Efficacy and Mechanism of Action of Methenamine Hippurate (Hiprex™) in the Management of Recurrent Urinary Tract Infections in Women
Phase: PHASE4
Conditions: Urinary Tract Infections
Sponsor: University of Texas Southwestern Medical Center

STUDY PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
Official title: Efficacy and mechanism of action of methenamine 
hippurate (Hiprex™) in the management of recurrent urinary tract 
infections in women 
 
 
NCT number: NCT04709601 
IRB Approved Document date: 11-09-22 

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Principal Investigator: Philippe Zimmern, MD 
Co-Investigators: Kimberly Williams, Research Assistant 
Study Title: Efficacy and mechanism of action of methenamine hippurate (Hiprex™) in the 
management of recurrent urinary tract infections in women 
Sponsor/Funding Source: 
1. Purpose: 
Urinary tract infections (UTIs) are the most common bacterial infection in women. According to 
current guidelines, typical treatment consists of a short course of culture-proven antibiotics1; 
however, UTIs can relapse. Recurrent UTIs (RUTIs) can be detrimental to the patient’s health by 
increasing the chance of a UTI complication, such as potentially life-threatening sepsis (urosepsis) 
or permanent kidney damage from pyelonephritis. In addition, every time a UTI occurs, the 
patient will experience bothersome symptoms of urinary frequency and burning on urination and 
require prompt antibiotic treatment to eliminate the infection. Such repeated exposure to 
antibiotics can lead to adverse side-effects from the antibiotics used as well as an increase the 
development of antibiotic resistance. For patients with RUTIs, there is a need to consider a 
prophylactic approach to lessen the frequency and severity of these recurrent episodes. 
Various prophylactic agents against UTIs have been studied, such as estrogen, cranberry 
juice/tablets, acupuncture, probiotics, and antiseptics, which differ from antibiotics in that they 
can affect a variety of microorganisms as opposed to just bacteria2. Hiprex (methenamine 
hippurate) is one of the most popular antiseptics prescribed for RUTIs. Hiprex has been around 
for nearly a century, yet limited information is known on its exact mechanism of action in the 
urine and there are no strategies in place to target its use to each treated individual. 
Furthermore, despite several trials against different daily antibiotic prophylaxis, its role in the 
management of RUTIs has not been solidly established. Methenanime hippurate functions by 
producing formaldehyde, which inhibits bacterial growth [cit, Validus]. Previous studies have 
shown a modest decrease in the rate of re-infection in women with RUTIs after beginning Hiprex 
compared to the rate prior to initiating the medication; however, these studies have failed to 
produce meaningful results regarding women with RUTIs who do not have a complicated 
infection involving urinary catheters for example.  Hiprex metabolism and excretion in the urine 
has been studied in the 60’s, 70’s and 80’s. Although it is known that formaldehyde production 
is enhanced by an acid environment, urinary pH has not been routinely tested in patients who 
take this medication, a regrettable oversight which might affect the efficacy of this compound in 
vivo. 
Therefore, the purpose of this study is to measure the concentration of formaldehyde in the urine 
of women with RUTIs on Hiprex; and then, assuming its urinary presence is confirmed at the 

