Comparison of Methods for Prevention of Urinary Tract Infection Following Botox Injection: a Non-Inferiority Trial
Phase: PHASE4
Conditions: Overactive Bladder, Urinary Tract Infections
Sponsor: Vanderbilt University Medical Center

Research Protocol  
IRB submission version: 10/6/2018 
 
 
 
 
 
NCT03508921 
 
 
Comparison of Methods for Prevention of Urinary Tract Infection 
Following Botox Injection 
 
Protocol/SAP 
 
October 6, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Research Protocol  
IRB submission version: 10/6/2018 
 
 
Research Protocol 
 
Initial Visit 
 
Study population. Enrollment is planned to achieve a total of 68 patients, with each subject undergoing two 
injections. All patients will receive 2 injections over the study time period as part of this cross-over study. 
Participants must be adult patients (age 18 or older) with medication-refractory non-neurogenic OAB subject to 
the following inclusion and exclusion criteria (Table 1). Patients who elect to proceed with intravesical BTX-A 
injection as third line therapy, and are deemed appropriate for treatment by the clinician, will be considered for 
eligibility. Patients presenting for injection will be screened and consented prior to the first injection, and this 
consent will apply for the duration of the study (over two injections).  
 
Demographic and clinical data: Participants will complete a standardized questionnaire assessing 
demographics and pertinent medical history including surgical history, current and past OAB therapy, history of 
urinary tract infections (UTIs) and urinary retention, and self-reported diagnoses of comorbid medical conditions. 
We will supplement this information with abstracted data from electronic medical records on past medical and 
surgical history, urinalysis, urine culture data, and post-void residual. 
Note: Recurrent UTI will be defined as three or greater culture documented UTIs within a 12 month period. 
 
Urinary tract infection: At enrollment, patients will complete a medical history questionnaire which will include 
information related to prior UTIs. Eligible patients will provide urine specimen for analysis along with physician 
assessment. Diagnosis of symptomatic UTI prior to injection is to be made at the discretion of the clinician with 
exception of nitrite positive urinalysis. Patients with nitrite positive urine on the day of injection, regardless of 
symptoms, will be excluded from enrollment. Nitrite positive urinalyses will be sent for urine culture, and patients 
may be enrolled in the trial at a later date following treatment. On the day of injection a voided urine specimen 
will be obtained from all patients and sent for urine culture. This allows for assessment of the bladder milieu at 
the time of injection, however will not be used for treatment purposes unless patient subsequently becomes 
symptomatic. Post-void residual will be obtained, per standard clinic protocol, for all patients receiving treatment. 
This will be done with bladder scanner in clinic and with catheterized specimen for patients receiving an injection 
in the operating room if PVR not previously recorded in the medical record within 8 weeks prior to injection.  
 
Assessment of overactive bladder: Participants will complete baseline standardized, validated 
questionnaires documenting urinary symptoms and quality of life.  Instruments will include the American 
Urologic Association Symptom Index (AUA-SI), Overactive Bladder Questionnaire short-form (OABq-SF), 
Patient Perception of Bladder Control questionnaire (PPBC) and the Patient’s Global Impression of 
Improvement (PGII). 
 
Inclusion/exclusion criteria. Study criteria are listed in the Table. A diagnosis of OAB and the decision to 
proceed to third line treatment will be determined by clinician according to AUA guidelines. 
 
 
 
 
 
 
 
 
 
 
Table 1. Criteria for study participation. 
Inclusion criteria 
Exclusion criteria 
• 
 ≥ 18 years of age 
• 
Post void residual urine >250ml on two occasions 

Research Protocol  
IRB submission version: 10/6/2018 
 
 
 
Day of Injection 
New Patients: 
New patients will undergo complete history and focused physical exam. PVR will be obtained at initial clinic visit. 
If PVR has not performed or is not on file on the day of injection, PVR will be obtained prior to injection. If PVR 
>250cc, it will be repeated after double void. If again greater than >250cc, patient will be excluded from 
enrollment for that injection. Physician will be responsible for determining if patient has symptomatic UTI on the 
day of injection, and exclude the patient if appropriate (UA will be utilized in making this decision).  
 
