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    Clinical Trial Results:
    A Phase IIb Randomized, Placebo- and Active Comparator (Tolterodine)-Controlled, 2-Part Clinical Study of the Efficacy and Safety of MK-4618 in Patients with Overactive Bladder A 52-week Extension to: A Phase IIb Randomized, Placebo- and Active Comparator (Tolterodine)-Controlled, 2-Part Clinical Study of the Efficacy and Safety of MK-4618 in Patients with Overactive Bladder

    Summary
    EudraCT number
    		 2010-022121-15
    Trial protocol
    		 SE   DE   GB   DK   AT   NO   PL   IT  
    Global end of trial date
    10 Oct 2013

    Results information
    Results version number
    		 v2(current)
    This version publication date
    15 Jul 2016
    First version publication date
    19 Apr 2015
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    4618-008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01314872
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Oct 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Oct 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    (1.) To investigate a dose-related reduction in average number of daily micturitions of vibegron compared with placebo at Week 8 in participants with Overactive Bladder (OAB). (2.) To assess the safety and tolerability of treatment with the selected vibegron (MK-4618) doses either alone or dosed concomitantly with tolterodine ER. The primary hypothesis of the base study is that administration of vibegron demonstrates a dose-related reduction, compared with placebo, in average number of daily micturitions in participants with OAB after 8 weeks of treatment.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Mar 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 75
    Country: Number of subjects enrolled
    Poland: 38
    Country: Number of subjects enrolled
    Sweden: 47
    Country: Number of subjects enrolled
    United Kingdom: 67
    Country: Number of subjects enrolled
    Austria: 9
    Country: Number of subjects enrolled
    Denmark: 47
    Country: Number of subjects enrolled
    Germany: 104
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    United States: 525
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Canada: 20
    Country: Number of subjects enrolled
    Japan: 288
    Country: Number of subjects enrolled
    Korea, Republic of: 38
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    New Zealand: 20
    Country: Number of subjects enrolled
    Peru: 35
    Country: Number of subjects enrolled
    Puerto Rico: 5
    Country: Number of subjects enrolled
    Russian Federation: 15
    Country: Number of subjects enrolled
    South Africa: 54
    Worldwide total number of subjects
    1395
    EEA total number of subjects
    391
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    982
    From 65 to 84 years
    413
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This was a 2-Part, randomized, double blind placebo- and active-controlled, parallel-group study of vibegron in men and women with OAB. Participants enrolled in Part 1 were not eligible to participate in Part 2. Participants who completed Part 1 or Part 2 were eligible to enroll in an optional 1-year safety extension.

    Period 1
    Period 1 title
    Treatment Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1: placebo
    Arm description
    		 Participants received two placebo matching vibegron tablets and one placebo matching tolterodine extended release (ER) capsule, taken orally each morning, for 8 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo matching vibegron
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo matching vibegron tablets, taken orally each morning.

    Investigational medicinal product name
    placebo matching tolterodine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a placebo matching tolterodine ER capsule, taken orally each morning.

    Arm title
    		 Part 1: vibegron 3 mg
    Arm description
    		 Participants received one vibegron 3 mg tablet, one placebo matching vibegron tablet, and one placebo matching tolterodine ER capsule, taken orally each morning, for 8 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    vibegron
    Investigational medicinal product code
    Other name
    MK-4618
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received vibegron tablets at dosages of 3 mg, 15 mg, 50 mg, or 100 mg depending on their vibegron Arm assignment, taken orally each morning.

    Investigational medicinal product name
    placebo matching tolterodine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Other use
    Dosage and administration details
    Participants received a placebo matching tolterodine ER capsule, taken orally each morning.

    Investigational medicinal product name
    placebo matching vibegron
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo matching vibegron tablets, taken orally each morning.

    Arm title
    		 Part 1: vibegron 15 mg
    Arm description
    		 Participants received one vibegron 15 mg tablet, one placebo matching vibegron tablet, and one placebo matching tolterodine ER capsule, taken orally each morning, for 8 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    vibegron
    Investigational medicinal product code
    Other name
    MK-4618
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received vibegron tablets at dosages of 3 mg, 15 mg, 50 mg, or 100 mg depending on their vibegron Arm assignment, taken orally each morning.

    Investigational medicinal product name
    placebo matching tolterodine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a placebo matching tolterodine ER capsule, taken orally each morning.

    Investigational medicinal product name
    placebo matching vibegron
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo matching vibegron tablets, taken orally each morning.

    Arm title
    		 Part 1: vibegron 50 mg
    Arm description
    		 Participants received one vibegron 50 mg tablet, one placebo matching vibegron tablet, and one placebo matching tolterodine ER capsule, taken orally each morning, for 8 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    vibegron
    Investigational medicinal product code
    Other name
    4618
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received vibegron tablets at dosages of 3 mg, 15 mg, 50 mg, or 100 mg depending on their vibegron Arm assignment, taken orally each morning.

    Investigational medicinal product name
    placebo matching vibegron
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo matching vibegron tablets, taken orally each morning.

    Investigational medicinal product name
    placebo matching tolterodine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a placebo matching tolterodine ER capsule, taken orally each morning.

    Arm title
    		 Part 1: vibegron 100 mg
    Arm description
    		 Participants received two vibegron 50 mg tablets and one placebo matching tolterodine ER capsule, taken orally each morning, for 8 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    vibegron
    Investigational medicinal product code
    Other name
    MK-4618
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received vibegron tablets at dosages of 3 mg, 15 mg, 50 mg, or 100 mg depending on their vibegron Arm assignment, taken orally each morning.

    Investigational medicinal product name
    placebo matching tolterodine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a placebo matching tolterodine ER capsule, taken orally each morning.

    Arm title
    		 Part 1: tolterodine ER 4 mg
    Arm description
    		 Participants received one tolterodine ER 4 mg capsule and two placebo matching vibegron tablets, taken orally each morning, for 8 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    tolterodine ER
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received one tolterodine ER 4 mg capsule, taken orally once a day.

    Investigational medicinal product name
    placebo matching vibegron
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo matching vibegron tablets, taken orally each morning.

    Arm title
    		 Part 1: vibegron 50 mg + tolterodine ER 4 mg/vibegron 50 mg
    Arm description
    		 Participants received one vibegron 50 mg tablet and one placebo matching vibegron tablet, taken orally each morning, for 8 weeks. They also received one tolterodine ER 4 mg capsule for the first 4 weeks and one placebo matching tolterodine ER capsule for the second 4 weeks, both taken orally each morning.
    Arm type
    		 Experimental

    Investigational medicinal product name
    vibegron
    Investigational medicinal product code
    Other name
    MK-4618
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received vibegron tablets at dosages of 3 mg, 15 mg, 50 mg, or 100 mg depending on their vibegron Arm assignment, taken orally each morning.

    Investigational medicinal product name
    placebo matching vibegron
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    participants received placebo matching vibegron tablets, taken orally each morning.

    Investigational medicinal product name
    placebo matching tolterodine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a placebo matching tolterodine ER capsule, taken orally each morning.

    Investigational medicinal product name
    tolterodine ER
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received one tolterodine ER 4 mg capsule, taken orally each morning.

    Arm title
    		 Part 2: placebo
    Arm description
    		 Participants received two placebo matching vibegron tablets and one placebo matching tolterodine ER capsule, taken orally each morning, for 4 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo matching tolterodine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a placebo matching tolterodine ER capsule, taken orally each morning.

    Investigational medicinal product name
    placebo matching vibegron
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo matching vibegron tablets, taken orally each morning.

    Arm title
    		 Part 2: vibegron 100 mg
    Arm description
    		 Participants received two vibegron 50 mg tablets and one placebo matching tolterodine ER capsule, taken orally each morning, for 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    placebo matching tolterodine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a placebo matching tolterodine ER capsule, taken orally each morning.

