CONTENT2: Dysport® Treatment of Urinary Incontinence in Adults Subjects With Neurogenic Detrusor Overactivity (NDO) Due to Spinal Cord Injury or Multiple Sclerosis - Study 2

• Sponsor: Ipsen (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02660359
• Collaborator: (none)
• Enrollment: 258
• Locations: 82
• Arms: 4
• Actual Duration (Months): 35.8
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to provide confirmatory evidence of the safety and efficacy of two Dysport® doses (600 units [U] and 800 U), compared to placebo in reducing urinary incontinence (UI) in adult subjects treated for neurogenic detrusor overactivity (NDO) due to spinal cord injury (SCI) or multiple sclerosis (MS).

Condition or Disease	Intervention/Treatment	Phase
Urinary Incontinence; Overactive Bladder	Biological: Botulinum toxin type A; Biological: Botulinum toxin type A; Drug: Placebo; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 258 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III, Multicentre, Randomised, Double Blind, Parallel Group, Placebo Controlled Study To Assess The Efficacy And Safety Of One Or More Intradetrusor Treatments Of 600 Or 800 Units Of Dysport® For The Treatment Of Urinary Incontinence In Subjects With Neurogenic Detrusor Overactivity Due To Spinal Cord Injury Or Multiple Sclerosis
• Actual Study Start Date: Jul 8, 2016
• Actual Primary Completion Date: Nov 9, 2018
• Actual Study Completion Date: Jul 4, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 600 U Dysport® Group	Biological: Botulinum toxin type A; 600 U intra detrusor injection in two treatment periods (Initial and Retreatment phase) delivered at 30 injection points.; Other Names: AbobotulinumtoxinA (Dysport®) Clostridium BTX-A-haemagglutinin complex
Placebo Comparator: 600 U Dysport® Placebo Group	Drug: Placebo; AbobotulinumtoxinA Placebo 600 U intra detrusor injection in two treatment periods (Initial and Retreatment phase) delivered at 30 injection points
Experimental: 800 U Dysport® Group	Biological: Botulinum toxin type A; 800 U intra detrusor injection in two treatment periods (Initial and Retreatment phase) delivered at 30 injection points; Other Names: AbobotulinumtoxinA (Dysport®) Clostridium BTX-A-haemagglutinin complex
Placebo Comparator: 800 U Dysport® Placebo Group	Drug: Placebo; AbobotulinumtoxinA Placebo 800 U intra detrusor injection in two treatment periods (Initial and Retreatment phase) delivered at 30 injection points

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline in Weekly Number of UI Episodes at Week 6 of DBPC Cycle [Baseline and Week 6 of DBPC Cycle]

   The weekly number of UI episodes was measured using a 7-day bladder diary. Bladder diaries that contained data recorded on at least 5 days were included in the analysis. The least square (LS) mean of the change in weekly number of UI episodes at 6 weeks after the first study treatment was calculated using a mixed model repeated measures (MMRM) analysis.

Secondary Outcome Measures

1. Percentage of Subjects With No Episodes of UI at Week 6 of DBPC Cycle [Baseline and Week 6 of DBPC Cycle]

   The weekly number of UI episodes was measured using a 7-day bladder diary. Bladder diaries that contained data recorded on at least 5 days were included in the analysis. The number of subjects with no UI episodes at 6 weeks after the first study treatment was recorded. Percentage of subjects with no episodes of UI (≥100% Improvement) was calculated as: Total number of subjects with no weekly number of UI episodes at Week 6 / Total number of subjects with any number of UI events at Week 6.

2. Percentage of Subjects With a UI Response at Improvement Levels ≥30%, ≥50%, and ≥75% at Week 6 of the DBPC Cycle [Baseline and Week 6 of DBPC Cycle]

   The weekly number of UI episodes was measured using a 7-day bladder diary. Bladder diaries that contained data recorded on at least 5 days were included in the analysis. The percentage of subjects showing an improvement of ≥30%, ≥50% and ≥75% was calculated as: Total number of subjects with UI response level >=30% or >=50% or >=75% improvement at Week 6 / Total number of subjects with any UI response at Week 6.

3. Median Time Between Treatments [Day of first treatment (baseline) to day of retreatment, up to 2 years]

   Duration of effect for time between treatments was calculated by: (the date of the first retreatment visit - date of first treatment administration in the DBPC cycle). The median number of days between treatments was determined and subjects with no retreatment were censored at the last visit.

4. Mean Change From Baseline in Volume Per Void at Week 6 of DBPC Cycle [Baseline and Week 6 of DBPC Cycle]

   The volume per void was measured during one 24-hour period of the 7-day bladder diary. The LS mean of the change in volume per void at 6 weeks after the first study treatment was calculated using a MMRM analysis.

5. Mean Change From Baseline in Maximum Cystometric Capacity (MCC) at Week 6 of DBPC Cycle [Baseline and Week 6 of DBPC Cycle]

   Subjects included in the urodynamic subset (84.9% of randomised subjects) had a standardised urodynamic filling cystometry assessment at baseline (Screening) and again at Week 6 to determine the MCC. The LS mean of the change in MCC at 6 weeks after the first study treatment was calculated using an analysis of covariance (ANCOVA).

6. Mean Change From Baseline in Maximum Detrusor Pressure (MDP) During Storage at Week 6 of DBPC Cycle [Baseline and Week 6 of DBPC Cycle]

   Subjects included in the urodynamic subset (84.9% of randomised subjects) had a standardised urodynamic filling cystometry assessment at baseline (Screening) and again at Week 6 to determine the MDP. The LS mean of the change in MDP at 6 weeks after the first study treatment was calculated using an ANCOVA.

