Clinical trial NCT02358993
Conditions: Urinary Tract Infections Catheter-Related Infections
Keywords: Urinary Tract Infections Catheter-Related Infections Pelvic Reconstructive Surgery Urogynecology Urinary catheterization Post-operative Infections Methenamine hippurate
Sponsor: University of Pennsylvania
Start date: 2014-12-01; Completion date: 2020-09-30
Enrollment: 201 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The investigators will determine the efficacy of an innovative short regimen of methenamine hippurate on prevention of post-operative UTI in patients requiring short-term catheterization after pelvic reconstructive surgery through a single-blind, randomized controlled trial. Primary outcome will be the rate of symptomatic UTI within 3 weeks of catheter removal. The investigators will study cost-effectiveness, antibiotic resistance profiles, and adverse drug effects. Findings may reduce antibiotic use and nosocomial UTIs.

Detailed description:
Prevention of post-operative urinary tract infections (UTI) is becoming important for both the individual patient and the health system. Complications of UTI include pyelonephritis and bacteremia, requiring hospitalization and parenteral antibiotics. Additionally, recurrent exposure to antibiotics commonly given for UTIs increases the risk of antibiotic resistance to uropathogens. UTIs also increase economic burdens on the health care system, with each episode costing nearly 600 dollars. UTIs associated with catheterization are particularly costly for hospitals, resulting in decreased hospital quality measures and lack of compensation.

This is particularly important after pelvic reconstructive surgery, as reported rates of UTI reach up to 20-25%. Urinary retention requiring short-term indwelling catheterization, common in these women, contributes to the risk of UTIs by increasing the risk of bacteriuria by 5-10% per day and through the dislodging of bacterial colonies during catheter removal. Balancing prevention and resistance and cost is key. A meta-analysis by Marschall et al indicated the benefit of a short dose of antibiotic prophylaxis at catheter removal in general post-surgical patients. However, data is lacking on the effects of daily antibiotic prophylaxis on resistance and cost.

A possible alternative to antibiotics presents itself in methenamine hippurate, a urinary antiseptic which forms formaldehyde in the presence of acidic urine. It is relatively inexpensive, and does not induce resistance in vivo. Prior studies have shown that daily use of methenamine can decrease the risk of post-operative UTI.

The purpose of our study was to investigate the efficacy of a short course of methenamine hippurate at catheter removal to that of a short course of ciprofloxacin in prevention of UTIs after short-term indwelling catheterization. Additionally, we investigated factors that influence post-operative UTIs, the rate of culture-proven UTIs after prophylaxis, the antibiotic resistance profile of those undergoing prophylaxis, and the cost effectiveness of prophylaxis.

Arms: arm 1: Methenamine hippurate is a medication that exhibits antibacterial activity by converting to formaldehyde in the presence of acidic urine. It is currently FDA approved for the prophylaxis of recurrent urinary tract infections. It has been previously used in studies for prevention of UTI after gynecologic surgery. Dosage will be methenamine hippurate 1g, 1 tablet by mouth every 12 hours for 24 hours (total of two doses), with the first dose taken at least one hour prior to catheter removal. arm 2: Ciprofloxacin is a commonly used antibiotic commonly used for prevention of UTI after catheterization. It belongs to a class of antibiotics known as the fluoroquinolones. Dosage will be ciprofloxacin 500 mg, 1 tablet by mouth every 12 hours for 24 hours (total of two doses), with the first dose taken at least one hour prior to catheter removal.
Interventions: intervention 1: methenamine hippurate intervention 2: Ciprofloxacin
Intervention descriptions: intervention 1: A urinary antiseptic used for prevention of UTI intervention 2: An antibiotic used for treatment and prevention of UTI

Protocol documents:
Prot_SAP_000.pdf: 
The Efficacy and Cost-Effectiveness of a 24-hour course of 
Methenamine Hippurate For Preventing Post-Operative 
Urinary Tract Infection 
 
NCT02358993 
 
April 4, 2019 


Page 1 of 22
Protocol Details
Basic Info
Conﬁrmation Number:
cihdibib
Protocol Number:
820117
Created By:
CHU, CHRISTINE M
Principal Investigator:
ARYA, LILY A
Protocol Title:
The Efﬁcacy and Cost-Effectiveness of a 24-hour course of Methenamine Hippurate For Preventing Post-Ope
Urinary Tract Infection
Short Title:
Short-Course Methamine Hippurate for Prevention of Post-Operative UTI
Protocol Description:
We will determine the efﬁcacy of an innovative short regimen of methenamine hippurate on 
prevention of post-operative UTI in patients requiring short-term catheterization after pelvic 
reconstructive surgery through a randomized, double-blinded, placebo-controlled trial. Primary 
outcome will be the rate of symptomatic UTI within 3 weeks of surgery. We will study cost-
effectiveness, antibiotic resistance proﬁles, and adverse drug effects. Findings may reduce 
antibiotic use and nosocomial UTIs.
Submission Type:
Biomedical Research
Application Type:
FULL
Resubmission*
Yes
Hospital Sites
Will any research activities and/or services be conducted at a Penn Medicine afﬁliated hospital site?
No
Study Personnel
Principal Investigator
Name:
ARYA, LILY A
Dept / School / Div:
4333 - OB-Obstetrics and Gynecology
Campus Address
Mail Code
4283
Address:
HUP
3400 SPRUCE ST
City State Zip:
PHILADELPHIA PA 19104-4283
Phone:
215-662-4144
Fax:
-
Pager:
Email:
larya@obgyn.upenn.edu
HS Training Completed:
Yes
Training Expiration Date:
09/16/2016
Name of course completed :
CITI Protection of Human Subjects Research Training - ORA


Page 2 of 22
Study Contacts
Name:
KINGLEE, MICHELLE
Dept / School / Div:
10616 - CI-Center for Cellular Immunotherapy
Campus Address
Mail Code
6160
Address:
Suite 810 3701 Market Street
Research Science Center
1000 Courtyard-HUP
City State Zip:
Philadelphia PA 19104-6160
Phone:
215-615-6569
Fax:
-
Pager:
Email:
kingleem@uphs.upenn.edu
HS Training Completed:
Yes
Training Expiration Date:
05/27/2017
Name of course completed :
CITI Protection of Human Subjects Research Training - ORA
Name:
LEE, DANIEL D
Dept / School / Div:
4333 - OB-Obstetrics and Gynecology
Campus Address
Mail Code
4283
Address:
HUP 
3400 SPRUCE ST 
City State Zip:
PHILADELPHIA PA 19104-4283
Phone:
215-662-2459
Fax:
Pager:
Email:
daniel1@upenn.edu
HS Training Completed:
Yes
Training Expiration Date:
07/28/2017
Name of course completed :
CITI Protection of Human Subjects Research Training - ORA
Name:
NOLAN, BRIDGET
Dept / School / Div:
2100 - Health System
Campus Address
Mail Code
Address:
3701 Market Street 
Penn Fertility Care 
City State Zip:
Philadelphia PA 19104-0000
Phone:
Fax:
Pager:
Email:
bridget.nolan@uphs.upenn.edu
HS Training Completed:
Yes
Training Expiration Date:
09/09/2018
Name of course completed :
CITI Protection of Human Subjects Research Training - ORA


Page 3 of 22
Other Investigator
Name:
HARVIE, HEIDI S
Dept / School / Div:
4333 - OB-Obstetrics and Gynecology
Campus Address
Mail Code
4283
Address:
3701 Market Street
Suite 800
City State Zip:
Philadelphia PA 19104-4283
Phone:
215-615-4023
Fax:
-
Pager:
Email:
hharvie@obgyn.upenn.edu
HS Training Completed:
Yes
Training Expiration Date:
12/05/2016
Name of course completed :
CITI Protection of Human Subjects Research Training - ORA
Responsible Org (Department/School/Division):
4333 - OB-Obstetrics and Gynecology
Key Study Personnel
Name:
SMITH, ARIANA L
Department/School/Division:
SU-Surgery Administration
HS Training Completed:
Yes
Training Expiration Date:
08/14/2014
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
Name:
STEIDER, ELIZABETH M
Department/School/Division:
WM-Ctr for Res on Reprod and Women's Health
HS Training Completed:
Yes
Training Expiration Date:
04/14/2018
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
Name:
FLICK, LORRAINE C
Department/School/Division:
WM-Ctr for Res on Reprod and Women's Health
HS Training Completed:
Yes
Training Expiration Date:
02/10/2019
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
Name:
LEVIN, PAMELA J
Department/School/Division:
OB-Obstetrics and Gynecology
HS Training Completed:
Yes
Training Expiration Date:
08/12/2016
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA


Page 4 of 22
Name:
ANDY, UDUAK U
Department/School/Division:
OB-Obstetrics and Gynecology
HS Training Completed:
Yes
Training Expiration Date:
05/24/2014
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
Disclosure of Signiﬁcant Financial Interests*
Does any person who is responsible for the design, conduct, or reporting of this research protocol have 
a FINANCIAL INTEREST?
No
Penn Intellectual Property*
To the best of the Principal Investigator's knowledge, does this protocol involve the testing, 
development or evaluation of a drug, device, product, or other type of intellectual property (IP) that is 
owned by or assigned to the University of Pennsylvania?
Certiﬁcation
I have reviewed the Financial Disclosure and Presumptively Prohibited Conﬂicts for Faculty 
Participating in Clinical Trials and the Financial Disclosure Policy for Research and Sponsored 
Projects  with all persons who are responsible for the design, conduct, or reporting of this research; and 
all required Disclosures have been attached to this application.
Yes
Biomedical Research
Clinical Trial*
Is this a clinical trial?
Investigator Initiated Trial*
Is this an investigator initiated trial?
Yes
If Yes, please be aware that the investigator may be required to create and manage a record of this trial 
in https://clinicaltrials.gov.
Drugs or Devices*
Does this research study involve Drugs or Devices?
Yes: Drugs, products or devices are used in accordance with FDA approval.
IND Exemption
For studies that fall under an IND exemption, please provide the number below
For studies including IND or IDE's, please provide the number(s) below
IDE Review*
NOTE: For research involving investigational devices, you are required to review the guidance on 
Managing Research Device Inventory. Consult the Penn Manual for Clinical Research: https://
www.med.upenn.edu/pennmanual/secure/investigational-product-management-at-sites-not-using-
investigational-drug-services-(ids).html Please check the box Yes if you have reviewed the guidance.
Yes


Page 5 of 22
Research Device Management*
Please indicate how research device(s) will be managed.
Not Applicable (no investigational devices)
Drug, Herbal Product or Other Chemical Element Management *
Please indicate how drugs, herbal products or other chemical entities will be managed.
The drug, herbal product or other chemical entity will be received, stored and dispensed by the research 
team (please provide information in the protocol summary as to how this will be conducted)
Radiation Exposure*
Are research subjects receiving any radiation exposure (e.g. X-rays, CT, Fluoroscopy, DEXA, pQCT, 
FDG, Tc-99m, etc.) that they would not receive if they were not enrolled in this protocol?
No
Gene Transfer*
Does this research involve gene transfer (including all vectors) to human subjects?
No
Human Source Material*
Does this research include collection or use of human source material (i.e., human blood, blood 
products, tissues or body ﬂuids)?
Yes
CACTIS and CT Studies*
Does the research involve Center for Advanced Computed Tomography Imaging Services (CACTIS) 
and CT studies that research subjects would not receive if they were not part of this protocol?
No
CAMRIS and MRI Studies*
Does the research involve Center for Advanced Magnetic Resonance Imaging and Spectroscopy 
(CAMRIS) and MRI studies that research subjects would not receive if they were not part of this 
protocol?
No
Investigational Agent or Device within the Operating Room*
Does the research project involve the use of an investigational agent or device within the Operating 
Room?
No
Cancer Related research not being conducted by an NCI cooperative group*
Does this protocol involve cancer-related studies in any of the following categories?
No
Processing of Materials*
Will the research involve processing (such as over encapsulating, or compounding)?
Yes
In-House Manufacturing of Materials*
Will the research involve processing (such as over encapsulating, or compounding)?
Yes
Medical Information Disclosure*
Does the research proposal involve the use and disclosure of research subject's medical information for 
research purposes?
Yes
If the answer is YES, indicate which items is is provided with this submission:
Modiﬁed research informed consent document that incorporates HIPAA requirements


