Seven Versus Fourteen Day Treatment for Male Urinary Tract Infection
Phase: NA
Conditions: Urinary Tract Infections
Sponsor: VA Office of Research and Development

Protocol 9.0, 02/19/2019 
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Seven vs. 14 Days Treatment for Male Urinary Tract Infection 
 
 
 
A randomized placebo-controlled trial of 7 vs. 14 days of antimicrobial treatment for men with 
UTI 
 
Sponsor: VA Merit Review, award #1I01CX000830-01A2 
 
Intervention: 7 days of antimicrobial treatment (ciprofloxacin or 
trimethoprim/sulfamethoxazole) followed by 7 days of placebo vs. 14 days of antimicrobial 
treatment 
Principal Investigator: Dimitri Drekonja, MD, MS 
Co-Investigator, and Michael E. DeBakey VAMC site investigator: Barbara Trautner, MD, PhD 
 
Protocol version: 9.0 
 
 

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Table of contents 
 
 
 
 
 
 
 
Page 
1. Introduction 
 
 
 
 
 
 
 
3 
a. Background 
 
 
 
 
 
 
3 
b. Preliminary studies and current status 
 
 
5 
2. Research design and methods  
 
 
 
 
8 
a. Study type 
 
 
 
 
 
 
8 
b. Summary of study description 
 
 
 
8 
c. Details of specific study areas 
 
 
 
11 
d. Inclusion and exclusion criteria 
 
 
 
14 
e. Method of identifying potential subjects 
 
 
15 
f. Patient contact and enrollment 
 
 
 
16 
g. Sampling of the intestinal microbiota  
 
 
17 
h. Subject compensation  
 
 
 
 
18 
i. Potential complications during therapy 
 
 
18 
j. Follow-up and outcome assessment  
 
 
19 
k. Safety and monitoring 
 
 
 
 
19 
l. Definitions for safety and monitoring 
 
 
20 
m. Anticipated adverse events 
 
 
 
 
21 
n. Statistical methods 
 
 
 
 
 
23 
o. Proposed timetable 
 
 
 
 
 
24 
3. Summary 
 
 
 
 
 
 
 
25 
4. References 
 
 
 
 
 
 
 
26 

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1. Introduction 
1.a. Background 
Urinary tract infection occurring in males (hereafter, male UTI) is a common infection 
among both hospitalized and ambulatory men. Most patients are treated in the outpatient 
setting, with only a minority requiring hospitalization1, 2. Data from the 2000 National 
Ambulatory Medical Care Survey demonstrate that male UTI led to 1.8 million annual office 
visits and 420,000 annual Emergency Department visits in the U.S.1, 2. Within the VA health 
care system, over 33,000 non-hospitalized men have at least one UTI episode in a 12-month 
period3.  Treatment is typically with oral antimicrobials, for durations ranging from 3 days to 
several weeks.  
Few data from randomized trials are available to guide treatment duration for male UTI. At 
one extreme of the treatment duration spectrum, a Scandinavian study found no significant 
difference in clinical cure or recurrence rates among men with febrile UTI randomized to 14 
vs. 28 days of ciprofloxacin4. At the other end of the spectrum, in a study of UTI treatment 
duration among patients with spinal cord injury (85% male), 3 days treatment yielded a 
higher rate of symptomatic relapse than did 14 days treatment, in both short and long-term 
follow-up5. No other randomized clinical trials are available that directly assess the impact of 
duration of treatment for male UTI on efficacy; accordingly, the conventional 
recommendation to treat for 7-14 days is based largely on expert opinion6-8. Currently, 7, 10, 
and 14-day antimicrobial courses are commonly used to treat UTI in male veterans UTI3. 
In addition to the lack of evidence regarding optimal treatment duration, two well-
documented trends are making management of male UTI progressively more challenging. 
First, Gram-negative bacilli, the causative microorganisms for most UTIs, are becoming 
increasingly resistant to most relevant antimicrobials; consequently, few reliably active oral 
agents are available for UTI therapy, which is often initiated empirically, before culture 
results are known. Second, Clostridium difficile infection, which is almost invariably 
precipitated by antimicrobial use, is increasingly frequent and severe9, 10. 
Increasing antimicrobial resistance among Gram-negative bacilli. Antimicrobial resistance 
among Gram-negative bacilli, a major public health threat, has attracted considerable 
attention from governmental organizations, professional societies, and leaders in the field of 
infectious diseases11. Perversely, as resistance among Gram-negative bacilli has increased, 
the development of new antimicrobials that target these organisms has decreased11.  
The problem of Gram-negative resistance is particularly relevant for treating UTI, because 
the vast majority of UTIs are caused by enteric Gram-negative bacilli, in particular 
Escherichia coli, but also Klebsiella species, Enterobacter species, and others8, 12. Guidelines 
recommend that when the local prevalence of susceptibility to a particular drug among 
uropathogens falls below 80%, that drug should no longer be used as empiric therapy for 
UTI13, 14. Currently, many locations, including the MVAMC, have E. coli susceptibility rates 
of only 65-70% for both ciprofloxacin and trimethoprim-sulfamethoxazole (TMP-SMZ) 
(MVAMC antibiogram, January 2012 through June 2012). These drugs are traditional 
cornerstones of UTI treatment in the ambulatory setting because of their excellent oral 

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bioavailability and their track record of tolerability and effectiveness across most types of 
UTI, including febrile UTI and pyelonephritis15, 16. In contrast, alternative oral agents, 
including β-lactams, nitrofurantoin, and fosfomycin, have inferior efficacy (β-lactams, 
fosfomycin)17, 18 and/or achieve low tissue drug levels (nitrofurantoin, fosfomycin)13, 18, 
limiting their appeal for UTI therapy, especially for patients with fever or clinical 
manifestations suggesting pyelonephritis13, 18.  
The rising prevalence of resistance to ciprofloxacin and TMP-SMZ has led providers to use 
broader-spectrum empirical therapy, such as a parenteral dose of a more predictably active 
agent combined with empiric oral ciprofloxacin or TMP-SMZ. This practice adds to the 
selective pressure for the development of antimicrobial resistance, thereby causing future 
infections to be even more difficult to treat. 
Increased incidence and severity of Clostridium difficile infection. Beginning in the early 
2000’s, an increasing incidence and severity of C. difficile infection was observed, first in 
Canada and subsequently worldwide9, 10, 19, 20. Multiple factors have been proposed to explain 
these increases, including increased antimicrobial use, emergence of a new fluoroquinolone-
resistant strain of C. difficile during a time of increased fluoroquinolone use, increased 
sporulation and toxin production by this epidemic strain, and better recognition and diagnosis 
of C. difficile infection on the part of clinicians9, 10. Whatever the explanation, C. difficile 
now rivals methicillin-resistant Staphylococcus aureus as the leading cause of nosocomial 
infections21, and is also increasingly prevalent in the community22. Thus, efforts to decrease 
its incidence, including through reduced antimicrobial use, are urgently needed.  
Relationship between antimicrobial use, antimicrobial resistance, and C. difficile infection. 
The relationship between antimicrobial use and subsequent antimicrobial resistance is 
complicated. First, although some patient-level studies have demonstrated the development 
of resistance during or after receipt of antimicrobial therapy23-25, in clinical practice the link 
between past antimicrobial use and subsequent infection with a drug-resistant organism is 
difficult to prove. Additionally, most patients in whom a resistant organism emerges do not 
develop a subsequent drug-resistant infection, but rather become carriers of resistant 
organisms as part of their normal bacterial microbiota. Because carriage of resistant 
microorganisms is a clinically silent phenomenon, this is an under-recognized harm of 
antimicrobial use. However, the fecal microbiota serves as the source of many infections, 
including UTIs. In addition, microorganisms can spread easily among household contacts, 
thus increasing the population at risk for infection with a resistant organism26, 27. Countries 
with high levels of antimicrobial use typically have correspondingly high rates of 
antimicrobial resistance among clinical isolates, as compared with countries with lower 
levels of use28, 29. Similarly, individual centers have documented a temporal relationship 
between antimicrobial use and antimicrobial resistance, with increased use being followed 
shortly thereafter by a corresponding increase in resistance30. 
Antimicrobial use is also closely linked to C. difficile infection, almost all cases of which are 
preceded by antimicrobial therapy. Increased antimicrobial use is associated with increased 
C. difficile infection31, 32, and reduced antimicrobial use has been used successfully to combat 
outbreaks of C. difficile infection33-35. Accordingly, a joint Clinical Practice Guideline for C. 
difficile infection from the Society for Healthcare Epidemiology of America and the 

