Trial Outcomes & Findings for Randomized Study Comparing Docetaxel Plus Dasatinib to Docetaxel Plus Placebo in Castration-resistant Prostate Cancer (NCT NCT00744497)

Last Updated: 2016-10-17

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1930 participants

Primary outcome timeframe

From randomization to death or date of last contact (maximum reached: 45 months)

Results posted on

2016-10-17

Participant Flow

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.

Participant milestones

Participant milestones
Measure	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
Overall Study STARTED	760	762
Overall Study Received Treatment	757	761
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	760	762

Reasons for withdrawal

Reasons for withdrawal
Measure	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
Overall Study Withdrawal by Subject	21	18
Overall Study Death	11	9
Overall Study Lost to Follow-up	4	2
Overall Study Poor compliance/noncompliance	9	5
Overall Study No longer meets study criteria	7	3
Overall Study Administrative Reason By Sponsor	25	8
Overall Study Disease progression	312	219
Overall Study Study drug toxicity	68	141
Overall Study Adverse event unrelated to study drug	78	122
Overall Study Patient requested to stop study drug	65	80
Overall Study Maximum clinical benefit	141	142
Overall Study Not defined	19	13

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=760 Participants 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 n=762 Participants 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 n=1522 Participants Total of all reporting groups
Age, Customized Younger than 65 years	263 participants n=5 Participants	251 participants n=7 Participants	514 participants n=5 Participants
Age, Customized 65 to younger than 75 years	323 participants n=5 Participants	333 participants n=7 Participants	656 participants n=5 Participants
Age, Customized 75 years or older	174 participants n=5 Participants	178 participants n=7 Participants	352 participants n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Male	760 Participants n=5 Participants	762 Participants n=7 Participants	1522 Participants n=5 Participants
Race/Ethnicity, Customized Asian	56 Participants n=5 Participants	55 Participants n=7 Participants	111 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	34 Participants n=5 Participants	23 Participants n=7 Participants	57 Participants n=5 Participants
Race/Ethnicity, Customized White	645 Participants n=5 Participants	656 Participants n=7 Participants	1301 Participants n=5 Participants
Race/Ethnicity, Customized Other	24 Participants n=5 Participants	27 Participants n=7 Participants	51 Participants n=5 Participants
Type of metastatic disease Bone disease only	286 Participants n=5 Participants	307 Participants n=7 Participants	593 Participants n=5 Participants
Type of metastatic disease Visceral/nodal disease only	73 Participants n=5 Participants	80 Participants n=7 Participants	153 Participants n=5 Participants
Type of metastatic disease Both bone and visceral/nodal disease	399 Participants n=5 Participants	373 Participants n=7 Participants	772 Participants n=5 Participants
Type of metastatic disease No evidence of metastatic disease	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization to death or date of last contact (maximum reached: 45 months)

Population: All participants who were randomized to receive any treatment

Outcome measures

Outcome measures
Measure	Placebo n=760 Participants 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 n=762 Participants 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
Overall Survival: Time From Randomization to Date of Death	21.2 Months Interval 20.0 to 23.4	21.5 Months Interval 20.3 to 22.8

SECONDARY outcome

Timeframe: 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)

Population: Participants with at least 1 target lesion at baseline

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.

Outcome measures

Outcome measures
Measure	Placebo n=383 Participants 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 n=381 Participants 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
Percentage of Participants With an Objective Tumor Response by Modified Response Evaluation Criteria in Solid Tumors (RECIST)	31.85 Percentage of participants Interval 27.21 to 36.78	30.45 Percentage of participants Interval 25.86 to 35.34

SECONDARY outcome

Timeframe: 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)

Population: All participants who were randomized to receive any treatment

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.

Outcome measures

Outcome measures
Measure	Placebo n=760 Participants 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 n=762 Participants 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
Time to First Skeletal-related Event (SRE)	31.1 Months Interval 28.8 to NA=Not estimable; insufficient number of participants with events	NA Months NA=Not estimable; insufficient number of participants with events

SECONDARY outcome

Timeframe: 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)

Population: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=335 Participants 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 n=321 Participants 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
Percentage of Participants With A Reduction in Urinary N-telopeptide (uNTx) Level From Baseline	60.60 Percentage of participants Interval 55.14 to 65.86	66.04 Percentage of participants Interval 60.58 to 71.21

SECONDARY outcome

Timeframe: 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)

Population: All participants who were randomized to receive any treatment

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.

