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Randomized Study Comparing Docetaxel Plus Dasatinib to Docetaxel Plus Placebo in Castration-resistant Prostate Cancer (READY)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00744497
First received: August 29, 2008
Last updated: August 23, 2016
Last verified: August 2016
Results First Received: November 15, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Condition: Prostatic Neoplasms
Interventions: Drug: Placebo
Drug: Dasatinib
Drug: Docetaxel
Drug: Prednisone

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
1930 participants enrolled, 1522 randomized to a treatment group (762 dasatinib, 760 placebo). 408 not randomized. Reasons for non-randomization include 7 adverse events, 42 withdrew consent, 6 deaths, 2 lost to follow up, 3 poor/non compliance, 332 no longer met study criteria, 1 administrative reason by sponsor, and 15 non-specified reasons.

Reporting Groups
  Description
Placebo Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily

Participant Flow:   Overall Study
    Placebo   Dasatinib
STARTED   760 [1]   762 [1] 
Received Treatment   757   761 
COMPLETED   0   0 
NOT COMPLETED   760   762 
Withdrawal by Subject                21                18 
Death                11                9 
Lost to Follow-up                4                2 
Poor compliance/noncompliance                9                5 
No longer meets study criteria                7                3 
Administrative Reason By Sponsor                25                8 
Disease progression                312                219 
Study drug toxicity                68                141 
Adverse event unrelated to study drug                78                122 
Patient requested to stop study drug                65                80 
Maximum clinical benefit                141                142 
Not defined                19                13 
[1] Randomized



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who were randomized to receive any treatment

Reporting Groups
  Description
Placebo Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Total Total of all reporting groups

Baseline Measures
   Placebo   Dasatinib   Total 
Overall Participants Analyzed 
[Units: Participants]
 760   762   1522 
Age, Customized 
[Units: Participants]
     
Younger than 65 years   263   251   514 
65 to younger than 75 years   323   333   656 
75 years or older   174   178   352 
Gender 
[Units: Participants]
     
Female   0   0   0 
Male   760   762   1522 
Race/Ethnicity, Customized 
[Units: Participants]
     
Asian   56   55   111 
Native Hawaiian or Other Pacific Islander   1   1   2 
Black or African American   34   23   57 
White   645   656   1301 
Other   24   27   51 
Type of metastatic disease 
[Units: Participants]
     
Bone disease only   286   307   593 
Visceral/nodal disease only   73   80   153 
Both bone and visceral/nodal disease   399   373   772 
No evidence of metastatic disease   2   2   4 


  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Overall Survival: Time From Randomization to Date of Death   [ Time Frame: From randomization to death or date of last contact (maximum reached: 45 months) ]

Measure Type Primary
Measure Title Overall Survival: Time From Randomization to Date of Death
Measure Description Overall survival is defined as time in months from the randomization date to the date of death due to any cause (in the randomized population). If the patient did not die, survival was censored on the last date he or she was known to be alive.
Time Frame From randomization to death or date of last contact (maximum reached: 45 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who were randomized to receive any treatment

Reporting Groups
  Description
Placebo Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily

Measured Values
   Placebo   Dasatinib 
Participants Analyzed 
[Units: Participants]
 760   762 
Overall Survival: Time From Randomization to Date of Death 
[Units: Months]
Median (95% Confidence Interval)
 21.2 
 (20.0 to 23.4) 
 21.5 
 (20.3 to 22.8) 


Statistical Analysis 1 for Overall Survival: Time From Randomization to Date of Death
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.9009
Hazard Ratio (HR) [4] 0.99
95.53% Confidence Interval 0.87 to 1.13
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Confidence intervals for median overall survival calculated using Brookmeyer and Crowley method. Compared survival in arms by 2-sided, alpha=0.0447 level, log-rank test, stratified by bisphosphonate intake (yes/no) and urinary N-telopeptide category (<60 vs ≥60 nmol/mmol creatinine) defined at randomization. Null hypothesis was survival equal in both arms. Power calculations were that ≥858 deaths would lead to ≥90% power at 5% level for rejecting null hypothesis, given true hazard ratio of 0.8.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  An interim analysis on survival was performed and the final test was corrected for multiplicity.
[4] Other relevant estimation information:
  No text entered.



2.  Secondary:   Percentage of Participants With an Objective Tumor Response by Modified Response Evaluation Criteria in Solid Tumors (RECIST)   [ Time Frame: At baseline and every 12 weeks thereafter to end of treatment, at end of treatment, and at follow-up (within 42 days of end of dosing) ]

Measure Type Secondary
Measure Title Percentage of Participants With an Objective Tumor Response by Modified Response Evaluation Criteria in Solid Tumors (RECIST)
Measure Description Objective tumor response rate=the percentage of randomized participants with a best tumor response of partial (PR) or complete response (CR), within 42 days of end of dosing, divided by total number of patients who were evaluable (with at least 1 target lesion at baseline). By RECIST: CR=disappearance of clinical and radiologic evidence of target and nontarget lesions confirmed by another evaluation at least 6 weeks later. PR=a >30% or greater decrease in the sum of longest diameter (LD) of target lesions in reference to the baseline sum LD confirmed by another evaluation at least 6 weeks later. Stable disease=neither sufficient increase to qualify for PD nor shrinkage to qualify for PR, and at least 8 weeks since start of study therapy. Progressive disease=a 20% or greater increase in sum of LD of all target lesions, taking as reference the smallest sum of LD at or following baseline, or unequivocal progression on existing nontarget lesions, or new lesions are present.
Time Frame At baseline and every 12 weeks thereafter to end of treatment, at end of treatment, and at follow-up (within 42 days of end of dosing)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants with at least 1 target lesion at baseline

Reporting Groups
  Description
Placebo Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily

Measured Values
   Placebo   Dasatinib 
Participants Analyzed 
[Units: Participants]
 383   381 
Percentage of Participants With an Objective Tumor Response by Modified Response Evaluation Criteria in Solid Tumors (RECIST) 
[Units: Percentage of participants]
Number (95% Confidence Interval)
 31.85 
 (27.21 to 36.78) 
 30.45 
 (25.86 to 35.34) 


Statistical Analysis 1 for Percentage of Participants With an Objective Tumor Response by Modified Response Evaluation Criteria in Solid Tumors (RECIST)
Groups [1] All groups
Odds Ratio (OR) [2] 0.935
95% Confidence Interval 0.688 to 1.271
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Since superiority of the dasatinib treatment group was not demonstrated for Overall Survival, secondary endpoints were not tested. The odds ratio is presented for experimental to control group.
[2] Other relevant estimation information:
  No text entered.



