Is Less More? Does Decreasing OnabotulinumtoxinA Injection Sites in the Bladder Increase Patient Satisfaction While Maintaining Efficacy?
Phase: PHASE4
Conditions: Overactive Bladder, Overactive Bladder Syndrome, Urinary Urgency, Urinary Incontinence, Urinary Frequency/Urgency, Urinary Bladder, Overactive
Sponsor: Corewell Health East

1
IS LESS MORE? 
DOES DECREASING ONABOTULINUMTOXINA INJECTION SITES IN THE BLADDER 
INCREASE PATIENT SATISFACTION WHILE MAINTAINING EFFICACY?
Principal Investigator:
Larry Sirls, MD
PROTOCOL DATE: JANUARY 24, 2020
VERSION: 6
TABLE OF CONTENTS
I. DEFINITIONS OF TERMS………………………
2
II. BACKGROUND AND RATIONALE……………..
2
III. OBJECTIVES AND ENDPOINTS………………..
3
IV. METHODOLOGY……………………………....
4
V. RISKS AND BENEFITS………………………...
8
VI. ELIGIBILITY CRITERIA………………………... 10
VII. DATA ANALYSIS……………………………...
11
VIII. DATA SAFETY MONITORING PLAN…………..
12
IX. REFERENCES…………………………………
14
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020

2
I.
Abbreviations
AE
Adverse Event
AUA
American Urological Society
BTX
OnabotulinumtoxinA
CRQIP
Clinical Research Quality and Process Improvement Program 
FDA
Food and Drug Administration
GRA
Global Response Assessment 
ICIQ-SF
International Consultation on Incontinence Questionnaire-Short Form 
IDO
Idiopathic Detrusor Overactivity
IRB
Investigational Review Board
NDA
Neurogenic Detrusor Overactivity
OAB
Overactive Bladder
OABq-SF
Overactive Bladder Questionnaire-Short Form 
PI
Principal Investigator
PTNS
Percutaneous Tibial Nerve Stimulation
PVR
Post Void Residual 
QoL
Quality of Life
SNS
Sacral Neuromodulation
SUFU
Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction
U
Units
UA
Urinalysis 
UCx
Urine Culture
UTI
Urinary Tract Infection
VAS
Visual Analog Scale
II.
Background and Rationale
Overactive bladder (OAB) is a common condition with a prevalence ranging from 5.9% to 
16.9% in the United States and has been found to increase with age.1-4 OAB has a negative 
impact on health related quality of life (QoL),5, 6 and OAB patients have more anxiety and 
depression than controls.7, 8 Primary treatments for OAB include behavioral modifications, 
such as decreased caffeine intake and timed voiding, and pelvic floor physical therapy.  
Second line therapy includes anticholinergic medicine/beta-3 adrenoceptor agonists.  
Unfortunately, compliance and adherence to these medications decreases over time likely 
due to side effects and/or efficacy.9-13 Per American Urological Association and the Society 
of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (AUA/SUFU) 
guidelines, onabotulinumtoxinA (BTX) is a third line recommendation for OAB along with 
percutaneous tibial nerve stimulation (PTNS) and sacral neuromodulation (SNS).14 
The Food and Drug Administration (FDA) first gave BTX initial approval for use in 1989. 
BTX, however, was first described for use in the urinary bladder by Stohrer and colleagues 
in 1999.15 It was FDA approved for use in neurogenic detrusor overactivity in 2011 and 
refractory idiopathic detrusor overactivity or overactive bladder in 2013. Since 1999 many 
studies have looked at the delivery and dosage of this neurotoxin into the bladder for OAB.  
In the beginning, patients were receiving BTX through as many as fifty injection sites, but 
after many studies confirmed similar efficacy, it is now common practice to inject BTX 
through ten injection sites.16-19 Similarly, studies have looked at the appropriate dosage of 
BTX for OAB; the results of these studies have indicated 100 units(U) as the best dose for 
non-neurogenic patients with OAB.20-22 
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020