7. Mean Change From Baseline in Volume at First Involuntary Detrusor Contraction (Vol@1stIDC) at Week 6 of DBPC Cycle [Baseline and Week 6 of DBPC Cycle]

   Subjects included in the urodynamic subset (84.9% of randomised subjects) had a standardised urodynamic filling cystometry assessment at baseline (Screening) and again at Week 6 to determine the Vol@1stIDC which is the instilled volume when first IDC commences. Subjects who did not exhibit a post-treatment IDC at Week 6 had Vol@1stIDC imputed using the recorded corrected MCC volume at Week 6. The LS mean of the change in Vol@1stIDC at 6 weeks after the first study treatment was calculated using an ANCOVA.

8. Percentage of Subjects With No Involuntary Detrusor Contraction (IDCs) During Storage at Week 6 of DBPC Cycle [Baseline and Week 6 of DBPC Cycle]

   Subjects included in the urodynamic subset (84.9% of randomised subjects) had a standardised urodynamic filling cystometry assessment at baseline (Screening) and again at Week 6 to determine the occurrence of IDCs. The percentage of subjects without IDCs at 6 weeks after the first study treatment was recorded.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Urinary Incontinence for at least 3 months prior to Screening as a result of Neurogenic Detrusor Overactivity due to Spinal Cord Injury or Multiple Sclerosis.

• Subjects with Spinal Cord Injury must have a stable neurological injury at T1 level or below which occurred at least 6 months prior to Screening.

• Subjects with Multiple Sclerosis must be clinically stable in the investigator's opinion, with no exacerbation (relapse) of MS for at least 3 months prior to Screening.

• Subjects must have had an inadequate response after at least 4 weeks of oral medications used in the treatment of NDO (e.g. anticholinergics, beta-3 agonists) and/or have intolerable side-effects.

• Routinely performing Clean Intermittent Catheterization (CIC) to ensure adequate bladder emptying.

• An average of at least two episodes per day of Urinary Incontinence recorded on the screening bladder diary.

Key Exclusion Criteria:

• Any current condition (other than NDO) that may impact on bladder function.

• Previous or current, tumour or malignancy affecting the spinal column or spinal cord, or any other unstable cause of SCI.

• Any condition that will prevent cystoscopic treatment administration or CIC usage, e.g. urethral strictures.

• Current indwelling bladder catheter, or removal of indwelling bladder catheter less than 4 weeks prior to Screening.

• BTX-A treatment within 9 months prior to Screening for any urological condition (e.g. detrusor or urethral sphincter treatments).

