APOLLO: BOTOX® Intravesical Instillation in Participants With Overactive Bladder and Urinary Incontinence

• Sponsor: Allergan (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03320850
• Collaborator: (none)
• Enrollment: 383
• Locations: 63
• Arms: 8
• Actual Duration (Months): 33.5
• Patients Per Site: 6.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study will evaluate the efficacy and safety of BOTOX® intravesical instillation in participants with overactive bladder and urinary incontinence.

Condition or Disease	Intervention/Treatment	Phase
Urinary Incontinence; Overactive Bladder With Urinary Incontinence	Drug: OnabotulinumtoxinA and Hydrogel admixture; Drug: Placebo and Hydrogel admixture	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 383 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, Single-treatment, 2-stage, Dose-finding Study Evaluating the Efficacy and Safety of BOTOX® Intravesical Instillation in Participants With Overactive Bladder and Urinary Incontinence
• Actual Study Start Date: Oct 4, 2017
• Actual Primary Completion Date: Jul 21, 2020
• Actual Study Completion Date: Jul 21, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 100U cohort - BOTOX® plus Hydrogel admixture 100U BOTOX® (onabotulinumtoxinA) and Hydrogel admixture administered as a single intravesical instillation on Day 1	Drug: OnabotulinumtoxinA and Hydrogel admixture; BOTOX® (onabotulinumtoxinA) and Hydrogel admixture administered as a single intravesical instillation; Other Names: BOTOX® Botulinum Toxin Type A
Placebo Comparator: 100U cohort - Placebo plus Hydrogel admixture Placebo and Hydrogel admixture administered as a single intravesical instillation on Day 1	Drug: Placebo and Hydrogel admixture; Placebo and Hydrogel admixture administered as a single intravesical instillation
Experimental: 300U cohort - BOTOX® plus Hydrogel admixture 300U BOTOX® (onabotulinumtoxinA) and Hydrogel admixture administered as a single intravesical instillation on Day 1	Drug: OnabotulinumtoxinA and Hydrogel admixture; BOTOX® (onabotulinumtoxinA) and Hydrogel admixture administered as a single intravesical instillation; Other Names: BOTOX® Botulinum Toxin Type A
Placebo Comparator: 300U cohort - Placebo plus Hydrogel admixture Placebo and Hydrogel admixture administered as a single intravesical instillation on Day 1	Drug: Placebo and Hydrogel admixture; Placebo and Hydrogel admixture administered as a single intravesical instillation
Experimental: 400U cohort - BOTOX® plus Hydrogel admixture 400U BOTOX® (onabotulinumtoxinA) and Hydrogel admixture administered as a single intravesical instillation on Day 1	Drug: OnabotulinumtoxinA and Hydrogel admixture; BOTOX® (onabotulinumtoxinA) and Hydrogel admixture administered as a single intravesical instillation; Other Names: BOTOX® Botulinum Toxin Type A
Placebo Comparator: 400U cohort - Placebo plus Hydrogel admixture Placebo and Hydrogel admixture administered as a single intravesical instillation on Day 1	Drug: Placebo and Hydrogel admixture; Placebo and Hydrogel admixture administered as a single intravesical instillation
Experimental: 500U cohort - BOTOX® plus Hydrogel admixture 500U BOTOX® (onabotulinumtoxinA) and Hydrogel admixture administered as a single intravesical instillation on Day 1	Drug: OnabotulinumtoxinA and Hydrogel admixture; BOTOX® (onabotulinumtoxinA) and Hydrogel admixture administered as a single intravesical instillation; Other Names: BOTOX® Botulinum Toxin Type A
Placebo Comparator: 500U cohort - Placebo plus Hydrogel admixture Placebo and Hydrogel admixture administered as a single intravesical instillation on Day 1	Drug: Placebo and Hydrogel admixture; Placebo and Hydrogel admixture administered as a single intravesical instillation

Outcome Measures

Primary Outcome Measures

1. Stage 2: Change From Baseline in the Average Number of Urinary Incontinence Episodes (UIEs) Per Day [Baseline (3 consecutive days during Day -14 to Day -1) to 3 consecutive days in the Week prior to Week 12]

   The participant recorded urinary incontinence (lack of voluntary control over urination) in a 3-day bladder diary. The average number of UIEs per day is the average of the 3-day diary entries. A negative change from Baseline indicates improvement. Baseline is defined as the last non-missing assessment before the first dose of study treatment. An analysis of covariance (ANCOVA) model was used for analyses.

2. Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAEs) in the Treatment Period [Up to End of Study (Stage 1: Up to 114 days and Stage 2: Up to 35.1 weeks)]

   An adverse event (AE) is any untoward medical occurrence in a participants or clinical study investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. A TEAE is an AE that occurs or worsens after receiving study drug.