3
BTX has transitioned over the years from a procedure conducted in the operating room to 
one that is commonly done in the clinic or physician office. Consequently, there has been 
continuing interest in reducing the number of injection sites further to make the technique 
more tolerable and more efficient. Preclinical studies in rats have shown similar effects of 
BTX between four and eight injection sites.23  Additionally, Avallone et al recently published 
a pilot study which evaluated the use of one, two and three total injection sites (one for each 
100 U).  Their population included idiopathic detrusor overactivity (IDO) as well as 
neurogenic detrusor overactivity (NDO) patients. They found administering BTX via one to 
three sites had similar clinical efficacy and rates of adverse events compared to the 
established protocol for the respective groups.24 
Due to these findings, we propose a randomized study where refractory OAB patients 
receive 100 U of BTX over either 3 or 10 injection sites.  We will maintain the currently 
accepted dilution standard for BTX as there have not been studies specifically researching 
this factor yet.  BTX will be reconstituted at a concentration of 10 U per 1 cc; 100 U will be 
reconstituted with 10 cc of injectable saline.  
We have chosen three sites over one injection site specifically because an MRI study 
completed by Mehnert et al25 reported, on average, 17.6% of injected BTX was found at the 
middle or lateral aspects outside of the bladder dome. There was, however, one patient who 
had contrast beyond the bladder base. Of note, this study had two arms: a 30-site group and 
a 10-site group with three neurogenic detrusor overactivity patients in each. The 30-site 
group had 300 U of BTX diluted in 27 cc of injectable saline plus 3 cc of gadopentetate (MRI 
contrast agent) while the 10-site group had 300 U of BTX diluted in 9 cc of injectable saline 
plus 1 cc of gadopentetate.  Despite nearly 20% of the injected BTX being found outside of 
the bladder, coverage of the detrusor muscle itself was not significantly different between 
the two groups; at about 30% detrusor coverage, this was found to be sufficient enough to 
report similar success rates as reported in the literature.25  Due to the findings in this study 
that 20% of the injection can be found outside of the bladder, we decided against a single 
injection and opted for three injection sites.
OAB is a prevalent condition affecting up to one of every 6 adults.4  BTX is a well-
established third line therapy for refractory OAB.  Decreasing the number of injection sites 
may improve patient tolerability and satisfaction with this office-based procedure and 
potentially reduce the rates of adverse events (AEs) including hematuria and urinary tract 
infection (UTI).   
Although a pilot study has been published regarding injection sites as few as one for 100 U 
of BTX, there has not been a randomized study comparing fewer injections sites to what is 
commonly practiced (ten injection sites).  We hypothesize that a 3-site injection method is as 
effective as 10-site method and will lead to higher patient satisfaction.
III.
Objectives and Endpoints
The primary aim of this study is to determine whether distributing 100 U of 
onabotulinumtoxinA over less injection sites (three) is just as effective as common practice 
(ten). 
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020

4
Our secondary aim is to assess whether less injection sites has fewer complications (UTI/ 
hematuria) and leads to better patient satisfaction and tolerability as this procedure is done 
in the office while the patient is awake.  
We hypothesize that a 3-site injection method is as effective as a 10-site method and will 
lead to higher patient satisfaction. The primary outcome will be incontinence episodes per 
day assessed at 3 months after BTX injection. Secondary outcomes will include voiding 
symptom scores and voiding diary parameters as measured by the Overactive Bladder 
Questionnaire-Short Form (OABq-SF), International Consultation on Incontinence 
Questionnaire-Short Form (ICIQ-SF), Global Response Assessment (GRA), Visual Analog 
Scale (VAS) on the day of injection to assess for pain, satisfaction, and tolerability, and 3-
day voiding diaries to be completed throughout the study. 
IV.
Methodology
Although a pilot study has been published regarding injection sites as few as one for 100 U 
of BTX, there has not been a randomized study comparing fewer injections sites to what is 
commonly practiced (ten injection sites). 
Patients diagnosed with OAB and that have failed first and second line treatments will be              
presented with all third line therapies including BTX, SNS, and PTNS. Patients choosing 
BTX    will be offered an opportunity to enroll in this study.  If patients are already clinical 
responders and currently receiving BTX therapy, they are eligible for randomization if they 
choose to participate in the study.  If they had prior BTX and were clinical non-responders 
they will not be eligible. Clinical non-responders are patients who previously reported no 
subjective improvement in their symptoms by 3 months after their injection. If a patient was 
an initial responder (with subjective improvement reported by the patient), and the effect has 
since worn off, the earliest they can receive re-injection will be 3 months after their initial 
injection. All repeat injections will be done at with a minimum of 3 months in between 
injections.
Consent to send out pre-screening activities may be done by telephone script with all 
elements of information sheet included. Participant agreement is consent to send pre-
screening activities. Once the participant is present for enrollment visit, a formal consent will 
be performed for study participation. Informed consent will be obtained from all patients prior 
to conducting any study activities.  Consented patients will complete the OAB-q SF, ICIQ-SF, 
3-day voiding diary and enrollment questionnaire (demographics, medical history, 
concomitant medications, etc.) prior to study enrollment.  A urinalysis (UA) will be collected at 
this visit as well and a urine culture (UCx) will be performed, if necessary. If the patient meets 
the eligibility criteria, they will be randomized (1:1) into the 3-injection site group or the 10-
injection site group.  We plan on performing a stratified randomization so the number of BTX 
naïve and previous BTX responder patients will be equivalent in both arms in order to 
minimize selection bias.  Patients will be blinded to the number of injections they will receive.  
Adverse events and concomitant medications will be assessed at each follow-up visit.  A 
diary will also be completed, collected and reviewed at each follow-up visit. GRA will also be 
gathered at each follow up visit.  Visual Analog Scores will be gathered at the end of the 
injection visit to assess for patient satisfaction, pain, and tolerability.  
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020

