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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	v1
This version publication date	27 Jan 2021
First version publication date	27 Jan 2021
Other versions	v2

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

RVT-901-3003

ISRCTN number

US NCT number

NCT03492281

WHO universal trial number (UTN)

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

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

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?

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

Independent data monitoring committee (IDMC) involvement?

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

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

871

From 65 to 84 years

632

85 years and over

Subject disposition

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Recruitment details

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 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

Are arms mutually exclusive

Yes

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

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

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
Physician decision	1	-	3
Consent withdrawn by subject	21	14	13
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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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. 999999=population not analyzed.
Units: micturitions
arithmetic mean (standard deviation)	( )	( )	( )	-
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. 999999=population not analyzed.
Units: UUI episodes
arithmetic mean (standard deviation)	( )	( )	( )	-
Average number of urgency episodes over 24 hours in all OAB subjects
An urgency episode was defined as the “Need to Urinate Immediately” as indicated on the PVD. "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). 999999=population not analyzed.
Units: urgency episodes
arithmetic mean (standard deviation)	( )	( )	( )	-
Average number of total incontinence episodes over 24 hours in OAB Wet subjects
Total incontinence was 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. 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 > the total number of stress urinary incontinence episodes from the previous visit diary.
Units: total incontinence episodes
arithmetic mean (standard deviation)	( )	( )	( )	-
Coping Score from the OAB Questionnaire Long Form (OAB-q LF, 1-week recall) in all OAB subjects
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. 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 [ranging from 8 to 48]) 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. n=518, 524, 416.
Units: Units on a scale
arithmetic mean (standard deviation)	( )	( )	( )	-
Average volume voided per micturition in all OAB subjects
A micturition/void was defined as “Urinated in Toilet” as indicated on the 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 volume voided per micturition was calculated as the arithmetic mean of all voids for which a subject recorded the volume. 999999=population not analyzed. n=514, 524, 415 (only subjects with evaluable data were analyzed).
Units: milliliters
arithmetic mean (standard deviation)	( )	( )	( )	-
Health-related Quality of Life (HRQL) TS from the OAB-q LF (1-week recall) in all OAB subjects
TS=total score. The OAB-q LF is a validated patient-reported outcome. The 25 questions comprising the 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. n=518, 524, 416 (evaluable subjects).
Units: Units on a scale
arithmetic mean (standard deviation)	( )	( )	( )	-
Symptom Bother Score from the OAB-q LF (1-week recall) in all OAB subjects
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 [ranging from 8 to 48]) is transformed to a unified score, ranging 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. n=518, 524, 416.
Units: Units on a scale
arithmetic mean (standard deviation)	( )	( )	( )	-
Overall bladder symptoms based on PGI of Severity (PGI-Severity) in all OAB subjects
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. 999999=population not analyzed. n=519, 525, 417 (only subjects with evaluable data were analyzed).
Units: Units on a scale
arithmetic mean (standard deviation)	( )	( )	( )	-
Overall control over bladder symptoms based on PGI of Control (PGI-Control) in all OAB subjects
The 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. 999999=population not analyzed. n=519, 525, 417 (only subjects with evaluable data were analyzed).
Units: Units on a scale
arithmetic mean (standard deviation)	( )	( )	( )	-

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.

