Clinical trial NCT02162810
Conditions: Hypospadias
Keywords: hypospadias
Sponsor: Francis Schneck
Start date: 2014-05-01; Completion date: 2022-05-01
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
The primary objective of this study is to determine the efficacy of administering a course of postoperative oral steroids in pediatric patients undergoing proximal hypospadias repair as prevention against complications. Specifically, the study aims to assess if the steroids i) decrease the incidence of wound breakdown, fistula formation, stenosis or stricture formation, and the need for subsequent redo-hypospadias surgeries and/or fistula repairs and ii) improve the quality of wound healing including the overall cosmetic appearance of the phallus (i.e. location of the urethral meatus).

Detailed description:
Hypospadias repair is a surgery that is, unfortunately, fraught with a high complication rate with problems that include urethrocutaneous fistula formation, complete wound breakdown, glans dehiscence, urethral diverticulum formation, retraction of the urethral meatus, urethral stricture, and meatal stenosis . Failure of a proximal hypospadias repair (i.e. the development of a post-operative complication) is unpredictable, and few modifiable risk factors having been identified. Complications necessitate subsequent surgical intervention for pediatric patients, which must be carried out under general anesthesia. Evidence regarding the harms of multiple general anesthetics for children is increasing. Additionally, with each surgical revision comes the morbidity associated with another post-surgical convalescence. Thus, any measure that can be gained as a way to increase the rate of success of proximal hypospadias repair would be of help to all pediatric urologists and patients with hypospadias. The proposed intervention of administering a 5 day course of placebo versus oral steroids at a dose equivalent to what is given for outpatient treatment of asthma exacerbations, is expected to have very low risk. This would be the only variation from the current practice and one that has never been studied in the past. Thus, it would be worthwhile to perform use scientific methods to determine if the administration of a short course of oral steroids is of benefit to healing and minimization of post-operative complications for hypospadias patients.

Arms: arm 1: Systemic high-dose steroids (30 mg/kg methylprednisolone) have been shown in a randomized, double-blind, placebo-controlled trial in humans not to negatively impact wound infection or dehiscence rates, instead benefitting patients in the postoperative period in ways such as decreasing pain. An acute course of oral systemic steroids has been routinely used in patients under the age of 12 with asthma exacerbations (liquid prednisolone at 1-2 mg/kg/day in 1-2 divided doses for up to 10 days, although usually given for 5 days, which is at least 19 times less than the dose proven to be safe in the randomized controlled trial mentioned above) and proven to be safe without adverse effects. Effect of prednisolone on the systemic response and wound healing after colonic surgery. arm 2: Simple Syrup will be used as the placebo
Interventions: intervention 1: Prednisolone intervention 2: placebo-controlled
Intervention descriptions: intervention 1: In order to analyze the data, we will establish a chart which will show the degree of cosmetic appearance, incidences and degree of complications. This we be assessed on a mild to severe scale. intervention 2: In order to analyze the data, we will establish a chart which will show the degree of cosmetic appearance, incidences and degree of complications. This we be assessed on a mild to severe scale.

Protocol documents:
Prot_SAP_000.pdf: 
June 6, 2019 
 
 
NCT02162810  
 
Study Title:  Effect of Steroids on Post-Operative Complications Following Proximal Hypospadias 
Repair 
 
Study Objective: 
The primary objective of this study is to determine the efficacy of administering a short course 
of postoperative oral steroids in pediatric patients undergoing proximal hypospadias repair as 
prevention against complications. Specifically, the study aims to assess if the use of steroids i) 
decreases the incidence of fistula formation, glans dehiscence, wound breakdown, meatal 
stenosis, urethral stricture formation, or diverticula formation, and the need for subsequent 
redo-hypospadias surgeries and/or fistula repairs and ii) improves the quality of wound healing 
including the overall cosmetic appearance of the phallus (i.e. the location of the urethral 
meatus). 
Study Design:   
This is an experimental study that will be prospective, randomized, placebo-controlled, and 
double-blind. There will be no cross-over arm. 
 
