A Randomized Clinical Trial of 100 Units of Intradetrusor Onabotulinum Toxin A for Refractory Overactive Bladder - Is 10 Injections Less Painful Than 20 Injections?
Phase: PHASE4
Conditions: Overactive Bladder
Sponsor: Wake Forest University Health Sciences

Official Title:  A Randomized Clinical Trial of 100 Units of Intradetrusor 
Onabotulinum Toxin A for Refractory Overactive Bladder – Is 10 Injections less 
painful than 20 Injections? 
NCT04124939 
IRB-Approved Date:  4/25/22 
 

Wake Forest Baptist Health Department of Urology 
Protocol# IRB00059454  
Protocol version: 1 
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Study Title: A Randomized Clinical Trial of 100 Units of Intradetrusor 
Onabotulinum Toxin A for Refractory Overactive Bladder – Is 10 Injections less 
painful than 20 Injections? 
Principal Investigator:  Catherine Matthews, MD 
 
Wake Forest Baptist Health, Winston Salem, NC 
  
Co-Investigators: 
Whitney Smith, MD 
 
 
Wake Forest Baptist Health, Winston Salem, NC 
 
 
Gopal Badlani, MD 
 
Wake Forest Baptist Health, Winston Salem, NC 
 
 
Robert Evans, MD 
 
Wake Forest Baptist Health, Winston Salem, NC 
 
 
Majid Mirzazadeh, MD 
 
Wake Forest Baptist Health, Winston Salem, NC 
 
 
 
Candace Parker-Autry, MD 
 
Wake Forest Baptist Health, Winston Salem, NC 
 
 
Andre Plair, MD 
 
Wake Forest Baptist Health, Winston Salem, NC 
 
 
 
Amr El Haraki, MD 
 
Wake Forest Baptist Health, Winston Salem, NC 
 
 
 
Katherine Hines, MD 
 
Wake Forest Baptist Health, Winston Salem, NC 
 
 
 
Anna Zdroik, DO 
 
Wake Forest Baptist Health, Winston Salem, NC 
 
 
 
 
 
Sponsor or Funding Source: None at present.  
 

Wake Forest Baptist Health Department of Urology 
Protocol# IRB00059454  
Protocol version: 1 
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Background, Rationale, and Context:  
Non-neurogenic Overactive bladder (OAB) is a chronic condition characterized by 
urinary urgency and frequency and can be associated with urinary incontinence.  It can 
be a particularly bothersome syndrome with a worldwide prevalence of approximately 
10.7% and is projected to be as high as 20.1% in 2018 [1]. The American Urological 
Association (AUA) and the Society of Urodynamics, Female Pelvic Medicine and 
Urogenital Reconstruction (SUFU) have established a combined set of guidelines for the 
treatment of OAB, amended in 2015, to help the clinician diagnose and treat patients in 
a tiered approach [2]. First line treatments are aimed at behavioral modifications (fluid 
management, bladder retraining, urge suppression techniques, pelvic floor muscle 
exercises, and physical therapy). Second line therapies are oral pharmacologics, and the 
two classes of medications are the antimuscarinics and a beta-3 agonist. Third line 
therapies, used to treat the patient with OAB that is refractory to first and second line 
therapies, include these three options: intradetrusor onabotulinumtoxinA (Botox®, 
Allergan, Inc.), sacral neuromodulation (SNM), and peripheral tibial nerve stimulation 
(PTNS). 
The United States Food and Drug Administration (FDA) has approved a dose of 
100 units of Botox® for refractory OAB based on rates of improvement of continence 
episodes while weighing adverse events [the most common being urinary tract infections 
(UTIs) and urinary retention requiring clean intermittent catheterization (CIC)]. However, 
what is not known is the optimal number of injections of the 100 units. The AUA/SUFU 
OAB guidelines do not recommend a specific number of injection sites. The European 
Association of Urology consensus report [3] recommends 10 Units/ml per injection (10 
one ml injections for 100 units). However, this was not based on randomized trials, and 
no studies have been done that directly compare different numbers of injection sites. The 
package insert for Botox® recommends 100 units combined with 10 cc of saline to be 
distributed in 20 injections (0.5 cc per injection) [4]. However, a literature search involving 
the methods of administration shows a range of 10 - 30 injections for 100 units of Botox® 
[3,5,11].  
One of the concerns about administering Botox® into the bladder is the patient’s 
comfort during the procedure as he or she is usually awake during this office based 
procedure. Patient experience is becoming a more important aspect of patient care, and 
is a marker for which provider are being measured. Currently, there are ongoing studies 
to assess whether or not 10 injections of Botox delivers the equivalent efficacy of 20 
injections of Botox in a national, multi-institutional trial. Uniquely, we would like to assess 
if there is a difference in the pain of procedure with 10 injections versus 20 injections.  
Our hypothesis is that Botox® distributed in 10 injections will result less pain of 
procedure perceived by the patient compared to the pain perceived by the patients 
receiving 20 injections. 
 
