Bosutinib Treatment Extension Study Only For Subjects With Chronic Myeloid Leukemia (CML) Who Have Previously Participated In Bosutinib Studies B1871006 Or B1871008

Sponsor
Pfizer (Industry)
Overall Status
Completed
CT.gov ID
NCT01903733
Collaborator
(none)
281
91
81.2
3.1
0

Study Details

Study Description

Brief Summary

The objective of the study is to provide long term access to bosutinib treatment and assess long term safety, tolerability and duration of clinical benefit, without any formal hypothesis testing; therefore, there is no formal primary endpoint.

Condition or Disease Intervention/Treatment Phase
N/A

Study Design

Study Type:
Interventional
Actual Enrollment :
281 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Official Title:
AN OPEN-LABEL BOSUTINIB TREATMENT EXTENSION STUDY FOR SUBJECTS WITH CHRONIC MYELOID LEUKEMIA (CML) WHO HAVE PREVIOUSLY PARTICIPATED IN BOSUTINIB STUDIES B1871006 OR B1871008
Actual Study Start Date :
Aug 28, 2013
Actual Primary Completion Date :
Jun 5, 2020
Actual Study Completion Date :
Jun 5, 2020

Outcome Measures

Primary Outcome Measures

  1. 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) [From first dose of drug up to 30 days after last dose (up to approximately 14 years)]

    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.

  2. 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) [From first dose of drug up to 30 days after last dose (up to approximately 14 years)]

    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.

  3. 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) [From first dose of drug up to 30 days after last dose (up to approximately 14 years)]

    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.

  4. Number of Participants With Laboratory Test Abnormalities Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 4.03) [From first dose of drug up to 30 days after last dose (up to approximately 14 years)]

    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.

  5. Number of Participants With Adverse Events as Reason for Treatment Discontinuation [From first dose of drug up to 30 days after last dose (up to approximately 14 years)]

    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.

  6. Number of Participants With Diarrhea After Switch From Bosutinib Clinical Formulation to Bosutinib Commercial Formulation [Last 6 months on clinical formulation and first 6 months on commercial formulation]

    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.

  7. Number of Participants With Breakpoint Cluster Region Abelson Protooncogene (BCR-ABL) Mutations Present at Time of Bosutinib Treatment Discontinuation [Post-baseline on Day 1 (maximum up to 14 years)]

    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.

  8. Overall Survival (OS) Rate at Year 10 [Year 10]

    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.

  9. Plasma Steady-State Trough Concentrations (Ctrough) of Bosutinib [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]

    Ctrough refers to plasma concentration of bosutinib observed just before treatment administration.

  10. Kaplan-Meier Estimate of Probability of Maintaining Major Cytogenetic Response (MCyR) at Year 10: B1871006 Participants [Year 10]

    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.

  11. Kaplan-Meier Estimate of Probability of Maintaining Complete Cytogenetic Response (CCyR) at Year 10: B1871006 Participants [Year 10]

    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.

  12. Kaplan-Meier Estimate of Probability of Maintaining Complete Hematologic Response (CHR) at Year 10: B1871006 Participants [Year 10]

    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.

  13. Cumulative Incidence of Progression/Death Events at Year 10: B1871006 Participants [Year 10]

    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.

  14. Cumulative Incidence of Rate of Transformation to Accelerated Phase (AP) or Blast Phase (BP) at Year 10: B1871006 Participants [Year 10]

