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

Sponsor
Ariad Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT01207440
Collaborator
(none)
449
Enrollment
42
Locations
7
Arms
99.6
Actual Duration (Months)
10.7
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the efficacy of ponatinib in patients with chronic myeloid leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast phase (BP) or with philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who either are resistant or intolerant to either dasatinib or nilotinib, or have the (T)hreonine-315-(I)soleucine (T315I) mutation.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

The preliminary analysis of the phase 1 clinical trial revealed evidence of clinical antitumor activity in patients with resistance to approved second-generation tyrosine kinase inhibitors (TKI), dasatinib and nilotinib, including patients with the T315I mutation of the BCR-ABL gene (BCR-ABL). This Phase 1 study, taken together with the strong preclinical data that characterize ponatinib, provides the rationale for moving to a pivotal phase 2 trial of this agent in a population of patients with chronic myeloid leukemia (CML) and Ph+ Acute Lymphoblastic Leukemia (ALL) who are resistant or intolerant to prior TKI therapy and in those patients with the T315I mutation.

PACE is a multi-center, international, phase 2, uncontrolled, open-label trial of oral ponatinib in patients with Philadelphia chromosome-positive (Ph+) disease. The study enrolled 449 patients. Participants assigned to 1 of 6 cohorts in accordance with disease group and received:

  • Ponatinib 45 mg

This multi-center trial is conducted worldwide. The overall time to participate in this study is 96 months after last dose of study drug treatment.

Study Design

Study Type:
Interventional
Actual Enrollment :
449 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients With Refractory Chronic Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia
Actual Study Start Date :
Sep 30, 2010
Actual Primary Completion Date :
Dec 20, 2018
Actual Study Completion Date :
Jan 17, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Cohort A: CP-CML R-I

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).

Drug: Ponatinib
Ponatinib tablets.
Other Names:
  • AP24534
  • Iclusig

    		•
    Experimental: Cohort B: CP-CML with T315I Mutation

    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).

    Drug: Ponatinib
    Ponatinib tablets.
    Other Names:
  • AP24534
  • Iclusig

    		•
    Experimental: Cohort C: Accelerated Phase (AP)-CML R-I

    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).

    Drug: Ponatinib
    Ponatinib tablets.
    Other Names:
  • AP24534
  • Iclusig

    		•
    Experimental: Cohort D: AP-CML with T315I Mutation

    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).

    Drug: Ponatinib
    Ponatinib tablets.
    Other Names:
  • AP24534
  • Iclusig

    		•
    Experimental: Cohort E: Blast Phase (BP)-CML/Ph+ ALL R-I

    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).

    Drug: Ponatinib
    Ponatinib tablets.
    Other Names:
  • AP24534
  • Iclusig

    		•
    Experimental: Cohort F: BP-CML or Ph+ ALL with T315I Mutation

    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).

    Drug: Ponatinib
    Ponatinib tablets.
    Other Names:
  • AP24534
  • Iclusig

    		•
    Experimental: Unassigned to Cohorts A-F

    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).

    Drug: Ponatinib
    Ponatinib tablets.
    Other Names:
  • AP24534
  • Iclusig

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of CP-CML Participants With Major Cytogenetic Response (MCyR) [Up to 12 months after initiation of study treatment]

      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.

    2. Percentage of AP-CML Participants With Major Hematologic Response (MaHR) [Up to 6 months after initiation of study treatment]

      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.

    3. Percentage of BP-CML/Ph+ ALL Participants With MaHR [Up to 6 months after initiation of study treatment]

      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.

    Secondary Outcome Measures

    1. Percentage of CP-CML Participants With CHR [Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose)]

      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).

    2. Percentage of CP-CML Participants With Confirmed MCyR [Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose)]

      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.

    3. Percentage of CP-CML Participants With Major Molecular Response (MMR) [Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose)]

      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).

    4. Percentage of AP-CML or BP-CML/Ph+ ALL Participants With MCyR [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)]

      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.

    5. Percentage of AP-CML or BP-CML/Ph+ ALL Participants With Confirmed MCyR [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)]

      Confirmed MCyR is defined as 2 assessments of CCyR or PCyR at least 28 days apart.

    6. Percentage of AP-CML or BP-CML/Ph+ ALL Participants With MMR [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)]

      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).

    7. Time to Response [Up to approximately 48 months after first dose]

      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.

    8. Duration of Response [Up to approximately 48 months after first dose]

      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.

    9. Progression-free Survival (PFS) [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)]

      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.

    10. Overall Survival (OS) [From the first dose of study treatment until death (Up to 96 months post last dose)]

      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.

    11. Number of Participants With Treatment-Emergent Adverse Event (TEAE) and Serious AE (SAE) [From first dose up to 30 days after last dose of the study drug (Up to approximately 49 months)]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Participants must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ ALL

    • Previously treated with and developed resistance or intolerance to dasatinib or nilotinib OR developed the T3151 mutation after any tyrosine kinase inhibitor (TKI) therapy

    • ≥18 years old

    • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

    • Minimum life expectancy of ≥3 months

    • Adequate kidney function

    • Adequate liver function

    • Normal pancreatic function

    • Normal QT Fridericia-corrected interval (QTcF) ≤450 ms for males and ≤470 ms for females

    • Negative pregnancy test (if woman of childbearing potential)

    • Agree to use effective form of contraception (as applicable)

    • Ability to comply with study procedures, in the Investigator's opinion

    Exclusion Criteria:

    • Received prior TKI treatment within 7 days prior to receiving the first dose of ponatinib, or have not recovered from adverse events (except alopecia) due to agents previously administered.

    • Received other therapies as follows:

    1. For CML chronic phase (CP) and accelerated phase (AP) participants, received hydroxyurea or anagrelide within 24 hours prior to receiving the first dose of ponatinib; interferon, cytarabine, or immunotherapy within 14 days prior to first dose of ponatinib; or any other cytotoxic chemotherapy, radiotherapy, or investigational therapy within 28 days prior to receiving the first dose of ponatinib.

    2. For CML blast phase (BP) participants, received chemotherapy within 14 days prior to the first dose of ponatinib.

    3. For Ph+ ALL participants, received corticosteroids within 24 hours before the first dose of ponatinib; or vincristine within 7 days prior to the first dose of ponatinib; or received other chemotherapy within 14 days prior to the first dose of ponatinib.

    • Underwent stem cell transplant <60 days prior to receiving first dose of ponatinib

    • Evidence of on-going graft versus-host disease (GVHD), or GVHD requiring immunosuppressive therapy

    • Taking medications that are known to be associated with Torsades de Pointes

    • Require concurrent treatment with immunosuppressive agents (other than corticosteroids prescribed for a short course of therapy)

    • Previously treated with ponatinib

    • CML CP participants are excluded if they are in Complete cytogenetic response (CCyR)

    • Participants with CML AP, CML BP, or Ph+ ALL are excluded if they are in Major Hematologic Response (MaHR).

    • Have active Central Nervous System (CNS) disease

    • Have significant or active cardiovascular disease

    • Have a significant bleeding disorder unrelated to CML or Ph+ALL

    • Have a history of pancreatitis or alcohol abuse

    • Have uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL)

    • Have malabsorption syndrome or other gastrointestinal illness that could affect absorption of ponatinib

    • Diagnosed with another primary malignancy in the past 3 years

    • Pregnant or lactating

    • Underwent major surgery within 14 days prior to first dose of ponatinib

    • Have ongoing or active infection

    • Suffer from any other condition or illness that would compromise safety or interfere with evaluation of the drug