Secondary Outcome Measures

1. Stage 2: Change From Baseline in the Average Number of Micturition Episodes Per Day [Baseline (3 consecutive days during Days -14 to Day -1) to 3 consecutive days in the Week prior to Week 12]

   The participant recorded the number of micturition (urination in toilet or catherization) episodes per day in a 3-day bladder diary. The average number of micturition episodes per day is the average of the 3-day diary entries. A negative change from Baseline indicates improvement. Baseline is defined as the last non-missing assessment before the first dose of study treatment. ANCOVA model was used for analyses.

2. Stage 2: Change From Baseline in the Average Volume Voided Per Micturition [Baseline (3 consecutive days during Days -14 to Day -1) to 3 consecutive days in the Week prior to Week 12]

   Volume voided per micturition was recorded over one 24-hour period during the 3-day bladder diary. The volume voided during each 24-hour period was divided by the number of micturitions during the period. The average volume voided per micturition is the average of the 3-day diary entries. A negative change from Baseline indicates improvement. Baseline is defined as the last non-missing assessment before the first dose of study treatment. ANCOVA model was used for analyses.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Symptoms of OAB (frequency/urgency) with urinary incontinence for at least 6 months

• Inadequate response or limiting side effects with pharmacotherapy for the treatment of OAB

Exclusion Criteria:

• Overactive Bladder caused by neurological condition

• Patient has predominance of stress incontinence

• History or evidence of pelvic or urological abnormality

• Prior use of BOTOX for any urological condition

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35249
2	Coastal Clinical Research, Inc., an AMR company	Mobile	Alabama	United States	36608
3	Urological Assoc. of South AZ	Tucson	Arizona	United States	85715
4	Hope Clinical Research	Canoga Park	California	United States	91303
5	San Bernardino Urological Associates Medical Group	San Bernardino	California	United States	92404
6	Wr-McCr, Llc	San Diego	California	United States	92108
7	San Diego Clinical Trials	San Diego	California	United States	92120
8	Sutter Institute for Medical Health	Vacaville	California	United States	95688
9	West Coast Urology	Whittier	California	United States	90603
10	The Urology Center of Colorado	Denver	Colorado	United States	80211
11	Urology Associates, P.C	Englewood	Colorado	United States	80113
12	Adult and Pediatric Urology	Bridgeport	Connecticut	United States	06606
13	Women's Health Specialty Care	Farmington	Connecticut	United States	06032
14	CT Clinical Research Center/Urologist Specialist	Middlebury	Connecticut	United States	06762
15	Innovative Medical Research of South FL, Inc.	Aventura	Florida	United States	33180
16	South Florida Medical Research	Aventura	Florida	United States	33180
17	Manatee Medical Research Institute	Bradenton	Florida	United States	34205
18	Sunrise Medical Research	Lauderdale Lakes	Florida	United States	33319
19	Urological Research Network	Miramar	Florida	United States	33029
20	Florida Urology Partners	N. Redington Beach	Florida	United States	33708
21	Renstar Medical Research	Ocala	Florida	United States	34471
22	Clinical Research Center of Florida	Pompano Beach	Florida	United States	33060
23	Pinellas Urology, Inc.	Saint Petersburg	Florida	United States	33710
24	North Idaho Urology	Coeur d'Alene	Idaho	United States	83814
25	Idaho Urologic Institute	Meridian	Idaho	United States	83642
26	Comprehensive Urological Care	Lake Barrington	Illinois	United States	60010
27	Urogynecology Associates, PC	Carmel	Indiana	United States	46032
28	First Urology,PSC	Jeffersonville	Indiana	United States	47130
29	The Iowa Clinic	West Des Moines	Iowa	United States	50266
30	DelRicht Research, LLC	New Orleans	Louisiana	United States	70115
31	Regional Urology, LLC	Shreveport	Louisiana	United States	71106
32	Chesapeake Urology Associates	Hanover	Maryland	United States	21076
33	Chesapeake Urology	Owings Mills	Maryland	United States	21117
34	Bay State Clinical Trials, Inc.	Watertown	Massachusetts	United States	02472
35	Women's Health Care Specialists	Kalamazoo	Michigan	United States	49009
36	Michigan Institute of Urology	Troy	Michigan	United States	48084
37	Adult Pediatric Urology & Urogynecology	Omaha	Nebraska	United States	68114
38	Excel Clinical Research	Las Vegas	Nevada	United States	89109
39	Premier Urology Group	Edison	New Jersey	United States	08837
40	Delaware Valley Urology	Mount Laurel	New Jersey	United States	08043
41	Western New York Urology Associates	Cheektowaga	New York	United States	14225
42	AccuMed Research Associates	Garden City	New York	United States	11530
43	Urological Surgeons of Long Island	Garden City	New York	United States	11530
44	Manhattan Medical Research Practice PLLC	New York	New York	United States	10016
45	Urology Institute of Long Island	Plainview	New York	United States	11803
46	Associated Medical Professionals- Urology	Syracuse	New York	United States	13210
47	American Health Research	Charlotte	North Carolina	United States	28207
48	Carolina Institute for Clinical Research	Fayetteville	North Carolina	United States	28304
49	Associated Urologists of North Carolina	Raleigh	North Carolina	United States	27612
50	Lyndhurst Clinical Research	Winston-Salem	North Carolina	United States	27103
51	Clinical Research Solutions, LLC	Middleburg Heights	Ohio	United States	44130
52	The Center for Men's & Women's Urology	Gresham	Oregon	United States	97030
53	Urologic Consultants of SE PA	Bala-Cynwyd	Pennsylvania	United States	19004
54	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
55	Urology Clinics of North Texas	Dallas	Texas	United States	75231
56	Houston Metro Urology	Houston	Texas	United States	77027
57	Virginia Urology	Richmond	Virginia	United States	23235
58	Urology of Virginia	Virginia Beach	Virginia	United States	23462
59	Washington Urology and Urogynecology Associates	Kirkland	Washington	United States	98034
60	Multicare Allenmore Hospital	Tacoma	Washington	United States	98405
61	Aurora Research Institute	West Allis	Wisconsin	United States	53227
62	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N 3M5
63	Toronto Western Hospital	Toronto	Ontario	Canada	M5T 2S8

