Clinical trial NCT02995967
Conditions: Overactive Bladder
Sponsor: University of Alabama at Birmingham
Start date: 2016-11-01; Completion date: 2017-12-31
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The specific aim of this trial is to determine if hydrodistention at the time of intradetrusor injection of botulinum toxin A has additional benefit in patients with refractory overactive bladder (OAB) and urgency symptoms compared to intradetrusor injection of botulinum toxin A alone.

Consented patients will be randomized to hydrodistention at a pressure of 80 cm H2O for 5 minutes, prior to the intradetrusor injection of 100 units of botulinum toxin A (hydrodistention group) or intradetrusor injection of 100 units of botulinum toxin A alone (botulinum toxin A alone group).

The primary aim will be subjective improvement measured as change from baseline at 12 weeks using the OAB-q bother subscale.

Detailed description:

Arms: arm 1: Just the intradetrusor injection of 100 units of botulinum toxin A alone arm 2: Hydrodistention at a pressure of 80 cm H2O for 5 minutes, prior to the intradetrusor injection of 100 units of botulinum toxin A
Interventions: intervention 1: Hydrodistention intervention 2: Botulinum toxin-A
Intervention descriptions: intervention 1: The hydrodistention will then be performed with the bladder filled at a pressure of 80 cm H2O and noted to be full as evidenced by no further influx of water into the bladder. This volume will be held in the bladder for 5 minutes. intervention 2: Intradetrusor injection of 100 units of botulinum toxin a

Protocol documents:
Prot_SAP_000.pdf: 
 
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Cover Page 
 
A Randomized Controlled Trial to Evaluate Botulinum Toxin A alone versus Botulinum 
Toxin A with hydrodistention for the Treatment of Refractory Overactive Bladder  
(HydrA Study) 
NCT02995967 
 


 
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Research Protocol 
 
A Randomized Controlled Trial to Evaluate Botulinum Toxin A alone versus Botulinum 
Toxin A with hydrodistention for the Treatment of Refractory Overactive Bladder  
(HydrA Study) 
 
Joseph Malek, MD1 
Isuzu Meyer, MD1 
Tracey Wilson, MD2 
L. Keith Lloyd, MD2 
Alicia Ballard, MD1 
David Ellington, MD1 
Holly E. Richter, PhD, MD1 
1.  Division of Urogynecology and Pelvic Reconstructive Surgery, Department of Obstetrics 
and Gynecology, University of Alabama Birmingham, Birmingham, AL 
2. Department of Urology, University of Alabama Birmingham, Birmingham, AL 
 
 


 
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Corresponding Author:  
Joseph Malek, MD  
1700 6th Avenue South, Suite 10382 
Birmingham, AL 35233 
Phone: (205) 996-5466 
Fax: (205) 975-8893 
Email: jmalek@uabmc.edu 
 
FINANCIAL DISCLAIMER/CONFLICT OF INTEREST: NONE 
 
JM Malek: Protocol/project development, data collection, manuscript writing/editing 
 
 


 
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Abstract 
 
The specific aim of this randomized, single-blinded controlled trial is to determine if 
hydrodistention at the time of intradetrusor injection of botulinum toxin A has additional benefit 
in patients with refractory overactive bladder (OAB) and urgency symptoms compared to 
intradetrusor injection of botulinum toxin A alone.   
 
Consented patients will be randomized to hydrodistention at a pressure of 80 cm H2O for 
5 minutes, prior to the intradetrusor injection of 100 units of botulinum toxin A (hydrodistention 
group) or intradetrusor injection of 100 units of botulinum toxin A alone (botulinum toxin A 
alone group).  The primary aim will be subjective improvement measured as change from 
baseline at 12 weeks using the OAB-q bother subscale.  Secondary aims will include number of 
urgency urinary incontinence (UUI) episodes, total number of voids, percentage of patients 
requiring clean intermittent self-catheterization, elevated post-void residual, health related 
quality of life, patient global impression of improvement, patient satisfaction, rate of urinary tract 
infection post-operatively, and 24 week subjective improvement using the OAB-q.   
 
