Safety and Efficacy Study of Enzalutamide Versus Bicalutamide in Men With Prostate Cancer (STRIVE)

• ClinicalTrials.gov Identifier: NCT01664923
• Recruitment Status: Completed
• First Posted: August 14, 2012
• Results First Posted: May 23, 2016
• Last Update Posted: January 30, 2019
• Sponsor: Pfizer
• Collaborators: Astellas Pharma Inc; Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
• Information provided by (Responsible Party): Pfizer

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Prostate Cancer
• Interventions: Drug: Enzalutamide; Drug: Bicalutamide
• Enrollment: 396

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Enzalutamide	Bicalutamide Then Enzalutamide
Arm/Group Description	Participants received enzalutamide 160 milligram (mg), self-administered as four 40-mg capsules, and 1 bicalutamide matching placebo capsule once per day, by mouth for up to 29 months in double blind (DB) phase. Participants who completed DB phase and consented to participate in open label phase, received enzalutamide 160 mg, self-administered as four 40-mg capsules once per day by mouth for up to 36 months in open label phase.	Participants received bicalutamide 50 mg, self-administered as 1 capsule, once per day by mouth and 4 enzalutamide matching placebo capsules for up to 29 months in DB phase. Participants who completed DB phase and consented to participate in open label phase, received enzalutamide 160 mg, self-administered as four 40-mg capsules, once per day by mouth for up to 36 months in open label phase.
Period Title: Period1:Double Blind Phase-29 Months
Started	198	198
Received Study Treatment	197	198
Completed	93	38
Not Completed	105	160
Reason Not Completed
Death	8	6
Lost to Follow-up	0	1
Protocol Violation	2	0
Withdrawal by Subject	12	8
Disease Progression	65	132
Adverse Event	14	9
Other	3	4
Randomized, But Not treated	1	0
Period Title: Period 2: Open-label Phase-36 Months
Started	93	38
Treated	93	37
Completed	52	15
Not Completed	41	23
Reason Not Completed
Death	3	1
On Treatment	1	1
Disease progression	28	9
Other	3	1
Adverse Event	4	7
Withdrawal by Subject	2	4

Baseline Characteristics

Arm/Group Title		Enzalutamide	Bicalutamide	Total
Arm/Group Description		Participants received enzalutamide 160 mg, self-administered as four 40-mg capsules, once per day by mouth and 1 bicalutamide-placebo capsule in DB phase.	Participants received bicalutamide 50 mg, self-administered as 1 capsule, once per day by mouth and 4 enzalutamide-placebo capsules in DB phase.	Total of all reporting groups
Overall Number of Baseline Participants		198	198	396
Baseline Analysis Population Description		[Not Specified]
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	198 participants	198 participants	396 participants
	< 65 years	39 19.7%	25 12.6%	64 16.2%
	65-74 years	82 41.4%	76 38.4%	158 39.9%
	≥ 75 years	77 38.9%	97 49.0%	174 43.9%
Sex/Gender, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	198 participants	198 participants	396 participants
	Male	198 100.0%	198 100.0%	396 100.0%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
United States	Number Analyzed	198 participants	198 participants	396 participants
		198 100.0%	198 100.0%	396 100.0%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was defined as time from randomization to earliest objective evidence of prostate specific-antigen (PSA) progression, radiographic progression, or death on study. PSA progression was defined as ≥ 25% increase in PSA with an absolute increase ≥ 2 ng/mL above the nadir and was to be confirmed by a second consecutive assessment. Radiographic progression in bone was based on The Prostate Cancer Clinical Trials Working Group (PCWG2) guidelines defined as at least 2 new lesions on bone scan. Radiographic progression in soft tissue on Computerized Tomography/Magnetic Resonance Imaging (CT/MRI) was based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). CT/MRI and bone scans were read locally by the same radiologist (or nuclear medicine physician for interpretation of bone scans) whenever possible. Participants not known to have had a PFS event at the time of the analysis data cutoff were censored at the date of last assessment.
Time Frame	From randomization until the data cut-off date of 09 February 2015, median duration of treatment was 14.7 months in the enzalutamide arm and 8.4 months in the bicalutamide arm.

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: all participants randomly assigned to study treatment.

Arm/Group Title	Enzalutamide	Bicalutamide
Arm/Group Description:	Participants received enzalutamide 160 mg, self-administered as four 40-mg capsules, once per day by mouth and 1 bicalutamide-placebo capsule in DB phase.	Participants received bicalutamide 50 mg, self-administered as 1 capsule, once per day by mouth and 4 enzalutamide-placebo capsules in DB phase.
Overall Number of Participants Analyzed	198	198
Median (95% Confidence Interval); Unit of Measure: months
	19.4 [1]; (16.5 to NA)	5.7; (5.6 to 8.1)

[1]

The upper limit of the 95% confidence interval was not available because an insufficient number of participants had an event at the time of analysis.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide, Bicalutamide
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value based on log-rank test stratified by disease stage at study entry as reported on the case report form (CRF).
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.240
	Confidence Interval	(2-Sided) 95%; 0.181 to 0.320
	Estimation Comments	Hazard ratio is based on a Cox regression model (with treatment as the only covariate) stratified by disease stage at study entry and is relative to bicalutamide with < 1 favoring enzalutamide.

2. Secondary Outcome

Title	Time to PSA Progression
Description	PSA progression was defined as ≥ 25% increase in PSA with an absolute increase ≥ 2 ng/mL above the nadir and was to be confirmed by a second consecutive assessment at least 3 weeks later. Participants not known to have had PSA progression were censored at the date of last PSA assessment.
Time Frame	From randomization until the data cut-off date of 09 February 2015, median duration of treatment was 14.7 months in the enzalutamide arm and 8.4 months in the bicalutamide arm.

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: all participants randomly assigned to study treatment.

Arm/Group Title	Enzalutamide	Bicalutamide
Arm/Group Description:	Participants received enzalutamide 160 mg, self-administered as four 40-mg capsules, once per day by mouth and 1 bicalutamide-placebo capsule in DB phase.	Participants received bicalutamide 50 mg, self-administered as 1 capsule, once per day by mouth and 4 enzalutamide-placebo capsules in DB phase.
Overall Number of Participants Analyzed	198	198
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (19.4 to NA)	8.3; (5.7 to 8.5)

[1]

The median time to PSA progression and its upper limit of the 95% confidence interval were not available because an insufficient number of participants had an event at the time of analysis.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide, Bicalutamide
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value based on log-rank test stratified by disease stage at study entry as reported on the CRF.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.190
	Confidence Interval	(2-Sided) 95%; 0.137 to 0.264
	Estimation Comments	Hazard ratio is based on a Cox regression model (with treatment as the only covariate) stratified by disease stage at study entry and is relative to bicalutamide with < 1 favoring enzalutamide.

3. Secondary Outcome

Title	Percentage of Participants With a PSA Response ≥ 50%
Description	PSA response was defined as a reduction in PSA of at least 50% from baseline at any post baseline assessment confirmed by a second PSA assessment at least 3 weeks later.
Time Frame	From randomization until the data cut-off date of 09 February 2015, median duration of treatment was 14.7 months in the enzalutamide arm and 8.4 months in the bicalutamide arm.

Outcome Measure Data

Analysis Population Description

Evaluable intent-to-treat population: all participants randomly assigned to study treatment and had a baseline and at least 1 post baseline PSA measurement.

Arm/Group Title	Enzalutamide	Bicalutamide
Arm/Group Description:	Participants received enzalutamide 160 mg, self-administered as four 40-mg capsules, once per day by mouth and 1 bicalutamide-placebo capsule in DB phase.	Participants received bicalutamide 50 mg, self-administered as 1 capsule, once per day by mouth and 4 enzalutamide-placebo capsules in DB phase.
Overall Number of Participants Analyzed	192	195
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	81.3; (75.0 to 86.5)	31.3; (24.8 to 38.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide, Bicalutamide
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Comparison of the 2 treatment groups using the Cochran-Mantel-Haenszel mean score test stratified by disease stage at study entry.
Method of Estimation	Estimation Parameter	Difference in rates
	Estimated Value	50.0
	Confidence Interval	(2-Sided) 95%; 41.4 to 58.5
	Estimation Comments	Enzalutamide response rate minus bicalutamide response rate.