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proper acid urinary pH, evaluate if such a therapy has favorable effects in decreasing the rate of 
RUTIs over time. 
2. Background: 
UTIs contribute to about 25% of all infections worldwide2. In the US alone, UTIs incurred an 
estimated societal cost, including health care costs and productivity losses, of $3.5 billion in 
20153. Women are especially likely to contract UTIs compared to men at a ratio of 8:1 and have 
a 50-60% chance of experiencing at least one UTI in their lifetime2,4. Almost a quarter of these 
UTIs will recur within the next 6 months5. Risk factors of RUTIs include medical conditions, such 
as pregnancy, diabetes, immunosuppression, and abnormal urinary tracts2; however, women 
without any of these comorbidities are still at risk of RUTIs. While recurrence is already a 
complication of UTIs, other complications can arise including acute renal failure or multi-organ 
system involvement with progression into bacteremia and then life-threatening sepsis and 
shock6.  
Treatment of RUTIs does not differ greatly from the treatment of their uncomplicated 
counterparts in that both still require culture-based antibiotics. However, patients with frequent 
UTIs will require repeated courses of antibiotics, a process which in time exposes to adverse side-
effects from the medication and enhances the risk of antibiotic resistance7. Thus, in patients with 
a history of RUTIs, prophylaxis should be considered once the treatment of the active UTI has 
been completed. 
RUTI prevention has been attempted via lifestyle modifications and/or supplements. By drinking 
at least 2-3 liters of fluids a day and voiding frequently, patients will be able to eliminate bacteria 
from their urinary tracts. Reducing the number of new sexual partners will also decrease the risk 
of UTIs as will proper hygiene around the time of intercourse2. Women are encouraged to wipe 
from front to back to limit the number of bacteria tracking from the anal and genital areas to the 
urethra2. Prophylactic agents can take many forms. Aside from treatment of active infections, 
low-dose antibiotics (most commonly taken daily or post-coitally) have been shown to be 
effective at preventing UTIs8; however, they still expose to the risks of antibiotic resistance 
and/or allergies. Vaginal estrogens have been shown to decrease the rate of UTIs by decreasing 
vaginal wall atrophy and conferring an unfavorable environment for the colonization of 
uropathogens with little worry of systemic absorption2. Estrogen, along with probiotics, also 
increase the proliferation of beneficial bacteria like Lactobacillus, an important aspect of the 
natural genito-urinary microbiome protective mechanism. In animal models, D-mannose and 
cranberry juice/tablets have been found to block receptors that allow bacteria to attach to the 
bladder wall thus limiting colonization. However, despite having moderate efficacy against RUTIs, 
long-term adherence to D-mannose treatment was found to be questionable9 and the amount 
of D-mannose or cranberry realistically reaching the urinary bladder after an oral intake remains 
questionable and under study. 

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Hiprex (methenamine hippurate) is one of the most widely prescribed antiseptics for the 
prophylaxis of RUTIs[cit]. Earliest recorded usage of methenamine as a urinary antiseptic was 
described in 189910. Methenamine is hydrolyzed to ammonia and formaldehyde, which is 
bacteriostatic or bactericidal depending on its concentration11,12. The rate of this hydrolysis was 
found to be greater in solutions with lower pHs, achieving formaldehyde concentrations of 
clinical use at prescription dosage when the pH was less than 6.010,13,14. Although the urine pH 
range varies from 5 to 8, a recent study from our group in post-menopausal women identified an 
average urine pH around 6.0 with daily variability in several patients, possibly related to diet 
intake15. Furthermore, as methenamine is hydrolyzed, the production of ammonia alkalinizes the 
solution, slowing down the reaction. Thus, in 1961, in order to increase efficacy, its formulation 
with adding hippurate, which increases the acidity of urine, as Hiprex, was developed13. 
A literature review on the metabolism and urinary excretion of methenamine produced sparse 
results. Studies by Gollamudi and Strom detailed the use of silica cartridges to determine the 
concentration of methenamine and formaldehyde in a solution and test this new method on 
human urine after administration of Hiprex to subjects16,17. However, this work has limitations, 
since only 11 participants were tested and the urine samples were only taken after the first dose 
of Hiprex rather than after several days or months of Hiprex intake. Strom also analyzed the 
kinetics of methenamine, finding that a methenamine concentration of 750 µg/mL at pH 6.0 
could produce bactericidal concentrations of formaldehyde after 3 hr and that the hydrolysis of 
methenamine occurred 20 times faster at a pH of 5.0 versus 6.014. Another study determined 
that the concentration of formaldehyde in urine adequate to produce a bacteriostatic effect (25 
µg/mL) could be attained by adding 0.6 mg/mL of methenamine to urine at a pH ≤ 5.7 or 1 mg/mL 
at pH ≤ 5.8518. Because the two latter experiments produced their results ex vivo, the rate of 
excretion of methenamine into the urine and the proof of its metabolism of conversion to 
formaldehyde in a patient’s urine after an oral intake of 1 gm twice a day as currently 
recommended remains untested. 
There are several studies reporting on the efficacy of Hiprex; however, most only include 
patients with specific comorbid conditions. After excluding men, Table 1 includes a review of 
these studies. A case series found that the administration of Hiprex resulted in a decrease in 
catheter changes among patients with indwelling catheters19. Another long-term study reported 
that, after starting Hiprex, a decrease in the rate of reinfection of UTIs in geriatric patients 
hospitalized was noted at two years, especially in those who were supervised while taking their 
medications20; however, the rate of UTIs prior to starting Hiprex was not given. A review of 
Hiprex, containing 2032 patients across 13 studies, indicated that short-term treatment (1 week 
or less) of Hiprex in women without renal tract abnormalities led to a significant decline in UTIs21. 
However, the authors admitted that given the heterogeneity in the populations studied and the 
outcomes measured, there was no clear consensus amongst these studies.  
Although the literature offers no recommendation for the length of time to prescribe Hiprex, the 
current knowledge on Hiprex suggests a possible role of longer courses to fully evaluate its 