    Investigational medicinal product name
    vibegron
    Investigational medicinal product code
    Other name
    MK-4618
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received vibegron tablets at dosages of 3 mg, 15 mg, 50 mg, or 100 mg depending on their vibegron Arm assignment, taken orally each morning.

    Arm title
    		 Part 2: tolterodine ER 4 mg
    Arm description
    		 Participants received one tolterodine ER 4 mg capsule and two placebo matching vibegron tablets, taken orally each morning, for 4 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    placebo matching vibegron
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo matching vibegron tablets, taken orally each morning.

    Investigational medicinal product name
    tolterodine ER
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received one tolterodine ER 4 mg capsule, taken orally once a day.

    Arm title
    		 Part 2: vibegron 100 mg + tolterodine ER 4 mg
    Arm description
    		 Participants received two vibegron 50 mg tablets and one tolterodine ER 4 mg capsule, taken orally each morning, for 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    tolterodine ER
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received one tolterodine ER 4 mg capsule, taken orally once a day.

    Investigational medicinal product name
    vibegron
    Investigational medicinal product code
    Other name
    MK-4618
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received vibegron tablets at dosages of 3 mg, 15 mg, 50 mg, or 100 mg depending on their vibegron Arm assignment, taken orally each morning.

    Number of subjects in period 1
    		Part 1: placebo Part 1: vibegron 3 mg Part 1: vibegron 15 mg Part 1: vibegron 50 mg Part 1: vibegron 100 mg Part 1: tolterodine ER 4 mg Part 1: vibegron 50 mg + tolterodine ER 4 mg/vibegron 50 mg Part 2: placebo Part 2: vibegron 100 mg Part 2: tolterodine ER 4 mg Part 2: vibegron 100 mg + tolterodine ER 4 mg
    Started
    141
    144
    134
    150
    149
    135
    134
    64
    112
    122
    110
    Completed
    131
    138
    128
    143
    142
    128
    126
    57
    106
    118
    107
    Not completed
    10
    6
    6
    7
    7
    7
    8
    7
    6
    4
    3
         Consent withdrawn by subject
    3
    1
    -
    2
    3
    1
    3
    2
    2
    2
    1
         Physician decision
    -
    1
    -
    1
    -
    -
    -
    -
    -
    1
    -
         Adverse event, non-fatal
    4
    2
    3
    2
    2
    4
    4
    2
    3
    -
    1
         Lost to follow-up
    -
    1
    2
    2
    1
    1
    1
    1
    1
    -
    -
         Lack of efficacy
    1
    -
    -
    -
    -
    1
    -
    2
    -
    -
    -
         Protocol deviation
    2
    1
    1
    -
    1
    -
    -
    -
    -
    1
    1
    Period 2
    Period 2 title
    Extension Study
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Extension Study: vibegron 50 mg
    Arm description
    		 Participants in Base Study/Part 1 who received vibegron 50 mg continued their treatment in the Extension Study. In addition, participants in Base Study/Part 1 who received vibegron 3 mg received vibegron 50 mg in the Extension Study. Also, participants in Base Study/Part 1 who received vibegron 50 mg + tolterodine ER for 4 weeks, followed by vibegron 50 mg alone for 4 weeks, remained on vibegron 50 mg in the Extension Study. In the extension, participants received one vibegron 50 mg tablet, one placebo matching vibegron tablet, and one placebo matching tolterodine ER capsule, taken orally each morning, for 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    vibegron
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were randomized to receive vibegron tablets at dosages of 3 mg, 15 mg, 50 mg, or 100 mg, taken orally each morning.

    Investigational medicinal product name
    placebo matching tolterodine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a placebo matching tolterodine ER capsule, taken orally each morning.

    Investigational medicinal product name
    placebo matching vibegron
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo matching vibegron tablets, taken orally each morning.

    Arm title
    		 Extension Study: vibegron 100 mg
    Arm description
    		 Participants in Base Study/Part 1 or Part 2 who received vibegron 100 mg continued their treatment in the Extension Study. In addition, participants in Base Study/Part 1 who received vibegron 15 mg received vibegron 100 mg in the Extension Study. In the extension, participants received two vibegron 50 mg tablets and one placebo matching tolterodine ER capsule, taken orally each morning, for 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    placebo matching tolterodine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a placebo matching tolterodine ER capsule, taken orally each morning.

    Investigational medicinal product name
    vibegron
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received vibegron tablets at dosages of 3 mg, 15 mg, 50 mg, or 100 mg, taken orally each morning.

    Arm title
    		 Extension Study: tolterodine ER 4 mg
    Arm description
    		 Participants in Base Study/Part 1 or Part 2 who received tolterodine ER 4 mg continued their treatment in the Extension Study. In addition, participants in Base Study/Part 1 who received placebo also received tolterodine ER 4 mg in the Extension Study. In the extension, participants received one tolterodine ER 4 mg capsule and two placebo matching vibegron tablets, taken orally each morning, for 52 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    placebo matching vibegron
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo matching vibegron tablets, taken orally each morning.

    Investigational medicinal product name
    tolterodine ER
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received one tolterodine ER 4 mg capsule, taken orally each morning.

    Arm title
    		 Extension Study: vibegron 100 mg + tolterodine ER 4 mg
    Arm description
    		 Participants in Base Study/Part 1 who received vibegron 100 mg + tolterodine ER 4 mg continued their treatment in the Extension Study. In addition, participants in Base Study/Part 2 who received placebo were assigned to the vibegron 100 mg + tolterodine ER 4 mg arm in the Extension Study. In the extension, participants received two vibegron 50 mg tablets and one tolterodine ER 4 mg capsule, taken orally each morning, for 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    tolterodine ER
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received one tolterodine ER 4 mg capsule, taken orally once a day.

    Investigational medicinal product name
    vibegron
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received vibegron tablets at dosages of 3 mg, 15 mg, 50 mg, or 100 mg, taken orally each morning.

    Number of subjects in period 2 [1]
    		Extension Study: vibegron 50 mg Extension Study: vibegron 100 mg Extension Study: tolterodine ER 4 mg Extension Study: vibegron 100 mg + tolterodine ER 4 mg
    Started
    223
    248
    240
    134
    Completed
    175
    188
    187
    110
    Not completed
    48
    60
    53
    24
         Consent withdrawn by subject
    14
    17
    12
    4
         Adverse event, non-fatal
    13
    16
    24
    9
         Pregnancy
    -
    -
    -
    1
         Non-compliance with study drug
    3
    3
    1
    2
         Study terminated by sponsor
    2
    2
    3
    -
         Lost to follow-up
    6
    7
    2
    6
         Lack of efficacy
    7
    12
    9
    2
         Protocol deviation
    3
    3
    2
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Participants who completed Part 1 or Part 2 of the Base Study were eligible to enroll in an optional 1-year safety extension.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Part 1: placebo
    Reporting group description
    		 Participants received two placebo matching vibegron tablets and one placebo matching tolterodine extended release (ER) capsule, taken orally each morning, for 8 weeks.

    Reporting group title
    Part 1: vibegron 3 mg
    Reporting group description
    		 Participants received one vibegron 3 mg tablet, one placebo matching vibegron tablet, and one placebo matching tolterodine ER capsule, taken orally each morning, for 8 weeks.

    Reporting group title
    Part 1: vibegron 15 mg
    Reporting group description
    		 Participants received one vibegron 15 mg tablet, one placebo matching vibegron tablet, and one placebo matching tolterodine ER capsule, taken orally each morning, for 8 weeks.