Objectives: 
● Primary endpoint: The primary endpoint to be assessed is the difference in pain 
of procedure experienced by those receiving 100 units of Botox ® in 10 injections 
versus those receiving 100 units of Botox in 20 injections. Our hypothesis is that 
those receiving 10 injections will perceive less pain. 

Wake Forest Baptist Health Department of Urology 
Protocol# IRB00059454  
Protocol version: 1 
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○ Pain of procedure:  
■ Pain of procedure: To assess pain of procedure, we will use the 11 
point Numeric Pain Rating Scale (NPRS). We expect that the 
patients receiving 10 injections will have less pain associated with 
the procedure. The patients will rate their level of pain immediately 
following the completion of bladder injections by selecting a whole 
number from 0 to 10 that represents their level of pain (0 is no pain 
at all and 10 is the most severe pain) during the procedure. This 
scale has been validated, and correlates similarly to other pain 
scales [7]. 
● Secondary endpoints: Secondary endpoints to be assessed will be efficacy, OAB 
symptoms (nocturia, urgency, and frequency), post void residual volume (PVR) at 
2 weeks and 12 week post-procedure, disease specific bother, health related 
quality of life (HRQoL), the patient’s perceptions of change, and adverse events 
as detailed below: 
○ Efficacy: The reduction in mean urge incontinence episodes which will be 
calculated by averaging the amount of urge urinary incontinence episodes 
over 3 days as recorded in a bladder diary. Success will be defined as a 
greater than 50% reduction in urge incontinence episodes after 
intradetrusor Botox® based on 3-day bladder diaries collected at baseline 
and 12 weeks post-injection. This outcome measure is consistent with 
results reported in previous trials involving Botox® for overactive bladder 
[6].  
○ Disease specific bother and HRQoL: To assess OAB symptoms other than 
incontinence and impact on quality of life, we will administer the Overactive 
Bladder Questionnaire Short Form (OABq-SF) at baseline, at 2 weeks, and 
at 12 weeks post-procedure. This is an abbreviated version of the 
Overactive Bladder Questionnaire (OABq) developed to evaluate the bother 
and health related quality of life for patients with overactive bladder. The 
OAB-SF contains 6 items to assess symptom bother and 13 items to assess 
HRQOL. This questionnaire is commonly used, and has been validated for 
use in clinical practice [8]. 
○ PVR at 2 weeks and 12 weeks: To measure PVR at 2 weeks and 12 weeks, 
we will use a bladder scanner which measures volume based on ultrasound. 
The provider may also chose to measure PVR by straight catheterization at 
his or her discretion. 
○ Patient’s Global Impression of Change (PGIC) scale: In order to help 
determine the clinical significance of change, we will utilize the PGIC scale 
[16] administered at 2 weeks and 12 weeks post-injection. 

