A Randomized Trial of Betadine Bladder Irrigations vs. Standard of Care Prior to Indwelling Catheter Removal to Reduce Bacteriuria and Catheter-Associated Urinary Tract Infections
Phase: PHASE4
Conditions: Catheter; Infection (Indwelling Catheter), Catheter Infection, Catheter-Related Infections, Catheter Bacteraemia, Urinary Tract Infections
Sponsor: Corewell Health East

IRB NUMBER: 2018-001
IRB APPROVAL DATE: 10/25/2018
1
A Randomized Trial of Betadine Bladder Irrigations vs. Standard of Care 
Prior to Indwelling Catheter Removal to Reduce Bacteriuria and Catheter-
Associated Urinary Tract Infections
Principal Investigator 
Jay Hollander MD
Co-Investigators 
Paul Chittick MD
Matthew Sims MD
Bobby Boyanton MD 
Spencer Hiller MD
Deborah Hasenau RN
PROTOCOL DATE: SEPTEMBER 26, 2018
TABLE OF CONTENTS
I.
BACKGROUND AND RATIONALE…………………………………..
2
II.
OBJECTIVES AND ENDPOINT………………………………………
3
III.
METHODOLOGY……………………………………………………
3
IV.
RISKS AND BENEFITS………………………………………………
6
V.
ELIGIBILITY CRITERIA…………………………………………….
7
VI.
DATA ANALYSIS……………………………………………………
8
VII.
DATA SAFETY MONITORING PLAN………………………………..
10
VIII.
REFERENCES……………………………………………………….
11
APPENDIX A: QUESTIONNAIRE…………………………………………
12

IRB NUMBER: 2018-001
IRB APPROVAL DATE: 10/25/2018
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I.
BACKGROUND AND RATIONALE
Indwelling urinary catheters are routinely used in the care of hospitalized patients for a variety of 
reasons, including monitoring of urine output in critically ill patients, relief of urinary 
obstruction, and prevention of contamination of decubitus ulcers. Bacteriuria increases by 3-10% 
each day a catheter is left in place1, 2 meaning that by 30 days, generally 100% of patients with 
indwelling catheters will have bacteria in their urine. The majority of these people do not have 
urinary tract infections (UTIs), they are merely colonized and do not require treatment.
 
Over the last decade, there has been great emphasis on reducing the incidence of hospital-
acquired infections, including catheter-associated UTI (CAUTI). Hospitals have had relatively 
good results, though there is certainly still room for improvement. To define a standard (and 
ultimately to compare hospitals against each other), a surveillance definition for CAUTI3 has 
been developed by the National Healthcare Safety Network (NHSN). While useful for 
surveillance, the definition does not correlate with clinical UTIs, leading to over diagnosis and 
over-reporting of UTIs (in other words, those with merely bladder colonization being diagnosed 
as having a UTI). Despite continuing progress in standard methods of reducing infection rates 
(including decreasing the number of catheters inserted, ensuring proper catheter maintenance, 
and removing catheters when no long necessary) we continue to have unacceptably high rates of 
CAUTIs. As hospital-acquired infection rates are increasingly tied to reimbursement from 
governmental agencies, there is a great need to reduce infection, either by meeting surveillance 
criteria or through novel clinical approaches.
 
Studies from the 1980s and 1990s investigated a variety of compounds for local instillations into 
the bladder in attempts to decrease bacteriuria and prevent infections. One of the more promising 
solutions instilled was povidone-iodine.  A single preoperative instillation of 1% povidone-
iodine prior to prostatectomy in patients with indwelling catheters reduced the rate of post-
operative bacteriuria from 100% to 22.5% 4. Similarly, bladder irrigation with 2% povidone-
iodine prior to prostatectomy in patients with indwelling catheters was well tolerated and 
achieved urine sterilization in 75% of patients in another study5. While neither of these studies 
looked at reducing rates of CAUTI, we hypothesize that they could provide a benefit, given their 
effectiveness at decreasing bacteriuria in patients with indwelling catheters.  Both studies 