• Any neuromodulation/electrostimulation usage for urinary symptoms/incontinence within 4 weeks prior to Screening. Any implanted neuromodulation device must be switched off at least 4 weeks prior to Screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Instituto Urológico Buenos Aires	Buenos Aires		Argentina	1060
2	Centro de Urologia	Buenos Aires		Argentina	C1120AAS
3	Centro Urológico Profesor Bengió	Córdoba		Argentina	X5000
4	Hospital Privado - Centro Médico de Córdoba	Córdoba		Argentina	X5016KEH
5	Instituto Médico Rodriguez Alfici	Godoy Cruz		Argentina	M5501AAP
6	Prince of Wales Hospital (POWH)	Sydney		Australia	2031
7	Westmead Hospital	Westmead		Australia	2145
8	Antwerp University hospital	Antwerp		Belgium
9	Hôpital Erasme	Brussels		Belgium	1070
10	Ourthe-Amblève	Esneux		Belgium	4130
11	Universidade Estadual de Campinas - Cidade Universitária Zeferino Vaz	Campinas		Brazil	13083-970
12	Hospital de Clinicas, Federal University of Paraná	Curitiba		Brazil	80060-900
13	Hospital São Vicente de Paulo	Passo Fundo		Brazil	99010-080
14	Santa Casa de Misericórdia de Porto Alegre - Hospital Santa Clara	Porto Alegre		Brazil	90020-090
15	Hospital Moinhos de Vento	Pôrto Alegre		Brazil	90560-030
16	Hospital São Lucas da PUCRS	Pôrto Alegre		Brazil	90610-000
17	Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo	Ribeirao Preto		Brazil	14048-900
18	Faculdade de Medicina do ABC	Santo André		Brazil	09060-650
19	Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo	Sao Paulo		Brazil	05422-970
20	Hospital Alemão Oswaldo Cruz	São Paulo		Brazil	01323-020
21	Clínica Uromed	Santiago		Chile	7500787
22	Hospital del Trabajador	Santiago		Chile	7501241
23	Clínica Las Condes	Santiago		Chile	7591046
24	Solano & Terront Servicios Medicos LTDA- Unidad Integral de Endocrinologia	Bogotá		Colombia	110221
25	Fundación Valle del Lili	Cali		Colombia	760032
26	Centro Medico Imbanaco	Cali		Colombia	760042
27	Asociacion IPS Medicos Internistas de Caldas	Manizales		Colombia	170004
28	Centro de Investigaciones Clinicas - CIC	Medellin		Colombia	5001000
29	Hôpital Raymond-Poincaré	Garches		France
30	Centre Hospitalier Régional Universitaire de Lille (CHRU) - Hôpital Claude Huriez	Lille Cedex		France
31	Hôpital de la Conception	Marseille CEDEX 5		France
32	Groupe Hospitalo-Universitaire Pierre Caremau	Nimes Cedex 9		France
33	Hopital de la Source	Orleans		France
34	Hôpital Tenon	Paris Cedex 20		France
35	Hopital Pitie-Salpetriere	Paris		France
36	Centre Hospitalier Lyon-Sud	Pierre-Bénite		France
37	CHU de Rennes - Hôpital Pontchaillou	Rennes		France
38	CHU de ROUEN - Hôpital Charles Nicolle	Rouen Cedex		France
39	Hôpital Rangueil	Toulouse Cedex 9		France
40	Universitätsklinikum Bonn Klinik und Poliklinik für Urologie	Bonn		Germany	53127
41	Kliniken Maria Hilf GmbH - Krankenhaus St. Franziskus	Monchengladbach		Germany
42	Universitätsklinikum Münster	Münster		Germany	48149
43	Rambam Medical Center	Haifa		Israel	31096
44	Carmel Medical Center	Haifa		Israel	34362
45	Meir Medical Center	Kfar Saba		Israel	44281
46	Rabin Medical Center - Davidoff Center	Petah Tikva		Israel	49100
47	The Chaim Sheba Medical Center	Ramat Gan		Israel	52621
48	Estetines Chirurgijos Centas, UAB	Kaunas		Lithuania	49476
49	Vilnius University Hospital Santariskiu Klinikos	Vilnius		Lithuania	8661
50	Centro Medico Puerta de Hierro - Colima	Colima		Mexico	28018
51	Clinstile, S.A. de C.V.	Cuauhtémoc		Mexico	06700
52	Hospital Universitario "Dr. José Eleuterio González"	Monterrey		Mexico	64460
53	Consultorio Privado	Zapopan		Mexico	45040
54	Clínica San Pablo Surco	Lima		Peru	15023
55	Clinica Good Hope	Lima		Peru	Lima18
56	Clinica Internacional Sede Lima	Lima		Peru	Lima1
57	Clínica Anglo Americana	Lima		Peru	Lima27
58	Instituto de Ginecología y Reproducción	Lima		Peru	Lima33
59	Unidad de Investigación de la Clínica Internacional Sede San Borja	Lima		Peru	Lima41
60	Scientific research institute of urology and interventional radiology n. a. N. A. Lopatkin	Moscow		Russian Federation	105425
61	Ministry of healthcare of the Russian Federation	Moscow		Russian Federation	129226
62	Penza Regional Clinical Hospital n.a. N.N.Burdenko	Penza		Russian Federation	440026
63	Rostov State Medical University	Rostov-on-Don		Russian Federation	344022
64	St. Petersburg Research Institute of Phthisiopulmonology	Saint Petersburg		Russian Federation	194064
65	Pavlov First Saint Petersburg State Medical University	Saint Petersburg		Russian Federation	197089
66	City Hospital No. 40	Saint Petersburg		Russian Federation	197706
67	Hospital Orkli	Saint Petersburg		Russian Federation
68	Complexo Hospitalario Universitario A Coruña	A Coruña		Spain
69	Fundacio Puigvert	Barcelona		Spain	08025
70	Fundació GAEM	Barcelona		Spain
71	Hospital Universitario Vall d'Hebron	Barcelona		Spain
72	Hospital Universitario La Paz	Madrid		Spain
73	Hospital Universitario Virgen del Rocío	Sevilla		Spain
74	Hospital Universitari i Politècnic La Fe	Valencia		Spain
75	Municipal Healthcare Institution "Regional Clinical Center of Urology and Nephrology n.a. V.I. Shapoval", Urology Department	Kharkiv		Ukraine	61037
76	Kiev City Clinical Hospital No. 3	Kiev		Ukraine	02125
77	NHS Grampian - Aberdeen Royal Infirmary	Aberdeen		United Kingdom	AB25 2ZN
78	Bedford Hospital	Bedford		United Kingdom	MK42 9DJ
79	National Hospital for Neurology and Neurosurgery - UCL	London		United Kingdom	WC1N 3BG
80	Sheffield Teaching Hospitals NHS Foundation Trust - Royal Hallamshire Hospital	Sheffield		United Kingdom	S10 2JF
81	Royal National Orthopaedic Hospital Trust	Stanmore		United Kingdom	HA7 4LP
82	The Mid Yorkshire Hospitals NHS Trust - Pinderfields Hospital	Wakefield		United Kingdom	WF1 4DG

Sponsors and Collaborators

• Ipsen

Investigators

• Study Director: Ipsen Medical Director, Ipsen

Study Documents (Full-Text)

• Study Protocol - Apr 16, 2018
• Statistical Analysis Plan - Sep 21, 2018

More Information

Publications

None provided.

• Responsible Party: Ipsen
• ClinicalTrials.gov Identifier: NCT02660359
• Other Study ID Numbers: D-FR-52120-223; 2015-000507-44
• First Posted: Jan 21, 2016
• Last Update Posted: Jul 20, 2021
• Last Verified: Jul 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Multiple Sclerosis; Spinal Cord Injuries; Urinary Incontinence; Enuresis; Urinary Bladder, Overactive; Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA; Hemagglutinins

Study Results

Participant Flow

Recruitment Details	A total of 258 subjects with urinary incontinence (UI) caused by neurogenic detrusor overactivity (NDO) due to spinal cord injury (SCI) or multiple sclerosis (MS) were enrolled at 67 study sites worldwide. One of the 258 randomised subjects did not receive any treatment. The study was terminated early by the sponsor due to lack of recruitment.
Pre-assignment Detail	Subjects were randomised to 1 of 4 sequences: A) placebo in a double-blind placebo-controlled (DBPC) cycle then Dysport® 600 Units (U) in subsequent double-blind cycles: B) placebo in DBPC cycle then Dysport® 800 U in subsequent cycles: C) Dysport® 600 U in all cycles: D) Dysport® 800 U in all cycles. The minimum retreatment interval was 12 weeks.