Wake Forest Baptist Health Department of Urology 
Protocol# IRB00059454  
Protocol version: 1 
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○ Adverse events: Specific to intradetrusor injections of Botox®, the most 
common adverse events are urinary retention requiring intermittent 
catheterization (approximately 4%) [9] and urinary tract infections 
(approximately 15.5%-35%) [10]. Patients will be closely monitored for 
urinary tract infections as they will undergo urinanalysis and assessment of 
symptoms at their post-operative visits. 
Methods and Measures 
● Design:   
- 
This study is a randomized clinical trial to assess whether or not 10 
injections of 100 units of intradetrusor Botox® toxin is perceived as less 
painful compared to 20 injections of 100 units of intradetrusor Botox® toxin 
for the treatment of refractory OAB. Refractory OAB is defined as persistent 
urinary frequency and urgency despite behavioral modifications, failing a 
trial of 2 medications (anticholinergics or beta 3 agonists), have a 
contraindication to the medications, or are unable to tolerate medications 
due to allergies or side effects.  
- 
The primary outcome will be assessed by the patient completing the pain of 
procedure questionnaire, the NPRS, to be completed by the patient 
immediately after the procedure. The patient will receive the questionnaire 
from the nurse or medical assistant after the provider has performed the 
procedure. We will then compare mean value of the NPRS for the 10 
injection group to the 20 injection group. 
- 
Efficacy will be assessed by comparing study participant’s reduction in urge 
urinary incontinence episodes based on a 3 day voiding diary to be shared 
by the participant at baseline and 12 weeks post-procedure. This diary is 
dispensed to all patients during their visit prior to procedure visit as a part 
of standard of care. If subjects demonstrate a 50% reduction in urge 
incontinence episodes on a 3-day bladder diary, they will be categorized as 
“treatment success” whereas those who do not will be categorized as 
“treatment failure.” This dichotomous outcome will define efficacy as a 
secondary endpoint. 
- 
All eligible participants will be considered for the study. Patients will be 
counseled about the study in the office setting. Upon enrollment, patients 
will share a 3-day voiding diary. Diary is dispensed to all patients when they 
decide to undergo injection procedure. Disease specific bother and health 
related quality of life questionnaires will be completed following consenting. 
As per standard of care, urinalysis and post-void residual volume will be 
measurement. The only assessment in this list that is not part of standard 
clinical care are the questionnaires. If patients are on medications for 

Wake Forest Baptist Health Department of Urology 
Protocol# IRB00059454  
Protocol version: 1 
Page 6 of 21 
overactive bladder, they will be required to stop at least 3 weeks prior to 
undergoing the baseline 3 day voiding diary.  
After consenting to enrollment in the study, the patients will be scheduled for Botox® 
injections in the office. Randomization will be performed using random sequence number 
generation in blocks of 10 with randomization assignment concealed in sequentially 
numbered opaque envelopes. Randomization will be performed before the study startup 
by the coordinator using online available tool (sealed envelope). Envelopes with 50% 
carrying 10 injections instructions, and 50% carrying 20 injections instructions are 
prepared in advance, sealed, numbered 1 to 50, and stored in a locked cabinet at the 
Urology clinic at Charlois Blvd. Three envelopes will be carried to the Greensboro Wake 
Health System during coordinator’s scheduled clinic days. And then coordinator will bring 
those packets back to the Charlois Blvd Urology clinic on a regular base.  On the day of 
the procedure, the provider will select the next numbered envelope that will contain the 
randomization assignment for the number of injections. Subjects will be blinded to the 
randomization result. All patients will undergo a urinalysis prior to the procedure. If there 
is concern for an acute, untreated urinary tract infection, the patient does not undergo the 
procedure, and is treated with antibiotics while a urine culture is sent. All participants will 
be given preoperative antibiotics (except aminoglycosides). 100 units of Botox® will be 
combined with 20 cc saline for the purposes of 20 injections, or 100 units of Botox® will 
be combined with 10 cc of sterile saline for the purpose of 10 injections. Lidocaine Jelly 
locally. And the bladder will be instilled with 30ml of Marcaine and 5ml of NaHCo3 solution 
through a catheter for at least 15 minutes prior to the procedure. Cystoscopy with either 
a rigid or flexible cystoscope (per surgeon preference) will be performed using sterile 
technique. The Botox® will be injected in a grid like pattern avoiding the trigone as seen 
below. Study patients do not know the number of injections received in the bladder. 
There are two providers in the room for each procedure. Injection counting will be 
verbalized as Injection 1, Injection 2… to up to Injection 20 by non-injecting provider. 
A patient and a provider who is injecting will hear total of 20 counts. Providers will 
know the randomization prior to procedure, and a decision will be cleared between 
two providers whether to account pseudo injection at odd or even number for patients 
receiving 10 injections. A patient randomized to 10 injections will receive 10 
injections at alternate count. All patients will be informed in advance about the 
procedure at the time of consenting.The patient will be allowed to void on her own post-
procedure. Immediately after the procedure, the patient will receive a questionnaire to 
rate the pain of procedure using the numeric pain scale. The patient will then be 
discharged to home.Figure 1: Diagram showing sites of injections for patients undergoing 
10 injections of 100 units of Botox®. 
 
