Trimethoprim-sulfamethoxazole vs. Placebo After Hypospadias Repair: a Multicenter, Double-blind, Randomized Trial
Phase: NA
Conditions: Hypospadias
Sponsor: Ann & Robert H Lurie Children's Hospital of Chicago

 
 
 
 
PROPHY Study 
 
Prophylactic Antibiotics or Placebo after Hypospadias Repair 
 
 
 
 
 
Trimethoprim-sulfamethoxazole vs. placebo after hypospadias repair: 
a multicenter, double-blind, randomized trial 
 
ClinicalTrials.gov Identifier: NCT02096159 
 
 
 
 
 
CLINICAL TRIAL PROTOCOL (v6.11.15) 
 
 
 
 
 
 
 
 
 
 
Ann & Robert H. Lurie Children’s Hospital of Chicago 
Northwestern University Feinberg School of Medicine (Chicago, IL, USA) 
Mark A. Faasse, MD MPH 
Dennis B. Liu, MD 
Earl Y. Cheng, MD 
 
The Hospital for Sick Children 
University of Toronto (Toronto, CA)   
Walid A. Farhat, MD 
 
 

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CONTENTS 
 
1. Overview ................................................................................................................................................. 5 
1.1. Title 
1.2. Study Summary 
1.3. Aim, Hypothesis, and Outcomes 
1.4. Study Centers and Principal Investigators 
2. Background ............................................................................................................................................. 6 
2.1. Prior Research and Relevant Knowledge 
2.2. Contemporary Importance 
3. Methods .................................................................................................................................................. 8 
3.1. Study Design 
3.2. Eligibility Criteria 
3.2.1. Inclusion Criteria 
3.2.2. Exclusion Criteria 
3.3. Study Medications (Antibiotic and Placebo) 
3.3.1. Suppliers 
3.3.2. Placebo Stability 
3.3.3. Shipping and Storage 
3.3.4. Inventory 
3.4. Randomization Tables 
3.4.1. Randomization Tables for On-site Study Participants 
3.4.2. Randomization Tables for Off-site Study Participants 
3.5. Study Recruitment and Initial Screening 
3.6. Pre-operative Procedures 
3.7. Peri-operative/Day of Surgery Procedures  
3.7.1. Verification of Eligibility 
3.7.2. Study Medication Prescription 
3.7.3. Intra-operative Procedures 
3.7.4. Intra-operative Data Collection 
3.7.5. Final Review of Eligibility 
3.7.6. Preparation and Dispensing of Study Medication for On-Site Cases 
3.7.7. Preparation and Dispensing of Study Medication for Off-Site Cases 
3.7.8. Other Post-operative Medications 
3.7.9. Discharge Instructions 
3.7.10. Initial Follow-up Appointments 
3.8. Post-operative Follow-up Procedures and Outcomes Assessment 
3.8.1. Study Participant Monitoring 
3.8.2. Reporting and Management of Study Participant Issues and Adverse Events 
3.8.3. Dressing and Stent Removal 
3.8.4. Month One Follow-up 
3.8.5. Assessment of Adherence to Study Medication 
3.8.6. Six-Month Follow-up 
3.8.7. Five-Year Follow-up 
3.8.8. PRN Encounters 
3.9. Early Discontinuation of Study Medication 
3.10. Subject Withdrawal 
3.11. Unblinding 
3.12. Site Initiation and Readiness 
4. Definition of Study Outcomes .............................................................................................................. 18 
4.1. Primary Outcome Measures 

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4.2. Secondary Outcome Measures 
5. Data ....................................................................................................................................................... 20 
5.1. REDCap Data Instruments/Electronic Case Report Forms (eCRFs) 
5.2. Data Management and Security 
5.3. Data Quality 
5.4. Data Transfer and Data Sharing Contracts 
6. Statistical Analysis and Data Monitoring ............................................................................................. 22 
6.1. Data Analysis and Reporting 
6.1.1. Intention-to-treat Analysis 
6.1.2. Per-protocol Analysis 
6.1.3. Descriptive Statistics 
6.1.4. Analysis of Primary and Secondary Outcomes 
6.1.5. Homogeneity and Exploratory Analyses 
6.2. Power and Sample Size 
6.3. Interim Analysis 
6.4. Data and Safety Monitoring Committee 
7. Rationale for Study Design ................................................................................................................... 25 
7.1. Superiority vs. Non-inferiority Trial 
7.2. Utilization of Composite Primary Outcome 
7.3. Use of TMP-SMX as the Antibiotic Agent 
7.4. Study Medication Dosing 
7.5. Limitation of Inclusion to Distal/Mid-shaft Hypospadias Repairs 
7.6. Eligibility of Previously Circumcised Patients 
7.7. Exclusion of Cases with Foreskin Reconstruction 
7.8. Pre-operative Testosterone Use 
7.9. Duration of Follow-up 
8. Informed Consent, Ethical Review, and Regulations ........................................................................... 30 
8.1. Informed Consent 
8.2. Ethical Review 
8.3. Compliance with Regulations 
8.4. Protocol Amendments 
8.5. Protocol Deviations and Violations 
8.6. Trial Postponement and Early Termination 
8.7. Study Documentation 
8.8. Clinical Trial Registration 
9. Organization ......................................................................................................................................... 32 
9.1. Steering Committee and Protocol Development 
9.2. Publication of Study Results 
9.3. Publications Committee 
9.4. Timetable 
9.5. Financial Support 
9.6. Participant Costs and Compensation 
10. Appendices ........................................................................................................................................... 34 
 
 

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1. 
Overview 
 
1.1 
Title 
 
The official title of the study is Prophylactic Antibiotics or Placebo After Hypospadias Repair 
(PROPHY). In materials intended for laypersons, “Preventive” may be used instead of “Prophylactic.” 
 
1.2 
Study Summary 
 
The PROPHY Study is a multicenter, double-blind, randomized trial of prophylactic oral antibiotics vs. 
placebo after primary mid-to-distal hypospadias repair with open-drainage urethral stenting. 
 
1.3 
Aim, Hypothesis, and Outcomes 
 
Aim: The principal aim of this study is to evaluate the impact of a 10-day post-operative course of 
prophylactic trimethoprim-sulfamethoxazole (TMP-SMX) on the rate of infectious and wound healing-
related complications following primary repair of mid-to-distal shaft hypospadias with open-drainage 
urethral stenting. 
 
Hypothesis: The research hypothesis is that administration of prophylactic TMP-SMX reduces the 
aggregate risk of infectious and wound healing-related complications. At present, the investigators believe 
there is clinical equipoise with respect to whether antibiotic prophylaxis after repair of mid-to-distal 
hypospadias is beneficial. 
 
Outcomes: The primary outcome is a composite variable of symptomatic urinary tract infection (UTI), 
cellulitis/wound infection, meatal stenosis, urethral stricture, urethrocutaneous fistula, glans/urethral 
dehiscence, and/or urethral diverticulum. Rationale for use of a composite outcome is provided in Section 
7.2. Detailed definitions of each primary outcome measure are provided in Section 4.1. 
 
Secondary outcomes include acute adverse drug reactions (ADRs), stratified by severity, and C. difficile 
colitis. Detailed definitions of each secondary outcome measure are provided in Section 4.2. 
 
1.4 
Study Centers and Principal Investigators 
 
The initial study centers and respective principal investigators are: 
 
• Ann & Robert H. Lurie Children’s Hospital of Chicago (Lurie Children’s; Chicago, IL, USA) – Primary 
Study Center 
Earl Y. Cheng, MD (Principal Investigator) 
Mark A. Faasse, MD MPH; Dennis B. Liu, MD (Co-Investigators) 
 
• The Hospital for Sick Children (SickKids; Toronto, Canada) 
Walid A. Farhat, MD 
 
Other centers may join the study with agreement and approval of principal investigators from the initial 
study centers. All participating centers and surgeons must confirm their intention to adhere to this 
protocol prior to initiating involvement in the study. 
 
 
 

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2. 
Background 
 
2.1 
Prior Research and Relevant Knowledge 
 
Hypospadias is a congenital anomaly affecting approximately 1/150 males, in which the urethral meatus 
(urethral opening) is abnormally located along the ventral aspect (underside) of the penis, instead of in its 
normal position at the end of the penis.1 The degree of abnormal positioning is variable, from near the 
glans (head) of the penis (distal) to the perineum (proximal). Surgical repair is the only form of treatment 
for hypospadias, and the rate of hypospadias surgery in boys under 3 years-old was 468 per 100,000 in 
2002.2 A urethral stent or catheter is commonly secured to remain in situ following hypospadias repair, 
with open drainage to a diaper in children who are not yet toilet-trained. 
 
According to a survey conducted in 2009, 91% of pediatric urologists used antibiotic prophylaxis 
following hypospadias surgery with urethral stenting.3 However, via personal communication, the study 
investigators have found that as few as 40-50% of attendings at leading academic institutions routinely 
use prophylactic antibiotics in this setting. 
 
Evidence from a recent retrospective cohort study by Kanaroglou et al. supports the omission of antibiotic 
prophylaxis, as patients who received 2 mg/kg of trimethoprim daily until stent removal (n=78) had a 
similar incidence of complications as controls (n=71).4 No UTIs occurred in the control group, and the 
only wound infection was diagnosed in the group that received prophylaxis. The overall complication rate 
was 18.2% in the prophylactic group vs. 15.3% in the non-prophylactic group (95% confidence interval 
[CI] for between-group difference [BGD], -11% to 16%). 
 
The results of Kanaroglou et al. contrast with those of two randomized but non-placebo-controlled trials 
of prophylactic sulfamethoxazole (SMX, unspecified dosing; n=84)5 and cephalexin TID (dose 
unspecified; n=101)6 published in 1983 and 2004, respectively. The former study reported that 
prophylactic SMX reduced the incidence of fever from 10% to 0% (95% CI for BGD, 0-24%). The latter 
study reported a 19% absolute reduction in symptomatic UTI, from 25% to 6% (95% CI for BGD, 3-
34%). Rates of urethrocutaneous fistulas and meatal stenosis were 6% vs. 18% and 2% vs. 8% in patients 
who did and did not receive antibiotic prophylaxis, respectively. Although this study was inadequately 
powered to find these differences statistically significant, it has been hypothesized that bacterial infection 
may contribute to wound healing-related complications of hypospadias repair.7 Nevertheless, the findings 
of Kanaroglou et al. did not validate any benefit of prophylactic antibiotics in this regard. 
 