Page 6 of 22
CTRC Resources*
Does the research involve CTRC resources?
No
Pathology and Laboratory Medicine Resources*
Will samples be collected by hospital phlebotomy and/or processed or analyzed by any of the clinical 
laboratories of the University of Pennsylvania Health System?
Yes
Clinical Laboratory Services*
Will samples be collected by UPHS phlebotomy and/or analyzed by the hospital laboratory?
No
Anatomic Pathology Services*
Will tissue specimens (other than blood) be collected for clinical, diagnostic, or research purposes OR 
be processed through surgical pathology, cytopathology, neuropathology, or hematopathology?
No
Research Involves Apheresis, Cell Collection, and/or Blood Product Collection*
Does this research involve collection of blood products in the Penn Donor Center and/or the use of 
apheresis for treatment or collection of cells or other blood components?
No
Research involving blood transfusion or drug infusions*
Will your research involve blood transfusion or infusion of study drug in 3 Ravdin Apheresis Unit for 
research purposes?
No
Trial in Radiation Oncology
Is this research a prospective trial being done in Radiation Oncology, and if so, has this protocol been 
approved by the Radiation Oncology Protocol committee?
N/A
Study in Radiation Oncology
Is this research a retrospective study being done in Radiation Oncology, and if so, has this project been 
reviewed by the Radiation Oncology Clinical Research Group?
N/A
Use of UPHS services*
Does your study require the use of University of Pennsylvania Health System (UPHS) services, tests or 
procedures*, whether considered routine care or strictly for research purposes?
Yes
Primary Focus*
Clinical Trial (prospectively assigning subjects to health-related interventions to evaluate outcomes)
Protocol Interventions
Sociobehavioral (i.e. cognitive or behavioral therapy)
x Drug
Device - therapeutic
Device - diagnostic (assessing a device for sensitivity or speciﬁcity in disease diagnosis)
Surgical
Diagnostic test/procedure (research-related diagnostic test or procedure)
Obtaining human tissue for basic research or biospecimen bank
Survey instrument
None of the above


Page 7 of 22
The following documents are currently attached to this item:
There are no documents attached for this item.
Department budget code
None
Multi-Center Research
Penn as lead
1.  Is this a multi-center study where Penn is serving as the Lead Site or the Penn PI is serving as the 
Lead Investigator?
Management of Information for Multi-Center Research
Not Applicable
Penn irb of record
2. Is this a multi-center study where the Penn IRB will be asked to serve as the IRB of Record for other 
external study sites?
Other Sites
No other sites
Protocol
Abstract
Catheter-associated urinary tract infection (UTI) is the most common post-operative nosocomial 
infection. An agent that prevents catheter-associated UTI but is not associated with antibiotic resistance 
is not known. Methenamine hippurate has similar pharmacokinetics as short-course antibiotics that 
prevent catheter-associated UTI, such as ciproﬂoxacin. Our aim is to compare the efﬁcacy of an 
innovative short regimen of methenamine hippurate, an antiseptic that is converted into formaldehyde in 
urine, with the efﬁcacy of short-course ciproﬂoxacin for preventing post-operative UTI in 
urogynecologic surgery. We propose a randomized, blinded non-inferiority trial to determine the 
efﬁcacy of two doses of methenamine hippurate compared with the urology standard of 
ﬂuoroquinolones at catheter withdrawal for reducing post-operative UTI in patients requiring short-term 
indwelling catheterization after pelvic reconstructive surgery. The primary outcome will be the rate of 
symptomatic UTI requiring treatment within three weeks of surgery. We will perform cost-effectiveness 
analysis comparing the cost of prophylaxis with methenamine to the cost of prophylaxis with 
ciproﬂoxacin. We plan to describe the resistance proﬁle of positive urine cultures and adverse effects of 
methenamine. This study is innovative because it involves 1) a two-dose regimen of a non-antibiotic 
prophylactic and 2) cost-effectiveness analysis. The ﬁndings will help reduce the rate of antibiotic use 
and nosocomial UTIs, which are associated with morbidity and serve as important indicators of quality 
of care.
Objectives
Overall objectives
SPECIFIC AIMS Primary Aim: To determine if the efﬁcacy of prophylaxis with a 24 hour course of 
methenamine hippurate (two doses) is non-inferior to the efﬁcacy of a 24-hour course of 
ﬂuoroquinolones in prevention of post-operative urinary tract infections after short-term indwelling 
catheterization following surgery for pelvic ﬂoor disorders. Secondary aim: - To determine if 
prophylaxis with methenamine hippurate is more cost-effective than prophylaxis with ﬂuoroquinolones 


Page 8 of 22
in patients undergoing short-term indwelling catheterization. - To determine the antibiotic resistance 
proﬁle of post-operative urinary tract infections that develop after short-term indwelling catheterization 
after surgery for pelvic ﬂoor disorders, with methenamine as compared to ﬂuoroquinolones. - To 
determine the prevalence of side effects that may accompany use of methenamine hippurate 
prophylaxis. - To describe factors that inﬂuence patient medication compliance with short-term 
methenamine hippurate and ciproﬂoxacin prophylaxis.
Primary outcome variable(s)
PRIMARY OUTCOME: Treatment of clinically suspected UTI within three weeks of surgery. This is 
deﬁned as any symptomatic UTI requiring treatment with antibiotics as determined by the development 
of 2 or more of the following symptoms, in the absence of vaginal symptoms: urinary frequency; 
urinary urgency; dysuria; fever over 38ºC/100.4ºF; suprapubic, ﬂank, or back pain; and/or chills. 
Patients will be encouraged to undergo urine culture prior to empiric treatment, but a positive urine 
culture will not be required as part of the primary outcome. We feel that this more accurately reﬂects 
the diagnosis and treatment of UTI in the clinical setting as: 1) it may not always be possible to delay 
treatment until patients are able to undergo urine culture; 2) accuracy of self-reported symptoms for the 
diagnosis of UTI is high;28 3) the probability of UTI in patients with combinations of symptoms is very 
high.29
Secondary outcome variable(s)
SECONDARY OUTCOME:  - cost-effectiveness of prophylaxis with methenamine hippurate for 
prevention of post-operative UTI compared to prophylaxis with ﬂuoroquinolones - rate of culture-
positive symptomatic UTI  - prevalence of antibiotic resistance in positive post-operative cultures - 
prevalence of side effects following a 24-hour course of methenamine hippurate - factors that may 
inﬂuence patient compliance with short-course of chemoprophylaxis. Cost-effectiveness data: We plan 
to perform a cost-effectiveness analysis from a societal perspective, which will be expressed as 
incremental cost per UTI prevented. Routine costs of prevention of UTI with methenamine hippurate 
prophylaxis will be compared with costs of prevention of UTI with ﬂuoroquinolone prophylaxis. We 
plan to capture incremental direct health care costs, which will be estimated using the resource costing 
method. Direct medical service standard of care use (such as number and types of physician visits, 
hospital admissions lengths, emergency transport and emergency room visits), and direct medical costs 
(such as antibiotic treatment of UTI, prophylaxis with methenamine or ciproﬂoxacin, urine laboratory 
tests, or treatment of complications like pyelonephritis) will be monetized by multiplying the number of 
units of each resource used per treatment arm by the average unit cost of these items in dollars. Detailed 
individual cost data will not be collected. This method allows a consistent capture of resource use when 
costs are incurred across multiple health systems or payers. Cost for each direct medical service use, 
direct non-medical items, and indirect items will be assigned based on national Medicare 
reimbursement rates or other standardized unit costs.  Among patients who undergo urine culture as part 
of standard of care for UTI, the rate of positive cultures will be identiﬁed. As per standard of care, 
antibiotic resistance will be collected by sensitivity testing on all positive urine cultures identiﬁed from 
samples collected for evaluation of symptomatic UTI in post-operative patients. Bacterial species and 
sensitivities will be identiﬁed and recorded.  To determine medication compliance rates, any unused 
medication will be returned to the ofﬁce at their post-operative follow-up visit. As per routine care, 
investigators will also ask patients during the weekly routine post-operative call and routine post-
operative visits about their compliance with the second dose of medication. Adverse effects from the 
administration of methenamine and ﬂuoroquinolones will be collected. Patients will be asked to 
document any side effects, including nausea, vomiting, pruritis, and rash, that may occur within 24 
hours of the administration of the last dose of methenamine or antibiotic.
Background
URINARY 
TRACT 
INFECTIONS 
ASSOCIATED 
WITH 
SHORT-TERM 
INDWELLING 
CATHETERIZATION:  Catheter-associated urinary tract infection (UTI) is the most common 
nosocomial infection in the United States. The risk of UTI in women following pelvic reconstructive 
surgery is 9-48%.(1-4) Almost 50% women who undergo pelvic reconstructive surgery develop urinary 
retention that requires short-term catheterization. (2) In a recent study, over 80% women who required 
catheterization after pelvic reconstructive surgery used an indwelling catheter for at least 24 hours. (5) 
The risk of bacteriuria is estimated to be 5-10% for each day of indwelling catheterization. (6,7) UTIs 
occur frequently after catheter removal, (8,9) likely due to dislodgement of bacterial colonization in 
bioﬁlms in the catheter.  COMPLICATIONS AND COSTS ASSOCIATED WITH UTI:  Prevention of 
post-operative UTI is important for both patient and health care systems. UTIs increase the economic 