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Royal North Shore Hospital St Leonards New South Wales Australia 2065
    2 Princess Alexandra Hospital Woolloongabba Queensland Australia 4102
    3 Royal Adelaide Hospital Adelaide South Australia Australia 5000
    4 Alfred Hospital Box Hill Victoria Australia 3128
    5 Peter MacCallum Cancer Centre East Melbourne Victoria Australia 3002
    6 UCL Bruxelles Bruxelles Belgium 1200
    7 UZ Leuven Leuven Belgium 3000
    8 Institut Bergonie Bordeaux France 33076
    9 Hopital Andre Mignot Le Chesnay France 78157
    10 Hopital Claude Huriez CHRU Lille France 59307
    11 Chu Brabois Nancy France 54551
    12 Hopital Archet Nice France 6202
    13 Hopital St. Louis Paris France 75010
    14 Hopital Edouard Herriot Pierre-Benite France 69495
    15 Entre Hospitalier Universitaire Poitiers France 86021
    16 Hopital de Purpan Toulouse France 31059
    17 Charite - Universitatsmedizin Berlin, Berlin Germany 13353
    18 Klinikum der Goethe Universitat, Frankfurt Germany 60590
    19 Universitatsklinikum Jena Jena Germany 07747
    20 University of Heidelberg Mannheim Germany 68169
    21 III. Med. Klinik und Poliklinik Munchen Germany 81675
    22 Universita di Bologna Bologna Italy 40138
    23 University of Modena Modena Italy 41124
    24 University of Milano Bicocca Monza Italy 20052
    25 University of Turin Orbassano (TO) Italy 10043
    26 University Tor Vergata Roma Italy 144
    27 The Catholic University of Korea, Seoul St.Mary's Hospital Seoul Korea, Republic of 137-701
    28 VU University Medical Center Amsterdam Netherlands 1081 HV
    29 University Medical Center Groeningen Groningen Netherlands 9713 GZ
    30 Singapore General Hospital Singapore Singapore 169608
    31 Hospital Clinic Barcelona Spain 8036
    32 La Paz Madrid Spain 28046
    33 Hospital Universitario de Salamanca Salamanca Spain 37007
    34 Hospital Clinico of Valencia Valencia Spain 46010
    35 Lund University Lund Sweden 22185
    36 Karolinska Hospital Stockholm Sweden 17176
    37 University Hospital Uppsala Uppsala Sweden 75185
    38 Gartnavel General Hospital Glasgow United Kingdom G12 0XB
    39 Royal Liverpool University Hospital Liverpool United Kingdom L7 8XP
    40 Hammersmith Hospital London United Kingdom W12 0NN
    41 Royal Victoria Infirmary Newcastle United Kingdom NE2 4HH
    42 University of Nottingham Nottingham United Kingdom NG5 1PB

    Sponsors and Collaborators

    • Ariad Pharmaceuticals

    Investigators

    • Study Director: Medical Director Clinical Science, Takeda

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Ariad Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01207440
    Other Study ID Numbers:
    • AP24534-10-201
    • 2010-020414-28
    First Posted:
    Sep 23, 2010
    Last Update Posted:
    Feb 2, 2021
    Last Verified:
    Jan 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Keywords provided by Ariad Pharmaceuticals
    CML
    ALL
    PH
    ponatinib
    Ph+ALL
    T315I mutation
    Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
    Additional relevant MeSH terms:
    Leukemia
    Leukemia, Myeloid
    Precursor Cell Lymphoblastic Leukemia-Lymphoma
    Leukemia, Lymphoid
    Leukemia, Myelogenous, Chronic, BCR-ABL Positive
    Ponatinib

    Study Results

    Participant Flow

    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 Detail 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
    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

    Baseline Characteristics

    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
    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 Participants 203 64 65 18 48 46 5 449
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    61.0
    52.0
    60.0
    54.0
    54.0
    56.0
    63.0
    59.0
    Sex: Female, Male (Count of Participants)
    Female
    108
    53.2%
    16
    25%
    40
    61.5%
    7
    38.9%
    17
    35.4%
    20
    43.5%
    3
    60%
    211
    47%
    Male
    95
    46.8%
    48
    75%
    25
    38.5%
    11
    61.1%
    31
    64.6%
    26
    56.5%
    2
    40%
    238
    53%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    13
    6.4%
    8
    12.5%
    6
    9.2%
    1
    5.6%
    2
    4.2%
    12
    26.1%
    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%
    407
    90.6%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race/Ethnicity, Customized (Count of Participants)
    American Indian/Alaska native
    1
    0.5%
    0
    0%
    1
    1.5%
    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%
    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%
    25
    5.6%
    White
    174
    85.7%
    42
    65.6%
    47
    72.3%
    9
    50%
    39
    81.3%
    38
    82.6%
    3
    60%
    352
    78.4%
    Unknown
    3
    1.5%
    3
    4.7%
    2
    3.1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    8
    1.8%
    Other
    1
    0.5%
    1
    1.6%
    0
    0%
    1
    5.6%
    0
    0%
    0
    0%
    0
    0%
    3
    0.7%
    Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (Count of Participants)
    ECOG=0
    139
    68.5%
    47
    73.4%
    33
    50.8%
    12
    66.7%
    15
    31.3%
    16
    34.8%
    5
    100%
    267
    59.5%
    ECOG=1
    60
    29.6%
    17
    26.6%
    25
    38.5%
    6
    33.3%
    20
    41.7%
    19
    41.3%
    0
    0%
    147
    32.7%
    ECOG=2
    4
    2%
    0
    0%
    7
    10.8%
    0
    0%
    12
    25%
    11
    23.9%
    0
    0%
    34
    7.6%
    Time From Diagnosis to First Dose (years) [Median (Full Range) ]
    Median (Full Range) [years]
    7.85
    4.78
    7.13
    6.61
    3.96
    1.63
    4.80
    6.09

    Outcome Measures

    1. Primary Outcome
    Title Percentage of CP-CML Participants With Major Cytogenetic Response (MCyR)
    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

    Outcome Measure Data

    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
    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).
    Measure Participants 203 64
    Number (95% Confidence Interval) [percentage of participants]
    50.7
    25%
    70.3
    109.8%
    2. Primary Outcome
    Title Percentage of AP-CML Participants With Major Hematologic Response (MaHR)
    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

    Outcome Measure Data

    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
    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).
    Measure Participants 65 18
    Number (95% Confidence Interval) [percentage of participants]
    56.9
    28%
    55.6
    86.9%
    3. Primary Outcome
    Title Percentage of BP-CML/Ph+ ALL Participants With MaHR
    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

    Outcome Measure Data

    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
    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).
    Measure Participants 48 46
    Number (95% Confidence Interval) [percentage of participants]
    35.4
    17.4%
    32.6
    50.9%
    4. Secondary Outcome
    Title Percentage of CP-CML Participants With CHR
    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)

    Outcome Measure Data

    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
    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).
    Measure Participants 203 64
    Number (95% Confidence Interval) [percentage of participants]
    94.6
    46.6%
    92.2
    144.1%
    5. Secondary Outcome
    Title Percentage of CP-CML Participants With Confirmed MCyR
    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)

    Outcome Measure Data

    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
    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).
    Measure Participants 203 64
    Number (95% Confidence Interval) [percentage of participants]
    40.9
    20.1%
    62.5
    97.7%
    6. Secondary Outcome
    Title Percentage of CP-CML Participants With Major Molecular Response (MMR)
    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)

    Outcome Measure Data

    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
    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).
    Measure Participants 203 64
    Number (95% Confidence Interval) [percentage of participants]
    35.0
    17.2%
    57.8
    90.3%
    7. Secondary Outcome
    Title Percentage of AP-CML or BP-CML/Ph+ ALL Participants With MCyR
    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)

    Outcome Measure Data

    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
    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).
    Measure Participants 65 18 48 46
    Number (95% Confidence Interval) [percentage of participants]
    33.8
    16.7%
    55.6
    86.9%
    27.1
    41.7%
    34.8
    193.3%
    8. Secondary Outcome
    Title Percentage of AP-CML or BP-CML/Ph+ ALL Participants With Confirmed MCyR
    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)

    Outcome Measure Data

    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
    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).
    Measure Participants 65 18 48 46
    Number (95% Confidence Interval) [percentage of participants]
    24.6
    12.1%
    38.9
    60.8%
    20.8
    32%
    15.2
    84.4%
    9. Secondary Outcome
    Title Percentage of AP-CML or BP-CML/Ph+ ALL Participants With MMR
    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)

    Outcome Measure Data

    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
    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).
    Measure Participants 65 18 48 46
    Number (95% Confidence Interval) [percentage of participants]
    18.5
    9.1%
    33.3
    52%
    18.8
    28.9%
    4.3
    23.9%
    10. Secondary Outcome
    Title Time to Response
    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

    Outcome Measure Data

    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
    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).
    Measure Participants 203 64 65 18 48 46
    Hematologic Response
    13.0
    10.0
    21.0
    20.5
    28.0
    24.0
    Cytogenetic Response
    85.0
    84.0
    113.5
    83.0
    28.0
    56.0
    Molecular Response
    173.0
    167.0
    340.5
    335.5
    56.0
    63.0
    11. Secondary Outcome
    Title Duration of Response
    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

    Outcome Measure Data

    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
    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).
    Measure Participants 203 64 65 18 48 46
    Hematologic Response
    NA
    NA
    360.0
    732.0
    196.0
    108.0
    Cytogenetic Response
    NA
    NA
    NA
    728.0
    NA
    63.0
    Molecular Response
    NA
    NA
    560.0
    222.0
    NA
    98.0
    12. Secondary Outcome
    Title Progression-free Survival (PFS)
    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)

    Outcome Measure Data

    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
    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).
    Measure Participants 203 64 65 18 48 46
    Median (95% Confidence Interval) [days]
    NA
    1809.0
    432.0
    959.0
    111.0
    83.0
    13. Secondary Outcome
    Title Overall Survival (OS)
    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)