Demographics and baseline data will be analyzed by Student’s t-test and chi-squared test 
or Fisher’s Exact test as appropriate. 
Specific aims 
Primary aim: To determine if hydrodistention at the time of intradetrusor injection of botulinum 
toxin A has additional symptomatic benefit in patients with overactive bladder (OAB) and 
urgency symptoms compared to botulinum toxin A injection alone in a single blind, randomized 
controlled trial using subjective improvement as measured by the OAB-q bother subscale at 12 
weeks. 


 
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Secondary aims: Secondary aims will include number of urgency urinary incontinence (UUI) 
episodes, total number of voids, proportion of subjects requiring clean intermittent self-
catheterization, elevated post-void residual, health related quality of life, patient global 
impression of improvement, patient satisfaction, rate of urinary tract infection post-operatively, 
and 24 week subjective improvement using the OAB-q.   
Null hypothesis: In subjects with refractory overactive bladder, hydrodistention at the time of 
intradetrusor injection of botulinum toxin A will result in no difference in OAB-q score 
compared to botulinum toxin A injection without hydrodistention.   
Background 
Overactive bladder (OAB) is a common condition that affects approximately 17% of 
women in the United States [1].  Overactive bladder is defined by the International Continence 
Society as “urinary urgency, usually accompanied by frequency and nocturia, with or without 
urgency urinary incontinence, in the absence of urinary tract infection or other obvious 
pathology” [2].  Approximately one third of these women will have urgency urinary incontinence 
(UUI) with the prevalence increasing with age [1].  The economic burden of this disease is 
significant with the estimated annual cost of OAB in the United States being $25 billion [3].   
Anticholinergic medications have long been the mainstay of treatment for OAB but have 
significant side effects including dry mouth and constipation [4] which has led to poor patient 
compliance and high discontinuation rates in clinical practice [5].  Botulinum toxin A injected 
into the detrusor muscle during cystoscopy was Food and Drug Administration approved for the 
treatment of refractory OAB symptoms in 2013.  This approval was based on two large 
randomized controlled trials that included 1,105 patients randomly assigned to placebo or 100 


 
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units of intradetrusor botulinum toxin A.  A primary endpoint of 12 weeks showed a significant 
decrease in daily episodes of UUI episodes in the botulinum toxin A group compared to placebo 
[6,7].  Another double-blind, double-placebo-controlled, randomized trial compared 
anticholinergic use versus botulinum toxin A which showed a decrease in the number of episodes 
of UUI in the active group without any significant difference between treatments [8].  In this 
trial, both groups showed no significant differences in improvement in quality of life, but only 
13% of patients in the anticholinergic group and 27% in the botulinum toxin A group reported 
complete resolution of UUI episodes [8].  Thus, we believe there is much room for improvement 
in the treatment of OAB symptoms.   
Hydrodistention has been a treatment modality for interstitial cystitis (IC) since the early 
1900s [9, 10].  It is thought that any efficacy for the treatment of IC is probably related to 
damage to mucosal afferent nerve endings in the bladder [11].  There are very limited studies on 
the use of hydrodistention for urgency and OAB symptoms.  Dunn et al in a small study found 
that 14 of 20 patients with urgency and UUI reported resolution of their symptoms after 
prolonged bladder distention [12].  They also found that the bladder capacity in all patients 
increased after hydrodistention.  In a retrospective review of patients undergoing 
hydrodistention, Cole et al found that in patients who had undergone the procedure for frequency 
and urgency symptoms with no pain component, 50% at 1 month, 19% at 3 months, and 7% at 6 
months reported improvement in symptoms [13].  Other studies have shown no benefit from 
hydrodistention in the treatment of urgency and OAB symptoms [14, 15].   
There are currently no studies investigating hydrodistention at the time of intradetrusor 
botulinum toxin A in patients with refractory OAB symptoms.  We believe that patients may 
have additive benefit from a hydrodistention performed with botulinum toxin A injection as the 