    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.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • Only subjects previously participating in two specific studies are eligible to enroll into this study. Enrollment is not open to subjects if not previously enrolled in studies B1871006 or B1871008.
Exclusion Criteria:
  • All subjects are excluded unless previously participating in studies B1871006 or B1871008.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Orlando Health, Inc Orlando Florida United States 32806
2 Emory University Hospital Atlanta Georgia United States 30322
3 The Emory Clinic Atlanta Georgia United States 30322
4 Winship Cancer Institute, Emory University Atlanta Georgia United States 30322
5 Northside Hospital Inc., - GCS/Northside Atlanta Georgia United States 30342
6 Northside Hospital, Inc. - Central Research Department Atlanta Georgia United States 30342
7 Indiana Blood and Marrow Transplantation Indianapolis Indiana United States 46237
8 Siouxland Hematology-Oncology Associates, LLP Sioux City Iowa United States 51101
9 Rcca Md,Llc Bethesda Maryland United States 20817
10 Hudson Valley Hematology and Oncology Associates Hawthorne New York United States 10532
11 Penn State Milton S. Hershey Medical Center Hershey Pennsylvania United States 17033-0850
12 The University of Texas MD Anderson Cancer Center Houston Texas United States 77030
13 The University of Texas, MD Anderson Cancer Center Houston Texas United States 77030
14 Instituto Medico Especializado Alexander Fleming Cd. Autonoma De Buenos Aires Buenos Aires Argentina C1426ANZ
15 Hospital Italiano de la Plata La Plata Buenos Aires Argentina 1900
16 Hospital Dr. Jose Ramon Vidal Corrientes Argentina 3400
17 Royal Brisbane & Women's Hospital Herston Queensland Australia 4029
18 Royal Adelaide Hospital Adelaide South Australia Australia 5000
19 GHDC (Grand Hopital de Charleroi) Charleroi Belgium 6000
20 Universidade Estadual de Campinas / Centro de Hematologia e Hemoterapia Campinas SP Brazil 13083-878
21 Faculdade de Medicina do ABC - Centro de Estudos e Pesquisa em Hematologia e Oncologia (CEPHO) Santo Andre SP Brazil 09060-650
22 Alberta Health Services - Department of Medical Oncology - Cross Cancer Institute Edmonton Alberta Canada T6G 1Z2
23 Vancouver General Hospital Vancouver British Columbia Canada V5Z1M9
24 Princess Margaret Cancer Centre Toronto Ontario Canada M5G 2M9
25 Sir Mortimer B. Davis-Jewish General Hospital Montreal Quebec Canada H3T 1E2
26 Instituto Oncologico, Clinica Renaca Renaca V Region Chile 2540364
27 Instituto Oncologico Renaca V Region Chile 2540488
28 Peking Union Medical College Hospital Beijing Beijing China 100730
29 The First affiliated Hospital of College of Medicine, Zhejiang University Hangzhou Zhejiang China 310003
30 Chinese People's Liberation Army General Hospital Beijing China 100853
31 Ruijin Hospital- Shanghai Jiaotong University School of Medicine Shanghai China 200025
32 Blood Disease Hospital, Chinese Academy of Medical Science & Peking Union Medical College Tianjin China 300020
33 Fundacion Santa Fe de Bogota Bogota Cundinamarca Colombia 110111
34 Helsingin Yliopistollinen Keskussairaala, Hematologian poliklinikka Helsinki Finland 00290
35 CHU de CAEN Caen Cedex 9 France 14033
36 CHU Hotel Dieu - Service Hematologie Nantes cedex 1 France 44093
37 CHU de Poitiers Poitiers Cedex France 86021
38 CHU Poitiers Poitiers France 86021
39 Strasbourg Oncologie Liberale -Centre de Radiotherapie, Clinique Ste Anne Strasbourg France 67000
40 Pamela Youde Nethersole Eastern Hospital Chai Wan Hong Kong
41 Department of Medicine & Therapeutics, Prince of Wales Hospital Shatin, New Territories Hong Kong
42 Egyesitett Szent Istvan es Szent Laszlo Korhaz-Rendelointezet Budapest Hungary 1097
43 Somogy Megyei Kaposi Mor Oktato Korhaz, Belgyogyaszati Osztaly Kaposvar Hungary 7400
44 Christian Medical College. Vellore Vellore Tamil NADU India 632004
45 A.O.U. Policlinico S.Orsola Malpighi Bologna BO Italy 40138
46 ASST Monza - Ospedale san Gerardo Monza Monza AND Brianza Italy 20090
47 A.O.U. San Luigi Gonzaga di Orbassano Orbassano TO Italy 10043
48 Ospedale S. Eugenio - UOC Ematologia Roma Italy 00144
49 Toyohashi Municipal Hospital Toyohashi Aichi Japan 4418570
50 Akita University Hospital Akita City Akita Japan 010-8543
51 National Hospital Organization Kyushu Cancer Center Fukuoka-shi Fukuoka Japan 811-1395
52 Kanazawa University Hospital Kanazawa-shi Ishikawa Japan 920-8641
53 Kindai University Hospital Osakasayama-city Osaka Japan 589-8511
54 Osaka University Hospital Suita-city Osaka Japan 565-0871
55 Hamamatsu University School of Medicine University Hospital Hamamatsu-shi Shizuoka Japan 431-3192
56 Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital Tokyo Japan 113-8677
57 The Catholic University of Korea, Seoul St. Mary's Hospital Seoul Korea, Republic of 06591
58 Riga East Clinical University Hospital Riga Latvia LV-1079
59 VU University Medical Center Amsterdam Netherlands 1081 HV
60 University Medical Center Groningen, Department of Hematology Groningen Netherlands 9713 GZ
61 Unidad de Investigacion de Hematologia - Hospital Nacional Edgardo Rebagliati Martins Lima Peru 11
62 Uniwersyteckie Centrum Kliniczne Gdansk Poland 80-214
63 Uniwersyteckie Centrum Kliniczne GdaƄsk Poland 80-952
64 SP ZOZ Szpital Uniwersytecki w Krakowie Krakow Poland 31-501
65 Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie Lublin Poland 20-081
66 State Budgetary Institution of Healthcare of Sverdlovsk Region Ekaterinburg Sverdlovsk Region Russian Federation 620102
67 Federal State-Funded Institution National Research Center of Hematology of the Ministry of Moscow Russian Federation 125167
68 State Budgetary Institution of Rostov Region - Rostov Regional Clinical Hospital Rostov-on-Don Russian Federation 344015
69 State Budgetary Educational Institution of Higher Professional Education Rostov-on-Don Russian Federation 344022
70 State Budgetary Institution of Healthcare - Leningrad Regional Clinical Hospital Saint Petersburg Russian Federation 194291
71 Clinic "Institute of Pediatric Oncology, Hematology and Transplantation n.a. R.M. Gorbachova" Saint Petersburg Russian Federation 197022
72 Federal State Budgetary Institution "Federal Almazov Medical Research Centre" Saint Petersburg Russian Federation 197341
73 State Budgetary Institution of Healthcare Samara Regional Clinical Hospital n.a. V.D. Seredavin Samara Russian Federation 443095
74 Singapore General Hospital Singapore Singapore 169608
75 Wits Clinical Research-Chris Hani Baragwanath Hospital Soweto Gauteng South Africa 2013
76 Hospital Clinic Barcelona Barcelona Spain 08036
77 Hospital Universitario La Princesa Madrid Spain 28006
78 Hospital Universitario La Paz Madrid Spain 28046
79 Hospital Universitario Madrid Sanchinarro, Centro Integral Oncologico Clara Campal Madrid Spain 28050
80 Hospital Virgen de la Salud Toledo Spain 45004
81 Hospital Clinico Universitario De Valencia (CHUV) Valencia Spain 46010
82 Division of Hematology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Bangkok Thailand 10700
83 Gaziantep Universitesi Tip Fakultesi Sahinbey Uygulama ve Arastirma Hastanesi Gaziantep Sehit Kamil Turkey 27310
84 Hacettepe Universitesi Tip Fakultesi Ankara Turkey 06100
85 Municipal Institution "Cherkasy Regional Oncology Dispensary" Cherkasy Ukraine 18009
86 MI "Dnipropetrovsk City Multi-field Clinical Hospital #4" of DRC Hematology Center Dnipropetrovsk Ukraine 49102
87 State Institution "National Research Center for Radiation Medicine of the National Academy of Kyiv Ukraine 03115
88 Kyiv City Clinical Hospital #9, SI "Institute of Hematology and Transfusiology of NAMS of Ukraine" Kyiv Ukraine 04112
89 State Institution "Institute of Blood Pathology and Transfusion Medicine of Lviv Ukraine 79044
90 Freeman Hospital Newcastle Upon Tyne United Kingdom NE7 7DN
91 Nottingham University Hospitals NHS Trust Nottinhgam United Kingdom NG5 1PB

Sponsors and Collaborators

  • Pfizer

Investigators

  • Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

More Information

Additional Information:

Publications

None provided.
Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT01903733
Other Study ID Numbers:
  • B1871040
  • 2013-000691-15
First Posted:
Jul 19, 2013
Last Update Posted:
Jul 19, 2022
Last Verified:
Jun 1, 2022
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Keywords provided by Pfizer
Additional relevant MeSH terms:

Study Results

Participant Flow

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 Detail 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
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 250 284 119 167
Safety Analysis Set 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

