Clinical trial NCT05308979
Conditions: Overactive Bladder Urinary Urge Incontinence Overactive Bladder Syndrome Urinary Incontinence, Urge Urge Incontinence Urinary Urgency Urinary Frequency
Sponsor: University of California, Irvine
Start date: 2022-05-01; Completion date: 2024-03-31
Enrollment: 116 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Patients with either overactive bladder (OAB) or urgency urinary incontinence (UUI) with be randomized (like a flip of a coin) to receive 100 units of bladder Botox® at either one injection site or ten injection sites. Efficacy and patient satisfaction will be measured by questionnaires.

Detailed description:
Intradetrusor (bladder) Botulinum toxin A (BTA or Botox®) is a well-established treatment for urinary urgency incontinence (UUI).\[1,2\] While this treatment's efficacy in comparison to alternative therapies including anticholinergic medications and sacral neuromodulation for treatment of UUI has been studied, the ideal number of injection sites within the bladder has not been well established. \[3,4\] Intradetrusor BTA injections are often completed as an office procedure while the patient is awake. Each injection site can cause discomfort for the patient during the procedure. Urinary tract infection and urinary retention are risks associated with this procedure and could potentially be related to number of injection sites. Currently, there is a lack of information in the literature regarding the optimal number of intravesical BTA injection sites.

Prior studies evaluated efficacy using 100u BTA spread across 20 injections sites, however current practices at local institutions safely use 10 injections sites based on studies showing similar effect and adverse event profiles between use of 10, 20, and 40 injection sites.\[5,6\] Research using animal models has shown diffuse distribution of BTA within the entire detrusor muscle after just a single BTA injection at one site.\[7\] This has been corroborated in human studies.\[8\] A recently published observational pilot study shows promise for single site intradetrusor Botox® injection as it reported a lower rate of urinary retention and similar durability.\[9\] Similar clinical efficacy with only one to three intravesical BTA injection\[s\] has also been reported.\[10\]

In this study, participants will be randomized to receive 100u BTA via intradetrusor injection at one injection site (experimental) versus 10 injection sites (control). Investigators hypothesize that one injection will have similar efficacy to multiple injections and potentially better tolerability and patient satisfaction, due to decreased procedure time and less pain, along with potential for lower adverse event rates, specifically urinary retention and urinary tract infections.

Arms: arm 1: 100u Botox® injected at one intradetrusor site arm 2: 100u Botox® injected at 10 intradetrusor sites
Interventions: intervention 1: OnabotulinumtoxinA 100 UNT [Botox]
Intervention descriptions: intervention 1: Intradetrusor (Bladder) Botox Injection at 1 vs 10 injection sites

Protocol documents:
Prot_SAP_000.pdf: 
      Southern California Permanente Medical Group 
 
Protocol Number: Intradetrusor Botulinum Toxin A: Are less injections better? V2_09 Mar 2022 
Investigator Initiated Clinical Trial Protocol  
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Page 1 of 20 
 
Protocol Number 
KPSC-US-IBT-01  
Title 
 
Intradetrusor Botulinum Toxin A: Are less 
injections better? 
Study Phase 
N/A 
 
 
             Investigator Name 
Department  
Carly Crowder, MD 
Obstetrics and Gynecology 
Site Address  
Kaiser Permanente- San Canyon  
Street Address 
 
6650 Alton Pwky 
City, State and Zip code 
Irvine, CA 92618 
Phone Number 
833-574-2273 
Email Address 
crowderc@hs.uci.edu 
 
 
 
 
Study Site Name 
 
Kaiser Permanente- – Sand 
Canyon 
 
Street Address 
 
6650 Alton Pwky 
City, State and Zip code 
Irvine, CA 92618 
 
 
 
Version Number and Date 
 
 
V2_09 Mar 2022 
 
 
 
 
 