 
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increased bladder capacity gained by the distention will be sustained for a longer period of time 
in the setting of botulinum toxin A.   
Significance 
No studies have been performed examining hydrodistention in the setting of intradetrusor 
botulinum toxin A for the treatment of refractory OAB symptoms.   
Study Design 
Inclusion criteria 
1. Women with refractory overactive bladder symptoms, failing a credible behavioral 
therapy intervention and medical therapy or not tolerating medical therapy.  Patients who 
are on medical therapy will stop the medical therapy for at least 2 weeks prior to 
botulinum toxin A treatment in the study 
2. Female ≥ 18 years old 
3. Desires further treatment for OAB symptoms. 
4. Express understanding and ability to perform clean intermittent self-catheterization 
(CISC) if required. 
5. Ability to consent 
6. Ability to complete all study related items and interviews 
Exclusion Criteria 
1. Post void residual urine volume > 150 mL as assessed by catheter or ultrasound 
2. History of intradetrusor botulinum toxin A injection 
3. History of or current cancer of the genitourinary or gynecology tract 


 
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4. Neurogenic bladder 
5. Interstitial cystitis 
6. Current urinary tract infection (can be treated and re-considered for study) 
7. Current active sacral neuromodulation device  
8. Non-English speaking 
9. History of chronic pelvic pain 
10. Hematuria not previously evaluated 
Intervention 
Hydrodistention at a pressure of 80 cm H2O for 5 minutes prior to intradetrusor injection of 100 
units of botulinum toxin A (hydrodistention group) or intradetrusor injection of 100 units of 
botulinum toxin A alone (botulinum toxin A alone group). 
Primary outcome 
The primary outcome will be measured as change from baseline at 12 weeks using the OAB-q 
bother subscale which consists of eight questions assessing symptom bother with a possible 
score from 0 to 100 with a higher score indicating greater symptom bother.   
Secondary outcomes 
1. Number of UUI episodes as reported in a 3-day bladder diary at 12 weeks as measured in 
change from baseline.   
2. Total number of voids reported in the 3-day bladder diary at 12 weeks as measured in 
change from baseline. 


 
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3. Proportion of subjects requiring clean intermittent self-catheterization (CISC) post-
operatively as reported at 2 week post-operative visit.  CISC will be initiated at post-void 
residual volumes of > 300 mL or > 150 mL in the presence of bothersome retention 
symptoms. 
4. Post-void residual volume (PVR) at the 2 week follow-up visit measured with catheter or 
bladder scan. 
5. Rate of urinary tract infection (UTI) as assessed by positive urine culture in patients 
having symptoms (dysuria, urgency, frequency, temperature ≥ 38 degrees Celcius, and/or 
suprapubic pain) at the 2 weeks post-operative visit.  Subjects who call throughout the 
study complaining of symptoms but are unable to give a urine culture in clinic will also 
be treated and reported as having had a UTI. 
6. Health related quality of life (HRQL) will be measured as a change from baseline at 12 
weeks using the OAB-q HRQL subscale part which consists of 25 questions that assess 
HRQL addressing coping, concern, sleep, and social interaction where the scoring scale 
is from 0 to 100 with a higher score indicating a better quality of life. 
7. Patient global impression of improvement at 12 weeks as measured using the Patient 
Global Impression of Improvement Questionnaire (PGI-I).   
8. Patient satisfaction at 12 weeks as measured using Patient Satisfaction Questionnaire 
(PSQ). 
9. Subjective outcome at 24 weeks using the OAB-q 
Protocol in detail 
 
Women seen in the urogynecology and urology clinics at University of Alabama at 
Birmingham who are seeking treatment for refractory OAB symptoms will be screened.  Patients 


 
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who have failed a credible behavioral therapy intervention and medical therapy or not tolerating 
medical therapy will be evaluated for this study.  Those patients satisfying the 
inclusion/exclusion criteria will be offered to participate in the study.  Informed consent will be 
reviewed and signed with patients wishing to proceed.   
 
