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Ponatinib for Chronic Myeloid Leukemia (CML) Evaluation and Ph+ Acute Lymphoblastic Leukemia (ALL) (PACE)

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ClinicalTrials.gov Identifier: NCT01207440
Recruitment Status : Completed
First Posted : September 23, 2010
Results First Posted : January 29, 2020
Last Update Posted : February 2, 2021
Sponsor:
Information provided by (Responsible Party):
Takeda ( Ariad Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Chronic Myeloid Leukemia
Ph+ Acute Lymphoblastic Leukemia
Intervention Drug: Ponatinib
Enrollment 449
Recruitment Details Participants took part in the study at 66 investigative sites in the Australia, Belgium, Canada, France, Germany, Italy, the Netherlands, Republic of Korea, Singapore, Spain, Sweden, the United Kingdom and the United States from 30 September 2010 to 17 January 2019.
Pre-assignment Details Participants were assigned to 1 of 6 cohorts: chronic myeloid leukemia (CML) in chronic (CP), accelerated (AP), or blast phase (BP), or with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) who were resistant or intolerant (R-I) to either dasatinib or nilotinib or had (T)hreonine-315-(I)soleucine (T315I) mutation.
Arm/Group Title Cohort A: CP-CML R-I Cohort B: CP-CML With T315I Mutation Cohort C: AP-CML R-I Cohort D: AP-CML With T315I Mutation Cohort E: BP-CML/Ph+ ALL R-I Cohort F: BP-CML or Ph+ ALL With T315I Mutation Unassigned to Cohorts A-F
Hide Arm/Group Description CP-CML participants R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). CP-CML participants who had T315I mutation of breakpoint cluster region-Abelson complex (BCR-ABL) were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). AP-CML R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). AP-CML participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). BP-CML or Ph+ ALL R-I to dasatinib or nilotinib or Ph+ ALL R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). BP-CML or Ph+ ALL participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). Participants who were not assigned to any of the cohorts and have no T315I mutation at study entry and were not resistant or intolerant to dasatinib or nilotinib, administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Period Title: Overall Study
Started 203 64 65 18 48 46 5
Completed 0 0 0 0 0 0 0
Not Completed 203 64 65 18 48 46 5
Reason Not Completed
Adverse Event             46             11             7             2             6             6             2
Death             6             3             2             2             7             5             1
Lack of Efficacy             13             2             5             1             2             3             0
Lost to Follow-up             0             0             2             1             0             0             0
Non-compliance with Study Drug             3             0             1             0             0             0             0
Physician Decision             6             5             5             0             1             0             0
Progressive Disease             19             10             19             7             23             27             0
Protocol Violation             2             0             0             0             0             0             0
Site Terminated by Sponsor             69             19             12             2             3             0             2
Withdrawal by Subject             29             4             5             3             2             2             0
Reason Not Specified             10             10             7             0             4             3             0
Arm/Group Title Cohort A: CP-CML R-I Cohort B: CP-CML With T315I Mutation Cohort C: AP-CML R-I Cohort D: AP-CML With T315I Mutation Cohort E: BP-CML/Ph+ ALL R-I Cohort F: BP-CML or Ph+ ALL With T315I Mutation Unassigned to Cohorts A-F Total
Hide Arm/Group Description CP-CML participants R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). CP-CML participants who had T315I mutation of breakpoint cluster region-Abelson complex (BCR-ABL) were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). AP-CML R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). AP-CML participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). BP-CML or Ph+ ALL R-I to dasatinib or nilotinib or Ph+ ALL R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). BP-CML or Ph+ ALL participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). Participants who were not assigned to any of the cohorts and have no T315I mutation at study entry and were not resistant or intolerant to dasatinib or nilotinib, administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). Total of all reporting groups
Overall Number of Baseline Participants 203 64 65 18 48 46 5 449
Hide Baseline Analysis Population Description
The safety population included all participants who received at least 1 dose of ponatinib.
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 203 participants 64 participants 65 participants 18 participants 48 participants 46 participants 5 participants 449 participants
61.0
(22 to 94)
52.0
(18 to 87)
60.0
(23 to 82)
54.0
(24 to 78)
54.0
(18 to 74)
56.0
(18 to 80)
63.0
(51 to 71)
59.0
(18 to 94)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 203 participants 64 participants 65 participants 18 participants 48 participants 46 participants 5 participants 449 participants
Female
108
  53.2%
16
  25.0%
40
  61.5%
7
  38.9%
17
  35.4%
20
  43.5%
3
  60.0%
211
  47.0%
Male
95
  46.8%
48
  75.0%
25
  38.5%
11
  61.1%
31
  64.6%
26
  56.5%
2
  40.0%
238
  53.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 203 participants 64 participants 65 participants 18 participants 48 participants 46 participants 5 participants 449 participants
Hispanic or Latino
13
   6.4%
8
  12.5%
6
   9.2%
1
   5.6%
2
   4.2%
12
  26.1%
0
   0.0%
42
   9.4%
Not Hispanic or Latino
190
  93.6%
56
  87.5%
59
  90.8%
17
  94.4%
46
  95.8%
34
  73.9%
5
 100.0%
407
  90.6%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 203 participants 64 participants 65 participants 18 participants 48 participants 46 participants 5 participants 449 participants
American Indian/Alaska native
1
   0.5%
0
   0.0%
1
   1.5%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
2
   0.4%
Asian
17
   8.4%
14
  21.9%
8
  12.3%
3
  16.7%
8
  16.7%
7
  15.2%
2
  40.0%
59
  13.1%
Black/African American
7
   3.4%
4
   6.3%
7
  10.8%
5
  27.8%
1
   2.1%
1
   2.2%
0
   0.0%
25
   5.6%
White
174
  85.7%
42
  65.6%
47
  72.3%
9
  50.0%
39
  81.3%
38
  82.6%
3
  60.0%
352
  78.4%
Unknown
3
   1.5%
3
   4.7%
2
   3.1%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
8
   1.8%
Other
1
   0.5%
1
   1.6%
0
   0.0%
1
   5.6%
0
   0.0%
0
   0.0%
0
   0.0%
3
   0.7%
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 203 participants 64 participants 65 participants 18 participants 47 participants 46 participants 5 participants 448 participants
ECOG=0
139
  68.5%
47
  73.4%
33
  50.8%
12
  66.7%
15
  31.9%
16
  34.8%
5
 100.0%
267
  59.6%
ECOG=1
60
  29.6%
17
  26.6%
25
  38.5%
6
  33.3%
20
  42.6%
19
  41.3%
0
   0.0%
147
  32.8%
ECOG=2
4
   2.0%
0
   0.0%
7
  10.8%
0
   0.0%
12
  25.5%
11
  23.9%
0
   0.0%
34
   7.6%
[1]
Measure Description: ECOG-PS measured on-therapy assessed participant's performance status on 5 point scale: 0=Fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (>50% of waking hrs), capable of all self care, unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair >50% of waking hrs; 4=completely disabled, cannot carry on any self care, totally confined to bed/chair; 5=dead.
[2]
Measure Analysis Population Description: 1 participant from the cohort F had missing ECOG data.