Page 9 of 22
burden on both patients and physicians, as each episode of UTI costs approximately $600. (10) 
Complications from short-term catheterization include pyelonephritis, perinephric abscesses, and 
bacteremia (UTIs are the cause of 15% of all nosocomial bloodstream infections). (11) Catheter-
associated UTI (CAUTI) has become costly for hospitals as well; since October 1, 2008, the Centers for 
Medicare and Medicaid Services (CMS) have not provided hospitals compensation for CAUTIs. (10) 
As part of hospital quality measurement, the National Healthcare Safety Network monitors and reports 
CAUTIs, and prevention of CAUTI is one of the National Patient Safety Goals set by the Joint 
Commission.  PROPHYLAXIS FOR PREVENTION OF POST-OPERATIVE UTI:  Catheter-
associated UTI likely occurs during catheter removal when bacteria colonized in the catheter are 
dislodged into the bladder. Chemoprevention with antibiotics or antiseptics such as methenamine can 
potentially decrease the chance of UTI after post-operative catheterisation. However, prophylaxis is not 
routinely used for prevention of urinary tract infections after catheterization. In a study by Wazait et al, 
40% of providers involved in the management of indwelling catheters do not use prophylactic 
antibiotics for catheter removal.(12) A Cochrane review examining the use of prophylactic antibiotics 
for short-term catheterization showed weak and limited evidence that it reduced the rate of bacteriuria, 
and suggested caution in interpreting the results because of the limited literature.(13) American 
Urologic Association (AUA) and the American College of Obstetrics and Gynecology (ACOG) 
recommend consideration of prophylactic antibiotics for catheter removal, but does not require 
antibiotic use. AUA guidelines suggest that ﬁrst-line antibiotics such as either ﬂuoroquinolones (like 
ciproﬂoxacin or levoﬂoxacin) or trimethoprim-sulfamethoxazole may be warranted at the time of 
catheter removal following urinary tract surgery, especially in patients with risk factors such as 
advanced age, anatomic anomalies, and immunodeﬁciencies; however, treatment may also be deferred 
and based on urine culture at catheter removal.(14) ACOG guidelines suggest that daily antibiotic 
prophylaxis should be considered in women discharged with an indwelling urinary catheter after 
urogynacologic surgery.(15)  The above recommendations for chemoprophylaxis for short-term post-
operative catheter use are mostly based on non-gynecologic populations and there are no speciﬁc 
recommendations on the choice and dose of the agent. However, several randomized controlled trials 
have explored the efﬁcacy of short courses of antibiotic prophylaxis at catheter removal for preventing 
UTI. In a recent meta-analysis of 7 studies, Marschall et al concluded that antibiotic prophylaxis at 
catheter removal was beneﬁcial in reducing symptomatic UTI, with subgroup analysis indicating 
signiﬁcant beneﬁt in post-surgical patients but not in general mixed hospital populations. (16) Of the 
four RCT or prospective cohort studies looking at gynecologic or urogynecologic populations solely, 3 
showed some beneﬁt to antibiotic prophylaxis, while 1 showed showed no beneﬁt to antibiotic use. 
(17-20) COMPLICATIONS OF ANTIBIOTIC PROPHYLAXIS:  Though a short course of antibiotic 
prophylaxis at catheter removal may be effective for preventing post-operative UTI, widespread 
adoption of antibiotic prophylaxis would increase the risk of antibiotic resistance. Multi-drug resistance 
is already prevalent in North America; in 2000, the SENTRY study reported that in nosocomial UTIs, 
rates of antibiotic resistance of four common uropathogens were 59, 31, 43 and 29% for ampicillin, 
amoxicillin/clavulanate, trimethoprim-sulfamethoxazole, and ciproﬂoxacin, respectively. (21) The 
rising cost of increased antibiotic use must also be considered, as well as the potential for adverse 
medication effects, which can be severe.  METHENAMINE IS NOT AN ANTIBIOTIC:   A possible 
alternative to antibiotics is methenamine hippurate, a urinary antiseptic currently used for prophylaxis 
for recurrent urinary tract infections. The mechanism of action of methenamine hippurate is through the 
formation of formaldehyde in the presence of acidic urine. Hippurate, also known as hippuric acid, 
acidiﬁes the urine, which allows for greater production of formaldehyde. Methenamine hippurate is 
relatively inexpensive at about $2 per pill (22) (compared to $3-17 per pill for commonly used 
antibiotic prophylaxis). (23-25) While resistance to methenamine hippurate can be induced with some 
difﬁculty in vitro, it has not been reported in vivo. (26) Daily methenamine reduces UTI after 
gynecologic surgery: Daily methenamine hippurate throughout catheterization has been shown to be 
effective for decreasing post-operative UTI after gynecologic surgery .Three studies reported that daily 
methenamine decreases post-operative UTI as well as post-operative bacteriuria, (2,27,28) while one 
additional study showed signiﬁcant difference in bacteriuria but did not report the rate of symptomatic 
UTI. (29) A Cochrane meta-analysis conﬁrmed that methenamine reduces the risk of post-operative 
UTI. Two subgroup analysis in mixed surgical and non-surgical populations that excluded the presence 
of renal tract abnormalities and neurogenic bladder showed signiﬁcant reduction in symptomatic 
bacteriuria (RR 0.24, CI 0.07-0.89) and bacteriuria (RR 0.56 CI 0.37-0.83).(30) Subgroup analysis of 
the effect of treatment less than 7 days, which essentially limited analysis to studies only involving 
patients with post-surgical short-term indwelling catheter, showed even greater beneﬁts, with the risk 
ratio for bacteriuria and symptomatic bacteriuria be 0.48 (CI 0.23-0.99) and 0.14 (CI 0.05-0.38), 
respectively.(30) These studies used a wide variety of regimens of methenamine ranging from 1g to 4g 


Page 10 of 22
daily in divided dosages.(30) Duration also ranged widely, generally initiated before catheterization to 
several days after catheterization, with treatment courses ranging from a minimum of ﬁve to as many as 
thirteen days.(30)  INNOVATION  Although catheter-associated UTI are an important indicator of 
quality of care, and health care systems are not reimbursed for these nosocomial infections, an effective 
agent that prevents catheter-associated UTI but does not increase antibiotic resistance has not been 
identiﬁed. We plan to investigate the efﬁcacy of a short course of methenamine (two doses in a 24-hour 
period) for preventing UTI after short-term indwelling catheterization. Additionally, investigation of 
short course antibiotic prophylaxis at catheter removal in the urogynecologic population is innovative, 
since it is common practice in urology, but has not been studied signiﬁcantly in the urogynecology 
population, where commonly daily prophylaxis is given. RATIONALE FOR A 24-HOUR DOSE OF 
METHENAMINE HIPPURATE:  For several reasons, we anticipate that two doses of methenamine 
hippurate, with the ﬁrst dose administered 2 hours prior to catheter removal, will reduce the rate of UTI 
following short-term catheterization, and will be non-inferior to antibiotic prophylaxis with 
ﬂuoroquinolones.  1) Unlike antibiotics commonly used for UTI prophylaxis, methenamine becomes 
active only in the bladder, and thus concentrates its full antimicrobial effect in the area of choice.  2) 
Short courses of antibiotics administered 1-2 hours prior to catheter removal have been shown to reduce 
the rate of UTI post-catheterization.(9,16) 3) The pharmacokinetics of methenamine is similar to that of 
antibiotics used in short courses for prophylaxis, such as ciproﬂoxacin, trimethoprim-sulfamethoxazole 
(TMP-SMX), and nitrofurantoin. Methenamine hippurate has a half-life of 4.5 hours, and reaches the 
antimicrobial concentration (MIC of formaldehyde) of 13 microgram/mL 30 minutes to 1 hour after 
oral intake. A single 2 gram dose will yield 18-60 micrograms/mL (with typical daily doses as one dose 
every 12 hours). Methenamine is renally cleared, with 90% excreted within 24 hours. (26) Comparable 
antibiotics have half-lives ranging from 3 - 5 hours (ciproﬂoxacin), 8-10 hours (TMP-SMX), and 20 
minutes-1 hour (nitrofurantoin), with serum drug levels peaking at 20 minutes to 4 hours. (31-33) 
Elimination is also comparable, ranging from 30-40% in urine (nitrofurantoin), (31) 40-50% in urine 
(and 20-50% in feces within 5 days for ciproﬂoxacin), (32) 80%/67% in urine (sulfamethoxazole and 
trimethoprim, respectively, within 72 hours). (33) 4) Prior studies suggest that acidiﬁcation of urine by 
additional acidifying agents is not required for effectiveness of methenamine hippurate. (34)  This 
suggests that two doses of methenamine hippurate, with the ﬁrst dose initiated 2 hours prior to catheter 
removal is reasonable and potentially effective for preventing post-operative UTI.  Beneﬁts of a 24-hour 
dose of methenamine:  A short course of methenamine hippurate for preventing post-operative UTI will 
decrease the cost and complications of post-operative UTI; minimize drug resistance, adverse effects 
and cost of treatment; and likely increase medication compliance. There are currently no studies to 
demonstrate the effectiveness of a short-course of methenamine hippurate as chemoprophylaxis for 
post-operative UTI. If successful, a short course of methenamine hippurate would be a revolutionary 
and attractive non-antibiotic chemoprophylaxis alternative to a short-course of a commonly used 
antibiotics such as the ﬂuoroquinolones or a longer course of methenamine.  Justiﬁcation for Non-
Inferiority Trial  We believe that a non-inferiority trial between two active arms would be more 
clinically useful than a placebo-controlled trial. As stated above, both methenamine and 
ﬂuoroquinolones (such as ciproﬂoxacin or levoﬂoxacin) are accepted to be effective in reducing the rate 
of bacteriuria. Additionally, current urology practice is to give a ﬁrst-line antibiotic (either the 
ﬂuoroquinolones or trimethoprim-sulfoxazole) at catheter withdrawal at prophylaxis. Our study is 
innovative in that this Is not current standard practice in urogynecology; having two active arms would 
change antibiotic use in urogynecology by showing the effectiveness of a lower dose of antibiotic 
prophylaxis for catheter removal, as well as comparing this to the effectiveness of an antibiotic 
alternative for catheter removal prophylaxis in the urogynecologic population. Both of the results from 
these active arms would help to decrease use of antibiotics in current urogynecology practice.  
References  [1] Sutkin G, Alperin M, Meyn L, Wiesenfeld HC, Ellison R, Zyczynski HM. Symptomatic 
urinary tract infections after surgery for prolapse and/or incontinence. Int.Urogynecol.J. 2010;21 
955-61.  [2] Schiotz HA. Comparison of 1 and 3 days' transurethral Foley catheterization after 
retropubic incontinence surgery. Int.Urogynecol. J. Pelvic Floor Dysfunct. 1996;7 98-101.  [3] Schiotz 
HA, Guttu K. Value of urinary prophylaxis with methenamine in gynecologic surgery. Acta 
Obstet.Gynecol.Scand. 2002;81 743-6.  [4] Anger JT, Litwin MS, Wang Q, Pashos CL, Rodriguez LV. 
Complications of sling surgery among female Medicare beneﬁciaries. Obstet.Gynecol. 2007;109 
707-14.  [5] Dieter AA, Amundsen CL, Edenﬁeld AL, Kawasaki A, Levin PJ, Visco AG, et al. Oral 
antibiotics to prevent postoperative urinary tract infection: a randomized controlled trial. Obstet 
Gynecol. 2014 Jan;123(1):96-103.  [6] Nosocomial infection of the urinary tract. Turck M, Stamm W. 
Am J Med. 1981 Mar;70(3):651-4.  [7] Hakvoort RA, Thijs SD, Bouwmeester FW, Broekman AM, 
Ruhe IM, Vernooij MM, et al. Comparing clean intermittent catheterisation and transurethral indwelling 
catheterisation for incomplete voiding after vaginal prolapse surgery: a multicentre randomised trial. 


