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

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ClinicalTrials.gov Identifier: NCT00317642
Recruitment Status : Completed
First Posted : April 25, 2006
Results First Posted : September 15, 2011
Last Update Posted : April 14, 2014
Sponsor:
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Acute Myelogenous Leukemia
Interventions Drug: clofarabine (IV formulation)
Drug: placebo
Drug: cytarabine
Enrollment 326
Recruitment Details  
Pre-assignment Details 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
Hide 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 [1] 158 [1]
Received >= 1 Study Drug (Safety Set) 161 155
Completed 41 [2] 28 [2]
Not Completed 122 135
Reason Not Completed
Not Received Either Study Drug             1             3
Physician Decision             15             7
Participant declined treatment             14             3
Adverse Event             17             5
Treatment Failure             56             102
Disease Recurrence             1             2
Death             14             7
Not Continue to Consolidation             2             0
Withdrawal by Subject             0             1
Referred For Transplantation             1             0
AML Not Centrally Confirmed             1             5
[1]
AML Centrally Confirmed
[2]
achieved remission and completed consolidation
Arm/Group Title Clofarabine (IV Formulation) and Cytarabine Placebo and Cytarabine Total
Hide 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 Number of Baseline Participants 162 158 320
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 162 participants 158 participants 320 participants
67.0  (6.36) 67.1  (5.82) 67.0  (6.09)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 162 participants 158 participants 320 participants
Female
48
  29.6%
57
  36.1%
105
  32.8%
Male
114
  70.4%
101
  63.9%
215
  67.2%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 162 participants 158 participants 320 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%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 162 participants 158 participants 320 participants
American Indian or Alaska Native
0
   0.0%
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%
0
   0.0%
Black or African American
7
   4.3%
11
   7.0%
18
   5.6%
White
150
  92.6%
142
  89.9%
292
  91.3%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
2
   1.2%
3
   1.9%
5
   1.6%
Height (cm)  
Mean (Standard Deviation)
Unit of measure:  Centimeter
Number Analyzed 162 participants 158 participants 320 participants
171.5  (10.27) 170.5  (8.92) 171.0  (9.62)
Weight(kg)  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 162 participants 158 participants 320 participants
81.21  (17.862) 83.03  (17.281) 82.11  (17.574)
Body Surface Area (BSA)  
Mean (Standard Deviation)
Unit of measure:  M^2
Number Analyzed 162 participants 158 participants 320 participants
1.941  (0.2383) 1.959  (0.2338) 1.950  (0.2359)
Eastern Cooperative Oncology Group Performance Status   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 162 participants 158 participants 320 participants
ECOG 0 57 48 105
ECOG 1 79 92 171
ECOG 2 26 18 44
[1]
Measure Description: Eastern Cooperative Oncology Group Performance Status (ECOG PS) is a scale ranging from 0-5, with 0 (fully active); 1 (capable of light work); 2 (no work but all self-care); 3 (limited self-care); 4 (completely disabled); 5 (dead).
Karyotype   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 162 participants 158 participants 320 participants
Favorable 1 0 1
Intermediate 65 84 149
Unfavorable 86 70 156
Not Assessed 8 3 11
unknown 2 1 3
[1]
Measure Description: Favorable karyotype was defined as any abnormality of chromosome 16; Intermediate karyotype was defined as normal (no abnormalities); Unfavorable karyotype was defined as any other abnormality
1.Primary Outcome
Title Overall Survival – Overall and by Calculated Strata (CSR 7-April-11)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 162 157 88 83 74 74
Median (95% Confidence Interval)
Unit of Measure: months
6.6
(5.1 to 9.3)
6.4
(4.7 to 7.3)
5.1
(3.5 to 8.7)
5.5
(4.1 to 7.2)
8.7
(5.3 to 11.1)
7.2
(4.6 to 8.9)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.9951
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.00
Confidence Interval (2-Sided) 95%
0.78 to 1.28
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.4674
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.13
Confidence Interval (2-Sided) 95%
0.81 to 1.57
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.3963
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.85
Confidence Interval (2-Sided) 95%
0.58 to 1.24
Estimation Comments [Not Specified]
2.Primary Outcome
Title Overall Survival - Overall and by Randomized Strata (CSR 9-July-12)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 162 158 86 84 76 74
Median (95% Confidence Interval)
Unit of Measure: months
6.6
(5.1 to 9.3)
6.3
(4.7 to 7.3)
4.8
(2.9 to 7.3)
6.3
(4.1 to 7.8)
9.7
(5.9 to 12.7)
6.6
(4.3 to 8.8)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.8209
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.97
Confidence Interval (2-Sided) 95%
0.77 to 1.23
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine - In Stratum < 6 Months, Placebo and Cytarabine - In Stratum < 6 Months
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5071
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.11
Confidence Interval (2-Sided) 95%
0.81 to 1.53
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine In Stratum >= 6 Months, Placebo and Cytarabine In Stratum >= 6 Months
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2906
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.83
Confidence Interval (2-Sided) 95%
0.59 to 1.17
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Best Response Per Independent Response Review Panel (IRRP) Assessment – Overall and by Calculated Strata (CSR 7-April-11)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 162 157 88 83 74 74
Measure Type: Number
Unit of Measure: percentage of participants
Overall Remission (CR + CRi) 46.9 22.9 45.5 22.9 48.6 23.0
Complete Remission (CR) 35.2 17.8 33.0 18.1 37.8 17.6
CR with incomplete blood count recovery (CRi) 11.7 5.1 12.5 4.8 10.8 5.4
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Clofarabine (IV Formulation) and Cytarabine, Placebo and Cytarabine
Comments Full Analysis Set (FAS) population - overall remission (OR)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Clofarabine (IV Formulation) and Cytarabine, Placebo and Cytarabine
Comments Full Analysis Set (FAS) population - Complete Remission (CR)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0005
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Show Statistical Analysis 3 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.0022
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 4 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.0019
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 5 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.0353
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 6 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.0096
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
4.Secondary Outcome
Title Duration of Remission (DOR) Per IRRP Assessment-Overall and by Calculated Strata (CSR 7-April-11)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 76 36 40 19 36 17
Median (95% Confidence Interval)
Unit of Measure: months
7.6
(5.4 to 11.5)
3.8
(3.3 to 12.1)
5.7
(5.3 to 7.7)
6.3
(2.3 to 7.2)
11.5
(6.8 to 15.5)
3.8 [1] 
(3.3 to NA)
[1]
N/A = There were an insufficient number of events to allow estimation of the upper limit.
