Clinical trial NCT04246996
Conditions: Postoperative Urinary Tract Infection Pelvic Organ Prolapse Stress Urinary Incontinence
Keywords: gentamicin sulfate pelvic organ prolapse surgery midurethral sling bladder instillation
Sponsor: Kaiser Permanente
Start date: 2020-01-29; Completion date: 2021-12-05
Enrollment: 370 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Urinary tract infection (UTI) is a common problem after surgery for pelvic organ prolapse and stress urinary incontinence. This prospective, randomized, single-masked (subject), two-parallel armed study aims to determine the effect of a single postoperative intravesical instillation of 80 mg of gentamicin sulfate in 50 mL of saline versus usual care on the proportion of women treated for UTI within 6 weeks following surgery for pelvic organ prolapse (POP) or stress urinary incontinence (SUI).

Detailed description:

Arms: arm 1: At the completion of the subjects surgery but prior to awakening from anesthesia, 80mg of gentamicin in 50 mL of normal saline will be infused into the subject's bladder through the standard-of-care transurethral catheter by the surgeon. The surgeon will then clamp the catheter and label the catheter with the clamping time. The catheter will be clamped to prevent the gentamicin from immediately flowing out of the bladder and thus allow the gentamicin time to have an effect. The subject will then proceed as usual to the postoperative anesthesia care unit. A member of the subject's care team will unclamp the catheter after 1 hour. The subject will otherwise have usual pre-operative and post-operative care. arm 2: If the patient is randomized to no instillation, at the end of the surgery but prior to awakening from anesthesia, the surgeon will clamp the catheter and label the catheter with the clamping time. The purpose of clamping the catheter for subjects receiving usual care will be to ensure patients are masked to study arm assignment if they wake up and notice their catheter. The subject will then proceed as usual to the postoperative anesthesia care unit. A member of the subject's care team will unclamp the catheter after 1 hour. The subject will otherwise have usual pre-operative and post-operative care.
Interventions: intervention 1: gentamicin sulfate intervention 2: Catheter clamping only
Intervention descriptions: intervention 1: Subjects in the gentamicin arm will receive an bladder instillation of 80mg of gentamicin sulfate in 50 mL of normal saline through a standard-of-care Foley catheter. intervention 2: Subjects in the control arm will have their standard-of-care transurethral catheter clamped for 1 hour post-placement to maintain subject masking to study arm.

Protocol documents:
Prot_SAP_000.pdf: 
Official Study Title – Gentamicin Intravesical Efficacy for Infection of Urinary Tract 
 
NCT Number – 4246996  
 
Document Date – Approved by UC San Diego IRB on June 9, 2020 
 
The following document contains a portion of the research plan for this study approved by the 
UC San Diego on June 6, 2020.  This portion of the research plan outlines the study protocol and 
statistical analysis plan. 
 
 
 
 
 
Mary Rieger, MD, MAS 


 
 
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microscopic level not previously well studied. 
8. 
PROGRESS REPORT 
Not applicable 
 
9. 
RESEARCH DESIGN AND METHODS 
Overview 
This is a prospective, randomized, single-blinded (subject), two-parallel armed, comparison of 
a single postoperative intravesical instillation of 80 mg of gentamicin sulfate in 50 mL of saline with 
no instillation on the proportion of women treated clinically for UTI within 6 weeks after undergoing 
urogynecologic surgery.  
The randomization scheme will be stratified based on the type of urogynecologic surgery 
performed given that different risk factors for post-operative UTI depending on type of surgery.  
Transvaginal, versus transabdominal, prolapse surgeries have a higher rate of post-operative UTIs.  
Midurethral sling surgery also increases the risk for UTI compared to a surgery without.  Additionally, 
our planned second site Kaiser Permanente performs relatively more transabdominal prolapse 
repairs than is done at UCSD.  Therefore we plan the following strata with a 1:1:1:1 allocation 
between the strata: (1) transabdominal prolapse repair with midurethral sling, (2) transabdominal 
prolapse repair without midurethral sling, (3) transvaginal prolapse repair with midurethral sling, and 
(4) transvaginal prolapse repair without midurethral sling. 
 