3.  Secondary:   Time to First Skeletal-related Event (SRE)   [ Time Frame: From day of randomization to date of first SRE or to last SRE assessment, if subsequent cancer therapy begun or no SRE (maximum reached: 42 months) ]

Measure Type Secondary
Measure Title Time to First Skeletal-related Event (SRE)
Measure Description Time to first SRE is defined as the time in months from the date of randomization to the date of first SRE (unless SRE occurred while the patient was undergoing subsequent cancer therapy). Participants with a first SRE while on subsequent cancer therapy, those who died without a reported SRE, and those who did not have an SRE were censored on the date of their last SRE assessment prior to start of subsequent cancer therapy, if any. Participants who had no SRE assessments were censored on the day they were randomized.
Time Frame From day of randomization to date of first SRE or to last SRE assessment, if subsequent cancer therapy begun or no SRE (maximum reached: 42 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who were randomized to receive any treatment

Reporting Groups
  Description
Placebo Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily

Measured Values
   Placebo   Dasatinib 
Participants Analyzed 
[Units: Participants]
 760   762 
Time to First Skeletal-related Event (SRE) 
[Units: Months]
Median (95% Confidence Interval)
 31.1 [1] 
 (28.8 to N/A) 
 NA [1] 
[1] NA=Not estimable; insufficient number of participants with events


Statistical Analysis 1 for Time to First Skeletal-related Event (SRE)
Groups [1] All groups
Hazard Ratio (HR) [2] 0.81
95% Confidence Interval 0.64 to 1.02
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Since superiority of the dasatinib treatment group was not demonstrated for Overall Survival, secondary endpoints were not tested. The hazard ratio is presented for experimental to control group.
[2] Other relevant estimation information:
  No text entered.



4.  Secondary:   Percentage of Participants With A Reduction in Urinary N-telopeptide (uNTx) Level From Baseline   [ Time Frame: At baseline, prior to each docetaxel infusion (every 3 weeks) to end of treatment, at end of treatment, and at follow-up (within 14 days of end of dosing) ]

Measure Type Secondary
Measure Title Percentage of Participants With A Reduction in Urinary N-telopeptide (uNTx) Level From Baseline
Measure Description The percentage of participants who had an on-study uNTx value confirmed (at least 3 weeks later) within normal limits (or ≥3 and <60 nmol/mmol creatinine, if normal limits were missing) or an on-study uNTx level reduction from baseline of ≥35%, even when on-study uNTx value remained abnormal.
Time Frame At baseline, prior to each docetaxel infusion (every 3 weeks) to end of treatment, at end of treatment, and at follow-up (within 14 days of end of dosing)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants who entered the study with baseline urinary N-telopeptide values higher than the upper limit of normal (ULN), or ≥60 nmol/mmol creatinine, if ULN was missing

Reporting Groups
  Description
Placebo Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily

Measured Values
   Placebo   Dasatinib 
Participants Analyzed 
[Units: Participants]
 335   321 
Percentage of Participants With A Reduction in Urinary N-telopeptide (uNTx) Level From Baseline 
[Units: Percentage of participants]
Number (95% Confidence Interval)
 60.60 
 (55.14 to 65.86) 
 66.04 
 (60.58 to 71.21) 


Statistical Analysis 1 for Percentage of Participants With A Reduction in Urinary N-telopeptide (uNTx) Level From Baseline
Groups [1] All groups
Odds Ratio (OR) [2] 1.280
95% Confidence Interval 0.930 to 1.763
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Since superiority of the dasatinib treatment group was not demonstrated for Overall Survival, secondary endpoints were not tested. The odds ratio is presented for experimental to control group.
[2] Other relevant estimation information:
  No text entered.



5.  Secondary:   Progression-free Survival (PFS)   [ Time Frame: From day of randomization to disease progression or death (or to last clinical assessment, if subsequent cancer therapy started or no progression or death) (maximum reached: approximately 43 months) ]

Measure Type Secondary
Measure Title Progression-free Survival (PFS)
Measure Description PFS is defined as the time from the randomization date until the date of earliest evidence of disease progression or death, for participants who progressed or died before subsequent cancer therapy. Those who progressed or died while on subsequent cancer therapy and those who did not die or progress were censored at their last radiologic bone scan/imaging, skeletal related-event, or tumor assessment or at measurement of prostate specific antigen levels, whichever occurred last prior to start of subsequent cancer therapy ,if any. Participants with no assessments were censored on the day of randomization.
Time Frame From day of randomization to disease progression or death (or to last clinical assessment, if subsequent cancer therapy started or no progression or death) (maximum reached: approximately 43 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who were randomized to receive any treatment

Reporting Groups
  Description
Placebo Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily

Measured Values
   Placebo   Dasatinib 
Participants Analyzed 
[Units: Participants]
 760   762 
Progression-free Survival (PFS) 
[Units: Months]
Median (95% Confidence Interval)
 11.1 
 (10.8 to 11.7) 
 11.8 
 (11.1 to 13.4) 


Statistical Analysis 1 for Progression-free Survival (PFS)
Groups [1] All groups
Hazard Ratio (HR) [2] 0.92
95% Confidence Interval 0.82 to 1.05
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Since superiority of the dasatinib treatment group was not demonstrated for Overall Survival, secondary endpoints were not tested. The hazard ratio is presented for experimental to control group.
[2] Other relevant estimation information:
  No text entered.



6.  Secondary:   Time to Prostate Specific Antigen (PSA) Progression   [ Time Frame: From randomization to date of first PSA measurement leading to confirmed PSA progression (or to last bone scan assessment, if no progression or if cancer therapy started) (maximum reached: 30 months) ]

Measure Type Secondary
Measure Title Time to Prostate Specific Antigen (PSA) Progression
Measure Description PSA progression is defined as the time from randomization to the date of the first PSA level measurement that led to confirmed PSA progression, for participants who had not started subsequent cancer therapy. For participants who did not progress or who progressed on cancer therapy, PSA progression is defined as the time from randomization to the date of the last PSA level measurement before the start of cancer therapy, if any. Participants who had no on-study PSA level measurements were censored on the day they were randomized.
Time Frame From randomization to date of first PSA measurement leading to confirmed PSA progression (or to last bone scan assessment, if no progression or if cancer therapy started) (maximum reached: 30 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who were randomized to receive any treatment

Reporting Groups
  Description
Placebo Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily

Measured Values
   Placebo   Dasatinib 
Participants Analyzed 
[Units: Participants]
 760   762 
Time to Prostate Specific Antigen (PSA) Progression 
[Units: Months]
Median (95% Confidence Interval)
 6.9 
 (6.5 to 7.4) 
 7.2 
 (6.6 to 7.9) 


Statistical Analysis 1 for Time to Prostate Specific Antigen (PSA) Progression
Groups [1] All groups
Hazard Ratio (HR) [2] 0.89
95% Confidence Interval 0.79 to 1.01
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Since superiority of the dasatinib treatment group was not demonstrated for Overall Survival, secondary endpoints were not tested. The hazard ratio is presented for experimental to control group.
[2] Other relevant estimation information:
  No text entered.