Time From Diagnosis to First Dose  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 203 participants 64 participants 65 participants 18 participants 48 participants 46 participants 5 participants 449 participants
7.85
(0.45 to 27.43)
4.78
(1.16 to 19.49)
7.13
(0.33 to 28.47)
6.61
(1.17 to 15.90)
3.96
(0.62 to 27.21)
1.63
(0.46 to 14.14)
4.80
(1.74 to 18.60)
6.09
(0.33 to 28.47)
1.Primary Outcome
Title Percentage of CP-CML Participants With Major Cytogenetic Response (MCyR)
Hide Description MCyR is defined as percentage of participants with complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). Cytogenetic response is the percentage of Philadelphia chromosome positive (Ph+) metaphases in bone marrow (BM). Response is further defined as MCyR: CCyR or PCyR, where CCyR: no Ph+ cells; PCyR: 1 to 35% Ph+ cells.
Time Frame Up to 12 months after initiation of study treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. The data for this outcome measure is applicable for Cohorts A and B only.
Arm/Group Title Cohort A: CP-CML R-I Cohort B: CP-CML With T315I Mutation
Hide Arm/Group Description:
CP-CML participants R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
CP-CML participants who had T315I mutation of breakpoint cluster region-Abelson complex (BCR-ABL) were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Overall Number of Participants Analyzed 203 64
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
50.7
(43.6 to 57.8)
70.3
(57.6 to 81.1)
2.Primary Outcome
Title Percentage of AP-CML Participants With Major Hematologic Response (MaHR)
Hide Description MaHR is defined as percentage of participants with complete hematologic response (CHR) or no evidence of leukemia (NEL). Response criteria for CHR is reported as white blood cells (WBC)≤institutional upper limit of normal, absolute neutrophil count (ANC)≥1000/mm^3, platelets≥100,000/mm^3, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement; Response criteria for NEL is reported as WBC≤institutional upper limit of normal, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement, at least 1 of the following: (i) 20,000/mm^3≤platelets<100,000/mm^3; (ii) 500/mm^3≤ANC<1000/mm^3.
Time Frame Up to 6 months after initiation of study treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. The data for this outcome measure is applicable for Cohorts C and D only.
Arm/Group Title Cohort C: AP-CML R-I Cohort D: AP-CML With T315I Mutation
Hide Arm/Group Description:
AP-CML R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
AP-CML participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Overall Number of Participants Analyzed 65 18
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
56.9
(44.0 to 69.2)
55.6
(30.8 to 78.5)
3.Primary Outcome
Title Percentage of BP-CML/Ph+ ALL Participants With MaHR
Hide Description MaHR is defined as percentage of participants with CHR or NEL. Response criteria for CHR is reported as WBC≤institutional upper limit of normal, ANC≥1000/mm^3, platelets ≥100,000/mm^3, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement; Response criteria for NEL is reported as WBC≤ institutional upper limit of normal, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement, at least 1 of the following: (i) 20,000/mm^3 ≤platelets<100,000/mm^3; (ii) 500/mm^3≤ANC<1000/mm^3.
Time Frame Up to 6 months after initiation of study treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. The data for this outcome measure is applicable for Cohorts E and F only.
Arm/Group Title Cohort E: BP-CML/Ph+ ALL R-I Cohort F: BP-CML or Ph+ ALL With T315I Mutation
Hide Arm/Group Description:
BP-CML or Ph+ ALL R-I to dasatinib or nilotinib or Ph+ ALL R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
BP-CML or Ph+ ALL participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Overall Number of Participants Analyzed 48 46
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
35.4
(22.2 to 50.5)
32.6
(19.5 to 48.0)
4.Secondary Outcome
Title Percentage of CP-CML Participants With CHR
Hide Description Response criteria for CHR is reported as WBC≤institutional upper limit of normal, platelets<450,000/mm^3, no blasts or promyelocytes in peripheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement (including no hepatomegaly or splenomegaly).
Time Frame Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. The data for this outcome measure is applicable for Cohorts A and B only.
Arm/Group Title Cohort A: CP-CML R-I Cohort B: CP-CML With T315I Mutation
Hide Arm/Group Description:
CP-CML participants R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
CP-CML participants who had T315I mutation of breakpoint cluster region-Abelson complex (BCR-ABL) were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Overall Number of Participants Analyzed 203 64
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
94.6
(90.5 to 97.3)
92.2
(82.7 to 97.4)
5.Secondary Outcome
Title Percentage of CP-CML Participants With Confirmed MCyR
Hide Description Confirmed MCyR is defined as 2 assessments of CCyR or PCyR at least 28 days apart. For CP participants entering the trial in PCyR, confirmed MCyR is defined as 2 assessments of CCyR at least 28 days apart.
Time Frame Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. The data for this outcome measure is applicable for Cohorts A and B only.
Arm/Group Title Cohort A: CP-CML R-I Cohort B: CP-CML With T315I Mutation
Hide Arm/Group Description:
CP-CML participants R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
CP-CML participants who had T315I mutation of breakpoint cluster region-Abelson complex (BCR-ABL) were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Overall Number of Participants Analyzed 203 64
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
40.9
(34.1 to 48.0)
62.5
(49.5 to 74.3)
6.Secondary Outcome
Title Percentage of CP-CML Participants With Major Molecular Response (MMR)
Hide Description MMR is defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL ≤0.1% on the international scale (equivalent to a 3-log reduction in transcript).
Time Frame Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. The data for this outcome measure is applicable for Cohorts A and B only.
Arm/Group Title Cohort A: CP-CML R-I Cohort B: CP-CML With T315I Mutation
Hide Arm/Group Description:
CP-CML participants R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
CP-CML participants who had T315I mutation of breakpoint cluster region-Abelson complex (BCR-ABL) were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Overall Number of Participants Analyzed 203 64
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
35.0
(28.4 to 42.0)
57.8
(44.8 to 70.1)
7.Secondary Outcome
Title Percentage of AP-CML or BP-CML/Ph+ ALL Participants With MCyR
Hide Description MCyR is defined as percentage of participants with CCyR or PCyR. Cytogenetic response is the percentage of Ph+ metaphases in BM. Response is further defined as MCyR: CCyR or PCyR, where CCyR: no Ph+ cells; PCyR: 1 to 35% Ph+ cells.
Time Frame Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. The data for this outcome measure is applicable for Cohorts C to F only.
Arm/Group Title Cohort C: AP-CML R-I Cohort D: AP-CML With T315I Mutation Cohort E: BP-CML/Ph+ ALL R-I Cohort F: BP-CML or Ph+ ALL With T315I Mutation
Hide Arm/Group Description:
AP-CML R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
AP-CML participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
BP-CML or Ph+ ALL R-I to dasatinib or nilotinib or Ph+ ALL R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
BP-CML or Ph+ ALL participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Overall Number of Participants Analyzed 65 18 48 46
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
33.8
(22.6 to 46.6)
55.6
(30.8 to 78.5)
27.1
(15.3 to 41.8)
34.8
(21.4 to 50.2)
8.Secondary Outcome
Title Percentage of AP-CML or BP-CML/Ph+ ALL Participants With Confirmed MCyR
Hide Description Confirmed MCyR is defined as 2 assessments of CCyR or PCyR at least 28 days apart.
Time Frame Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. The data for this outcome measure is applicable for Cohorts C to F only.