      Southern California Permanente Medical Group 
 
Protocol Number: Intradetrusor Botulinum Toxin A: Are less injections better? V2_09 Mar 2022 
Investigator Initiated Clinical Trial Protocol  
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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ............................................................................................................................................ 4 
PROTOCOL SUMMARY ................................................................................................................................................ 5 
1 
INTRODUCTION ................................................................................................................................................... 7 
1.1  
Background ................................................................................................................................................... 7 
1.2  
Hypothesis .................................................................................................... Error! Bookmark not defined. 
2 
OBJECTIVES AND PURPOSE ............................................................................. Error! Bookmark not defined. 
3 
STUDY DESIGN .................................................................................................................................................... 7 
3.1 
Treatment Arms ............................................................................................................................................ 8 
3.2 
Study Duration .............................................................................................................................................. 8 
4 
STUDY PRODUCT INFORMATION ...................................................................................................................... 8 
4.1 
Description .................................................................................................................................................... 8 
4.2  
Dosage, Preparation and Administration ...................................................................................................... 8 
4.3 
Toxicity and Safety Information ..................................................................................................................... 8 
4.4 
Concomitant Medications/ Treatments .......................................................................................................... 8 
5 
SELECTION AND WITHDRAWAL OF PATIENTS ................................................................................................ 9 
5.1 
Inclusion Criteria ........................................................................................................................................... 9 
5.2 
Exclusion Criteria .......................................................................................................................................... 9 
5.3 
Withdrawal Criteria ........................................................................................................................................ 9 
6 
STRATIFICATION/ RANDOMIZATION SCHEME ................................................................................................. 9 
7 
ASSESSMENT OF EFFICACY AND SAFETY ...................................................... Error! Bookmark not defined. 
7.1 
Adverse Events Reporting .......................................................................................................................... 10 
7.1.1 
Adverse Event Definition .................................................................................................................... 10 
7.1.2 
Time Period and Frequency for Event Assessment and Follow-up .................................................... 10 
7.1.3 
Serious Adverse Event Definition ....................................................................................................... 10 
7.1.4 
Serious Adverse Event Reporting ...................................................................................................... 10 
8 
STUDY SCHEDULE: CLINICAL/ LABORATORY EVALUATIONS ..................................................................... 10 
8.1 
Study Procedure ......................................................................................................................................... 11 
8.1.1 
Informed Consent ............................................................................................................................... 11 
8.1.2 
Eligibility Review ................................................................................................................................. 11 
8.1.3 
Insert Study Procedure ....................................................................................................................... 11 
8.2 
Clinical Evaluations ..................................................................................................................................... 13 


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8.2.1 
Insert Clinical Evaluation .................................................................................................................... 13 
8.2.2 
Adverse Event Assessment ................................................................................................................ 14 
8.3 
Laboratory Evaluations ............................................................................................................................... 14 
8.3.1 
Insert Laboratory Evaluation .............................................................................................................. 14 
8.4 
Study Calendar ........................................................................................................................................... 14 
9 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS .................................................................... 15 
9.1 
Primary Endpoints ....................................................................................................................................... 15 
9.2 
Secondary Endpoints .................................................................................................................................. 15 
10 
DATA HANDLING AND RECORD KEEPING ................................................................................................. 15 
10.1 
Source Documentation ................................................................................................................................ 15 
10.2 
Case Report Forms ..................................................................................................................................... 15 
10.3 
Record Retention ........................................................................................................................................ 15 
10.4 
Data Management ....................................................................................................................................... 15 
11 
STUDY OVERSIGHT ...................................................................................................................................... 16 
11.1 
Data Safety Monitoring Board (DSMB) ....................................................................................................... 16 
11.2 
Study Site Monitoring .................................................................................................................................. 16 
12 
STATISTICAL CONSIDERATIONS ................................................................................................................ 16 
12.1 
Study Hypothesis ........................................................................................................................................ 16 
12.2 
Sample Size Considerations ....................................................................................................................... 16 
12.3 
Final Analysis Plan ...................................................................................................................................... 16 
13 
REGISTRATION GUIDELINE ......................................................................................................................... 17 
14 
BIOHAZARD CONTAINMENT ........................................................................................................................ 17 
15 
ETHICAL AND REGULATORY CONSIDERATIONS ...................................................................................... 18 
15.1 
Institutional Review Board ........................................................................................................................... 18 
15.2 
Informed Consent Process .......................................................................................................................... 18 
15.3 
Exclusion of Women, Minorities, and Children (Special Populations) ......................................................... 18 
15.4 
Privacy and Confidentiality .......................................................................................................................... 18 
15.5 Future Use of Stored Specimens and Other Identifiable Data………………………………………….………….18 
 
16 
REFERENCES/ATTACHMENTS .................................................................................................................... 19 
17 
APPENDICES ................................................................................................................................................. 20 
18 
SIGNATURE .................................................................................................................................................... 20 
 


      Southern California Permanente Medical Group 
 
Protocol Number: Intradetrusor Botulinum Toxin A: Are less injections better? V2_09 Mar 2022 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DHHS 
Department of Health and Human Services 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
FWA 
Federal Wide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
BTA 
Botulinum Toxin A 
UTI 
Urinary Tract Infection 
OAB 
Overactive Bladder 
UUI 
Urinary Urgency Incontinence 
PVR 
Post Void Residual 
SNM 
Sacral Neuromodulation 
PTNS 
Percutaneous Tibial Nerve Stimulation 
OAB-Q (LF) 
Overactive Bladder Questionnaire (Long Form) 
VAS 
Visual Analogue Scale 
PGI-I 
Patient Global Impression – Improvement 


      Southern California Permanente Medical Group 
 
Protocol Number: Intradetrusor Botulinum Toxin A: Are less injections better? V2_09 Mar 2022 
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PROTOCOL SUMMARY 
 
 
 
 
 
 
 