    Reporting group title
    Part 1: vibegron 50 mg
    Reporting group description
    		 Participants received one vibegron 50 mg tablet, one placebo matching vibegron tablet, and one placebo matching tolterodine ER capsule, taken orally each morning, for 8 weeks.

    Reporting group title
    Part 1: vibegron 100 mg
    Reporting group description
    		 Participants received two vibegron 50 mg tablets and one placebo matching tolterodine ER capsule, taken orally each morning, for 8 weeks.

    Reporting group title
    Part 1: tolterodine ER 4 mg
    Reporting group description
    		 Participants received one tolterodine ER 4 mg capsule and two placebo matching vibegron tablets, taken orally each morning, for 8 weeks.

    Reporting group title
    Part 1: vibegron 50 mg + tolterodine ER 4 mg/vibegron 50 mg
    Reporting group description
    		 Participants received one vibegron 50 mg tablet and one placebo matching vibegron tablet, taken orally each morning, for 8 weeks. They also received one tolterodine ER 4 mg capsule for the first 4 weeks and one placebo matching tolterodine ER capsule for the second 4 weeks, both taken orally each morning.

    Reporting group title
    Part 2: placebo
    Reporting group description
    		 Participants received two placebo matching vibegron tablets and one placebo matching tolterodine ER capsule, taken orally each morning, for 4 weeks.

    Reporting group title
    Part 2: vibegron 100 mg
    Reporting group description
    		 Participants received two vibegron 50 mg tablets and one placebo matching tolterodine ER capsule, taken orally each morning, for 4 weeks.

    Reporting group title
    Part 2: tolterodine ER 4 mg
    Reporting group description
    		 Participants received one tolterodine ER 4 mg capsule and two placebo matching vibegron tablets, taken orally each morning, for 4 weeks.

    Reporting group title
    Part 2: vibegron 100 mg + tolterodine ER 4 mg
    Reporting group description
    		 Participants received two vibegron 50 mg tablets and one tolterodine ER 4 mg capsule, taken orally each morning, for 4 weeks.

    Reporting group values
    		 Part 1: placebo Part 1: vibegron 3 mg Part 1: vibegron 15 mg Part 1: vibegron 50 mg Part 1: vibegron 100 mg Part 1: tolterodine ER 4 mg Part 1: vibegron 50 mg + tolterodine ER 4 mg/vibegron 50 mg Part 2: placebo Part 2: vibegron 100 mg Part 2: tolterodine ER 4 mg Part 2: vibegron 100 mg + tolterodine ER 4 mg Total
    Number of subjects
    		 141 144 134 150 149 135 134 64 112 122 110 1395
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.6 ( 9 ) 59.4 ( 8.7 ) 58.6 ( 8.1 ) 60.3 ( 8.7 ) 60.3 ( 8.3 ) 59.1 ( 8.1 ) 59.4 ( 8.5 ) 56.3 ( 10.6 ) 57.2 ( 10.1 ) 57.9 ( 10.9 ) 55.5 ( 11.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 128 131 125 129 135 121 119 57 101 110 95 1251
        Male
    		 13 13 9 21 14 14 15 7 11 12 15 144

    End points

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    End points reporting groups
    Reporting group title
    Part 1: placebo
    Reporting group description
    		 Participants received two placebo matching vibegron tablets and one placebo matching tolterodine extended release (ER) capsule, taken orally each morning, for 8 weeks.

    Reporting group title
    Part 1: vibegron 3 mg
    Reporting group description
    		 Participants received one vibegron 3 mg tablet, one placebo matching vibegron tablet, and one placebo matching tolterodine ER capsule, taken orally each morning, for 8 weeks.

    Reporting group title
    Part 1: vibegron 15 mg
    Reporting group description
    		 Participants received one vibegron 15 mg tablet, one placebo matching vibegron tablet, and one placebo matching tolterodine ER capsule, taken orally each morning, for 8 weeks.

    Reporting group title
    Part 1: vibegron 50 mg
    Reporting group description
    		 Participants received one vibegron 50 mg tablet, one placebo matching vibegron tablet, and one placebo matching tolterodine ER capsule, taken orally each morning, for 8 weeks.

    Reporting group title
    Part 1: vibegron 100 mg
    Reporting group description
    		 Participants received two vibegron 50 mg tablets and one placebo matching tolterodine ER capsule, taken orally each morning, for 8 weeks.

    Reporting group title
    Part 1: tolterodine ER 4 mg
    Reporting group description
    		 Participants received one tolterodine ER 4 mg capsule and two placebo matching vibegron tablets, taken orally each morning, for 8 weeks.

    Reporting group title
    Part 1: vibegron 50 mg + tolterodine ER 4 mg/vibegron 50 mg
    Reporting group description
    		 Participants received one vibegron 50 mg tablet and one placebo matching vibegron tablet, taken orally each morning, for 8 weeks. They also received one tolterodine ER 4 mg capsule for the first 4 weeks and one placebo matching tolterodine ER capsule for the second 4 weeks, both taken orally each morning.

    Reporting group title
    Part 2: placebo
    Reporting group description
    		 Participants received two placebo matching vibegron tablets and one placebo matching tolterodine ER capsule, taken orally each morning, for 4 weeks.

    Reporting group title
    Part 2: vibegron 100 mg
    Reporting group description
    		 Participants received two vibegron 50 mg tablets and one placebo matching tolterodine ER capsule, taken orally each morning, for 4 weeks.

    Reporting group title
    Part 2: tolterodine ER 4 mg
    Reporting group description
    		 Participants received one tolterodine ER 4 mg capsule and two placebo matching vibegron tablets, taken orally each morning, for 4 weeks.

    Reporting group title
    Part 2: vibegron 100 mg + tolterodine ER 4 mg
    Reporting group description
    		 Participants received two vibegron 50 mg tablets and one tolterodine ER 4 mg capsule, taken orally each morning, for 4 weeks.
    Reporting group title
    Extension Study: vibegron 50 mg
    Reporting group description
    		 Participants in Base Study/Part 1 who received vibegron 50 mg continued their treatment in the Extension Study. In addition, participants in Base Study/Part 1 who received vibegron 3 mg received vibegron 50 mg in the Extension Study. Also, participants in Base Study/Part 1 who received vibegron 50 mg + tolterodine ER for 4 weeks, followed by vibegron 50 mg alone for 4 weeks, remained on vibegron 50 mg in the Extension Study. In the extension, participants received one vibegron 50 mg tablet, one placebo matching vibegron tablet, and one placebo matching tolterodine ER capsule, taken orally each morning, for 52 weeks.

    Reporting group title
    Extension Study: vibegron 100 mg
    Reporting group description
    		 Participants in Base Study/Part 1 or Part 2 who received vibegron 100 mg continued their treatment in the Extension Study. In addition, participants in Base Study/Part 1 who received vibegron 15 mg received vibegron 100 mg in the Extension Study. In the extension, participants received two vibegron 50 mg tablets and one placebo matching tolterodine ER capsule, taken orally each morning, for 52 weeks.

    Reporting group title
    Extension Study: tolterodine ER 4 mg
    Reporting group description
    		 Participants in Base Study/Part 1 or Part 2 who received tolterodine ER 4 mg continued their treatment in the Extension Study. In addition, participants in Base Study/Part 1 who received placebo also received tolterodine ER 4 mg in the Extension Study. In the extension, participants received one tolterodine ER 4 mg capsule and two placebo matching vibegron tablets, taken orally each morning, for 52 weeks.

    Reporting group title
    Extension Study: vibegron 100 mg + tolterodine ER 4 mg
    Reporting group description
    		 Participants in Base Study/Part 1 who received vibegron 100 mg + tolterodine ER 4 mg continued their treatment in the Extension Study. In addition, participants in Base Study/Part 2 who received placebo were assigned to the vibegron 100 mg + tolterodine ER 4 mg arm in the Extension Study. In the extension, participants received two vibegron 50 mg tablets and one tolterodine ER 4 mg capsule, taken orally each morning, for 52 weeks.

