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Trial record 1 of 1 for:    B1871040
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Bosutinib Treatment Extension Study Only For Subjects With Chronic Myeloid Leukemia (CML) Who Have Previously Participated In Bosutinib Studies B1871006 Or B1871008

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ClinicalTrials.gov Identifier: NCT01903733
Recruitment Status : Completed
First Posted : July 19, 2013
Results First Posted : August 17, 2021
Last Update Posted : July 19, 2022
Sponsor:
Information provided by (Responsible Party):
Pfizer

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label)
Condition Chronic Myeloid Leukemia
Intervention Drug: bosutinib
Enrollment 281
Recruitment Details This study was offered to participants randomized to bosutinib arm in B1871008 (NCT00574873) or dosed with bosutinib in B1871006 (NCT00261846). Participants enrolled in this study were who in any of the parent studies (B1871008 or B1871006) at time of protocol approval 1) receiving bosutinib, benefiting per investigator, 2) discontinued bosutinib, being followed-up,3) completed parent study. Per enrolment criteria, 281 participants were enrolled in this study and 21 participants were from China.
Pre-assignment Details Per protocol data from 2 parent studies were combined with data from this study (B1871040) for all analyses. Reporting arms were based on parent study, disease phase and line of therapy (CP1L,CP2L,CP3L/CP4L,ADV).The B1871040 data from 21 participants enrolled in China were not included in results because the Human Genetics Resources Administration of China did not approve the use of the data in accordance with its regulations. This data has been excluded from all our analyses.
Arm/Group Title Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV
Hide Arm/Group Description Participants from B1871008 with Philadelphia chromosome-positive (Ph+) chronic phase 1st line (CP1L) chronic myeloid leukemia (CML) who either continued to receive the same bosutinib dose as at the time of completion of B1871008 or continued to be followed for survival. Dose for bosutinib was 500 milligram (mg) orally once daily (adjusted dose varied from 200 mg to 600 mg once daily). Treatment continued until the end of the study, disease progression, unacceptable toxicity, death, withdrawal of consent or study discontinuation whichever occurred first. Follow-up continued till end of the study or death due to any cause whichever occurred first. Participants remained in this study, either for treatment or for follow-up, until the last participant enrolled in 1 of the parent studies reached 10 years of follow-up, as calculated from the date of his/her first dose of bosutinib administered in parent study. Participants from B1871006 with Ph+ chronic phase 2nd line (CP2L) CML who were resistant or intolerant to imatinib either continued to receive the same bosutinib dose as at the time of completion of B1871006 or continued to be followed for survival. Dose for bosutinib was 500 mg orally once daily (adjusted dose varied from 200 mg to 600 mg once daily). Treatment continued until the end of the study, disease progression, unacceptable toxicity, death, withdrawal of consent or study discontinuation whichever occurred first. Follow-up continued till end of the study or death due to any cause whichever occurred first. Participants remained in this study, either for treatment or for follow-up, until the last participant enrolled in 1 of the parent studies reached 10 years of follow-up, as calculated from the date of his/her first dose of bosutinib administered in parent study. Participants from B1871006 with Ph+ chronic phase 3rd line (CP3L)/4th line (CP4L) CML who were resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib either continued to receive the same bosutinib dose as at the time of completion of B1871006 or continued to be followed for survival. Dose for bosutinib was 500 mg orally once daily (adjusted dose varied from 200 mg to 600 mg once daily). Treatment continued until the end of the study, disease progression, unacceptable toxicity, death, withdrawal of consent or study discontinuation whichever occurred first. Follow-up continued till end of the study or death due to any cause whichever occurred first. Participants remained in this study, either for treatment or for follow-up, until the last participant enrolled in 1 of the parent studies reached 10 years of follow-up, as calculated from the date of his/her first dose of bosutinib administered in parent study. Advanced (ADV) participants from B1871006 with Ph+ accelerated phase (AP), blast phase (BP) CML, Ph+ acute lymphoblastic leukemia (ALL) and resistant or intolerant to imatinib only or resistant or intolerant to imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) including dasatinib and/or nilotinib who either continued to receive the same bosutinib dose as at the time of completion of B1871008 or continued to be followed for survival. Dose for bosutinib was 500 mg orally once daily (adjusted dose varied from 200 mg to 600 mg once daily). Treatment continued until the end of the study, disease progression, unacceptable toxicity, death, withdrawal of consent or study discontinuation whichever occurred first. Follow-up continued till end of the study or death due to any cause whichever occurred first. Participants remained in this study, either for treatment or for follow-up, until the last participant enrolled in 1 of the parent studies reached 10 years of follow-up, as calculated from the date of his/her first dose of bosutinib administered in parent study.
Period Title: Overall Study
Started 250 284 119 167
Full Analysis Set [1] 250 284 119 167
Safety Analysis Set [2] 248 284 119 167
Enrolled in B1871040 124 90 28 18
Treated in B1871040 98 69 13 8
Completed 144 158 58 48
Not Completed 106 126 61 119
Reason Not Completed
Death             23             54             30             98
Participant refused further follow-up             35             38             13             9
Lost to Follow-up             18             19             6             9
Other             10             15             12             3
Missing             2             0             0             0
Investigator request             18             0             0             0
[1]
(participants randomized to bosutinib arm in B1871008 and all dosed participants in B1871006)
[2]
(all dosed participants in B1871008 and B1871006)
Arm/Group Title Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Total
Hide Arm/Group Description Participants from B1871008 with Philadelphia chromosome-positive (Ph+) chronic phase 1st line (CP1L) chronic myeloid leukemia (CML). Participants from B1871006 with Ph+ chronic phase 2nd line (CP2L) CML who were resistant or intolerant to imatinib. Participants from B1871006 with Ph+ chronic phase 3rd line (CP3L)/4th line (CP4L) CML who were resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib. Participants from B1871006 with Ph+ accelerated phase (AP), blast phase (BP) CML or Ph+ acute lymphoblastic leukemia (ALL) and resistant or intolerant to imatinib only or resistant and intolerant to imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) including dasatinib and/or nilotinib. Total of all reporting groups
Overall Number of Baseline Participants 250 284 119 167 820
Hide Baseline Analysis Population Description
The full analysis set included all participants randomized to the bosutinib arm from B1871008 and all dosed participants from B1871006.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 250 participants 284 participants 119 participants 167 participants 820 participants
47.9  (14.4) 51.9  (15.1) 55.1  (13.0) 50.1  (15.4) 50.8  (14.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 250 participants 284 participants 119 participants 167 participants 820 participants
Female
101
  40.4%
135
  47.5%
66
  55.5%
69
  41.3%
371
  45.2%
Male
149
  59.6%
149
  52.5%
53
  44.5%
98
  58.7%
449
  54.8%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 250 participants 284 participants 119 participants 167 participants 820 participants
American Indian or Alaska Native
0
   0.0%
1
   0.4%
0
   0.0%
0
   0.0%
1
   0.1%
Asian
83
  33.2%
61
  21.5%
15
  12.6%
37
  22.2%
196
  23.9%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
2
   0.8%
16
   5.6%
6
   5.0%
19
  11.4%
43
   5.2%
White
160
  64.0%
186
  65.5%
87
  73.1%
102
  61.1%
535
  65.2%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
5
   2.0%
20
   7.0%
11
   9.2%
9
   5.4%
45
   5.5%
1.Primary Outcome
Title Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 3.0)
Hide Description An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was any untoward medical occurrence at any dose that: resulted in death, was life threatening (immediate risk of death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions), resulted in congenital anomaly/birth defect. Treatment-emergent adverse events were defined as any event increasing in severity from baseline or any new event started during bosutinib therapy or within 30 days of the last dose of study drug.
Time Frame From first dose of drug up to 30 days after last dose (up to approximately 14 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set included all dosed participants for both B1871006 and B1871008.
Arm/Group Title Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Bosutinib, Total
Hide Arm/Group Description:
Participants from B1871008 with Philadelphia chromosome-positive (Ph+) chronic phase 1st line (CP1L) chronic myeloid leukemia (CML).
Participants from B1871006 with Ph+ chronic phase 2nd line (CP2L) CML who were resistant or intolerant to imatinib.
Participants from B1871006 with Ph+ chronic phase 3rd line (CP3L)/4th line (CP4L) CML who were resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib.
Participants from B1871006 with Ph+ accelerated phase (AP), blast phase (BP) CML or Ph+ acute lymphoblastic leukemia (ALL) and resistant or intolerant to imatinib only or resistant and intolerant to imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) including dasatinib and/or nilotinib.
Participants from B1871008 CP1L cohort and B1871006 CP2L, CP3L/CP4L and ADV cohorts.
