Clinical trial NCT02297100
Conditions: Interstitial Cystitis
Keywords: women interstitial cystitis bladder pain syndrome botox onabotulinum toxin A
Sponsor: Wake Forest University Health Sciences
Start date: 2014-12-01; Completion date: 2018-01-10
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research study is to identify the optimal usage of Onabotulinumtoxin A in interstitial cystitis. Onabotulinumtoxin A, more commonly known by the trade name Botox®, is a medication that comes from the bacteria Clostridium botulinum. It works by blocking the release of the neurotransmitter acetylcholine(a chemical messenger that carries signals between nerve cells and other cells in the body). Blocking that neurotransmitter results in decreased muscle activity.

Detailed description:
The purpose of this study is to evaluate the efficacy of intravesicular Onabotulinumtoxin A injections for the treatment of interstitial cystitis (IC). Specifically, we hypothesize that trigonal Onabotulinumtoxin A injections is an effective treatment for IC and will result in more subjective and objective symptom relief than posterior wall Onabotulinumtoxin A injections.

Arms: arm 1: Subjects in the experimental cohort will receive a one time dose of 100 units of Onabotulinumtoxin A diluted in 10 mL of preservative free normal saline and injected in 1.0 mL boluses in a set pattern across the upper aspect of the trigone of the urinary bladder. arm 2: Each group will receive a total of 100 units of botox spread out among 10 separate injections. Subjects in the control group will have 10 injections made about the periphery of the trigone. The control cohort will receive a one time dose of Onabotulinumtoxin A using the same dilution and number of boluses, but boluses will be administered at random sites on the posterior bladder wall (excluding the trigone).
Interventions: intervention 1: Onabotulinumtoxin A intervention 2: injections upper aspect of trigone of urinary bladder intervention 3: injections on posterior bladder wall excluding the trigone
Intervention descriptions: intervention 1: 100 units of botox spread out among 10 separate injections intervention 2: We hypothesize that injections into the trigone should be more effective in the treatment of IC than injections elsewhere in the bladder. intervention 3: We hypothesize that injections into the trigone should be more effective in the treatment of IC than injections elsewhere in the bladder.

Protocol documents:
Prot_SAP_000.pdf: 
 
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The Impact of Injection Location on the Efficacy of Intravesicular 
Onabotulinumtoxin A in Interstitial Cystitis 
 
PI: Dr. Robert Evans MD 
Sub-Investigator: Dr. Marc Colaco MD, MBA 
Study Coordinator:  Janet Shuping, CCRC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Address for Correspondence: 
Janet Shuping, CCRC 
Department of Urology Clinical Research 
140 Charlois Blvd. 
Winston-Salem, NC 27103 
Phone: (336) 716-2612 
FAX: (336) 716-4220 
E-mail: jshuping@wakehealth.edu 


 
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BACKGROUND, RATIONALE, AND CONTEXT 
Interstitial cystitis (IC), also referred to as painful bladder syndrome (PBS), is a 
heterogenous chronic disease of unknown etiology that impacts up to 8 million women in 
America.1 Patients suffer from vague pelvic pain that can be exacerbated by bladder 
filling, and is often associated with urinary frequency and urgency.2 Since Alexander 
Skene’s inception of the term in 1887, research into the etiology and pathophysiology of 
this disease has not been successful in elucidating a specific mechanism, revealing more 
questions than answers. As a result, treatment is difficult. Although there are many oral, 
intravesicular, and procedural treatments available, many patients remain refractory and 
require a more substantial treatment. Onabotulinumtoxin A may be that treatment.  
 
Onabotulinumtoxin A has long been considered an efficacious treatment for various 
bladder pathologies such as overactive bladder (OAB) and neurogenic bladder. For the 
treatment of IC current AUA guidelines list intradetrusor Onabotulinumtoxin A injections 
as a fifth-line treatment option with grade C evidence (observational studies that are 
inconsistent, have small sample sizes, or have other problems that potentially confound 
interpretation of data).3 This option is based upon six observational studies that 
demonstrated highly variable amounts of short and long efficacy rates (from 20% to 86% 
at 3 months).4–9 Since the release of these guidelines other studies have confirmed 
Onabotulinumtoxin A’s efficacy.10,11 While prior studies demonstrated the efficacy of 
intravesicular Onabotulinumtoxin A as a treatment, they largely did not address the 
importance of injection location. With the majority of bladder nociceptor and 
parasympathetic fibers located in the trigone,10–12it stands to reason that injections to this 
area should have a more significant effect on bladder pain than injections elsewhere. The 
purpose of this study is to identify the importance of injection location for intravesicular 
Onabotulinumtoxin A.  
 
