Conditions: Urethral Stricture
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 5
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the efficacy of clostridium histolyticum collagenase (XIAFLEX®) in treating urethral strictures.

Detailed description:
This is an open-label, pilot study to explore the efficacy of clostridium histolyticum collagenase (XIAFLEX®) in treating urethral strictures. Subjects will be followed for 2 years from the initial drug treatment.

Arms:
arm 1: Patients will undergo instillation of local anesthesia (20 mL of 2% urethral lidocaine jelly), the patient will undergo cystoscopy, transurethral injection (via a 70 cm 4.8 Fr flexible cystoscopic needle with a 23 gauge needle tip manufactured by Laborie®, Ontario, Canada) of 0.08ml of XIAFLEX® (0.58 mg of XIAFLEX® mixed with 0.39 mL of sterile diluent) in a single location within the stricture, chased by an additional 0.25 mL of reconstituted XIAFLEX® to allow for clearance of the original 0.08 mL of reconstituted XIAFLEX® from the transurethral syringe into the urethral stricture.

Interventions: intervention 1: Clostridium Histolyticum Collagenase intervention 2: Saline
Intervention descriptions: intervention 1: 0.08ml of XIAFLEX® (0.58 mg of XIAFLEX® mixed with 0.39 mL of sterile diluent) in a single location within the stricture, chased by an additional 0.25 mL of reconstituted XIAFLEX® to allow for clearance of the original 0.08 mL of reconstituted XIAFLEX® from the transurethral syringe into the urethral stricture. This is based on 0.25 mL residual fluid that remains within the lumen of the injeTAK syringe. Thus, by adding the additional 0.25 mL of XIAFLEX® as a chase, we are expecting the original total of 0.08 mL of XIAFLEX® to be injected into the area of scarring. intervention 2: 0.08ml of injectable normal saline

Protocol document:
Prot_SAP_000.pdf: 
Protocol: CHC v6.0 01/25/2021 
1 
Clostridium histolyticum collagenase injection treatment for urethral disease: a 
prospective, single-center, open-label study 
Principal Investigator: 
Name 
Lucas Wiegand, MD 
University of South Florida 
Address 
2 Tampa General Circle, 4th Floor 
Tampa, FL 33606 
Telephone 
813-250-2799
Email 
lwiegand@usf.edu
Sub-Investigator: 
Name 
Kevin Heinsimer, MD 
Email 
kheinsimer@usf.edu 
Study Site: 
Name 
USF Health South Tampa Center for Advanced 
Healthcare 
Address 
2 Tampa General Circle 
Tampa, FL 33606 
NCT02948842


Protocol: CHC v6.0 01/25/2021 
 
2 
TABLE OF CONTENTS 
1.0 SYNOPSIS ............................................................................................................................................. 4 
2.0 BACKGROUND ................................................................................................................................... 8 
2.1 Urethral Stricture Disease ............................................................................................................. 8 
2.1.1 Treatment of Urethral Stricture ............................................................................................... 8 
2.2 Clostridium Histolyticum Collagenase ......................................................................................... 8 
2.2.1 Animal Studies: Toxicity Data ................................................................................................ 8 
3.0 STUDY OBJECTIVES ......................................................................................................................... 9 
4.0 STUDY POPULATION ..................................................................................................................... 10 
4.1 Inclusion Criteria ......................................................................................................................... 10 
4.2 Exclusion Criteria ......................................................................................................................... 10 
5.0 STUDY DRUG AND DEVICE .......................................................................................................... 11 
5.1 Study Agent ................................................................................................................................... 11 
5.2 Dose Rationale .............................................................................................................................. 11 
5.3 Risks/Benefits ................................................................................................................................ 12 
5.4 Dosage and Administration ......................................................................................................... 12 
5.5 Formulation .................................................................................................................................. 13 
5.6 Packaging and Labeling ............................................................................................................... 13 
5.7 Storage and Handling................................................................................................................... 13 
5.8 Drug Accountability ..................................................................................................................... 13 
5.9 Concomitant and Prohibited Medications ................................................................................. 14 
5.10 Injection Device .......................................................................................................................... 14 
6.0 METHODS .......................................................................................................................................... 14 
6.1 Subject Identification ................................................................................................................... 14 
6.2 Limited Waiver of Consent .......................................................................................................... 14 
6.3 Consent Process ............................................................................................................................ 15 
6.4 Duration of Study Participation .................................................................................................. 15 
6.5 Study Visits ................................................................................................................................... 15 
6.5.1 Baseline/Screening ................................................................................................................ 16 
6.5.2 Treatment 1 (Day 0) . ............................................................................................................ 16 
6.5.3 Post-treatment (Days 2 or 3) ................................................................................................. 17 
6.5.4 Post-treatment (Days 14, 28, 42, 56, 70, 84 ± 3 days) .......................................................... 17 
6.5.5 Follow-up (6, 9, 12, 18 and 24 months (± 7 days)) ............................................................... 18 
6.5.6 Unscheduled Visits ............................................................................................................... 18 
6.5.7 Early Termination ................................................................................................................. 18 
6.6 Sample Size Justification ............................................................................................................. 19 
6.7 Statistical Analysis Plan ............................................................................................................... 19 
7.0 BENEFITS ........................................................................................................................................... 20 
8.0 RISKS .................................................................................................................................................. 20 
9.0 SAFETY MONITORING .................................................................................................................. 22 
9.1 Adverse Events ............................................................................................................................. 23 
9.2 Serious Adverse Events ................................................................................................................ 23 
9.3 Unanticipated Adverse Events .................................................................................................... 24 
9.4 Study Stopping Criteria ............................................................................................................... 24 
10.0 DATA HANDLING AND MONITORING .................................................................................... 25 
11.0 CONFLICTS OF INTEREST .......................................................................................................... 25 
12.0 REFERENCES .................................................................................................................................. 25 
13.0 SCHEDULE OF ASSESSMENTS .................................................................................................. 27 
 
