
30
  21.9%
Participants with Prior Radiotherapy to Brain  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 18 participants 18 participants 32 participants 48 participants 15 participants 137 participants
No
6
 100.0%
13
  72.2%
17
  94.4%
24
  75.0%
36
  75.0%
14
  93.3%
110
  80.3%
Yes
0
   0.0%
5
  27.8%
1
   5.6%
8
  25.0%
12
  25.0%
1
   6.7%
27
  19.7%
1.Primary Outcome
Title Recommended Phase 2 Dose (RP2D) of Brigatinib
Hide Description The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of Cycle 1).
Time Frame 28 days
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all enrolled participants who received at least one dose of study drug.
Arm/Group Title Brigatinib
Hide Arm/Group Description:
All participants who received brigatinib, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Overall Number of Participants Analyzed 137
Mean (Full Range)
Unit of Measure: mg
NA [1] 
(90 to 180)
[1]
RP2D for this study is a dose range.
2.Primary Outcome
Title Objective Response Rate (ORR)
Hide Description ORR assessed by the investigator, is defined as the percentage of the participants with complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid tumors (RECIST) v1.1 after the initiation of study treatment. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters. Crzb=Crizotinib.
Time Frame From Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) included all participants who received at least one dose of study drug. Participants with anaplastic lymphoma kinase (ALK) and non-small cell lung cancer (NSCLC) were evaluated for this outcome measure. Number analyzed is the number of participants with data evaluable for specific category.
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description:
Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years).
Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
Overall Number of Participants Analyzed 1 14 6 28 25 5
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
With Prior Treatment with Crizotinib Number Analyzed 1 participants 13 participants 5 participants 25 participants 23 participants 4 participants
0
(0 to 0)
53.8
(25.1 to 80.8)
60.0
(14.7 to 94.7)
76.0
(54.9 to 90.6)
65.2
(42.7 to 83.6)
25.0
(0.6 to 80.6)
Without Prior Treatment with Crizotinib Number Analyzed 0 participants 1 participants 1 participants 3 participants 2 participants 1 participants
100.0
(2.5 to 100.0)
100.0
(2.5 to 100.0)
100.0
(29.2 to 100.0)
100.0
(15.8 to 100.0)
100.0
(2.5 to 100.0)
3.Secondary Outcome
Title Number of Participants Who Had at Least One Treatment-Emergent Adverse Event (TEAE)
Hide Description An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame From first dose of study drug up to 30 days following the last dose of the study treatment or the investigator/participant decision to discontinue treatment, whichever occurs first (approximately up to 7.4 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all enrolled participants who received at least one dose of study drug.
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description:
Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years).
Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
Overall Number of Participants Analyzed 6 18 18 32 48 15
Measure Type: Count of Participants
Unit of Measure: Participants
6
 100.0%
18
 100.0%
18
 100.0%
32
 100.0%
48
 100.0%
15
 100.0%
4.Secondary Outcome
Title Maximum Tolerated Dose (MTD) Assessed in Dose Escalation Phase of the Study
Hide Description The MTD is defined as the highest dose at which ≤ 1 of 6 evaluable participants experience a DLT within the first 28 days of treatment (end of Cycle 1).
Time Frame Up to Cycle 1 (28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all enrolled participants who received at least one dose of study drug. Participants enrolled in the dose escalation phase were included in the analysis.
Arm/Group Title Brigatinib
Hide Arm/Group Description:
All participants received brigatinib tablets, orally, once daily (QD) starting at 30 mg in each cycle of 28 days.
Overall Number of Participants Analyzed 66
Measure Type: Number
Unit of Measure: mg
NA [1] 
[1]
MTD criteria was not met.
5.Secondary Outcome
Title Number of Participants With Dose Limiting Toxicities (DLTs) Assessed in Dose Escalation Phase of the Study
Hide Description DLT include any toxicity that is possibly, probably, or definitely drug-related. Toxicity grades will be defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. DLTs are defined by the following: A) Non-hematologic toxicities: Any grade ≥3 non-hematologic toxicity, with the exception of self-limiting or medically controllable toxicities (eg, nausea, vomiting, fatigue, electrolyte disturbances, hypersensitivity reactions) lasting < 3 days, and excluding alopecia. B) Hematologic toxicities: Febrile neutropenia not related to underlying disease (fever, > 101°F; ANC<500); Prolonged grade 4 neutropenia (> 7 days); Neutropenic infection: ≥ grade 3 neutropenia with ≥ grade 3 infection; Thrombocytopenia ≥ grade 3 with bleeding or grade 4 lasting ≥ 7 days. C) Missed ≥ 25% of planned doses of brigatinib over 28 days due to treatment-related AEs in the first cycle.
Time Frame Up to Cycle 1 (28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
DLT-evaluable population included participants who received ≥75% of planned study drug doses during Cycle 1.
Arm/Group Title Brigatinib 30 mg Brigatinib 60 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 240 mg Brigatinib 300 mg
Hide Arm/Group Description:
Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Overall Number of Participants Analyzed 3 3 5 3 3 6 2
Measure Type: Number
Unit of Measure: participants
0 0 0 0 0 1 1
6.Secondary Outcome
Title Cmax: Maximum Observed Plasma Concentration for Brigatinib at Cycle 1 Day 1
Hide Description [Not Specified]
Time Frame Cycle 1 (28-days cycle): Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here number of participants analyzed is the participants who were evaluable for this outcome measure. Participants of brigatinib 90 mg QD-180 mg QD arm were included as per treatment received at each time point.
Arm/Group Title Brigatinib 30 mg Brigatinib 60 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 240 mg Brigatinib 300 mg
Hide Arm/Group Description:
Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Overall Number of Participants Analyzed 3 3 50 11 44 10 2
Mean (Standard Deviation)
Unit of Measure: ng/mL
125.6  (41.07) 406.3  (102) 493  (289.5) 793.7  (828.7) 1185  (607.6) 1515  (637.9) 895  (487.9)
7.Secondary Outcome
Title Cmax: Maximum Observed Plasma Concentration for Brigatinib at Cycle 2 Day 1
Hide Description [Not Specified]
Time Frame Cycle 2 (28-days cycle): Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here number of participants analyzed is the participants with data available for analysis for this outcome measure. Participants of brigatinib 90 mg QD-180 mg QD arm were included as per treatment received at each time point.