Primary and secondary study endpoints:   
The study aims to assess if the steroids i) decrease the incidence of glans dehiscence, wound 
breakdown, fistula formation, meatal stenosis, urethral stricture formation, urethral 
diverticulum formation, meatal regression, and the need for subsequent redo-hypospadias 
surgeries and/or fistula repairs and ii) improve the quality of wound healing including the 
overall cosmetic appearance of the phallus (i.e. location of the urethral meatus) 
The catheter removal visit (7-10 days after surgery) & the initial follow up visit (6-12 weeks after 
surgery) as well as data from 1 year postoperatively, after toilet training, and after puberty. We 
plan to analyze and present preliminary data when we have data on a significant cohort from 
the first 2-3 timepoints as it will be many years until we have the post-puberty followups since 
we operate on these subjects, on average, under age 2 or so. 
Inclusion criteria: 
All male patients’ ages ranging from 3 months to 16 years seen at Department of Urology and 
diagnosed with hypospadias will be included in this study. 
 


Exclusion criteria: 
Patients taking steroids at the time of surgery or within six weeks of surgery 
Patients with a history of steroid hypersensitivity reactions 
Patients who are immunocompromised or taking immunomodulatory medications 
Patients with fungal infections 
Females 
 
Selection will be based on parent willingness to allow the child to participate in the study. 
Enrollment goal:   300 
Recruitment methods: 
The clinician will discuss the project during the routine clinical exam and provide an age 
appropriate explanation with the patient and the patient's parents. If the patient's parents and 
patient express interest in study participation, the clinician will provide the parents and patient 
with the IRB approved informed consent document during the subject's routine clinical exam. 
During the initial visit in the Urology Outpatient Clinic, the clinical diagnosis of hypospadias will 
be made by a physician, nurse practitioner, or a physician assistant. An initial documentation of 
the degree of hypospadias will be made. The patients will be scheduled to undergo surgery to 
repair the hypospadias when it is clinically indicated, and surgery will typically take place when 
the child is between 6 and 12 months of age. The age range for this study will be 3 months to 16 
years to allow for collection of data during follow up visits until the subjects reach puberty. 
Ideally, the surgeon or a co-investigator will review the study with the parent of the patient 
during the child's diagnostic-surgical listing visit and, if participation is desired, the surgeon will 
obtain written informed consent. If the consent is not obtained at the diagnostic-surgical listing 
visit, a co-investigator will contact the parent by telephone 1-2 weeks prior to listed surgery to 
explain the study and inquire if there is interest in participation; if so, the consent form will be 
mailed or faxed to the parent for review. The purpose of this pre-surgery phone call is to 
eliminate any coercion that might play a role if the study were to be introduced to the parent on 
the day of the surgery alone and to give the parent time to consider the study before agreeing 
to participate. These patients will be identified at the existing weekly Division of Pediatric 
Urology Pre-Operative conference at which the surgeons/co-investigators meet to review the 
upcoming listed cases. A co-investigator will then meet with the interested parent on the day of 
the surgery to answer any questions as well as to review the study and consent form. If the 
parent wishes to enroll their child in the study at this point, the surgeon will obtain written and 
verbal consent for participation. The decision about whether or not to participate in the study 
will not change the type or the quality of the surgery that is performed. 
 
 


Purpose, specific aims or objectives, and hypotheses to be tested: 
 
The primary objective of this study is to determine the efficacy of administering a course of 
postoperative oral steroids as a preventative measure against complications/a means of 
enhancing repair in patients undergoing surgery for proximal hypospadias. 
 
It is our hypothesis that a short course of postoperative steroids will facilitate healing of 
hypospadias to the degree that it will minimize the risk of wound complications. This hypothesis 
is based on the known scientific effects of corticosteroids on healing as well as the experience 
of the senior investigator. It is only through completion of a prospective, double-blinded, 
randomized, placebo-controlled study that we will be able to clearly and convincingly 
demonstrate that the risks of wound complications is significantly lowered with steroids to 
justify their routine use in this patient population. 
 
