Conditions: Overactive Bladder Overactive Bladder Syndrome Urinary Urgency Urinary Incontinence Urinary Frequency/Urgency Urinary Bladder, Overactive
Keywords: OnabotulinumtoxinA Bladder Injections
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 6
Healthy volunteers: no

Brief summary:
Patients with overactive bladder (OAB) will be randomly assigned (like a flip of a coin) to receive 100 units of onabotulinumtoxinA injected into the bladder at either 3 sites or 10 sites. Patient satisfaction and the effectiveness of the medication will be evaluated.

Detailed description:
Overactive bladder (OAB) is a common condition which often has a negative impact on health related quality of life. Primary and secondary treatments include behavior modification, pelvic floor physical therapy, and OAB medications. OnabotulinumtoxinA (BTX) is a well-established third line therapy for refractory OAB.

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. While ten injection sites is commonly practiced, there has been continuing interest in reducing the number of injection sites to make the technique more tolerable and more efficient.

In this study, refractory OAB patients will be randomized to receive 100 units of BTX over 3 or 10 injection sites. The investigators hypothesize that 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 including hematuria and urinary tract infection.

Arms:
arm 1: OnabotulinumtoxinA 100Unit injection into 3 sites throughout the bladder arm 2: OnabotulinumtoxinA 100Unit injection into 10 sites throughout the bladder

Interventions: intervention 1: OnabotulinumtoxinA 100Unit Injection
Intervention descriptions: intervention 1: Initial treatment with the option of repeat injections every 3 months

Protocol document:
ICF_001.pdf: 
IRB # 2018-119                                                                                                                                        Page 1 of 10 
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CONSENT FORM AND AUTHORIZATION FOR DISCLOSURE OF
PROTECTED HEALTH INFORMATION
 
STUDY TITLE: IS LESS MORE? DOES DECREASING ONABOTULINUMTOXINA SITES 
IN THE BLADDER INCREASE PATIENT SATISFACTION WHILE MAINTAINING 
EFFICACY?
Principal Investigator: Larry Sirls, M.D.
Address: 3535 West 13 Mile Road
                Royal Oak, MI 48073
Research Locations: 
William Beaumont Hospital - Royal Oak & Comprehensive Urology – Royal Oak
INTRODUCTION 
Why is this study being done?
You are being asked to participate in a research study.  The purpose of research is to look at 
the nature of disease and try to develop improved methods to diagnose and treat disease. The 
doctor or clinician in charge of the study believes you meet the initial requirements to take 
part in the study.  Before agreeing to participate, it is important for you to read and 
understand the following explanation of the research procedures.  This Consent and 
Authorization form describes the purpose, procedures, benefits, risks and discomforts of the 
study.  It also describes the alternatives available to you, and your right to withdraw (quit) 
from the study at any time.  
Please read this information carefully and ask as many questions as you like before deciding 
whether or not you would like to take part in this research study.
Overactive bladder (OAB) causes the sudden need to urinate. It has a negative impact on 
health-related quality of life. In the body, certain chemicals travel from nerve cells to muscle 
cells to make the bladder contract so that you can urinate. With OAB, these muscles contract 
uncontrollably and you frequently feel like you must empty your bladder. OnabotulinumtoxinA 
injected into the bladder works on the nerves and bladder muscle, blocking the signals that 
trigger OAB. 
The goal of this study is to determine if three injection sites of onabotulinumtoxinA is just as 
effective as the common practice of ten injection sites. This study is also being done to 
determine if less injection sites has fewer complications and leads to better patient satisfaction 
and tolerability, because this procedure is performed in the doctor’s office while you are 
awake.
A total of 192 patients will take part in this study at Beaumont.
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/21/2020
IRB EXPIRATION DATE: 02/20/2021


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How long will I be in the study?
If you decide to take part in this study, your participation is expected to last up to 12 months. 
You may not take part in this study if you are currently enrolled in another related research 
study which could alter or influence the study results.
DESCRIPTION OF THE STUDY
What will happen if I take part in the research study?
You are being asked to take part in this research study because you have been diagnosed with 
overactive bladder and your doctor has recommended onabotulinumtoxinA injections as a 
treatment.
If you agree to take part in this study you will be randomly assigned to the three-injection 
group or the ten-injection group. Randomization is like “the flip of a coin.”  The study team will 
know which group you are in, but you will not. This is called “blinding.” Blinding is done to 
ensure that the results are not affected by a placebo effect (the power of suggestion).
Screening Evaluation/Visit 1
The study will be explained to you in detail, and you will have as much time as you need to 
ask questions.  You will be asked to read and sign this Consent and Authorization form before 
any study-related procedures are performed.  The following tests and procedures will be done 
to determine if you qualify to participate in this study:

Review demographic information (birth date, gender etc.) 