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Infectious Disease Society of America recommends limiting the duration of antimicrobial 
therapy a way to decrease the incidence of C. difficile infection36.  
In summary, antimicrobial use is associated with increases in antimicrobial resistance and C. 
difficile infection; therefore, effective strategies to minimize unnecessary antimicrobial use 
are urgently needed. One potential method to decrease unnecessary antimicrobial use is to 
define the minimal effective treatment duration for various diseases, and to use this minimal 
duration routinely. This approach has been successfully applied to other infectious diseases, 
including ventilator-associated tracheitis23, ventilator-associated pneumonia24, and 
cellulitis37. For these disorders, shorter-duration treatment performed as well as longer-
duration treatment, and in the respiratory infections was associated with less colonization and 
infection with drug-resistant microorganisms, with or without a trend toward lower mortality-
-without any reduction in efficacy. For male UTI, if 14 days of therapy yields no clinically 
relevant benefit to that observed with 7 days of therapy, but induces greater resistance in a 
similar manner as seen in the studies of ventilator-associated pneumonia and tracheitis, then 
patients treated longer are exposed to potential harms without any benefit. Alternatively, if 
longer-duration treatment does provide benefits, then a substantial proportion of men with a 
UTI are being treated for an inappropriately short duration, and may be experiencing worse 
symptom control and increased rates of recurrence. Accordingly, we propose to conduct a 
randomized clinical trial to investigate whether 7 days of antimicrobial treatment is non-
inferior to 14 days of antimicrobial treatment for men with a UTI. 
 
1.b. Preliminary studies and current status 
Historically, UTIs in both males and females were treated with longer courses of 
antimicrobials than are commonly used today, ranging from 7 days for simple cystitis  (i.e., 
bladder infection or lower-tract disease), to up to 6 weeks for pyelonephritis (i.e., kidney 
infection or upper-tract disease), which is more serious but also comparatively uncommon38. 
UTI treatment has been studied much more extensively in women than in men; consequently, 
optimal treatment durations are more clearly defined for women than for men13. In women, 
cystitis can be treated effectively with 3 days of a fluoroquinolone or TMP-SMZ, 5 days of 
nitrofurantoin, or a single dose of fosfomycin tromethamine; likewise, pyelonephritis can be 
treated effectively with 5 days of high-dose levofloxacin, 7 days of standard-dose 
ciprofloxacin, or 14 days of TMP-SMZ13, 39. 
In contrast, little is known regarding the optimal treatment duration for male UTI. This is due 
in part to the paucity of randomized trials, as compared to UTI in women. It also relates to 
the additional structures present in the male genitourinary tract, including the prostate gland, 
epididymis, and seminal vesicles, involvement of which is hypothesized to necessitate 
longer-duration therapy, since they may serve as sanctuaries or reservoirs from which 
residual bacteria can emerge and cause a recurrent infection6. Also complicating efforts to 
identify the optimal treatment duration in men is the broader range of entities that constitute 
the full spectrum of male UTI. Such syndromes range from simple cystitis (manifested as 
voiding symptoms in the absence of constitutional manifestations, including fever), to febrile 
UTI (voiding symptoms with documented fever), to pyelonephritis (fever with flank pain, 

Protocol 9.0, 02/19/2019 
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with or without voiding symptoms). Finally, UTIs can be categorized as complicated vs. 
uncomplicated. Although consensus is lacking as to which specific conditions define a UTI 
as being “complicated,” the accepted underlying principle is that these are factors that, when 
present, make UTI more likely to occur, more difficult to treat successfully, and less 
predictable as to microbiological etiology7, 8, 40. Published reviews have recommended 
longer-duration treatment for complicated male UTI, but because these recommendations are 
based largely on expert opinion, and because of disagreement as to what constitutes a 
complicated UTI, they confuse more than clarify the issue of optimal treatment duration. 
Previous clinical trials. The most robust evidence for treatment duration in the field of male 
UTI comes from a non-blinded Scandinavian trial of 114 men with febrile UTI who were 
randomized to receive 14 vs. 28 days of ciprofloxacin4. All patients experienced resolution of 
signs and symptoms of infection during therapy, and cure rates (defined as remaining 
symptom-free for two weeks after treatment cessation) were not significantly different 
between groups (92% vs. 97%, respectively)4. Notably, however, treatment durations less 
than 14 days were not investigated, and this trial included only men with febrile UTI, a 
syndrome that although clinically important is relatively uncommon.  
Most men diagnosed with UTI are afebrile, but instead experience new onset of dysuria, 
frequency, and/or supra-pubic tenderness41. The presence of fever is thought to represent 
some component of invasive disease, which presumably can be localized within the prostate, 
kidney, or other tissues, although in practice the actual primary focus is rarely sought or 
defined, since such knowledge confers no known clinical benefit. Thus, the finding that 14 
days of therapy for febrile male UTI performed as well as did 28 days suggests that for men 
with the less severe UTI syndrome of cystitis extending the duration of treatment beyond 14 
days is unlikely to be beneficial.  
At the other end of the treatment duration spectrum, in a trial of UTI treatment among spinal 
cord injury patients, the 60 subjects (85% male, all without fever) were randomized to 
receive 3 vs. 14 days of ciprofloxacin 5. Although clinical cure (defined as resolution of 
symptoms by 19-23 days after treatment initiation) was not significantly different between 
the 3 and 14-day treatment groups (63% vs. 53%, respectively), relapse was significantly 
more common in the 3-day group (33% vs. 0%; P = .001)5. This suggests that 3 days of 
treatment may be insufficient for UTI in men with spinal cord injuries, and perhaps also--
although this has not been specifically studied-- in other men. 
Previous observational studies. Observational data indicate that in practice the treatment 
duration used for male UTI varies significantly, and may influence the likelihood of both 
recurrence and adverse events. At the MVAMC, we retrospectively examined the records of 
225 patients (90% male) diagnosed with UTI in 2007-8 for (i) appropriateness of the 
diagnosis and the associated treatment duration and (ii) clinical outcome42. Treatment 
durations ranged from 3 to 14 days among men and women alike. Notably, among the 152 
men with complicated UTI, recurrence was significantly more common among those treated 
for only 3-7 days, compared with 10-14 days (35% vs. 17%; P = .02)42. This indicates that 
for men with complicated UTI (75% of the study population), shorter-duration therapy may 
predispose to recurrent infection. 