Title 
Intradetrustor Botulinum Toxin A: Are less injections better? 
Short Title 
Bladder Botox 
Protocol Number 
KPSC-US-01 
Study Phase 
N/A 
Study Site(s) 
Kaiser Permanente – Sand Canyon, Kaiser Permanente -Anaheim, UCI 
Number of Subjects 
Approx 40 at KPSC, 60 at UCI, 20 at PSJH   
Study Arms 
2 arms: One Botox® injection site (study) or 10 Botox® injection sites 
(control/standard of carl) 
Indication 
Overactive Bladder (Urinary urgency and frequency) and urinary urgency 
incontinence 
Primary Purpose 
Our primary objective is to evaluate the efficacy of intradetrusor Botox® for 
treatment of OAB or UUI based on patient questionnaire scores (OAB-q) in one 
versus ten Botox® injection [s].  
Overview of Study 
Design 
We plan for a prospective, single-blinded, non-inferiority analyzed, randomized 
controlled trial. We will evaluate the efficacy, safety, and tolerability of one 
intradetrusor Botox® injection (study) versus ten injections (control/standard of 
care). The patient will be blinded . There will be 1:1 randomization.  
Investigational Product 
Administration 
Not applicable, no investigational product. 
Eligibility Criteria 
Inclusion criteria:  
Female, at least 18 years old with diagnosis of overactive bladder (urinary 
urgency or frequency, OAB) or urinary urgency incontinence (UUI) 
Exclusion criteria: 
• Have a diagnosis of neurogenic bladder 
• Received intravesical botox injections within prior 6 months 
• Current treatment with either: SNM, PTNS, or OAB medications – 
need wash out as below 
• SNM – turn device off for at least 2 weeks prior to procedure, off 
during 3-month follow up window 
• PTNS – no treatments within 2 weeks of start, none during 3-month 
post-procedure follow up window 
• OAB meds – 2 week wash out period prior to injection, none during 3-
month post-procedure follow up window 


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Protocol Number: Intradetrusor Botulinum Toxin A: Are less injections better? V2_09 Mar 2022 
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• Currently pregnant or trying to get pregnant 
• Contraindications to Botox® - hypersensitivity to Botox®, inability to 
self-catheterize/refusal to have indwelling catheter 
• Have a UTI (can enroll after treatment) 
• Have urinary retention (PVR>150cc on two occasions) 
• Do not speak English or Spanish 
 
Study Endpoint 
The primary outcome variable will be the OAB-q symptoms severity subscale 
score (urinary symptom questionnaire) as a marker of efficacy. The secondary 
outcome variables will include UTI rate, PVR, urinary retention, inter-injection 
interval, catheter use within 3 months, PGI-I, and VAS pain score. 
Statistical Methods 
The target sample size was determined by using the typical standard 
deviation of the OAB-q score (20 points per literature review) and the known 
minimally important clinical difference of 10 points of the OAB-q severity 
subscale, our primary outcome. Using this data, we calculated the sample size 
of N=102 maximum total (expect to enroll ~40 at KP, ~60 at UCI, ~20 at 
PSJH), 51 subjects in each arm for a 80% power with 5% significance level. 
With an estimated 15% lost to follow up rate, we calculated need to enroll 
116 subjects.  
 
 


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1 INTRODUCTION 
1.1  
Background 
Intradetrusor (bladder) Botulinum toxin A (BTA or Botox®) is a well-established treatment for urinary 
urgency incontinence (UUI). 1,2 While this treatment’s efficacy in comparison to alternative therapies 
including anticholinergic medications and sacral neuromodulation for treatment of UUI has been studied, 
the ideal number of injection sites within the bladder has not been well established.3,4 Intradetrusor BTA 
injections are often completed as an office procedure while the patient is awake. Each injection site can 
cause discomfort for the patient during the procedure. Urinary tract infection and urinary retention are risks 
associated with this procedure and could potentially be related to number of injection sites. Currently, there 
is a lack of information in the literature regarding the optimal number of intravesical BTA injection sites. 
Prior studies evaluated efficacy using 100u BTA spread across 20 injections sites, however current 
practices at local institutions safely use 10 injections sites based on studies showing similar effect and 
adverse event profiles between use of 10, 20, and 40 injection sites.5,6 Research using animal models has 
shown diffuse distribution of BTA within the entire detrusor muscle after just a single BTA injection at one 
site.7 This has been corroborated in human studies.8 A recently published observational pilot study shows 
promise for single site intradetrusor Botox® injection as it reported a lower rate of urinary retention and 
similar durability.9 Similar clinical efficacy with only one to three intravesical BTA injection[s] has also been 
reported.10  
 
1.2 Hypothesis 
We hypothesize that one injection of intradetrusor Botox® will have similar efficacy to ten injections, better 
tolerability, due to decreased procedure time and less pain, along with potential for lower adverse event 
rates, specifically urinary retention and urinary tract infections. 
2 OBJECTIVES AND PURPOSE 
2.1 PRIMARY OBJECTIVE 
Our primary objective is to evaluate the efficacy of intradetrusor Botox® in an outpatient population 
based on patient questionnaire scores (OAB-q) in one versus ten Botox® injection [s].  
 