4. Secondary Outcome

Title	Duration of Radiographic PFS
Description	Duration of radiographic PFS was defined as the time from randomization to the earliest objective evidence of radiographic disease progression or death on study and was to be evaluated for participants with metastatic disease at study entry. Radiographic disease progression in bone was based on PCWG2 guidelines defined as at least 2 new lesions on bone scan. Radiographic disease progression in soft tissue on CT/MRI was based on RECIST 1.1. CT/MRI and bone scans were read locally by the same radiologist (or nuclear medicine physician for interpretation of bone scans) whenever possible. Participants not known to have had radiographic progression at the time of analysis data cutoff were censored at the date of last radiographic assessment.
Time Frame	From randomization until the data cut-off date of 09 February 2015, median duration of treatment was 14.7 months in the enzalutamide arm and 8.4 months in the bicalutamide arm.

Outcome Measure Data

Analysis Population Description

All participants with metastatic disease at study entry and randomly assigned to study treatment.

Arm/Group Title	Enzalutamide	Bicalutamide
Arm/Group Description:	Participants received enzalutamide 160 mg, self-administered as four 40-mg capsules, once per day by mouth and 1 bicalutamide-placebo capsule in DB phase.	Participants received bicalutamide 50 mg, self-administered as 1 capsule, once per day by mouth and 4 enzalutamide-placebo capsules in DB phase.
Overall Number of Participants Analyzed	128	129
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (16.7 to NA)	8.3; (8.1 to 11.1)

[1]

The median duration of radiographic PFS and its upper limit of the 95% confidence interval were not available because an insufficient number of participants had an event at the time of analysis.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide, Bicalutamide
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	P-value is based on an unstratified log-rank test.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.324
	Confidence Interval	(2-Sided) 95%; 0.211 to 0.497
	Estimation Comments	Hazard ratio is based on an unstratified Cox-regression model (with treatment as the only covariate) and is relative to bicalutamide with < 1 favoring enzalutamide.

5. Secondary Outcome

Title	Quality of Life: Time to Degradation of Functional Assessment of Cancer Therapy - Prostate (FACT-P)
Description	The FACT-P is a multidimensional, self-reported quality of life instrument consisting of 27 core items that assess patient function in 4 domains: physical, social/family, emotional, and functional well-being, and supplemented by 12 site-specific items to assess for prostate-related symptoms. Each item is rated on a 0 to 4 Likert-type scale, and then combined to produce subscale scores for each domain, as well as a global quality of life score (0 to 156) with higher scores representing better quality of life. Time to degradation of FACT-P was defined as the time from randomization to first assessment with at least a 10-point decrease from baseline in the global FACT-P score for each participant. Participants with no score degradation at the time of analysis data cutoff were censored at the date of last assessment showing no degradation.
Time Frame	From randomization until the data cut-off date of 09 February 2015, median duration of treatment was 14.7 months in the enzalutamide arm and 8.4 months in the bicalutamide arm.

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: all participants randomly assigned to study treatment.

Arm/Group Title	Enzalutamide	Bicalutamide
Arm/Group Description:	Participants received enzalutamide 160 mg, self-administered as four 40-mg capsules, once per day by mouth and 1 bicalutamide-placebo capsule in DB phase.	Participants received bicalutamide 50 mg, self-administered as 1 capsule, once per day by mouth and 4 enzalutamide-placebo capsules in DB phase.
Overall Number of Participants Analyzed	198	198
Median (95% Confidence Interval); Unit of Measure: months
	8.4; (6.3 to 11.4)	8.3; (6.1 to 11.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide, Bicalutamide
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4945
	Comments	This secondary endpoint was not adjusted for multiple comparisons.
	Method	Log Rank
	Comments	P-value is based on a log-rank test stratified by disease stage at study entry.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.910
	Confidence Interval	(2-Sided) 95%; 0.695 to 1.192
	Estimation Comments	Hazard ratio is based on a Cox regression model (with treatment as the only covariate) stratified by disease stage at study entry and is relative to bicalutamide with < 1 favoring enzalutamide.

6. Secondary Outcome

Title	Best Overall Soft Tissue Response
Description	Best overall soft tissue response is defined as partial response (PR) or complete response (CR) while on study treatment based on investigator assessment of target, nontarget, and new lesions using RECIST 1.1. Only participants in the metastatic population with measurable soft tissue disease (at least 1 target lesion identified per RECIST 1.1) at screening were included in the analysis. All percentages are based on number of participants with metastatic and measurable soft tissue disease at screening in each treatment group.
Time Frame	From randomization until the data cut-off date of 09 February 2015, median duration of treatment was 14.7 months in the enzalutamide arm and 8.4 months in the bicalutamide arm.

Outcome Measure Data

Analysis Population Description

All participants who were randomly assigned to study treatment and had metastatic and measurable soft tissue disease at screening.

Arm/Group Title	Enzalutamide	Bicalutamide
Arm/Group Description:	Participants received enzalutamide 160 mg, self-administered as four 40-mg capsules, once per day by mouth and 1 bicalutamide-placebo capsule in DB phase.	Participants received bicalutamide 50 mg, self-administered as 1 capsule, once per day by mouth and 4 enzalutamide-placebo capsules in DB phase.
Overall Number of Participants Analyzed	35	43
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	60.0; (42.11 to 76.13)	14.0; (5.30 to 27.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide, Bicalutamide
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	This secondary endpoint was not adjusted for multiple comparisons.
	Method	Cochran-Mantel-Haenszel
	Comments	Based on unstratified Cochran-Mantel-Haenszel mean score test.
Method of Estimation	Estimation Parameter	Difference in objective response rate
	Estimated Value	46.05
	Confidence Interval	(2-Sided) 95%; 26.79 to 65.30
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Percentage of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. An SAE was an AE resulting in any of following outcomes or deemed significant for any other reason: death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), persistent or significant disability or incapacity, congenital anomaly. A treatment emergent AE defined as an event that emerged during treatment period (From first dose of study drug until end of open label phase [up to maximum duration of 65 months]) that was absent before treatment, or worsened during treatment period relative to pre-treatment state. AE included both serious and non- SAE. Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An AE was considered related to study drug if event was assessed by investigator as probably or possibly related.
Time Frame	From first dose of study drug until the end of open label phase (up to maximum duration of 65 months)

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least 1 dose of study drug.

Arm/Group Title	Enzalutamide	DB Phase: Bicalutamide	Open Label Phase: Bicalutamide Crossover to Enzalutamide
Arm/Group Description:	Participants received enzalutamide 160 mg, self-administered as four 40-mg capsules, and 1 bicalutamide matching placebo capsule once per day, by mouth for up to 29 months in DB phase. Participants who completed DB phase and consented to participate in open label phase, received enzalutamide 160 mg, self-administered as four 40-mg capsules once per day by mouth for up to 36 months in open label phase.	Participants received bicalutamide 50 mg, self-administered as 1 capsule, once per day by mouth and 4 enzalutamide matching placebo capsules for up to 29 months in DB phase.	Participants who received bicalutamide 50 mg in DB phase and consented to participate in open label phase, received enzalutamide 160 mg, self-administered as four 40-mg capsules, once per day by mouth in open label phase for up to 36 months.
Overall Number of Participants Analyzed	197	198	37
Measure Type: Number; Unit of Measure: percentage of participants
Any AE	96.4	90.4	97.3
AE Leading to Study Drug Discontinuation	16.2	13.1	24.3
AE Leading to Death	4.6	3.0	8.1
Serious AE	38.6	30.3	43.2
AE Related to Study Drug	66.5	53.5	70.3
Serious AE Related to Study Drug	7.6	3.5	2.7

