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A Phase 1 Study of MDV3100 in Patients With Castration-Resistant (Hormone-Refractory) Prostate Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00510718
Recruitment Status : Completed
First Posted : August 2, 2007
Results First Posted : October 3, 2019
Last Update Posted : October 3, 2019
Sponsor:
Collaborators:
Astellas Pharma Inc
Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
Information provided by (Responsible Party):
Pfizer

Study Type Interventional
Study Design Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Prostate Cancer
Hormone Refractory Prostate Cancer
Intervention Drug: MDV3100
Enrollment 140
Recruitment Details  
Pre-assignment Details  
Arm/Group Title MDV3100 (Enzalutamide): No Previous Chemotherapy MDV3100 (Enzalutamide): Post Chemotherapy
Hide Arm/Group Description Participants with no prior exposure to chemotherapy received single oral dose of MDV3100 in 1 out of the 7 cohorts of 30, 60, 150, 240, 360, 480 or 600 milligram per day (mg/day) dose on Day 1 and were followed up for 6 days in single dose (dose escalation) period. Dose escalation from 30 to 600 mg/day continued until the maximum tolerated dose (MTD) was determined or until a dose of 600 mg/day was evaluated. After dose-escalation, the cohorts receiving 60-600 mg/day dose were expanded in multiple dose (dose expansion) period, where participants received MDV3100 according to their dose in single dose period for 84 days. This was followed by long-term dosing period in which participants continued to receive 160 mg/day dose of MDV3100 until withdrew of consent, dose limiting toxicity (DLT) or disease progression occurred. Participants were followed up for 30 days after last dose of study drug for safety follow up. Participants with prior exposure to chemotherapy single oral dose of MDV3100 in 1 out of the 7 cohorts of 30, 60, 150, 240, 360, 480 or 600 mg/day dose on Day 1 and were followed up for 6 days in single dose (dose escalation) period. Dose escalation from 30 to 600 mg/day continued until the MTD was determined or until a dose of 600 mg/day was evaluated. After dose-escalation, the cohorts receiving 60-600 mg/day dose were expanded in multiple dose (dose expansion) period, where participants received MDV3100 according to their dose in single dose period, for 84 days. This was followed by long-term dosing period in which participants continued to receive 160 mg/day dose of MDV3100 until withdrew of consent, DLT or disease progression occurred. Participants were followed up for 30 days after last dose.
Period Title: Single Dose Period: 1 Week
Started 15 12
30 mg/Day 3 0
60 mg/Day 3 0
150/160 mg/Day 2 1
240 mg/Day 3 0
360 mg/Day 4 2
480 mg/Day 0 6
600 mg/Day 0 3
Completed 15 12
Not Completed 0 0
Period Title: Multiple Dose Period: 12 Weeks
Started 65 [1] 75 [1]
30 mg/Day 3 0
60 mg/Day 15 12
150/160 mg/Day 15 13
240 mg/Day 17 12
360 mg/Day 15 13
480 mg/Day 0 22
600 mg/Day 0 3
Completed 50 43
Not Completed 15 32
Reason Not Completed
Adverse Event             1             8
PSA Disease Progression             3             6
Radiologic Disease Progression             8             11
Clinical Disease Progression             1             3
Withdrawal by Subject             1             3
Other             1             1
[1]
Participants who completed single dose period + new participants enrolled in multiple dose period.
Arm/Group Title MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day Total
Hide Arm/Group Description Participants received 30 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days. Participants received 60 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days. Participants who received 150 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period. This dose was then changed subsequently to 160 mg/day according to Protocol amendment. Participants continued to receive the same dose in multiple dose period for 84 days. Participants received 240 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days. Participants received 360 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days. Participants received 480 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days. Participants received 600 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days. Total of all reporting groups
Overall Number of Baseline Participants 3 27 28 29 28 22 3 140
Hide Baseline Analysis Population Description
Safety population included all enrolled participants who received at least 1 dose of study drug.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 27 participants 28 participants 29 participants 28 participants 22 participants 3 participants 140 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
1
  33.3%
15
  55.6%
10
  35.7%
8
  27.6%
10
  35.7%
7
  31.8%
3
 100.0%
54
  38.6%
>=65 years
2
  66.7%
12
  44.4%
18
  64.3%
21
  72.4%
18
  64.3%
15
  68.2%
0
   0.0%
86
  61.4%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 27 participants 28 participants 29 participants 28 participants 22 participants 3 participants 140 participants
Female
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Male
3
 100.0%
27
 100.0%
28
 100.0%
29
 100.0%
28
 100.0%
22
 100.0%
3
 100.0%
140
 100.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 27 participants 28 participants 29 participants 28 participants 22 participants 3 participants 140 participants
Hispanic or Latino
0
   0.0%
3
  11.1%
0
   0.0%
1
   3.4%
1
   3.6%
0
   0.0%
0
   0.0%
5
   3.6%
Not Hispanic or Latino
3
 100.0%
24
  88.9%
28
 100.0%
27
  93.1%
27
  96.4%
22
 100.0%
3
 100.0%
134
  95.7%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
1
   3.4%
0
   0.0%
0
   0.0%
0
   0.0%
1
   0.7%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 27 participants 28 participants 29 participants 28 participants 22 participants 3 participants 140 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   3.6%
0
   0.0%
0
   0.0%
1
   0.7%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
1
   3.7%
0
   0.0%
1
   3.4%
2
   7.1%
0
   0.0%
0
   0.0%
4
   2.9%
White
3
 100.0%
26
  96.3%
28
 100.0%
28
  96.6%
25
  89.3%
22
 100.0%
3
 100.0%
135
  96.4%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1.Primary Outcome
Title Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs)
Hide Description An adverse events (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the 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/incapacity; congenital anomaly. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. AEs included both SAEs and non-SAEs.
Time Frame Baseline up to 30 days after last dose of study treatment (approximately maximum of 129 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all enrolled participants who received at least 1 dose of study drug.
Arm/Group Title MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day MDV3100 (Enzalutamide) 160 mg /Day: Long Term Dosing Period
Hide Arm/Group Description:
Participants received 30 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 60 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants who received 150 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period. This dose was then changed subsequently to 160 mg/day according to Protocol amendment. Participants continued to receive the same dose in multiple dose period for 84 days.
