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A Study of Clofarabine and Cytarabine for Older Patients With Relapsed or Refractory Acute Myelogenous Leukemia (AML)(CLASSIC I)

Sponsor
Genzyme, a Sanofi Company (Industry)
Overall Status
Completed
CT.gov ID
NCT00317642
Collaborator
(none)
326
Enrollment
57
Locations
2
Arms
65
Duration (Months)
5.7
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Clofarabine (injection) is approved by the Food and Drug Administration (FDA) for the treatment of pediatric patients 1 to 21 years old with relapsed acute or refractory lymphoblastic leukemia (ALL) who have had at least 2 prior treatment regimens.

There is no recommended standard treatment for relapsed or refractory acute myelogenous leukemia in older patients. Cytarabine is the most commonly used drug to treat these patients. This study will determine if there is benefit by combining clofarabine with cytarabine. Patients will be randomized to receive up to 3 cycles of treatment with either placebo in combination with cytarabine or clofarabine in combination with cytarabine. Randomization was stratified by remission status following the first induction regimen (no remission [i.e., CR1 = refractory] or remission <6 months vs CR1 = remission ≥6 months). CR1 is defined as remission after first pre-study induction regimen. The safety and tolerability of clofarabine in combination with cytarabine and cytarabine alone will be monitored throughout the study.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

After screening and eligibility assessment, patients were randomized (in a 1:1 ratio) to receive either clofarabine or matching placebo, in addition to cytarabine. Randomization was stratified by remission status following the first induction regimen (CR1): no remission [i.e., CR1 = refractory] or remission <6 months vs remission ≥6 months. During randomization by interactive voice response system (IVRS), there were 10 participants misclassified to the CR1 <6 months stratum and 12 participants misclassified to CR1 ≥6 months stratum. The error did not affect the participants' treatment, only the stratification. Due to the misclassification, outcomes that used strata in their analysis were analyzed twice: once with the 'randomized stratification' which includes the misclassification and once with the 'calculated stratification' in which participants appear in the 'correct' strata.

Two clinical study reports were written for this study.

  1. Clinical study report dated 7 April 2011 includes the entire treatment period of all participants plus much of the follow-up. At that time, 33 participants in the Clofarabine+cytarabine group and 29 participants in the placebo+cytarabine group were still being follow-up post treatment. Results were reported on clinicaltrials.gov in August 2011. Outcomes that used strata reported the 'calculated strata' on clinicaltrials.gov.

  2. Clinical study report dated 9 July 2012 includes all patient treatment experience plus all long-term follow-up (a minimum of 2 years from the end of treatment or until the patient died). The study was completed at that time. Outcomes that used strata reported the 'randomized strata' on clinicaltrials.gov. AE records on clinicaltrials.gov reflect the final database.

Outcomes that changed between the two clinical study reports due to the additional long-term follow-up data are reported twice on clinicaltrials.gov (once from each clinical study report) and the appropriate report date is included in the outcome description. Outcomes from the 9 July 2012 report represent more complete data.

Study Design

Study Type:
Interventional
Actual Enrollment :
326 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase III Randomized, Double-blind, Controlled Study Comparing Clofarabine and Cytarabine Versus Cytarabine Alone in Adult Patients 55 Years and Older With Acute Myelogenous Leukemia (AML) Who Have Relapsed or Are Refractory After Receiving up to Two Prior Induction Regimens
Study Start Date :
Aug 1, 2006
Actual Primary Completion Date :
Jan 1, 2012
Actual Study Completion Date :
Jan 1, 2012

Arms and Interventions

Arm Intervention/Treatment
Experimental: clofarabine (IV formulation) and cytarabine

Participants received clofarabine (40 mg/m^2) administered as a 1-hour infusion followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour infusion. Participants could receive up to 3 cycles of treatment (induction, re-induction, and consolidation) Complete induction cycle = 5 consecutive days of treatment Re-induction cycle = 5 consecutive days of treatment at the original or modified dose Consolidation cycle = 4 consecutive days of treatment at the original or modified dose

Drug: clofarabine (IV formulation)
clofarabine (IV formulation) infusion 40mg/m^2 / day up to 3 cycles
Other Names:
  • Clolar®
  • Evoltra®

    • Drug: cytarabine
    cytarabine IV infusion 1g/m^2/day for up to 3 cycles
    Experimental: placebo and cytarabine

    Participants received placebo administered as a 1-hour infusion followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour infusion. Patients could receive up to 3 cycles of treatment (induction, re-induction, and consolidation)

    Drug: placebo
    placebo (sodium Chloride) 1-hour IV infusion

    Drug: cytarabine
    cytarabine IV infusion 1g/m^2/day for up to 3 cycles

    Outcome Measures

    Primary Outcome Measures

    1. Overall Survival - Overall and by Calculated Strata (CSR 7-April-11) [Day 1 (randomization) up to approximately 4 years]

      Overall survival (OS) for the Full Analysis Set (FAS) and for the 2 calculated strata. OS was defined as the number of months from date of randomization until date of death due to any cause.

    2. Overall Survival - Overall and by Randomized Strata (CSR 9-July-12) [Day 1 (randomization) up to approximately 4 years]

      Overall survival (OS) for the Full Analysis Set (FAS) and for the 2 randomized strata. OS was defined as the number of months from date of randomization until date of death due to any cause.

    Secondary Outcome Measures

    1. Best Response Per Independent Response Review Panel (IRRP) Assessment - Overall and by Calculated Strata (CSR 7-April-11) [Day 12 up to approximately 6 months]

      Percentage of participants whose best response was assessed by the IRRP as complete remission (CR) or complete remission with incomplete peripheral blood count recovery (CRi) using the revised International Working Group for Response Criteria (Cheson 2003). CR is defined on morphologic criteria at a single response assessment: a bone marrow aspirate or biopsy of <5% blasts, with evidence of normal hematopoiesis; absence of Auer rods in the blasts that are present; absence of extramedullary disease; absence of a unique phenotype determined at the pretreatment specimen, as assessed by immunophenotyping; only rare evidence of circulating blasts. If present, evidence of a regenerating bone marrow; recovery of peripheral counts (platelets ≥100*10^9/L and absolute neutrophil count (ANC) ≥1.0*10^9/L). CRi met all criteria for CR except for either residual neutropenia (ANC <1.0*10^9/L) or thrombocytopenia (platelet count <100*10^9/L).

    2. Duration of Remission (DOR) Per IRRP Assessment-Overall and by Calculated Strata (CSR 7-April-11) [Day 12 to approximately 4 years]

      DOR was defined as the time from first CR or CRi to the date of first objective documentation of disease recurrence, initiation of alternative antileukemic therapy [including hematopoietic stem cell transplant] while in remission, or death due to any cause, whichever occurred first. CR is defined on morphologic criteria at a single response assessment: a bone marrow aspirate or biopsy of <5% blasts, with evidence of normal hematopoiesis; absence of Auer rods in the blasts that are present; absence of extramedullary disease; absence of a unique phenotype determined at the pretreatment specimen, as assessed by immunophenotyping; only rare evidence of circulating blasts. If present, evidence of a regenerating bone marrow; recovery of peripheral counts (platelets ≥100*10^9/L and absolute neutrophil count (ANC) ≥1.0*10^9/L). CRi met all criteria for CR except for either residual neutropenia (ANC <1.0*10^9/L) or thrombocytopenia (platelet count <100*10^9/L).

    3. Duration of Remission (DOR) Per IRRP Assessment-Overall and by Randomized Strata (CSR 9-July-12) [Day 12 to approximately 4 years]

      DOR was defined as the time from first CR or CRi to the date of first objective documentation of disease recurrence, initiation of alternative antileukemic therapy [including hematopoietic stem cell transplant] while in remission, or death due to any cause, whichever occurred first. CR is defined on morphologic criteria at a single response assessment: a bone marrow aspirate or biopsy of <5% blasts, with evidence of normal hematopoiesis; absence of Auer rods in the blasts that are present; absence of extramedullary disease; absence of a unique phenotype determined at the pretreatment specimen, as assessed by immunophenotyping; only rare evidence of circulating blasts. If present, evidence of a regenerating bone marrow; recovery of peripheral counts (platelets ≥100*10^9/L and absolute neutrophil count (ANC) ≥1.0*10^9/L). CRi met all criteria for CR except for either residual neutropenia (ANC <1.0*10^9/L) or thrombocytopenia (platelet count <100*10^9/L).

    4. Disease-free Survival by IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11) [Day 12 to approximately 4 years]

      Disease-free survival was defined as the time from first complete remission (CR) or complete remission with incomplete peripheral blood count recovery (CRi) until the date of first objective documentation of disease recurrence or death due to any cause, whichever occurred first. See Outcome #3 for definition of CR and CRi. Disease recurrence - reappearance of leukemic blasts in the peripheral blood, confirmed by ≥5% blasts in the bone marrow, and reappearance or development of pathologically proven extramedullary disease.

    5. Disease-free Survival by IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12) [Day 12 to approximately 4 years]

      Disease-free survival was defined as the time from first complete remission (CR) or complete remission with incomplete peripheral blood count recovery (CRi) until the date of first objective documentation of disease recurrence or death due to any cause, whichever occurred first. See Outcome #3 for definition of CR and CRi. Disease recurrence - reappearance of leukemic blasts in the peripheral blood, confirmed by ≥5% blasts in the bone marrow, and reappearance or development of pathologically proven extramedullary disease.

    6. Event-free Survival by IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11) [Day 1 (randomization) up to approximately 4 years]

      Event-free survival (EFS) was defined as the time from randomization to the date of treatment failure, first disease recurrence (for participants who achieved remission), or death due to any cause, whichever occurred first. Treatment Failure - ≥5% leukemic blasts by bone marrow exam, with no evidence of hematologic response (ie, <30% decrease in % leukemic blasts). Disease recurrence - reappearance of leukemic blasts in the peripheral blood, confirmed by ≥5% blasts in the bone marrow, and reappearance or development of pathologically proven extramedullary disease.

    7. Event-free Survival by IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12) [Day 1 (randomization) up to approximately 4 years]

      Event-free survival (EFS) was defined as the time from randomization to the date of treatment failure, first disease recurrence (for participants who achieved remission), or death due to any cause, whichever occurred first. Treatment Failure - ≥5% leukemic blasts by bone marrow exam, with no evidence of hematologic response (ie, <30% decrease in % leukemic blasts). Disease recurrence - reappearance of leukemic blasts in the peripheral blood, confirmed by ≥5% blasts in the bone marrow, and reappearance or development of pathologically proven extramedullary disease.

    8. Four-Month Event-free Survival Per IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11) [Day 1 (randomization) to Day 122]

      Four-month event-free survival (EFS) was defined as achieving an EFS of at least 122 days, where EFS is defined as the time from randomization to the date of treatment failure, first disease recurrence (for participants who achieved remission), or death due to any cause, whichever occurred first. Treatment Failure - ≥5% leukemic blasts by bone marrow exam, with no evidence of hematologic response (ie, <30% decrease in % leukemic blasts). Disease recurrence - reappearance of leukemic blasts in the peripheral blood, confirmed by ≥5% blasts in the bone marrow, and reappearance or development of pathologically proven extramedullary disease.

    9. Four-Month Event-free Survival Per IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12) [Day 1 (randomization) to Day 122]

      Four-month event-free survival (EFS) was defined as achieving an EFS of at least 122 days, where EFS is defined as the time from randomization to the date of treatment failure, first disease recurrence (for participants who achieved remission), or death due to any cause, whichever occurred first. Treatment Failure - ≥5% leukemic blasts by bone marrow exam, with no evidence of hematologic response (ie, <30% decrease in % leukemic blasts). Disease recurrence - reappearance of leukemic blasts in the peripheral blood, confirmed by ≥5% blasts in the bone marrow, and reappearance or development of pathologically proven extramedullary disease.

    10. Participants With Adverse Events (CSR 7-April-11) [Day 1 up to a maximum of 4 years (includes up to a maximum of 3 cycles of therapy plus 45 days follow up. Related AEs are followed to resolution.)]