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efficacy in the management of RUTIs. Fortunately, many women evaluated for RUTIs will not have 
any of the examined comorbid conditions as listed in Table 1, and many will present without an 
overt risk factor for UTIs; thus, it is important to include these women in future studies.  
Hiprex can cause various mild side-effects, such as rashes, diarrhea, sore throat, abdominal pain, 
and bladder “stinging”20,21. Although the side-effects are typically self-limited and non-severe, 
hemorrhagic cystitis was found in the case of an accidental ingestion of 8 g of methenamine 
mandelate by a 2½-year-old22. Despite the side-effect being due to a different formulation of 
methenamine from Hiprex as well as the dose being much higher than the recommended 
maximum of 500 mg, this rare case still underlines the importance of ensuring that Hiprex is 
effective enough so that its benefit outweighs its potential risks. 
In summary, RUTIs can be debilitating in a large proportion of women. Despite the popularity of 
Hiprex as an RUTI prophylactic agent, there are still large gaps of knowledge regarding its use. 
Among them are its in vivo metabolism, including the measurements of urinary excretion of both 
methenamine and formaldehyde, the optimization of urine pH under 6.0 to enhance Hiprex 
presumed mechanism of action, and on the clinical side, the effectiveness and safety of Hiprex in 
geriatric patients as well as those with comorbidities, along with its cost-effectiveness over other 
long-term prophylactic agents for RUTI management.  
Table 1: Literature review on the effect of Hiprex (HX) in women 
Author and 
Year 
Study 
Design 
Number 
of 
Subjects 
Indication 
Hiprex dose 
Outcome 
Measures 
Findings 
Furness 
197523 
RCT 
  226  
Pregnant with 
asymptomatic 
bacteriuria 
1 g BID for ≥7 
days vs 
methenamine 
mandelate 1 g 
QID vs no 
treatment 
Symptomatic 
UTI, adverse 
events 
• 
No significant 
difference in 
symptomatic 
UTI 
• 
No relevant 
adverse events 
Gundersen 
198624 
RCT 
   50 
Post-
menopausal 
1 g BID for 6 
months vs 
placebo 
Symptomatic 
UTI, 
bacteriuria, 
adverse 
events 
• 
Decrease in 
symptomatic 
UTI with HX 
• 
Side-effects of 
nausea and 
rash 
Hoivik 
198425 
RCT 
   52 
Pre-menopausal 
1 g QD or BID vs 
placebo 
(duration of 
treatment 
unknown) 
Symptomatic 
UTI, adverse 
events 
• 
Decrease in 
symptomatic 
UTI with HX 
• 
Side-effect of 
bladder 
stinging 
Knoff 
198526 
RCT 
  64 
After 
gynecological 
operations 
requiring short-
2 g BID for 7 
days vs placebo 
Symptomatic 
UTI, 
bacteriuria, 
adverse 
events 
• 
Decrease in 
symptomatic 
UTI with HX 
(3.2% of HX vs 