At enrollment, any subjects who are using medical therapy including anticholinergic or β3 
agonist medications will stop these therapies for at least 2 weeks prior to treatment.  Baseline 
clinical data including OAB-q and a 3 day bladder diary will be collected as well as clinical and 
demographic information.  Data from subjects’ urodynamic testing will be abstracted from the 
clinical chart if performed within the prior 12 months of the enrollment date.  If no urodynamics 
testing is available then we will not collect this information for those subjects.  Subjects will also 
be counseled on the possible need for clean intermittent self-catheterization (CISC) and 
instructions on how and when to perform CISC will be given in clinic.  Subjects will be 
randomized the day of the scheduled procedure.  Subjects will be blinded to which group they 
are assigned. 
 
Subjects randomized to the botulinum toxin A alone group will undergo intradetrusor 
injection of 100 units of botulinum toxin A diluted in 10 cc of sterile normal saline and injected 
in volumes of 0.5cc in a grid-like pattern using rigid cystoscopy in the operating room under 
monitored anesthesia care (MAC) or general anesthesia.  Those subjects randomized to the 
hydrodistention group will undergo hydrodistention of the bladder in the operating room just 
prior to the botulinum toxin A injection.  The hydrodistention will be performed with a water 
pressure of 80 cm H2O as measured by the height of the sterile water source above the pubic 
symphysis in the operative room.  The bladder will be filled and noted to be full as evidenced by 
no further influx of water into the bladder.  The bladder will be emptied and this volume will be 


 
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recorded as initial bladder volume.  The hydrodistention will then be performed with the bladder 
filled at a pressure of 80 cm H2O and noted to be full as evidenced by no further influx of water 
into the bladder.  This volume will be held in the bladder for 5 minutes.  Upon emptying, the 
volume will be recorded as the hydrodistention volume.  After the hydrodistention, these 
subjectss will then receive intradetrusor injection of 100 units of botulinum toxin A in a grid like 
pattern using rigid cystoscopy as described above. 
Subjects will be seen for a 2 week post-operative visit.  It will be recorded if subjects 
have had to use CISC including how many days.  CISC will be initiated at post-void residual 
volumes of > 300 mL or > 150 mL in the presence of bothersome retention symptoms.  Subjects 
with symptoms of UTI including dysuria, urgency, frequency, temperature ≥ 38 degrees Celsius 
and/or suprapubic pain will have urine culture sent and treated accordingly for UTI.  If subjects 
call with symptoms of urinary tract infection but are unable to present for urine culture will also 
be treated and reported as an UTI.   
Subjects will follow up for scheduled post-operative care at a 6 and 12 weeks at which 
time they will complete the OAB-q, PGI-I, and PSQ for the 12 week primary outcome data.  
Subjects will complete a 3 day bladder diary during the week prior to the 12 week visit and bring 
the information with them to the visit.  At the 24 week follow up visit, patients will complete the 
OAB-q.  All follow up visits at 2 weeks, 6 weeks, 12 weeks, and 24 weeks will be plus or minus 
a 1 week window from the date of procedure.   
Randomization/Allocation 
 
Patients will be randomized to the hydrodistention group or botulinum toxin A alone 
group in a 1:1 fashion using variable size permuted blocks of 4, 6, and 8.  This will be done by a 


 
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member of the research team on the day of the procedure.  Subjects will be blinded to which 
group they are assigned.  Allocation concealment will be ensured by using a centralized service 
to provide sequentially numbered, opaque, sealed envelopes. 
Confidentiality 
Extensive efforts will be made to ensure and maintain participant confidentiality.  All identifying 
information will be maintained in a secure area at all times.  Participants will be assigned a Study 
ID number at study enrollment taken from the randomization log.  This Study ID will be used to 
label all data collection sheets.   
Power analysis 
A sample size of 27 patients per group provides 80% power to detect a difference of 15 points or 
more at a 0.05 level of significance. For this determination, we estimated the mean OAB-q 
bother score in the control group to be 45 and the standard deviation of the change in severity 
scores to be 19 points based on a prior studies by Coyne, et al [16, 17].  We hypothesized a 15 
point difference to be meaningful based on feasibility, clinical significance, and prior reported 
minimally important difference (MID) [17].  Allowing for a 10% dropout rate, we will recruit a 
total of 60 patients, 30 per group.   
Data analysis 
Demographics and baseline data will be analyzed by Student’s paired t-test and chi-squared test 
or Fisher’s Exact test as appropriate. 
Project schedule 
• February to May 2016: start up and obtain IRB approval 