Differences in published results such as these may occur for a variety of reasons. Although Kanaroglou et 
al. reported on consecutive patients, reducing the risk of selection bias, the results of their study may 
 
1 Gallentine ML, Morey AF, Thompson IM. Hypospadias: A contemporary epidemiologic assessment. Urol 2001; 57:788-790. 
2 Pohl HG, Joyce GF, Wise M, Cilento BG. Pediatric urologic disorders. In: Litwin MS, Saigal CS, eds. Urologic Diseases in 
America. US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute 
of Diabetes and Digestive and Kidney Diseases. Washington, DC: U.S. Government Printing Office, 2007; NIH Publication No. 
07-5512:461-481. 
3 Hsieh MH, Wildenfels P, Gonzales ET. Surgical antibiotic practices among pediatric urologists in the United States. J Ped Urol 
2011; 7:192-197. 
4 Kanaroglou N, Wehbi EJ, Alotay A et al. Is there a role for prophylactic antibiotics after stented hypospadias repair? J Urol 
2013; 190:1535-1539. 
5 Shohet I, Alagam M, Shafir R et al. Post-operative catheterization and prophylactic antimicrobials in children with hypospadias. 
Urol 1983; 22:391-393. 
6 Ben Meir D and Livne PM. Is prophylactic antimicrobial treatment necessary after hypospadias repair? J Urol 2004; 171:2621-
2622. 
7 Bayne AP and Jones EA. Complications of hypospadias repair. In: Taneja SS (ed.), Complications of urologic surgery: 
prevention and management. 4th ed. Philadelphia, PA: Saunders Elsevier; 2010. p. 713-722. 

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reflect unmeasured variables that changed over time, such as surgeon experience, refinements in surgical 
technique, or other aspects of patient care. Differences in follow-up and failure to capture relevant 
outcomes may have also biased the results. Potential compromises of the aforementioned randomized 
trials’ validity include their relatively small size and therefore vulnerability to chance bias from imbalance 
in baseline variables. As neither was placebo-controlled and blinded, ascertainment bias may have also 
occurred. In addition, improvements in surgical technique, development of antimicrobial resistance, and 
other changes in the decade since Ben Meir and Livne’s study may have reduced the marginal benefit of 
prophylactic antibiotics after hypospadias repair. 
 
Medication dosing may have also contributed to variable outcomes, as the dose of TMP utilized in the 
study reported by Kanaroglou et al. was a standard “prophylactic” dose (2 mg/kg once daily). By 
comparison, Ben Meir et al. utilized a therapeutic dosing schedule for administration of cephalexin (TID), 
although the amount was not reported.  
 
2.2 
Contemporary Importance 
 
During recent years, antimicrobial agents have received increasing attention from public health experts. 
More judicious use of antibiotics is imperative to prevent further escalation of antimicrobial resistance, 
which poses a grave threat to human health8 and has contributed substantially to rising healthcare costs.9 
Adverse drug reactions and alteration of native flora, which may cause antibiotic-associated diarrhea, C. 
difficile colitis, and other consequences, represent additional disadvantages of antibiotic use.10 
 
On the other hand, health-care providers and organizations are under pressure to do whatever possible to 
prevent catheter-associated UTIs (CAUTI), which are now being used as a quality metric.11 In certain 
circumstances, such as when removing urinary catheters, prophylactic antibiotics may be beneficial.12 Of 
note, a 2012 Cochrane Review did not support routine use of prophylactic antibiotics during urethral 
catheterization.13 
 
In light of these issues, as well as the discrepancy in results of previously published trials (see Section 
2.1), a well-powered, placebo-controlled randomized trial that aims to provide evidence supporting either 
the rational use or avoidance of prophylactic antibiotics after hypospadias repair is timely. If the results of 
this study indicate that prophylactic antibiotics are beneficial, additional research may be necessary to 
identify the optimal dose and duration of prophylaxis. 
 
 
 
 
8 Howell L, ed. Global risks 2013, 8th edition: an initiative of the Risk Response Network. 
World Economic Forum, 2013. 
9 Smith R and Coast J. The true cost of antimicrobial resistance. BMJ 2013; 346:f1493. 
10 Sammons JS and Toltzis P. Recent trends in the epidemiology and treatment of C. difficile infection in children. Curr Opin 
Pediatr 2013; 25:116-121. 
11 http://www.cdc.gov/HAI/ca_uti/uti.html (accessed 9/3/2013) 
12 Marschall J, Carpenter CR, Fowler S et al. Antibiotic prophylaxis for urinary tract infections after removal of urinary catheter: 
meta-analysis. BMJ 2013; 346:f3147. 
13 Niël-Weise BS, van den Broek PJ, da Silva EMK et al. Urinary catheter policies for long-term bladder drainage. Cochrane 
Database Syst Rev 2012; 8:CD004201. 

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3.  
Methods 
 
3.1 
Study Design 
 
The study is a 1:1 parallel-group, double-blind, randomized trial, with targeted enrollment of 630 boys 
who undergo primary hypospadias repair with open-drainage urethral stenting for 5-10 days. Study 
participants will receive 0.5 mL/kg of TMP-SMX (4 mg/kg TMP) or placebo by mouth (PO) twice daily 
(BID) for 10 days post-operatively. 
 
Physician follow-up visits are planned for 1 and 6 months post-operatively. A chart review and survey of 
all study participants will be conducted 5 years post-operatively to capture late-presenting complications. 
 
3.2 
Eligibility Criteria 
 
3.2.1 
Inclusion Criteria 
 
a) age < 6 years 
b) mid-to-distal shaft hypospadias (subjectively assessed by attending surgeon) 
c) single-stage hypospadias repair 
d) length of urethral repair (urethroplasty) ≤ 2.0 cm 
e) open-drainage urethral stent, with the proximal end positioned in the urinary bladder and 
intended duration of stenting of 5-10 days post-operatively 
 
3.2.2 
Exclusion Criteria 
 
a) previous hypospadias repair 
b) contraindication or elevated risk of adverse reactions to TMP-SMX, including: 
a. prior allergic or adverse reaction 
b. cross-reactivity with an existing medication 
c. human immunodeficiency virus (HIV) 
c) poorly controlled diabetes mellitus or other immune-compromising conditions 
d) any patient condition deemed by the attending surgeon to present an elevated risk of infection 
or of adverse outcome(s) from potential infection (e.g., endocarditis related to congenital heart 
disease) 
e) receipt of oral or intravenous (IV) antibiotics within 7 days prior to hypospadias surgery 
f) foreskin reconstruction 
g) prescription of post-operative oral antibiotic prophylaxis (other than study medication) 
 
3.3 
Study Medications (Antibiotic and Placebo) 
 
3.3.1 
Suppliers 
 
The antibiotic used for this study will be TMP-SMX 40-200 mg/5 mL (see Appendix A). Placebo will be 
formulated to approximate the appearance, odor, taste, texture, and pH of the active medication as closely 
as possible and prepared by a certified compounding pharmacy. 
 
Necessary arrangements will be made for participating study centers to obtain the antibiotic and placebo. 
If necessary, study medications will be distributed from Lurie Children’s. 
 
3.3.2 
Placebo Stability 
 

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The stability of placebo formulation(s) will be evaluated and documented by the laboratory of Gagan 
Kaushal, PhD (Pharmaceutical Sciences, Thomas Jefferson University). 
 
3.3.3 
Shipping and Storage 
 
Both study medications should be shipped and stored according to manufacturer/producer specifications. 
All pertinent regulatory guidelines should also be observed (e.g., inclusion of a No-Objection Letter from 
Health Canada when importing medications to Canada). 
 
3.3.4 
Inventory 
 
Based on the weight of prior patients undergoing hypospadias repair, we anticipate that each study 
participant will require an average of 100-150 mL of study medication. At the time of study initiation, 
each participating center will stock an agreed-upon quantity (e.g., 1.0-3.0 L) of both antibiotic and 
placebo. For the duration of the study, pharmacy staff at each study center will monitor inventory of study 
medications and order additional supplies as necessary, taking necessary lead-time into consideration. 
 
3.4 
Randomization Tables 
 
Study participants will be randomized 1:1 to antibiotic or placebo treatment in blocks of 10, stratified by 
study center. 
 
3.4.1 
Randomization Tables for On-site Study Participants 
 
For allocation of patients undergoing surgery at facilities with on-site preparation of study medication 
bottles, randomization tables will be generated and uploaded into the REDCap randomization module 
prior to the beginning of the study. Please reference Section 3.7.6 for directions regarding patient 
assignment and medication preparation. 
 
3.4.2 
Randomization Tables for Off-site Study Participants 
 
Separate randomization tables will be created by the statistician (or other designee not involved in patient 
care during the study) to be used for patients undergoing surgery at locations where day-of-surgery 
preparation of study medication is unavailable. The tables will allow preparation of study medication 
prior to surgery without recording the allocation in REDCap until final confirmation of eligibility to 
participate in the study. Each table will have one block of 10 allocations (5 TMP-SMX, 5 placebo). 
 
At the time of study initiation, pharmacies at each study center with potential off-site participants will 
receive at least two randomization tables for off-site participants. When use of the first off-site 
randomization table has been completed (i.e., all 10 study medication bottles prepared and dispensed), 
pharmacy staff should proceed to use the next randomization table, while notifying the statistician or 
designee to generate the subsequent table. 
 
At their discretion, pharmacy staff may utilize the off-site randomization tables either electronically or on 
paper. Creating multiple copies of the randomization tables should be avoided, as this may lead to errors 
in record-keeping and dispensing of study medication bottles. 
 
3.5 
Study Recruitment and Initial Screening 
 
At each study center, Institutional Review Board (IRB)-approved methods should be followed in 
recruiting patients with mid-to-distal shaft hypospadias and obtaining consent for study participation prior 

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to or on the day of surgery. Patients with proximal hypospadias defects or any condition that presents an 
elevated risk of infection or of adverse outcome from potential infection (e.g., endocarditis related to 
congenital heart disease) should not be invited to participate. Recruitment materials may include an 
educational brochure regarding the study (Appendix B), referral to prophystudy.info, and/or a copy of the 
consent form. 
 