The primary outcome variable will be the OAB-q (urinary symptom questionnaire) symptom severity 
subscale score. The secondary outcome variables will include UTI rate, PVR, urinary retention, inter-
injection interval, catheter use within 3 months, PGI-I, and VAS pain score. 
 
3 STUDY DESIGN 
 
We plan for a prospective, single-blinded, non-inferiority randomized controlled trial. We will evaluate the 
efficacy, safety, and tolerability of one intradetrusor Botox® injection (study) versus ten injections 
(control/standard of care). The patient will be blinded. There will be 1:1 randomization. The physician doing 
the procedure will not be blinded. 
 


      Southern California Permanente Medical Group 
 
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 3.1 
Treatment Arms 
 
There will be two arms for this trial: study arm (one injection) and control arm (10 
injections). Across all sites we will plan to enroll 116 maximum participants with anticipated 
enrollment at Kaiser Permanente being approximately 40 participants.  
3.2 
Study Duration 
 
We anticipate completion of enrollment with approximately 1.5 years. Each subject will 
participate in the study for 3 months (one 3 week post-procedure visit and one 3 month 
post-procedure visit). Charts will be reviewed for approximately 6-12 months after 
procedure completion.  
4 
STUDY PRODUCT INFORMATION 
4.1 Description 
Botox® (onabotulinumtoxina) is an FDA approved treatment of OAB, urinary urgency and frequency, and 
urinary urgency incontinence via intradetrusor injection. A standard approved dose of 100units will be 
injected into the detrusor muscle. There is no investigational drug being studied in this trial.  
 
4.2 
Dosage, Preparation and Administration 
 
The physician will inject 10 mL of (100u/10mL) Botulinum Toxin A in either one or ten sites  
located in the midline, supra-trigonal posterior bladder wall at a depth of 3mm into the 
detrusor. Each participant will undergo one injection procedure for the duration of the 
study.  
4.3 
Toxicity and Safety Information 
 
The most common adverse reactions associated with intradetrusor administration of 
Botox® include urinary tract infection and urinary retention. These will be monitored as 
described below in adverse events section.  
4.4 
Concomitant Medications/ Treatments 
 
Current treatment with either: SNM, PTNS, or OAB medications – need wash out as below: 
1 SNM – turn device off for at least 2 weeks prior to procedure, off during 3-month follow up window 
2 PTNS – no treatments within 2 weeks of start, none during 3-month post-procedure follow up 
window 
3 OAB meds – 2 week wash out period prior to injection, none during 3-month post-procedure follow 
up window 


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Protocol Number: Intradetrusor Botulinum Toxin A: Are less injections better? V2_09 Mar 2022 
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5 
SELECTION AND WITHDRAWAL OF PATIENTS 
 
Inclusion Criteria 
 
1 Female 
2 18 years old or greater 
3 Diagnosis of overactive bladder (urinary urgency or frequency, OAB) or urinary urgency 
incontinence (UUI) 
 
Exclusion Criteria 
 
1 Have a diagnosis of neurogenic bladder 
2 Received intravesical Botox® injections within prior 6 months 
3 Current treatment with either: SNM, PTNS, or OAB medications – need wash out as below 
4 SNM – turn device off for at least 2 weeks prior to procedure, off during 3-month follow up window 
5 PTNS – no treatments within 2 weeks of start, none during 3-month post-procedure follow up 
window 
6 OAB meds – 2 week wash out period prior to injection, none during 3-month post-procedure follow 
up window 
7 Currently pregnant or trying to get pregnant 
8 Contraindications to Botox® - hypersensitivity to Botox®, inability to self-catheterize/refusal to have 
indwelling catheter 
9 Have a UTI (can enroll after treatment) 
10 Have urinary retention (PVR>150cc on two occasions) 
11 Do not speak English or Spanish 
Withdrawal Criteria 
 
Subjects are only receiving one procedure as part of the study, thus would only be 
withdrawn prior to undergoing the procedure if they had exclusion criteria or voluntarily 
withdrew.  
6 
STRATIFICATION/ RANDOMIZATION SCHEME 
 
Subjects will be randomized via permuted blocks in a 1:1 fashion to either the study group (1 injection) or 
the control/standard of care group (10 injections). The pre-assigned randomization by permuted block 
design will be determined at the time of the procedure by opening of a sealed, opaque envelope containing 
the group allocation.  
 