We hypothesize that injections into the trigone should be more effective in the treatment 
of IC than injections elsewhere in the bladder. The lack of evidence on this topic has been 
noted by several authors and is important to the understanding and future use of 
Onabotulinumtoxin A in the treatment of IC. 
 
Objectives 
The purpose of this study is to evaluate the efficacy of intravesicular Onabotulinumtoxin 
A injections for the treatment of interstitial cystitis (IC). Specifically, we hypothesize that 
trigonal Onabotulinumtoxin A injections is an effective treatment for IC and will result in 
more subjective and objective symptom relief than posterior wall Onabotulinumtoxin A 
injections. 
 
Specific Aims 
Patients diagnosed as having refractory IC will receive a one time dose of intravesicular 
Onabotulinumtoxin A with injections randomly assigned to either the posterior wall or 
trigone. Patients will be evaluated for subjective IC symptoms and objective flow 
performance prior to treatment as well as 30 and 90 days. This will test the hypothesis 
that intravesicular Onabotulinumtoxin A is an effective treatment for IC and that 
injections to the trigone are more effective than injections elsewhere. 


 
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MATERIALS AND METHODS 
 
Design 
This is a single center, prospective, randomized clinical trial. Subjects will consist of 
patients referred to the urology clinic at Wake Forest University Baptist Medical Center 
with interstitial cystitis for whom conservative management/oral medications have failed 
and Onabotulinumtoxin A is recommended. These patients will all have undergone 
evaluation by Dr. Robert Evans: an expert in the management of pelvic pain syndromes 
who sees >300 new patients each year.  
 
Upon initial evaluation all subjects will undergo assessment including history taking and 
physical examination, urinalysis, subjective symptom assessment using self-reporting 
questionnaires, and objective symptom assessment using uroflowometry as well as the 
measurement of post void residuals.  
 
After initial assessment subjects will be randomized into either the control or 
experimental cohorts. Subjects will receive a single dose of PO ciprofloxacin prior to 
injection unless culture or allergies dictate to use a different antibiotic.  Each group will 
receive a total of 100 units of botox spread out among 10 separate injections.  Subjects in 
the control group will have 10 injections made about the periphery of the trigone.  
Subjects in the experimental cohort will receive a one time dose of 100 units of 
Onabotulinumtoxin A diluted in 10 mL of preservative free normal saline and injected in 
1.0 mL boluses in a set pattern across the upper aspect of the trigone of the urinary 
bladder. Meanwhile, those subjects randomized to the control cohort will also receive a 
one time dose of Onabotulinumtoxin A using the same dilution and number of boluses, 
but boluses will be administered at random sites on the posterior bladder wall (excluding 
the trigone). Post –treatment, subjects will remain at the site for at least 30 minutes for 
observation and will demonstrate their ability to void before leaving.  All procedures will 
be performed using the facilities of Wake Forest Baptist Medical Center. 
 
After the procedure subjects will be scheduled for clinical follow-up at 2 weeks for a 
measurement of post void residual and adverse event collection.  At the day 30 and 90 
day follow-up visits patients will again undergo evaluation including collection of 
adverse events, concomitant medications, history taking and physical examination, 
urinalysis, subjective symptom assessment using self-reporting questionnaires, and 
objective symptom assessment using uroflowometry as well as the measurement of post 
void residuals.  At day 45 and day 60 we will call to verify if patient has had any adverse 
events or changes in concomitant medications.  We will then analyze the data generated 
by these follow-up visits to measure the efficacy of Onabotulinumtoxin A injections for 
interstitial cystitis as well as impact of injection location, if any. 
 
 
 
 
 


 
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a. For subjects who are of child-bearing potential  
b. Subjects will remain at site on Day 0 after treatment for at least 30 minutes for observation.  Subjects must also demonstrate 
their ability to void before leaving.
 
Procedures, Tests and Evaluations 
Screening 
and 
Baseline 
Study Day 0 
in Clinic 
Week 2 
Clinic visit 
 
Day 30 
Clinic Visit 
 
Day 45 
Phone call 
Day 60  
Phone call 
 
Day 90 
Clinic 
Visit 
 
Day 0 
Day 14 +3 
Day 30 +3 
Day 45 +3 
Day 60 +3 
Day 90 +3 
Informed Consent 
X 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
Medical History verification 
 
X 
X 
 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion Verification 
X 
 
 
 
 
 
Physical Examination (PE) 
X 
 
X 
 
 
X 
Uroflowometry 
X 
 
X 
 
 
X 
Pregnancy Test 
Xa 
 
 
 
 
 
Antibiotic dose 
X 
 
 
 
 
 
Post-Treatment Observation and Void 
Xb 
 
 
 
 
 