    Primary: Base Study/Part 1: Change from Baseline in Average Daily Number of Micturitions at Week 8

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    End point title
    		 Base Study/Part 1: Change from Baseline in Average Daily Number of Micturitions at Week 8 [1]
    End point description
    Participants were required to keep a voiding diary, recording the occurrence of each micturition. The average daily number of micturitions was calculated as the total number of micturitions that occurred over a week (4 to 10 days) during the Base Study, divided by the total number of days of voiding kept in the participant's diary. Baseline was defined as the average daily number of daily micturitions that occurred during the week of placebo run-in prior to Week 0 visit. This endpoint was based on the full analysis set population, which included all randomized participants who received at least one dose of study treatment and have either baseline data or at least one post-randomization observation for the analysis endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Week 8
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Participants in this treatment group took MK-4618 50 mg + tolterodine ER 4 mg for the first 4 weeks and MK-4618 50 mg in the later 4 weeks. This treatment group was not statistically analyzed.
    End point values
    		 Part 1: placebo Part 1: vibegron 3 mg Part 1: vibegron 15 mg Part 1: vibegron 50 mg Part 1: vibegron 100 mg Part 1: tolterodine ER 4 mg Part 1: vibegron 50 mg + tolterodine ER 4 mg/vibegron 50 mg
    Number of subjects analysed
    141
    144
    132
    148
    148
    134
    134
    Units: Average Daily Number of Micturitions
        least squares mean (confidence interval 95%)
    -1.16 (-1.5 to -0.82)
    -1.62 (-1.95 to -1.29)
    -1.61 (-1.96 to -1.27)
    -1.8 (-2.13 to -1.47)
    -2.07 (-2.4 to -1.74)
    -1.71 (-2.05 to -1.36)
    -2.05 (-2.4 to -1.7)
    Statistical analysis title
    		 Difference in Least Squares (LS) Means
    Statistical analysis description
    Difference in LS Means: vibegron 3 mg vs. placebo at Week 8
    Comparison groups
    Part 1: placebo v Part 1: vibegron 3 mg
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.056
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS means
    Point estimate
    -0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.92
         upper limit
    		 0.01
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: vibegron 15 mg vs. placebo at Week 8
    Comparison groups
    Part 1: placebo v Part 1: vibegron 15 mg
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.064
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.93
         upper limit
    		 0.03
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: vibegron 50 mg vs. placebo at Week 8
    Comparison groups
    Part 1: placebo v Part 1: vibegron 50 mg
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.11
         upper limit
    		 -0.18
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: vibegron 100 mg vs. placebo at Week 8
    Comparison groups
    Part 1: placebo v Part 1: vibegron 100 mg
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.37
         upper limit
    		 -0.44
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: tolterodine ER 4 mg vs. placebo at Week 8
    Comparison groups
    Part 1: placebo v Part 1: tolterodine ER 4 mg
    Number of subjects included in analysis
    275
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.026
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.02
         upper limit
    		 -0.07

    Primary: Base Study/Part 1 + Part 2: Number of Participants Who Experienced an Adverse Event (AE)

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    End point title
    		 Base Study/Part 1 + Part 2: Number of Participants Who Experienced an Adverse Event (AE) [2]
    End point description
    An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not it is considered related to the study drug. This endpoint was based on the all participants as treated population, which consisted of all randomized participants who received at least one dose of study treatment. Participants were included in the treatment group corresponding to the study treatment they actually received.
    End point type
    Primary
    End point timeframe
    Part 1: up to 8 weeks; Part 2: up to 4 weeks. The time frame was an additional 2 weeks for participants not continuing to the Extension Study.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for Base Study/Part 1 + Part 2: Number of Participants Who Experienced an Adverse Event (AE).
    End point values
    		 Part 1: placebo Part 1: vibegron 3 mg Part 1: vibegron 15 mg Part 1: vibegron 50 mg Part 1: vibegron 100 mg Part 1: tolterodine ER 4 mg Part 1: vibegron 50 mg + tolterodine ER 4 mg/vibegron 50 mg Part 2: placebo Part 2: vibegron 100 mg Part 2: tolterodine ER 4 mg Part 2: vibegron 100 mg + tolterodine ER 4 mg
    Number of subjects analysed
    141
    144
    134
    148
    149
    135
    134
    64
    112
    122
    110
    Units: Participants
    66
    55
    70
    62
    70
    68
    69
    22
    37
    48
    40
    No statistical analyses for this end point

    Primary: Base Study/Part 1 + Part 2: Number of Participants Who Had Study Medication Withdrawn Due to an AE

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    End point title
    		 Base Study/Part 1 + Part 2: Number of Participants Who Had Study Medication Withdrawn Due to an AE [3]
    End point description
    An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not it is considered related to the study drug. This endpoint was based on the all participants as treated population, which consisted of all randomized participants who received at least one dose of study treatment. Participants were included in the treatment group corresponding to the study treatment they actually received.
    End point type
    Primary
    End point timeframe
    Part 1: up to 8 weeks; Part 2: up to 4 weeks
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for Base Study/Part 1 + Part 2: Number of Participants Who Had Study Medication Withdrawn Due to an AE.
    End point values
    		 Part 1: placebo Part 1: vibegron 3 mg Part 1: vibegron 15 mg Part 1: vibegron 50 mg Part 1: vibegron 100 mg Part 1: tolterodine ER 4 mg Part 1: vibegron 50 mg + tolterodine ER 4 mg/vibegron 50 mg Part 2: placebo Part 2: vibegron 100 mg Part 2: tolterodine ER 4 mg Part 2: vibegron 100 mg + tolterodine ER 4 mg
    Number of subjects analysed
    141
    144
    134
    148
    149
    135
    134
    64
    112
    122
    110
    Units: Participants
    3
    3
    4
    2
    2
    4
    3
    2
    4
    0
    2
    No statistical analyses for this end point

    Primary: Extension Study: Number of Participants Who Experienced an AE

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    End point title
    		 Extension Study: Number of Participants Who Experienced an AE [4]
    End point description
    An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not it is considered related to the study drug. This endpoint was based on the all participants as treated population, which consisted of all randomized participants who received at least one dose of study treatment. Participants were included in the treatment group corresponding to the study treatment they actually received.
    End point type
    Primary
    End point timeframe
    Up to Week 54 of the Extension Study
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for Extension Study: Number of Participants Who Experienced an AE.
    End point values
    		 Extension Study: vibegron 50 mg Extension Study: vibegron 100 mg Extension Study: tolterodine ER 4 mg Extension Study: vibegron 100 mg + tolterodine ER 4 mg
    Number of subjects analysed
    223
    248
    240
    134
    Units: Participants
    134
    157
    158
    82
    No statistical analyses for this end point

    Primary: Extension Study: Number of Participants Who Had Study Medication Withdrawn Due to an AE

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    End point title
    		 Extension Study: Number of Participants Who Had Study Medication Withdrawn Due to an AE [5]
    End point description
    An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not it is considered related to the study drug. This endpoint was based on the all participants as treated population, which consisted of all randomized participants who received at least one dose of study treatment. Participants were included in the treatment group corresponding to the study treatment they actually received.
    End point type
    Primary
    End point timeframe
    Up to Week 52 of the Extension Study
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for Extension Study: Number of Participants Who Had Study Medication Withdrawn Due to an AE.
    End point values
    		 Extension Study: vibegron 50 mg Extension Study: vibegron 100 mg Extension Study: tolterodine ER 4 mg Extension Study: vibegron 100 mg + tolterodine ER 4 mg
    Number of subjects analysed
    223
    248
    240
    134
    Units: Participants
    11
    14
    24
    7
    No statistical analyses for this end point