An electronic case report form (eCRF) will be created in the study’s REDCap database (Appendix C) for 
patients whose parent(s)/legally authorized representative(s) (LAR) indicate a desire to enroll in the study. 
Depending on IRB regulations, Protected Health Information (PHI) will be entered either into the eCRF 
or an off-line registry by which the REDCap Study ID corresponding to each patient can be identified. 
 
Enrollment information will include screening questions pertinent to eligibility criteria (see Section 3.2). 
For patients with a potentially immune-compromising comorbidity, their pediatrician or other relevant 
specialist(s) should be contacted to assess its current status of control (i.e., well vs. poorly controlled). 
Cross-reactivity of medications with TMP-SMX should be assessed using Epocrates, Lexicomp, or other 
clinical pharmaceutical software. 
 
3.6 
Pre-operative Procedures 
 
For study purposes, pre-operative use of topical or intramuscular (IM) testosterone is left to surgeons’ 
discretion. When a decision to administer testosterone is made, physicians should document 
measurements of glans width and stretched penile length at the initial clinic visit. These data may 
facilitate post hoc analysis of the relationship between testosterone use, change in penile size, and surgical 
outcomes. As described by Aaronson (1994), stretched penile length should be measured by gripping the 
glans gently but firmly enough to stretch the penis to its full length and recording the distance along the 
dorsal aspect from the symphysis pubis to the tip of the glans, disregarding the prepuce.14 
 
For (potential) study participants who may undergo hypospadias repair at an off-site facility, a weight 
should be obtained within 30 days prior to surgery and documented in the eCRF. This will facilitate 
preparation of study medication in advance of the day of surgery. 
 
3.7 
Peri-operative/Day of Surgery Procedures 
 
3.7.1 
Verification of Eligibility 
 
On the day of surgery, study personnel should verify that the patient has not received oral or IV 
antibiotics within 7 days prior to surgery. Contact information, medical conditions, current medications, 
allergy history, and information regarding pre-operative testosterone use should also be confirmed and 
documented in the REDCap Preop Verification data instrument. 
 
3.7.2 
Study Medication Prescription 
 
For patients undergoing surgery at a location with on-site pharmacists, the prescription for study 
medication may be completed when the patient arrives and is weighed pre-operatively, however, 
randomization and preparation of the medication should be deferred until final, intra-operative 
confirmation of patient eligibility (see Section 3.7.6). For off-site surgeries, the prescription must be 
provided further in advance to allow earlier preparation of study medication (see Section 3.7.7). 
 
3.7.3 
Intra-operative Procedures 
 
14 Aaronson IA. Micropenis: medical and surgical implications. J Urol 1994; 152:4-14. 

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Use of peri-operative IV antibiotics is recommended but not required. Generally speaking, cefazolin or an 
alternate agent such as clindamycin or vancomycin (for patients with penicillin allergies) should be 
administered. The initial dose should ideally be administered within 1 hour prior to incision (2 hours for 
vancomycin). Redosing guidelines should be followed 
(http://www.medscape.com/viewarticle/742992_11). Surgical scrub technique will not be standardized 
but should be documented in the REDCap Surgery data instrument. 
 
A catheterized urine culture may optionally be collected as part of routine care at the outset of the 
procedure, with documentation of whether the culture was collected prior to or following IV 
administration of prophylactic antibiotics. The results will be used to assess baseline levels of bacteriuria 
and its possible relationship to post-operative complications. Patient management should not be affected 
by intra-operative cultures unless there are symptoms/signs of infection post-operatively. 
 
No standardization of surgical technique is required, but various technical aspects should be documented 
in the Surgery data instrument. At the conclusion of the case, either absorbable or non-absorbable 
suture(s) may be used to secure the urethral stent in place. Follow-up should be arranged per Section 
3.8.3, according to the suture type. 
 
3.7.4 
Intra-operative Data Collection 
 
The meatal location should be assessed with the patient under anesthesia. If the hypospadias defect is 
subjectively regarded as “proximal,” the patient should be excluded from the study, regardless of the 
eventual length of the urethral repair. 
 
Penile measurements (glans width and stretched penile length) should be taken after sterile preparation of 
the surgical field. Stretched penile length should be measured by lifting the glans via traction suture to 
stretch the penis to its full length and recording the distance along the dorsal aspect from the symphysis 
pubis to the tip of the glans, disregarding the prepuce.15 Incision time should be regarded as the time of 
skin incision, not placement of the glans traction suture. 
 
A skeletonized portion of the REDCap Surgery data instrument is available to facilitate intra-operative 
recording of data, such as the time of peri-operative antibiotic administration and incision, intra-operative 
measurements, and case duration (Appendix D). This “Cheat Sheet” also includes a guide for final 
verification of criteria for study eligibility (Section 3.7.5). 
 
Point-of-care data entry to the Surgery data instrument by the attending surgeon or designee is 
encouraged. Paper CRFs may also be utilized. Study coordinators should verify documentation of 
necessary data. 
 
3.7.5 
Final Review of Eligibility  
 
The final review of eligibility for study participation will occur after completion of the urethroplasty. The 
surgeon must confirm (a) his/her subjective impression that the hypospadias defect was distal or midshaft, 
(b) the urethroplasty length was no greater than 2.0 cm, (c) the surgical repair will be completed in a 
single stage (with circumcision, if the patient was not previously circumcised), and (d) an open-drainage 
urethral stent will be used, with the proximal end positioned in the urinary bladder and intended duration 
of stenting of 5-10 days post-operatively. When a patient’s final eligibility for participation has been 
 
15 Aaronson, 1994. 

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determined, a study coordinator/investigator or other personnel should notify pharmacy staff to fill the 
previously provided prescription (for on-site cases). 
 
3.7.6 
Preparation and Dispensing of Study Medication for On-Site Cases 
 
For on-site cases, pharmacy staff should await notification of participants’ final eligibility before 
preparing study medication. When confirmed, the REDCap Study Medication Dispensing data instrument 
will be used to assess each study subject’s eligibility and allow one-click randomization to antibiotic or 
placebo using the REDCap randomization module. Once randomization is performed in REDCap, a study 
subject’s allocation cannot be changed. 
 
Pharmacists will calculate the total amount (mL) of study medication to be dispensed for each participant 
by multiplying the child’s weight (kg) by 10 and adding 10 mL for minor spillage or inaccuracies in dose 
administration. Bottles will be labeled with “PROPHY Study Medication,” as well as the patient’s name, 
Study ID number, instructions for weight-based dosing (“__ mL PO BID x 10 days”), contact information 
for a study coordinator, expiration date, and any other study center-specific requirements, such as 
Canadian Qualified Investigator labeling and translation. Provision of syringes marked with the desired 
volume for each dose is encouraged. 
 
Study medication should be dispensed in a double-blind fashion. Other than pharmacy staff, all 
individuals involved in the care of study participants and/or conduct of the study must remain unaware of 
participants’ allocation until completion or termination of the study, except in circumstances described by 
Section 3.10. 
 
3.7.7 
Preparation and Dispensing of Study Medication for Off-Site Cases 
 
When a study medication prescription is received for off-site cases, the pharmacy staff should identify the 
next assignment in the off-site randomization table. Study medication bottles should be prepared and 
labeled as described in Section 3.7.6. The pharmacy staff should record the patient’s Study ID, name, and 
an “X” in the “Prepared” column of the randomization table. No record of the allocation should be 
entered into REDCap at this time. 
 
Study medication will be dispensed to personnel who will transport the medication to the off-site location 
on the day of surgery. Following surgery, this individual (or designee) should notify the pharmacy of 
whether the patient was eligible for the study and received study medication. If so, pharmacy staff will 
record an “X” in the “Dispensed” column of the randomization table and enter the participant’s allocation 
into the eCRF (REDCap Study Medication Dispensing data instrument). Blinding of both patients and 
study personnel (other than pharmacy staff) to the allocation should be maintained in this process. 
 
If an off-site patient is ineligible for the study, the study medication should be returned to the pharmacy. 
Pharmacy staff will record an “X” in the “Not Dispensed/Reassigned” column, and this study medication 
assignment will be given to the next off-site study participant, regardless of whether one or more 
subsequent off-site assignments were prepared in the interim.  
 
3.7.8 
Other Post-operative Medications 
 
At the discretion of each attending surgeon, any medications other than oral antibiotics may be prescribed 
for patients post-operatively; topical preparations containing antibiotics are also permissible. All post-
operative medications should be recorded in the REDCap Surgery data instrument. 
 
3.7.9 
Discharge Instructions 

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Discharge instructions may be adapted according to center/attending-specific preferences. Caregivers 
should be instructed to administer study medication twice daily for 10 days post-operatively, retain 
possession of the medication bottle(s) with any leftover contents, and report any concerns to a study 
coordinator/investigator as soon as possible, including symptoms/signs of UTI, cellulitis/wound infection, 
medication intolerance, diarrhea, rash, or other ADRs. 
 
3.7.10 Initial Follow-up Appointments 
 
Initial follow-up may include an appointment for dressing removal. When the urethral stent is secured by 
non-absorbable suture(s), a visit should be scheduled for stent removal 5-10 days post-operatively. 
Patients whose stent is secured with absorbable suture(s) may receive an appointment on or as close as 
possible to (but not later than) post-operative day 10. If the stent falls out prior to this date, a study 
coordinator should be informed, and this appointment may be cancelled. All patients should have a 
physician visit scheduled for approximately 1 month post-operatively. 
 
3.8 
Post-operative Follow-up Procedures and Outcomes Assessment 
 
3.8.1 
Study Participant Monitoring 
 
Periodic emails or telephone calls should be used to monitor study participants, encourage adherence to 
BID administration of study medication, and remind caregivers to report any symptoms/signs of infection 
or ADR as well as if/when the urethral stent falls out. Participants should be reminded to discontinue 
study medication on post-operative day 10 and to retain possession of their study medication bottle(s) 
with any residual medication, which should be returned at the time of their next follow-up visit. 
Reminders of follow-up appointments may also be provided. 
 