Participants received 240 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 360 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 480 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 600 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
All participants after multiple dose period, continued to receive 160 mg/day oral dose of Enzalutamide in long term dosing period until they voluntarily withdrew, experienced a DLT or were diagnosed with disease progression.
Overall Number of Participants Analyzed 3 27 28 29 28 22 3 18
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
6
  22.2%
14
  50.0%
8
  27.6%
6
  21.4%
1
   4.5%
1
  33.3%
10
  55.6%
2.Primary Outcome
Title Percentage of Participants With at Least 1 Dose-limiting Toxicity (DLT): Multiple Dose Period
Hide Description DLT was defined as a national cancer institute's common toxicity criteria for adverse events (NCI-CTCAE) version 3.0 grade 3 or greater toxicity regardless of perceived causality that is not improved by the use of adequate/maximal medical intervention. Grade 3 alopecia, fever without neutropenia, nausea, vomiting, fatigue, and self-limited or medically controllable adverse events were not considered as DLTs.
Time Frame Baseline up to first 35 days of the study treatment in multiple dose period
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all enrolled participants who received at least 1 dose of study drug.
Arm/Group Title MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day
Hide Arm/Group Description:
Participants received 30 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 60 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants who received 150 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period. This dose was then changed subsequently to 160 mg/day according to Protocol amendment. Participants continued to receive the same dose in multiple dose period for 84 days.
Participants received 240 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 360 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 480 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 600 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Overall Number of Participants Analyzed 3 27 28 29 28 22 3
Measure Type: Number
Unit of Measure: percentage of participants
0 0 0 0 1 1 2
3.Primary Outcome
Title Maximum Tolerated Dose (MTD) of MDV3100: Multiple Dose Period
Hide Description Tolerability was defined as if less than (<) 4/12 in participants with no prior exposure to MDV3100 (chemo-naive) and < 4/12 prior chemotherapy participants experienced a DLT within the first 35 days of the multiple dose period. For doses higher than 360 mg/day, tolerability was defined if <8/24 participants previously treated with chemotherapy experience a DLT within the first 35 days of the multiple dose period. MTD was defined as a dose below the intolerable dose.
Time Frame Baseline up to first 35 days of the study treatment in multiple dose period
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all enrolled participants who received at least 1 dose of study drug.
Arm/Group Title MDV3100 (Enzalutamide) : All Participants
Hide Arm/Group Description:
Participants received single oral dose of MDV3100 in 1 out of the 7 cohorts of 30, 60, 150, 240, 360, 480 or 600 mg/day dose on Day 1 and were followed up for 6 days in single dose (dose escalation) period. Dose escalation from 30 to 600 mg/day continued until the MTD was determined or until a dose of 600 mg/day was evaluated. After dose-escalation, the cohorts receiving 60-600 mg/day dose were expanded in multiple dose (dose expansion) period, where participants received MDV3100 according to their dose in single dose period for 84 days.
Overall Number of Participants Analyzed 140
Measure Type: Number
Unit of Measure: milligrams per day
240
4.Secondary Outcome
Title Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours Post Dose (AUC[0-24]) of MDV3100: Single Dose Period
Hide Description [Not Specified]
Time Frame Pre-dose, 0.5, 1, 2, 4, 6, 24 hours post dose on Day 1 of Single Dose Period
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) evaluable population: all participants who received study drug and had sufficient PK samples for calculation of at least 1 MDV3100 PK parameter. Here, "Overall Number of Participants Analyzed" signifies participants who were evaluable for this outcome measure.
Arm/Group Title MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day
Hide Arm/Group Description:
Participants received 30 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 60 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants who received 150 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period. This dose was then changed subsequently to 160 mg/day according to Protocol amendment. Participants continued to receive the same dose in multiple dose period for 84 days.
Participants received 240 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 360 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 480 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 600 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Overall Number of Participants Analyzed 3 3 3 3 6 0 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: microgram*hour per milliliter
5.43
(11.80%)
15.64
(3.50%)
38.21
(23.64%)
58.39
(47.64%)
79.26
(19.29%)
5.Secondary Outcome
Title Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Measurable Concentration (AUC[0-t]) of MDV3100: Single Dose Period
Hide Description [Not Specified]
Time Frame Pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72, 96, 120 hours postdose on Day 1 of Single Dose Period
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: all participants who received study drug and had sufficient PK samples for calculation of at least 1 MDV3100 PK parameter. Here, "Overall Number of Participants Analyzed" signifies participants who were evaluable for this outcome measure.
Arm/Group Title MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day
Hide Arm/Group Description:
Participants received 30 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 60 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants who received 150 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period. This dose was then changed subsequently to 160 mg/day according to Protocol amendment. Participants continued to receive the same dose in multiple dose period for 84 days.
Participants received 240 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 360 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 480 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 600 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Overall Number of Participants Analyzed 3 3 3 3 3 4 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: microgram*hour per milliliter
21.2
(14.2%)
53.1
(4.1%)
145.3
(10.0%)
208.5
(44.0%)
320.2
(12.9%)
363.4
(38.7%)
391.9
(14.0%)
6.Secondary Outcome
Title Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC[0-inf]) of MDV3100: Single Dose Period
Hide Description [Not Specified]
Time Frame Pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72, 96, 120 hours post dose on Day 1 of Single Dose Period
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: all participants who received study drug and had sufficient PK samples for calculation of at least 1 MDV3100 PK parameter. Here, "Overall Number of Participants Analyzed" signifies participants who were evaluable for this outcome measure.
Arm/Group Title MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day
Hide Arm/Group Description:
Participants received 30 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 60 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants who received 150 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period. This dose was then changed subsequently to 160 mg/day according to Protocol amendment. Participants continued to receive the same dose in multiple dose period for 84 days.
Participants received 240 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 360 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 480 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 600 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Overall Number of Participants Analyzed 3 3 3 3 5 4 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: microgram*hour per milliliter
51.3
(39.8%)
92.7
(19.0%)
331.5
(14.6%)
459.2
(32.7%)
706.7
(17.7%)
952.7
(42.4%)
865.0
(34.6%)
7.Secondary Outcome
Title Time to Reach Maximum Plasma Concentration (Tmax) of MDV3100: Single Dose Period
Hide Description [Not Specified]
Time Frame Pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72, 96, 120 hours post dose on Day 1 of Single Dose Period
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: all participants who received study drug and had sufficient PK samples for calculation of at least 1 MDV3100 PK parameter.