      Number of participants with treatment emergent adverse events (TEAEs) or death due to related AE. Related AEs for the combination arm can be related to either clofarabine or cytarabine. Grade 1 = Mild AE, Grade 2 = Moderate AE, Grade 3 = Severe AE, Grade 4 = Life Threatening AE, Grade 5 = Death

    Eligibility Criteria

    Criteria

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

    • Have a diagnosis of Acute Myelogenous Leukemia (AML) according to World Health Organization (WHO) classification

    • Relapsed after receiving up to 2 prior induction regimens (i.e. first or second relapse)or are refractory to not more than one prior combination chemotherapy induction regimen

    • Be ≥ 55 years of age

    • Have an Eastern Cooperative Oncology Group (ECOG) score of 0-2

    • Be able to comply with study procedures and follow-up examinations

    • Be nonfertile or agree to use birth control during the study through the end of treatment visit and for at least 90 days after the last dose of study drug

    • Have adequate liver and renal function as indicated by certain laboratory values

    Exclusion Criteria:

    • Received previous treatment with clofarabine

    • Received bolus, intermediate or high-dose cytarabine as induction therapy unless certain remission criteria are met

    • Have received a hematopoietic stem cell transplant (HSCT) within the previous 3 months

    • Have moderate or severe graft versus host disease (GVHD), whether acute or chronic

    • Are receiving any other chemotherapy or investigational therapy. Patients must have been off prior AML therapy for at least 2-6 weeks prior to entering study.

    • Have a psychiatric disorder that would interfere with consent, study participation, or follow-up

    • Have an active, uncontrolled infection

    • Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system

    • Have been diagnosed with another malignancy, unless disease-free for at least 5 years; patients with treated nonmelanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed; patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease are eligible if hormonal therapy has been initiated or the malignancy has been surgically removed.

    • Have clinical evidence suggestive of central nervous system (CNS) involvement with leukemia unless lumbar puncture confirms absence of leukemic blasts in the cerebrospinal fluid(CSF)

    • Known HIV positivity

    • Are pregnant or lactating

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Mayo Clinical Hospital Scottsdale Arizona United States
    2 Arizona Cancer Center Tucson Arizona United States
    3 University of Arkansas for Medical Sciences, Arkansas Cancer Research Center Little Rock Arkansas United States
    4 Scripps Cancer Center La Jolla California United States
    5 UCLA School of Medicine Los Angeles California United States
    6 University of Southern California, Kenneth Norris Cancer Center Los Angeles California United States
    7 Stanford Comprehensive Cancer Center Stanford California United States
    8 University of Colorado Health Science Center Aurora Colorado United States
    9 Rocky Mountain Cancer Center Denver Colorado United States
    10 Cancer Center of Central Connecticut Southington Connecticut United States
    11 Northwestern University Chicago Illinois United States
    12 Rush University Medical Center Chicago Illinois United States
    13 Evanston Northwestern Healthcare Evanston Illinois United States
    14 University of Kansas Medical Center Kansas City Kansas United States
    15 University of Kentucky, Markey Cancer Center Lexington Kentucky United States
    16 Louisiana State University Health Science Center Shreveport Louisiana United States
    17 Harold Alfond Center for Cancer Care Augusta Maine United States
    18 Beth Israel Deaconess Medical Center Boston Massachusetts United States
    19 Josephine Ford Cancer Center Detroit Michigan United States
    20 Dartmouth Hitchcock Medical Center Lebanon New Hampshire United States
    21 The Cancer Center at Hackensack University Medical Center Hackensack New Jersey United States
    22 Roswell Park Cancer Center Buffalo New York United States
    23 Mt. Sinai School of Medicine New York New York United States
    24 New York Medical Center Valhalla New York United States
    25 Mecklenburg Medical Group Charlotte North Carolina United States
    26 Duke University Medical Center Durham North Carolina United States
    27 Wake Forest University School of Medicine Winston-Salem North Carolina United States
    28 Gabrail Cancer Center Canton Ohio United States
    29 University of Oklahoma Health Sciences Center Oklahoma City Oklahoma United States
    30 Oregon Health Science University Portland Oregon United States
    31 Medical University of South Carolina Charleston South Carolina United States
    32 University of Tennessee Medical Center Knoxville Tennessee United States
    33 Sarah Cannon Research Institute Nashville Tennessee United States
    34 Vanderbilt University Medical Center Nashville Tennessee United States
    35 UT Southwestern Medical Center, Simmons Comprehensive Cancer Center Dallas Texas United States
    36 MD Anderson Cancer Center Houston Texas United States
    37 Cancer Care Centers of South Texas San Antonio Texas United States
    38 University of Texas Health Sciences Center San Antonio Texas United States
    39 University of Utah - Huntsman Cancer Institute Salt Lake City Utah United States
    40 West Virginia University Hospitals, Mary Babb Randolph Cancer Center Morgantown West Virginia United States
    41 Medical College of Wisconsin Milwaukee Wisconsin United States
    42 Saint John Regional Hospital Saint John New Brunswick Canada
    43 Juravinski Cancer Center Hamilton Ontario Canada
    44 Hopital Maisonneuve-Rosemont Montreal Quebec Canada
    45 Service Maladies du Sang, CHU Angers Angers Cedex 01 France
    46 Hopital Claude Huriez CHRU de Lille Lille France
    47 Hopital Edouard Herriot Lyon France
    48 Institut Paoli Calmettes Marseille France
    49 Hopital Hotel Dieu Nantes France
    50 Hopital Purpan Toulouse France
    51 Medizinische Hochschule Hannover, Zentrum fur Innere Medizin, Abt. Haematologie / Onkologie Hannover Germany
    52 Medizinische Klinik der Technischen, Universität München Munich Germany
    53 Universitatsklinikum Ulm Ulm Germany 89081
    54 Ospedali Riuniti Bergamo Bergamo Italy
    55 A.O Ospedale Niguarda Ca'Granda Milano Italy
    56 N.O. San Gerardo Monza Italy
    57 Azienda Ospedaliera "Antonio Cardarelli" Napoli Italy

    Sponsors and Collaborators

    • Genzyme, a Sanofi Company

    Investigators

    • Study Director: Medical Monitor, Genzyme, a Sanofi Company

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Genzyme, a Sanofi Company
    ClinicalTrials.gov Identifier:
    NCT00317642
    Other Study ID Numbers:
    • CLO34100405
    • 2008-001043-19
    First Posted:
    Apr 25, 2006
    Last Update Posted:
    Apr 14, 2014
    Last Verified:
    Mar 1, 2014
    Keywords provided by Genzyme, a Sanofi Company
    acute myelogenous leukemia
    acute myeloid leukemia
    relapsed AML
    refractory AML
    clofarabine
    cytarabine
    CLO341
    clolar
    Additional relevant MeSH terms:
    Leukemia
    Leukemia, Myeloid
    Leukemia, Myeloid, Acute
    Cytarabine
    Clofarabine

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail 352 patients screened and 326 randomized, 163 to each treatment group. One participant withdrew after being randomized to the Placebo and Cytarabine Group and was excluded from efficacy analysis.
    Arm/Group Title Clofarabine (IV Formulation) and Cytarabine Placebo and Cytarabine
    Arm/Group Description Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation.
    Period Title: Overall Study
    STARTED 163 163
    Full Analysis Set 162 158
    Received >= 1 Study Drug (Safety Set) 161 155
    COMPLETED 41 28
    NOT COMPLETED 122 135

    Baseline Characteristics

    Arm/Group Title Clofarabine (IV Formulation) and Cytarabine Placebo and Cytarabine Total
    Arm/Group Description Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Total of all reporting groups
    Overall Participants 162 158 320
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    67.0
    (6.36)
    67.1
    (5.82)
    67.0
    (6.09)
    Sex: Female, Male (Count of Participants)
    Female
    48
    29.6%
    57
    36.1%
    105
    32.8%
    Male
    114
    70.4%
    101
    63.9%
    215
    67.2%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    9
    5.6%
    6
    3.8%
    15
    4.7%
    Not Hispanic or Latino
    153
    94.4%
    152
    96.2%
    305
    95.3%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    3
    1.9%
    2
    1.3%
    5
    1.6%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    7
    4.3%
    11
    7%
    18
    5.6%
    White
    150
    92.6%
    142
    89.9%
    292
    91.3%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    2
    1.2%
    3
    1.9%
    5
    1.6%
    Height (cm) (centimeter) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [centimeter]
    171.5
    (10.27)
    170.5
    (8.92)
    171.0
    (9.62)
    Weight(kg) (kg) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kg]
    81.21
    (17.862)
    83.03
    (17.281)
    82.11
    (17.574)
    Body Surface Area (BSA) (m^2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [m^2]
    1.941
    (0.2383)
    1.959
    (0.2338)
    1.950
    (0.2359)
    Eastern Cooperative Oncology Group Performance Status (Number) [Number]
    ECOG 0
    57
    35.2%
    48
    30.4%
    105
    32.8%
    ECOG 1
    79
    48.8%
    92
    58.2%
    171
    53.4%
    ECOG 2
    26
    16%
    18
    11.4%
    44
    13.8%
    Karyotype (participants) [Number]
    Favorable
    1
    0.6%
    0
    0%
    1
    0.3%
    Intermediate
    65
    40.1%
    84
    53.2%
    149
    46.6%
    Unfavorable
    86
    53.1%
    70
    44.3%
    156
    48.8%
    Not Assessed
    8
    4.9%
    3
    1.9%
    11
    3.4%
    unknown
    2
    1.2%
    1
    0.6%
    3
    0.9%

    Outcome Measures

    1. Primary Outcome
    Title Overall Survival - Overall and by Calculated Strata (CSR 7-April-11)
    Description Overall survival (OS) for the Full Analysis Set (FAS) and for the 2 calculated strata. OS was defined as the number of months from date of randomization until date of death due to any cause.
    Time Frame Day 1 (randomization) up to approximately 4 years

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set (FAS)-all randomized participants whose baseline AML diagnosis was centrally confirmed. Strata are calculated according to duration of the first remission based on case report forms (CRF) data and do not include the IVRS mistakes. One participant's strata (placebo group) could not be calculated so the participant was excluded.
    Arm/Group Title Clofarabine (IV Formulation) and Cytarabine (FAS) Placebo and Cytarabine (FAS) Clofarabine and Cytarabine - In Stratum < 6 Months Placebo and Cytarabine - In Stratum < 6 Months Clofarabine and Cytarabine In Stratum >= 6 Months Placebo and Cytarabine In Stratum >= 6 Months
    Arm/Group Description Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation.
    Measure Participants 162 157 88 83 74 74
    Median (95% Confidence Interval) [months]
    6.6
    6.4
    5.1
    5.5
    8.7
    7.2
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Clofarabine (IV Formulation) and Cytarabine (FAS), Placebo and Cytarabine (FAS)
    Comments Full Analysis Set (FAS) population
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.9951
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.00
    Confidence Interval (2-Sided) 95%
    0.78 to 1.28
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine - In Stratum < 6 Months, Placebo and Cytarabine - In Stratum < 6 Months
    Comments Participants stratified by calculated strata remission after first pre-study induction regimen (CR1) < 6 months
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.4674
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.13
    Confidence Interval (2-Sided) 95%
    0.81 to 1.57
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine In Stratum >= 6 Months, Placebo and Cytarabine In Stratum >= 6 Months
    Comments Participants stratified by calculated strata CR1>= 6 months
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.3963
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.85
    Confidence Interval (2-Sided) 95%
    0.58 to 1.24
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Best Response Per Independent Response Review Panel (IRRP) Assessment - Overall and by Calculated Strata (CSR 7-April-11)
    Description Percentage of participants whose best response was assessed by the IRRP as complete remission (CR) or complete remission with incomplete peripheral blood count recovery (CRi) using the revised International Working Group for Response Criteria (Cheson 2003). CR is defined on morphologic criteria at a single response assessment: a bone marrow aspirate or biopsy of <5% blasts, with evidence of normal hematopoiesis; absence of Auer rods in the blasts that are present; absence of extramedullary disease; absence of a unique phenotype determined at the pretreatment specimen, as assessed by immunophenotyping; only rare evidence of circulating blasts. If present, evidence of a regenerating bone marrow; recovery of peripheral counts (platelets ≥100*10^9/L and absolute neutrophil count (ANC) ≥1.0*10^9/L). CRi met all criteria for CR except for either residual neutropenia (ANC <1.0*10^9/L) or thrombocytopenia (platelet count <100*10^9/L).
    Time Frame Day 12 up to approximately 6 months