7.  Secondary:   Percentage of Participants With a Reduction in Pain Intensity From Baseline   [ Time Frame: At baseline, prior to each docetaxel infusion (every 3 weeks), at end of treatment, and at follow-up (within 14 days of end of dosing) ]

Measure Type Secondary
Measure Title Percentage of Participants With a Reduction in Pain Intensity From Baseline
Measure Description The percentage of participants with a reduction in pain intensity from baseline was defined as the number of participants who achieved a 30% or more decrease in pain intensity from baseline for at least 2 consecutive pain assessments (at least 14 days apart) within 14 days of end of dosing divided by the number of randomized participants who had a baseline pain intensity of at least 2. Pain intensity was assessed based on question 3 of the brief pain inventory questionnaire.
Time Frame At baseline, prior to each docetaxel infusion (every 3 weeks), at end of treatment, and at follow-up (within 14 days of end of dosing)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants with a baseline pain intensity of 2 or greater

Reporting Groups
  Description
Placebo Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily

Measured Values
   Placebo   Dasatinib 
Participants Analyzed 
[Units: Participants]
 467   419 
Percentage of Participants With a Reduction in Pain Intensity From Baseline 
[Units: Percentage of participants]
Number (95% Confidence Interval)
 71.52 
 (67.19 to 75.57) 
 66.59 
 (61.85 to 71.09) 


Statistical Analysis 1 for Percentage of Participants With a Reduction in Pain Intensity From Baseline
Groups [1] All groups
Odds Ratio (OR) [2] 0.791
95% Confidence Interval 0.594 to 1.052
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Since superiority of the dasatinib treatment group was not demonstrated for Overall Survival, secondary endpoints were not tested. The odds ratio is presented for of experimental to control group.
[2] Other relevant estimation information:
  No text entered.



8.  Other Pre-specified:   Number of Participants With Serious Adverse Event (SAEs), Drug-related SAEs, Drug-related AEs, Drug-related AEs Leading to Discontinuation, and All Deaths   [ Time Frame: Continuously throughout study to <=30 days after last dose of study drug; included AEs with an onset date >= day 1 and <= last dose date + 30 days ]

Measure Type Other Pre-specified
Measure Title Number of Participants With Serious Adverse Event (SAEs), Drug-related SAEs, Drug-related AEs, Drug-related AEs Leading to Discontinuation, and All Deaths
Measure Description AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Drug-related=having certain, probable, possible, or missing relationship to study drug
Time Frame Continuously throughout study to <=30 days after last dose of study drug; included AEs with an onset date >= day 1 and <= last dose date + 30 days  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who received treatment

Reporting Groups
  Description
Placebo Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily

Measured Values
   Placebo   Dasatinib 
Participants Analyzed 
[Units: Participants]
 757   761 
Number of Participants With Serious Adverse Event (SAEs), Drug-related SAEs, Drug-related AEs, Drug-related AEs Leading to Discontinuation, and All Deaths 
[Units: Participants]
   
All deaths   505   506 
Deaths within 30 days of end of treatment   50   79 
All SAEs   317   381 
Drug-related SAEs   90   150 
All Drug-related AEs   482   553 
Drug-related AEs leading to discontinuation   76   144 

No statistical analysis provided for Number of Participants With Serious Adverse Event (SAEs), Drug-related SAEs, Drug-related AEs, Drug-related AEs Leading to Discontinuation, and All Deaths



9.  Other Pre-specified:   Number of Participants With Drug-Related Adverse Events (AEs) of Special Interest   [ Time Frame: Continuously throughout study to <=30 days after last dose of study drug; included AEs with an onset date >= day 1 and <= last dose date + 30 days ]

Measure Type Other Pre-specified
Measure Title Number of Participants With Drug-Related Adverse Events (AEs) of Special Interest
Measure Description AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. AEs of Special Interest=recognized events in other agents within this drug class or events for which safety data from nonclinical and clinical studies with dasatinib indicate that careful evaluation is warranted. Drug-related=having certain, probable, possible, or missing relationship to study drug. Drug-related AEs of Special Interest are identified by the medical and safety representatives of the sponsor based on MedDRA preferred terms or laboratory data. ANC=absolute neutrophil count.
Time Frame Continuously throughout study to <=30 days after last dose of study drug; included AEs with an onset date >= day 1 and <= last dose date + 30 days  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who received treatment

Reporting Groups
  Description
Placebo Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily

Measured Values
   Placebo   Dasatinib 
Participants Analyzed 
[Units: Participants]
 757   761 
Number of Participants With Drug-Related Adverse Events (AEs) of Special Interest 
[Units: Participants]
   
Diarrhea   167   229 
Nausea/vomiting   127   170 
Fatigue   216   236 
Myalgias/arthralgias   29   29 
Rash   46   72 
Gastrointestinal tract bleeding   6   14 
Central nervous system bleeding   1   2 
Other hemorrhage   14   24 
Pulmonary arterial hypertension   0   0 
Fluid retention: Superficial edema   77   76 
Fluid retention: Pleural effusion   13   87 
Fluid retention: Other   37   52 

No statistical analysis provided for Number of Participants With Drug-Related Adverse Events (AEs) of Special Interest



10.  Other Pre-specified:   Number of Participants With Abnormalities in Results of Clinical Laboratory Tests in Hematology   [ Time Frame: At baseline, within 3 days prior to each infusion of docetaxel (each cycle) and at end of treatment. If docetaxel is discontinued, every other cycle. ]

Measure Type Other Pre-specified
Measure Title Number of Participants With Abnormalities in Results of Clinical Laboratory Tests in Hematology
Measure Description Abnormalities were graded according to the Common Toxicity Criteria (CTC), version 3.0, of the National Cancer Institute. CTC are graded from 1 (least severe) to 4 (life threatening ). Grade 3 and 4 criteria are defined as follows: Absolute neutrophil count, Grade 3, neutrophils <1.0-0.5*10^9/L; Grade 4, <0.5*10^9/L. Hemoglobin, Grade 3, <4.9-4.0 mmol/L; Grade 4, <4.0 mmol/L. Platelets, Grade 3, <50.0-25.0*10^9/L; Grade 4, <25.0*10^9/L. Leukocytes, Grade 3, <2.0-1.0*10^9/L; Grade 4, <1.0*10^9/L.
Time Frame At baseline, within 3 days prior to each infusion of docetaxel (each cycle) and at end of treatment. If docetaxel is discontinued, every other cycle.  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who received treatment