5
Patients will be asked to remain off any oral anticholinergic or beta-3 agonist medications, 
PTNS therapy, or any neuromodulation throughout the entirety of the study.
Patients will follow up two weeks post-injection (±7days) for an office visit. OAB-q SF, GRA, 
ICIQ-SF, 3-day voiding diary, UA and post void residual (PVR) will be collected. If necessary, 
a UCx will be ordered for evaluation. 
At 3, 6, 9, and 12 months post-injection (± 14 days), patients will return for follow-up 
appointments. OAB-q SF, GRA, ICIQ-SF, patient satisfaction, 3-day voiding diary, and UA 
will be collected. If necessary, a UCx will be ordered for evaluation.  We will also assess for 
adverse events and concomitant medications at each of these visits. Specific adverse events 
we will be tracking include urinary retention (inability to void), elevated PVR of greater than 
300 cc, UTI, excessive bleeding at injection sites that requires cautery, and systemic BTX 
effects (systemic weakness). If at any visit the patient is found to have a UTI, they will be 
prompted to repeat that visits questionnaires and 3-day diary at an unscheduled visit once 
the prescribed UTI treatment has been completed. At the unscheduled visit AEs will be 
reviewed and a clinical decision will be made by an investigator if UTI symptoms are still 
present after treatment completion. The unscheduled visit will occur at the urology research 
clinic. 
If a repeat botox injection is given at the 3, 6, or 9 month visit, the subject will have a 2 week 
follow up visit identical to visit 3 in the schedule of events before continuing to be followed 
every 3 months.
While in-person visits are preferable, if the patient is unwilling or unable to attend a study visit 
(specifically visits 4-7) they will not be withdrawn from the study. In order to assess patient 
safety and provide continuing follow-up, the patient may be contacted by phone and/or mail. If 
necessary, study information may be collected by either or both of these methods; phone 
(current medications, AE assessment) and/or mail (questionnaires, voiding diary). If a patient 
requires a remote visit, they may complete at least one, but not all visits remotely. 
Schedule of Research Activities
Consent 
and 
Screening
Enrollment 
and 
Treatment
2 Weeks 
Post-BTX 
Visit
(±7 days) 
3 Months 
Post-BTX 
Visitd
(± 14 days) 
6 Months  
Post-BTX 
Visitd 
(± 14 days)
9 Months 
Post-BTX 
Visitd 
(± 14 days) 
12 Months 
Post-BTX 
Visit 
(± 14 days)
Visit 1
Visit 2 
Visit 3 
Visit 4
Visit 5
Visit 6
Visit 7
Consent
X
Eligibility
X
Demographics, 
Medical History
X
OABq-SF
ICIQ-SF
X
X
X
X
X
X
3-day Voiding 
Diary
X
X
X
X
X
X
Urinalysis, 
Urine Culture 
as needed
X
X
X
X
X
X
X
Pregnancy test 
before injection 
as neededa 
X
X
X
X
X
Post void 
residual (PVR)b
X
BTX injection
X
Repeat BTX 
X
X
X
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020