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In a separate study using VA administrative data for FY2009, we identified 33,336 unique 
male veterans treated for UTI, defined as having a diagnostic code for UTI combined with a 
prescription for an antimicrobial typically used for UTI 3. Of these men, 35% received 7 or 
fewer days of treatment, whereas the remaining 65% received more than 7 days of treatment. 
Recurrence rates were not appreciably different between patients receiving shorter- vs. 
longer-duration treatment (3.9% vs. 4.2%, respectively, P = .16). However, subsequent C. 
difficile infection was significantly more common among patients receiving longer-duration 
treatment. That is, whereas in the total population C. difficile infection occurred in 144 
(0.4%) of the 33,336 UTI patients, it occurred in only 0.3% of patients receiving shorter-
duration (≤ 7d) treatment, compared to 0.5% of those receiving longer-duration (> 7d) 
treatment (P = .02). With multivariable adjustment for age, Charlson comorbidity score, and 
UTI-specific comorbidities (prostatic hypertrophy, urinary calculi, etc), a borderline 
significant trend persisted toward increased C. difficile infection with treatment durations 
greater than 7 days (odds ratio 1.42, 95% confidence interval 0.97 to 2.07). Thus, longer-
duration therapy was not associated with a reduction in recurrence, but may be associated 
with increased C. difficile infection. 
Adverse drug events. Adverse drug events are an increasingly recognized consequence of 
antimicrobial use. Using active surveillance, the percentage of antimicrobial-treated subjects 
who report adverse events has been as high as 30%15-17. Commonly reported adverse events 
are generally mild, and include nausea, diarrhea, headache, and dizziness.  However, more 
serious adverse drug events, including allergy, C. difficile infection, and interactions with 
other medications also occur with antimicrobial use, and are frequent enough such that 
antimicrobials are the cause of up to 20% of adverse drug events diagnosed in emergency 
departments43. Although some adverse drug events, such as anaphylaxis, are unlikely to be 
affected by treatment duration, many others, including nausea, diarrhea, C. difficile infection, 
headache, and dizziness, conceivably could be reduced or avoided by use of shorter-duration 
therapy. The issue of adverse drug events has become more important given the recent 
warning by the US Food and Drug Administration that use of fluoroquinolone antimicrobials 
is associated with musculoskeletal and nervous system adverse events 
(http://www.fda.gov/Drugs/DrugSafety/ucm500143.htm). Thus, determining the shortest 
possible treatment duration for male UTI, a common cause of fluoroquinolone use, is 
increasingly important. 
In summary, the available observational and clinical trial evidence indicates that for male 
UTI 28 days therapy offers no demonstrable clinical benefit over 14 days, even within the 
febrile UTI subset, whereas a much shorter treatment duration, e.g., 3 days, may increase the 
risk of recurrent UTI, even among men with less severe UTI syndromes. This suggests that 
the optimal treatment duration should be longer than 3 days, but not longer than 14 days, 
which comports with current recommendations for 7-14 days of treatment. However, C. 
difficile infection may be more frequent among patients treated for more than 7 days, 
compared to 7 days or fewer. Minor adverse drug events are common with UTI treatment, 
but whether their frequency is influenced by treatment duration is unknown. Additionally, 
although the effect of treatment duration on intestinal carriage of antimicrobial-resistant 
organisms is unknown for UTI, in other infectious diseases longer treatment durations have 
been associated with increased colonization and infection with drug-resistant organisms, 
compared with shorter treatment durations. Thus, since longer treatment may have 

Protocol 9.0, 02/19/2019 
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demonstrable harms, apart from the obvious cost and convenience issues, for longer-duration 
treatment to be justified it should confer demonstrable clinical benefit. Accordingly, a 
randomized trial of shorter vs. longer-duration treatment for male UTI is needed, to 
determine whether 7 days of treatment is non-inferior to 14 days of treatment. 
2.  Research design and methods 
 
2.a. Study type 
We propose to conduct a randomized, double-blind, placebo-controlled trial to determine 
whether, among men with UTI, 7 days of antimicrobial treatment is non-inferior to 14 days 
of treatment for resolution of UTI symptoms. The proposed trial will randomize 290 men 
with UTI to 7 vs. 14 days of treatment. Antimicrobial selection will be at the discretion of the 
treating clinician. The primary endpoint will be resolution of pre-therapy UTI symptoms, as 
assessed 14 days after the last dose of active antimicrobial. Secondary outcomes will include 
intestinal carriage of antimicrobial-resistant Gram-negative bacilli, recurrence of 
symptomatic UTI, and adverse drug events. 
 
2.b. Summary of study description 
The study was initially proposed as a single site study, conducted at the Minneapolis VA 
Health Care System, which includes the Minneapolis VA Medical Center and the affiliated 
Community Based Outpatient Clinics(CBOCs). To address slow enrollment, a second site 
(the Michael E. DeBakey Veterans Affairs Medical Center [MEDVAMC] and their affiliated 
CBOCs) has been approved by the VA Merit Review Program. Any changes to the protocol 
and consent will be initiated by the PI, and MEDVAMC IRB approval must be sought prior 
to implementing changes at that site, except when necessary to eliminate apparent immediate 
hazards to the subject. To minimize the possibility that the decision to participate is 
influenced by the initial duration of therapy prescribed, every effort will be made to enroll 
patients prior to their being prescribed antimicrobial treatment. This will be done by close 
collaboration with nurse-managers in the clinics and by having the study coordinator screen 
for eligible patients. Additionally, because we are intervening only on treatment duration, 
and all enrolled patients will receive at least 7 days of antimicrobial treatment, we will be 
able to identify and enroll patients seen during off-hours, or those who were missed during 
regular hours, several days after their initial clinical presentation, but before they have 
completed 7 days of treatment. Thus, although we plan to enroll the majority of patients at 
the time of initiating therapy, we will be able to recruit sufficient numbers of subjects without 
needing to maintain the multiple shifts of study personnel typically needed to enroll patients 
presenting during evening, night, or weekend tours.  
Potential subjects will be identified by the chief complaint elicited by the intake nurses in the 
outpatient clinics and urgent care, and by notifications/reports from the pharmacy service 
regarding new UTI prescriptions (if such reports are able to be generated). Nurse managers 
or physicians will add study coordinator as a signer on CPRS record and give patient an “opt 
out” flyer when patients with symptoms of dysuria, urinary frequency, urgency, hematuria, 

Protocol 9.0, 02/19/2019 
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perineal pain, supra-pubic pain, costovertebral angle tenderness, or flank pain come into 
hospital. The nurse managers of the involved clinics have indicated that this would not overly 
burden their staff or resources. Patients presenting with UTI during evening, night, 
weekends, or holidays will be identified by searching recent outpatient clinic encounters for 
the specific diagnostic codes relevant to UTI. Each day, study staff will review the list of 
patients newly assigned any of these codes, i.e., the potential subjects, and their medical 
records to determine (i) the validity of the UTI diagnosis and (ii) whether the patient meets 
eligibility criteria, as detailed below. 
Patients who pass this screen will be contacted, will receive a brief study description, and 
will be invited to a study visit at which study participation will be further discussed. The visit 
must occur before the patient completes 7 days of treatment and will be conducted in person 
at the participating study site or via mail. Patients will be asked to bring their current 
antimicrobial with them, if they meet with study staff in person. At the visit, 
inclusion/exclusion criteria will be verified, any questions will be answered, and written 
informed consent will be obtained. Patients at the MVAMC (and possibly later at the 
MEDVAMC) will also be invited to participate in a sub-study that investigates the effect of 
treatment duration on the intestinal carriage of antimicrobial-resistant Gram-negative bacilli 
(hereafter, resistance sub-study). After providing consent, subjects will be randomized to 7 
vs. 14 days of antimicrobial treatment (of the same agent their provider prescribed for them), 
and will exchange days 8-14 of their current medication for a special medication supply 
provided by the study. All medications provided by the patients will be collected and 
returned to the study site’s research pharmacy for disposal when possible. Patients who 
complete study visit via mail, will be instructed to dispose of days 8-14 of their original 
prescription and use only the study medication. Subjects will be provided with a notebook 
and will be instructed to record in it their UTI symptoms and any potential adverse drug 
events, to facilitate accurate recall during follow-up.  
The special medication supply to be given to the subjects will be a 7-day pill container 
loaded with a sufficient supply of medication to complete a 14-day course of treatment when 
combined with the clinically prescribed medication, which will be used for days 1-7. For 
example, a patient with a study visit that falls on day 4 of treatment will take their clinically 
prescribed antimicrobials through day 7, and will complete treatment using the 7-day supply 
of study medication for days 8-14. We will enroll only patients treated initially with 
ciprofloxacin and TMP-SMZ, which are used to treat over 90% of male VA patients with 
UTI 3. In addition to being the most frequently used medications for male UTI, both agents 
are highly bioavailable with oral administration, and achieve excellent penetration into the 
male genitourinary tract (6, 8). Study medications (both active antimicrobial and placebo) 
will be different in appearance from clinically prescribed medication. Both subjects and 
investigators will be blinded to duration of active antimicrobial therapy. Patients who cannot 
attend the study visit in person will have the medication for days 8-14 mailed to them using 
overnight delivery after the research pharmacist receives the signed consent and HIPAA 
authorization forms. 
After enrollment, subjects will be contacted by telephone on or about the scheduled day of 
medication completion, and again at days 7, 14, and 28 (± 2) after medication completion. 
On the day of medication cessation, study staff will verify medication adherence (by patient 