A study coordinator should also contact participants on or shortly after post-operative day 15 specifically 
to assess for occurrence of medication intolerance, diarrhea, rash, and other ADRs, which are secondary 
study outcomes when occurring within 14 days post-operatively. This opportunity should also be used to 
confirm medications and topical agents used since surgery. Another contact should occur on or shortly 
after post-operative day 31 to assess for primary outcomes, unless a follow-up appointment is scheduled 
to occur in the same time frame. Data from these contacts should be recorded in the REDCap Month One 
Followup data instrument. 
 
3.8.2 
Reporting and Management of Study Participant Issues and Adverse Events 
 
Issues with study participants, including study outcomes, that are recognized during routinely scheduled 
follow-up visits should be documented in the corresponding REDCap data instrument. Issues that are 
evaluated or diagnosed by healthcare encounters/visits outside of routine follow-up visits should be 
documented in the PRN Encounters data instrument, including if those encounters/visits occur at other 
medical facilities. If no healthcare encounter occurs to evaluate an issue that is reported or discovered 
outside of routine follow-up visits, it should be recorded in the Patient Contacts, Adverse Events & 
Protocol Deviations data instrument. 
 
Any unfavorable change in a study participant’s medical condition should be considered an adverse event, 
including but not limited to changes related to occurrence of any primary or secondary study outcomes 
(infections, post-operative complications, and/or ADRs). Study coordinators should be made aware of all 
possible adverse events, and these cases should be reviewed immediately with the patient’s attending 
physician. In addition to relevant documentation described in the preceding paragraph, adverse events 
should also be recorded in the Patient Contacts, Adverse Events & Protocol Deviations data instrument. 

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Study coordinators and PIs are responsible for adhering to local IRB guidelines on reporting of adverse 
events. The Lurie Children’s IRB requires adverse events to be classified as serious, unexpected, and/or 
related or possibly related to the patient’s participation in the PROPHY Study, with these designations 
being defined as follows: 
• 
a serious adverse event involves hospitalization or prolongation thereof, life-threatening injury, 
persistent or significant disability, death, or development of a condition that would (have) likely 
jeopardize(-d) the patient’s life or ability to conduct normal life functions if it remains(-ed) 
untreated; 
• 
an unexpected event is unanticipated, including in terms of severity or frequency of occurrence to 
a particular research subject, given the nature of the research procedures and population being 
studied; 
•  an event is related or possibly related to study participation if it is related or possibly related to 
the patient’s receipt of prophylactic antibiotics (or lack thereof) post-operatively. 
All serious or unexpected adverse events that are related or possibly related to study participation must be 
reported to the primary study center (Lurie Children’s) within 10 days of their recognition. 
 
Study participants’ attending and/or treating physician(s) are responsible for deciding on appropriate 
management of reported issues. This may include arrangements for a clinic visit to the patient’s primary 
care physician/pediatrician or urologist, Emergency Room (ER) visit, hospital admission, urine culture, 
wound culture, C. difficile testing, temporary or permanent discontinuation of study medication, initiation 
of an alternative (known) antibiotic, or other management. 
 
In the event of nonspecific symptoms/signs that may be referable to an infection (e.g., fever, hypothermia, 
apnea, bradycardia, lethargy, and vomiting) or symptoms/signs of UTI (dysuria or 
suprapubic/costovertebral pain or tenderness), patients will be instructed to be seen as soon as possible for 
evaluation, whether in the ER, primary care physician/pediatrician’s clinic, or urology clinic. Evaluation 
for alternate (non-UTI) causes of nonspecific symptoms/signs should be performed. If clinically 
indicated, a urine specimen should be collected for both urinalysis and culture via the urethral stent (prior 
to its removal), suprapubic aspirate, urethral catheterization, or urine bag ± Credé maneuver. Because of 
poor specificity, use of bagged specimens is discouraged unless other alternatives are deemed 
unacceptable. A study coordinator should follow-up on the results of any cultures collected. 
 
If symptoms/signs of infection are present, the decision to initiate treatment with known antibiotics will 
be made by the treating physician. If the patient’s condition does not allow deferral of treatment until 
culture results are available, empiric antibiotics should be initiated. If the patient is still taking study 
medication at this time, it should be discontinued. Selection of the antibiotic agent(s) to be used 
empirically is at the physician’s discretion, keeping in mind that the patient may or may not have been 
receiving TMP-SMX. The patient’s clinical record should subsequently be reviewed for relevant data to 
be documented in both the PRN Encounters and Patient Contacts, Adverse Events & Protocol Deviations 
data instruments. 
 
If medication intolerance occurs (i.e., isolated vomiting or spitting up on at least 2 consecutive occasions 
after taking study medication), routine advice regarding administration of the medication with food or 
milk, etc., will be provided. If medication intolerance persists, study medication may be discontinued – 
temporarily or permanently – at the discretion of the attending physician. 
 
If symptoms/signs of other mild ADRs, including diarrhea, occur while the patient is on study 
medication, the participant will be instructed to temporarily discontinue it. Testing for C. difficile is 
advised for evaluation of diarrhea unless it has already resolved by the time study personnel become 
aware of it. For symptoms/signs of a mild hypersensitivity reaction (i.e., generalized 

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erythema/rash, urticaria, periorbital edema, or angioedema), caregivers will be instructed to administer 
diphenhydramine until symptom resolution. Study medication should be restarted at the attending’s 
discretion when symptoms improve/resolve or when 48 hours have elapsed since discontinuation of the 
medication. If symptoms recur or worsen with resumption of study medication, it should be permanently 
discontinued. 
 
If symptoms/signs of a moderate-to-severe ADR (as defined in Section 4.2) occur, the study medication 
should be permanently discontinued, with further management as directed by the patient’s treating 
physician(s). Unblinding may be necessary to direct patient care (see Section 3.10). If study medication is 
permanently discontinued because of an ADR, an alternative prophylactic antibiotic may be initiated at 
the discretion of the attending physician, with documentation in the Patient Contacts, Adverse Events & 
Protocol Deviations data instrument. 
 
If a study participant requires emergent assessment by a physician for any reason and is unable to come to 
the study center, a study coordinator will invite treating physicians at outside institutions to contact 
him/her to discuss collection and reporting of culture results, study criteria for infection, etc. Medical 
records from outside institutions may be obtained with the participant’s permission. 
 
3.8.3 
Dressing and Stent Removal 
 
At surgeons’ discretion, a clinic visit may be scheduled for dressing removal. All patients whose stent is 
secured with a non-absorbable suture should be scheduled to have a clinic visit with a nurse or physician 
5-10 days post-operatively for stent removal. Patients whose stent is secured with an absorbable suture 
should receive an appointment on or as close as possible to (but not later than) post-operative day 10, 
which can be cancelled if the stent falls out prior to this date. 
 
If it is part of routine care, a urine culture may optionally be collected at one or both of these clinic visits, 
with documentation of whether it was collected and its eventual results in the appropriate REDCap data 
instrument (Dressing Removal or Stent Removal). As in the case of urine cultures collected intra-
operatively, patients with positive post-operative cultures should not be managed differently unless they 
manifest symptoms/signs of infection. 
 
Routine assessment should be performed at the time of dressing and stent removal. If symptoms/signs of 
infection, wound healing-related complications, medication intolerance, diarrhea, rash, or other ADR are 
evident, a study coordinator should be notified, and the case should be reviewed with the patient’s 
attending physician to determine subsequent management. Patients with possible cellulitis/wound 
infection should be examined by a physician for diagnostic confirmation. A study coordinator should be 
notified if any cultures are collected, in order to follow-up on results. 
 
Nurses with research certification may enter data relevant to dressing and/or stent removal directly into 
REDCap. Otherwise, they should utilize paper CRFs and submit these to a study coordinator for data 
entry. Occurrence of primary and secondary outcomes should only be documented in REDCap by study 
coordinators or physicians. 
 
3.8.4 
Month One Follow-up 
 
Early post-operative monitoring of study participants by telephone calls or emails is described in Section 
3.8.1. All patients should have a physician visit scheduled for approximately 1 month post-operatively. 
The primary purpose of this visit is to confirm the occurrence or absence of symptoms/signs of infection, 
as UTI and cellulitis/wound infection are primary study outcomes when occurring within 30 days post-
operatively. If the 1-month clinic visit occurs prior to post-operative day 30, it should be supplemented by 

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a telephone call or email on or shortly after post-operative day 31 to confirm absence of symptoms/signs 
of infection. Data from the 1-month clinic visit and/or other routine contacts occurring at this time should 
be recorded in the REDCap Month One Followup data instrument. Any receipt of antibiotics (other than 
study medication) during the first 30 days after surgery should also be documented. 
 
The 1-month clinic visit should also include assessment of other primary outcomes by reviewing voiding 
symptoms (strength and singularity of the urinary stream) and physical examination, noting the adequacy 
of meatal caliber, dehiscence, and/or evidence of urethrocutaneous fistulae or urethral diverticulae. If any 
symptoms/signs of meatal stenosis or urethral stricture are identified, urethral calibration with an 8 Fr 
catheter/sound/dilator should be attempted. Inability to introduce the catheter/sound/dilator through the 
urethral meatus is considered diagnostic of meatal stenosis, whereas ability to pass the 8 Fr instrument 
beyond the meatus but not into the urinary bladder should prompt further evaluation (e.g., cystoscopy) for 
urethral stricture (see Section 4.1). A study coordinator should be notified if any cultures are collected, in 
order to follow-up on results. 
 
3.8.5 
Assessment of Adherence to Study Medication 
 
Each patient’s study medication bottle(s) should be collected after post-operative day 10. This may occur 
at the 1-month clinic visit. The volume of residual medication should be measured either by pharmacy 
staff or other personnel and recorded in the REDCap eCRF. 
 
3.8.6 
Six-Month Follow-up 
 
The final scheduled follow-up appointment for the PROPHY Study should be approximately 6 months 
post-operatively. At that time, participants will be advised of symptoms/signs relevant to primary 
outcomes that may present at a later date. If any occur, the parent(s)/ caregiver(s) will be requested to 
contact a study coordinator to arrange a PRN follow-up appointment. 
 
3.8.7 
Five-Year Follow-up 
 
Five years post-operatively, a chart review and brief survey of parent(s)/caregiver(s) will be conducted to 
assess if late-presenting complications have occurred, using the REDCap Five-Year Followup data 
instrument. If applicable, permission to obtain relevant medical records from other facilities may also be 
requested at this time. Periodic contacts should occur approximately annually between the 6-month visit 
and 5-year follow-up survey in order to verify and maintain accurate contact information for study 
participants. 
 
