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

Sponsor
Pfizer (Industry)
Overall Status
Completed
CT.gov ID
NCT00510718
Collaborator
Astellas Pharma Inc (Industry), Medivation LLC, a wholly owned subsidiary of Pfizer Inc. (Industry)
140
Enrollment
9
Locations
1
Arm
128.3
Actual Duration (Months)
15.6
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a multi-center open-label dose-escalation study of a novel compound (MDV3100) to treat patients with castration-resistant (hormone-refractory) prostate cancer. Additional patients will be enrolled in expanded cohorts at doses determined to be tolerable. Patients who tolerate the drug and do not progress will be allowed to continue to look for PSA response.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

This is a Phase 1, open-label, uncontrolled, dose-escalation study with dose-expansion at doses determined to be tolerated. Patients who tolerate the drug and do not progress will be allowed to continue treatment. The study endpoints are safety and tolerability and pharmacokinetics. PSA values will also be collected to look for PSA response.

Study Design

Study Type:
Interventional
Actual Enrollment :
140 participants
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A PHASE 1, OPEN-LABEL, DOSE-ESCALATION SAFETY AND PHARMACOKINETIC STUDY OF MDV3100 IN PATIENTS WITH CASTRATION-RESISTANT PROSTATE CANCER
Actual Study Start Date :
Jul 23, 2007
Actual Primary Completion Date :
Dec 8, 2008
Actual Study Completion Date :
Apr 2, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: 1

MDV3100

Drug: MDV3100
MDV3100 daily until progression or dose-limiting toxicity
Other Names:
  • enzalutamide
  • Xtandi

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) [Baseline up to 30 days after last dose of study treatment (approximately maximum of 129 months)]

      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.

    2. Percentage of Participants With at Least 1 Dose-limiting Toxicity (DLT): Multiple Dose Period [Baseline up to first 35 days of the study treatment in multiple dose period]

      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.

    3. Maximum Tolerated Dose (MTD) of MDV3100: Multiple Dose Period [Baseline up to first 35 days of the study treatment in multiple dose period]

      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.

    Secondary Outcome Measures

    1. Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours Post Dose (AUC[0-24]) of MDV3100: Single Dose Period [Pre-dose, 0.5, 1, 2, 4, 6, 24 hours post dose on Day 1 of Single Dose Period]

    2. Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Measurable Concentration (AUC[0-t]) of MDV3100: Single Dose Period [Pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72, 96, 120 hours postdose on Day 1 of Single Dose Period]

    3. Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC[0-inf]) of MDV3100: Single Dose Period [Pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72, 96, 120 hours post dose on Day 1 of Single Dose Period]

    4. Time to Reach Maximum Plasma Concentration (Tmax) of MDV3100: Single Dose Period [Pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72, 96, 120 hours post dose on Day 1 of Single Dose Period]

    5. Maximum Plasma Concentration (Cmax) of MDV3100: Single Dose Period [Pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72, 96, 120 hours post dose on Day 1 of Single Dose Period]

    6. Apparent Terminal Elimination Half-Life (T1/2) of MDV3100: Single Dose Period [Pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72, 96, 120 hours post dose on Day 1 of Single Dose Period]

      T 1/2 is the time measured for the plasma concentration of MDV3100 to decrease by one half.

    7. Apparent Volume of Distribution (V/F) of MDV3100: Single Dose Period [Pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72, 96, 120 hours post dose on Day 1 of Single Dose Period]

      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.

    8. Apparent Total Plasma Clearance (CL/F) of MDV3100: Single Dose Period [Pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72, 96, 120 hours post dose on Day 1 of Single Dose Period]

      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.

    9. Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours Post Dose (AUC[0-24]) of MDV3100: Multiple Dose Period [Pre-dose, 0.5, 1, 2, 24 hours post dose on Day 84 of Multiple Dose Period]

    10. Time to Reach Maximum Plasma Concentration (Tmax) of MDV3100: Multiple Dose Period [Pre-dose, 0.5, 1, 2, 24 hours post dose on Day 84 of Multiple Dose Period]

    11. Maximum Plasma Concentration (Cmax) of MDV3100: Multiple Dose Period [Pre-dose, 0.5, 1, 2, 24 hours post dose on Day 84 of Multiple Dose Period]

    12. Minimum Observed Plasma Concentration (Cmin) of MDV3100: Multiple Dose Period [Pre-dose on Day 1 of Multiple Dose Period]

    13. Apparent Total Plasma Clearance (CL/F) of MDV3100: Multiple Dose Period [Pre-dose, 0.5, 1, 2, 24 hours post dose on Day 84 of Multiple Dose Period]

      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.