7  ASSESSMENT OF EFFICACY AND SAFETY 


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7.1 
Adverse Events Reporting 
7.1.1 
Adverse Event Definition 
Adverse Event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
All adverse events, including those that are reported by the patient spontaneously, those the 
study investigator observes, and those that the study investigator elicits in response to open-
ended questions. Recorded adverse events should be assessed by the study investigator 
indicating the causal relationship of the event with the study drug and whether it meets the criteria 
for a Serious Adverse Event. 
7.1.2 
Time Period and Frequency for Event Assessment and Follow-up 
 
Adverse events will be collected from the procedure date through at least 
3 months after the Botox® injection procedure.  
7.1.3 
Serious Adverse Event Definition 
SERIOUS ADVERSE EVENT (SAE) is an adverse event or suspected adverse reaction if, in 
the view of either the study investigator, meets one or more of the following criteria: 
Ø Results in death 
Ø Is a life-threatening adverse event (places the subject at immediate risk of death from 
the event as it occurred) 
Ø Results in inpatient hospitalization or prolongation of existing hospitalization 
Ø Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
Ø Results in a congenital anomaly/ birth defect 
Ø An important medical event that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
7.1.4 
Serious Adverse Event Reporting 
If the site personnel identifies a potential SAE the Investigator will be notified immediately.  If the 
study investigator determines that the adverse event meets the criteria for an SAE, the 
Investigator will report the event as follows:  document the SAE in the adverse event log. t The 
study investigator will also notify the KPSC Institutional Review Board (IRB) of unanticipated 
SAEs within 10 business days per the KPSC IRB SOP 502, Principal Investigator Reportable 
Event and Incident Requirements.   
8 
STUDY SCHEDULE: CLINICAL/ LABORATORY EVALUATIONS 


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8.1 
Study Procedure 
8.1.1 
Informed Consent 
 
Subjects will typically have the time between their clinic initial/consultation visit and their procedure 
appointment (typically at least 1 week) to consider whether to consent. If the study is not discussed at their 
prior visit or via telephone script prior to procedure appointment, subjects will be given up to 60 min to 
consider and ask the Investigator questions. Participants will be consented by the Principal Investigator or 
any of the physician co-investigators who will be performing the Botox® procedure. The participant will be 
provided a copy of the signed informed consent.  
8.1.2 
Eligibility Review 
 
Eligibility will be assessed by review of inclusion and exclusion criteria posted in all recruitment locations by 
co-investigators. After consent and enrollment  the participants will be screened and randomized via 
permuted blocks in a 1:1 fashion to either the study group (1 injection) or the control group/standard of care 
(10 injections). The pre-assigned randomization by permuted block design will be determined at the time of 
the procedure by opening of a sealed, opaque envelope containing the group allocation.  
 
Pre-Procedure Requirements 
Prior to the procedure each subject will have the following (at either prior/consultation visit or procedure 
visit see study calendar below): 
 
[ ] sign consent form 
(prior to any non-standard of care procedures) 
[ ] Post-void residual 
[ ] Urinalysis (formal UA OR poct udip) 
[ ] OAB-Q LF Questionnaire completion 
 
8.1.3 
Study Procedure 
 
Botox Injection Procedure 
 
Arm 1: 1 injection  
Subjects will be blinded to the allocation group by turning the cystoscope screen away from patient. 
Cystoscopic injection will be standardized using an injection cystoscope and 100-200 mL of intravesical 
fluid. Subjects undergoing the procedure in clinic will receive a lidocaine instillation prior to the procedure 
along with a urethral lidocaine jelly. The physician will inject 10 mL of (100u/10mL) Botulinum Toxin A in 
one midline, supra-trigonal posterior bladder wall site at a depth of 3mm, as diagramed below. The bladder 
trigone and ureteral orifices will not be injected. Each subject will undergo a single injection procedure as 
part of this trial. Each subject will void prior to leaving clinic.  
 


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Fig 1: 1 injection location 
 
 
Arm 2: 10 Injections   
 
Subjects will be blinded to the allocation group by turning the cystoscope screen away from patient. 
Cystoscopic injection will be standardized using an injection cystoscope and 100-200 mL of intravesical 
fluid. Subjects undergoing the procedure in clinic will receive lidocaine instillation prior to the procedure 
along with a urethral lidocaine jelly. The physician will inject 10 mL of (100u/10mL) Botulinum Toxin A in ten 
1mL aliquots at ten supra-trigonal posterior bladder wall sites at a depth of 3mm, as diagramed below. The 
bladder trigone and ureteral orifices will not be injected. Each subject will undergo a single injection 
procedure as part of this trial. Each subject will void prior to leaving clinic.  