Subject analysis sets values	Placebo: Full Analysis Set	Vibegron 75 mg: Full Analysis Set	Tolterodine ER 4 mg: Full Analysis Set	Placebo: OAB Wet	Vibegron 75 mg: OAB Wet	Tolterodine ER 4 mg: OAB Wet
Number of subjects	520	526	417	405	403	319
Age categorical
Units:
Age continuous
Units: years
arithmetic mean (standard deviation)	( )	( )	( )	( )	( )	( )
Gender categorical
Units: Subjects
Female
Male
Race/Ethnicity, Customized
Units: Subjects
American Indian or Alaska
Asian
Black or African American
White
Puerto Rican
White and Black or African American
Hispanic
Filipino
Morrocan
Multiracial
White, Black or African American
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. 999999=population not analyzed.
Units: micturitions
arithmetic mean (standard deviation)	11.75 ( 4.007 )	11.31 ( 3.420 )	11.48 ( 3.153 )	999999 ( 999999 )	999999 ( 999999 )	999999 ( 999999 )
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. 999999=population not analyzed.
Units: UUI episodes
arithmetic mean (standard deviation)	999999 ( 999999 )	999999 ( 999999 )	999999 ( 999999 )	3.49 ( 3.053 )	3.43 ( 2.894 )	3.42 ( 2.592 )
Average number of urgency episodes over 24 hours in all OAB subjects
An urgency episode was defined as the “Need to Urinate Immediately” as indicated on the PVD. "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). 999999=population not analyzed.
Units: urgency episodes
arithmetic mean (standard deviation)	8.13 ( 4.668 )	8.11 ( 4.400 )	7.92 ( 3.883 )	999999 ( 999999 )	999999 ( 999999 )	999999 ( 999999 )
Average number of total incontinence episodes over 24 hours in OAB Wet subjects
Total incontinence was 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. 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 > the total number of stress urinary incontinence episodes from the previous visit diary.
Units: total incontinence episodes
arithmetic mean (standard deviation)	999999 ( 999999 )	999999 ( 999999 )	999999 ( 999999 )	4.17 ( 3.823 )	4.14 ( 3.631 )	4.06 ( 3.071 )
Coping Score from the OAB Questionnaire Long Form (OAB-q LF, 1-week recall) in all OAB subjects
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. 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 [ranging from 8 to 48]) 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. n=518, 524, 416.
Units: Units on a scale
arithmetic mean (standard deviation)	58.74 ( 27.140 )	57.57 ( 28.090 )	59.77 ( 26.399 )	999999 ( 999999 )	999999 ( 999999 )	999999 ( 999999 )
Average volume voided per micturition in all OAB subjects
A micturition/void was defined as “Urinated in Toilet” as indicated on the 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 volume voided per micturition was calculated as the arithmetic mean of all voids for which a subject recorded the volume. 999999=population not analyzed. n=514, 524, 415 (only subjects with evaluable data were analyzed).
Units: milliliters
arithmetic mean (standard deviation)	148.3 ( 60.67 )	155.4 ( 63.07 )	147.0 ( 60.79 )	999999 ( 999999 )	999999 ( 999999 )	999999 ( 999999 )
Health-related Quality of Life (HRQL) TS from the OAB-q LF (1-week recall) in all OAB subjects
TS=total score. The OAB-q LF is a validated patient-reported outcome. The 25 questions comprising the 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. n=518, 524, 416 (evaluable subjects).
Units: Units on a scale
arithmetic mean (standard deviation)	63.74 ( 23.473 )	62.71 ( 24.916 )	64.53 ( 22.902 )	999999 ( 999999 )	999999 ( 999999 )	999999 ( 999999 )
Symptom Bother Score from the OAB-q LF (1-week recall) in all OAB subjects
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 [ranging from 8 to 48]) is transformed to a unified score, ranging 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. n=518, 524, 416.
Units: Units on a scale
arithmetic mean (standard deviation)	50.07 ( 20.642 )	49.68 ( 21.961 )	48.01 ( 20.611 )	999999 ( 999999 )	999999 ( 999999 )	999999 ( 999999 )
Overall bladder symptoms based on PGI of Severity (PGI-Severity) in all OAB subjects
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. 999999=population not analyzed. n=519, 525, 417 (only subjects with evaluable data were analyzed).
Units: Units on a scale
arithmetic mean (standard deviation)	3.03 ( 0.645 )	3.02 ( 0.619 )	2.99 ( 0.639 )	999999 ( 999999 )	999999 ( 999999 )	999999 ( 999999 )
Overall control over bladder symptoms based on PGI of Control (PGI-Control) in all OAB subjects
The 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. 999999=population not analyzed. n=519, 525, 417 (only subjects with evaluable data were analyzed).
Units: Units on a scale
arithmetic mean (standard deviation)	3.16 ( 0.964 )	3.23 ( 0.911 )	3.17 ( 0.934 )	999999 ( 999999 )	999999 ( 999999 )	999999 ( 999999 )

End points

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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

Subject analysis set title

Vibegron 75 mg: Full Analysis Set

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Tolterodine ER 4 mg: Full Analysis Set

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Placebo: OAB Wet

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Vibegron 75 mg: OAB Wet

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Tolterodine ER 4 mg: OAB Wet

Subject analysis set type

Full analysis

Subject analysis set description

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
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.

LS Mean Difference: Vibegron 75 mg minus Placebo

Statistical analysis description

LS=least squares

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

< 0.001 ^[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.

LS Mean Difference: Tolterodine ER minus Placebo

Comparison groups

Placebo: Full Analysis Set v Tolterodine ER 4 mg: 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

Top of page

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
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.

LS Mean Difference: Vibegron 75 mg minus Placebo

Comparison groups

Placebo: OAB Wet v Vibegron 75 mg: 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.