Relevant prior experience and gaps in current knowledge.  Scientific or scholarly background 
for, rationale for, and significance of the research based on existing literature and how it will 
add to existing knowledge: 
 
Proximal hypospadias repair is a surgery for males who are born with an abnormally located 
urethral meatus that can be on the proximal third of the shaft of the penis, at the penoscrotal 
junction, in the scrotum, or on the perineum. With this procedure, a urethra is constructed and 
pathologic penile curvature is corrected in order to relocate the meatal opening to the glans 
penis. The goals of hypospadias surgery are to allow for normal function of the penis, which 
includes the ability to void a straight, non-obstructed urinary stream without spray or dribbling, 
to have a straight erection, and to propel ejaculate, with a normal penile appearance. 
Unfortunately, proximal hypospadias repair has a relatively high postoperative complication 
rate (reports range from 12-60% with a sum 207/677 [31%] from: Aoki, 2008; Bush, 2013; 
Braga, 2007; Chuang, 1995; Ghanem, 2011; Gopal, 2008; Hayashi, 2007; de Mattos e Silva, 
2009; Powell, 2000; Shukla, 2004; Snodgrass, 2011). The known complications include fistula 
formation, glans dehiscence, wound breakdown, meatal stenosis, urethral stricture formation, 
diverticula formation, and meatal retraction with a poor cosmetic result, and all of these 
require surgical treatment under general anesthesia. 
 
As a result, past efforts have been made to determine risk factors for known complications, 
which has led to the identification of the meatal location as the most significant risk factor for 
development of a postoperative complication in primary hypospadias repair.(Bush, 2013) 
Regrettably, this factor is inherent to the degree of the disease that the child presents with at 
the time of diagnosis and thus, is not modifiable. Potentially modifiable factors such as type of 
suture material, suturing technique, surgeon, and use of a urethral stent have not been found 
to be associated with post-operative complications. Because the high risk for postoperative 
complications has persisted over the past decades, efforts are needed to identify novel ways in 
which the high complication rate and associated morbidity can be reduced. 
 


Surgeons have been greatly interested in the effects of corticosteroids on wound healing for 
years as steroids have been shown to affect all major steps of the wound healing process, 
which is divided into 3 overlapping phases known as inflammatory, proliferative, and 
remodeling. In fact, it is due to a presumed attenuation of the inflammatory phase that steroids 
have been shown to improve the rate of healing.(Bosanquet, 2013) Nonetheless, there have 
been no published studies on how steroids would influence healing as related to hypospadias 
repair and, in turn, the associated complication rate. It is reasonable to assume that there may 
be some benefit from the use of corticosteroids as they are known to decrease the expression 
of cytokines in wounded tissue including TGF-b1, platelet-derived growth factor, tumor necrosis 
factor, and interleukin-1a. This action decreases the chemotactic and mitogenic stimulus for 
other inflammatory cells and the infiltration of polymorphonuclear leukocytes. Additionally, 
corticosteroids reduce mesenchymal cell expression of keratinocyte growth factor, which alters 
fibroblast proliferation such that application of a steroid to a wound will delay re-
epithelialization,(Wang, 2013; Namkoong, 2013) and the resultant decreased type I procollagen 
synthesis will cause wounds to heal with reduced contraction,(Franz, 2007; Bosanquet, 2013) a 
desired outcome in hypospadias repair in particular given the need for tubular healing free of 
narrowings that can generate turbulence or wall pressure changes. While wound tensile 
strength has been shown to decrease in animal studies when cortisone is chronically 
administered at a dose of 15-40 mg/kg/day,(Wang, 2013) systemic high-dose steroids (30 
mg/kg methylprednisolone, which is 5-13 times greater strength than the doses used in the 
animal studies) have been shown in a randomized, double-blind, placebo-controlled trial in 
humans not to negatively impact wound infection or dehiscence rates, more clinically relevant 
measures, instead benefitting patients in the postoperative period in ways such as decreasing 
pain.(Schulze, 1997) Additionally, a Cochrane review of 54 randomized studies of adult cardiac 
surgery patients found that prophylactic corticosteroids did not increase postoperative 
infection or impair wound healing.(Dieleman, 2011) Of note is that the beneficial findings were 
associated with acute as opposed to chronic steroid use. 
 