Study Procedures/Activities 
A woman scheduled to undergo urogynecologic surgery will be informed by her surgeon she is 
eligible for study enrollment at her standard-of-care pre-operative appointment.  At that time, if the 
patient wishes, written informed consent will be obtained and the patient will be assigned a study 
identification (ID) number.  On the day of surgery, the patient will meet with her surgeon briefly again 
in the pre-operative area to confirmed continued design to participate in the study and to review the 
surgical plan.  Premenopausal subjects (i.e. last menstrual period less than 1 year ago) who have not 
previously undergone hysterectomy undergo a urine pregnancy test as part of their standard clinical 
care to assure non-pregnant status on day of surgery. The results of this test will be utilized to 
determine final study eligibility, i.e. those who are determined to be pregnant will be excluded from 
the study.  Regardless of study group assignment, the subject will receive pre-operative intravenous 
prophylactic antibiotics, which is the standard of care per hospital policy.  Once the subject is in the 
operating room and has undergone induction of anesthesia and placement of a transurethral catheter 
for clinical care, a urine sample will then be obtained at the start of the case.  A vaginal swab will also 
be obtained.  The process of obtaining these samples will take less than 1 minute and will not 
significantly prolong anesthesia time.  These samples will be saved for microbiome analysis.  The 
planned surgery will then be performed.  Then, while still under general anesthesia and during the 
final safety cystoscopy performed for the subject’s standard clinical care, if the patient has not had 
any intraoperative events that exclude her from the study, the surgeon will open the patient’s 
randomization envelop to determine study arm assignment (to gentamicin or no instillation group). 
After a final foley catheter is placed, for the subject’s standard clinical care, another urine sample for 
microbiome analysis will be obtained, as will a vaginal swab for vaginal microbiome analysis.  Then, if 
the patient is randomized to gentamicin, 80mg of gentamicin in 50 mL of normal saline will be infused 
into the patient’s bladder through the standard-of-care transurethral catheter by the surgeon.  The 
surgeon will then clamp the catheter and label the catheter with the clamping time.  If the patient is 
randomized to no instillation, the surgeon will clamp the catheter and label the catheter with the 
clamping time.  The purpose of clamping the catheter for subjects receiving usual care will be to 
ensure patients are blinded if they wake up and notice their catheter.  The subject will then proceed 


 
 
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as usual to the postoperative anesthesia care unit (PACU), with instructions for the PACU nurse to 
unclamp the catheter 1 hour after the clamping time. All patients will then receive usual postoperative 
care including an active voiding trial as indicated.  During the voiding trial, which is performed as part 
of the subject’s standard clinical care, the transurethral catheter is disconnected from the collection 
bag.  Then the subject’s bladder is backfilled with approximately 300 mL of sterile water or saline.  
The catheter is then removed and the patient is instructed to urinate.  The voided volume is 
measured.  The post-void residual is also measured non-invasively by bladder scan. 
After surgery, as is part of routine care, the patients will call the surgeon’s office if they have 
UTI symptoms and these calls will be addressed in the usual fashion by the nursing and physician 
office staff.  The patients will give catheterized urine samples as indicated for UTI symptoms which 
will be processed at a UCSD laboratory.  
At 6 weeks after surgery the patient will be seen for a standard-of-care postoperative 
appointment.  At this time, the patient will undergo some standard-of-care health questions related to 
post-operative healing and any adverse health events since surgery.  For the specific purposes of the 
study and at the FDA’s recommendation, all patients at the 6 week post-operative visit will be asked 
whether they have experienced new onset of hearing loss, tinnitus, dizziness, or vertigo since 
surgery. For the purposes of the study, if the patient does not come to their post-operative 
appointment, they will be called at to see whether they have been treated for UTI or have UTI 
symptoms since surgery.  They will also be asked about any other adverse health events since 
surgery.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Schedule of Participant Visits 
 