Arm/Group Title	Placebo	Dysport® 600 U	Dysport® 800 U
Arm/Group Description	Subjects were administered placebo on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 millilitres (mL) divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 600 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 800 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.
Period Title: Overall Study
STARTED	86	86	85
Subjects Entered in the Dysport Cycles	56	86	85
COMPLETED	0	0	1
NOT COMPLETED	86	86	84

Baseline Characteristics

Arm/Group Title	Placebo	Dysport® 600 U	Dysport® 800 U	Total
Arm/Group Description	Subjects were administered placebo on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 600 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 800 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Total of all reporting groups
Overall Participants	86	86	85	257
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	80 93%	82 95.3%	77 90.6%	239 93%
>=65 years	6 7%	4 4.7%	8 9.4%	18 7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.2 (13.16)	42.5 (12.10)	42.0 (14.72)	42.2 (13.31)
Sex: Female, Male (Count of Participants)
Female	36 41.9%	29 33.7%	30 35.3%	95 37%
Male	50 58.1%	57 66.3%	55 64.7%	162 63%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	8 9.3%	13 15.1%	9 10.6%	30 11.7%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	1 1.2%	1 0.4%
Black or African American	2 2.3%	4 4.7%	4 4.7%	10 3.9%
White	55 64%	52 60.5%	56 65.9%	163 63.4%
More than one race	7 8.1%	5 5.8%	3 3.5%	15 5.8%
Unknown or Not Reported	14 16.3%	12 14%	12 14.1%	38 14.8%
Aetiology of NDO (Count of Participants)
SCI	62 72.1%	64 74.4%	65 76.5%	191 74.3%
MS	24 27.9%	22 25.6%	20 23.5%	66 25.7%

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline in Weekly Number of UI Episodes at Week 6 of DBPC Cycle
Description	The weekly number of UI episodes was measured using a 7-day bladder diary. Bladder diaries that contained data recorded on at least 5 days were included in the analysis. The least square (LS) mean of the change in weekly number of UI episodes at 6 weeks after the first study treatment was calculated using a mixed model repeated measures (MMRM) analysis.
Time Frame	Baseline and Week 6 of DBPC Cycle

Outcome Measure Data

Analysis Population Description

Results are presented for the mITT population (all randomised subjects who received at least 1 administration of study treatment). Subjects were analysed as randomised (planned treatment). Only subjects with data available for analysis at Week 6 of DBPC cycle are presented.

Arm/Group Title	Placebo	Dysport® 600 U	Dysport® 800 U
Arm/Group Description	Subjects were administered placebo on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 600 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 800 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.
Measure Participants	76	82	73
Least Squares Mean (Standard Error) [Weekly UI episodes]	-12.86 (1.95)	-21.83 (1.91)	-22.62 (1.88)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport® 600 U
	Comments	Treatment group, visit (Week 6), treatment-by-visit interaction, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [Botulinum toxin [BTX]-naïve or BTX-non-naïve]) and study baseline value (weekly number of UI episodes) as fixed effect variables, and subject as a random effect.
	Type of Statistical Test	Superiority
	Comments	If both p-values for the 2 primary tests (the test of Dysport® 800 U vs. placebo and the test of Dysport® 600 U vs. placebo) were lower than 0.05, both were declared statistically significant. If 1 of the primary tests had a p-value greater than or equal to 0.05, then the other test was declared statistically significant if its p-value was lower than 0.025 and only the significant dose continued in the hierarchal testing strategy.
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	MMLM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-8.97
	Confidence Interval	(2-Sided) 95%; -13.5 to -4.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport® 800 U
	Comments	Treatment group, visit (Week 6), treatment-by-visit interaction, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [Botulinum toxin [BTX]-naïve or BTX-non-naïve]) and study baseline value (weekly number of UI episodes) as fixed effect variables, and subject as a random effect.
	Type of Statistical Test	Superiority
	Comments	If both p-values for the 2 primary tests (the test of Dysport® 800 U vs. placebo and the test of Dysport® 600 U vs. placebo) were lower than 0.05, both were declared statistically significant. If 1 of the primary tests had a p-value greater than or equal to 0.05, then the other test was declared statistically significant if its p-value was lower than 0.025 and only the significant dose continued in the hierarchal testing strategy.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	MMLM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-9.76
	Confidence Interval	(2-Sided) 95%; -14.41 to -5.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Subjects With No Episodes of UI at Week 6 of DBPC Cycle
Description	The weekly number of UI episodes was measured using a 7-day bladder diary. Bladder diaries that contained data recorded on at least 5 days were included in the analysis. The number of subjects with no UI episodes at 6 weeks after the first study treatment was recorded. Percentage of subjects with no episodes of UI (≥100% Improvement) was calculated as: Total number of subjects with no weekly number of UI episodes at Week 6 / Total number of subjects with any number of UI events at Week 6.
Time Frame	Baseline and Week 6 of DBPC Cycle

Outcome Measure Data

Analysis Population Description

Results are presented for the mITT population (all randomised subjects who received at least 1 administration of study treatment). Subjects were analysed as randomised (planned treatment). Only subjects with data available for analysis at Week 6 of DBPC cycle are presented.