Outcome measures

Outcome measures
Measure	Placebo n=760 Participants 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 n=762 Participants 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
Progression-free Survival (PFS)	11.1 Months Interval 10.8 to 11.7	11.8 Months Interval 11.1 to 13.4

SECONDARY outcome

Timeframe: 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)

Population: All participants who were randomized to receive any treatment

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.

Outcome measures

Outcome measures
Measure	Placebo n=760 Participants 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 n=762 Participants 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
Time to Prostate Specific Antigen (PSA) Progression	6.9 Months Interval 6.5 to 7.4	7.2 Months Interval 6.6 to 7.9

SECONDARY outcome

Timeframe: 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)

Population: Participants with a baseline pain intensity of 2 or greater

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.

Outcome measures

Outcome measures
Measure	Placebo n=467 Participants 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 n=419 Participants 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
Percentage of Participants With a Reduction in Pain Intensity From Baseline	71.52 Percentage of participants Interval 67.19 to 75.57	66.59 Percentage of participants Interval 61.85 to 71.09

OTHER_PRE_SPECIFIED outcome

Timeframe: 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

Population: All participants who received treatment

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

Outcome measures

Outcome measures
Measure	Placebo n=757 Participants 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 n=761 Participants 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
Number of Participants With Serious Adverse Event (SAEs), Drug-related SAEs, Drug-related AEs, Drug-related AEs Leading to Discontinuation, and All Deaths All deaths	505 Participants	506 Participants
Number of Participants With Serious Adverse Event (SAEs), Drug-related SAEs, Drug-related AEs, Drug-related AEs Leading to Discontinuation, and All Deaths Deaths within 30 days of end of treatment	50 Participants	79 Participants
Number of Participants With Serious Adverse Event (SAEs), Drug-related SAEs, Drug-related AEs, Drug-related AEs Leading to Discontinuation, and All Deaths All SAEs	317 Participants	381 Participants
Number of Participants With Serious Adverse Event (SAEs), Drug-related SAEs, Drug-related AEs, Drug-related AEs Leading to Discontinuation, and All Deaths Drug-related SAEs	90 Participants	150 Participants
Number of Participants With Serious Adverse Event (SAEs), Drug-related SAEs, Drug-related AEs, Drug-related AEs Leading to Discontinuation, and All Deaths All Drug-related AEs	482 Participants	553 Participants
Number of Participants With Serious Adverse Event (SAEs), Drug-related SAEs, Drug-related AEs, Drug-related AEs Leading to Discontinuation, and All Deaths Drug-related AEs leading to discontinuation	76 Participants	144 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 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

Population: All participants who received treatment

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.

Outcome measures

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

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Population: All participants who received treatment

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.

Outcome measures

Outcome measures
Measure	Placebo n=757 Participants 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 n=761 Participants 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
Number of Participants With Abnormalities in Results of Clinical Laboratory Tests in Hematology Absolute neutrophil count (All grades)	84 Participants	161 Participants
Number of Participants With Abnormalities in Results of Clinical Laboratory Tests in Hematology Absolute neutrophil count (Grades 3 and 4)	41 Participants	46 Participants
Number of Participants With Abnormalities in Results of Clinical Laboratory Tests in Hematology Hemoglobin (All grades)	712 Participants	720 Participants
Number of Participants With Abnormalities in Results of Clinical Laboratory Tests in Hematology Hemoglobin (Grades 3 and 4)	44 Participants	59 Participants
Number of Participants With Abnormalities in Results of Clinical Laboratory Tests in Hematology Platelets (All grades)	108 Participants	100 Participants
Number of Participants With Abnormalities in Results of Clinical Laboratory Tests in Hematology Platelets (Grades 3 and 4)	6 Participants	3 Participants
Number of Participants With Abnormalities in Results of Clinical Laboratory Tests in Hematology Leukocytes (All grades)	128 Participants	149 Participants
Number of Participants With Abnormalities in Results of Clinical Laboratory Tests in Hematology Leukocytes (Grades 3 and 4)	32 Participants	30 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: At baseline, within 3 days prior to each infusion of docetaxel (each cycle), to end of treatment. If docetaxel is discontinued, every other cycle.