    Other Outcome Measures

    1. Percentage of Participants With Prostate Specific Antigen (PSA) Response at Day 84: Multiple Dose Period [Baseline, Day 84]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A and Older
    Sexes Eligible for Study:
    Male
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. Histologically or cytologically confirmed adenocarcinoma of the prostate;

    2. Ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analogue or inhibitor, or orchiectomy (i.e., surgical or medical castration);

    3. Progressive disease after medical or surgical castration,

    Exclusion Criteria:
    1. Metastases in the brain or active epidural disease. (Note: patients with treated epidural disease are allowed);

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Dana-Farber Cancer Institute (DFCI) Boston Massachusetts United States 02115
    2 Beth Israel Deaconess Medical Center (BIDMC) Boston Massachusetts United States 02215
    3 Memorial Sloan-Kettering Cancer Center New York New York United States 10065
    4 MSKCC- Sidney Kimmel Center New York New York United States 10065
    5 Oregon Health & Science University Portland Oregon United States 97239
    6 Investigational Pharmacy Services Houston Texas United States 77030-4009
    7 The University of Texas M.D. Anderson Cancer Center Houston Texas United States 77030-4009
    8 Seattle Cancer Care Alliance Seattle Washington United States 98109
    9 University of Washington Medical Center Seattle Washington United States 98195

    Sponsors and Collaborators

    • Pfizer
    • Astellas Pharma Inc
    • Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

    Investigators

    • Study Director: Pfizer Pfizer CT.gov Call Center, Pfizer

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Pfizer
    ClinicalTrials.gov Identifier:
    NCT00510718
    Other Study ID Numbers:
    • S-3100-1-01
    • C3431009
    • NCT00513812
    First Posted:
    Aug 2, 2007
    Last Update Posted:
    Oct 3, 2019
    Last Verified:
    Sep 1, 2019
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Keywords provided by Pfizer
    Prostate
    Cancer
    Hormone
    Refractory
    Castration
    Additional relevant MeSH terms:
    Prostatic Neoplasms

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title MDV3100 (Enzalutamide): No Previous Chemotherapy MDV3100 (Enzalutamide): Post Chemotherapy
    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: Single Dose Period: 1 Week
    STARTED 65 75
    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

    Baseline Characteristics

    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
    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 Participants 3 27 28 29 28 22 3 140
    Age (Count of Participants)
    <=18 years
    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%
    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%
    86
    61.4%
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Male
    3
    100%
    27
    100%
    28
    100%
    29
    100%
    28
    100%
    22
    100%
    3
    100%
    140
    100%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    3
    11.1%
    0
    0%
    1
    3.4%
    1
    3.6%
    0
    0%
    0
    0%
    5
    3.6%
    Not Hispanic or Latino
    3
    100%
    24
    88.9%
    28
    100%
    27
    93.1%
    27
    96.4%
    22
    100%
    3
    100%
    134
    95.7%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    1
    3.4%
    0
    0%
    0
    0%
    0
    0%
    1
    0.7%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    3.6%
    0
    0%
    0
    0%
    1
    0.7%
    Asian
    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%
    Black or African American
    0
    0%
    1
    3.7%
    0
    0%
    1
    3.4%
    2
    7.1%
    0
    0%
    0
    0%
    4
    2.9%
    White
    3
    100%
    26
    96.3%
    28
    100%
    28
    96.6%
    25
    89.3%
    22
    100%
    3
    100%
    135
    96.4%
    More than one race
    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%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs)
    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)

    Outcome Measure Data

    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
    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.
    Measure Participants 3 27 28 29 28 22 3 18
    Count of Participants [Participants]
    0
    0%
    6
    22.2%
    14
    50%
    8
    27.6%
    6
    21.4%
    1
    4.5%
    1
    33.3%
    10
    7.1%
    2. Primary Outcome
    Title Percentage of Participants With at Least 1 Dose-limiting Toxicity (DLT): Multiple Dose Period
    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

    Outcome Measure Data

    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
    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.
    Measure Participants 3 27 28 29 28 22 3
    Number [percentage of participants]
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    3.6%
    1
    4.5%
    2
    66.7%
    3. Primary Outcome
    Title Maximum Tolerated Dose (MTD) of MDV3100: Multiple Dose Period
    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

    Outcome Measure Data

    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
    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.
    Measure Participants 140
    Number [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
    Description
    Time Frame Pre-dose, 0.5, 1, 2, 4, 6, 24 hours post dose on Day 1 of Single Dose Period

    Outcome Measure Data

    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
    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.
    Measure Participants 3 3 3 3 6 0 0
    Geometric Mean (Geometric Coefficient of Variation) [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
    Description
    Time Frame Pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72, 96, 120 hours postdose on Day 1 of Single Dose Period

    Outcome Measure Data

    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
    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.
    Measure Participants 3 3 3 3 3 4 3
    Geometric Mean (Geometric Coefficient of Variation) [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
    Description
    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

    Outcome Measure Data

    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
    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.
    Measure Participants 3 3 3 3 5 4 3
    Geometric Mean (Geometric Coefficient of Variation) [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
    Description
    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

    Outcome Measure Data

    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
    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.
    Measure Participants 3 3 3 3 6 6 3
    Median (Full Range) [hours]
    1.98
    0.50
    0.53
    1.00
    1.03
    1.54
    1.03
    8. Secondary Outcome
    Title Maximum Plasma Concentration (Cmax) of MDV3100: Single Dose Period
    Description
    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

    Outcome Measure Data

    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
    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.
    Measure Participants 3 3 3 3 6 6 3
    Geometric Mean (Geometric Coefficient of Variation) [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
    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

    Outcome Measure Data

    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
    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.
    Measure Participants 3 3 3 3 5 4 3
    Mean (Standard Deviation) [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
    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

    Outcome Measure Data

    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
    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.
    Measure Participants 3 3 3 3 5 4 3
    Geometric Mean (Geometric Coefficient of Variation) [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
    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