Adverse Events

Time Frame	From first dose of study drug until the end of open label phase (up to maximum duration of 65 months)
Adverse Event Reporting Description	Same event may appear as AE and SAE, what is presented are distinct events. Event may be categorized as serious in 1 participant and as non-serious in another participant or 1 participant may have experienced both serious and non-serious event during study
Arm/Group Title	Enzalutamide	DB Phase: Bicalutamide	Open Label Phase: Bicalutamide Crossover to Enzalutamide
Arm/Group Description	Participants received enzalutamide 160 mg, self-administered as four 40-mg capsules, once per day by mouth and 1 bicalutamide-placebo capsule for up to 29 months in DB phase. Participants who completed DB phase and consented to participate in open label phase, received same treatment for up to 36 months in open label phase.	Participants received bicalutamide 50 mg, self-administered as 1 capsule, once per day by mouth and 4 enzalutamide-placebo capsules for up to 29 months in DB phase.	Participants who received bicalutamide 50 mg in DB phase and consented to participate in open label phase, received enzalutamide 160 mg, self-administered as four 40-mg capsules, once per day by mouth in open label phase for up to 36 months.
All-Cause Mortality
	Enzalutamide	DB Phase: Bicalutamide	Open Label Phase: Bicalutamide Crossover to Enzalutamide
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	Enzalutamide	DB Phase: Bicalutamide	Open Label Phase: Bicalutamide Crossover to Enzalutamide
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	76/197 (38.58%)	60/198 (30.30%)	16/37 (43.24%)
Blood and lymphatic system disorders
Anaemia † 1	4/197 (2.03%)	4/198 (2.02%)	2/37 (5.41%)
Lymphadenitis † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Cardiac disorders
Acute coronary syndrome † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Acute myocardial infarction † 1	2/197 (1.02%)	1/198 (0.51%)	1/37 (2.70%)
Angina pectoris † 1	5/197 (2.54%)	0/198 (0.00%)	0/37 (0.00%)
Aortic valve disease † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Atrial fibrillation † 1	2/197 (1.02%)	1/198 (0.51%)	0/37 (0.00%)
Atrial flutter † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Atrioventricular block † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Bradycardia † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Cardiac failure † 1	1/197 (0.51%)	1/198 (0.51%)	1/37 (2.70%)
Cardiac failure congestive † 1	5/197 (2.54%)	2/198 (1.01%)	2/37 (5.41%)
Cardio-respiratory arrest † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Coronary artery disease † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Palpitations † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Stress cardiomyopathy † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Supraventricular tachycardia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Ventricular tachycardia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Myocardial infarction † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Ventricular fibrillation † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Arrhythmia † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Atrioventricular block complete † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Ear and labyrinth disorders
Vertigo † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Endocrine disorders
Inappropriate antidiuretic hormone secretion † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Gastrointestinal disorders
Abdominal pain † 1	0/197 (0.00%)	1/198 (0.51%)	1/37 (2.70%)
Constipation † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Diarrhoea † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Diverticulum intestinal haemorrhagic † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Duodenal ulcer † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Dysphagia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Gastric haemorrhage † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Gastric ulcer † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Gastrointestinal haemorrhage † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Ileus † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Large intestinal stenosis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Odynophagia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Rectal haemorrhage † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Small intestinal obstruction † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Upper gastrointestinal haemorrhage † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Duodenal perforation † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Lower gastrointestinal haemorrhage † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Ascites † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Duodenal ulcer perforation † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
General disorders
Asthenia † 1	5/197 (2.54%)	1/198 (0.51%)	0/37 (0.00%)
Chest pain † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Device occlusion † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Fatigue † 1	1/197 (0.51%)	2/198 (1.01%)	0/37 (0.00%)
General physical health deterioration † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Non-cardiac chest pain † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Pyrexia † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Disease progression † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Hepatobiliary disorders
Cholecystitis acute † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Cholecystitis chronic † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Hepatic failure † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Infections and infestations
Bronchitis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Cellulitis † 1	3/197 (1.52%)	0/198 (0.00%)	0/37 (0.00%)
Hepatitis B † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Lobar pneumonia † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Peritonitis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Pneumonia † 1	6/197 (3.05%)	4/198 (2.02%)	0/37 (0.00%)
Pulmonary sepsis † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Pyelonephritis † 1	1/197 (0.51%)	2/198 (1.01%)	0/37 (0.00%)
Pyelonephritis acute † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Sepsis † 1	1/197 (0.51%)	3/198 (1.52%)	1/37 (2.70%)
Septic shock † 1	1/197 (0.51%)	2/198 (1.01%)	0/37 (0.00%)
Skin infection † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Subcutaneous abscess † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Urinary tract infection † 1	2/197 (1.02%)	6/198 (3.03%)	1/37 (2.70%)
Urosepsis † 1	1/197 (0.51%)	3/198 (1.52%)	0/37 (0.00%)
Appendicitis perforated † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Cystitis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Urinary bladder abscess † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Appendicitis † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Wound infection † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Device related infection † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Osteomyelitis † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Postoperative wound infection † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Injury, poisoning and procedural complications
Fall † 1	5/197 (2.54%)	0/198 (0.00%)	1/37 (2.70%)
Head injury † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Hip fracture † 1	2/197 (1.02%)	1/198 (0.51%)	1/37 (2.70%)
Injury † 1	0/197 (0.00%)	2/198 (1.01%)	0/37 (0.00%)
Overdose † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Pubis fracture † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Rib fracture † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Spinal compression fracture † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Subdural haematoma † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Craniocerebral injury † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Femoral neck fracture † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Urinary bladder rupture † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Alcohol poisoning † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Cystitis radiation † 1	0/197 (0.00%)	0/198 (0.00%)	2/37 (5.41%)
Radius fracture † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Ulna fracture † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Femur fracture † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Investigations
Alanine aminotransferase increased † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Aspartate aminotransferase increased † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Liver function test abnormal † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
International normalised ratio increased † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Troponin increased † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Metabolism and nutrition disorders
Decreased appetite † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Dehydration † 1	2/197 (1.02%)	1/198 (0.51%)	1/37 (2.70%)
Diabetic ketoacidosis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Gout † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Hypercalcaemia † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Hyperglycaemia † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Hypoglycaemia † 1	0/197 (0.00%)	1/198 (0.51%)	1/37 (2.70%)
Hypokalaemia † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Hypovolaemia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Malnutrition † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Back pain † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Intervertebral disc displacement † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Lumbar spinal stenosis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Muscular weakness † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Musculoskeletal pain † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Osteoarthritis † 1	1/197 (0.51%)	0/198 (0.00%)	1/37 (2.70%)
Pathological fracture † 1	1/197 (0.51%)	2/198 (1.01%)	0/37 (0.00%)
Spinal column stenosis † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Spondylolisthesis † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Bladder transitional cell carcinoma † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Cancer pain † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Colon cancer † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Colon cancer metastatic † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Erythroleukaemia † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Intraductal papillary mucinous neoplasm † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Metastases to adrenals † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Metastases to liver † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Metastases to spine † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Metastatic pain † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Myelofibrosis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Pancreatic carcinoma † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Prostate cancer metastatic † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Renal cell carcinoma † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Squamous cell carcinoma of lung † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Squamous cell carcinoma of skin † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Transitional cell carcinoma † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Tumour necrosis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Basal cell carcinoma † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Bladder cancer † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Cholangiocarcinoma † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Small cell lung cancer † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Malignant melanoma † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Nervous system disorders
Amnesia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Carotid artery stenosis † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Cerebrovascular accident † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Cervical cord compression † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Convulsion † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Dizziness † 1	1/197 (0.51%)	0/198 (0.00%)	1/37 (2.70%)