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term 
catheterization 
27.6% of 
placebo) 
• 
Decrease in 
bacteriuria with 
HX (3.2% of HX 
vs 41.4% of 
placebo) 
• 
Side-effects of 
sore throat 
Ladehoff 
198427 
RCT 
300 
After 
gynecological 
operations 
requiring short-
term 
catheterization 
500 mg BID for 
8-13 days vs no 
treatment 
Bacteriuria, 
adverse 
events 
• 
Decrease in 
bacteriuria with 
HX (30.3% of 
HX vs 45.6% of 
no treatment) 
• 
Side-effect of 
nausea 
Parvio 
197620 
Case 
series 
52 
Post-
menopausal 
with RUTIs who 
are hospitalized 
> 2 years 
No treatment 
for 6 months 
then HX 1 g BID 
for 6 months 
Symptomatic 
UTI, side-
effects 
• 
Decrease in UTI 
reinfections 
with HX (17 
cases without 
HX vs unknown 
number while 
on HX) 
• 
Side-effects of 
“soreness of 
the mouth” and 
abdominal pain 
Schiotz 
200228 
RCT 
150 
After 
gynecological 
operations 
requiring short-
term 
catheterization 
1 g BID for 5 
days vs placebo 
Symptomatic 
UTI, 
bacteriuria  
• 
Decrease in 
symptomatic 
UTI with HX 
(2.7% of HX vs 
13.9% of 
placebo) 
• 
No significant 
difference in 
bacteriuria 
• 
Side-effects of 
nausea and 
rash 
Thomlinson 
196829 
Quasi-
RCT 
130 
After 
gynecological 
operations 
requiring 
catheterization 
1 g BID with 
sodium acid 
phosphate 2g 
TID for 7 days 
vs no treatment 
Bacteriuria, 
side-effects 
• 
No significant 
difference in 
bacteriuria 
• 
No side-effects 
Tyreman 
198630 
RCT 
109 
After 
gynecological 
operations 
requiring short-
term 
catheterization 
1 g TID for 5 
days vs no 
treatment 
Symptomatic 
UTI, 
bacteriuria, 
adverse 
events 
• 
Decrease in 
symptomatic 
UTI (2.2% of HX 
vs 28.6% of no 
treatment) 
• 
Decrease in 
bacteriuria with 
HX (9.8% of HX 

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vs 37.9% of no 
treatment) 
• 
No side-effects 
 
3. Concise Summary of Project: 
Study Design: 
There will be two parts to this project. Part 1 will be a prospective assessment of the urinary 
effects of Hiprex in women with RUTIs, such as acidity and concentration of formaldehyde, to 
determine the best oral concentration to inhibit bacterial growth in urine for each enrolled 
patient. Part 2 will be a long-term assessment of Hiprex on RUTI evolution in women with a 
longstanding history of RUTIs, with Hiprex taken at a proper dosing (as established in Part 1) and 
with regular urine checks at subsequent visits up to one year of follow-up. 
Part 1: Women between age 50 and 85 presenting to the outpatient UTSW Urology clinic who 
are currently taking Hiprex (or any methenamine-containing product) or are willing to be started 
on Hiprex and do not meet exclusion criteria (see below) will be invited to participate in the study. 
During their first study visit (V1), they will be consented for this long-term prospective study. The 
documentation of RUTI based on the current definition of 3 documented and treated UTIs in the 
past year or 2 in the past 6 months will be recorded.  A 3 day diary with recordings of urine pH 
before each meal and before bed will be obtained to document that the patient has consistent 
low urine pH (<6), a critical condition for methenamine conversion to formaldehyde. Then the 
patient will be asked to take a tablet of Hiprex 1gm and to provide one subsequent urine samples 
at 1 hour after the intake of Hiprex. These midstream urine samples will be processed and 
transferred to our Lab on campus (K2 building) before being sent to our partnering lab at UTD 
run by Dr. Larry Reitzer for testing, including urine pH testing, and the measurements of 
methenamine and aldehyde produced in these urine samples. 
Part 2: 
Patients already on a methenamine drug will be queried on the history of their exposure 
(duration of intake, effect on RUTI, current urine pHs, etc). Patients will provide a urine sample. 
If the urine culture is negative, the patient will begin their prescription of Hiprex by manufacturer 
recommendations (if not already doing so). If the urine culture returns positive, they will be 
treated with a course of culture-based antibiotics and will begin Hiprex once their urine results 
confirm a negative culture.  
Based on our preliminary data on seven women followed for one year, the levels in urine (ratioed 
to urinary creatinine to account for urine dilution) remain fairly stable over time. 