    Outcome Measure Data

    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
    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.
    Measure Participants 3 3 3 3 5 4 3
    Geometric Mean (Geometric Coefficient of Variation) [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
    Description
    Time Frame Pre-dose, 0.5, 1, 2, 24 hours post dose on Day 84 of Multiple Dose Period

    Outcome Measure Data

    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
    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.
    Measure Participants 3 20 22 29 14 1 0
    Geometric Mean (Geometric Coefficient of Variation) [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
    (NA)
    13. Secondary Outcome
    Title Time to Reach Maximum Plasma Concentration (Tmax) of MDV3100: Multiple Dose Period
    Description
    Time Frame Pre-dose, 0.5, 1, 2, 24 hours post dose on Day 84 of Multiple Dose Period

    Outcome Measure Data

    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
    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.
    Measure Participants 3 21 23 29 16 1 0
    Median (Full Range) [hours]
    2.07
    1.07
    1.00
    1.08
    1.57
    0.00
    14. Secondary Outcome
    Title Maximum Plasma Concentration (Cmax) of MDV3100: Multiple Dose Period
    Description
    Time Frame Pre-dose, 0.5, 1, 2, 24 hours post dose on Day 84 of Multiple Dose Period

    Outcome Measure Data

    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
    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.
    Measure Participants 3 21 23 29 16 1 0
    Geometric Mean (Geometric Coefficient of Variation) [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
    (NA)
    15. Secondary Outcome
    Title Minimum Observed Plasma Concentration (Cmin) of MDV3100: Multiple Dose Period
    Description
    Time Frame Pre-dose on Day 1 of Multiple Dose Period

    Outcome Measure Data

    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
    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.
    Measure Participants 3 22 24 25 21 16 3
    Mean (Standard Deviation) [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
    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

    Outcome Measure Data

    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
    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.
    Measure Participants 3 20 22 29 14 1 0
    Mean (Standard Deviation) [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
    (NA)
    17. Other Pre-specified Outcome
    Title Percentage of Participants With Prostate Specific Antigen (PSA) Response at Day 84: Multiple Dose Period
    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

    Outcome Measure Data

    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
    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.
    Measure Participants 3 24 24 20 21 11 0
    Number (95% Confidence Interval) [percentage of participants]
    33.3
    1110%
    50.0
    185.2%
    66.7
    238.2%
    75.0
    258.6%
    71.4
    255%
    45.5
    206.8%