    Outcome Measure Data

    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
    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).
    Measure Participants 203 64 65 18 48 46
    Median (95% Confidence Interval) [days]
    NA
    NA
    1689.0
    1847.0
    209.0
    200.0
    14. Secondary Outcome
    Title Number of Participants With Treatment-Emergent Adverse Event (TEAE) and Serious AE (SAE)
    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)

    Outcome Measure Data

    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
    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).
    Measure Participants 203 64 65 18 48 46 5
    TEAE
    203
    100%
    64
    100%
    65
    100%
    18
    100%
    48
    100%
    46
    100%
    5
    100%
    SAE
    132
    65%
    39
    60.9%
    44
    67.7%
    13
    72.2%
    41
    85.4%
    37
    80.4%
    3
    60%

    Adverse Events

    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
    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 (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 41/203 (20.2%) 18/64 (28.1%) 30/65 (46.2%) 9/18 (50%) 40/48 (83.3%) 39/46 (84.8%) 2/5 (40%)
    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 (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 132/203 (65%) 39/64 (60.9%) 44/65 (67.7%) 13/18 (72.2%) 41/48 (85.4%) 37/46 (80.4%) 3/5 (60%)
    Blood and lymphatic system disorders
    Anaemia 7/203 (3.4%) 0/64 (0%) 4/65 (6.2%) 0/18 (0%) 2/48 (4.2%) 2/46 (4.3%) 0/5 (0%)
    Febrile neutropenia 1/203 (0.5%) 0/64 (0%) 1/65 (1.5%) 1/18 (5.6%) 5/48 (10.4%) 5/46 (10.9%) 0/5 (0%)
    Pancytopenia 1/203 (0.5%) 0/64 (0%) 1/65 (1.5%) 1/18 (5.6%) 2/48 (4.2%) 1/46 (2.2%) 0/5 (0%)
    Splenic infarction 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Hyperviscosity syndrome 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Hyperleukocytosis 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Lymphadenopathy 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Neutropenia 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 2/46 (4.3%) 0/5 (0%)
    Thrombocytopenia 1/203 (0.5%) 1/64 (1.6%) 4/65 (6.2%) 0/18 (0%) 2/48 (4.2%) 1/46 (2.2%) 0/5 (0%)
    Cardiac disorders
    Atrial fibrillation 11/203 (5.4%) 4/64 (6.3%) 0/65 (0%) 0/18 (0%) 3/48 (6.3%) 2/46 (4.3%) 0/5 (0%)
    Cardiac failure congestive 5/203 (2.5%) 3/64 (4.7%) 1/65 (1.5%) 0/18 (0%) 1/48 (2.1%) 1/46 (2.2%) 0/5 (0%)
    Coronary artery disease 4/203 (2%) 6/64 (9.4%) 1/65 (1.5%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Acute myocardial infarction 2/203 (1%) 1/64 (1.6%) 1/65 (1.5%) 2/18 (11.1%) 2/48 (4.2%) 0/46 (0%) 0/5 (0%)
    Angina pectoris 10/203 (4.9%) 4/64 (6.3%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Cardiac arrest 2/203 (1%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Coronary artery stenosis 2/203 (1%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Atrial tachycardia 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Pericardial effusion 3/203 (1.5%) 1/64 (1.6%) 1/65 (1.5%) 0/18 (0%) 1/48 (2.1%) 1/46 (2.2%) 0/5 (0%)
    Sinus tachycardia 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Acute coronary syndrome 3/203 (1.5%) 3/64 (4.7%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Cardiopulmonary failure 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Cardiac failure 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 1/18 (5.6%) 3/48 (6.3%) 0/46 (0%) 1/5 (20%)
    Atrial flutter 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Atrioventricular block complete 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Cardiac tamponade 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Cardiogenic shock 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Pericarditis 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Right ventricular failure 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Tachycardia 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Coronary artery occlusion 2/203 (1%) 1/64 (1.6%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Acute left ventricular failure 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Angina unstable 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Aortic valve stenosis 1/203 (0.5%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Arrhythmia supraventricular 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Arteriosclerosis coronary artery 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Arteriospasm coronary 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Bradycardia 0/203 (0%) 1/64 (1.6%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Cardiac Discomfort 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Cardiac failure acute 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Cardio-respiratory arrest 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Congestive cardiomyopathy 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Dressler's syndrome 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Ischaemic cardiomyopathy 0/203 (0%) 1/64 (1.6%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Left ventricular dysfunction 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Mitral valve incompetence 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Sinus node dysfunction 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Ventricular tachycardia 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Cardiac failure chronic 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Bundle branch block right 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Left ventricular failure 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Myocardial infarction 3/203 (1.5%) 4/64 (6.3%) 2/65 (3.1%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Ear and labyrinth disorders
    Vertigo positional 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Vertigo 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Endocrine disorders
    Thyroid mass 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Eye disorders
    Retinal vein occlusion 2/203 (1%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Cataract 1/203 (0.5%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Cystoid macular oedema 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Retinal artery occlusion 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Retinal vein thrombosis 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Ulcerative keratitis 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Vision blurred 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Macular fibrosis 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Gastrointestinal disorders
    Pancreatitis 10/203 (4.9%) 4/64 (6.3%) 3/65 (4.6%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Abdominal pain 7/203 (3.4%) 1/64 (1.6%) 4/65 (6.2%) 1/18 (5.6%) 4/48 (8.3%) 1/46 (2.2%) 0/5 (0%)
    Constipation 3/203 (1.5%) 1/64 (1.6%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Diarrhoea 1/203 (0.5%) 1/64 (1.6%) 1/65 (1.5%) 1/18 (5.6%) 1/48 (2.1%) 1/46 (2.2%) 0/5 (0%)
    Gastritis 2/203 (1%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Vomiting 0/203 (0%) 1/64 (1.6%) 1/65 (1.5%) 0/18 (0%) 2/48 (4.2%) 0/46 (0%) 0/5 (0%)
    Colitis 2/203 (1%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Hiatus hernia 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Ileus 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Nausea 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Oesophagitis 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Haemorrhoidal haemorrhage 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Ascites 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Rectal haemorrhage 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Retroperitoneal haematoma 0/203 (0%) 0/64 (0%) 2/65 (3.1%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Gastrointestinal haemorrhage 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 2/46 (4.3%) 1/5 (20%)
    Abdominal distension 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Acute abdomen 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Dysphagia 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Gastric haemorrhage 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Gastritis haemorrhagic 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Stomatitis 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Appendicitis Noninfective 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Colitis Ischaemic 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Faecaloma 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Fistula of small intestine 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Gastric ulcer haemorrhage 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Inguinal hernia 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Large intestinal obstruction 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Small intestinal obstruction 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Upper gastrointestinal haemorrhage 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Gastrooesophageal reflux disease 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Peritoneal haemorrhage 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Mesenteric arterial occlusion 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Abdominal pain upper 2/203 (1%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Pancreatitis acute 5/203 (2.5%) 1/64 (1.6%) 2/65 (3.1%) 0/18 (0%) 2/48 (4.2%) 0/46 (0%) 0/5 (0%)