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Therefore, we don’t need to follow women on Hiprex as closely as we intended to at the start of 
this project.  Now we suggest that patients return to clinic at  3 months, 6 months,  and 12 months 
after the onset of their Hiprex treatment to provide urine samples. During these follow-up visits, 
patients will also fill out a standardized, validated questionnaire regarding UTI symptoms31. Data 
concerning common Hiprex side-effects and compliance with self-administration of Hiprex will 
also be collected. Hiprex will be stopped when clinically indicated based on the onset of such 
side-effects. Urine acidity and concentration of methenamine and formaldehyde will be analyzed 
in these urine samples. Hiprex dosage will be increased if concentration of formaldehyde is not 
above the threshold for bacteriostatic effects. 
Outcome variables and endpoints: 
Primary outcome: 
To confirm that the use of Hiprex will decrease the recurrence of symptomatic UTIs, our primary 
outcome will be the number of UTI events (namely UTI symptoms with positive urine cultures, or 
UTI-like episodes requiring antibiotic treatment) during the 1 year of the study period. 
Secondary outcomes: 
• Severity of UTI symptoms based on validated questionnaire, with the expectation of a 
decrease in UTI symptom severity while on Hiprex. 
0.00
100.00
200.00
300.00
400.00
500.00
600.00
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52
Methenamine (uM)
Time (weeks)
uM Methenamine in Urine normalized to CreaƟnime
H1
H4
H5
H7
H9
H10

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• Duration of intervals between UTI episodes considering that Hiprex may lessen the 
frequency of oral antibiotics usage to treat symptomatic UTI episodes. 
• Reduction in number of hospital admission and IV antibiotics (PICC line) for urosepsis 
and/or pyelonephritis compared to the pre-Hiprex situation. 
• Frequency and severity of adverse effects related to Hiprex, requiring treatment 
interruption, dose adjustment, or discontinuation. 
• Evaluation of possible gradual increase in bacterial resistance to formaldehyde by testing 
its concentration in the urine at each visit, urine acidity, and ability to kill established 
bacterial strains (UTI89, CFT073) 
Recruitment: 
All patients will be recruited from the urology practice of the PI (WCB3 4th floor).  
As part of a pilot study, we plan on enrolling 100 patients over 18 months to gather sufficient 
data to power a more extensive randomized control trial later on, using either a placebo or a 
competitive low-dose antibiotic, such as Macrobid or Septra, based on the efficacy of Hiprex 
given at the proper dosing and in the right urinary pH milieu in this small cohort of RUTI women. 
The PI is raising the enrollment goal due to COVID being tentatively over and the team is able to 
recruit more subjects due to this. 
4. Study Procedures: 
Initial visit: 
Patients will be consented for the study. Patients will also be advised to return to clinic sooner 
than scheduled follow-up visits if they start to develop symptoms of a UTI (pain with urination, 
cloudy or bloody urine, etc.) or experience any side-effects that may be attributed to Hiprex. 
Patients who have previously been on a methenamine-containing substance will be asked 
about their medication history, including the length of time on the medication, the dosage and 
any changes to dosage, and side-effects experienced while taking the medication. Patients will 
be prescribed Hiprex 1 g PO BID for 3 months with 4 refills (total of 1 year). Urine samples will 
be obtained from patients prior to their first dose intake. Those will be mid-stream urine 
sample, with a collection volume around 30 ml.  
Those with negative cultures (after 48-72 hours) will begin their first dose of Hiprex. Those with 
positive cultures will be treated with a course of culture-based antibiotics and will start their 
first dose of Hiprex when they can produce negative urine cultures. Using a formaldehyde 
assay, the concentration of formaldehyde in the urine samples with negative cultures of each 
patient will be measured. A pH meter will be used to determine the acidity of the urine 
samples. 