Overall Number of Participants Analyzed 248 284 119 167 818
Measure Type: Count of Participants
Unit of Measure: Participants
Treatment-Emergent AEs
241
  97.2%
283
  99.6%
119
 100.0%
165
  98.8%
808
  98.8%
Treatment-emergent SAEs
102
  41.1%
124
  43.7%
44
  37.0%
98
  58.7%
368
  45.0%
2.Primary Outcome
Title Number of Participants With Grade 3 or 4 Treatment-Emergent Adverse Events (AEs) Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 3.0)
Hide Description An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AEs were assessed according to severity grading based on NCI CTCAE version 3.0. Grade 1 =mild; Grade 2 =moderate; Grade 3 =severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4 =life-threatening or disabling, urgent intervention indicated; Grade 5 =death. Treatment-emergent adverse events were defined as any event increasing in severity from baseline or any new event started during bosutinib therapy or within 30 days of the last dose of study drug.
Time Frame From first dose of drug up to 30 days after last dose (up to approximately 14 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set included all dosed participants for both B1871006 and B1871008.
Arm/Group Title Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Bosutinib, Total
Hide Arm/Group Description:
Participants from B1871008 with Philadelphia chromosome-positive (Ph+) chronic phase 1st line (CP1L) chronic myeloid leukemia (CML).
Participants from B1871006 with Ph+ chronic phase 2nd line (CP2L) CML who were resistant or intolerant to imatinib.
Participants from B1871006 with Ph+ chronic phase 3rd line (CP3L)/4th line (CP4L) CML who were resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib.
Participants from B1871006 with Ph+ accelerated phase (AP), blast phase (BP) CML or Ph+ acute lymphoblastic leukemia (ALL) and resistant or intolerant to imatinib only or resistant and intolerant to imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) including dasatinib and/or nilotinib.
Participants from B1871008 CP1L cohort and B1871006 CP2L, CP3L/CP4L and ADV cohorts.
Overall Number of Participants Analyzed 248 284 119 167 818
Measure Type: Count of Participants
Unit of Measure: Participants
191
  77.0%
223
  78.5%
84
  70.6%
144
  86.2%
642
  78.5%
3.Primary Outcome
Title Number of Participants With Treatment-Emergent Treatment Related Adverse Events (AEs) Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 3.0)
Hide Description An AE was any untoward medical occurrence in a participant who received study drug. Treatment-emergent adverse events were defined as any event increasing in severity from baseline or any new event started during bosutinib therapy or within 30 days of the last dose of study drug. Related TEAEs were those AEs who were related to the study treatment as judged by the investigator.
Time Frame From first dose of drug up to 30 days after last dose (up to approximately 14 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set included all dosed participants for both B1871006 and B1871008.
Arm/Group Title Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Bosutinib, Total
Hide Arm/Group Description:
Participants from B1871008 with Philadelphia chromosome-positive (Ph+) chronic phase 1st line (CP1L) chronic myeloid leukemia (CML).
Participants from B1871006 with Ph+ chronic phase 2nd line (CP2L) CML who were resistant or intolerant to imatinib.
Participants from B1871006 with Ph+ chronic phase 3rd line (CP3L)/4th line (CP4L) CML who were resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib.
Participants from B1871006 with Ph+ accelerated phase (AP), blast phase (BP) CML or Ph+ acute lymphoblastic leukemia (ALL) and resistant or intolerant to imatinib only or resistant and intolerant to imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) including dasatinib and/or nilotinib.
Participants from B1871008 CP1L cohort and B1871006 CP2L, CP3L/CP4L and ADV cohorts.
Overall Number of Participants Analyzed 248 284 119 167 818
Measure Type: Count of Participants
Unit of Measure: Participants
235
  94.8%
282
  99.3%
119
 100.0%
161
  96.4%
797
  97.4%
4.Primary Outcome
Title Number of Participants With Laboratory Test Abnormalities Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 4.03)
Hide Description Laboratory parameters included Chemistry: high alkaline phosphatase; high alanine aminotransferase; high aspartate aminotransferase; high blood bilirubin; high creatinine. Hematology: absolute neutrophils count decreased; anemia; platelet count decreased; white blood cells (WBC) decreased. Abnormalities in laboratory tests were graded per NCI CTCAE version 4.03 as Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling.
Time Frame From first dose of drug up to 30 days after last dose (up to approximately 14 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set included all dosed participants for both B1871006 and B1871008.
Arm/Group Title Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Bosutinib, Total
Hide Arm/Group Description:
Participants from B1871008 with Philadelphia chromosome-positive (Ph+) chronic phase 1st line (CP1L) chronic myeloid leukemia (CML).
Participants from B1871006 with Ph+ chronic phase 2nd line (CP2L) CML who were resistant or intolerant to imatinib.
Participants from B1871006 with Ph+ chronic phase 3rd line (CP3L)/4th line (CP4L) CML who were resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib.
Participants from B1871006 with Ph+ accelerated phase (AP), blast phase (BP) CML or Ph+ acute lymphoblastic leukemia (ALL) and resistant or intolerant to imatinib only or resistant and intolerant to imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) including dasatinib and/or nilotinib.
Participants from B1871008 CP1L cohort and B1871006 CP2L, CP3L/CP4L and ADV cohorts.
Overall Number of Participants Analyzed 248 284 119 167 818
Measure Type: Count of Participants
Unit of Measure: Participants
Grade 1
45
  18.1%
59
  20.8%
28
  23.5%
18
  10.8%
150
  18.3%
Grade 2
86
  34.7%
80
  28.2%
39
  32.8%
24
  14.4%
229
  28.0%
Grade 3
84
  33.9%
102
  35.9%
27
  22.7%
41
  24.6%
254
  31.1%
Grade 4
33
  13.3%
42
  14.8%
23
  19.3%
82
  49.1%
180
  22.0%
5.Primary Outcome
Title Number of Participants With Adverse Events as Reason for Treatment Discontinuation
Hide Description An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.
Time Frame From first dose of drug up to 30 days after last dose (up to approximately 14 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set included all dosed participants for both B1871006 and B1871008.
Arm/Group Title Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Bosutinib, Total
Hide Arm/Group Description:
Participants from B1871008 with Philadelphia chromosome-positive (Ph+) chronic phase 1st line (CP1L) chronic myeloid leukemia (CML).
Participants from B1871006 with Ph+ chronic phase 2nd line (CP2L) CML who were resistant or intolerant to imatinib.
Participants from B1871006 with Ph+ chronic phase 3rd line (CP3L)/4th line (CP4L) CML who were resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib.
Participants from B1871006 with Ph+ accelerated phase (AP), blast phase (BP) CML or Ph+ acute lymphoblastic leukemia (ALL) and resistant or intolerant to imatinib only or resistant and intolerant to imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) including dasatinib and/or nilotinib.
Participants from B1871008 CP1L cohort and B1871006 CP2L, CP3L/CP4L and ADV cohorts.
Overall Number of Participants Analyzed 248 284 119 167 818
Measure Type: Count of Participants
Unit of Measure: Participants
84
  33.9%
79
  27.8%
37
  31.1%
32
  19.2%
232
  28.4%
6.Primary Outcome
Title Number of Participants With Diarrhea After Switch From Bosutinib Clinical Formulation to Bosutinib Commercial Formulation
Hide Description The incidence of diarrhea was collected and analyzed before and after the switch from the clinical formulation of bosutinib to the commercial formulation of bosutinib.
Time Frame Last 6 months on clinical formulation and first 6 months on commercial formulation
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set included all dosed participants for both B1871006 and B1871008. Here, 'Overall number of participants analyzed'= participants evaluable for this outcome measure who received commercial formulation.
Arm/Group Title Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Bosutinib, Total
Hide Arm/Group Description:
Participants from B1871008 with Philadelphia chromosome-positive (Ph+) chronic phase 1st line (CP1L) chronic myeloid leukemia (CML).
Participants from B1871006 with Ph+ chronic phase 2nd line (CP2L) CML who were resistant or intolerant to imatinib.
Participants from B1871006 with Ph+ chronic phase 3rd line (CP3L)/4th line (CP4L) CML who were resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib.
Participants from B1871006 with Ph+ accelerated phase (AP), blast phase (BP) CML or Ph+ acute lymphoblastic leukemia (ALL) and resistant or intolerant to imatinib only or resistant and intolerant to imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) including dasatinib and/or nilotinib.
Participants from B1871008 CP1L cohort and B1871006 CP2L, CP3L/CP4L and ADV cohorts.