Reporting Groups
  Description
Placebo Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily

Measured Values
   Placebo   Dasatinib 
Participants Analyzed 
[Units: Participants]
 757   761 
Number of Participants With Abnormalities in Results of Clinical Laboratory Tests in Hematology 
[Units: Participants]
   
Absolute neutrophil count (All grades)   84   161 
Absolute neutrophil count (Grades 3 and 4)   41   46 
Hemoglobin (All grades)   712   720 
Hemoglobin (Grades 3 and 4)   44   59 
Platelets (All grades)   108   100 
Platelets (Grades 3 and 4)   6   3 
Leukocytes (All grades)   128   149 
Leukocytes (Grades 3 and 4)   32   30 

No statistical analysis provided for Number of Participants With Abnormalities in Results of Clinical Laboratory Tests in Hematology



11.  Other Pre-specified:   Number of Participants With Abnormalities in Results of Clinical Laboratory Tests Assessing Liver Function, Renal Function, and Electrolytes   [ Time Frame: At baseline, within 3 days prior to each infusion of docetaxel (each cycle), to end of treatment. If docetaxel is discontinued, every other cycle. ]

Measure Type Other Pre-specified
Measure Title Number of Participants With Abnormalities in Results of Clinical Laboratory Tests Assessing Liver Function, Renal Function, and Electrolytes
Measure Description ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal. Abnormalities were graded according to the Common Toxicity Criteria (CTC), version 3.0, of the National Cancer Institute. CTC are graded from 1 (least severe) to 4 (life threatening). ALP, ALT, and AST, Grade 3, >5.0-20.0*ULN; Grade 4, >20.0*ULN. Total bilirubin, Grade 3, >3.0–10.0*ULN; Grade 4, >10.0*ULN. Creatinine, Grade 3, >3.0–6.0*ULN; Grade 4, >6.0*ULN. Hypercalcemia(serum calcium, mmol/L), Grade 3, >3.1-3.4; Grade 4, >3.4. Hypocalcemia (serum calcium, mmol/L), Grade 3, <1.75-1.5; Grade 4, <1.5. Hyperkalemia(serum calcium, mmol/L), Grade 3, >6.0-7.0; Grade 4, >7.0. Hypokalemia(serum calcium, mmol/L), Grade 3, <3.0-2.5; Grade 4, <2.5. Hypernatremia (serum calcium, mmol/L), Grade 3, >155-160; Grade 4, >160. Hyponatremia (serum sodium, mmol/L), Grade 3, <130-120; Grade 4, <120. Phosphorus (serum sodium, mmol/L), Grade 3, <0.6-0.3; Grade 4, <0.3.
Time Frame At baseline, within 3 days prior to each infusion of docetaxel (each cycle), to end of treatment. If docetaxel is discontinued, every other cycle.  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who received treatment

Reporting Groups
  Description
Placebo Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily

Measured Values
   Placebo   Dasatinib 
Participants Analyzed 
[Units: Participants]
 757   761 
Number of Participants With Abnormalities in Results of Clinical Laboratory Tests Assessing Liver Function, Renal Function, and Electrolytes 
[Units: Participants]
   
ALP (All grades)   447   375 
ALP (Grades 3 and 4)   91   68 
ALT (All grades)   186   256 
ALT (Grades 3 and 4)   5   6 
AST (All grades)   212   266 
AST (Grades 3 and 4)   4   5 
Total bilirubin (All grades)   49   41 
Total bilirubin (Grades 3 and 4)   1   3 
Creatinine (All grades)   153   184 
Creatinine (Grades 3 and 4)   3   5 
Hypercalcemia (All grades)   56   34 
Hypercalcemia (Grades 3 and 4)   1   1 
Hypocalcemia (All grades)   308   377 
Hypocalcemia (Grades 3 and 4)   23   25 
Hyperkalemia (All grades)   164   152 
Hyperkalemia (Grades 3 and 4)   11   14 
Hypokalemia (All grades)   107   152 
Hypokalemia (Grades 3 and 4)   6   16 
Hypernatremia (All grades)   93   101 
Hypernatremia (Grades 3 and 4)   0   0 
Hyponatremia (All grades)   230   241 
Hyponatremia (Grades 3 and 4)   36   43 
Phosporus (All grades)   189   257 
Phosphorus (Grades 3 and 4)   43   93 

No statistical analysis provided for Number of Participants With Abnormalities in Results of Clinical Laboratory Tests Assessing Liver Function, Renal Function, and Electrolytes



12.  Other Pre-specified:   Number of Participants With Abnormal Results in Urinalysis   [ Time Frame: At baseline, within 3 days prior to each infusion of docetaxel (each cycle), to end of treatment. If docetaxel is discontinued, every other cycle. ]

Measure Type Other Pre-specified
Measure Title Number of Participants With Abnormal Results in Urinalysis
Measure Description Abnormal=positive, defined as the presence of >=30 mg/dL of protein; a small, moderate, or large amount of blood; or >0 g/dL glucose in urine. BL=baseline; neg=negative
Time Frame At baseline, within 3 days prior to each infusion of docetaxel (each cycle), to end of treatment. If docetaxel is discontinued, every other cycle.  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who received treatment.

Reporting Groups
  Description
Placebo Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily

Measured Values
   Placebo   Dasatinib 
Participants Analyzed 
[Units: Participants]
 757   761 
Number of Participants With Abnormal Results in Urinalysis 
[Units: Participants]
   
Protein, urine: postive   246   336 
Blood, urine: positive   289   307 
Glucose, urine: positive   179   154 

No statistical analysis provided for Number of Participants With Abnormal Results in Urinalysis



13.  Other Pre-specified:   Number of Participants by Maximal On-study Fridericia-corrected QTc Interval   [ Time Frame: At baseline, approximately 12 weeks after starting treatment, and then whenever clinically indicated up to within 30 days of end of dosing ]

Measure Type Other Pre-specified
Measure Title Number of Participants by Maximal On-study Fridericia-corrected QTc Interval
Measure Description QTc interval measured by electrocardiogram (ECG). Although a participant may have had several ECGs, only the longest QTc interval was included.
Time Frame At baseline, approximately 12 weeks after starting treatment, and then whenever clinically indicated up to within 30 days of end of dosing  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who received treatment. n=number evaluable

Reporting Groups
  Description
Placebo Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily

Measured Values
   Placebo   Dasatinib 
Participants Analyzed 
[Units: Participants]
 757   761 
Number of Participants by Maximal On-study Fridericia-corrected QTc Interval 
[Units: Participants]
   