LS Mean Difference: Tolterodine ER minus Placebo

Comparison groups

Placebo: OAB Wet v Tolterodine ER 4 mg: 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

Top of page

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
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.

LS Mean Difference: Vibegron 75 mg minus Placebo

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

= 0.002 ^[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.

LS Mean Difference: Tolterodine ER minus Placebo

Comparison groups

Placebo: Full Analysis Set v Tolterodine ER 4 mg: 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

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

Top of page

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

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.

Difference in Proportion: 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

< 0.0001 ^[19]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportion

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.

Difference in Proportion: Tolterodine ER:Placebo

Comparison groups

Placebo: OAB Wet v Tolterodine ER 4 mg: 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 proportion

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

Top of page

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

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.

Difference in Proportion: 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

= 0.036 ^[24]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportion

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.

Difference in Proportion: Tolterodine ER:Placebo

Comparison groups

Placebo: OAB Wet v Tolterodine ER 4 mg: 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 proportion

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

Top of page

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.

Difference in Proportion: Vibegron 75 mg:Placebo

Comparison groups

Placebo: Full Analysis Set v Vibegron 75 mg: 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 proportion

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.

Difference in Proportion: Tolterodine ER:Placebo

Comparison groups

Placebo: Full Analysis Set v Tolterodine ER 4 mg: 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 proportion

Point estimate

3.7

Confidence interval

level

95%

sides

2-sided

lower limit

-2.5

upper limit

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

Top of page

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.

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
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.

LS Mean Difference: Vibegron 75 mg minus Placebo

Comparison groups

Placebo: OAB Wet v Vibegron 75 mg: 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.

LS Mean Difference: Tolterodine ER minus Placebo

Comparison groups

Placebo: OAB Wet v Tolterodine ER 4 mg: 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

Top of page

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.

LS Mean Difference: Vibegron 75 mg minus Placebo

Comparison groups

Placebo: Full Analysis Set v Vibegron 75 mg: 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

Variability estimate

Standard error of the mean

Dispersion value

1.24

Notes
[39] - Hypothesis testing was performed for vibegron minus placebo.

LS Mean Difference: Tolterodine ER minus Placebo

Comparison groups

Placebo: Full Analysis Set v Tolterodine ER 4 mg: 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

Top of page

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
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.

LS Mean Difference: Vibegron 75 mg minus Placebo

Comparison groups

Placebo: Full Analysis Set v Vibegron 75 mg: 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.

LS Mean Difference: Tolterodine ER minus Placebo

Comparison groups

Placebo: Full Analysis Set v Tolterodine ER 4 mg: 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

Top of page

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.

LS Mean Difference: Vibegron 75 mg minus Placebo

Comparison groups

Placebo: Full Analysis Set v Vibegron 75 mg: 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.

LS Mean Difference: Tolterodine ER minus Placebo

Comparison groups

Placebo: Full Analysis Set v Tolterodine ER 4 mg: 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

Top of page

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.

LS Mean Difference: Vibegron 75 mg minus Placebo

Comparison groups

Placebo: Full Analysis Set v Vibegron 75 mg: 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.

LS Mean Difference: Tolterodine ER minus Placebo

Comparison groups

Placebo: Full Analysis Set v Tolterodine ER 4 mg: 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

Top of page

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

Difference in Proportion: Vibegron 75 mg:Placebo

Comparison groups

Placebo: Full Analysis Set v Vibegron 75 mg: 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 proportion

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.

Difference in Proportion: Tolterodine ER:Placebo

Comparison groups

Placebo: Full Analysis Set v Tolterodine ER 4 mg: 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 proportion

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

Top of page

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.

Difference in Proportion: 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

< 0.001 ^[63]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportion

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.

Difference in Proportion: Tolterodine ER:Placebo

Comparison groups

Placebo: OAB Wet v Tolterodine ER 4 mg: 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 proportion

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

Top of page

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.

LS Mean Difference: Vibegron 75 mg minus Placebo

Comparison groups

Placebo: Full Analysis Set v Vibegron 75 mg: 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.

LS Mean Difference: Tolterodine ER minus Placebo

Comparison groups

Placebo: Full Analysis Set v Tolterodine ER 4 mg: 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

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

Top of page

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.

LS Mean Difference: Vibegron 75 mg minus Placebo

Comparison groups

Placebo: Full Analysis Set v Vibegron 75 mg: 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.