Page 11 of 22
BJOG. 2011;118(9):1055-60.  [8] Harding GK, Nicolle LE, Ronald AR, Preiksaitis JK, Forward KR, 
Low DE Cheang M: How long should catheter-acquired urinary tract infection in women be treated? A 
randomized controlled study. Ann Intern Med 1991;114:713-719.  [9] Duclos JM, Larrouturou P, Sarkis 
P: Timing of antibiotic prophylaxis with cefotaxime for prostatic resection: better in the operative 
period or at urethral catheter removal? Am J Surg 1992;164:21S23S  [10] Saint S. Clinical and 
economic consequences of nosocomial catheter-related bacteriuria. Am.J.Infect.Control 2000;28 68-75.  
[11] Warren JW. Catheter-associated urinary tract infections. Infect Dis Clin North Am 1997;11(3): 
609-22  [12] Wazait HD, van der Meullen J, Patel HRH et al. Antibiotics on urethral catheter 
withdrawal: a hit and miss affair. J Hosp Infect 2004. 58(4): 297-302 [13] Lusardi G, Lipp A, Shaw C. 
Antibiotic prophylaxis for short-term catheter bladder drainage in adults. Cochrane Database Syst Rev. 
2013 Jul 3;7:CD005428 [14] Wolf JS, Jr, et al. Best practice policy statement on urologic surgery 
antimicrobial prophylaxis. J Urol. 2008;179(4):1379-90. [15] ACOG Committee on Practice Bulletins--
Gynecology. ACOG practice bulletin No. 104: antibiotic prophylaxis for gynecologic procedures. 
Obstet Gynecol. 2009;113(5):1180-9. [16] Marschall J, Carpenter CR, Fowler S, Trautner BW, CDC 
Prevention Epicenters Program. Antibiotic prophylaxis for urinary tract infections after removal of 
urinary catheter: meta-analysis. BMJ 2013;346 f3147.  [17] Ghezzi F, et al. Prophylactic single-dose 
pruliﬂoxacin for catheter-associated urinary tract infection after tension-free vaginal tape procedure. Int 
Urogynecol J Pelvic Floor Dysfunct. 2007;18(7):753-7.  [18] Rogers RG, et al. A randomized, double-
blind, placebo-controlled comparison of the effect of nitrofurantoin monohydrate macrocrystals on the 
development of urinary tract infections after surgery for pelvic organ prolapse and/or stress urinary 
incontinence with suprapubic catheterization. Am J Obstet Gynecol. 2004;191(1):182-7.  [19] Baertschi 
U, Kunz J. Comparative study on the question of systemic chemoprophylaxis following gynecological 
surgery. Schweiz Med Wochenschr. 1976;106(11):380-5. [20] Dieter AA, Amundsen CL, Edenﬁeld AL, 
Kawasaki A, Levin PJ, Visco AG, et al. Oral antibiotics to prevent postoperative urinary tract infection: 
a randomized controlled trial. Obstet Gynecol. 2014 Jan;123(1):96-103. [21] Gordon KA, Jones RN; 
SENTRY Participant Groups (Europe, Latin America, North America). Susceptibility patterns of orally 
administered antimicrobials among urinary tract infection pathogens from hospitalized patients in North 
America: comparison report to Europe and Latin America. Results from the SENTRY Antimicrobial 
Surveillance Program (2000). Diagn Microbiol Infect Dis. 2003 Apr;45(4):295-301.  [22] 
Methenamine. In: Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc. [updated 2/1/14; accessed 
2/21/14]. 
http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7265?hl=6550/. 
 
[23] 
Ciproﬂoxacin (systemic). In: Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc. [updated 2/19/14; 
accessed 
2/21/14]. 
http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/533571/. 
 
[24] 
Nitrofurantoin. In: Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc. [updated 2/14/14; accessed 
2/21/14]. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7376/.  [25] Sulfamethoxazole and 
Trimethoprim. In: Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc. [updated 2/1/14; accessed 
2/21/14]. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6665/.  [26] Methenamine. In: 
Micromedex 2.0. Martindale - The Complete Drug Reference. Ann Arbor, MI: Truven Health Analytics. 
[updated 8/20/2010; accessed 2/21/14]. http://www.micromedexsolutions.com/micromedex2/librarian/.  
[27] Tyreman NO, Andersson PO, Kroon L, Orstam S. Urinary tract infection after vaginal surgery. 
Effect of prophylactic treatment with methenamine hippurate. Acta Obstet.Gynecol.Scand. 1986;65 
731-3.  [28] Knoff T. Methenamine hippurate. Short-term catheterization in gynecologic surgery. A 
double-blind comparison of Hiprex and placebo. Tidsskr.Nor.Laegeforen. 1985;105 498-9.  [29] 
Ladehoff P, Jacobsen JC, Olsen H, Pedersen GT, Sorensen T. The preventive effect of methenamine 
hippurate (Haiprex) on urinary infections after short-term catheterization. A clinical study. 
Ugeskr.Laeger 1984;146 1433-4.  [30] Lee BS, Bhuta T, Simpson JM, Craig JC. Methenamine 
hippurate for preventing urinary tract infections. Cochrane Database Syst Rev. 2012 Oct 
17;10:CD003265. doi 0.1002/14651858.CD003265.pub3.  [31] Nitrofurantoin. In: Micromedex 2.0. 
Martindale - The Complete Drug Reference. Ann Arbor, MI: Truven Health Analytics. [updated 
8/20/2010; accessed 2/21/14]. http://www.micromedexsolutions.com/micromedex2/librarian/.  [32] 
Ciproﬂoxacin. In: Micromedex 2.0. Martindale - The Complete Drug Reference. Ann Arbor, MI: 
Truven 
Health 
Analytics. 
[updated 
8/20/2010; 
accessed 
2/21/14]. 
http://
www.micromedexsolutions.com/micromedex2/librarian/.  [33] Sulfamethoxazole/Trimethoprim. In: 
Micromedex 2.0. Martindale - The Complete Drug Reference. Ann Arbor, MI: Truven Health Analytics. 
[updated 8/20/2010; accessed 2/21/14]. http://www.micromedexsolutions.com/micromedex2/librarian/.  
[34] Strom JG Jr, Jun HW. Effect of urine pH and ascorbic acid on the rate of conversion of 
methenamine to formaldehyde. Biopharm Drug Dispos. 1993;14(1):61-9.


Page 12 of 22
Study Design
Phase*
Not applicable
Design
This study will be conducted as a randomized, blinded study among patients requiring short-term 
indwelling transurethral catheterization following pelvic reconstructive surgery.
Study duration
RECRUITMENT We plan to recruit women from 5 sites in 3 departments in the University of 
Pennsylvania Health System: 1) Urogynecology at Hospital of University of Pennsylvania (HUP), 2) 
Urogynecology at Pennsylvania Hospital (PAH) and 3) Urology at Pennsylvania Hospital (PAH). Last 
year, the combined surgical volume of these cases at our three clinics was 532 subjects; thus, we 
anticipate we will be able to easily recruit and collect data from the proposed sample size of 144 (72 
participants per arm) in about eight months.   FOLLOW UP VISITS:  Patients will follow up for a total 
of 6 weeks after surgery through three weekly follow-up calls and one 6-week postoperative visit. 
Urogynecology nurses will contact study participants once a week for the ﬁrst three weeks following 
surgery per routine practice in our ofﬁces. Six weeks following surgery, patients will return to the ofﬁce 
for a routine post-operative assessment with the investigating physicians.  PROJECT DATES  Research 
Proposal March 2014 IRB Approval August/September 2014  Data Collection September 2014 - 
September 2015 Data Entry November 2014 - October 2015 Data Analysis November 2015 Abstract 
Submission December 2015
Resources necessary for human research protection
Describe research staff and justify that the staff are adequate in number and qualiﬁcations to conduct 
the research. Describe how you will ensure that all staff assisting with the research are adequately 
informed about the protocol and their research related duties. Please allow adequate time for the 
researchers to conduct and complete the research. Please conﬁrm that there are adequate facilities for 
the research.
Key Personnel: Primary Investigator: Christine Chu, MD  Co-Investigator, Mentor: Lily Arya, MD, MS 
Co-Investigator, Mentor: Heidi Harvie, MD, MBA, MSCE (Cost-effectiveness analysis) Co-
Investigator, Mentor: Darren Linkin, MD, MSCE (Infectious Diseases)  Co-Investigator: Ariana Smith, 
MD Co-Investigator: Pamela Levin, MD Co-Investigator: Uduak Andy, MD Co-Investigator: Avita 
Pahwa, MD The above investigators, as well as the urogynecologic nurses who help with routine 
clinical care and will be in touch per routine care with post-operative patients, will be made informed of 
protocol and research-related duties through reading material as well as research meetings after the 
protocol is approved. Additionally, the primary investigator will be in touch with each of the support 
staff and co-investigators weekly to help coordinate duties, provide updates, and to answer any 
questions that may occur through the course of this study.  The proposed clinical study is a multi-
disciplinary collaboration between the Divisions of Urogynecology (OB/GYN), Urology (Surgery) and 
Infectious Diseases (Internal Medicine). We will recruit patients from ﬁve sites, including:  the Division 
of Urogynecology (OB/GYN) at the Hospital of University of Pennsylvania (HUP)  the Division of 
Urogynecology (OB/GYN) at Pennsylvania Hospital (PAH)  the Division of Urogynecology (OB/GYN) 
at Chestnut Hill Hospital (CHH) the Division of Urology (Surgery) at Pennsylvania Hospital (PAH). the 
Division of Urology (Surgery) at the Hospital of University of Pennsylvania (HUP)  Last year, the 
combined surgical volume of these cases at our three clinics was 532 subjects; thus, we anticipate we 
will be able to easily recruit the proposed sample size in eight months. Therefore, there should be 
enough time to recruit, as well as conduct and complete research, within the next year.  The University 
of Pennsylvania Health System (UPHS) is an academic tertiary care referral center that draws patients 
from a wide geographic area. The four urogynecology clinics are located at the Hospital of the 
University of Pennsylvania, an inner city teaching hospital; Pennsylvania Hospital, a largely private 
urban hospital; and Chestnut Hill Hospital, a suburban community hospital. The Division of 
Urogynecology ofﬁces cares for the full spectrum of pelvic organ prolapse, urinary incontinence, fecal 
incontinence, and other pelvic ﬂoor dysfunction related disorders. The Division of Urology has female 
urology clinics at both the Hospital of the University of Pennsylvania and Pennsylvania Hospital, as 
well as inpatient services at Pennsylvania Hospital.   The clinical and research infrastructure of these 
two hospitals are completely integrated with electronic inpatient and outpatient medical records, shared 
clinical responsibilities, on-call schedule. Additionally, we have a staff of clinical and research nurses to 
help coordinate with patient follow-up visits and routine post-operative care. No radiologic or 