Arm/Group Title Brigatinib 30 mg Brigatinib 60 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 240 mg Brigatinib 300 mg
Hide Arm/Group Description:
Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Overall Number of Participants Analyzed 2 3 15 10 63 7 0
Mean (Standard Deviation)
Unit of Measure: ng/mL
249.50  (167.58) 491.67  (223.95) 634.07  (310.05) 942.30  (472.33) 1694.3  (1014.3) 2280.0  (1308.5)
8.Secondary Outcome
Title Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Brigatinib at Cycle 1 Day 1
Hide Description [Not Specified]
Time Frame Cycle 1 (28-days cycle): Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here, number of participants analyzed is the participants who were evaluable for this outcome measure. Participants of brigatinib 90 mg QD-180 mg QD arm were included as per treatment received at each time point.
Arm/Group Title Brigatinib 30 mg Brigatinib 60 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 240 mg Brigatinib 300 mg
Hide Arm/Group Description:
Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Overall Number of Participants Analyzed 3 3 50 11 44 10 2
Median (Full Range)
Unit of Measure: hours
3.9
(3.8 to 4.0)
1.0
(0.48 to 4.0)
2.0
(0.48 to 24)
2.0
(0.98 to 6.0)
2.0
(0.60 to 25)
2.0
(1.0 to 4.0)
4.05
(4 to 4.1)
9.Secondary Outcome
Title Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Brigatinib at Cycle 2 Day 1
Hide Description [Not Specified]
Time Frame Cycle 2 (28-days cycle): Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here, number of participants analyzed is the participants with data available for analyses for this outcome measure. Participants of brigatinib 90 mg QD-180 mg QD arm were included as per treatment received at each time point.
Arm/Group Title Brigatinib 30 mg Brigatinib 60 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 240 mg Brigatinib 300 mg
Hide Arm/Group Description:
Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Overall Number of Participants Analyzed 2 3 15 10 63 7 0
Median (Full Range)
Unit of Measure: hours
2.49
(0.98 to 4.0)
1.00
(0.50 to 1.8)
2.00
(0.98 to 8.0)
3.00
(0.50 to 6.1)
2.10
(0.50 to 6.2)
2.00
(1.0 to 4.0)
10.Secondary Outcome
Title AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Post-dose for Brigatinib at Cycle 1 Day 1
Hide Description [Not Specified]
Time Frame Cycle 1 (28-days cycle): Day 1 multiple time points (up to 24 hours) post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here, number of participants analyzed is the participants who were evaluable for this outcome measure. Participants of brigatinib 90 mg QD-180 mg QD arm were included as per treatment received at each time point.
Arm/Group Title Brigatinib 30 mg Brigatinib 60 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 240 mg Brigatinib 300 mg
Hide Arm/Group Description:
Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Overall Number of Participants Analyzed 3 3 15 11 63 7 2
Mean (Standard Deviation)
Unit of Measure: h*ng/mL
1320.9  (576.29) 3900  (430.31) 5710.1  (3268.4) 9895.5  (11772) 13204  (6306.9) 16800  (7571.1) 12356  (5869)
11.Secondary Outcome
Title AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Post-dose for Brigatinib at Cycle 2 Day 1
Hide Description [Not Specified]
Time Frame Cycle 2 (28-days cycle): Day 1 multiple time points (up to 24 hours) post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here, number of participants analyzed is the participants with data available for analyses for this outcome measure. Participants of brigatinib 90 mg QD-180 mg QD arm were included as per treatment received at each time point.
Arm/Group Title Brigatinib 30 mg Brigatinib 60 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 240 mg Brigatinib 300 mg
Hide Arm/Group Description:
Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Overall Number of Participants Analyzed 2 3 15 10 63 7 0
Mean (Standard Deviation)
Unit of Measure: h*ng/mL
2689.0  (1145.5) 5069.0  (1664.7) 9142.1  (4076.7) 13888  (7011.4) 23478  (14463) 30117  (19921)
12.Secondary Outcome
Title T1/2: Terminal Phase Elimination Half-life for Brigatinib at Cycle 2 Day 1
Hide Description [Not Specified]
Time Frame Cycle 2 (28-days cycle): Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here, number of participants analyzed is the participants with data available for analyses for this outcome measure. Participants of brigatinib 90 mg QD-180 mg QD arm were included as per treatment received at each time point.
Arm/Group Title Brigatinib 30 mg Brigatinib 60 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 240 mg Brigatinib 300 mg
Hide Arm/Group Description:
Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).
Overall Number of Participants Analyzed 2 3 15 10 63 7 0
Mean (Standard Deviation)
Unit of Measure: hours
31.55  (2.758) 30.93  (5.873) 28.69  (10.06) 25.52  (7.958) 24.90  (7.437) 21.77  (4.007)
13.Secondary Outcome
Title Best Overall Response
Hide Description Best overall response is defined as percentage of participants with CR, PR, stable disease (SD) or progressive disease (PD) as per of RECIST v1.1 as evaluated by investigator. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. Disease progression for target lesion: SLD increased by at least 20% from smallest value on study and SLD must also demonstrate an absolute increase of at least 5 mm or development of any new lesion. PD for non-target lesion: unequivocal progression of existing non-target lesions. SD for neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Time Frame Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all participants who received at least one dose of study drug. Participants with ALK and NSCLC were evaluated for this outcome measure. Number analyzed is the number of participants with data evaluable for specific category.
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description:
Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years).
Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
Overall Number of Participants Analyzed 1 14 6 28 25 5
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
With Prior Treatment with Crizotinib: Complete Response Number Analyzed 1 participants 13 participants 5 participants 25 participants 23 participants 4 participants
0.0
(0.0 to 0.0)
0.0
(0.0 to 0.0)
0.0
(0.0 to 0.0)
12.0
(2.5 to 31.2)
8.7
(1.1 to 28.0)
0.0
(0.0 to 0.0)
Without Prior Treatment with Crizotinib: Complete Response Number Analyzed 0 participants 1 participants 1 participants 3 participants 2 participants 1 participants
0.0
(0.0 to 0.0)
100.0
(2.5 to 100.0)
33.3
(0.8 to 90.6)
0.0
(0.0 to 0.0)
100.0
(2.5 to 100.0)
With Prior Treatment with Crizotinib: Partial Response Number Analyzed 1 participants 13 participants 5 participants 25 participants 23 participants 4 participants
0.0
(0.0 to 0.0)
53.8
(25.1 to 80.8)
60.0
(14.7 to 94.7)
64.0
(42.5 to 82.0)
56.5
(34.5 to 76.8)
25.0
(0.6 to 80.6)
Without Prior Treatment with Crizotinib: Partial Response Number Analyzed 0 participants 1 participants 1 participants 3 participants 2 participants 1 participants
100.0
(2.5 to 100.0)
0.0
(0.0 to 0.0)
66.7
(9.4 to 99.2)
100.0
(15.8 to 100.0)
0.0
(0.0 to 0.0)
With Prior Treatment with Crizotinib: Stable Disease Number Analyzed 1 participants 13 participants 5 participants 25 participants 23 participants 4 participants
100.0
(2.5 to 100.0)
23.1
(5.0 to 53.8)
0.0
(0.0 to 0.0)
12.0
(2.5 to 31.2)
13.0
(2.8 to 33.6)
75.0
(19.4 to 99.4)
Without Prior Treatment with Crizotinib: Stable Disease Number Analyzed 0 participants 1 participants 1 participants 3 participants 2 participants 1 participants
0.0
(0.0 to 0.0)
0.0
(0.0 to 0.0)
0.0
(0.0 to 0.0)
0.0
(0.0 to 0.0)
0.0
(0.0 to 0.0)
With Prior Treatment with Crizotinib: Progressive Disease Number Analyzed 1 participants 13 participants 5 participants 25 participants 23 participants 4 participants
0.0
(0.0 to 0.0)
0.0
(0.0 to 0.0)
0.0
(0.0 to 0.0)
8.0
(1.0 to 26.0)
21.7
(7.5 to 43.7)
0.0
(0.0 to 0.0)
Without Prior Treatment with Crizotinib: Progressive Disease Number Analyzed 0 participants 1 participants 1 participants 3 participants 2 participants 1 participants
0.0
(0.0 to 0.0)
0.0
(0.0 to 0.0)
0.0
(0.0 to 0.0)
0.0
(0.0 to 0.0)
0.0
(0.0 to 0.0)
14.Secondary Outcome
Title Duration of Response
Hide Description Duration of response is defined as time interval from time that measurement criteria are first met for CR/PR (whichever is first recorded) until first date that progressive disease is objectively documented or death due to any cause. Participants who did not progress nor die were censored at last valid response assessment.CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis.CR for non-target lesion:disappearance of all extranodal non-target lesions,all lymph nodes must be non-pathological in size(<10mm short axis) and normalization of tumor marker level.PR:at least a 30% decrease in SLD of target lesions.PD for target lesion:SLD increased by at least 20% from smallest value and must also demonstrate an absolute increase of >=5 mm or development of any new lesion.PD for non-target lesion:unequivocal progression of existing non-target lesions.Duration of response calculated by Kaplan-Meier estimation.
Time Frame Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all participants who received at least one dose of study drug. Participants who were responders among those who had ALK and NSCLC were evaluated for this outcome measure. Number analyzed is the number of participants with data evaluable for specific category.
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description:
Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years).
Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
Overall Number of Participants Analyzed 0 8 4 22 17 2
Median (95% Confidence Interval)
Unit of Measure: months
With Prior Treatment with Crizotinib Number Analyzed 0 participants 7 participants 3 participants 19 participants 15 participants 1 participants
11.1
(3.8 to 16.7)
4.0
(3.7 to 29.5)
14.8
(7.9 to 25.1)
20.4
(7.5 to 51.6)
29.7 [1] 
(NA to NA)
Without Prior Treatment with Crizotinib Number Analyzed 0 participants 1 participants 1 participants 3 participants 2 participants 1 participants
30.4 [1] 
(NA to NA)
60.3 [1] 
(NA to NA)
52.0
(5.6 to 52.0)
20.8
(9.2 to 32.4)
NA [2] 
(NA to NA)
[1]
95% CI was not estimable due to low number of participants with events.
[2]
Duration of response was not estimable due to low number of participants with events.
15.Secondary Outcome
Title Progression Free Survival (PFS)
Hide Description PFS is defined as the time interval from the date of the first dose of the study treatment until the first date at which disease progression is objectively documented, or death due to any cause, whichever occurs first. Disease progression for target lesion: SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest) and SLD must also demonstrate an absolute increase of at least 5 mm or development of any new lesion. Disease progression for non-target lesion: Unequivocal progression of existing non-target lesions. (Subjective judgment by experienced reader).
Time Frame Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here, overall number of participants analyzed is the participants who were evaluable for this outcome measure.
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description:
Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years).
Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
Overall Number of Participants Analyzed 5 15 17 21 40 7
Median (95% Confidence Interval)
Unit of Measure: months
1.8
(1.0 to 5.5)
12.6
(0.9 to 47.9)
5.4
(0.8 to 63.9)
11.0
(0.5 to 53.6)
5.4
(0.1 to 69.9)
5.4
(1.8 to 31.5)
16.Secondary Outcome
Title Overall Survival (OS)
Hide Description OS is defined as the time interval from the date of the first dose of the study treatment until death due to any cause.
Time Frame Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here, overall number of participants analyzed is the participants who were evaluable for this outcome measure.
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description:
Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years).
Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
Overall Number of Participants Analyzed 6 11 12 17 25 11
Median (95% Confidence Interval)
Unit of Measure: months
5.3
(2.3 to 12.6)
11.6
(4.0 to 47.6)
7.3
(0.5 to 28.6)
17.9
(1.4 to 35.0)
7.3
(0.1 to 55.0)
8.3
(3.3 to 22.3)
17.Secondary Outcome
Title Intracranial Objective Response Rate
Hide Description Intracranial objective response rate is defined as the percentage of the participants with CR or PR in the intracranial CNS per modification of RECIST v1.1 after the initiation of study drug. CR for target lesion: disappearance of all extranodal lesions. CR for non-target lesion: disappearance of all extranodal non-target lesions and normalization of tumor marker level. PR: at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters.
Time Frame Screening and at 8-week intervals thereafter (approximately up to 50 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set. ALK+ NSCLC participants with measurable and non-measurable brain metastases at baseline were evaluated for this outcome measure. Here, number analyzed is the number of participants who were evaluable for specific category.
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description:
Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years).
Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
Overall Number of Participants Analyzed 0 8 1 18 16 3
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Measurable Brain Metastases Number Analyzed 0 participants 2 participants 0 participants 5 participants 7 participants 1 participants
100
(15.8 to 100)
80
(28.4 to 99.5)
42.9
(9.9 to 81.6)
100
(2.5 to 100)
Only Non-Measurable Brain Metastases Number Analyzed 0 participants 6 participants 1 participants 13 participants 9 participants 2 participants
16.7
(0.4 to 64.1)
100
(2.5 to 100)
46.2
(19.2 to 74.9)
44.4
(13.7 to 78.8)
50.0
(1.3 to 98.7)
18.Secondary Outcome
Title Duration of Intracranial Response
Hide Description Intracranial duration of response is defined as the time interval from the time that the measurement criteria are first met for CR/PR in brain metastases (whichever is first recorded) until the first date that progressive disease is objectively documented or death due to any cause. Participants who did not progress nor die were censored at the last valid response assessment. Duration intracranial of response was calculated by Kaplan-Meier estimation.
Time Frame Screening and at 8-week intervals thereafter (approximately up to 50 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set. ALK+ NSCLC participants with measurable and non-measurable brain metastases at baseline were evaluated for this outcome measure.
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description:
Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years).
Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
Overall Number of Participants Analyzed 0 8 1 18 16 3
Median (95% Confidence Interval)
Unit of Measure: months
12.9 [1] 
(NA to NA)
5.0 [1] 
(NA to NA)
11.4
(7.5 to 11.4)
29.2
(5.5 to 29.2)
11.3
(3.6 to 18.9)
[1]
Upper and lower limit of duration of intracranial response was not reached due to low number of participants with events.
19.Secondary Outcome
Title Intracranial Progression Free Survival (PFS)
Hide Description PFS is defined as the time interval from the date of the first dose of the study treatment until the first date at which disease progression in brain, or death due to any cause, whichever occurs first. Intracranial PFS was calculated by Kaplan-Meier estimation.
Time Frame Screening and at 8-week intervals thereafter (approximately up to 50 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set. ALK+ NSCLC participants with measurable and non-measurable brain metastases at baseline were evaluated for this outcome measure.
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description:
Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years).
Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years).
Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
Overall Number of Participants Analyzed 0 8 1 18 16 3
Median (95% Confidence Interval)
Unit of Measure: months
36.8
(5.5 to 36.8)
6.7 [1] 
(NA to NA)
NA [2] 
(9.4 to NA)
14.4
(7.3 to 31.1)
7.3
(3.1 to 22.3)
[1]
Upper limit of 95% CI was not reached due to low number of participants with events.
[2]
Progression-free survival was not reached due to low number of participants with events.
Time Frame All-Cause Mortality: From first dose up to the End of the Study (Up to 8.4 years). Serious and other adverse events: From first dose of study drug up to 30 days following the last dose of the study treatment or the investigator/participant decision to discontinue treatment, whichever occurs first (approximately up to 7.4 years)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Hide Arm/Group Description Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years). Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years). Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
All-Cause Mortality
Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   6/6 (100.00%)   11/18 (61.11%)   12/18 (66.67%)   17/32 (53.13%)   25/48 (52.08%)   11/15 (73.33%) 
Hide Serious Adverse Events
Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/6 (16.67%)   10/18 (55.56%)   10/18 (55.56%)   14/32 (43.75%)   30/48 (62.50%)   11/15 (73.33%) 
Cardiac disorders             
Atrial fibrillation  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Supraventricular tachycardia  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  2/48 (4.17%)  0/15 (0.00%) 
Cardiac failure congestive  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Cardiac tamponade  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Angina unstable  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Tachycardia  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Cardio-respiratory arrest  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Pericardial effusion  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Eye disorders             
Blindness  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Gastrointestinal disorders             
Pancreatitis  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  1/15 (6.67%) 
Abdominal wall haematoma  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Bezoar  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Colitis  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Gastric ulcer haemorrhage  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Haemorrhoids  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Oesophageal compression  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Rectal ulcer  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Intestinal obstruction  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
General disorders             
Non-cardiac chest pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  2/48 (4.17%)  1/15 (6.67%) 
Pyrexia  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  1/15 (6.67%) 
Death  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Influenza like illness  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Sudden death  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Immune system disorders             
Food allergy  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Infections and infestations             
Pneumonia  1  0/6 (0.00%)  2/18 (11.11%)  3/18 (16.67%)  1/32 (3.13%)  4/48 (8.33%)  0/15 (0.00%) 
Bronchitis  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Sepsis  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Device related infection  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Device related sepsis  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Atypical mycobacterial lower respiratory tract infection  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Pneumonia pseudomonal  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Urinary tract infection  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Viral infection  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Cellulitis  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Respiratory tract infection  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Injury, poisoning and procedural complications             
Post procedural haemorrhage  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Radiation necrosis  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Radiation pneumonitis  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Femur fracture  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Radiation associated cardiac failure  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Road traffic accident  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Investigations             
Alanine aminotransferase increased  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  0/48 (0.00%)  0/15 (0.00%) 