Arm/Group Title MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day
Hide Arm/Group Description:
Participants received 30 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 60 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants who received 150 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period. This dose was then changed subsequently to 160 mg/day according to Protocol amendment. Participants continued to receive the same dose in multiple dose period for 84 days.
Participants received 240 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 360 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 480 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 600 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Overall Number of Participants Analyzed 3 3 3 3 6 6 3
Median (Full Range)
Unit of Measure: hours
1.98
(0.42 to 4.00)
0.50
(0.48 to 1.00)
0.53
(0.50 to 1.98)
1.00
(0.57 to 1.00)
1.03
(0.53 to 2.20)
1.54
(0.53 to 2.08)
1.03
(1.03 to 2.00)
8.Secondary Outcome
Title Maximum Plasma Concentration (Cmax) of MDV3100: Single Dose Period
Hide Description [Not Specified]
Time Frame Pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72, 96, 120 hours post dose on Day 1 of Single Dose Period
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: all participants who received study drug and had sufficient PK samples for calculation of at least 1 MDV3100 PK parameter.
Arm/Group Title MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day
Hide Arm/Group Description:
Participants received 30 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 60 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants who received 150 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period. This dose was then changed subsequently to 160 mg/day according to Protocol amendment. Participants continued to receive the same dose in multiple dose period for 84 days.
Participants received 240 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 360 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 480 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 600 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Overall Number of Participants Analyzed 3 3 3 3 6 6 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: microgram per milliliter
0.43
(15.97%)
1.65
(28.77%)
3.30
(22.85%)
5.19
(18.64%)
6.68
(39.61%)
5.93
(66.03%)
5.17
(19.51%)
9.Secondary Outcome
Title Apparent Terminal Elimination Half-Life (T1/2) of MDV3100: Single Dose Period
Hide Description T 1/2 is the time measured for the plasma concentration of MDV3100 to decrease by one half.
Time Frame Pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72, 96, 120 hours post dose on Day 1 of Single Dose Period
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: all participants who received study drug and had sufficient PK samples for calculation of at least 1 MDV3100 PK parameter. Here, "Overall Number of Participants Analyzed" signifies participants who were evaluable for this outcome measure.
Arm/Group Title MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day
Hide Arm/Group Description:
Participants received 30 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 60 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants who received 150 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period. This dose was then changed subsequently to 160 mg/day according to Protocol amendment. Participants continued to receive the same dose in multiple dose period for 84 days.
Participants received 240 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 360 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 480 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 600 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Overall Number of Participants Analyzed 3 3 3 3 5 4 3
Mean (Standard Deviation)
Unit of Measure: hours
164.9  (69.8) 100.5  (30.9) 143.7  (34.8) 138.9  (22.6) 149.1  (26.1) 144.0  (68.4) 130.4  (37.7)
10.Secondary Outcome
Title Apparent Volume of Distribution (V/F) of MDV3100: Single Dose Period
Hide Description Volume of distribution is defined as the theoretical volume in which the total amount of MDV3100 would need to be uniformly distributed to produce the desired plasma concentration of MDV3100. Apparent volume of distribution after oral dose (V/F) is influenced by the fraction absorbed.
Time Frame Pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72, 96, 120 hours post dose on Day 1 of Single Dose Period
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: all participants who received study drug and had sufficient PK samples for calculation of at least 1 MDV3100 PK parameter. Here, "Overall Number of Participants Analyzed" signifies participants who were evaluable for this outcome measure.
Arm/Group Title MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day
Hide Arm/Group Description:
Participants received 30 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 60 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants who received 150 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period. This dose was then changed subsequently to 160 mg/day according to Protocol amendment. Participants continued to receive the same dose in multiple dose period for 84 days.
Participants received 240 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 360 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 480 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 600 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Overall Number of Participants Analyzed 3 3 3 3 5 4 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liters
131.7
(15.6%)
90.5
(16.0%)
91.89
(13.31%)
103.8
(48.5%)
108.2
(15.8%)
97.4
(30.7%)
126.4
(8.8%)
11.Secondary Outcome
Title Apparent Total Plasma Clearance (CL/F) of MDV3100: Single Dose Period
Hide Description Clearance of a MDV3100 is a measure of the rate at which a MDV3100 is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.
Time Frame Pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72, 96, 120 hours post dose on Day 1 of Single Dose Period
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: all participants who received study drug and had sufficient PK samples for calculation of at least 1 MDV3100 PK parameter. Here, "Overall Number of Participants Analyzed" signifies participants who were evaluable for this outcome measure.
Arm/Group Title MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day
Hide Arm/Group Description:
Participants received 30 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 60 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants who received 150 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period. This dose was then changed subsequently to 160 mg/day according to Protocol amendment. Participants continued to receive the same dose in multiple dose period for 84 days.
Participants received 240 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 360 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 480 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 600 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Overall Number of Participants Analyzed 3 3 3 3 5 4 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liters per hour
0.585
(39.810%)
0.647
(18.988%)
0.453
(14.583%)
0.523
(32.679%)
0.509
(17.711%)
0.504
(42.437%)
0.694
(34.625%)
12.Secondary Outcome
Title Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours Post Dose (AUC[0-24]) of MDV3100: Multiple Dose Period
Hide Description [Not Specified]
Time Frame Pre-dose, 0.5, 1, 2, 24 hours post dose on Day 84 of Multiple Dose Period
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: all participants who received study drug and had sufficient PK samples for calculation of at least 1 MDV3100 PK parameter. Here, "Overall Number of Participants Analyzed" signifies participants who were evaluable for this outcome measure.
Arm/Group Title MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day
Hide Arm/Group Description:
Participants received 30 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 60 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants who received 150 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period. This dose was then changed subsequently to 160 mg/day according to Protocol amendment. Participants continued to receive the same dose in multiple dose period for 84 days.
Participants received 240 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 360 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 480 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 600 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Overall Number of Participants Analyzed 3 20 22 29 14 1 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: microgram*hour per milliliter
60.0
(21.0%)
109.8
(34.4%)
291.7
(24.9%)
395.7
(27.4%)
488.9
(23.9%)
463.1 [1] 
(NA%)
[1]
Geometric coefficient of variation could not be estimated as only 1 participant was analyzed.