Page 13 of 22
laboratory facilities will be used in this study. The Division of Infectious Diseases (Internal Medicine) 
has over 20 academic and research faculty who offer consultative services to departments conducting 
clinical trials and/or translation research, including extensive expertise in hospital-acquired infections 
and antibiotic resistance research.  Clinical research facilities of the Division of Urogynecology are 
located in close proximity to all patient activity. Fellows have their own dedicated desk stations and a 
state-of-the-art computer and printer. The PC has word-processing, spreadsheet, and statistical database 
analysis programs (STATA). The fellows have full access to secretarial support, information services, 
slide preparation and poster presentations assistance, and videotaping/editing services. Each fellows 
computer is connected to the main hospital network, which allows for easy and rapid retrieval of 
inpatient data, biomedical library access, and free access to the Internet. Literature searches may be 
conducted from the fellows ofﬁce through these means. Additionally, the Biomedical Library is in close 
proximity and has extensive facilities for literature searches, journals, and inter-library loan. The library 
periodically holds courses on updated methods of database searches, and experienced medical librarians 
are always on staff.  The Clinical Center for Epidemiology and Biostatistics (CCEB) provides a Clinical 
Research Certiﬁcate Program for clinicians associated with the university and provides a foundation in 
biostatistics, research methodology, epidemiology and grant writing to allow those completing to 
coursework to have the tools to pursue a career as an independent researcher. CCEB will provide 
biostatistics support for this project. The CCEB has been actively involved in clinically- and 
pharmacologically-oriented research since 1978. As a Type II Center, it is the primary home for 
epidemiology and biostatistics at the University of Pennsylvania. It is an interdisciplinary and 
interdepartmental program of more than 275 individuals and includes clinical and non-clinical faculty, 
fellows, research staff, biostatisticians, and clerical staff. Many studies in the CCEB have focused 
exclusively on women's health issues.  Additionally, should patients require additional medical services 
as a consequence of the research, such as adverse reactions to medications, patients will have 24-hour 
access to the on-call physician or to the medical ofﬁces of the co-investigators, where the patients can 
be examined and referred to additional medical services if necessary.
Characteristics of the Study Population
Target population
Adult patients requiring short-term indwelling transurethral catheterization for at least 24 hours 
following pelvic reconstructive surgery for pelvic organ prolapse, incontinence, or both.
Subjects enrolled by Penn Researchers
370
Subjects enrolled by Collaborating Researchers
0
Accrual
This trial will be an non-inferiority trial, intended to determine if a short course of methenamine 
hippurate is no worse than a short course of ﬂuroquinolones (ciproﬂoxacin at Pennsylvania Hospital, 
levoﬂoxacin at HUP, based on current practice and ﬂuoroquinolone availability at each site) in 
prevention of post-operative UTI in short-term indwelling catheterization. Our primary outcome is the 
treatment of UTI by symptoms, a clinically relevant outcome. In the only study to look at this primary 
outcome after treatment with prophylactic antibiotics during short-term catheterization in 
urogynecologic surgery, the percentage of patients requiring treatment for UTIs after prophylactic 
antibiotics was 22%. If we assume a non-inferiority margin of 15%, a clinically relevant margin and 
commonly used in non-inferiority/equivalence trials for studies examining antibiotic use for urinary 
tract infections, as well as 80% power and a one-sided alpha of 0.025, 120 participants in each arm 
(total of 240 patients) will be required. Of all patients that undergo pelvic reconstructive surgery at our 
institution, approximately 75% are discharged home with an indwelling catheter. With a potential 15% 
drop-out rate, we therefore anticipate that we will need to recruit about 370 eligible patients in our 
clinics.  As listed before, review of the surgeons logs over the last 12 months shows that this study is 
feasible due to the large volume of pelvic reconstructive surgery procedures in Urogynecology and 
Urology. Last year, the combined surgical volume of these cases at our three clinics was 532 subjects; 
thus, we anticipate we will be able to easily recruit the proposed sample size in one year. We plan to 


Page 14 of 22
recruit women from 4 sites in 3 departments in the University of Pennsylvania Health System: 1) 
Urogynecology at Hospital of University of Pennsylvania (HUP), 2) Urogynecology at Pennsylvania 
Hospital (PAH) and 3) Urology at Pennsylvania Hospital (PAH). Physician investigators are present at 
all three sites, and will have opportunity to screen patients planning for surgery for pelvic organ 
prolapse, urinary incontinence, or both, for participation.
Key inclusion criteria
Inclusion criteria: female; patients who are able to read and write English; 18 years of age or older; 
underwent surgery for pelvic organ prolapse, urinary incontinence, or both; require post-operative 
short-term transurethral catheterization for greater than 24 hours.
Key exclusion criteria
Exclusion criteria: patients undergoing surgical intervention for sacral neuromodulation, or mesh 
excision; patients requiring long-term catheterization secondary to injury to the urinary tract; patients 
who pass their post-operative trial void and thus, do not require additional catheterization; patients 
requiring catheterization for less than 24 hours; pregnant patients; patients who are breast-feeding; 
allergy to methenamine hippurate or ﬂuroquinolones (either ciproﬂoxacin or levoﬂoxacin); impaired 
renal or hepatic function; pre-operative urinary retention; patients who are currently using 
sulfonamides; patients who have severe dehydration; patients using tizanidine; patients sensitive to 
quinolones class; patients using theophylline; patients with myasthenia gravis; patients with 
prolongation of QT interval.
Vulnerable Populations
Children Form
Pregnant women (if the study procedures may affect the condition of the pregnant woman or 
fetus) Form
Fetuses and/or Neonates Form
Prisoners Form
Other
x None of the above populations are included in the research study
The following documents are currently attached to this item:
There are no documents attached for this item.
Populations vulnerable to undue inﬂuence or coercion
All patients will be advised that participation in the study is completely voluntary, and does not involve 
any monetary compensation, which will minimize the risk of coercion for the economically 
disadvantaged. Patients will also be assured that their participation will not affect their care or 
treatment. Also, each person will be provided the opportunity to decline or participate in the study 
through the process of thorough informed consent. Penn employees and students who may be 
approached during their evaluation in the urogynecology clinics will be told that their decision to 
participate will not impact their standing with the University.
Subject recruitment
We plan to recruit women from 3 departments in the University of Pennsylvania Health System: 1) 
Urogynecology at Hospital of University of Pennsylvania (HUP), 2) Urogynecology at Pennsylvania 
Hospital (PAH) and 3) Urology at Pennsylvania Hospital (PAH). Physician investigators, who are 
present at all clinics associated with these departments, will screen patients planning for surgery for 
pelvic organ prolapse, urinary incontinence, or both, for participation. Patients may also be pre-
screened for eligibility using the electronic medical record. Following conﬁrmation of eligibility, the 
physicians will obtain informed consent preoperatively prior to surgery.
Will the recruitment plan propose to use any Penn media services (communications, marketing, etc.) for 
outreach via social media avenues (examples include: Facebook, Twitter, blogging, texting, etc.) or does 
the study team plan to directly use social media to recruit for the research?
No


Page 15 of 22
The following documents are currently attached to this item:
There are no documents attached for this item.
Subject compensation*
Will subjects be ﬁnancially compensated for their participation?
No
The following documents are currently attached to this item:
There are no documents attached for this item.
If there is subject compensation, provide the schedule for compensation per study visit or session 
and total amount for entire participation, either as text or separate document
None.
Study Procedures
Suicidal Ideation and Behavior
Does this research qualify as a clinical investigation that will utilize a test article (ie- drug or biological) 
which may carry a potential for central nervous system (CNS) effect(s)?
No
Procedures
RECRUITMENT  We plan to recruit women from 3 clinical sites associated with 3 departments in the 
University of Pennsylvania Health System: 1) Urogynecology at Hospital of University of Pennsylvania 
(HUP), 2) Urogynecology at Pennsylvania Hospital (PAH) and 3) Urology at Pennsylvania Hospital 
(PAH). Physician investigators, who are present at all sites, will screen patients planning for surgery for 
pelvic organ prolapse, urinary incontinence, or both, for participation. Following conﬁrmation of 
eligibility, the physicians will obtain informed consent prior to surgery at the planned preoperative visit. 
Last year, the combined surgical volume of these cases at our three clinics was 532 subjects; thus, we 
anticipate we will be able to easily recruit the proposed sample size in twelve months. ENROLLMENT 
AND BASELINE VISIT:  Patients who are being discharged home with an indwelling catheter 
following pelvic reconstructive surgery will be enrolled into the study. With regards to outpatient 
surgery (such as a suburethral sling), this will occur within a few hours after surgery for patients who 
fail their trial of void. Following inpatient surgery (such as sacrocolpopexy, uterosacral or sacrospinous 
ligament ﬁxation, or colpocleisis), patients who are being discharged from the hospital with an 
indwelling catheter will be enrolled into the study. As per standard of care, all subjects will be 
scheduled for an ofﬁce visit for catheter removal 24 to 72 hours after placement of the indwelling 
catheter per surgeon preference. Demographic information will be collected from the patients medical 
record (age, menopausal status, concurrent estrogen use, ethnicity, level of education, medical 
comorbidities, history of recurrent UTIs, and duration of hospitalization). Data regarding the patients 
surgical intervention (procedure type, surgical complications, operative time) will be collected from the 
operative record. At the time of catheter removal, subjects will be randomized to either methenamine 
hippurate or ﬂuoroquinolones, using sealed, opaque, sequentially numbered envelopes. All patients, and 
all physicians and nurses directly involved in patient calls and clinical interaction, will be masked to 
treatment allocation. Only the nurses involved in catheter removal, but not decisions on the primary 
outcome, will open the envelope, and distribute the allocated medication to the patient, who will take 
one dose at the ofﬁce. A 24-hour course of ﬂuoroquinolones, as per AUA guidelines, are the ﬁrst-line 
antibiotics for catheter removal, and will be one of the active arms of the study. Due to differences of 
ofﬁce practice and formulary availability, the ﬂuroquinolone of choice at each site will be different; this 
is clinically relevant as different urology practices across the country use different ﬂuoroquinolones for 
prophylaxis. At HUP and Radnor, the 24 hour course of ﬂuoroquinolone used will be one dose of 500 
mg of levoﬂoxacin, as per ofﬁce practice and formulary availability. At the other sites (Pennsylvania 
Hospital, Chestnut Hill Hospital), the 24 hour course of ﬂuoroquinolone as per ofﬁce practice will be 
two doses of 500 mg of ciproﬂoxacin, 12 hours apart. Methenamine hippurate will be given as two 
doses of 1g of methenamine hippurate, taken 12 hours apart. The patient will not be told which 


Page 16 of 22
medication they are taking. The methenamine, ciproﬂoxacin, and levoﬂoxacin used in this study are all 
similar in shape, although not in color. Following catheter removal one to two hours after the ﬁrst dose 
of medication, patients will be given a white vial or bag with the second dose of medication (if given 
methenamine or ciproﬂoxacin) and will be instructed to take second dose of the study medication at 
home about 12 hour later.  As part of standard of care, nurses perform void trials per practice guidelines 
by backﬁlling the bladder with 300 cc normal saline, removing the catheter, and prompting the patient 
to void immediately. If a patient fails her trial of void, majority of the patients at our site are taught 
intermittent self-catheterization. If an indwelling catheter is replaced, the allocated treatment (drug or 
placebo) will be re-administered at repeat trial of void/repeat catheter withdrawal. No further drug will 
be given if the patient performs intermittent self-catheterization after the failed trial of void.  FOLLOW 
UP VISITS:  Three weekly follow-up calls and one postoperative visit are planned.  It is standard of 
care of our clinical practices in the ofﬁce for a clinical urogynecology nurses to routinely contact 
patients post-surgery to ask about any symptoms or complications from the procedures they underwent. 
In this study, per routine ofﬁce practice, urogynecology nurses will call study participants once a week 
for the ﬁrst three weeks following surgery. As per routine, using a structured form, patients will be 
asked about symptoms of UTI, any treatment for UTI, any urine laboratory testing, visits, and treatment 
for suspected UTI from other providers other than the urogynecology clinic (e.g. ER, primary care 
doctor), treatment of complications secondary to UTI (such as pyelonephritis and sepsis), and any 
additional use of antibiotic for infections other than UTI. Questions related solely to the study 
medication will include compliance with medications given, and side effects within 24 hours of taking 
medication.  At any time during the study, as per standard of care of all urogynecology patients, patients 
who feel that they may have UTIs will be encouraged to call the urogynecology clinical nurses or the 
on-call physician with their symptoms. These encounters, any testing, and any empiric treatment are 
documented in the electronic medical system. If the diagnosis of UTI is unclear at any time, per 
standard of care, the patient will be asked to come into the ofﬁce for physical examination and further 
diagnostic testing. If patients are suspected of having UTI, treatment for UTI will be initiated. As per 
routine ofﬁce care for treatment of UTI, if possible, all patients will be asked to give a specimen for 
urinalysis and urine culture prior to beginning empiric treatment. Four to eight weeks following surgery, 
as per standard of care, patients will return to the ofﬁce for a routine post-operative assessment with the 
investigating physicians. The patients will undergo routine post-operative physical examination and 
answer the above questions. Any methenamine or ciproﬂoxacin that has not been taken as instructed 
will be returned at this time. At their post-operative visit, the patient will be asked if they were aware of 
which medication they were taking to assess blinding.
The following documents are currently attached to this item:
There are no documents attached for this item.
Deception
Does your project use deception?
No
International Research
Are you conducting research outside of the United States?
No
Analysis Plan
Categorical variables will be analyzed using chi-squared or Fishers exact test and parametric or non-
parametric t-tests for continuous variables. Bivariable analysis will be used to determine variables (risk 
factors) that are independently associated with post-operative UTI. Duration of catheterization between 
groups will be compared using the Mann-Whitney test to compare difference in medians. The primary 
outcome will be the rate of clinically suspected UTI requiring treatment within the ﬁrst three weeks 
following surgery. Comparison with ﬂuoroquinolones will be performed using relative risk ratio. 
Analysis will be performed by intention to treat. If imbalances in baseline demographics are identiﬁed, 
multivariate analyses for post-operative UTI will be performed to control the inequality. Cost-
effectiveness analysis will be performed by monetizing the collected resource utilization data in each 
treatment arm, including use of intervention resources, UTI treatment resources, as well as primary and 
secondary care resources. Incremental cost-effectiveness ratios will be calculated to compare difference 
in costs between prophylaxis with methenamine and prophylaxis with ﬂuroquinolones to the difference 
in effect on the incidence of post-operative UTI.  Prevalence of adverse effects will be measured as 