IRB NUMBER: 2018-001
IRB APPROVAL DATE: 10/25/2018
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reported that a low concentration of 1 or 2% was well tolerated by patients. A study from the 
Netherlands evaluated use of pre-removal povidone-iodine bladder irrigation6. No reduction in 
bacteriuria was found in cultures at days 4 to 14 after removal, though there was a trend towards 
less bacteriuria in the first 3 days after removal. Additionally, more than half of the patients had 
only had catheters in place for 3 days or less prior to removal, and only 13.6% of patients had 
positive urine cultures prior to removal, which may have minimized the potential differences. 
A single dose of povidone-iodine prior to catheter removal seems a novel and promising practice 
for several reasons. First, we suspect it will be helpful in reducing rates of NHSN defined 
CAUTI, as these are still diagnosed for 2 days after the catheter is removed. Results of a recent 
review revealed that 15-20% of diagnosed CAUTIs at Beaumont occurred during this window. 
Second, using multiple doses of povidone-iodine would be inadvisable, since we suspect bacteria 
over time would become resistant even to this antiseptic. Third, we suspect use of an antiseptic is 
preferable to an antibacterial for preventing further antimicrobial resistance development. 
Finally, use of this method, as opposed to the suggested use of systemic antibiotics at time of 
removal7, is potentially preferable from the downstream standpoint of less antimicrobial 
resistance and reduced risk of Clostridium difficile infection.
II.
OBJECTIVE AND ENDPOINT
Objective:
To evaluate the effectiveness of Betadine irrigation solution (2% povidone-iodine) instilled into 
the bladder immediately prior to indwelling catheter removal to decrease the risk of subsequent 
bacteriuria, leading to decreased rates of NHSN defined CAUTI.
Endpoint:
Presence or absence of NHSN defined CAUTI at 48-72 hours after indwelling urinary catheter 
removal, as assessed by urinalysis (UA), urine culture (UC), and UTI Symptom Assessment 
questionnaire (UTISA)8.
III.
METHODOLOGY
A total of 110 men will be enrolled in this randomized trial, which will be conducted at 
Beaumont Hospital, Royal Oak. Eligible patients will be consented and randomized into 1 of 2 

IRB NUMBER: 2018-001
IRB APPROVAL DATE: 10/25/2018
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groups. Ideally, fifty-five men will be in each group. 120 men may need to be enrolled to achieve 
the desired number of patients completing the 48-72-hour post-catheter removal visit, which is 
the study endpoint.
Despite optimal “clean catch” collection techniques, it is often difficult to obtain a non-
contaminated urine sample from females without performing sterile catheterization due to the 
chronically colonized vaginal flora. In order to minimize patient risks and difficulty with 
recruitment associated with additional catheterization, we have chosen to exclude females from 
this initial study. The male anatomy allows for adequate sample collection via “clean-catch” 
alone. By enrolling only males we hope to reduce the possibility of contamination in the clean-
catch specimens collected at the 48-72 hour follow up visit9. Future studies would include 
females as well.
Study staff will review patient charts from all Beaumont Hospital, Royal Oak units (including 
rehabilitation units) in order to identify patients who may be eligible to participate.  Appropriate 
patients will be approached, the study will be described to them in detail, and informed consent 
will be obtained. Eligibility criteria will be reviewed, including current antibiotic use, which is 
exclusionary. If the patient meets all of the inclusion criteria and none of the exclusion criteria, a 
urine sample will be obtained for UA and UC. All urine test results will be for research purposes 
only and not part of the patient’s clinical chart/electronic medical record. All UA and UC results, 
collected for research, will be reviewed by one of the study investigators. If a patient develops 
symptoms at any point in the study, a UA and UC could be obtained at the care provider’s 
discretion.
Patients will be randomized 1:1 to receive either standard of care (catheter removal with no 
bladder irrigation) or bladder irrigation with 2% povidone-iodine solution immediately prior to 
catheter removal. Randomization envelopes will be provided by the biostatistician and stored in a 
secure location in Urology Research. At the time research staff contact the pharmacist with the 
Betadine request, group assignment will be verified. 

IRB NUMBER: 2018-001
IRB APPROVAL DATE: 10/25/2018
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The first group will receive standard of care (SOC) only (indwelling catheter removal without 
any other interventions). If the patient is randomized to the SOC arm, the research nurse will 
simply remove the indwelling catheter.  The second group will receive a single dose of 
approximately 60 cc of 2% povidone-iodine (Betadine) placed into the bladder. When the patient 
is randomized to the Betadine rinse arm, the research pharmacist will be contacted. The 
pharmacist will prepare and deliver the Betadine filled syringe to the research staff for 
instillation. The Betadine solution will be instilled through the catheter and left to dwell for 10 
minutes, drained, and then the catheter will be removed. Research staff will be trained by a 
physician to remove the catheter using aseptic technique and prevent introduction of bacteria. To 
ensure patients are able to adequately void after catheter removal, designated study personnel 
(Urologists), will manage the study patient’s voiding trial. 
 