5.Secondary Outcome
Title Duration of Remission (DOR) Per IRRP Assessment-Overall and by Randomized Strata (CSR 9-July-12)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 76 36 36 20 40 16
Median (95% Confidence Interval)
Unit of Measure: months
7.7
(5.7 to 11.5)
3.8
(3.3 to 12.1)
6.7
(4.0 to 8.8)
6.3
(2.3 to 7.2)
10.2
(6.8 to 20.2)
3.8 [1] 
(3.3 to NA)
[1]
There were an insufficient number of events to allow estimation of the upper limit.
6.Secondary Outcome
Title Disease-free Survival by IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 76 36 40 19 36 17
Median (95% Confidence Interval)
Unit of Measure: months
8.1
(6.7 to 10.3)
7.0
(3.9 to 12.1)
5.7
(4.4 to 9.7)
6.7
(3.9 to 8.1)
10.3
(7.5 to 15.5)
9.1 [1] 
(3.7 to NA)
[1]
NA = There were an insufficient number of events to allow estimation of the upper limit.
7.Secondary Outcome
Title Disease-free Survival by IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 76 36 36 20 40 16
Median (95% Confidence Interval)
Unit of Measure: months
9.5
(6.9 to 15.4)
7.0
(3.9 to 9.8)
6.7
(3.9 to 9.7)
6.7
(3.9 to 8.1)
15.4
(9.2 to 20.5)
9.2
(3.7 to 13.1)
8.Secondary Outcome
Title Event-free Survival by IRRP Assessment – Overall and by Calculated Strata (CSR 7-April-11)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 162 157 88 83 74 74
Median (95% Confidence Interval)
Unit of Measure: months
1.9
(1.1 to 2.9)
1.0
(0.9 to 1.1)
1.4
(1.0 to 2.9)
1.0
(0.7 to 1.2)
2.0
(1.2 to 6.6)
1.0
(0.9 to 1.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Clofarabine (IV Formulation) and Cytarabine, Placebo and Cytarabine
Comments Full Analysis Set (FAS) population.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.63
Confidence Interval (2-Sided) 95%
0.49 to 0.80
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.0131
Comments [Not Specified]
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
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.0022
Comments [Not Specified]
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
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Event-free Survival by IRRP Assessment – Overall and by Randomized Strata (CSR 9-July-12)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 162 158 86 84 76 74
Median (95% Confidence Interval)
Unit of Measure: months
1.9
(1.1 to 2.9)
1.0
(0.8 to 1.1)
1.1
(0.8 to 2.5)
1.0
(0.7 to 1.2)
2.8
(1.2 to 8.1)
1.0
(0.8 to 1.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Clofarabine (IV Formulation) and Cytarabine, Placebo and Cytarabine
Comments Full Analysis Set (FAS) population.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.63
Confidence Interval (2-Sided) 95%
0.49 to 0.79
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine - In Stratum < 6 Months, Placebo and Cytarabine - In Stratum < 6 Months
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0486
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.73
Confidence Interval (2-Sided) 95%
0.53 to 1.01
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine In Stratum >= 6 Months, Placebo and Cytarabine In Stratum >= 6 Months
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.52
Confidence Interval (2-Sided) 95%
0.37 to 0.74
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Four-Month Event-free Survival Per IRRP Assessment – Overall and by Calculated Strata (CSR 7-April-11)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 162 157 88 83 74 74
Measure Type: Number
Unit of Measure: percentage of participants
37.7 16.6 35.2 16.9 40.5 16.2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Clofarabine (IV Formulation) and Cytarabine, Placebo and Cytarabine
Comments Full Analysis Set (FAS) population
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.0088
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 3 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.0017
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
11.Secondary Outcome
Title Four-Month Event-free Survival Per IRRP Assessment – Overall and by Randomized Strata (CSR 9-July-12)
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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
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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
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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.
Overall Number of Participants Analyzed 162 158 86 84 76 74
Measure Type: Number
Unit of Measure: percentage of participants
38.9 17.1 31.4 17.9 47.4 16.2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Clofarabine (IV Formulation) and Cytarabine, Placebo and Cytarabine
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine - In Stratum < 6 Months, Placebo and Cytarabine - In Stratum < 6 Months
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0506
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Clofarabine and Cytarabine In Stratum >= 6 Months, Placebo and Cytarabine In Stratum >= 6 Months
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
12.Secondary Outcome
Title Participants With Adverse Events (CSR 7-April-11)
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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.)
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Hide 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
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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.