Sponsors and Collaborators

• Allergan

Investigators

• Study Director: Till Geib, Allergan

Study Documents (Full-Text)

• Study Protocol - Dec 20, 2018
• Statistical Analysis Plan - Mar 7, 2019

More Information

Additional Information:

• Additional information on study locations near you may be found at AllerganClinicalTrials.com.

Publications

None provided.

• Responsible Party: Allergan
• ClinicalTrials.gov Identifier: NCT03320850
• Other Study ID Numbers: 1839-201-021
• First Posted: Oct 25, 2017
• Last Update Posted: Aug 13, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Urinary Incontinence; Enuresis; Urinary Bladder, Overactive; Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA

Study Results

Participant Flow

Arm/Group Title	Stage 1: Placebo + Hydrogel Admixture	Stage 1: BOTOX® 100U + Hydrogel Admixture	Stage 1: BOTOX® 300U + Hydrogel Admixture	Stage 1: BOTOX® 400U + Hydrogel Admixture	Stage 1: BOTOX® 500U + Hydrogel Admixture	Stage 2: Placebo + Hydrogel Admixture	Stage 2: BOTOX® 100U + Hydrogel Admixture	Stage 2: BOTOX® 300U + Hydrogel Admixture	Stage 2: BOTOX® 400U + Hydrogel Admixture	Stage 2: BOTOX® 500U + Hydrogel Admixture
Arm/Group Description	BOTOX® matching-placebo and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 100 units (U) (onabotulinumtoxinA; botulinum toxin Type A) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 300U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 400U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 500U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® matching-placebo and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 100U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 300U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 400U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 500U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.
Period Title: Overall Study
STARTED	18	12	18	22	19	58	57	60	60	59
Safety Population	18	12	18	22	19	57	57	60	60	58
COMPLETED	18	12	18	21	17	49	50	53	50	50
NOT COMPLETED	0	0	0	1	2	9	7	7	10	9