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Figure 2: Arm 2: 10 injection locations 
 
 
 
Post-Procedure Requirements 
[ ] Confirm ability to void after procedure 
[ ] Subject completes visual analogue scale of pain 
[ ] Procedure note using study dotphrase:  .procbotoxstudy 
[ ] RX prophylactic antibiotic 
- 
Macrobid 100 mg BID x 3 day  
OR 2nd line if allergies 
- 
Bactrim DS BID x 3 day 
 3 week follow up visit 
 
[ ] PVR 
[ ] OAB-Q LF 
 3 month follow up visit 
 
[ ] OAB-Q LF 
[ ] PGI-I 
8.2 
Clinical Evaluations 
8.2.1 Clinical Evaluation 
Subjects will be screened at their initial consultation visit for inclusion in 
the study. If the screening exams, tests and/or procedures allow and the 
subject desires to enroll, then the subject will have the following 
procedures and tests done. This study includes 3 visits which will take 


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about 60 minutes each. These will include a procedure visit, a 3-week 
follow up visit, and a 3 month follow up. 
 
1. Procedure visit for intradetrusor Botox® injection, collection of pre-procedure OAB-q, VAS pain scale 
after procedure 
2. 3-week follow up visit, including collection of post-void residual via urethral catheterization or bladder 
scan (ultrasound) and post-procedure OAB-q 
3. 3-month follow up visit, either in person or via telephone with collection of OAB-q and symptoms 
improvement questionnaire (PGI-I) 
8.2.2 
Adverse Event Assessment 
 
Participants will be assessed for adverse events from the time of their 
injection procedure through at least 3 months post procedure. There will 
be specific evaluation for urinary retention (PVR collected at 3 week follow 
up visit) and UTI (UA pre-procedure and UCx post-procedure if 
symptomatic). See Section 7.1 regarding adverse event reporting.  
8.3 
Laboratory Evaluations 
 
8.3.1 
Insert Laboratory Evaluation 
A standard of care lab urinalysis or clinic point of care urine dip evaluation 
will be collected prior to the Botox® injection procedure. There will not be 
any other standard required labs. If participants are exhibiting UTI 
symptoms, a standard of care work up with urine culture will be 
completed.  
8.4 
Schedule of Assessments  
 
Procedures  
 
Consultation 
clinic visit (prior 
to study 
enrollment) 
Procedure Visit 
3 wk Follow-Up 
3 month Follow-Up 
Estimated visit time 
60min 
60 min 
60 min 
60 min 
Recruit 
X 
 
 
 
Urinalysis 
X 
 
 
 
PVR 
X 
 
X 
 
Sign Consent 
X 
OR X 
 
 
Questionnaire (OAB-q 
LF)  
X 
OR X 
X 
 
VAS-Pain Score 
 
X (after 
procedure) 
 
 


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Questionnaire (OAB-q 
LF, PGI-I) 
 
 
 
X 
Telephone Call (if 
unable to present for 
in-person visit) 
 
 
 
X 
 
9 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
The outcome status (in terms of toxicity, response, reason off study, progression, and survival) of all 
eligible patients will be reported. All eligible patients who begin treatment will be included in the 
analysis of efficacy, safety, and tolerability of the Botox® procedure.  
9.1 
Primary Endpoints 
 
The primary outcome variable will be the OAB-q symptoms severity subscale score 
(urinary symptom questionnaire) as a marker of efficacy.  
9.2 
Secondary Endpoints 
 
The secondary outcome variables will include UTI rate, PVR, urinary retention, inter-
injection interval, catheter use within 3 months, PGI-I, and VAS pain score. 
10 
DATA HANDLING AND RECORD KEEPING 
10.1 
Source Documentation 
 
Documentation that will be considered as source will be the electronic medical records and questionnaires 
(OAB-Q, PGI-I, and VAS-pain). 
10.2 
Case Report Forms 
 
10.3 
CRF attached as appendix. The electronic medical record and questionnaires (OAB-Q, PGI-I, and 
VAS-pain) will be considered data sources. Study data will be captured using REDCap for data 
management purposes.Record Retention 
 
Data will be stored securely in REDCap and retained through presentation and publication 
of study results. At site for 1 year after the IRB has closed out the study. Following that all 
study related documents will be archived for 15 years at Iron Mountain Retention facility 
(8700  Mercury Lane, Pico Rivera, CA 90660). 
10.4 
Data Management 
 
Data will be stored securely in KPSC REDCap. This data will be encrypted and password 
protected on the KPSCnetwork via REDCap. Only delegated study personnel will have 
access to the database. 


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11 
STUDY OVERSIGHT 
11.1 
Data Safety Monitoring Board  
 
An independent Data Safety Monitoring Board (DSMB) has been chartered and will meet as specified in the 
DSMB charter agreement to assist with safety oversight. The DSMB will report back to the PI. See 
Appendix D, DSMB Charter for details.  
11.2 
Study Site Monitoring 
 
Internal monitoring of sites will be conducted quarterly by the PI and site lead investigators, 
Dr. Crowder, Dr. Whitcomb, Dr. Brueseke, respectively. The monitoring will be done 
remotely through scheduled teleconferences with the lead investigator and/or designee. 
On-site visits will also be conducted quarterly. See satellite site management plan, 
appendix E for details. 
12 
STATISTICAL CONSIDERATIONS 
12.1 
Study Hypothesis 
 
