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    Clinical Trial Results:
    An International Phase 3, Randomized, Double-Blind, Placebo- and Active (Tolterodine)-Controlled Multicenter Study to Evaluate the Safety and Efficacy of Vibegron in Patients with Symptoms of Overactive Bladder

    Summary
    EudraCT number
    		 2017-003293-14
    Trial protocol
    		 LV   HU   EE   BG   LT  
    Global end of trial date
    04 Feb 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    19 Mar 2021
    First version publication date
    27 Jan 2021
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Alignment with ClinicalTrials.gov summary.

    Trial information

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    Trial identification
    Sponsor protocol code
    RVT-901-3003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03492281
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Urovant Sciences GmbH
    Sponsor organisation address
    Viaduktstrasse 8 4051, Basel, Switzerland,
    Public contact
    Clinical Trial Information Contact, Urovant Sciences GmbH, 41 (42) 2155999, info@urovant.com
    Scientific contact
    Clinical Trial Information Contact, Urovant Sciences GmbH, 41 (42) 2155999, info@urovant.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
    05 Oct 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study was conducted to evaluate the efficacy of vibegron compared to placebo in subjects with symptoms of overactive bladder (OAB), specifically the frequency of micturitions and frequency of urge urinary incontinence episodes, and to evaluate the safety and tolerability of treatment with vibegron.
    Protection of trial subjects
    Each investigator obtained approval of the study from a properly constituted Institutional Review Board (IRB), Research Ethics Board (REB), or Independent Ethics Committee (IEC) prior to study initiation. This study was conducted in compliance with Good Clinical Practice (GCP). Prior to participating in any study procedures, the study was discussed with each subject and/or with the subject’s legally authorized representative, and written informed consent was obtained.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Mar 2018
    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
    Canada: 26
    Country: Number of subjects enrolled
    Hungary: 27
    Country: Number of subjects enrolled
    Latvia: 17
    Country: Number of subjects enrolled
    Lithuania: 3
    Country: Number of subjects enrolled
    Poland: 82
    Country: Number of subjects enrolled
    United States: 1363
    Worldwide total number of subjects
    1518
    EEA total number of subjects
    129
    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)
    871
    From 65 to 84 years
    632
    85 years and over
    15

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Of 3149 subjects screened for this study, 1518 were randomized (after a 2-week, single-blind placebo Run-in Period), and 1515 received 1 dose of double-blind study drug in the Treatment Period (Safety Set: placebo, N = 540; vibegron, N = 545; tolterodine, N = 430).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received matching placebo, orally, once daily for 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match vibegron 75-mg tablet, administered as a single tablet, orally, once daily

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match tolterodine extended release (ER) 4-mg capsule, administered as a single capsule, orally, once daily

    Arm title
    		 Vibegron 75 mg
    Arm description
    		 Subjects received vibegron 75 milligrams (mg), orally, once daily for 12 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
    Vibegron 75-mg tablet, administered as a single tablet, orally, once daily

    Arm title
    		 Tolterodine ER 4 mg
    Arm description
    		 Subjects received tolterodine ER 4 mg, orally, once daily for 12 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tolterodine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Tolterodine ER 4-mg capsule, administered as a single capsule, orally, once daily

    Number of subjects in period 1 [1]
    		Placebo Vibegron 75 mg Tolterodine ER 4 mg
    Started
    540
    545
    430
    Completed
    486
    502
    385
    Not completed
    54
    43
    45
         Withdrawn Due To Sponsor
    1
    -
    1
         Adverse event, serious fatal
    -
    -
    1
         Consent withdrawn by subject
    21
    14
    13
         Physician decision
    1
    -
    3
         Adverse event, non-fatal
    6
    8
    13
         Lost to follow-up
    14
    15
    10
         Captured As Other In Database
    8
    6
    3
         Lack of efficacy
    3
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Of 3149 subjects screened for this study, 1518 were randomized, and 1515 received 1 dose of double-blind study drug in the Treatment Period (Safety Set). Baseline data are reported for members of the Safety Set.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo, orally, once daily for 12 weeks.

    Reporting group title
    Vibegron 75 mg
    Reporting group description
    		 Subjects received vibegron 75 milligrams (mg), orally, once daily for 12 weeks.

    Reporting group title
    Tolterodine ER 4 mg
    Reporting group description
    		 Subjects received tolterodine ER 4 mg, orally, once daily for 12 weeks.

    Reporting group values
    		 Placebo Vibegron 75 mg Tolterodine ER 4 mg Total
    Number of subjects
    		 540 545 430 1515
    Age categorical
    Units:
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.9 ( 13.35 ) 60.4 ( 13.49 ) 59.8 ( 13.27 ) -
    Gender categorical
    Units: Subjects
        Female
    		 459 463 364 1286
        Male
    		 81 82 66 229
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska
    		 3 2 0 5
        Asian
    		 30 28 27 85
        Black or African American
    		 85 78 72 235
        White
    		 418 435 326 1179
        Puerto Rican
    		 1 1 1 3
        White and Black or African American
    		 1 0 0 1
        Hispanic
    		 2 1 0 3
        Filipino
    		 0 0 1 1
        Morrocan
    		 0 0 1 1
        Multiracial
    		 0 0 1 1
        White, Black or African American
    		 0 0 1 1
    Average number of micturitions per 24 hours in all overactive bladder (OAB) subjects
    A micturition/void was defined as “Urinated in Toilet” as indicated on the Patient Voiding Diary (PVD). The number of micturitions was defined as the number of times a subject voided in the toilet as indicated on the PVD. The average daily number of micturitions was calculated using the daily entries in the PVD (which was to be completed prior to each study visit) as the total number of micturitions that occurred on a Complete Diary Day (CDD) divided by the number of CDDs in the PVD. n=537, 544, and 430 for Placebo, Vibegron 75 mg, and Tolterodine ER 4 mg, respectively.
    Units: micturitions per 24 hours
        arithmetic mean (standard deviation)
    		 11.72 ( 3.971 ) 11.38 ( 3.508 ) 11.53 ( 3.184 ) -
    Average number of urge urinary incontinence (UUI) episodes per 24 hours in OAB Wet subjects
    The number of UUI episodes was defined as the number of times a subject had checked “urge” as the main reason for the leakage in the PVD, regardless of whether more than one reason for leakage in addition to “urge” was checked. OAB Wet subjects were those subjects with an average of ≥8.0 micturitions per Diary Day (DD); with an average of ≥1.0 UUI episodes per DD; and, if stress urinary incontinence was present, with a total number of UUI episodes greater than the total number of stress urinary incontinence episodes from the previous visit diary. n=537, 544, and 430.
    Units: UUI episodes per 24 hours
        arithmetic mean (standard deviation)
    		 2.80 ( 2.978 ) 2.78 ( 3.10 ) 2.72 ( 2.616 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo, orally, once daily for 12 weeks.