Arm/Group Title	Placebo	Dysport® 600 U	Dysport® 800 U
Arm/Group Description	Subjects were administered placebo on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 600 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 800 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.
Measure Participants	76	82	73
Number [Percentage of Subjects]	1.3	36.6	26.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport® 600 U
	Comments	Treatment group, recorded stratification factors, visit, treatment-by-visit interaction, study baseline- by-visit interaction and study baseline weekly number of UI episodes as fixed effect.
	Type of Statistical Test	Superiority
	Comments	This secondary endpoint was included in the hierarchical analysis and was tested for both doses at the 0.05 level using a hierarchical methodology.
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Generalised linear mixed model (GLMM)
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	45.55
	Confidence Interval	(2-Sided) 95%; 6.09 to 340.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport® 800 U
	Comments	Treatment group, recorded stratification factors, visit, treatment-by-visit interaction, study baseline-by-visit interaction and study baseline weekly number of UI episodes as fixed effect.
	Type of Statistical Test	Superiority
	Comments	This secondary endpoint was included in the hierarchical analysis and was tested for both doses at the 0.05 level using a hierarchical methodology.
Statistical Test of Hypothesis	p-Value	0.0009
	Comments
	Method	GLMM
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	31.69
	Confidence Interval	(2-Sided) 95%; 4.17 to 240.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Subjects With a UI Response at Improvement Levels ≥30%, ≥50%, and ≥75% at Week 6 of the DBPC Cycle
Description	The weekly number of UI episodes was measured using a 7-day bladder diary. Bladder diaries that contained data recorded on at least 5 days were included in the analysis. The percentage of subjects showing an improvement of ≥30%, ≥50% and ≥75% was calculated as: Total number of subjects with UI response level >=30% or >=50% or >=75% improvement at Week 6 / Total number of subjects with any UI response at Week 6.
Time Frame	Baseline and Week 6 of DBPC Cycle

Outcome Measure Data

Analysis Population Description

Results are presented for the mITT population (all randomised subjects who received at least 1 administration of study treatment). Subjects were analysed as randomised (planned treatment). Only subjects with data available for analysis at Week 6 of DBPC cycle are presented.

Arm/Group Title	Placebo	Dysport® 600 U	Dysport® 800 U
Arm/Group Description	Subjects were administered placebo on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 600 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 800 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.
Measure Participants	76	82	73
≥30% Improvement	55.3	81.7	76.7
≥50% Improvement	38.2	72.0	61.6
≥75% Improvement	17.1	62.2	50.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport® 600 U
	Comments	Treatment comparison at ≥30% Improvement Level: Dysport® 600 U versus Placebo.
	Type of Statistical Test	Superiority
	Comments	Treatment group, recorded stratification factors, visit, treatment-by-visit interaction, study baseline-by-visit interaction and study baseline weekly number of UI episodes as fixed effect.
Statistical Test of Hypothesis	p-Value	0.0007
	Comments	This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
	Method	GLMM
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.55
	Confidence Interval	(2-Sided) 95%; 1.72 to 7.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport® 800 U
	Comments	Treatment comparison at ≥30% Improvement Level: Dysport® 800 U versus Placebo
	Type of Statistical Test	Superiority
	Comments	Treatment group, recorded stratification factors, visit, treatment-by-visit interaction, study baseline-by-visit interaction and study baseline weekly number of UI episodes as fixed effect.
Statistical Test of Hypothesis	p-Value	0.0037
	Comments	This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
	Method	GLMM
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.94
	Confidence Interval	(2-Sided) 95%; 1.43 to 6.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport® 600 U
	Comments	Treatment comparison at ≥50% Improvement level: Dysport® 600 U versus Placebo
	Type of Statistical Test	Superiority
	Comments	Treatment group, recorded stratification factors, visit, treatment-by-visit interaction, study baseline-by-visit interaction and study baseline weekly number of UI episodes as fixed effect.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
	Method	GLMM
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.98
	Confidence Interval	(2-Sided) 95%; 2.03 to 7.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport® 800 U
	Comments	Treatment comparison at ≥50% Improvement level: Dysport® 800 U versus Placebo
	Type of Statistical Test	Superiority
	Comments	Treatment group, recorded stratification factors, visit, treatment-by- visit interaction, study baseline-by-visit interaction and study baseline weekly number of UI episodes as fixed effect.
Statistical Test of Hypothesis	p-Value	0.0034
	Comments	This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
	Method	GLMM
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.73
	Confidence Interval	(2-Sided) 95%; 1.40 to 5.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport® 600 U
	Comments	Treatment comparison at ≥75% Improvement level: Dysport® 600 U versus Placebo
	Type of Statistical Test	Superiority
	Comments	Treatment group, recorded stratification factors, visit, treatment-by-visit interaction, study baseline-by-visit interaction and study baseline weekly number of UI episodes as fixed effect.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
	Method	GLMM
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	7.38
	Confidence Interval	(2-Sided) 95%; 3.5 to 15.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport® 800 U
	Comments	Treatment comparison at ≥75% Improvement level: Dysport® 800 U versus Placebo
	Type of Statistical Test	Superiority
	Comments	Treatment group, recorded stratification factors, visit, treatment-by-visit interaction, study baseline-by-visit interaction and study baseline weekly number of UI episodes as fixed effect.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
	Method	GLMM
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.28
	Confidence Interval	(2-Sided) 95%; 2.48 to 11.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Median Time Between Treatments
Description	Duration of effect for time between treatments was calculated by: (the date of the first retreatment visit - date of first treatment administration in the DBPC cycle). The median number of days between treatments was determined and subjects with no retreatment were censored at the last visit.
Time Frame	Day of first treatment (baseline) to day of retreatment, up to 2 years

Outcome Measure Data

Analysis Population Description

Results are presented for the mITT population (all randomised subjects who received at least 1 administration of study treatment). Subjects were analysed as randomised (planned treatment).