Overall Number of Participants Analyzed 161 155
Measure Type: Number
Unit of Measure: participants
Any Treatment Emergent AE 161 155
Any Related Treatment Emergent AE 157 133
Any Treatment Emergent Grade >=3 AE 157 133
Any Related Treatment Related Grade >=3 AE 127 83
Discontinue of study medication due to AE 17 5
Discontinue of study medication due to related AE 14 3
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
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Clofarabine (IV Formulation) and Cytarabine Placebo and Cytarabine Overall
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   97/161 (60.25%)   76/155 (49.03%)   173/316 (54.75%) 
Blood and lymphatic system disorders       
Bone marrow failure  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Febrile neutropenia  1  25/161 (15.53%)  19/155 (12.26%)  44/316 (13.92%) 
Leukopenia  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Lymphadenitis  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Neutropenia  1  2/161 (1.24%)  4/155 (2.58%)  6/316 (1.90%) 
Pancytopenia  1  0/161 (0.00%)  2/155 (1.29%)  2/316 (0.63%) 
Thrombocytopenia  1  2/161 (1.24%)  3/155 (1.94%)  5/316 (1.58%) 
Cardiac disorders       
Acute myocardial infarction  1  3/161 (1.86%)  0/155 (0.00%)  3/316 (0.95%) 
Angina pectoris  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Atrial fibrillation  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Atrial flutter  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Bradycardia  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Cardiac arrest  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Cardiac failure  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Cardiac failure congestive  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Cardio-respiratory arrest  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Cardiogenic shock  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Myocardial infarction  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Myocardial ischaemia  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Pericarditis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Stress cardiomyopathy  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Supraventricular tachycardia  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Tachycardia  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Eye disorders       
Blindness unilateral  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Gastrointestinal disorders       
Abdominal pain  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Caecitis  1  0/161 (0.00%)  2/155 (1.29%)  2/316 (0.63%) 
Colitis  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Diarrhoea  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Gastrointestinal haemorrhage  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Lower gastrointestinal haemorrhage  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Melaena  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
General disorders       
Asthenia  1  3/161 (1.86%)  1/155 (0.65%)  4/316 (1.27%) 
Death  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Fatigue  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Generalised oedema  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Hypothermia  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Inflammation  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Multi-organ failure  1  3/161 (1.86%)  1/155 (0.65%)  4/316 (1.27%) 
Oedema peripheral  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Pain  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Pyrexia  1  7/161 (4.35%)  9/155 (5.81%)  16/316 (5.06%) 
Hepatobiliary disorders       
Venoocclusive liver disease  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Immune system disorders       
Anaphylactic reaction  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Graft versus host disease  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Infections and infestations       
Alpha haemolytic streptococcal infection  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Appendicitis  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Bacteraemia  1  7/161 (4.35%)  3/155 (1.94%)  10/316 (3.16%) 
Bacterial infection  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Bacterial sepsis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Bronchopulmonary aspergillosis  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Cellulitis  1  0/161 (0.00%)  3/155 (1.94%)  3/316 (0.95%) 
Clostridial infection  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Clostridium difficile colitis  1  3/161 (1.86%)  2/155 (1.29%)  5/316 (1.58%) 
Corynebacterium sepsis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Device related infection  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Diverticulitis  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Enterobacter bacteraemia  1  0/161 (0.00%)  2/155 (1.29%)  2/316 (0.63%) 
Enterobacter sepsis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Enterococcal bacteraemia  1  6/161 (3.73%)  1/155 (0.65%)  7/316 (2.22%) 
Enterococcal sepsis  1  3/161 (1.86%)  0/155 (0.00%)  3/316 (0.95%) 
Escherichia bacteraemia  1  4/161 (2.48%)  0/155 (0.00%)  4/316 (1.27%) 
Escherichia infection  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Escherichia sepsis  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Fungal infection  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Haematoma infection  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Herpes zoster  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Keratitis herpetic  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Klebsiella bacteraemia  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Klebsiella sepsis  1  0/161 (0.00%)  2/155 (1.29%)  2/316 (0.63%) 
Lobar pneumonia  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Neutropenic sepsis  1  4/161 (2.48%)  0/155 (0.00%)  4/316 (1.27%) 
Oral herpes  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Parainfluenzae virus infection  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Pneumonia  1  13/161 (8.07%)  12/155 (7.74%)  25/316 (7.91%) 
Pneumonia bacterial  1  3/161 (1.86%)  0/155 (0.00%)  3/316 (0.95%) 
Pneumonia fungal  1  5/161 (3.11%)  0/155 (0.00%)  5/316 (1.58%) 
Pneumonia viral  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Pseudomonal bacteraemia  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Sepsis  1  8/161 (4.97%)  3/155 (1.94%)  11/316 (3.48%) 
Sepsis syndrome  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Septic shock  1  6/161 (3.73%)  0/155 (0.00%)  6/316 (1.90%) 
Serratia sepsis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Sinusitis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Staphylococcal bacteraemia  1  2/161 (1.24%)  2/155 (1.29%)  4/316 (1.27%) 
Staphylococcal infection  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Staphylococcal scalded skin syndrome  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Staphylococcal sepsis  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Streptococcal bacteraemia  1  4/161 (2.48%)  0/155 (0.00%)  4/316 (1.27%) 
Streptococcal sepsis  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Systemic candida  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Upper respiratory fungal infection  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Urinary tract infection  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Urinary tract infection bacterial  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Urinary tract infection enterococcal  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Zygomycosis  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Injury, poisoning and procedural complications       
Femoral neck fracture  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Refractoriness to platelet transfusion  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Subdural haematoma  1  3/161 (1.86%)  1/155 (0.65%)  4/316 (1.27%) 