Overall Number of Participants Analyzed 119 82 13 8 222
Measure Type: Count of Participants
Unit of Measure: Participants
Clinical formulation (last 6 months)
25
  21.0%
22
  26.8%
3
  23.1%
5
  62.5%
55
  24.8%
Commercial formulation (first 6 months)
34
  28.6%
27
  32.9%
4
  30.8%
5
  62.5%
70
  31.5%
7.Primary Outcome
Title Number of Participants With Breakpoint Cluster Region Abelson Protooncogene (BCR-ABL) Mutations Present at Time of Bosutinib Treatment Discontinuation
Hide Description BCR-ABL is a gene resulting from the 9:22 chromosomal translocation (Philadelphia chromosome). In this outcome measure, the number of participants who had emergent mutation or new BCR-ABL mutations (participants who had a post-baseline mutation which was not present at baseline) were reported.
Time Frame Post-baseline on Day 1 (maximum up to 14 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The full analysis set included all participants randomized to the bosutinib arm from B1871008 and all dosed participants from B1871006.
Arm/Group Title Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV
Hide Arm/Group Description:
Participants from B1871008 with Philadelphia chromosome-positive (Ph+) chronic phase 1st line (CP1L) chronic myeloid leukemia (CML).
Participants from B1871006 with Ph+ chronic phase 2nd line (CP2L) CML who were resistant or intolerant to imatinib.
Participants from B1871006 with Ph+ chronic phase 3rd line (CP3L)/4th line (CP4L) CML who were resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib.
Participants from B1871006 with Ph+ accelerated phase (AP), blast phase (BP) CML or Ph+ acute lymphoblastic leukemia (ALL) and resistant or intolerant to imatinib only or resistant and intolerant to imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) including dasatinib and/or nilotinib.
Overall Number of Participants Analyzed 250 284 119 167
Measure Type: Count of Participants
Unit of Measure: Participants
7
   2.8%
28
   9.9%
13
  10.9%
14
   8.4%
8.Primary Outcome
Title Overall Survival (OS) Rate at Year 10
Hide Description OS was defined as the time from randomization (B1871008) and time from first dose (B1871006) to the occurrence of death due to any cause or censoring. Kaplan-Meier analysis was used for determination of OS. Percentage of participants who were alive were estimated in this outcome measure.
Time Frame Year 10
Hide Outcome Measure Data
Hide Analysis Population Description
The full analysis set included all participants randomized to the bosutinib arm from B1871008 and all dosed participants from B1871006.
Arm/Group Title Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV
Hide Arm/Group Description:
Participants from B1871008 with Philadelphia chromosome-positive (Ph+) chronic phase 1st line (CP1L) chronic myeloid leukemia (CML).
Participants from B1871006 with Ph+ chronic phase 2nd line (CP2L) CML who were resistant or intolerant to imatinib.
Participants from B1871006 with Ph+ chronic phase 3rd line (CP3L)/4th line (CP4L) CML who were resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib.
Participants from B1871006 with Ph+ accelerated phase (AP), blast phase (BP) CML or Ph+ acute lymphoblastic leukemia (ALL) and resistant or intolerant to imatinib only or resistant and intolerant to imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) including dasatinib and/or nilotinib.
Overall Number of Participants Analyzed 250 284 119 167
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
88.2
(83.3 to 93.2)
71.5
(64.4 to 78.7)
60.4
(47.2 to 73.7)
34.2
(25.0 to 43.4)
9.Primary Outcome
Title Plasma Steady-State Trough Concentrations (Ctrough) of Bosutinib
Hide Description Ctrough refers to plasma concentration of bosutinib observed just before treatment administration.
Time Frame One pre-dose sample was collected at the first scheduled visit (after approval and implementation of protocol amendment 1) following at least 2 weeks of uninterrupted dosing at the same dose level
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacokinetic (PK) analysis set included participants who received at least 1 dose of bosutinib and had 1 reported bosutinib concentration.
Arm/Group Title Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg Bosutinib 500 mg Bosutinib 600 mg
Hide Arm/Group Description:
Participants received uninterrupted once daily oral 200 mg dose of bosutinib for at least 2 weeks in study B1871040.
Participants received uninterrupted once daily oral 300 mg dose of bosutinib for at least 2 weeks in study B1871040.
Participants received uninterrupted once daily oral 400 mg dose of bosutinib for at least 2 weeks in study B1871040.
Participants received uninterrupted once daily oral 500 mg dose of bosutinib for at least 2 weeks in study B1871040.
Participants received uninterrupted once daily oral 600 mg dose of bosutinib for at least 2 weeks in study B1871040.
Overall Number of Participants Analyzed 6 28 23 69 8
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nanogram per milliliter
62.2
(31.3%)
62.0
(65.9%)
82.2
(53.2%)
93.3
(45.2%)
99.4
(78.2%)
10.Primary Outcome
Title Kaplan-Meier Estimate of Probability of Maintaining Major Cytogenetic Response (MCyR) at Year 10: B1871006 Participants
Hide Description Cytogenetic response (CyR) is based on prevalence of Ph+ cells. Duration for MCyR: time from first response to confirmed loss, progression of disease, or on-treatment death due to any cause, or censoring analyzed for responders only. Confirmed loss was defined as 2 consecutive non-responses at least 28 days apart. MCyR was categorized as either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). Response was achieved when there was 0% (CCyR) or 1-35% (PCyR) Ph+ cells analyzed from conventional cytogenetics based on the analysis of 20 to 100 metaphases or <1% (CCyR) or 1-35% (PCyR) Ph+ cells analyzed from fluorescence in-situ hybridization (FISH) based on analysis of at least 200 nuclei. CCyR may be imputed on a specific date if an MMR or better is achieved and denoted on the CRF on that date for B1871040 study visits. The Kaplan-Meier analysis was used to analyze percentage of participants maintaining MCyR at Year 10.
Time Frame Year 10
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Hide Analysis Population Description
The evaluable analysis set for cytogenetic population were those dosed participants from B1871006 with valid baseline efficacy assessment from B1871006 with >=20 metaphases or at least 1 Ph+ metaphase from baseline bone marrow cytogenetic assessment and who achieved MCyR (responders). "N"=evaluable participants. Data for this outcome measure was planned to be collected and analyzed for participants from B1871006 only and not for reporting arm "Bosutinib CP1L" (participants from B1871008).
Arm/Group Title Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV
Hide Arm/Group Description:
Participants from B1871006 with Ph+ chronic phase 2nd line (CP2L) CML who were resistant or intolerant to imatinib.
Participants from B1871006 with Ph+ chronic phase 3rd line (CP3L)/4th line (CP4L) CML who were resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib.
Participants from B1871006 with Ph+ accelerated phase (AP), blast phase (BP) CML or Ph+ acute lymphoblastic leukemia (ALL) and resistant or intolerant to imatinib only or resistant and intolerant to imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) including dasatinib and/or nilotinib.
Overall Number of Participants Analyzed 157 47 54
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
65.3
(56.6 to 74.0)
55.3
(36.3 to 74.4)
30.6
(16.4 to 44.7)
11.Primary Outcome
Title Kaplan-Meier Estimate of Probability of Maintaining Complete Cytogenetic Response (CCyR) at Year 10: B1871006 Participants
Hide Description Duration for CCyR was defined as time from first response to confirmed loss, progression of disease, or on-treatment death due to any cause, or censoring analyzed for responders only. Confirmed loss was defined as 2 consecutive assessments with >0 Ph+ metaphases or >=1% positive cells from FISH at least 28 days apart or progression or death. CCyR was achieved when there was 0% Ph+ cells analysed from conventional cytogenetics with 20 to 100 metaphases or <1% Ph+ cells analysed from FISH with at least 200 nuclei. CCyR may be imputed on a specific date if MMR or better is achieved and denoted on the CRF on that date for B1871040 study visits. The Kaplan-Meier analysis was used to analyze percentage of participants maintaining CCyR at Year 10.
Time Frame Year 10
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Hide Analysis Population Description
The evaluable analysis set for cytogenetic population were those dosed participants from B1871006 with a valid baseline efficacy assessment from B1871006 with >=20 metaphases or at least 1 Ph+ metaphase from the baseline bone marrow cytogenetic assessment and who achieved CCyR (responders). "N"=evaluable participants. Data for this outcome measure was planned to be collected and analyzed for participants from B1871006 only and not for reporting arm "Bosutinib CP1L" (participants from B1871008).
Arm/Group Title Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV
Hide Arm/Group Description:
Participants from B1871006 with Ph+ chronic phase 2nd line (CP2L) CML who were resistant or intolerant to imatinib.
Participants from B1871006 with Ph+ chronic phase 3rd line (CP3L)/4th line (CP4L) CML who were resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib.