Encephalopathy † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Headache † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Hemiparesis † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Hypoglycaemic encephalopathy † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Metabolic encephalopathy † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Presyncope † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Syncope † 1	3/197 (1.52%)	2/198 (1.01%)	1/37 (2.70%)
Transient ischaemic attack † 1	5/197 (2.54%)	1/198 (0.51%)	0/37 (0.00%)
Cognitive disorder † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Subarachnoid haemorrhage † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Dyskinesia † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Haemorrhage intracranial † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Haemorrhagic stroke † 1	0/197 (0.00%)	0/198 (0.00%)	2/37 (5.41%)
Hydrocephalus † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Psychiatric disorders
Delirium † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Mental status changes † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Suicide attempt † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Renal and urinary disorders
Bladder obstruction † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Bladder outlet obstruction † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Calculus bladder † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Dysuria † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Haematuria † 1	5/197 (2.54%)	4/198 (2.02%)	1/37 (2.70%)
Hydronephrosis † 1	4/197 (2.03%)	1/198 (0.51%)	0/37 (0.00%)
Nephrolithiasis † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Postrenal failure † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Renal failure † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Renal failure acute † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Urinary retention † 1	1/197 (0.51%)	2/198 (1.01%)	1/37 (2.70%)
Urinary tract obstruction † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Vesical fistula † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Cystitis haemorrhagic † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Obstructive uropathy † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Urethral stenosis † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Reproductive system and breast disorders
Prostatic calcification † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Respiratory, thoracic and mediastinal disorders
Asthma † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Chronic obstructive pulmonary disease † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Pleural effusion † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Pneumothorax † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Pulmonary embolism † 1	1/197 (0.51%)	2/198 (1.01%)	0/37 (0.00%)
Pulmonary oedema † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Respiratory failure † 1	0/197 (0.00%)	3/198 (1.52%)	0/37 (0.00%)
Acute respiratory failure † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Epistaxis † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Skin and subcutaneous tissue disorders
Dermatitis psoriasiform † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Rash maculo-papular † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Skin ulcer † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Surgical and medical procedures
Umbilical hernia repair † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Vascular disorders
Accelerated hypertension † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Aortic stenosis † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Deep vein thrombosis † 1	0/197 (0.00%)	3/198 (1.52%)	0/37 (0.00%)
Hypertension † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Hypotension † 1	2/197 (1.02%)	1/198 (0.51%)	0/37 (0.00%)
Peripheral artery thrombosis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Orthostatic hypotension † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (16.1)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Enzalutamide	DB Phase: Bicalutamide	Open Label Phase: Bicalutamide Crossover to Enzalutamide
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	187/197 (94.92%)	179/198 (90.40%)	36/37 (97.30%)
Blood and lymphatic system disorders
Haemorrhagic anaemia † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Increased tendency to bruise † 1	2/197 (1.02%)	0/198 (0.00%)	1/37 (2.70%)
Iron deficiency anaemia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Leukocytosis † 1	2/197 (1.02%)	1/198 (0.51%)	0/37 (0.00%)
Anaemia † 1	22/197 (11.17%)	21/198 (10.61%)	3/37 (8.11%)
Lymphadenitis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Lymphadenopathy † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Neutropenia † 1	3/197 (1.52%)	0/198 (0.00%)	0/37 (0.00%)
Pancytopenia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Thrombocytopenia † 1	1/197 (0.51%)	3/198 (1.52%)	0/37 (0.00%)
Cardiac disorders
Angina pectoris † 1	2/197 (1.02%)	1/198 (0.51%)	0/37 (0.00%)
Aortic valve disease † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Aortic valve stenosis * 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Arrhythmia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Arteriosclerosis coronary artery † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Atrial fibrillation † 1	4/197 (2.03%)	5/198 (2.53%)	3/37 (8.11%)
Atrial flutter † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Atrial thrombosis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Atrioventricular block second degree † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Bradycardia † 1	2/197 (1.02%)	2/198 (1.01%)	1/37 (2.70%)
Cardiac failure congestive † 1	4/197 (2.03%)	3/198 (1.52%)	2/37 (5.41%)
Cardiomegaly † 1	0/197 (0.00%)	1/198 (0.51%)	1/37 (2.70%)
Coronary artery disease † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Mitral valve incompetence † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Myocardial ischaemia † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Palpitations † 1	2/197 (1.02%)	1/198 (0.51%)	0/37 (0.00%)
Sick sinus syndrome † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Sinus bradycardia † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Sinus tachycardia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Supraventricular tachycardia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Tachycardia † 1	1/197 (0.51%)	3/198 (1.52%)	0/37 (0.00%)
Ventricular extrasystoles † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Ventricular tachycardia † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Cardiomyopathy † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Congenital, familial and genetic disorders
Branchial cyst † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Phimosis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Type V hyperlipidaemia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Ear and labyrinth disorders
Cerumen impaction † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Deafness † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Deafness bilateral † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Ear discomfort † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Ear haemorrhage † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Ear pain † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Hearing impaired † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Otorrhoea † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Tinnitus † 1	2/197 (1.02%)	1/198 (0.51%)	0/37 (0.00%)
Vertigo † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Vertigo positional † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Vestibular disorder † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Endocrine disorders
Hyperparathyroidism † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Hypothyroidism † 1	5/197 (2.54%)	1/198 (0.51%)	0/37 (0.00%)
Inappropriate antidiuretic hormone secretion † 1	0/197 (0.00%)	1/198 (0.51%)	1/37 (2.70%)
Thyroid cyst † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Eye disorders
Astigmatism † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Cataract † 1	4/197 (2.03%)	3/198 (1.52%)	1/37 (2.70%)
Cataract nuclear † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Conjunctivitis † 1	3/197 (1.52%)	0/198 (0.00%)	1/37 (2.70%)
Diabetic retinopathy † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Dry eye † 1	0/197 (0.00%)	1/198 (0.51%)	1/37 (2.70%)
Eye irritation † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Eye pain † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Eye pruritus † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Lacrimation increased † 1	3/197 (1.52%)	0/198 (0.00%)	0/37 (0.00%)
Macular degeneration † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Ocular hyperaemia † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Photophobia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Posterior capsule opacification † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Retinal tear † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Vision blurred † 1	4/197 (2.03%)	2/198 (1.01%)	0/37 (0.00%)
Visual impairment † 1	4/197 (2.03%)	0/198 (0.00%)	0/37 (0.00%)
Gastrointestinal disorders
Abdominal pain † 1	15/197 (7.61%)	6/198 (3.03%)	1/37 (2.70%)
Constipation † 1	29/197 (14.72%)	33/198 (16.67%)	6/37 (16.22%)
Diarrhoea † 1	26/197 (13.20%)	29/198 (14.65%)	9/37 (24.32%)
Nausea † 1	38/197 (19.29%)	32/198 (16.16%)	9/37 (24.32%)
Vomiting † 1	12/197 (6.09%)	17/198 (8.59%)	3/37 (8.11%)
Abdominal adhesions † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Abdominal discomfort † 1	4/197 (2.03%)	2/198 (1.01%)	0/37 (0.00%)
Abdominal distension † 1	4/197 (2.03%)	3/198 (1.52%)	0/37 (0.00%)
Abdominal hernia † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Abdominal pain lower † 1	3/197 (1.52%)	3/198 (1.52%)	0/37 (0.00%)
Abdominal pain upper † 1	3/197 (1.52%)	2/198 (1.01%)	0/37 (0.00%)
Abdominal tenderness † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Acquired oesophageal web † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Anal fissure † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Ascites † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Bowel movement irregularity † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Colitis † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Colitis ulcerative † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Defaecation urgency † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Diverticulum † 1	3/197 (1.52%)	2/198 (1.01%)	0/37 (0.00%)
Dry mouth † 1	3/197 (1.52%)	2/198 (1.01%)	0/37 (0.00%)
Duodenal ulcer † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Duodenitis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Dyspepsia † 1	6/197 (3.05%)	5/198 (2.53%)	1/37 (2.70%)
Dysphagia † 1	4/197 (2.03%)	4/198 (2.02%)	0/37 (0.00%)
Erosive oesophagitis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Faecal incontinence † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Faeces discoloured † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Flatulence † 1	9/197 (4.57%)	5/198 (2.53%)	0/37 (0.00%)
Frequent bowel movements † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Gastric haemorrhage † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Gastric ulcer † 1	4/197 (2.03%)	1/198 (0.51%)	0/37 (0.00%)
Gastritis † 1	8/197 (4.06%)	2/198 (1.01%)	0/37 (0.00%)
Gastritis haemorrhagic † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Gastrointestinal angiodysplasia † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Gastrointestinal disorder † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Gastrointestinal haemorrhage † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Gastrointestinal pain † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Gastrooesophageal reflux disease † 1	10/197 (5.08%)	2/198 (1.01%)	6/37 (16.22%)
Gingival swelling † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Haematochezia † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Haemorrhoids † 1	2/197 (1.02%)	2/198 (1.01%)	0/37 (0.00%)
Hiatus hernia † 1	2/197 (1.02%)	2/198 (1.01%)	0/37 (0.00%)