If the patient is not yet toilet-trained at the time of 5-year follow-up and/or his parent(s)/caregiver(s) have 
not had an opportunity to observe him voiding, a subsequent contact will be arranged to occur after toilet-
training and observance of voiding. If concerns for potential complications are identified and have not yet 
been addressed, the participants will be asked to schedule a PRN follow-up appointment. 
 
Longer-term follow-up assessments will require separate IRB authorization. Outcomes that may be 
relevant to longer-term follow-up include voiding symptoms, patient satisfaction with penile appearance, 
and sexual function. 
 
3.8.8 
PRN Encounters 
 
Data should be recorded in the REDCap PRN Encounters data instrument for all PRN (unscheduled) 
visits that occur for evaluation of concerns related to the patient’s hypospadias surgery. This should 
include visits to the study site ER, primary care physician/pediatrician, and outside hospital ERs. A study 

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coordinator should be notified or investigate if any cultures were collected, in order to follow-up on 
results. Permission to obtain relevant records from other medical facilities will be requested from study 
participants. 
 
3.9 
Early Discontinuation of Study Medication 
 
Study medication should be temporarily discontinued if a mild ADR occurs (see Section 3.8.2). It should 
be permanently discontinued under the following circumstances: 
• initiation of treatment with known antibiotics for a symptomatic UTI or cellulitis/wound infection 
less than 10 days post-operatively; 
• initiation of treatment with trimethoprim and/or sulfamethoxazole for any other reason less than 10 
days post-operatively; 
• symptoms/signs of a moderate-to-severe ADR; 
• recurrent symptoms/signs of a mild ADR; 
• subject withdrawal from the study; or 
• any other reason deemed appropriate by a treating physician. 
 
A study coordinator and the patient’s attending physician should be notified if study medication is 
discontinued. Follow-up should continue per protocol, and all data will be analyzed on an intention-to-
treat basis. 
 
3.10 
Subject Withdrawal 
 
Study participants may opt to withdraw from the study at any time. Subjects will also be withdrawn if 
they do not have surgery after enrollment, eligibility criteria are not satisfied, or the study is discontinued. 
The reason(s) for withdrawal should be recorded in the REDCap Subject Withdrawal data instrument. 
Data collected to date will be included in the study analysis unless the parent(s)/LAR indicate a 
preference otherwise. 
 
3.11 
Unblinding 
 
In the event that a patient’s clinical management depends critically on knowledge of whether the patient 
received TMP-SMX or placebo, a study coordinator will contact a pharmacist, data manager, or 
statistician to provide emergency unblinding. Data of patients for whom unblinding is required will still 
be analyzed according to an intention-to-treat principle. 
 
3.12 
Site Initiation and Readiness 
 
A dry run/dummy test may be used to confirm readiness at each study center. The dry run may include 
simulated recruitment of potential study participants, collection of study-related data prior to and on the 
“day of surgery,” alerting of the pharmacy to perform randomization and dispense study medication, and 
post-operative follow-up, with data entry into REDCap eCRFs. Management of atypical scenarios, such 
as a participant’s development of symptoms/signs of UTI, should be considered. 
 
 
 

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4. 
Definition of Study Outcomes 
 
4.1 
Primary Outcome Measures 
 
The components of the primary outcome are defined as follows: 
 
• symptomatic UTI within 30 days post-operatively – both of the following criteria must be satisfied 
(modeled after the CDC and AAP definitions16,17): 
1. one or more of the following symptoms/signs: fever > 38°C, hypothermia < 36°C, or 
apnea/bradycardia/lethargy/vomiting with no other likely alternate cause(s); dysuria; suprapubic 
or costovertebral pain or tenderness; AND 
2. positive urine culture, as defined by ≥ 50,000 cfu/mL of no more than 2 species of 
microorganisms AND (dipstick positive for leukocyte esterase at trace or greater levels OR 
pyuria > 5 wbc/hpf, unless urinalysis was not obtained) 
• cellulitis/wound infection within 30 days post-operatively: (erythema OR warmth) AND tenderness to 
gentle palpation, OR purulent drainage with positive wound culture; 
• meatal stenosis: urethral meatus unable to accommodate an 8Fr catheter or sound/dilator 
• urethral stricture: < 8Fr stenosis, proximal to the urethral meatus 
• urethrocutaneous fistula: multiple urinary streams, including urine leakage from a location proximal to 
the urethral meatus, or a visible fistula 
• dehiscence: ventral separation of the reconstructed glans penis/urethra 
• urethral diverticulum: “ballooning” of the urethra evident on physical examination, during voiding, or 
by cystoscopic evaluation 
 
When urine or wound cultures are positive, study coordinators should ensure documentation of relevant 
symptoms/signs before recording a diagnosis of symptomatic UTI or wound infection. 
 
4.2 
Secondary Outcome Measures 
 
Secondary outcome measures include acute ADRs (within 14 days post-operatively), stratified by 
severity, and diagnosis of C. difficile colitis within 6 months post-operatively. Stratification of ADRs is 
modeled after the Brown scale of hypersensitivity reactions.18,19 
 
a) Acute adverse drug reactions (ADRs) 
 
1) Mild 
• medication intolerance: isolated vomiting/spitting up on at least 2 consecutive occasions after 
administration of study medication  
• isolated diarrhea: loose or watery stools, with increase in frequency to twice the usual number 
per day in infants, or 3 or more per day in older children; C. difficile assay negative or not 
obtained (with duration, if applicable) 
• mild hypersensitivity reactions (HR): generalized erythema/rash, urticaria, periorbital edema, 
angioedema 
 
2) Moderate-to-Severe 
• blistering 
 
16 http://www.cdc.gov/nhsn/pdfs/pscmanual/17pscnosinfdef_current.pdf (accessed 11/1/2014) 
17 Roberts KB, Downs SM, Finnell SM et al. Urinary tract infection: clinical practice guidelines for the diagnosis and 
management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 2011; 128:595-610. 
18 Brown SGA. Clinical features and severity grading of anaphylaxis. J  Allergy Clin Immunol 2004;114:371-376. 
19 Brown AFT. Current management of anaphylaxis. Emerg 2009; 21:213-223. 

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• Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), hepatic necrosis, blood 
dyscrasia, or other severe reaction 
• moderate-severe HR: 
- 
one or more symptoms/signs of mild HR; AND 
- 
cough, dyspnea, stridor, wheezing, cyanosis/hypoxia, drooling, vomiting, diaphoresis, 
abdominal pain, hypotension, or altered mental status 
b) Diagnosis of C. difficile colitis within 6 months post-operatively 
 
If occurring within 14 days post-operatively, diarrhea and C. difficile colitis will be regarded as mutually 
exclusive outcome measures (i.e., if a patient is documented to have C. difficile colitis, he will not be 
reported as also having had diarrhea). 
 
 
 

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5. 
Data 
 
5.1 
REDCap Data Instruments/Electronic Case Report Forms (eCRFs) 
 
REDCap is a mature, freely available, and secure Clinical Research Information System developed at 
Vanderbilt University and utilized by over 1400 institutions worldwide (http://www.project-redcap.org). 
Study data will be recorded using data instruments/electronic Case Report Forms (eCRFs) programmed in 
REDCap (Appendix C). Data instruments may also be available on paper, however, any data collected on 
paper should be transferred into REDCap as soon as possible. Training on data entry and use of REDCap 
should be provided to all users prior to study initiation and on a PRN basis thereafter. 
 
Protected Health Information (PHI) should not be included in the database for patients enrolled at study 
centers where inclusion of such information is not permitted. Instead, study coordinators should maintain 
a secure registry off-line of which Study ID corresponds to each patient. All data from each study center 
will be de-identified for analysis. 
 
5.2 
Data Management and Security 
 
Records containing subject medical information must be handled in accordance with the requirements of 
the HIPPA Privacy Rule. Such records must not be shared with or accessed by any person or for any 
purpose not contemplated by the informed consent. Furthermore, case report forms and other documents 
to be transferred to the investigator should be completed in strict accordance with the instructions 
provided by the investigator, including the instructions regarding the coding of subject identities. 
 
REDCap has application-level security that restricts access to study data based on user roles and 
permissions. User roles and permissions within REDCap should be restricted to the minimum number of 
data instruments that each individual needs to access. In addition to application-level security, all access 
to REDCap at Lurie Children’s/Northwestern Univerity is over SSL (https). This prevents any third party 
from deciphering data sent between a user of REDCap and the system itself. This is the same level of 
encryption used on online banking, e-commerce, and other sensitive websites. 
 
Each participating study center is responsible for ensuring that sufficient mechanisms are in place for 
secure data entry and storage. At Lurie Children’s/Northwestern University, REDCap is HIPAA-
compliant. A network firewall controls access to the REDCap application servers by only allowing traffic 
from known subnets, minimal set of data ports and minimal protocols. Thus, access is denied or closed by 
default. Behind this firewall is a two-tiered system design. One server hosts the web server and 
application specific code. A second server hosts the database. Traffic between these two servers is again 
restricted by IP, port, and shared access key, and never leaves the private network. This ensures that only 
the trusted application server can talk to the database server and prevents unauthorized access to the 
database server from direct external attacks. To protect data in the case of corruption or system error, all 
data are backed up on a nightly basis with full redundancy. 
 
5.3 
Data Quality 
 
Whenever feasible, database programming will be put in place to identify outliers and prompt verification 
of data entry. An audit log will identify variables that are changed after initial data entry. Study 
coordinators and/or data manager(s) will regularly review data to ensure completeness. 
 
If any study personnel develop concerns regarding the integrity or quality of study data, these should be 
reported to a study coordinator and/or PI as soon as possible. The concerns and results of subsequent 

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investigation should be documented. Any protocol deviations/violations should be reported to the relevant 
IRB, as per Section 8.5. 
 
5.4 
Data Transfer and Data Sharing Contracts 
 
Deidentified data from all study centers will periodically be transferred to the primary study center for 
review by the Data and Safety Monitoring Committee and statistical analysis. Data will be analyzed and 
reported on a pooled, aggregate basis, without stratification or comparison of outcomes by study center. 
Relevant data sharing contracts will be established. 
 