6
Injectionc
GRA
X
X
X
X
X
VAS
X
Xe
Xe
Xe
Concomitant 
Medications
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
a If the patient has the potential to be pregnant (ie. pre-menopausal and/or no surgical history of hysterectomy/oophorectomy), 
a pregnancy test will be checked prior to all BTX injections.
b If the PVR is elevated at 2 week follow-up appointment, additional follow up for management of elevated PVR will be at the 
discretion of the provider (see below for definition and additional detail).
c Repeat injections will be offered at the clinician’s discretion.  Patients will be eligible for repeat injections 3 months after initial 
injection.  Patients will be allowed to undergo repeat injections at a minimum of a 3 month interval. Injection will not be offered 
at the 12 month visit as this is the final study visit.
d If a patient is re-injected with Botox they will have a 2 week follow-up visit during which, time, the same activities as shown in 
visit 3 will be conducted.
e If patients request a repeat BTX injection, a VAS questionnaire will be performed post injection.
Injection Procedure
The injection procedure consists of injections of 100 U for IDO at 3 or 10 injection sites. The 
BTX will be reconstituted at a concentration of 10 U per 1 cc as is common practice. For 
example, a 100 U dose will be diluted with 10 cc of injectable saline.  The diagram below 
shows the injection sites at the bladder base (just beyond the trigone). The procedure 
requires local lidocaine anesthesia only. 
Figure 1.  3- and 10- site cystoscopic injection locations are outlined in the bladder.
Pre- and post-procedure antibiotics will be given at the discretion of the provider.  After a 
negative urine analysis or if a patient has a positive dipstick (positive leukocyte esterase 
3-site injection 
Additional 7 sites for 10-
site injection
Dome of the bladder
Injection sites
Ureteral orifices
Trigone
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020

7
and/or positive nitrites and/or positive blood) but is asymptomatic for a UTI, will proceed with 
Botox injections at the clinicians discretion. The patient’s urethra will be prepped with 
betadine and 50 ml of 1% liquid lidocaine plain will be instilled, via catheter, into the patient’s 
bladder and left for 10 minutes. 
A flexible cystoscope will be used for the in-office procedure.  This will be sterilized per 
standard office procedure between uses.  A one-time use, Laborie injeTAK, 23-gauge 
cystoscopic injection needle will be utilized as this is the needle used in both practices.  The 
needle is retractable and can be adjusted to 0, 2, 3, 4, and 5 mm lengths.  The needle will 
be extended out to 3 mm.  Bladder wall thickness is dependent on the condition of the 
patient’s bladder as well as degree of distention. Based on the literature, average bladder 
wall thickness on ultrasound of patients with OAB ranges from 4 to 6 mm.26 This can of 
course vary with degree of distention. Based on these findings, and in conjunction with 
previously mentioned MRI findings of nearly 20% extravasation using a 4 mm needle 
depth25, we opted for a 3 mm needle depth.  
Additionally, a recent meta-analysis showed no difference in efficacy or safety according to 
depth of injection (suburothelial vs. intradetrusor).27 Based on these findings, we will leave it 
up to the surgeon to decide between suburothelial or intradetrusor injections.  This data, 
however, will be collected for analysis at the end of the study.  
The patient will receive BTX injections according to the group to which they have been 
randomized. If the patient has been randomized into the 3 injection group, they will receive 
an additional 7 “sham injections” with the needle retracted (no break in the mucosa). We 
decided on this as a sham treatment instead of actually puncturing the mucosa without 
injecting BTX because the point of our study is also to assess patient satisfaction and 
tolerability as well as rates of adverse events (ie hematuria and UTI). In order to do this, we 
want to puncture the mucosa less (3 vs 10).  For the 3 injection group, every 3rd injection will 
be an actual mucosal penetration and injection (for 3 total injections containing BTX) in 
order to keep the patient blinded as best as possible. The 3 BTX injections will still be 
placed in the location as outlined in the diagram (Figure 1). The other 7 injection’s will be 
verbally emphasized by the clinician but will not have mucosal penetration with the needle.  
It has been our experience that patients have variable sensation with needle penetration, 
sometimes no or minimal sensation to a clear sensation of a needle poke.  The provider will 
verbalize the injection number to the patient whether it is a true injection or not in order to 
keep a believable pace.  All patients will be told “This is injection #1.  This is injection #2.  
This is injection #3.” and so forth.  Care will also be taken to prevent the patient from seeing 
the syringe so they cannot guess the arm of the study to which they were randomized.  All 
patients will think they are receiving ten injections. Post-injection, the patient will be 
evaluated for hemostasis.  Cautery will be used if deemed necessary by the physician.  If 
hemostasis is achieved, this will conclude the visit.  
If at the 2 week follow-up the patient has an elevated post-void residual (PVR)  <350cc and 
is symptomatic or if the patient has a PVR > 350 cc and is non-symptomatic, the patient may 
be placed on either clean intermittent catheterization (CIC), one time straight catheter with 
close follow-up or indwelling foley catheter.  Management for elevated post void residual 
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020