Baseline Characteristics

Arm/Group Title Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Total
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 Participants 250 284 119 167 820
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]
47.9
(14.4)
51.9
(15.1)
55.1
(13.0)
50.1
(15.4)
50.8
(14.8)
Sex: Female, Male (Count of 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) (Count of Participants)
American Indian or Alaska Native
0
0%
1
0.4%
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%
Black or African American
2
0.8%
16
5.6%
6
5%
19
11.4%
43
5.2%
White
160
64%
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%
Unknown or Not Reported
5
2%
20
7%
11
9.2%
9
5.4%
45
5.5%

Outcome Measures

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)
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)

Outcome Measure Data

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
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.
Measure Participants 248 284 119 167 818
Treatment-Emergent AEs
241
96.4%
283
99.6%
119
100%
165
98.8%
808
98.5%
Treatment-emergent SAEs
102
40.8%
124
43.7%
44
37%
98
58.7%
368
44.9%
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)
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)

Outcome Measure Data

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
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.
Measure Participants 248 284 119 167 818
Count of Participants [Participants]
191
76.4%
223
78.5%
84
70.6%
144
86.2%
642
78.3%
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)
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)

Outcome Measure Data

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
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.
Measure Participants 248 284 119 167 818
Count of Participants [Participants]
235
94%
282
99.3%
119
100%
161
96.4%
797
97.2%
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)
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)

Outcome Measure Data

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
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.
Measure Participants 248 284 119 167 818
Grade 1
45
18%
59
20.8%
28
23.5%
18
10.8%
150
18.3%
Grade 2
86
34.4%
80
28.2%
39
32.8%
24
14.4%
229
27.9%
Grade 3
84
33.6%
102
35.9%
27
22.7%
41
24.6%
254
31%
Grade 4
33
13.2%
42
14.8%
23
19.3%
82
49.1%
180
22%
5. Primary Outcome
Title Number of Participants With Adverse Events as Reason for Treatment Discontinuation
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)

Outcome Measure Data

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
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.
Measure Participants 248 284 119 167 818
Count of Participants [Participants]
84
33.6%
79
27.8%
37
31.1%
32
19.2%
232
28.3%
6. Primary Outcome
Title Number of Participants With Diarrhea After Switch From Bosutinib Clinical Formulation to Bosutinib Commercial Formulation
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

Outcome Measure Data

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
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.
Measure Participants 119 82 13 8 222
Clinical formulation (last 6 months)
25
10%
22
7.7%
3
2.5%
5
3%
55
6.7%
Commercial formulation (first 6 months)
34
13.6%
27
9.5%
4
3.4%
5
3%
70
8.5%
7. Primary Outcome
Title Number of Participants With Breakpoint Cluster Region Abelson Protooncogene (BCR-ABL) Mutations Present at Time of Bosutinib Treatment Discontinuation
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)

Outcome Measure Data

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
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.
Measure Participants 250 284 119 167
Count of Participants [Participants]
7
2.8%
28
9.9%
13
10.9%
14
8.4%
8. Primary Outcome
Title Overall Survival (OS) Rate at Year 10
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

Outcome Measure Data

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
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.
Measure Participants 250 284 119 167
Number (95% Confidence Interval) [percentage of participants]
88.2
35.3%
71.5
25.2%
60.4
50.8%
34.2
20.5%
9. Primary Outcome
Title Plasma Steady-State Trough Concentrations (Ctrough) of Bosutinib
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

Outcome Measure Data

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
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.
Measure Participants 6 28 23 69 8
Geometric Mean (Geometric Coefficient of Variation) [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
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

Outcome Measure Data

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
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.
Measure Participants 157 47 54
Number (95% Confidence Interval) [percentage of participants]
65.3
26.1%
55.3
19.5%
30.6
25.7%
11. Primary Outcome
Title Kaplan-Meier Estimate of Probability of Maintaining Complete Cytogenetic Response (CCyR) at Year 10: B1871006 Participants
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

Outcome Measure Data

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
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.
Measure Participants 130 36 42
Number (95% Confidence Interval) [percentage of participants]
63.4
25.4%
40.8
14.4%
29.6
24.9%
12. Primary Outcome
Title Kaplan-Meier Estimate of Probability of Maintaining Complete Hematologic Response (CHR) at Year 10: B1871006 Participants
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

Outcome Measure Data

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
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.
Measure Participants 245 86 36
Number (95% Confidence Interval) [percentage of participants]
44.1
17.6%
45.1
15.9%
NA
NaN
13. Primary Outcome
Title Cumulative Incidence of Progression/Death Events at Year 10: B1871006 Participants
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

Outcome Measure Data

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
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.
Measure Participants 284 119 167
Number (95% Confidence Interval) [percentage of participants]
23.9
9.6%
26.9
9.5%
55.7
46.8%
14. Primary Outcome
Title Cumulative Incidence of Rate of Transformation to Accelerated Phase (AP) or Blast Phase (BP) at Year 10: B1871006 Participants
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

Outcome Measure Data

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
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.
Measure Participants 284 119 79
Number (95% Confidence Interval) [percentage of participants]
5.3
2.1%
4.2
1.5%
3.8
3.2%