 
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• May 2016 until August 2017: Recruitment and Enrollment 
• September 2017 to March 2018: Data analysis, manuscript completion 
 
 


 
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References for OAB Hydro 
1. 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. 
2. Haylen BT, de Ridder D, Freeman RM, et al. An International Urogynecological 
Association (IUGA)/International Continence Society (ICS) joint report on the 
terminology for female pelvic floor dysfunction. Int Urogynecol J. 2010;21:5. 
3. Onukwugha E, Zuckerman IH, McNally D, Coyne KS, Vats V, Mullins CD.  The total 
economic burden of overactive bladder in the United States: a disease-specific approach. 
Am J Manag Care. 2009;15:S90. 
4. Chapple CR, Khullar V, Gabriel Z et al: The effects of antimuscarinic treatments in 
overactive bladder: an update of a systematic review and metaanalysis. Eur Urol 2008; 
54: 543. 
5. Brøstrom S and Hallas J: Persistence of antimuscarinic drug use. Eur J Clin Pharmacol 
2009; 65: 309. 
6. Nitti VW, Dmochowski R, Herschorn S, et al. OnabotulinumtoxinA for the treatment of 
patients with overactive bladder and urinary incontinence: results of a phase 3, 
randomized, placebo controlled trial. J Urol 2013;189:2186-2193. 
7. Chapple C, Sievert K-D, MacDiarmid S, et al. OnabotulinumtoxinA 100 u significantly 
improves all idiopathic overactive bladder symptoms and quality of life in patients with 
overactive bladder and urinary incontinence: a randomized, double-blind, placebo-
controlled trial. Eur Urol 2013;64:249-256. 
8. Visco AG, Brubaker L, Richter HE, Nygaard I, Paraiso MF, Menefee SA, et al. 
Anticholinergic therapy vs. onabotulinumtoxina for urgency urinary incontinence. N Engl 
J Med 2012;367:1803-13. 
9. Frontz WA. Discussion. Trans Am Assoc Genitourin Surg 1922;15:434–5. 
10. Bumpus HC. Interstitial cystitis: its treatment by overdistention of the bladder. Med Clin 
North Am 1930;13:1495–8. 
11. Dunn M, Ramsden PD, Roberts JB, et al. Interstitial cystitis, treated by prolonged bladder 
distension. Br J Urol 1977; 49(7):641–5. 
12. Dunn M, Smith JC, and Ardran GM: Prolonged bladder distension as a treatment of 
urgency and urge incontinence. BrJ Urol 46: 645-652, 1974. 
13. Cole EE, Scarpero HM and Dmochowski RR. Are patient symptoms predictive of the 
diagnostic and/or therapeutic value of hydrodistention? Neurourol Urodyn. 
2005;24(7):638-42. 
14. McCahy PJ, Styles RA. Prolonged bladder distension: experience in the treatment of 
detrusor overactivity and interstitial cystitis. Eur Urol 1995; 28(4):325–7. 
15. Taub HC, Stein M. Bladder distention therapy for symptomatic relief of frequency and 
urgency: a ten year review. Urology 1994;43:36–9. 


 
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16. Coyne K, Revicki D, Hunt T, et al. Psychometric validation of an overactive bladder 
symptom and health-related quality of life questionnaire: the OAB-q. Qual Life Res 
2002;11:563-74. 
17. Coyne KS, Matza LS, Thompson CL, et al.  Determining the importance of change in the 
overactive bladder questionnaire.  J Urol.  2006 Aug; 176: 627-32.