Arm/Group Title Cohort C: AP-CML R-I Cohort D: AP-CML With T315I Mutation Cohort E: BP-CML/Ph+ ALL R-I Cohort F: BP-CML or Ph+ ALL With T315I Mutation
Hide Arm/Group Description:
AP-CML R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
AP-CML participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
BP-CML or Ph+ ALL R-I to dasatinib or nilotinib or Ph+ ALL R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
BP-CML or Ph+ ALL participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Overall Number of Participants Analyzed 65 18 48 46
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
24.6
(14.8 to 36.9)
38.9
(17.3 to 64.3)
20.8
(10.5 to 35.0)
15.2
(6.3 to 28.9)
9.Secondary Outcome
Title Percentage of AP-CML or BP-CML/Ph+ ALL Participants With MMR
Hide Description MMR is defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL ≤0.1% on the international scale (equivalent to a 3-log reduction in transcript).
Time Frame Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. The data for this outcome measure is applicable for Cohorts C to F only.
Arm/Group Title Cohort C: AP-CML R-I Cohort D: AP-CML With T315I Mutation Cohort E: BP-CML/Ph+ ALL R-I Cohort F: BP-CML or Ph+ ALL With T315I Mutation
Hide Arm/Group Description:
AP-CML R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
AP-CML participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
BP-CML or Ph+ ALL R-I to dasatinib or nilotinib or Ph+ ALL R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
BP-CML or Ph+ ALL participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Overall Number of Participants Analyzed 65 18 48 46
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
18.5
(9.9 to 30.0)
33.3
(13.3 to 59.0)
18.8
(8.9 to 32.6)
4.3
(0.5 to 14.8)
10.Secondary Outcome
Title Time to Response
Hide Description Time to response is defined as the interval from the first dose of study treatment until the criteria for response are first met, censored at the last assessment of response. Median time to response was estimated using the Kaplan-Meier method.
Time Frame Up to approximately 48 months after first dose
Hide Outcome Measure Data
Hide Analysis Population Description
Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. Median time to response was reported for responders only. Participants who did not achieve the specified response were censored at the last response assessment. Number analyzed: participants with data available at given time-point.
Arm/Group Title Cohort A: CP-CML R-I Cohort B: CP-CML With T315I Mutation Cohort C: AP-CML R-I Cohort D: AP-CML With T315I Mutation Cohort E: BP-CML/Ph+ ALL R-I Cohort F: BP-CML or Ph+ ALL With T315I Mutation
Hide Arm/Group Description:
CP-CML participants R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
CP-CML participants who had T315I mutation of breakpoint cluster region-Abelson complex (BCR-ABL) were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
AP-CML R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
AP-CML participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
BP-CML or Ph+ ALL R-I to dasatinib or nilotinib or Ph+ ALL R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
BP-CML or Ph+ ALL participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Overall Number of Participants Analyzed 203 64 65 18 48 46
Median (Full Range)
Unit of Measure: days
Hematologic Response Number Analyzed 192 participants 59 participants 37 participants 10 participants 17 participants 15 participants
13.0
(1 to 417)
10.0
(4 to 1008)
21.0
(12 to 112)
20.5
(14 to 176)
28.0
(14 to 168)
24.0
(11 to 57)
Cytogenetic Response Number Analyzed 103 participants 45 participants 22 participants 10 participants 13 participants 16 participants
85.0
(56 to 343)
84.0
(49 to 333)
113.5
(26 to 280)
83.0
(25 to 295)
28.0
(28 to 168)
56.0
(27 to 112)
Molecular Response Number Analyzed 71 participants 37 participants 12 participants 6 participants 9 participants 2 participants
173.0
(55 to 1686)
167.0
(81 to 756)
340.5
(55 to 1364)
335.5
(107 to 925)
56.0
(54 to 113)
63.0
(59 to 67)
11.Secondary Outcome
Title Duration of Response
Hide Description Duration of Response is defined as the interval between the first assessment at which the criteria for response are met until the criteria for progression are met, censored at the last date at which the criteria for response are met. Duration of response was estimated by the Kaplan-Meier method as the probability of remaining in response.
Time Frame Up to approximately 48 months after first dose
Hide Outcome Measure Data
Hide Analysis Population Description
Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. Number analyzed is number of participants with data available for analysis at given time-point
Arm/Group Title Cohort A: CP-CML R-I Cohort B: CP-CML With T315I Mutation Cohort C: AP-CML R-I Cohort D: AP-CML With T315I Mutation Cohort E: BP-CML/Ph+ ALL R-I Cohort F: BP-CML or Ph+ ALL With T315I Mutation
Hide Arm/Group Description:
CP-CML participants R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
CP-CML participants who had T315I mutation of breakpoint cluster region-Abelson complex (BCR-ABL) were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
AP-CML R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
AP-CML participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
BP-CML or Ph+ ALL R-I to dasatinib or nilotinib or Ph+ ALL R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
BP-CML or Ph+ ALL participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Overall Number of Participants Analyzed 203 64 65 18 48 46
Median (Full Range)
Unit of Measure: days
Hematologic Response Number Analyzed 192 participants 59 participants 37 participants 10 participants 17 participants 15 participants
NA [1] 
(36 to 2172)
NA [1] 
(33 to 2171)
360.0
(35 to 2079)
732.0
(42 to 1334)
196.0
(54 to 1811)
108.0
(54 to 1038)
Cytogenetic Response Number Analyzed 103 participants 45 participants 22 participants 10 participants 13 participants 16 participants
NA [1] 
(1 to 1963)
NA [1] 
(1 to 1903)
NA [2] 
(1 to 1779)
728.0
(28 to 1569)
NA [2] 
(1 to 1770)
63.0
(1 to 673)
Molecular Response Number Analyzed 71 participants 37 participants 12 participants 6 participants 9 participants 2 participants
NA [1] 
(78 to 1891)
NA [1] 
(1 to 1899)
560.0
(1 to 1666)
222.0
(1 to 783)
NA [2] 
(1 to 1742)
98.0
(1 to 98)
[1]
Duration of response was not reached for Cohorts A and B due to fewer number of participants with events.
[2]
Duration of response was not reached due to fewer number of participants with events.
12.Secondary Outcome
Title Progression-free Survival (PFS)
Hide Description PFS is defined as the interval from the first dose of study treatment until the criteria for progression or death are met, censored at the last response assessment. Progression from CP is reported as death, development of AP or BP, loss of CHR (in the absence of cytogenetic response), confirmed by development in complete blood counts (CBCs) at least 4 weeks apart, loss of MCyR, increasing WBC in participant without CHR defined by doubling of WBC to >20K on 2 occasions at least 4 weeks apart; Progression from AP is reported as death, development of confirmed BP, loss of previous major or minor hematologic response over a 2-week period, no decrease from baseline levels in percentage blasts in peripheral blood or BM on all assessments over a 4-week period; Progression from BP or Ph+ ALL is reported as death, increasing blasts in peripheral blood or BM over a 4 week period.
Time Frame Every 12 weeks ± 2 weeks from last dose of study drug or the investigator/participant decision to discontinue treatment, whichever occurred later (Up to approximately 96 months after last dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib.
Arm/Group Title Cohort A: CP-CML R-I Cohort B: CP-CML With T315I Mutation Cohort C: AP-CML R-I Cohort D: AP-CML With T315I Mutation Cohort E: BP-CML/Ph+ ALL R-I Cohort F: BP-CML or Ph+ ALL With T315I Mutation
Hide Arm/Group Description:
CP-CML participants R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
CP-CML participants who had T315I mutation of breakpoint cluster region-Abelson complex (BCR-ABL) were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
AP-CML R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
AP-CML participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
BP-CML or Ph+ ALL R-I to dasatinib or nilotinib or Ph+ ALL R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
BP-CML or Ph+ ALL participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Overall Number of Participants Analyzed 203 64 65 18 48 46
Median (95% Confidence Interval)
Unit of Measure: days
NA [1] 
(1285.0 to NA)
1809.0 [1] 
(1028.0 to NA)
432.0
(335.0 to 714.0)
959.0
(186.0 to 1847.0)
111.0
(55.0 to 169.0)
83.0
(55.0 to 150.0)
[1]
PFS was not reached for Cohorts A and B due to fewer number of participants with events.
