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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00744497
First received: August 29, 2008
Last updated: August 19, 2014
Last verified: August 2014
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
A total of 1930 participants were enrolled, and 1522 were randomized to a treatment group; 1518 received at least 1 dose of dasatinib (761) or placebo (757).

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     43 [2]   39 [2]
NOT COMPLETED     717     723  
Withdrawal by Subject                 21                 17  
Death                 11                 7  
Lost to Follow-up                 4                 2  
Poor compliance/noncompliance                 9                 4  
No longer meets study criteria                 7                 3  
Disease progression                 307                 208  
Study drug toxicity                 68                 140  
Adverse event unrelated to study drug                 77                 122  
Patient requested to stop study drug                 64                 72  
Maximum clinical benefit                 141                 138  
Other                 8                 10  
[1] Randomized
[2] Remained on study drug



  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  
Number of Participants  
[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
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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  
Number of 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% Confidence Interval ( 0.87 to 1.13 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Confidence intervals calculated using Brookmeyer and Crowley method. Analysis compared survival in arms by 2-sided, alpha=0.05 level, log-rank test, stratified by bisphosphonate intake (yes/no) and urinary N-telopeptide category (<60 vs ≥60 nmol/mmol creatinine) as defined at randomization. Null hypothesis was that survival was equal in both arms. Power calculations indicated that ≥858 deaths would lead to ≥90% power at 5% level for rejecting null hypothesis, given a 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. Final P-value was adjusted using an alpha spending function.
[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  
Number of 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  
Number of Participants Analyzed  
[units: participants]
  760     762  
Time to First Skeletal-related Event (SRE)  
[units: Months]
Median ( 95% Confidence Interval )
  31.1  
  ( 28.8 to NA ) [1]
  NA  
  ( NA to NA ) [1]
[1] Not estimable, due to the low percentage of participants experiencing skeletal-related 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  
Number of 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  
Number of 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  
Number of 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 of 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  
Number of 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 Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation   [ Time Frame: Continuously throughout study to >=30 days after last dose of study drug until resolution of drug-related toxicity, or when toxicity was deemed irreversible, whichever shorter. ]

Measure Type Other Pre-specified
Measure Title Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation
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 until resolution of drug-related toxicity, or when toxicity was deemed irreversible, whichever shorter.  
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  
Number of Participants Analyzed  
[units: participants]
  757     761  
Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation  
[units: Participants]
   
All deaths     461     451  
Deaths on or within 30 days of treatment     49     77  
All SAEs     317     376  
Drug-related SAEs     90     148  
AEs leading to discontinuation     186     293  
Drug-related AEs leading to discontinuation     75     143  

No statistical analysis provided for Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, and Drug-related AEs Leading to Discontinuation



9.  Other Pre-specified:   Number of Participants With Adverse Events (AEs) of Special Interest   [ Time Frame: Continuously throughout study to >=30 days after last dose of study drug until resolution of drug-related toxicity, or when toxicity was deemed irreversible, whichever was shorter ]

Measure Type Other Pre-specified
Measure Title Number of Participants With 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. 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 until resolution of drug-related toxicity, or when toxicity was deemed irreversible, whichever was shorter  
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  
Number of Participants Analyzed  
[units: participants]
  757     761  
Number of Participants With Adverse Events (AEs) of Special Interest  
[units: Participants]
   
Myelosuppression: Hemoglobin (n=746, 739)     712     720  
Myelosuppression: White blood cells (n=746, 738)     128     149  
Myelosuppression: ANC (n=745, 737)     84     161  
Myelosuppression: Platelets (n=746, 738)     108     100  
Hypocalcemia (n=739, 719)     308     377  
Hypophosphotemia (n=733, 720)     189     257  
Hypmagnesemia (n=734, 721)     108     98  
Diarrhea     314     426  
Nausea/vomiting     268     323  
Fatigue     330     338  
Myalgias/arthralgias     170     142  
Rash     115     147  
Gastrointestinal tract bleeding     39     72  
Central nervous system bleeding     1     4  
Other hemorrhage     134     120  
Pulmonary arterial hypertension     0     0  
Fluid retention: Superficial edema     237     184  
Fluid retention: Pleural effusion     30     118  
Fluid retention: Other     85     98  