Baseline Characteristics

Arm/Group Title	Stage 1: Placebo + Hydrogel Admixture	Stage 1: BOTOX® 100U + Hydrogel Admixture	Stage 1: BOTOX® 300U + Hydrogel Admixture	Stage 1: BOTOX® 400U + Hydrogel Admixture	Stage 1: BOTOX® 500U + Hydrogel Admixture	Stage 2: Placebo + Hydrogel Admixture	Stage 2: BOTOX® 100U + Hydrogel Admixture	Stage 2: BOTOX® 300U + Hydrogel Admixture	Stage 2: BOTOX® 400U + Hydrogel Admixture	Stage 2: BOTOX® 500U + Hydrogel Admixture	Total
Arm/Group Description	BOTOX® matching-placebo and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 100 units (U) (onabotulinumtoxinA; botulinum toxin Type A) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 300U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 400U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 500U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® matching-placebo and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 100U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 300U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 400U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 500U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	Total of all reporting groups
Overall Participants	18	12	18	22	19	58	57	60	60	59	383
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.7 (13.8)	54.7 (13.0)	56.2 (12.1)	62.4 (8.6)	55.3 (13.2)	57.2 (12.2)
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.9 (11.17)	60.4 (9.93)	59.1 (11.33)	59.8 (9.10)	60.7 (9.38)	59.6 (10.20)
Sex: Female, Male (Count of Participants)
Female	17 94.4%	12 100%	15 83.3%	18 81.8%	17 89.5%	53 91.4%	53 93%	54 90%	54 90%	54 91.5%	347 90.6%
Male	1 5.6%	0 0%	3 16.7%	4 18.2%	2 10.5%	5 8.6%	4 7%	6 10%	6 10%	5 8.5%	36 9.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 11.1%	2 16.7%	3 16.7%	1 4.5%	0 0%	5 8.6%	9 15.8%	5 8.3%	11 18.3%	7 11.9%	45 11.7%
Not Hispanic or Latino	16 88.9%	10 83.3%	15 83.3%	21 95.5%	19 100%	53 91.4%	48 84.2%	55 91.7%	49 81.7%	52 88.1%	338 88.3%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 1.7%	0 0%	1 0.3%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	1 1.7%	0 0%	1 1.7%	1 1.7%	0 0%	3 0.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	4 22.2%	4 33.3%	4 22.2%	1 4.5%	7 36.8%	12 20.7%	13 22.8%	10 16.7%	9 15%	16 27.1%	80 20.9%
White	13 72.2%	8 66.7%	14 77.8%	20 90.9%	11 57.9%	44 75.9%	44 77.2%	48 80%	49 81.7%	43 72.9%	294 76.8%
More than one race	0 0%	0 0%	0 0%	1 4.5%	1 5.3%	1 1.7%	0 0%	0 0%	0 0%	0 0%	3 0.8%
Unknown or Not Reported	1 5.6%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 1.7%	0 0%	0 0%	2 0.5%
Stage 1: Average Number of Urinary Incontinence Episodes (UIE) (episodes per day) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [episodes per day]	7.1 (3.4)	4.7 (2.5)	5.8 (2.7)	4.4 (2.7)	5.3 (3.0)	5.5 (3.0)
Stage 2: Average Number of Urinary Incontinence Episodes (episodes per day) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [episodes per day]	6.06 (3.162)	5.60 (4.267)	4.46 (2.738)	4.56 (3.073)	5.92 (3.302)	5.30 (3.386)
Stage 1: Average Number of Micturition Episodes per Day (episodes per day) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [episodes per day]	10.6 (2.4)	10.9 (3.5)	10.0 (1.6)	11.3 (2.4)	11.8 (2.9)	10.9 (2.6)
Stage 2: Average Number of Micturition Episodes per Day (episodes per day) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [episodes per day]	11.12 (3.049)	10.97 (2.938)	10.91 (2.678)	9.88 (2.030)	10.70 (2.822)	10.71 (2.738)
Stage 1: Average Volume Voided per Micturition (milliliter (mL)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [milliliter (mL)]	189.2 (64.1)	189.8 (94.0)	182.5 (79.3)	150.0 (54.7)	199.4 (70.0)	180.4 (71.9)
Stage 2: Average Volume Voided per Micturition (mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mL]	179.10 (59.421)	173.28 (66.615)	167.10 (67.940)	194.50 (67.414)	199.58 (74.154)	182.79 (68.025)

Outcome Measures

1. Primary Outcome

Title	Stage 2: Change From Baseline in the Average Number of Urinary Incontinence Episodes (UIEs) Per Day
Description	The participant recorded urinary incontinence (lack of voluntary control over urination) in a 3-day bladder diary. The average number of UIEs per day is the average of the 3-day diary entries. A negative change from Baseline indicates improvement. Baseline is defined as the last non-missing assessment before the first dose of study treatment. An analysis of covariance (ANCOVA) model was used for analyses.
Time Frame	Baseline (3 consecutive days during Day -14 to Day -1) to 3 consecutive days in the Week prior to Week 12

Outcome Measure Data

Analysis Population Description

Participants from the Intent-to-treat (ITT) Analysis Set, all randomized participants in Stage 2, with data available for analysis at Baseline and Week 12. As per protocol, this endpoint is only applicable to the Stage 2 arms.