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In the lab of Dr Reitzer, the following studies will be performed on de-identified urine samples: 
Sample preparation: The urine samples will be frozen at -80°C. Upon thawing for assay, the urine 
will be adjusted to pH 8.0 by adding 50 mM HEPES buffer and checked with pH paper in order to 
prevent methenamine breakdown, which occurs rapidly at pH < 6. The sample will be centrifuged 
to remove particulates and the soluble portion filter sterilized. 
Formaldehyde assay: A variety of formaldehyde assays are available (summarized in X1). We will 
use a glutathione-dependent formaldehyde dehydrogenase (FDH)-based assay (X2). The urine 
sample will be diluted 10- to 1000-fold and placed in a microtiter dish well. The reaction will also 
contain 50 mM HEPES buffer (pH 8), 0.5 mM reduced glutathione, 0.5 mM NAD, and FDH (the 
FrmA protein) purified from Escherichia coli. The increase in NADH is proportional to the amount 
of formaldehyde. The mM extinction coefficient for NADH is 6.27. To ensure the linearity of the 
reaction, a known amount of formaldehyde will be added to this reaction in a separate reaction.  
Methenamine assay: Methenamine breaks down to formaldehyde at acidic pHs (i.e., less than 
pH6). Standard assays for methenamine involve conversion of methenamine to formaldehyde. 
This becomes a problem when methenamine and formaldehyde are present together. To prevent 
this problem, we brought the pH of the urine sample to 8.0, which prevents methenamine 
degradation. To measure methenamine, the sample will be treated with acid (0.25 N HCl at 60° 
C for 10 minutes), which will completely convert the methenamine to formaldehyde. This 
solution will be neutralized, brought to pH 8.0, and assayed for formaldehyde as described above. 
The assay measures the sum of methenamine and formaldehyde, and the methenamine 
concentration is obtained by subtracting the formaldehyde from the first assay. 
Follow-up: 
Patients will be asked to return to clinic for 3 follow-up visits at: 3 months (V1), 6 months (V2), 
and 12 months (V3) after starting Hiprex. This research visit timing corresponds to standard-of-
care clinic visits include those at 3 months, 6 months, and 12 months.  
At each of these visits, patients will be asked to withhold their first dose of Hiprex until they arrive 
to clinic. Urine samples will be collected at baseline, then 1 hours after the dose intake. These 
samples will be tested according to the same protocol in the lab of Dr. Reitzer. In addition, 
patients will be administered a UTI Symptom Assessment (UTISA) questionnaire and queried 
about any UTI symptoms and Hiprex-associated symptoms since their last visit. If the 
concentration of methenamine/formaldehyde in the urine sample is found to be inadequate for 
bacteriostatic or bactericidal activity, the dosage might be increased to 1.5 PO BID, and/or diet-
adjustment might be considered to decrease urine pH if found to be not sufficiently acidic. For 
patients unable to reach appropriate low pH urinary levels after the above modifications, they 
will be removed from the study and will not continue with the longitudinal portion. 

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Data: 
The dataset will be extracted from EPIC and will include demographic data (age, gender, race, 
height, weight) as well as culture data from prior urinary tract infections, comorbid conditions 
(i.e. diabetes, renal insufficiency, etc.), hormonal status, methenamine usage history, and 
urological history (including possible surgical interventions). See Excel document. 
5. Sub-Study Procedures: 
None. 
6. Criteria for Inclusion of Subjects: 
a. Female 
b. Age 50 – 85 
c. Have RUTIs (at least 2 UTIs within the past 6 months or 3 within the past year)32 
 