Page 17 of 22
percentages. Rate of urine cultures performed by patients treated for symptomatic UTI, as well as the 
rate of culture-positive UTI will be noted; comparison with ﬂuoroquinolones will be performed using 
relative risk ratio, with analysis by intention to treat. Positive cultures will be analyzed for percentage of 
uropathogen type, type of uropathogen showing resistance, and overall percentage of cultures showing 
resistance.
The following documents are currently attached to this item:
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Data conﬁdentiality
x Paper-based records will be kept in a secure location and only be accessible to personnel involved 
in the study.
x Computer-based ﬁles will only be made available to personnel involved in the study through the 
use of access privileges and passwords.
Prior to access to any study-related information, personnel will be required to sign statements 
agreeing to protect the security and conﬁdentiality of identiﬁable information.
x Wherever feasible, identiﬁers will be removed from study-related information.
A Certiﬁcate of Conﬁdentiality will be obtained, because the research could place the subject at 
risk of criminal or civil liability or cause damage to the subject's ﬁnancial standing, 
employability, or liability.
A waiver of documentation of consent is being requested, because the only link between the 
subject and the study would be the consent document and the primary risk is a breach of 
conﬁdentiality. (This is not an option for FDA-regulated research.)
Precautions are in place to ensure the data is secure by using passwords and encryption, because 
the research involves web-based surveys.
Audio and/or video recordings will be transcribed and then destroyed to eliminate audible 
identiﬁcation of subjects.
Subject Conﬁdentiality
Extensive efforts will be made to ensure and maintain participant conﬁdentiality. Data from patients 
will be recorded on data collection forms, which will be associated with a Subject ID number only. The 
patient name, medical record numbers, or other identiﬁers will not be present on the data collection 
forms themselves. The 6-digit Participant ID number will be composed by the sequential ordering of 
participants. At each site, a log book will be kept in for data management purposes to match Subject ID 
number with patient medical record numbers if chart review is needed for missing data. This will also 
be maintained in a secure and locked ﬁling system at all times. Any additional source documentation 
that may associate the patient and PHI to data (such as consent forms) will also be kept in a secure and 
locked ﬁling system at all times. Additionally, any data collection forms will also be kept in a separate 
secure and locked ﬁling system at all times.  At the University of Pennsylvania, the participant will be 
logged in the Excel spread sheet using their assigned Subject ID number. The Excel spreadsheet form 
will be stored in a password-secured ﬁle and a physical backup copy of this ﬁle will be made at the end 
of every other week and the copy stored in a separate, secure area/ﬁling system.
Sensitive Research Information*
Does this research involve collection of sensitive information about the subjects that should be excluded 
from the electronic medical record?
No
Subject Privacy
Privacy refers to the person's desire to control access of others to themselves. Privacy concerns people, 
whereas conﬁdentiality concerns data. Describe the strategies to protect privacy giving consideration to 
the following: The degree to which privacy can be expected in the proposed research and the safeguards 
that will be put into place to respect those boundaries. The methods used to identify and contact 
potential participants. The settings in which an individual will be interacting with an investigator. The 
privacy guidelines developed by relevant professions, professional associations and scholarly 
disciplines (e.g., psychiatry, genetic counseling, oral history, anthropology, psychology). 


Page 18 of 22
Patients will be identiﬁed and screened by physician investigators at each site involved in patient care in 
their ofﬁces. The patient will be located in a private room prior to surgery before discussing the study 
and enrollment with the patient. Consent, which will be given prior to surgery in the pre-operative 
holding area, will also be conducted in a private room. During the study, interactions with the patient 
will involve routine post-operative care by the physician investigators and urogynecologic nurses, which 
is conducted in physicians' ofﬁces. It will also involve routine post-operative telephone calls, done in a 
private manner in the ofﬁce setting, in the usual manner. Patients may also interact through telephone 
calls with the on-call physician in the cases of after hour question, care, or emergency, as per routine 
post-operative care.
Data Disclosure
Will the data be disclosed to anyone who is not listed under Personnel?
No.
Data Protection*
x Name
x Street address, city, county, precinct, zip code, and equivalent geocodes
x All elements of dates (except year) for dates directly related to an individual and all ages over 89
x Telephone and fax number
x Electronic mail addresses
Social security numbers
x Medical record numbers
Health plan ID numbers
Account numbers
Certiﬁcate/license numbers
Vehicle identiﬁers and serial numbers, including license plate numbers
Device identiﬁers/serial numbers
Web addresses (URLs)
Internet IP addresses
Biometric identiﬁers, incl. ﬁnger and voice prints
Full face photographic images and any comparable images
Any other unique identifying number, characteristic, or code
None
Does your research request both a waiver of HIPAA authorization for collection of patient information 
and involve providing Protected Health Information ("PHI") that is classiﬁed as a "limited data set" 
(city/town/state/zip code, dates except year, ages less than 90 or aggregate report for over 90) to a 
recipient outside of the University of Pennsylvania covered entity?
No
Tissue Specimens Obtained as Part of Research*
Are Tissue Specimens being obtained for research?
No
Tissue Specimens - Collected during regular care*
Will tissue specimens be collected during regulator clinical care (for treatment or diagnosis)?
No
Tissue Specimens - otherwise discarded*
Would specimens otherwise be discarded?
No


Page 19 of 22
Tissue Specimens - publicly available*
Will tissue specimens be publicly available?
No
Tissue Specimens - Collected as part of research protocol*
Will tissue specimens be collected as part of the research protocol?
No
Tissue Specimens - Banking of blood, tissue etc. for future use*
Does research involve banking of blood, tissue, etc. for future use?
No
Genetic testing
If genetic testing is involved, describe the nature of the tests, including if the testing is predicative or 
exploratory in nature. If predictive, please describe plan for disclosing results to subjects and provision 
of genetic counseling. Describe how subject conﬁdentiality will be protected Note: If no genetic testing 
is to be obtained, write: "Not applicable."
Not applicable.
Consent
1. Consent Process
Overview
Informed consent will be obtained by the investigator in the preoperative area, although the patient will 
be identiﬁed and recruited in the clinic as a potential participant for the study. The subjects will have as 
much time between the initial recruitment and the consent as needed to consider participation. 
Additionally, at any time from the time of recruitment to the time of hospital discharge with an 
indwelling catheter, the patient may choose to consent and participate in the study. The patient may also 
choose to withdraw from the study at any time.  Investigators will emphasize that participation (or lack 
of participation) in the study: 1) not inﬂuence their evaluation, care, or treatment 2) is completely 
voluntary 3) does not involve any ﬁnancial compensation 4) may be terminated at any time. Layman 
terms will be used by those obtaining the consent. The consent will be written at a 6th grade reading 
level. All questions will be answered to the patient's satisfaction and understanding before informed 
consent is obtained.
Children and Adolescents
Not applicable.
Adult Subjects Not Competent to Give Consent
Yes, all adult subjects who meet inclusion criteria will be able to give informed consent.
2. Waiver of Consent
Waiver or Alteration of Informed Consent*
No Waiver Requested
Minimal Risk*
Impact on Subject Rights and Welfare*
Waiver Essential to Research*
Additional Information to Subjects
Written Statement of Research*
No


Page 20 of 22
If no written statement will be provided, please provide justiﬁciation
The following documents are currently attached to this item:
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Risk / Beneﬁt
Potential Study Risks
Physical Risks:  Because this is a clinical trial of methenamine, there are possible physical risks to the 
patients secondary to the medication in use and the clinical outcome. However, this is minimal since 
methenamine is 1) a FDA-approved medication available in the United States and regularly used for 
prevention of UTIs, and 2) has relatively few and mild side effects.  Methenamine hippurate is a 
medication that exhibits antibacterial activity by converting to formaldehyde in the presence of acidic 
urine. It is currently FDA approved for the prophylaxis of recurrent urinary tract infections. The most 
common side effects are rash (3.5% or less), nausea (3.5% or less), upset stomach (3.5% or less), and 
dysuria (3.5% or less). Serious side effects include immune hypersensitivity reaction and pneumonia.(1) 
In the studies which examined the use of methenamine for prophylaxis for UTI after gynecologic 
surgery, only 6 patients treated with methenamine out of a total of 6 studies displayed mild 
dermatologic and gastrointestinal side effects. No patients displayed any serious side effects. 
Additionally, there was no signiﬁcant difference in presentation of side effects between placebo and 
treatment groups. The doses used in this study is signiﬁcantly less than the doses used in the studies 
above, which further decreases the risk of physical harm.  Methenamine is contraindicated in severe 
renal and hepatic impairment, which are exclusion criteria in this study. (1)  The second risk is from the 
potential development of urinary tract infection after short-term indwelling catheter use. However, 
patient eligible for participation in this study would be at risk of urinary tract infection even if they were 
not participating in this study because they have opted to undergo pelvic reconstructive surgery.  
Additionally, the methenamine hippurate may be preventative for urinary tract infection, so 
participation in this study may be beneﬁcial. Additionally, there may be risk with use of 
ﬂuroquinolones, though the dose will be minimal and patients will be unlikely to undergo side effects. 
Oral ciproﬂoxacin is commonly used in clinical practice with minimal problems, for urinary tract 
infections as well as other infections. The most common side effects of ciproﬂoxacin in adults include: 
Rash (up to 1.8% ), diarrhea (1.6% to 4.8% ); nausea (2.5% to 4%), vomiting (1% to 4.8% ), headache 
(oral extended-release tablets, 3%). Life-threatening adverse effects are rare, but diverse, and include:  
Cardiovascular: Cardiorespiratory arrest (up to 1% ), Myocardial infarction (up to 1% ), Prolonged QT 
interval, Syncope (up to 1% ), Torsades de pointes  Dermatologic: Photosensitivity (up to 1% ), 
Stevens-Johnson syndrome (up to 1% ), Toxic epidermal necrolysis (up to 1% ) Gastrointestinal: 
Clostridium difﬁcile diarrhea (up to 1% ), Gastrointestinal hemorrhage (up to 1% ), Pancreatitis (up to 
1% ), Pseudomembranous enterocolitis Hematologic: Agranulocytosis, Aplastic anemia, Bone marrow 
depression, Hemolytic anemia, Leukopenia (0.4% ), Pancytopenia (0.1% ), Thrombocytopenia Hepatic: 
Hepatic necrosis (up to 1% ), Hepatitis (up to 1% ), Hepatotoxicity, Liver failure Immunologic: Immune 
hypersensitivity reaction (up to 1% ) Musculoskeletal: Myasthenia gravis, Exacerbation, Rupture of 
tendon, Tendinitis Neurologic: Raised intracranial pressure, Seizure (up to 1% ) Ophthalmic: Retinal 
detachment Psychiatric: Depression (up to 1% ), Psychotic disorder (up to 1% ) Renal: Acute renal 
failure (up to 1% ), Hemorrhagic cystitis (up to 1% ) [2] Levoﬂoxacin is also commonly used in 
practice for the treatment of infections including urinary tract infections. Common side effects include: 
Diarrhea (5% ), Nausea (7% ); Dizziness (3% ), Headache (6% ), Insomnia (4% ). Life-threatening side 
effects are uncommon, but include: Cardiovascular: Cardiac arrest (0.1% to 1% ), Prolonged QT 
interval, Torsades de pointes, Ventricular tachycardia (0.1% to 1% ) Dermatologic: Erythema 
multiforme, Stevens-Johnson syndrome Endocrine metabolic: Hypoglycemia (0.1% to 1% ) 
Hematologic: Aplastic anemia, Pancytopenia, Thrombocytopenic purpura Hepatic: Hepatitis, Liver 
failure Immunologic: Anaphylactoid reaction, Immune hypersensitivity reaction (0.1% to 1% ) 
Musculoskeletal: Myasthenia gravis, Exacerbation, Rupture of tendon, Tendinitis (0.1% to 1% ) 
Neurologic: Peripheral neuropathy, Seizure (0.1% to 1% ) Ophthalmic: Retinal detachment Renal: 
Acute renal failure (0.1% to 1% ) [3] However, risk will be minimized by the short course of 
ﬂuroquinolones, as well as exclusion of patient with allergies to either ciproﬂoxacin or levoﬂoxacin, or 
hepatic and renal issues. Again, both antibiotics are commonly used in inpatient and outpatient settings 
for treatment of infections with minimal risk, so risk to the patient (compared with beneﬁt) should be 