Participants from B1871006 with Ph+ accelerated phase (AP), blast phase (BP) CML or Ph+ acute lymphoblastic leukemia (ALL) and resistant or intolerant to imatinib only or resistant and intolerant to imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) including dasatinib and/or nilotinib.
Overall Number of Participants Analyzed 130 36 42
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
63.4
(54.0 to 72.8)
40.8
(22.0 to 59.6)
29.6
(14.6 to 44.7)
12.Primary Outcome
Title Kaplan-Meier Estimate of Probability of Maintaining Complete Hematologic Response (CHR) at Year 10: B1871006 Participants
Hide Description Duration for CHR was defined as time from first response to confirmed loss, progression of disease, or on-treatment death due to any cause, or censoring analyzed for responders only. Confirmed loss was defined as 2 consecutive non-responses at least 14 days apart. Complete hematologic response was considered when participants met all of the following criteria: White blood cells equal to or less than (<=) institutional upper limit of normal (ULN), no blasts or promyelocytes in blood, <20% basophils in blood, no extramedullary involvement (including hepatomegaly or splenomegaly), myelocytes and metamyelocytes <5% in blood, platelets <450*10^9 per liter (/L). The following were applicable only to advanced phase: <=5% bone marrow blasts, absolute neutrophil count >=1.0*10^9/L, platelets >=100*10^9/L. The Kaplan-Meier analysis was used to analyze percentage of participants maintaining CHR at Year 10.
Time Frame Year 10
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Hide Analysis Population Description
The evaluable analysis set for hematologic population were those dosed participants from B1871006 with a valid baseline efficacy assessment from B1871006 and a valid baseline hematologic assessment and who achieved CHR (responders). "N"=evaluable participants. Data for this outcome measure was planned to be collected and analyzed for participants from B1871006 only and not for reporting arm "Bosutinib CP1L" (participants from B1871008).
Arm/Group Title Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV
Hide Arm/Group Description:
Participants from B1871006 with Ph+ chronic phase 2nd line (CP2L) CML who were resistant or intolerant to imatinib.
Participants from B1871006 with Ph+ chronic phase 3rd line (CP3L)/4th line (CP4L) CML who were resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib.
Participants from B1871006 with Ph+ accelerated phase (AP), blast phase (BP) CML or Ph+ acute lymphoblastic leukemia (ALL) and resistant or intolerant to imatinib only or resistant and intolerant to imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) including dasatinib and/or nilotinib.
Overall Number of Participants Analyzed 245 86 36
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
44.1
(35.2 to 52.9)
45.1
(29.3 to 60.9)
NA [1] 
(NA to NA)
[1]
The percentage and 95% CI was not estimable since BM blasts were not always assessed in later years for ADV participants.
13.Primary Outcome
Title Cumulative Incidence of Progression/Death Events at Year 10: B1871006 Participants
Hide Description Progression free survival (PFS):interval from date of first dose of bosutinib in parent study until earlier date of progression or death from any cause. Participants without events censored at last evaluation date. PD:evolution from CP (or return to CP for ADV participants) to AP or BP (on 2 consecutive assessments at least 1 week apart), evolution from AP to BP (on 2 consecutive assessments at least 1 week apart) and one of following conditions occurred after dose escalation or presence of AEs prohibiting dose escalation: for 2nd or later line, loss of MCyR (need at least 30% increase); for all lines of treatment, loss of CHR confirmed by 2 assessments >=2 weeks apart; for all lines of treatment, increasing WBC defined as doubling of WBC over a period of >=1 month with second WBC >20*10^9/L confirmed at least 1 week later. Percentage of participants with PFS/death events based on cumulative incidence method adjusting for competing event of treatment discontinuation without event.
Time Frame Year 10
Hide Outcome Measure Data
Hide Analysis Population Description
The full analysis set from B1871006 included all dosed participants from the study B1871006. Data for this outcome measure was planned to be collected and analyzed for participants from B1871006 only and not for reporting arm "Bosutinib CP1L" (participants from B1871008).
Arm/Group Title Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV
Hide Arm/Group Description:
Participants from B1871006 with Ph+ chronic phase 2nd line (CP2L) CML who were resistant or intolerant to imatinib.
Participants from B1871006 with Ph+ chronic phase 3rd line (CP3L)/4th line (CP4L) CML who were resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib.
Participants from B1871006 with Ph+ accelerated phase (AP), blast phase (BP) CML or Ph+ acute lymphoblastic leukemia (ALL) and resistant or intolerant to imatinib only or resistant and intolerant to imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) including dasatinib and/or nilotinib.
Overall Number of Participants Analyzed 284 119 167
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
23.9
(19.5 to 29.5)
26.9
(20.0 to 36.2)
55.7
(48.6 to 63.8)
14.Primary Outcome
Title Cumulative Incidence of Rate of Transformation to Accelerated Phase (AP) or Blast Phase (BP) at Year 10: B1871006 Participants
Hide Description Time to transformation was defined as the time from first dose in the parent study to the first date of confirmed transformation to AP or BP. Confirmed transformation was defined as 2 consecutive assessments at least 1 week apart or 1 assessment confirmed by progression of disease or death. For participants without transformation, censorship was at the last evaluation date. Percentage of participants with time to transformation to AP/BP was reported based on cumulative incidence method adjusting for the competing risk of treatment discontinuation without the event.
Time Frame Year 10
Hide Outcome Measure Data
Hide Analysis Population Description
The full analysis set from B1871006 included all dosed participants from the study B1871006. Data for this outcome measure was planned to be collected and analyzed for participants from B1871006 only and not for reporting arm "Bosutinib, CP1L" (participants from B1871008). For "Bosutinib ADV" reporting arm, data was analyzed for participants with AP who had BP transformation only.
Arm/Group Title Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV
Hide Arm/Group Description:
Participants from B1871006 with Ph+ chronic phase 2nd line (CP2L) CML who were resistant or intolerant to imatinib.
Participants from B1871006 with Ph+ chronic phase 3rd line (CP3L)/4th line (CP4L) CML who were resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib.
Participants from B1871006 with Ph+ accelerated phase (AP), blast phase (BP) CML or Ph+ acute lymphoblastic leukemia (ALL) and resistant or intolerant to imatinib only or resistant and intolerant to imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) including dasatinib and/or nilotinib.
Overall Number of Participants Analyzed 284 119 79
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
5.3
(3.2 to 8.6)
4.2
(1.8 to 9.9)
3.8
(1.3 to 11.5)
Time Frame From first dose of study drug and up to 30 days after last dose (up to approximately 14 years)
Adverse Event Reporting Description All-cause mortality: The total number of deaths during study, from randomization (B1871008)/first dose (B1871006) and up to the end of the study are reported for all treated participants and includes deaths which occurred after 30 days post last study drug dose. SAEs and other AEs: Analysis performed on safety set. Data from the 2 parent studies was combined with the data from this study for the analysis of safety as planned.
 
Arm/Group Title Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Bosutinib, Total
Hide Arm/Group Description Participants from B1871008 with Philadelphia chromosome-positive (Ph+) chronic phase 1st line (CP1L) chronic myeloid leukemia (CML). Participants from B1871006 with Ph+ chronic phase 2nd line (CP2L) CML who were resistant or intolerant to imatinib. Participants from B1871006 with Ph+ chronic phase 3rd line (CP3L)/4th line (CP4L) CML who were resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib. Participants from B1871006 with Ph+ accelerated phase (AP), blast phase (BP) CML or Ph+ acute lymphoblastic leukemia (ALL) and resistant or intolerant to imatinib only or resistant and intolerant to imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) including dasatinib and/or nilotinib. Participants from B1871008 CP1L cohort and B1871006 CP2L, CP3L/CP4L and ADV cohorts.