    Reporting group title
    Vibegron 75 mg
    Reporting group description
    		 Subjects received vibegron 75 milligrams (mg), orally, once daily for 12 weeks.

    Reporting group title
    Tolterodine ER 4 mg
    Reporting group description
    		 Subjects received tolterodine ER 4 mg, orally, once daily for 12 weeks.

    Subject analysis set title
    Placebo: Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects received matching placebo, orally, once daily for 12 weeks. The Full Analysis Set is defined as all randomized OAB subjects who took at least 1 dose of double-blind study treatment and had at least 1 evaluable change from baseline micturition measurement.

    Subject analysis set title
    Vibegron 75 mg: Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects received vibegron 75 milligrams (mg), orally, once daily for 12 weeks. The Full Analysis Set is defined as all randomized OAB Subjects who took at least 1 dose of double-blind study treatment and had at least 1 evaluable change from baseline micturition measurement.

    Subject analysis set title
    Tolterodine ER 4 mg: Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects received tolterodine extended release (ER) 4 mg, orally, once daily for 12 weeks. The Full Analysis Set is defined as all randomized OAB subjects who took at least 1 dose of double-blind study treatment and had at least 1 evaluable change from baseline micturition measurement.

    Subject analysis set title
    Placebo: OAB Wet
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who met the definition of OAB Wet at study entry (based on the PVD) received matching placebo, orally, once daily for 12 weeks. OAB Wet subjects were defined as those with an average of ≥8.0 micturitions per Diary Day; with an average of ≥1.0 UUI episodes per Diary Day; and, if stress urinary incontinence was present, with a total number of UUI episodes greater than the total number of stress urinary incontinence episodes from the previous visit diary. Analysis was conducted in members of the Full Analysis Set for Incontinence (FAS-I) Population, comprised of all randomized OAB Wet subjects who took at least 1 dose of double-blind study treatment and had at least 1 evaluable change from the Baseline UUI measurement.

    Subject analysis set title
    Vibegron 75 mg: OAB Wet
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who met the definition of OAB Wet at study entry (based on the PVD) received vibegron 75 milligrams (mg), orally, once daily for 12 weeks. OAB Wet subjects were defined as those with an average of ≥8.0 micturitions per Diary Day; with an average of ≥1.0 UUI episodes per Diary Day; and, if stress urinary incontinence was present, with a total number of UUI episodes greater than the total number of stress urinary incontinence episodes from the previous visit diary. Analysis was conducted in members of the FAS-I Population, comprised of all randomized OAB Wet subjects who took at least 1 dose of double-blind study treatment and had at least 1 evaluable change from the Baseline UUI measurement.

    Subject analysis set title
    Tolterodine ER 4 mg: OAB Wet
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who met the definition of OAB Wet at study entry (based on the PVD) received tolterodine extended release (ER) 4 mg, orally, once daily for 12 weeks. OAB Wet subjects were defined as those with an average of ≥8.0 micturitions per Diary Day; with an average of ≥1.0 UUI episodes per Diary Day; and, if stress urinary incontinence was present, with a total number of UUI episodes greater than the total number of stress urinary incontinence episodes from the previous visit diary. Analysis was conducted in members of the FAS-I Population, comprised of all randomized OAB Wet subjects who took at least 1 dose of double-blind study treatment and had at least 1 evaluable change from the Baseline UUI measurement.

    Primary: Change from Baseline (CFB) at Week 12 in the average number of micturitions per 24 hours in all overactive bladder (OAB) subjects

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    End point title
    		 Change from Baseline (CFB) at Week 12 in the average number of micturitions per 24 hours in all overactive bladder (OAB) subjects
    End point description
    A micturition/void is defined as “Urinated in Toilet” as indicated on the PVD. The number of micturitions is defined as the number of times a subject voided in the toilet as indicated on the PVD. The average daily number of micturitions was calculated using the daily entries in the PVD (which was to be completed prior to each study visit) as the total number of micturitions that occurred on a Complete Diary Day (CDD) divided by the number of CDDs in the PVD. CFB was calculated as the post-BL value minus the BL value. "Per 24 hours” corresponds to one Diary Day (i.e., time between when the subject got up for the day each morning and time the sujbject got up for the day the next morning as recorded in the PVD). Covariates included in the mixed model for repeated measures are study visit (Weeks 2, 4, 8, and 12), OAB type (wet/dry), sex, region (U.S./non-U.S.), BL number of micturitions, and treatment by study visit interaction. FAS=Full Analysis Set.
    End point type
    Primary
    End point timeframe
    Baseline; Week 12
    End point values
    		 Placebo: Full Analysis Set Vibegron 75 mg: Full Analysis Set Tolterodine ER 4 mg: Full Analysis Set
    Number of subjects analysed
    475 [1]
    492 [2]
    378 [3]
    Units: micturitions per 24 hours
        least squares mean (standard error)
    -1.3 ( 0.14 )
    -1.8 ( 0.14 )
    -1.6 ( 0.15 )
    Notes
    [1] - FAS. Only subjects with evaluable data were analyzed.
    [2] - FAS. Only subjects with evaluable data were analyzed.
    [3] - FAS. Only subjects with evaluable data were analyzed.
    Statistical analysis title
    		 LS Mean Difference: Vibegron 75 mg minus Placebo
    Statistical analysis description
    LS=least squares
    Comparison groups
    Placebo: Full Analysis Set v Vibegron 75 mg: Full Analysis Set
    Number of subjects included in analysis
    967
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [4]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.15
    Notes
    [4] - Hypothesis testing was performed for vibegron minus placebo.
    Statistical analysis title
    		 LS Mean Difference: Tolterodine ER minus Placebo
    Comparison groups
    Tolterodine ER 4 mg: Full Analysis Set v Placebo: Full Analysis Set
    Number of subjects included in analysis
    853
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0988 [5]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Notes
    [5] - Comparisons between tolterodine ER and placebo are considered descriptive.