No statistical analysis provided for Number of Participants With 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  
Number of 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  
Number of 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  
Number of 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 by Electrocardiogram   [ 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 by Electrocardiogram
Measure Description No text entered.
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  
Number of Participants Analyzed  
[units: participants]
  757     761  
Number of Participants by Maximal On-study Fridericia-corrected QTc Interval by Electrocardiogram  
[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 by Electrocardiogram



14.  Other Pre-specified:   Number of Participants With Changes From Baseline in Fridericia-corrected QTc Interval by Electrocardiogram   [ 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 by Electrocardiogram
Measure Description No text entered.
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  
Number of Participants Analyzed  
[units: participants]
  757     761  
Number of Participants With Changes From Baseline in Fridericia-corrected QTc Interval by Electrocardiogram  
[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 by Electrocardiogram



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 by Echocardiogram   [ 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 by Echocardiogram
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  
Number of 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 by Echocardiogram  
[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 by Echocardiogram




  Serious Adverse Events
  Hide Serious Adverse Events

Time Frame No text entered.
Additional Description No text entered.

Reporting Groups
  Description
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
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

Serious Adverse Events
    Dasatinib     Placebo  
Total, serious adverse events      
# participants affected / at risk     376/761 (49.41%)     317/757 (41.88%)  
Blood and lymphatic system disorders      
Haemorrhagic anaemia † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Disseminated intravascular coagulation † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Neutropenia † 1    
# participants affected / at risk     19/761 (2.50%)     18/757 (2.38%)  
Agranulocytosis † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Anaemia † 1    
# participants affected / at risk     21/761 (2.76%)     15/757 (1.98%)  
Febrile bone marrow aplasia † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Febrile neutropenia † 1    
# participants affected / at risk     32/761 (4.20%)     27/757 (3.57%)  
Hypochromic anaemia † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Thrombocytopenia † 1    
# participants affected / at risk     1/761 (0.13%)     2/757 (0.26%)  
Normochromic normocytic anaemia † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Leukopenia † 1    
# participants affected / at risk     9/761 (1.18%)     7/757 (0.92%)  
Cardiac disorders      
Acute coronary syndrome † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Myocardial infarction † 1    
# participants affected / at risk     2/761 (0.26%)     1/757 (0.13%)  
Supraventricular tachycardia † 1    
# participants affected / at risk     1/761 (0.13%)     2/757 (0.26%)  
Angina pectoris † 1    
# participants affected / at risk     2/761 (0.26%)     1/757 (0.13%)  
Cardiac failure congestive † 1    
# participants affected / at risk     1/761 (0.13%)     3/757 (0.40%)  
Sick sinus syndrome † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Supraventricular tachyarrhythmia † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Atrial flutter † 1    
# participants affected / at risk     0/761 (0.00%)     2/757 (0.26%)  
Cardiopulmonary failure † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Coronary artery disease † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Pericardial effusion † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Tachycardia † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Atrial fibrillation † 1    
# participants affected / at risk     8/761 (1.05%)     8/757 (1.06%)  
Cardiac failure † 1    
# participants affected / at risk     1/761 (0.13%)     3/757 (0.40%)  
Cardio-respiratory arrest † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Myocardial ischaemia † 1    
# participants affected / at risk     2/761 (0.26%)     2/757 (0.26%)  
Atrioventricular block second degree † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Cardiac disorder † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Acute myocardial infarction † 1    
# participants affected / at risk     3/761 (0.39%)     0/757 (0.00%)  
Arrhythmia † 1    
# participants affected / at risk     2/761 (0.26%)     0/757 (0.00%)  
Cardiac arrest † 1    
# participants affected / at risk     2/761 (0.26%)     1/757 (0.13%)  
Left ventricular dysfunction † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Congenital, familial and genetic disorders      
Hydrocele † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Eye disorders      
Maculopathy † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Amaurosis fugax † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Gastrointestinal disorders      
Constipation † 1    