13.Secondary Outcome
Title Overall Survival (OS)
Hide Description OS is defined as the interval from the first dose of study treatment until death, censored at the last date at which participant was known to be alive.
Time Frame From the first dose of study treatment until death (Up to 96 months post last dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib.
Arm/Group Title Cohort A: CP-CML R-I Cohort B: CP-CML With T315I Mutation Cohort C: AP-CML R-I Cohort D: AP-CML With T315I Mutation Cohort E: BP-CML/Ph+ ALL R-I Cohort F: BP-CML or Ph+ ALL With T315I Mutation
Hide Arm/Group Description:
CP-CML participants R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
CP-CML participants who had T315I mutation of breakpoint cluster region-Abelson complex (BCR-ABL) were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
AP-CML R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
AP-CML participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
BP-CML or Ph+ ALL R-I to dasatinib or nilotinib or Ph+ ALL R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
BP-CML or Ph+ ALL participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Overall Number of Participants Analyzed 203 64 65 18 48 46
Median (95% Confidence Interval)
Unit of Measure: days
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
1689.0 [2] 
(969.0 to NA)
1847.0
(281.0 to 2143.0)
209.0
(119.0 to 379.0)
200.0
(150.0 to 279.0)
[1]
Median OS has not been reached for Cohort A and B due to fewer number of participants with events.
[2]
Upper limit of 95% confidence interval was not estimable due to fewer number of participants with events.
14.Secondary Outcome
Title Number of Participants With Treatment-Emergent Adverse Event (TEAE) and Serious AE (SAE)
Hide Description An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy.
Time Frame From first dose up to 30 days after last dose of the study drug (Up to approximately 49 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The safety population included all participants who received at least 1 dose of ponatinib.
Arm/Group Title Cohort A: CP-CML R-I Cohort B: CP-CML With T315I Mutation Cohort C: AP-CML R-I Cohort D: AP-CML With T315I Mutation Cohort E: BP-CML/Ph+ ALL R-I Cohort F: BP-CML or Ph+ ALL With T315I Mutation Unassigned to Cohorts A-F
Hide Arm/Group Description:
CP-CML participants R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
CP-CML participants who had T315I mutation of breakpoint cluster region-Abelson complex (BCR-ABL) were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
AP-CML R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
AP-CML participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
BP-CML or Ph+ ALL R-I to dasatinib or nilotinib or Ph+ ALL R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
BP-CML or Ph+ ALL participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Participants who were not assigned to any of the cohorts and have no T315I mutation at study entry and were not resistant or intolerant to dasatinib or nilotinib, administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Overall Number of Participants Analyzed 203 64 65 18 48 46 5
Measure Type: Count of Participants
Unit of Measure: Participants
TEAE
203
 100.0%
64
 100.0%
65
 100.0%
18
 100.0%
48
 100.0%
46
 100.0%
5
 100.0%
SAE
132
  65.0%
39
  60.9%
44
  67.7%
13
  72.2%
41
  85.4%
37
  80.4%
3
  60.0%
Time Frame SAEs and Other AEs: From first dose up to 30 days after last dose of the study drug (Up to approximately 49 months); All-Cause Mortality: Up to approximately 8 years
Adverse Event Reporting Description At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
 
Arm/Group Title Cohort A: CP-CML R-I Cohort B: CP-CML With T315I Mutation Cohort C: AP-CML R-I Cohort D: AP-CML With T315I Mutation Cohort E: BP-CML/Ph+ ALL R-I Cohort F: BP-CML or Ph+ ALL With T315I Mutation Unassigned AP/CP-CML
Hide Arm/Group Description CP-CML participants R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). CP-CML participants who had T315I mutation of breakpoint cluster region-Abelson complex (BCR-ABL) were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). AP-CML R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). AP-CML participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). BP-CML or Ph+ ALL R-I to dasatinib or nilotinib or Ph+ ALL R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). BP-CML or Ph+ ALL participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). Participants who were not assigned to any of the cohorts and have no T315I mutation at study entry and were not R-I to dasatinib or nilotinib, administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
All-Cause Mortality
Cohort A: CP-CML R-I Cohort B: CP-CML With T315I Mutation Cohort C: AP-CML R-I Cohort D: AP-CML With T315I Mutation Cohort E: BP-CML/Ph+ ALL R-I Cohort F: BP-CML or Ph+ ALL With T315I Mutation Unassigned AP/CP-CML
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   41/203 (20.20%)   18/64 (28.13%)   30/65 (46.15%)   9/18 (50.00%)   40/48 (83.33%)   39/46 (84.78%)   2/5 (40.00%) 
Hide Serious Adverse Events
Cohort A: CP-CML R-I Cohort B: CP-CML With T315I Mutation Cohort C: AP-CML R-I Cohort D: AP-CML With T315I Mutation Cohort E: BP-CML/Ph+ ALL R-I Cohort F: BP-CML or Ph+ ALL With T315I Mutation Unassigned AP/CP-CML
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   132/203 (65.02%)   39/64 (60.94%)   44/65 (67.69%)   13/18 (72.22%)   41/48 (85.42%)   37/46 (80.43%)   3/5 (60.00%) 
Blood and lymphatic system disorders               
Anaemia  1  7/203 (3.45%)  0/64 (0.00%)  4/65 (6.15%)  0/18 (0.00%)  2/48 (4.17%)  2/46 (4.35%)  0/5 (0.00%) 
Febrile neutropenia  1  1/203 (0.49%)  0/64 (0.00%)  1/65 (1.54%)  1/18 (5.56%)  5/48 (10.42%)  5/46 (10.87%)  0/5 (0.00%) 
Pancytopenia  1  1/203 (0.49%)  0/64 (0.00%)  1/65 (1.54%)  1/18 (5.56%)  2/48 (4.17%)  1/46 (2.17%)  0/5 (0.00%) 
Splenic infarction  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Hyperviscosity syndrome  1 [1]  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Hyperleukocytosis  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Lymphadenopathy  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Neutropenia  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  2/46 (4.35%)  0/5 (0.00%) 
Thrombocytopenia  1  1/203 (0.49%)  1/64 (1.56%)  4/65 (6.15%)  0/18 (0.00%)  2/48 (4.17%)  1/46 (2.17%)  0/5 (0.00%) 
Cardiac disorders               
Atrial fibrillation  1  11/203 (5.42%)  4/64 (6.25%)  0/65 (0.00%)  0/18 (0.00%)  3/48 (6.25%)  2/46 (4.35%)  0/5 (0.00%) 
Cardiac failure congestive  1 [2]  5/203 (2.46%)  3/64 (4.69%)  1/65 (1.54%)  0/18 (0.00%)  1/48 (2.08%)  1/46 (2.17%)  0/5 (0.00%) 
Coronary artery disease  1  4/203 (1.97%)  6/64 (9.38%)  1/65 (1.54%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Acute myocardial infarction  1 [3]  2/203 (0.99%)  1/64 (1.56%)  1/65 (1.54%)  2/18 (11.11%)  2/48 (4.17%)  0/46 (0.00%)  0/5 (0.00%) 
Angina pectoris  1  10/203 (4.93%)  4/64 (6.25%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Cardiac arrest  1 [4]  2/203 (0.99%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Coronary artery stenosis  1  2/203 (0.99%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Atrial tachycardia  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Pericardial effusion  1  3/203 (1.48%)  1/64 (1.56%)  1/65 (1.54%)  0/18 (0.00%)  1/48 (2.08%)  1/46 (2.17%)  0/5 (0.00%) 
Sinus tachycardia  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Acute coronary syndrome  1  3/203 (1.48%)  3/64 (4.69%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  1/5 (20.00%) 
Cardiopulmonary failure  1 [5]  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Cardiac failure  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  1/18 (5.56%)  3/48 (6.25%)  0/46 (0.00%)  1/5 (20.00%) 
Atrial flutter  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Atrioventricular block complete  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Cardiac tamponade  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Cardiogenic shock  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Pericarditis  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Right ventricular failure  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Tachycardia  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Coronary artery occlusion  1  2/203 (0.99%)  1/64 (1.56%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Acute left ventricular failure  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Angina unstable  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Aortic valve stenosis  1  1/203 (0.49%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Arrhythmia supraventricular  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Arteriosclerosis coronary artery  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Arteriospasm coronary  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Bradycardia  1  0/203 (0.00%)  1/64 (1.56%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Cardiac Discomfort  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Cardiac failure acute  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Cardio-respiratory arrest  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Congestive cardiomyopathy  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Dressler's syndrome  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Ischaemic cardiomyopathy  1  0/203 (0.00%)  1/64 (1.56%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Left ventricular dysfunction  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Mitral valve incompetence  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Sinus node dysfunction  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Ventricular tachycardia  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Cardiac failure chronic  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Bundle branch block right  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Left ventricular failure  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Myocardial infarction  1  3/203 (1.48%)  4/64 (6.25%)  2/65 (3.08%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Ear and labyrinth disorders               
