Bosutinib Treatment Extension Study Only For Subjects With Chronic Myeloid Leukemia (CML) Who Have Previously Participated In Bosutinib Studies B1871006 Or B1871008
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
Outcome Measures
Primary Outcome Measures
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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
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 | GdaĆsk | 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.- B1871040
- 2013-000691-15
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
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%
|
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%
|
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%
|
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%
|
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%
|
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%
|
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%
|
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%
|
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)
|
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%
|
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%
|
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
|
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%
|
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
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 |
ClinicalTrials.gov_Inquiries@pfizer.com |
- B1871040
- 2013-000691-15