Arm/Group Title	Stage 2: Placebo + Hydrogel Admixture	Stage 2: BOTOX® 100U + Hydrogel Admixture	Stage 2: BOTOX® 300U + Hydrogel Admixture	Stage 2: BOTOX® 400U + Hydrogel Admixture	Stage 2: BOTOX® 500U + Hydrogel Admixture
Arm/Group Description	BOTOX® matching-placebo and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 100U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 300U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 400U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 500U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.
Measure Participants	57	57	60	60	58
Least Squares Mean (Standard Error) [episodes per day]	-2.72 (0.534)	-1.62 (0.539)	-0.89 (0.521)	-1.52 (0.520)	-1.85 (0.530)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 2: Placebo + Hydrogel Admixture, Stage 2: BOTOX® 100U + Hydrogel Admixture
	Comments	The null hypothesis is that there is no difference between each (BOTOX® and Hydrogel admixture group) and (placebo and Hydrogel admixture) in the mean change from Baseline in daily average number of UIEs at Week 12.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0845
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95%; -0.15 to 2.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.635
	Estimation Comments	Least square estimates and contrast t-test were used to compare specified treatment groups and were based on ANCOVA model with Baseline value as covariate and treatment group, sex (male, female) as factors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage 2: Placebo + Hydrogel Admixture, Stage 2: BOTOX® 300U + Hydrogel Admixture
	Comments	The null hypothesis is that there is no difference between each (BOTOX® and Hydrogel admixture group) and (placebo and Hydrogel admixture) in the mean change from Baseline in daily average number of UIEs at Week 12.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0041
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	1.83
	Confidence Interval	(2-Sided) 95%; 0.59 to 3.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.633
	Estimation Comments	Least square estimates and contrast t-test were used to compare specified treatment groups and were based on ANCOVA model with Baseline value as covariate and treatment group, sex (male, female) as factors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Stage 2: Placebo + Hydrogel Admixture, Stage 2: BOTOX® 400U + Hydrogel Admixture
	Comments	The null hypothesis is that there is no difference between each (BOTOX® and Hydrogel admixture group) and (placebo and Hydrogel admixture) in the mean change from Baseline in daily average number of UIEs at Week 12.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0600
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	1.19
	Confidence Interval	(2-Sided) 95%; -0.05 to 2.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.632
	Estimation Comments	Least square estimates and contrast t-test were used to compare specified treatment groups and were based on ANCOVA model with Baseline value as covariate and treatment group, sex (male, female) as factors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Stage 2: Placebo + Hydrogel Admixture, Stage 2: BOTOX® 500U + Hydrogel Admixture
	Comments	The null hypothesis is that there is no difference between each (BOTOX® and Hydrogel admixture group) and (placebo and Hydrogel admixture) in the mean change from Baseline in daily average number of UIEs at Week 12.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1702
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; -0.37 to 2.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.631
	Estimation Comments	Least square estimates and contrast t-test were used to compare specified treatment groups and were based on ANCOVA model with Baseline value as covariate and treatment group, sex (male, female) as factors.

2. Primary Outcome

Title	Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAEs) in the Treatment Period
Description	An adverse event (AE) is any untoward medical occurrence in a participants or clinical study investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. A TEAE is an AE that occurs or worsens after receiving study drug.
Time Frame	Up to End of Study (Stage 1: Up to 114 days and Stage 2: Up to 35.1 weeks)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set included all randomized and treated participants in Stages 1 and 2.

Arm/Group Title	Stage 1: Placebo + Hydrogel Admixture	Stage 1: BOTOX® 100U + Hydrogel Admixture	Stage 1: BOTOX® 300U + Hydrogel Admixture	Stage 1: BOTOX® 400U + Hydrogel Admixture	Stage 1: BOTOX® 500U + Hydrogel Admixture	Stage 2: Placebo + Hydrogel Admixture	Stage 2: BOTOX® 100U + Hydrogel Admixture	Stage 2: BOTOX® 300U + Hydrogel Admixture	Stage 2: BOTOX® 400U + Hydrogel Admixture	Stage 2: BOTOX® 500U + Hydrogel Admixture
Arm/Group Description	BOTOX® matching-placebo and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 100 units (U) (onabotulinumtoxinA; botulinum toxin Type A) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 300U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 400U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 500U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® matching-placebo and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 100U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 300U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 400U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 500U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.
Measure Participants	18	12	18	22	19	57	57	60	60	58
Count of Participants [Participants]	6 33.3%	4 33.3%	4 22.2%	10 45.5%	6 31.6%	25 43.1%	30 52.6%	30 50%	38 63.3%	25 42.4%

3. Secondary Outcome

Title	Stage 2: Change From Baseline in the Average Number of Micturition Episodes Per Day
Description	The participant recorded the number of micturition (urination in toilet or catherization) episodes per day in a 3-day bladder diary. The average number of micturition episodes per day is the average of the 3-day diary entries. A negative change from Baseline indicates improvement. Baseline is defined as the last non-missing assessment before the first dose of study treatment. ANCOVA model was used for analyses.
Time Frame	Baseline (3 consecutive days during Days -14 to Day -1) to 3 consecutive days in the Week prior to Week 12

Outcome Measure Data

Analysis Population Description

Participants from the ITT Analysis Set, all randomized participants in Stage 2, with data available for analysis at Baseline and Week 12. As per protocol, this endpoint is only applicable to the Stage 2 arms.