    Secondary: Base Study/Part 1: Change from Baseline in Average Daily Number of Urge Incontinence Episodes at Week 8

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    End point title
    		 Base Study/Part 1: Change from Baseline in Average Daily Number of Urge Incontinence Episodes at Week 8 [6]
    End point description
    Participants were required to keep a voiding diary, recording the occurrence of each urge incontinence episode. The average daily number of urge incontinence episodes was calculated as the total number of times a participant experienced such an episode over a week (4 to 10 days) during the Base Study, divided by the total number of days of voiding kept in the participant's diary. This endpoint was based on the full analysis set population, which included all randomized participants who received at least one dose of study treatment and have either baseline data or at least one post-randomization observation for the analysis endpoint. This outcome measure included OAB Wet (OAB with urinary urgency incontinence) participants only. Baseline was defined as the average daily number of urge incontinence episodes that occurred during the week of placebo run-in prior to Week 0 visit.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 8
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Participants in this treatment group took MK-4618 50 mg + tolterodine ER 4 mg for the first 4 weeks and MK-4618 50 mg in the later 4 weeks. This treatment group was not statistically analyzed.
    End point values
    		 Part 1: placebo Part 1: vibegron 3 mg Part 1: vibegron 15 mg Part 1: vibegron 50 mg Part 1: vibegron 100 mg Part 1: tolterodine ER 4 mg Part 1: vibegron 50 mg + tolterodine ER 4 mg/vibegron 50 mg
    Number of subjects analysed
    118
    113
    111
    121
    122
    100
    111
    Units: Number of Urge Incontinence Episodes
        least squares mean (confidence interval 95%)
    -1.24 (-1.52 to -0.95)
    -1.52 (-1.81 to -1.23)
    -1.81 (-2.1 to -1.51)
    -1.95 (-2.23 to -1.67)
    -1.95 (-2.23 to -1.67)
    -1.69 (-2 to -1.38)
    -1.71 (-2.01 to -1.42)
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: vibegron 3 mg vs. placebo at Week 8
    Comparison groups
    Part 1: placebo v Part 1: vibegron 3 mg
    Number of subjects included in analysis
    231
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.167
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.68
         upper limit
    		 0.12
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: vibegron 15 mg vs. placebo at Week 8
    Comparison groups
    Part 1: placebo v Part 1: vibegron 15 mg
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.97
         upper limit
    		 -0.17
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: vibegron 50 mg vs. placebo at Week 8
    Comparison groups
    Part 1: placebo v Part 1: vibegron 50 mg
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.11
         upper limit
    		 -0.33
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: vibegron 100 mg vs. placebo at Week 8
    Comparison groups
    Part 1: placebo v Part 1: vibegron 100 mg
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 -0.32
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: tolterodine ER 4 mg vs. placebo at Week 8
    Comparison groups
    Part 1: placebo v Part 1: tolterodine ER 4 mg
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.87
         upper limit
    		 -0.04

    Secondary: Base Study/Part 1: Change from Baseline in Average Daily Number of Total Incontinence Episodes at Week 8

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    End point title
    		 Base Study/Part 1: Change from Baseline in Average Daily Number of Total Incontinence Episodes at Week 8 [7]
    End point description
    Participants were required to keep a voiding diary, recording the occurrence of each total incontinence episode. The average daily number of total incontinence episodes was calculated as the total number of times a participant experienced such an episode over a week (4 to 10 days) during the Base Study, divided by the total number of days of voiding kept in the participant's diary. This endpoint was based on the full analysis set population, which included all randomized participants who received at least one dose of study treatment and have either baseline data or at least one post-randomization observation for the analysis endpoint. This outcome measure included OAB Wet participants only. Baseline was defined as the average daily number of total incontinence episodes that occurred during the week of placebo run-in prior to Week 0 visit.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 8
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Participants in this treatment group took MK-4618 50 mg + tolterodine ER 4 mg for the first 4 weeks and MK-4618 50 mg in the later 4 weeks. This treatment group was not statistically analyzed.
    End point values
    		 Part 1: placebo Part 1: vibegron 3 mg Part 1: vibegron 15 mg Part 1: vibegron 50 mg Part 1: vibegron 100 mg Part 1: tolterodine ER 4 mg Part 1: vibegron 50 mg + tolterodine ER 4 mg/vibegron 50 mg
    Number of subjects analysed
    118
    113
    111
    121
    122
    100
    111
    Units: Incontinence Episodes
        least squares mean (confidence interval 95%)
    -1.52 (-1.84 to -1.21)
    -1.71 (-2.02 to -1.39)
    -2.01 (-2.33 to -1.69)
    -2.13 (-2.43 to -1.82)
    -2.11 (-2.41 to -1.8)
    -1.86 (-2.2 to -1.52)
    -2 (-2.32 to -1.68)
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: vibegron 3 mg vs. placebo at Week 8
    Comparison groups
    Part 1: placebo v Part 1: vibegron 3 mg
    Number of subjects included in analysis
    231
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.401
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.61
         upper limit
    		 0.25
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: vibegron 15 mg vs. placebo at Week 8
    Comparison groups
    Part 1: placebo v Part 1: vibegron 15 mg
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.029
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.91
         upper limit
    		 -0.05
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: vibegron 50 mg vs. placebo at Week 8
    Comparison groups
    Part 1: placebo v Part 1: vibegron 50 mg
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.02
         upper limit
    		 -0.18
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: vibegron 100 mg vs. placebo at Week 8
    Comparison groups
    Part 1: placebo v Part 1: vibegron 100 mg
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.01
         upper limit
    		 -0.16
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: tolterodine ER 4 mg vs. placebo at Week 8
    Comparison groups
    Part 1: placebo v Part 1: tolterodine ER 4 mg
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.14
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.78
         upper limit
    		 0.11

    Secondary: Base Study/Part 1: Change from Baseline in Average Daily Number of Strong Urge Episodes at Week 8

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    End point title
    		 Base Study/Part 1: Change from Baseline in Average Daily Number of Strong Urge Episodes at Week 8 [8]
    End point description
    Participants were required to keep a voiding diary, recording the occurrence of each strong urge episode. The average daily number of strong urge episodes was calculated as the total number of times a participant experienced such an episode over a week (4 to 10 days) during the Base Study, divided by the total number of days of voiding kept in the participant's diary. Baseline was defined as the average daily number of strong urge episodes that occurred during the week of placebo run-in prior to Week 0 visit. This endpoint was based on the full analysis set population, which included all randomized participants who received at least one dose of study treatment and have either baseline data or at least one post-randomization observation for the analysis endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 8
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Participants in this treatment group took MK-4618 50 mg + tolterodine ER 4 mg for the first 4 weeks and MK-4618 50 mg in the later 4 weeks. This treatment group was not statistically analyzed.
    End point values
    		 Part 1: placebo Part 1: vibegron 3 mg Part 1: vibegron 15 mg Part 1: vibegron 50 mg Part 1: vibegron 100 mg Part 1: tolterodine ER 4 mg Part 1: vibegron 50 mg + tolterodine ER 4 mg/vibegron 50 mg
    Number of subjects analysed
    141
    144
    132
    148
    148
    134
    134
    Units: Strong Urge Episodes
        least squares mean (confidence interval 95%)
    -1.59 (-2.07 to -1.11)
    -1.77 (-2.24 to -1.3)
    -2.27 (-2.76 to -1.78)
    -2.36 (-2.82 to -1.89)
    -2.83 (-3.3 to -2.37)
    -2.53 (-3.03 to -2.04)
    -2.73 (-3.22 to -2.24)
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: vibegron 3 mg vs. placebo at Week 8
    Comparison groups
    Part 1: placebo v Part 1: vibegron 3 mg
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.598
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.84
         upper limit
    		 0.49
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: vibegron 15 mg vs. placebo at Week 8
    Comparison groups
    Part 1: placebo v Part 1: vibegron 15 mg
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.052
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.35
         upper limit
    		 0.01
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: vibegron 50 mg vs. placebo at Week 8
    Comparison groups
    Part 1: placebo v Part 1: vibegron 50 mg
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.024
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.43
         upper limit
    		 -0.1
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: vibegron 100 mg vs. placebo at Week 8
    Comparison groups
    Part 1: placebo v Part 1: vibegron 100 mg
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 -0.58
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: tolterodine ER 4 mg vs. placebo at Week 8
    Comparison groups
    Part 1: placebo v Part 1: tolterodine ER 4 mg
    Number of subjects included in analysis
    275
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.62
         upper limit
    		 -0.26