8
(PVR) will be at the discretion of the provider. If the patient is a clinical non-responder by 3 
months follow-up, subsequent management will be at the clinician’s discretion. These 
patients will be followed, and data will be collected.  We plan on conducting an intent to treat 
analysis which will identify any subject not assessed at 3 months after the first BTX injection 
as a treatment failure.  However, patients who are clinical responders by 3 months and have 
return of symptoms will be eligible for retreatment. If patients undergo re-treatment, they will 
continue to receive the same number of injections they originally received.  In other words, if 
they were originally randomized into the 3 injection arm, they will receive 3 injections at 
retreatment. 
After any retreatment, patients will have a 2 Week Follow-up visit before continuing to be 
followed every 3 months. Findings of an elevated PVR will be addressed as stated above. 
If the patient had systemic BTX effects the patient will not be offered repeat injections.  If 
they have hematuria, UTI(s), or temporary urinary retention, they can be offered retreatment 
at the patient and clinician’s discretion. 
V.
Risks and Benefits
Possible Risks of OnabotulinumtoxinA:
Side effects and discomforts that have been observed in patients who have received 
treatment with this study medication for their OAB symptoms include:
Most Frequent (occurring more than 10% of the time):

weakness of the bladder muscle resulting in difficulty in urination or an inability to urinate 
or empty the bladder (urinary retention) for an extended period (less than a month in 
most cases, but could be longer)
Less Frequent (occurring from 1% to 10% of the time):

constipation
Rare (occurring less than 1% of the time):

generalized weakness
Possible Risks of Injection Procedure:
As with any injection, patients may experience local pain/soreness, bleeding, bruising, 
infection, and/or swelling.  Some people feel faint or pass-out when being injected with 
medications. 
The following side effects have been observed in patients who have received treatment with 
this study medication for their OAB symptoms:
Most Frequent (occurring more than 10% of the time):

urinary tract infection
Less Frequent (occurring from 1% to 10% of the time):

blood in the urine

difficulty or painful urination
Rare (occurring less than 1% of the time)
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020

9

temporary bleeding at the injection site resulting in a blood clot in the bladder tissue

urosepsis (an infection that occurs when urinary tract infection spreads to the 
bloodstream)
The following side effects have not been observed previously with study medication 
injections but could possibly happen:
Less Frequent (occurring from 1% to 10% of the time):

permanent tissue damage from repeated injections

accidental bladder wall puncture resulting in onabotulinumtoxinA introduction into 
abdominal space or near-by structures

injury from the cystoscope resulting in temporary urethral swelling, urethral injury, 
blockage of urine flow, or overstretching of the bladder

increased blood pressure

headache

decreased heart rate
Rare (occurring less than 1% of the time):

local pain/soreness

bleeding

bruising

infection

swelling

feeling faint or passing out when being injected
Possible Risks of Cystoscopy
Less Frequent (occurring more than 1% but less than 10% of the time):

discomfort or pain

cramps

infection

painful or difficult urination
Rare (occurring less than 1% of the time):

bleeding (blood in urine)

inability to pass urine after the procedure

trauma

urinary tract infection

puncture of the bladder

temporary swelling or injury to the urethra

overstretching of the bladder

a change in urinary frequency

urgency in urination, including urgency resulting in episodes of urge incontinence
Risks of Antibiotic (Medicine to Prevent Infection)
Less Frequent (occurring more than 1% but less than 10% of the time):

Diarrhea
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020

10

Nausea and vomiting

Stomach cramping
Rare (occurring less than 1% of the time):

Headache

Itching 

Rash

Allergic reaction
There may be no direct benefit in taking part in this study. Symptoms of OAB may improve, 
but this cannot be guaranteed. Information gained from the results of this study may be of 
benefit to others in the future, with a similar medical condition. 
VI.
 Eligibility Criteria
 Inclusion criteria:
-
Women and men > 18 years of age
-
Self-reported failed conservative care of behavioral modifications and/or oral 
medications for the treatment of OAB
-
Average urinary frequency of > 8 voids per day as recorded on initial 3-day voiding 
diary
-
Self-reported bladder symptoms > 3 months
-
Discontinued antimuscarinics/beta-3 agonists for > 2 weeks prior to study enrollment. 
May restart antimuscarinics/beta-3 agonists if indicated > 6 weeks after Botox 
injections.
-
Previous onabotulinumA injection at least three months prior to study enrollment
-
Capable of giving informed consent
-
Capable and willing to follow all study-related procedures
Exclusion criteria:
-
Pregnant or planning to become pregnant during study duration
-
Diagnosis of neurogenic bladder with the exception of highly functioning stroke 
patients.
-
If a patient has had a previous neuromodulation device placed, it will have to be 
turned off for 2 weeks for a washout period prior to enrollment and remain off 
throughout the study
-
Previous non-responders to BTX therapy
-
Known hypersensitivity to onabotulinumtoxinA
-
Previous infection at onabotulinumtoxinA injection site
-
Patient cannot be receiving PTNS therapy. If patient is receiving PTNS, they need to 
stop for 1 month prior to entering the study.
-
Refusal to self-catheterize or have indwelling catheter in the event of urinary 
retention
-
Use of investigational drug/device therapy within past 4 weeks
-
Participation in any clinical investigation involving or impacting gynecologic, urinary 
or renal function within past 4 weeks
-
Current or past history of any physical condition that, in the investigator’s opinion, 
might put the subject at risk or interfere with study results interpretation 
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020