    Primary: CFB at Week 12 in the average number of urge urinary incontinence (UUI) episodes per 24 hours in OAB Wet subjects

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    End point title
    		 CFB at Week 12 in the average number of urge urinary incontinence (UUI) episodes per 24 hours in OAB Wet subjects
    End point description
    The number of UUI episodes is defined as the number of times a subject had checked “urge” as the main reason for the leakage in the PVD, regardless of whether more than one reason for leakage in addition to “urge” was checked. The average daily number of UUI episodes was calculated using the daily entries in the PVD (which was to be completed prior to each study visit) as the total number of UUI episodes that occurred on a CDD divided by the number of CCDs in the PVD. CFB was calculated as the post-BL value minus the BL value. "Per 24 hours” corresponds to one Diary Day (i.e., time between when subject got up for the day each morning and time subject got up for the day the next morning as recorded in the PVD). Covariates included in the mixed model for repeated measures were study visit (Weeks 2, 4, 8, and 12), sex, region (U.S./non-U.S.), BL number of UUI episodes and treatment by study visit interaction. FAS-I=Full Analysis Set for Incontinence.
    End point type
    Primary
    End point timeframe
    Baseline; Week 12
    End point values
    		 Placebo: OAB Wet Vibegron 75 mg: OAB Wet Tolterodine ER 4 mg: OAB Wet
    Number of subjects analysed
    372 [6]
    383 [7]
    286 [8]
    Units: UUI episodes per 24 hours
        least squares mean (standard error)
    -1.4 ( 0.13 )
    -2.0 ( 0.13 )
    -1.8 ( 0.14 )
    Notes
    [6] - FAS-I. Only those subjects with evaluable data were analyzed.
    [7] - FAS-I. Only those subjects with evaluable data were analyzed.
    [8] - FAS-I. Only those subjects with evaluable data were analyzed.
    Statistical analysis title
    		 LS Mean Difference: Vibegron 75 mg minus Placebo
    Comparison groups
    Vibegron 75 mg: OAB Wet v Placebo: OAB Wet
    Number of subjects included in analysis
    755
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [9]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 -0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.14
    Notes
    [9] - Hypothesis testing was performed for vibegron minus placebo.
    Statistical analysis title
    		 LS Mean Difference: Tolterodine ER minus Placebo
    Comparison groups
    Tolterodine ER 4 mg: OAB Wet v Placebo: OAB Wet
    Number of subjects included in analysis
    658
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0123 [10]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.15
    Notes
    [10] - Comparisons between tolterodine ER and placebo are considered descriptive.

    Secondary: CFB at Week 12 in the average number of urgency episodes over 24 hours in all OAB subjects

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    End point title
    		 CFB at Week 12 in the average number of urgency episodes over 24 hours in all OAB subjects
    End point description
    An urgency episode is defined as the “Need to Urinate Immediately” as indicated on the PVD. CFB is calculated as the post-BL value minus the BL value. "Over 24 hours” corresponds to one Diary Day (i.e., time between when the subject got up for the day each morning and time the subject got up for the day the next morning as recorded in the PVD). Covariates included in the mixed model for repeated measures were study visit (Weeks 2, 4, 8, and 12), OAB type (wet/dry), sex, region (U.S./non-U.S.), BL number of urgency episodes, and treatment by study visit interaction.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 12
    End point values
    		 Placebo: Full Analysis Set Vibegron 75 mg: Full Analysis Set Tolterodine ER 4 mg: Full Analysis Set
    Number of subjects analysed
    475 [11]
    492 [12]
    378 [13]
    Units: urgency episodes over 24 hours
        least squares mean (standard error)
    -2.0 ( 0.19 )
    -2.7 ( 0.19 )
    -2.5 ( 0.21 )
    Notes
    [11] - FAS. Only subjects with evaluable data were analyzed.
    [12] - FAS. Only subjects with evaluable data were analyzed.
    [13] - FAS. Only subjects with evaluable data were analyzed.
    Statistical analysis title
    		 LS Mean Difference: Vibegron 75 mg minus Placebo
    Comparison groups
    Vibegron 75 mg: Full Analysis Set v Placebo: Full Analysis Set
    Number of subjects included in analysis
    967
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002 [14]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.22
    Notes
    [14] - Hypothesis testing was performed for vibegron minus placebo.
    Statistical analysis title
    		 LS Mean Difference: Tolterodine ER minus Placebo
    Comparison groups
    Tolterodine ER 4 mg: Full Analysis Set v Placebo: Full Analysis Set
    Number of subjects included in analysis
    853
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0648 [15]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.23
    Notes
    [15] - Comparisons between tolterodine ER and placebo are considered descriptive.

    Secondary: Percentage of OAB Wet subjects with at least a 75% reduction from Baseline in UUI episodes per 24 hours at Week 12

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    End point title
    		 Percentage of OAB Wet subjects with at least a 75% reduction from Baseline in UUI episodes per 24 hours at Week 12
    End point description
    The number of UUI episodes is defined as the number of times a subject had checked “urge” as the main reason for the leakage in the PVD, regardless of whether more than one reason for leakage in addition to “urge” was checked. The average daily number of UUI episodes was calculated using the daily entries in the PVD (which was to be completed prior to each study visit) as the total number of UUI episodes that occurred on a CDD divided by the number of CCDs in the PVD. CFB was calculated as the post-BL value minus the BL value. "Per 24 hours” corresponds to one Diary Day (i.e., time between when subject got up for the day each morning and time subject got up for the day the next morning as recorded in the PVD).
    End point type
    Secondary
    End point timeframe
    Baseline; Week 12
    End point values
    		 Placebo: OAB Wet Vibegron 75 mg: OAB Wet Tolterodine ER 4 mg: OAB Wet
    Number of subjects analysed
    405 [16]
    403 [17]
    319 [18]
    Units: percentage of subjects
    number (not applicable)
        Unadjusted
    36.8
    52.4
    47.6
        Adjusted for sex
    32.8
    49.3
    42.2
    Notes
    [16] - FAS-I. The multiple imputation method was used for missing values.
    [17] - FAS-I. The multiple imputation method was used for missing values.
    [18] - FAS-I. The multiple imputation method was used for missing values.
    Statistical analysis title
    		 Difference in Percentage: Vibegron 75 mg:Placebo
    Comparison groups
    Vibegron 75 mg: OAB Wet v Placebo: OAB Wet
    Number of subjects included in analysis
    808
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [19]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in percentage
    Point estimate
    16.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.7
         upper limit
    		 23.4
    Notes
    [19] - The Cochran-Mantel-Haenszel risk difference estimate was stratified by sex (female/male), with weights proposed by Greenland and Robins.
    Statistical analysis title
    		 Difference in Percentage: Tolterodine ER:Placebo
    Comparison groups
    Tolterodine ER 4 mg: OAB Wet v Placebo: OAB Wet
    Number of subjects included in analysis
    724
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012 [20]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in percentage
    Point estimate
    9.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.1
         upper limit
    		 16.7
    Notes
    [20] - The Cochran-Mantel-Haenszel risk difference estimate was stratified by sex (female/male), with weights proposed by Greenland and Robins.