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report) and will inquire regarding the presence of (i) UTI symptoms, (ii) signs or symptoms 
of C. difficile infection, (iii) other adverse drug events, and (iv) possible infectious 
complications (retreatment, receipt of care outside the VA system, etc.). Adverse drug events 
will be elicited first via an open-ended question, then by inquiring specifically regarding a 
list of typical antimicrobial-related adverse drug events symptoms such as nausea, vomiting, 
diarrhea, dizziness, rash, thrush, and headache. Similar assessments (excluding medication 
adherence) will be performed at 7, 14, and 28 days after stopping study medication.  
Resolution of UTI symptoms, the primary outcome, will be assessed 7 and 14 (± 2) days after 
completing medication. However, after study completion and unblinding of treatment 
allocation, the outcome assessment corresponding to 14 days after last receipt of active 
antimicrobial will be used for analysis. That is, for subjects in the shorter-duration group, the 
7 day assessment will be used, whereas for subjects in the longer-duration group, the 14 day 
assessment will be used, such that all subjects are assessed 14 days after their last dose of 
active antimicrobial. Additionally, with the 7 days post-treatment call, subjects in the 
resistance sub-study will be reminded to obtain a stool swab and to return it using the 
provided mailer. After the final (28d) follow-up call, subjects will have completed their 
participation in this study. If at any time subjects report new or unresolved UTI symptoms, or 
symptoms consistent with C. difficile infection or other adverse drug events, they will be 
directed to seek medical care from their primary care provider or the MVAMC or 
MEDVAMC Emergency Department. 
A 3-member data safety monitoring board (DSMB) will be formed to oversee the safety of 
this trial, assisted by a biostatistician with experience in clinical trials. Under the direction of 
the DSMB, the biostatistician will conduct 2 interim analyses, when approximately 33% and 
66% of the planned 290 subjects have been evaluated for the primary endpoint. An alpha-
spending function approach as described by Lan & DeMets is proposed44, testing for both 
non-inferiority and futility. Additionally, rates of adverse events in the treatment groups will 
be monitored by the DSMB, and reported to the MVAMC institutional review board. 
After enrollment and follow-up are concluded, and laboratory testing complete, results will 
be analyzed using a per-protocol analysis, with subjects analyzed according to which 
treatment they received. An intention-to-treat analysis will be performed as a secondary 
analysis. We will test our primary hypothesis that 7 days of antimicrobial treatment is non-
inferior to 14 days of treatment for the resolution of UTI symptoms by comparing the 
proportion of subjects in each group reporting resolution of pre-therapy UTI symptoms at 14 
days after completing active antimicrobial therapy. For the purposes of statistical power 
calculation, treatment inferiority is defined as >10% efficacy between treatment groups. A 
sample size of 290 subjects (145/group) was calculated, using a one-sided alpha level of 
0.025 and power of 85%, to allow detection of a minimum clinically significant absolute 
difference of 10% (e.g., 90% for 14-day treatment, vs. 80% for 7-day treatment). To adjust 
for potential loss of subjects to follow-up, we initially increased our enrollment goal by 10% 
(29 subjects), for a total sample size of 319, but have since opted to remove this 10% margin 
as there has been no loss to follow-up to date. 
Both treatment groups will be assumed to be superior to no treatment, based on prior studies 
of UTI demonstrating that spontaneous cure occurs in a minority (7-28%) of subjects45, 46. 
Accordingly, it would be unethical to include a placebo-only treatment group. 

Protocol 9.0, 02/19/2019 
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2.c. Details of specific study areas 
Selection of treatment duration. Our decision to compare 7 vs. 14 days treatment duration 
was based on prior studies4, 5, 15, the range of current expert recommendations7, 8, 47, and 
current practice within the VA system (unpublished data)4. The choice of 14 days for the 
longer-duration treatment arm was relatively straightforward. As outlined in the “prior 
clinical trials” section above, 14 days was the shorter duration arm in the Swedish study that 
found no significant efficacy difference between 14 vs. 28 days of treatment4. Also, 14 days 
frequently appears in reviews as the upper-limit of recommended treatment duration for male 
UTI7, 8, 40, 47. Finally, among 33,000 male UTI episodes treated in the VA system in fiscal 
year 2009, only a small minority (8%) received more than 14 days of therapy3. 
In contrast, the choice of 7 days for the shorter-duration treatment arm was more difficult, 
since no prior clinical trial of male UTI has used this duration. However, since the 3 vs. 14-
day study by Dow et al. among spinal cord injury patients showed a statistically significant 
increased risk of symptomatic recurrence among subjects receiving 3 days of treatment, we 
believe that there is not clinical equipoise between 3 and 14 days treatment duration. This 
belief is reinforced by our own observational data from the MVAMC showing an increase in 
recurrence among subjects receiving shorter-duration treatment (as discussed above), and the 
fact that experts typically offer only guarded endorsement for the possibility of using 3-day 
therapy (which is widely accepted as appropriate for women with uncomplicated cystitis) for 
treating male UTI, and even then only in young, otherwise healthy men with no complicating 
conditions40. 
Although 7 days is a widely recommended lower-limit of treatment duration for male UTI7, 8, 
40, in our VA administrative data of male UTI treatment, we observed that 10 days of 
treatment was actually more common than 7 days, which might suggest that a 10-day 
duration should be studied. However, if we were to compare 10 vs. 14-day therapy, a 
between-arm treatment duration difference of only 4 days would make our groups prone to 
crossover contamination, with those allocated to 14 days of treatment needing to miss only a 
few doses of antimicrobials to merge with the 10-day group. Additionally, the favorable 
impact on resistance selection, C. difficile infection, and other adverse drug events of a 4-day 
(29%) reduction in treatment duration is likely to be less than with a 7-day (50%) reduction. 
Therefore, we selected 7 days for the shorter-duration treatment arm. 
Blinding. Because our primary outcome is subjective (i.e., patient symptom reports), we are 
planning to blind participants, investigators, and clinicians to the duration of active treatment, 
to minimize potential bias that could be introduced if patients knew that they were receiving 
shorter-duration treatment. There are difficulties inherent to this approach. First, since we are 
proposing to randomize subjects only to different treatment durations (not to different 
antimicrobials), we are not in control over which antimicrobials will be prescribed. 
Fortunately, 90% of diagnosed outpatient male UTIs in the VA system, both nationally and at 
the MVAMC, are treated with ciprofloxacin (65%) or TMP-SMZ (25%)3. The remaining 
10% are treated with a wide variety of agents, including nitrofurantoin, cephalexin, 
amoxicillin, amoxicillin/clavulanate, etc. We opted to include only patients receiving 
ciprofloxacin and TMP-SMZ, since the other antimicrobials are used so infrequently that no 