Investigations       
Aspartate aminotransferase increased  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Blood bilirubin increased  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Blood phosphorus decreased  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Ejection fraction decreased  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Electrocardiogram QT prolonged  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Lipase increased  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Troponin I increased  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
White blood cell count decreased  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Metabolism and nutrition disorders       
Acidosis  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Dehydration  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Fluid overload  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Hyperuricaemia  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Hypokalaemia  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Metabolic acidosis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Tumour lysis syndrome  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Musculoskeletal and connective tissue disorders       
Back pain  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Muscle disorder  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Osteoarthritis  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Acute myeloid leukaemia  1  4/161 (2.48%)  5/155 (3.23%)  9/316 (2.85%) 
Leukaemia  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Neoplasm malignant  1  2/161 (1.24%)  4/155 (2.58%)  6/316 (1.90%) 
Nervous system disorders       
Cerebral haemorrhage  1  2/161 (1.24%)  2/155 (1.29%)  4/316 (1.27%) 
Cerebral infarction  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Cerebrovascular accident  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Convulsion  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Encephalopathy  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Hypoxic-ischaemic encephalopathy  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Neuropathy peripheral  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Neurotoxicity  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Peripheral sensorimotor neuropathy  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Somnolence  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Status epilepticus  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Syncope  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Psychiatric disorders       
Agitation  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Confusional state  1  0/161 (0.00%)  2/155 (1.29%)  2/316 (0.63%) 
Mental status changes  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Renal and urinary disorders       
Anuria  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Haematuria  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Renal failure  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Renal failure acute  1  5/161 (3.11%)  1/155 (0.65%)  6/316 (1.90%) 
Renal failure chronic  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Renal infarct  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Respiratory, thoracic and mediastinal disorders       
Acute respiratory distress syndrome  1  4/161 (2.48%)  0/155 (0.00%)  4/316 (1.27%) 
Acute respiratory failure  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Dyspnoea  1  1/161 (0.62%)  3/155 (1.94%)  4/316 (1.27%) 
Epistaxis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Haemoptysis  1  0/161 (0.00%)  2/155 (1.29%)  2/316 (0.63%) 
Hypoxia  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Interstitial lung disease  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Lung infiltration  1  0/161 (0.00%)  2/155 (1.29%)  2/316 (0.63%) 
Pneumonia aspiration  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Pulmonary alveolar haemorrhage  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Pulmonary haemorrhage  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Pulmonary oedema  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Respiratory distress  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Respiratory failure  1  1/161 (0.62%)  4/155 (2.58%)  5/316 (1.58%) 
Skin and subcutaneous tissue disorders       
Drug eruption  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Exfoliative rash  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Generalised erythema  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Palmar-plantar erythrodysaesthesia syndrome  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Rash  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Toxic epidermal necrolysis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Vascular disorders       
Deep vein thrombosis  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Hypertension  1  0/161 (0.00%)  2/155 (1.29%)  2/316 (0.63%) 
Hypotension  1  4/161 (2.48%)  4/155 (2.58%)  8/316 (2.53%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Clofarabine (IV Formulation) and Cytarabine Placebo and Cytarabine Overall
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   161/161 (100.00%)   154/155 (99.35%)   315/316 (99.68%) 
Blood and lymphatic system disorders       
Anaemia  1  26/161 (16.15%)  18/155 (11.61%)  44/316 (13.92%) 
Coagulopathy  1  10/161 (6.21%)  1/155 (0.65%)  11/316 (3.48%) 
Disseminated intravascular coagulation  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Febrile bone marrow aplasia  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Febrile neutropenia  1  58/161 (36.02%)  35/155 (22.58%)  93/316 (29.43%) 
Haemoglobinaemia  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Hypercoagulation  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Hyperfibrinogenaemia  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Hypofibrinogenaemia  1  0/161 (0.00%)  2/155 (1.29%)  2/316 (0.63%) 
Hypoprothrombinaemia  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Leukocytosis  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Leukopenia  1  9/161 (5.59%)  7/155 (4.52%)  16/316 (5.06%) 
Lymph node pain  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Lymphadenopathy  1  3/161 (1.86%)  5/155 (3.23%)  8/316 (2.53%) 
Lymphatic disorder  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Monocytosis  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Neutropenia  1  17/161 (10.56%)  10/155 (6.45%)  27/316 (8.54%) 
Pancytopenia  1  3/161 (1.86%)  0/155 (0.00%)  3/316 (0.95%) 
Splenomegaly  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Thrombocytopenia  1  27/161 (16.77%)  23/155 (14.84%)  50/316 (15.82%) 
Cardiac disorders       
Angina pectoris  1  5/161 (3.11%)  2/155 (1.29%)  7/316 (2.22%) 
Aortic valve calcification  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Aortic valve incompetence  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Aortic valve stenosis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Arrhythmia  1  2/161 (1.24%)  3/155 (1.94%)  5/316 (1.58%) 
Arrhythmia supraventricular  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Atrial fibrillation  1  6/161 (3.73%)  3/155 (1.94%)  9/316 (2.85%) 
Atrial flutter  1  5/161 (3.11%)  0/155 (0.00%)  5/316 (1.58%) 
Atrioventricular block  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Atrioventricular block first degree  1  3/161 (1.86%)  0/155 (0.00%)  3/316 (0.95%) 
Bradycardia  1  3/161 (1.86%)  14/155 (9.03%)  17/316 (5.38%) 
Bundle branch block left  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Bundle branch block right  1  3/161 (1.86%)  0/155 (0.00%)  3/316 (0.95%) 