<450 msecs (n=600, 548)   550   497 
450-500 msecs (n=600, 548)   43   48 
>500 msecs (n=600, 548)   7   3 

No statistical analysis provided for Number of Participants by Maximal On-study Fridericia-corrected QTc Interval



14.  Other Pre-specified:   Number of Participants With Changes From Baseline in Fridericia-corrected QTc Interval   [ Time Frame: At baseline, approximately 12 weeks after starting treatment, and then whenever clinically indicated up to within 30 days of end of dosing ]

Measure Type Other Pre-specified
Measure Title Number of Participants With Changes From Baseline in Fridericia-corrected QTc Interval
Measure Description QTc interval measured by electrocardiogram (ECG). Although a participant may have had several ECGs, only the longest QTc interval was included.
Time Frame At baseline, approximately 12 weeks after starting treatment, and then whenever clinically indicated up to within 30 days of end of dosing  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who received treatment. n=number evaluable

Reporting Groups
  Description
Placebo Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily

Measured Values
   Placebo   Dasatinib 
Participants Analyzed 
[Units: Participants]
 757   761 
Number of Participants With Changes From Baseline in Fridericia-corrected QTc Interval 
[Units: Participants]
   
0 to 30 msecs increase (n=591, 540)   203   199 
>30 to 60 msecs increase (n=591, 540)   52   47 
>60 msecs increase (n=591, 540)   32   26 
Decrease (n=591, 540)   304   268 

No statistical analysis provided for Number of Participants With Changes From Baseline in Fridericia-corrected QTc Interval



15.  Other Pre-specified:   Number of Participants With and Without Pericardial Effusion at Baseline and On-study and With Left Ventricular Ejection Fraction (LVEF) <40% and >=40% On-study   [ Time Frame: At baseline, approximately 12 weeks after start of treatment, and thereafter whenever clinically indicated ]

Measure Type Other Pre-specified
Measure Title Number of Participants With and Without Pericardial Effusion at Baseline and On-study and With Left Ventricular Ejection Fraction (LVEF) <40% and >=40% On-study
Measure Description BL=baseline; OS=on-study
Time Frame At baseline, approximately 12 weeks after start of treatment, and thereafter whenever clinically indicated  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who were randomized to receive any treatment

Reporting Groups
  Description
Placebo Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily

Measured Values
   Placebo   Dasatinib 
Participants Analyzed 
[Units: Participants]
 760   762 
Number of Participants With and Without Pericardial Effusion at Baseline and On-study and With Left Ventricular Ejection Fraction (LVEF) <40% and >=40% On-study 
[Units: Participants]
   
Pericardial effusion at BL/absent OS   3   1 
Pericardial effusion at BL/present OS   0   1 
Pericardial effusion at BL/not reported OS   1   0 
Pericardial effusion absent at BL/ absent OS   584   545 
Pericardial effusion absent at BL/present OS   24   26 
Pericardial effusion absent at BL/not reported OS   132   184 
Pericardial not reported at BL   16   5 
LVEF OS <40%   2   2 
LVEF OS >=40%   607   566 
LVEF not reported OS   151   194 

No statistical analysis provided for Number of Participants With and Without Pericardial Effusion at Baseline and On-study and With Left Ventricular Ejection Fraction (LVEF) <40% and >=40% On-study




  Serious Adverse Events
  Hide Serious Adverse Events

Time Frame Day 1 up to 30 days post last dose of study therapy
Additional Description Study initiated: October 2008; Study Completion: July 2015

Reporting Groups
  Description
Placebo Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily

Serious Adverse Events
    Placebo   Dasatinib
Total, serious adverse events     
# participants affected / at risk   317/757 (41.88%)   381/761 (50.07%) 
Blood and lymphatic system disorders     
Febrile bone marrow aplasia † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Hypochromic anaemia † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Leukopenia † 1     
# participants affected / at risk   7/757 (0.92%)   9/761 (1.18%) 
Anaemia † 1     
# participants affected / at risk   15/757 (1.98%)   21/761 (2.76%) 
Agranulocytosis † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Neutropenia † 1     
# participants affected / at risk   18/757 (2.38%)   19/761 (2.50%) 
Normochromic normocytic anaemia † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Disseminated intravascular coagulation † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Thrombocytopenia † 1     
# participants affected / at risk   2/757 (0.26%)   1/761 (0.13%) 
Febrile neutropenia † 1     
# participants affected / at risk   27/757 (3.57%)   32/761 (4.20%) 
Haemorrhagic anaemia † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Cardiac disorders     
Supraventricular tachycardia † 1     
# participants affected / at risk   2/757 (0.26%)   1/761 (0.13%) 
Cardiopulmonary failure † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Sinus node dysfunction † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Acute coronary syndrome † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Coronary artery disease † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Atrial flutter † 1     
# participants affected / at risk   2/757 (0.26%)   0/761 (0.00%) 
Cardiac arrest † 1     
# participants affected / at risk   1/757 (0.13%)   2/761 (0.26%) 
Cardio-respiratory arrest † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Tachycardia † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Acute myocardial infarction † 1     
# participants affected / at risk   0/757 (0.00%)   3/761 (0.39%) 
Cardiac failure † 1     
# participants affected / at risk   3/757 (0.40%)   1/761 (0.13%) 
Myocardial ischaemia † 1     
# participants affected / at risk   2/757 (0.26%)   2/761 (0.26%) 
Pericardial effusion † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Atrial fibrillation † 1     
# participants affected / at risk   8/757 (1.06%)   8/761 (1.05%) 
Atrioventricular block second degree † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Left ventricular dysfunction † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Supraventricular tachyarrhythmia † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Cardiac failure congestive † 1     
# participants affected / at risk   3/757 (0.40%)   1/761 (0.13%) 
Myocardial infarction † 1     
# participants affected / at risk   1/757 (0.13%)   2/761 (0.26%) 
Angina pectoris † 1     
# participants affected / at risk   1/757 (0.13%)   2/761 (0.26%) 
Arrhythmia † 1     
# participants affected / at risk   0/757 (0.00%)   2/761 (0.26%) 
Cardiac disorder † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Congenital, familial and genetic disorders     
Hydrocele † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Eye disorders     
Maculopathy † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Amaurosis fugax † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Gastrointestinal disorders     
Abdominal hernia † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Dyspepsia † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Enterovesical fistula † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Gastric haemorrhage † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Large intestinal obstruction † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Reflux gastritis † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Stomatitis † 1     
# participants affected / at risk   1/757 (0.13%)   2/761 (0.26%) 
Colitis † 1     
# participants affected / at risk   0/757 (0.00%)   4/761 (0.53%) 
Diverticular perforation † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Gastritis erosive † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Melaena † 1     
# participants affected / at risk   1/757 (0.13%)   2/761 (0.26%) 
Mouth ulceration † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Nausea † 1     
# participants affected / at risk   7/757 (0.92%)   13/761 (1.71%) 
Anal fissure † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Anal fistula † 1     
# participants affected / at risk   0/757 (0.00%)   2/761 (0.26%) 
Gastrooesophageal reflux disease † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Intra-abdominal haemorrhage † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Megacolon † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Periodontal disease † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Subileus † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Duodenal ulcer haemorrhage † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Gastric ulcer † 1     
# participants affected / at risk   3/757 (0.40%)   2/761 (0.26%) 
Proctalgia † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Proctitis † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Volvulus † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Abdominal pain † 1     
# participants affected / at risk   3/757 (0.40%)   6/761 (0.79%) 
Abdominal pain upper † 1     
# participants affected / at risk   3/757 (0.40%)   1/761 (0.13%) 
Duodenal ulcer perforation † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Haematochezia † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Intestinal perforation † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Peptic ulcer † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Haematemesis † 1     
# participants affected / at risk   2/757 (0.26%)   0/761 (0.00%) 
Ileus † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Inguinal hernia † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Rectal haemorrhage † 1     
# participants affected / at risk   5/757 (0.66%)   8/761 (1.05%) 
Diarrhoea † 1     
# participants affected / at risk   10/757 (1.32%)   44/761 (5.78%) 
Enteritis † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Gastric ulcer perforation † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Intestinal obstruction † 1     
# participants affected / at risk   2/757 (0.26%)   1/761 (0.13%) 
Vomiting † 1     
# participants affected / at risk   10/757 (1.32%)   14/761 (1.84%) 
Constipation † 1     
# participants affected / at risk   10/757 (1.32%)   5/761 (0.66%) 
Dysphagia † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Gastrointestinal haemorrhage † 1     
# participants affected / at risk   7/757 (0.92%)   8/761 (1.05%) 
Gastrointestinal ulcer † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Lower gastrointestinal haemorrhage † 1     
# participants affected / at risk   0/757 (0.00%)   2/761 (0.26%) 
Oesophagitis † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Toothache † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Upper gastrointestinal haemorrhage † 1     
# participants affected / at risk   0/757 (0.00%)   3/761 (0.39%) 
General disorders     
Device occlusion † 1     
# participants affected / at risk   2/757 (0.26%)   0/761 (0.00%) 
Hyperthermia † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Pain † 1     
# participants affected / at risk   9/757 (1.19%)   7/761 (0.92%) 
Peripheral swelling † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Pyrexia † 1     
# participants affected / at risk   14/757 (1.85%)   29/761 (3.81%) 
Death † 1     
# participants affected / at risk   2/757 (0.26%)   3/761 (0.39%) 
Face oedema † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Influenza like illness † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Mucosal inflammation † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Oedema † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Malaise † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Oedema peripheral † 1     
# participants affected / at risk   3/757 (0.40%)   6/761 (0.79%) 
Sudden death † 1     
# participants affected / at risk   3/757 (0.40%)   0/761 (0.00%) 
Fatigue † 1     
# participants affected / at risk   9/757 (1.19%)   15/761 (1.97%) 
Multi-organ failure † 1     
# participants affected / at risk   1/757 (0.13%)   3/761 (0.39%) 
Performance status decreased † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
General physical health deterioration † 1     
# participants affected / at risk   1/757 (0.13%)   4/761 (0.53%) 
Chest pain † 1     
# participants affected / at risk   8/757 (1.06%)   9/761 (1.18%) 
Condition aggravated † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Generalised oedema † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Disease progression † 1     
# participants affected / at risk   0/757 (0.00%)   2/761 (0.26%) 
Localised oedema † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Asthenia † 1     
# participants affected / at risk   7/757 (0.92%)   13/761 (1.71%) 
Chills † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Hepatobiliary disorders     
Cholecystitis † 1     
# participants affected / at risk   1/757 (0.13%)   2/761 (0.26%) 
Cholecystitis acute † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Cholelithiasis † 1     
# participants affected / at risk   2/757 (0.26%)   1/761 (0.13%) 
Hepatic pain † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Hepatotoxicity † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Immune system disorders     
Hypersensitivity † 1     
# participants affected / at risk   1/757 (0.13%)   3/761 (0.39%) 
Anaphylactic reaction † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Drug hypersensitivity † 1     
# participants affected / at risk   0/757 (0.00%)   2/761 (0.26%) 
Infections and infestations     
Diverticulitis † 1     
# participants affected / at risk   3/757 (0.40%)   1/761 (0.13%) 
Empyema † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Gastroenteritis † 1     
# participants affected / at risk   3/757 (0.40%)   3/761 (0.39%) 
Scrotal abscess † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Bronchitis † 1     
# participants affected / at risk   3/757 (0.40%)   1/761 (0.13%) 
Cellulitis † 1     