13.Secondary Outcome
Title Time to Reach Maximum Plasma Concentration (Tmax) of MDV3100: Multiple Dose Period
Hide Description [Not Specified]
Time Frame Pre-dose, 0.5, 1, 2, 24 hours post dose on Day 84 of Multiple Dose Period
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: all participants who received study drug and had sufficient PK samples for calculation of at least 1 MDV3100 PK parameter. Here, "Overall Number of Participants Analyzed" signifies participants who were evaluable for this outcome measure.
Arm/Group Title MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day
Hide Arm/Group Description:
Participants received 30 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 60 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants who received 150 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period. This dose was then changed subsequently to 160 mg/day according to Protocol amendment. Participants continued to receive the same dose in multiple dose period for 84 days.
Participants received 240 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 360 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 480 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 600 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Overall Number of Participants Analyzed 3 21 23 29 16 1 0
Median (Full Range)
Unit of Measure: hours
2.07
(1.00 to 3.92)
1.07
(0.50 to 23.67)
1.00
(0.00 to 25.80)
1.08
(0.00 to 26.17)
1.57
(0.48 to 24.08)
0.00
(0.00 to 0.00)
14.Secondary Outcome
Title Maximum Plasma Concentration (Cmax) of MDV3100: Multiple Dose Period
Hide Description [Not Specified]
Time Frame Pre-dose, 0.5, 1, 2, 24 hours post dose on Day 84 of Multiple Dose Period
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: all participants who received study drug and had sufficient PK samples for calculation of at least 1 MDV3100 PK parameter. Here, "Overall Number of Participants Analyzed" signifies participants who were evaluable for this outcome measure.
Arm/Group Title MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day
Hide Arm/Group Description:
Participants received 30 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 60 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants who received 150 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period. This dose was then changed subsequently to 160 mg/day according to Protocol amendment. Participants continued to receive the same dose in multiple dose period for 84 days.
Participants received 240 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 360 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 480 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 600 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Overall Number of Participants Analyzed 3 21 23 29 16 1 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: microgram per milliliter
2.76
(21.10%)
5.49
(28.88%)
14.07
(25.36%)
18.91
(26.57%)
24.57
(21.00%)
27.90 [1] 
(NA%)
[1]
Geometric coefficient of variation could not be estimated as only 1 participant was analyzed.
15.Secondary Outcome
Title Minimum Observed Plasma Concentration (Cmin) of MDV3100: Multiple Dose Period
Hide Description [Not Specified]
Time Frame Pre-dose on Day 1 of Multiple Dose Period
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: all participants who received study drug and had sufficient PK samples for calculation of at least 1 MDV3100 PK parameter. Here, "Overall Number of Participants Analyzed" signifies participants who were evaluable for this outcome measure.
Arm/Group Title MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day
Hide Arm/Group Description:
Participants received 30 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 60 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants who received 150 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period. This dose was then changed subsequently to 160 mg/day according to Protocol amendment. Participants continued to receive the same dose in multiple dose period for 84 days.
Participants received 240 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 360 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 480 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 600 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Overall Number of Participants Analyzed 3 22 24 25 21 16 3
Mean (Standard Deviation)
Unit of Measure: microgram per milliliter
0.10  (0.03) 0.00  (0.00) 0.04  (0.19) 0.00  (0.00) 0.00  (0.00) 0.00  (0.00) 1.89  (0.55)
16.Secondary Outcome
Title Apparent Total Plasma Clearance (CL/F) of MDV3100: Multiple Dose Period
Hide Description Clearance of a MDV3100 is a measure of the rate at which a MDV3100 is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.
Time Frame Pre-dose, 0.5, 1, 2, 24 hours post dose on Day 84 of Multiple Dose Period
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: all participants who received study drug and had sufficient PK samples for calculation of at least 1 MDV3100 PK parameter. Here, "Overall Number of Participants Analyzed" signifies participants who were evaluable for this outcome measure.
Arm/Group Title MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day
Hide Arm/Group Description:
Participants received 30 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 60 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants who received 150 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period. This dose was then changed subsequently to 160 mg/day according to Protocol amendment. Participants continued to receive the same dose in multiple dose period for 84 days.
Participants received 240 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 360 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 480 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 600 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Overall Number of Participants Analyzed 3 20 22 29 14 1 0
Mean (Standard Deviation)
Unit of Measure: liters per hour
0.507  (0.111) 0.580  (0.245) 0.530  (0.149) 0.628  (0.179) 0.755  (0.176) 1.037 [1]   (NA)
[1]
Standard deviation could not be estimated as only 1 participant was analyzed.
17.Other Pre-specified Outcome
Title Percentage of Participants With Prostate Specific Antigen (PSA) Response at Day 84: Multiple Dose Period
Hide Description Prostate-specific antigen is a glycoprotein considered as a biomarker for the response to therapy in men with prostate cancer. A 50 percent (%) decline in PSA from baseline to the PSA level at Day 84 was considered as a PSA response.
Time Frame Baseline, Day 84
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis population included all enrolled participants who received at least 1 dose of study drug. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
Arm/Group Title MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day
Hide Arm/Group Description:
Participants received 30 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 60 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants who received 150 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period. This dose was then changed subsequently to 160 mg/day according to Protocol amendment. Participants continued to receive the same dose in multiple dose period for 84 days.
Participants received 240 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 360 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 480 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Participants received 600 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days.
Overall Number of Participants Analyzed 3 24 24 20 21 11 0
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
33.3
(0.8 to 90.6)
50.0
(29.1 to 70.9)
66.7
(44.7 to 84.4)
75.0
(50.9 to 91.3)
71.4
(47.8 to 88.7)
45.5
(16.7 to 76.6)
Time Frame Baseline up to 30 days after last dose of study treatment (approximately maximum of 129 months)
Adverse Event Reporting Description Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or participant may have experienced both SAE and NSAE. Analysis population included all enrolled participants who received at least 1 dose of study drug.