48-72 hours after catheter removal a urine sample will be obtained to repeat UA and UC. If 
enrolled patients are still inpatient at this time point, study staff will see the patient in the hospital 
and conduct the Visit 2 activities. If the patient has been discharged from the hospital, this visit 
will occur in the Urology Research office. While not ideal or preferred, if the patient is not 
available for an in-person visit, the questionnaire may be completed over the phone, or sent to 
the patient and returned by mail (returned by USPS, email, or fax).  In addition to the UA and 
UC, the UTISA questionnaire will also be completed. The UTISA questionnaire is a validated 
tool which will be utilized to assess the “severity” and “bothersomeness” of the most frequently 
reported signs and symptoms of uncomplicated UTI8.  The Beaumont laboratory will evaluate all 
collected specimens. If a patient develops symptoms suggestive of a UTI, then further testing 
may be performed at the discretion of their managing physician or one of the study 
investigators. Research staff will also contact patients by phone at 7 and 28 days after catheter 
removal. At that time the UTISA will be administered to assess urinary symptoms, including 
diagnosed UTIs since the time of catheter removal. The UTISA may be completed verbally over 
the phone or by mail (returned by USPS, mail, or fax). If the patient’s responses indicate a 
possible UTI, the patient will be referred to their primary care provider and/or other health care 
provider for evaluation.

IRB NUMBER: 2018-001
IRB APPROVAL DATE: 10/25/2018
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Patients requiring reinsertion of an indwelling catheter prior to study completion will be 
withdrawn from the study. Patients that do not comply with the study protocol may also be 
withdrawn from the study by the Principal Investigator (PI).
SCHEDULE OF ACTIVITIES
Screening & 
Treatment Visit
Inpatient Visit
Visit 2 
48-72 Hours
Clinic or Inpatient 
Visit
Visit 3 
7 ± 3 days
Phone Call
Visit 4
28 ± 3 days
 Phone Call
Informed Consent
X
Review Inclusion and Exclusion 
Criteria
X
Review of Current Antibiotic 
Medication Use
X
X
X
X
Urine collection: UA & UC
X
X
UTISA Questionnaire
Xa
Xb
Xb
Indwelling Catheter Removal
X
Betadine Bladder Irrigation
Xc
Assess for Adverse Events
X
X
X
X
aAt Visit 2 the UTISA may be completed in person, over the phone, or by mail (returned via USPS, email, or fax).
bAt visits 3 and 4 the UTISA may be completed over the phone or by mail (returned via USPS, email, or fax).
cBetadine Bladder Irrigation will only be completed with those patients who are randomized to the treatment group.
IV.
RISKS AND BENEFITS
Potential Benefits: This intervention may be beneficial for both patients and the hospital. The 
rate of hospital acquired CAUTIs may be reduced without increasing the risk of antimicrobial 
resistance. 
Potential Risks: 
Risks of Urinary Catheterization: 
Less Frequent (occurring from 1% to 10% of the time):

Temporary inability to urinate

Bleeding

Mild cramping

Urinary tract infection

IRB NUMBER: 2018-001
IRB APPROVAL DATE: 10/25/2018
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Risks of Betadine:
Less Frequent (occurring from 1% to 10% of the time):

Local irritation of the bladder
Rare (occurring less than 1% of the time):

Allergic reaction
Unknown Risk:

Brown discoloration of urine
Risks of Bladder Irrigation:
Less Frequent (occurring from 1% to 10% of the time):

Discomfort while the indwelling urinary catheter is clamped
All patients will be closely monitored by the research staff during the instillation, if applicable, 
and during catheter removal. All unanticipated problems will be reported to Beaumont’s 
Investigational Review Board (IRB) per policy.
V.
COMPENSATION
Patients will be reimbursed for time and travel during the course of the study, as outlined in the 
table below. Stipend checks will be sent, via US mail, in the amount listed below after each 
completed visit which is eligible to receive a stipend. If patients are unable to complete all study 
visits, they will be paid only for the visits they were able to complete. 
Visit
Stipend Per Visit
Screening and Treatment Visit
$25.00
Study Visit 2
$25.00
Study Visit 3
$0.00
Study Visit 4
$0.00 
Maximum Total (if all visits are included)
$50.00 