Aspartate aminotransferase increased  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Metabolism and nutrition disorders             
Failure to thrive  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Hyperglycaemia  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Hyponatraemia  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Insulin resistance  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Dehydration  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Musculoskeletal and connective tissue disorders             
Back pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Bone pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Intervertebral disc protrusion  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Muscular weakness  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Pain in extremity  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Neoplasm progression  1  0/6 (0.00%)  4/18 (22.22%)  1/18 (5.56%)  1/32 (3.13%)  5/48 (10.42%)  0/15 (0.00%) 
Pericardial effusion malignant  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  3/32 (9.38%)  1/48 (2.08%)  0/15 (0.00%) 
Metastases to central nervous system  1  1/6 (16.67%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Cancer pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  2/48 (4.17%)  0/15 (0.00%) 
Intracranial tumour haemorrhage  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Malignant ascites  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Metastatic malignant melanoma  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Basal cell carcinoma  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  1/15 (6.67%) 
Chronic myeloid leukaemia recurrent  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Malignant pleural effusion  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Metastases to meninges  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Penile squamous cell carcinoma  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Nervous system disorders             
Seizure  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Syncope  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Central nervous system haemorrhage  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Cerebral haemorrhage  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Cognitive disorder  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Embolic stroke  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Haemorrhage intracranial  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  2/48 (4.17%)  0/15 (0.00%) 
Haemorrhagic stroke  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Headache  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  1/15 (6.67%) 
Ischaemic stroke  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Nervous system disorder  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Transient ischaemic attack  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Ataxia  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Central nervous system lesion  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Cerebral ischaemia  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Dysarthria  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Hydrocephalus  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Presyncope  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Status epilepticus  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Psychiatric disorders             
Mental status changes  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Confusional state  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  3/48 (6.25%)  0/15 (0.00%) 
Suicidal ideation  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Renal and urinary disorders             
Acute kidney injury  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Respiratory, thoracic and mediastinal disorders             
Dyspnoea  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  1/32 (3.13%)  2/48 (4.17%)  4/15 (26.67%) 
Hypoxia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  2/15 (13.33%) 
Pulmonary embolism  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Pneumonitis  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  1/32 (3.13%)  2/48 (4.17%)  0/15 (0.00%) 
Cough  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  2/15 (13.33%) 
Pleural effusion  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  1/48 (2.08%)  1/15 (6.67%) 
Respiratory failure  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  2/48 (4.17%)  0/15 (0.00%) 
Acute respiratory distress syndrome  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Haemoptysis  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Pneumothorax  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Dyspnoea exertional  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Pleuritic pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Skin and subcutaneous tissue disorders             
Eczema  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Rash maculo-papular  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Vascular disorders             
Haematoma  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
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 5%
Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   6/6 (100.00%)   17/18 (94.44%)   17/18 (94.44%)   31/32 (96.88%)   45/48 (93.75%)   15/15 (100.00%) 
Blood and lymphatic system disorders             
Anaemia  1  0/6 (0.00%)  1/18 (5.56%)  3/18 (16.67%)  5/32 (15.63%)  4/48 (8.33%)  3/15 (20.00%) 
Increased tendency to bruise  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  2/48 (4.17%)  1/15 (6.67%) 
Cardiac disorders             
Sinus tachycardia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  2/32 (6.25%)  1/48 (2.08%)  0/15 (0.00%) 
Palpitations  1  0/6 (0.00%)  2/18 (11.11%)  1/18 (5.56%)  0/32 (0.00%)  2/48 (4.17%)  0/15 (0.00%) 
Sinus bradycardia  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  2/32 (6.25%)  0/48 (0.00%)  0/15 (0.00%) 
Atrial fibrillation  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Atrial flutter  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Cardiac failure congestive  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Ear and labyrinth disorders             
Tinnitus  1  0/6 (0.00%)  2/18 (11.11%)  0/18 (0.00%)  2/32 (6.25%)  1/48 (2.08%)  1/15 (6.67%) 
Deafness unilateral  1  1/6 (16.67%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Vertigo  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Ear discomfort  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Ear pain  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Endocrine disorders             
Hypothyroidism  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  3/32 (9.38%)  2/48 (4.17%)  0/15 (0.00%) 
Hyperthyroidism  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Eye disorders             
Vision blurred  1  0/6 (0.00%)  1/18 (5.56%)  2/18 (11.11%)  6/32 (18.75%)  5/48 (10.42%)  0/15 (0.00%) 
Dry eye  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Visual impairment  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  1/15 (6.67%) 
Blepharospasm  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Lacrimation increased  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Photopsia  1  1/6 (16.67%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Vitreous floaters  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  0/48 (0.00%)  0/15 (0.00%) 
Asthenopia  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Cataract  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  2/32 (6.25%)  0/48 (0.00%)  0/15 (0.00%) 