Vertigo positional  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Vertigo  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Endocrine disorders               
Thyroid mass  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Eye disorders               
Retinal vein occlusion  1  2/203 (0.99%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Cataract  1  1/203 (0.49%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Cystoid macular oedema  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Retinal artery occlusion  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Retinal vein thrombosis  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Ulcerative keratitis  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Vision blurred  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Macular fibrosis  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Gastrointestinal disorders               
Pancreatitis  1  10/203 (4.93%)  4/64 (6.25%)  3/65 (4.62%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Abdominal pain  1  7/203 (3.45%)  1/64 (1.56%)  4/65 (6.15%)  1/18 (5.56%)  4/48 (8.33%)  1/46 (2.17%)  0/5 (0.00%) 
Constipation  1  3/203 (1.48%)  1/64 (1.56%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Diarrhoea  1  1/203 (0.49%)  1/64 (1.56%)  1/65 (1.54%)  1/18 (5.56%)  1/48 (2.08%)  1/46 (2.17%)  0/5 (0.00%) 
Gastritis  1  2/203 (0.99%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Vomiting  1  0/203 (0.00%)  1/64 (1.56%)  1/65 (1.54%)  0/18 (0.00%)  2/48 (4.17%)  0/46 (0.00%)  0/5 (0.00%) 
Colitis  1  2/203 (0.99%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Hiatus hernia  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Ileus  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Nausea  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Oesophagitis  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Haemorrhoidal haemorrhage  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  1/5 (20.00%) 
Ascites  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Rectal haemorrhage  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  1/5 (20.00%) 
Retroperitoneal haematoma  1  0/203 (0.00%)  0/64 (0.00%)  2/65 (3.08%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Gastrointestinal haemorrhage  1 [6]  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  2/46 (4.35%)  1/5 (20.00%) 
Abdominal distension  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Acute abdomen  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Dysphagia  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Gastric haemorrhage  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Gastritis haemorrhagic  1 [7]  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Stomatitis  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Appendicitis Noninfective  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Colitis Ischaemic  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Faecaloma  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  1/5 (20.00%) 
Fistula of small intestine  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Gastric ulcer haemorrhage  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Inguinal hernia  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Large intestinal obstruction  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Small intestinal obstruction  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Upper gastrointestinal haemorrhage  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Gastrooesophageal reflux disease  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Peritoneal haemorrhage  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Mesenteric arterial occlusion  1 [7]  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Abdominal pain upper  1  2/203 (0.99%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Pancreatitis acute  1  5/203 (2.46%)  1/64 (1.56%)  2/65 (3.08%)  0/18 (0.00%)  2/48 (4.17%)  0/46 (0.00%)  0/5 (0.00%) 
General disorders               
Pyrexia  1  5/203 (2.46%)  3/64 (4.69%)  5/65 (7.69%)  2/18 (11.11%)  2/48 (4.17%)  2/46 (4.35%)  1/5 (20.00%) 
Non-cardiac chest pain  1  4/203 (1.97%)  1/64 (1.56%)  2/65 (3.08%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Asthenia  1  1/203 (0.49%)  0/64 (0.00%)  1/65 (1.54%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Chest pain  1  2/203 (0.99%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Chills  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  2/48 (4.17%)  0/46 (0.00%)  0/5 (0.00%) 
Pain  1  1/203 (0.49%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Systemic inflammatory response syndrome  1  0/203 (0.00%)  2/64 (3.13%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Implant site pain  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Impaired healing  1  2/203 (0.99%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Gait disturbance  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Oedema peripheral  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Vascular stent occlusion  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Fatigue  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Multiple organ dysfunction syndrome  1 [8]  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  1/46 (2.17%)  0/5 (0.00%) 
Hepatobiliary disorders               
Bile duct stone  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Cholangitis  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Cholelithiasis  1  2/203 (0.99%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Cholecystitis  1  1/203 (0.49%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Cholecystitis acute  1  1/203 (0.49%)  1/64 (1.56%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Portal vein thrombosis  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Non-alcoholic steatohepatitis  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Venoocclusive liver disease  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Biliary dilatation  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Gallbladder obstruction  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Hyperbilirubinaemia  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Immune system disorders               
Hypersensitivity  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Graft versus host disease in skin  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Anaphylactic reaction  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Anaphylactoid reaction  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Drug hypersensitivity  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Infections and infestations               
Pneumonia  1 [9]  10/203 (4.93%)  5/64 (7.81%)  8/65 (12.31%)  1/18 (5.56%)  4/48 (8.33%)  5/46 (10.87%)  0/5 (0.00%) 
Cellulitis  1  4/203 (1.97%)  1/64 (1.56%)  2/65 (3.08%)  1/18 (5.56%)  2/48 (4.17%)  0/46 (0.00%)  0/5 (0.00%) 
Sepsis  1 [10]  2/203 (0.99%)  1/64 (1.56%)  2/65 (3.08%)  1/18 (5.56%)  2/48 (4.17%)  2/46 (4.35%)  1/5 (20.00%) 
Upper respiratory tract infection  1  2/203 (0.99%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Urinary tract infection  1  5/203 (2.46%)  2/64 (3.13%)  0/65 (0.00%)  1/18 (5.56%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Bacterial infection  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Bronchitis  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Diverticulitis  1  2/203 (0.99%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Herpes oesophagitis  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Osteomyelitis  1  2/203 (0.99%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Respiratory syncytial virus infection  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Wound infection  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Bacteraemia  1  1/203 (0.49%)  0/64 (0.00%)  1/65 (1.54%)  1/18 (5.56%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Appendicitis  1  0/203 (0.00%)  0/64 (0.00%)  2/65 (3.08%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Breast cellulitis  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Clostridium difficile colitis  1  3/203 (1.48%)  0/64 (0.00%)  2/65 (3.08%)  0/18 (0.00%)  2/48 (4.17%)  0/46 (0.00%)  0/5 (0.00%) 
Infection  1  0/203 (0.00%)  0/64 (0.00%)  2/65 (3.08%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Localised infection  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Lung infection  1  1/203 (0.49%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Pharyngitis streptococcal  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Pneumonia fungal  1 [11]  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Pulmonary tuberculosis  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Respiratory tract infection  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Septic shock  1 [12]  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  2/46 (4.35%)  0/5 (0.00%) 
Splenic abscess  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Klebsiella sepsis  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  2/46 (4.35%)  0/5 (0.00%) 
Catheter site cellulitis  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Gastroenteritis  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  2/48 (4.17%)  0/46 (0.00%)  0/5 (0.00%) 