Population: All participants who received treatment

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.

Outcome measures

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

OTHER_PRE_SPECIFIED outcome

Timeframe: At baseline, within 3 days prior to each infusion of docetaxel (each cycle), to end of treatment. If docetaxel is discontinued, every other cycle.

Population: All participants who received treatment.

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

Outcome measures

Outcome measures
Measure	Placebo n=757 Participants 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 n=761 Participants 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
Number of Participants With Abnormal Results in Urinalysis Protein, urine: postive	246 Participants	336 Participants
Number of Participants With Abnormal Results in Urinalysis Blood, urine: positive	289 Participants	307 Participants
Number of Participants With Abnormal Results in Urinalysis Glucose, urine: positive	179 Participants	154 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: At baseline, approximately 12 weeks after starting treatment, and then whenever clinically indicated up to within 30 days of end of dosing

Population: All participants who received treatment. n=number evaluable

QTc interval measured by electrocardiogram (ECG). Although a participant may have had several ECGs, only the longest QTc interval was included.

Outcome measures

Outcome measures
Measure	Placebo n=757 Participants 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 n=761 Participants 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
Number of Participants by Maximal On-study Fridericia-corrected QTc Interval <450 msecs (n=600, 548)	550 Participants	497 Participants
Number of Participants by Maximal On-study Fridericia-corrected QTc Interval 450-500 msecs (n=600, 548)	43 Participants	48 Participants
Number of Participants by Maximal On-study Fridericia-corrected QTc Interval >500 msecs (n=600, 548)	7 Participants	3 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: At baseline, approximately 12 weeks after starting treatment, and then whenever clinically indicated up to within 30 days of end of dosing

Population: All participants who received treatment. n=number evaluable

QTc interval measured by electrocardiogram (ECG). Although a participant may have had several ECGs, only the longest QTc interval was included.

Outcome measures

Outcome measures
Measure	Placebo n=757 Participants 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 n=761 Participants 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
Number of Participants With Changes From Baseline in Fridericia-corrected QTc Interval 0 to 30 msecs increase (n=591, 540)	203 Participants	199 Participants
Number of Participants With Changes From Baseline in Fridericia-corrected QTc Interval >30 to 60 msecs increase (n=591, 540)	52 Participants	47 Participants
Number of Participants With Changes From Baseline in Fridericia-corrected QTc Interval >60 msecs increase (n=591, 540)	32 Participants	26 Participants
Number of Participants With Changes From Baseline in Fridericia-corrected QTc Interval Decrease (n=591, 540)	304 Participants	268 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: At baseline, approximately 12 weeks after start of treatment, and thereafter whenever clinically indicated

Population: All participants who were randomized to receive any treatment

BL=baseline; OS=on-study

Outcome measures

Outcome measures
Measure	Placebo n=760 Participants 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 n=762 Participants 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
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 Pericardial effusion absent at BL/ absent OS	584 Participants	545 Participants
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 Pericardial effusion at BL/absent OS	3 Participants	1 Participants
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 Pericardial effusion at BL/present OS	0 Participants	1 Participants
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 Pericardial effusion at BL/not reported OS	1 Participants	0 Participants
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 Pericardial effusion absent at BL/present OS	24 Participants	26 Participants
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 Pericardial effusion absent at BL/not reported OS	132 Participants	184 Participants
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 Pericardial not reported at BL	16 Participants	5 Participants
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 LVEF OS <40%	2 Participants	2 Participants
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 LVEF OS >=40%	607 Participants	566 Participants
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 LVEF not reported OS	151 Participants	194 Participants

Adverse Events

Placebo

Serious events: 317 serious events

Other events: 701 other events

Deaths: 0 deaths

Dasatinib

Serious events: 381 serious events

Other events: 716 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Bristol-Myers Squibb Study Director