    Secondary: Extension Study: Change From Baseline in Average Daily Number of Micturitions at Week 52

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    End point title
    		 Extension Study: Change From Baseline in Average Daily Number of Micturitions at Week 52
    End point description
    Participants were required to keep a voiding diary, recording the daily occurrence of each micturition. The average daily number of micturitions was calculated as the total number of recorded micturitions that occurred during the 52-week Extension Study, divided by the total number of days of voiding kept in the participant's diary. Baseline was defined as the value at Week 0 of the Base Study. This endpoint was based on the full analysis set population, which included all randomized participants who received at least one dose of study treatment and have either baseline data or at least one post-randomization observation for the analysis endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52 of Extension Study
    End point values
    		 Extension Study: vibegron 50 mg Extension Study: vibegron 100 mg Extension Study: tolterodine ER 4 mg Extension Study: vibegron 100 mg + tolterodine ER 4 mg
    Number of subjects analysed
    223
    246
    240
    134
    Units: Average Daily Number of Micturitions
        least squares mean (confidence interval 95%)
    -2.53 (-2.87 to -2.2)
    -2.77 (-3.08 to -2.45)
    -2.15 (-2.47 to -1.83)
    -3.25 (-3.67 to -2.83)
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: vibegron 100 mg + tolterodine ER 4 mg vs. vibegron 100 mg at Week 52
    Comparison groups
    Extension Study: vibegron 100 mg v Extension Study: vibegron 100 mg + tolterodine ER 4 mg
    Number of subjects included in analysis
    380
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 0.03
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: vibegron 100 mg + tolterodine ER 4 mg vs. tolterodine ER 4 mg at Week 52
    Comparison groups
    Extension Study: tolterodine ER 4 mg v Extension Study: vibegron 100 mg + tolterodine ER 4 mg
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.62
         upper limit
    		 -0.58

    Secondary: Extension Study: Change from Baseline in Average Daily Number of Urge Incontinence Episodes at Week 52

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    End point title
    		 Extension Study: Change from Baseline in Average Daily Number of Urge Incontinence Episodes at Week 52
    End point description
    Participants were required to keep a voiding diary, recording the occurrence of each urge incontinence episode. The average daily number of urge incontinence episodes was calculated as the total number of times a participant experienced such an episode during 52-week Extension Study, divided by the total number of days of voiding kept in the participant's diary. This endpoint was based on the full analysis set population, which included all randomized participants who received at least one dose of study treatment and have either baseline data or at least one post-randomization observation for the analysis endpoint. This outcome measure included OAB Wet participants only. Baseline was defined as the value at Week 0 of the Base Study.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52 of Extension Study
    End point values
    		 Extension Study: vibegron 50 mg Extension Study: vibegron 100 mg Extension Study: tolterodine ER 4 mg Extension Study: vibegron 100 mg + tolterodine ER 4 mg
    Number of subjects analysed
    179
    200
    189
    112
    Units: Avg Daily No of Urge Incontinence Eps
        least squares mean (confidence interval 95%)
    -2.43 (-2.72 to -2.14)
    -2.15 (-2.43 to -1.87)
    -2.23 (-2.51 to -1.94)
    -2.44 (-2.79 to -2.09)
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Difference in LS Means: vibegron 100 mg + tolterodine ER 4 mg vs. vibegron 100 mg at Week 52
    Comparison groups
    Extension Study: vibegron 100 mg v Extension Study: vibegron 100 mg + tolterodine ER 4 mg
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.71
         upper limit
    		 0.13
    Statistical analysis title
    		 Difference in LS Means
    Comparison groups
    Extension Study: vibegron 100 mg + tolterodine ER 4 mg v Extension Study: tolterodine ER 4 mg
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.64
         upper limit
    		 0.21

    Secondary: Extension Study: Change from Baseline in Average Daily Number of Total Incontinence Episodes at Week 52

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    End point title
    		 Extension Study: Change from Baseline in Average Daily Number of Total Incontinence Episodes at Week 52
    End point description
    Participants were required to keep a voiding diary, recording the occurrence of each total incontinence episode. The average daily number of total incontinence episodes was calculated as the total number of times a participant experienced such an episode during 52-week Extension Study, divided by the total number of days of voiding kept in the participant's diary. This endpoint was based on the full analysis set population, which included all randomized participants who received at least one dose of study treatment and have either baseline data or at least one post-randomization observation for the analysis endpoint. This outcome measure included OAB Wet participants only. Baseline was defined as the value at Week 0 of the Base Study.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52 of Extension Study
    End point values
    		 Extension Study: vibegron 50 mg Extension Study: vibegron 100 mg Extension Study: tolterodine ER 4 mg Extension Study: vibegron 100 mg + tolterodine ER 4 mg
    Number of subjects analysed
    179
    200
    189
    112
    Units: Avg Daily No of Total Incontinence Eps
        least squares mean (confidence interval 95%)
    -2.7 (-3.03 to -2.36)
    -2.42 (-2.74 to -2.09)
    -2.5 (-2.83 to -2.17)
    -2.48 (-2.89 to -2.07)
    Statistical analysis title
    		 Difference in LS Means
    Comparison groups
    Extension Study: vibegron 100 mg + tolterodine ER 4 mg v Extension Study: tolterodine ER 4 mg
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in LS Means
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 0.51
    Statistical analysis title
    		 Difference in LS Means
    Comparison groups
    Extension Study: vibegron 100 mg + tolterodine ER 4 mg v Extension Study: vibegron 100 mg
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.56
         upper limit
    		 0.43

    Secondary: Extension Study: Change From Baseline in Average Daily Number of Strong Urge Episodes at Week 52

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    End point title
    		 Extension Study: Change From Baseline in Average Daily Number of Strong Urge Episodes at Week 52
    End point description
    Participants were required to keep a voiding diary, recording the occurrence of each strong urge episode. The average daily number of strong urge episodes was calculated as the total number of times a participant experienced such an episode during 52-week Extension Study, divided by the total number of days of voiding kept in the participant's diary. Baseline was defined as the value at Week 0 of the Base Study. This endpoint was based on the full analysis set population, which included all randomized participants who received at least one dose of study treatment and have either baseline data or at least one post-randomization observation for the analysis endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52 of Extension Study
    End point values
    		 Extension Study: vibegron 50 mg Extension Study: vibegron 100 mg Extension Study: tolterodine ER 4 mg Extension Study: vibegron 100 mg + tolterodine ER 4 mg
    Number of subjects analysed
    223
    246
    240
    134
    Units: Avg Daily Number of Strong Urge Episodes
        least squares mean (confidence interval 95%)
    -3.11 (-3.55 to -2.67)
    -3.42 (-3.84 to -3)
    -2.94 (-3.36 to -2.52)
    -4.18 (-4.74 to -3.63)
    Statistical analysis title
    		 Difference in LS Means
    Comparison groups
    Extension Study: vibegron 100 mg + tolterodine ER 4 mg v Extension Study: vibegron 100 mg
    Number of subjects included in analysis
    380
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.45
         upper limit
    		 -0.08
    Statistical analysis title
    		 Difference in LS Means
    Comparison groups
    Extension Study: vibegron 100 mg + tolterodine ER 4 mg v Extension Study: tolterodine ER 4 mg
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.93
         upper limit
    		 -0.56