    Secondary: Percentage of OAB Wet subjects with a 100% reduction from Baseline in UUI episodes per 24 hours at Week 12

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    End point title
    		 Percentage of OAB Wet subjects with a 100% reduction from Baseline in UUI episodes per 24 hours at Week 12
    End point description
    The number of UUI episodes is defined as the number of times a subject had checked “urge” as the main reason for the leakage in the PVD, regardless of whether more than one reason for leakage in addition to “urge” was checked. The average daily number of UUI episodes was calculated using the daily entries in the PVD (which was to be completed prior to each study visit) as the total number of UUI episodes that occurred on a CDD divided by the number of CCDs in the PVD. CFB was calculated as the post-BL value minus the BL value. "Per 24 hours” corresponds to one Diary Day (i.e., time between when subject got up for the day each morning and time subject got up for the day the next morning as recorded in the PVD).
    End point type
    Secondary
    End point timeframe
    Baseline; Week 12
    End point values
    		 Placebo: OAB Wet Vibegron 75 mg: OAB Wet Tolterodine ER 4 mg: OAB Wet
    Number of subjects analysed
    405 [21]
    403 [22]
    319 [23]
    Units: percentage of subjects
    number (not applicable)
        Unadjusted
    22.5
    28.8
    26.6
        Adjusted for sex
    19.0
    25.3
    20.9
    Notes
    [21] - FAS-I. The multiple imputation method was used for missing values.
    [22] - FAS-I. The multiple imputation method was used for missing values.
    [23] - FAS-I. The multiple imputation method was used for missing values.
    Statistical analysis title
    		 Difference in Percentage: Vibegron 75 mg:Placebo
    Comparison groups
    Vibegron 75 mg: OAB Wet v Placebo: OAB Wet
    Number of subjects included in analysis
    808
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.036 [24]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in percentage
    Point estimate
    6.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 12.1
    Notes
    [24] - The Cochran-Mantel-Haenszel risk difference estimate was stratified by sex (female/male), with weights proposed by Greenland and Robins.
    Statistical analysis title
    		 Difference in Percentage: Tolterodine ER:Placebo
    Comparison groups
    Tolterodine ER 4 mg: OAB Wet v Placebo: OAB Wet
    Number of subjects included in analysis
    724
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5447 [25]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in percentage
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 7.8
    Notes
    [25] - The Cochran-Mantel-Haenszel risk difference estimate was stratified by sex (female/male), with weights proposed by Greenland and Robins.

    Secondary: Percentage of all OAB subjects with at least a 50% reduction from Baseline in urgency episodes per 24 hours at Week 12

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    End point title
    		 Percentage of all OAB subjects with at least a 50% reduction from Baseline in urgency episodes per 24 hours at Week 12
    End point description
    An urgency episode is defined as the “Need to Urinate Immediately” as indicated on the PVD. CFB is calculated as the post-BL value minus the BL value. "Per 24 hours” corresponds to one Diary Day (i.e., time between when the subject got up for the day each morning and time the subject got up for the day the next morning as recorded in the PVD).
    End point type
    Secondary
    End point timeframe
    Baseline; Week 12
    End point values
    		 Placebo: Full Analysis Set Vibegron 75 mg: Full Analysis Set Tolterodine ER 4 mg: Full Analysis Set
    Number of subjects analysed
    520 [26]
    526 [27]
    417 [28]
    Units: percentage of subjects
    number (not applicable)
        Unadjusted
    38.3
    43.2
    41.2
        Adjusted for sex
    32.8
    39.5
    36.4
    Notes
    [26] - FAS. The multiple imputation method was used for missing values.
    [27] - FAS. The multiple imputation method was used for missing values.
    [28] - FAS. The multiple imputation method was used for missing values.
    Statistical analysis title
    		 Difference in Percentage: Vibegron 75 mg:Placebo
    Comparison groups
    Vibegron 75 mg: Full Analysis Set v Placebo: Full Analysis Set
    Number of subjects included in analysis
    1046
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0235 [29]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in percentage
    Point estimate
    6.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 12.7
    Notes
    [29] - The Cochran-Mantel-Haenszel risk difference estimate was stratified by sex and OAB type (wet/dry), with weights proposed by Greenland and Robins.
    Statistical analysis title
    		 Difference in Percentage: Tolterodine ER:Placebo
    Comparison groups
    Tolterodine ER 4 mg: Full Analysis Set v Placebo: Full Analysis Set
    Number of subjects included in analysis
    937
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.24 [30]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in percentage
    Point estimate
    3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 10
    Notes
    [30] - The Cochran-Mantel-Haenszel risk difference estimate was stratified by sex and OAB type (wet/dry), with weights proposed by Greenland and Robins.