    General disorders
    Pyrexia 5/203 (2.5%) 3/64 (4.7%) 5/65 (7.7%) 2/18 (11.1%) 2/48 (4.2%) 2/46 (4.3%) 1/5 (20%)
    Non-cardiac chest pain 4/203 (2%) 1/64 (1.6%) 2/65 (3.1%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Asthenia 1/203 (0.5%) 0/64 (0%) 1/65 (1.5%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Chest pain 2/203 (1%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Chills 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 2/48 (4.2%) 0/46 (0%) 0/5 (0%)
    Pain 1/203 (0.5%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Systemic inflammatory response syndrome 0/203 (0%) 2/64 (3.1%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Implant site pain 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Impaired healing 2/203 (1%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Gait disturbance 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Oedema peripheral 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Vascular stent occlusion 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Fatigue 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Multiple organ dysfunction syndrome 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 1/46 (2.2%) 0/5 (0%)
    Hepatobiliary disorders
    Bile duct stone 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Cholangitis 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Cholelithiasis 2/203 (1%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Cholecystitis 1/203 (0.5%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Cholecystitis acute 1/203 (0.5%) 1/64 (1.6%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Portal vein thrombosis 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Non-alcoholic steatohepatitis 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Venoocclusive liver disease 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Biliary dilatation 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Gallbladder obstruction 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Hyperbilirubinaemia 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Immune system disorders
    Hypersensitivity 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Graft versus host disease in skin 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Anaphylactic reaction 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Anaphylactoid reaction 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Drug hypersensitivity 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Infections and infestations
    Pneumonia 10/203 (4.9%) 5/64 (7.8%) 8/65 (12.3%) 1/18 (5.6%) 4/48 (8.3%) 5/46 (10.9%) 0/5 (0%)
    Cellulitis 4/203 (2%) 1/64 (1.6%) 2/65 (3.1%) 1/18 (5.6%) 2/48 (4.2%) 0/46 (0%) 0/5 (0%)
    Sepsis 2/203 (1%) 1/64 (1.6%) 2/65 (3.1%) 1/18 (5.6%) 2/48 (4.2%) 2/46 (4.3%) 1/5 (20%)
    Upper respiratory tract infection 2/203 (1%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Urinary tract infection 5/203 (2.5%) 2/64 (3.1%) 0/65 (0%) 1/18 (5.6%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Bacterial infection 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Bronchitis 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Diverticulitis 2/203 (1%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Herpes oesophagitis 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Osteomyelitis 2/203 (1%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Respiratory syncytial virus infection 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Wound infection 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Bacteraemia 1/203 (0.5%) 0/64 (0%) 1/65 (1.5%) 1/18 (5.6%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Appendicitis 0/203 (0%) 0/64 (0%) 2/65 (3.1%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Breast cellulitis 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Clostridium difficile colitis 3/203 (1.5%) 0/64 (0%) 2/65 (3.1%) 0/18 (0%) 2/48 (4.2%) 0/46 (0%) 0/5 (0%)
    Infection 0/203 (0%) 0/64 (0%) 2/65 (3.1%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Localised infection 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Lung infection 1/203 (0.5%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Pharyngitis streptococcal 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Pneumonia fungal 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Pulmonary tuberculosis 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Respiratory tract infection 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Septic shock 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 2/46 (4.3%) 0/5 (0%)
    Splenic abscess 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Klebsiella sepsis 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 2/46 (4.3%) 0/5 (0%)
    Catheter site cellulitis 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Gastroenteritis 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 2/48 (4.2%) 0/46 (0%) 0/5 (0%)
    Haematoma infection 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Otitis externa 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Pneumonia respiratory syncytial viral 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Post procedural infection 2/203 (1%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Abdominal sepsis 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Arthritis bacterial 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Arthritis viral 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Cholecystitis infective 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Clostridium difficile infection 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Genital infection bacterial 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Otitis media chronic 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Peritonitis 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Pneumonia mycoplasmal 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Pyelonephritis 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Pyelonephritis acute 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Systemic infection 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Viral infection 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Wound infection staphylococcal 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Pneumonia staphylococcal 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Gangrene 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Gastroenteritis norovirus 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Kidney infection 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Urosepsis 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Oesophageal candidiasis 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Atypical pneumonia 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Device related sepsis 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Infectious colitis 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Pneumonia influenzal 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Postoperative wound infection 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Staphylococcal bacteraemia 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Pneumocystis jirovecii pneumonia 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Injury, poisoning and procedural complications
    Subarachnoid haemorrhage 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Concussion 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Peripancreatic fluid collection 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Procedural vomiting 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Fall 1/203 (0.5%) 0/64 (0%) 1/65 (1.5%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Subdural haematoma 2/203 (1%) 0/64 (0%) 2/65 (3.1%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Post procedural haematoma 1/203 (0.5%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Post procedural haemorrhage 1/203 (0.5%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Procedural pain 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Traumatic intracranial haemorrhage 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Pneumonitis chemical 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Peripheral artery restenosis 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Head injury 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Humerus fracture 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Spinal column injury 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Wound dehiscence 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Wrist fracture 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Investigations