All-Cause Mortality
Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Bosutinib, Total
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   23/248 (9.27%)   55/284 (19.37%)   30/119 (25.21%)   98/167 (58.68%)   206/818 (25.18%) 
Hide Serious Adverse Events
Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Bosutinib, Total
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   102/248 (41.13%)   124/284 (43.66%)   44/119 (36.97%)   98/167 (58.68%)   368/818 (44.99%) 
Blood and lymphatic system disorders           
Thrombocytopenia * 1  6/248 (2.42%)  5/284 (1.76%)  1/119 (0.84%)  8/167 (4.79%)  20/818 (2.44%) 
Anaemia * 1  6/248 (2.42%)  3/284 (1.06%)  0/119 (0.00%)  6/167 (3.59%)  15/818 (1.83%) 
Febrile neutropenia * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  8/167 (4.79%)  9/818 (1.10%) 
Neutropenia * 1  2/248 (0.81%)  0/284 (0.00%)  4/119 (3.36%)  2/167 (1.20%)  8/818 (0.98%) 
Leukocytosis * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  3/167 (1.80%)  4/818 (0.49%) 
Hyperleukocytosis * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  2/167 (1.20%)  2/818 (0.24%) 
Granulocytopenia * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Iron deficiency anaemia * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Leukopenia * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Leukostasis syndrome * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Lymphadenopathy * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Pancytopenia * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Splenomegaly * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Cardiac disorders           
Pericardial effusion * 1  6/248 (2.42%)  5/284 (1.76%)  2/119 (1.68%)  2/167 (1.20%)  15/818 (1.83%) 
Cardiac failure congestive * 1  2/248 (0.81%)  6/284 (2.11%)  1/119 (0.84%)  1/167 (0.60%)  10/818 (1.22%) 
Atrial fibrillation * 1  1/248 (0.40%)  4/284 (1.41%)  3/119 (2.52%)  1/167 (0.60%)  9/818 (1.10%) 
Coronary artery disease * 1  3/248 (1.21%)  2/284 (0.70%)  2/119 (1.68%)  1/167 (0.60%)  8/818 (0.98%) 
Acute myocardial infarction * 1  1/248 (0.40%)  3/284 (1.06%)  1/119 (0.84%)  2/167 (1.20%)  7/818 (0.86%) 
Cardiac failure * 1  0/248 (0.00%)  4/284 (1.41%)  1/119 (0.84%)  1/167 (0.60%)  6/818 (0.73%) 
Pericarditis * 1  2/248 (0.81%)  1/284 (0.35%)  1/119 (0.84%)  1/167 (0.60%)  5/818 (0.61%) 
Angina pectoris * 1  0/248 (0.00%)  3/284 (1.06%)  1/119 (0.84%)  0/167 (0.00%)  4/818 (0.49%) 
Myocardial infarction * 1  0/248 (0.00%)  0/284 (0.00%)  3/119 (2.52%)  1/167 (0.60%)  4/818 (0.49%) 
Left ventricular dysfunction * 1  0/248 (0.00%)  2/284 (0.70%)  0/119 (0.00%)  1/167 (0.60%)  3/818 (0.37%) 
Angina unstable * 1  0/248 (0.00%)  2/284 (0.70%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Pericardial haemorrhage * 1  0/248 (0.00%)  2/284 (0.70%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Tachycardia * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  2/167 (1.20%)  2/818 (0.24%) 
Acute coronary syndrome * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Aortic valve stenosis * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Arrhythmia * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Arteriosclerosis coronary artery * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Bradycardia * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Bundle branch block right * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Cardiac disorder * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Cardiac failure acute * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Cardiorenal syndrome * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Coronary artery stenosis * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Cardiac arrest * 1  3/248 (1.21%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  4/818 (0.49%) 
Extrasystoles * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Hypertensive cardiomyopathy * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Palpitations * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Pleuropericarditis * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Ventricular fibrillation * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Congenital, familial and genetic disorders           
Cytogenetic abnormality * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Hydrocele * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Ear and labyrinth disorders           
Deafness unilateral * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Vestibular disorder * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Endocrine disorders           
Goitre * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Thyroid mass * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Eye disorders           
Glaucoma * 1  1/248 (0.40%)  1/284 (0.35%)  0/119 (0.00%)  1/167 (0.60%)  3/818 (0.37%) 
Cataract * 1  1/248 (0.40%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Visual impairment * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  2/818 (0.24%) 
Diplopia * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Retinopathy * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Retinopathy hypertensive * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Vitreous haemorrhage * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Gastrointestinal disorders           
Diarrhoea * 1  9/248 (3.63%)  8/284 (2.82%)  1/119 (0.84%)  4/167 (2.40%)  22/818 (2.69%) 
Abdominal pain * 1  3/248 (1.21%)  3/284 (1.06%)  0/119 (0.00%)  5/167 (2.99%)  11/818 (1.34%) 
Vomiting * 1  3/248 (1.21%)  2/284 (0.70%)  0/119 (0.00%)  5/167 (2.99%)  10/818 (1.22%) 
Nausea * 1  1/248 (0.40%)  0/284 (0.00%)  1/119 (0.84%)  6/167 (3.59%)  8/818 (0.98%) 
Gastritis * 1  3/248 (1.21%)  1/284 (0.35%)  1/119 (0.84%)  1/167 (0.60%)  6/818 (0.73%) 
Pancreatitis acute * 1  1/248 (0.40%)  3/284 (1.06%)  0/119 (0.00%)  1/167 (0.60%)  5/818 (0.61%) 
Gastrointestinal haemorrhage * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  3/167 (1.80%)  4/818 (0.49%) 
Inguinal hernia * 1  0/248 (0.00%)  3/284 (1.06%)  1/119 (0.84%)  0/167 (0.00%)  4/818 (0.49%) 
Pancreatitis * 1  2/248 (0.81%)  1/284 (0.35%)  0/119 (0.00%)  1/167 (0.60%)  4/818 (0.49%) 
Colitis * 1  0/248 (0.00%)  2/284 (0.70%)  1/119 (0.84%)  0/167 (0.00%)  3/818 (0.37%) 
Rectal haemorrhage * 1  0/248 (0.00%)  1/284 (0.35%)  1/119 (0.84%)  1/167 (0.60%)  3/818 (0.37%) 
Abdominal pain upper * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  1/167 (0.60%)  2/818 (0.24%) 
Gastric ulcer * 1  2/248 (0.81%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Gastrointestinal disorder * 1  2/248 (0.81%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Haematochezia * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  1/167 (0.60%)  2/818 (0.24%) 
Intestinal obstruction * 1  0/248 (0.00%)  2/284 (0.70%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Toothache * 1  0/248 (0.00%)  2/284 (0.70%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Abdominal adhesions * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Abdominal distension * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Abdominal pain lower * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Anal fistula * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Ascites * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Colitis ischaemic * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Dental caries * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Duodenal ulcer haemorrhage * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Dysphagia * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Enteritis * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Epigastric discomfort * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Faecaloma * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Food poisoning * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Gastric haemorrhage * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Gastric ulcer haemorrhage * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Gastritis erosive * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Gastritis haemorrhagic * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Gastrointestinal necrosis * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Gastrooesophageal reflux disease * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Haemorrhoids * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Ileus * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Intestinal haemorrhage * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Intestinal ischaemia * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Large intestinal stenosis * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Lower gastrointestinal haemorrhage * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Melaena * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Mesenteric artery embolism * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Oesophageal perforation * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Proctitis * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Rectal polyp * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Retroperitoneal haemorrhage * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Small intestinal obstruction * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Umbilical hernia * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
General disorders           
Pyrexia * 1  8/248 (3.23%)  8/284 (2.82%)  2/119 (1.68%)  11/167 (6.59%)  29/818 (3.55%) 
Disease progression * 1  0/248 (0.00%)  3/284 (1.06%)  1/119 (0.84%)  8/167 (4.79%)  12/818 (1.47%) 
Chest pain * 1  1/248 (0.40%)  3/284 (1.06%)  0/119 (0.00%)  4/167 (2.40%)  8/818 (0.98%) 
General physical health deterioration * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  6/167 (3.59%)  7/818 (0.86%) 
Asthenia * 1  0/248 (0.00%)  4/284 (1.41%)  0/119 (0.00%)  1/167 (0.60%)  5/818 (0.61%) 
Pain * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  2/167 (1.20%)  3/818 (0.37%) 
Chills * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  1/167 (0.60%)  2/818 (0.24%) 
Death * 1  1/248 (0.40%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Multiple organ dysfunction syndrome * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  2/167 (1.20%)  2/818 (0.24%) 
Oedema * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  1/167 (0.60%)  2/818 (0.24%) 
Adhesion * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Adverse drug reaction * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Malaise * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Mucosal inflammation * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Oedema peripheral * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Sudden death * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Swelling * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Hepatobiliary disorders           