Haematoma infection  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Otitis externa  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Pneumonia respiratory syncytial viral  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Post procedural infection  1  2/203 (0.99%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Abdominal sepsis  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Arthritis bacterial  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Arthritis viral  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Cholecystitis infective  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Clostridium difficile infection  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Genital infection bacterial  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Otitis media chronic  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Peritonitis  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Pneumonia mycoplasmal  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Pyelonephritis  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Pyelonephritis acute  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Systemic infection  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Viral infection  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Wound infection staphylococcal  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Pneumonia staphylococcal  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Gangrene  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Gastroenteritis norovirus  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Kidney infection  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Urosepsis  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Oesophageal candidiasis  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Atypical pneumonia  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Device related sepsis  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Infectious colitis  1 [1]  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Pneumonia influenzal  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Postoperative wound infection  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Staphylococcal bacteraemia  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Pneumocystis jirovecii pneumonia  1 [13]  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Injury, poisoning and procedural complications               
Subarachnoid haemorrhage  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Concussion  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Peripancreatic fluid collection  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Procedural vomiting  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Fall  1  1/203 (0.49%)  0/64 (0.00%)  1/65 (1.54%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Subdural haematoma  1  2/203 (0.99%)  0/64 (0.00%)  2/65 (3.08%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Post procedural haematoma  1  1/203 (0.49%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Post procedural haemorrhage  1  1/203 (0.49%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Procedural pain  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Traumatic intracranial haemorrhage  1 [5]  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Pneumonitis chemical  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Peripheral artery restenosis  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Head injury  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Humerus fracture  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Spinal column injury  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Wound dehiscence  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Wrist fracture  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Investigations               
Lipase increased  1  4/203 (1.97%)  3/64 (4.69%)  1/65 (1.54%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Platelet count decreased  1  2/203 (0.99%)  0/64 (0.00%)  2/65 (3.08%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Alanine aminotransferase increased  1  3/203 (1.48%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Neutrophil count decreased  1  2/203 (0.99%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Blood alkaline phosphatase increased  1  1/203 (0.49%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Ejection fraction decreased  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  2/48 (4.17%)  1/46 (2.17%)  0/5 (0.00%) 
Gamma-glutamyltransferase increased  1  1/203 (0.49%)  0/64 (0.00%)  2/65 (3.08%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Blood bilirubin increased  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Aspartate aminotransferase increased  1  1/203 (0.49%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Urine analysis abnormal  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Hepatic enzyme increased  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
International normalised ratio increased  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Liver function test increased  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Blood potassium increased  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Haemoglobin decreased  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
JC polyomavirus test positive  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Metabolism and nutrition disorders               
Hyponatraemia  1  4/203 (1.97%)  1/64 (1.56%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Dehydration  1 [1]  4/203 (1.97%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  2/48 (4.17%)  1/46 (2.17%)  0/5 (0.00%) 
Diabetes mellitus  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Hyperkalaemia  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Electrolyte imbalance  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Tumour lysis syndrome  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Failure to thrive  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Fluid overload  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Fluid retention  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Hyperuricaemia  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Hypercalcaemia  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Hyperglycaemia  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Musculoskeletal and connective tissue disorders               
Arthralgia  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Back pain  1  1/203 (0.49%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Flank pain  1  2/203 (0.99%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Myalgia  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Spinal osteoarthritis  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Lumbar spinal stenosis  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Bone pain  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  2/48 (4.17%)  1/46 (2.17%)  0/5 (0.00%) 
Musculoskeletal pain  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Spinal column stenosis  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Osteoarthritis  1  2/203 (0.99%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Intervertebral disc protrusion  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)               
Neoplasm progression  1 [14]  6/203 (2.96%)  2/64 (3.13%)  7/65 (10.77%)  4/18 (22.22%)  14/48 (29.17%)  8/46 (17.39%)  0/5 (0.00%) 
Myelodysplastic syndrome  1  3/203 (1.48%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Malignant melanoma  1  2/203 (0.99%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Malignant pleural effusion  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Basal cell carcinoma  1  1/203 (0.49%)  0/64 (0.00%)  2/65 (3.08%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Blast crisis in myelogenous leukaemia  1 [15]  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  1/18 (5.56%)  1/48 (2.08%)  1/46 (2.17%)  0/5 (0.00%) 
Squamous cell carcinoma of skin  1  3/203 (1.48%)  0/64 (0.00%)  2/65 (3.08%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Chloroma  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Colon cancer  1  2/203 (0.99%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Skin squamous cell carcinoma metastatic  1 [13]  2/203 (0.99%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Large cell lung cancer recurrent  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Non-hodgkin's lymphoma  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Squamous cell carcinoma  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Vulval cancer  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Central nervous system leukaemia  1 [16]  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Acute lymphocytic leukaemia recurrent  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Pancreatic carcinoma  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Neuroendocrine carcinoma metastatic  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Bowen's disease  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Nervous system disorders               
Cerebrovascular accident  1 [17]  5/203 (2.46%)  4/64 (6.25%)  1/65 (1.54%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Headache  1  2/203 (0.99%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Transient ischaemic attack  1  2/203 (0.99%)  2/64 (3.13%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Ataxia  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Cerebral artery stenosis  1  0/203 (0.00%)  2/64 (3.13%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Cerebral infarction  1  5/203 (2.46%)  3/64 (4.69%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Haemorrhagic cerebral infarction  1 [17]  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Haemorrhagic transformation stroke  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