Review of your medical and surgical history, review of medications you are currently 
taking and medications that you have taken in the past

Collection of urine samples for laboratory tests. These tests include:
o
A urine pregnancy test for all women of childbearing potential.  The result of the 
pregnancy test must be negative for you to participate in this study. 
o
Urinalysis and/or urine culture

Complete questionnaires about your urinary symptoms  

Receive a 3-day voiding (urination) diary to complete before Visit 2 – you will be 
instructed on how to complete the diary
Enrollment and Treatment/Visit 2 
You must bring the completed voiding (urination) diary with you to this visit. If you meet the 
eligibility criteria, you will be enrolled in the study and randomized into the three-injection 
group or the ten-injection group. If you do not meet the eligibility criteria, you will not be able 
to participate in this study.  The following assessment and procedures will be conducted:

Review of medications you are currently taking and medications that you have taken in 
the past

Evaluation of any new medical events that have occurred since your last visit

Collection of urine samples for laboratory tests. These tests include:
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/21/2020
IRB EXPIRATION DATE: 02/20/2021


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o
A urine pregnancy test for all women of childbearing potential.  The result of the 
pregnancy test must be negative for you to participate in this study and to 
receive onabotulinumtoxinA. 
o
Urinalysis and/or urine culture

The study doctor may order an antibiotic (medication to prevent urinary tract infection) 
to take by mouth before and after the procedure. 

Cystoscopy (a cystoscope is a long thin tube with a camera that the study doctor can 
see through).  The cystoscope is inserted through your urethra (tube that transmits 
urine from the bladder to the exterior of the body during urination) and into your 
bladder.  This procedure will allow your study doctor to see what your urethra and your 
bladder looks like.

Injection of onabotulinumtoxinA into your bladder. The doctor will use a needle to inject 
the medication into your bladder. You will be given local anesthesia (numbing medicine) 
to decrease the discomfort of the procedure.

Complete study questionnaire

Evaluation of any side effects

Receive a 3-day voiding (urination) diary to complete before Visit 3 – you will be 
instructed on how to complete the diary
2 Week Follow-up/Visit 3 through 12 Month Follow-up/Visit 7

Review any medications you are taking and any adverse events you may have 
experienced. 

Collection of urine sample for urinalysis and pregnancy (at visits 4, 5, 6, 7), if applicable

Post void residual (at visits 3 or 2 weeks after a repeat injection). 

Complete questionnaires about your urinary symptoms  

Receive a 3-day voiding (urination) diary to complete before your next visit – you will 
be instructed on how to complete the diary

Visit 4, 5, 6, and 7 may be conducted by phone and mail if necessary.
Unscheduled visits

Unscheduled visits may be necessary for repeating questionnaires and voiding diaries 
when a UTI is confirmed. 
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IRB APPROVAL DATE: 02/21/2020
IRB EXPIRATION DATE: 02/20/2021