Cholelithiasis * 1  2/248 (0.81%)  4/284 (1.41%)  0/119 (0.00%)  1/167 (0.60%)  7/818 (0.86%) 
Cholecystitis * 1  0/248 (0.00%)  1/284 (0.35%)  1/119 (0.84%)  1/167 (0.60%)  3/818 (0.37%) 
Cholecystitis acute * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  2/167 (1.20%)  3/818 (0.37%) 
Gallbladder disorder * 1  0/248 (0.00%)  2/284 (0.70%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Bile duct stone * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Cholecystitis chronic * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Drug-induced liver injury * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Gallbladder polyp * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Hepatic function abnormal * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Perforation bile duct * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Immune system disorders           
Drug hypersensitivity * 1  1/248 (0.40%)  1/284 (0.35%)  0/119 (0.00%)  1/167 (0.60%)  3/818 (0.37%) 
Anaphylactic shock * 1  2/248 (0.81%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Hypersensitivity * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Infections and infestations           
Pneumonia * 1  10/248 (4.03%)  15/284 (5.28%)  0/119 (0.00%)  19/167 (11.38%)  44/818 (5.38%) 
Sepsis * 1  1/248 (0.40%)  4/284 (1.41%)  1/119 (0.84%)  6/167 (3.59%)  12/818 (1.47%) 
Cellulitis * 1  3/248 (1.21%)  3/284 (1.06%)  1/119 (0.84%)  1/167 (0.60%)  8/818 (0.98%) 
Urinary tract infection * 1  2/248 (0.81%)  4/284 (1.41%)  0/119 (0.00%)  1/167 (0.60%)  7/818 (0.86%) 
Bronchitis * 1  2/248 (0.81%)  3/284 (1.06%)  1/119 (0.84%)  0/167 (0.00%)  6/818 (0.73%) 
Gastroenteritis * 1  3/248 (1.21%)  3/284 (1.06%)  0/119 (0.00%)  0/167 (0.00%)  6/818 (0.73%) 
Influenza * 1  0/248 (0.00%)  4/284 (1.41%)  1/119 (0.84%)  1/167 (0.60%)  6/818 (0.73%) 
Upper respiratory tract infection * 1  1/248 (0.40%)  2/284 (0.70%)  1/119 (0.84%)  0/167 (0.00%)  4/818 (0.49%) 
Appendicitis * 1  1/248 (0.40%)  1/284 (0.35%)  1/119 (0.84%)  0/167 (0.00%)  3/818 (0.37%) 
Atypical pneumonia * 1  1/248 (0.40%)  2/284 (0.70%)  0/119 (0.00%)  0/167 (0.00%)  3/818 (0.37%) 
Bacteraemia * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  3/167 (1.80%)  3/818 (0.37%) 
Clostridium difficile colitis * 1  0/248 (0.00%)  2/284 (0.70%)  1/119 (0.84%)  0/167 (0.00%)  3/818 (0.37%) 
Infection * 1  1/248 (0.40%)  2/284 (0.70%)  0/119 (0.00%)  0/167 (0.00%)  3/818 (0.37%) 
Appendicitis perforated * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  2/818 (0.24%) 
Device related infection * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  1/167 (0.60%)  2/818 (0.24%) 
Erysipelas * 1  0/248 (0.00%)  2/284 (0.70%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Gastroenteritis viral * 1  0/248 (0.00%)  2/284 (0.70%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Infectious pleural effusion * 1  1/248 (0.40%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Large intestine infection * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  2/818 (0.24%) 
Pharyngitis * 1  1/248 (0.40%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Pyelonephritis acute * 1  0/248 (0.00%)  2/284 (0.70%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Septic shock * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  1/167 (0.60%)  2/818 (0.24%) 
Sinusitis * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  1/167 (0.60%)  2/818 (0.24%) 
Staphylococcal bacteraemia * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  1/167 (0.60%)  2/818 (0.24%) 
Tooth abscess * 1  1/248 (0.40%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Tooth infection * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  2/818 (0.24%) 
Urinary tract infection bacterial * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  2/167 (1.20%)  2/818 (0.24%) 
Abscess limb * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Arthritis bacterial * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Arthritis infective * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Bacterial sepsis * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Brain abscess * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Bronchiolitis * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Catheter bacteraemia * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Cellulitis of male external genital organ * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Clostridium difficile infection * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Cystitis * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Dengue fever * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Dermatitis infected * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Diverticulitis * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Eczema infected * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Enterococcal sepsis * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Enterocolitis infectious * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Escherichia bacteraemia * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Escherichia sepsis * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Febrile infection * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Fungal infection * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Gastrointestinal infection * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Gingival abscess * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Hepatitis A * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Infected dermal cyst * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Kidney infection * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Malaria * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Meningitis * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Orchitis * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Perirectal abscess * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Pharyngotonsillitis * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Pneumonia bacterial * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Pneumonia fungal * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Pneumonia necrotising * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Post procedural infection * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Pseudomembranous colitis * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Pseudomonal sepsis * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Pulmonary mycosis * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Pyelonephritis * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Salmonella bacteraemia * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Salmonellosis * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Staphylococcal sepsis * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Streptococcal sepsis * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Subcutaneous abscess * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Injury, poisoning and procedural complications           
Contusion * 1  1/248 (0.40%)  2/284 (0.70%)  0/119 (0.00%)  0/167 (0.00%)  3/818 (0.37%) 
Facial bones fracture * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  2/818 (0.24%) 
Road traffic accident * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  1/167 (0.60%)  2/818 (0.24%) 
Subdural haematoma * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  1/167 (0.60%)  2/818 (0.24%) 
Upper limb fracture * 1  0/248 (0.00%)  2/284 (0.70%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Abdominal injury * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Cervical vertebral fracture * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Clavicle fracture * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Exposure during pregnancy * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Failure to anastomose * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Fall * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Fibula fracture * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Gastrointestinal stoma complication * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Humerus fracture * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Injury * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Lower limb fracture * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Muscle injury * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Overdose * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Post procedural complication * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Post procedural haematoma * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Post procedural haematuria * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Post procedural swelling * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Procedural haemorrhage * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Rib fracture * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Seroma * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Skin laceration * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Skull fracture * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Subdural haemorrhage * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Tooth fracture * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Transfusion reaction * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Traumatic lung injury * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Vascular pseudoaneurysm * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Wound haematoma * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Investigations           
Alanine aminotransferase increased * 1  8/248 (3.23%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  9/818 (1.10%) 
Aspartate aminotransferase increased * 1  4/248 (1.61%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  5/818 (0.61%) 
Blood bilirubin increased * 1  1/248 (0.40%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Blood creatinine increased * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  2/818 (0.24%) 
Lipase increased * 1  1/248 (0.40%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Amylase increased * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Blood creatine phosphokinase increased * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Blood glucose increased * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Blood lactate dehydrogenase increased * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Blood pressure increased * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Hepatic enzyme increased * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Intraocular pressure increased * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Liver function test increased * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Transaminases increased * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Weight decreased * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Metabolism and nutrition disorders           