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set (FAS)-all randomized participants whose baseline AML diagnosis was centrally confirmed. Strata are calculated according to duration of the first remission based on case report forms (CRF) data and do not include the IVRS mistakes. One participant's strata (placebo group) could not be calculated so the participant was excluded.
    Arm/Group Title Clofarabine (IV Formulation) and Cytarabine Placebo and Cytarabine Clofarabine and Cytarabine - In Stratum < 6 Months Placebo and Cytarabine - In Stratum < 6 Months Clofarabine and Cytarabine In Stratum >= 6 Months Placebo and Cytarabine In Stratum >= 6 Months
    Arm/Group Description Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation.
    Measure Participants 162 157 88 83 74 74
    Overall Remission (CR + CRi)
    46.9
    29%
    22.9
    14.5%
    45.5
    14.2%
    22.9
    NaN
    48.6
    NaN
    23.0
    NaN
    Complete Remission (CR)
    35.2
    21.7%
    17.8
    11.3%
    33.0
    10.3%
    18.1
    NaN
    37.8
    NaN
    17.6
    NaN
    CR with incomplete blood count recovery (CRi)
    11.7
    7.2%
    5.1
    3.2%
    12.5
    3.9%
    4.8
    NaN
    10.8
    NaN
    5.4
    NaN
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Clofarabine (IV Formulation) and Cytarabine (FAS), Placebo and Cytarabine (FAS)
    Comments Full Analysis Set (FAS) population - overall remission (OR)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Clofarabine (IV Formulation) and Cytarabine (FAS), Placebo and Cytarabine (FAS)
    Comments Full Analysis Set (FAS) population - Complete Remission (CR)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0005
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine - In Stratum < 6 Months, Placebo and Cytarabine - In Stratum < 6 Months
    Comments Participants stratified by calculated strata - CR1 <6 months [Overall Remission (CR+CRi)]
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0022
    Comments
    Method Fisher Exact
    Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine In Stratum >= 6 Months, Placebo and Cytarabine In Stratum >= 6 Months
    Comments Participants stratified by calculated strata - CR1 >=6 months [Overall Remission (CR+CRi)]
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0019
    Comments
    Method Fisher Exact
    Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine - In Stratum < 6 Months, Placebo and Cytarabine - In Stratum < 6 Months
    Comments Participants stratified by calculated strata - CR1 <6 months [Complete Remission (CR)]
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0353
    Comments
    Method Fisher Exact
    Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine In Stratum >= 6 Months, Placebo and Cytarabine In Stratum >= 6 Months
    Comments Participants stratified by calculated strata - CR1 >=6 months [Complete Remission (CR)]
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0096
    Comments
    Method Fisher Exact
    Comments
    3. Secondary Outcome
    Title Duration of Remission (DOR) Per IRRP Assessment-Overall and by Calculated Strata (CSR 7-April-11)
    Description DOR was defined as the time from first CR or CRi to the date of first objective documentation of disease recurrence, initiation of alternative antileukemic therapy [including hematopoietic stem cell transplant] while in remission, or death due to any cause, whichever occurred first. CR is defined on morphologic criteria at a single response assessment: a bone marrow aspirate or biopsy of <5% blasts, with evidence of normal hematopoiesis; absence of Auer rods in the blasts that are present; absence of extramedullary disease; absence of a unique phenotype determined at the pretreatment specimen, as assessed by immunophenotyping; only rare evidence of circulating blasts. If present, evidence of a regenerating bone marrow; recovery of peripheral counts (platelets ≥100*10^9/L and absolute neutrophil count (ANC) ≥1.0*10^9/L). CRi met all criteria for CR except for either residual neutropenia (ANC <1.0*10^9/L) or thrombocytopenia (platelet count <100*10^9/L).
    Time Frame Day 12 to approximately 4 years

    Outcome Measure Data

    Analysis Population Description
    Participants in the FAS who achieved OR (CR + CRi). Strata are calculated according to duration of the first remission based on case report forms (CRF) data and do not include the IVRS mistakes.
    Arm/Group Title Clofarabine (IV Formulation) and Cytarabine Placebo and Cytarabine Clofarabine and Cytarabine - In Stratum < 6 Months Placebo and Cytarabine - In Stratum < 6 Months Clofarabine and Cytarabine In Stratum >= 6 Months Placebo and Cytarabine In Stratum >= 6 Months
    Arm/Group Description Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation.
    Measure Participants 76 36 40 19 36 17
    Median (95% Confidence Interval) [months]
    7.6
    3.8
    5.7
    6.3
    11.5
    3.8
    4. Secondary Outcome
    Title Duration of Remission (DOR) Per IRRP Assessment-Overall and by Randomized Strata (CSR 9-July-12)
    Description DOR was defined as the time from first CR or CRi to the date of first objective documentation of disease recurrence, initiation of alternative antileukemic therapy [including hematopoietic stem cell transplant] while in remission, or death due to any cause, whichever occurred first. CR is defined on morphologic criteria at a single response assessment: a bone marrow aspirate or biopsy of <5% blasts, with evidence of normal hematopoiesis; absence of Auer rods in the blasts that are present; absence of extramedullary disease; absence of a unique phenotype determined at the pretreatment specimen, as assessed by immunophenotyping; only rare evidence of circulating blasts. If present, evidence of a regenerating bone marrow; recovery of peripheral counts (platelets ≥100*10^9/L and absolute neutrophil count (ANC) ≥1.0*10^9/L). CRi met all criteria for CR except for either residual neutropenia (ANC <1.0*10^9/L) or thrombocytopenia (platelet count <100*10^9/L).
    Time Frame Day 12 to approximately 4 years

    Outcome Measure Data

    Analysis Population Description
    Participants in the FAS who achieved OR (CR + CRi). Strata are as randomized by the IVRS, therefore strata include the IVRS mistakes.
    Arm/Group Title Clofarabine (IV Formulation) and Cytarabine Placebo and Cytarabine Clofarabine and Cytarabine - In Stratum < 6 Months Placebo and Cytarabine - In Stratum < 6 Months Clofarabine and Cytarabine In Stratum >= 6 Months Placebo and Cytarabine In Stratum >= 6 Months
    Arm/Group Description Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation.
    Measure Participants 76 36 36 20 40 16
    Median (95% Confidence Interval) [months]
    7.7
    3.8
    6.7
    6.3
    10.2
    3.8
    5. Secondary Outcome
    Title Disease-free Survival by IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11)
    Description Disease-free survival was defined as the time from first complete remission (CR) or complete remission with incomplete peripheral blood count recovery (CRi) until the date of first objective documentation of disease recurrence or death due to any cause, whichever occurred first. See Outcome #3 for definition of CR and CRi. Disease recurrence - reappearance of leukemic blasts in the peripheral blood, confirmed by ≥5% blasts in the bone marrow, and reappearance or development of pathologically proven extramedullary disease.
    Time Frame Day 12 to approximately 4 years

    Outcome Measure Data

    Analysis Population Description
    Participants in the FAS who achieved OR (CR + CRi). Strata are calculated according to duration of the first remission based on case report forms (CRF) data and do not include the IVRS mistakes.
    Arm/Group Title Clofarabine (IV Formulation) and Cytarabine Placebo and Cytarabine Clofarabine and Cytarabine - In Stratum < 6 Months Placebo and Cytarabine - In Stratum < 6 Months Clofarabine and Cytarabine In Stratum >= 6 Months Placebo and Cytarabine In Stratum >= 6 Months
    Arm/Group Description Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation.
    Measure Participants 76 36 40 19 36 17
    Median (95% Confidence Interval) [months]
    8.1
    7.0
    5.7
    6.7
    10.3
    9.1
    6. Secondary Outcome
    Title Disease-free Survival by IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12)
    Description Disease-free survival was defined as the time from first complete remission (CR) or complete remission with incomplete peripheral blood count recovery (CRi) until the date of first objective documentation of disease recurrence or death due to any cause, whichever occurred first. See Outcome #3 for definition of CR and CRi. Disease recurrence - reappearance of leukemic blasts in the peripheral blood, confirmed by ≥5% blasts in the bone marrow, and reappearance or development of pathologically proven extramedullary disease.
    Time Frame Day 12 to approximately 4 years

    Outcome Measure Data

    Analysis Population Description
    Participants in the FAS who achieved OR (CR + CRi). Strata are as randomized by the IVRS, therefore strata include the IVRS mistakes.
    Arm/Group Title Clofarabine (IV Formulation) and Cytarabine Placebo and Cytarabine Clofarabine and Cytarabine - In Stratum < 6 Months Placebo and Cytarabine - In Stratum < 6 Months Clofarabine and Cytarabine In Stratum >= 6 Months Placebo and Cytarabine In Stratum >= 6 Months
    Arm/Group Description Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation.
    Measure Participants 76 36 36 20 40 16
    Median (95% Confidence Interval) [months]
    9.5
    7.0
    6.7
    6.7
    15.4
    9.2
    7. Secondary Outcome
    Title Event-free Survival by IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11)
    Description Event-free survival (EFS) was defined as the time from randomization to the date of treatment failure, first disease recurrence (for participants who achieved remission), or death due to any cause, whichever occurred first. Treatment Failure - ≥5% leukemic blasts by bone marrow exam, with no evidence of hematologic response (ie, <30% decrease in % leukemic blasts). Disease recurrence - reappearance of leukemic blasts in the peripheral blood, confirmed by ≥5% blasts in the bone marrow, and reappearance or development of pathologically proven extramedullary disease.
    Time Frame Day 1 (randomization) up to approximately 4 years

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set (FAS)-all randomized participants whose baseline AML diagnosis was centrally confirmed. Strata are calculated according to duration of the first remission based on case report forms (CRF) data and do not include the IVRS mistakes. One participant's strata (placebo group) could not be calculated so the participant was excluded.
    Arm/Group Title Clofarabine (IV Formulation) and Cytarabine Placebo and Cytarabine Clofarabine and Cytarabine - In Stratum < 6 Months Placebo and Cytarabine - In Stratum < 6 Months Clofarabine and Cytarabine In Stratum >= 6 Months Placebo and Cytarabine In Stratum >= 6 Months
    Arm/Group Description Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation.
    Measure Participants 162 157 88 83 74 74
    Median (95% Confidence Interval) [months]
    1.9
    1.0
    1.4
    1.0
    2.0
    1.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Clofarabine (IV Formulation) and Cytarabine (FAS), Placebo and Cytarabine (FAS)
    Comments Full Analysis Set (FAS) population.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0001
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.63
    Confidence Interval (2-Sided) 95%
    0.49 to 0.80
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine - In Stratum < 6 Months, Placebo and Cytarabine - In Stratum < 6 Months
    Comments Participants stratified by randomization strata CR1 <6 months
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0131
    Comments
    Method Log Rank
    Comments Comparison P-value is from a log-rank test with no strata
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.67
    Confidence Interval (2-Sided) 95%
    0.49 to 0.93
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine In Stratum >= 6 Months, Placebo and Cytarabine In Stratum >= 6 Months
    Comments Participants stratified by randomization strata CR1 >=6 months
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0022
    Comments
    Method Log Rank
    Comments Comparison p-value is from a log-rank test with no strata.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.57
    Confidence Interval () 95%
    0.40 to 0.83
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    8. Primary Outcome
    Title Overall Survival - Overall and by Randomized Strata (CSR 9-July-12)
    Description Overall survival (OS) for the Full Analysis Set (FAS) and for the 2 randomized strata. OS was defined as the number of months from date of randomization until date of death due to any cause.
    Time Frame Day 1 (randomization) up to approximately 4 years