Arm/Group Title	Placebo	Dysport® 600 U	Dysport® 800 U
Arm/Group Description	Subjects were administered placebo on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 600 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 800 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.
Measure Participants	86	86	85
Median (Full Range) [Days]	132.0	238.5	210.0

5. Secondary Outcome

Title	Mean Change From Baseline in Volume Per Void at Week 6 of DBPC Cycle
Description	The volume per void was measured during one 24-hour period of the 7-day bladder diary. The LS mean of the change in volume per void at 6 weeks after the first study treatment was calculated using a MMRM analysis.
Time Frame	Baseline and Week 6 of DBPC Cycle

Outcome Measure Data

Analysis Population Description

Results are presented for the mITT population (all randomised subjects who received at least 1 administration of study treatment). Subjects were analysed as randomised (planned treatment). Only subjects with data available for analysis at Week 6 of DBPC cycle are presented.

Arm/Group Title	Placebo	Dysport® 600 U	Dysport® 800 U
Arm/Group Description	Subjects were administered placebo on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 600 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 800 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.
Measure Participants	74	77	72
Least Squares Mean (Standard Error) [mL]	-6.00 (17.80)	90.14 (17.45)	84.78 (17.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport® 600 U
	Comments	Treatment group, visit (Week 6), treatment-by-visit interaction, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [BTX-naïve or BTX-non-naïve]) and study baseline value (total volume per void) as fixed effect variables, and subject as a random effect.
	Type of Statistical Test	Superiority
	Comments	This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	96.14
	Confidence Interval	(2-Sided) 95%; 53.10 to 139.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport® 800 U
	Comments	Treatment group, visit (Week 6), treatment-by-visit interaction, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [BTX-naïve or BTX-non-naïve]) and study baseline value (total volume per void) as fixed effect variables, and subject as a random effect.
	Type of Statistical Test	Superiority
	Comments	This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	90.78
	Confidence Interval	(2-Sided) 95%; 47.07 to 134.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Mean Change From Baseline in Maximum Cystometric Capacity (MCC) at Week 6 of DBPC Cycle
Description	Subjects included in the urodynamic subset (84.9% of randomised subjects) had a standardised urodynamic filling cystometry assessment at baseline (Screening) and again at Week 6 to determine the MCC. The LS mean of the change in MCC at 6 weeks after the first study treatment was calculated using an analysis of covariance (ANCOVA).
Time Frame	Baseline and Week 6 of DBPC Cycle

Outcome Measure Data

Analysis Population Description

Results are presented for the urodynamic population (all subjects in the mITT population included in the urodynamic subset at randomisation). Subjects were analysed as randomised (planned treatment). Only subjects with data available for analysis at Week 6 of DBPC cycle are presented.

Arm/Group Title	Placebo	Dysport® 600 U	Dysport® 800 U
Arm/Group Description	Subjects were administered placebo on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 600 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 800 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.
Measure Participants	62	76	63
Least Squares Mean (Standard Error) [mL]	3.5 (22.83)	178.5 (21.38)	171.9 (21.58)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport® 600 U
	Comments	Treatment group, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [BTX- naïve or BTX-non-naïve]) and baseline value of MCC as covariates.
	Type of Statistical Test	Superiority
	Comments	This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	175.0
	Confidence Interval	(2-Sided) 95%; 122.90 to 227.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport® 800 U
	Comments	Treatment group, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [BTX- naïve or BTX-non-naïve]) and baseline value of MCC as covariates.
	Type of Statistical Test	Superiority
	Comments	This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	168.4
	Confidence Interval	(2-Sided) 95%; 113.6 to 223.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Mean Change From Baseline in Maximum Detrusor Pressure (MDP) During Storage at Week 6 of DBPC Cycle
Description	Subjects included in the urodynamic subset (84.9% of randomised subjects) had a standardised urodynamic filling cystometry assessment at baseline (Screening) and again at Week 6 to determine the MDP. The LS mean of the change in MDP at 6 weeks after the first study treatment was calculated using an ANCOVA.
Time Frame	Baseline and Week 6 of DBPC Cycle

Outcome Measure Data

Analysis Population Description

Results are presented for the urodynamic population (all subjects in the mITT population included in the urodynamic subset at randomisation). Subjects were analysed as randomised (planned treatment). Only subjects with data available for analysis at Week 6 of DBPC cycle are presented.

Arm/Group Title	Placebo	Dysport® 600 U	Dysport® 800 U
Arm/Group Description	Subjects were administered placebo on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 600 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 800 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.
Measure Participants	54	71	57
Least Squares Mean (Standard Error) [centimetres of water]	-3.7 (3.84)	-36.7 (3.48)	-36.2 (3.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport® 600 U
	Comments	Treatment group, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [BTX- naïve or BTX-non-naïve]) and baseline value of MDP as covariates.
	Type of Statistical Test	Superiority
	Comments	This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-32.9
	Confidence Interval	(2-Sided) 95%; -41.5 to -24.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport® 800 U
	Comments	Treatment group, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [BTX- naïve or BTX-non-naïve]) and baseline value of MDP as covariates.
	Type of Statistical Test	Superiority
	Comments	This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-32.5
	Confidence Interval	(2-Sided) 95%; -41.5 to -23.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Mean Change From Baseline in Volume at First Involuntary Detrusor Contraction (Vol@1stIDC) at Week 6 of DBPC Cycle
Description	Subjects included in the urodynamic subset (84.9% of randomised subjects) had a standardised urodynamic filling cystometry assessment at baseline (Screening) and again at Week 6 to determine the Vol@1stIDC which is the instilled volume when first IDC commences. Subjects who did not exhibit a post-treatment IDC at Week 6 had Vol@1stIDC imputed using the recorded corrected MCC volume at Week 6. The LS mean of the change in Vol@1stIDC at 6 weeks after the first study treatment was calculated using an ANCOVA.
Time Frame	Baseline and Week 6 of DBPC Cycle

Outcome Measure Data

Analysis Population Description

Results are presented for the urodynamic population (all subjects in the mITT population included in the urodynamic subset at randomisation). Subjects were analysed as randomised (planned treatment). Only subjects with data available for analysis at Week 6 of DBPC cycle are presented.