    Lipase increased 4/203 (2%) 3/64 (4.7%) 1/65 (1.5%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Platelet count decreased 2/203 (1%) 0/64 (0%) 2/65 (3.1%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Alanine aminotransferase increased 3/203 (1.5%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Neutrophil count decreased 2/203 (1%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Blood alkaline phosphatase increased 1/203 (0.5%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Ejection fraction decreased 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 2/48 (4.2%) 1/46 (2.2%) 0/5 (0%)
    Gamma-glutamyltransferase increased 1/203 (0.5%) 0/64 (0%) 2/65 (3.1%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Blood bilirubin increased 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Aspartate aminotransferase increased 1/203 (0.5%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Urine analysis abnormal 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Hepatic enzyme increased 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    International normalised ratio increased 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Liver function test increased 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Blood potassium increased 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Haemoglobin decreased 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    JC polyomavirus test positive 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Metabolism and nutrition disorders
    Hyponatraemia 4/203 (2%) 1/64 (1.6%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Dehydration 4/203 (2%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 2/48 (4.2%) 1/46 (2.2%) 0/5 (0%)
    Diabetes mellitus 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Hyperkalaemia 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Electrolyte imbalance 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Tumour lysis syndrome 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Failure to thrive 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Fluid overload 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Fluid retention 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Hyperuricaemia 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Hypercalcaemia 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Hyperglycaemia 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Back pain 1/203 (0.5%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Flank pain 2/203 (1%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Myalgia 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Spinal osteoarthritis 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Lumbar spinal stenosis 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Bone pain 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 2/48 (4.2%) 1/46 (2.2%) 0/5 (0%)
    Musculoskeletal pain 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Spinal column stenosis 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Osteoarthritis 2/203 (1%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Intervertebral disc protrusion 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm progression 6/203 (3%) 2/64 (3.1%) 7/65 (10.8%) 4/18 (22.2%) 14/48 (29.2%) 8/46 (17.4%) 0/5 (0%)
    Myelodysplastic syndrome 3/203 (1.5%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Malignant melanoma 2/203 (1%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Malignant pleural effusion 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Basal cell carcinoma 1/203 (0.5%) 0/64 (0%) 2/65 (3.1%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Blast crisis in myelogenous leukaemia 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 1/18 (5.6%) 1/48 (2.1%) 1/46 (2.2%) 0/5 (0%)
    Squamous cell carcinoma of skin 3/203 (1.5%) 0/64 (0%) 2/65 (3.1%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Chloroma 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Colon cancer 2/203 (1%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Skin squamous cell carcinoma metastatic 2/203 (1%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Large cell lung cancer recurrent 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Non-hodgkin's lymphoma 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Squamous cell carcinoma 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Vulval cancer 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Central nervous system leukaemia 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Acute lymphocytic leukaemia recurrent 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Pancreatic carcinoma 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Neuroendocrine carcinoma metastatic 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Bowen's disease 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Nervous system disorders
    Cerebrovascular accident 5/203 (2.5%) 4/64 (6.3%) 1/65 (1.5%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Headache 2/203 (1%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Transient ischaemic attack 2/203 (1%) 2/64 (3.1%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Ataxia 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Cerebral artery stenosis 0/203 (0%) 2/64 (3.1%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Cerebral infarction 5/203 (2.5%) 3/64 (4.7%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Haemorrhagic cerebral infarction 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Haemorrhagic transformation stroke 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    IVth nerve paralysis 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Spinal cord compression 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Cerebellar infarction 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Cerebral haemorrhage 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Cerebral ischaemia 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Dizziness 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Migraine 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Somnolence 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Syncope 3/203 (1.5%) 1/64 (1.6%) 2/65 (3.1%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Haemorrhage intracranial 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Brain oedema 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Loss of consciousness 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Paraesthesia 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Status epilepticus 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Dementia 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Facial Paralysis 1/203 (0.5%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Iiird nerve paralysis 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Neuropathy peripheral 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Carotid artery stenosis 5/203 (2.5%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Cerebrovascular disorder 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Encephalopathy 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Hypoaesthesia 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Intracranial aneurysm 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Lacunar infarction 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Memory impairment 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Sciatica 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Seizure 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Carotid artery occlusion 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Product Issues
    Device dislocation 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Psychiatric disorders
    Confusional state 3/203 (1.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Mental status changes 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 2/46 (4.3%) 0/5 (0%)
    Delirium 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Renal and urinary disorders
    Renal failure 2/203 (1%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Nephrolithiasis 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Acute kidney injury 2/203 (1%) 2/64 (3.1%) 2/65 (3.1%) 0/18 (0%) 3/48 (6.3%) 0/46 (0%) 0/5 (0%)
    Renal artery stenosis 2/203 (1%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Haematuria 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Urinary retention 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Dysuria 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Reproductive system and breast disorders
    Prostatic obstruction 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Prostatitis 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Haemorrhagic ovarian cyst 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Ovarian cyst 1/203 (0.5%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 2/203 (1%) 3/64 (4.7%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Hypoxia 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Pneumothorax 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Pulmonary embolism 3/203 (1.5%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 3/48 (6.3%) 0/46 (0%) 0/5 (0%)
    Epistaxis 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Pleural effusion 2/203 (1%) 1/64 (1.6%) 1/65 (1.5%) 0/18 (0%) 1/48 (2.1%) 1/46 (2.2%) 1/5 (20%)