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set (FAS) - composed of all randomized participants whose baseline AML diagnosis was centrally confirmed. Strata are as randomized by the IVRS, therefore strata include the IVRS mistakes.
    Arm/Group Title Clofarabine (IV Formulation) and Cytarabine (FAS) Placebo and Cytarabine (FAS) Clofarabine and Cytarabine - In Stratum < 6 Months Placebo and Cytarabine - In Stratum < 6 Months Clofarabine and Cytarabine In Stratum >= 6 Months Placebo and Cytarabine In Stratum >= 6 Months
    Arm/Group Description Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation.
    Measure Participants 162 158 86 84 76 74
    Median (95% Confidence Interval) [months]
    6.6
    6.3
    4.8
    6.3
    9.7
    6.6
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Clofarabine (IV Formulation) and Cytarabine (FAS), Placebo and Cytarabine (FAS)
    Comments Full Analysis Set (FAS) population
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.8209
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.97
    Confidence Interval (2-Sided) 95%
    0.77 to 1.23
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine - In Stratum < 6 Months, Placebo and Cytarabine - In Stratum < 6 Months
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.5071
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.11
    Confidence Interval (2-Sided) 95%
    0.81 to 1.53
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine In Stratum >= 6 Months, Placebo and Cytarabine In Stratum >= 6 Months
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.2906
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.83
    Confidence Interval (2-Sided) 95%
    0.59 to 1.17
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    9. Secondary Outcome
    Title Event-free Survival by IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12)
    Description Event-free survival (EFS) was defined as the time from randomization to the date of treatment failure, first disease recurrence (for participants who achieved remission), or death due to any cause, whichever occurred first. Treatment Failure - ≥5% leukemic blasts by bone marrow exam, with no evidence of hematologic response (ie, <30% decrease in % leukemic blasts). Disease recurrence - reappearance of leukemic blasts in the peripheral blood, confirmed by ≥5% blasts in the bone marrow, and reappearance or development of pathologically proven extramedullary disease.
    Time Frame Day 1 (randomization) up to approximately 4 years

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set - composed of all randomized participants whose baseline AML diagnosis was centrally confirmed. Strata are as randomized by the IVRS, therefore strata include the IVRS mistakes.
    Arm/Group Title Clofarabine (IV Formulation) and Cytarabine Placebo and Cytarabine Clofarabine and Cytarabine - In Stratum < 6 Months Placebo and Cytarabine - In Stratum < 6 Months Clofarabine and Cytarabine In Stratum >= 6 Months Placebo and Cytarabine In Stratum >= 6 Months
    Arm/Group Description Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation.
    Measure Participants 162 158 86 84 76 74
    Median (95% Confidence Interval) [months]
    1.9
    1.0
    1.1
    1.0
    2.8
    1.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Clofarabine (IV Formulation) and Cytarabine (FAS), Placebo and Cytarabine (FAS)
    Comments Full Analysis Set (FAS) population.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <.0001
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.63
    Confidence Interval (2-Sided) 95%
    0.49 to 0.79
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine - In Stratum < 6 Months, Placebo and Cytarabine - In Stratum < 6 Months
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0486
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.73
    Confidence Interval (2-Sided) 95%
    0.53 to 1.01
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine In Stratum >= 6 Months, Placebo and Cytarabine In Stratum >= 6 Months
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0002
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.52
    Confidence Interval (2-Sided) 95%
    0.37 to 0.74
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    10. Secondary Outcome
    Title Four-Month Event-free Survival Per IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11)
    Description Four-month event-free survival (EFS) was defined as achieving an EFS of at least 122 days, where EFS is defined as the time from randomization to the date of treatment failure, first disease recurrence (for participants who achieved remission), or death due to any cause, whichever occurred first. Treatment Failure - ≥5% leukemic blasts by bone marrow exam, with no evidence of hematologic response (ie, <30% decrease in % leukemic blasts). Disease recurrence - reappearance of leukemic blasts in the peripheral blood, confirmed by ≥5% blasts in the bone marrow, and reappearance or development of pathologically proven extramedullary disease.
    Time Frame Day 1 (randomization) to Day 122

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set (FAS)-all randomized participants whose baseline AML diagnosis was centrally confirmed. Strata are calculated according to duration of the first remission based on case report forms (CRF) data and do not include the IVRS mistakes. One participant's strata (placebo group) could not be calculated so the participant was excluded.
    Arm/Group Title Clofarabine (IV Formulation) and Cytarabine Placebo and Cytarabine Clofarabine and Cytarabine - In Stratum < 6 Months Placebo and Cytarabine - In Stratum < 6 Months Clofarabine and Cytarabine In Stratum >= 6 Months Placebo and Cytarabine In Stratum >= 6 Months
    Arm/Group Description Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation.
    Measure Participants 162 157 88 83 74 74
    Number [percentage of participants]
    37.7
    23.3%
    16.6
    10.5%
    35.2
    11%
    16.9
    NaN
    40.5
    NaN
    16.2
    NaN
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Clofarabine (IV Formulation) and Cytarabine (FAS), Placebo and Cytarabine (FAS)
    Comments Full Analysis Set (FAS) population
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine - In Stratum < 6 Months, Placebo and Cytarabine - In Stratum < 6 Months
    Comments Participants stratified by randomization strata CR1 <6 months.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0088
    Comments
    Method Fisher Exact
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine In Stratum >= 6 Months, Placebo and Cytarabine In Stratum >= 6 Months
    Comments Participants stratified by randomization strata CR1 >=6 months
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0017
    Comments
    Method Fisher Exact
    Comments
    11. Secondary Outcome
    Title Four-Month Event-free Survival Per IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12)
    Description Four-month event-free survival (EFS) was defined as achieving an EFS of at least 122 days, where EFS is defined as the time from randomization to the date of treatment failure, first disease recurrence (for participants who achieved remission), or death due to any cause, whichever occurred first. Treatment Failure - ≥5% leukemic blasts by bone marrow exam, with no evidence of hematologic response (ie, <30% decrease in % leukemic blasts). Disease recurrence - reappearance of leukemic blasts in the peripheral blood, confirmed by ≥5% blasts in the bone marrow, and reappearance or development of pathologically proven extramedullary disease.
    Time Frame Day 1 (randomization) to Day 122

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set - composed of all randomized participants whose baseline AML diagnosis was centrally confirmed. Strata are as randomized by the IVRS, that is the strata include the IVRS mistakes.
    Arm/Group Title Clofarabine (IV Formulation) and Cytarabine Placebo and Cytarabine Clofarabine and Cytarabine - In Stratum < 6 Months Placebo and Cytarabine - In Stratum < 6 Months Clofarabine and Cytarabine In Stratum >= 6 Months Placebo and Cytarabine In Stratum >= 6 Months
    Arm/Group Description Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation.
    Measure Participants 162 158 86 84 76 74
    Number [percentage of participants]
    38.9
    24%
    17.1
    10.8%
    31.4
    9.8%
    17.9
    NaN
    47.4
    NaN
    16.2
    NaN
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Clofarabine (IV Formulation) and Cytarabine (FAS), Placebo and Cytarabine (FAS)
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine - In Stratum < 6 Months, Placebo and Cytarabine - In Stratum < 6 Months
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0506
    Comments
    Method Fisher Exact
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine In Stratum >= 6 Months, Placebo and Cytarabine In Stratum >= 6 Months
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Fisher Exact
    Comments
    12. Secondary Outcome
    Title Participants With Adverse Events (CSR 7-April-11)
    Description Number of participants with treatment emergent adverse events (TEAEs) or death due to related AE. Related AEs for the combination arm can be related to either clofarabine or cytarabine. Grade 1 = Mild AE, Grade 2 = Moderate AE, Grade 3 = Severe AE, Grade 4 = Life Threatening AE, Grade 5 = Death
    Time Frame Day 1 up to a maximum of 4 years (includes up to a maximum of 3 cycles of therapy plus 45 days follow up. Related AEs are followed to resolution.)

    Outcome Measure Data

    Analysis Population Description
    Safety Set - Participants in the Full Analysis Set (FAS) who received at least 1 dose of study drug.
    Arm/Group Title Clofarabine (IV Formulation) and Cytarabine Placebo and Cytarabine
    Arm/Group Description Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation.
    Measure Participants 161 155
    Any Treatment Emergent AE
    161
    99.4%
    155
    98.1%
    Any Related Treatment Emergent AE
    157
    96.9%
    133
    84.2%
    Any Treatment Emergent Grade >=3 AE
    157
    96.9%
    133
    84.2%
    Any Related Treatment Related Grade >=3 AE
    127
    78.4%
    83
    52.5%
    Discontinue of study medication due to AE
    17
    10.5%
    5
    3.2%
    Discontinue of study medication due to related AE
    14
    8.6%
    3
    1.9%