    Adverse Events

    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
    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 (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    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 (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/3 (0%) 6/27 (22.2%) 14/28 (50%) 8/29 (27.6%) 6/28 (21.4%) 1/22 (4.5%) 1/3 (33.3%) 10/18 (55.6%)
    Blood and lymphatic system disorders
    Anaemia 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 2/28 (7.1%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Cardiac disorders
    Myocardial infarction 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 2/18 (11.1%)
    Pericardial effusion 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Acute myocardial infarction 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 2/18 (11.1%)
    Coronary artery thrombosis 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Myocardial ischaemia 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Gastrointestinal disorders
    Abdominal pain 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Constipation 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Gastrointestinal haemorrhage 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Upper gastrointestinal haemorrhage 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Intestinal obstruction 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    General disorders
    Fatigue 0/3 (0%) 0/27 (0%) 0/28 (0%) 2/29 (6.9%) 2/28 (7.1%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Asthenia 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 2/28 (7.1%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Chest pain 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Pyrexia 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Localised oedema 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Oedema peripheral 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Pain 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Infections and infestations
    Cellulitis 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Device related infection 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Gastroenteritis viral 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Pneumonia 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 2/18 (11.1%)
    Pneumonia bacterial 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Pyelonephritis 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Injury, poisoning and procedural complications
    Ankle fracture 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Investigations
    Activated partial thromboplastin time prolonged 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Aspartate aminotransferase increased 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Haemoglobin decreased 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Metabolism and nutrition disorders
    Dehydration 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/3 (0%) 2/27 (7.4%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Back pain 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Musculoskeletal pain 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Spinal column stenosis 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastatic pain 0/3 (0%) 0/27 (0%) 2/28 (7.1%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Hepatic cancer metastatic 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Lung squamous cell carcinoma stage unspecified 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Nervous system disorders
    Convulsion 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 1/22 (4.5%) 1/3 (33.3%) 0/18 (0%)
    Nerve root compression 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Spinal cord compression 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 2/18 (11.1%)
    Transient ischaemic attack 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Aphasia 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Dizziness 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Leukoencephalopathy 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Nerve compression 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Pyramidal tract syndrome 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Cerebrovascular accident 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Lacunar infarction 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Syncope 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Psychiatric disorders
    Confusional state 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 1/3 (33.3%) 0/18 (0%)
    Renal and urinary disorders
    Renal failure acute 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Urinary tract obstruction 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Reproductive system and breast disorders
    Pelvic pain 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Pulmonary embolism 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 2/18 (11.1%)
    Vascular disorders
    Deep vein thrombosis 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Hypertension 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Hypotension 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Other (Not Including 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 (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/3 (100%) 27/27 (100%) 27/28 (96.4%) 29/29 (100%) 28/28 (100%) 21/22 (95.5%) 3/3 (100%) 17/18 (94.4%)
    Blood and lymphatic system disorders
    Anaemia 1/3 (33.3%) 5/27 (18.5%) 3/28 (10.7%) 4/29 (13.8%) 3/28 (10.7%) 2/22 (9.1%) 0/3 (0%) 1/18 (5.6%)
    Disseminated intravascular coagulation 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Leukopenia 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Lymphopenia 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Thrombocytopenia 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 2/22 (9.1%) 0/3 (0%) 0/18 (0%)
    Cardiac disorders
    Coronary artery disease 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 2/18 (11.1%)
    Nodal rhythm 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Angina pectoris 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Aortic valve incompetence 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Arrhythmia 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 2/28 (7.1%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Atrioventricular block 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Atrioventricular block first degree 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Bundle branch block right 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Extrasystoles 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Myocardial infarction 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Right ventricular hypertrophy 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Tachycardia 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Ventricular arrhythmia 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Ventricular extrasystoles 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Congenital, familial and genetic disorders
    Spondylolisthesis 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Ear and labyrinth disorders
    Ear discomfort 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Tinnitus 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 2/29 (6.9%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Vestibular disorder 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Deafness 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Deafness unilateral 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Ear pain 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Hearing impaired 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Vertigo 1/3 (33.3%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Endocrine disorders
    Adrenal insufficiency 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Hyperparathyroidism 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Hypothyroidism 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Thyroid mass 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Eye disorders