Arm/Group Title	Stage 2: Placebo + Hydrogel Admixture	Stage 2: BOTOX® 100U + Hydrogel Admixture	Stage 2: BOTOX® 300U + Hydrogel Admixture	Stage 2: BOTOX® 400U + Hydrogel Admixture	Stage 2: BOTOX® 500U + Hydrogel Admixture
Arm/Group Description	BOTOX® matching-placebo and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 100U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 300U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 400U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 500U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.
Measure Participants	46	49	52	55	52
Least Squares Mean (Standard Error) [episodes per day]	-1.64 (0.519)	-0.91 (0.514)	-0.86 (0.486)	-1.00 (0.480)	-1.11 (0.492)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 2: Placebo + Hydrogel Admixture, Stage 2: BOTOX® 100U + Hydrogel Admixture
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2361
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; -0.48 to 1.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.617
	Estimation Comments	Least square estimates and contrast t-test were used to compare specified treatment groups and were based on ANCOVA model with Baseline value as covariate and treatment group, sex (male, female) as factors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage 2: Placebo + Hydrogel Admixture, Stage 2: BOTOX® 300U + Hydrogel Admixture
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1985
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; -0.41 to 1.98
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.608
	Estimation Comments	Least square estimates and contrast t-test were used to compare specified treatment groups and were based on ANCOVA model with Baseline value as covariate and treatment group, sex (male, female) as factors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Stage 2: Placebo + Hydrogel Admixture, Stage 2: BOTOX® 400U + Hydrogel Admixture
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2923
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95%; -0.56 to 1.84
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.607
	Estimation Comments	Least square estimates and contrast t-test were used to compare specified treatment groups and were based on ANCOVA model with Baseline value as covariate and treatment group, sex (male, female) as factors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Stage 2: Placebo + Hydrogel Admixture, Stage 2: BOTOX® 500U + Hydrogel Admixture
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3769
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	0.54
	Confidence Interval	(2-Sided) 95%; -0.66 to 1.74
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.609
	Estimation Comments	Least square estimates and contrast t-test were used to compare specified treatment groups and were based on ANCOVA model with Baseline value as covariate and treatment group, sex (male, female) as factors.

4. Secondary Outcome

Title	Stage 2: Change From Baseline in the Average Volume Voided Per Micturition
Description	Volume voided per micturition was recorded over one 24-hour period during the 3-day bladder diary. The volume voided during each 24-hour period was divided by the number of micturitions during the period. The average volume voided per micturition is the average of the 3-day diary entries. A negative change from Baseline indicates improvement. Baseline is defined as the last non-missing assessment before the first dose of study treatment. ANCOVA model was used for analyses.
Time Frame	Baseline (3 consecutive days during Days -14 to Day -1) to 3 consecutive days in the Week prior to Week 12

Outcome Measure Data

Analysis Population Description

Participants from the ITT Analysis Set, all randomized participants in Stage 2, with data available for analysis at Baseline and Week 12. As per protocol, this endpoint is only applicable to the Stage 2 arms.

Arm/Group Title	Stage 2: Placebo + Hydrogel Admixture	Stage 2: BOTOX® 100U + Hydrogel Admixture	Stage 2: BOTOX® 300U + Hydrogel Admixture	Stage 2: BOTOX® 400U + Hydrogel Admixture	Stage 2: BOTOX® 500U + Hydrogel Admixture
Arm/Group Description	BOTOX® matching-placebo and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 100U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 300U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 400U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.	BOTOX® 500U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.
Measure Participants	46	49	52	55	51
Least Squares Mean (Standard Error) [mL]	12.61 (11.251)	5.56 (11.214)	4.61 (10.576)	11.28 (10.349)	21.94 (10.779)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 2: Placebo + Hydrogel Admixture, Stage 2: BOTOX® 100U + Hydrogel Admixture
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5911
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-7.05
	Confidence Interval	(2-Sided) 95%; -32.87 to 18.77
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.107
	Estimation Comments	Least square estimates and contrast t-test were used to compare specified treatment groups and were based on ANCOVA model with Baseline value as covariate and treatment group, sex (male, female) as factors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage 2: Placebo + Hydrogel Admixture, Stage 2: BOTOX® 300U + Hydrogel Admixture
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5375
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-8.00
	Confidence Interval	(2-Sided) 95%; -33.52 to 17.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.956
	Estimation Comments	Least square estimates and contrast t-test were used to compare specified treatment groups and were based on ANCOVA model with Baseline value as covariate and treatment group, sex (male, female) as factors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Stage 2: Placebo + Hydrogel Admixture, Stage 2: BOTOX® 400U + Hydrogel Admixture
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9173
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-1.33
	Confidence Interval	(2-Sided) 95%; -26.47 to 23.81
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.764
	Estimation Comments	Least square estimates and contrast t-test were used to compare specified treatment groups and were based on ANCOVA model with Baseline value as covariate and treatment group, sex (male, female) as factors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Stage 2: Placebo + Hydrogel Admixture, Stage 2: BOTOX® 500U + Hydrogel Admixture
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4730
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	9.33
	Confidence Interval	(2-Sided) 95%; -16.24 to 34.90
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.981
	Estimation Comments	Least square estimates and contrast t-test were used to compare specified treatment groups and were based on ANCOVA model with Baseline value as covariate and treatment group, sex (male, female) as factors.