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Base Study/Part 1: up to 8 weeks; Base Study/Part 2: up to 4 weeks (time frame was additional 2 weeks for Parts 1 and 2 participants not continuing to Extension Study); Extension Study: up to 54 weeks (including 2 week follow-up).
    Adverse event reporting additional description
    All participants as treated population consisted of all randomized participants who received at least one dose of study treatment. Participants were included in treatment group corresponding to study treatment they actually received. Two randomized participants who were not treated were excluded from Part 1: vibegron 50 mg arm.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Part 1: placebo
    Reporting group description
    		 Participants received two placebo matching vibegron tablets and one placebo matching tolterodine ER capsule, taken orally each morning, for 8 weeks.

    Reporting group title
    Part 1: vibegron 3 mg
    Reporting group description
    		 Participants received one vibegron 3 mg tablet, one placebo matching vibegron tablet, and one placebo matching tolderodine ER capsule, taken orally each morning, for 8 weeks.

    Reporting group title
    Part 1: vibegron 15 mg
    Reporting group description
    		 Participants received one vibegron 15 mg tablet, one placebo matching vibegron tablet, and one placebo matching tolderodine ER capsule, taken orally each morning, for 8 weeks.

    Reporting group title
    Part 1: vibegron 50 mg
    Reporting group description
    		 Participants received one vibegron 50 mg tablet, one placebo matching vibegron tablet, and one placebo matching tolterodine ER capsule, taken orally each morning, for 8 weeks.

    Reporting group title
    Part 1: vibegron 100 mg
    Reporting group description
    		 Participants received two vibegron 50 mg tablets and one placebo matching tolterodine ER capsule, taken orally each morning, for 8 weeks.

    Reporting group title
    Part 1: tolterodine ER 4 mg
    Reporting group description
    		 Participants received one tolterodine ER 4 mg capsule and two placebo matching vibegron tablets, taken orally each morning, for 8 weeks.

    Reporting group title
    Part 1: vibegron 50 mg + tolterodine ER 4 mg/vibegron 50 mg
    Reporting group description
    		 Participants received one vibegron 50 mg tablet and one placebo matching vibegron tablet, taken orally each morning, for 8 weeks. They also received one tolterodine ER 4 mg capsule for the first 4 weeks and one placebo matching tolterodine ER capsule for the second 4 weeks, both taken orally each morning.

    Reporting group title
    Part 2: placebo
    Reporting group description
    		 Participants received two placebo matching vibegron tablets and one placebo matching tolterodine ER capsule, taken orally each morning, for 4 weeks.

    Reporting group title
    Part 2: vibegron 100 mg + tolterodine ER 4 mg
    Reporting group description
    		 Participants received two vibegron 50 mg tablets and one tolterodine ER 4 mg capsule, taken orally each morning, for 4 weeks.

    Reporting group title
    Part 2: tolterodine ER 4 mg
    Reporting group description
    		 Participants received one tolterodine ER 4 mg capsule and two placebo matching vibegron tablets, taken orally each morning, for 4 weeks.

    Reporting group title
    Part 2: vibegron 100 mg
    Reporting group description
    		 Participants received two vibegron 50 mg tablets and one placebo matching tolterodine ER capsule, taken orally each morning, for 4 weeks.

    Reporting group title
    Extension Study: tolterodine ER 4 mg
    Reporting group description
    		 Participants received one tolterodine ER 4 mg capsule and two placebo matching vibegron tablets, taken orally each morning, for 52 weeks.

    Reporting group title
    Extension Study: vibegron 100 mg
    Reporting group description
    		 Participants received two vibegron 50 mg tablets and one placebo matching tolterodine ER capsule, taken orally each morning, for 52 weeks.

    Reporting group title
    Extension Study: vibegron 50 mg
    Reporting group description
    		 Participants received one vibegron 50 mg tablet, one placebo matching vibegron tablet, and one placebo matching tolterodine ER capsule, taken orally each morning, for 52 weeks.

    Reporting group title
    Extension Study: vibegron 100 mg + tolterodine ER 4 mg
    Reporting group description
    		 Participants received two vibegron 50 mg tablets and one tolterodine ER 4 mg capsule, taken orally each morning, for 52 weeks.