Ileus † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Impaired gastric emptying † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Large intestine polyp † 1	0/197 (0.00%)	2/198 (1.01%)	0/37 (0.00%)
Mesenteric artery stenosis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Mouth haemorrhage † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Oesophageal achalasia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Oesophageal dilatation † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Oesophageal disorder † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Oesophageal stenosis † 1	0/197 (0.00%)	2/198 (1.01%)	0/37 (0.00%)
Oesophagitis † 1	3/197 (1.52%)	0/198 (0.00%)	0/37 (0.00%)
Pancreatic atrophy † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Pancreatic cyst † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Rectal discharge † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Rectal haemorrhage † 1	3/197 (1.52%)	1/198 (0.51%)	1/37 (2.70%)
Rectal tenesmus † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Retching † 1	1/197 (0.51%)	1/198 (0.51%)	1/37 (2.70%)
Salivary hypersecretion † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Stomatitis † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Tongue discolouration † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Tongue ulceration † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Tooth loss † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Toothache † 1	3/197 (1.52%)	2/198 (1.01%)	0/37 (0.00%)
Umbilical hernia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
General disorders
Asthenia † 1	16/197 (8.12%)	5/198 (2.53%)	2/37 (5.41%)
Fatigue † 1	82/197 (41.62%)	56/198 (28.28%)	10/37 (27.03%)
Pyrexia † 1	5/197 (2.54%)	12/198 (6.06%)	1/37 (2.70%)
Chest discomfort † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Chest pain † 1	6/197 (3.05%)	2/198 (1.01%)	0/37 (0.00%)
Chills † 1	5/197 (2.54%)	2/198 (1.01%)	0/37 (0.00%)
Device dislocation † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Device occlusion † 1	0/197 (0.00%)	1/198 (0.51%)	1/37 (2.70%)
Discomfort † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Early satiety † 1	3/197 (1.52%)	1/198 (0.51%)	0/37 (0.00%)
Face oedema † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Gait disturbance † 1	6/197 (3.05%)	1/198 (0.51%)	1/37 (2.70%)
Generalised oedema † 1	0/197 (0.00%)	3/198 (1.52%)	0/37 (0.00%)
Inflammation † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Influenza like illness † 1	5/197 (2.54%)	5/198 (2.53%)	0/37 (0.00%)
Injection site reaction † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Local swelling † 1	4/197 (2.03%)	1/198 (0.51%)	0/37 (0.00%)
Localised oedema † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Malaise † 1	1/197 (0.51%)	2/198 (1.01%)	0/37 (0.00%)
Mucosal inflammation † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Oedema † 1	2/197 (1.02%)	1/198 (0.51%)	0/37 (0.00%)
Oedema peripheral † 1	17/197 (8.63%)	10/198 (5.05%)	1/37 (2.70%)
Pain † 1	7/197 (3.55%)	5/198 (2.53%)	0/37 (0.00%)
Suprapubic pain † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Temperature intolerance † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Thirst † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Non-cardiac chest pain † 1	2/197 (1.02%)	5/198 (2.53%)	0/37 (0.00%)
Hepatobiliary disorders
Cholangitis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Cholelithiasis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Gallbladder disorder † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Hepatic cirrhosis † 1	0/197 (0.00%)	2/198 (1.01%)	0/37 (0.00%)
Hyperbilirubinaemia † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Liver injury † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Immune system disorders
Drug hypersensitivity † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Seasonal allergy † 1	2/197 (1.02%)	1/198 (0.51%)	0/37 (0.00%)
Infections and infestations
Abscess limb † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Abscess soft tissue † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Acute sinusitis † 1	2/197 (1.02%)	0/198 (0.00%)	1/37 (2.70%)
Appendicitis † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Asymptomatic bacteriuria † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Axillary candidiasis † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Bacteraemia † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Bacterial disease carrier † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Bacteriuria † 1	0/197 (0.00%)	1/198 (0.51%)	1/37 (2.70%)
Bronchitis † 1	7/197 (3.55%)	1/198 (0.51%)	0/37 (0.00%)
Candida infection † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Cellulitis † 1	5/197 (2.54%)	1/198 (0.51%)	0/37 (0.00%)
Chronic sinusitis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Cystitis † 1	1/197 (0.51%)	0/198 (0.00%)	1/37 (2.70%)
Diverticulitis † 1	3/197 (1.52%)	0/198 (0.00%)	0/37 (0.00%)
Ear infection † 1	1/197 (0.51%)	2/198 (1.01%)	0/37 (0.00%)
Fungal infection † 1	1/197 (0.51%)	0/198 (0.00%)	1/37 (2.70%)
Furuncle † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Gastroenteritis viral † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Genital infection fungal † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Gingival infection † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Gingivitis † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Helicobacter infection † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Hepatitis B † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Herpes zoster † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Hordeolum † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Incision site infection † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Infected cyst † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Influenza † 1	5/197 (2.54%)	1/198 (0.51%)	0/37 (0.00%)
Kidney infection † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Klebsiella bacteraemia † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Lobar pneumonia † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Mucosal infection † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Nasopharyngitis † 1	8/197 (4.06%)	11/198 (5.56%)	0/37 (0.00%)
Onychomycosis † 1	2/197 (1.02%)	1/198 (0.51%)	0/37 (0.00%)
Oral candidiasis † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Oral herpes † 1	0/197 (0.00%)	1/198 (0.51%)	1/37 (2.70%)
Oropharyngitis fungal † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Otitis externa † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Otitis media † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Peripheral nerve infection † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Peritonitis † 1	1/197 (0.51%)	0/198 (0.00%)	1/37 (2.70%)
Pharyngitis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Pneumonia † 1	5/197 (2.54%)	6/198 (3.03%)	1/37 (2.70%)
Postoperative wound infection † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Respiratory tract infection † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Rhinitis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Sinusitis † 1	6/197 (3.05%)	5/198 (2.53%)	0/37 (0.00%)
Skin infection † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Tinea infection † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Tinea pedis † 1	4/197 (2.03%)	0/198 (0.00%)	0/37 (0.00%)
Tooth abscess † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Tooth infection † 1	1/197 (0.51%)	2/198 (1.01%)	0/37 (0.00%)
Upper respiratory tract infection † 1	8/197 (4.06%)	8/198 (4.04%)	0/37 (0.00%)
Urinary bladder abscess † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Urinary tract infection † 1	14/197 (7.11%)	21/198 (10.61%)	7/37 (18.92%)
Viral upper respiratory tract infection † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Wound infection † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Wound infection staphylococcal † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Injury, poisoning and procedural complications
Alcohol poisoning † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Ankle fracture † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Clavicle fracture † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Compression fracture † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Contrast media reaction † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Contusion † 1	5/197 (2.54%)	1/198 (0.51%)	0/37 (0.00%)
Cystitis radiation † 1	1/197 (0.51%)	1/198 (0.51%)	1/37 (2.70%)
Eschar † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Excoriation † 1	3/197 (1.52%)	1/198 (0.51%)	0/37 (0.00%)
Facial bones fracture † 1	1/197 (0.51%)	2/198 (1.01%)	0/37 (0.00%)
Fall † 1	39/197 (19.80%)	19/198 (9.60%)	8/37 (21.62%)
Femoral neck fracture † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Fibula fracture † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Foot fracture † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Fracture † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Fractured coccyx † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Hand fracture † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Head injury † 1	2/197 (1.02%)	1/198 (0.51%)	0/37 (0.00%)
Humerus fracture † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Incision site pain † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Joint injury † 1	1/197 (0.51%)	2/198 (1.01%)	0/37 (0.00%)
Laceration † 1	10/197 (5.08%)	3/198 (1.52%)	0/37 (0.00%)
Limb injury † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Lumbar vertebral fracture † 1	0/197 (0.00%)	1/198 (0.51%)	1/37 (2.70%)
Meniscus injury † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Muscle strain † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Procedural pain † 1	1/197 (0.51%)	4/198 (2.02%)	2/37 (5.41%)
Radiation injury † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Radiation pneumonitis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Radius fracture † 1	4/197 (2.03%)	0/198 (0.00%)	0/37 (0.00%)
Rib fracture † 1	7/197 (3.55%)	6/198 (3.03%)	0/37 (0.00%)
Skeletal injury † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Spinal column injury † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Spinal compression fracture † 1	4/197 (2.03%)	1/198 (0.51%)	0/37 (0.00%)
Splinter † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Stress fracture † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Thoracic vertebral fracture † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Vth nerve injury † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Wound † 1	2/197 (1.02%)	1/198 (0.51%)	0/37 (0.00%)
Bone contusion † 1	3/197 (1.52%)	0/198 (0.00%)	0/37 (0.00%)
Investigations
Alanine aminotransferase increased † 1	1/197 (0.51%)	3/198 (1.52%)	0/37 (0.00%)
Aspartate aminotransferase increased † 1	1/197 (0.51%)	5/198 (2.53%)	0/37 (0.00%)
Blood albumin decreased † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Blood alkaline phosphatase increased † 1	5/197 (2.54%)	11/198 (5.56%)	0/37 (0.00%)
Blood bicarbonate decreased † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Blood bilirubin increased † 1	3/197 (1.52%)	1/198 (0.51%)	0/37 (0.00%)
Blood calcium increased † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Blood cholesterol increased † 1	2/197 (1.02%)	2/198 (1.01%)	0/37 (0.00%)
Blood creatine phosphokinase increased † 1	6/197 (3.05%)	7/198 (3.54%)	0/37 (0.00%)
Blood creatinine increased † 1	5/197 (2.54%)	7/198 (3.54%)	1/37 (2.70%)
Blood glucose increased † 1	0/197 (0.00%)	3/198 (1.52%)	1/37 (2.70%)
Blood lactate dehydrogenase increased † 1	1/197 (0.51%)	4/198 (2.02%)	0/37 (0.00%)
Blood lactic acid increased † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Blood parathyroid hormone increased † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Blood potassium increased † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Blood pressure increased † 1	3/197 (1.52%)	1/198 (0.51%)	2/37 (5.41%)
Blood sodium decreased † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Blood urine present † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Cardiac murmur † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Face and mouth X-ray abnormal † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Haemoglobin decreased † 1	0/197 (0.00%)	4/198 (2.02%)	1/37 (2.70%)
Helicobacter test positive † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