    Adverse Events

    Time Frame Day 1 up to a maximum of 4 years (includes up to a maximum of 3 cycles of therapy plus 45 days follow up. Related AEs are followed to resolution.)
    Adverse Event Reporting Description In the event a single participant has experienced both a serious and a non-serious form of the same adverse event term, the individual has been included in the numerator ("number of affected participants") of both adverse event tables. Adverse event information is from the final database supporting the clinical study report dated 9-July-12.
    Arm/Group Title Clofarabine (IV Formulation) and Cytarabine Placebo and Cytarabine Overall
    Arm/Group Description Participants received clofarabine 40 mg/m^2 administered as a 1-hour intravenous (IV) infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction (if the participant had not achieved remission following induction but hematological improvement was noted), and consolidation. Participants received placebo (sodium chloride) administered as a 1-hour IV infusion, followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour IV infusion for 5 days (induction and re-induction) or 4 days (consolidation). Participants could receive up to 3 cycles of treatment: induction, re-induction, and consolidation. Combined total for the two Arms/Groups
    All Cause Mortality
    Clofarabine (IV Formulation) and Cytarabine Placebo and Cytarabine Overall
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Clofarabine (IV Formulation) and Cytarabine Placebo and Cytarabine Overall
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 97/161 (60.2%) 76/155 (49%) 173/316 (54.7%)
    Blood and lymphatic system disorders
    Bone marrow failure 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Febrile neutropenia 25/161 (15.5%) 19/155 (12.3%) 44/316 (13.9%)
    Leukopenia 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Lymphadenitis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Neutropenia 2/161 (1.2%) 4/155 (2.6%) 6/316 (1.9%)
    Pancytopenia 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Thrombocytopenia 2/161 (1.2%) 3/155 (1.9%) 5/316 (1.6%)
    Cardiac disorders
    Acute myocardial infarction 3/161 (1.9%) 0/155 (0%) 3/316 (0.9%)
    Angina pectoris 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Atrial fibrillation 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Atrial flutter 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Bradycardia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Cardiac arrest 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Cardiac failure 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Cardiac failure congestive 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Cardio-respiratory arrest 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Cardiogenic shock 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Myocardial infarction 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Myocardial ischaemia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Pericarditis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Stress cardiomyopathy 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Supraventricular tachycardia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Tachycardia 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Eye disorders
    Blindness unilateral 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Gastrointestinal disorders
    Abdominal pain 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Caecitis 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Colitis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Diarrhoea 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Gastrointestinal haemorrhage 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Lower gastrointestinal haemorrhage 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Melaena 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    General disorders
    Asthenia 3/161 (1.9%) 1/155 (0.6%) 4/316 (1.3%)
    Death 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Fatigue 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Generalised oedema 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Hypothermia 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Inflammation 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Multi-organ failure 3/161 (1.9%) 1/155 (0.6%) 4/316 (1.3%)
    Oedema peripheral 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Pain 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Pyrexia 7/161 (4.3%) 9/155 (5.8%) 16/316 (5.1%)
    Hepatobiliary disorders
    Venoocclusive liver disease 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Immune system disorders
    Anaphylactic reaction 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Graft versus host disease 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Infections and infestations
    Alpha haemolytic streptococcal infection 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Appendicitis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Bacteraemia 7/161 (4.3%) 3/155 (1.9%) 10/316 (3.2%)
    Bacterial infection 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Bacterial sepsis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Bronchopulmonary aspergillosis 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Cellulitis 0/161 (0%) 3/155 (1.9%) 3/316 (0.9%)
    Clostridial infection 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Clostridium difficile colitis 3/161 (1.9%) 2/155 (1.3%) 5/316 (1.6%)
    Corynebacterium sepsis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Device related infection 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Diverticulitis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Enterobacter bacteraemia 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Enterobacter sepsis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Enterococcal bacteraemia 6/161 (3.7%) 1/155 (0.6%) 7/316 (2.2%)
    Enterococcal sepsis 3/161 (1.9%) 0/155 (0%) 3/316 (0.9%)
    Escherichia bacteraemia 4/161 (2.5%) 0/155 (0%) 4/316 (1.3%)
    Escherichia infection 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Escherichia sepsis 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Fungal infection 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Haematoma infection 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Herpes zoster 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Keratitis herpetic 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Klebsiella bacteraemia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Klebsiella sepsis 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Lobar pneumonia 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Neutropenic sepsis 4/161 (2.5%) 0/155 (0%) 4/316 (1.3%)
    Oral herpes 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Parainfluenzae virus infection 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Pneumonia 13/161 (8.1%) 12/155 (7.7%) 25/316 (7.9%)
    Pneumonia bacterial 3/161 (1.9%) 0/155 (0%) 3/316 (0.9%)
    Pneumonia fungal 5/161 (3.1%) 0/155 (0%) 5/316 (1.6%)
    Pneumonia viral 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Pseudomonal bacteraemia 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Sepsis 8/161 (5%) 3/155 (1.9%) 11/316 (3.5%)
    Sepsis syndrome 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Septic shock 6/161 (3.7%) 0/155 (0%) 6/316 (1.9%)
    Serratia sepsis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Sinusitis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Staphylococcal bacteraemia 2/161 (1.2%) 2/155 (1.3%) 4/316 (1.3%)
    Staphylococcal infection 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Staphylococcal scalded skin syndrome 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Staphylococcal sepsis 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Streptococcal bacteraemia 4/161 (2.5%) 0/155 (0%) 4/316 (1.3%)
    Streptococcal sepsis 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Systemic candida 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Upper respiratory fungal infection 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Urinary tract infection 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Urinary tract infection bacterial 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Urinary tract infection enterococcal 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Zygomycosis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Injury, poisoning and procedural complications
    Femoral neck fracture 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Refractoriness to platelet transfusion 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Subdural haematoma 3/161 (1.9%) 1/155 (0.6%) 4/316 (1.3%)
    Investigations
    Aspartate aminotransferase increased 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Blood bilirubin increased 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Blood phosphorus decreased 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Ejection fraction decreased 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Electrocardiogram QT prolonged 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Lipase increased 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Troponin I increased 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    White blood cell count decreased 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Metabolism and nutrition disorders
    Acidosis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Dehydration 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Fluid overload 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Hyperuricaemia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Hypokalaemia 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Metabolic acidosis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Tumour lysis syndrome 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Musculoskeletal and connective tissue disorders
    Back pain 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Muscle disorder 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Osteoarthritis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia 4/161 (2.5%) 5/155 (3.2%) 9/316 (2.8%)
    Leukaemia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Neoplasm malignant 2/161 (1.2%) 4/155 (2.6%) 6/316 (1.9%)
    Nervous system disorders
    Cerebral haemorrhage 2/161 (1.2%) 2/155 (1.3%) 4/316 (1.3%)
    Cerebral infarction 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Cerebrovascular accident 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Convulsion 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Encephalopathy 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Hypoxic-ischaemic encephalopathy 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Neuropathy peripheral 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Neurotoxicity 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Peripheral sensorimotor neuropathy 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Somnolence 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Status epilepticus 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Syncope 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Psychiatric disorders
    Agitation 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Confusional state 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Mental status changes 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Renal and urinary disorders
    Anuria 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Haematuria 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Renal failure 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Renal failure acute 5/161 (3.1%) 1/155 (0.6%) 6/316 (1.9%)
    Renal failure chronic 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Renal infarct 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome 4/161 (2.5%) 0/155 (0%) 4/316 (1.3%)
    Acute respiratory failure 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Dyspnoea 1/161 (0.6%) 3/155 (1.9%) 4/316 (1.3%)
    Epistaxis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Haemoptysis 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Hypoxia 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Interstitial lung disease 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Lung infiltration 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Pneumonia aspiration 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Pulmonary alveolar haemorrhage 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Pulmonary haemorrhage 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Pulmonary oedema 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Respiratory distress 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Respiratory failure 1/161 (0.6%) 4/155 (2.6%) 5/316 (1.6%)
    Skin and subcutaneous tissue disorders
    Drug eruption 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Exfoliative rash 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Generalised erythema 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Palmar-plantar erythrodysaesthesia syndrome 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Rash 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Toxic epidermal necrolysis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Vascular disorders
    Deep vein thrombosis 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Hypertension 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Hypotension 4/161 (2.5%) 4/155 (2.6%) 8/316 (2.5%)
    Other (Not Including Serious) Adverse Events
    Clofarabine (IV Formulation) and Cytarabine Placebo and Cytarabine Overall
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 161/161 (100%) 154/155 (99.4%) 315/316 (99.7%)
    Blood and lymphatic system disorders
    Anaemia 26/161 (16.1%) 18/155 (11.6%) 44/316 (13.9%)
    Coagulopathy 10/161 (6.2%) 1/155 (0.6%) 11/316 (3.5%)
    Disseminated intravascular coagulation 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Febrile bone marrow aplasia 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Febrile neutropenia 58/161 (36%) 35/155 (22.6%) 93/316 (29.4%)
    Haemoglobinaemia 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Hypercoagulation 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Hyperfibrinogenaemia 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Hypofibrinogenaemia 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Hypoprothrombinaemia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Leukocytosis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Leukopenia 9/161 (5.6%) 7/155 (4.5%) 16/316 (5.1%)
    Lymph node pain 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Lymphadenopathy 3/161 (1.9%) 5/155 (3.2%) 8/316 (2.5%)
    Lymphatic disorder 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Monocytosis 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Neutropenia 17/161 (10.6%) 10/155 (6.5%) 27/316 (8.5%)
    Pancytopenia 3/161 (1.9%) 0/155 (0%) 3/316 (0.9%)
    Splenomegaly 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Thrombocytopenia 27/161 (16.8%) 23/155 (14.8%) 50/316 (15.8%)
    Cardiac disorders
    Angina pectoris 5/161 (3.1%) 2/155 (1.3%) 7/316 (2.2%)
    Aortic valve calcification 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Aortic valve incompetence 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Aortic valve stenosis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Arrhythmia 2/161 (1.2%) 3/155 (1.9%) 5/316 (1.6%)
    Arrhythmia supraventricular 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Atrial fibrillation 6/161 (3.7%) 3/155 (1.9%) 9/316 (2.8%)
    Atrial flutter 5/161 (3.1%) 0/155 (0%) 5/316 (1.6%)
    Atrioventricular block 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Atrioventricular block first degree 3/161 (1.9%) 0/155 (0%) 3/316 (0.9%)
    Bradycardia 3/161 (1.9%) 14/155 (9%) 17/316 (5.4%)
    Bundle branch block left 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Bundle branch block right 3/161 (1.9%) 0/155 (0%) 3/316 (0.9%)
    Cardiac aneurysm 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Cardiac failure 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Cardiac failure congestive 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Cardiac valve disease 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Cardiomegaly 4/161 (2.5%) 0/155 (0%) 4/316 (1.3%)
    Conduction disorder 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Diastolic dysfunction 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Dilatation atrial 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Dilatation ventricular 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Extrasystoles 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Heart valve incompetence 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Intracardiac thrombus 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Ischaemic cardiomyopathy 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Left atrial dilatation 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Left ventricular dysfunction 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Left ventricular hypertrophy 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Mitral valve incompetence 4/161 (2.5%) 3/155 (1.9%) 7/316 (2.2%)
    Myocardial infarction 1/161 (0.6%) 4/155 (2.6%) 5/316 (1.6%)
    Myocardial ischaemia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Nodal arrhythmia 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Palpitations 2/161 (1.2%) 3/155 (1.9%) 5/316 (1.6%)
    Pericardial effusion 3/161 (1.9%) 6/155 (3.9%) 9/316 (2.8%)
    Pulmonary valve incompetence 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Sinus arrhythmia 3/161 (1.9%) 0/155 (0%) 3/316 (0.9%)
    Sinus bradycardia 3/161 (1.9%) 2/155 (1.3%) 5/316 (1.6%)
    Sinus tachycardia 12/161 (7.5%) 6/155 (3.9%) 18/316 (5.7%)
    Supraventricular extrasystoles 1/161 (0.6%) 3/155 (1.9%) 4/316 (1.3%)
    Supraventricular tachycardia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Tachycardia 25/161 (15.5%) 14/155 (9%) 39/316 (12.3%)