    Serious adverse events
    		 Part 1: placebo Part 1: vibegron 3 mg Part 1: vibegron 15 mg Part 1: vibegron 50 mg Part 1: vibegron 100 mg Part 1: tolterodine ER 4 mg Part 1: vibegron 50 mg + tolterodine ER 4 mg/vibegron 50 mg Part 2: placebo Part 2: vibegron 100 mg + tolterodine ER 4 mg Part 2: tolterodine ER 4 mg Part 2: vibegron 100 mg Extension Study: tolterodine ER 4 mg Extension Study: vibegron 100 mg Extension Study: vibegron 50 mg Extension Study: vibegron 100 mg + tolterodine ER 4 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 141 (1.42%)
    1 / 144 (0.69%)
    0 / 134 (0.00%)
    1 / 148 (0.68%)
    0 / 149 (0.00%)
    1 / 135 (0.74%)
    1 / 134 (0.75%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    2 / 122 (1.64%)
    0 / 112 (0.00%)
    18 / 240 (7.50%)
    8 / 248 (3.23%)
    14 / 223 (6.28%)
    1 / 134 (0.75%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    1 / 240 (0.42%)
    1 / 248 (0.40%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma stage IV
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 144 (0.69%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    1 / 240 (0.42%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device dislocation
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    1 / 223 (0.45%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    1 / 248 (0.40%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    1 / 148 (0.68%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    1 / 240 (0.42%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    1 / 240 (0.42%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    1 / 240 (0.42%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    1 / 223 (0.45%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    1 / 240 (0.42%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    1 / 122 (0.82%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    1 / 223 (0.45%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    1 / 240 (0.42%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    1 / 240 (0.42%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    1 / 223 (0.45%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    1 / 248 (0.40%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle rupture
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    1 / 240 (0.42%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    1 / 223 (0.45%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    1 / 248 (0.40%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    1 / 240 (0.42%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    1 / 248 (0.40%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    1 / 248 (0.40%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    2 / 223 (0.90%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    1 / 122 (0.82%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    1 / 223 (0.45%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    1 / 223 (0.45%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune thrombocytopenia
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    1 / 240 (0.42%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    1 / 248 (0.40%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroesophageal reflux disease
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    1 / 122 (0.82%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    1 / 223 (0.45%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    1 / 240 (0.42%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    1 / 248 (0.40%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    1 / 240 (0.42%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    1 / 223 (0.45%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    1 / 223 (0.45%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    1 / 223 (0.45%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    1 / 240 (0.42%)
    0 / 248 (0.00%)
    2 / 223 (0.90%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    1 / 240 (0.42%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    1 / 240 (0.42%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Borrelia infection
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    1 / 240 (0.42%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    2 / 240 (0.83%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
    1 / 223 (0.45%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    1 / 240 (0.42%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 144 (0.00%)
    0 / 134 (0.00%)
    0 / 148 (0.00%)
    0 / 149 (0.00%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    0 / 122 (0.00%)
    0 / 112 (0.00%)
    1 / 240 (0.42%)
    0 / 248 (0.00%)
    0 / 223 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1: placebo Part 1: vibegron 3 mg Part 1: vibegron 15 mg Part 1: vibegron 50 mg Part 1: vibegron 100 mg Part 1: tolterodine ER 4 mg Part 1: vibegron 50 mg + tolterodine ER 4 mg/vibegron 50 mg Part 2: placebo Part 2: vibegron 100 mg + tolterodine ER 4 mg Part 2: tolterodine ER 4 mg Part 2: vibegron 100 mg Extension Study: tolterodine ER 4 mg Extension Study: vibegron 100 mg Extension Study: vibegron 50 mg Extension Study: vibegron 100 mg + tolterodine ER 4 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 141 (22.70%)
    21 / 144 (14.58%)
    27 / 134 (20.15%)
    30 / 148 (20.27%)
    33 / 149 (22.15%)
    33 / 135 (24.44%)
    27 / 134 (20.15%)
    6 / 64 (9.38%)
    20 / 110 (18.18%)
    21 / 122 (17.21%)
    5 / 112 (4.46%)
    70 / 240 (29.17%)
    73 / 248 (29.44%)
    59 / 223 (26.46%)
    38 / 134 (28.36%)
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    2 / 141 (1.42%)
    3 / 144 (2.08%)
    6 / 134 (4.48%)
    4 / 148 (2.70%)
    11 / 149 (7.38%)
    5 / 135 (3.70%)
    2 / 134 (1.49%)
    0 / 64 (0.00%)
    1 / 110 (0.91%)
    1 / 122 (0.82%)
    0 / 112 (0.00%)
    1 / 240 (0.42%)
    4 / 248 (1.61%)
    7 / 223 (3.14%)
    1 / 134 (0.75%)
         occurrences all number
    2
    3
    6
    5
    11
    5
    2
    0
    1
    1
    0
    2
    4
    8
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 141 (4.96%)
    3 / 144 (2.08%)
    6 / 134 (4.48%)
    6 / 148 (4.05%)
    10 / 149 (6.71%)
    4 / 135 (2.96%)
    6 / 134 (4.48%)
    2 / 64 (3.13%)
    7 / 110 (6.36%)
    5 / 122 (4.10%)
    2 / 112 (1.79%)
    6 / 240 (2.50%)
    4 / 248 (1.61%)
    13 / 223 (5.83%)
    5 / 134 (3.73%)
         occurrences all number
    8
    3
    6
    8
    13
    4
    7
    4
    7
    6
    2
    7
    4
    13
    5
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 141 (2.13%)
    5 / 144 (3.47%)
    6 / 134 (4.48%)
    6 / 148 (4.05%)
    1 / 149 (0.67%)
    4 / 135 (2.96%)
    6 / 134 (4.48%)
    2 / 64 (3.13%)
    4 / 110 (3.64%)
    1 / 122 (0.82%)
    1 / 112 (0.89%)
    9 / 240 (3.75%)
    7 / 248 (2.82%)
    2 / 223 (0.90%)
    9 / 134 (6.72%)
         occurrences all number
    4
    5
    6
    6
    1
    4
    6
    2
    4
    1
    1
    9
    7
    2
    9
    Dry mouth
         subjects affected / exposed
    2 / 141 (1.42%)
    5 / 144 (3.47%)
    6 / 134 (4.48%)
    7 / 148 (4.73%)
    3 / 149 (2.01%)
    14 / 135 (10.37%)
    11 / 134 (8.21%)
    4 / 64 (6.25%)
    13 / 110 (11.82%)
    8 / 122 (6.56%)
    1 / 112 (0.89%)
    18 / 240 (7.50%)
    8 / 248 (3.23%)
    8 / 223 (3.59%)
    6 / 134 (4.48%)
         occurrences all number
    2
    5
    6
    8
    3
    14
    11
    4
    14
    8
    1
    18
    8
    8
    6
    Diarrhoea
         subjects affected / exposed
    5 / 141 (3.55%)
    4 / 144 (2.78%)
    2 / 134 (1.49%)
    1 / 148 (0.68%)
    5 / 149 (3.36%)
    7 / 135 (5.19%)
    6 / 134 (4.48%)
    0 / 64 (0.00%)
    1 / 110 (0.91%)
    2 / 122 (1.64%)
    0 / 112 (0.00%)
    10 / 240 (4.17%)
    9 / 248 (3.63%)
    9 / 223 (4.04%)
    2 / 134 (1.49%)
         occurrences all number
    6
    4
    2
    1
    5
    8
    6
    0
    1
    2
    0
    10
    10
    9
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    14 / 141 (9.93%)
    3 / 144 (2.08%)
    7 / 134 (5.22%)
    8 / 148 (5.41%)
    6 / 149 (4.03%)
    3 / 135 (2.22%)
    3 / 134 (2.24%)
    0 / 64 (0.00%)
    2 / 110 (1.82%)
    1 / 122 (0.82%)
    4 / 112 (3.57%)
    20 / 240 (8.33%)
    24 / 248 (9.68%)
    12 / 223 (5.38%)
    15 / 134 (11.19%)
         occurrences all number
    15
    3
    8
    9
    6
    3
    4
    0
    2
    1
    4
    25
    30
    18
    19
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 141 (1.42%)
    2 / 144 (1.39%)
    1 / 134 (0.75%)
    0 / 148 (0.00%)
    3 / 149 (2.01%)
    2 / 135 (1.48%)
    1 / 134 (0.75%)
    0 / 64 (0.00%)
    0 / 110 (0.00%)
    1 / 122 (0.82%)
    1 / 112 (0.89%)
    10 / 240 (4.17%)
    14 / 248 (5.65%)
    9 / 223 (4.04%)
    9 / 134 (6.72%)
         occurrences all number
    2
    3
    1
    0
    3
    2
    1
    0
    0
    1
    1
    10
    14
    9
    9
    Urinary tract infection
         subjects affected / exposed
    5 / 141 (3.55%)
    5 / 144 (3.47%)
    5 / 134 (3.73%)
    8 / 148 (5.41%)
    6 / 149 (4.03%)
    4 / 135 (2.96%)
    7 / 134 (5.22%)
    2 / 64 (3.13%)
    5 / 110 (4.55%)
    8 / 122 (6.56%)
    2 / 112 (1.79%)
    27 / 240 (11.25%)
    22 / 248 (8.87%)
    27 / 223 (12.11%)
    8 / 134 (5.97%)
         occurrences all number
    5
    5
    5
    8
    6
    5
    8
    2
    5
    8
    2
    44
    33
    42
    8

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Mar 2011
    Extension Study, Amendment 008-10. The primary reason for this amendment was to add the 12-month safety and efficacy extension to the base study 008-00. Patients completing the base had the opportunity to receive an additional 1 year of treatment if they participated in the extension.
    16 May 2012
    Extension Study, Amendment 008-11. The primary reason for this amendment was to update the extension study protocol with the dose of vibegron 100 mg that patients enrolled in Part 2 of the base study who completed it would receive in the extension. Vibegron 100 mg was updated as the monotherapy dose and the dose to be administered concomitantly with tolterodine ER 4 mg. The protocol previously had indicated “X” mg.
    16 May 2012
    Base Study, Amendment 008-02. The primary reasons for this amendment were as follows: 1) To allow for the inclusion of women of childbearing potential, expanding the age range from 40-75 to 18-75. 2) To update the base protocol with the dose of vibegron for Part 2 of the base study. Vibegron 100 mg was selected as the monotherapy dose and the dose to be administered concomitantly with tolterodine ER 4 mg.The protocol previously had indicated “X” mg. 3) To remove the exclusion criteria that had prohibited use of beta-adrenergic blocking agents (beta blockers), calcium channel blockers, direct acting vasodilators, angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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