Eye pain  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Eyelid margin crusting  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Eyelid oedema  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Dyschromatopsia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Eye swelling  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Cataract cortical  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Gastrointestinal disorders             
Nausea  1  3/6 (50.00%)  8/18 (44.44%)  9/18 (50.00%)  16/32 (50.00%)  33/48 (68.75%)  8/15 (53.33%) 
Diarrhoea  1  1/6 (16.67%)  8/18 (44.44%)  7/18 (38.89%)  17/32 (53.13%)  21/48 (43.75%)  8/15 (53.33%) 
Constipation  1  1/6 (16.67%)  6/18 (33.33%)  5/18 (27.78%)  9/32 (28.13%)  8/48 (16.67%)  4/15 (26.67%) 
Vomiting  1  1/6 (16.67%)  1/18 (5.56%)  5/18 (27.78%)  9/32 (28.13%)  19/48 (39.58%)  5/15 (33.33%) 
Abdominal pain  1  3/6 (50.00%)  1/18 (5.56%)  2/18 (11.11%)  6/32 (18.75%)  5/48 (10.42%)  2/15 (13.33%) 
Dry mouth  1  0/6 (0.00%)  3/18 (16.67%)  0/18 (0.00%)  5/32 (15.63%)  2/48 (4.17%)  2/15 (13.33%) 
Abdominal distension  1  0/6 (0.00%)  4/18 (22.22%)  1/18 (5.56%)  1/32 (3.13%)  4/48 (8.33%)  0/15 (0.00%) 
Abdominal discomfort  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  2/32 (6.25%)  5/48 (10.42%)  0/15 (0.00%) 
Gastrooesophageal reflux disease  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  2/32 (6.25%)  3/48 (6.25%)  3/15 (20.00%) 
Dyspepsia  1  0/6 (0.00%)  4/18 (22.22%)  1/18 (5.56%)  2/32 (6.25%)  1/48 (2.08%)  1/15 (6.67%) 
Dysphagia  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  2/32 (6.25%)  2/48 (4.17%)  3/15 (20.00%) 
Aphthous ulcer  1  0/6 (0.00%)  3/18 (16.67%)  0/18 (0.00%)  1/32 (3.13%)  2/48 (4.17%)  0/15 (0.00%) 
Flatulence  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  2/48 (4.17%)  1/15 (6.67%) 
Stomatitis  1  0/6 (0.00%)  2/18 (11.11%)  2/18 (11.11%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Cheilitis  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Mouth ulceration  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Abdominal rigidity  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Abdominal pain upper  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  3/32 (9.38%)  6/48 (12.50%)  0/15 (0.00%) 
Lip dry  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Lip swelling  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Oesophageal irritation  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Oesophageal pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Toothache  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Hypoaesthesia oral  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  1/15 (6.67%) 
Hyperaesthesia teeth  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  1/15 (6.67%) 
Abdominal pain lower  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Eructation  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Haemorrhoids  1  0/6 (0.00%)  2/18 (11.11%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Abnormal faeces  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Enterocolitis  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Haematochezia  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
General disorders             
Fatigue  1  2/6 (33.33%)  9/18 (50.00%)  9/18 (50.00%)  16/32 (50.00%)  19/48 (39.58%)  12/15 (80.00%) 
Oedema peripheral  1  1/6 (16.67%)  1/18 (5.56%)  4/18 (22.22%)  6/32 (18.75%)  5/48 (10.42%)  4/15 (26.67%) 
Pyrexia  1  0/6 (0.00%)  3/18 (16.67%)  2/18 (11.11%)  6/32 (18.75%)  7/48 (14.58%)  2/15 (13.33%) 
Pain  1  0/6 (0.00%)  3/18 (16.67%)  2/18 (11.11%)  4/32 (12.50%)  3/48 (6.25%)  1/15 (6.67%) 
Chest discomfort  1  0/6 (0.00%)  3/18 (16.67%)  0/18 (0.00%)  3/32 (9.38%)  5/48 (10.42%)  2/15 (13.33%) 
Non-cardiac chest pain  1  0/6 (0.00%)  1/18 (5.56%)  2/18 (11.11%)  1/32 (3.13%)  3/48 (6.25%)  3/15 (20.00%) 
Influenza like illness  1  0/6 (0.00%)  1/18 (5.56%)  2/18 (11.11%)  4/32 (12.50%)  3/48 (6.25%)  1/15 (6.67%) 
Asthenia  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  1/32 (3.13%)  5/48 (10.42%)  1/15 (6.67%) 
Chills  1  0/6 (0.00%)  3/18 (16.67%)  0/18 (0.00%)  3/32 (9.38%)  2/48 (4.17%)  2/15 (13.33%) 
Gait disturbance  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  2/32 (6.25%)  4/48 (8.33%)  0/15 (0.00%) 
Peripheral swelling  1  0/6 (0.00%)  2/18 (11.11%)  0/18 (0.00%)  2/32 (6.25%)  2/48 (4.17%)  0/15 (0.00%) 
Chest pain  1  1/6 (16.67%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  1/48 (2.08%)  0/15 (0.00%) 
Thirst  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Axillary pain  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Exercise tolerance decreased  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Feeling abnormal  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Feeling jittery  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Swelling face  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  1/15 (6.67%) 
Mucosal inflammation  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Swelling  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Temperature intolerance  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Immune system disorders             
Seasonal allergy  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  3/48 (6.25%)  0/15 (0.00%) 
Contrast media allergy  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Infections and infestations             
Upper respiratory tract infection  1  1/6 (16.67%)  0/18 (0.00%)  3/18 (16.67%)  12/32 (37.50%)  7/48 (14.58%)  3/15 (20.00%) 
Nasopharyngitis  1  0/6 (0.00%)  1/18 (5.56%)  4/18 (22.22%)  5/32 (15.63%)  7/48 (14.58%)  1/15 (6.67%) 
Urinary tract infection  1  0/6 (0.00%)  3/18 (16.67%)  0/18 (0.00%)  6/32 (18.75%)  9/48 (18.75%)  1/15 (6.67%) 
Sinusitis  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  4/32 (12.50%)  3/48 (6.25%)  4/15 (26.67%) 
Pneumonia  1  0/6 (0.00%)  1/18 (5.56%)  2/18 (11.11%)  2/32 (6.25%)  1/48 (2.08%)  2/15 (13.33%) 
Bronchitis  1  0/6 (0.00%)  2/18 (11.11%)  0/18 (0.00%)  3/32 (9.38%)  0/48 (0.00%)  2/15 (13.33%) 
Influenza  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Oral candidiasis  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  2/48 (4.17%)  1/15 (6.67%) 
Viral infection  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Vulvovaginal mycotic infection  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Conjunctivitis viral  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Diarrhoea infectious  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Folliculitis  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  2/15 (13.33%) 
Fungal skin infection  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Infectious pleural effusion  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Laryngitis viral  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Nail infection  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Nasal herpes  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Onychomycosis  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Otitis externa  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  1/15 (6.67%) 
Paronychia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Skin candida  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Vaginal infection  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Cellulitis  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  2/48 (4.17%)  0/15 (0.00%) 
Gastroenteritis viral  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  2/32 (6.25%)  0/48 (0.00%)  1/15 (6.67%) 