Dehydration * 1  2/248 (0.81%)  2/284 (0.70%)  1/119 (0.84%)  3/167 (1.80%)  8/818 (0.98%) 
Failure to thrive * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  3/167 (1.80%)  3/818 (0.37%) 
Gout * 1  1/248 (0.40%)  1/284 (0.35%)  0/119 (0.00%)  1/167 (0.60%)  3/818 (0.37%) 
Fluid retention * 1  0/248 (0.00%)  1/284 (0.35%)  1/119 (0.84%)  0/167 (0.00%)  2/818 (0.24%) 
Hypoglycaemia * 1  0/248 (0.00%)  2/284 (0.70%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Acidosis * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Decreased appetite * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Hyperglycaemia * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Hypophosphataemia * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Hypovolaemia * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Musculoskeletal and connective tissue disorders           
Back pain * 1  2/248 (0.81%)  2/284 (0.70%)  2/119 (1.68%)  0/167 (0.00%)  6/818 (0.73%) 
Gouty arthritis * 1  1/248 (0.40%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Intervertebral disc disorder * 1  2/248 (0.81%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Osteoarthritis * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  1/167 (0.60%)  2/818 (0.24%) 
Spinal osteoarthritis * 1  1/248 (0.40%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Arthralgia * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Bone cyst * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Bone pain * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Groin pain * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Intervertebral disc protrusion * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Joint range of motion decreased * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Lumbar spinal stenosis * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Mandibular mass * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Musculoskeletal stiffness * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Myalgia * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Myositis * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Neck pain * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Osteochondrosis * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Osteonecrosis * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Pain in extremity * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Rotator cuff syndrome * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Spinal stenosis * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Synovitis * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)           
Blast cell crisis * 1  1/248 (0.40%)  3/284 (1.06%)  0/119 (0.00%)  2/167 (1.20%)  6/818 (0.73%) 
Adenocarcinoma gastric * 1  3/248 (1.21%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  3/818 (0.37%) 
Basal cell carcinoma * 1  1/248 (0.40%)  2/284 (0.70%)  0/119 (0.00%)  0/167 (0.00%)  3/818 (0.37%) 
Blast crisis in myelogenous leukaemia * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  3/167 (1.80%)  3/818 (0.37%) 
Squamous cell carcinoma of skin * 1  0/248 (0.00%)  2/284 (0.70%)  0/119 (0.00%)  1/167 (0.60%)  3/818 (0.37%) 
Chronic myeloid leukaemia * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  1/167 (0.60%)  2/818 (0.24%) 
Squamous cell carcinoma * 1  0/248 (0.00%)  1/284 (0.35%)  1/119 (0.84%)  0/167 (0.00%)  2/818 (0.24%) 
Angiomyolipoma * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Anogenital warts * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Bladder squamous cell carcinoma stage unspecified * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Bowen's disease * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Central nervous system leukaemia * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Chloroma * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Cholangiocarcinoma * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Chronic myelomonocytic leukaemia * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Colon cancer * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Colon cancer metastatic * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Follicle centre lymphoma, follicular grade I, II, III * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Gastric cancer * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Invasive ductal breast carcinoma * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Keratoacanthoma * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Laryngeal neoplasm * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Leukaemia * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Lipoma * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Lung adenocarcinoma * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Malignant melanoma * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Melanocytic naevus * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Neoplasm prostate * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Neoplasm skin * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Non-small cell lung cancer * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Paraproteinaemia * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Prostate cancer * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Uterine leiomyoma * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Nervous system disorders           
Headache * 1  3/248 (1.21%)  0/284 (0.00%)  2/119 (1.68%)  8/167 (4.79%)  13/818 (1.59%) 
Syncope * 1  1/248 (0.40%)  4/284 (1.41%)  0/119 (0.00%)  0/167 (0.00%)  5/818 (0.61%) 
Cerebrovascular accident * 1  2/248 (0.81%)  1/284 (0.35%)  0/119 (0.00%)  1/167 (0.60%)  4/818 (0.49%) 
Subarachnoid haemorrhage * 1  0/248 (0.00%)  2/284 (0.70%)  0/119 (0.00%)  2/167 (1.20%)  4/818 (0.49%) 
Cerebral haemorrhage * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  2/167 (1.20%)  3/818 (0.37%) 
Cerebral infarction * 1  0/248 (0.00%)  2/284 (0.70%)  0/119 (0.00%)  1/167 (0.60%)  3/818 (0.37%) 
Cerebellar infarction * 1  0/248 (0.00%)  2/284 (0.70%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Dizziness * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  2/818 (0.24%) 
Nervous system disorder * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  2/167 (1.20%)  2/818 (0.24%) 
Paraesthesia * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  1/167 (0.60%)  2/818 (0.24%) 
Seizure * 1  2/248 (0.81%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Carotid arteriosclerosis * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Carpal tunnel syndrome * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Encephalitis post varicella * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Encephalopathy * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Epilepsy * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Hemiparesis * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Intraventricular haemorrhage * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Ischaemic stroke * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Loss of consciousness * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Monoparesis * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Parkinson's disease * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Partial seizures * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Radiculopathy * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Speech disorder * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Trigeminal neuralgia * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Pregnancy, puerperium and perinatal conditions           
Pregnancy * 1  2/248 (0.81%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Psychiatric disorders           
Mental status changes * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  1/167 (0.60%)  2/818 (0.24%) 
Anxiety * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Completed suicide * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Confusional state * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Depression * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Disorientation * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Dissociative disorder * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Hallucination * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Hallucination, visual * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Renal and urinary disorders           
Acute kidney injury * 1  5/248 (2.02%)  6/284 (2.11%)  1/119 (0.84%)  3/167 (1.80%)  15/818 (1.83%) 
Renal failure * 1  1/248 (0.40%)  2/284 (0.70%)  1/119 (0.84%)  1/167 (0.60%)  5/818 (0.61%) 
Haematuria * 1  1/248 (0.40%)  2/284 (0.70%)  0/119 (0.00%)  0/167 (0.00%)  3/818 (0.37%) 
Calculus urinary * 1  2/248 (0.81%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Calculus bladder * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Chronic kidney disease * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Cystitis haemorrhagic * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
End stage renal disease * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Nephrolithiasis * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Prerenal failure * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Renal artery stenosis * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Renal disorder * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Renal impairment * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Tubulointerstitial nephritis * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Urinary retention * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Reproductive system and breast disorders           
Menorrhagia * 1  0/248 (0.00%)  2/284 (0.70%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Breast hyperplasia * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Cervical dysplasia * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Dysfunctional uterine bleeding * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Metrorrhagia * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Pelvic pain * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Vaginal haemorrhage * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Respiratory, thoracic and mediastinal disorders           