International normalised ratio fluctuation † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
International normalised ratio increased † 1	1/197 (0.51%)	2/198 (1.01%)	0/37 (0.00%)
Intraocular pressure increased † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Low density lipoprotein increased † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Lymphocyte count decreased † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Lymphocyte count increased † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Neutrophil count decreased † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Neutrophil count increased † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Occult blood positive † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Platelet count decreased † 1	4/197 (2.03%)	0/198 (0.00%)	0/37 (0.00%)
Protein total decreased † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Protein total increased † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Red blood cell count decreased † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Residual urine volume increased † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Urine ketone body present † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Urine leukocyte esterase positive † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Vitamin D increased † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Weight decreased † 1	16/197 (8.12%)	13/198 (6.57%)	3/37 (8.11%)
Weight increased † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
White blood cell count decreased † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
White blood cell count increased † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Haematocrit decreased † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Blood urea increased † 1	1/197 (0.51%)	2/198 (1.01%)	0/37 (0.00%)
Hepatic enzyme increased † 1	1/197 (0.51%)	0/198 (0.00%)	1/37 (2.70%)
Metabolism and nutrition disorders
Acidosis † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Decreased appetite † 1	28/197 (14.21%)	17/198 (8.59%)	6/37 (16.22%)
Dehydration † 1	13/197 (6.60%)	6/198 (3.03%)	1/37 (2.70%)
Diabetes mellitus † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Diabetes mellitus inadequate control † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Failure to thrive † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Gout † 1	3/197 (1.52%)	3/198 (1.52%)	0/37 (0.00%)
Hypercalcaemia † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Hyperchloraemia † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Hypercholesterolaemia † 1	5/197 (2.54%)	1/198 (0.51%)	3/37 (8.11%)
Hyperglycaemia † 1	11/197 (5.58%)	14/198 (7.07%)	2/37 (5.41%)
Hyperkalaemia † 1	6/197 (3.05%)	4/198 (2.02%)	0/37 (0.00%)
Hyperlipidaemia † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Hypermagnesaemia † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Hypernatraemia † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Hypoalbuminaemia † 1	3/197 (1.52%)	4/198 (2.02%)	0/37 (0.00%)
Hypocalcaemia † 1	3/197 (1.52%)	4/198 (2.02%)	1/37 (2.70%)
Hypoglycaemia † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Hypokalaemia † 1	13/197 (6.60%)	11/198 (5.56%)	2/37 (5.41%)
Hypomagnesaemia † 1	4/197 (2.03%)	4/198 (2.02%)	1/37 (2.70%)
Hyponatraemia † 1	10/197 (5.08%)	4/198 (2.02%)	2/37 (5.41%)
Hypophosphataemia † 1	1/197 (0.51%)	2/198 (1.01%)	0/37 (0.00%)
Increased appetite † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Insulin resistance † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Iron deficiency † 1	1/197 (0.51%)	0/198 (0.00%)	1/37 (2.70%)
Lactic acidosis † 1	1/197 (0.51%)	1/198 (0.51%)	1/37 (2.70%)
Malnutrition † 1	0/197 (0.00%)	2/198 (1.01%)	1/37 (2.70%)
Metabolic acidosis † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Polydipsia † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Type 1 diabetes mellitus † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Type 2 diabetes mellitus † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Vitamin B complex deficiency † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Vitamin B12 deficiency † 1	3/197 (1.52%)	0/198 (0.00%)	1/37 (2.70%)
Vitamin D deficiency † 1	1/197 (0.51%)	0/198 (0.00%)	1/37 (2.70%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	45/197 (22.84%)	29/198 (14.65%)	5/37 (13.51%)
Back pain † 1	41/197 (20.81%)	34/198 (17.17%)	3/37 (8.11%)
Muscular weakness † 1	13/197 (6.60%)	6/198 (3.03%)	1/37 (2.70%)
Musculoskeletal pain † 1	16/197 (8.12%)	11/198 (5.56%)	2/37 (5.41%)
Pain in extremity † 1	23/197 (11.68%)	10/198 (5.05%)	1/37 (2.70%)
Bone pain † 1	6/197 (3.05%)	2/198 (1.01%)	2/37 (5.41%)
Bunion † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Bursitis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Cervical spinal stenosis † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Coccydynia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Costochondritis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Exostosis † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Flank pain † 1	3/197 (1.52%)	5/198 (2.53%)	1/37 (2.70%)
Foot deformity † 1	2/197 (1.02%)	1/198 (0.51%)	0/37 (0.00%)
Groin pain † 1	6/197 (3.05%)	4/198 (2.02%)	0/37 (0.00%)
Intervertebral disc compression † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Intervertebral disc degeneration † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Joint crepitation † 1	0/197 (0.00%)	2/198 (1.01%)	1/37 (2.70%)
Joint instability † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Joint stiffness † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Joint swelling † 1	0/197 (0.00%)	2/198 (1.01%)	0/37 (0.00%)
Limb discomfort † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Lumbar spinal stenosis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Mobility decreased † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Muscle atrophy † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Muscle haemorrhage † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Muscle spasms † 1	7/197 (3.55%)	6/198 (3.03%)	1/37 (2.70%)
Muscle tightness † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Muscle twitching † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Musculoskeletal chest pain † 1	13/197 (6.60%)	4/198 (2.02%)	2/37 (5.41%)
Musculoskeletal discomfort † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Musculoskeletal disorder † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Musculoskeletal stiffness † 1	3/197 (1.52%)	0/198 (0.00%)	0/37 (0.00%)
Myalgia † 1	10/197 (5.08%)	5/198 (2.53%)	1/37 (2.70%)
Neck pain † 1	5/197 (2.54%)	4/198 (2.02%)	2/37 (5.41%)
Osteoarthritis † 1	7/197 (3.55%)	1/198 (0.51%)	0/37 (0.00%)
Osteolysis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Osteopenia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Osteoporosis † 1	3/197 (1.52%)	0/198 (0.00%)	0/37 (0.00%)
Pain in jaw † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Pathological fracture † 1	0/197 (0.00%)	1/198 (0.51%)	1/37 (2.70%)
Plantar fasciitis † 1	3/197 (1.52%)	0/198 (0.00%)	0/37 (0.00%)
Psoriatic arthropathy † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Rotator cuff syndrome † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Scoliosis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Spinal column stenosis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Spinal disorder † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Spinal osteoarthritis † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Spinal pain † 1	1/197 (0.51%)	0/198 (0.00%)	1/37 (2.70%)
Spondylitis † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Spondylolisthesis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Tendon disorder † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Tendon pain † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Tendonitis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Trigger finger † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Vertebral foraminal stenosis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Arthritis † 1	3/197 (1.52%)	4/198 (2.02%)	1/37 (2.70%)
Inguinal mass † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign salivary gland neoplasm † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Bladder neoplasm † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Cancer pain † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Colon adenoma † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Colon cancer † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Basal cell carcinoma † 1	5/197 (2.54%)	1/198 (0.51%)	0/37 (0.00%)
Lipoma † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Lung adenocarcinoma † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Metastases to bone † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Plasma cell myeloma † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Renal oncocytoma † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Seborrhoeic keratosis † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Skin papilloma † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Small cell lung cancer † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Squamous cell carcinoma of skin † 1	2/197 (1.02%)	2/198 (1.01%)	0/37 (0.00%)
Thyroid neoplasm † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Tumour pain † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Nervous system disorders
Dizziness † 1	26/197 (13.20%)	15/198 (7.58%)	6/37 (16.22%)
Headache † 1	14/197 (7.11%)	15/198 (7.58%)	1/37 (2.70%)
Altered state of consciousness † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Amnesia † 1	7/197 (3.55%)	0/198 (0.00%)	3/37 (8.11%)
Aphasia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Ataxia † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Balance disorder † 1	3/197 (1.52%)	1/198 (0.51%)	2/37 (5.41%)
Carotid artery occlusion † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Carpal tunnel syndrome † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Cerebellar infarction † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Cerebrovascular accident † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Cervical radiculopathy † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Cognitive disorder † 1	2/197 (1.02%)	0/198 (0.00%)	1/37 (2.70%)
Dementia † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Depressed level of consciousness † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Diabetic neuropathy † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Disturbance in attention † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Dysaesthesia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Dysarthria † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Dysgeusia † 1	8/197 (4.06%)	3/198 (1.52%)	1/37 (2.70%)
Encephalopathy † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Essential tremor † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Hemiparesis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Hypersomnia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Hypoaesthesia † 1	4/197 (2.03%)	3/198 (1.52%)	0/37 (0.00%)
Hypogeusia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Hyposmia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Lethargy † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Memory impairment † 1	8/197 (4.06%)	3/198 (1.52%)	0/37 (0.00%)
Migraine † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Neuropathy peripheral † 1	7/197 (3.55%)	0/198 (0.00%)	2/37 (5.41%)
Paraesthesia † 1	8/197 (4.06%)	4/198 (2.02%)	0/37 (0.00%)
Parkinson's disease † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Parosmia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Peripheral sensory neuropathy † 1	2/197 (1.02%)	0/198 (0.00%)	1/37 (2.70%)
Peroneal nerve palsy † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Presyncope † 1	5/197 (2.54%)	1/198 (0.51%)	0/37 (0.00%)
Restless legs syndrome † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Sciatica † 1	3/197 (1.52%)	2/198 (1.01%)	0/37 (0.00%)
Transient ischaemic attack † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Tremor † 1	3/197 (1.52%)	1/198 (0.51%)	0/37 (0.00%)