We hypothesize that one intradetrusor Botox® injection site has similar efficacy to ten injections sites based 
on OAB-Q symptoms severity score change from pre-procedure to 3-week post-procedure with a minimal 
clinical important difference of 10.  
12.2 
Sample Size Considerations 
 
The target sample size was determined by using the typical standard deviation of the OAB-q symptom 
severity score (20 points per literature review) and the known minimally important clinical difference of 10 
points of the OAB-q severity subscale, our primary outcome. Using this data, we calculated the sample size 
of N=102 maximum total (expect to enroll ~40 at KP, ~60 at UCI, ~20 PSJH), 51 subjects in each arm for 
an 80% power with 5% significance level. Based on review of prior clinical data at UCI and KP, we expect 
to complete enrollment within 1 – 1.5 years. With an estimated 15% lost to follow up rate, we calculated 
need to enroll 116 subjects. 
12.3 
Final Analysis Plan 
 
We will describe the study population, including patient age, race/ethnicity, baseline severity scores (OAB-
Q), BMI, medical history (prior surgery, menopausal status, prior Botox, etc.), overall, by arm, and stratified 
by study site (KPSC, UCI, PSJH).  We will summarize continuous measures using means and standard 
deviations and categorical measures using percentages.  We will compare study arms using the t-test or 
Fisher’s exact test, as appropriate. 
 
We will examine the outcome measures (OAB-Q and any secondary measures) to 
determine whether they are approximately normally distributed.  If not, we will apply a 


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transformation prior to analysis to make the analytic variable approximately normal.  If no 
transformation successfully achieves approximate normality, we will apply non-parametric 
tests for analysis, including Wilcoxon’s rank-sum test instead of the t-test and quantile 
regression instead of linear regression. 
 
We will analyze the main study outcome (OAB-Q score) initially using a t-test to compare 
the two study arms, overall and stratified by study site.  We will further analyze the 
outcome using generalized estimating equations to account for correlation within study 
sites.  These models will adjust for any potential differences in age, race/ethnicity, baseline 
severity scores, or any other baseline measures, and will account for any potential 
differences between study sites. 
 
Secondary outcomes will be analyzed in the same manner as the primary outcome. 
 
Primary analyses will be performed using intention-to-treat to determine study arm.  If 
multiple individuals are not treated according to the randomization plan, we will perform a 
sensitivity analysis using as-treated, per-protocol study arms. 
 
For any individuals who are lost to follow-up, we will first compare those individuals who 
are lost to those who complete follow-up in terms of demographics, baseline 
characteristics and any outcome assessments prior to the time that they are lost to follow-
up.  For primary analysis of OAB-Q scores, we will analyze complete data including only 
those who have completed the follow-up questionnaires within the prescribed timeframes.  
If more than 10% are lost to follow-up, we will additionally perform multiple imputation in an 
attempt to capture data of those lost to follow-up. 
 
13 
REGISTRATION GUIDELINE 
 
The patients will be enrolled and registered for the study in person, however if needed this number can be 
used: 833-574-2273. In order to register a patient the following forms and records will be needed: informed 
consent, confirmation of meeting inclusion/exclusion criteria via checklist review, Screening Enrollment Log, 
Patient Enrollment Log,Patient Screening #, Patient ID Log, completion of pre-procedure OAB-Q. Patient 
will be randomized via permuted block design in a 1:1 fashion to one of the two arms,  Arm 1: 1 Injection or 
Arm 2: 10 injections  at their Botox® procedure visit.  
 
14 
BIOHAZARD CONTAINMENT 
Not applicable. 


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15 
ETHICAL AND REGULATORY CONSIDERATIONS 
All institutional and Federal regulations concerning the Informed Consent form will be fulfilled.  The 
study will be conducted in adherence to ICH Good Clinical Practice. 
15.1  
Institutional Review Board 
This study protocol, the informed consent form(s), any information intended for distribution to 
subjects, and any relevant supporting information will be submitted to KPSC IRB by the Principal 
Investigator and review and approved by KPSC IRB prior to initiation of the study. 
 
The Principal Investigator is responsible for submitting all reportable events as defined by KPSC-
IRB SOP-502 to KPSC IRB within the appropriate reporting periods. 
15.2  
Informed Consent Process 
Written informed consent, in compliance with 21 CFR 50 will be obtained before any study-related 
procedures are initiated. Informed consent will be obtained from each patient or patient’s legally 
authorized representative (LAR) or the patient’s legal guardian. Informed consent includes the 
principle that it is critical that the individual be informed about the potential risks and benefits of 
participating in this study. This information will allow individuals to make a personal risk-versus-
benefit decision and understand the following general principles: 
1. Participation in this program is entirely voluntary. 
2. Patients may withdraw from participation in this program at any time without penalty or loss of 
benefits to which they are otherwise entitled. 
3. Refusal to participate in this study involves no penalty. 
4. The individual is free to ask any questions that will allow him/her to understand the nature of 
this study. 
15.3 
Exclusion of Women, Minorities, and Children (Special Populations) 
 
This study will enroll women and minorities, specifically Spanish speakers. Children will not 
be enrolled as intradetrusor Botox® is not approved for treatment of OAB or UUI in a 
pediatric population. Currently pregnant or trying to get pregnant are excluded.  
15.4 
Privacy and Confidentiality 
 
All subject identifiers and PHI will be recorded and maintained 
electronically in RedCap. Dr. Crowder as PI will have access to all PHI 
along with all other co-investigators during the process of their clinical 
duties as the physicians enrolling and completing the study procedure.  