    Dry eye 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Erythema of eyelid 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Lacrimation increased 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 2/18 (11.1%)
    Ocular hyperaemia 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 2/18 (11.1%)
    Vision blurred 1/3 (33.3%) 2/27 (7.4%) 1/28 (3.6%) 1/29 (3.4%) 2/28 (7.1%) 1/22 (4.5%) 0/3 (0%) 1/18 (5.6%)
    Blepharitis 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Conjunctivitis 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Diplopia 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Ectropion 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Eye pain 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Eye swelling 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Eyelid ptosis 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Glare 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Ocular icterus 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Photophobia 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Refraction disorder 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Visual acuity reduced 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Visual disturbance 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Vitreous floaters 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Gastrointestinal disorders
    Abdominal discomfort 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Abdominal pain 1/3 (33.3%) 3/27 (11.1%) 1/28 (3.6%) 3/29 (10.3%) 4/28 (14.3%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Abdominal pain upper 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Colonic polyp 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Constipation 2/3 (66.7%) 10/27 (37%) 8/28 (28.6%) 7/29 (24.1%) 11/28 (39.3%) 6/22 (27.3%) 1/3 (33.3%) 6/18 (33.3%)
    Defaecation urgency 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Diarrhoea 2/3 (66.7%) 7/27 (25.9%) 8/28 (28.6%) 3/29 (10.3%) 4/28 (14.3%) 9/22 (40.9%) 1/3 (33.3%) 8/18 (44.4%)
    Diverticulum 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Diverticulum intestinal haemorrhagic 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Dyspepsia 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 1/29 (3.4%) 4/28 (14.3%) 2/22 (9.1%) 0/3 (0%) 1/18 (5.6%)
    Gastrooesophageal reflux disease 1/3 (33.3%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 1/18 (5.6%)
    Intestinal mass 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Vomiting 0/3 (0%) 5/27 (18.5%) 3/28 (10.7%) 1/29 (3.4%) 6/28 (21.4%) 4/22 (18.2%) 2/3 (66.7%) 1/18 (5.6%)
    Abdominal distension 0/3 (0%) 2/27 (7.4%) 1/28 (3.6%) 2/29 (6.9%) 5/28 (17.9%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Abdominal hernia 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Abdominal pain lower 1/3 (33.3%) 2/27 (7.4%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Colitis 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Dental discomfort 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Dry mouth 1/3 (33.3%) 0/27 (0%) 2/28 (7.1%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Dysphagia 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Eructation 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Faecal volume decreased 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Faeces discoloured 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Faeces hard 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Flatulence 2/3 (66.7%) 1/27 (3.7%) 2/28 (7.1%) 2/29 (6.9%) 2/28 (7.1%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Frequent bowel movements 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Gastritis 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Gastritis erosive 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Gastritis haemorrhagic 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Gastrointestinal pain 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Haematochezia 0/3 (0%) 2/27 (7.4%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Haemorrhoids 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Hyperchlorhydria 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Hypoaesthesia oral 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Irritable bowel syndrome 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Lip dry 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Lip exfoliation 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Lip swelling 0/3 (0%) 0/27 (0%) 0/28 (0%) 2/29 (6.9%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Lip ulceration 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Mouth ulceration 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Nausea 1/3 (33.3%) 6/27 (22.2%) 11/28 (39.3%) 6/29 (20.7%) 19/28 (67.9%) 11/22 (50%) 2/3 (66.7%) 0/18 (0%)
    Oesophagitis 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Oral pain 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Oral soft tissue disorder 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Paraesthesia oral 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Pruritus ani 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Rectal haemorrhage 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Retching 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Salivary hypersecretion 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Stomatitis 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Tongue coated 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Toothache 1/3 (33.3%) 0/27 (0%) 1/28 (3.6%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    General disorders
    Asthenia 0/3 (0%) 3/27 (11.1%) 4/28 (14.3%) 5/29 (17.2%) 3/28 (10.7%) 4/22 (18.2%) 0/3 (0%) 0/18 (0%)
    Chest discomfort 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Chest pain 0/3 (0%) 3/27 (11.1%) 3/28 (10.7%) 2/29 (6.9%) 3/28 (10.7%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Chills 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 1/29 (3.4%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 1/18 (5.6%)
    Face oedema 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Facial pain 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Fatigue 2/3 (66.7%) 17/27 (63%) 19/28 (67.9%) 20/29 (69%) 23/28 (82.1%) 16/22 (72.7%) 1/3 (33.3%) 13/18 (72.2%)
    Feeling abnormal 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Feeling cold 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Gait disturbance 0/3 (0%) 1/27 (3.7%) 3/28 (10.7%) 3/29 (10.3%) 3/28 (10.7%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Influenza like illness 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Irritability 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Local swelling 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Localised oedema 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Malaise 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Mass 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Mucosal dryness 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Mucosal inflammation 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Nodule 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Oedema 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 2/22 (9.1%) 0/3 (0%) 1/18 (5.6%)
    Oedema peripheral 1/3 (33.3%) 6/27 (22.2%) 9/28 (32.1%) 5/29 (17.2%) 6/28 (21.4%) 1/22 (4.5%) 0/3 (0%) 3/18 (16.7%)
    Pain 0/3 (0%) 4/27 (14.8%) 2/28 (7.1%) 3/29 (10.3%) 3/28 (10.7%) 2/22 (9.1%) 0/3 (0%) 2/18 (11.1%)
    Pyrexia 0/3 (0%) 4/27 (14.8%) 4/28 (14.3%) 2/29 (6.9%) 1/28 (3.6%) 2/22 (9.1%) 1/3 (33.3%) 1/18 (5.6%)
    Sluggishness 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Thirst 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Atrophy 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Cyst 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Injection site nodule 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Hepatobiliary disorders