 
 
 

Wake Forest Baptist Health Department of Urology 
Protocol# IRB00059454  
Protocol version: 1 
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Figure 1: Diagram showing sites of injections for patients undergoing 10 injections of 
100 units of Botox®. 
 
 
 
 
 
 
Figure 2: Diagram showing sites of injections for patients undergoing 20 injections of 
100 units of Botox® 
 
- 
At two weeks, the patient will return to clinic for a standard office visit. She 
will have a post void residual checked using either a bladder scan or 
catheter, and a urinalysis (urine culture will be sent per clinic protocol). If a 
urine culture grows any bacteria, and the patient is symptomatic, she will be 
treated with culture specific antibiotics. She will then be asked about 
symptoms of a urinary tract infection, if they have been treated for a urinary 
tract infection, difficulty emptying the bladder, or required intermittent or an 

Wake Forest Baptist Health Department of Urology 
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Protocol version: 1 
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indwelling Foley catheter since the Botox® therapy. Subjects will complete 
the PGI-C and the OAB-SF. The patient will be sent home with a 3-day 
bladder diary to complete just prior to the 12-week visit. 
- 
At 12 weeks, the patient will return to clinic and her 3-day bladder diary will 
be reviewed. A post void residual volume will be checked using either a 
bladder scan or catheter, and a urinalysis will be sent per standard practice 
(urine culture will be sent per clinic protocol). If a urine culture grows any 
amount of bacteria and the patient is symptomatic, she will be treated with 
culture specific antibiotics. She will then be asked about symptoms of a 
urinary tract infection, if they have been treated for a urinary tract infection, 
difficulty emptying her bladder, or required intermittent or an indwelling 
Foley catheter since the Botox® therapy. She will again take the OABq-SF 
and PGIC. 
● Setting:  
- 
This study will take place at two Urology clinic locations at Wake Forest 
Baptist Medical Center, 140 Charlois Boulevard in Winston Salem, NC and 
3903 North Elm Street in Greensboro, NC. 
Subjects Selection Criteria 
● Inclusion criteria: Subjects must meet the following inclusion criteria in order to 
be eligible for the study 
1. Female gender 
2. At least 18 years of age 
3. Have already decided to undergo intradetrusor Botox® injections for 
treatment of refractory overactive bladder. 
4. Able and willing to learn clean intermittent catheterization (or care provider 
is willing and able to perform intermittent catheterization). 
5. Understands and is willing to undergo follow up and complete 
questionnaires as described in this protocol 
6. Able to give informed consent 
● Exclusion Criteria: 
1. Male gender 
2. Neurological conditions (Examples: Cerebral vascular accident within 6 
months prior to treatment, Parkinson's disease, Multiple Sclerosis, and 
Spina Bifida). 
3. Acute urinary tract infection  
4. Treatment with Botox® toxin for other conditions 
5. Allergy to Botox® toxin 
6. Hematuria that has not been worked up 
7. Known bladder malignancy 