Adverse Events

Time Frame	Up to End of Study (Stage 1: Up to 114 days and Stage 2: Up to 35.1 weeks)
Adverse Event Reporting Description	All-Cause Mortality: ITT Analysis Set included all randomized participants. Serious Adverse Events and Other Adverse Events: Safety Analysis Set included all randomized and treated participants in Stages 1 and 2.
Arm/Group Title	Stage 1: Placebo + Hydrogel Admixture		Stage 1: BOTOX® 100U + Hydrogel Admixture		Stage 1: BOTOX® 300U + Hydrogel Admixture		Stage 1: BOTOX® 400U + Hydrogel Admixture		Stage 1: BOTOX® 500U + Hydrogel Admixture		Stage 2: Placebo + Hydrogel Admixture		Stage 2: BOTOX® 100U + Hydrogel Admixture		Stage 2: BOTOX® 300U + Hydrogel Admixture		Stage 2: BOTOX® 400U + Hydrogel Admixture		Stage 2: BOTOX® 500U + Hydrogel Admixture
Arm/Group Description	BOTOX® matching-placebo and hydrogel admixture administered as a single intravesical instillation on Day 1.		BOTOX® 100 units (U) (onabotulinumtoxinA; botulinum toxin Type A) and hydrogel admixture administered as a single intravesical instillation on Day 1.		BOTOX® 300U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.		BOTOX® 400U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.		BOTOX® 500U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.		BOTOX® matching-placebo and hydrogel admixture administered as a single intravesical instillation on Day 1.		BOTOX® 100U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.		BOTOX® 300U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.		BOTOX® 400U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.		BOTOX® 500U (onabotulinumtoxinA) and hydrogel admixture administered as a single intravesical instillation on Day 1.
All Cause Mortality
	Stage 1: Placebo + Hydrogel Admixture		Stage 1: BOTOX® 100U + Hydrogel Admixture		Stage 1: BOTOX® 300U + Hydrogel Admixture		Stage 1: BOTOX® 400U + Hydrogel Admixture		Stage 1: BOTOX® 500U + Hydrogel Admixture		Stage 2: Placebo + Hydrogel Admixture		Stage 2: BOTOX® 100U + Hydrogel Admixture		Stage 2: BOTOX® 300U + Hydrogel Admixture		Stage 2: BOTOX® 400U + Hydrogel Admixture		Stage 2: BOTOX® 500U + Hydrogel Admixture
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/58 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/59 (0%)
Serious Adverse Events
	Stage 1: Placebo + Hydrogel Admixture		Stage 1: BOTOX® 100U + Hydrogel Admixture		Stage 1: BOTOX® 300U + Hydrogel Admixture		Stage 1: BOTOX® 400U + Hydrogel Admixture		Stage 1: BOTOX® 500U + Hydrogel Admixture		Stage 2: Placebo + Hydrogel Admixture		Stage 2: BOTOX® 100U + Hydrogel Admixture		Stage 2: BOTOX® 300U + Hydrogel Admixture		Stage 2: BOTOX® 400U + Hydrogel Admixture		Stage 2: BOTOX® 500U + Hydrogel Admixture
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		1/57 (1.8%)		3/57 (5.3%)		1/60 (1.7%)		2/60 (3.3%)		0/58 (0%)
Cardiac disorders
Supraventricular tachycardia	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		1/57 (1.8%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Infections and infestations
Cellulitis	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		1/57 (1.8%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Influenza	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		1/57 (1.8%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Injury, poisoning and procedural complications
Road traffic accident	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		1/57 (1.8%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Fall	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		1/57 (1.8%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Hip fracture	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		1/57 (1.8%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		1/57 (1.8%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Nervous system disorders
Cerebrovascular accident	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		1/60 (1.7%)		0/58 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		1/60 (1.7%)		0/58 (0%)
Acute respiratory failure	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		1/57 (1.8%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Vascular disorders
Peripheral artery thrombosis	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		0/57 (0%)		1/60 (1.7%)		0/60 (0%)		0/58 (0%)
Peripheral vascular disorder	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		0/57 (0%)		1/60 (1.7%)		0/60 (0%)		0/58 (0%)
Other (Not Including Serious) Adverse Events