    Respiratory failure 0/203 (0%) 0/64 (0%) 2/65 (3.1%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Chronic obstructive pulmonary disease 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 2/46 (4.3%) 1/5 (20%)
    Dyspnoea exertional 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Pleuritic pain 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Pulmonary hypertension 2/203 (1%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Pneumonitis 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Lung disorder 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Skin and subcutaneous tissue disorders
    Angioedema 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Erythema 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Erythema multiforme 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Hyperkeratosis 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Skin ulcer 2/203 (1%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Acute febrile neutrophilic dermatosis 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Dermatitis exfoliative generalised 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Skin swelling 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Diabetic foot 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Mucocutaneous haemorrhage 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Rash erythematous 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Rash maculo-papular 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Social circumstances
    Immobile 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Vascular disorders
    Hypertension 11/203 (5.4%) 0/64 (0%) 2/65 (3.1%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Hypotension 2/203 (1%) 1/64 (1.6%) 2/65 (3.1%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Deep vein thrombosis 4/203 (2%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 1/46 (2.2%) 0/5 (0%)
    Hot flush 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Peripheral ischaemia 3/203 (1.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Extremity necrosis 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Hypertensive crisis 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Embolism venous 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Thrombophlebitis superficial 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Peripheral arterial occlusive disease 10/203 (4.9%) 4/64 (6.3%) 1/65 (1.5%) 1/18 (5.6%) 1/48 (2.1%) 1/46 (2.2%) 0/5 (0%)
    Peripheral artery stenosis 4/203 (2%) 3/64 (4.7%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Peripheral artery occlusion 4/203 (2%) 1/64 (1.6%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Peripheral vascular disorder 2/203 (1%) 1/64 (1.6%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Dry gangrene 1/203 (0.5%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Aortic arteriosclerosis 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Temporal arteritis 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Varicose vein 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Vasculitis 1/203 (0.5%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Coeliac artery occlusion 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Embolism arterial 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Intermittent claudication 2/203 (1%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Other (Not Including 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 (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 203/203 (100%) 64/64 (100%) 65/65 (100%) 18/18 (100%) 48/48 (100%) 46/46 (100%) 5/5 (100%)
    Blood and lymphatic system disorders
    Anaemia 39/203 (19.2%) 7/64 (10.9%) 20/65 (30.8%) 7/18 (38.9%) 14/48 (29.2%) 11/46 (23.9%) 1/5 (20%)
    Febrile neutropenia 1/203 (0.5%) 1/64 (1.6%) 2/65 (3.1%) 0/18 (0%) 3/48 (6.3%) 3/46 (6.5%) 0/5 (0%)
    Hypochromasia 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Leukopenia 7/203 (3.4%) 0/64 (0%) 5/65 (7.7%) 2/18 (11.1%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Lymphadenopathy 6/203 (3%) 0/64 (0%) 2/65 (3.1%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 1/5 (20%)
    Neutropenia 42/203 (20.7%) 6/64 (9.4%) 24/65 (36.9%) 4/18 (22.2%) 13/48 (27.1%) 7/46 (15.2%) 0/5 (0%)
    Thrombocytopenia 90/203 (44.3%) 18/64 (28.1%) 32/65 (49.2%) 4/18 (22.2%) 16/48 (33.3%) 7/46 (15.2%) 1/5 (20%)
    Cardiac disorders
    Angina pectoris 9/203 (4.4%) 4/64 (6.3%) 3/65 (4.6%) 0/18 (0%) 3/48 (6.3%) 0/46 (0%) 0/5 (0%)
    Atrial fibrillation 10/203 (4.9%) 3/64 (4.7%) 1/65 (1.5%) 0/18 (0%) 2/48 (4.2%) 4/46 (8.7%) 1/5 (20%)
    Cardiac failure 1/203 (0.5%) 1/64 (1.6%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Cardiomyopathy 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 3/48 (6.3%) 0/46 (0%) 0/5 (0%)
    Palpitations 6/203 (3%) 1/64 (1.6%) 2/65 (3.1%) 1/18 (5.6%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Pericardial effusion 5/203 (2.5%) 1/64 (1.6%) 2/65 (3.1%) 0/18 (0%) 3/48 (6.3%) 2/46 (4.3%) 0/5 (0%)
    Tachycardia 3/203 (1.5%) 1/64 (1.6%) 1/65 (1.5%) 0/18 (0%) 2/48 (4.2%) 4/46 (8.7%) 0/5 (0%)
    Ear and labyrinth disorders
    Tinnitus 8/203 (3.9%) 1/64 (1.6%) 1/65 (1.5%) 1/18 (5.6%) 1/48 (2.1%) 0/46 (0%) 1/5 (20%)
    Vertigo 8/203 (3.9%) 1/64 (1.6%) 3/65 (4.6%) 1/18 (5.6%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Endocrine disorders
    Adrenal insufficiency 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Hypothyroidism 7/203 (3.4%) 2/64 (3.1%) 4/65 (6.2%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Eye disorders
    Blepharitis 3/203 (1.5%) 1/64 (1.6%) 2/65 (3.1%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Cataract 7/203 (3.4%) 1/64 (1.6%) 1/65 (1.5%) 1/18 (5.6%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Conjunctival hyperaemia 2/203 (1%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Dry eye 16/203 (7.9%) 5/64 (7.8%) 4/65 (6.2%) 2/18 (11.1%) 4/48 (8.3%) 3/46 (6.5%) 1/5 (20%)
    Eye pain 8/203 (3.9%) 4/64 (6.3%) 2/65 (3.1%) 0/18 (0%) 3/48 (6.3%) 0/46 (0%) 0/5 (0%)
    Eyelid disorder 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Eyelid oedema 3/203 (1.5%) 1/64 (1.6%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Vision blurred 13/203 (6.4%) 6/64 (9.4%) 3/65 (4.6%) 1/18 (5.6%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Visual acuity reduced 1/203 (0.5%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Visual impairment 3/203 (1.5%) 1/64 (1.6%) 1/65 (1.5%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 1/5 (20%)
    Vitreous floaters 1/203 (0.5%) 0/64 (0%) 1/65 (1.5%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Gastrointestinal disorders
    Abdominal discomfort 8/203 (3.9%) 3/64 (4.7%) 3/65 (4.6%) 0/18 (0%) 1/48 (2.1%) 1/46 (2.2%) 1/5 (20%)
    Abdominal distension 12/203 (5.9%) 7/64 (10.9%) 4/65 (6.2%) 1/18 (5.6%) 3/48 (6.3%) 1/46 (2.2%) 1/5 (20%)
    Abdominal pain 75/203 (36.9%) 21/64 (32.8%) 20/65 (30.8%) 7/18 (38.9%) 7/48 (14.6%) 10/46 (21.7%) 2/5 (40%)
    Abdominal pain upper 40/203 (19.7%) 10/64 (15.6%) 11/65 (16.9%) 2/18 (11.1%) 6/48 (12.5%) 8/46 (17.4%) 2/5 (40%)
    Ascites 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 1/18 (5.6%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Constipation 89/203 (43.8%) 21/64 (32.8%) 16/65 (24.6%) 7/18 (38.9%) 21/48 (43.8%) 13/46 (28.3%) 3/5 (60%)
    Dental necrosis 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Diarrhoea 43/203 (21.2%) 10/64 (15.6%) 17/65 (26.2%) 7/18 (38.9%) 15/48 (31.3%) 4/46 (8.7%) 0/5 (0%)
    Dry mouth 20/203 (9.9%) 6/64 (9.4%) 4/65 (6.2%) 0/18 (0%) 4/48 (8.3%) 1/46 (2.2%) 0/5 (0%)
    Dyspepsia 12/203 (5.9%) 6/64 (9.4%) 4/65 (6.2%) 0/18 (0%) 2/48 (4.2%) 2/46 (4.3%) 0/5 (0%)
    Dysphagia 3/203 (1.5%) 1/64 (1.6%) 2/65 (3.1%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 1/5 (20%)
    Gastrooesophageal reflux disease 10/203 (4.9%) 8/64 (12.5%) 2/65 (3.1%) 0/18 (0%) 2/48 (4.2%) 0/46 (0%) 1/5 (20%)
    Gingival bleeding 3/203 (1.5%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 2/48 (4.2%) 2/46 (4.3%) 1/5 (20%)
    Haemorrhoids 4/203 (2%) 1/64 (1.6%) 1/65 (1.5%) 1/18 (5.6%) 2/48 (4.2%) 2/46 (4.3%) 0/5 (0%)
    Mouth haemorrhage 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 2/46 (4.3%) 0/5 (0%)
    Nausea 53/203 (26.1%) 24/64 (37.5%) 22/65 (33.8%) 5/18 (27.8%) 16/48 (33.3%) 12/46 (26.1%) 1/5 (20%)
    Odynophagia 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 2/18 (11.1%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Rectal haemorrhage 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 1/5 (20%)
    Stomatitis 11/203 (5.4%) 2/64 (3.1%) 4/65 (6.2%) 1/18 (5.6%) 2/48 (4.2%) 3/46 (6.5%) 0/5 (0%)
    Toothache 13/203 (6.4%) 0/64 (0%) 3/65 (4.6%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Vomiting 38/203 (18.7%) 12/64 (18.8%) 17/65 (26.2%) 6/18 (33.3%) 14/48 (29.2%) 11/46 (23.9%) 0/5 (0%)
    General disorders
    Asthenia 40/203 (19.7%) 8/64 (12.5%) 5/65 (7.7%) 4/18 (22.2%) 3/48 (6.3%) 8/46 (17.4%) 0/5 (0%)
    Chest pain 13/203 (6.4%) 4/64 (6.3%) 1/65 (1.5%) 1/18 (5.6%) 1/48 (2.1%) 0/46 (0%) 1/5 (20%)