Wake Forest Baptist Health Department of Urology 
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8. Previous history of bladder augmentation 
9. Currently pregnant (with no plans to become pregnant within 6 months of 
enrollment) or breastfeeding 
10. Currently taking aminoglycoside antibiotics 
11. PVR >150 cc (measured by bladder scan or by catheterization) prior to 
enrollment 
12. History of bladder pain syndrome. 
● Sample Size:  
• This study is unique as there are no previous trials assessing pain of 
procedure associated with intravesical administration of bladder Botox. To 
calculate sample size in the study, we will assume an effect of size of 1. We 
expect that patients receiving 20 injections will be within the moderate pain 
range (between 5 to 7 on the NPR scale). Therefor we will assume a mean 
NPR rating for patients receiving 20 injections would be 6 with a standard 
deviation of 2. Patients receiving 10 injections will be expected to have less 
pain and be in the mild pain range (from 1 to 4 on the NPR scale). Based 
on this, we would need 16 patients in each group. Accounting for a 20% 
drop out rate, we would need to accrue 20 patients in each group. 
● Statistical Analysis:  
1. Primary endpoint: Each patient will be asked to rate her pain level of 
procedure by completing the NPRS immediately after her procedure. The 
mean NPRS score of each group (10 injections vs 20 injections) will be 
calculated and compared using a paired T test.  
2.   Secondary endpoints 
▪ 
Each patient’s mean number of urge urinary incontinence episodes 
will be calculated by averaging the number of urge urinary 
incontinence episodes collected over 3 days as recorded on a 
bladder diary. This will be calculated pre-intervention at baseline and 
at 12 weeks. As previously described, “treatment success” is defined 
achieving greater than 50% reduction in the number of urge urinary 
incontinence episodes at 12 weeks after treatment with Botox®. A 
“treatment failure” will be defined as achieving less than 50% 
reduction in the number of urge urinary incontinence episodes at 12 
weeks after treatment with Botox®. Our hypothesis is that there will 
be more significantly “treatment responders” in patients receiving 20 
injections compared to 10 injections. To assess for clinical 
significance Chi square (Χ2) will be used. 

Wake Forest Baptist Health Department of Urology 
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Protocol version: 1 
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▪ 
OABq-SF and PGIC collected from the group receiving 20 injections 
and the group receiving 10 injections. The mean will be calculated 
for each of the outcomes and for each of the groups. The result will 
be compared using paired t-test.  
▪ 
We will compare the mean number of patients with urinary retention 
and UTIs in patients in both groups (those receiving 20 injections and 
those receiving 10 injections). To test for significance we will use the 
t-test. 
Interventions and Interactions 
● This study will use the FDA approved dose for refractory overactive bladder which 
is 100 units of onabotulinum toxin A (Botox®). 
● Per surgeon preference, a flexible cystoscope or a rigid cystoscope will be used to 
inject the Botox® in the wall of the bladder.  
● Injections will be in a grid-like fashion. 
● We will use a 3 day bladder diary obtained from the International Urogynecological 
Association (IUGA) for baseline and 12 week follow up. (Appendix 1) 
● Immediately after the treatment, patients will be asked to rate their pain using the 
Numeric Pain Scale. Please see appendix. 
● Patients will be assessed for adverse events, symptom specific and global quality 
of life using the form in the appendix. 
● All surveys will be handed to the patients by nursing. Patients will fill out the forms 
before seeing a physician. 
Outcome Measures: Outcome measures to be assessed include: pain of procedure, 
urge urinary incontinence episodes, efficacy, bother, HRQoL, PGIC, urinary tract 
infection, urinary retention requiring catheterization. 
 

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Calendar of Events: 
Form/Intervention 
Baseline 
Day of 
Procedure 
(Botox 
Injections) 
2 weeks 
12 weeks 
ICF 
x 
 
 
 
PVR 
x 
 
x 
x 
Urinalysis 
x 
x 
x 
x 
Study Inclusion 
Form 
x 
 
 
 
Bladder Diary 
x 
* 
 
x 
Randomization 
 
x 
 
 
Pain Scale 
 
x 
 
 
OABq-SF 
x 
 
x 
x 
PGIC 
 
 
x 
x 
Adverse Events 
Questionnare 
 
 
x 
x 
Completion of 
Study Form 
 
 
 
x 
*: Collect the completed Diary 
 
Human Subjections Projection 
Subject Recruitment Methods:  Patients evaluated in the office setting and who are 
diagnosed with refractory overactive bladder will be counseled regarding their options for 
treatment. The 3 treatment options include: intradetrusor injection of onabotulinum toxin, 
sacral neuromodulation, and percutaneous tibial nerve stimulation. After weighing the 
risks and benefits of all procedures, patients opting for therapy with onabotulinum toxin A 
will be considered for the trial. A member of the study team will discuss eligibility, review 
the inclusion/exclusion criteria, and answer questions. Informed consent will be signed. 
Three day diary provided during the at visit as per Standard of Care will be reviewed 
belonging all participants in order to capture the information. Any patient who wishes to 
withdraw from the study may do so at any time. If the patient chooses to withdraw, they 
will be presented with the option to allow the data collected up to that point to be retained, 
or have it removed. 