IVth nerve paralysis  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Spinal cord compression  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Cerebellar infarction  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Cerebral haemorrhage  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Cerebral ischaemia  1 [5]  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Dizziness  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Migraine  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Somnolence  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  1/5 (20.00%) 
Syncope  1  3/203 (1.48%)  1/64 (1.56%)  2/65 (3.08%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Haemorrhage intracranial  1 [1]  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Brain oedema  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Loss of consciousness  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Paraesthesia  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Status epilepticus  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Dementia  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Facial Paralysis  1  1/203 (0.49%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Iiird nerve paralysis  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Neuropathy peripheral  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Carotid artery stenosis  1  5/203 (2.46%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Cerebrovascular disorder  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Encephalopathy  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Hypoaesthesia  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Intracranial aneurysm  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Lacunar infarction  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Memory impairment  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Sciatica  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Seizure  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Carotid artery occlusion  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Product Issues               
Device dislocation  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Psychiatric disorders               
Confusional state  1  3/203 (1.48%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Mental status changes  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  2/46 (4.35%)  0/5 (0.00%) 
Delirium  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Renal and urinary disorders               
Renal failure  1  2/203 (0.99%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Nephrolithiasis  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Acute kidney injury  1  2/203 (0.99%)  2/64 (3.13%)  2/65 (3.08%)  0/18 (0.00%)  3/48 (6.25%)  0/46 (0.00%)  0/5 (0.00%) 
Renal artery stenosis  1  2/203 (0.99%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Haematuria  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  1/5 (20.00%) 
Urinary retention  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  1/5 (20.00%) 
Dysuria  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Reproductive system and breast disorders               
Prostatic obstruction  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Prostatitis  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Haemorrhagic ovarian cyst  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Ovarian cyst  1  1/203 (0.49%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Respiratory, thoracic and mediastinal disorders               
Dyspnoea  1  2/203 (0.99%)  3/64 (4.69%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  1/5 (20.00%) 
Hypoxia  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Pneumothorax  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Pulmonary embolism  1  3/203 (1.48%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  3/48 (6.25%)  0/46 (0.00%)  0/5 (0.00%) 
Epistaxis  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Pleural effusion  1  2/203 (0.99%)  1/64 (1.56%)  1/65 (1.54%)  0/18 (0.00%)  1/48 (2.08%)  1/46 (2.17%)  1/5 (20.00%) 
Respiratory failure  1  0/203 (0.00%)  0/64 (0.00%)  2/65 (3.08%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Chronic obstructive pulmonary disease  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  2/46 (4.35%)  1/5 (20.00%) 
Dyspnoea exertional  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Pleuritic pain  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Pulmonary hypertension  1  2/203 (0.99%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Pneumonitis  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Lung disorder  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Skin and subcutaneous tissue disorders               
Angioedema  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Erythema  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Erythema multiforme  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Hyperkeratosis  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Skin ulcer  1  2/203 (0.99%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Acute febrile neutrophilic dermatosis  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Dermatitis exfoliative generalised  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Skin swelling  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Diabetic foot  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Mucocutaneous haemorrhage  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Rash erythematous  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Rash maculo-papular  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Social circumstances               
Immobile  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Vascular disorders               
Hypertension  1  11/203 (5.42%)  0/64 (0.00%)  2/65 (3.08%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Hypotension  1 [18]  2/203 (0.99%)  1/64 (1.56%)  2/65 (3.08%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Deep vein thrombosis  1  4/203 (1.97%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  1/46 (2.17%)  0/5 (0.00%) 
Hot flush  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Peripheral ischaemia  1 [5]  3/203 (1.48%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Extremity necrosis  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Hypertensive crisis  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Embolism venous  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Thrombophlebitis superficial  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Peripheral arterial occlusive disease  1  10/203 (4.93%)  4/64 (6.25%)  1/65 (1.54%)  1/18 (5.56%)  1/48 (2.08%)  1/46 (2.17%)  0/5 (0.00%) 
Peripheral artery stenosis  1  4/203 (1.97%)  3/64 (4.69%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  1/5 (20.00%) 
Peripheral artery occlusion  1  4/203 (1.97%)  1/64 (1.56%)  0/65 (0.00%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Peripheral vascular disorder  1  2/203 (0.99%)  1/64 (1.56%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Dry gangrene  1  1/203 (0.49%)  1/64 (1.56%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Aortic arteriosclerosis  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Temporal arteritis  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Varicose vein  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Vasculitis  1  1/203 (0.49%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Coeliac artery occlusion  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Embolism arterial  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Intermittent claudication  1  2/203 (0.99%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
1
Term from vocabulary, MedDRA version 19.0
Indicates events were collected by systematic assessment
[1]
One treatment-emergent death occurred during treatment with ponatinib in Cohort E and is not related.
[2]
Two treatment-emergent deaths (1-Cohort B, 1-Cohort E) occurred during treatment with ponatinib and are not related.
[3]
One treatment-emergent death occurred during treatment with ponatinib in Cohort A and is related.
[4]
Four treatment-emergent deaths (2-Cohort A, 1-Cohort B, 1-Cohort F) occurred during treatment with ponatinib and one in Cohort F is related.
[5]
One treatment-emergent death occurred during treatment with ponatinib in Cohort F and is not related.
[6]
One treatment-emergent death occurred during treatment with ponatinib in Unassigned AP/CP-CML and is related.
[7]
One treatment-emergent death occurred during treatment with ponatinib in Cohort E and is related.
[8]
Two treatment-emergent deaths (1-Cohort E, 1-Cohort F) occurred during treatment with ponatinib and are not related.
[9]
Two treatment-emergent deaths occurred during treatment with ponatinib in Cohort A and one is related.
[10]
Three treatment-emergent deaths (1-Cohort D, 1-Cohort E, 1-Cohort F) occurred during treatment with ponatinib and are not related.
[11]
One treatment-emergent death occurred during treatment with ponatinib in Cohort D and is related.
[12]
Three treatment-emergent deaths (1-Cohort C, 2-Cohort F) occurred during treatment with ponatinib and are not related.
[13]
One treatment-emergent death occurred during treatment with ponatinib in Cohort A and is not related.
[14]
Twenty-four treatment-emergent deaths (4-Cohort A, 1-Cohort B, 2-Cohort C, 2-Cohort D, 10-Cohort E, 5 Cohort F) occurred during treatment with ponatinib and are not related.
[15]
Three treatment-emergent deaths (1-Cohort C, 1-Cohort E, 1-Cohort F) occurred during treatment with ponatinib and are not related.
[16]
One treatment-emergent death occurred during treatment with ponatinib in Cohort D and is not related.
[17]
One treatment-emergent death occurred during treatment with ponatinib in Cohort B and is not related.
[18]
One treatment-emergent death occurred during treatment with ponatinib in Cohort C and is not related.