IRB NUMBER: 2018-001
IRB APPROVAL DATE: 10/25/2018
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VI.
ELIGIBILITY CRITERIA 
Inclusion:
1) Provide written informed consent and the willingness and ability to comply with all 
aspects of study requirements
2) Male
3) Inpatients ≥ 18 years of age with an indwelling catheter in place for at least 5 days with a 
plan for removal
Exclusion:
1) Patients planned for discharge with an indwelling catheter in place
2) Patients unable to report urinary symptoms accurately
3) Patients with hyper-sensitivity or allergic reaction to Betadine, iodine, shellfish or other 
related compounds 
4) Clinical signs or symptoms of urinary tract infection at the time of consent
5) Patients currently being treated for UTI
6) Patients currently taking any antibiotic medication, other than those listed in Appendix B
7) Patients already taking medications known to potentially irritate the bladder, such as, but 
not limited to, cyclophosphamide, ifosfamide, and other chemotherapeutic agents
8) Patients with history of bladder cancer, pelvic radiation or interstitial cystitis
9) Patients unable to comply with study requirements 
10) Any other condition which, per investigators’ judgment, may increase patient risk and/or 
impede the reliability of study data
VII.
DATA ANALYSIS
An infection rate of 25% is anticipated at day 2 post catheter removal for the SOC group. A 
difference has been shown of a 75% drop in infection rate using povidone-iodine bladder 
irrigation5. A power analysis using these estimates yields 55 patients needed in each arm to have 
80% power at a 0.05 significance level to detect a difference of 25% versus 6.25%. We estimate 
at most a 10% dropout rate and plan to enroll 60 patients per arm to account for this.
Descriptive statistics will be provided for all data collected. Categorical variables will be 
reported as counts and percent frequencies. All continuous variables will be reported as means 

IRB NUMBER: 2018-001
IRB APPROVAL DATE: 10/25/2018
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+/- the standard deviation followed by the median, minimum to maximum or the median (25th, 
75th percentiles) then minimum to maximum dependent on the normality of the data. 
The endpoint of presence or absence of bacteriuria at 48-72 hours post catheter removal will be 
examined with a Fisher’s exact tests, odds ratio and 95% confidence intervals. If any differences 
are found in what appear to be confounders for UA, a multivariate logistic regression analysis 
may be completed adjusting for these differences.
The categorical variables will be examined using Pearson’s Chi-square tests where appropriate 
(expected frequency >5), otherwise Fisher’s exact tests will be used. Continuous variables will 
be examined for normality. Normally distributed variables will be analyzed using t-tests. Non-
normally distributed variables will be examined using non-parametric Kruskal-Wallis tests.
REDCap (Research Electronic Data Capture) is the web-based software program that will be 
utilized for data collection and management. Urology Research will be responsible for all data 
management responsibilities including, but not limited to, database creation, data entry and query 
resolution. Data analyses will be performed by a Beaumont Biostatistician utilizing statistical 
software.  
 
VIII.
DATA SAFETY MONITORING PLAN
Ongoing safety monitoring will be performed by the study staff, including the PI and co-
investigators. The PI will have ultimate responsibility of assuring patient safety. A Medical 
Safety Monitor (MSM) will be assigned by the PI. The MSM will be a physician who is not 
involved in the study and who has no conflict of interest. The MSM will review Serious Adverse 
Events (SAEs) and will determine expectedness and causality of the event. The MSM may 
suggest protocol modifications to prevent the occurrence of adverse events (e.g., modifying the 
protocol to require frequent measurement of laboratory values predictive of the event or to 
improve expeditious identification of SAEs). If the MSM is unavailable for an extended period 
(i.e. extended vacation, illness, etc.) a back-up MSM will be nominated by the study PI. Safety 
issues will also be addressed in the annual reports to Beaumont’s IRB.

IRB NUMBER: 2018-001
IRB APPROVAL DATE: 10/25/2018
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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