VIIth nerve paralysis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Visual field defect † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Vocal cord paralysis † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Muscle spasticity † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Periodic limb movement disorder † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Post-traumatic headache † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Syncope † 1	7/197 (3.55%)	3/198 (1.52%)	1/37 (2.70%)
Psychiatric disorders
Anxiety † 1	13/197 (6.60%)	3/198 (1.52%)	0/37 (0.00%)
Depression † 1	15/197 (7.61%)	8/198 (4.04%)	2/37 (5.41%)
Insomnia † 1	22/197 (11.17%)	9/198 (4.55%)	2/37 (5.41%)
Abnormal dreams † 1	2/197 (1.02%)	1/198 (0.51%)	0/37 (0.00%)
Agitation † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Alcoholism † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Apathy † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Confusional state † 1	6/197 (3.05%)	2/198 (1.01%)	0/37 (0.00%)
Delirium † 1	1/197 (0.51%)	2/198 (1.01%)	0/37 (0.00%)
Depressed mood † 1	0/197 (0.00%)	2/198 (1.01%)	0/37 (0.00%)
Disorientation † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Emotional distress † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Hallucination † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Libido decreased † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Mental status changes † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Mood altered † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Mood swings † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Nervousness † 1	3/197 (1.52%)	0/198 (0.00%)	0/37 (0.00%)
Personality change † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Restlessness † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Sleep disorder † 1	3/197 (1.52%)	0/198 (0.00%)	0/37 (0.00%)
Sleep terror † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Suicidal ideation † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Renal and urinary disorders
Haematuria † 1	16/197 (8.12%)	13/198 (6.57%)	3/37 (8.11%)
Renal failure acute † 1	7/197 (3.55%)	12/198 (6.06%)	1/37 (2.70%)
Bladder neck obstruction † 1	1/197 (0.51%)	0/198 (0.00%)	1/37 (2.70%)
Bladder outlet obstruction † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Bladder spasm † 1	1/197 (0.51%)	3/198 (1.52%)	0/37 (0.00%)
Calculus bladder † 1	2/197 (1.02%)	1/198 (0.51%)	0/37 (0.00%)
Chromaturia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Cystitis noninfective † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Dysuria † 1	2/197 (1.02%)	7/198 (3.54%)	0/37 (0.00%)
Enuresis † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Haemorrhage urinary tract † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Hydronephrosis † 1	6/197 (3.05%)	8/198 (4.04%)	1/37 (2.70%)
Hypertonic bladder † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Incontinence † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Microalbuminuria † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Micturition urgency † 1	9/197 (4.57%)	1/198 (0.51%)	0/37 (0.00%)
Nephrolithiasis † 1	3/197 (1.52%)	1/198 (0.51%)	0/37 (0.00%)
Nocturia † 1	3/197 (1.52%)	4/198 (2.02%)	2/37 (5.41%)
Oliguria † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Pneumaturia † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Pollakiuria † 1	11/197 (5.58%)	7/198 (3.54%)	0/37 (0.00%)
Proteinuria † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Pyuria † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Renal cyst † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Renal failure † 1	1/197 (0.51%)	3/198 (1.52%)	0/37 (0.00%)
Renal failure chronic † 1	3/197 (1.52%)	1/198 (0.51%)	1/37 (2.70%)
Renal impairment † 1	0/197 (0.00%)	2/198 (1.01%)	0/37 (0.00%)
Renal pain † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Stress urinary incontinence † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Urethral haemorrhage † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Urethral stenosis † 1	0/197 (0.00%)	2/198 (1.01%)	0/37 (0.00%)
Urethritis noninfective † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Urge incontinence † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Urinary hesitation † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Urinary incontinence † 1	10/197 (5.08%)	8/198 (4.04%)	1/37 (2.70%)
Urinary retention † 1	5/197 (2.54%)	7/198 (3.54%)	0/37 (0.00%)
Urinary tract obstruction † 1	3/197 (1.52%)	3/198 (1.52%)	0/37 (0.00%)
Urine flow decreased † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Reproductive system and breast disorders
Balanoposthitis † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Benign prostatic hyperplasia † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Breast pain † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Breast tenderness † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Erectile dysfunction † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Genital discomfort † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Genital lesion † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Genital rash † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Gynaecomastia † 1	2/197 (1.02%)	2/198 (1.01%)	0/37 (0.00%)
Nipple pain † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Pelvic pain † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Penile oedema † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Penile swelling † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Priapism † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Prostatic pain † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Prostatitis † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Prostatomegaly † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Scrotal swelling † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Testicular pain † 1	4/197 (2.03%)	0/198 (0.00%)	0/37 (0.00%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea † 1	19/197 (9.64%)	12/198 (6.06%)	1/37 (2.70%)
Acute respiratory failure † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Alveolar lung disease † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Aspiration † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Atelectasis † 1	1/197 (0.51%)	2/198 (1.01%)	1/37 (2.70%)
Chronic obstructive pulmonary disease † 1	2/197 (1.02%)	1/198 (0.51%)	0/37 (0.00%)
Cough † 1	14/197 (7.11%)	9/198 (4.55%)	1/37 (2.70%)
Dysphonia † 1	5/197 (2.54%)	0/198 (0.00%)	0/37 (0.00%)
Dyspnoea exertional † 1	5/197 (2.54%)	2/198 (1.01%)	0/37 (0.00%)
Dyspnoea paroxysmal nocturnal † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Emphysema † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Epistaxis † 1	3/197 (1.52%)	1/198 (0.51%)	0/37 (0.00%)
Hiccups † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Hypoxia † 1	0/197 (0.00%)	2/198 (1.01%)	0/37 (0.00%)
Increased upper airway secretion † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Nasal congestion † 1	4/197 (2.03%)	3/198 (1.52%)	0/37 (0.00%)
Nasal dryness † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Oropharyngeal pain † 1	6/197 (3.05%)	1/198 (0.51%)	0/37 (0.00%)
Pleural effusion † 1	2/197 (1.02%)	2/198 (1.01%)	0/37 (0.00%)
Pneumonia aspiration † 1	0/197 (0.00%)	2/198 (1.01%)	0/37 (0.00%)
Pneumothorax † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Productive cough † 1	5/197 (2.54%)	2/198 (1.01%)	0/37 (0.00%)
Pulmonary fibrosis † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Pulmonary hypertension † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Pulmonary vascular disorder † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Rales † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Respiratory disorder † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Respiratory failure † 1	0/197 (0.00%)	2/198 (1.01%)	0/37 (0.00%)
Respiratory tract congestion † 1	2/197 (1.02%)	1/198 (0.51%)	0/37 (0.00%)
Rhinitis allergic † 1	2/197 (1.02%)	1/198 (0.51%)	0/37 (0.00%)
Rhinorrhoea † 1	3/197 (1.52%)	1/198 (0.51%)	0/37 (0.00%)
Rhonchi † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Sinus congestion † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Sinus disorder † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Sleep apnoea syndrome † 1	5/197 (2.54%)	0/198 (0.00%)	0/37 (0.00%)
Throat irritation † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Upper-airway cough syndrome † 1	4/197 (2.03%)	0/198 (0.00%)	0/37 (0.00%)
Wheezing † 1	2/197 (1.02%)	2/198 (1.01%)	0/37 (0.00%)
Skin and subcutaneous tissue disorders
Rash † 1	12/197 (6.09%)	9/198 (4.55%)	3/37 (8.11%)
Actinic keratosis † 1	3/197 (1.52%)	2/198 (1.01%)	0/37 (0.00%)
Alopecia † 1	4/197 (2.03%)	2/198 (1.01%)	0/37 (0.00%)
Blister † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Decubitus ulcer † 1	0/197 (0.00%)	2/198 (1.01%)	0/37 (0.00%)
Dermatitis allergic † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Dermatitis contact † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Diabetic foot † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Dry skin † 1	5/197 (2.54%)	3/198 (1.52%)	0/37 (0.00%)
Ecchymosis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Eczema † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Erythema † 1	3/197 (1.52%)	1/198 (0.51%)	0/37 (0.00%)
Hair growth abnormal † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Hyperhidrosis † 1	7/197 (3.55%)	2/198 (1.01%)	0/37 (0.00%)
Hyperkeratosis † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Ingrowing nail † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Lentigo † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Night sweats † 1	1/197 (0.51%)	2/198 (1.01%)	0/37 (0.00%)
Pain of skin † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Photodermatosis † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Pigmentation disorder † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Pruritus † 1	5/197 (2.54%)	3/198 (1.52%)	1/37 (2.70%)
Psoriasis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Rash generalised † 1	0/197 (0.00%)	0/198 (0.00%)	1/37 (2.70%)
Rash macular † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Rash maculo-papular † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Rash pruritic † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Skin discolouration † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Skin disorder † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Skin hypopigmentation † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Skin lesion † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Skin ulcer † 1	2/197 (1.02%)	1/198 (0.51%)	1/37 (2.70%)
Swelling face † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Surgical and medical procedures
Cataract operation † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Skin neoplasm excision † 1	0/197 (0.00%)	1/198 (0.51%)	1/37 (2.70%)
Vascular disorders
Hot flush † 1	34/197 (17.26%)	20/198 (10.10%)	2/37 (5.41%)
Hypertension † 1	25/197 (12.69%)	10/198 (5.05%)	5/37 (13.51%)
Accelerated hypertension † 1	1/197 (0.51%)	1/198 (0.51%)	0/37 (0.00%)
Aortic arteriosclerosis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Arteriovenous fistula † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Blood pressure inadequately controlled † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Deep vein thrombosis † 1	3/197 (1.52%)	1/198 (0.51%)	1/37 (2.70%)
Flushing † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Haematoma † 1	1/197 (0.51%)	1/198 (0.51%)	1/37 (2.70%)
Hypotension † 1	4/197 (2.03%)	5/198 (2.53%)	4/37 (10.81%)
Intermittent claudication † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Jugular vein thrombosis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Orthostatic hypotension † 1	2/197 (1.02%)	2/198 (1.01%)	1/37 (2.70%)
Peripheral arterial occlusive disease † 1	2/197 (1.02%)	0/198 (0.00%)	0/37 (0.00%)
Peripheral artery stenosis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Peripheral coldness † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Peripheral ischaemia † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Peripheral vascular disorder † 1	1/197 (0.51%)	2/198 (1.01%)	0/37 (0.00%)
Thrombophlebitis superficial † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Thrombosis † 1	1/197 (0.51%)	0/198 (0.00%)	0/37 (0.00%)
Varicose vein † 1	0/197 (0.00%)	1/198 (0.51%)	0/37 (0.00%)
Aortic aneurysm † 1	1/197 (0.51%)	0/198 (0.00%)	1/37 (2.70%)
† Indicates events were collected by systematic assessment; * Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (16.1)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