    Chills 16/203 (7.9%) 4/64 (6.3%) 6/65 (9.2%) 4/18 (22.2%) 7/48 (14.6%) 2/46 (4.3%) 1/5 (20%)
    Fatigue 60/203 (29.6%) 21/64 (32.8%) 22/65 (33.8%) 8/18 (44.4%) 16/48 (33.3%) 9/46 (19.6%) 1/5 (20%)
    Feeling hot 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    General physical health deterioration 1/203 (0.5%) 2/64 (3.1%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Hernia 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Influenza like illness 10/203 (4.9%) 3/64 (4.7%) 4/65 (6.2%) 0/18 (0%) 1/48 (2.1%) 1/46 (2.2%) 0/5 (0%)
    Localised oedema 1/203 (0.5%) 1/64 (1.6%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Non-cardiac chest pain 13/203 (6.4%) 6/64 (9.4%) 3/65 (4.6%) 0/18 (0%) 2/48 (4.2%) 2/46 (4.3%) 0/5 (0%)
    Oedema peripheral 36/203 (17.7%) 8/64 (12.5%) 9/65 (13.8%) 5/18 (27.8%) 12/48 (25%) 5/46 (10.9%) 1/5 (20%)
    Pain 19/203 (9.4%) 7/64 (10.9%) 8/65 (12.3%) 3/18 (16.7%) 8/48 (16.7%) 3/46 (6.5%) 0/5 (0%)
    Performance status decreased 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Peripheral swelling 5/203 (2.5%) 4/64 (6.3%) 5/65 (7.7%) 2/18 (11.1%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Pyrexia 52/203 (25.6%) 13/64 (20.3%) 20/65 (30.8%) 11/18 (61.1%) 16/48 (33.3%) 12/46 (26.1%) 0/5 (0%)
    Hepatobiliary disorders
    Cholelithiasis 3/203 (1.5%) 1/64 (1.6%) 2/65 (3.1%) 1/18 (5.6%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Immune system disorders
    Seasonal allergy 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Infections and infestations
    Bacteraemia 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 3/48 (6.3%) 2/46 (4.3%) 0/5 (0%)
    Breast cellulitis 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Bronchitis 19/203 (9.4%) 5/64 (7.8%) 3/65 (4.6%) 0/18 (0%) 1/48 (2.1%) 1/46 (2.2%) 1/5 (20%)
    Cellulitis 6/203 (3%) 1/64 (1.6%) 4/65 (6.2%) 1/18 (5.6%) 4/48 (8.3%) 2/46 (4.3%) 0/5 (0%)
    Conjunctivitis 9/203 (4.4%) 2/64 (3.1%) 2/65 (3.1%) 2/18 (11.1%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Cystitis 5/203 (2.5%) 0/64 (0%) 1/65 (1.5%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Ear infection 1/203 (0.5%) 1/64 (1.6%) 2/65 (3.1%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Folliculitis 8/203 (3.9%) 6/64 (9.4%) 3/65 (4.6%) 1/18 (5.6%) 1/48 (2.1%) 2/46 (4.3%) 1/5 (20%)
    Fungaemia 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Gastroenteritis 6/203 (3%) 1/64 (1.6%) 2/65 (3.1%) 1/18 (5.6%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Infection 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Influenza 11/203 (5.4%) 1/64 (1.6%) 2/65 (3.1%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Lower respiratory tract infection 4/203 (2%) 1/64 (1.6%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Mastitis 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Mastoiditis 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Nail infection 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Nasopharyngitis 26/203 (12.8%) 7/64 (10.9%) 9/65 (13.8%) 5/18 (27.8%) 1/48 (2.1%) 2/46 (4.3%) 1/5 (20%)
    Oral candidiasis 4/203 (2%) 1/64 (1.6%) 1/65 (1.5%) 1/18 (5.6%) 3/48 (6.3%) 1/46 (2.2%) 0/5 (0%)
    Otitis externa 0/203 (0%) 2/64 (3.1%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Otitis media acute 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Periodontitis 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Pharyngitis 2/203 (1%) 1/64 (1.6%) 0/65 (0%) 2/18 (11.1%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Pneumonia 7/203 (3.4%) 1/64 (1.6%) 2/65 (3.1%) 1/18 (5.6%) 4/48 (8.3%) 1/46 (2.2%) 0/5 (0%)
    Respiratory tract infection 2/203 (1%) 0/64 (0%) 1/65 (1.5%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Sinusitis 17/203 (8.4%) 7/64 (10.9%) 3/65 (4.6%) 0/18 (0%) 1/48 (2.1%) 1/46 (2.2%) 0/5 (0%)
    Tonsillitis 4/203 (2%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Tooth abscess 1/203 (0.5%) 0/64 (0%) 2/65 (3.1%) 1/18 (5.6%) 1/48 (2.1%) 1/46 (2.2%) 0/5 (0%)
    Tooth infection 6/203 (3%) 0/64 (0%) 4/65 (6.2%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Upper respiratory tract infection 16/203 (7.9%) 18/64 (28.1%) 9/65 (13.8%) 2/18 (11.1%) 6/48 (12.5%) 2/46 (4.3%) 1/5 (20%)
    Urinary tract infection 18/203 (8.9%) 5/64 (7.8%) 9/65 (13.8%) 3/18 (16.7%) 2/48 (4.2%) 1/46 (2.2%) 2/5 (40%)
    Injury, poisoning and procedural complications
    Arthropod bite 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Fall 9/203 (4.4%) 1/64 (1.6%) 1/65 (1.5%) 0/18 (0%) 3/48 (6.3%) 0/46 (0%) 0/5 (0%)
    Hand fracture 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Head injury 1/203 (0.5%) 1/64 (1.6%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Laceration 3/203 (1.5%) 1/64 (1.6%) 1/65 (1.5%) 1/18 (5.6%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Ligament sprain 4/203 (2%) 1/64 (1.6%) 1/65 (1.5%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Procedural pain 5/203 (2.5%) 2/64 (3.1%) 2/65 (3.1%) 2/18 (11.1%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Skin injury 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Subcutaneous haematoma 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Tendon rupture 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Transfusion reaction 1/203 (0.5%) 0/64 (0%) 1/65 (1.5%) 1/18 (5.6%) 2/48 (4.2%) 1/46 (2.2%) 0/5 (0%)
    Transfusion related complication 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Investigations
    Alanine aminotransferase increased 39/203 (19.2%) 12/64 (18.8%) 15/65 (23.1%) 4/18 (22.2%) 7/48 (14.6%) 5/46 (10.9%) 0/5 (0%)
    Amylase increased 19/203 (9.4%) 2/64 (3.1%) 6/65 (9.2%) 1/18 (5.6%) 4/48 (8.3%) 1/46 (2.2%) 0/5 (0%)
    Aspartate aminotransferase increased 31/203 (15.3%) 11/64 (17.2%) 11/65 (16.9%) 5/18 (27.8%) 7/48 (14.6%) 6/46 (13%) 0/5 (0%)
    Blood alkaline phosphatase increased 20/203 (9.9%) 5/64 (7.8%) 9/65 (13.8%) 0/18 (0%) 3/48 (6.3%) 0/46 (0%) 0/5 (0%)
    Blood bilirubin increased 2/203 (1%) 1/64 (1.6%) 4/65 (6.2%) 1/18 (5.6%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Blood cholesterol increased 9/203 (4.4%) 3/64 (4.7%) 1/65 (1.5%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Blood creatinine increased 8/203 (3.9%) 4/64 (6.3%) 5/65 (7.7%) 0/18 (0%) 5/48 (10.4%) 1/46 (2.2%) 0/5 (0%)
    Blood glucose increased 1/203 (0.5%) 2/64 (3.1%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Blood phosphorus decreased 1/203 (0.5%) 1/64 (1.6%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Blood triglycerides increased 6/203 (3%) 2/64 (3.1%) 1/65 (1.5%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Gamma-glutamyltransferase increased 16/203 (7.9%) 5/64 (7.8%) 5/65 (7.7%) 3/18 (16.7%) 2/48 (4.2%) 0/46 (0%) 0/5 (0%)
    Haemoglobin decreased 2/203 (1%) 1/64 (1.6%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Lipase increased 56/203 (27.6%) 15/64 (23.4%) 10/65 (15.4%) 2/18 (11.1%) 8/48 (16.7%) 3/46 (6.5%) 0/5 (0%)
    N-terminal prohormone brain natriuretic peptide increased 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Neutrophil count decreased 8/203 (3.9%) 2/64 (3.1%) 0/65 (0%) 3/18 (16.7%) 5/48 (10.4%) 2/46 (4.3%) 0/5 (0%)
    Platelet count decreased 15/203 (7.4%) 3/64 (4.7%) 6/65 (9.2%) 1/18 (5.6%) 2/48 (4.2%) 3/46 (6.5%) 0/5 (0%)
    Platelet count increased 3/203 (1.5%) 1/64 (1.6%) 1/65 (1.5%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Weight decreased 23/203 (11.3%) 5/64 (7.8%) 7/65 (10.8%) 0/18 (0%) 5/48 (10.4%) 2/46 (4.3%) 1/5 (20%)
    White blood cell count decreased 4/203 (2%) 1/64 (1.6%) 2/65 (3.1%) 1/18 (5.6%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 28/203 (13.8%) 7/64 (10.9%) 10/65 (15.4%) 2/18 (11.1%) 7/48 (14.6%) 8/46 (17.4%) 0/5 (0%)
    Dehydration 6/203 (3%) 4/64 (6.3%) 1/65 (1.5%) 1/18 (5.6%) 3/48 (6.3%) 0/46 (0%) 0/5 (0%)
    Gout 3/203 (1.5%) 5/64 (7.8%) 1/65 (1.5%) 1/18 (5.6%) 3/48 (6.3%) 0/46 (0%) 1/5 (20%)
    Hyperamylasaemia 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Hypercholesterolaemia 6/203 (3%) 4/64 (6.3%) 2/65 (3.1%) 0/18 (0%) 2/48 (4.2%) 0/46 (0%) 0/5 (0%)
    Hyperglycaemia 8/203 (3.9%) 7/64 (10.9%) 9/65 (13.8%) 0/18 (0%) 3/48 (6.3%) 2/46 (4.3%) 0/5 (0%)
    Hyperkalaemia 6/203 (3%) 3/64 (4.7%) 1/65 (1.5%) 2/18 (11.1%) 5/48 (10.4%) 3/46 (6.5%) 0/5 (0%)
    Hyperuricaemia 16/203 (7.9%) 3/64 (4.7%) 3/65 (4.6%) 2/18 (11.1%) 5/48 (10.4%) 1/46 (2.2%) 1/5 (20%)
    Hypocalcaemia 7/203 (3.4%) 1/64 (1.6%) 8/65 (12.3%) 1/18 (5.6%) 5/48 (10.4%) 4/46 (8.7%) 0/5 (0%)
    Hypokalaemia 12/203 (5.9%) 4/64 (6.3%) 3/65 (4.6%) 2/18 (11.1%) 11/48 (22.9%) 4/46 (8.7%) 1/5 (20%)
    Hypomagnesaemia 2/203 (1%) 2/64 (3.1%) 3/65 (4.6%) 0/18 (0%) 3/48 (6.3%) 1/46 (2.2%) 0/5 (0%)
    Hyponatraemia 10/203 (4.9%) 2/64 (3.1%) 3/65 (4.6%) 2/18 (11.1%) 2/48 (4.2%) 1/46 (2.2%) 0/5 (0%)
    Hypophosphataemia 10/203 (4.9%) 3/64 (4.7%) 3/65 (4.6%) 1/18 (5.6%) 5/48 (10.4%) 1/46 (2.2%) 0/5 (0%)
    Iron overload 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 3/48 (6.3%) 0/46 (0%) 0/5 (0%)
    Type 2 diabetes mellitus 1/203 (0.5%) 2/64 (3.1%) 2/65 (3.1%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 1/5 (20%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 72/203 (35.5%) 18/64 (28.1%) 22/65 (33.8%) 6/18 (33.3%) 10/48 (20.8%) 6/46 (13%) 1/5 (20%)