 
Arm/Group Title MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day MDV3100 (Enzalutamide) 160 mg /Day: Long Term Dosing Period
Hide Arm/Group Description Participants received 30 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days. Participants received 60 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days. Participants who received 150 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period. This dose was then changed subsequently to 160 mg/day according to Protocol amendment. Participants continued to receive the same dose in multiple dose period for 84 days. Participants received 240 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days. Participants received 360 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days. Participants received 480 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days. Participants received 600 mg of Enzalutamide on Day 1 and were followed for 6 days in single dose period and continued to receive the same dose in multiple dose period for 84 days. All participants after multiple dose period, continued to receive 160 mg/day oral dose of Enzalutamide in long term dosing period until they voluntarily withdrew, experienced a DLT or were diagnosed with disease progression.
All-Cause Mortality
MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day MDV3100 (Enzalutamide) 160 mg /Day: Long Term Dosing Period
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/-- 
Hide Serious Adverse Events
MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day MDV3100 (Enzalutamide) 160 mg /Day: Long Term Dosing Period
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/3 (0.00%)   6/27 (22.22%)   14/28 (50.00%)   8/29 (27.59%)   6/28 (21.43%)   1/22 (4.55%)   1/3 (33.33%)   10/18 (55.56%) 
Blood and lymphatic system disorders                 
Anaemia * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  2/28 (7.14%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Cardiac disorders                 
Myocardial infarction * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  2/18 (11.11%) 
Pericardial effusion * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Acute myocardial infarction * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  2/18 (11.11%) 
Coronary artery thrombosis * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Myocardial ischaemia * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Gastrointestinal disorders                 
Abdominal pain * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Constipation * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Gastrointestinal haemorrhage * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Upper gastrointestinal haemorrhage * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Intestinal obstruction * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
General disorders                 
Fatigue * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  2/29 (6.90%)  2/28 (7.14%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Asthenia * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  2/28 (7.14%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Chest pain * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Pyrexia * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Localised oedema * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Oedema peripheral * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Pain * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Infections and infestations                 
Cellulitis * 1  0/3 (0.00%)  1/27 (3.70%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Device related infection * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Gastroenteritis viral * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Pneumonia * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  2/18 (11.11%) 
Pneumonia bacterial * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Pyelonephritis * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Injury, poisoning and procedural complications                 
Ankle fracture * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Investigations                 
Activated partial thromboplastin time prolonged * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Aspartate aminotransferase increased * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Haemoglobin decreased * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Metabolism and nutrition disorders                 
Dehydration * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Musculoskeletal and connective tissue disorders                 
Arthralgia * 1  0/3 (0.00%)  2/27 (7.41%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Back pain * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Musculoskeletal pain * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Spinal column stenosis * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                 
Metastatic pain * 1  0/3 (0.00%)  0/27 (0.00%)  2/28 (7.14%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Hepatic cancer metastatic * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Lung squamous cell carcinoma stage unspecified * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Nervous system disorders                 
Convulsion * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  1/22 (4.55%)  1/3 (33.33%)  0/18 (0.00%) 
Nerve root compression * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Spinal cord compression * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  2/18 (11.11%) 
Transient ischaemic attack * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Aphasia * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Dizziness * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Leukoencephalopathy * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Nerve compression * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Pyramidal tract syndrome * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Cerebrovascular accident * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Lacunar infarction * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Syncope * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Psychiatric disorders                 
Confusional state * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  1/3 (33.33%)  0/18 (0.00%) 
Renal and urinary disorders                 
Renal failure acute * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Urinary tract obstruction * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Reproductive system and breast disorders                 
Pelvic pain * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Respiratory, thoracic and mediastinal disorders                 
Pleural effusion * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Pulmonary embolism * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  2/18 (11.11%) 
Vascular disorders                 
Deep vein thrombosis * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Hypertension * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Hypotension * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA v10.0
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
MDV3100 (Enzalutamide) 30 mg/Day MDV3100 (Enzalutamide) 60 mg /Day MDV3100 (Enzalutamide) 150/160 mg/Day MDV3100 (Enzalutamide) 240 mg /Day MDV3100 (Enzalutamide) 360 mg /Day MDV3100 (Enzalutamide) 480 mg /Day MDV3100 (Enzalutamide) 600 mg /Day MDV3100 (Enzalutamide) 160 mg /Day: Long Term Dosing Period
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   3/3 (100.00%)   27/27 (100.00%)   27/28 (96.43%)   29/29 (100.00%)   28/28 (100.00%)   21/22 (95.45%)   3/3 (100.00%)   17/18 (94.44%) 
Blood and lymphatic system disorders                 
Anaemia * 1  1/3 (33.33%)  5/27 (18.52%)  3/28 (10.71%)  4/29 (13.79%)  3/28 (10.71%)  2/22 (9.09%)  0/3 (0.00%)  1/18 (5.56%) 
Disseminated intravascular coagulation * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Leukopenia * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Lymphopenia * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Thrombocytopenia * 1  0/3 (0.00%)  1/27 (3.70%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  2/22 (9.09%)  0/3 (0.00%)  0/18 (0.00%) 
Cardiac disorders                 
Coronary artery disease * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  2/18 (11.11%) 