# participants affected / at risk   3/757 (0.40%)   9/761 (1.18%) 
Cystitis † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Oesophageal infection † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Peritonitis † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Pyelonephritis acute † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Tooth infection † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Cellulitis of male external genital organ † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Lower respiratory tract infection † 1     
# participants affected / at risk   0/757 (0.00%)   5/761 (0.66%) 
Endocarditis † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Infection † 1     
# participants affected / at risk   4/757 (0.53%)   8/761 (1.05%) 
Lobar pneumonia † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Lung infection † 1     
# participants affected / at risk   0/757 (0.00%)   2/761 (0.26%) 
Oral candidiasis † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Respiratory tract infection † 1     
# participants affected / at risk   1/757 (0.13%)   4/761 (0.53%) 
Sepsis † 1     
# participants affected / at risk   6/757 (0.79%)   7/761 (0.92%) 
Upper respiratory tract infection † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Urinary tract infection † 1     
# participants affected / at risk   7/757 (0.92%)   10/761 (1.31%) 
Candida infection † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Clostridium difficile colitis † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Gangrene † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Herpes zoster † 1     
# participants affected / at risk   2/757 (0.26%)   0/761 (0.00%) 
Intestinal sepsis † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Neutropenic sepsis † 1     
# participants affected / at risk   0/757 (0.00%)   2/761 (0.26%) 
Balanoposthitis infective † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Device related infection † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Encephalitis † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Enterocolitis bacterial † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Fungal oesophagitis † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Influenza † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Pneumonia † 1     
# participants affected / at risk   22/757 (2.91%)   33/761 (4.34%) 
Septic shock † 1     
# participants affected / at risk   3/757 (0.40%)   10/761 (1.31%) 
Urosepsis † 1     
# participants affected / at risk   4/757 (0.53%)   1/761 (0.13%) 
Abscess intestinal † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Bacteraemia † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Bronchopneumonia † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Gastrointestinal infection † 1     
# participants affected / at risk   1/757 (0.13%)   3/761 (0.39%) 
Pneumonia streptococcal † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Staphylococcal sepsis † 1     
# participants affected / at risk   0/757 (0.00%)   2/761 (0.26%) 
Anal abscess † 1     
# participants affected / at risk   2/757 (0.26%)   1/761 (0.13%) 
Appendicitis † 1     
# participants affected / at risk   3/757 (0.40%)   1/761 (0.13%) 
Clostridium difficile infection † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Device related sepsis † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Erysipelas † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Infective exacerbation of chronic obstructive airways disease † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Neutropenic infection † 1     
# participants affected / at risk   3/757 (0.40%)   3/761 (0.39%) 
Perirectal abscess † 1     
# participants affected / at risk   2/757 (0.26%)   0/761 (0.00%) 
Injury, poisoning and procedural complications     
Fracture † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Gastroenteritis radiation † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Hip fracture † 1     
# participants affected / at risk   1/757 (0.13%)   2/761 (0.26%) 
Radiation proctitis † 1     
# participants affected / at risk   0/757 (0.00%)   4/761 (0.53%) 
Venous injury † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Accidental overdose † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Contusion † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Femoral neck fracture † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Gastrointestinal anastomotic leak † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Infusion related reaction † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Joint injury † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Multiple fractures † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Tracheal obstruction † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Upper limb fracture † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Anastomotic leak † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Clavicle fracture † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Femur fracture † 1     
# participants affected / at risk   2/757 (0.26%)   2/761 (0.26%) 
Lower limb fracture † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Thoracic vertebral fracture † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Ulna fracture † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Procedural complication † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Rib fracture † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Fall † 1     
# participants affected / at risk   3/757 (0.40%)   1/761 (0.13%) 
Spinal compression fracture † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Lumbar vertebral fracture † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Overdose † 1     
# participants affected / at risk   6/757 (0.79%)   11/761 (1.45%) 
Spinal fracture † 1     
# participants affected / at risk   3/757 (0.40%)   0/761 (0.00%) 
Investigations     
Aspartate aminotransferase increased † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Bone marrow myelogram abnormal † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Haemoglobin decreased † 1     
# participants affected / at risk   3/757 (0.40%)   9/761 (1.18%) 
Neutrophil count † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Neutrophil count decreased † 1     
# participants affected / at risk   2/757 (0.26%)   0/761 (0.00%) 
Transaminases increased † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Weight decreased † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Haemoglobin † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Alanine aminotransferase increased † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Clostridium test positive † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Eastern Cooperative Oncology Group performance status worsened † 1     
# participants affected / at risk   0/757 (0.00%)   3/761 (0.39%) 
Platelet count decreased † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Urine output decreased † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Blood creatinine increased † 1     
# participants affected / at risk   1/757 (0.13%)   2/761 (0.26%) 
Metabolism and nutrition disorders     
Malnutrition † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Hyperkalaemia † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Hypokalaemia † 1     
# participants affected / at risk   2/757 (0.26%)   3/761 (0.39%) 
Dehydration † 1     
# participants affected / at risk   11/757 (1.45%)   21/761 (2.76%) 
Hypercalcaemia † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Hyponatraemia † 1     
# participants affected / at risk   3/757 (0.40%)   2/761 (0.26%) 
Tumour lysis syndrome † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Fluid overload † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Hypomagnesaemia † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Hypophagia † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Metabolic acidosis † 1     
# participants affected / at risk   0/757 (0.00%)   2/761 (0.26%) 
Hypoglycaemia † 1     
# participants affected / at risk   4/757 (0.53%)   3/761 (0.39%) 
Decreased appetite † 1     
# participants affected / at risk   4/757 (0.53%)   3/761 (0.39%) 
Hyperglycaemia † 1     
# participants affected / at risk   3/757 (0.40%)   2/761 (0.26%) 
Hypocalcaemia † 1     
# participants affected / at risk   6/757 (0.79%)   4/761 (0.53%) 
Hypophosphataemia † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Musculoskeletal and connective tissue disorders     
Muscle spasms † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Neck pain † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Osteonecrosis † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Systemic lupus erythematosus † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Fistula † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Musculoskeletal pain † 1     
# participants affected / at risk   3/757 (0.40%)   1/761 (0.13%) 
Osteonecrosis of jaw † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Bone pain † 1     
# participants affected / at risk   7/757 (0.92%)   4/761 (0.53%) 
Flank pain † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Musculoskeletal chest pain † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Groin pain † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Hypercreatinaemia † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Pain in extremity † 1     
# participants affected / at risk   3/757 (0.40%)   3/761 (0.39%) 
Pathological fracture † 1     
# participants affected / at risk   1/757 (0.13%)   2/761 (0.26%) 
Spinal pain † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Arthralgia † 1     
# participants affected / at risk   2/757 (0.26%)   1/761 (0.13%) 
Back pain † 1     
# participants affected / at risk   12/757 (1.59%)   7/761 (0.92%) 
Muscular weakness † 1     
# participants affected / at risk   4/757 (0.53%)   3/761 (0.39%) 
Osteoarthritis † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Rotator cuff syndrome † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Adenosquamous cell lung cancer † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Neoplasm progression † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Rectal adenocarcinoma † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Renal neoplasm † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Astrocytoma malignant † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Cancer pain † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Prostate cancer † 1     