# participants affected / at risk     5/761 (0.66%)     10/757 (1.32%)  
Gastric haemorrhage † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Gastritis erosive † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Inguinal hernia † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Stomatitis † 1    
# participants affected / at risk     2/761 (0.26%)     1/757 (0.13%)  
Dyspepsia † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Enteritis † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Haematemesis † 1    
# participants affected / at risk     0/761 (0.00%)     2/757 (0.26%)  
Nausea † 1    
# participants affected / at risk     14/761 (1.84%)     7/757 (0.92%)  
Upper gastrointestinal haemorrhage † 1    
# participants affected / at risk     3/761 (0.39%)     0/757 (0.00%)  
Ileus † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Abdominal pain upper † 1    
# participants affected / at risk     1/761 (0.13%)     3/757 (0.40%)  
Colitis † 1    
# participants affected / at risk     4/761 (0.53%)     0/757 (0.00%)  
Colonic obstruction † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Gastric ulcer † 1    
# participants affected / at risk     2/761 (0.26%)     3/757 (0.40%)  
Gastrointestinal haemorrhage † 1    
# participants affected / at risk     8/761 (1.05%)     7/757 (0.92%)  
Melaena † 1    
# participants affected / at risk     2/761 (0.26%)     1/757 (0.13%)  
Mouth ulceration † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Peptic ulcer † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Abdominal pain † 1    
# participants affected / at risk     6/761 (0.79%)     3/757 (0.40%)  
Diverticular perforation † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Duodenal ulcer haemorrhage † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Duodenal ulcer perforation † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Gastric ulcer perforation † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Gastrointestinal ulcer † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Haematochezia † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Intestinal perforation † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Proctitis † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Rectal haemorrhage † 1    
# participants affected / at risk     8/761 (1.05%)     5/757 (0.66%)  
Diarrhoea † 1    
# participants affected / at risk     44/761 (5.78%)     10/757 (1.32%)  
Dysphagia † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Enterovesical fistula † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Intestinal obstruction † 1    
# participants affected / at risk     1/761 (0.13%)     2/757 (0.26%)  
Oesophagitis † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Reflux gastritis † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Subileus † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Anal fistula † 1    
# participants affected / at risk     2/761 (0.26%)     0/757 (0.00%)  
Gastrooesophageal reflux disease † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Intra-abdominal haemorrhage † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Periodontal disease † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Volvulus † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Anal fissure † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Lower gastrointestinal haemorrhage † 1    
# participants affected / at risk     2/761 (0.26%)     0/757 (0.00%)  
Megacolon † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Proctalgia † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Toothache † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Vomiting † 1    
# participants affected / at risk     14/761 (1.84%)     10/757 (1.32%)  
General disorders      
Chest pain † 1    
# participants affected / at risk     9/761 (1.18%)     8/757 (1.06%)  
Pyrexia † 1    
# participants affected / at risk     29/761 (3.81%)     14/757 (1.85%)  
Face oedema † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Mucosal inflammation † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Oedema † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Spinal pain † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Death † 1    
# participants affected / at risk     3/761 (0.39%)     3/757 (0.40%)  
Multi-organ failure † 1    
# participants affected / at risk     2/761 (0.26%)     1/757 (0.13%)  
Device occlusion † 1    
# participants affected / at risk     0/761 (0.00%)     2/757 (0.26%)  
Generalised oedema † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Disease progression † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Malaise † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Performance status decreased † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Asthenia † 1    
# participants affected / at risk     13/761 (1.71%)     7/757 (0.92%)  
Chills † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Influenza like illness † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Localised oedema † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Sudden death † 1    
# participants affected / at risk     0/761 (0.00%)     3/757 (0.40%)  
Fatigue † 1    
# participants affected / at risk     15/761 (1.97%)     9/757 (1.19%)  
General physical health deterioration † 1    
# participants affected / at risk     3/761 (0.39%)     1/757 (0.13%)  
Hyperthermia † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Oedema peripheral † 1    
# participants affected / at risk     6/761 (0.79%)     4/757 (0.53%)  
Pain † 1    
# participants affected / at risk     7/761 (0.92%)     9/757 (1.19%)  
Hepatobiliary disorders      