Arm/Group Title	Placebo	Dysport® 600 U	Dysport® 800 U
Arm/Group Description	Subjects were administered placebo on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 600 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 800 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.
Measure Participants	60	72	58
Least Squares Mean (Standard Error) [mL]	15.9 (23.34)	168.7 (22.09)	185.5 (22.80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport® 600 U
	Comments	Treatment group, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [BTX- naïve or BTX-non-naïve]) and baseline value of Vol@1stIDC as covariates.
	Type of Statistical Test	Superiority
	Comments	This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	152.8
	Confidence Interval	(2-Sided) 95%; 99.2 to 206.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport® 800 U
	Comments	Treatment group, recorded stratification factors (aetiology of NDO [SCI or MS], prior intradetrusor [BTX- naïve or BTX-non-naïve]) and baseline value of Vol@1stIDC as covariates.
	Type of Statistical Test	Superiority
	Comments	This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	169.7
	Confidence Interval	(2-Sided) 95%; 111.7 to 227.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Percentage of Subjects With No Involuntary Detrusor Contraction (IDCs) During Storage at Week 6 of DBPC Cycle
Description	Subjects included in the urodynamic subset (84.9% of randomised subjects) had a standardised urodynamic filling cystometry assessment at baseline (Screening) and again at Week 6 to determine the occurrence of IDCs. The percentage of subjects without IDCs at 6 weeks after the first study treatment was recorded.
Time Frame	Baseline and Week 6 of DBPC Cycle

Outcome Measure Data

Analysis Population Description

Results are presented for the urodynamic population (all subjects in the mITT population included in the urodynamic subset at randomisation). Subjects were analysed as randomised (planned treatment). Only subjects with data available for analysis at Week 6 of DBPC cycle are presented.