Protocol 9.0, 02/19/2019 
12 
 
valid outcome comparisons could be made, and some are dosed more than the twice-daily 
ciprofloxacin and TMP-SMZ, increasing the burden on our research pharmacy. 
To achieve double-blinding, all patients will take their clinically prescribed medications on 
days 1-7. However, all patients will receive study medication for days 8-14. Specifically, all 
patients will be given a supply of medication that is different in appearance from their 
clinically prescribed medication for days 8-14. This different-appearing medication will be 
either:  
1) active antibiotic (ciprofloxacin or TMP/SMZ, based on what they were initially 
prescribed) from an alternate manufacturer, different in both color and imprint from the 
clinically prescribed drug, or  
2) a placebo tablet, similar in size to both the antimicrobials (approximately 1 gram), that 
will be provided by the VA Cooperative Study Pharmacy in Albuquerque, New Mexico.  
Thus, all subjects will receive pills that are different in appearance from the initial antibiotic 
for days 8-14, effectively blinding their allocation. Because there is a possibility of subjects 
unblinding themselves by using pill-identifier websites, an assessment of blinding will be 
performed, using a validated blinding index. Of note, similar trials have used 
overencapsulation to blind participants15, a method that can be foiled by patients simply 
removing the gelatin capsule. Research pharmacy staff will prepare 4 different types of 
containers with these tablets. The containers for the longer-duration subjects will contain 
ciprofloxacin or TMP-SMZ for days 8-14, and the study coordinator will instruct the patient 
to use their clinically supplied drug for days 1-7. Those for the shorter-duration subjects will 
contain placebo for days 8-14, with again the clinically supplied drug used for days 1-7.  
The logistics of blinding are as follows: at enrollment, the study coordinator will notify the 
pharmacy that a patient has been enrolled, and whether ciprofloxacin or TMP-SMZ is being 
used. Since we are stratifying based on catheter use (see below), the coordinator will inform 
the pharmacy to use the randomization schedule appropriate to the patient’s catheter status 
and antimicrobial received. Working from this randomization schedule, the pharmacy will 
send a prepared container with study drug for days 8-14 to the appropriate location, with 
neither the study coordinator nor the patient knowing whether the tablets are antimicrobial or 
placebo. The research pharmacies at the MVAMC and MEDVAMC will be charged with 
tracking and dispensing study medications, a function that they routinely provide for other 
double-blinded studies. The research pharmacy staff can also unblind the patient in the event 
of a clinical emergency for which unblinding is deemed necessary. Criteria for unblinding 
will be admission to the hospital for suspected urosepsis or severe drug reaction, or any other 
scenario as directed by the local institutional review board, which reviews all study-related 
serious adverse events. The effectiveness of blinding will be assessed by asking patients 
which treatment they think they received 7 days after completing the study medication. 
Randomization. Randomization will be used to ensure that baseline characteristics, including 
any potential confounders, are equally distributed between the 2 treatment groups. To ensure 
relatively equal sample size between the shorter and longer therapy duration groups, block 
randomization will be used. However, since the proposed sample size is 290 subjects, it is 
possible that uncommon factors may be unevenly distributed with a simple 1:1 

Protocol 9.0, 02/19/2019 
13 
 
randomization plan. Accordingly, we plan to stratify our randomization by presence of 
urinary catheter use, a potential confounder that occurs in approximately 10% of male UTI 
patients at the MVAMC (unpublished data). This will create 2 strata, each of which will have 
its own randomization schedule, using permuted blocks of 4. Separate randomization tables 
will be used at the MVAMC and MEDVAMC to avoid any confusion with multiple 
randomizations occurring in a short time, and to obviate the need to wait for a randomization 
slot from the MVAMC. Urinary catheter use is relatively uncommon, but is hypothesized by 
some authorities to require longer-duration therapy40, 48. Thus, by allocating this factor in a 
relatively equal distribution we will ensure that outcomes are not affected by an imbalance in 
this potentially more difficult-to-treat form of male UTI. Although we initially planned to 
enroll patients with febrile UTI, because of reviewer concerns, and an ongoing Dutch study 
specifically addressing treatment duration in men with febrile UTI49, we have opted to forego 
including patients with febrile UTI. Since less than 2% of subjects treated in the outpatient 
setting for male UTI are febrile (unpublished data), this should not significantly affect our 
enrollment. 
Sample size calculations. To determine an appropriate sample size, we first established the 
minimum significant difference in the primary outcome (resolution of UTI symptoms) that 
would be clinically relevant. Literature review identified UTI studies that used absolute 
differences of 10% to 20% for the minimum significant difference4, 15, 49. Separately, we 
queried four international UTI experts as to what difference in treatment success they would 
view as clinically significant. The range of their responses was also 10-20%, with a mean of 
12.5%.  Using the conservative lower-limit (10%) as the minimum significant difference the 
proposed study should be able to detect, and a percentage of subjects experiencing resolution 
of symptoms with 14 days therapy of 90%4, we then calculated a total sample size of 290 
subjects needed to detect such a difference with 85% power, using a one-sided alpha of 
0.025. Accordingly, a group size of 145 subjects (290 total) would provide 85% power to 
detect a 10% absolute between-group difference in the primary outcome (i.e., 90% vs. 80%). 
As mentioned, the additional 10% of patients originally built in to account for loss to follow-
up is considered unnecessary, as there have been no losses to follow-up at the first interim 
analysis. 
The above calculation assumes a conservative 90% for the outcome of resolution of UTI 
symptoms. However, in the trial of men with febrile UTI, resolution occurred in 92% (14d) 
and 97% (28d) of subjects. If we were to assume that 95% of subjects will have resolution of 
symptoms, instead of the more conservative 90%, then the total number of subjects needed to 
achieve 85% power to detect a 10% absolute between-group difference in the primary 
outcome would decrease. However, this may be an overly optimistic projection. Accordingly, 
we have planned our study using the more conservative assumption of a 90% symptom 
resolution rate, to minimize the risk of conducting an under-powered trial. 
For the resistance sub-study, based on anecdotal data we estimated that 40% of subjects 
receiving 14 days of treatment would acquire intestinal carriage of a drug-resistant Gram-
negative bacillus, compared to 20% of subjects receiving 7 days of treatment. Using a two-
sided alpha of 0.05, and 80% power, 91 subjects in each group (182 subjects total) will be 
needed. This is 57% of the planned total enrollment, which we believe is feasible based on 
our pre-trial planning. To simplify the logistics of adding a second site, the MEDVAMC will 

Protocol 9.0, 02/19/2019 
14 
 
not enroll patients into the sub-study, unless this is changed via an amendment to the protocol 
after study activities have commenced. 
 
2.d. Inclusion and exclusion criteria 
Inclusion criteria (must have all). With the addition of the MEDVAMC as a second site, 
there will be significant efforts to ensure that enrollment there is consistent with enrollment 
at the MVAMC. This will include communication between study coordinators, investigator 
oversight, and weekly calls during the study roll-out phase at the MEDVAMC. These are 
deemed necessary since there is some degree of judgement needed as to determining whether 
documented symptoms meet inclusion criteria (for instance, whether “pain in the lower back 
and side” qualifies as “flank pain”.  
1- Male gender 
2- New-onset (within 7 days) of at least one of the following symptoms/findings: dysuria, 
urinary frequency, urgency, hematuria, perineal pain, supra-pubic pain, costovertebral 
angle tenderness, or flank pain 
3- Treated as an outpatient (Primary Care Center or Emergency Department), with < 24 
hours observation in the hospital or Emergency Department following the time of initial 
diagnosis 
4- Prescribed treatment with at least 7 days, but not more than 14 days, of either 
ciprofloxacin or TMP-SMZ 
Exclusion criteria (must have none) 
1- Admission to the hospital (for > 24h) at the time of diagnosis 
2- Documented fever at time of initial evaluation (≥ 38.0 Celsius) 
3- Previous enrollment in the study 
4- Treatment for UTI in past 14 days 
5- Not able to give informed consent 
6- Unwilling to either: 
a. return for study visit 
b. participate in a home visit 
c. participate via mail 
7- Symptoms thought more likely to be caused by a non-UTI diagnosis (e.g., urinary 
calculus, sexually transmitted infection, etc.) 

Protocol 9.0, 02/19/2019 
15 
 
8- Other antimicrobial therapy (new or ongoing) prescribed for a non-UTI diagnosis (e.g., 
cellulitis, pneumonia, etc.) 
9- Treatment initiated with an empiric antimicrobial to which the organism isolated in the 
urine culture is non-susceptible based on standard laboratory criteria 
10- Treatment initiated with an empiric antimicrobial regimen that is underdosed, based on 
current guidelines and reviews 
Inclusion criteria were selected to identify male patients with a symptomatic UTI, treated 
without hospitalization. Identifying patients with a symptomatic UTI (vs. asymptomatic 
bacteriuria) is crucial, since patients with asymptomatic bacteriuria cannot be expected to 
improve with antimicrobials, and thus their inclusion would bias the study towards finding no 
significant difference according to treatment duration. Although we anticipate that most 
subjects will have a urinalysis and urine culture performed, we have found that over 20% of 
subjects treated for UTI at the MVAMC are treated without one or the other test being 
obtained42. Accordingly, although we will record the results of any urine testing obtained, 
performance of urinalysis or culture will not be required for inclusion, although the study 
coordinator will work closely to increase the rates of urine culture ordering as part of 
enrolling patients through the involved clinics. Since UTI is largely a clinical diagnosis, with 
the culture being obtained mainly to help providers identify the causative pathogen and 
potentially adjust antimicrobial treatment, we believe that including patients without such 
urine testing (which reflects everyday practice) is appropriate. 
 