Page 21 of 22
minimal. Any patients with any side effects will be told to discontinue use of the medications and be 
evaluated by a physician, and any serious adverse events will be reported to the IRB. There are no 
psychological, social, economic, monetary, or legal risks to this study.  Loss of conﬁdentiality:  Any 
study in which personal health information (PHI) is collected has the potential risk of loss of 
conﬁdentiality. However, extensive efforts will be made to ensure and maintain security of PHI and 
maintain participant conﬁdentiality.   Patients will be identiﬁed and screened by physician investigators 
at each site involved in patient care in their ofﬁces. The patient will be brought into a private room 
before discussing the study and enrollment with the patient in the privacy of a private room. During the 
study, interactions patient will involve routine post-operative care by the physician investigators and 
urogynecologic nurses, which is conducted in physicians' ofﬁces. It will also involve routine post-
operative telephone calls, done in a private manner in the ofﬁce setting, in the usual manner. Data from 
patients will be recorded on data collection forms, which will be associated with a Subject ID number 
only. The patient name, medical record numbers, or other identiﬁers will not be present on the data 
collection forms themselves. The Participant ID number will be composed by the sequential ordering of 
participants. At each site, a log book will be kept in for data management purposes to match Subject ID 
number with patient medical record numbers if chart review is needed for missing data. This will also 
be maintained in a secure and locked ling system at all times. Any additional source documentation that 
may associate the patient and PHI to data (such as consent forms) will also be kept in a secure and 
locked ling system at all times. Additionally, any data collection forms will also be kept in a separate 
secure and locked ling system at all times. One year after the study has been completed, any forms with 
patient identiﬁers (such as logs and consents) will be destroyed.  At the University of Pennsylvania, the 
participant will be logged in the Excel spread sheet using their assigned Subject ID number. The Excel 
spreadsheet form will be stored in a password-secured ﬁle and a physical backup copy of this ﬁle will 
be made at the end of every other week and the copy stored in a separate, secure area/ﬁling system.  [1] 
Methenamine. In: Micromedex 2.0. Martindale - The Complete Drug Reference. Ann Arbor, MI: 
Truven 
Health 
Analytics. 
[updated 
8/20/2010; 
accessed 
2/21/14]. 
http://
www.micromedexsolutions.com/micromedex2/librarian/.  [2] Ciproﬂoxacin. In: Micromedex 2.0. 
Martindale - The Complete Drug Reference. Ann Arbor, MI: Truven Health Analytics. [updated 
8/20/2010; accessed 2/21/14]. http://www.micromedexsolutions.com/micromedex2/librarian/.  [3] 
Levoﬂoxacin. In: Micromedex 2.0. Martindale - The Complete Drug Reference. Ann Arbor, MI: Truven 
Health Analytics. [updated 8/20/2010; accessed 2/21/14]. http://www.micromedexsolutions.com/
micromedex2/librarian/.
Potential Study Beneﬁts
Potential beneﬁts to the individual subject include prevention of urinary tract infection, or a decreased 
risk of urinary tract infection, after short-term indwelling catheterization. Additionally, if a short course 
of methenamine hippurate is effective in decreasing the risk of UTIs, it would be an exciting and 
attractive chemoprophylaxis alternative to antibiotics, potentially decreasing the cost and complications 
of post-operative UTI; minimizing drug resistance, adverse effects and cost of treatment; and 
potentially increasing medication compliance. This would potentially decreased economic burdens on 
patients and health systems. Additionally, catheter-associated UTIs are measures of quality monitored 
by the National Healthcare Safety Network.
Alternatives to Participation (optional)
Patients are not required to participate in the study. Patients who require short-term indwelling catheters 
after pelvic reconstructive surgery may or may not be given prophylactic antibiotics based on their 
physicians routine practice. They will participate in routine post-operative care.
Data and Safety Monitoring
This study contains low risks, as both of these medications are already used in clinical practice for 
prophylaxis of urinary tract infections. Study progress and safety will be reviewed by the PI. Review of 
the rate of subject accrual, adherence to inclusion/exclusion criteria will occur to assure that participants 
meet the eligibility criteria. There will be ongoing collection of data on adverse events and compliance 
to the treatment protocol throughout the study by research staff.
The following documents are currently attached to this item:
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Risk / Beneﬁt Assessment
The beneﬁts of this treatment outweigh the risks. As discussed before, there is risk of physical harm and 


Page 22 of 22
loss of conﬁdentiality as part of participation in this study. However, the risk of physical harm is 
minimal secondary to rarity and minor adverse effects of methenamine and ﬂuoroquinolones, and 
minimization of the dose administered in this study. Additionally, these medications are already being 
used for prophylaxis of urinary tract infections in the urogynecology/urology practice. The loss of 
conﬁdentiality will be minimized by careful and secure management of all paper and electronic 
documentation of patient data. Additionally, all patients undergoing pelvic reconstructive surgery are at 
risk of urinary tract infection. Participation in this study would not increase this risk, but could 
potentially beneﬁt the patient by decreasing this risk. If this trial is successful, beneﬁts to society and 
health care systems could result in decreased antibiotic resistance, decreased health-care associated 
infections, and decreased cost secondary to these infections.
General Attachments
The following documents are currently attached to this item:
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ICF_001.pdf: 
The Efficacy and Cost-Effectiveness of a 24-hour course of 
Methenamine Hippurate For Preventing Post-Operative 
Urinary Tract Infection 
 
NCT02358993 
 
April 18, 2017 


TITLE OR ACRONYM 
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UNIVERSITY OF PENNSYLVANIA 
RESEARCH SUBJECT 
INFORMED CONSENT AND HIPAA AUTHORIZATION FORM 
Protocol Title:  
The Efficacy and Cost-Effectiveness of a 24-hour course of 
Methenamine Hippurate for Preventing Post-Operative 
Urinary Tract Infection 
Principal 
Investigator: 
Dr. Lily A. Arya 
1000 Courtyard Building, HUP, 3400 Spruce St, Philadelphia, 
PA 19104,  
Phone: 215 662-6035    
Emergency 
Contact: 
Urogynecology Doctor on call 
Phone: 215 662-6035  
Urology Doctor on call 
Phone: 215-829-3000    
You are being invited to participate in a research study. Your participation is voluntary which 
means you can choose whether or not you want to participate. If you choose not to participate, 
there will be no loss of benefits to which you are otherwise entitled. Before you can make your 
decision, you will need to know what the study is about, the possible risks and benefits of being 
in this study, and what you will have to do in this study. The research team is going to talk to 
you about the research study, and they will give you this consent form to read. You may also 
decide to discuss it with your family, friends, or family doctor. You may find some of the medical 
language difficult to understand. Please ask the study doctor and/or the research team about 
this form. If you decide to participate, you will be asked to sign this form. 
Why am I being asked to volunteer?  
You are being asked to volunteer because you have decided to undergo surgical repair of pelvic 
organ prolapse, incontinence, or both, and may potentially require a short-term catheter – a 
drainage tube in your bladder, also known as an indwelling catheter – for a few days after your 
surgery. Catheterization may put you at higher risk of urinary tract infections. You are being 
asked to participate in a research study to determine if a short course of methenamine hippurate 
is effective in decreasing the risk of urinary tract infection after short-term indwelling 
catheterization for pelvic reconstructive surgery. 
What is the purpose of this research study? 
Patients who undergo pelvic reconstructive surgery (that is, surgery for pelvic organ prolapse, 
incontinence, or both) may require short-term indwelling catheterization after surgery because of 
urinary retention. Urinary retention occurs when patients are unable to empty their bladders 
completely or properly. Catheterization puts patients at higher risk of urinary tract infections. The 
purpose of this study is to determine whether using a medication called methenamine hippurate 
will prevent urinary tract infections in patients requiring a short-term catheter after pelvic 
reconstructive surgery.  
Methenamine hippurate is FDA-approved and has few, mild side effects. This medication has 
been shown to be effective in 5-13 day courses in studies for prevention of urinary tract infection 
after short-term indwelling catheterization for gynecologic surgical procedures. This study will 
examine the effectiveness of a short course (a 2 dose course) of methenamine hippurate for 
prevention of urinary tract infection after short-term indwelling catheterization for pelvic 
reconstructive surgeries. The use of two doses of methenamine hippurate for the prevention of 
IRB Approval From: 04/18/2017 to: 04/17/2018


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urinary tract infections associated with catheter use after pelvic reconstructive surgery IS 
INVESTIGATIONAL. This means that the treatment may not necessarily provide any benefits.  
 
How long will I be in the study?  
 
You will be part of the study until 6 weeks after your surgery. 
 
A total of 230 subjects will be involved in this study, which will only be conducted at sites affiliated 
with Penn. 
 
What am I being asked to do? 
 
If you choose to participate in this study, you will be randomly assigned (like flipping a coin) to 
take either two doses of methenamine hippurate or two doses of a placebo medication, which is a 
medication that has no medical effect. You will be randomly assigned at the time of this consent, 
which will be prior to your surgery. This study is double-blinded, meaning that neither you nor the 
investigators and physicians involved in your care will know which medications (methenamine or 
placebo) you have been assigned to take. 
 
After your surgery, your bladder function will be tested. If you are able to urinate, you will not be 
eligible to be part of this study. If you are unable to urinate completely and require a urinary 
catheter, you will be randomly assigned to receive either methenamine hippurate or placebo. The 
day that you are scheduled to return to the office for catheter removal, you will take the first dose 
of medication two hours before catheter removal. The second dose you will take about 12 hours 
after your catheter is removed.  
 