Adverse Events

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
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 (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 23/248 (9.3%) 55/284 (19.4%) 30/119 (25.2%) 98/167 (58.7%) 206/818 (25.2%)
Serious Adverse Events
Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Bosutinib, Total
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 102/248 (41.1%) 124/284 (43.7%) 44/119 (37%) 98/167 (58.7%) 368/818 (45%)
Blood and lymphatic system disorders
Thrombocytopenia 6/248 (2.4%) 5/284 (1.8%) 1/119 (0.8%) 8/167 (4.8%) 20/818 (2.4%)
Anaemia 6/248 (2.4%) 3/284 (1.1%) 0/119 (0%) 6/167 (3.6%) 15/818 (1.8%)
Febrile neutropenia 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 8/167 (4.8%) 9/818 (1.1%)
Neutropenia 2/248 (0.8%) 0/284 (0%) 4/119 (3.4%) 2/167 (1.2%) 8/818 (1%)
Leukocytosis 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 3/167 (1.8%) 4/818 (0.5%)
Hyperleukocytosis 0/248 (0%) 0/284 (0%) 0/119 (0%) 2/167 (1.2%) 2/818 (0.2%)
Granulocytopenia 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Iron deficiency anaemia 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Leukopenia 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Leukostasis syndrome 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Lymphadenopathy 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Pancytopenia 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Splenomegaly 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Cardiac disorders
Pericardial effusion 6/248 (2.4%) 5/284 (1.8%) 2/119 (1.7%) 2/167 (1.2%) 15/818 (1.8%)
Cardiac failure congestive 2/248 (0.8%) 6/284 (2.1%) 1/119 (0.8%) 1/167 (0.6%) 10/818 (1.2%)
Atrial fibrillation 1/248 (0.4%) 4/284 (1.4%) 3/119 (2.5%) 1/167 (0.6%) 9/818 (1.1%)
Coronary artery disease 3/248 (1.2%) 2/284 (0.7%) 2/119 (1.7%) 1/167 (0.6%) 8/818 (1%)
Acute myocardial infarction 1/248 (0.4%) 3/284 (1.1%) 1/119 (0.8%) 2/167 (1.2%) 7/818 (0.9%)
Cardiac failure 0/248 (0%) 4/284 (1.4%) 1/119 (0.8%) 1/167 (0.6%) 6/818 (0.7%)
Pericarditis 2/248 (0.8%) 1/284 (0.4%) 1/119 (0.8%) 1/167 (0.6%) 5/818 (0.6%)
Angina pectoris 0/248 (0%) 3/284 (1.1%) 1/119 (0.8%) 0/167 (0%) 4/818 (0.5%)
Myocardial infarction 0/248 (0%) 0/284 (0%) 3/119 (2.5%) 1/167 (0.6%) 4/818 (0.5%)
Left ventricular dysfunction 0/248 (0%) 2/284 (0.7%) 0/119 (0%) 1/167 (0.6%) 3/818 (0.4%)
Angina unstable 0/248 (0%) 2/284 (0.7%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Pericardial haemorrhage 0/248 (0%) 2/284 (0.7%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Tachycardia 0/248 (0%) 0/284 (0%) 0/119 (0%) 2/167 (1.2%) 2/818 (0.2%)
Acute coronary syndrome 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Aortic valve stenosis 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Arrhythmia 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Arteriosclerosis coronary artery 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Bradycardia 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Bundle branch block right 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Cardiac disorder 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Cardiac failure acute 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Cardiorenal syndrome 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Coronary artery stenosis 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Cardiac arrest 3/248 (1.2%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 4/818 (0.5%)
Extrasystoles 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Hypertensive cardiomyopathy 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Palpitations 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Pleuropericarditis 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Ventricular fibrillation 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Congenital, familial and genetic disorders
Cytogenetic abnormality 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Hydrocele 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Ear and labyrinth disorders
Deafness unilateral 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Vestibular disorder 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Endocrine disorders
Goitre 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Thyroid mass 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Eye disorders
Glaucoma 1/248 (0.4%) 1/284 (0.4%) 0/119 (0%) 1/167 (0.6%) 3/818 (0.4%)
Cataract 1/248 (0.4%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Visual impairment 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 2/818 (0.2%)
Diplopia 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Retinopathy 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Retinopathy hypertensive 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Vitreous haemorrhage 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Gastrointestinal disorders
Diarrhoea 9/248 (3.6%) 8/284 (2.8%) 1/119 (0.8%) 4/167 (2.4%) 22/818 (2.7%)
Abdominal pain 3/248 (1.2%) 3/284 (1.1%) 0/119 (0%) 5/167 (3%) 11/818 (1.3%)
Vomiting 3/248 (1.2%) 2/284 (0.7%) 0/119 (0%) 5/167 (3%) 10/818 (1.2%)
Nausea 1/248 (0.4%) 0/284 (0%) 1/119 (0.8%) 6/167 (3.6%) 8/818 (1%)
Gastritis 3/248 (1.2%) 1/284 (0.4%) 1/119 (0.8%) 1/167 (0.6%) 6/818 (0.7%)
Pancreatitis acute 1/248 (0.4%) 3/284 (1.1%) 0/119 (0%) 1/167 (0.6%) 5/818 (0.6%)
Gastrointestinal haemorrhage 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 3/167 (1.8%) 4/818 (0.5%)
Inguinal hernia 0/248 (0%) 3/284 (1.1%) 1/119 (0.8%) 0/167 (0%) 4/818 (0.5%)
Pancreatitis 2/248 (0.8%) 1/284 (0.4%) 0/119 (0%) 1/167 (0.6%) 4/818 (0.5%)
Colitis 0/248 (0%) 2/284 (0.7%) 1/119 (0.8%) 0/167 (0%) 3/818 (0.4%)
Rectal haemorrhage 0/248 (0%) 1/284 (0.4%) 1/119 (0.8%) 1/167 (0.6%) 3/818 (0.4%)
Abdominal pain upper 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 1/167 (0.6%) 2/818 (0.2%)
Gastric ulcer 2/248 (0.8%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Gastrointestinal disorder 2/248 (0.8%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Haematochezia 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 1/167 (0.6%) 2/818 (0.2%)
Intestinal obstruction 0/248 (0%) 2/284 (0.7%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Toothache 0/248 (0%) 2/284 (0.7%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Abdominal adhesions 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Abdominal distension 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Abdominal pain lower 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Anal fistula 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Ascites 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Colitis ischaemic 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Dental caries 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Duodenal ulcer haemorrhage 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Dysphagia 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Enteritis 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Epigastric discomfort 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Faecaloma 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Food poisoning 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Gastric haemorrhage 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Gastric ulcer haemorrhage 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Gastritis erosive 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Gastritis haemorrhagic 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Gastrointestinal necrosis 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Gastrooesophageal reflux disease 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Haemorrhoids 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Ileus 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Intestinal haemorrhage 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Intestinal ischaemia 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Large intestinal stenosis 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Lower gastrointestinal haemorrhage 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Melaena 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Mesenteric artery embolism 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Oesophageal perforation 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Proctitis 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Rectal polyp 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Retroperitoneal haemorrhage 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Small intestinal obstruction 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Umbilical hernia 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