    Secondary: CFB at Week 12 in the average number of total incontinence episodes over 24 hours in OAB Wet subjects

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    End point title
    		 CFB at Week 12 in the average number of total incontinence episodes over 24 hours in OAB Wet subjects
    End point description
    Total incontinence is defined as having any reason for “Accidental Urine Leakage” and/or “Accidental Urine Leakage” checked, as indicated on the PVD. It is assumed that if the subject recorded a reason for leakage then the accidental urine leakage occurred. CFB is calculated as the post-BL value minus the BL value. "Over 24 hours” corresponds to one Diary Day (i.e., time between when the subject got up for the day each morning and time the subject got up for the day the next morning as recorded in the PVD). Covariates included in the mixed model for repeated measures were study visit (Weeks 2, 4, 8, and 12), sex, region (U.S./non-U.S.), BL number of incontinence episodes, and treatment by study visit interaction. hr = hours.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 12
    End point values
    		 Placebo: OAB Wet Vibegron 75 mg: OAB Wet Tolterodine ER 4 mg: OAB Wet
    Number of subjects analysed
    372 [31]
    383 [32]
    286 [33]
    Units: total incontinence episodes over 24 hr
        least squares mean (standard error)
    -1.6 ( 0.15 )
    -2.3 ( 0.15 )
    -2.0 ( 0.16 )
    Notes
    [31] - FAS-I. Only subjects with evaluable data were analyzed.
    [32] - FAS-I. Only subjects with evaluable data were analyzed.
    [33] - FAS-I. Only subjects with evaluable data were analyzed.
    Statistical analysis title
    		 LS Mean Difference: Vibegron 75 mg minus Placebo
    Comparison groups
    Vibegron 75 mg: OAB Wet v Placebo: OAB Wet
    Number of subjects included in analysis
    755
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [34]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 -0.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Notes
    [34] - Hypothesis testing was performed for vibegron minus placebo.
    Statistical analysis title
    		 LS Mean Difference: Tolterodine ER minus Placebo
    Comparison groups
    Tolterodine ER 4 mg: OAB Wet v Placebo: OAB Wet
    Number of subjects included in analysis
    658
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0074 [35]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.17
    Notes
    [35] - Comparisons between tolterodine ER and placebo are considered descriptive.

    Secondary: CFB at Week 12 in the Coping Score from the Overactive Bladder Questionnaire Long Form (OAB-q LF, 1-week recall) in all OAB subjects

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    End point title
    		 CFB at Week 12 in the Coping Score from the Overactive Bladder Questionnaire Long Form (OAB-q LF, 1-week recall) in all OAB subjects
    End point description
    The OAB-q LF is a validated patient-reported outcome. 8 questions of the OAB-q LF ask subjects how well they have coped with their bladder symptoms during the previous week, as a measure of quality of life (QoL). Each question has a response ranging from “not coping" (= 1) to “coping well” (= 6). These questions make up the coping scale. The raw score (sum of question scores [from 8 to 48]) is transformed to a unified score, from 0 to 100. Higher scores correspond to a higher QoL, and lower scores represent a lower QoL. CFB is calculated as the post-BL value minus the BL value. Covariates included in the MMRM were study visit (Weeks 2, 4, 8, and 12), sex, region (U.S./non-U.S.), OAB type (wet/dry), BL score, and treatment by study visit interaction. If < 50% of items were available, the subscore was regarded as missing; however, if ≥ 50% of items were available, the subscore included missing items imputed as the average of the remaining non-missing items for the subscore.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 12
    End point values
    		 Placebo: Full Analysis Set Vibegron 75 mg: Full Analysis Set Tolterodine ER 4 mg: Full Analysis Set
    Number of subjects analysed
    504 [36]
    512 [37]
    400 [38]
    Units: units on a scale
        least squares mean (standard error)
    12.9 ( 1.32 )
    16.5 ( 1.31 )
    16.0 ( 1.39 )
    Notes
    [36] - FAS. Only subjects with evaluable data were analyzed.
    [37] - FAS. Only subjects with evaluable data were analyzed.
    [38] - FAS. Only subjects with evaluable data were analyzed.
    Statistical analysis title
    		 LS Mean Difference: Vibegron 75 mg minus Placebo
    Comparison groups
    Vibegron 75 mg: Full Analysis Set v Placebo: Full Analysis Set
    Number of subjects included in analysis
    1016
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0039 [39]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 6
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.24
    Notes
    [39] - Hypothesis testing was performed for vibegron minus placebo.
    Statistical analysis title
    		 LS Mean Difference: Tolterodine ER minus Placebo
    Comparison groups
    Tolterodine ER 4 mg: Full Analysis Set v Placebo: Full Analysis Set
    Number of subjects included in analysis
    904
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.021 [40]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 5.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.32
    Notes
    [40] - Comparisons between tolterodine ER and placebo are considered descriptive.

    Secondary: CFB at Week 12 in the average volume voided per micturition in all OAB subjects

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    End point title
    		 CFB at Week 12 in the average volume voided per micturition in all OAB subjects
    End point description
    A micturition/void is defined as “Urinated in Toilet” as indicated on the PVD. The number of micturitions is defined as the number of times a subject voided in the toilet as indicated on the PVD. CFB is calculated as the post-BL value minus the BL value. Covariates included in the mixed model for repeated measures were study visit (Weeks 2, 4, 8, and 12), OAB type (wet/dry), sex, region (U.S./non-U.S.), BL volume (milliliters [mL]), and treatment by study visit interaction.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 12
    End point values
    		 Placebo: Full Analysis Set Vibegron 75 mg: Full Analysis Set Tolterodine ER 4 mg: Full Analysis Set
    Number of subjects analysed
    478 [41]
    490 [42]
    375 [43]
    Units: mL per micturition
        least squares mean (standard error)
    2.2 ( 3.28 )
    23.5 ( 3.26 )
    15.5 ( 3.52 )
    Notes
    [41] - FAS. Only subjects with evaluable data were analyzed.
    [42] - FAS. Only subjects with evaluable data were analyzed.
    [43] - FAS. Only subjects with evaluable data were analyzed.
    Statistical analysis title
    		 LS Mean Difference: Vibegron 75 mg minus Placebo
    Comparison groups
    Vibegron 75 mg: Full Analysis Set v Placebo: Full Analysis Set
    Number of subjects included in analysis
    968
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [44]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    21.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.3
         upper limit
    		 28.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.52
    Notes
    [44] - Hypothesis testing was performed for vibegron minus placebo.
    Statistical analysis title
    		 LS Mean Difference: Tolterodine ER minus Placebo
    Comparison groups
    Tolterodine ER 4 mg: Full Analysis Set v Placebo: Full Analysis Set
    Number of subjects included in analysis
    853
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [45]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    13.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.9
         upper limit
    		 20.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.76
    Notes
    [45] - Comparisons between tolterodine ER and placebo are considered descriptive.