 
 

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6. 
Statistical Analysis and Data Monitoring 
 
6.1 
Data Analysis and Reporting 
 
6.1.1 
Intention-to-treat Analysis 
 
The primary analysis will be based on the intention-to-treat (ITT) principle. All randomized patients will 
be analyzed in the group to which they were allocated, regardless of whether they actually received the 
intended treatment or whether a protocol deviation/violation occurred. No adjustments for multiple 
comparisons will be used since a single primary endpoint has been defined and thresholds adjusting for 
interim analyses will be applied. 
 
6.1.2 
Per-protocol Analysis 
 
Inclusion in the per-protocol analysis will require the following: 
• completion of the 10-day course of assigned study medication with at least 80% adherence, as assessed 
by the volume of residual study medication, unless study medication was discontinued either 
temporarily or permanently (see Section 3.9.1); and 
• completion of the 6-month physician follow-up visit or 5-year follow-up survey. 
 
6.1.3 
Descriptive Statistics 
 
Descriptive statistics will be prepared for all variables at all assessments and reviewed for data quality. 
The number of patients with missing data for each assessment and/or variable will be analyzed. There will 
be no imputation of missing data in the primary analyses; however, sensitivity analyses may be conducted 
using multiple imputation to ensure that final conclusions are consistent across different assumptions for 
the missing data mechanism. 
 
Baseline demographic and clinical characteristics will be compared between the treatment arms using the 
Wilcoxon rank-sum test for continuous variables and Fisher’s exact test for categorical variables. In a 
randomized trial such as this, baseline differences can generally be attributed to chance, but if differences 
are found, the primary analyses may also be performed with uni- or multi-variate adjustment. A similar 
approach will be taken for any other baseline variables identified a priori by the study investigators as 
being of potential prognostic value, such as pre-operative testosterone use, glans size, asymptomatic 
bacteriuria, perioperative IV antibiotic use, administration of locoregional anesthesia, length of urethral 
repair, ratio of length of repair to penile shaft length, neourethral coverage, and case duration.20 
 
6.1.4 
Analysis of Primary and Secondary Outcomes 
 
The primary outcome measure is a binary (i.e., “any or none”) variable as defined in Section 4.1, where 0 
indicates no complications and 1 indicates occurrence of at least one complication (symptomatic UTI, 
cellulitis, etc.). Fisher’s exact test will be used to test the unadjusted difference in primary outcome 
between the two groups. 
 
The secondary endpoints are also binary variables and will be analyzed using the same methods. 
Secondary endpoints include all individual components of the primary outcome (symptomatic UTI, 
cellulitis/wound infection, meatal stenosis, urethral stricture, urethrocutaneous fistula, dehiscence, and 
urethral diverticulum) and secondary outcomes (acute ADR or C. difficile colitis). 
 
 
20 Roberts C and Torgerson DJ. Baseline imbalance in randomized controlled trials. BMJ 1999; 319:185. 

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Ninety-five percent confidence intervals will be calculated for all estimated differences between groups. 
 
6.1.5 
Homogeneity and Exploratory Analyses 
 
Breslow-Day testing for homogeneity will be performed to determine consistency of results between 
study centers. Logistic regression may be used to test for a difference between groups adjusted for study 
center, surgeon, and various baseline characteristics and risk factors as described in Section 6.2.3. 
Kaplan-Meier estimates may be used to analyze time-to-complications. The frequency of specific 
organisms being isolated in urine and wound cultures from patients with symptomatic UTI and wound 
infections will be compared between treatment groups using Fisher’s exact test. 
 
6.2 
Power and Sample Size 
 
We made the following assumptions in calculating the desired sample size of 630 study subjects: 
(1) rate of the primary outcome in patients receiving prophylactic antibiotics: 10% 
(2) statistical power: 90% 
(3) absolute difference in primary outcome rate to be detected: 10% (NNTT 10) 
(4) dropout rate: 10% 
 
Symptomatic UTI occurs in 0-6% of patients receiving antibiotic prophylaxis following hypospadias 
repair,21,22 with a 2-5% incidence of urethrocutaneous fistula, 3-5% risk of meatal stenosis/stricture, and 
1-2% risk of dehiscence following distal/mid-shaft repairs.23 Urethral diverticulae seldom if ever occur 
after mid-distal hypospadias repair but are included in the primary outcome for the sake of thoroughness. 
The sum of the aforementioned complication rates is 6-18%, however, it is likely that some patients 
experience more than one complication. For purposes of our binary primary outcome (i.e., “any or no 
complications”), such patients will be counted only once. Therefore, calculation of sample size for this 
study will be based on an assumed 10% aggregate risk of complications. This assumption is also 
consistent with the overall 11% complication rate of primary hypospadias repairs reported by Kanaroglou 
et al., keeping in mind that some proximal repairs were also included in this series.24 
 
We desire a power of 90% to detect a 10% absolute difference in complication rate as statistically 
significant (NNTT 10). We consider 10% to be a reasonable threshold given that complications of 
hypospadias repair are almost unequivocally not life-threatening, and the outcome of medical or surgical 
intervention for these complications is generally positive. Presently available data are insufficient to 
quantify the full extent of potential costs related to antibiotic prophylaxis (treatment of multi-drug 
resistant infections, etc.). 
 
Utilizing these parameters, the necessary sample size is 286 patients per group 
(http://www.cct.cuhk.edu.hk/stat/proportion/Casagrande.htm). With allowance for a 10% dropout rate, a 
total of 630 study subjects is required. 
 
6.3 
Interim Analysis 
 
Unless prompted earlier by safety concerns or poor accrual, a formal interim analysis of primary 
outcomes will be conducted when 300 patients have completed 6 months of follow-up. Descriptive 
reports will be prepared on the data quality and occurrence of adverse events. For analysis, a group 
 
21 Kanaroglou et al., 2013. 
22 Ben Meir and Livne, 2004. 
23 Bayne AP and Jones EA, 2010. 
24 Kanaroglou et al., 2013. 

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sequential design will be used. Group sequential testing cut-offs are designed to maintain the overall type 
I error rate for the study. According to O’Brien-Fleming boundaries, in order to maintain an overall 
alpha/type I error rate of 0.05, an alpha of 0.0054 should be used for one interim analysis and an alpha of 
0.0492 for the final analysis.25 
 
Assuming a 10% complication rate in one group comprised of 150 patients at the time of interim analysis, 
with an alpha of 0.0054, a complication rate of ≥ 22% in the other group of 150 patients would be 
identified as statistically significant (p=0.0046) and warrant early termination of the study 
(http://www.vassarstats.net/propdiff_ind.html). If interim review reveals the baseline rate of 
complications to be substantially different than the 10% assumed for sample size calculations, 
consideration will be given to amending the requisite sample size in order to achieve the desired statistical 
power. Analysis of secondary outcomes will not factor into study termination, as the study medication is a 
widely utilized antimicrobial agent with a well-established safety profile.26 
 
If accrual of subjects has been less than anticipated prior to the interim analysis, the Steering Committee 
may consider making an a priori decision to close the study and proceed with the final analysis instead. 
An alpha of 0.05 would be used in this circumstance. 
 
6.4 
Data and Safety Monitoring Committee 
 
The Data and Safety Monitoring Committee (DSMC) will consist of a pediatric urologist from a non-
participating institution, a pediatric infectious disease specialist, an independent statistician, and the study 
statistician (non-voting member). The frequency of DSMC meetings will be self-determined but not less 
than annual. A letter summarizing DSMC activity and recommendations will be filed with the IRB at 
each participating institution after each meeting. Concerns should be reviewed with the Steering 
Committee. 
 
DSMC meetings will include a report from the Steering Committee regarding recruitment progress, 
completeness of participant follow-up, protocol deviations/violations, episodes requiring unblinding, and 
availability of resources for study continuation and completion. The DSMC will monitor study and data 
quality (e.g., confirmation of patient eligibility, accurate recording of study medication assignments, etc.), 
adverse events, and study outcomes. The DSMC may also evaluate the integrity of procedures relevant to 
randomization, blinding, and documentation of outcome measures. 
 
 
 
 
25 O’Brien PC and Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979; 35:549-556. 
26 May DB. Trimethoprim-sulfamethoxazole: an overview. In: UpToDate, Basow DS (ed); UpToDate, Waltham, MA; 2013. 

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7. 
Rationale for Study Design 
 
7.1 
Superiority vs. Non-inferiority Trial 
 
In Section 2.1 (Prior Research and Relevant Knowledge), we noted that prior studies have suggested that 
prophylactic antibiotics may reduce the risk of post-operative UTI and wound healing-related 
complications. However, this benefit was not identified by Kanaroglou et al. and has not been 
demonstrated by a placebo-controlled trial. Therefore, we elected to design this study as a well-powered 
superiority trial, specifically to answer the question of whether administration of prophylactic TMP-SMX 
reduces the aggregate risk of infectious and wound healing-related complications following mid-to-distal 
hypospadias repairs. 
 
The study has been designed with parameters by which antibiotics may be proven superior to placebo on 
interim or final analysis. Our goal is to recruit a sample size large enough to achieve sufficient (90%) 
power to detect a clinically meaningful difference in primary outcomes, so that if no such difference is 
found (i.e., the study is “negative”), it will be regarded as convincing evidence that antibiotics do not 
affect the outcomes of mid-to-distal hypospadias repairs relative to placebo. 
 
A non-inferiority trial design would generally be considered appropriate in circumstances where the 
outcome of a particular intervention (e.g., prophylactic TMP-SMX) has already been established as 
superior to placebo and is now being compared with a “new” intervention.27 The results of such a trial 
would be interpreted as demonstrating that the new treatment is superior, non-inferior, or inferior to the 
old treatment, with the possibility that the data may be inconclusive.28 This complexity is unnecessary for 
purposes of addressing the research question relevant to this study. 
 
7.2 
Utilization of Composite Primary Outcome 
 
The clinical question relevant to selection of outcome measures in this study was: “What complications 
might administration of prophylactic antibiotics be expected to prevent following hypospadias repair?” 
Broadly speaking, there are three possibilities: 
 
1) symptomatic UTI; 
2) cellulitis/wound infection; and 
3) infection-related impairment of wound healing (whether the infection was recognized or not), 
which may contribute to meatal stenosis, urethral stricture, urethrocutaneous fistula, dehiscence, 
and/or urethral diverticulum). 
 