Exclusion criteria were selected both to ensure patient safety and for statistical and practical 
reasons. Specifically, hospitalized patients are excluded because of their severity of illness, 
including a higher likelihood of bacteremia, which may require longer treatment duration 
and/or parenteral therapy. Patients previously enrolled in the study were excluded to ensure 
statistical independence. Patients prescribed less than 7 days of antimicrobial therapy are 
excluded since they will be difficult to identify before their treatment has ended. Patients 
prescribed more than 14 days of antimicrobial therapy are excluded because this generally 
indicates a patient being treated for suspected concomitant prostatitis, for which longer-
duration therapy is beneficial6. 
 
2.e. Method of identifying potential subjects 
Patients with UTI symptoms will be identified at the time of their initial clinic nursing visit, 
and the study coordinator will be notified and patient given the “opt out” flyer. The 
outpatient clinic areas of the MVAMC and MEDVAMC have been used for study 
recruitment in the past, with good results. The study coordinators will regularly meet with 
clinic staff to remind them of the UTI trial, and the principal investigator at the MVAMC and 
the co-investigator at the MEDVAMC will ask for cooperation form primary care clinicians 
through several methods, including emails, announcements at staff meetings, and other 
meetings. 

Protocol 9.0, 02/19/2019 
16 
 
For patients presenting in off-tour hours (evenings, nights, weekends, and holidays), we have 
established and piloted a system for rapidly identifying patients at the MVAMC who have 
recently been diagnosed with UTI. Using Vista, diagnostic codes relevant to UTI will be 
searched to identify potential participants. This is essential, since success of the trial will 
depend on identifying potential subjects, reviewing their eligibility status, contacting them, 
and enrolling them before they have completed 7 days of treatment. Using an “Outpatient 
Diagnosis/Procedure Code Search” function, we were able to electronically search for these 
ICD-10 codes among all outpatient encounters at the MVAMC, and can limit our searches to 
specific dates and clinics. In our pre-trial planning, we asked a sample of patients about 
participation in a hypothetical study. Over 50% indicated that they would be willing to 
participate, in principle, and over 1/3 were reasonably certain that they would participate.  
 
Finally, we will ask the pharmacy service to generate a daily electronic report of 
prescriptions for 7-14 days of ciprofloxacin or trimethoprim/sulfamethoxazole. This list will 
be used as an additional method for identifying potential subjects that are not found via the 
ICD-10 codes or direct referral. 
 
Currently, recruitment at the MVAMC is at 4.6 subjects/month. Assuming a 30% higher rate 
at the MEDVAMC, based on 33% more male UTI episodes annually and approximately 30% 
larger population served, we anticipate a recruitment rate at the MEDVAMC of 6/month. 
With a combined rate of 10.6/month, we anticipate 16.8 months to enroll the additional 179 
subjects needed. With funding approved through December 2018, there is sufficient time to 
both enroll and follow the required number of subjects. 
 
 
2.f. Patient contact and enrollment 
After being identified as a potential subject (i.e., a man presenting with urinary symptoms) 
patients will be contacted by the study coordinator, either by phone or a letter sent to them if 
unable to reach by phone, and the study will be explained to them in detail. Eligible subjects 
willing to participate in the study will be consented and randomized to shorter vs. longer 
duration therapy, presuming that their provider subsequently ordered either ciprofloxacin or 
TMP-SMZ for 7 to 14 days. As mentioned above, eligible subjects can enroll by returning to 
the Minneapolis VAMC or the MEDVAMC for a study visit, via a home visit, or by mail. 
Home visits and mail enrollment are being offered as preliminary enrollment has been slower 
than anticipated, with the single largest reason for not enrolling being time constraints of 
scheduling a visit at the MVAMC or difficulty arranging transportation.  
Home visits will be conducted in the greater Minneapolis/St. Paul or Houston metropolitan 
area by the study coordinator after review of the medical record for any safety issues, using 
methods used by Home and Community Care nurses at the Minneapolis VA. Any patient 
with a behavioral flag, history of inappropriate behavior, or other indications of a possible 
safety issue will NOT be eligible for home enrollment. The study coordinator will be 
reimbursed for mileage driven based on the current allowable federal reimbursement rate per 
local facility policy. 

Protocol 9.0, 02/19/2019 
17 
 
Mail enrollment will be offered to eligible subjects who live outside of the greater 
Minneapolis/St. Paul or Houston metropolitan area, or who prefer to not have an in-person 
study visit. Such subjects will be identified by the study coordinator, have the study 
explained to them in detail via telephone, and then have an informed consent and HIPAA 
authorization form sent to them. Subjects that were unable to be reached by phone will have 
a letter sent to them explaining that they may be eligible for a study. Study staff contact 
information will be included in that letter so they may call staff if interested in participating. 
To ensure there is no unnecessary time delay, the subject will also be sent the mail 
enrollment forms with the letter. Study staff will attempt to reach subject via telephone after 
sending the letter and mail enrollment forms. After receiving the signed forms from the 
subject, the research pharmacist will release the study medication to the subject. All 
shipments will be by overnight delivery, with the study coordinator remaining in contact as 
needed via telephone to answer any questions and to ensure that the subject understands 
when to begin the study medication. 
Subjects not seen and evaluated on the day of treatment initiation will be contacted using the 
contact information listed in CPRS. In order to avoid “cold-calling” patients, all men 
presenting to the involved outpatient clinics with urinary symptoms will be provided an 
informational sheet regarding the study, and informing them that they may be contacted via 
telephone. A number to call to opt-out of such contact will be included. 
 
2.g. Sampling of the intestinal microbiota (currently only offered at the MVAMC) 
Subjects in the resistance sub-study will provide 2 samples of their intestinal microbiota, the 
first obtained via rectal swab performed by study staff at the time of enrollment at the 
MVAMC (or self-collected at home for mail enrollment), the second collected and submitted 
by mail 1 week after completion of study medication. Subjects enrolled via home visit can 
enroll in the sub-study using self-collected swabs. Although obtaining a rectal swab is mildly 
invasive and may cause slight discomfort, it has been performed in numerous research 
studies and is part of routine clinical activity in many U.S. hospitals50. We anticipated that 
only a minority of subjects would agree to this sampling; however, during our mock-
enrollment exercise we were surprised to find that 95% of the 19 patients who agreed in 
principle to participate in the main trial also indicated willingness to participate in the 
resistance sub-study. Since it is unlikely that patients will feel confident in their ability to 
collect their own rectal swabs, for the second sample we will ask them to swab a stool 
specimen and return the swab in a provided mailer, similar to the well-established practice of 
screening for colon cancer using home-collected fecal occult blood cards. 
Swabs will be delivered to and processed in the research laboratory of Dr. James Johnson, 
which has extensive experience in the isolation, characterization, and storage of enteric 
bacteria, especially E. coli. For this study, the required microbiological techniques are 
relatively straightforward, and the number of samples per week modest, such that the time 
and space required for this sub-study will not be onerous. Swabs will be entered into a 
registry as they are received, with a study number used to link clinical and laboratory 
information. Swabs will be plated onto plain and antimicrobial-supplemented modified 
Mueller-Hinton agar plates (i.e., Mueller-Hinton agar containing bile salts and neutral red), to 

Protocol 9.0, 02/19/2019 
18 
 
selectively recover and detect the lactose-fermentation characteristic of any Gram-negative 
bacilli in the specimen, both generically and specifically those resistant to the included 
antimicrobials (i.e., ciprofloxacin and TMP-SMZ). 
From plates yielding growth of Gram-negative bacilli, 1 representative of up to 3 of the most-
numerous colony morphologies per plate will be identified to the species level using the API-
20E system (BioMerieux, Durham, NC). Susceptibility to 22 antimicrobial agents will be 
determined by disk diffusion, using methods, control strains, and interpretive criteria as 
specific by the Clinical and Laboratory Standards Institute. For each Gram-negative bacillus 
isolated, a semi-quantitative measure of growth will be recorded. Specimens will be scored 
for presence of resistant organisms using four different endpoints: (1) any detectable Gram-
negative bacilli, (2) any Gram-negative bacilli resistant to ciprofloxacin (or TMP-SMZ), (3) 
density of ciprofloxacin (or TMP-SMZ)-resistant Gram-negative bacilli, and (4) a Gram-
negative bacilli resistance score, which will be the sum of all unique resistance markers 
detected among the various Gram-negative bacilli isolated from the specimen. 
 