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Below is a table describing what will occur at each study visit:  
Screening
Enrollment/
Treatment
2
Week 
Follow
-up
3 
Month 
Follow
-up
6 
Month 
Follow
-up
9 
Month 
Follow
-up
12 
Month 
Follow
-up
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Consent
x
Medical History
x
Questionnaires
x
x
x
x
x
x
x
3-Day Voiding 
Diary
x
x
x
x
x
x
Urine sample
x
x
x
x
x
x
x
BTX injection
x
Post void 
residual
x
Repeat BTX 
injection 
x
x
x
 Repeat injections will be offered at the clinician’s discretion. Participants will be eligible for repeat injections 3 month after 
initial injection.
Depending on your symptoms, you may request another injection at, or any time after, Visit 4 
(3 Month Follow-up). This will be discussed with your doctor. If you have a repeat injection 
you would then have a 2 Week Follow-up visit and follow the above schedule.
FDA Clinical Trial Information 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
PARTICIPANT RESPONSIBILITIES 
You will be asked to note any side effects or medical problems you may experience while you 
are taking part in this study.  For any illnesses or injuries, you should contact the study doctor 
immediately at the number listed in this Consent and Authorization form or in an emergency 
call 911 (or go to the nearest hospital emergency room).  
RISKS, SIDE EFFECTS AND DISCOMFORTS
Ask your doctor what the standard of care risks are as well as the study risks. In this study the 
risks listed below are the same risks if you are not participating in this study.
What side effects or risks can I expect from being in the study?
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IRB APPROVAL DATE: 02/21/2020
IRB EXPIRATION DATE: 02/20/2021


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Risks of onabotulinumtoxinA:
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). A catheter may need to be inserted into the 
bladder to drain all the urine.
Less frequent (occurring more than 1%, but less than 10% of the time) 

Constipation
Rare (occurring less than 1% of the time) 

Generalized weakness
Risks of the injection procedure:
As with any injection, participants may experience local pain/soreness, bleeding, bruising, 
infection, and/or swelling. Some people feel faint or pass-out when being injected with 
medications.
Most frequent (occurring more than 10% of the time)

Urinary tract infection
Less frequent (occurring more than 1%, but less than 10% of the time) 

Blood in the urine

Difficulty or painful urination
Rare (occurring less than 1% of the time)

Temporary bleeding at the injection site resulting in a blood clot in the bladder tissue

Urosepsis (an infection that occurs when the urinary tract infection spreads to the 
bloodstream)
The following side effects have not been observed previously with onabotulinumtoxinA 
injections but could possibly happen:
Less frequent (occurring more than 1%, but less than 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 (long thin tube with a camera that the study doctor can see 
through) 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
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/21/2020
IRB EXPIRATION DATE: 02/20/2021


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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 (the sudden urge to urinate), including urgency resulting in episodes of 
incontinence (the accidental leakage of urine)
Risks of Antibiotic (Medicine to Prevent Infection)
Less frequent (occurring more than 1% but less than 10% of the time):

Diarrhea

Nausea and vomiting

Stomach cramping
Rare (occurring less than 1% of the time):

Headache

Itching 

Rash

Allergic reaction
If you are required to stop taking a medication for overactive bladder you may experience an 
increase in your urinary symptoms (urinary urgency, frequency, and/or urge urinary 
incontinence).
There is a rare risk of breach of confidentiality (release of information which personally 
identifies you).  
Pregnancy Warning 
If you are a woman who is pregnant or becomes pregnant during the research study, there 
could be harmful effects to you or your unborn child. It is important you not be pregnant or 
breast-feeding during your study participation. If you are a woman of childbearing potential 
you must have a negative pregnancy test before entering the study.
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/21/2020
IRB EXPIRATION DATE: 02/20/2021


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BENEFITS
What are the benefits of taking part in this study?
There may be no direct benefit to you from taking part in this study. However, we hope to 
show that participants in the three-injection group have fewer complications, less pain, better 
tolerance of the procedure and greater patient satisfaction. Information gained from the 
results of this study may be of benefit to others in the future, with a similar medical condition. 
ALTERNATIVE OPTIONS
What are my choices other than taking part in this study?  
You do not have to take part in this study to receive treatment for your condition. 
Conservative adjustments you can make at home to help with the condition include avoidance 
of caffeine, carbonated beverages, and alcohol, which are known to be irritants to the bladder.
Alternative treatments that are available to treat overactive bladder include numerous oral 
medications that act by their effects on the nerves that supply the bladder. When taken on a 
regular basis, they may help to relieve symptoms of overactive bladder. These may cause side 
effects such as dry mouth and constipation.
Neuromodulation devices, which stimulate and regulate the nerves that supply the bladder, 
can also be utilized for treatment. This type of therapy can be provided in office based setting 
treatments or by surgically implanted devices that provide similar therapy. This may decrease 
urgency and frequency and help with urinary incontinence. Risks associated with this 
treatment include uncomfortable stimulation, migration of device leads, infection, and 
ineffective nerve stimulation.
ECONOMIC CONSIDERATIONS
What are the costs of taking part in this study?
All procedures are routine and you would have had them done even if you were not taking 
part in this study. They will be billed to your health insurance company and/or group health 
plans as usual (for example, urine laboratory tests (7), cystoscopy (1-5), and the 
onabotulinumtoxinA 100U vial (1-5).
If these routine care costs are not covered by your health insurance/group health plan, the 
cost will be your responsibility. 
COMPENSATION
What happens if I am injured because I took part in this study?
Your involvement in this study is voluntary. The possible risks and side effects which might 
occur during the course of the research study have been described in this Consent and 
Authorization form.
A research injury is any physical injury or illness caused by the medications, devices, or 
procedures required by the study which are administered, used, or performed appropriately.  
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/21/2020
IRB EXPIRATION DATE: 02/20/2021