Established patients:  
Established patients continuing injection will be screened and consented on the day of presentation for injection. 
PVR within 8 weeks must be documented in chart. If no PVR documented within 8 weeks, must repeat PVR prior 
to injection with either a bladder scanner or catheterized value. UA obtained per existing clinic policy. Eligibility 
determined by provider based on UA and PVR.  
 
Demographic information including comorbidities will be abstracted from patients’ electronic medical records, 
and a focused history and physical will be performed on day of injection.  
  
Injection protocol: All patients will undergo injection per a standardized protocol of 1ml injection per site at a 
concentration of 10 units/ml. For patients undergoing injection in the clinic setting, an intravesical instillation of 
diluted local anesthetic will be used prior to injection, if no allergy to anesthetic is reported. For those performed 
in the operating room, anesthesia will be administered per the discretion of anesthesiology team. The number of 
units injected will be documented and accounted for during analysis by stratifying patients according to the 
amount of BTX-A injected.  
 
Antibiotic protocol: On the day of injection patients will be randomized to either the experimental or control 
arm according to a computer generated randomization scheme (see explanation of randomization below).  
Patients randomized to the experimental arm will receive a single dose of trimethoprim/sulfamethoxazole 
(800/160mg) peri-procedurally. Patients randomized to the control arm will receive one dose of 
trimethoprim/sulfamethoxazole peri-procedurally and additionally be prescribed trimethoprim/sulfamethoxazole 
twice daily for three days. Patients who are allergic will receive amoxicillin/clavulanic acid (875/125mg) twice 
daily for three days. If allergic to both of the above antibiotics, patients will receive 100mg nitrofurantoin BID for 
three days. Our budget reflects published data regarding our local antibiogram and population estimates for 
antibiotic allergies.   
 
3-week Post-Procedure Visit: 
 
 
All patients at 3-week post-procedure visit will receive: 
a. AUA-SI, PPBC, OABq-SF, PPBC (per standard clinical practice) 
b. PVR  (per standard clinical practice) 
c. UA  (per standard clinical practice) 
d. Urine culture if determined necessary by physician (per standard clinical practice) 
• 
Medication refractory OAB, identified per 
AUA guidelines 
 
• 
Untreated, symptomatic UTI 
• 
Comorbid neurological conditions, including spinal 
cord injury, systemic neurologic illnesses (i.e. multiple 
sclerosis, Parkinson’s disease) or central nervous 
system disease (i.e. brain tumor, stroke) 
• 
Prior pelvic irradiation 
• 
Current or prior bladder malignancy 
• 
Hematuria lacking a clinically appropriate evaluation 
• 
Chronic catheterization or SIC 

Research Protocol  
IRB submission version: 10/6/2018 
 
 
e. Post-Botox 3-Week Post Procedure Survey 
 
Symptoms Assessment: Participants will complete standardized, validated questionnaires documenting 
urinary symptoms and quality of life for comparison.  Instruments will include the American Urologic 
Association Symptom Index (AUA-SI), Overactive Bladder Questionnaire short-form (OABq-SF), Patient 
Perception of Bladder Control questionnaire (PPBC) and the Patient’s Global Impression of Improvement 
(PGII). 
 
 
Urinary tract infection: Patients will be assessed at a 3-week follow up visit with urinalysis. If a patient reports 
symptoms concerning for UTI, urine culture and antibiotic treatment will be ordered at the discretion of the 
clinician. All patients will be provided with instructions for reporting adverse events including clinic nurse contact 
information should symptoms of UTI develop. Given that our institution is a tertiary referral center and patients 
may report to local providers, a system will be in place to obtain all outside urine culture and antibiotic records 
for analysis.  
Note: For the purposes of this study, UTI will be defined as ≥105 bacterial colonies in the presence of symptoms.  
 
Treatment success: Patients will be assessed at post-procedure appointments at 3 weeks and a phone call at 
3 months. Follow up visit will consist of urinalysis, ultrasound PVR, patient-reported questionnaires, and 
recording of adverse events. Efficacy of injection will be assessed via inter-injection times for patients receiving 
multiple injections and will be followed for the duration of the study period.  
 