	Stage 1: Placebo + Hydrogel Admixture		Stage 1: BOTOX® 100U + Hydrogel Admixture		Stage 1: BOTOX® 300U + Hydrogel Admixture		Stage 1: BOTOX® 400U + Hydrogel Admixture		Stage 1: BOTOX® 500U + Hydrogel Admixture		Stage 2: Placebo + Hydrogel Admixture		Stage 2: BOTOX® 100U + Hydrogel Admixture		Stage 2: BOTOX® 300U + Hydrogel Admixture		Stage 2: BOTOX® 400U + Hydrogel Admixture		Stage 2: BOTOX® 500U + Hydrogel Admixture
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/18 (33.3%)		4/12 (33.3%)		4/18 (22.2%)		4/22 (18.2%)		6/19 (31.6%)		10/57 (17.5%)		17/57 (29.8%)		17/60 (28.3%)		16/60 (26.7%)		19/58 (32.8%)
Gastrointestinal disorders
Abdominal pain	0/18 (0%)		1/12 (8.3%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Vomiting	0/18 (0%)		1/12 (8.3%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Gastric ulcer	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		1/19 (5.3%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Diarrhoea	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		2/57 (3.5%)		3/60 (5%)		0/60 (0%)		1/58 (1.7%)
General disorders
Asthenia	0/18 (0%)		1/12 (8.3%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Instillation site discomfort	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		1/19 (5.3%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Infections and infestations
Upper respiratory tract infection	1/18 (5.6%)		0/12 (0%)		0/18 (0%)		1/22 (4.5%)		1/19 (5.3%)		3/57 (5.3%)		3/57 (5.3%)		1/60 (1.7%)		2/60 (3.3%)		1/58 (1.7%)
Asymptomatic bacteriuria	1/18 (5.6%)		0/12 (0%)		0/18 (0%)		1/22 (4.5%)		0/19 (0%)		5/57 (8.8%)		8/57 (14%)		8/60 (13.3%)		4/60 (6.7%)		9/58 (15.5%)
Urinary tract infection	0/18 (0%)		0/12 (0%)		1/18 (5.6%)		0/22 (0%)		0/19 (0%)		3/57 (5.3%)		2/57 (3.5%)		1/60 (1.7%)		2/60 (3.3%)		3/58 (5.2%)
Vulvovaginal mycotic infection	0/17 (0%)		0/12 (0%)		0/15 (0%)		1/18 (5.6%)		0/17 (0%)		0/53 (0%)		0/53 (0%)		0/54 (0%)		0/54 (0%)		0/54 (0%)
Bronchitis	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		1/19 (5.3%)		0/57 (0%)		1/57 (1.8%)		1/60 (1.7%)		4/60 (6.7%)		1/58 (1.7%)
Nasopharyngitis	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		1/19 (5.3%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Pneumonia	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		1/19 (5.3%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Bacteriuria	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		1/57 (1.8%)		1/57 (1.8%)		5/60 (8.3%)		1/60 (1.7%)		4/58 (6.9%)
Metabolism and nutrition disorders
Acetonaemia	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		1/19 (5.3%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Hyperglycaemia	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		1/19 (5.3%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/18 (5.6%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Muscle spasms	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		1/19 (5.3%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Nervous system disorders
Dysgeusia	0/18 (0%)		1/12 (8.3%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Headache	0/18 (0%)		1/12 (8.3%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Renal and urinary disorders
Leukocyturia	1/18 (5.6%)		0/12 (0%)		1/18 (5.6%)		0/22 (0%)		0/19 (0%)		1/57 (1.8%)		1/57 (1.8%)		2/60 (3.3%)		1/60 (1.7%)		5/58 (8.6%)
Proteinuria	1/18 (5.6%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Dysuria	0/18 (0%)		1/12 (8.3%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		1/57 (1.8%)		2/57 (3.5%)		1/60 (1.7%)		3/60 (5%)		2/58 (3.4%)
Urethral pain	0/18 (0%)		0/12 (0%)		1/18 (5.6%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Haematuria	0/18 (0%)		0/12 (0%)		0/18 (0%)		1/22 (4.5%)		1/19 (5.3%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Reproductive system and breast disorders
Pelvic pain	1/18 (5.6%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Respiratory, thoracic and mediastinal disorders
Nasal congestion	0/18 (0%)		0/12 (0%)		0/18 (0%)		0/22 (0%)		1/19 (5.3%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Skin and subcutaneous tissue disorders
Dermatitis allergic	0/18 (0%)		0/12 (0%)		1/18 (5.6%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Night sweats	0/18 (0%)		0/12 (0%)		1/18 (5.6%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)
Vascular disorders
Hypertension	1/18 (5.6%)		1/12 (8.3%)		0/18 (0%)		0/22 (0%)		0/19 (0%)		0/57 (0%)		0/57 (0%)		0/60 (0%)		0/60 (0%)		0/58 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

A disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 90 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.