Urinalysis/Urine Culture 
X 
 
X 
 
 
X 
Questionnaires—PUF, O’Leary-Sant 
X 
 
X 
 
 
X 
Bladder Post-void Residual 
X 
X 
X 
 
 
X 
IP injections 
X 
 
 
 
 
 
AEs 
X 
X 
X 
X 
X 
X 


 
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Subject selection criteria 
Written informed consent will be obtained from all subjects before enrollment. Once 
participants have been appropriately consented, the minimal amount of clinical data 
required will be abstracted from their electronic medical record. Other extracted 
information will include their past medical history, such as comorbidities, current 
medications, and any symptoms of IC they experience. Furthermore, physical exam 
findings, laboratory results, intra-operative findings, and pathology reports will be 
reviewed.  Patients will complete questionnaires that have been well-established to assist 
in IC diagnosis and assessment of disease severity and response to treatment, and are part 
of routine clinical diagnosis and treatment. These include the O’Leary-Sant Interstitial 
and the Pelvic Pain and Urgency/Frequency Patient Symptom Scale (PUF).  Each of 
these questionnaires are well established in the literature to help the urologist identify and 
treat patients with IC.  Their scores on these questionnaires must >10 for either the ICSS 
or ICPI, and >10 on the PUF.  Both the O’Leary/Sant questionnare and PUF questionnare 
ask about the voiding patterns and pain levels of IC patients.   
 
Inclusion Criteria 
Subjects should only be included if they meet the following conditions: 
1.  Adult females between the ages of 18 and 80 inclusive  
2. Patients being treated for IC who are refractory to conservative 
management and oral therapy.  
3. willing and able to initiate catheterization post-treatment 
These patients will all have undergone evaluation by Dr. Robert Evans, an expert 
in the management of pelvic pain syndromes who sees >300 new patients each 
year. Subjects will be drawn from the patient population undergoing chronic 
management for their IC. The clinical diagnosis of IC will be based on the 
recently published AUA Guidelines definition: “An unpleasant sensation (pain, 
pressure, or discomfort) perceived to be related to the urinary bladder, associated 
with lower urinary tract symptoms for more than six weeks duration, in the 
absence of infection or other identifiable causes.” 
Exclusion Critera 
Subjects should be excluded if any of the following applies: 
1. Any history of bladder cancer, uterine cancer, ovarian cancer, vaginal 
cancer, urethral diverticulum, spinal cord injury, stroke, Parkinson’s 
disease, multiple sclerosis, spina bifida, cyclophosphamide treatment, 
radiation treatment to the pelvis, bladder tuberculosis, genital herpes. 
2. Currently on or requiring anti-platelet/anti-coagulant concomitant therapy 
or having been on anti-platelet/ anti-coagulant therapy within the past 3 
months 


 
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3. Pregnancy.   Pregnancy is an absolute contraindication to undergoing 
these procedures. Thus, as part of their normal pre-operative work up, 
which is standard of care, pregnancy tests are administered if they are 
women of child-bearing age, are sexually active, and are within 10 days of 
the normal menstrual period. If positive, they will be excluded as they will 
not undergo the procedure. 
4. An active urinary tract infection as shown during clean-catch urinalysis at 
screening visit.  Subject may be re-screened if UTI is successfully treated 
and urinalysis is negative at rescreening.   
5. A history of hypersensitivity or allergy to any botulinum toxin preparation 
6.  A post-void residual (PVR) urine volume >200mL at baseline 
7. Treatment with botulinum toxin during the 12 week period prior to the 
trial 
8. Current treatment with aminoglicosides or other drugs that interfere with 
neuromuscular transmission or with muscle relaxants.   
 
 
Sample Size and Randomization 
Each study arm will consist of 20 subjects for a total study population of 40. This number 
was chosen using estimates of symptom relief using our current patient population as 
reference. 
Patients will be randomized to either the control or experimental cohort using a computer 
generated randomization table. Providers will not be aware of the subjects’ cohort status 
until immediately prior to injection. 
 
 
Power Analysis 
We expect that treatment will result in a large effect and as such have set an anticipated 
Cohen's d as 0.95. Using this value along with standard study values of α=0.05 and 
β=0.80 we calculated a minimum total study group requirement of 38 subjects with 19 
subjects in each arm. 
 
Outcome Measure(s) 
The primary outcome will be a measurement of subjective patient pain using the Pelvic 
Pain and Urinary Urgency Frequency (PUF) questionnaire and the O’Leary-Sant 
Symptom and Problem Indexes. Patients will be asked to complete this questionnaire 
prior to treatment administration and at 30 and 90 days post treatment. The PUF and 
O’Leary Sant are previously validated tools that have been used by numerous researchers 
to evaluate pelvic pain. Secondary outcomes will be objective data as to patient 
performance in uroflowmetry as well as measurement of post void residuals. Patients will 


 
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again undergo these assessments prior to treatment and at 30 and 90 days post treatment 
to assess objective treatment effectiveness. 
 