Cardiac aneurysm  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Cardiac failure  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Cardiac failure congestive  1  0/161 (0.00%)  2/155 (1.29%)  2/316 (0.63%) 
Cardiac valve disease  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Cardiomegaly  1  4/161 (2.48%)  0/155 (0.00%)  4/316 (1.27%) 
Conduction disorder  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Diastolic dysfunction  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Dilatation atrial  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Dilatation ventricular  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Extrasystoles  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Heart valve incompetence  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Intracardiac thrombus  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Ischaemic cardiomyopathy  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Left atrial dilatation  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Left ventricular dysfunction  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Left ventricular hypertrophy  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Mitral valve incompetence  1  4/161 (2.48%)  3/155 (1.94%)  7/316 (2.22%) 
Myocardial infarction  1  1/161 (0.62%)  4/155 (2.58%)  5/316 (1.58%) 
Myocardial ischaemia  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Nodal arrhythmia  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Palpitations  1  2/161 (1.24%)  3/155 (1.94%)  5/316 (1.58%) 
Pericardial effusion  1  3/161 (1.86%)  6/155 (3.87%)  9/316 (2.85%) 
Pulmonary valve incompetence  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Sinus arrhythmia  1  3/161 (1.86%)  0/155 (0.00%)  3/316 (0.95%) 
Sinus bradycardia  1  3/161 (1.86%)  2/155 (1.29%)  5/316 (1.58%) 
Sinus tachycardia  1  12/161 (7.45%)  6/155 (3.87%)  18/316 (5.70%) 
Supraventricular extrasystoles  1  1/161 (0.62%)  3/155 (1.94%)  4/316 (1.27%) 
Supraventricular tachycardia  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Tachycardia  1  25/161 (15.53%)  14/155 (9.03%)  39/316 (12.34%) 
Tricuspid valve incompetence  1  3/161 (1.86%)  3/155 (1.94%)  6/316 (1.90%) 
Ventricular arrhythmia  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Ventricular extrasystoles  1  4/161 (2.48%)  2/155 (1.29%)  6/316 (1.90%) 
Ventricular hypertrophy  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Ventricular hypokinesia  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Ventricular tachycardia  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Congenital, familial and genetic disorders       
Atrial septal defect  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Hydrocele  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Ear and labyrinth disorders       
Cerumen impaction  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Ear congestion  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Ear pain  1  2/161 (1.24%)  3/155 (1.94%)  5/316 (1.58%) 
Hypoacusis  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Tinnitus  1  2/161 (1.24%)  2/155 (1.29%)  4/316 (1.27%) 
Vertigo  1  4/161 (2.48%)  2/155 (1.29%)  6/316 (1.90%) 
Endocrine disorders       
Adrenal disorder  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Adrenal insufficiency  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Cushingoid  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Hyperadrenalism  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Hypothyroidism  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Thyroid mass  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Eye disorders       
Blepharitis  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Cataract  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Conjunctival cyst  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Conjunctival haemorrhage  1  5/161 (3.11%)  3/155 (1.94%)  8/316 (2.53%) 
Conjunctival hyperaemia  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Conjunctival pallor  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Conjunctivitis  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Diplopia  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Dry eye  1  7/161 (4.35%)  7/155 (4.52%)  14/316 (4.43%) 
Erythema of eyelid  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Eye haemorrhage  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Eye irritation  1  3/161 (1.86%)  2/155 (1.29%)  5/316 (1.58%) 
Eye pain  1  3/161 (1.86%)  2/155 (1.29%)  5/316 (1.58%) 
Eye swelling  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Eyelid oedema  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Eyelid ptosis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Gaze palsy  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Lacrimation increased  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Miosis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Ocular dysmetria  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Ocular hyperaemia  1  0/161 (0.00%)  2/155 (1.29%)  2/316 (0.63%) 
Ocular icterus  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Optic neuropathy  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Papilloedema  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Periorbital oedema  1  4/161 (2.48%)  1/155 (0.65%)  5/316 (1.58%) 
Photophobia  1  3/161 (1.86%)  1/155 (0.65%)  4/316 (1.27%) 
Pupillary reflex impaired  1  0/161 (0.00%)  2/155 (1.29%)  2/316 (0.63%) 
Pupils unequal  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Retinal haemorrhage  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Scleral disorder  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Scleral haemorrhage  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Scleral oedema  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Vision blurred  1  8/161 (4.97%)  4/155 (2.58%)  12/316 (3.80%) 
Visual acuity reduced  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Visual impairment  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Vitreous detachment  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Vitreous floaters  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Gastrointestinal disorders       
Abdominal discomfort  1  5/161 (3.11%)  3/155 (1.94%)  8/316 (2.53%) 
Abdominal distension  1  18/161 (11.18%)  13/155 (8.39%)  31/316 (9.81%) 
Abdominal hernia  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Abdominal pain  1  30/161 (18.63%)  18/155 (11.61%)  48/316 (15.19%) 
Abdominal pain lower  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Abdominal pain upper  1  5/161 (3.11%)  6/155 (3.87%)  11/316 (3.48%) 
Abdominal tenderness  1  3/161 (1.86%)  2/155 (1.29%)  5/316 (1.58%) 
Anal inflammation  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Aphthous stomatitis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Ascites  1  3/161 (1.86%)  1/155 (0.65%)  4/316 (1.27%) 
Caecitis  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Chapped lips  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Cheilitis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Colitis  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Colonic polyp  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Colonic pseudo-obstruction  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Constipation  1  66/161 (40.99%)  72/155 (46.45%)  138/316 (43.67%) 
Crohn's disease  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Diarrhoea  1  109/161 (67.70%)  63/155 (40.65%)  172/316 (54.43%) 
Diverticulum  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Dry mouth  1  9/161 (5.59%)  6/155 (3.87%)  15/316 (4.75%) 
Dyspepsia  1  12/161 (7.45%)  19/155 (12.26%)  31/316 (9.81%) 
Dysphagia  1  7/161 (4.35%)  4/155 (2.58%)  11/316 (3.48%) 
Epigastric discomfort  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Eructation  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Faecal incontinence  1  5/161 (3.11%)  5/155 (3.23%)  10/316 (3.16%) 