Arm/Group Title	Placebo	Dysport® 600 U	Dysport® 800 U
Arm/Group Description	Subjects were administered placebo on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 600 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.	Subjects were administered Dysport® 800 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.
Measure Participants	59	74	58
Number [Percentage of Subjects]	3.4	52.7	50.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport® 800 U
	Comments	Treatment group, recorded stratification factors, visit, treatment-by-visit interaction, study baseline-by-visit interaction and study baseline weekly number of UI episodes as fixed effect.
	Type of Statistical Test	Superiority
	Comments	This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	GLMM
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	31.1
	Confidence Interval	(2-Sided) 95%; 7.05 to 137.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport® 800 U
	Comments	Treatment group, recorded stratification factors, visit, treatment-by-visit interaction, study baseline-by- visit interaction and study baseline weekly number of UI episodes as fixed effect.
	Type of Statistical Test	Superiority
	Comments	This secondary endpoint was not included within the hierarchical testing procedure and was analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 type one error rate.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	GLMM
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	28.08
	Confidence Interval	(2-Sided) 95%; 6.24 to 126.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Treatment emergent adverse events are presented for the full DBPC cycle (i.e. approximately 32 weeks for both Dysport® groups and approximately 19 weeks for the Placebo group).
Adverse Event Reporting Description	The safety population included all subjects who received at least 1 administration of study treatment (including only partial administration). Safety subjects were analysed according to their actual treatment received. One subject randomised to placebo received Dysport 600 U, and 1 subject randomised to Dysport 800 U did not receive treatment and was not included in the safety population. Number of deaths (all causes) is presented for the duration of the study (up to a maximum of 115 weeks).
Arm/Group Title	Placebo		Dysport® 600 U		Dysport® 800 U
Arm/Group Description	Subjects were administered placebo on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.		Subjects were administered Dysport® 600 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.		Subjects were administered Dysport® 800 U on Day 1 of the DBPC cycle. All study treatments were injected into the detrusor muscle via cystoscopy in a total volume of 15 mL divided into 30 injection points of 0.5 mL each. Subjects were followed-up by telephone at Week 1 and Week 4; and attended clinic visits at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits were scheduled every 12 weeks until end of study, or until retreatment was required.
All Cause Mortality
	Placebo		Dysport® 600 U		Dysport® 800 U
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/85 (0%)		1/87 (1.1%)		0/85 (0%)
Serious Adverse Events
	Placebo		Dysport® 600 U		Dysport® 800 U
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/85 (0%)		9/87 (10.3%)		8/85 (9.4%)
Blood and lymphatic system disorders
Anaemia	0/85 (0%)	0	1/87 (1.1%)	1	1/85 (1.2%)	1
General disorders
Chest pain	0/85 (0%)	0	1/87 (1.1%)	2	0/85 (0%)	0
Gait disturbance	0/85 (0%)	0	0/87 (0%)	0	1/85 (1.2%)	1
Infections and infestations
Urinary tract infection	0/85 (0%)	0	1/87 (1.1%)	1	1/85 (1.2%)	1
Diverticulitis	0/85 (0%)	0	0/87 (0%)	0	1/85 (1.2%)	1
Osteomyelitis	0/85 (0%)	0	1/87 (1.1%)	1	0/85 (0%)	0
Osteomyelitis chronic	0/85 (0%)	0	1/87 (1.1%)	1	0/85 (0%)	0
Perineal abscess	0/85 (0%)	0	1/87 (1.1%)	1	0/85 (0%)	0
Soft tissue infection	0/85 (0%)	0	1/87 (1.1%)	1	0/85 (0%)	0
Testicular abscess	0/85 (0%)	0	1/87 (1.1%)	1	0/85 (0%)	0
Urosepsis	0/85 (0%)	0	0/87 (0%)	0	1/85 (1.2%)	1
Orchitis	0/85 (0%)	0	0/87 (0%)	0	1/85 (1.2%)	1
Injury, poisoning and procedural complications
Femur fracture	0/85 (0%)	0	1/87 (1.1%)	1	0/85 (0%)	0
Metabolism and nutrition disorders
Hyperglycaemia	0/85 (0%)	0	1/87 (1.1%)	2	0/85 (0%)	0
Nervous system disorders
Cerebrovascular accident	0/85 (0%)	0	1/87 (1.1%)	1	1/85 (1.2%)	1
Multiple sclerosis relapse	0/85 (0%)	0	1/87 (1.1%)	1	1/85 (1.2%)	1
Ataxia	0/85 (0%)	0	1/87 (1.1%)	1	0/85 (0%)	0
Multiple sclerosis	0/85 (0%)	0	1/87 (1.1%)	2	0/85 (0%)	0
Renal and urinary disorders
Haematuria	0/85 (0%)	0	1/87 (1.1%)	1	0/85 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/85 (0%)	0	1/87 (1.1%)	2	0/85 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Dysport® 600 U		Dysport® 800 U
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/85 (40%)		40/87 (46%)		42/85 (49.4%)
Blood and lymphatic system disorders
Anaemia	0/85 (0%)	0	2/87 (2.3%)	2	1/85 (1.2%)	1
Gastrointestinal disorders
Diarrhoea	3/85 (3.5%)	3	3/87 (3.4%)	7	4/85 (4.7%)	4
Constipation	1/85 (1.2%)	1	4/87 (4.6%)	4	2/85 (2.4%)	2
Abdominal pain	2/85 (2.4%)	2	1/87 (1.1%)	2	2/85 (2.4%)	2
Abdominal pain lower	2/85 (2.4%)	2	0/87 (0%)	0	2/85 (2.4%)	2
Nausea	0/85 (0%)	0	2/87 (2.3%)	2	0/85 (0%)	0
General disorders
Pyrexia	1/85 (1.2%)	1	3/87 (3.4%)	5	2/85 (2.4%)	2
Fatigue	0/85 (0%)	0	1/87 (1.1%)	1	2/85 (2.4%)	2
Malaise	1/85 (1.2%)	1	2/87 (2.3%)	2	0/85 (0%)	0
Infections and infestations
Urinary tract infection	17/85 (20%)	21	19/87 (21.8%)	24	22/85 (25.9%)	34
Bacteriuria	0/85 (0%)	0	6/87 (6.9%)	6	1/85 (1.2%)	1
Upper respiratory tract infection	1/85 (1.2%)	1	0/87 (0%)	0	4/85 (4.7%)	4
Influenza	5/85 (5.9%)	5	2/87 (2.3%)	2	1/85 (1.2%)	1
Nasopharyngitis	0/85 (0%)	0	1/87 (1.1%)	1	2/85 (2.4%)	2
Pharyngitis	2/85 (2.4%)	2	1/87 (1.1%)	1	1/85 (1.2%)	1
Injury, poisoning and procedural complications
Anaesthetic complication cardiac	0/85 (0%)	0	2/87 (2.3%)	2	1/85 (1.2%)	1
Investigations
Nitrite urine present	2/85 (2.4%)	2	2/87 (2.3%)	2	0/85 (0%)	0
Blood urine present	2/85 (2.4%)	2	0/87 (0%)	0	0/85 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	2/85 (2.4%)	2	3/87 (3.4%)	5	5/85 (5.9%)	6
Arthralgia	0/85 (0%)	0	2/87 (2.3%)	3	1/85 (1.2%)	1
Myalgia	0/85 (0%)	0	0/87 (0%)	0	2/85 (2.4%)	2
Nervous system disorders
Headache	0/85 (0%)	0	1/87 (1.1%)	1	3/85 (3.5%)	5
Muscle spasticity	0/85 (0%)	0	2/87 (2.3%)	2	1/85 (1.2%)	1
Neuralgia	0/85 (0%)	0	2/87 (2.3%)	2	0/85 (0%)	0
Dizziness	2/85 (2.4%)	2	0/87 (0%)	0	0/85 (0%)	0
Psychiatric disorders
Depression	0/85 (0%)	0	0/87 (0%)	0	2/85 (2.4%)	2
Renal and urinary disorders
Haematuria	4/85 (4.7%)	4	5/87 (5.7%)	5	4/85 (4.7%)	4
Leukocyturia	0/85 (0%)	0	1/87 (1.1%)	1	2/85 (2.4%)	3
Bladder pain	2/85 (2.4%)	2	1/87 (1.1%)	1	0/85 (0%)	0
Reproductive system and breast disorders
Erectile dysfunction	0/85 (0%)	0	0/87 (0%)	0	2/85 (2.4%)	2
Vascular disorders
Haemorrhage	0/85 (0%)	0	2/87 (2.3%)	2	1/85 (1.2%)	1
Hypotension	2/85 (2.4%)	2	2/87 (2.3%)	2	1/85 (1.2%)	1

Limitations/Caveats

This study was terminated early by the sponsor on 04 October 2018, due to slow subject recruitment (258 subjects randomised compared to 330 planned subjects). Only primary and key secondary efficacy analyses were performed.

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Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.