Rhinitis  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  1/15 (6.67%) 
Ear infection bacterial  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Kidney infection  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Oral herpes  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Vulvovaginal candidiasis  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Herpes zoster  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  2/48 (4.17%)  0/15 (0.00%) 
Injury, poisoning and procedural complications             
Skin Laceration  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Rib fracture  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  2/32 (6.25%)  0/48 (0.00%)  0/15 (0.00%) 
Procedural pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Radiation neuropathy  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Radiation pneumonitis  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Fall  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  4/32 (12.50%)  2/48 (4.17%)  1/15 (6.67%) 
Arthropod bite  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Corneal abrasion  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  0/48 (0.00%)  0/15 (0.00%) 
Foot fracture  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Joint dislocation  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Investigations             
Amylase increased  1  0/6 (0.00%)  5/18 (27.78%)  5/18 (27.78%)  10/32 (31.25%)  9/48 (18.75%)  3/15 (20.00%) 
Lipase increased  1  0/6 (0.00%)  5/18 (27.78%)  4/18 (22.22%)  12/32 (37.50%)  6/48 (12.50%)  3/15 (20.00%) 
Aspartate aminotransferase increased  1  0/6 (0.00%)  3/18 (16.67%)  7/18 (38.89%)  10/32 (31.25%)  9/48 (18.75%)  2/15 (13.33%) 
Alanine aminotransferase increased  1  0/6 (0.00%)  3/18 (16.67%)  3/18 (16.67%)  6/32 (18.75%)  5/48 (10.42%)  1/15 (6.67%) 
Blood insulin increased  1  0/6 (0.00%)  4/18 (22.22%)  2/18 (11.11%)  4/32 (12.50%)  5/48 (10.42%)  0/15 (0.00%) 
Weight decreased  1  0/6 (0.00%)  2/18 (11.11%)  0/18 (0.00%)  5/32 (15.63%)  6/48 (12.50%)  2/15 (13.33%) 
Blood creatine phosphokinase increased  1  0/6 (0.00%)  2/18 (11.11%)  2/18 (11.11%)  4/32 (12.50%)  4/48 (8.33%)  1/15 (6.67%) 
Lymphocyte count decreased  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  2/32 (6.25%)  2/48 (4.17%)  1/15 (6.67%) 
Weight increased  1  0/6 (0.00%)  1/18 (5.56%)  2/18 (11.11%)  1/32 (3.13%)  4/48 (8.33%)  1/15 (6.67%) 
Blood alkaline phosphatase increased  1  0/6 (0.00%)  2/18 (11.11%)  1/18 (5.56%)  1/32 (3.13%)  2/48 (4.17%)  1/15 (6.67%) 
Blood testosterone decreased  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  4/48 (8.33%)  1/15 (6.67%) 
Blood thyroid stimulating hormone decreased  1  0/6 (0.00%)  2/18 (11.11%)  1/18 (5.56%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Blood bilirubin increased  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  2/32 (6.25%)  0/48 (0.00%)  0/15 (0.00%) 
Blood lactate dehydrogenase increased  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  2/32 (6.25%)  1/48 (2.08%)  1/15 (6.67%) 
Blood thyroid stimulating hormone increased  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  1/32 (3.13%)  3/48 (6.25%)  0/15 (0.00%) 
Activated partial thromboplastin time prolonged  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Electrocardiogram QT prolonged  1  2/6 (33.33%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  2/48 (4.17%)  1/15 (6.67%) 
Bacterial test positive  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Ejection fraction decreased  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Heart rate increased  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Urinary sediment present  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Urine leukocyte esterase positive  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
White blood cells urine positive  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Blood creatinine increased  1  0/6 (0.00%)  2/18 (11.11%)  2/18 (11.11%)  4/32 (12.50%)  3/48 (6.25%)  1/15 (6.67%) 
Blood alkaline phosphatase decreased  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  0/48 (0.00%)  0/15 (0.00%) 
Blood magnesium decreased  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  1/15 (6.67%) 
Blood phosphorus decreased  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Blood sodium increased  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Electrocardiogram T wave abnormal  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Haematocrit decreased  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Haemoglobin decreased  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
White blood cell count increased.  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Metabolism and nutrition disorders             
Decreased appetite  1  0/6 (0.00%)  5/18 (27.78%)  1/18 (5.56%)  10/32 (31.25%)  12/48 (25.00%)  5/15 (33.33%) 
Hypophosphataemia  1  0/6 (0.00%)  0/18 (0.00%)  2/18 (11.11%)  7/32 (21.88%)  4/48 (8.33%)  1/15 (6.67%) 
Hypomagnesaemia  1  0/6 (0.00%)  0/18 (0.00%)  3/18 (16.67%)  4/32 (12.50%)  2/48 (4.17%)  3/15 (20.00%) 
Hypokalaemia  1  0/6 (0.00%)  3/18 (16.67%)  1/18 (5.56%)  5/32 (15.63%)  5/48 (10.42%)  3/15 (20.00%) 
Hyponatraemia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  4/32 (12.50%)  3/48 (6.25%)  1/15 (6.67%) 
Dehydration  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  1/32 (3.13%)  2/48 (4.17%)  1/15 (6.67%) 
Hyperglycaemia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  2/32 (6.25%)  2/48 (4.17%)  0/15 (0.00%) 
Increased appetite  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Hyperlipidaemia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Hypoalbuminaemia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  2/32 (6.25%)  1/48 (2.08%)  0/15 (0.00%) 
Gout  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Hyperuricaemia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Musculoskeletal and connective tissue disorders             
Muscle spasms  1  1/6 (16.67%)  1/18 (5.56%)  4/18 (22.22%)  8/32 (25.00%)  13/48 (27.08%)  3/15 (20.00%) 
Back pain  1  1/6 (16.67%)  3/18 (16.67%)  5/18 (27.78%)  11/32 (34.38%)  10/48 (20.83%)  1/15 (6.67%) 
Musculoskeletal pain  1  0/6 (0.00%)  2/18 (11.11%)  1/18 (5.56%)  3/32 (9.38%)  8/48 (16.67%)  3/15 (20.00%) 
Arthralgia  1  1/6 (16.67%)  4/18 (22.22%)  1/18 (5.56%)  10/32 (31.25%)  10/48 (20.83%)  0/15 (0.00%) 
Pain in extremity  1  1/6 (16.67%)  3/18 (16.67%)  3/18 (16.67%)  2/32 (6.25%)  3/48 (6.25%)  2/15 (13.33%) 
Musculoskeletal chest pain  1  2/6 (33.33%)  1/18 (5.56%)  1/18 (5.56%)  4/32 (12.50%)  3/48 (6.25%)  1/15 (6.67%) 
Joint swelling  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  5/32 (15.63%)  2/48 (4.17%)  0/15 (0.00%) 
Myalgia  1  0/6 (0.00%)  4/18 (22.22%)  1/18 (5.56%)  6/32 (18.75%)  3/48 (6.25%)  1/15 (6.67%) 
Bone pain  1  1/6 (16.67%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  6/48 (12.50%)  0/15 (0.00%) 
Musculoskeletal discomfort  1  0/6 (0.00%)  0/18 (0.00%)  2/18 (11.11%)  3/32 (9.38%)  2/48 (4.17%)  0/15 (0.00%) 
Flank pain  1  0/6 (0.00%)  2/18 (11.11%)  2/18 (11.11%)  3/32 (9.38%)  0/48 (0.00%)  0/15 (0.00%) 
Muscular weakness  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  5/32 (15.63%)  1/48 (2.08%)  0/15 (0.00%) 
Pain in jaw  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  2/15 (13.33%) 
Arthritis  1  1/6 (16.67%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  2/48 (4.17%)  0/15 (0.00%) 
Fracture pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  0/48 (0.00%)  0/15 (0.00%) 