3-month Post-Procedure Phone Call: 
 
 
All patients at 3-month post-procedure visit will receive: 
a. AUA-SI, PPBC, OABq-SF, PPBC (per standard clinical practice) 
b. Post-Botox 3-Month Post Procedure Survey 
 
Symptoms assessment: Participants will be asked, by phone, standardized, validated questionnaires 
documenting urinary symptoms and quality of life for comparison.  Instruments will include the American 
Urologic Association Symptom Index (AUA-SI), Overactive Bladder Questionnaire short-form (OABq-SF), 
Patient Perception of Bladder Control questionnaire (PPBC) and the Patient’s Global Impression of 
Improvement (PGII). 
 
 
Urinary tract infection: Patients will be asked about presence and frequency of UTI including treatment and 
duration of treatment.  
 
Treatment success: Patients will be assessed at post-procedure phone call at 3 months. Efficacy of injection 
will be assessed via inter-injection times for patients receiving multiple injections and will be followed for the 
duration of the study period.  
 
 
2nd Injection: 
Patients will have been consented at the beginning of the study to include both 1st and second injections and 
therefore do not need to be re-consented. The exact protocol is followed as stated above, however, patients 
will receive the treatment from the arm NOT received after the first injection. For example, patients who 
received extended 3 day course of antibiotics after the first injection, will receive only peri-procedural antibiotics 
after the 2nd injection.  
 

Research Protocol  
IRB submission version: 10/6/2018 
 
 
The timing of the second injection will be determined by the clinician and patient based on symptoms and will 
not be standardized. 
 
Randomization  
Every patient will receive Extended Dose Antibiotics (EDA) and Peri-Procedural Antibiotics (PPA). The patients 
will be randomized to receive EDA or PPA at the first visit or second visit. A block randomization with block 
sizes of 2 and 4 will be used. The exact numbers of size 2- and size 4- blocks will be randomly chosen so that 
approximately 70% of blocks will be allocated to ‘block of size 4’.  
 
 
Statistical analysis plan 
The primary endpoint is the presence (Yes/No) of urinary tract infection 3 weeks post procedure. We will 
estimate the probability of urinary tract infection for both treatment groups. Baseline patient-characteristics data 
will be collected and tabulated. The trial design (crossover) will guarantee that the baseline covariates will be 
distributed similarly for both treatment groups. Carryover effect is minimized since the time between the first 
and second injections is sufficiently long for any residual treatment effect from the first period to wear off. For 
each treatment, the probability of UTI will be estimated and presented with 95% Wilson confidence intervals. 
We aim to establish non-inferiority of EDA to PPA with the non-inferiority margin of 10 percentage points. We 
will estimate the proportion of patients who will have infection with EDA but not with PPA.  
 
Sample size and power were computed using the method described in Chow et al 1 .To compute the sample 
size, we need to specify, in addition to the usual parameters (type I error rate of 5%, type II error rate of 10%, 
non-inferiority margin of 0.10, and difference under the alternative of 0), the variance of difference, which takes 
value of 1 if only EDA is successful, -1 if only PPA is successful, and 0 if EDA and PPA yield the same 
outcome. This variance, in turn, depends on the true probability of infection with EDA and PPA and also 
concordance of the result (success/failure) within a given patient. Under a pessimistic scenario where 
P[infection] is 25% and 35%, and the concordance is weak (Knowing the result of other treatment only 
changes the probability by 5 percentage points for the patient), the variance is 0.40, and the corresponding 
sample size is 68. Even if the true P[infection] is 35% and 45%, we will maintain the excellent power as shown 
below in the Table.   
 
Power with n=68 
 
P[infection] with EDA 0.25 
0.25 
0.35 
0.35 
P[infection] with PPA 0.35 
0.35 
0.45 
0.45 
Concordance  
+0.05 +0.10  +0.05 +0.10 
Power  
 
90% 
92% 
83% 
86% 
 
1 Chow SS, Shao J, Wang H. Sample size calculation in clinical research. New York: Marcel Dekker, 2003.