 
2.h. Subject compensation 
Subjects will receive $40 at the time of enrollment in the parent trial to compensate them for 
their travel and time commitment, regardless of whether they choose to participate in the 
resistance sub-study. Subjects enrolling in the resistance sub-study will receive $20 for the 
first fecal swab (obtained at the study visit/after mail enrollment), and an additional $30 for 
the second fecal swab. The higher compensation for the second swab reflects the extra effort 
and inconvenience subjects may experience with collecting and mailing the sample. This 
yields a maximum possible compensation of $90. Finally, patients who received their initial 
antibiotics through the VA pharmacy and were charged a co-pay will have this co-pay 
waived or refunded to them in accordance with VA policy. 
 
2.i. Potential complications during therapy 
During treatment for their UTI episode, subjects may experience a number of possible 
unexpected events, some of which could represent complications of the antimicrobials they 
are receiving. It is unknown whether treatment duration will affect the frequency or severity 
of any of these events. The most common adverse drug events associated with antimicrobial 
therapy include nausea, vomiting, diarrhea, dizziness, and headache. Less frequently 
encountered adverse drug events include allergic reactions (including rash, renal injury, and 
anaphylaxis), C. difficile infection, and increased or decreased effect of other medications, 
including warfarin. Because subjects are not being assigned to specific antimicrobials by 
study personnel, extensive discussion regarding the potential harms of the antimicrobial their 
provider prescribed is beyond the scope of the study. Instead, at the time of enrollment study 
personnel will briefly review potential generic harms of antimicrobials, will inform patients 
that treatment duration may or may not influence the probability of experiencing any harms, 
and will remind subjects to report any adverse events to their primary care provider or the 

Protocol 9.0, 02/19/2019 
19 
 
MVAMC or MEDVAMC Emergency Department. A further assessment of adverse drug 
events will be conducted during each study contact, with the details of any reported potential 
harms being recorded. 
 
2.j. Follow-up and outcome assessment 
Follow-up telephone contacts will occur at four time points, i.e., (i) on or about the time of 
medication cessation, (ii) 7 (± 2) days after medication cessation, (iii) 14 (± 2) days after 
medication cessation and (iv) 28 (± 2) days after medication cessation.  
(i) The first contact is primarily to assess for medication adherence and any adverse drug 
effects. Study personnel will inquire regarding adherence and will screen for adverse drug 
events, both via an open-ended question and by specifically inquiring regarding the common 
symptoms of nausea, vomiting, diarrhea, dizziness, headache, and drug allergy. Subjects will 
be encouraged to refer to their symptom diary to ensure accurate recall.  
(ii) At the second contact (7 days after medication cessation, either 7 or 14 days after the last 
dose of active antimicrobial), resolution of UTI symptoms (the primary outcome) will be 
assessed. Additionally, adverse events will again be assessed, subjects will be asked whether 
there has been interval retreatment for UTI, and which treatment (active or placebo) they 
think they received. Subjects in the resistance sub-study will be reminded during this call to 
obtain and return a stool swab in the provided mailer.  
(iii) At the third contact (14 days after medication cessation, either 14 or 21 days after the last 
dose of active antimicrobial), resolution of UTI symptoms will again be assessed, and 
subjects will again be asked about adverse events and interval retreatment for UTI. After 
unblinding, the assessment occurring 14 days after the last dose of active antimicrobial will 
be used for analysis.  
(iv) The fourth contact (28 days after medication cessation) will again include an assessment 
of adverse drug events and an inquiry as to any retreatment for UTI. All subjects having 
reported initial resolution of their UTI symptoms will be assessed for the secondary outcome 
of recurrent UTI, defined as recurrence of UTI symptoms and receipt of antimicrobial 
treatment.  
If at any time subjects report new or unresolved UTI symptoms, symptoms consistent with C. 
difficile infection, or any other potential complication of antimicrobial therapy, they will be 
directed to seek medical care from their primary provider or the MVAMC or MEDVAMC 
Emergency Department. Severity of reported adverse events will be assessed and recorded 
(see section 2.m) 
 
2.k. Safety and monitoring 
Subject-specific safety monitoring will be performed via symptom review during the 
telephone contacts. Additionally, subjects will be given contact information for the primary 

Protocol 9.0, 02/19/2019 
20 
 
investigator and the study coordinator, and will be encouraged to contact study personnel if 
any suspected adverse events occur between scheduled study calls, in addition to contacting 
their primary care provider or the MVAMC or MEDVAMC Emergency Department. Serious 
adverse events will be reported by study personnel to the local Institutional Review Board 
(IRB) per MVAMC and MEDVAMC policy, and each such event will be reviewed by the 
IRB to determine whether it was potentially study-related. Monitoring to detect an excess of 
clinical outcomes or adverse events in either arm (including treatment failure for the initial 
UTI, recurrence of UTI, and adverse drug events, including C. difficile infection) will be 
performed by an independent DSMB that will include at least one biostatistician with clinical 
trial experience. 
Study records will be maintained within the MVAMC and MEDVAMC on secure research 
drives, accessible only to the research team. Any paper records will be stored in a locked file 
cabinet in the principal investigator’s locked office (3B-126) at the MVAMC, and in the 
office of the co-investigator at the MEDVAMC. 
2.l. Definitions for safety and monitoring. 
Adverse event: an adverse event (AE) is any untoward medical occurrence associated with 
the antimicrobial treatment, whether or not the event is considered related to the 
antimicrobial. 
Adverse reaction: any adverse event caused by antimicrobial treatment. 
Suspected adverse reaction (SAR): any adverse event for which there is a reasonable 
possibility that the antimicrobial treatment caused the adverse event. “Reasonable 
possibility” means there is evidence to suggest a causal relationship between the 
antimicrobial treatment and the adverse event. Suspected adverse reaction implies a lesser 
degree of certainty about causality than “adverse reaction,” which means any adverse event 
caused by the antimicrobial treatment. 
Serious adverse event (SAE) or serious suspected adverse reaction: An adverse event or 
suspected adverse reaction is considered “serious” if, in the view of either the investigator, or 
the IRB, it results in any of the following outcomes: 
-Death 
-Life-threatening adverse event 
-Inpatient hospitalization for ≥ 24 hours or prolongation of an existing hospitalization 
-Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
 

Protocol 9.0, 02/19/2019 
21 
 
Unexpected adverse event or unexpected suspected adverse reaction: an adverse event or 
suspected adverse reaction is considered unexpected or unanticipated if it is not listed in the 
protocol. 
Life-threatening: An adverse event or suspected adverse reaction that places the subject at 
immediate risk of death. It does not include an AE or SAR that, had it occurred in a more 
severe form, might have caused death. 
2.m. Anticipated adverse events 
The following lists anticipated adverse events, including some that are rare but serious: 
-Diarrhea 
-Nausea 
-Vomiting 
-Headache 
-Drug allergy 
-Pain at tendon insertions 
-Blood sugar fluctuations among diabetic patients, including severe decreases leading to 
coma 
-Psychiatric side effects such as disturbance in attention, memory impairment, and delirium 
-Abdominal aortic aneurysm rupture 
 
Note that failure to resolve UTI symptoms (i.e., not meeting the primary outcome), is not 
considered an adverse event, but rather will be recorded in the assessment of the primary 
outcome. Severity of adverse events will be determined using a severity scale (grade 0-5) 
adapted from the Common Terminology Criteria for Adverse Events, version 4.0, as listed 
below. 
 