    Back pain 50/203 (24.6%) 8/64 (12.5%) 10/65 (15.4%) 3/18 (16.7%) 8/48 (16.7%) 7/46 (15.2%) 1/5 (20%)
    Bone pain 32/203 (15.8%) 6/64 (9.4%) 8/65 (12.3%) 3/18 (16.7%) 8/48 (16.7%) 1/46 (2.2%) 0/5 (0%)
    Flank pain 2/203 (1%) 0/64 (0%) 3/65 (4.6%) 1/18 (5.6%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Limb discomfort 1/203 (0.5%) 2/64 (3.1%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Muscle spasms 32/203 (15.8%) 6/64 (9.4%) 4/65 (6.2%) 1/18 (5.6%) 3/48 (6.3%) 4/46 (8.7%) 2/5 (40%)
    Muscular weakness 4/203 (2%) 1/64 (1.6%) 2/65 (3.1%) 0/18 (0%) 3/48 (6.3%) 0/46 (0%) 0/5 (0%)
    Musculoskeletal pain 22/203 (10.8%) 5/64 (7.8%) 4/65 (6.2%) 2/18 (11.1%) 3/48 (6.3%) 3/46 (6.5%) 2/5 (40%)
    Myalgia 47/203 (23.2%) 18/64 (28.1%) 14/65 (21.5%) 4/18 (22.2%) 10/48 (20.8%) 3/46 (6.5%) 0/5 (0%)
    Neck pain 13/203 (6.4%) 1/64 (1.6%) 3/65 (4.6%) 0/18 (0%) 2/48 (4.2%) 2/46 (4.3%) 0/5 (0%)
    Osteoarthritis 6/203 (3%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 1/5 (20%)
    Pain in extremity 56/203 (27.6%) 9/64 (14.1%) 11/65 (16.9%) 5/18 (27.8%) 6/48 (12.5%) 6/46 (13%) 1/5 (20%)
    Limb mass 3/203 (1.5%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Nervous system disorders
    Aphasia 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Ataxia 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Burning sensation 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Depressed level of consciousness 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Dizziness 34/203 (16.7%) 12/64 (18.8%) 7/65 (10.8%) 2/18 (11.1%) 4/48 (8.3%) 0/46 (0%) 0/5 (0%)
    Dysgeusia 3/203 (1.5%) 6/64 (9.4%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Facial paralysis 3/203 (1.5%) 0/64 (0%) 1/65 (1.5%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Headache 87/203 (42.9%) 27/64 (42.2%) 18/65 (27.7%) 7/18 (38.9%) 15/48 (31.3%) 12/46 (26.1%) 1/5 (20%)
    Hypoaesthesia 11/203 (5.4%) 2/64 (3.1%) 1/65 (1.5%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Migraine 6/203 (3%) 0/64 (0%) 1/65 (1.5%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Neuropathy peripheral 15/203 (7.4%) 1/64 (1.6%) 2/65 (3.1%) 0/18 (0%) 1/48 (2.1%) 1/46 (2.2%) 0/5 (0%)
    Paraesthesia 15/203 (7.4%) 5/64 (7.8%) 1/65 (1.5%) 1/18 (5.6%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Radiculopathy 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Sciatica 11/203 (5.4%) 0/64 (0%) 4/65 (6.2%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 1/5 (20%)
    Somnolence 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 1/48 (2.1%) 1/46 (2.2%) 1/5 (20%)
    Vith nerve disorder 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Psychiatric disorders
    Anxiety 10/203 (4.9%) 3/64 (4.7%) 11/65 (16.9%) 4/18 (22.2%) 4/48 (8.3%) 3/46 (6.5%) 0/5 (0%)
    Confusional state 4/203 (2%) 1/64 (1.6%) 1/65 (1.5%) 2/18 (11.1%) 2/48 (4.2%) 3/46 (6.5%) 0/5 (0%)
    Depression 13/203 (6.4%) 2/64 (3.1%) 5/65 (7.7%) 0/18 (0%) 3/48 (6.3%) 1/46 (2.2%) 1/5 (20%)
    Hallucination 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Hallucination, visual 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Insomnia 25/203 (12.3%) 5/64 (7.8%) 10/65 (15.4%) 1/18 (5.6%) 10/48 (20.8%) 1/46 (2.2%) 0/5 (0%)
    Libido decreased 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Renal and urinary disorders
    Acute kidney injury 3/203 (1.5%) 1/64 (1.6%) 1/65 (1.5%) 0/18 (0%) 3/48 (6.3%) 0/46 (0%) 0/5 (0%)
    Chronic kidney disease 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Dysuria 6/203 (3%) 2/64 (3.1%) 3/65 (4.6%) 2/18 (11.1%) 3/48 (6.3%) 1/46 (2.2%) 0/5 (0%)
    Haematuria 2/203 (1%) 0/64 (0%) 2/65 (3.1%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Hypertonic bladder 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Pollakiuria 7/203 (3.4%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 3/48 (6.3%) 0/46 (0%) 1/5 (20%)
    Renal colic 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Urinary incontinence 4/203 (2%) 1/64 (1.6%) 2/65 (3.1%) 1/18 (5.6%) 1/48 (2.1%) 1/46 (2.2%) 1/5 (20%)
    Urinary retention 4/203 (2%) 1/64 (1.6%) 3/65 (4.6%) 1/18 (5.6%) 0/48 (0%) 2/46 (4.3%) 0/5 (0%)
    Reproductive system and breast disorders
    Breast mass 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Erectile dysfunction 9/203 (4.4%) 6/64 (9.4%) 4/65 (6.2%) 4/18 (22.2%) 1/48 (2.1%) 0/46 (0%) 1/5 (20%)
    Testicular pain 0/203 (0%) 1/64 (1.6%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Respiratory, thoracic and mediastinal disorders
    Asthma 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Catarrh 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Cough 36/203 (17.7%) 11/64 (17.2%) 15/65 (23.1%) 3/18 (16.7%) 8/48 (16.7%) 6/46 (13%) 1/5 (20%)
    Dysphonia 14/203 (6.9%) 5/64 (7.8%) 1/65 (1.5%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Dyspnoea 30/203 (14.8%) 14/64 (21.9%) 12/65 (18.5%) 4/18 (22.2%) 11/48 (22.9%) 3/46 (6.5%) 1/5 (20%)
    Epistaxis 16/203 (7.9%) 3/64 (4.7%) 6/65 (9.2%) 1/18 (5.6%) 5/48 (10.4%) 3/46 (6.5%) 0/5 (0%)
    Nasal congestion 2/203 (1%) 1/64 (1.6%) 2/65 (3.1%) 1/18 (5.6%) 4/48 (8.3%) 2/46 (4.3%) 0/5 (0%)
    Oropharyngeal pain 12/203 (5.9%) 6/64 (9.4%) 4/65 (6.2%) 3/18 (16.7%) 8/48 (16.7%) 1/46 (2.2%) 0/5 (0%)
    Pharyngeal erythema 2/203 (1%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Pleural effusion 10/203 (4.9%) 2/64 (3.1%) 7/65 (10.8%) 2/18 (11.1%) 8/48 (16.7%) 4/46 (8.7%) 1/5 (20%)
    Productive cough 6/203 (3%) 2/64 (3.1%) 2/65 (3.1%) 1/18 (5.6%) 0/48 (0%) 1/46 (2.2%) 0/5 (0%)
    Sleep apnoea syndrome 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Skin and subcutaneous tissue disorders
    Alopecia 19/203 (9.4%) 4/64 (6.3%) 5/65 (7.7%) 4/18 (22.2%) 4/48 (8.3%) 3/46 (6.5%) 0/5 (0%)
    Dry skin 84/203 (41.4%) 28/64 (43.8%) 21/65 (32.3%) 4/18 (22.2%) 15/48 (31.3%) 9/46 (19.6%) 4/5 (80%)
    Ecchymosis 2/203 (1%) 1/64 (1.6%) 4/65 (6.2%) 0/18 (0%) 1/48 (2.1%) 1/46 (2.2%) 1/5 (20%)
    Erythema 22/203 (10.8%) 6/64 (9.4%) 6/65 (9.2%) 1/18 (5.6%) 3/48 (6.3%) 4/46 (8.7%) 0/5 (0%)
    Exfoliative rash 7/203 (3.4%) 2/64 (3.1%) 4/65 (6.2%) 0/18 (0%) 0/48 (0%) 1/46 (2.2%) 2/5 (40%)
    Generalised erythema 1/203 (0.5%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Hyperhidrosis 17/203 (8.4%) 7/64 (10.9%) 4/65 (6.2%) 1/18 (5.6%) 1/48 (2.1%) 3/46 (6.5%) 1/5 (20%)
    Hyperkeratosis 4/203 (2%) 0/64 (0%) 3/65 (4.6%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Night sweats 15/203 (7.4%) 10/64 (15.6%) 4/65 (6.2%) 1/18 (5.6%) 2/48 (4.2%) 2/46 (4.3%) 0/5 (0%)
    Photosensitivity reaction 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Pruritus 29/203 (14.3%) 6/64 (9.4%) 6/65 (9.2%) 1/18 (5.6%) 2/48 (4.2%) 1/46 (2.2%) 0/5 (0%)
    Rash 28/203 (13.8%) 3/64 (4.7%) 10/65 (15.4%) 3/18 (16.7%) 2/48 (4.2%) 3/46 (6.5%) 0/5 (0%)
    Rash erythematous 39/203 (19.2%) 21/64 (32.8%) 9/65 (13.8%) 2/18 (11.1%) 11/48 (22.9%) 8/46 (17.4%) 0/5 (0%)
    Rash generalised 0/203 (0%) 1/64 (1.6%) 1/65 (1.5%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Rash macular 9/203 (4.4%) 4/64 (6.3%) 0/65 (0%) 1/18 (5.6%) 2/48 (4.2%) 0/46 (0%) 0/5 (0%)
    Rash maculo-papular 21/203 (10.3%) 11/64 (17.2%) 4/65 (6.2%) 1/18 (5.6%) 3/48 (6.3%) 0/46 (0%) 0/5 (0%)
    Rash papular 14/203 (6.9%) 4/64 (6.3%) 5/65 (7.7%) 1/18 (5.6%) 3/48 (6.3%) 1/46 (2.2%) 2/5 (40%)
    Rash pruritic 21/203 (10.3%) 6/64 (9.4%) 5/65 (7.7%) 3/18 (16.7%) 2/48 (4.2%) 1/46 (2.2%) 1/5 (20%)
    Skin disorder 1/203 (0.5%) 1/64 (1.6%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Skin exfoliation 12/203 (5.9%) 6/64 (9.4%) 2/65 (3.1%) 1/18 (5.6%) 0/48 (0%) 2/46 (4.3%) 1/5 (20%)
    Skin lesion 4/203 (2%) 1/64 (1.6%) 3/65 (4.6%) 1/18 (5.6%) 0/48 (0%) 2/46 (4.3%) 0/5 (0%)
    Urticaria 0/203 (0%) 0/64 (0%) 1/65 (1.5%) 1/18 (5.6%) 2/48 (4.2%) 2/46 (4.3%) 0/5 (0%)
    Social circumstances
    Activities of daily living impaired 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Vascular disorders
    Flushing 8/203 (3.9%) 2/64 (3.1%) 4/65 (6.2%) 0/18 (0%) 1/48 (2.1%) 0/46 (0%) 0/5 (0%)
    Haemorrhage 0/203 (0%) 0/64 (0%) 0/65 (0%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Hot flush 12/203 (5.9%) 1/64 (1.6%) 4/65 (6.2%) 0/18 (0%) 0/48 (0%) 0/46 (0%) 1/5 (20%)
    Hypertension 68/203 (33.5%) 21/64 (32.8%) 13/65 (20%) 8/18 (44.4%) 13/48 (27.1%) 8/46 (17.4%) 2/5 (40%)
    Hypotension 6/203 (3%) 0/64 (0%) 1/65 (1.5%) 0/18 (0%) 3/48 (6.3%) 1/46 (2.2%) 0/5 (0%)
    Peripheral ischaemia 0/203 (0%) 2/64 (3.1%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)
    Peripheral venous disease 0/203 (0%) 0/64 (0%) 0/65 (0%) 1/18 (5.6%) 0/48 (0%) 0/46 (0%) 0/5 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.

    Results Point of Contact

    Name/Title Medical Director
    Organization Takeda
    Phone +1-877-825-3327
    Email trialdisclosures@takeda.com
    Responsible Party:
    Ariad Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01207440
    Other Study ID Numbers:
    • AP24534-10-201
    • 2010-020414-28
    First Posted:
    Sep 23, 2010
    Last Update Posted:
    Feb 2, 2021
    Last Verified:
    Jan 1, 2021