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All data will be kept on a secure password protected and encrypted hospital issued 
computers and contained within password protected files. Source documents will be kept 
in a locked drawer on Wake Forest Baptist Health property. 
Informed Consent: Signed informed consent will be obtained from each subject. The 
principal investigator and co-investigators will obtain informed consent. The informed 
consent process will take place in the Urology offices in either Winston-Salem, NC or 
Greensboro, NC. 
Confidentiality and Privacy: Confidentiality will be protected by collecting only the 
information needed to assess study outcomes, minimizing the collection of any 
information to the fullest extent possible that could directly identify subjects, and 
maintaining all study information in a secure manner. To help ensure subject privacy and 
confidentiality, only a unique study identifier will appear on the data collection form. Any 
collected patient identifying information corresponding to the unique study identifier will 
be maintained on a linkage file, stored separately from the data. The linkage file will be 
kept secure, with access limited to designated study personnel. Following data collection, 
subject identifying information will be destroyed 3 years after closure of the study by 
shredding, consistent with data validation and study design, producing an anonymous 
analytical data set. Data access will be limited to study staff. Data and records will be kept 
locked and secured, with any computer data password protected. No reference to any 
individual participant will appear in reports, presentations, or publications that may arise 
from the study. 
Data and Safety Monitoring: The principal investigator will be responsible for the overall 
monitoring of the data and safety of study participants. The principal investigator will be 
assisted by other members of the study staff. 
Reporting of Unanticipated Problems, Adverse Events or Deviations: Any 
unanticipated issues, serious and unexpected adverse events, deviations or protocol 
changes will be promptly reported to the principal investigator or member of the research 
team, the IRB, sponsor, and appropriate government agency if appropriate. 

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Appendix 1: IUGA 3 day Bladder Diary Sample 
 

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Appendix 1: IUGA 3 Day Bladder Diary to be completed by the patient. 
 

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Appendix 2: Pain assessment to be completed immediately after the procedure 

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Medical Record Number: ____________________ 
 
 
 
Date: ____________________________________ 
 
 
 
 
 
 
1 Since your last visit, have you been diagnosed with a UTI? 
Yes 
No 
2 Do you have any of the following symptoms? 
 
 
3 - Burning with urination 
Yes 
No 
4 - Blood in the urine 
Yes 
No 
5 - Fever 
Yes 
No 
6 
Since your last visit, have you been evaluated in the 
emergency room? 
Yes 
No 
7 
Since your last visit, have you been evaluated by your 
primary doctor? 
Yes 
No 
8 
Since your last visit, have you required a urinary catheter, 
(intermittent or indwelling)? 
Yes 
No 
9 
Since your last visit, have you seen blood in your urine that 
lasted more than 48 hr.? 
Yes 
No 
10 Since your last visit, have you had difficulty swallowing? 
Yes 
No 
11 Since your last visit, have you had difficulty breathing? 
Yes 
No 
 
Appendix 3: Follow up Adverse Event questionnaire to be completed at  2 weeks and12 
weeks 
 

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Appendix 4: OAB Short Form for Bother to be completed at baseline, 2 weeks and 12 
weeks. 
 

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Appendix 5: OAB Short Form for Bother to be completed at baseline, 2 weeks and 12 
weeks. 

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Appendix 6: PGI scale to be completed by patients at week 2 and week 12. 
References: 

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bladder, urinary incontinence and bladder outlet obstruction. 
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Heinrich 
& 
Schurch, 
Brigitte 
& 
Wyndaele, 
Jean-Jacques. 
(2008). 
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doi: 
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