While the first two possibilities may appear obvious, hypothesis-generating evidence of the third is found 
in the previously discussed data published by Ben Meir and Livne (see Section 2.1). Congruent with this 
hypothesis, a contemporary chapter on hypospadias complications includes bacterial infection 
(recognized or unrecognized) as a potential factor in wound healing-related complications.29 
 
It should be noted that each of these complications (UTI, wound infection, stenosis/stricture, fistula, 
dehiscence, and urethral diverticulum) is generally cause for substantial, though not life-threatening, 
clinical concern, requiring pharmacologic or elective surgical intervention. Because of this similarity, we 
 
27 Motulsky H. Testing for equivalence or noninferiority. In: Intuitive biostatistics: a nonmathematical guide to statistical 
thinking. 2nd ed. New York, NY: Oxford University Press; 2010. p. 150-155. 
28 Piaggio G, Elbourne DR, Altman DG et al. Reporting of noninferiority and equivalence randomized trials: an extension of the 
CONSORT statement. JAMA 2006;295:1152-1160. 
29 Bayne AP and Jones EA, 2010. 

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believe it is reasonable to utilize the composite rate as the primary measure of the impact that antibiotic 
prophylaxis has on the outcome of hypospadias repair. 
 
During the early post-operative period following hypospadias repair, the surgical site is usually 
characterized by substantial edema and erythema, making it difficult to diagnose cellulitis/wound 
infection with confidence. This provides additional rationale for intermediate-term assessment of wound 
healing-related complications to which wound infection may contribute. 
 
We recognize that numerous variables may contribute to the development of wound healing-related 
complications of hypospadias repair, including patient-specific factors, surgical technique, and post-
operative hygiene. By achieving randomized assignment to which patients and providers remain blinded, 
the influence of these confounding variables on the outcomes of interest should be mitigated. 
 
7.3 
Use of TMP-SMX as the Antibiotic Agent 
 
Anecdotally, TMP-SMX is the most commonly utilized antibiotic in the United States for prophylaxis 
following hypospadias repair. It is currently used by a majority of pediatric urologists at Lurie Children’s, 
and it is mentioned as the author’s preference for post-operative prophylaxis in the current chapter on 
hypospadias in Campbell-Walsh Urology.30 
 
At Lurie Children’s, 2012 bacterial susceptibility reports indicated the following percentages of urinary 
isolates to be sensitive to TMP-SMX: 
• gram-negative rods (GNR): Acinetobacter 100%, Citrobacter freundii 61%, C. koseri 100%, 
Enterobacter aerogenes 100%, E. cloacae 77%, Escherichia coli 61%, Klebsiella oxytoca 91%, K. 
pneumoniae 81%, Morganella morganii 86%, Proteus mirabilis 80%, Serratia marcescens 100% 
• gram-positive cocci (GPC): Staphylococus aureus 100%, S. epidermidis 69%, other Staph. spp. 81% 
 
Of note, the Lurie Children’s antibiogram indicates that urinary and non-urinary GPC are 26-40% more 
likely to be susceptible to TMP-SMX than to cefazolin. Susceptibility of urinary GNR to cefazolin is not 
reported, but sensitivity of non-urinary GNR to cefazolin is generally similar to lower. 
 
7.4 
Study Medication Dosing 
 
Dosing of antibiotic prophylaxis following hypospadias repair is variable among pediatric urologists, both 
within the group at Lurie Children’s and throughout the published literature. Several surgeons in the Lurie 
Children’s group use a therapeutic dose of TMP-SMX (i.e., 0.5 mL/kg, or 4 mg/kg TMP, BID). Another 
uses 0.5 mL/kg TMP-SMX once daily, while another uses a sub-therapeutic dose of cephalexin (10 mg/kg 
BID). 
 
In the study by Kanaroglou et al., which did not find a difference in outcomes between patients who did 
and did not receive antibiotic prophylaxis, TMP alone was administered at a sub-therapeutic dose of 2 
mg/kg once daily. By contrast, Ben Meir and Livne, who did identify a lower incidence of UTI in patients 
who received antibiotics, used cephalexin on a therapeutic dosing schedule (TID; the amount was not 
indicated). 
 
Because the primary aim of this study is to address the controversy of whether administration of 
antibiotics provides any benefit following hypospadias repair, a full therapeutic dose of TMP-SMX (i.e., 
4 mg/kg TMP BID) will be utilized. In the event that no difference in outcomes is seen between the study 
 
30 Snodgrass WT. Hypospadias. In: Wein AJ, Kavoussi LR et al., editors. Campbell-Walsh Urology. 10th ed. Philadelphia, PA: 
Saunders Elsevier; 2012. p. 3503-3536. 

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groups, we wish to avoid criticism that the antibiotic dose may have been insufficient. We recognize that 
cost and the risk of antibiotic side effects may be somewhat increased on account of this decision, and if 
antibiotics are found to have beneficial effects, subsequent research may be necessary to identify the 
optimal dose to balance risks and benefits. 
 
7.5 
Limitation of Inclusion to Distal/Mid-shaft Hypospadias Repairs 
 
The complication rates associated with repair of proximal hypospadias are substantially higher than for 
distal/mid-shaft hypospadias.31 To increase homogeneity and reduce the sample size required to achieve 
desired statistical power, patients with proximal hypospadias (as defined by subjective intra-operative 
assessment or length of urethral repair > 2.0 cm) will be excluded from the study. 
 
7.6 
Eligibility of Previously Circumcised Patients 
 
Patients who have had previous circumcision are eligible for the PROPHY Study. Recently published 
reports have consistently indicated low rates of post-operative complications (0-5%) in patients who 
undergo hypospadias repair following previous circumcision.32,33,34,35 The rarity of urethroplasty 
complications in these series likely reflects the fact that contemporary techniques of mid-to-distal 
hypospadias repair do not commonly rely on use of preputial tissue. 
 
7.7 
Exclusion of Cases with Foreskin Reconstruction 
 
Foreskin reconstruction (preputioplasty) is an alternative to circumcision with hypospadias repair. At 
present, it remains uncertain whether foreskin reconstruction increases the likelihood of urethroplasty 
complications, such as urethrocutaneous fistulae.36,37,38 There are no published data on the risk of 
infectious complications. However, the additive risk of foreskin dehiscence is 2.5-10%.39,40,41,42,43,44  
 
Based on these data, inclusion of cases with foreskin reconstruction would increase the heterogeneity of 
the study population with respect to the likelihood of dehiscence. A higher baseline risk of complications 
would also increase the sample size required to achieve desired statistical power. Because cases with 
foreskin reconstruction are relatively uncommon, their inclusion would also increase the risk of chance 
 
31 Marrocco G, Vallasciani S, Fiocca G et al. Hypospadias surgery: a 10-year review. Pediatr Surg Int 2004; 20:200-203. 
32 Snodgrass WT, Khavari R. Prior circumcision does not complicate repair of hypospadias with an intact prepuce. J Urol 2006; 
176:296-298. 
33 Pieretti RV, Pieretti A, Pieretti-Vanmarcke R. Circumcised hypospadias. Pediatr Surg Int 2009; 25:53-55. 
34 Rashed FK, Gholizade R. Comparison of distal hypospadias repair in circumcised patients and uncircumcised patients. ISRN 
Urol 2013; doi:10.1155/2013/957581. 
35 Chalmers D, Wiedel CA, Siparsky GL et al. Discovery of hypospadias during newborn circumcision should not preclude 
completion of the procedure. J Pediatr 2014; 164:1171-1174. 
36 Snodgrass W, Dajusta D, Villanueva C et al. Foreskin reconstruction does not increase urethroplasty or skin complications 
after distal TIP hypospadias repair. J Ped Urol 2013; 9:401-408. 
37 Suoub M, Dave S, El-Hout Y et al. Distal hypospadias repair with or without foreskin reconstruction: a single-surgeon 
experience. J Ped Urol 2008; 4:377-380. 
38 Fasching G, Arneitz C, Gritsch-Olipp G. Foreskin reconstruction and preservation of a thin distal urethra: a challenge in 
tubularized incised plate urethroplasty. Pediatr Surg Int 2011; 27:755-760. 
39 Ibid. 
40 Papouis G, Kaselas C, Skoumis K et al. Repair of distal hypospadias and preputioplasty in one operation: risks and advantages. 
Urol Int. 2009; 82:183-186. 
41 Suoub M et al., 2008. 
42 Leclair MD, Benyoucef N, Héloury Y. [Morbidity of foreskin reconstruction in distal hypospadias repair surgery] (French). 
Prog Urol 2008; 18:475-479. 
43 Snodgrass WT, Koyle MA, Baskin LS et al. Foreskin preservation in penile surgery. J Urol 2006; 176:711-714. 
44 Klijn AJ, Dik P, de Jong TP. Results of preputial reconstruction in 77 boys with distal hypospadias. J Urol 2001; 165:1255-
1257. 

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bias, while not contributing substantially to recruitment. Therefore, patients for whom foreskin 
reconstruction is performed will be excluded from the study. 
 
7.8 
Pre-operative Testosterone Use 
 
At the discretion of attending surgeons, testosterone (T) is sometimes administered as part of routine 
care prior to hypospadias repair, either topically or by IM injection. The goals of using T may include 
short-term penile growth, increased availability of tissue for reconstructive purposes, and improved tissue 
vascularity. For most pediatric urologists, use of T is less common prior to mid-to-distal hypospadias 
repairs than proximal repairs (which are excluded from this study). 
 
To date, the only prospective study of pre-operative androgen stimulation for hypospadias repairs was a 
randomized trial of dihydrotestosterone (DHT) transdermal gel, in which DHT reduced rates of 
dehiscence (0% vs. 8%) and reoperation (3% vs. 24%) in patients undergoing primary hypospadias repair, 
the majority of whom had a mid-distal hypospadias defect.45 This study was relatively small (n=75), 
lacked a placebo control, and did not provide stratification of complications by hypospadias severity. The 
results of this study have not been replicated. At Lurie Children’s, DHT is costly and impractical to obtain 
on a routine basis. 
 