Bristol-Myers Squibb

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=757 participants at risk 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 n=761 participants at risk 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
Gastrointestinal disorders Dyspepsia	7.8% 59/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	6.6% 50/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Respiratory, thoracic and mediastinal disorders Dyspnoea	16.8% 127/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	20.2% 154/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Eye disorders Lacrimation increased	11.4% 86/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	6.3% 48/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Musculoskeletal and connective tissue disorders Muscle spasms	5.5% 42/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	2.0% 15/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Skin and subcutaneous tissue disorders Nail disorder	15.7% 119/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	10.5% 80/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
General disorders Pain	8.2% 62/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	6.2% 47/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
General disorders Pyrexia	9.4% 71/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	17.3% 132/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Gastrointestinal disorders Stomatitis	6.2% 47/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	6.2% 47/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Blood and lymphatic system disorders Anaemia	18.8% 142/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	28.5% 217/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Investigations Haemoglobin decreased	3.6% 27/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	6.4% 49/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
General disorders Mucosal inflammation	6.9% 52/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	9.2% 70/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Musculoskeletal and connective tissue disorders Musculoskeletal pain	7.3% 55/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	8.1% 62/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Gastrointestinal disorders Nausea	30.5% 231/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	37.8% 288/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
General disorders Oedema	6.2% 47/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	4.7% 36/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Musculoskeletal and connective tissue disorders Bone pain	9.2% 70/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	8.0% 61/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Respiratory, thoracic and mediastinal disorders Cough	14.8% 112/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	18.0% 137/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Metabolism and nutrition disorders Dehydration	3.0% 23/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	5.8% 44/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Respiratory, thoracic and mediastinal disorders Epistaxis	5.4% 41/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	4.3% 33/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Nervous system disorders Headache	8.6% 65/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	10.8% 82/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	5.3% 40/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	4.6% 35/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
General disorders Oedema peripheral	27.3% 207/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	21.3% 162/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Investigations Weight decreased	10.2% 77/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	15.9% 121/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
General disorders Fatigue	43.5% 329/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	43.9% 334/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Blood and lymphatic system disorders Neutropenia	8.9% 67/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	10.4% 79/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Respiratory, thoracic and mediastinal disorders Pleural effusion	3.7% 28/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	15.4% 117/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Skin and subcutaneous tissue disorders Rash	9.9% 75/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	13.9% 106/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Infections and infestations Urinary tract infection	8.9% 67/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	9.6% 73/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Gastrointestinal disorders Abdominal pain	8.9% 67/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	8.7% 66/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Nervous system disorders Dysgeusia	19.4% 147/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	21.7% 165/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Renal and urinary disorders Haematuria	5.8% 44/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	6.0% 46/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Musculoskeletal and connective tissue disorders Pain in extremity	16.9% 128/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	15.1% 115/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Skin and subcutaneous tissue disorders Alopecia	43.1% 326/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	40.9% 311/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
General disorders Chest pain	4.5% 34/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	6.4% 49/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Psychiatric disorders Insomnia	12.5% 95/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	10.0% 76/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Musculoskeletal and connective tissue disorders Myalgia	7.1% 54/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	6.6% 50/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Nervous system disorders Neuropathy peripheral	14.4% 109/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	10.9% 83/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Nervous system disorders Peripheral sensory neuropathy	14.0% 106/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	12.9% 98/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Musculoskeletal and connective tissue disorders Arthralgia	16.4% 124/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	13.7% 104/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Musculoskeletal and connective tissue disorders Back pain	25.6% 194/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	19.4% 148/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Metabolism and nutrition disorders Decreased appetite	19.9% 151/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	27.2% 207/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Gastrointestinal disorders Diarrhoea	41.2% 312/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	54.4% 414/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Vascular disorders Hypertension	5.5% 42/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	2.9% 22/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Musculoskeletal and connective tissue disorders Muscular weakness	6.7% 51/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	5.0% 38/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Gastrointestinal disorders Vomiting	15.5% 117/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	21.8% 166/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Investigations Weight increased	8.5% 64/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	4.7% 36/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
General disorders Asthenia	18.9% 143/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	21.4% 163/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Gastrointestinal disorders Constipation	25.0% 189/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	20.6% 157/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Nervous system disorders Dizziness	8.1% 61/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	8.4% 64/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Skin and subcutaneous tissue disorders Dry skin	6.1% 46/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	7.1% 54/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Metabolism and nutrition disorders Hyperglycaemia	7.3% 55/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	5.4% 41/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Metabolism and nutrition disorders Hypocalcaemia	3.2% 24/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	5.3% 40/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015
Nervous system disorders Paraesthesia	7.8% 59/757 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015	5.8% 44/761 • Day 1 up to 30 days post last dose of study therapy Study initiated: October 2008; Study Completion: July 2015