General disorders
Pyrexia 8/248 (3.2%) 8/284 (2.8%) 2/119 (1.7%) 11/167 (6.6%) 29/818 (3.5%)
Disease progression 0/248 (0%) 3/284 (1.1%) 1/119 (0.8%) 8/167 (4.8%) 12/818 (1.5%)
Chest pain 1/248 (0.4%) 3/284 (1.1%) 0/119 (0%) 4/167 (2.4%) 8/818 (1%)
General physical health deterioration 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 6/167 (3.6%) 7/818 (0.9%)
Asthenia 0/248 (0%) 4/284 (1.4%) 0/119 (0%) 1/167 (0.6%) 5/818 (0.6%)
Pain 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 2/167 (1.2%) 3/818 (0.4%)
Chills 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 1/167 (0.6%) 2/818 (0.2%)
Death 1/248 (0.4%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Multiple organ dysfunction syndrome 0/248 (0%) 0/284 (0%) 0/119 (0%) 2/167 (1.2%) 2/818 (0.2%)
Oedema 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 1/167 (0.6%) 2/818 (0.2%)
Adhesion 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Adverse drug reaction 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Malaise 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Mucosal inflammation 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Oedema peripheral 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Sudden death 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Swelling 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Hepatobiliary disorders
Cholelithiasis 2/248 (0.8%) 4/284 (1.4%) 0/119 (0%) 1/167 (0.6%) 7/818 (0.9%)
Cholecystitis 0/248 (0%) 1/284 (0.4%) 1/119 (0.8%) 1/167 (0.6%) 3/818 (0.4%)
Cholecystitis acute 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 2/167 (1.2%) 3/818 (0.4%)
Gallbladder disorder 0/248 (0%) 2/284 (0.7%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Bile duct stone 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Cholecystitis chronic 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Drug-induced liver injury 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Gallbladder polyp 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Hepatic function abnormal 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Perforation bile duct 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Immune system disorders
Drug hypersensitivity 1/248 (0.4%) 1/284 (0.4%) 0/119 (0%) 1/167 (0.6%) 3/818 (0.4%)
Anaphylactic shock 2/248 (0.8%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Hypersensitivity 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Infections and infestations
Pneumonia 10/248 (4%) 15/284 (5.3%) 0/119 (0%) 19/167 (11.4%) 44/818 (5.4%)
Sepsis 1/248 (0.4%) 4/284 (1.4%) 1/119 (0.8%) 6/167 (3.6%) 12/818 (1.5%)
Cellulitis 3/248 (1.2%) 3/284 (1.1%) 1/119 (0.8%) 1/167 (0.6%) 8/818 (1%)
Urinary tract infection 2/248 (0.8%) 4/284 (1.4%) 0/119 (0%) 1/167 (0.6%) 7/818 (0.9%)
Bronchitis 2/248 (0.8%) 3/284 (1.1%) 1/119 (0.8%) 0/167 (0%) 6/818 (0.7%)
Gastroenteritis 3/248 (1.2%) 3/284 (1.1%) 0/119 (0%) 0/167 (0%) 6/818 (0.7%)
Influenza 0/248 (0%) 4/284 (1.4%) 1/119 (0.8%) 1/167 (0.6%) 6/818 (0.7%)
Upper respiratory tract infection 1/248 (0.4%) 2/284 (0.7%) 1/119 (0.8%) 0/167 (0%) 4/818 (0.5%)
Appendicitis 1/248 (0.4%) 1/284 (0.4%) 1/119 (0.8%) 0/167 (0%) 3/818 (0.4%)
Atypical pneumonia 1/248 (0.4%) 2/284 (0.7%) 0/119 (0%) 0/167 (0%) 3/818 (0.4%)
Bacteraemia 0/248 (0%) 0/284 (0%) 0/119 (0%) 3/167 (1.8%) 3/818 (0.4%)
Clostridium difficile colitis 0/248 (0%) 2/284 (0.7%) 1/119 (0.8%) 0/167 (0%) 3/818 (0.4%)
Infection 1/248 (0.4%) 2/284 (0.7%) 0/119 (0%) 0/167 (0%) 3/818 (0.4%)
Appendicitis perforated 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 2/818 (0.2%)
Device related infection 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 1/167 (0.6%) 2/818 (0.2%)
Erysipelas 0/248 (0%) 2/284 (0.7%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Gastroenteritis viral 0/248 (0%) 2/284 (0.7%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Infectious pleural effusion 1/248 (0.4%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Large intestine infection 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 2/818 (0.2%)
Pharyngitis 1/248 (0.4%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Pyelonephritis acute 0/248 (0%) 2/284 (0.7%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Septic shock 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 1/167 (0.6%) 2/818 (0.2%)
Sinusitis 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 1/167 (0.6%) 2/818 (0.2%)
Staphylococcal bacteraemia 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 1/167 (0.6%) 2/818 (0.2%)
Tooth abscess 1/248 (0.4%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Tooth infection 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 2/818 (0.2%)
Urinary tract infection bacterial 0/248 (0%) 0/284 (0%) 0/119 (0%) 2/167 (1.2%) 2/818 (0.2%)
Abscess limb 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Arthritis bacterial 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Arthritis infective 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Bacterial sepsis 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Brain abscess 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Bronchiolitis 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Catheter bacteraemia 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Cellulitis of male external genital organ 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Clostridium difficile infection 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Cystitis 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Dengue fever 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Dermatitis infected 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Diverticulitis 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Eczema infected 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Enterococcal sepsis 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Enterocolitis infectious 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Escherichia bacteraemia 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Escherichia sepsis 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Febrile infection 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Fungal infection 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Gastrointestinal infection 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Gingival abscess 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Hepatitis A 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Infected dermal cyst 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Kidney infection 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Malaria 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Meningitis 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Orchitis 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Perirectal abscess 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Pharyngotonsillitis 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Pneumonia bacterial 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Pneumonia fungal 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Pneumonia necrotising 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Post procedural infection 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Pseudomembranous colitis 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Pseudomonal sepsis 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Pulmonary mycosis 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Pyelonephritis 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Salmonella bacteraemia 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Salmonellosis 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Staphylococcal sepsis 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Streptococcal sepsis 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Subcutaneous abscess 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Injury, poisoning and procedural complications