    Tricuspid valve incompetence 3/161 (1.9%) 3/155 (1.9%) 6/316 (1.9%)
    Ventricular arrhythmia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Ventricular extrasystoles 4/161 (2.5%) 2/155 (1.3%) 6/316 (1.9%)
    Ventricular hypertrophy 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Ventricular hypokinesia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Ventricular tachycardia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Congenital, familial and genetic disorders
    Atrial septal defect 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Hydrocele 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Ear and labyrinth disorders
    Cerumen impaction 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Ear congestion 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Ear pain 2/161 (1.2%) 3/155 (1.9%) 5/316 (1.6%)
    Hypoacusis 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Tinnitus 2/161 (1.2%) 2/155 (1.3%) 4/316 (1.3%)
    Vertigo 4/161 (2.5%) 2/155 (1.3%) 6/316 (1.9%)
    Endocrine disorders
    Adrenal disorder 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Adrenal insufficiency 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Cushingoid 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Hyperadrenalism 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Hypothyroidism 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Thyroid mass 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Eye disorders
    Blepharitis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Cataract 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Conjunctival cyst 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Conjunctival haemorrhage 5/161 (3.1%) 3/155 (1.9%) 8/316 (2.5%)
    Conjunctival hyperaemia 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Conjunctival pallor 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Conjunctivitis 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Diplopia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Dry eye 7/161 (4.3%) 7/155 (4.5%) 14/316 (4.4%)
    Erythema of eyelid 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Eye haemorrhage 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Eye irritation 3/161 (1.9%) 2/155 (1.3%) 5/316 (1.6%)
    Eye pain 3/161 (1.9%) 2/155 (1.3%) 5/316 (1.6%)
    Eye swelling 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Eyelid oedema 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Eyelid ptosis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Gaze palsy 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Lacrimation increased 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Miosis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Ocular dysmetria 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Ocular hyperaemia 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Ocular icterus 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Optic neuropathy 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Papilloedema 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Periorbital oedema 4/161 (2.5%) 1/155 (0.6%) 5/316 (1.6%)
    Photophobia 3/161 (1.9%) 1/155 (0.6%) 4/316 (1.3%)
    Pupillary reflex impaired 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Pupils unequal 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Retinal haemorrhage 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Scleral disorder 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Scleral haemorrhage 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Scleral oedema 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Vision blurred 8/161 (5%) 4/155 (2.6%) 12/316 (3.8%)
    Visual acuity reduced 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Visual impairment 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Vitreous detachment 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Vitreous floaters 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Gastrointestinal disorders
    Abdominal discomfort 5/161 (3.1%) 3/155 (1.9%) 8/316 (2.5%)
    Abdominal distension 18/161 (11.2%) 13/155 (8.4%) 31/316 (9.8%)
    Abdominal hernia 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Abdominal pain 30/161 (18.6%) 18/155 (11.6%) 48/316 (15.2%)
    Abdominal pain lower 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Abdominal pain upper 5/161 (3.1%) 6/155 (3.9%) 11/316 (3.5%)
    Abdominal tenderness 3/161 (1.9%) 2/155 (1.3%) 5/316 (1.6%)
    Anal inflammation 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Aphthous stomatitis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Ascites 3/161 (1.9%) 1/155 (0.6%) 4/316 (1.3%)
    Caecitis 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Chapped lips 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Cheilitis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Colitis 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Colonic polyp 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Colonic pseudo-obstruction 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Constipation 66/161 (41%) 72/155 (46.5%) 138/316 (43.7%)
    Crohn's disease 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Diarrhoea 109/161 (67.7%) 63/155 (40.6%) 172/316 (54.4%)
    Diverticulum 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Dry mouth 9/161 (5.6%) 6/155 (3.9%) 15/316 (4.7%)
    Dyspepsia 12/161 (7.5%) 19/155 (12.3%) 31/316 (9.8%)
    Dysphagia 7/161 (4.3%) 4/155 (2.6%) 11/316 (3.5%)
    Epigastric discomfort 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Eructation 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Faecal incontinence 5/161 (3.1%) 5/155 (3.2%) 10/316 (3.2%)
    Faeces discoloured 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Flatulence 10/161 (6.2%) 4/155 (2.6%) 14/316 (4.4%)
    Gastric antral vascular ectasia 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Gastritis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Gastrointestinal haemorrhage 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Gastrointestinal inflammation 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Gastrointestinal sounds abnormal 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Gastrooesophageal reflux disease 2/161 (1.2%) 5/155 (3.2%) 7/316 (2.2%)
    Gingival bleeding 5/161 (3.1%) 2/155 (1.3%) 7/316 (2.2%)
    Gingival cyst 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Gingival pain 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Gingivitis 6/161 (3.7%) 1/155 (0.6%) 7/316 (2.2%)
    Glossodynia 0/161 (0%) 3/155 (1.9%) 3/316 (0.9%)
    Haematemesis 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Haematochezia 5/161 (3.1%) 3/155 (1.9%) 8/316 (2.5%)
    Haemorrhoidal haemorrhage 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Haemorrhoids 13/161 (8.1%) 9/155 (5.8%) 22/316 (7%)
    Hiatus hernia 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Hypoaesthesia oral 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Ileus 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Inguinal hernia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Intestinal dilatation 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Intestinal obstruction 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Lip blister 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Lip dry 4/161 (2.5%) 5/155 (3.2%) 9/316 (2.8%)
    Lip haemorrhage 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Lip ulceration 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Melaena 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Mouth haemorrhage 11/161 (6.8%) 7/155 (4.5%) 18/316 (5.7%)
    Mouth ulceration 3/161 (1.9%) 9/155 (5.8%) 12/316 (3.8%)
    Mucous stools 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Nausea 117/161 (72.7%) 82/155 (52.9%) 199/316 (63%)
    Neutropenic colitis 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Odynophagia 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Oesophageal dilatation 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Oesophageal pain 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Oesophagitis 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Oral disorder 2/161 (1.2%) 4/155 (2.6%) 6/316 (1.9%)
    Oral mucosal discolouration 1/161 (0.6%) 3/155 (1.9%) 4/316 (1.3%)
    Oral mucosal erythema 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Oral pain 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Pancreatic mass 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Pancreatitis 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Parotid gland enlargement 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Poor dental condition 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Proctalgia 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Rectal haemorrhage 2/161 (1.2%) 4/155 (2.6%) 6/316 (1.9%)
    Rectal ulcer 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Retching 3/161 (1.9%) 1/155 (0.6%) 4/316 (1.3%)
    Salivary hypersecretion 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Stomatitis 17/161 (10.6%) 10/155 (6.5%) 27/316 (8.5%)
    Tongue blistering 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Tongue coated 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Tongue discolouration 2/161 (1.2%) 4/155 (2.6%) 6/316 (1.9%)
    Tongue exfoliation 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Tongue haematoma 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Tongue ulceration 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Tooth disorder 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Toothache 8/161 (5%) 3/155 (1.9%) 11/316 (3.5%)
    Umbilical hernia 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Upper gastrointestinal haemorrhage 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Vomiting 71/161 (44.1%) 42/155 (27.1%) 113/316 (35.8%)
    General disorders
    Adverse event 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Asthenia 32/161 (19.9%) 33/155 (21.3%) 65/316 (20.6%)
    Catheter site discharge 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Catheter site erosion 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Catheter site erythema 6/161 (3.7%) 13/155 (8.4%) 19/316 (6%)
    Catheter site haematoma 4/161 (2.5%) 0/155 (0%) 4/316 (1.3%)
    Catheter site haemorrhage 6/161 (3.7%) 4/155 (2.6%) 10/316 (3.2%)
    Catheter site inflammation 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Catheter site oedema 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Catheter site pain 12/161 (7.5%) 9/155 (5.8%) 21/316 (6.6%)
    Catheter site pruritus 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Catheter site rash 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Catheter site related reaction 2/161 (1.2%) 5/155 (3.2%) 7/316 (2.2%)
    Catheter site swelling 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Chest discomfort 4/161 (2.5%) 4/155 (2.6%) 8/316 (2.5%)
    Chest pain 3/161 (1.9%) 2/155 (1.3%) 5/316 (1.6%)
    Chills 38/161 (23.6%) 23/155 (14.8%) 61/316 (19.3%)
    Crepitations 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Cyst 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Device occlusion 3/161 (1.9%) 1/155 (0.6%) 4/316 (1.3%)
    Discomfort 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Early satiety 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Face oedema 2/161 (1.2%) 2/155 (1.3%) 4/316 (1.3%)
    Facial pain 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Fatigue 57/161 (35.4%) 49/155 (31.6%) 106/316 (33.5%)
    Feeling cold 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Feeling hot 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Gait disturbance 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    General physical health deterioration 3/161 (1.9%) 2/155 (1.3%) 5/316 (1.6%)
    Generalised oedema 9/161 (5.6%) 4/155 (2.6%) 13/316 (4.1%)
    Hypothermia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Infusion site discolouration 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Infusion site induration 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Injection site haemorrhage 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Injection site inflammation 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Injection site pain 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Injection site reaction 4/161 (2.5%) 1/155 (0.6%) 5/316 (1.6%)
    Malaise 2/161 (1.2%) 2/155 (1.3%) 4/316 (1.3%)
    Mass 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Medical device complication 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Mucosal dryness 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Mucosal inflammation 21/161 (13%) 19/155 (12.3%) 40/316 (12.7%)
    Nodule 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Non-cardiac chest pain 6/161 (3.7%) 3/155 (1.9%) 9/316 (2.8%)
    Oedema 4/161 (2.5%) 5/155 (3.2%) 9/316 (2.8%)
    Oedema peripheral 82/161 (50.9%) 71/155 (45.8%) 153/316 (48.4%)
    Pain 22/161 (13.7%) 8/155 (5.2%) 30/316 (9.5%)
    Pyrexia 53/161 (32.9%) 39/155 (25.2%) 92/316 (29.1%)
    Tenderness 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Thrombosis in device 3/161 (1.9%) 1/155 (0.6%) 4/316 (1.3%)
    Visceral oedema 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Hepatobiliary disorders
    Bile duct stone 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Cholecystitis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Cholelithiasis 4/161 (2.5%) 4/155 (2.6%) 8/316 (2.5%)
    Dilatation intrahepatic duct acquired 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Gallbladder polyp 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Hepatic cyst 2/161 (1.2%) 2/155 (1.3%) 4/316 (1.3%)
    Hepatic failure 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Hepatic function abnormal 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Hepatic lesion 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Hepatic steatosis 2/161 (1.2%) 2/155 (1.3%) 4/316 (1.3%)
    Hepatitis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Hepatomegaly 0/161 (0%) 3/155 (1.9%) 3/316 (0.9%)
    Hepatosplenomegaly 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Hepatotoxicity 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Hyperbilirubinaemia 15/161 (9.3%) 12/155 (7.7%) 27/316 (8.5%)
    Jaundice 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Immune system disorders
    Anaphylactic reaction 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Drug hypersensitivity 9/161 (5.6%) 1/155 (0.6%) 10/316 (3.2%)
    Hypogammaglobulinaemia 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Infections and infestations
    Abscess limb 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Acute sinusitis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Alpha haemolytic streptococcal infection 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Anal abscess 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Anorectal infection 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Bacteraemia 8/161 (5%) 4/155 (2.6%) 12/316 (3.8%)
    Bacterial infection 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Bacterial sepsis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Bacteriuria 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Bronchopulmonary aspergillosis 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Bullous impetigo 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Candida pneumonia 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Candidiasis 6/161 (3.7%) 3/155 (1.9%) 9/316 (2.8%)
    Catheter site cellulitis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Catheter site infection 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Cellulitis 5/161 (3.1%) 9/155 (5.8%) 14/316 (4.4%)
    Clostridial infection 3/161 (1.9%) 1/155 (0.6%) 4/316 (1.3%)
    Clostridium difficile colitis 5/161 (3.1%) 3/155 (1.9%) 8/316 (2.5%)
    Cystitis 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Cystitis bacterial 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Cytomegalovirus infection 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Cytomegalovirus viraemia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Device related infection 6/161 (3.7%) 5/155 (3.2%) 11/316 (3.5%)
    Diarrhoea infectious 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Diverticulitis 2/161 (1.2%) 2/155 (1.3%) 4/316 (1.3%)
    Enterobacter bacteraemia 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Enterococcal bacteraemia 9/161 (5.6%) 3/155 (1.9%) 12/316 (3.8%)
    Enterococcal infection 4/161 (2.5%) 2/155 (1.3%) 6/316 (1.9%)
    Enterococcal sepsis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Escherichia bacteraemia 2/161 (1.2%) 2/155 (1.3%) 4/316 (1.3%)
    Escherichia infection 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Escherichia sepsis 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Escherichia urinary tract infection 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Eye infection 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Eye infection fungal 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Eye infection staphylococcal 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Folliculitis 1/161 (0.6%) 6/155 (3.9%) 7/316 (2.2%)
    Fungal infection 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Fungal skin infection 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Furuncle 3/161 (1.9%) 1/155 (0.6%) 4/316 (1.3%)
    Gastroenteritis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Genital herpes 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Hepatosplenic candidiasis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Herpes simplex 2/161 (1.2%) 4/155 (2.6%) 6/316 (1.9%)
    Herpes zoster 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Infection 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Klebsiella bacteraemia 4/161 (2.5%) 1/155 (0.6%) 5/316 (1.6%)
    Lobar pneumonia 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Localised infection 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Lung infection 3/161 (1.9%) 1/155 (0.6%) 4/316 (1.3%)