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These medications, devices, or procedures are different from the medical treatment you would 
have received if you had not taken part in the study.
Should you experience a research injury, there are no designated funds provided for 
subsequent medical care or compensation by either the study doctor/clinician or Beaumont. 
What are my rights if I take part in this study?
You are not giving up any of your legal rights by signing this form.
CONFIDENTIALITY, DISCLOSURE AND USE OF YOUR INFORMATION
Will my medical information be kept private?
We will keep your personal health information as confidential as possible.  It is not likely your 
information will be given to others without your permission.  In order for this research study to 
take place, you must also authorize the researchers to access and use some of your protected 
health information (PHI). PHI is information which could identify you as an individual such as 
name, address, date of birth, etc. By signing this Consent and Authorization Form, you give 
Beaumont permission to use and/or disclose (release) your health information related to this 
research. Your medical and billing records collected for the purpose of the study will remain 
confidential, but may be disclosed (released) or used by the following and/or their 
representatives: 

The investigators (study doctor/clinician, research staff)

Beaumont and its’ parent, Beaumont Health and affiliated hospitals

The Food and Drug Administration

Other governmental regulatory agencies (domestic and/or foreign) 

Your health insurance company and/or group health plans and their intermediaries 
(companies contracted to process claims) may also have access to your medical and billing 
records of the study.
The purpose for this disclosure (release) or use is, for example, to assure compliance with the 
study protocol, to evaluate the effectiveness of the study, and/or to provide protection to you 
as a research study participant. The disclosure and use of your information will continue after 
your involvement in the study has ended. There is no expiration date for the use of your 
medical and billing records from the study. Any information about you disclosed to the parties 
identified above may be re-disclosed by them; however, such re-disclosure is not under the 
protections of this Consent and Authorization. 
You will not be identified in any publication or other release of study results, data, and other 
information (such as in professional writings, at professional meetings, and/or advertising or 
other promotional materials). 
If you decide to withdraw your authorization for the researchers to access and use your 
protected health information before the end of the study, you will be withdrawn from the 
research study. However, where the study relied on your Consent and Authorization for the 
time you participated in the study, your Consent and Authorization cannot be withdrawn and 
the information already collected may still be used and disclosed as you previously authorized. 
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/21/2020
IRB EXPIRATION DATE: 02/20/2021


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STOPPING STUDY PARTICIPATION
What if I decide to stop taking part in the study?
Taking part in this research study is completely voluntary. You may choose not to take part or 
to stop being in the study (withdraw) at any time without penalty or loss of benefits to which 
you are otherwise entitled, or without jeopardizing your medical care by your doctor at 
Beaumont. However, if you do not agree to sign this Consent and Authorization form, you will 
not be able to take part in this study. 
If you decide to withdraw from the study you will need to notify the study doctor/clinician of 
your decision to stop taking part in the study. Written notification is preferred. This notice may 
be sent to Larry T. Sirls, MD at William Beaumont Hospital, 3535 West 13 Mile Road, Suite 
438, Royal Oak, MI 48073. 
Your participation in this study may be stopped by the study doctor/clinician or study sponsor, 
without your consent, for any reason, which will be explained to you. Examples include:

The study procedures appear to be medically harmful to you. 