11
-
Pelvic radiation treatment
VII.       Data Analysis
Statistical Analysis       
Primary Effectiveness
The primary efficacy endpoint is defined as at least a 50% reduction in number of urgency 
related incontinence episodes at 3 months. The number of urgency incontinent episodes per 
day is measured as the average of two, 3-day, consecutive bladder diaries. Patients shall be 
classified as treatment successes or treatment failures based on this criterion. 
The primary hypothesis is that the proportion of patients who are treatment successes with 
BTX-3 is non-inferior with a margin of 15% to that with BTX-10 at 3 months.
Ho:  pBTX-3  ≤  pBTX-10 – 0.15 vs            Ha: pBTX-3  >  pBTX-10 – 0.15
In the hypothesis equations, 0.15 is the clinical equivalence margin for the non-inferiority test of 
this hypothesis. 
Sample Size and Power Calculation  
One hundred seventy-eight (178 patients will be randomized in this study, 89 per group to 
achieve 80% power to detect a non-inferiority margin difference between the group proportions 
of 0.15. The reference group (BTX-10) proportion is 0.85. The treatment group proportion (BTX-
3) is assumed to be larger than 0.70 under the null hypothesis of inferiority. The power was 
computed for the case when the actual treatment group proportion is 0.85, that is both BTX-10 
and BTX-3 had the same response rate of 0.85. The test statistic used is the one-sided Z test 
with a Type I error rate of 0.025.
Table Non Inferiority Sample size; Margin of 0.15 and expected delta=0
Power
N1
N2
N
Reference (BTX-10) 
Responder Rate
BTX-3
Responder  Rate|H0
BTX-3 Responder  
Rate|Ha
0.8
147
147
294
0.7
0.55
0.7
0.85
168
168
336
0.7
0.55
0.7
0.9
197
197
394
0.7
0.55
0.7
0.8
131
131
262
0.75
0.6
0.75
0.85
150
150
300
0.75
0.6
0.75
0.9
176
176
352
0.75
0.6
0.75
0.8
112
112
224
0.8
0.65
0.8
0.85
128
128
256
0.8
0.65
0.8
0.9
150
150
300
0.8
0.65
0.8
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020

12
Table Non Inferiority Sample size; Margin of 0.15 and expected delta=0
Power
N1
N2
N
Reference (BTX-10) 
Responder Rate
BTX-3
Responder  Rate|H0
BTX-3 Responder  
Rate|Ha
0.8
89
89
178
0.85
0.7
0.85
0.85
102
102
204
0.85
0.7
0.85
0.9
120
120
240
0.85
0.7
0.85
0.8
63
63
126
0.9
0.75
0.9
0.85
72
72
144
0.9
0.75
0.9
0.9
85
85
170
0.9
0.75
0.9
At 3 months, the percentage of patients who are successfully treated will be computed for each 
treatment group. Patients who exit the study early citing reasons of inadequate urge or 
incontinence reduction will be included in this analysis as treatment failures. Treatment-failure 
patients are otherwise known as non-responders. 
The success rate in the BTX-3 group will be compared to that in the BTX-10 group using a non-
inferiority at α = 0.025 and δ =.15 as shown earlier in this protocol.  
Data analyses
A biostatistician will perform all statistical analyses using SAS or similar statistical software. 
Descriptive statistics will be calculated. A completer analysis will be conducted for those who 
finish the study per protocol. The primary endpoint will be assessed comparing incontinence 
episodes per day at 3 months after BTX injection. This comparison will also be made for all 
other visits using t-tests or chi-square tests, as appropriate.
Secondary endpoints will include adverse events and comparisons between 3-site and 10-site 
groups looking at the GRA responses between 3-site and 10-site groups at 3 months (± 14 
days) post injection, 3-day voiding diary and OABq-SF and ICIQ-SF at 3 months (± 14 days) 
post-injection. We will also compare post-injection VAS scores to assess for tolerability, 
satisfaction, and pain. Changes from baseline will also be analyzed. This comparison will also 
be made for all other visits using appropriate statistical tests.
In addition to a completer analysis, we also plan on conducting an intent to treat analyses which 
will identify any subject not assessed at 3 months after the first BTX injection as a treatment 
failure. In order to assess for all possible situations, 4 different scenarios will be run: 1) All 
dropouts will be considered non-responders for both groups 2) All dropouts will be considered 
responders for both groups, 3) Dropouts in the BTX 10 group will be considered responders and 
those in the BTX 3 group, non-responders, and 4) Dropouts in the BTX 10 group will be 
considered non-responders while those in the BTX 3 group, responders.
VIII.    Data Safety Monitoring Plan
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020