Cholecystitis acute † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Hepatic pain † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Hepatotoxicity † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Cholelithiasis † 1    
# participants affected / at risk     1/761 (0.13%)     2/757 (0.26%)  
Cholecystitis † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Immune system disorders      
Hypersensitivity † 1    
# participants affected / at risk     3/761 (0.39%)     1/757 (0.13%)  
Anaphylactic reaction † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Drug hypersensitivity † 1    
# participants affected / at risk     2/761 (0.26%)     0/757 (0.00%)  
Infections and infestations      
Erysipelas † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Infectious peritonitis † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Neutropenic sepsis † 1    
# participants affected / at risk     2/761 (0.26%)     0/757 (0.00%)  
Respiratory tract infection † 1    
# participants affected / at risk     4/761 (0.53%)     1/757 (0.13%)  
Staphylococcal sepsis † 1    
# participants affected / at risk     2/761 (0.26%)     0/757 (0.00%)  
Upper respiratory tract infection † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Bronchitis † 1    
# participants affected / at risk     1/761 (0.13%)     3/757 (0.40%)  
Endocarditis † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Influenza † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Lower respiratory tract infection † 1    
# participants affected / at risk     5/761 (0.66%)     0/757 (0.00%)  
Pyelonephritis acute † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Urosepsis † 1    
# participants affected / at risk     1/761 (0.13%)     4/757 (0.53%)  
Abscess intestinal † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Bacteraemia † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Candidiasis † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Cellulitis † 1    
# participants affected / at risk     9/761 (1.18%)     3/757 (0.40%)  
Cellulitis of male external genital organ † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Diverticulitis † 1    
# participants affected / at risk     1/761 (0.13%)     3/757 (0.40%)  
Lobar pneumonia † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Peritonitis † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Tooth infection † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Cystitis † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Fungal oesophagitis † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Herpes zoster † 1    
# participants affected / at risk     0/761 (0.00%)     2/757 (0.26%)  
Neutropenic infection † 1    
# participants affected / at risk     3/761 (0.39%)     3/757 (0.40%)  
Oesophageal infection † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Oral candidiasis † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Perirectal abscess † 1    
# participants affected / at risk     0/761 (0.00%)     2/757 (0.26%)  
Pneumonia † 1    
# participants affected / at risk     32/761 (4.20%)     22/757 (2.91%)  
Scrotal abscess † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Anal abscess † 1    
# participants affected / at risk     1/761 (0.13%)     2/757 (0.26%)  
Bronchopneumonia † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Clostridial infection † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Gangrene † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Gastrointestinal infection † 1    
# participants affected / at risk     4/761 (0.53%)     1/757 (0.13%)  
Infective exacerbation of chronic obstructive airways disease † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Pneumonia streptococcal † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Septic shock † 1    
# participants affected / at risk     9/761 (1.18%)     3/757 (0.40%)  
Balanoposthitis infective † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Clostridium difficile colitis † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Device related infection † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Device related sepsis † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Gastroenteritis † 1    
# participants affected / at risk     3/761 (0.39%)     3/757 (0.40%)  
Sepsis † 1    
# participants affected / at risk     6/761 (0.79%)     6/757 (0.79%)  
Urinary tract infection † 1    
# participants affected / at risk     10/761 (1.31%)     7/757 (0.92%)  
Appendicitis † 1    
# participants affected / at risk     1/761 (0.13%)     3/757 (0.40%)  
Empyema † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Infection † 1    
# participants affected / at risk     8/761 (1.05%)     4/757 (0.53%)  
Lung infection † 1    
# participants affected / at risk     2/761 (0.26%)     0/757 (0.00%)  
Injury, poisoning and procedural complications      
Clavicle fracture † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Femur fracture † 1    
# participants affected / at risk     2/761 (0.26%)     2/757 (0.26%)  
Joint injury † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Procedural complication † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Spinal fracture † 1    
# participants affected / at risk     0/761 (0.00%)     3/757 (0.40%)  
Fracture † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Gastroenteritis radiation † 1    
# participants affected / at risk     4/761 (0.53%)     1/757 (0.13%)  
Overdose † 1    