    Hepatosplenomegaly 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Cholelithiasis 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Immune system disorders
    Hypersensitivity 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Infections and infestations
    Axillary candidiasis 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Blastocystis infection 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Bronchitis 0/3 (0%) 0/27 (0%) 3/28 (10.7%) 2/29 (6.9%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 1/18 (5.6%)
    Candidiasis 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Cellulitis 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Clostridial infection 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Cystitis 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Diverticulitis 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Ear infection 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Eye infection 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 1/3 (33.3%) 0/18 (0%)
    Furuncle 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Gastroenteritis viral 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Gastrointestinal infection 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Influenza 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Localised infection 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Nasopharyngitis 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 2/18 (11.1%)
    Oral herpes 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Pharyngitis 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Pneumonia 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Pneumonia bacterial 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Respiratory tract infection 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Rhinitis 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Sepsis 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Sinusitis 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 2/29 (6.9%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Tinea infection 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Tooth abscess 0/3 (0%) 2/27 (7.4%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Upper respiratory tract infection 0/3 (0%) 3/27 (11.1%) 4/28 (14.3%) 4/29 (13.8%) 1/28 (3.6%) 2/22 (9.1%) 0/3 (0%) 3/18 (16.7%)
    Urinary tract infection 0/3 (0%) 3/27 (11.1%) 0/28 (0%) 1/29 (3.4%) 1/28 (3.6%) 2/22 (9.1%) 0/3 (0%) 2/18 (11.1%)
    Viral infection 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Ear infection staphylococcal 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Injury, poisoning and procedural complications
    Contusion 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 2/18 (11.1%)
    Fracture 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Hand fracture 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Humerus fracture 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Jaw fracture 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Joint injury 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Lumbar vertebral fracture 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Medical device pain 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Muscle strain 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Post procedural haematuria 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Rib fracture 0/3 (0%) 0/27 (0%) 2/28 (7.1%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Spinal compression fracture 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Sunburn 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Thermal burn 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Tongue injury 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Excoriation 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Fall 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 4/18 (22.2%)
    Procedural pain 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Road traffic accident 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Skin laceration 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Thoracic vertebral fracture 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Upper limb fracture 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 2/18 (11.1%)
    Investigations
    Activated partial thromboplastin time prolonged 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Alanine aminotransferase increased 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Aspartate aminotransferase increased 0/3 (0%) 0/27 (0%) 0/28 (0%) 2/29 (6.9%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Blood alkaline phosphatase increased 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Blood calcium increased 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Blood cholesterol increased 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Blood creatine phosphokinase increased 0/3 (0%) 2/27 (7.4%) 1/28 (3.6%) 1/29 (3.4%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Blood creatinine increased 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 2/28 (7.1%) 1/22 (4.5%) 0/3 (0%) 2/18 (11.1%)
    Blood phosphorus decreased 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Blood phosphorus increased 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Blood potassium decreased 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 2/28 (7.1%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Blood potassium increased 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Blood pressure increased 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Blood triglycerides increased 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Blood urea increased 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Bone density decreased 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Cardiac murmur 1/3 (33.3%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Electrocardiogram QT corrected interval prolonged 0/3 (0%) 0/27 (0%) 4/28 (14.3%) 1/29 (3.4%) 3/28 (10.7%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Electrocardiogram QT prolonged 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Electrocardiogram T wave abnormal 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Electrocardiogram abnormal 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Fibrin D dimer increased 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Haemoglobin decreased 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Heart rate increased 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Heart rate irregular 1/3 (33.3%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Immunoglobulins increased 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Light chain analysis increased 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Neutrophil count increased 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Occult blood positive 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Urine output decreased 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Weight decreased 0/3 (0%) 6/27 (22.2%) 1/28 (3.6%) 2/29 (6.9%) 1/28 (3.6%) 3/22 (13.6%) 0/3 (0%) 1/18 (5.6%)
    Weight increased 0/3 (0%) 3/27 (11.1%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    White blood cell count increased 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Vitamin D decreased 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Metabolism and nutrition disorders
    Anorexia 0/3 (0%) 6/27 (22.2%) 8/28 (28.6%) 4/29 (13.8%) 9/28 (32.1%) 4/22 (18.2%) 1/3 (33.3%) 2/18 (11.1%)