13
Ongoing safety monitoring will be performed by the study staff, including the Principal 
Investigator (PI) and co-investigators. The PI will have ultimate responsibility of assuring 
patient safety. Safety issues will also be addressed in the annual reports to Beaumont’s 
Investigational Review Board (IRB).
Additional data safety monitoring procedures include:

Research Administration’s Clinical Research Quality and Process Improvement 
Program (CRQIP) will perform in-house monitoring of the first patient enrolled after 
the completion of visit 1

An audit of the study records after the first 10 patients are enrolled and at the half 
way point of enrollment by Urology Research Nurse that is not directly involved with 
the research study.  This will be done to ensure the safety of patients and lack of 
significant adverse effects. Additional auditing may occur, as needed.

Throughout the study all adverse effects will be reported to the research nurse and 
then to the PI at the time of the event. Adverse events, serious adverse events, and 
unanticipated problems not listed in the risks section of this protocol will be reported 
per IRB guidelines.
Once 25 patients have been randomized to each arm, we will assess the efficacy/futility of BTX 
injections based on the 3-month follow-up visit data.
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020

14
IX.   References
1.
Wang Y, Xu K, Hu H, et al. Prevalence, risk factors, and impact on health related quality 
of life of overactive bladder in China. Neurourol Urodyn 2011; 30: 1448-1455. 2011/08/08. DOI: 
10.1002/nau.21072.
2.
Milsom I, Abrams P, Cardozo L, et al. How widespread are the symptoms of an 
overactive bladder and how are they managed? A population-based prevalence study. BJU Int 
2001; 87: 760-766.
3.
Irwin DE, Milsom I, Hunskaar S, et al. Population-based survey of urinary incontinence, 
overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC 
study. Eur Urol 2006; 50: 1306-1314; discussion 1314-1305. 2006/10/20. DOI: 
10.1016/j.eururo.2006.09.019.
4.
Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive 
bladder in the United States. World J Urol 2003; 20: 327-336. 2003/06/18. DOI: 
10.1007/s00345-002-0301-4.
5.
Coyne KS, Sexton CC, Irwin DE, et al. The impact of overactive bladder, incontinence 
and other lower urinary tract symptoms on quality of life, work productivity, sexuality and 
emotional well-being in men and women: results from the EPIC study. BJU Int 2008; 101: 1388-
1395. DOI: 10.1111/j.1464-410X.2008.07601.x.
6.
Bartoli S, Aguzzi G and Tarricone R. Impact on quality of life of urinary incontinence and 
overactive bladder: a systematic literature review. Urology 2010; 75: 491-500. 2009/12/04. DOI: 
10.1016/j.urology.2009.07.1325.
7.
Coyne KS, Kvasz M, Ireland AM, et al. Urinary incontinence and its relationship to 
mental health and health-related quality of life in men and women in Sweden, the United 
Kingdom, and the United States. Eur Urol 2012; 61: 88-95. 2011/07/26. DOI: 
10.1016/j.eururo.2011.07.049.
8.
Zorn BH, Montgomery H, Pieper K, et al. Urinary incontinence and depression. J Urol 
1999; 162: 82-84. DOI: 10.1097/00005392-199907000-00020.
9.
Dmochowski RR and Newman DK. Impact of overactive bladder on women in the United 
States: results of a national survey. Curr Med Res Opin 2007; 23: 65-76. DOI: 
10.1185/030079907X159533.
10.
Chancellor MB, Migliaccio-Walle K, Bramley TJ, et al. Long-term patterns of use and 
treatment failure with anticholinergic agents for overactive bladder. Clin Ther 2013; 35: 1744-
1751. 2013/10/03. DOI: 10.1016/j.clinthera.2013.08.017.
11.
Shaya FT, Blume S, Gu A, et al. Persistence with overactive bladder pharmacotherapy 
in a Medicaid population. Am J Manag Care 2005; 11: S121-129.
12.
Yu YF, Nichol MB, Yu AP, et al. Persistence and adherence of medications for chronic 
overactive bladder/urinary incontinence in the california medicaid program. Value Health 2005; 
8: 495-505. DOI: 10.1111/j.1524-4733.2005.00041.x.
13.
Wagg AS, Foley S, Peters J, et al. Persistence and adherence with mirabegron vs 
antimuscarinics in overactive bladder: Retrospective analysis of a UK General Practice 
prescription database. Int J Clin Pract 2017 2017/09/14. DOI: 10.1111/ijcp.12996.
14.
Gormley EA, Lightner DJ, Faraday M, et al. Diagnosis and treatment of overactive 
bladder (non-neurogenic) in adults: AUA/SUFU guideline amendment. J Urol 2015; 193: 1572-
1580. 2015/01/23. DOI: 10.1016/j.juro.2015.01.087.
15.
Stohrer M, Schurch B, Kramer G, et al. Botulinum A-toxin in the treatment of detrusor 
hyperreflexia in spinal cord injured patients: A new alternative to medical and surgical 
procedures? Neurouorlogy and Urodynamics, 1999, p. 401.
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020