Nodal rhythm * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Angina pectoris * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Aortic valve incompetence * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Arrhythmia * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  2/28 (7.14%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Atrioventricular block * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Atrioventricular block first degree * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Bundle branch block right * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Extrasystoles * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Myocardial infarction * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Right ventricular hypertrophy * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Tachycardia * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Ventricular arrhythmia * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Ventricular extrasystoles * 1  0/3 (0.00%)  1/27 (3.70%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Congenital, familial and genetic disorders                 
Spondylolisthesis * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Ear and labyrinth disorders                 
Ear discomfort * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Tinnitus * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  2/29 (6.90%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Vestibular disorder * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Deafness * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Deafness unilateral * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Ear pain * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Hearing impaired * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Vertigo * 1  1/3 (33.33%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Endocrine disorders                 
Adrenal insufficiency * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Hyperparathyroidism * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Hypothyroidism * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Thyroid mass * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Eye disorders                 
Dry eye * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Erythema of eyelid * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Lacrimation increased * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  2/18 (11.11%) 
Ocular hyperaemia * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  2/18 (11.11%) 
Vision blurred * 1  1/3 (33.33%)  2/27 (7.41%)  1/28 (3.57%)  1/29 (3.45%)  2/28 (7.14%)  1/22 (4.55%)  0/3 (0.00%)  1/18 (5.56%) 
Blepharitis * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Conjunctivitis * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Diplopia * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Ectropion * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Eye pain * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Eye swelling * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Eyelid ptosis * 1  0/3 (0.00%)  1/27 (3.70%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Glare * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Ocular icterus * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Photophobia * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Refraction disorder * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Visual acuity reduced * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Visual disturbance * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Vitreous floaters * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Gastrointestinal disorders                 
Abdominal discomfort * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Abdominal pain * 1  1/3 (33.33%)  3/27 (11.11%)  1/28 (3.57%)  3/29 (10.34%)  4/28 (14.29%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Abdominal pain upper * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Colonic polyp * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Constipation * 1  2/3 (66.67%)  10/27 (37.04%)  8/28 (28.57%)  7/29 (24.14%)  11/28 (39.29%)  6/22 (27.27%)  1/3 (33.33%)  6/18 (33.33%) 
Defaecation urgency * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Diarrhoea * 1  2/3 (66.67%)  7/27 (25.93%)  8/28 (28.57%)  3/29 (10.34%)  4/28 (14.29%)  9/22 (40.91%)  1/3 (33.33%)  8/18 (44.44%) 
Diverticulum * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Diverticulum intestinal haemorrhagic * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Dyspepsia * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  1/29 (3.45%)  4/28 (14.29%)  2/22 (9.09%)  0/3 (0.00%)  1/18 (5.56%) 
Gastrooesophageal reflux disease * 1  1/3 (33.33%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  1/18 (5.56%) 
Intestinal mass * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Vomiting * 1  0/3 (0.00%)  5/27 (18.52%)  3/28 (10.71%)  1/29 (3.45%)  6/28 (21.43%)  4/22 (18.18%)  2/3 (66.67%)  1/18 (5.56%) 
Abdominal distension * 1  0/3 (0.00%)  2/27 (7.41%)  1/28 (3.57%)  2/29 (6.90%)  5/28 (17.86%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Abdominal hernia * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Abdominal pain lower * 1  1/3 (33.33%)  2/27 (7.41%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Colitis * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Dental discomfort * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Dry mouth * 1  1/3 (33.33%)  0/27 (0.00%)  2/28 (7.14%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Dysphagia * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Eructation * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Faecal volume decreased * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Faeces discoloured * 1  0/3 (0.00%)  1/27 (3.70%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Faeces hard * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Flatulence * 1  2/3 (66.67%)  1/27 (3.70%)  2/28 (7.14%)  2/29 (6.90%)  2/28 (7.14%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Frequent bowel movements * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Gastritis * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Gastritis erosive * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Gastritis haemorrhagic * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Gastrointestinal pain * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Haematochezia * 1  0/3 (0.00%)  2/27 (7.41%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Haemorrhoids * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Hyperchlorhydria * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Hypoaesthesia oral * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Irritable bowel syndrome * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Lip dry * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Lip exfoliation * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Lip swelling * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  2/29 (6.90%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Lip ulceration * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Mouth ulceration * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Nausea * 1  1/3 (33.33%)  6/27 (22.22%)  11/28 (39.29%)  6/29 (20.69%)  19/28 (67.86%)  11/22 (50.00%)  2/3 (66.67%)  0/18 (0.00%) 
Oesophagitis * 1  0/3 (0.00%)  1/27 (3.70%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Oral pain * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Oral soft tissue disorder * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Paraesthesia oral * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Pruritus ani * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Rectal haemorrhage * 1  0/3 (0.00%)  1/27 (3.70%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Retching * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Salivary hypersecretion * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Stomatitis * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Tongue coated * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Toothache * 1  1/3 (33.33%)  0/27 (0.00%)  1/28 (3.57%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
General disorders                 
Asthenia * 1  0/3 (0.00%)  3/27 (11.11%)  4/28 (14.29%)  5/29 (17.24%)  3/28 (10.71%)  4/22 (18.18%)  0/3 (0.00%)  0/18 (0.00%) 
Chest discomfort * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Chest pain * 1  0/3 (0.00%)  3/27 (11.11%)  3/28 (10.71%)  2/29 (6.90%)  3/28 (10.71%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Chills * 1  0/3 (0.00%)  1/27 (3.70%)  1/28 (3.57%)  1/29 (3.45%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  1/18 (5.56%) 
Face oedema * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Facial pain * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Fatigue * 1  2/3 (66.67%)  17/27 (62.96%)  19/28 (67.86%)  20/29 (68.97%)  23/28 (82.14%)  16/22 (72.73%)  1/3 (33.33%)  13/18 (72.22%) 