    Decreased appetite 1/3 (33.3%) 6/27 (22.2%) 3/28 (10.7%) 5/29 (17.2%) 1/28 (3.6%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Dehydration 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Diabetes mellitus 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Failure to thrive 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Gout 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Hyperkalaemia 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Hypertriglyceridaemia 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Hypoalbuminaemia 0/3 (0%) 0/27 (0%) 0/28 (0%) 3/29 (10.3%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Hypocalcaemia 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Hypokalaemia 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 2/28 (7.1%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Hypomagnesaemia 0/3 (0%) 0/27 (0%) 0/28 (0%) 2/29 (6.9%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Hyponatraemia 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Hypophosphataemia 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Vitamin D deficiency 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 1/3 (33.3%) 11/27 (40.7%) 8/28 (28.6%) 7/29 (24.1%) 8/28 (28.6%) 5/22 (22.7%) 0/3 (0%) 8/18 (44.4%)
    Back pain 2/3 (66.7%) 11/27 (40.7%) 5/28 (17.9%) 8/29 (27.6%) 9/28 (32.1%) 6/22 (27.3%) 1/3 (33.3%) 5/18 (27.8%)
    Bone pain 0/3 (0%) 2/27 (7.4%) 2/28 (7.1%) 3/29 (10.3%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Flank pain 0/3 (0%) 4/27 (14.8%) 2/28 (7.1%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Groin pain 0/3 (0%) 1/27 (3.7%) 2/28 (7.1%) 2/29 (6.9%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Joint effusion 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Joint stiffness 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Joint swelling 1/3 (33.3%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Muscle spasms 0/3 (0%) 0/27 (0%) 2/28 (7.1%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 1/18 (5.6%)
    Muscle twitching 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Muscular weakness 0/3 (0%) 3/27 (11.1%) 3/28 (10.7%) 5/29 (17.2%) 2/28 (7.1%) 3/22 (13.6%) 0/3 (0%) 0/18 (0%)
    Musculoskeletal pain 1/3 (33.3%) 9/27 (33.3%) 2/28 (7.1%) 5/29 (17.2%) 5/28 (17.9%) 4/22 (18.2%) 1/3 (33.3%) 4/18 (22.2%)
    Myalgia 0/3 (0%) 1/27 (3.7%) 3/28 (10.7%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Myopathy 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Musculoskeletal chest pain 0/3 (0%) 4/27 (14.8%) 2/28 (7.1%) 1/29 (3.4%) 1/28 (3.6%) 1/22 (4.5%) 1/3 (33.3%) 1/18 (5.6%)
    Osteitis 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Osteonecrosis 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 1/28 (3.6%) 1/22 (4.5%) 0/3 (0%) 2/18 (11.1%)
    Osteoporosis 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 2/18 (11.1%)
    Osteoporotic fracture 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Pain in extremity 0/3 (0%) 9/27 (33.3%) 6/28 (21.4%) 9/29 (31%) 6/28 (21.4%) 3/22 (13.6%) 0/3 (0%) 4/18 (22.2%)
    Pain in jaw 0/3 (0%) 0/27 (0%) 2/28 (7.1%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Pathological fracture 0/3 (0%) 2/27 (7.4%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Trigger finger 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Muscle atrophy 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Musculoskeletal discomfort 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Neck pain 0/3 (0%) 3/27 (11.1%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 1/3 (33.3%) 2/18 (11.1%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenoma benign 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Basal cell carcinoma 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Squamous cell carcinoma 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Acrochordon 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Squamous cell carcinoma of skin 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 2/18 (11.1%)
    Metastases to central nervous system 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Nervous system disorders
    Amnesia 0/3 (0%) 3/27 (11.1%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Balance disorder 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Burning sensation 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Clumsiness 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Cognitive disorder 0/3 (0%) 3/27 (11.1%) 1/28 (3.6%) 1/29 (3.4%) 4/28 (14.3%) 4/22 (18.2%) 1/3 (33.3%) 1/18 (5.6%)
    Coordination abnormal 0/3 (0%) 1/27 (3.7%) 2/28 (7.1%) 1/29 (3.4%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Cranial nerve disorder 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Disturbance in attention 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 1/29 (3.4%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Dizziness 2/3 (66.7%) 4/27 (14.8%) 7/28 (25%) 5/29 (17.2%) 7/28 (25%) 4/22 (18.2%) 0/3 (0%) 1/18 (5.6%)
    Dysarthria 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Dysgeusia 0/3 (0%) 1/27 (3.7%) 5/28 (17.9%) 3/29 (10.3%) 8/28 (28.6%) 3/22 (13.6%) 0/3 (0%) 1/18 (5.6%)
    Headache 0/3 (0%) 6/27 (22.2%) 2/28 (7.1%) 6/29 (20.7%) 5/28 (17.9%) 5/22 (22.7%) 1/3 (33.3%) 2/18 (11.1%)
    Hypoaesthesia 1/3 (33.3%) 2/27 (7.4%) 3/28 (10.7%) 2/29 (6.9%) 1/28 (3.6%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Hypogeusia 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Judgement impaired 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Memory impairment 0/3 (0%) 1/27 (3.7%) 3/28 (10.7%) 1/29 (3.4%) 1/28 (3.6%) 3/22 (13.6%) 0/3 (0%) 2/18 (11.1%)
    Mental impairment 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Mental retardation severity unspecified 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Migraine 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Neuralgia 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Neuropathy 0/3 (0%) 3/27 (11.1%) 1/28 (3.6%) 3/29 (10.3%) 0/28 (0%) 2/22 (9.1%) 0/3 (0%) 1/18 (5.6%)
    Neuropathy peripheral 0/3 (0%) 1/27 (3.7%) 2/28 (7.1%) 1/29 (3.4%) 1/28 (3.6%) 2/22 (9.1%) 0/3 (0%) 1/18 (5.6%)
    Paraesthesia 1/3 (33.3%) 2/27 (7.4%) 3/28 (10.7%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Peripheral sensory neuropathy 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 3/29 (10.3%) 2/28 (7.1%) 0/22 (0%) 0/3 (0%) 5/18 (27.8%)
    Restless legs syndrome 0/3 (0%) 2/27 (7.4%) 0/28 (0%) 1/29 (3.4%) 1/28 (3.6%) 1/22 (4.5%) 1/3 (33.3%) 0/18 (0%)
    Sciatica 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Sinus headache 2/3 (66.7%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Somnolence 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 2/22 (9.1%) 0/3 (0%) 0/18 (0%)
    Speech disorder 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Spinal cord compression 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 2/28 (7.1%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Syncope vasovagal 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Tremor 0/3 (0%) 2/27 (7.4%) 0/28 (0%) 0/29 (0%) 2/28 (7.1%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Vertigo positional 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Carotid artery stenosis 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Cubital tunnel syndrome 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Polyneuropathy 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 2/18 (11.1%)
    Presyncope 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Syncope 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 2/18 (11.1%)
    Transient ischaemic attack 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Psychiatric disorders
    Abnormal dreams 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Agitation 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Anxiety 0/3 (0%) 0/27 (0%) 2/28 (7.1%) 2/29 (6.9%) 0/28 (0%) 3/22 (13.6%) 0/3 (0%) 0/18 (0%)
    Confusional state 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 1/28 (3.6%) 5/22 (22.7%) 1/3 (33.3%) 1/18 (5.6%)
    Depression 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 2/29 (6.9%) 1/28 (3.6%) 4/22 (18.2%) 0/3 (0%) 0/18 (0%)
    Impatience 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Insomnia 1/3 (33.3%) 5/27 (18.5%) 2/28 (7.1%) 2/29 (6.9%) 5/28 (17.9%) 1/22 (4.5%) 1/3 (33.3%) 1/18 (5.6%)