Procedures/Interventions Performed Solely For Research Purposes 
The procedures/interventioned performed solely for research purposes include the collection of urine 
samples and vaginal swab samples immediately before and after the urogynecologic surgery, as well 
as the instillation of gentamicin (if randomized to that arm), and the clamping of the catheter in both 
study arms.  Post-operative questions regarding new onset of hearing loss, tinnitus, dizziness, or 
vertigo since surgery are also specifically for the study due to the FDA’s recommendation in the IND 
Visit Timing 
Purpose 
Location 
Time 
Required 
Testing 
1 
Within 4 weeks 
of surgery 
Standard-of-care 
preoperative 
counseling, 
study recruitment and 
informed consent 
process 
WPMC 
60 minutes 
Standard-of- 
care complete 
blood count, 
serum 
electrolytes, 
serum 
creatinine and 
blood urine 
nitrogen, 
pregnancy test 
for women of 
childbearing 
potential, and 
urinalysis 
and/or urine 
culture for all 
patients 
2 
Day of Surgery 
Surgery, 
Randomization, 
Study Intervention 
(gentamicin instillation 
versus only catheter 
clamping), Standard-
of-care post-operative 
care  
JMC/KOP 
Approximately 
8 hours 
(depending on 
surgery length) 
Standard of 
care pre-
operative 
pregnancy test 
for appropriate 
patients, 2 
catheterized 
urine 
specimens 
and 2 vaginal 
swab 
specimens for 
microbiome 
analysis 
3 
6 weeks after 
surgery day 
Standard-of-care 
postoperative 
assessment 
 
WPMC 
60 minutes 
Standard of 
care urinalysis 
and/or urine 
culture if UTI 
symptoms 


 
 
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approval process.  Finally, the telephone call at 6 weeks if the subject does not come to their 
scheduled follow up appointment will be for the purpose of collecting study data. All other aspects of 
the study are routine clinical care that the subjects would be undergoing even if they were not 
participants in the study. 
    
IND Requirement 
Gentamicin sulfate is FDA approved for treatment and prevention of bacterial infections in 
adults given by intramuscular or intravenous route.  Our study proposes the use of gentamicin sulfate 
80mg in 50 mL of normal saline administered directly into the bladder via transurethral catheter to 
prevent post-operative UTI infection.  The subject would have this standard-of-care catheter at the 
end of the surgery regardless of participation in the study.   Due to our proposal for a new route and 
indication, and Investigational New Drug application has been filed with the FDA (IND 146413) and 
we have been cleared to proceed with this proposed trial as of November 15, 2019.  See attached 
documents for IND correspondence with the FDA.   
 
Study Procedures for Obtaining Research Material 
All research material will be stored labeled with subject study ID rather than identifying 
characteristics.  All material will be collected specifically for research purposes and will not be saved 
for future use after the current study is concluded.  Urine samples will be collected by a transurethral 
catheter placed as part of the subject’s standard clinical care immediately before and after the 
surgery while the subject is still under general anesthesia.  Vaginal swabs will be collected at the 
same time.  Other study material will be collected by manual abstraction of data from the electronic 
medical record.  No audio or video recording will be performed as a part of the study.  No 
questionnaires will be used for the study. 
 
Data Collection 
An encrypted electronic database will be used to compile study data.  All subjects will have a 
unique study ID linked to protected health information stored separately in a locked room at WPMC 
only accessible to study personnel. The data will be entered into the database by study ID.   
Baseline subject data will be collected including patient name, medical record number, date of 
birth, telephone call for phone follow up, age, body mass index (BMI), parity, race, ethnicity, prior 
hysterectomy, history of diabetes mellitus, American Society of Anesthesiologists (ASA) Physical 
Status Class, menopausal status, use of hormone replacement therapy within 3 months, use of 
vaginal estrogen within 3 months, history of recurrent UTI, and positive pre-operative UTI. 
At the end of each surgery, the surgeon will record the following information on an OR Form 
which will be later entered into the data base – procedures performed, procedure start and end time, 
number of cystoscopies, resident and/or fellow involvement and year of training, estimated blood 
loss, IV antibiotic received pre-operatively and whether or not it was appropriately re-dosed as 
indicated.  These OR forms will be kept in a secured box in the Women’s Pelvic Medicine Center with 
only co-investigators and study staff having access.  The OR forms will be labeled by study ID. 
The following information will be extracted from the patient’s chart for the post-operative period 
- length of hospital stay in days, length of initial immediate post-operative catheterization (in days), 
results of initial active voiding trial, need for continued postoperative catheterization after hospital 
discharge (and if so -, type of post-operative catheterization [indwelling or intermittent] and duration 
[in days]), post-operative UTI treatment and urine culture result if applicable, patient reports of 
dizziness, tinnitus, hearing loss, or vertigo, and hospital readmission. This information will be added 
to the electronic database.   
Results of intraoperative urinary and vaginal microbiome results will also be added to the 
electronic database. 