    Secondary: CFB at Week 12 in the Health-related Quality of Life (HRQL) Total Score from the OAB-q LF (1-week recall) in all OAB subjects

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    End point title
    		 CFB at Week 12 in the Health-related Quality of Life (HRQL) Total Score from the OAB-q LF (1-week recall) in all OAB subjects
    End point description
    The OAB-q LF is a validated patient-reported outcome. The 25 questions comprising the Coping, Concern, Sleep and Social Interaction subscales of the OAB-q LF ask subjects how much their symptoms have affected their life over the last week. Each question has a response ranging from “None of the time" (= 1) to “All of the time” (= 6). The raw score (sum of question scores for the 4 subscales [ranging from 25 to 150]) is transformed to a unified score, ranging from 0 to 100. Higher scores correspond to a higher quality of life, and lower scores represent a lower quality of life. CFB is calculated as the post-BL value minus the BL value. Covariates included in the mixed model for repeated measures were study visit (Weeks 2, 4, 8, and 12), sex, region (U.S./non-U.S.), OAB type (wet/dry), BL score, and treatment by study visit interaction. If < 50% of items were available, the subscore (SS) was regarded as missing; if ≥ 50% of items were available, the SS included missing items for SS.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 12
    End point values
    		 Placebo: Full Analysis Set Vibegron 75 mg: Full Analysis Set Tolterodine ER 4 mg: Full Analysis Set
    Number of subjects analysed
    504 [46]
    512 [47]
    400 [48]
    Units: units on a scale
        least squares mean (standard error)
    10.8 ( 1.13 )
    14.6 ( 1.12 )
    13.7 ( 1.19 )
    Notes
    [46] - FAS. Only subjects with evaluable data were analyzed.
    [47] - FAS. Only subjects with evaluable data were analyzed.
    [48] - FAS. Only subjects with evaluable data were analyzed.
    Statistical analysis title
    		 LS Mean Difference: Vibegron 75 mg minus Placebo
    Comparison groups
    Vibegron 75 mg: Full Analysis Set v Placebo: Full Analysis Set
    Number of subjects included in analysis
    1016
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [49]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.7
         upper limit
    		 5.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.06
    Notes
    [49] - Hypothesis testing was performed for vibegron minus placebo.
    Statistical analysis title
    		 LS Mean Difference: Tolterodine ER minus Placebo
    Comparison groups
    Tolterodine ER 4 mg: Full Analysis Set v Placebo: Full Analysis Set
    Number of subjects included in analysis
    904
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0114
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 5.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.13

    Secondary: CFB at Week 12 in the Symptom Bother Score from the OAB-q LF (1-week recall) in all OAB subjects

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    End point title
    		 CFB at Week 12 in the Symptom Bother Score from the OAB-q LF (1-week recall) in all OAB subjects
    End point description
    The OAB-q LF is a validated patient-reported outcome. The first 8 questions of the OAB-q LF ask subjects how much they were bothered by their bladder symptoms during the previous week. Each question has a response ranging from “Not at all” (= 1) to “A very great deal” (= 6). These questions make up the symptom bother scale. The raw score (sum of question scores [from 8 to 48]) is transformed to a unified score, from 0 to 100. Higher scores correspond to the symptoms having a larger bother, and lower scores represent a lower amount of bother due to symptoms. CFB is calculated as the post-BL value minus the BL value. Covariates included in the MMRM were study visit (Weeks 2, 4, 8, and 12), sex, region (U.S./non-U.S.), OAB type (wet/dry), BL score, and treatment by study visit interaction. If < 50% of items were available, the SS was regarded as missing; if ≥ 50% of items were available, the SS included missing items imputed as the average of the remaining non-missing items for SS.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 12
    End point values
    		 Placebo: Full Analysis Set Vibegron 75 mg: Full Analysis Set Tolterodine ER 4 mg: Full Analysis Set
    Number of subjects analysed
    504 [50]
    512 [51]
    400 [52]
    Units: units on a scale
        least squares mean (standard error)
    -12.8 ( 1.25 )
    -19.6 ( 1.24 )
    -17.4 ( 1.31 )
    Notes
    [50] - FAS. Only subjects with evaluable data were analyzed.
    [51] - FAS. Only subjects with evaluable data were analyzed.
    [52] - FAS. Only subjects with evaluable data were analyzed.
    Statistical analysis title
    		 LS Mean Difference: Vibegron 75 mg minus Placebo
    Comparison groups
    Vibegron 75 mg: Full Analysis Set v Placebo: Full Analysis Set
    Number of subjects included in analysis
    1016
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [53]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -6.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.2
         upper limit
    		 -4.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.17
    Notes
    [53] - Hypothesis testing was performed for vibegron minus placebo.
    Statistical analysis title
    		 LS Mean Difference: Tolterodine ER minus Placebo
    Comparison groups
    Tolterodine ER 4 mg: Full Analysis Set v Placebo: Full Analysis Set
    Number of subjects included in analysis
    904
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [54]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -4.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.1
         upper limit
    		 -2.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.25
    Notes
    [54] - Comparisons between tolterodine ER and placebo are considered descriptive.

    Secondary: Percentage of all OAB subjects with an average number of micturitions < 8 per 24 hours at Week 12

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    End point title
    		 Percentage of all OAB subjects with an average number of micturitions < 8 per 24 hours at Week 12
    End point description
    A micturition/void is defined as “Urinated in Toilet” as indicated on the PVD. The number of micturitions is defined as the number of times a subject voided in the toilet as indicated on the PVD. A subject was defined as having an average of < 8 daily micturitions if the arithmetic mean of the number of micturitions per day in the PVD was less than 8 . "Per 24 hours” corresponds to one Diary Day (i.e., time between when the subject got up for the day each morning and time the subject got up for the day the next morning as recorded in the PVD).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo: Full Analysis Set Vibegron 75 mg: Full Analysis Set Tolterodine ER 4 mg: Full Analysis Set
    Number of subjects analysed
    520 [55]
    526 [56]
    417 [57]
    Units: percentage of subjects
    number (not applicable)
        Unadjusted
    28.7
    40.1
    35.0
        Adjusted for sex
    24.8
    37.2
    31.6
    Notes
    [55] - FAS
    [56] - FAS
    [57] - FAS
    Statistical analysis title
    		 Difference in Percentage: Vibegron 75 mg:Placebo
    Comparison groups
    Vibegron 75 mg: Full Analysis Set v Placebo: Full Analysis Set
    Number of subjects included in analysis
    1046
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [58]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in percentage
    Point estimate
    12.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.7
         upper limit
    		 18.1
    Notes
    [58] - The Cochran-Mantel-Haenszel (CMH) risk difference estimate was stratified by OAB type (wet/dry) and sex (female/male), with weights proposed by Greenland and Robins.
    Statistical analysis title
    		 Difference in Percentage: Tolterodine ER:Placebo
    Comparison groups
    Tolterodine ER 4 mg: Full Analysis Set v Placebo: Full Analysis Set
    Number of subjects included in analysis
    937
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0236 [59]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in percentage
    Point estimate
    6.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 12.8
    Notes
    [59] - The Cochran-Mantel-Haenszel (CMH) risk difference estimate was stratified by OAB type (wet/dry) and sex (female/male), with weights proposed by Greenland and Robins.