Pleural effusion * 1  12/248 (4.84%)  15/284 (5.28%)  8/119 (6.72%)  8/167 (4.79%)  43/818 (5.26%) 
Dyspnoea * 1  1/248 (0.40%)  7/284 (2.46%)  3/119 (2.52%)  5/167 (2.99%)  16/818 (1.96%) 
Pneumonitis * 1  1/248 (0.40%)  2/284 (0.70%)  1/119 (0.84%)  2/167 (1.20%)  6/818 (0.73%) 
Respiratory failure * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  5/167 (2.99%)  6/818 (0.73%) 
Pulmonary hypertension * 1  3/248 (1.21%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  4/818 (0.49%) 
Pulmonary oedema * 1  0/248 (0.00%)  1/284 (0.35%)  1/119 (0.84%)  1/167 (0.60%)  3/818 (0.37%) 
Acute pulmonary oedema * 1  2/248 (0.81%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Asthma * 1  0/248 (0.00%)  2/284 (0.70%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Chronic obstructive pulmonary disease * 1  1/248 (0.40%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Interstitial lung disease * 1  2/248 (0.81%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Lung disorder * 1  1/248 (0.40%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Pleuritic pain * 1  1/248 (0.40%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  2/818 (0.24%) 
Acute respiratory failure * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Bronchiectasis * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Bronchitis chronic * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Dyspnoea exertional * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Haemoptysis * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Lung infiltration * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Organising pneumonia * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Pleurisy * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Pneumonia aspiration * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Pulmonary embolism * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Pulmonary fibrosis * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Respiratory arrest * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Vocal cord polyp * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Skin and subcutaneous tissue disorders           
Rash * 1  1/248 (0.40%)  8/284 (2.82%)  1/119 (0.84%)  1/167 (0.60%)  11/818 (1.34%) 
Urticaria * 1  1/248 (0.40%)  0/284 (0.00%)  2/119 (1.68%)  1/167 (0.60%)  4/818 (0.49%) 
Angioedema * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Circumoral oedema * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Dermatitis * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Erythema multiforme * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Rash maculo-papular * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Skin disorder * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Skin lesion * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Social circumstances           
Pregnancy of partner * 1  2/248 (0.81%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  3/818 (0.37%) 
Surgical and medical procedures           
Allogenic bone marrow transplantation therapy * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Cyst removal * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Knee arthroplasty * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  1/167 (0.60%)  1/818 (0.12%) 
Vascular disorders           
Hypertension * 1  1/248 (0.40%)  2/284 (0.70%)  0/119 (0.00%)  1/167 (0.60%)  4/818 (0.49%) 
Hypotension * 1  0/248 (0.00%)  0/284 (0.00%)  0/119 (0.00%)  2/167 (1.20%)  2/818 (0.24%) 
Aortic stenosis * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Haemorrhage * 1  1/248 (0.40%)  0/284 (0.00%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Hypertensive crisis * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Peripheral arterial occlusive disease * 1  0/248 (0.00%)  0/284 (0.00%)  1/119 (0.84%)  0/167 (0.00%)  1/818 (0.12%) 
Thrombosis * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
Venous thrombosis * 1  0/248 (0.00%)  1/284 (0.35%)  0/119 (0.00%)  0/167 (0.00%)  1/818 (0.12%) 
1
Term from vocabulary, MedDRA v23.0
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Bosutinib, Total
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   239/248 (96.37%)   283/284 (99.65%)   119/119 (100.00%)   164/167 (98.20%)   805/818 (98.41%) 
Blood and lymphatic system disorders           
Thrombocytopenia * 1  80/248 (32.26%)  117/284 (41.20%)  45/119 (37.82%)  69/167 (41.32%)  311/818 (38.02%) 
Anaemia * 1  72/248 (29.03%)  87/284 (30.63%)  28/119 (23.53%)  64/167 (38.32%)  251/818 (30.68%) 
Neutropenia * 1  35/248 (14.11%)  46/284 (16.20%)  23/119 (19.33%)  35/167 (20.96%)  139/818 (16.99%) 
Leukopenia * 1  25/248 (10.08%)  37/284 (13.03%)  5/119 (4.20%)  25/167 (14.97%)  92/818 (11.25%) 
Gastrointestinal disorders           
Diarrhoea * 1  177/248 (71.37%)  244/284 (85.92%)  99/119 (83.19%)  124/167 (74.25%)  644/818 (78.73%) 
Nausea * 1  89/248 (35.89%)  132/284 (46.48%)  58/119 (48.74%)  78/167 (46.71%)  357/818 (43.64%) 
Vomiting * 1  88/248 (35.48%)  106/284 (37.32%)  47/119 (39.50%)  72/167 (43.11%)  313/818 (38.26%) 
Abdominal pain * 1  39/248 (15.73%)  77/284 (27.11%)  28/119 (23.53%)  34/167 (20.36%)  178/818 (21.76%) 
Abdominal pain upper * 1  40/248 (16.13%)  59/284 (20.77%)  21/119 (17.65%)  16/167 (9.58%)  136/818 (16.63%) 
Constipation * 1  18/248 (7.26%)  44/284 (15.49%)  16/119 (13.45%)  28/167 (16.77%)  106/818 (12.96%) 
Dyspepsia * 1  22/248 (8.87%)  29/284 (10.21%)  12/119 (10.08%)  12/167 (7.19%)  75/818 (9.17%) 
Toothache * 1  14/248 (5.65%)  19/284 (6.69%)  5/119 (4.20%)  3/167 (1.80%)  41/818 (5.01%) 
General disorders           
Pyrexia * 1  50/248 (20.16%)  79/284 (27.82%)  17/119 (14.29%)  59/167 (35.33%)  205/818 (25.06%) 
Fatigue * 1  42/248 (16.94%)  73/284 (25.70%)  27/119 (22.69%)  35/167 (20.96%)  177/818 (21.64%) 
Asthenia * 1  26/248 (10.48%)  45/284 (15.85%)  10/119 (8.40%)  19/167 (11.38%)  100/818 (12.22%) 
Oedema peripheral * 1  17/248 (6.85%)  32/284 (11.27%)  13/119 (10.92%)  18/167 (10.78%)  80/818 (9.78%) 
Pain * 1  7/248 (2.82%)  22/284 (7.75%)  7/119 (5.88%)  12/167 (7.19%)  48/818 (5.87%) 
Oedema * 1  15/248 (6.05%)  16/284 (5.63%)  4/119 (3.36%)  9/167 (5.39%)  44/818 (5.38%) 
Chest pain * 1  7/248 (2.82%)  21/284 (7.39%)  4/119 (3.36%)  11/167 (6.59%)  43/818 (5.26%) 
Infections and infestations           
Nasopharyngitis * 1  30/248 (12.10%)  40/284 (14.08%)  14/119 (11.76%)  9/167 (5.39%)  93/818 (11.37%) 
Upper respiratory tract infection * 1  39/248 (15.73%)  32/284 (11.27%)  12/119 (10.08%)  10/167 (5.99%)  93/818 (11.37%) 
Influenza * 1  26/248 (10.48%)  30/284 (10.56%)  13/119 (10.92%)  6/167 (3.59%)  75/818 (9.17%) 
Urinary tract infection * 1  15/248 (6.05%)  31/284 (10.92%)  7/119 (5.88%)  2/167 (1.20%)  55/818 (6.72%) 
Bronchitis * 1  17/248 (6.85%)  16/284 (5.63%)  7/119 (5.88%)  6/167 (3.59%)  46/818 (5.62%) 
Investigations           
Alanine aminotransferase increased * 1  90/248 (36.29%)  67/284 (23.59%)  19/119 (15.97%)  17/167 (10.18%)  193/818 (23.59%) 
Aspartate aminotransferase increased * 1  74/248 (29.84%)  59/284 (20.77%)  10/119 (8.40%)  17/167 (10.18%)  160/818 (19.56%) 
Lipase increased * 1  52/248 (20.97%)  29/284 (10.21%)  8/119 (6.72%)  9/167 (5.39%)  98/818 (11.98%) 
Blood creatinine increased * 1  23/248 (9.27%)  36/284 (12.68%)  16/119 (13.45%)  10/167 (5.99%)  85/818 (10.39%) 
Weight decreased * 1  16/248 (6.45%)  36/284 (12.68%)  7/119 (5.88%)  9/167 (5.39%)  68/818 (8.31%) 
Amylase increased * 1  30/248 (12.10%)  18/284 (6.34%)  6/119 (5.04%)  5/167 (2.99%)  59/818 (7.21%) 
Blood creatine phosphokinase increased * 1  23/248 (9.27%)  18/284 (6.34%)  2/119 (1.68%)  3/167 (1.80%)  46/818 (5.62%) 
Blood alkaline phosphatase increased * 1  20/248 (8.06%)  10/284 (3.52%)  6/119 (5.04%)  9/167 (5.39%)  45/818 (5.50%) 
Metabolism and nutrition disorders           
Decreased appetite * 1  23/248 (9.27%)  41/284 (14.44%)  15/119 (12.61%)  21/167 (12.57%)  100/818 (12.22%) 
Hypophosphataemia * 1  26/248 (10.48%)  12/284 (4.23%)  3/119 (2.52%)  10/167 (5.99%)  51/818 (6.23%) 
Hypokalaemia * 1  10/248 (4.03%)  16/284 (5.63%)  5/119 (4.20%)  10/167 (5.99%)  41/818 (5.01%) 
Musculoskeletal and connective tissue disorders           
Arthralgia * 1  32/248 (12.90%)  55/284 (19.37%)  21/119 (17.65%)  24/167 (14.37%)  132/818 (16.14%) 
Back pain * 1  26/248 (10.48%)  43/284 (15.14%)  15/119 (12.61%)  16/167 (9.58%)  100/818 (12.22%) 
Pain in extremity * 1  23/248 (9.27%)  35/284 (12.32%)  10/119 (8.40%)  19/167 (11.38%)  87/818 (10.64%) 
Myalgia * 1  16/248 (6.45%)  26/284 (9.15%)  6/119 (5.04%)  14/167 (8.38%)  62/818 (7.58%) 
Bone pain * 1  11/248 (4.44%)  20/284 (7.04%)  9/119 (7.56%)  11/167 (6.59%)  51/818 (6.23%) 
Musculoskeletal pain * 1  12/248 (4.84%)  11/284 (3.87%)  12/119 (10.08%)  9/167 (5.39%)  44/818 (5.38%) 
Muscle spasms * 1  14/248 (5.65%)  14/284 (4.93%)  8/119 (6.72%)  7/167 (4.19%)  43/818 (5.26%) 
Nervous system disorders           
Headache * 1  41/248 (16.53%)  54/284 (19.01%)  31/119 (26.05%)  30/167 (17.96%)  156/818 (19.07%) 
Dizziness * 1  25/248 (10.08%)  26/284 (9.15%)  18/119 (15.13%)  21/167 (12.57%)  90/818 (11.00%) 
Psychiatric disorders           
Insomnia * 1  12/248 (4.84%)  10/284 (3.52%)  10/119 (8.40%)  15/167 (8.98%)  47/818 (5.75%) 
Respiratory, thoracic and mediastinal disorders           
Cough * 1  32/248 (12.90%)  70/284 (24.65%)  26/119 (21.85%)  33/167 (19.76%)  161/818 (19.68%) 
Dyspnoea * 1  25/248 (10.08%)  34/284 (11.97%)  13/119 (10.92%)  30/167 (17.96%)  102/818 (12.47%) 
Pleural effusion * 1  26/248 (10.48%)  32/284 (11.27%)  20/119 (16.81%)  14/167 (8.38%)  92/818 (11.25%) 
Oropharyngeal pain * 1  15/248 (6.05%)  37/284 (13.03%)  11/119 (9.24%)  13/167 (7.78%)  76/818 (9.29%) 
Skin and subcutaneous tissue disorders           
Rash * 1  65/248 (26.21%)  105/284 (36.97%)  34/119 (28.57%)  52/167 (31.14%)  256/818 (31.30%) 
Pruritus * 1  20/248 (8.06%)  29/284 (10.21%)  20/119 (16.81%)  10/167 (5.99%)  79/818 (9.66%) 
Dry skin * 1  10/248 (4.03%)  22/284 (7.75%)  8/119 (6.72%)  4/167 (2.40%)  44/818 (5.38%) 
Vascular disorders           
Hypertension * 1  24/248 (9.68%)  30/284 (10.56%)  10/119 (8.40%)  11/167 (6.59%)  75/818 (9.17%) 
1
Term from vocabulary, MedDRA v23.0
*
Indicates events were collected by non-systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Pfizer ClinicalTrials.gov Call Center
Organization: Pfizer Inc.
Phone: 1-800-718-1021
EMail: ClinicalTrials.gov_Inquiries@pfizer.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01903733    
Other Study ID Numbers: B1871040
2013-000691-15 ( EudraCT Number )
First Submitted: July 16, 2013
First Posted: July 19, 2013
Results First Submitted: June 7, 2021
Results First Posted: August 17, 2021
Last Update Posted: July 19, 2022