Your bladder function will again be tested at the time of the catheter removal. If you are unable to 
urinate completely and require a second urinary catheter, you will again be assigned two doses of 
the same medication for the time of the second catheter removal. However, if you are able to 
urinate or if you are taught self-catheterization instead, you will not be given any additional doses 
of medication. 
 
Afterwards, you will be asked to call the office or come to the office at any time if you think you 
may have any symptoms of a urinary tract infection or any side effects from the medication. Just 
as you would for any urinary tract infection outside of the study, you will be asked to submit a 
urine sample for testing for possible infection. Physicians will help to determine whether this is a 
true urinary tract infection, and treat you with the usual antibiotic treatment if needed.   
 
Otherwise, you will participate in weekly phone calls after surgery for three weeks, as well as a 
post-surgery office visit scheduled at 6 weeks. This visit is routinely scheduled for all patients 
undergoing surgery regardless of participation in the study.   
 
During the three weekly phone calls, nurses or investigators will ask you whether you have 
experienced any symptoms of urinary tract infection, whether you were treated for any urinary 
tract infections at our office or by any other medical providers, whether you have had any 
complications because of any urinary tract infection you had (such as infection of the kidneys or 
hospital re-admission), and whether you have experienced any side effects from the medication. 
During your usual post-surgical office visit, physicians will ask you the same questions in addition 
to the routine physical examination. 
 
What are the possible risks or discomforts?  
 
The risks from methenamine hippurate are generally rare and mild, but exist. The most common 
side effects are rash, nausea, upset stomach, and pain with urination. All of these side effects 
happened in less than 4% (or 4 out of every 100) of people who used the drug. The most serious 
side effects of methenamine hippurate include allergic reactions and infection of the lungs 
(pneumonia).  
 
Additionally there is the potential loss of confidentiality; that is, someone could find out that you 
have participated in this study, and potentially any data on you that has been collected during the 
IRB Approval From: 04/18/2017 to: 04/17/2018


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study. This could potentially lead to embarrassment and loss of personal health information. 
However, we will decrease this risk through the following: all data needed for the study will be 
stripped of any identifiers (such as name and medical record number) and associated with an 
assigned subject identification number only, so that it cannot be directly linked to you. Also, all 
files, forms, and any consent forms or any other documents that could link to you will be locked in 
a secure area at all times. Only investigators involved in this study will have access to these files 
 
At any time in this study you are injured or harmed and require medical attention, you should 
inform your treating physician that you are in a research study. 
 
Research may involve risks that are currently unforeseeable.  
 
Reproductive risks:  Because of the effects of this drug, there could be serious harm to unborn 
children or children who are breast-feeding. These effects could also harm the mother.  It is also 
possible that harmful side effects that are not yet known could happen to both the mother and 
unborn or breast-feeding child.  If you are currently pregnant or if you are currently breast-
feeding, it is important that you inform the investigator because you will not be able participate 
in the study.  If you are able to become pregnant, you will be given a serum pregnancy test or a 
urine pregnancy test before entry into the study, which is routinely performed prior to scheduled 
surgeries.  You should not become pregnant while you are taking this drug.  If you do become 
pregnant, you must tell the investigator and consult an obstetrician or maternal-fetal specialist. If 
you are breast-feeding, you must tell the investigator and consult an obstetrician or a 
pediatrician.  
 
What if new information becomes available about the study? 
During the course of this study, we may find more information that could be important to you.  
This includes information that, once learned, might cause you to change your mind about being in 
the study.  We will notify you as soon as possible if such information becomes available. 
 
What are the possible benefits of the study?  
This study may benefit you by decreasing your risk of urinary tract infection after short-term 
catheterization. However, you may not get any benefit from being in this research study. 
 
Additionally, this study may benefit society by providing an alternative medication besides 
antibiotics to prevent urinary tract infection after short-term catheterization, which could decrease 
healthcare costs because of hospital-associated infections and decrease antibiotic resistance in 
hospitals. 
 
What other choices do I have if I do not participate?  
If you choose not to participate, and require short-term catheterization after pelvic reconstructive 
surgery, you may or may not be given medication (such as an antibiotic) to prevent urinary tract 
infections based on your physician’s routine practice.  
 
IRB Approval From: 04/18/2017 to: 04/17/2018


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Will I be paid for being in this study? 
You will not be paid for being in this study.  
 
Will I have to pay for anything? 
The medications (methenamine hippurate or placebo) will be provided without cost. However, you 
are still responsible for any deductibles or applicable co-pays for routine office visits (such as the 
post-surgical visit 6 weeks after your surgery), routine urinary tests in case of suspected urinary 
tract infection, and any necessary routine imaging and blood work.  Please talk to your doctor and 
study team about putting you in touch with a financial counselor to determine exactly what the 
deductible and co-pay will be for you; this is highly variable depending on your type of insurance. 
 
What happens if I am injured from being in the study?  
Potential injuries include side effects from the medication. Although, as noted before, the risk of 
major side effects is minimal, if you experience harm from the side effects, you should contact 
your on-call physician and seek care immediately from your primary care physician or from the 
emergency room, if your situation is emergent.  
 
We will offer you the care needed to treat injuries directly resulting from taking part in this 
research.  We may bill your insurance company or other third parties, if appropriate, for the costs 
of the care you get for the injury, but you may also be responsible for some of them. 
 
There are no plans for the University of Pennsylvania to pay you or give you other compensation 
for the injury.  You do not give up your legal rights by signing this form.   
 
If you think you have been injured as a result of taking part in this research study, tell the person 
in charge of the research study as soon as possible.  The researcher’s name and phone number 
are listed in the consent form.  Additionally, please contact the on-call physician for the physician 
who performed your surgery, who you can contact through the hospital operator at 215 662 4000. 
 
When is the study over?  Can I leave the study before it ends? 
This study is expected to end after all participants have completed all visits, and all information 
has been collected. This is expected to be approximately 1 to 1.5 years after the study starts. 
This study may also be stopped at any time by your physician or the study Sponsor without your 
consent because: 
• The Primary Investigator feels it is necessary for your health or safety.  Such an action 
would not require your consent, but you will be informed if such a decision is made 
and the reason for this decision. 
• You have not followed study instructions.  
• The Sponsor or the study’s Principal Investigator has decided to stop the study. 
IRB Approval From: 04/18/2017 to: 04/17/2018


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If you decide to participate, you are free to leave the study at anytime. Withdrawal will not 
interfere with your future care.   
 
Who can see or use my information?  How will my personal information be protected?   
We will do our best to make sure that the personal information obtained during the course of this 
research study will be kept private.  However, we cannot guarantee total privacy.  Your personal 
information may be given out if required by law.  If information from this study is published or 
presented at scientific meetings, your name and other personal information will not be used. 
Otherwise, only investigators and other personnel involved in the study and in routine patient care 
will be able to see or use your information. The Institutional Review Board (IRB) at the University 
of Pennsylvania will also have access to the records. Any information disclosed outside of the 
covered entity may not be protected. 
Extensive efforts will be made to ensure and maintain security of PHI and maintain participant 
confidentiality.   
During the study, any interactions with you will take place in a private room at your physician’s 
office. Post-operative telephone calls will be performed in a private manner in the office setting. 
Data will be recorded on data collection forms, which will be associated with an assigned Subject 
ID number only. Your name, medical record number, or other identifiers will not be present on the 
data collection forms themselves. Any consent forms, record logs, data collection forms, or other 
information will be stored in a secure and locked filing system at all times. Data will be entered 
electronically onto spreadsheets using assigned Subject ID numbers only. This Excel 
spreadsheet form will be stored in a password-secured file and a physical backup copy of this file 
will be made at the end of every other week and the copy stored in a separate, secure area/filing 
system. 
 
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as required by 
U.S. Law. This web site will not include information that can identify you. At most, the web site will 
include a summary of the results. You can search this web site at any time.  
 
Electronic Medical Records and Research Results  
 
What is an Electronic Medical Record?  
An Electronic Medical Record (EMR) is an electronic version of the record of your care within a 
health system. An EMR is simply a computerized version of a paper medical record.  
If you are receiving care or have received care within the University of Pennsylvania Health 
System (UPHS) (outpatient or inpatient) and are participating in a University of Pennsylvania 
research study,  results of research-related procedures (i.e. laboratory tests, imaging studies and 
clinical procedures) may be placed in your existing EMR maintained by UPHS.  
  
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Once placed in your EMR, these results are accessible to appropriate UPHS workforce members 
that are not part of the research team.  Information within your EMR may also be shared with 
others who are determined by UPHS to be appropriate to have access to your EMR (e.g. health 
insurance company, disability provider, etc).  
 
What information about me may be collected, used or shared with others?   
• Name, address, telephone number, date of birth 
• Email addresses 
• Personal and family medical history  
• Results from a physical examinations, tests or procedures 
• Records of office visits and telephone calls conducted for routine care 
• Records of your operation 
• Medical records related to illnesses or medical events that happen to you while you are in the 
study, if applicable 
 
Why is my information being used? 
Your information is used by the research team to contact you during the study. Your information 
and results of tests and procedures are used to: 
• do the research 
• oversee the research 
• to see if the research was done right.   
 
Who may use and share information about me?   
The following individuals may use or share your information for this research study: 
The investigator for the study and the study team  
Clinical personnel who are part of your physician’s office and part of routine care 
IRB at the University of Pennsylvania 
 
Who, outside of the School of Medicine, might receive my information?  
IRB at the University of Pennsylvania 
FDA 
 
The Principal Investigator or study staff will inform you if there are any additions to the list above 
during your active participation in the trial. Any additions will be subject to University of 
Pennsylvania procedures developed to protect your privacy. 
 
How long may the School of Medicine use or disclose my personal health information?   
Your authorization for use of your personal health information for this specific study does not 
expire.  
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Your information may be held in a research database.  However, the School of Medicine may not 
re-use or re-disclose information collected in this study for a purpose other than this study unless: 
• 
You have given written authorization  
• 
The University of Pennsylvania’s Institutional Review Board grants permission 
• 
As permitted by law  
 
Can I change my mind about giving permission for use of my information? 
Yes. You may withdraw or take away your permission to use and disclose your health information 
at any time.  You do this by sending written notice to the investigator for the study.  If you 
withdraw your permission, you will not be able to stay in this study. 
 
What if I decide not to give permission to use and give out my health information? 
Then you will not be able to be in this research study. 
 
By signing this document you are permitting the School of Medicine to use and disclose personal 
health information collected about you for research purposes as described above. 
 
Who can I call with questions, complaints or if I’m concerned about my rights as a 
research subject? 
If you have questions, concerns or complaints regarding your participation in this research study 
or if you have any questions about your rights as a research subject, you should speak with the 
Principal Investigator listed on page one of this form.  If a member of the research team cannot 
be reached or you want to talk to someone other than those working on the study, you may 
contact the Office of Regulatory Affairs with any question, concerns or complaints at the 
University of Pennsylvania by calling (215) 898-2614. 
When you sign this form, you are agreeing to take part in this research study. This means that 
you have read the consent form, your questions have been answered, and you have decided to 
volunteer.  Your signature also means that you are permitting the University of Pennsylvania to 
use your personal health information collected about you for research purposes within our 
institution. You are also allowing the University of Pennsylvania to disclose that personal health 
information to outside organizations or people involved with the operations of this study. 
A copy of this consent and HIPAA authorization form will be given to you.  
 
 
________________________        
________________________________________ 
Name of Subject (Please Print)  
Signature of Subject  
Date 
 
 
 
________________________ 
________________________________________ 
Name of Person Obtaining 
Signature                                  
Date 
Consent (Please Print)  
IRB Approval From: 04/18/2017 to: 04/17/2018