Limb discomfort  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Musculoskeletal stiffness  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Groin pain  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Neck pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  0/48 (0.00%)  2/15 (13.33%) 
Osteopenia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Bursitis  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Tendonitis  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Pericardial effusion malignant  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  1/15 (6.67%) 
Melanocytic naevus  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Skin papilloma  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Tumour pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Basal cell carcinoma  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Dysplastic naevus  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Squamous cell carcinoma  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Nervous system disorders             
Headache  1  0/6 (0.00%)  8/18 (44.44%)  7/18 (38.89%)  14/32 (43.75%)  18/48 (37.50%)  6/15 (40.00%) 
Dizziness  1  0/6 (0.00%)  5/18 (27.78%)  1/18 (5.56%)  5/32 (15.63%)  3/48 (6.25%)  1/15 (6.67%) 
Peripheral sensory neuropathy  1  0/6 (0.00%)  1/18 (5.56%)  2/18 (11.11%)  6/32 (18.75%)  3/48 (6.25%)  0/15 (0.00%) 
Paraesthesia  1  1/6 (16.67%)  2/18 (11.11%)  1/18 (5.56%)  2/32 (6.25%)  3/48 (6.25%)  1/15 (6.67%) 
Dysgeusia  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  3/48 (6.25%)  1/15 (6.67%) 
Tremor  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  3/32 (9.38%)  3/48 (6.25%)  1/15 (6.67%) 
Amnesia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  2/32 (6.25%)  3/48 (6.25%)  0/15 (0.00%) 
Balance disorder  1  0/6 (0.00%)  2/18 (11.11%)  0/18 (0.00%)  2/32 (6.25%)  5/48 (10.42%)  0/15 (0.00%) 
Hypoaesthesia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  4/48 (8.33%)  1/15 (6.67%) 
Visual field defect  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  5/48 (10.42%)  1/15 (6.67%) 
Seizure  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  1/32 (3.13%)  1/48 (2.08%)  2/15 (13.33%) 
Aphasia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  3/48 (6.25%)  1/15 (6.67%) 
Disturbance in attention  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  2/32 (6.25%)  2/48 (4.17%)  0/15 (0.00%) 
Dysarthria  1  0/6 (0.00%)  2/18 (11.11%)  0/18 (0.00%)  0/32 (0.00%)  2/48 (4.17%)  0/15 (0.00%) 
Memory impairment  1  1/6 (16.67%)  1/18 (5.56%)  0/18 (0.00%)  2/32 (6.25%)  1/48 (2.08%)  0/15 (0.00%) 
Sinus headache  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  0/48 (0.00%)  0/15 (0.00%) 
Somnolence  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Syncope  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  1/15 (6.67%) 
Burning sensation  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Cognitive disorder  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Neuralgia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Parosmia  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Peripheral motor neuropathy  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Taste disorder  1  0/6 (0.00%)  2/18 (11.11%)  1/18 (5.56%)  1/32 (3.13%)  1/48 (2.08%)  1/15 (6.67%) 
Neuropathy peripheral  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Presyncope  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  0/48 (0.00%)  0/15 (0.00%) 
Dizziness postural  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Psychiatric disorders             
Insomnia  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  6/32 (18.75%)  6/48 (12.50%)  3/15 (20.00%) 
Anxiety  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  5/32 (15.63%)  2/48 (4.17%)  1/15 (6.67%) 
Depression  1  1/6 (16.67%)  0/18 (0.00%)  0/18 (0.00%)  4/32 (12.50%)  3/48 (6.25%)  0/15 (0.00%) 
Bruxism  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Anticipatory anxiety  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Confusional state  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  2/32 (6.25%)  1/48 (2.08%)  0/15 (0.00%) 
Disorientation  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Nervousness  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Stress  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Renal and urinary disorders             
Pollakiuria  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  2/32 (6.25%)  4/48 (8.33%)  0/15 (0.00%) 
Proteinuria  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  1/48 (2.08%)  2/15 (13.33%) 
Haematuria  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  2/32 (6.25%)  2/48 (4.17%)  0/15 (0.00%) 
Dysuria  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  2/48 (4.17%)  1/15 (6.67%) 
Renal failure  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Urinary retention  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Urinary tract pain  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Reproductive system and breast disorders             
Vulvovaginal dryness  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Nipple pain  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  0/15 (0.00%) 
Metrorrhagia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Breast pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  1/15 (6.67%) 
Respiratory, thoracic and mediastinal disorders             
Cough  1  1/6 (16.67%)  7/18 (38.89%)  6/18 (33.33%)  13/32 (40.63%)  14/48 (29.17%)  8/15 (53.33%) 
Dyspnoea  1  0/6 (0.00%)  4/18 (22.22%)  5/18 (27.78%)  7/32 (21.88%)  10/48 (20.83%)  4/15 (26.67%) 
Dyspnoea exertional  1  0/6 (0.00%)  1/18 (5.56%)  2/18 (11.11%)  1/32 (3.13%)  4/48 (8.33%)  1/15 (6.67%) 
Oropharyngeal pain  1  0/6 (0.00%)  2/18 (11.11%)  1/18 (5.56%)  5/32 (15.63%)  5/48 (10.42%)  2/15 (13.33%) 
Epistaxis  1  0/6 (0.00%)  2/18 (11.11%)  0/18 (0.00%)  1/32 (3.13%)  4/48 (8.33%)  2/15 (13.33%) 
Productive cough  1  0/6 (0.00%)  2/18 (11.11%)  1/18 (5.56%)  4/32 (12.50%)  5/48 (10.42%)  0/15 (0.00%) 
Nasal congestion  1  0/6 (0.00%)  2/18 (11.11%)  3/18 (16.67%)  0/32 (0.00%)  0/48 (0.00%)  3/15 (20.00%) 
Haemoptysis  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  2/48 (4.17%)  1/15 (6.67%) 
Hypoxia  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  1/32 (3.13%)  2/48 (4.17%)  2/15 (13.33%) 
Rhinorrhoea  1  1/6 (16.67%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  2/48 (4.17%)  0/15 (0.00%) 
Sinus congestion  1  1/6 (16.67%)  1/18 (5.56%)  0/18 (0.00%)  4/32 (12.50%)  1/48 (2.08%)  0/15 (0.00%) 
Dysphonia  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  1/32 (3.13%)  3/48 (6.25%)  1/15 (6.67%) 
Rhinitis allergic  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  1/32 (3.13%)  0/48 (0.00%)  0/15 (0.00%) 
Sputum discoloured  1  0/6 (0.00%)  1/18 (5.56%)  1/18 (5.56%)  1/32 (3.13%)  1/48 (2.08%)  0/15 (0.00%) 
Dry throat  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  1/15 (6.67%) 
Hiccups  1  0/6 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Laryngeal inflammation  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  2/32 (6.25%)  0/48 (0.00%)  0/15 (0.00%) 
Pleural effusion  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  1/15 (6.67%) 
Pleuritic pain  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  1/32 (3.13%)  0/48 (0.00%)  1/15 (6.67%) 
Throat irritation  1  0/6 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/32 (0.00%)  1/48 (2.08%)  0/15 (0.00%) 
Wheezing  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  2/15 (13.33%) 
Nasal dryness  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Pleurisy  1  0/6 (0.00%)  0/18 (0.00%)  0/18 (0.00%)  0/32 (0.00%)  0/48 (0.00%)  1/15 (6.67%) 
Pneumothorax