LS Mean Difference: Tolterodine ER minus Placebo

Comparison groups

Placebo: Full Analysis Set v Tolterodine ER 4 mg: 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

Top of page

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 name

MedDRA

Dictionary version

20.1

Reporting group title

Vibegron 75 mg

Reporting group description

Subjects received vibegron 75 milligrams (mg), orally, once daily for 12 weeks.

Reporting group title

Placebo

Reporting group description

Subjects received matching placebo, 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.

Serious adverse events	Vibegron 75 mg	Placebo	Tolterodine ER 4 mg
Total subjects affected by serious adverse events
subjects affected / exposed	8 / 545 (1.47%)	6 / 540 (1.11%)	10 / 430 (2.33%)
number of deaths (all causes)	0	0	1
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%)	1 / 540 (0.19%)	0 / 430 (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
Colorectal adenocarcinoma
subjects affected / exposed	1 / 545 (0.18%)	0 / 540 (0.00%)	0 / 430 (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%)	0 / 540 (0.00%)	1 / 430 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 545 (0.00%)	0 / 540 (0.00%)	1 / 430 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 545 (0.00%)	1 / 540 (0.19%)	0 / 430 (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
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 545 (0.00%)	1 / 540 (0.19%)	0 / 430 (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
Non-cardiac chest pain
subjects affected / exposed	1 / 545 (0.18%)	0 / 540 (0.00%)	0 / 430 (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%)	0 / 540 (0.00%)	1 / 430 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 545 (0.18%)	0 / 540 (0.00%)	0 / 430 (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%)	0 / 540 (0.00%)	1 / 430 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 545 (0.00%)	0 / 540 (0.00%)	1 / 430 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Panic attack
subjects affected / exposed	0 / 545 (0.00%)	0 / 540 (0.00%)	1 / 430 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Ejection fraction decreased
subjects affected / exposed	0 / 545 (0.00%)	1 / 540 (0.19%)	0 / 430 (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
Injury, poisoning and procedural complications
Post procedural complication
subjects affected / exposed	0 / 545 (0.00%)	0 / 540 (0.00%)	1 / 430 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 545 (0.00%)	1 / 540 (0.19%)	0 / 430 (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
Cardiac disorders
Aortic valve incompetence
subjects affected / exposed	0 / 545 (0.00%)	1 / 540 (0.19%)	0 / 430 (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
Atrial fibrillation
subjects affected / exposed	1 / 545 (0.18%)	0 / 540 (0.00%)	0 / 430 (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 / 540 (0.00%)	0 / 430 (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%)	1 / 540 (0.19%)	0 / 430 (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
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	1 / 545 (0.18%)	0 / 540 (0.00%)	1 / 430 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Encephalopathy
subjects affected / exposed	0 / 545 (0.00%)	0 / 540 (0.00%)	1 / 430 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 545 (0.00%)	0 / 540 (0.00%)	1 / 430 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 545 (0.00%)	0 / 540 (0.00%)	1 / 430 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
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%)	0 / 540 (0.00%)	1 / 430 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 545 (0.18%)	0 / 540 (0.00%)	0 / 430 (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 / 540 (0.00%)	0 / 430 (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 / 540 (0.00%)	0 / 430 (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%)	1 / 540 (0.19%)	0 / 430 (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
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 545 (0.00%)	1 / 540 (0.19%)	0 / 430 (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
Musculoskeletal and connective tissue disorders
Muscular weakness
subjects affected / exposed	0 / 545 (0.00%)	0 / 540 (0.00%)	1 / 430 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	1 / 545 (0.18%)	1 / 540 (0.19%)	0 / 430 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 545 (0.00%)	0 / 540 (0.00%)	1 / 430 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Urinary tract infection
subjects affected / exposed	0 / 545 (0.00%)	0 / 540 (0.00%)	1 / 430 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 545 (0.00%)	1 / 540 (0.19%)	0 / 430 (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
Lactic acidosis
subjects affected / exposed	0 / 545 (0.00%)	1 / 540 (0.19%)	0 / 430 (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

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Vibegron 75 mg	Placebo	Tolterodine ER 4 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	36 / 545 (6.61%)	38 / 540 (7.04%)	50 / 430 (11.63%)
Gastrointestinal disorders
Dry mouth
subjects affected / exposed	9 / 545 (1.65%)	5 / 540 (0.93%)	28 / 430 (6.51%)
occurrences all number	9	5	29
Infections and infestations
Urinary tract infection
subjects affected / exposed	27 / 545 (4.95%)	33 / 540 (6.11%)	24 / 430 (5.58%)
occurrences all number	32	36	28

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

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.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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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