While the long-term use of oral corticosteroids is associated with a variety of negative side 
effects, the pediatric asthma population is one that has demonstrated how adverse effects of 
oral corticosteroids “are rarely if ever associated with short courses of steroids.”(Weinberger, 
1982) Because an acute course of oral systemic steroids has been so routinely used in patients 
under the age of 12 with asthma exacerbations (liquid prednisolone at 1-2 mg/kg/day in 1-2 
divided doses for up to 10 days, although usually given for 5 days, which is at least 19 times less 
than the dose proven to be safe in the randomized controlled trial mentioned above) and 
proven to be safe, we believe that the above sum findings and the clinical observations of our 
senior investigator support a randomized placebo-controlled trial to evaluate whether a 5-day 
post-operative course of oral prednisolone at a dose of 1.5 mg/kg/day divided into two doses 
leads to improved outcomes in patients who have undergone surgical repair of hypospadias. 
 
 


Detailed description of all research activities (including screening and follow-up procedures) 
that will be performed for the purpose of this research study:  
Screening procedures will consist of a medical history and physical examination pre- and post-
operatively that are the same as the standard exams and medical/surgical workup that any 
patient would receive whether or not enrolled in the study. 
 
During the initial visit in the Urology Outpatient Clinic, the clinical diagnosis of hypospadias will 
be made by a physician, nurse practitioner, or a physician assistant. An initial documentation of 
the degree of hypospadias will be made. The patients will be scheduled to undergo surgery to 
repair the hypospadias when it is clinically indicated, and surgery will typically take place when 
the child is between 6 and 12 months of age. The age range for this study will be 3 months to 
16 years to allow for collection of data during follow up visits until the subjects reach puberty. 
Ideally, the surgeon or a co-investigator will review the study with the parent of the patient 
during the child's diagnostic-surgical listing visit and, if participation is desired, the surgeon will 
obtain written informed consent. If the consent is not obtained at the diagnostic-surgical listing 
visit, a co-investigator will contact the parent by telephone 1-2 weeks prior to listed surgery to 
explain the study and inquire if there is interest in participation; if so, the consent form will be 
mailed or faxed to the parent for review. The purpose of this pre-surgery phone call is to 
eliminate any coercion that might play a role if the study were to be introduced to the parent 
on the day of the surgery alone and to give the parent time to consider the study before 
agreeing to participate. These patients will be identified at the existing weekly Division of 
Pediatric Urology Pre-Operative conference at which the surgeons/co-investigators meet to 
review the upcoming listed cases. A co-investigator will then meet with the interested parent 
on the day of the surgery to answer any questions as well as to review the study and consent 
form. If the parent wishes to enroll their child in the study at this point, the surgeon will obtain 
written and verbal consent for participation. The decision about whether or not to participate 
in the study will not change the type or the quality of the surgery that is performed. 
 
During the initial visit in the Urology Outpatient Clinic, the clinical diagnosis of hypospadias will 
be made by a physician, nurse practitioner, or a physician assistant. An initial documentation of 
the degree of hypospadias will be made. The patients will be scheduled to undergo surgery to 
repair the hypospadias when it is clinically indicated, and surgery will typically take place when 
the child is between 6 and 12 months of age. The sample size for this study will be ages 3 
months of age to 16 years of age to allow for collection of data during follow up visits until the 
subjects reach puberty. Surgical consent will be obtained by the surgeon during the Childs 
normal clinical visit. Likewise, the surgeon, or a co-investigator, will review the study with the 
parent during the child’s clinic appointment and, if participation is desired after all questions 
have been addressed, the study consent will be obtained. The research pharmacist at Children’s 
Hospital of Pittsburgh of UPMC , Michelle J. Ung, PharmD, will be notified for preparation of the 
randomization of the steroid or placebo, aided by statisticians in the Clinical and Translational 
Science Institute at the University of Pittsburgh, and preparation of the 5-day prednisolone or 
placebo, which for this study the placebo will be a simple sugar syrup for this study, to be 
administered. 


 
The type of hypospadias repair will be determined by the surgeon in the operating room at the 
time of the surgery based on the clinical scenario. Children will be excluded if they are found 
upon the exam under anesthesia in the operating room at the time of surgery not to have 
proximal hypospadias. The final severity of the hypospadias will be documented by the surgeon 
based on an examination performed in the operating room under anesthesia just prior to 
initiation of the surgical repair. The need for short-term postoperative stenting will be decided 
at the time of the procedure. After the procedure, the pharmacy will deliver the medication, 
prednisolone versus placebo which will be blinded from the parents as well as the surgeon, to 
the OR and the surgeon will bring the medication to the families after surgery. At that time the 
parents are instructed on how to administer the steroid or placebo, twice daily for 5 days. This 
constitutes the focus of the study and is the only variation from standard treatment. Parents 
will be instructed to call for any suspected adverse reaction to the medication versus placebo 
and for any findings consistent with glans dehiscence, wound breakdown, fistula formation, 
diverticulum formation, meatal stenosis, or urethral stricture. 
 