# participants affected / at risk     11/761 (1.45%)     6/757 (0.79%)  
Contusion † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Infusion related reaction † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Multiple fractures † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Gastrointestinal anastomotic leak † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Lumbar vertebral fracture † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Upper limb fracture † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Fall † 1    
# participants affected / at risk     1/761 (0.13%)     3/757 (0.40%)  
Femoral neck fracture † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Hip fracture † 1    
# participants affected / at risk     2/761 (0.26%)     1/757 (0.13%)  
Lower limb fracture † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Spinal compression fracture † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Tracheal obstruction † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Accidental overdose † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Anastomotic leak † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Rib fracture † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Venous injury † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Ulna fracture † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Thoracic vertebral fracture † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Investigations      
Haemoglobin † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Urine output decreased † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Aspartate aminotransferase increased † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Blood creatinine increased † 1    
# participants affected / at risk     2/761 (0.26%)     1/757 (0.13%)  
Clostridium test positive † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
General physical condition abnormal † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Neutrophil count † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Bone marrow myelogram abnormal † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Alanine aminotransferase increased † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Eastern Cooperative Oncology Group performance status worsened † 1    
# participants affected / at risk     3/761 (0.39%)     0/757 (0.00%)  
Platelet count decreased † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Weight decreased † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Haemoglobin decreased † 1    
# participants affected / at risk     9/761 (1.18%)     3/757 (0.40%)  
Neutrophil count decreased † 1    
# participants affected / at risk     0/761 (0.00%)     2/757 (0.26%)  
Transaminases increased † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Metabolism and nutrition disorders      
Fluid overload † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Metabolic acidosis † 1    
# participants affected / at risk     2/761 (0.26%)     0/757 (0.00%)  
Decreased appetite † 1    
# participants affected / at risk     3/761 (0.39%)     4/757 (0.53%)  
Dehydration † 1    
# participants affected / at risk     21/761 (2.76%)     11/757 (1.45%)  
Hypokalaemia † 1    
# participants affected / at risk     3/761 (0.39%)     2/757 (0.26%)  
Hypomagnesaemia † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Hyponatraemia † 1    
# participants affected / at risk     2/761 (0.26%)     3/757 (0.40%)  
Hypophagia † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Hypocalcaemia † 1    
# participants affected / at risk     4/761 (0.53%)     6/757 (0.79%)  
Hypoglycaemia † 1    
# participants affected / at risk     3/761 (0.39%)     4/757 (0.53%)  
Hypophosphataemia † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Hypercalcaemia † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Hyperglycaemia † 1    
# participants affected / at risk     2/761 (0.26%)     3/757 (0.40%)  
Malnutrition † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Hyperkalaemia † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Tumour lysis syndrome † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Musculoskeletal and connective tissue disorders      
Back pain † 1    
# participants affected / at risk     7/761 (0.92%)     12/757 (1.59%)  
Musculoskeletal pain † 1    
# participants affected / at risk     1/761 (0.13%)     3/757 (0.40%)  
Pathological fracture † 1    
# participants affected / at risk     2/761 (0.26%)     1/757 (0.13%)  
Muscle spasms † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Systemic lupus erythematosus † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Groin pain † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Arthralgia † 1    
# participants affected / at risk     1/761 (0.13%)     2/757 (0.26%)  
Fistula † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Hypercreatinaemia † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Muscular weakness † 1    
# participants affected / at risk     3/761 (0.39%)     4/757 (0.53%)  
Osteonecrosis of jaw † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Bone pain † 1    
# participants affected / at risk     4/761 (0.53%)     7/757 (0.92%)  
Flank pain † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Neck pain † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Osteoarthritis † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Osteonecrosis † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Pain in extremity † 1    
# participants affected / at risk     3/761 (0.39%)     3/757 (0.40%)  
Musculoskeletal chest pain † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)      
Metastases to meninges † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Metastasis † 1    