Feeling abnormal * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Feeling cold * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Gait disturbance * 1  0/3 (0.00%)  1/27 (3.70%)  3/28 (10.71%)  3/29 (10.34%)  3/28 (10.71%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Influenza like illness * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Irritability * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Local swelling * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Localised oedema * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Malaise * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Mass * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Mucosal dryness * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Mucosal inflammation * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Nodule * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Oedema * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  2/22 (9.09%)  0/3 (0.00%)  1/18 (5.56%) 
Oedema peripheral * 1  1/3 (33.33%)  6/27 (22.22%)  9/28 (32.14%)  5/29 (17.24%)  6/28 (21.43%)  1/22 (4.55%)  0/3 (0.00%)  3/18 (16.67%) 
Pain * 1  0/3 (0.00%)  4/27 (14.81%)  2/28 (7.14%)  3/29 (10.34%)  3/28 (10.71%)  2/22 (9.09%)  0/3 (0.00%)  2/18 (11.11%) 
Pyrexia * 1  0/3 (0.00%)  4/27 (14.81%)  4/28 (14.29%)  2/29 (6.90%)  1/28 (3.57%)  2/22 (9.09%)  1/3 (33.33%)  1/18 (5.56%) 
Sluggishness * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Thirst * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Atrophy * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Cyst * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Injection site nodule * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Hepatobiliary disorders                 
Hepatosplenomegaly * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Cholelithiasis * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Immune system disorders                 
Hypersensitivity * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Infections and infestations                 
Axillary candidiasis * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Blastocystis infection * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Bronchitis * 1  0/3 (0.00%)  0/27 (0.00%)  3/28 (10.71%)  2/29 (6.90%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  1/18 (5.56%) 
Candidiasis * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Cellulitis * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Clostridial infection * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Cystitis * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Diverticulitis * 1  0/3 (0.00%)  1/27 (3.70%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Ear infection * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Eye infection * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  1/3 (33.33%)  0/18 (0.00%) 
Furuncle * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Gastroenteritis viral * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Gastrointestinal infection * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Influenza * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Localised infection * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Nasopharyngitis * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  2/18 (11.11%) 
Oral herpes * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Pharyngitis * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Pneumonia * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Pneumonia bacterial * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Respiratory tract infection * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Rhinitis * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Sepsis * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Sinusitis * 1  0/3 (0.00%)  1/27 (3.70%)  1/28 (3.57%)  2/29 (6.90%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Tinea infection * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Tooth abscess * 1  0/3 (0.00%)  2/27 (7.41%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Upper respiratory tract infection * 1  0/3 (0.00%)  3/27 (11.11%)  4/28 (14.29%)  4/29 (13.79%)  1/28 (3.57%)  2/22 (9.09%)  0/3 (0.00%)  3/18 (16.67%) 
Urinary tract infection * 1  0/3 (0.00%)  3/27 (11.11%)  0/28 (0.00%)  1/29 (3.45%)  1/28 (3.57%)  2/22 (9.09%)  0/3 (0.00%)  2/18 (11.11%) 
Viral infection * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Ear infection staphylococcal * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Injury, poisoning and procedural complications                 
Contusion * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  2/18 (11.11%) 
Fracture * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Hand fracture * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Humerus fracture * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Jaw fracture * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Joint injury * 1  0/3 (0.00%)  1/27 (3.70%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Lumbar vertebral fracture * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Medical device pain * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Muscle strain * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Post procedural haematuria * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Rib fracture * 1  0/3 (0.00%)  0/27 (0.00%)  2/28 (7.14%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Spinal compression fracture * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Sunburn * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Thermal burn * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Tongue injury * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Excoriation * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Fall * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  4/18 (22.22%) 
Procedural pain * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Road traffic accident * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Skin laceration * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Thoracic vertebral fracture * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Upper limb fracture * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  2/18 (11.11%) 
Investigations                 
Activated partial thromboplastin time prolonged * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Alanine aminotransferase increased * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Aspartate aminotransferase increased * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  2/29 (6.90%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Blood alkaline phosphatase increased * 1  0/3 (0.00%)  1/27 (3.70%)  1/28 (3.57%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Blood calcium increased * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Blood cholesterol increased * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Blood creatine phosphokinase increased * 1  0/3 (0.00%)  2/27 (7.41%)  1/28 (3.57%)  1/29 (3.45%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Blood creatinine increased * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  2/28 (7.14%)  1/22 (4.55%)  0/3 (0.00%)  2/18 (11.11%) 
Blood phosphorus decreased * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Blood phosphorus increased * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Blood potassium decreased * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  2/28 (7.14%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Blood potassium increased * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Blood pressure increased * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Blood triglycerides increased * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Blood urea increased * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Bone density decreased * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Cardiac murmur * 1  1/3 (33.33%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Electrocardiogram QT corrected interval prolonged * 1  0/3 (0.00%)  0/27 (0.00%)  4/28 (14.29%)  1/29 (3.45%)  3/28 (10.71%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Electrocardiogram QT prolonged * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Electrocardiogram T wave abnormal * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Electrocardiogram abnormal * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Fibrin D dimer increased * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Haemoglobin decreased * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Heart rate increased * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Heart rate irregular * 1  1/3 (33.33%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Immunoglobulins increased * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Light chain analysis increased * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Neutrophil count increased * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Occult blood positive * 1  0/3 (0.00%)  1/27 (3.70%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Urine output decreased * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Weight decreased * 1  0/3 (0.00%)  6/27 (22.22%)  1/28 (3.57%)  2/29 (6.90%)  1/28 (3.57%)  3/22 (13.64%)  0/3 (0.00%)  1/18 (5.56%) 