Safety data review at study team meetings

IRB NUMBER: 2018-001
IRB APPROVAL DATE: 10/25/2018
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IX.
REFERENCES
1. Warren, J. W., Platt, R.J., Rosner, B., & Kass, E. H. (1978). Antibiotic irrigation and catheter-
associated urinary-tract infections. New England Journal of Medicine, 299, 570-573. 
doi:10.1056/NEJM197809142991103
2. Haley, R.W., Hooton, T.M., Culver, D.H., Stanley, R.C., Emori, T.G., Hardison, C.D., Quade, 
D., Shachtman, R.H., Schaberg, D.R., Shah, B.V., Schatz, G.D. (1981). Nosocomial infections 
in U.S. hospitals, 1975-1976: estimated frequency by selected characteristics of patients. 
American Journal of Medicine, 70(4), 947-959.
3. Urinary Tract Infection (Catheter-Associated Urinary Tract Infection [CAUTI] and Non-
Catheter-Associated Urinary Tract Infection [UTI]) and Other Urinary System Infection 
[USI]) Events. National Healthcare Safety Network (NHSN) Patient Safety Component 
Manual (pp. 7.1-7.19) (2017, January). Retrieved from 
https://www.cdc.gov/nhsn/pdfs/pscmanual/pcsmanual_current.pdf
4. Richter,S., Kotliroff, O., & Nissenkorn, I. (1991). Single preoperative bladder instillation of 
povidone-iodine for the prevention of postprostatectomy bacteriuria and wound infection.  
Infect Control & Hospital Epidemiology, 12(10), 579-582.
5. Merimsky, E., Werbin, N., & Canetti, R. (1981). Pre-operative bladder irrigation with 
povidone-iodine.  British Journal of Urology, 53(4), 330-332.
6. Schneeberger, P.M., Vreede, R.W., Bogdanowicz, J.F., & van Dijk, W.C. (1992).  A 
randomized study of the effect of bladder irrigation with povidone-iodine before removal of an 
indwelling catheter.  Journal of Hospital Infection, 21(3), 223-229.
7. Marschall J., Carpenter, C.R., Fowler, S., & Trautner, B.W. (2013). Antibiotic prophylaxis for 
urinary tract infections after removal of urinary catheter: meta-analysis. BMJ, 346(3147). doi: 
10.1136/bmj.f3147.
8. Clayson, D., Wild, D., Doll, H., Keating, K., & Gondek, K. (2005). Validation of a patient-
administered questionnaire to measure the severity and bothersomeness of lower urinary tract 
symptoms in uncomplicated urinary tract infection (UTI): the UTI Symptom Assessment 
questionnaire. BJU International, 96(3), 350-359. doi: 10.1111/j.1464-410X.2005.05630.x
9. Frazee, B.W., Enriquez, K., Ng, V., & Alter, H. (2015). Abnormal urinalysis results are 
common, regardless of specimen collection technique, in women without urinary tract 
infections. Journal of Emergency Medicine, 48(6). doi: 10.1016/j.jemermed.2015.02.020.

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Appendix A: Urinary Tract Infection Symptom Assessment (UTISA) 
8. Please give an overall rating of the severity of your urinary tract infection symptoms as they are at this 
moment (Please circle the number of your answer)
0   No symptoms                      1   Mild                               2   Moderate                               3 Severe
Additional questions at Visits 3 and 4:
9. Since you last completed this questionnaire, have there been any changes in your urinary tract infection 
symptoms? (Please circle the number of your answer)
0  about the same
1  better (if patient responded 1=better, go to question 10)
2  worse
10. Please indicate how much better (Please circle the number of your answer)
6  a very great deal better
5  a great deal better
4  a good deal better
3  moderately better
2  somewhat better
1  a little better
About Your Symptoms and Their Impact on Your Life 
Please indicate whether you have had 
the following symptoms/problems in the 
past 24 hours and how severe they were: 
(Please circle one number for each 
symptom)
If you have experienced these 
symptoms/problems in the past 24 hours, 
please indicate how bothersome they were? 
(Please circle one number for each 
symptom)
Did not have   Mild     Moderate   Severe
SYMPTOMS
Not at all     A little       Moderately     A lot
        0                 1                 2               3
Frequency of urination (going to 
the toilet very often)
    0                 1                     2                 3
        0                 1                 2               3
Urgency of urination (a strong 
and uncontrollable urge to pass 
urine)
    0                 1                     2                 3
        0                 1                 2               3
Pain or burning when passing 
urine
    0                 1                     2                 3
        0                 1                 2               3
Not being able to empty your 
bladder completely/passing only 
small amounts of urine
 0                 1                     2                 3
        0                 1                 2               3
Pain or uncomfortable pressure 
in the lower abdomen/pelvic 
area caused by your urinary tract 
infection
    0                 1                     2                 3
        0                 1                 2               3
Lower back pain caused by your 
urinary tract infection
    0                 1                     2                 3
        0                 1                 2               3
Blood in your urine
    0                 1                     2                 3

IRB NUMBER: 2018-001
IRB APPROVAL DATE: 10/25/2018
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Appendix B: Antibiotic Medications which are NOT Exclusionary

Vancomycin (Vancocin)

Linezolid (Zyvox)

Daptomycin (Cubicin)

Clindamycin (Cleocin, Evoclin)

Metronidazole (Flagyl)