Faeces discoloured  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Flatulence  1  10/161 (6.21%)  4/155 (2.58%)  14/316 (4.43%) 
Gastric antral vascular ectasia  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Gastritis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Gastrointestinal haemorrhage  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Gastrointestinal inflammation  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Gastrointestinal sounds abnormal  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Gastrooesophageal reflux disease  1  2/161 (1.24%)  5/155 (3.23%)  7/316 (2.22%) 
Gingival bleeding  1  5/161 (3.11%)  2/155 (1.29%)  7/316 (2.22%) 
Gingival cyst  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Gingival pain  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Gingivitis  1  6/161 (3.73%)  1/155 (0.65%)  7/316 (2.22%) 
Glossodynia  1  0/161 (0.00%)  3/155 (1.94%)  3/316 (0.95%) 
Haematemesis  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Haematochezia  1  5/161 (3.11%)  3/155 (1.94%)  8/316 (2.53%) 
Haemorrhoidal haemorrhage  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Haemorrhoids  1  13/161 (8.07%)  9/155 (5.81%)  22/316 (6.96%) 
Hiatus hernia  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Hypoaesthesia oral  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Ileus  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Inguinal hernia  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Intestinal dilatation  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Intestinal obstruction  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Lip blister  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Lip dry  1  4/161 (2.48%)  5/155 (3.23%)  9/316 (2.85%) 
Lip haemorrhage  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Lip ulceration  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Melaena  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Mouth haemorrhage  1  11/161 (6.83%)  7/155 (4.52%)  18/316 (5.70%) 
Mouth ulceration  1  3/161 (1.86%)  9/155 (5.81%)  12/316 (3.80%) 
Mucous stools  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Nausea  1  117/161 (72.67%)  82/155 (52.90%)  199/316 (62.97%) 
Neutropenic colitis  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Odynophagia  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Oesophageal dilatation  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Oesophageal pain  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Oesophagitis  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Oral disorder  1  2/161 (1.24%)  4/155 (2.58%)  6/316 (1.90%) 
Oral mucosal discolouration  1  1/161 (0.62%)  3/155 (1.94%)  4/316 (1.27%) 
Oral mucosal erythema  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Oral pain  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Pancreatic mass  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Pancreatitis  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Parotid gland enlargement  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Poor dental condition  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Proctalgia  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Rectal haemorrhage  1  2/161 (1.24%)  4/155 (2.58%)  6/316 (1.90%) 
Rectal ulcer  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Retching  1  3/161 (1.86%)  1/155 (0.65%)  4/316 (1.27%) 
Salivary hypersecretion  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Stomatitis  1  17/161 (10.56%)  10/155 (6.45%)  27/316 (8.54%) 
Tongue blistering  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Tongue coated  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Tongue discolouration  1  2/161 (1.24%)  4/155 (2.58%)  6/316 (1.90%) 
Tongue exfoliation  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Tongue haematoma  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Tongue ulceration  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Tooth disorder  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Toothache  1  8/161 (4.97%)  3/155 (1.94%)  11/316 (3.48%) 
Umbilical hernia  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Upper gastrointestinal haemorrhage  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Vomiting  1  71/161 (44.10%)  42/155 (27.10%)  113/316 (35.76%) 
General disorders       
Adverse event  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Asthenia  1  32/161 (19.88%)  33/155 (21.29%)  65/316 (20.57%) 
Catheter site discharge  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Catheter site erosion  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Catheter site erythema  1  6/161 (3.73%)  13/155 (8.39%)  19/316 (6.01%) 
Catheter site haematoma  1  4/161 (2.48%)  0/155 (0.00%)  4/316 (1.27%) 
Catheter site haemorrhage  1  6/161 (3.73%)  4/155 (2.58%)  10/316 (3.16%) 
Catheter site inflammation  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Catheter site oedema  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Catheter site pain  1  12/161 (7.45%)  9/155 (5.81%)  21/316 (6.65%) 
Catheter site pruritus  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Catheter site rash  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Catheter site related reaction  1  2/161 (1.24%)  5/155 (3.23%)  7/316 (2.22%) 
Catheter site swelling  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Chest discomfort  1  4/161 (2.48%)  4/155 (2.58%)  8/316 (2.53%) 
Chest pain  1  3/161 (1.86%)  2/155 (1.29%)  5/316 (1.58%) 
Chills  1  38/161 (23.60%)  23/155 (14.84%)  61/316 (19.30%) 
Crepitations  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Cyst  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Device occlusion  1  3/161 (1.86%)  1/155 (0.65%)  4/316 (1.27%) 
Discomfort  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Early satiety  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Face oedema  1  2/161 (1.24%)  2/155 (1.29%)  4/316 (1.27%) 
Facial pain  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Fatigue  1  57/161 (35.40%)  49/155 (31.61%)  106/316 (33.54%) 
Feeling cold  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Feeling hot  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Gait disturbance  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
General physical health deterioration  1  3/161 (1.86%)  2/155 (1.29%)  5/316 (1.58%) 
Generalised oedema  1  9/161 (5.59%)  4/155 (2.58%)  13/316 (4.11%) 
Hypothermia  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Infusion site discolouration  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Infusion site induration  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Injection site haemorrhage  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Injection site inflammation  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Injection site pain  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Injection site reaction  1  4/161 (2.48%)  1/155 (0.65%)  5/316 (1.58%) 
Malaise  1  2/161 (1.24%)  2/155 (1.29%)  4/316 (1.27%) 
Mass  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Medical device complication  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Mucosal dryness  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Mucosal inflammation  1  21/161 (13.04%)  19/155 (12.26%)  40/316 (12.66%) 
Nodule  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Non-cardiac chest pain  1  6/161 (3.73%)  3/155 (1.94%)  9/316 (2.85%) 
Oedema  1  4/161 (2.48%)  5/155 (3.23%)  9/316 (2.85%) 
Oedema peripheral  1  82/161 (50.93%)  71/155 (45.81%)  153/316 (48.42%) 
Pain  1  22/161 (13.66%)  8/155 (5.16%)  30/316 (9.49%) 
Pyrexia  1  53/161 (32.92%)  39/155 (25.16%)  92/316 (29.11%) 
Tenderness  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Thrombosis in device  1  3/161 (1.86%)  1/155 (0.65%)  4/316 (1.27%) 