Weight increased * 1  0/3 (0.00%)  3/27 (11.11%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
White blood cell count increased * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Vitamin D decreased * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Metabolism and nutrition disorders                 
Anorexia * 1  0/3 (0.00%)  6/27 (22.22%)  8/28 (28.57%)  4/29 (13.79%)  9/28 (32.14%)  4/22 (18.18%)  1/3 (33.33%)  2/18 (11.11%) 
Decreased appetite * 1  1/3 (33.33%)  6/27 (22.22%)  3/28 (10.71%)  5/29 (17.24%)  1/28 (3.57%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Dehydration * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Diabetes mellitus * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Failure to thrive * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Gout * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Hyperkalaemia * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Hypertriglyceridaemia * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Hypoalbuminaemia * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  3/29 (10.34%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Hypocalcaemia * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Hypokalaemia * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  2/28 (7.14%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Hypomagnesaemia * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  2/29 (6.90%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Hyponatraemia * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Hypophosphataemia * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Vitamin D deficiency * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Musculoskeletal and connective tissue disorders                 
Arthralgia * 1  1/3 (33.33%)  11/27 (40.74%)  8/28 (28.57%)  7/29 (24.14%)  8/28 (28.57%)  5/22 (22.73%)  0/3 (0.00%)  8/18 (44.44%) 
Back pain * 1  2/3 (66.67%)  11/27 (40.74%)  5/28 (17.86%)  8/29 (27.59%)  9/28 (32.14%)  6/22 (27.27%)  1/3 (33.33%)  5/18 (27.78%) 
Bone pain * 1  0/3 (0.00%)  2/27 (7.41%)  2/28 (7.14%)  3/29 (10.34%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Flank pain * 1  0/3 (0.00%)  4/27 (14.81%)  2/28 (7.14%)  0/29 (0.00%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Groin pain * 1  0/3 (0.00%)  1/27 (3.70%)  2/28 (7.14%)  2/29 (6.90%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Joint effusion * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Joint stiffness * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Joint swelling * 1  1/3 (33.33%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Muscle spasms * 1  0/3 (0.00%)  0/27 (0.00%)  2/28 (7.14%)  0/29 (0.00%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  1/18 (5.56%) 
Muscle twitching * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Muscular weakness * 1  0/3 (0.00%)  3/27 (11.11%)  3/28 (10.71%)  5/29 (17.24%)  2/28 (7.14%)  3/22 (13.64%)  0/3 (0.00%)  0/18 (0.00%) 
Musculoskeletal pain * 1  1/3 (33.33%)  9/27 (33.33%)  2/28 (7.14%)  5/29 (17.24%)  5/28 (17.86%)  4/22 (18.18%)  1/3 (33.33%)  4/18 (22.22%) 
Myalgia * 1  0/3 (0.00%)  1/27 (3.70%)  3/28 (10.71%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Myopathy * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Musculoskeletal chest pain * 1  0/3 (0.00%)  4/27 (14.81%)  2/28 (7.14%)  1/29 (3.45%)  1/28 (3.57%)  1/22 (4.55%)  1/3 (33.33%)  1/18 (5.56%) 
Osteitis * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Osteonecrosis * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  1/28 (3.57%)  1/22 (4.55%)  0/3 (0.00%)  2/18 (11.11%) 
Osteoporosis * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  2/18 (11.11%) 
Osteoporotic fracture * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Pain in extremity * 1  0/3 (0.00%)  9/27 (33.33%)  6/28 (21.43%)  9/29 (31.03%)  6/28 (21.43%)  3/22 (13.64%)  0/3 (0.00%)  4/18 (22.22%) 
Pain in jaw * 1  0/3 (0.00%)  0/27 (0.00%)  2/28 (7.14%)  0/29 (0.00%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Pathological fracture * 1  0/3 (0.00%)  2/27 (7.41%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Trigger finger * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Muscle atrophy * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Musculoskeletal discomfort * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Neck pain * 1  0/3 (0.00%)  3/27 (11.11%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  1/3 (33.33%)  2/18 (11.11%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                 
Adenoma benign * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Basal cell carcinoma * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Squamous cell carcinoma * 1  0/3 (0.00%)  1/27 (3.70%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Acrochordon * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Squamous cell carcinoma of skin * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  2/18 (11.11%) 
Metastases to central nervous system * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Nervous system disorders                 
Amnesia * 1  0/3 (0.00%)  3/27 (11.11%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Balance disorder * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Burning sensation * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Clumsiness * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Cognitive disorder * 1  0/3 (0.00%)  3/27 (11.11%)  1/28 (3.57%)  1/29 (3.45%)  4/28 (14.29%)  4/22 (18.18%)  1/3 (33.33%)  1/18 (5.56%) 
Coordination abnormal * 1  0/3 (0.00%)  1/27 (3.70%)  2/28 (7.14%)  1/29 (3.45%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Cranial nerve disorder * 1  0/3 (0.00%)  0/27 (0.00%)  1/28 (3.57%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Disturbance in attention * 1  0/3 (0.00%)  1/27 (3.70%)  1/28 (3.57%)  1/29 (3.45%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Dizziness * 1  2/3 (66.67%)  4/27 (14.81%)  7/28 (25.00%)  5/29 (17.24%)  7/28 (25.00%)  4/22 (18.18%)  0/3 (0.00%)  1/18 (5.56%) 
Dysarthria * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Dysgeusia * 1  0/3 (0.00%)  1/27 (3.70%)  5/28 (17.86%)  3/29 (10.34%)  8/28 (28.57%)  3/22 (13.64%)  0/3 (0.00%)  1/18 (5.56%) 
Headache * 1  0/3 (0.00%)  6/27 (22.22%)  2/28 (7.14%)  6/29 (20.69%)  5/28 (17.86%)  5/22 (22.73%)  1/3 (33.33%)  2/18 (11.11%) 
Hypoaesthesia * 1  1/3 (33.33%)  2/27 (7.41%)  3/28 (10.71%)  2/29 (6.90%)  1/28 (3.57%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Hypogeusia * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Judgement impaired * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Memory impairment * 1  0/3 (0.00%)  1/27 (3.70%)  3/28 (10.71%)  1/29 (3.45%)  1/28 (3.57%)  3/22 (13.64%)  0/3 (0.00%)  2/18 (11.11%) 
Mental impairment * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  1/18 (5.56%) 
Mental retardation severity unspecified * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Migraine * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Neuralgia * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Neuropathy * 1  0/3 (0.00%)  3/27 (11.11%)  1/28 (3.57%)  3/29 (10.34%)  0/28 (0.00%)  2/22 (9.09%)  0/3 (0.00%)  1/18 (5.56%) 
Neuropathy peripheral * 1  0/3 (0.00%)  1/27 (3.70%)  2/28 (7.14%)  1/29 (3.45%)  1/28 (3.57%)  2/22 (9.09%)  0/3 (0.00%)  1/18 (5.56%) 
Paraesthesia * 1  1/3 (33.33%)  2/27 (7.41%)  3/28 (10.71%)  1/29 (3.45%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Peripheral sensory neuropathy * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  3/29 (10.34%)  2/28 (7.14%)  0/22 (0.00%)  0/3 (0.00%)  5/18 (27.78%) 
Restless legs syndrome * 1  0/3 (0.00%)  2/27 (7.41%)  0/28 (0.00%)  1/29 (3.45%)  1/28 (3.57%)  1/22 (4.55%)  1/3 (33.33%)  0/18 (0.00%) 
Sciatica * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Sinus headache * 1  2/3 (66.67%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Somnolence * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  2/22 (9.09%)  0/3 (0.00%)  0/18 (0.00%) 
Speech disorder * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  0/29 (0.00%)  0/28 (0.00%)  1/22 (4.55%)  0/3 (0.00%)  0/18 (0.00%) 
Spinal cord compression * 1  0/3 (0.00%)  0/27 (0.00%)  0/28 (0.00%)  1/29 (3.45%)  2/28 (7.14%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Syncope vasovagal * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)  0/29 (0.00%)  1/28 (3.57%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Tremor * 1  0/3 (0.00%)  2/27 (7.41%)  0/28 (0.00%)  0/29 (0.00%)  2/28 (7.14%)  0/22 (0.00%)  0/3 (0.00%)  0/18 (0.00%) 
Vertigo positional * 1  0/3 (0.00%)  1/27 (3.70%)  0/28 (0.00%)