Contusion 1/248 (0.4%) 2/284 (0.7%) 0/119 (0%) 0/167 (0%) 3/818 (0.4%)
Facial bones fracture 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 2/818 (0.2%)
Road traffic accident 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 1/167 (0.6%) 2/818 (0.2%)
Subdural haematoma 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 1/167 (0.6%) 2/818 (0.2%)
Upper limb fracture 0/248 (0%) 2/284 (0.7%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Abdominal injury 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Cervical vertebral fracture 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Clavicle fracture 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Exposure during pregnancy 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Failure to anastomose 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Fall 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Fibula fracture 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Gastrointestinal stoma complication 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Humerus fracture 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Injury 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Lower limb fracture 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Muscle injury 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Overdose 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Post procedural complication 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Post procedural haematoma 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Post procedural haematuria 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Post procedural swelling 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Procedural haemorrhage 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Rib fracture 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Seroma 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Skin laceration 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Skull fracture 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Subdural haemorrhage 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Tooth fracture 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Transfusion reaction 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Traumatic lung injury 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Vascular pseudoaneurysm 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Wound haematoma 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Investigations
Alanine aminotransferase increased 8/248 (3.2%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 9/818 (1.1%)
Aspartate aminotransferase increased 4/248 (1.6%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 5/818 (0.6%)
Blood bilirubin increased 1/248 (0.4%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Blood creatinine increased 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 2/818 (0.2%)
Lipase increased 1/248 (0.4%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Amylase increased 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Blood creatine phosphokinase increased 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Blood glucose increased 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Blood lactate dehydrogenase increased 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Blood pressure increased 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Hepatic enzyme increased 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Intraocular pressure increased 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Liver function test increased 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Transaminases increased 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Weight decreased 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Metabolism and nutrition disorders
Dehydration 2/248 (0.8%) 2/284 (0.7%) 1/119 (0.8%) 3/167 (1.8%) 8/818 (1%)
Failure to thrive 0/248 (0%) 0/284 (0%) 0/119 (0%) 3/167 (1.8%) 3/818 (0.4%)
Gout 1/248 (0.4%) 1/284 (0.4%) 0/119 (0%) 1/167 (0.6%) 3/818 (0.4%)
Fluid retention 0/248 (0%) 1/284 (0.4%) 1/119 (0.8%) 0/167 (0%) 2/818 (0.2%)
Hypoglycaemia 0/248 (0%) 2/284 (0.7%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Acidosis 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Decreased appetite 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Hyperglycaemia 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Hypophosphataemia 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Hypovolaemia 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Musculoskeletal and connective tissue disorders
Back pain 2/248 (0.8%) 2/284 (0.7%) 2/119 (1.7%) 0/167 (0%) 6/818 (0.7%)
Gouty arthritis 1/248 (0.4%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Intervertebral disc disorder 2/248 (0.8%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Osteoarthritis 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 1/167 (0.6%) 2/818 (0.2%)
Spinal osteoarthritis 1/248 (0.4%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Arthralgia 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Bone cyst 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Bone pain 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Groin pain 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Intervertebral disc protrusion 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Joint range of motion decreased 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Lumbar spinal stenosis 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Mandibular mass 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Musculoskeletal stiffness 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Myalgia 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Myositis 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Neck pain 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Osteochondrosis 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Osteonecrosis 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Pain in extremity 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Rotator cuff syndrome 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Spinal stenosis 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Synovitis 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Blast cell crisis 1/248 (0.4%) 3/284 (1.1%) 0/119 (0%) 2/167 (1.2%) 6/818 (0.7%)
Adenocarcinoma gastric 3/248 (1.2%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 3/818 (0.4%)
Basal cell carcinoma 1/248 (0.4%) 2/284 (0.7%) 0/119 (0%) 0/167 (0%) 3/818 (0.4%)
Blast crisis in myelogenous leukaemia 0/248 (0%) 0/284 (0%) 0/119 (0%) 3/167 (1.8%) 3/818 (0.4%)
Squamous cell carcinoma of skin 0/248 (0%) 2/284 (0.7%) 0/119 (0%) 1/167 (0.6%) 3/818 (0.4%)
Chronic myeloid leukaemia 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 1/167 (0.6%) 2/818 (0.2%)
Squamous cell carcinoma 0/248 (0%) 1/284 (0.4%) 1/119 (0.8%) 0/167 (0%) 2/818 (0.2%)