    Mental status changes 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Mood altered 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Mood swings 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Panic attack 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Nightmare 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Paranoia 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Phobia 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Restlessness 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Renal and urinary disorders
    Bladder pain 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Chromaturia 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Costovertebral angle tenderness 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Dysuria 1/3 (33.3%) 2/27 (7.4%) 1/28 (3.6%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Haematuria 1/3 (33.3%) 4/27 (14.8%) 1/28 (3.6%) 4/29 (13.8%) 1/28 (3.6%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Hydronephrosis 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Incontinence 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 3/18 (16.7%)
    Micturition urgency 0/3 (0%) 0/27 (0%) 2/28 (7.1%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Nocturia 0/3 (0%) 5/27 (18.5%) 2/28 (7.1%) 1/29 (3.4%) 5/28 (17.9%) 1/22 (4.5%) 0/3 (0%) 3/18 (16.7%)
    Pollakiuria 1/3 (33.3%) 3/27 (11.1%) 4/28 (14.3%) 2/29 (6.9%) 3/28 (10.7%) 0/22 (0%) 0/3 (0%) 6/18 (33.3%)
    Renal failure chronic 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Urethral haemorrhage 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Urethral pain 0/3 (0%) 2/27 (7.4%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Urinary incontinence 0/3 (0%) 2/27 (7.4%) 3/28 (10.7%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 2/18 (11.1%)
    Urinary retention 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Urine abnormality 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Urine odour abnormal 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Reproductive system and breast disorders
    Breast tenderness 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Genital erythema 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Gynaecomastia 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 2/18 (11.1%)
    Nipple pain 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Pelvic pain 1/3 (33.3%) 1/27 (3.7%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 1/18 (5.6%)
    Penile pain 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Testicular pain 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Balanitis 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Cough 1/3 (33.3%) 6/27 (22.2%) 5/28 (17.9%) 7/29 (24.1%) 3/28 (10.7%) 2/22 (9.1%) 0/3 (0%) 7/18 (38.9%)
    Dysphonia 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 1/18 (5.6%)
    Dyspnoea 1/3 (33.3%) 9/27 (33.3%) 7/28 (25%) 10/29 (34.5%) 6/28 (21.4%) 3/22 (13.6%) 0/3 (0%) 5/18 (27.8%)
    Dyspnoea exertional 0/3 (0%) 0/27 (0%) 3/28 (10.7%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Epistaxis 1/3 (33.3%) 0/27 (0%) 2/28 (7.1%) 2/29 (6.9%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Increased upper airway secretion 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Lung disorder 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Nasal congestion 0/3 (0%) 4/27 (14.8%) 2/28 (7.1%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 2/18 (11.1%)
    Pharyngolaryngeal pain 0/3 (0%) 2/27 (7.4%) 1/28 (3.6%) 1/29 (3.4%) 2/28 (7.1%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Pleural effusion 0/3 (0%) 1/27 (3.7%) 2/28 (7.1%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Pleuritic pain 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Postnasal drip 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Productive cough 0/3 (0%) 2/27 (7.4%) 3/28 (10.7%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Rales 0/3 (0%) 2/27 (7.4%) 0/28 (0%) 0/29 (0%) 3/28 (10.7%) 0/22 (0%) 0/3 (0%) 2/18 (11.1%)
    Rhinitis allergic 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 2/28 (7.1%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Rhinorrhoea 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Sinus congestion 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 1/18 (5.6%)
    Sleep apnoea syndrome 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Upper respiratory tract congestion 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Wheezing 0/3 (0%) 1/27 (3.7%) 2/28 (7.1%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 2/18 (11.1%)
    Asthma 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Rhonchi 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Skin and subcutaneous tissue disorders
    Actinic keratosis 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Alopecia 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Cold sweat 1/3 (33.3%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Dermal cyst 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Dermatitis acneiform 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Dry skin 0/3 (0%) 2/27 (7.4%) 1/28 (3.6%) 2/29 (6.9%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Ecchymosis 0/3 (0%) 1/27 (3.7%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 2/18 (11.1%)
    Erythema 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Hair growth abnormal 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Hyperhidrosis 0/3 (0%) 1/27 (3.7%) 4/28 (14.3%) 1/29 (3.4%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 1/18 (5.6%)
    Hyperkeratosis 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Hypoaesthesia facial 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 0/18 (0%)
    Nail disorder 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Night sweats 0/3 (0%) 2/27 (7.4%) 2/28 (7.1%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Palmar erythema 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Penile ulceration 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Pruritus 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 1/29 (3.4%) 0/28 (0%) 1/22 (4.5%) 0/3 (0%) 1/18 (5.6%)
    Purpura 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Rash 0/3 (0%) 4/27 (14.8%) 3/28 (10.7%) 4/29 (13.8%) 2/28 (7.1%) 1/22 (4.5%) 1/3 (33.3%) 1/18 (5.6%)
    Rash macular 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Rash maculo-papular 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Skin odour abnormal 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Skin ulcer 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Swelling face 0/3 (0%) 0/27 (0%) 0/28 (0%) 1/29 (3.4%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Urticaria 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Petechiae 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Schamberg's disease 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Skin lesion 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Vascular disorders
    Flushing 0/3 (0%) 2/27 (7.4%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Haemorrhage 0/3 (0%) 0/27 (0%) 1/28 (3.6%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Hot flush 1/3 (33.3%) 7/27 (25.9%) 7/28 (25%) 2/29 (6.9%) 6/28 (21.4%) 1/22 (4.5%) 1/3 (33.3%) 1/18 (5.6%)
    Hypertension 0/3 (0%) 1/27 (3.7%) 2/28 (7.1%) 2/29 (6.9%) 3/28 (10.7%) 2/22 (9.1%) 0/3 (0%) 1/18 (5.6%)
    Hypotension 0/3 (0%) 1/27 (3.7%) 1/28 (3.6%) 1/29 (3.4%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Temporal arteritis 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 1/28 (3.6%) 0/22 (0%) 0/3 (0%) 0/18 (0%)
    Aortic aneurysm 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)
    Vascular pseudoaneurysm 0/3 (0%) 0/27 (0%) 0/28 (0%) 0/29 (0%) 0/28 (0%) 0/22 (0%) 0/3 (0%) 1/18 (5.6%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.

    Results Point of Contact

    Name/Title Pfizer ClinicalTrials.gov Call Center
    Organization Pfizer Inc.
    Phone 1-800-718-1021
    Email ClinicalTrials.gov_Inquiries@pfizer.com
    Responsible Party:
    Pfizer
    ClinicalTrials.gov Identifier:
    NCT00510718
    Other Study ID Numbers:
    • S-3100-1-01
    • C3431009
    • NCT00513812
    First Posted:
    Aug 2, 2007
    Last Update Posted:
    Oct 3, 2019
    Last Verified:
    Sep 1, 2019