Adverse 
event 
Grade 
1 
2 
3 
4 
5 
Diarrhea 
Increase of <4 
stools per day 
over baseline; 
mild increase 
in 
ostomy output 
compared to 
baseline 
Increase of 4 - 
6 stools per 
day over 
baseline; 
moderate 
increase in 
ostomy output 
compared to 
baseline 
Increase of >=7 
stools per day 
over baseline; 
incontinence; 
hospitalization 
indicated; 
severe increase 
in ostomy 
output 
compared to 
baseline; 
limiting self 
care ADL 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated, 
intensive care 
unit utilization 
Death 
C. difficile 
infection 
(diarrhea 
Increase of <4 
stools per day 
over baseline; 
Increase of 4 - 
6 stools per 
Increase of >=7 
stools per day 
Life-
threatening 
Death 

Protocol 9.0, 02/19/2019 
22 
 
with a 
positive 
assay for C. 
difficile) 
mild increase 
in 
ostomy output 
compared to 
baseline 
day over 
baseline; 
moderate 
increase in 
ostomy output 
compared to 
baseline 
over baseline; 
incontinence; 
hospitalization 
indicated; 
severe increase 
in ostomy 
output 
compared to 
baseline; 
limiting self 
care ADL 
consequences; 
urgent 
intervention 
indicated, 
intensive care 
unit 
utilization, 
colectomy  
Nausea 
Loss of 
appetite 
without 
alteration in 
eating habits 
Oral intake 
decreased 
without 
significant 
weight loss, 
dehydration or 
malnutrition 
Inadequate oral 
caloric or fluid 
intake; tube 
feeding, TPN, 
or 
hospitalization 
indicated 
 
 
NA 
NA 
Vomiting 
1 - 2 episodes 
(separated by 5 
minutes) in 24 
hrs 
3 - 5 episodes 
(separated by 5 
minutes) in 24 
hrs 
>=6 episodes 
(separated by 5 
minutes) in 24 
hrs; tube 
feeding, TPN 
or 
hospitalization 
indicated 
 
 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
 
 
 
Death 
Headache 
Mild pain 
Moderate pain; 
limiting 
instrumental 
ADL 
Severe pain; 
limiting self 
care ADL 
NA 
NA 
Drug 
allergy 
Mild rash, no 
alteration of 
daily activities 
Moderate rash, 
treated with 
topical or oral 
medications 
Symptomatic 
bronchospasm, 
with or without 
urticaria; 
parenteral 
intervention 
indicated; 
allergy-related 
edema/angioed
ema; 
hypotension 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 

Protocol 9.0, 02/19/2019 
23 
 
Hypoglyce
mia 
(among 
diabetic 
patients) 
< lower limit of 
normal – 55 
mg/dL 
<55 – 40 
mg/dL 
<40 – 30 
mg/dL 
<30 mg/dL; 
life-
threatening 
consequences, 
seizures, coma 
Death 
Hyperglyce
mia 
(among 
diabetic 
patients) 
>ULN - 
160 mg/dL 
>160 - 250 
mg/dL 
>250 - 500 
mg/dL 
>500 mg/dL, 
life-
threatening 
consequences 
Death 
Pain at 
tendon 
insertion 
Mild pain 
Moderate pain, 
limiting 
Instrumental 
ADL 
Severe pain, 
limiting self 
care ADL 
Complete 
tendon 
rupture, need 
for surgery 
NA 
Abdominal 
aortic 
aneurysm 
rupture 
NA 
NA 
NA 
Eminent or 
emergent 
rupture 
necessitating 
surgery 
Death  
 
 
 
2.n. Statistical methods 
 
Primary outcome: resolution of UTI symptoms 14 days after completing active 
antimicrobial therapy. This outcome will be assessed in a binary manner. Subjects with 
persistent UTI symptoms or having received further antimicrobials because of UTI 
symptoms will be considered to have not met the primary outcome, whereas those 
without persistent UTI symptoms and not having received further antimicrobials will 
be considered to have met the primary outcome. The proportion of subjects meeting the 
primary outcome will be compared between the 2 treatment groups using a per-protocol 
analysis, with subjects analyzed according to which treatment they received. An intention-to-
treat analysis will be performed as a secondary analysis. Subjects reporting taking 7 or fewer 
days of study medication will be analyzed as having received shorter-duration therapy, 
whereas subjects reporting taking 8 or more days of study medication will be analyzed as 
having received longer-duration therapy. Non-inferiority testing of the differences in the 
group proportions of symptom resolution will be done using a z-statistic derived by the 
adaptive percentage non-inferiority margin approach described by Laster and Johnson51, 52. 
Exploratory sub-group analysis using multiple logistic regression will be performed to assess 
outcomes stratified by the following putatively clinically relevant characteristics: catheter-
associated UTI, functional or mechanical urinary tract obstruction, and diabetes. We 
anticipate that the proposed study will be under-powered for these analyses, and thus they 
will primarily be used as pilot data to identify potential specialized populations for future 
study. 
 

Protocol 9.0, 02/19/2019 
24 
 
Secondary outcome (1): recurrence rates at 28 days after completing study medication.  
The proportion of subjects reporting recurrence of symptomatic UTI (defined as for the study 
entry criteria, but occurring after the primary outcome assessment) in each group will be 
calculated, along with corresponding 95% confidence intervals. Between-group comparisons 
will be made using the Chi-square test.  
 
Secondary outcome (2): incidence of any adverse drug events in the 28 days after 
completing study medication.  
The incidence of adverse drug events, including nausea, vomiting, diarrhea, dizziness, 
headache, drug allergy, and C. difficile infection, both individually and in aggregate, will be 
compared between treatment groups. For subjective symptoms, subjects will be asked to use 
their symptom diary to quantify the number of days they experienced each adverse event. 
Severity will be determined using a severity scale (grade 0-5) adapted from the Common 
Terminology Criteria for Adverse Events, version 4.0. Adverse events will be analyzed first 
as whether a subject experienced any adverse drug event vs. none (Chi-square test), and then 
by comparing the number of days on which each subjective event was experienced (Mann-
Whitney U-test). Cases of suspected drug allergy will be reviewed by 2 Infectious Disease 
staff physicians (who are blinded to study group assignment) to assess: certainty of allergy 
diagnosis, relatedness to the prescribed antimicrobial, and clinical severity, based on 
information collected by study personnel and contained in the medical record. Subjects 
having a history of prior C. difficile infection will be recorded, but will not be excluded from 
analysis since these patients are a small but important subgroup, for which guidance 
regarding therapy duration is of particular interest. The randomization process should help 
ensure that there is no imbalance in such patients between treatment groups. 
 
Secondary outcome (3): intestinal carriage of antimicrobial-resistant Gram-negative 
bacilli after completing study medication, as compared to a baseline sample taken early 
in treatment. 
For the resistance sub-study, the outcomes of interest are (i) the proportion of subjects who 
develop newly detected intestinal carriage of antimicrobial-resistant Gram-negative bacilli 
between the baseline sample during treatment and the sample obtained 7 days after 
completing study medication (Chi-square test), (ii) the density of antimicrobial-resistant 
Gram-negative bacilli among samples with any growth (t-test or Mann-Whitney U-test, 
depending on the frequency distributions), and (iii) the overall resistance score, defined as 
the total number of antimicrobials which at least one of the isolated Gram-negative bacilli is 
resistant to (t-test or Mann-Whitney U-test).  
 
2.o. Proposed timetable 
Pre-study 
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
IRB approval 
Create 
database and 
Purchase 
supplies 
Hire 
personnel 
Patient 
enrollment 
Patient 
enrollment 
Patient 
enrollment 
Complete 
enrollment 
Data analysis 

Protocol 9.0, 02/19/2019 
25 
 
case-report 
forms 
Educate and 
coordinate 
with clinic 
staff and 
providers 
Patient 
enrollment 
Process 
rectal/stool 
swabs 
Assess 
rate of 
subject 
accrual 
Process 
rectal/stool 
swabs 
Process 
rectal/stool 
swabs 
 
Process 
rectal/stool 
swabs 
 
Presentation/ 
publication of 
results 
 
 
 
 
3. Summary 
We propose a single-center, randomized, double-blind, placebo-controlled trial of treatment 
duration for male UTI, which is a common but relatively understudied infectious disease in the 
VA population. The results of this study will allow clinicians to make an evidence-based 
treatment decision regarding an extremely common clinical condition among male veterans 
and non-veterans. This could help preserve the efficacy of valuable antimicrobials during a 
time of steadily increasing antimicrobial resistance and protect future male patients from 
insufficient or excessive antimicrobial therapy for their UTI. 
 
 

Protocol 9.0, 02/19/2019 
26 
 
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