# participants affected / at risk   3/757 (0.40%)   2/761 (0.26%) 
Colorectal cancer † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Malignant neoplasm progression † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Basal cell carcinoma † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Metastases to meninges † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Metastatic neoplasm † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Rectal cancer † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Squamous cell carcinoma of skin † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Squamous cell carcinoma of the oral cavity † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Non-small cell lung cancer † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Colorectal cancer recurrent † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Meningioma † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Metastatic squamous cell carcinoma † 1     
# participants affected / at risk   0/757 (0.00%)   2/761 (0.26%) 
Prostate cancer metastatic † 1     
# participants affected / at risk   10/757 (1.32%)   9/761 (1.18%) 
Metastasis † 1     
# participants affected / at risk   2/757 (0.26%)   2/761 (0.26%) 
Nervous system disorders     
Carotid artery stenosis † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Nerve root compression † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Paraparesis † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Haemorrhage intracranial † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
IIIrd nerve disorder † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Peripheral motor neuropathy † 1     
# participants affected / at risk   4/757 (0.53%)   1/761 (0.13%) 
Aphasia † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Cerebral haematoma † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Cerebral ischaemia † 1     
# participants affected / at risk   0/757 (0.00%)   3/761 (0.39%) 
Cerebrovascular accident † 1     
# participants affected / at risk   4/757 (0.53%)   2/761 (0.26%) 
Depressed level of consciousness † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Headache † 1     
# participants affected / at risk   1/757 (0.13%)   2/761 (0.26%) 
Ataxia † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Coma † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Monoplegia † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Neuralgia † 1     
# participants affected / at risk   2/757 (0.26%)   0/761 (0.00%) 
Central nervous system haemorrhage † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Cerebral haemorrhage † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Dysarthria † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Motor dysfunction † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Somnolence † 1     
# participants affected / at risk   1/757 (0.13%)   2/761 (0.26%) 
Ischaemic stroke † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Peripheral sensory neuropathy † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Syncope † 1     
# participants affected / at risk   5/757 (0.66%)   4/761 (0.53%) 
Intracranial pressure increased † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Seizure † 1     
# participants affected / at risk   0/757 (0.00%)   2/761 (0.26%) 
Transient ischaemic attack † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Dizziness † 1     
# participants affected / at risk   2/757 (0.26%)   1/761 (0.13%) 
Spinal cord compression † 1     
# participants affected / at risk   6/757 (0.79%)   4/761 (0.53%) 
Psychiatric disorders     
Agitation † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Disorientation † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Mental status changes † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Depression suicidal † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Anxiety † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Confusional state † 1     
# participants affected / at risk   2/757 (0.26%)   6/761 (0.79%) 
Psychotic disorder † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Renal and urinary disorders     
Acute kidney injury † 1     
# participants affected / at risk   4/757 (0.53%)   8/761 (1.05%) 
Haemoglobinuria † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Haemorrhage urinary tract † 1     
# participants affected / at risk   0/757 (0.00%)   2/761 (0.26%) 
Hydronephrosis † 1     
# participants affected / at risk   3/757 (0.40%)   6/761 (0.79%) 
Renal disorder † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Bladder neck obstruction † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Bladder obstruction † 1     
# participants affected / at risk   3/757 (0.40%)   3/761 (0.39%) 
Renal colic † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Urethral stenosis † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Renal impairment † 1     
# participants affected / at risk   3/757 (0.40%)   0/761 (0.00%) 
Urinary bladder haemorrhage † 1     
# participants affected / at risk   1/757 (0.13%)   3/761 (0.39%) 
Nephrotic syndrome † 1     
# participants affected / at risk   0/757 (0.00%)   2/761 (0.26%) 
Ureteric obstruction † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Ureteric stenosis † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Urinary bladder polyp † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Urinary retention † 1     
# participants affected / at risk   9/757 (1.19%)   9/761 (1.18%) 
Urinary tract obstruction † 1     
# participants affected / at risk   2/757 (0.26%)   3/761 (0.39%) 
Bladder outlet obstruction † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Dysuria † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Haematuria † 1     
# participants affected / at risk   18/757 (2.38%)   10/761 (1.31%) 
Renal failure † 1     
# participants affected / at risk   5/757 (0.66%)   5/761 (0.66%) 
Obstructive uropathy † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Urinary incontinence † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Urogenital haemorrhage † 1     
# participants affected / at risk   0/757 (0.00%)   2/761 (0.26%) 
Reproductive system and breast disorders     
Benign prostatic hyperplasia † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Prostatic obstruction † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Penile pain † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Oedema genital † 1     
# participants affected / at risk   1/757 (0.13%)   2/761 (0.26%) 
Testicular mass † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Dyspnoea † 1     
# participants affected / at risk   10/757 (1.32%)   21/761 (2.76%) 
Hypoxia † 1     
# participants affected / at risk   1/757 (0.13%)   3/761 (0.39%) 
Pneumothorax † 1     
# participants affected / at risk   0/757 (0.00%)   2/761 (0.26%) 
Productive cough † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Alveolitis † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Lung disorder † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Cough † 1     
# participants affected / at risk   1/757 (0.13%)   3/761 (0.39%) 
Interstitial lung disease † 1     
# participants affected / at risk   0/757 (0.00%)   2/761 (0.26%) 
Pulmonary oedema † 1     
# participants affected / at risk   0/757 (0.00%)   2/761 (0.26%) 
Respiratory failure † 1     
# participants affected / at risk   2/757 (0.26%)   7/761 (0.92%) 
Dyspnoea exertional † 1     
# participants affected / at risk   2/757 (0.26%)   0/761 (0.00%) 
Pleural effusion † 1     
# participants affected / at risk   1/757 (0.13%)   19/761 (2.50%) 
Pneumonitis † 1     
# participants affected / at risk   7/757 (0.92%)   7/761 (0.92%) 
Acute pulmonary oedema † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Pulmonary embolism † 1     
# participants affected / at risk   17/757 (2.25%)   5/761 (0.66%) 
Pulmonary hypertension † 1     
# participants affected / at risk   0/757 (0.00%)   2/761 (0.26%) 
Pulmonary congestion † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Pulmonary venous thrombosis † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Acute respiratory distress syndrome † 1     
# participants affected / at risk   0/757 (0.00%)   2/761 (0.26%) 
Acute respiratory failure † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Chronic obstructive pulmonary disease † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Lung infiltration † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Skin and subcutaneous tissue disorders     
Peau d'orange † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Rash † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Pyoderma gangrenosum † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Drug eruption † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Vascular disorders     
Deep vein thrombosis † 1     
# participants affected / at risk   10/757 (1.32%)   1/761 (0.13%) 
Hypotension † 1     
# participants affected / at risk   8/757 (1.06%)   3/761 (0.39%) 
Shock haemorrhagic † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Venous thrombosis limb † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Circulatory collapse † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Haematoma † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Aortic dissection † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Haemorrhage † 1     
# participants affected / at risk   1/757 (0.13%)   1/761 (0.13%) 
Vasculitis † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Embolism † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Infarction † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Thrombosis † 1     
# participants affected / at risk   0/757 (0.00%)   2/761 (0.26%) 
Vena cava thrombosis † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Venous thrombosis † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Hypertension † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Jugular vein thrombosis † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Peripheral vascular disorder † 1     
# participants affected / at risk   0/757 (0.00%)   1/761 (0.13%) 
Phlebitis † 1     
# participants affected / at risk   2/757 (0.26%)   0/761 (0.00%) 
Thrombophlebitis superficial † 1     
# participants affected / at risk   1/757 (0.13%)   0/761 (0.00%) 
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 18.0




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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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