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15.5 
Future Use of Stored Specimens and Other Identifiable Data 
 
There will not be specimens stored in this study. Participants will have 
opportunity to agree to future use of data within consent form.   
16 
REFERENCES/ATTACHMENTS 
 
1. Brubaker L, Richter HE, Visco A, et al. Refractory Idiopathic Urge Urinary Incontinence 
and Botulinum A Injection. J Urol. 2008;180(1):217-222. 
doi:10.1016/j.juro.2008.03.028 
2. Chapple C, Sievert KD, Macdiarmid S, et al. OnabotulinumtoxinA 100 U significantly 
improves all idiopathic overactive bladder symptoms and quality of life in patients with 
overactive bladder and urinary incontinence: A randomised, double-blind, placebo-
controlled trial. Eur Urol. 2013;64(2):249-256. doi:10.1016/j.eururo.2013.04.001 
3. Visco AG, Brubaker L, Richter HE, et al. Anticholinergic Therapy vs. 
OnabotulinumtoxinA for Urgency Urinary Incontinence. N Engl J Med. 
2012;367(19):1803-1813. doi:10.1056/nejmoa1208872 
4. Amundsen CL, Richter HE, Menefee SA, et al. Onabotulinumtoxin a vs sacral 
neuromodulation on refractory urgency urinary incontinence in women: A randomized 
clinical trial. JAMA - J Am Med Assoc. 2016;316(13):1366-1374. 
doi:10.1001/JAMA.2016.14617 
5. Nitti VW, Dmochowski R, Herschorn S, et al. OnabotulinumtoxinA for the treatment of 
patients with overactive bladder and urinary incontinence: Results of a phase 3, 
randomized, placebo controlled trial. J Urol. 2013;189(6):2186-2193. 
doi:10.1016/j.juro.2012.12.022 
6. Liao CH, Chen SF, Kuo HC. Different number of intravesical onabotulinumtoxinA 
injections for patients with refractory detrusor overactivity do not affect treatment 
outcome: A prospective randomized comparative study. Neurourol Urodyn. 
2016;35(6):717-723. doi:10.1002/nau.22780 
7. Coelho A, Cruz F, Cruz CD, Avelino A. Spread of onabotulinumtoxinA after bladder 
injection. Experimental study using the distribution of cleaved SNAP-25 as the marker 
of the toxin action. Eur Urol. 2012;61(6):1178-1184. doi:10.1016/j.eururo.2012.01.046 
8. Mehnert U, Boy S, Schmid M, et al. A morphological evaluation of botulinum 
neurotoxin A injections into the detrusor muscle using magnetic resonance imaging. 
World J Urol. 2009;27:397-403. doi:10.1007/s00345-008-0362-0 
9. Ton J, Downing P, Versi E, et al. Outcomes of a single trigone-only vs. 20 trigone-
sparing injections of OnabotulinumtoxinA for refractory overactive bladder (OAB). Int 
Urol Nephrol. 2021;53(6):1067-1072. doi:10.1007/s11255-021-02802-0 
10. Avallone MA, Sack BS, El-Arabi A, Guralnick ML, O’Connor RC. Less is more—A pilot 
study evaluating one to three intradetrusor sites for injection of OnabotulinumtoxinA for 
neurogenic and idiopathic detrusor overactivity. Neurourol Urodyn. 2017;36(4):1104-
1107. doi:10.1002/nau.23052 


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17 
APPENDICES 
 
Appendix A: Case Report Form – (excel spreadsheet, uploaded to IRIS) 
Appendix B: Informed Consent Form – uploaded to IRIS 
Appendix C: Questionnaires - OAB-Q LF (English, Spanish), PGI-I, VAS 
pain 
Appendix D: DSMB Charter (uploaded to IRIS) 
Appendix E: Satellite Site Management Plan 
 
18 
SIGNATURE 
 
This clinical trial protocol has been reviewed and approved in order to ensure compliance with Good 
Clinical Practices. 
This study will be performed in compliance with Good Clinical Practices, including the archiving of 
essential documents.  
 
Version Number and Date 
Version 2_09 Mar 2022  
 
 
Investigator Name 
Carly Crowder, MD 
 
 
Signature and Date