No prospective studies have addressed the impact of pre-operative T on the outcomes of hypospadias 
repairs. In 2011, Gorduza et al. reported that T administered less than 3 months prior to surgery was 
associated with a trend toward an increased risk of wound healing-related complications in proximal 
hypospadias repairs.46 Snodgrass et al. also observed a trend toward increased risk of glans dehiscence in 
patients receiving pre-operative T.47 As retrospective analyses, both of these studies are vulnerable to 
selection bias. A recent systematic review and meta-analysis of pre-operative hormonal stimulation 
concluded that the effect “remains unclear.”48 
 
Given the lack of consistent or prospective evidence indicating that pre-operative androgen stimulation 
affects the outcome of hypospadias repairs, the decision to utilize T will be left to the discretion of each 
surgeon on a patient-by-patient basis for purposes of this study. For patients who do receive pre-operative 
T, assessment of glans and penile size before and after administration is encouraged. This will facilitate 
multivariable analysis and improve the quality of hypothesis-generating comparison of outcomes in 
patients who did and did not receive T. 
 
7.9 
Duration of Follow-up 
 
Considerations pertinent to the duration of follow-up include a desire to ensure adequate time for 
detection of the majority of primary and secondary outcomes, while minimizing attrition of study 
participants and costs. Several previous studies have contributed to an understanding of how long after 
hypospadias repair complications may present. 
 
On one end of the spectrum, Ziada et al. indicated that “the majority” of complications in their 
contemporary series of mid-to-distal hypospadias repairs were evident prior to 6 weeks post-
 
45 Kaya C, Bektic J, Radmayr C et al. The efficacy of dihydrotestosterone transdermal gel before primary hypospadias surgery: a 
prospective, controlled, randomized study. J Urol 2008; 179:684-688. 
46 Gorduza DB, Gay CL, de Mattos E Silva E et al. Does androgen stimulation prior to hypospadias surgery increase the rate of 
healing complications? - A preliminary report. J Ped Urol 2011; 7:158-161. 
47 Snodgrass W, Cost N, Nakonezny PA et al. Analysis of risk factors for glans dehiscence after tubularized incised plate 
hypospadias repair. J Urol 2011; 185:1845-1851. 
48 Wright I, Cole E, Farrokhyar F et al. Effect of preoperative hormonal stimulation on postoperative complication rates after 
proximal hypospadias repair: a systematic review. J Urol 2013; 190:652-660. 

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operatively.49 58% of urethrocutaneous fistulas presented less than 1 month after primary hypospadias 
repair in Wood et al.’s series.50 Aulagne et al. reported that all complications in their series of proximal 
hypospadias repairs occurred within 6 months post-operatively.51 
 
However, Wood et al.,52 Powell et al.,53 Nuininga et al.,54 and Spinoit et al.55 reported that many 
complications presented more than 1 year post-operatively. Importantly, in this group of studies, it is 
unclear whether patients adhered to prescribed follow-up intervals, and late-presenting complications may 
have been evident and detected earlier if follow-up had been more rigorous. Unpublished data from Lurie 
Children’s support this hypothesis. 
 
Weighing these and other practical considerations, we elected to standardize scheduling of two physician 
clinic visits at 1 and 6 months post-operatively. Standardization is intended to prevent follow-up bias. 
Five years post-operatively, a chart review and survey will be conducted to assess whether late-presenting 
complications have occurred. In the studies cited above, at least 90% of complications have consistently 
presented by 5 years post-operatively. 
 
 
 
 
49 Ziada A, Hamza A, Abdel-Rassoul M et al. Outcomes of hypospadias repair in older children: a prospective study. J Urol 
2011; 185:2483-2486. 
50 Wood HM, Kay R, Angermeier KW et al. Timing of the presentation of urethrocutaneous fistulas after hypospadias repair in 
pediatric patients J Urol 2008; 180:1753-1756. 
51 Aulagne MB, Harper L, de Napoli-Cocci S et al. Long-term outcome of severe hypospadias. J Ped Urol 2010; 6:469-472. 
52 Wood et al., 2008. 
53 Powell CR, McAleer I, Alagiri M et al. Comparison of flaps versus grafts in proximal hypospadias surgery. J Urol 2000; 
163:1286-1289. 
54 Nuininga JE, DeGier RP, Verschuren R et al. Long-term outcome of different types of 1-stage hypospadias repair. J Urol 2005; 
174:1544-1548. 
55 Spinoit AF, Poelaert F, Groen LA et al. Hypospadias repair at a tertiary care center: long-term followup is mandatory to 
determine the real complication rate. J Urol 2013; 189:2276-2281. 

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8. 
Informed Consent, Ethical Review, and Regulations 
 
8.1 
Informed Consent 
 
Study investigators and study personnel are responsible for ensuring that all parent(s)/LAR of eligible 
patients understand the nature, risks, and benefits of study participation in plain language. Center-specific 
IRB-approved protocols regarding informed consent should be followed. Consent documentation should 
indicate that data collected during the PROPHY Study may also be used in future post hoc analyses and 
other research studies related to hypospadias. 
 
8.2 
Ethical Review 
The principal investigator at each study center will obtain IRB approval of the protocol and center-
specific supporting documents (e.g., the informed consent form) before initiating patient recruitment. 
  
8.3 
Compliance with Regulations 
 
Every effort will be made to conduct this study in accordance with the protocol and ethical principles 
stated in the 2000 version of the Declaration of Helsinki, as well as all applicable federal, state, and local 
laws, rules, and regulations. 
 
For participation of Canadian centers, a Clinical Trial Application (CTA) to Health Canada will be 
completed. No Objection Letters will be obtained from Health Canada and included with packages of 
medications shipped to Canada. 
 
8.4 
Protocol Amendments 
Protocol amendments must be approved by the Principal Investigators and relevant IRB(s) prior to 
implementation. 
 
8.5 
Protocol Deviations and Violations 
 
A protocol deviation is defined by the Lurie Children’s IRB as “any aberration, whether accidental, 
unintentional or intentional, from the IRB-approved protocol/research plan.” Major protocol deviations 
(i.e., violations) “are those that cause harm to subjects or others, place them at increased risk of harm, 
impact the scientific integrity of the research, or compromise the human subject protection program.” 
Study coordinators and PIs are responsible for following local IRB requirements on reporting protocol 
deviations and violations, as well as reporting protocol violations to the primary study center (Lurie 
Children’s) within 10 days of their recognition. 
 
8.6 
Trial Postponement and Early Termination 
 
The Steering Committee may elect to postpone or terminate the study early due to inadequate funding, 
poor accrual, or other concerns. Follow-up of previously enrolled participants should continue, if feasible. 
Trial postponement will be reported to the IRBs of all participating institutions, and resolution of 
outstanding issues (e.g., acquisition of additional funding) will be attempted. If this effort is successful, 
the trial will be resumed; if not, the trial will be concluded and results to date reported, if possible. The 
IRBs of all participating institutions will be advised of study completion or early termination. 
 
8.7 
Study Documentation 

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All documentation pertaining to the conduct of this study should be retained by the investigators. All 
eCRFs will be stored as original source documents. Any paper copies (consents, forms) should be 
managed in accordance with local IRB requirements. If requested, the principal investigators will provide 
regulatory agencies and IRBs with direct access to original source documents. 
 
8.8 
Clinical Trial Registration 
 
The study is registered with ClinicalTrials.gov (Identifier NCT02096159). 
 
 
 

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9. 
Organization 
 
9.1 
Steering Committee and Protocol Development 
 
The following individuals are members of the PROPHY Study Steering Committee and have contributed 
to and/or reviewed the protocol: 
 
• 
Mark Faasse, MD MPH (Lurie Children’s) 
• 
Earl Cheng, MD (Lurie Children’s) 
• 
Dennis Liu, MD (Lurie Children’s) 
• 
Walid Farhat, MD (SickKids) 
 
The Steering Committee will oversee all aspects of study design, execution, and publication. 
 
9.2 
Publication of Study Results 
 
All efforts will be made to ensure that the results arising from the trial are published in established peer-
reviewed journals. The trial protocol may also be published. Initial results will be analyzed and published 
when all participants have completed 6-month follow-up, with a subsequent publication of intermediate-
term results after completion of 5-year follow-up. 
 
CONSORT 2010 guidelines will be followed in manuscript preparation. Analysis of covariates, long-term 
follow-up data, and other considerations pertinent to the utility of prophylactic antibiotics following 
hypospadias repair may warrant additional publications. 
 
Study data will only be presented and published in aggregate, without stratification or comparison of 
outcomes by study center. No characteristics that may correspond to the identity of participating surgeons 
will be reported. 
 
9.3 
Publications Committee 
 
The Steering Committee will establish a Publications Committee consisting of at least one representative 
from each participating study center. The Committee will identify topics for publication and make writing 
group assignments for each. Investigators from participating study centers may submit ideas for 
consideration by the Committee. 
 
All proposed abstracts and manuscripts that utilize study data must be reviewed and approved by the 
Committee. Committee members should make every effort to ensure that assignment of responsibilities 
for preparation of abstracts and manuscripts is equitable among participating study centers and 
commensurate with the investment and contributions each has made to the study. 
 
9.4 
Timetable 
 
The sample size necessary to achieve desired power will be 630 patients. Assuming recruitment of 30-
50% of eligible patients (50-75 patients per year at Lurie Children’s and 100-150 patients per year at 
SickKids), the initially estimated timetable for all participants to be enrolled and complete 6 months of 
follow-up was 4-5 years. Final follow-up will be completed 5 years after study recruitment is complete. 
 
9.5 
Financial Support 
 

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The Children’s Hospital of Chicago (CHOC) Faculty Practice Plan has provided an annually renewable 
Faculty Development Grant for this clinical trial. Pursuit of additional avenues of funding support will be 
ongoing. 
 
9.6 
Participant Costs and Compensation 
 
Study medication will be provided free of charge, and there will be no research costs to study participants. 
Compensation/reimbursement may be provided with local IRB approval. The patient-physician 
encounters relevant to this study are part of routine care for patients who undergo hypospadias repair, 
therefore, financial payment for these services remains the responsibility of the patients’ insurance or 
parent(s)/LAR. 
 
 
 

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10. 
Appendices 
 
A. TMP-SMX package insert 
B. Educational brochure  
C. REDCap data instruments/eCRFs 
D. Skeletonized Intra-operative Data Instrument (“Cheat Sheet” & Eligibility Criteria)  
E. Assessment schedule