Visceral oedema  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Hepatobiliary disorders       
Bile duct stone  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Cholecystitis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Cholelithiasis  1  4/161 (2.48%)  4/155 (2.58%)  8/316 (2.53%) 
Dilatation intrahepatic duct acquired  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Gallbladder polyp  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Hepatic cyst  1  2/161 (1.24%)  2/155 (1.29%)  4/316 (1.27%) 
Hepatic failure  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Hepatic function abnormal  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Hepatic lesion  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Hepatic steatosis  1  2/161 (1.24%)  2/155 (1.29%)  4/316 (1.27%) 
Hepatitis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Hepatomegaly  1  0/161 (0.00%)  3/155 (1.94%)  3/316 (0.95%) 
Hepatosplenomegaly  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Hepatotoxicity  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Hyperbilirubinaemia  1  15/161 (9.32%)  12/155 (7.74%)  27/316 (8.54%) 
Jaundice  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Immune system disorders       
Anaphylactic reaction  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Drug hypersensitivity  1  9/161 (5.59%)  1/155 (0.65%)  10/316 (3.16%) 
Hypogammaglobulinaemia  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Infections and infestations       
Abscess limb  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Acute sinusitis  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Alpha haemolytic streptococcal infection  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Anal abscess  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Anorectal infection  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Bacteraemia  1  8/161 (4.97%)  4/155 (2.58%)  12/316 (3.80%) 
Bacterial infection  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Bacterial sepsis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Bacteriuria  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Bronchopulmonary aspergillosis  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Bullous impetigo  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Candida pneumonia  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Candidiasis  1  6/161 (3.73%)  3/155 (1.94%)  9/316 (2.85%) 
Catheter site cellulitis  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Catheter site infection  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Cellulitis  1  5/161 (3.11%)  9/155 (5.81%)  14/316 (4.43%) 
Clostridial infection  1  3/161 (1.86%)  1/155 (0.65%)  4/316 (1.27%) 
Clostridium difficile colitis  1  5/161 (3.11%)  3/155 (1.94%)  8/316 (2.53%) 
Cystitis  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Cystitis bacterial  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Cytomegalovirus infection  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Cytomegalovirus viraemia  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Device related infection  1  6/161 (3.73%)  5/155 (3.23%)  11/316 (3.48%) 
Diarrhoea infectious  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Diverticulitis  1  2/161 (1.24%)  2/155 (1.29%)  4/316 (1.27%) 
Enterobacter bacteraemia  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Enterococcal bacteraemia  1  9/161 (5.59%)  3/155 (1.94%)  12/316 (3.80%) 
Enterococcal infection  1  4/161 (2.48%)  2/155 (1.29%)  6/316 (1.90%) 
Enterococcal sepsis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Escherichia bacteraemia  1  2/161 (1.24%)  2/155 (1.29%)  4/316 (1.27%) 
Escherichia infection  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Escherichia sepsis  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Escherichia urinary tract infection  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Eye infection  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Eye infection fungal  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Eye infection staphylococcal  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Folliculitis  1  1/161 (0.62%)  6/155 (3.87%)  7/316 (2.22%) 
Fungal infection  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Fungal skin infection  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Furuncle  1  3/161 (1.86%)  1/155 (0.65%)  4/316 (1.27%) 
Gastroenteritis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Genital herpes  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Hepatosplenic candidiasis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Herpes simplex  1  2/161 (1.24%)  4/155 (2.58%)  6/316 (1.90%) 
Herpes zoster  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Infection  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Klebsiella bacteraemia  1  4/161 (2.48%)  1/155 (0.65%)  5/316 (1.58%) 
Lobar pneumonia  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Localised infection  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Lung infection  1  3/161 (1.86%)  1/155 (0.65%)  4/316 (1.27%) 
Lung infection pseudomonal  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Micrococcus infection  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Nasopharyngitis  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Oesophageal candidiasis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Onychomycosis  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Oral candidiasis  1  10/161 (6.21%)  8/155 (5.16%)  18/316 (5.70%) 
Oral fungal infection  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Oral herpes  1  9/161 (5.59%)  4/155 (2.58%)  13/316 (4.11%) 
Osteomyelitis  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Otitis externa  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Parainfluenzae virus infection  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Paronychia  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Pharyngitis  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Pharyngitis streptococcal  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Pneumonia  1  14/161 (8.70%)  9/155 (5.81%)  23/316 (7.28%) 
Pneumonia bacterial  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Pneumonia fungal  1  5/161 (3.11%)  2/155 (1.29%)  7/316 (2.22%) 
Pseudomonal bacteraemia  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Pseudomonal sepsis  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Pseudomonas infection  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Pulmonary mycosis  1  2/161 (1.24%)  3/155 (1.94%)  5/316 (1.58%) 
Respiratory syncytial virus infection  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Rhinitis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Sepsis  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Septic embolus  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Serratia bacteraemia  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Sinusitis  1  2/161 (1.24%)  2/155 (1.29%)  4/316 (1.27%) 
Sinusitis fungal  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Skin candida  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Skin infection  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Staphylococcal bacteraemia  1  9/161 (5.59%)  15/155 (9.68%)  24/316 (7.59%) 
Staphylococcal infection  1  4/161 (2.48%)  1/155 (0.65%)  5/316 (1.58%) 
Staphylococcal scalded skin syndrome  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Staphylococcal sepsis  1  3/161 (1.86%)  1/155 (0.65%)  4/316 (1.27%) 
Staphylococcal skin infection  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Stenotrophomonas infection  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Streptococcal bacteraemia  1  3/161 (1.86%)  4/155 (2.58%)  7/316 (2.22%) 
Streptococcal sepsis  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Subcutaneous abscess  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Tooth abscess  1  0/161 (0.00%)  3/155 (1.94%)  3/316 (0.95%) 