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Cohort A: CP-CML R-I Cohort B: CP-CML With T315I Mutation Cohort C: AP-CML R-I Cohort D: AP-CML With T315I Mutation Cohort E: BP-CML/Ph+ ALL R-I Cohort F: BP-CML or Ph+ ALL With T315I Mutation Unassigned AP/CP-CML
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   203/203 (100.00%)   64/64 (100.00%)   65/65 (100.00%)   18/18 (100.00%)   48/48 (100.00%)   46/46 (100.00%)   5/5 (100.00%) 
Blood and lymphatic system disorders               
Anaemia  1  39/203 (19.21%)  7/64 (10.94%)  20/65 (30.77%)  7/18 (38.89%)  14/48 (29.17%)  11/46 (23.91%)  1/5 (20.00%) 
Febrile neutropenia  1  1/203 (0.49%)  1/64 (1.56%)  2/65 (3.08%)  0/18 (0.00%)  3/48 (6.25%)  3/46 (6.52%)  0/5 (0.00%) 
Hypochromasia  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Leukopenia  1  7/203 (3.45%)  0/64 (0.00%)  5/65 (7.69%)  2/18 (11.11%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Lymphadenopathy  1  6/203 (2.96%)  0/64 (0.00%)  2/65 (3.08%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  1/5 (20.00%) 
Neutropenia  1  42/203 (20.69%)  6/64 (9.38%)  24/65 (36.92%)  4/18 (22.22%)  13/48 (27.08%)  7/46 (15.22%)  0/5 (0.00%) 
Thrombocytopenia  1  90/203 (44.33%)  18/64 (28.13%)  32/65 (49.23%)  4/18 (22.22%)  16/48 (33.33%)  7/46 (15.22%)  1/5 (20.00%) 
Cardiac disorders               
Angina pectoris  1  9/203 (4.43%)  4/64 (6.25%)  3/65 (4.62%)  0/18 (0.00%)  3/48 (6.25%)  0/46 (0.00%)  0/5 (0.00%) 
Atrial fibrillation  1  10/203 (4.93%)  3/64 (4.69%)  1/65 (1.54%)  0/18 (0.00%)  2/48 (4.17%)  4/46 (8.70%)  1/5 (20.00%) 
Cardiac failure  1  1/203 (0.49%)  1/64 (1.56%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  1/5 (20.00%) 
Cardiomyopathy  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  0/18 (0.00%)  3/48 (6.25%)  0/46 (0.00%)  0/5 (0.00%) 
Palpitations  1  6/203 (2.96%)  1/64 (1.56%)  2/65 (3.08%)  1/18 (5.56%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Pericardial effusion  1  5/203 (2.46%)  1/64 (1.56%)  2/65 (3.08%)  0/18 (0.00%)  3/48 (6.25%)  2/46 (4.35%)  0/5 (0.00%) 
Tachycardia  1  3/203 (1.48%)  1/64 (1.56%)  1/65 (1.54%)  0/18 (0.00%)  2/48 (4.17%)  4/46 (8.70%)  0/5 (0.00%) 
Ear and labyrinth disorders               
Tinnitus  1  8/203 (3.94%)  1/64 (1.56%)  1/65 (1.54%)  1/18 (5.56%)  1/48 (2.08%)  0/46 (0.00%)  1/5 (20.00%) 
Vertigo  1  8/203 (3.94%)  1/64 (1.56%)  3/65 (4.62%)  1/18 (5.56%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Endocrine disorders               
Adrenal insufficiency  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Hypothyroidism  1  7/203 (3.45%)  2/64 (3.13%)  4/65 (6.15%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Eye disorders               
Blepharitis  1  3/203 (1.48%)  1/64 (1.56%)  2/65 (3.08%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  1/5 (20.00%) 
Cataract  1  7/203 (3.45%)  1/64 (1.56%)  1/65 (1.54%)  1/18 (5.56%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Conjunctival hyperaemia  1  2/203 (0.99%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Dry eye  1  16/203 (7.88%)  5/64 (7.81%)  4/65 (6.15%)  2/18 (11.11%)  4/48 (8.33%)  3/46 (6.52%)  1/5 (20.00%) 
Eye pain  1  8/203 (3.94%)  4/64 (6.25%)  2/65 (3.08%)  0/18 (0.00%)  3/48 (6.25%)  0/46 (0.00%)  0/5 (0.00%) 
Eyelid disorder  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Eyelid oedema  1  3/203 (1.48%)  1/64 (1.56%)  0/65 (0.00%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Vision blurred  1  13/203 (6.40%)  6/64 (9.38%)  3/65 (4.62%)  1/18 (5.56%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Visual acuity reduced  1  1/203 (0.49%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  0/46 (0.00%)  1/5 (20.00%) 
Visual impairment  1  3/203 (1.48%)  1/64 (1.56%)  1/65 (1.54%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  1/5 (20.00%) 
Vitreous floaters  1  1/203 (0.49%)  0/64 (0.00%)  1/65 (1.54%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Gastrointestinal disorders               
Abdominal discomfort  1  8/203 (3.94%)  3/64 (4.69%)  3/65 (4.62%)  0/18 (0.00%)  1/48 (2.08%)  1/46 (2.17%)  1/5 (20.00%) 
Abdominal distension  1  12/203 (5.91%)  7/64 (10.94%)  4/65 (6.15%)  1/18 (5.56%)  3/48 (6.25%)  1/46 (2.17%)  1/5 (20.00%) 
Abdominal pain  1  75/203 (36.95%)  21/64 (32.81%)  20/65 (30.77%)  7/18 (38.89%)  7/48 (14.58%)  10/46 (21.74%)  2/5 (40.00%) 
Abdominal pain upper  1  40/203 (19.70%)  10/64 (15.63%)  11/65 (16.92%)  2/18 (11.11%)  6/48 (12.50%)  8/46 (17.39%)  2/5 (40.00%) 
Ascites  1  0/203 (0.00%)  1/64 (1.56%)  0/65 (0.00%)  1/18 (5.56%)  1/48 (2.08%)  0/46 (0.00%)  0/5 (0.00%) 
Constipation  1  89/203 (43.84%)  21/64 (32.81%)  16/65 (24.62%)  7/18 (38.89%)  21/48 (43.75%)  13/46 (28.26%)  3/5 (60.00%) 
Dental necrosis  1  0/203 (0.00%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  0/48 (0.00%)  0/46 (0.00%)  0/5 (0.00%) 
Diarrhoea  1  43/203 (21.18%)  10/64 (15.63%)  17/65 (26.15%)  7/18 (38.89%)  15/48 (31.25%)  4/46 (8.70%)  0/5 (0.00%) 
Dry mouth  1  20/203 (9.85%)  6/64 (9.38%)  4/65 (6.15%)  0/18 (0.00%)  4/48 (8.33%)  1/46 (2.17%)  0/5 (0.00%) 
Dyspepsia  1  12/203 (5.91%)  6/64 (9.38%)  4/65 (6.15%)  0/18 (0.00%)  2/48 (4.17%)  2/46 (4.35%)  0/5 (0.00%) 
Dysphagia  1  3/203 (1.48%)  1/64 (1.56%)  2/65 (3.08%)  0/18 (0.00%)  1/48 (2.08%)  0/46 (0.00%)  1/5 (20.00%) 
Gastrooesophageal reflux disease  1  10/203 (4.93%)  8/64 (12.50%)  2/65 (3.08%)  0/18 (0.00%)  2/48 (4.17%)  0/46 (0.00%)  1/5 (20.00%) 
Gingival bleeding  1  3/203 (1.48%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  2/48 (4.17%)  2/46 (4.35%)  1/5 (20.00%) 
Haemorrhoids  1  4/203 (1.97%)  1/64 (1.56%)  1/65 (1.54%)  1/18 (5.56%)  2/48 (4.17%)  2/46 (4.35%)  0/5 (0.00%) 
Mouth haemorrhage  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  1/18 (5.56%)  0/48 (0.00%)  2/46 (4.35%)  0/5 (0.00%) 
Nausea  1  53/203 (26.11%)  24/64 (37.50%)  22/65 (33.85%)  5/18 (27.78%)  16/48 (33.33%)  12/46 (26.09%)  1/5 (20.00%) 
Odynophagia  1  1/203 (0.49%)  0/64 (0.00%)  0/65 (0.00%)  2/18 (11.11%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%) 
Rectal haemorrhage  1  0/203 (0.00%)  0/64 (0.00%)  1/65 (1.54%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  1/5 (20.00%) 
Stomatitis  1  11/203 (5.42%)  2/64 (3.13%)  4/65 (6.15%)  1/18 (5.56%)  2/48 (4.17%)  3/46 (6.52%)  0/5 (0.00%) 
Toothache  1  13/203 (6.40%)  0/64 (0.00%)  3/65 (4.62%)  0/18 (0.00%)  0/48 (0.00%)  1/46 (2.17%)  0/5 (0.00%)