    Secondary: Percentage of OAB Wet subjects with at least a 50% reduction from Baseline in total incontinence episodes per 24 hours at Week 12

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    End point title
    		 Percentage of OAB Wet subjects with at least a 50% reduction from Baseline in total incontinence episodes per 24 hours at Week 12
    End point description
    Total incontinence is defined as having any reason for “Accidental Urine Leakage” and/or “Accidental Urine Leakage” checked, as indicated on the PVD. It is assumed that if the subject recorded a reason for leakage then the accidental urine leakage occurred. All events marked as having leakage, regardless of cause, or where “Accidental Leakage” was checked. were used in the analysis. "Per 24 hours” corresponds to one Diary Day (i.e., time between when the subject got up for the day each morning and time the subject got up for the day the next morning as recorded in the PVD. The multiple imputation method was used for missing values.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 12
    End point values
    		 Placebo: OAB Wet Vibegron 75 mg: OAB Wet Tolterodine ER 4 mg: OAB Wet
    Number of subjects analysed
    405 [60]
    403 [61]
    319 [62]
    Units: percentage of subjects
    number (not applicable)
        Unadjusted
    53.8
    64.0
    66.5
        Adjusted for sex
    49.9
    61.6
    61.5
    Notes
    [60] - FAS-I. Only subjects with evaluable data were analyzed.
    [61] - FAS-I. Only subjects with evaluable data were analyzed.
    [62] - FAS-I. Only subjects with evaluable data were analyzed.
    Statistical analysis title
    		 Difference in Percentage: Vibegron 75 mg:Placebo
    Comparison groups
    Placebo: OAB Wet v Vibegron 75 mg: OAB Wet
    Number of subjects included in analysis
    808
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [63]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in percentage
    Point estimate
    11.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.7
         upper limit
    		 18.6
    Notes
    [63] - The Cochran-Mantel-Haenszel risk difference estimate was stratified by sex (female/male), with weights proposed by Greenland and Robins.
    Statistical analysis title
    		 Difference in Percentage: Tolterodine ER:Placebo
    Comparison groups
    Tolterodine ER 4 mg: OAB Wet v Placebo: OAB Wet
    Number of subjects included in analysis
    724
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0022 [64]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in percentage
    Point estimate
    11.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.2
         upper limit
    		 18.9
    Notes
    [64] - The Cochran-Mantel-Haenszel risk difference estimate was stratified by sex (female/male), with weights proposed by Greenland and Robins.

    Secondary: CFB at Week 12 in overall bladder symptoms based on Patient Global Impression of Severity (PGI-Severity) in all OAB subjects

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    End point title
    		 CFB at Week 12 in overall bladder symptoms based on Patient Global Impression of Severity (PGI-Severity) in all OAB subjects
    End point description
    The Patient Global Impression (PGI) questions are designed to assess a subject’s overall impression of OAB. For the PGI-Severity score, subjects are asked to rate their OAB symptoms over the previous week with one of the following responses: 1 = none, 2 = mild, 3 = moderate, 4 = severe. CFB is calculated as the post-BL value minus the BL value. Covariates included in the mixed model for repeated measures were study visit (Weeks 2, 4, 8, and 12), OAB type (wet/dry), sex, region (U.S./non-U.S.), BL score, and treatment by study visit interaction.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 12
    End point values
    		 Placebo: Full Analysis Set Vibegron 75 mg: Full Analysis Set Tolterodine ER 4 mg: Full Analysis Set
    Number of subjects analysed
    484 [65]
    494 [66]
    382 [67]
    Units: units on a scale
        least squares mean (standard error)
    -0.5 ( 0.04 )
    -0.8 ( 0.04 )
    -0.7 ( 0.04 )
    Notes
    [65] - FAS. Only subjects with evaluable data were analyzed.
    [66] - FAS. Only subjects with evaluable data were analyzed.
    [67] - FAS. Only subjects with evaluable data were analyzed.
    Statistical analysis title
    		 LS Mean Difference: Vibegron 75 mg minus Placebo
    Comparison groups
    Vibegron 75 mg: Full Analysis Set v Placebo: Full Analysis Set
    Number of subjects included in analysis
    978
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [68]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.04
    Notes
    [68] - Hypothesis testing was performed for vibegron minus placebo.
    Statistical analysis title
    		 LS Mean Difference: Tolterodine ER minus Placebo
    Comparison groups
    Tolterodine ER 4 mg: Full Analysis Set v Placebo: Full Analysis Set
    Number of subjects included in analysis
    866
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0055 [69]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.05
    Notes
    [69] - Hypothesis testing was performed for vibegron minus placebo.