# participants affected / at risk     2/761 (0.26%)     2/757 (0.26%)  
Prostate cancer † 1    
# participants affected / at risk     2/761 (0.26%)     3/757 (0.40%)  
Cancer pain † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Colorectal cancer recurrent † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Metastatic squamous cell carcinoma † 1    
# participants affected / at risk     2/761 (0.26%)     0/757 (0.00%)  
Neoplasm progression † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Adenosquamous cell lung cancer † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Colorectal cancer † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Lip and/or oral cavity cancer † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Basal cell carcinoma † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Meningioma † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Metastatic neoplasm † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Astrocytoma malignant † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Prostate cancer metastatic † 1    
# participants affected / at risk     9/761 (1.18%)     10/757 (1.32%)  
Rectal cancer † 1    
# participants affected / at risk     0/761 (0.00%)     2/757 (0.26%)  
Squamous cell carcinoma of skin † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Neoplasm malignant † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Renal neoplasm † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Non-small cell lung cancer † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Nervous system disorders      
Cerebral ischaemia † 1    
# participants affected / at risk     3/761 (0.39%)     0/757 (0.00%)  
IIIrd nerve disorder † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Syncope † 1    
# participants affected / at risk     4/761 (0.53%)     5/757 (0.66%)  
Aphasia † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Ataxia † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Headache † 1    
# participants affected / at risk     2/761 (0.26%)     1/757 (0.13%)  
Cerebrovascular accident † 1    
# participants affected / at risk     2/761 (0.26%)     4/757 (0.53%)  
Encephalitis † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Ischaemic stroke † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Carotid artery stenosis † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Monoplegia † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Motor dysfunction † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Paraparesis † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Cerebral haemorrhage † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Convulsion † 1    
# participants affected / at risk     2/761 (0.26%)     0/757 (0.00%)  
Dizziness † 1    
# participants affected / at risk     1/761 (0.13%)     2/757 (0.26%)  
Peripheral motor neuropathy † 1    
# participants affected / at risk     1/761 (0.13%)     4/757 (0.53%)  
Depressed level of consciousness † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Haemorrhage intracranial † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Somnolence † 1    
# participants affected / at risk     2/761 (0.26%)     1/757 (0.13%)  
Spinal cord compression † 1    
# participants affected / at risk     4/761 (0.53%)     6/757 (0.79%)  
Transient ischaemic attack † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Central nervous system haemorrhage † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Cerebral haematoma † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Neuralgia † 1    
# participants affected / at risk     0/761 (0.00%)     2/757 (0.26%)  
Coma † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Dysarthria † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Intracranial pressure increased † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Nerve root compression † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Peripheral sensory neuropathy † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Psychiatric disorders      
Anxiety † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Depression suicidal † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Confusional state † 1    
# participants affected / at risk     6/761 (0.79%)     2/757 (0.26%)  
Disorientation † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Mental status changes † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Agitation † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Psychotic disorder † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Renal and urinary disorders      
Renal disorder † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Haematuria † 1    
# participants affected / at risk     10/761 (1.31%)     18/757 (2.38%)  
Urethral stenosis † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Urinary incontinence † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Bladder outlet obstruction † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Haemoglobinuria † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Haemorrhage urinary tract † 1    
# participants affected / at risk     2/761 (0.26%)     0/757 (0.00%)  
Hydronephrosis † 1    
# participants affected / at risk     6/761 (0.79%)     3/757 (0.40%)  
Renal failure † 1    
# participants affected / at risk     5/761 (0.66%)     5/757 (0.66%)  
Urinary bladder polyp † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Bladder obstruction † 1    
# participants affected / at risk     3/761 (0.39%)     3/757 (0.40%)  
Obstructive uropathy † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Renal impairment † 1    