Tooth infection  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Upper respiratory tract infection  1  2/161 (1.24%)  4/155 (2.58%)  6/316 (1.90%) 
Urinary tract infection  1  3/161 (1.86%)  0/155 (0.00%)  3/316 (0.95%) 
Urinary tract infection bacterial  1  2/161 (1.24%)  3/155 (1.94%)  5/316 (1.58%) 
Urinary tract infection enterococcal  1  4/161 (2.48%)  1/155 (0.65%)  5/316 (1.58%) 
Urinary tract infection pseudomonal  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Urinary tract infection staphylococcal  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Viral skin infection  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Vulvovaginal candidiasis  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Injury, poisoning and procedural complications       
Anal injury  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Bite  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Compression fracture  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Contusion  1  12/161 (7.45%)  17/155 (10.97%)  29/316 (9.18%) 
Corneal abrasion  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Eschar  1  0/161 (0.00%)  2/155 (1.29%)  2/316 (0.63%) 
Excoriation  1  9/161 (5.59%)  3/155 (1.94%)  12/316 (3.80%) 
Eye injury  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Face injury  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Fall  1  5/161 (3.11%)  1/155 (0.65%)  6/316 (1.90%) 
Head injury  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Infusion related reaction  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Laceration  1  5/161 (3.11%)  5/155 (3.23%)  10/316 (3.16%) 
Lip injury  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Muscle strain  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Nail avulsion  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Nail injury  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Overdose  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Periorbital haematoma  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Post procedural complication  1  0/161 (0.00%)  3/155 (1.94%)  3/316 (0.95%) 
Post procedural haematoma  1  2/161 (1.24%)  2/155 (1.29%)  4/316 (1.27%) 
Post procedural haematuria  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Post procedural haemorrhage  1  3/161 (1.86%)  1/155 (0.65%)  4/316 (1.27%) 
Post procedural swelling  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Post-traumatic pain  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Procedural hypotension  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Procedural pain  1  12/161 (7.45%)  19/155 (12.26%)  31/316 (9.81%) 
Procedural site reaction  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Refractoriness to platelet transfusion  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Scratch  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Skin injury  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Spinal compression fracture  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Spinal fracture  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Subdural haematoma  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Tongue injury  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Tooth fracture  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Transfusion reaction  1  9/161 (5.59%)  7/155 (4.52%)  16/316 (5.06%) 
Traumatic haematoma  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Urethral injury  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Wound  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Wound haemorrhage  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Wound secretion  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Investigations       
Activated partial thromboplastin time prolonged  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Alanine aminotransferase increased  1  40/161 (24.84%)  13/155 (8.39%)  53/316 (16.77%) 
Ammonia increased  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Aspartate aminotransferase increased  1  36/161 (22.36%)  8/155 (5.16%)  44/316 (13.92%) 
Bacterial test  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Bacterial test positive  1  2/161 (1.24%)  2/155 (1.29%)  4/316 (1.27%) 
Blast cells present  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Blood albumin decreased  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Blood alkaline phosphatase increased  1  11/161 (6.83%)  6/155 (3.87%)  17/316 (5.38%) 
Blood amylase increased  1  9/161 (5.59%)  2/155 (1.29%)  11/316 (3.48%) 
Blood beta-D-glucan increased  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Blood bicarbonate decreased  1  5/161 (3.11%)  0/155 (0.00%)  5/316 (1.58%) 
Blood bicarbonate increased  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Blood bilirubin increased  1  12/161 (7.45%)  1/155 (0.65%)  13/316 (4.11%) 
Blood calcium decreased  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Blood chloride decreased  1  2/161 (1.24%)  0/155 (0.00%)  2/316 (0.63%) 
Blood chloride increased  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Blood creatinine increased  1  6/161 (3.73%)  3/155 (1.94%)  9/316 (2.85%) 
Blood culture positive  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Blood glucose increased  1  2/161 (1.24%)  2/155 (1.29%)  4/316 (1.27%) 
Blood iron increased  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Blood lactate dehydrogenase increased  1  9/161 (5.59%)  4/155 (2.58%)  13/316 (4.11%) 
Blood magnesium decreased  1  3/161 (1.86%)  0/155 (0.00%)  3/316 (0.95%) 
Blood magnesium increased  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Blood osmolarity increased  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Blood phosphorus decreased  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Blood phosphorus increased  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Blood potassium decreased  1  2/161 (1.24%)  2/155 (1.29%)  4/316 (1.27%) 
Blood potassium increased  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Blood pressure increased  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Blood urea increased  1  2/161 (1.24%)  3/155 (1.94%)  5/316 (1.58%) 
Blood uric acid increased  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Blood urine present  1  1/161 (0.62%)  1/155 (0.65%)  2/316 (0.63%) 
Breath sounds abnormal  1  5/161 (3.11%)  7/155 (4.52%)  12/316 (3.80%) 
Cardiac murmur  1  6/161 (3.73%)  9/155 (5.81%)  15/316 (4.75%) 
Catheter culture positive  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Clostridium test positive  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Crystal urine present  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Culture stool positive  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Culture throat positive  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Culture urine positive  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Cytomegalovirus test positive  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Diagnostic procedure  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Electrocardiogram PR shortened  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Electrocardiogram QT prolonged  1  4/161 (2.48%)  5/155 (3.23%)  9/316 (2.85%) 
Electrocardiogram ST-T segment abnormal  1  0/161 (0.00%)  2/155 (1.29%)  2/316 (0.63%) 
Electrocardiogram T wave abnormal  1  2/161 (1.24%)  1/155 (0.65%)  3/316 (0.95%) 
Electrocardiogram abnormal  1  1/161 (0.62%)  2/155 (1.29%)  3/316 (0.95%) 
Enterococcus test positive  1  5/161 (3.11%)  3/155 (1.94%)  8/316 (2.53%) 
Escherichia test positive  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Fungal test positive  1  1/161 (0.62%)  0/155 (0.00%)  1/316 (0.32%) 
Gallop rhythm present  1  0/161 (0.00%)  1/155 (0.65%)  1/316 (0.32%) 
Gamma-gluta