    Secondary: CFB at Week 12 in overall control over bladder symptoms based on Patient Global Impression of Control (PGI-Control) in all OAB subjects

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    End point title
    		 CFB at Week 12 in overall control over bladder symptoms based on Patient Global Impression of Control (PGI-Control) in all OAB subjects
    End point description
    The Patient Global Impression (PGI) questions are designed to assess a subject’s overall impression of OAB. For the PGI-Control score, subjects were asked to rate how much control they had over their OAB symptoms over the previous week with one of the following responses: 1 = complete control, 2 = a lot of control, 3 = some control, 4 = only a little control, 5 = no control. CFB is calculated as the post-BL value minus the BL value. Covariates included in the mixed model for repeated measures were study visit (Weeks 2, 4, 8, and 12), OAB type (wet/dry), sex, region (U.S./non-U.S.), BL score, and treatment by study visit interaction.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 12
    End point values
    		 Placebo: Full Analysis Set Vibegron 75 mg: Full Analysis Set Tolterodine ER 4 mg: Full Analysis Set
    Number of subjects analysed
    484 [70]
    494 [71]
    382 [72]
    Units: units on a scale
        least squares mean (standard error)
    -0.7 ( 0.05 )
    -1.0 ( 0.05 )
    -0.9 ( 0.05 )
    Notes
    [70] - FAS. Only subjects with evaluable data were analyzed.
    [71] - FAS. Only subjects with evaluable data were analyzed.
    [72] - FAS. Only subjects with evaluable data were analyzed.
    Statistical analysis title
    		 LS Mean Difference: Vibegron 75 mg minus Placebo
    Comparison groups
    Vibegron 75 mg: Full Analysis Set v Placebo: Full Analysis Set
    Number of subjects included in analysis
    978
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [73]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.05
    Notes
    [73] - Hypothesis testing was performed for vibegron minus placebo.
    Statistical analysis title
    		 LS Mean Difference: Tolterodine ER minus Placebo
    Comparison groups
    Tolterodine ER 4 mg: Full Analysis Set v Placebo: Full Analysis Set
    Number of subjects included in analysis
    866
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [74]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Notes
    [74] - Comparisons between tolterodine ER and placebo are considered descriptive.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from the time the subject provided informed consent to participate in the study at the Screening Visit until completion of the Follow-up Visit (up to Day 113 or Early Withdrawal plus 28 days)
    Adverse event reporting additional description
    Treatment-emergent adverse events were collected in members of the Safety Set, comprised of all subjects who received at least 1 dose of study treatment. Subjects were included in the treatment group corresponding to the study treatment they actually received for the analysis of safety data.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Vibegron 75 mg
    Reporting group description
    		 Subjects received vibegron 75 milligrams (mg), orally, once daily for 12 weeks.

    Reporting group title
    Tolterodine ER 4 mg
    Reporting group description
    		 Subjects received tolterodine extended release (ER) 4 mg, orally, once daily for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo, orally, once daily for 12 weeks.

    Serious adverse events
    		 Vibegron 75 mg Tolterodine ER 4 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 545 (1.47%)
    10 / 430 (2.33%)
    6 / 540 (1.11%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cholangiocarcinoma
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 430 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colorectal adenocarcinoma
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 430 (0.00%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 430 (0.23%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 430 (0.23%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 430 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 430 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 430 (0.00%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 430 (0.23%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 430 (0.00%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 430 (0.23%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 430 (0.23%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 430 (0.23%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 430 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural complication
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 430 (0.23%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 430 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Aortic valve incompetence
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 430 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 430 (0.00%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 430 (0.00%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 430 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 545 (0.18%)
    1 / 430 (0.23%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 430 (0.23%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 430 (0.23%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 430 (0.23%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 430 (0.23%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 430 (0.00%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendix disorder
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 430 (0.00%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 430 (0.00%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 430 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 430 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 430 (0.23%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 545 (0.18%)
    0 / 430 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 430 (0.23%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 545 (0.00%)
    1 / 430 (0.23%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 430 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    0 / 545 (0.00%)
    0 / 430 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Vibegron 75 mg Tolterodine ER 4 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 545 (6.61%)
    50 / 430 (11.63%)
    38 / 540 (7.04%)
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    9 / 545 (1.65%)
    28 / 430 (6.51%)
    5 / 540 (0.93%)
         occurrences all number
    9
    29
    5
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    27 / 545 (4.95%)
    24 / 430 (5.58%)
    33 / 540 (6.11%)
         occurrences all number
    32
    28
    36

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Oct 2017
    - Changes were made to description of contraception requirements and methods for female subject. - Plan to use a paper diary as backup was added.
    01 Nov 2017
    - Inclusion and exclusion criterion were updated. - A note that paper diaries may be used was added. - Clarification that pelvic examinations may be part of the physical examination and clarification that urinalysis was to be performed if there was a positive dipstick result was made. - Follicle-stimulating hormone was removed from clinical laboratory test performed. - The timing for collection of paper diaries (if used) was added. - References to the Week 2 time point as a visit were reworded to clarify that a study visit does not occur at Week 2. - “Tablet” or “capsule” descriptors were added. - Wording was added to indicate the study treatment should be swallowed whole. - Wording was added to require a witnessed dose at the clinic at Run-In and Baseline Visits. - Pharmacokinetic (PK) sub-study language was changed. - Dispense study medication was language was combined. - Clarified that tablet/capsule count was to be recorded in the interactive voice or web response system rather than case report form. - Added adverse events suggestive of cystitis or urinary tract infection and moved liver test values to end of list.
    30 Jan 2018
    - Addition of exploratory efficacy endpoints - Change of 5% in response efficacy endpoint - Change in statistical analysis from Last Observation Carried Forward to multiple imputation; subgroup analyses to include primary mixed model for repeated measure analysis model with a subgroup by treatment interaction term. - Updated Schedule of Activities and visit events - Updated language around timing of data collection for adverse events (AEs) and serious adverse events. - Changed days of screening compliance - Replaced “discontinued” with “interrupted” - Removed study medication rechallenge in subjects with a grade 3 or higher drug-related AE reported - Updated Patient Voiding Diary and Urine Volume Collection instructions, training, and description - Updated instructions on Reminders for Diary Collection - Updated Electronic Diary instructions and training - Deletion of data collection of food/meal intake prior to PK sampling - Updated Major Adverse Cardiac and Cerebrovascular Events language to match clinical adjudication committee Charter - Addition of time frame around pregnancy and infant outcome
    12 Feb 2018
    Minor typographical/formatting errors were corrected.
    15 Nov 2018
    - The key secondary efficacy endpoints were reordered, and key/other secondary efficacy endpoints were added and removed. - Exploratory endpoints were reordered and analysis timepoints were updated for some endpoints. - Exploratory endpoints were added and removed. - Removed language indicating that AEs from time of informed consent to first dose of study treatment should be recorded as medical history. - One objective/hypothesis was added, four key secondary objectives/hypotheses were deleted, and the objectives/hypotheses were reordered and renumbered accordingly.

    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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