15
16.
Nitti VW. Botulinum toxin for the treatment of idiopathic and neurogenic overactive 
bladder: state of the art. Rev Urol 2006; 8: 198-208.
17.
Schulte-Baukloh H, Michael T, Stürzebecher B, et al. Botulinum-a toxin detrusor injection 
as a novel approach in the treatment of bladder spasticity in children with neurogenic bladder. 
Eur Urol 2003; 44: 139-143.
18.
Smith CP and Chancellor MB. Simplified bladder botulinum-toxin delivery technique 
using flexible cystoscope and 10 sites of injection. J Endourol 2005; 19: 880-882. DOI: 
10.1089/end.2005.19.880.
19.
Liao CH, Chen SF and 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: 717-723. 2015/04/24. 
DOI: 10.1002/nau.22780.
20.
Dmochowski R, Chapple C, Nitti VW, et al. Efficacy and safety of onabotulinumtoxinA for 
idiopathic overactive bladder: a double-blind, placebo controlled, randomized, dose ranging trial. 
J Urol 2010; 184: 2416-2422. 2010/10/16. DOI: 10.1016/j.juro.2010.08.021.
21.
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 2017; 197: S216-S223. 2016/12/22. DOI: 
10.1016/j.juro.2016.10.109.
22.
Schmid DM, Sauermann P, Werner M, et al. Experience with 100 cases treated with 
botulinum-A toxin injections in the detrusor muscle for idiopathic overactive bladder syndrome 
refractory to anticholinergics. J Urol 2006; 176: 177-185. DOI: 10.1016/S0022-5347(06)00590-
8.
23.
Huynh Le Maux A, Pignol B, Behr-Roussel D, et al. Does Reduction of Number of 
Intradetrusor Injection Sites of aboBoNTA (Dysport®) Impact Efficacy and Safety in a Rat Model 
of Neurogenic Detrusor Overactivity? Toxins (Basel) 2015; 7: 5462-5471. 2015/12/17. DOI: 
10.3390/toxins7124896.
24.
Avallone MA, Sack BS, El-Arabi A, et al. 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: 1104-1107. 2016/06/10. DOI: 
10.1002/nau.23052.
25.
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. 2009/01/15. DOI: 10.1007/s00345-008-0362-0.
26.
Oelke M, Khullar V and Wijkstra H. Review on ultrasound measurement of bladder or 
detrusor wall thickness in women: techniques, diagnostic utility, and use in clinical trials. World J 
Urol 2013; 31: 1093-1104. 2013/02/06. DOI: 10.1007/s00345-013-1030-6.
27.
Jo JK, Kim KN, Kim DW, et al. The effect of onabotulinumtoxinA according to site of 
injection in patients with overactive bladder: a systematic review and meta-analysis. World J 
Urol 2017 2017/11/09. DOI: 10.1007/s00345-017-2121-6.
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020