 
 
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Prior to final analysis, the investigators will make efforts to resolve any missing data by a final 
review of the electronic medical record.  
Based on previously published data regarding safety of intravesical gentamicin, we will focus 
specifically on gathering data related to suprapubic discomfort and development of antibiotic-resistant 
UTI.14,15 Other adverse events during the study period, including death and hospital admission, will 
also be recorded.  Per FDA request we will also monitor for ototoxicity including dizziness, vertigo, 
hearing loss, and tinnitus.  Study investigators will review the study database every 6 months to 
analyze incidence of adverse events.  If there is a 10% or greater incidence of serious adverse event 
among participants (i.e. unanticipated hospital admission), the research team will meet to discuss 
potential for serious adverse event to be related to intravesicular gentamicin, study modification, or 
termination.    
 
Data Analysis/Interpretation 
           Subjects’ data will be analyzed “as treated”. Preoperative and perioperative variables will be 
summarized by means with standard deviations for continuous variables and rates and proportions 
for categorical variables.  To determine whether any significant baseline differences exist between 
the study arms, preoperative and perioperative variables of the two study arms will be compared 
using chi-square test for categorical variables or Student t-test or Wilcoxon rank sum test for 
continuous variables.  
The primary outcome of the study, proportion of patients who are clinically treated for UTI, will 
be analyzed with a chi-squared test.  All adverse events will be listed with description of type and 
severity.  The proportion of patients with each type of postoperative adverse event (diarrhea, yeast 
infection, hospital admission with organ dysfunction, and death) in each arm will also be compared 
using a chi-squared test.  Statistical significance will be defined as α<0.05.    
In order to perform our sample size calculation, we first wanted to baseline postoperative UTI 
rates according to the definition of our primary outcome at our institution. Chart queries were 
performed for all GIVE-IT candidates during 2-month time period (Jan-Feb 2019; N=41) at Kaiser 
San Diego (our FPMRS fellowship sister institution), as it is currently our practice at UCSD (but not at 
Kaiser) to prescribe oral antibiotic prophylaxis following SUI surgery, which could alter UTI rate. The 
UTI rate in this chart query was 17%. To detect a meaningful reduction in UTI from 17% in controls to 
8% in intervention group (α = 0.05, one-tailed) with 80% power (β = 0.2), 166 subjects will be needed 
per arm.  This effect of 50% reduction as a meaningful outcome is derived from the similar effect of 
oral antibiotic post-operative UTI prophylaxis seen in a similar clinical trial.3 Accounting for 20% 
dropout or loss to follow-up, we will recruit 200 subjects per arm.   Our benchmark for successful 
recruitment will be approximately 50% recruitment completed 6 months after the first subject is 
enrolled.  In order to complete enrollment more rapidly, we anticipate adding Kaiser San Diego as a 
secondary study site.   
All of the patients in the study will be women. Based on a retrospective population-based 
cohort study of 149,554 American women, there was an 11.1% lifetime risk of undergoing a single 
surgery for prolapse or incontinence by age 80.17   In another population based cohort study  of 2270 
middle-aged and older racially diverse American women (44% white, 20% African American, 18% 
Asian, and 18% Latina or other), 19% of the Latina women, 7% of the Asian women, and 5% of the 
African American women reported bothersome prolapse.18   A study of the same cohort found that 
36% of Hispanic women, 25% of African American women, and 19% of Asian America women 
reported weekly urinary incontinence.19  The study will not specifically recruit or exclude minority 
ethnic groups.  Based on the clinical population at WPMC, approximately 30% of the subjects are 
expected to be Latina, 10% Asian, and 5% African American.   
 
10. HUMAN SUBJECTS