Angiomyolipoma 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Anogenital warts 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Bladder squamous cell carcinoma stage unspecified 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Bowen's disease 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Central nervous system leukaemia 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Chloroma 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Cholangiocarcinoma 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Chronic myelomonocytic leukaemia 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Colon cancer 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Colon cancer metastatic 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Follicle centre lymphoma, follicular grade I, II, III 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Gastric cancer 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Invasive ductal breast carcinoma 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Keratoacanthoma 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Laryngeal neoplasm 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Leukaemia 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Lipoma 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Lung adenocarcinoma 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Malignant melanoma 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Melanocytic naevus 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Neoplasm prostate 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Neoplasm skin 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Non-small cell lung cancer 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Paraproteinaemia 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Prostate cancer 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Uterine leiomyoma 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Nervous system disorders
Headache 3/248 (1.2%) 0/284 (0%) 2/119 (1.7%) 8/167 (4.8%) 13/818 (1.6%)
Syncope 1/248 (0.4%) 4/284 (1.4%) 0/119 (0%) 0/167 (0%) 5/818 (0.6%)
Cerebrovascular accident 2/248 (0.8%) 1/284 (0.4%) 0/119 (0%) 1/167 (0.6%) 4/818 (0.5%)
Subarachnoid haemorrhage 0/248 (0%) 2/284 (0.7%) 0/119 (0%) 2/167 (1.2%) 4/818 (0.5%)
Cerebral haemorrhage 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 2/167 (1.2%) 3/818 (0.4%)
Cerebral infarction 0/248 (0%) 2/284 (0.7%) 0/119 (0%) 1/167 (0.6%) 3/818 (0.4%)
Cerebellar infarction 0/248 (0%) 2/284 (0.7%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Dizziness 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 2/818 (0.2%)
Nervous system disorder 0/248 (0%) 0/284 (0%) 0/119 (0%) 2/167 (1.2%) 2/818 (0.2%)
Paraesthesia 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 1/167 (0.6%) 2/818 (0.2%)
Seizure 2/248 (0.8%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Carotid arteriosclerosis 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Carpal tunnel syndrome 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Encephalitis post varicella 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Encephalopathy 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Epilepsy 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Hemiparesis 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Intraventricular haemorrhage 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Ischaemic stroke 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Loss of consciousness 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Monoparesis 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Parkinson's disease 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Partial seizures 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Radiculopathy 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Speech disorder 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Trigeminal neuralgia 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Pregnancy, puerperium and perinatal conditions
Pregnancy 2/248 (0.8%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Psychiatric disorders
Mental status changes 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 1/167 (0.6%) 2/818 (0.2%)
Anxiety 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Completed suicide 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Confusional state 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Depression 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Disorientation 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Dissociative disorder 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Hallucination 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Hallucination, visual 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Renal and urinary disorders
Acute kidney injury 5/248 (2%) 6/284 (2.1%) 1/119 (0.8%) 3/167 (1.8%) 15/818 (1.8%)
Renal failure 1/248 (0.4%) 2/284 (0.7%) 1/119 (0.8%) 1/167 (0.6%) 5/818 (0.6%)
Haematuria 1/248 (0.4%) 2/284 (0.7%) 0/119 (0%) 0/167 (0%) 3/818 (0.4%)
Calculus urinary 2/248 (0.8%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Calculus bladder 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Chronic kidney disease 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Cystitis haemorrhagic 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
End stage renal disease 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Nephrolithiasis 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Prerenal failure 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Renal artery stenosis 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Renal disorder 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Renal impairment 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Tubulointerstitial nephritis 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Urinary retention 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Reproductive system and breast disorders
Menorrhagia 0/248 (0%) 2/284 (0.7%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Breast hyperplasia 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Cervical dysplasia 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Dysfunctional uterine bleeding 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Metrorrhagia 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Pelvic pain 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Vaginal haemorrhage 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion 12/248 (4.8%) 15/284 (5.3%) 8/119 (6.7%) 8/167 (4.8%) 43/818 (5.3%)
Dyspnoea 1/248 (0.4%) 7/284 (2.5%) 3/119 (2.5%) 5/167 (3%) 16/818 (2%)
Pneumonitis 1/248 (0.4%) 2/284 (0.7%) 1/119 (0.8%) 2/167 (1.2%) 6/818 (0.7%)
Respiratory failure 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 5/167 (3%) 6/818 (0.7%)
Pulmonary hypertension 3/248 (1.2%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 4/818 (0.5%)
Pulmonary oedema 0/248 (0%) 1/284 (0.4%) 1/119 (0.8%) 1/167 (0.6%) 3/818 (0.4%)
Acute pulmonary oedema 2/248 (0.8%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Asthma 0/248 (0%) 2/284 (0.7%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Chronic obstructive pulmonary disease 1/248 (0.4%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Interstitial lung disease 2/248 (0.8%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Lung disorder 1/248 (0.4%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Pleuritic pain 1/248 (0.4%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 2/818 (0.2%)