PI agrees not to independently publish the results before the publication of the multi-center PI paper. Sponsor shall review and comment 30 days prior to submission or disclosure. If publication or disclosure contains Sponsor Confidential Information, other than study data, PI agrees to remove Confidential Information from publication or disclosure. Sponsor may request that PI delay such publication for an additional 60 days to protect the patentability of any invention described.

Results Point of Contact

• Name/Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer Inc.
• Phone: 1-800-718-1021
• EMail: ClinicalTrials.gov_Inquiries@pfizer.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Penson DF, Armstrong AJ, Concepcion RS, Agarwal N, Olsson CA, Karsh LI, Dunshee CJ, Duggan W, Shen Q, Sugg J, Haas GP, Higano CS. Enzalutamide versus bicalutamide in patients with nonmetastatic castration-resistant prostate cancer: a prespecified subgroup analysis of the STRIVE trial. Prostate Cancer Prostatic Dis. 2022 Feb;25(2):363-365. doi: 10.1038/s41391-021-00465-7. Epub 2021 Oct 7. Erratum In: Prostate Cancer Prostatic Dis. 2021 Nov 30;:

Penson DF, Armstrong AJ, Concepcion R, Agarwal N, Olsson C, Karsh L, Dunshee C, Wang F, Wu K, Krivoshik A, Phung D, Higano CS. Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial. J Clin Oncol. 2016 Jun 20;34(18):2098-106. doi: 10.1200/JCO.2015.64.9285. Epub 2016 Jan 25.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01664923
• Other Study ID Numbers: MDV3100-09; C3431014 ( Other Identifier: Alias Study Number )
• First Submitted: August 10, 2012
• First Posted: August 14, 2012
• Results First Submitted: February 22, 2016
• Results First Posted: May 23, 2016
• Last Update Posted: January 30, 2019