7. Criteria for Exclusion of Subjects: 
a. Being on antibiotics at baseline (i.e. suppressive therapy or antibiotic therapy for 
urinary or non-urinary infections) 
b. Neurogenic bladder condition 
c. Using urinary catheters (including Foley catheter, intermittent catheterization, and 
suprapubic catheter) 
d. Uncontrolled diabetes (HbA1c > 9) 
e. Chronic renal failure defined as serum creatinine > 1.5 mg/dL 
f. History of liver disease  
g. Patients from out of town, in whom follow-up will not be possible 
h. Pregnancy 
i. Allergy to Hiprex 
j. Inability to take Hiprex reliably at home, such as having psychosis, dementia, or 
swallowing disorders 
k. Non-English speakers 
 
8. Sources of Research Material: 
Information from medical records will be included in a de-identified fashion. Confidential 
information will initially be recorded to facilitate returning to the medical record if needed for 
more information until the end of the study, at which time the confidential information will be 
destroyed. 
 
 

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9. Recruitment Methods and Consenting Process: 
Once a potential patient is identified, consent will be obtained in the office. All data will be de-
identified for analysis. An information sheet will be provided to all subjects. 
10. Potential Risks: 
a. To the participants who were already taking Hiprex, there are no direct risks because 
this study would not change their routines. 
b. To the participants who were not initially taking Hiprex, risks include any adverse side 
effects associated with the medication; however, patients will be monitored very 
closely after the start on Hiprex therapy. 
c. Tracked information will be used from patient records (EMR in EPIC), and identifiable 
information will be removed prior to analysis to ensure anonymity. Thus, all possible 
efforts will be made to protect patient confidentiality. Potential breach of PHI will be 
minimized with use of encrypted data devices stored in locked and protected areas. 
 
11. Subject Safety and Data Monitoring: 
Patients will be offered Hiprex, which, based on available literature since the 1960s, has not been 
known to lead to any serious or long-lasting side effects. However, patients will be given all 
relevant warnings and queried about new symptoms at each follow-up visit. Hiprex will be 
stopped when clinically indicated. Once the patient data has been analyzed, the data will be 
archived in a password-protected repository. 
12. Procedures to Maintain Confidentiality: 
Prior to data analysis, all patient names, ID numbers, or any other identifiable characteristics 
belonging to the patient will be removed from the dataset. Only the principal investigator and 
listed researchers will have access to the dataset, and the data will be stored electronically on a 
password-protected and secured UTSW computer. 
13. Potential Benefits: 
a. To the participants who were already taking Hiprex, there are direct benefits because 
this study will confirm that they are either taking Hiprex with adequate urinary dosing 
or need adjustments in Hiprex dose and/or urine pH to improve Hiprex efficacy. 
b. To the participants who were not initially taking Hiprex, benefits would include a 
possible reduction in the frequency and severity of RUTIs over time if Hiprex is shown 
to be metabolized in their urine to produce adequate formaldehyde levels. 
c. To the individuals not involved in this study, the study will provide directions for future 
randomized control trials involving Hiprex and another comparator. 
 

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14. Biostatistics: 
Since this is a pilot study, our goal is to enroll 100 patients with RUTIs willing to be closely 
monitored for 1 year on Hiprex once the appropriate dosing has been confirmed. The acquired 
data will inform power calculations for a future randomized control trial.  
References: 
1. 
Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the 
treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update 
by the Infectious Diseases Society of America and the European Society for Microbiology 
and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103-120. 
2. 
Al-Badr A, Al-Shaikh G. Recurrent Urinary Tract Infections Management in Women: A 
review. Sultan Qaboos Univ Med J. 2013;13(3):359-367. 
3. 
Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract infections: 
epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol. 
2015;13(5):269-284. 
4. 
Medina M, Castillo-Pino E. An introduction to the epidemiology and burden of urinary 
tract infections. Ther Adv Urol. 2019;11:1756287219832172. 
5. 
Foxman B, Gillespie B, Koopman J, et al. Risk factors for second urinary tract infection 
among college women. Am J Epidemiol. 2000;151(12):1194-1205. 
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Formaldehyde Assay in Fish Food Products Food Chem 2011 Jul 15;127(2):774-9. doi: 
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