    Lung infection pseudomonal 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Micrococcus infection 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Nasopharyngitis 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Oesophageal candidiasis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Onychomycosis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Oral candidiasis 10/161 (6.2%) 8/155 (5.2%) 18/316 (5.7%)
    Oral fungal infection 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Oral herpes 9/161 (5.6%) 4/155 (2.6%) 13/316 (4.1%)
    Osteomyelitis 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Otitis externa 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Parainfluenzae virus infection 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Paronychia 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Pharyngitis 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Pharyngitis streptococcal 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Pneumonia 14/161 (8.7%) 9/155 (5.8%) 23/316 (7.3%)
    Pneumonia bacterial 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Pneumonia fungal 5/161 (3.1%) 2/155 (1.3%) 7/316 (2.2%)
    Pseudomonal bacteraemia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Pseudomonal sepsis 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Pseudomonas infection 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Pulmonary mycosis 2/161 (1.2%) 3/155 (1.9%) 5/316 (1.6%)
    Respiratory syncytial virus infection 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Rhinitis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Sepsis 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Septic embolus 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Serratia bacteraemia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Sinusitis 2/161 (1.2%) 2/155 (1.3%) 4/316 (1.3%)
    Sinusitis fungal 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Skin candida 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Skin infection 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Staphylococcal bacteraemia 9/161 (5.6%) 15/155 (9.7%) 24/316 (7.6%)
    Staphylococcal infection 4/161 (2.5%) 1/155 (0.6%) 5/316 (1.6%)
    Staphylococcal scalded skin syndrome 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Staphylococcal sepsis 3/161 (1.9%) 1/155 (0.6%) 4/316 (1.3%)
    Staphylococcal skin infection 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Stenotrophomonas infection 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Streptococcal bacteraemia 3/161 (1.9%) 4/155 (2.6%) 7/316 (2.2%)
    Streptococcal sepsis 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Subcutaneous abscess 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Tooth abscess 0/161 (0%) 3/155 (1.9%) 3/316 (0.9%)
    Tooth infection 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Upper respiratory tract infection 2/161 (1.2%) 4/155 (2.6%) 6/316 (1.9%)
    Urinary tract infection 3/161 (1.9%) 0/155 (0%) 3/316 (0.9%)
    Urinary tract infection bacterial 2/161 (1.2%) 3/155 (1.9%) 5/316 (1.6%)
    Urinary tract infection enterococcal 4/161 (2.5%) 1/155 (0.6%) 5/316 (1.6%)
    Urinary tract infection pseudomonal 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Urinary tract infection staphylococcal 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Viral skin infection 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Vulvovaginal candidiasis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Injury, poisoning and procedural complications
    Anal injury 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Bite 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Compression fracture 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Contusion 12/161 (7.5%) 17/155 (11%) 29/316 (9.2%)
    Corneal abrasion 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Eschar 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Excoriation 9/161 (5.6%) 3/155 (1.9%) 12/316 (3.8%)
    Eye injury 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Face injury 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Fall 5/161 (3.1%) 1/155 (0.6%) 6/316 (1.9%)
    Head injury 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Infusion related reaction 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Laceration 5/161 (3.1%) 5/155 (3.2%) 10/316 (3.2%)
    Lip injury 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Muscle strain 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Nail avulsion 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Nail injury 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Overdose 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Periorbital haematoma 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Post procedural complication 0/161 (0%) 3/155 (1.9%) 3/316 (0.9%)
    Post procedural haematoma 2/161 (1.2%) 2/155 (1.3%) 4/316 (1.3%)
    Post procedural haematuria 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Post procedural haemorrhage 3/161 (1.9%) 1/155 (0.6%) 4/316 (1.3%)
    Post procedural swelling 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Post-traumatic pain 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Procedural hypotension 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Procedural pain 12/161 (7.5%) 19/155 (12.3%) 31/316 (9.8%)
    Procedural site reaction 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Refractoriness to platelet transfusion 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Scratch 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Skin injury 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Spinal compression fracture 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Spinal fracture 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Subdural haematoma 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Tongue injury 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Tooth fracture 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Transfusion reaction 9/161 (5.6%) 7/155 (4.5%) 16/316 (5.1%)
    Traumatic haematoma 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Urethral injury 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Wound 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Wound haemorrhage 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Wound secretion 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Investigations
    Activated partial thromboplastin time prolonged 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Alanine aminotransferase increased 40/161 (24.8%) 13/155 (8.4%) 53/316 (16.8%)
    Ammonia increased 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Aspartate aminotransferase increased 36/161 (22.4%) 8/155 (5.2%) 44/316 (13.9%)
    Bacterial test 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Bacterial test positive 2/161 (1.2%) 2/155 (1.3%) 4/316 (1.3%)
    Blast cells present 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Blood albumin decreased 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Blood alkaline phosphatase increased 11/161 (6.8%) 6/155 (3.9%) 17/316 (5.4%)
    Blood amylase increased 9/161 (5.6%) 2/155 (1.3%) 11/316 (3.5%)
    Blood beta-D-glucan increased 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Blood bicarbonate decreased 5/161 (3.1%) 0/155 (0%) 5/316 (1.6%)
    Blood bicarbonate increased 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Blood bilirubin increased 12/161 (7.5%) 1/155 (0.6%) 13/316 (4.1%)
    Blood calcium decreased 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Blood chloride decreased 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Blood chloride increased 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Blood creatinine increased 6/161 (3.7%) 3/155 (1.9%) 9/316 (2.8%)
    Blood culture positive 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Blood glucose increased 2/161 (1.2%) 2/155 (1.3%) 4/316 (1.3%)
    Blood iron increased 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Blood lactate dehydrogenase increased 9/161 (5.6%) 4/155 (2.6%) 13/316 (4.1%)
    Blood magnesium decreased 3/161 (1.9%) 0/155 (0%) 3/316 (0.9%)
    Blood magnesium increased 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Blood osmolarity increased 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Blood phosphorus decreased 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Blood phosphorus increased 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Blood potassium decreased 2/161 (1.2%) 2/155 (1.3%) 4/316 (1.3%)
    Blood potassium increased 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Blood pressure increased 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Blood urea increased 2/161 (1.2%) 3/155 (1.9%) 5/316 (1.6%)
    Blood uric acid increased 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Blood urine present 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Breath sounds abnormal 5/161 (3.1%) 7/155 (4.5%) 12/316 (3.8%)
    Cardiac murmur 6/161 (3.7%) 9/155 (5.8%) 15/316 (4.7%)
    Catheter culture positive 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Clostridium test positive 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Crystal urine present 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Culture stool positive 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Culture throat positive 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Culture urine positive 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Cytomegalovirus test positive 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Diagnostic procedure 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Electrocardiogram PR shortened 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Electrocardiogram QT prolonged 4/161 (2.5%) 5/155 (3.2%) 9/316 (2.8%)
    Electrocardiogram ST-T segment abnormal 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Electrocardiogram T wave abnormal 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Electrocardiogram abnormal 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Enterococcus test positive 5/161 (3.1%) 3/155 (1.9%) 8/316 (2.5%)
    Escherichia test positive 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Fungal test positive 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Gallop rhythm present 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Gamma-glutamyltransferase increased 3/161 (1.9%) 0/155 (0%) 3/316 (0.9%)
    Glucose urine present 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Haematocrit decreased 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Haemoglobin decreased 3/161 (1.9%) 1/155 (0.6%) 4/316 (1.3%)
    Heart rate decreased 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Heart rate increased 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Hepatic enzyme increased 3/161 (1.9%) 0/155 (0%) 3/316 (0.9%)
    International normalised ratio increased 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Lipase increased 10/161 (6.2%) 3/155 (1.9%) 13/316 (4.1%)
    Liver function test abnormal 3/161 (1.9%) 7/155 (4.5%) 10/316 (3.2%)
    Liver scan abnormal 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Lymph node palpable 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Monocyte count increased 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Neutrophil count decreased 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Nitrite urine present 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Platelet count decreased 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Protein total decreased 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Protein total increased 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Protein urine present 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Prothrombin time prolonged 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Pulmonary function test decreased 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    QRS axis abnormal 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Red blood cell count decreased 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Red blood cells urine positive 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Right ventricular systolic pressure increased 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Serum ferritin increased 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Spleen palpable 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Staphylococcus test positive 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Streptococcus test positive 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Transaminases increased 10/161 (6.2%) 1/155 (0.6%) 11/316 (3.5%)
    Troponin I increased 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Urinary sediment present 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Urine leukocyte esterase positive 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Urine output decreased 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Weight decreased 24/161 (14.9%) 11/155 (7.1%) 35/316 (11.1%)
    Weight increased 13/161 (8.1%) 7/155 (4.5%) 20/316 (6.3%)
    White blood cell count decreased 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    White blood cell count increased 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    White blood cells urine positive 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    pH urine increased 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Metabolism and nutrition disorders
    Acidosis 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Decreased appetite 57/161 (35.4%) 37/155 (23.9%) 94/316 (29.7%)
    Dehydration 8/161 (5%) 4/155 (2.6%) 12/316 (3.8%)
    Diabetes mellitus 8/161 (5%) 4/155 (2.6%) 12/316 (3.8%)
    Fluid overload 22/161 (13.7%) 17/155 (11%) 39/316 (12.3%)
    Fluid retention 9/161 (5.6%) 7/155 (4.5%) 16/316 (5.1%)
    Folate deficiency 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Glucose tolerance impaired 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Gout 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Hyperamylasaemia 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Hypercalcaemia 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Hyperglycaemia 17/161 (10.6%) 17/155 (11%) 34/316 (10.8%)
    Hyperkalaemia 5/161 (3.1%) 1/155 (0.6%) 6/316 (1.9%)
    Hyperlipasaemia 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Hypermagnesaemia 2/161 (1.2%) 2/155 (1.3%) 4/316 (1.3%)
    Hypernatraemia 4/161 (2.5%) 1/155 (0.6%) 5/316 (1.6%)
    Hyperphosphataemia 7/161 (4.3%) 7/155 (4.5%) 14/316 (4.4%)
    Hyperuricaemia 1/161 (0.6%) 3/155 (1.9%) 4/316 (1.3%)
    Hypoalbuminaemia 22/161 (13.7%) 8/155 (5.2%) 30/316 (9.5%)
    Hypocalcaemia 14/161 (8.7%) 5/155 (3.2%) 19/316 (6%)
    Hypoglycaemia 5/161 (3.1%) 3/155 (1.9%) 8/316 (2.5%)
    Hypokalaemia 61/161 (37.9%) 29/155 (18.7%) 90/316 (28.5%)
    Hypomagnesaemia 26/161 (16.1%) 13/155 (8.4%) 39/316 (12.3%)
    Hyponatraemia 15/161 (9.3%) 5/155 (3.2%) 20/316 (6.3%)
    Hypophagia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Hypophosphataemia 12/161 (7.5%) 7/155 (4.5%) 19/316 (6%)
    Hypovolaemia 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Iron overload 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Malnutrition 4/161 (2.5%) 1/155 (0.6%) 5/316 (1.6%)
    Metabolic acidosis 4/161 (2.5%) 1/155 (0.6%) 5/316 (1.6%)
    Polydipsia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Tumour lysis syndrome 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Type 2 diabetes mellitus 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Vitamin K deficiency 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 16/161 (9.9%) 7/155 (4.5%) 23/316 (7.3%)
    Arthritis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Arthropathy 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Back pain 29/161 (18%) 16/155 (10.3%) 45/316 (14.2%)
    Bone loss 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Bone pain 4/161 (2.5%) 3/155 (1.9%) 7/316 (2.2%)
    Bursitis 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Chondritis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Coccydynia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Flank pain 4/161 (2.5%) 1/155 (0.6%) 5/316 (1.6%)
    Groin pain 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Intervertebral disc degeneration 3/161 (1.9%) 2/155 (1.3%) 5/316 (1.6%)
    Intervertebral disc protrusion 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Joint effusion 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Joint range of motion decreased 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Joint swelling 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Limb discomfort 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Muscle atrophy 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Muscle spasms 8/161 (5%) 5/155 (3.2%) 13/316 (4.1%)
    Muscle tightness 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Muscular weakness 11/161 (6.8%) 1/155 (0.6%) 12/316 (3.8%)
    Musculoskeletal chest pain 3/161 (1.9%) 6/155 (3.9%) 9/316 (2.8%)
    Musculoskeletal discomfort 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Musculoskeletal pain 14/161 (8.7%) 9/155 (5.8%) 23/316 (7.3%)
    Myalgia 9/161 (5.6%) 7/155 (4.5%) 16/316 (5.1%)
    Myopathy 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Neck pain 5/161 (3.1%) 7/155 (4.5%) 12/316 (3.8%)
    Osteoarthritis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Osteolysis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Osteoporosis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Osteosclerosis 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Pain in extremity 27/161 (16.8%) 12/155 (7.7%) 39/316 (12.3%)
    Pain in jaw 3/161 (1.9%) 2/155 (1.3%) 5/316 (1.6%)