All patients will be seen by the surgeon in postoperative follow up in the Urology Outpatient 
Clinic 7-12 days after the surgery following completion of the 5-day course of prednisolone 
versus placebo. Stents will be removed at this time as is standard practice. The next follow up 
will be at 4 to 12 weeks postoperatively as is standard practice. At a minimum, participants will 
be asked to follow up again at 6-months postoperative, and after toilet training, and possibly 
one year after puberty up until 16 years of age, which does not deviate from standard practices. 
Each postoperative visit will include evaluation for glans dehiscence, wound breakdown, fistula 
formation, diverticulum formation, the presence of meatal stenosis, the presence of a urethral 
stricture, and the location of the urethral meatus/cosmetic appearance of the phallus in 
addition to the quality and progression of wound healing and the quality of the urinary stream. 
Any phone calls, emergency room, or office visits that take place outside of the scheduled 
follow-up visits will be tracked so that a phone or office interview can be arranged to make 
similar assessments if they are not made at the time of those encounters. Any return to the 
operating room for redo-hypospadias surgery as well as the intraoperative physical exam and 
findings will be noted. Any adverse events associated with the medication or placebo will be 
noted and classified in terms of severity, expectedness, and association with the medication or 
placebo. 
 
Data will be stored in RedCap, a secure server with de-identified patient information that can 
be accessed only by investigators on the study using their individualized usernames and 
passwords. Data analysis will be made on at least an annual basis to allow for early termination 
of the study in the case that one arm is unequivocally superior or inferior. 
 
 
 
 


Power analysis used and method of statistical analysis: 
We will need to enroll 64 patients in the study to reject a false null hypothesis if we assume that 
the complication rate for proximal hypospadias surgery is 30% and that the administration of 
prednisolone for five-days postoperatively at a dose of 1.5 mg/kg/day divided into two doses 
will decrease that rate to 5%.  We will need to enroll 196 patients in the study to reject a false 
null hypothesis if we assume that the complication rate for proximal hypospadias surgery is 25% 
and that the administration of prednisolone for five-days postoperatively at a dose of 1.5 
mg/kg/day divided into two doses will decrease that rate to 10%.  For this reason, we would like 
to accrue roughly 200 patients in the study, however, we will run statistical analyses at least 
yearly so that the study can be concluded early if indicated. 
 
Patients will be randomized by the research pharmacist with help from the statisticians at the 
Clinical and Translational Science Institute (CTSI) here at the University of Pittsburgh. The 
research pharmacist at Children’s Hospital of Pittsburgh will blind the researchers/surgeons to 
the identity of the oral solution (steroid versus placebo) being administered. The placebo group 
will serve as the study control to determine the change in complication rate achieved through 
the use of steroids.  
 
Statistical Analysis Plan: 
Demographic measures (median gestation, weight, follow-up in months, incidence of NICU stay, 
and incidence of comorbidities) will be compared between the steroid and placebo arms using 
appropriate statistical approach, i.e., t-tests, Fisher’s Exact test, or Wilcoxon Rank-sum test.  
We were unable to meet our enrollment goal sufficient to test our hypothesis for each 
complication (meatal retraction, meatal stenosis, glans dehiscence, skin breakdown along 
suture lines, urethra breakdown proximal to glans, urethrocutaneous fistula, suspected 
stricture, and suspected urethral diverticulum), therefore the incidence of complication overall 
between the steroid and placebo groups will be analyzed using Fisher’s Exact Test.     
Likewise, Fisher’s Exact Test will be used to test the quality of wound healing, including the 
location of the urethral meatus (subcoronal, distal shaft, proximal shaft, penoscrotal, scrotal 
perineal, and other), and the improvement of chordee (resolved/ improved/ described but not 
documented/ no improvement/ not described) in each category (degloving, ventral, and 
plication).