 
Analytical Plan 
Results will be analyzed initially using descriptive statistics.  Comparison between 
groups will be done using chi square tests for proportions, and t-tests or ANOVA 
procedures for continuous variables.  Regression analysis will be performed to identify 
independent outcome predictors.  Other inferential statistical analysis will be conducted 
as appropriate. 
 
 
 
Estimated Study Timeline 
The study treatment duration is 90 days from first evaluation and treatment to final 
follow-up. We estimate that the total study time (including IRB approval, patient 
recruitment, treatment, and data analysis following treatment) to be approximately 1 year 
and 4 months. 
 
 
 
Human Subjects Protection 
Informed Consent:  An IRB approved written informed consent will be obtained from 
each subject.  Dr. Robert Evans or the study coordinator will consent each of the potential 
subjects.  Informed consent will be acquired in the day hospital at Wake Forest 
University, or in the Wake Forest University Urology Out-patient Clinic. 
 
Confidentiality and Privacy:  Confidentiality will be protected by collecting only 
information needed to accomplish age and gender matching (i.e. patient’s age and patient 
gender), minimizing to the fullest extent possible the collection of any information that 
could directly identify subjects, and maintaining all study information in a secure manner.  
To help ensure subject privacy and confidentiality, only a unique study identifier will 
appear on the data collection form.  Any collected patient identifying information 
corresponding to the unique study identifier will be maintained on a separate master log.  
The master log will be kept secure, with access limited to designated study personnel.  
Following data collection subject identifying information will be destroyed at the earliest 
opportunity, consistent with data validation and study design, producing an anonymous 
analytical data set.  Data access will be limited to study staff.  Data and records will be 
kept locked and secured, with any computer data password protected.  No reference to 
any individual participant will appear in reports, presentations, or publications that may 
arise from the study. 
 
 
 
Data and Safety Monitoring 
The principal investigator and study coordinator will be responsible for the overall 
monitoring of the data and safety of study participants, and will ensure that the subjects’ 


 
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information is not revealed.  The principal investigator will be assisted by other members 
of the study staff. 
 
Budget 
Please see budget submitted separately as a spreadsheet. Letters on Wake Forest 
letterhead testifying to the institutional overhead costs will be forthcoming. 
 
REFERENCES 
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cystitis among adult females in the United States. J. Urol. 186, 540–544 (2011).  
2.   Wein, A. J., Kavoussi, L. R., Campbell, M. F., & Walsh, P. C. (2012). Campbell-
Walsh urology. Philadelphia, PA: Elsevier Saunders.  
3.   Hanno, P. M. et al. AUA Guideline for the Diagnosis and Treatment of Interstitial  
Cystitis/Bladder Pain Syndrome. The Journal of Urology 185, 2162–2170 (2011).  
4.   Smith, J. L. Case of the month. Interstitial cystitis. JAAPA 17, 48 (2004).  
5.   Kuo, H.-C. Preliminary results of suburothelial injection of botulinum a toxin in the 
treatment of chronic interstitial cystitis. Urol. Int. 75, 170–174 (2005).  
6.   Giannantoni, A. et al. Botulinum A toxin intravesical injection in patients with 
painful bladder syndrome: 1-year followup. J. Urol. 179, 1031–1034 (2008).  
7.   Giannantoni, A. et al. Botulinum A toxin intravesical injections in the treatment of 
painful bladder syndrome: a pilot study. Eur. Urol. 49, 704–709 (2006).  
8.   Ramsay, A. K., Small, D. R. & Conn, I. G. Intravesical botulinum toxin type A in 
chronic interstitial cystitis: results of a pilot study. Surgeon 5, 331–333 (2007).  
9.   Liu, H.-T. & Kuo, H.-C. Intravesical botulinum toxin A injections plus 
hydrodistension can reduce nerve growth factor production and control bladder pain 
in interstitial cystitis. Urology 70, 463–468 (2007).  
10. Pinto, R. et al. Persistent therapeutic effect of repeated injections of onabotulinum 
toxin a in refractory bladder pain syndrome/interstitial cystitis. J. Urol. 189, 548–553 
(2013).  
11. Pinto, R. et al. Trigonal injection of botulinum toxin A in patients with refractory 
bladder pain syndrome/interstitial cystitis. Eur. Urol. 58, 360–365 (2010).  
12. Andersson, K.-E. & Arner, A. Urinary bladder contraction and relaxation: physiology 
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