    Rotator cuff syndrome 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Scoliosis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Spinal column stenosis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Spinal osteoarthritis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign neoplasm of eye 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Eye naevus 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Lip neoplasm malignant stage unspecified 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Lipoma 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Lung neoplasm 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Meningioma 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Neoplasm malignant 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Neurilemmoma 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Seborrhoeic keratosis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Nervous system disorders
    Amnesia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Apraxia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Ataxia 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Burning sensation 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Carotid arteriosclerosis 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Central nervous system lesion 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Cerebral atrophy 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Cerebral haemorrhage 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Cerebral infarction 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Cerebral ischaemia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Cerebrovascular disorder 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Convulsion 3/161 (1.9%) 0/155 (0%) 3/316 (0.9%)
    Cranial nerve disorder 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Depressed level of consciousness 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Dizziness 19/161 (11.8%) 28/155 (18.1%) 47/316 (14.9%)
    Dizziness postural 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Dysaesthesia 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Dysgeusia 10/161 (6.2%) 4/155 (2.6%) 14/316 (4.4%)
    Dyskinesia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Encephalitis toxic 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Encephalopathy 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Headache 68/161 (42.2%) 44/155 (28.4%) 112/316 (35.4%)
    Hemiparesis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Hepatic encephalopathy 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Hyperaesthesia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Hypoaesthesia 3/161 (1.9%) 4/155 (2.6%) 7/316 (2.2%)
    Hypogeusia 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Hypokinesia 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Hyporeflexia 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Intention tremor 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Lethargy 3/161 (1.9%) 4/155 (2.6%) 7/316 (2.2%)
    Loss of consciousness 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Memory impairment 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Migraine 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Myoclonus 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Neuropathy peripheral 4/161 (2.5%) 2/155 (1.3%) 6/316 (1.9%)
    Nystagmus 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Paraesthesia 3/161 (1.9%) 2/155 (1.3%) 5/316 (1.6%)
    Peroneal nerve palsy 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Polyneuropathy 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Presyncope 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Restless legs syndrome 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Sciatica 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Sensory disturbance 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Sinus headache 3/161 (1.9%) 4/155 (2.6%) 7/316 (2.2%)
    Slow speech 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Somnolence 9/161 (5.6%) 7/155 (4.5%) 16/316 (5.1%)
    Speech disorder 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Syncope 6/161 (3.7%) 4/155 (2.6%) 10/316 (3.2%)
    Tension headache 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Tremor 9/161 (5.6%) 7/155 (4.5%) 16/316 (5.1%)
    Psychiatric disorders
    Aggression 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Agitation 9/161 (5.6%) 2/155 (1.3%) 11/316 (3.5%)
    Anger 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Anxiety 35/161 (21.7%) 20/155 (12.9%) 55/316 (17.4%)
    Confusional state 30/161 (18.6%) 13/155 (8.4%) 43/316 (13.6%)
    Delirium 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Depressed mood 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Depression 20/161 (12.4%) 8/155 (5.2%) 28/316 (8.9%)
    Disorientation 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Dysphoria 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Fear 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Flat affect 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Hallucination 3/161 (1.9%) 3/155 (1.9%) 6/316 (1.9%)
    Hallucination, visual 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Insomnia 51/161 (31.7%) 42/155 (27.1%) 93/316 (29.4%)
    Mental status changes 8/161 (5%) 4/155 (2.6%) 12/316 (3.8%)
    Mood altered 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Nightmare 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Panic attack 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Restlessness 2/161 (1.2%) 3/155 (1.9%) 5/316 (1.6%)
    Renal and urinary disorders
    Bladder dilatation 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Bladder mass 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Bladder spasm 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Chromaturia 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Dysuria 8/161 (5%) 3/155 (1.9%) 11/316 (3.5%)
    Enuresis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Haematuria 8/161 (5%) 11/155 (7.1%) 19/316 (6%)
    Incontinence 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Kidney enlargement 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Nephrolithiasis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Nocturia 2/161 (1.2%) 3/155 (1.9%) 5/316 (1.6%)
    Oliguria 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Pollakiuria 5/161 (3.1%) 6/155 (3.9%) 11/316 (3.5%)
    Polyuria 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Proteinuria 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Renal cyst 4/161 (2.5%) 4/155 (2.6%) 8/316 (2.5%)
    Renal disorder 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Renal failure 4/161 (2.5%) 4/155 (2.6%) 8/316 (2.5%)
    Renal failure acute 5/161 (3.1%) 2/155 (1.3%) 7/316 (2.2%)
    Renal failure chronic 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Renal tubular necrosis 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Urethritis noninfective 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Urinary incontinence 9/161 (5.6%) 6/155 (3.9%) 15/316 (4.7%)
    Urinary retention 1/161 (0.6%) 9/155 (5.8%) 10/316 (3.2%)
    Urine abnormality 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Urine flow decreased 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Reproductive system and breast disorders
    Balanitis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Breast haematoma 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Breast pain 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Gynaecomastia 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Ovarian cyst 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Pelvic pain 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Penile blister 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Penile haemorrhage 2/161 (1.2%) 2/155 (1.3%) 4/316 (1.3%)
    Penile pain 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Prostatomegaly 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Scrotal oedema 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Testicular pain 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Vaginal haemorrhage 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Vulvovaginal rash 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Vulvovaginal swelling 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Acute respiratory failure 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Asthma 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Atelectasis 8/161 (5%) 4/155 (2.6%) 12/316 (3.8%)
    Bronchial wall thickening 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Bronchospasm 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Chronic obstructive pulmonary disease 3/161 (1.9%) 2/155 (1.3%) 5/316 (1.6%)
    Cough 34/161 (21.1%) 26/155 (16.8%) 60/316 (19%)
    Dry throat 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Dysphonia 2/161 (1.2%) 2/155 (1.3%) 4/316 (1.3%)
    Dyspnoea 30/161 (18.6%) 18/155 (11.6%) 48/316 (15.2%)
    Dyspnoea exertional 8/161 (5%) 4/155 (2.6%) 12/316 (3.8%)
    Epistaxis 30/161 (18.6%) 19/155 (12.3%) 49/316 (15.5%)
    Haemoptysis 6/161 (3.7%) 10/155 (6.5%) 16/316 (5.1%)
    Hiccups 9/161 (5.6%) 2/155 (1.3%) 11/316 (3.5%)
    Hypoxia 9/161 (5.6%) 3/155 (1.9%) 12/316 (3.8%)
    Increased bronchial secretion 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Interstitial lung disease 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Laryngospasm 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Lung infiltration 8/161 (5%) 4/155 (2.6%) 12/316 (3.8%)
    Nasal congestion 7/161 (4.3%) 3/155 (1.9%) 10/316 (3.2%)
    Nasal dryness 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Nasal mucosal disorder 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Nasal ulcer 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Oropharyngeal blistering 3/161 (1.9%) 3/155 (1.9%) 6/316 (1.9%)
    Oropharyngeal pain 10/161 (6.2%) 11/155 (7.1%) 21/316 (6.6%)
    Oropharyngeal plaque 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Orthopnoea 1/161 (0.6%) 2/155 (1.3%) 3/316 (0.9%)
    Paranasal cyst 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Paranasal sinus hypersecretion 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Pharyngeal erythema 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Pharyngeal inflammation 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Pleural effusion 16/161 (9.9%) 15/155 (9.7%) 31/316 (9.8%)
    Pleuritic pain 3/161 (1.9%) 2/155 (1.3%) 5/316 (1.6%)
    Pneumonitis 0/161 (0%) 3/155 (1.9%) 3/316 (0.9%)
    Pneumothorax 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Productive cough 3/161 (1.9%) 0/155 (0%) 3/316 (0.9%)
    Pulmonary alveolar haemorrhage 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Pulmonary congestion 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Pulmonary fibrosis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Pulmonary haemorrhage 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Pulmonary hypertension 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Pulmonary oedema 8/161 (5%) 2/155 (1.3%) 10/316 (3.2%)
    Rales 9/161 (5.6%) 9/155 (5.8%) 18/316 (5.7%)
    Respiratory alkalosis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Respiratory distress 3/161 (1.9%) 0/155 (0%) 3/316 (0.9%)
    Respiratory failure 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Respiratory tract congestion 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Rhinalgia 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Rhinitis allergic 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Rhinorrhoea 3/161 (1.9%) 3/155 (1.9%) 6/316 (1.9%)
    Rhonchi 3/161 (1.9%) 2/155 (1.3%) 5/316 (1.6%)
    Sinus congestion 3/161 (1.9%) 2/155 (1.3%) 5/316 (1.6%)
    Sleep apnoea syndrome 0/161 (0%) 3/155 (1.9%) 3/316 (0.9%)
    Sputum discoloured 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Stridor 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Tachypnoea 1/161 (0.6%) 5/155 (3.2%) 6/316 (1.9%)
    Throat lesion 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Upper-airway cough syndrome 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Vocal cord polyp 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Wheezing 7/161 (4.3%) 2/155 (1.3%) 9/316 (2.8%)
    Skin and subcutaneous tissue disorders
    Actinic keratosis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Alopecia 14/161 (8.7%) 3/155 (1.9%) 17/316 (5.4%)
    Blister 7/161 (4.3%) 3/155 (1.9%) 10/316 (3.2%)
    Blood blister 3/161 (1.9%) 1/155 (0.6%) 4/316 (1.3%)
    Decubitus ulcer 8/161 (5%) 1/155 (0.6%) 9/316 (2.8%)
    Dermal cyst 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Dermatitis 1/161 (0.6%) 3/155 (1.9%) 4/316 (1.3%)
    Dermatitis allergic 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Drug eruption 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Dry skin 24/161 (14.9%) 13/155 (8.4%) 37/316 (11.7%)
    Ecchymosis 9/161 (5.6%) 20/155 (12.9%) 29/316 (9.2%)
    Erythema 19/161 (11.8%) 22/155 (14.2%) 41/316 (13%)
    Exfoliative rash 6/161 (3.7%) 2/155 (1.3%) 8/316 (2.5%)
    Generalised erythema 3/161 (1.9%) 0/155 (0%) 3/316 (0.9%)
    Heat rash 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Hidradenitis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Hyperhidrosis 12/161 (7.5%) 6/155 (3.9%) 18/316 (5.7%)
    Hyperkeratosis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Increased tendency to bruise 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Ingrowing nail 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Lentigo 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Leukocytoclastic vasculitis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Nail disorder 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Nail dystrophy 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Night sweats 5/161 (3.1%) 10/155 (6.5%) 15/316 (4.7%)
    Pain of skin 3/161 (1.9%) 1/155 (0.6%) 4/316 (1.3%)
    Palmar erythema 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Palmar-plantar erythrodysaesthesia syndrome 30/161 (18.6%) 2/155 (1.3%) 32/316 (10.1%)
    Papule 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Pemphigoid 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Petechiae 22/161 (13.7%) 24/155 (15.5%) 46/316 (14.6%)
    Photodermatosis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Pigmentation disorder 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Pruritus 19/161 (11.8%) 5/155 (3.2%) 24/316 (7.6%)
    Pruritus generalised 3/161 (1.9%) 2/155 (1.3%) 5/316 (1.6%)
    Purpura 2/161 (1.2%) 3/155 (1.9%) 5/316 (1.6%)
    Rash 40/161 (24.8%) 22/155 (14.2%) 62/316 (19.6%)
    Rash erythematous 14/161 (8.7%) 3/155 (1.9%) 17/316 (5.4%)
    Rash follicular 3/161 (1.9%) 0/155 (0%) 3/316 (0.9%)
    Rash generalised 17/161 (10.6%) 7/155 (4.5%) 24/316 (7.6%)
    Rash macular 3/161 (1.9%) 1/155 (0.6%) 4/316 (1.3%)
    Rash maculo-papular 4/161 (2.5%) 4/155 (2.6%) 8/316 (2.5%)
    Rash papular 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Rash pruritic 6/161 (3.7%) 1/155 (0.6%) 7/316 (2.2%)
    Rash vesicular 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Rosacea 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Scab 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Skin discolouration 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Skin disorder 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Skin exfoliation 23/161 (14.3%) 3/155 (1.9%) 26/316 (8.2%)
    Skin haemorrhage 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Skin hyperpigmentation 2/161 (1.2%) 2/155 (1.3%) 4/316 (1.3%)
    Skin lesion 5/161 (3.1%) 8/155 (5.2%) 13/316 (4.1%)
    Skin mass 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Skin ulcer 2/161 (1.2%) 0/155 (0%) 2/316 (0.6%)
    Stasis dermatitis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Subcutaneous nodule 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Swelling face 1/161 (0.6%) 4/155 (2.6%) 5/316 (1.6%)
    Toxic skin eruption 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Urticaria 2/161 (1.2%) 5/155 (3.2%) 7/316 (2.2%)
    Social circumstances
    Andropause 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Vascular disorders
    Aortic aneurysm 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Aortic arteriosclerosis 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Aortic calcification 0/161 (0%) 2/155 (1.3%) 2/316 (0.6%)
    Aortic disorder 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Arteriosclerosis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Deep vein thrombosis 6/161 (3.7%) 3/155 (1.9%) 9/316 (2.8%)
    Flushing 19/161 (11.8%) 11/155 (7.1%) 30/316 (9.5%)
    Haematoma 4/161 (2.5%) 3/155 (1.9%) 7/316 (2.2%)
    Hot flush 3/161 (1.9%) 2/155 (1.3%) 5/316 (1.6%)
    Hypertension 29/161 (18%) 21/155 (13.5%) 50/316 (15.8%)
    Hypotension 37/161 (23%) 33/155 (21.3%) 70/316 (22.2%)
    Infarction 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Jugular vein distension 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Jugular vein thrombosis 2/161 (1.2%) 1/155 (0.6%) 3/316 (0.9%)
    Lymphoedema 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Orthostatic hypotension 9/161 (5.6%) 4/155 (2.6%) 13/316 (4.1%)
    Pallor 2/161 (1.2%) 9/155 (5.8%) 11/316 (3.5%)
    Subclavian vein thrombosis 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Thrombosis 3/161 (1.9%) 1/155 (0.6%) 4/316 (1.3%)
    Vascular stenosis 0/161 (0%) 1/155 (0.6%) 1/316 (0.3%)
    Vasculitis 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Vena cava thrombosis 1/161 (0.6%) 1/155 (0.6%) 2/316 (0.6%)
    Venous insufficiency 1/161 (0.6%) 0/155 (0%) 1/316 (0.3%)
    Venous thrombosis limb 1/161 (0.6%) 3/155 (1.9%) 4/316 (1.3%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    In multi-site studies, PI can publish after Genzyme publishes or 18 months after study completion. PI gives Genzyme a draft 60 days before publication. Genzyme can ask that confidential information be removed, and can defer publication another 60 days upon notifying PI that it will file a patent application on inventions contained in the draft.

    Results Point of Contact

    Name/Title Genzyme Medical Information
    Organization Genzyme Corporation
    Phone 800-745-4447
    Email
    Responsible Party:
    Genzyme, a Sanofi Company
    ClinicalTrials.gov Identifier:
    NCT00317642
    Other Study ID Numbers:
    • CLO34100405
    • 2008-001043-19
    First Posted:
    Apr 25, 2006
    Last Update Posted:
    Apr 14, 2014
    Last Verified:
    Mar 1, 2014