You fail to follow directions for participating in the study. 

It is discovered you do not meet the study requirements. 

The study is canceled. 

It is determined to be in your best interest (for example, your disease has progressed 
despite treatment).
If your study doctor/clinician stops your participation, or you decide not to continue, you may 
be asked to have a final study visit or examination, in order for you to be discontinued from 
the study in a safe and orderly manner. 
CONTACTS
Who can answer my questions about the study?
You may talk to the study doctor/clinicians about any questions or concerns regarding your 
study participation, or you think you may have suffered a research-related injury. The 
doctor/clinician in charge of the study, Larry Sirls, MD may be reached at: 248-336-0123 to 
answer your questions. 
Your contact person is Erica Zagaja, RN. You may contact her at (248) 551-0642. 
If you have questions regarding your rights as a research participant, or have problems, 
concerns, complaints, want information or would like to offer input, you may contact the 
Institutional Review Board Chairperson at (248) 551-0662.  The Institutional Review Board is 
charged with the oversight of all human participant research conducted at Beaumont facilities.
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/21/2020
IRB EXPIRATION DATE: 02/20/2021


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STATEMENT OF VOLUNTARY PARTICIPATION
I have read the above, have asked questions and have received answers about this study to 
my satisfaction. I understand what I have read and willingly give my consent to participate in 
IS LESS MORE? DOES DECREASING ONABOTULINUMTOXINA SITES IN THE 
BLADDER INCREASE PATIENT SATISFACTION WHILE MAINTAINING EFFICACY?
I understand I will receive a signed copy of this document and will be promptly informed of 
any new findings regarding this study.  I further authorize the use or disclosure of my health 
and personal information contained in records as described above. 
______________________________________
RESEARCH PARTICIPANT NAME (PLEASE PRINT)
      
______________________________________             _______________     ___________________
 RESEARCH PARTICIPANT SIGNATURE
DATE
TIME
ALTERNATIVE SIGNATURE (for use only when participant is a minor, cognitively impaired or critically ill)
AS THE PERSONAL/LEGAL REPRESENTATIVE OF THE STUDY PARTICIPANT, PLEASE PRINT PARTICIPANTS NAME ON THIS 
LINE_____________________________________, AND CHECK ONE OF THE BOXES BELOW AS THE BASIS FOR YOUR 
AUTHORITY TO SIGN THIS CONSENT AND AUTHORIZATION:
 COURT-APPOINTED GUARDIAN
          
 DURABLE POWER OF ATTORNEY                
 NEXT OF KIN
                       
*COURT LETTER IS REQUIRED
         *ATTORNEY LETTER MUST BE PRESENT & VERIFIED BY 2 PHYSICIANS
__________________________________                       ________________________________
NAME (PLEASE PRINT)
                                            RELATIONSHIP TO PARTICIPANT   
_____________________________________                     _____________           ____________
SIGNATURE        
      DATE                          TIME
 
 WITNESS TO ENTIRE CONSENT PROCESS AND SIGNATURE ARE REQUIRED IF THE PARTICIPANT IS VISUALLY 
IMPAIRED, ILLITERATE OR NON-ENGLISH SPEAKING ONLY
  
_______________________________________
WITNESS NAME (PLEASE PRINT)
_______________________
     ________________
       ____________
WITNESS SIGNATURE              
 DATE
TIME
AUTHORIZED CONSENT PROVIDER STATEMENT:
I have explained this study and have offered the study participant an opportunity for any further 
discussion or clarification.
_________________________________               ____________                 ___________________
NAME (PLEASE PRINT)
                     CREDENTIALS
          
PHONE NUMBER
_________________________________                __________________          ____________
SIGNATURE
                                                     DATE 
             TIME
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/21/2020
IRB EXPIRATION DATE: 02/20/2021

Prot_SAP_002.pdf: 
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). 
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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.  
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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
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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
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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 
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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)
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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
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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 
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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
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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
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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
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14
IX.   References
1.
Wang Y, Xu K, Hu H, et al. Prevalence, risk factors, and impact on health related quality 
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IRB APPROVAL DATE: 02/03/2020
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020


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IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020
IRB NUMBER: 2018-119
IRB APPROVAL DATE: 02/03/2020