Acute respiratory failure 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Bronchiectasis 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Bronchitis chronic 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Dyspnoea exertional 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Haemoptysis 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Lung infiltration 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Organising pneumonia 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Pleurisy 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Pneumonia aspiration 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Pulmonary embolism 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Pulmonary fibrosis 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Respiratory arrest 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Vocal cord polyp 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Skin and subcutaneous tissue disorders
Rash 1/248 (0.4%) 8/284 (2.8%) 1/119 (0.8%) 1/167 (0.6%) 11/818 (1.3%)
Urticaria 1/248 (0.4%) 0/284 (0%) 2/119 (1.7%) 1/167 (0.6%) 4/818 (0.5%)
Angioedema 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Circumoral oedema 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Dermatitis 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Erythema multiforme 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Rash maculo-papular 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Skin disorder 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Skin lesion 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Social circumstances
Pregnancy of partner 2/248 (0.8%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 3/818 (0.4%)
Surgical and medical procedures
Allogenic bone marrow transplantation therapy 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Cyst removal 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Knee arthroplasty 0/248 (0%) 0/284 (0%) 0/119 (0%) 1/167 (0.6%) 1/818 (0.1%)
Vascular disorders
Hypertension 1/248 (0.4%) 2/284 (0.7%) 0/119 (0%) 1/167 (0.6%) 4/818 (0.5%)
Hypotension 0/248 (0%) 0/284 (0%) 0/119 (0%) 2/167 (1.2%) 2/818 (0.2%)
Aortic stenosis 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Haemorrhage 1/248 (0.4%) 0/284 (0%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Hypertensive crisis 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Peripheral arterial occlusive disease 0/248 (0%) 0/284 (0%) 1/119 (0.8%) 0/167 (0%) 1/818 (0.1%)
Thrombosis 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Venous thrombosis 0/248 (0%) 1/284 (0.4%) 0/119 (0%) 0/167 (0%) 1/818 (0.1%)
Other (Not Including Serious) Adverse Events
Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Bosutinib, Total
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 239/248 (96.4%) 283/284 (99.6%) 119/119 (100%) 164/167 (98.2%) 805/818 (98.4%)
Blood and lymphatic system disorders
Thrombocytopenia 80/248 (32.3%) 117/284 (41.2%) 45/119 (37.8%) 69/167 (41.3%) 311/818 (38%)
Anaemia 72/248 (29%) 87/284 (30.6%) 28/119 (23.5%) 64/167 (38.3%) 251/818 (30.7%)
Neutropenia 35/248 (14.1%) 46/284 (16.2%) 23/119 (19.3%) 35/167 (21%) 139/818 (17%)
Leukopenia 25/248 (10.1%) 37/284 (13%) 5/119 (4.2%) 25/167 (15%) 92/818 (11.2%)
Gastrointestinal disorders
Diarrhoea 177/248 (71.4%) 244/284 (85.9%) 99/119 (83.2%) 124/167 (74.3%) 644/818 (78.7%)
Nausea 89/248 (35.9%) 132/284 (46.5%) 58/119 (48.7%) 78/167 (46.7%) 357/818 (43.6%)
Vomiting 88/248 (35.5%) 106/284 (37.3%) 47/119 (39.5%) 72/167 (43.1%) 313/818 (38.3%)
Abdominal pain 39/248 (15.7%) 77/284 (27.1%) 28/119 (23.5%) 34/167 (20.4%) 178/818 (21.8%)
Abdominal pain upper 40/248 (16.1%) 59/284 (20.8%) 21/119 (17.6%) 16/167 (9.6%) 136/818 (16.6%)
Constipation 18/248 (7.3%) 44/284 (15.5%) 16/119 (13.4%) 28/167 (16.8%) 106/818 (13%)
Dyspepsia 22/248 (8.9%) 29/284 (10.2%) 12/119 (10.1%) 12/167 (7.2%) 75/818 (9.2%)
Toothache 14/248 (5.6%) 19/284 (6.7%) 5/119 (4.2%) 3/167 (1.8%) 41/818 (5%)
General disorders
Pyrexia 50/248 (20.2%) 79/284 (27.8%) 17/119 (14.3%) 59/167 (35.3%) 205/818 (25.1%)
Fatigue 42/248 (16.9%) 73/284 (25.7%) 27/119 (22.7%) 35/167 (21%) 177/818 (21.6%)
Asthenia 26/248 (10.5%) 45/284 (15.8%) 10/119 (8.4%) 19/167 (11.4%) 100/818 (12.2%)
Oedema peripheral 17/248 (6.9%) 32/284 (11.3%) 13/119 (10.9%) 18/167 (10.8%) 80/818 (9.8%)
Pain 7/248 (2.8%) 22/284 (7.7%) 7/119 (5.9%) 12/167 (7.2%) 48/818 (5.9%)
Oedema 15/248 (6%) 16/284 (5.6%) 4/119 (3.4%) 9/167 (5.4%) 44/818 (5.4%)
Chest pain 7/248 (2.8%) 21/284 (7.4%) 4/119 (3.4%) 11/167 (6.6%) 43/818 (5.3%)
Infections and infestations
Nasopharyngitis 30/248 (12.1%) 40/284 (14.1%) 14/119 (11.8%) 9/167 (5.4%) 93/818 (11.4%)
Upper respiratory tract infection 39/248 (15.7%) 32/284 (11.3%) 12/119 (10.1%) 10/167 (6%) 93/818 (11.4%)
Influenza 26/248 (10.5%) 30/284 (10.6%) 13/119 (10.9%) 6/167 (3.6%) 75/818 (9.2%)
Urinary tract infection 15/248 (6%) 31/284 (10.9%) 7/119 (5.9%) 2/167 (1.2%) 55/818 (6.7%)
Bronchitis 17/248 (6.9%) 16/284 (5.6%) 7/119 (5.9%) 6/167 (3.6%) 46/818 (5.6%)
Investigations
Alanine aminotransferase increased 90/248 (36.3%) 67/284 (23.6%) 19/119 (16%) 17/167 (10.2%) 193/818 (23.6%)
Aspartate aminotransferase increased 74/248 (29.8%) 59/284 (20.8%) 10/119 (8.4%) 17/167 (10.2%) 160/818 (19.6%)
Lipase increased 52/248 (21%) 29/284 (10.2%) 8/119 (6.7%) 9/167 (5.4%) 98/818 (12%)
Blood creatinine increased 23/248 (9.3%) 36/284 (12.7%) 16/119 (13.4%) 10/167 (6%) 85/818 (10.4%)
Weight decreased 16/248 (6.5%) 36/284 (12.7%) 7/119 (5.9%) 9/167 (5.4%) 68/818 (8.3%)
Amylase increased 30/248 (12.1%) 18/284 (6.3%) 6/119 (5%) 5/167 (3%) 59/818 (7.2%)
Blood creatine phosphokinase increased 23/248 (9.3%) 18/284 (6.3%) 2/119 (1.7%) 3/167 (1.8%) 46/818 (5.6%)
Blood alkaline phosphatase increased 20/248 (8.1%) 10/284 (3.5%) 6/119 (5%) 9/167 (5.4%) 45/818 (5.5%)
Metabolism and nutrition disorders
Decreased appetite 23/248 (9.3%) 41/284 (14.4%) 15/119 (12.6%) 21/167 (12.6%) 100/818 (12.2%)
Hypophosphataemia 26/248 (10.5%) 12/284 (4.2%) 3/119 (2.5%) 10/167 (6%) 51/818 (6.2%)
Hypokalaemia 10/248 (4%) 16/284 (5.6%) 5/119 (4.2%) 10/167 (6%) 41/818 (5%)
Musculoskeletal and connective tissue disorders
Arthralgia 32/248 (12.9%) 55/284 (19.4%) 21/119 (17.6%) 24/167 (14.4%) 132/818 (16.1%)
Back pain 26/248 (10.5%) 43/284 (15.1%) 15/119 (12.6%) 16/167 (9.6%) 100/818 (12.2%)
Pain in extremity 23/248 (9.3%) 35/284 (12.3%) 10/119 (8.4%) 19/167 (11.4%) 87/818 (10.6%)
Myalgia 16/248 (6.5%) 26/284 (9.2%) 6/119 (5%) 14/167 (8.4%) 62/818 (7.6%)
Bone pain 11/248 (4.4%) 20/284 (7%) 9/119 (7.6%) 11/167 (6.6%) 51/818 (6.2%)
Musculoskeletal pain 12/248 (4.8%) 11/284 (3.9%) 12/119 (10.1%) 9/167 (5.4%) 44/818 (5.4%)
Muscle spasms 14/248 (5.6%) 14/284 (4.9%) 8/119 (6.7%) 7/167 (4.2%) 43/818 (5.3%)
Nervous system disorders
Headache 41/248 (16.5%) 54/284 (19%) 31/119 (26.1%) 30/167 (18%) 156/818 (19.1%)
Dizziness 25/248 (10.1%) 26/284 (9.2%) 18/119 (15.1%) 21/167 (12.6%) 90/818 (11%)
Psychiatric disorders
Insomnia 12/248 (4.8%) 10/284 (3.5%) 10/119 (8.4%) 15/167 (9%) 47/818 (5.7%)
Respiratory, thoracic and mediastinal disorders
Cough 32/248 (12.9%) 70/284 (24.6%) 26/119 (21.8%) 33/167 (19.8%) 161/818 (19.7%)
Dyspnoea 25/248 (10.1%) 34/284 (12%) 13/119 (10.9%) 30/167 (18%) 102/818 (12.5%)
Pleural effusion 26/248 (10.5%) 32/284 (11.3%) 20/119 (16.8%) 14/167 (8.4%) 92/818 (11.2%)
Oropharyngeal pain 15/248 (6%) 37/284 (13%) 11/119 (9.2%) 13/167 (7.8%) 76/818 (9.3%)
Skin and subcutaneous tissue disorders
Rash 65/248 (26.2%) 105/284 (37%) 34/119 (28.6%) 52/167 (31.1%) 256/818 (31.3%)
Pruritus 20/248 (8.1%) 29/284 (10.2%) 20/119 (16.8%) 10/167 (6%) 79/818 (9.7%)
Dry skin 10/248 (4%) 22/284 (7.7%) 8/119 (6.7%) 4/167 (2.4%) 44/818 (5.4%)
Vascular disorders
Hypertension 24/248 (9.7%) 30/284 (10.6%) 10/119 (8.4%) 11/167 (6.6%) 75/818 (9.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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

Name/Title Pfizer ClinicalTrials.gov Call Center
Organization Pfizer Inc.
Phone 1-800-718-1021
Email ClinicalTrials.gov_Inquiries@pfizer.com
Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT01903733
Other Study ID Numbers:
  • B1871040
  • 2013-000691-15
First Posted:
Jul 19, 2013
Last Update Posted:
Jul 19, 2022
Last Verified:
Jun 1, 2022