# participants affected / at risk     0/761 (0.00%)     3/757 (0.40%)  
Urogenital haemorrhage † 1    
# participants affected / at risk     2/761 (0.26%)     0/757 (0.00%)  
Bladder neck obstruction † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Nephrotic syndrome † 1    
# participants affected / at risk     2/761 (0.26%)     0/757 (0.00%)  
Renal colic † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Renal failure acute † 1    
# participants affected / at risk     8/761 (1.05%)     4/757 (0.53%)  
Urinary retention † 1    
# participants affected / at risk     9/761 (1.18%)     9/757 (1.19%)  
Urinary tract obstruction † 1    
# participants affected / at risk     3/761 (0.39%)     2/757 (0.26%)  
Dysuria † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Ureteric obstruction † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Ureteric stenosis † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Urinary bladder haemorrhage † 1    
# participants affected / at risk     3/761 (0.39%)     1/757 (0.13%)  
Reproductive system and breast disorders      
Benign prostatic hyperplasia † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Testicular mass † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Penile pain † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Oedema genital † 1    
# participants affected / at risk     2/761 (0.26%)     1/757 (0.13%)  
Prostatic obstruction † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Respiratory, thoracic and mediastinal disorders      
Chronic obstructive pulmonary disease † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Dyspnoea † 1    
# participants affected / at risk     21/761 (2.76%)     10/757 (1.32%)  
Hypoxia † 1    
# participants affected / at risk     3/761 (0.39%)     1/757 (0.13%)  
Pleural effusion † 1    
# participants affected / at risk     18/761 (2.37%)     1/757 (0.13%)  
Productive cough † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Acute respiratory distress syndrome † 1    
# participants affected / at risk     2/761 (0.26%)     0/757 (0.00%)  
Interstitial lung disease † 1    
# participants affected / at risk     2/761 (0.26%)     0/757 (0.00%)  
Lung infiltration † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Pneumothorax † 1    
# participants affected / at risk     2/761 (0.26%)     0/757 (0.00%)  
Pulmonary embolism † 1    
# participants affected / at risk     5/761 (0.66%)     17/757 (2.25%)  
Pulmonary hypertension † 1    
# participants affected / at risk     2/761 (0.26%)     0/757 (0.00%)  
Respiratory failure † 1    
# participants affected / at risk     7/761 (0.92%)     2/757 (0.26%)  
Acute pulmonary oedema † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Alveolitis † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Dyspnoea exertional † 1    
# participants affected / at risk     0/761 (0.00%)     2/757 (0.26%)  
Pneumonitis † 1    
# participants affected / at risk     7/761 (0.92%)     7/757 (0.92%)  
Pulmonary congestion † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Pulmonary oedema † 1    
# participants affected / at risk     2/761 (0.26%)     0/757 (0.00%)  
Cough † 1    
# participants affected / at risk     3/761 (0.39%)     1/757 (0.13%)  
Lung disorder † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Pulmonary venous thrombosis † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Skin and subcutaneous tissue disorders      
Pyoderma gangrenosum † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Drug eruption † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Peau d'orange † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Rash † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Vascular disorders      
Haemorrhage † 1    
# participants affected / at risk     1/761 (0.13%)     1/757 (0.13%)  
Peripheral vascular disorder † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Thrombophlebitis superficial † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Circulatory collapse † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Phlebitis † 1    
# participants affected / at risk     0/761 (0.00%)     2/757 (0.26%)  
Vasculitis † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Deep vein thrombosis † 1    
# participants affected / at risk     1/761 (0.13%)     10/757 (1.32%)  
Embolism † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Hypotension † 1    
# participants affected / at risk     3/761 (0.39%)     8/757 (1.06%)  
Vena cava thrombosis † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Haematoma † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Hypertension † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Thrombosis † 1    
# participants affected / at risk     2/761 (0.26%)     0/757 (0.00%)  
Aortic dissection † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Infarction † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Jugular vein thrombosis † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Shock haemorrhagic † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Venous thrombosis † 1    
# participants affected / at risk     1/761 (0.13%)     0/757 (0.00%)  
Venous thrombosis limb † 1    
# participants affected / at risk     0/761 (0.00%)     1/757 (0.13%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 15.0




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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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