 


Protocol: CHC v6.0 01/25/2021 
 
3 
Abbreviations and Acronyms: 
 
DVIU – Direct vision internal urethrotomy 
CHC – Clostridium histolyticum collagenase 
AUA – American Urological Association 
RUG – Retrograde urethrogram 
VCUG – Voiding cystourethrogram 
PVR – Post-void residual  
ET – Early termination 
 
DSMB – Data safety monitoring board 
 
AE – Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol: CHC v6.0 01/25/2021 
 
4 
1.0 Synopsis 
 
Title 
Clostridium histolyticum collagenase injection treatment for urethral 
disease: a prospective pilot, single-center, open-label study 
 
Protocol Number CHC 
Phase 
II 
Study Design 
Pilot, open label drug study 
Study Center(s) 
Single-center (University of South Florida, Tampa, FL) 
Objectives 
Primary Objectives 
The primary objective is to assess the safety of clostridium histolyticum 
collagenase (XIAFLEX®) in treating urethral strictures. 
Safety variable:  
o The primary safety variable will be complication rates 
following XIAFLEX® treatment 
Complications – specifically focus on pain, fever, genital 
lesions, or postoperative adverse events related to 
XIAFLEX® treatment 
  
Secondary Objectives 
The secondary objectives are to assess the efficacy of XIAFLEX® 
treatment in improving obstructive voiding dysfunction, safety of 
XIAFLEX® administration into urethral strictures via a transurethral 
approach and the quality of life following XIAFLEX® treatment. 
 
Secondary efficacy variables: 
o The percentage of subjects needing further intervention for 
treatment of urethral stricture during the 2 years follow-up 
Further intervention – defined as any medical or surgical 
intervention for treatment of urethral stricture.  
o Urethral stricture recurrence during the 2 years follow-up 
o Elapsed time to urethral stricture recurrence during the 2 
years follow-up 
o Elapsed time to additional intervention for urethral stricture 
treatment during the 2 years follow-up 
o Improvement of obstructive voiding dysfunction – defined 
as change in uroflow and post-void residual measurements 
at baseline and 6-week post treatment and follow-up visits 
o    Quality of Life – change in AUA scores at baseline and 6-
week post treatment and follow-up visits 
Secondary safety variable: 
o Spongiofibrosis - incidence of formation of spongiofibrosis 
or change in length and extent of spongiofibrosis between 


Protocol: CHC v6.0 01/25/2021 
 
5 
the baseline and follow-up visits on ultrasound and 
cystoscopic evaluation  
o Normal urethra proximal to injected tissue – incidence of 
change in normal urethra structure proximal to injected 
tissue between baseline and follow-up visits  
 
 
Number of 
Subjects 
5 Patients  
Inclusion 
Criteria 
1) Males 
2) Age ≥ 18 years 
3) Failed prior proven conservative measures, including DVIU or 
balloon dilation of the stricture will be included in this study 
4) Able and willing to undergo regular intervention as well as 
evaluation as described below will be included in the study 
5) With a single bulbar stricture <2cm in size that can be identified on 
retrograde urethrogram or voiding cystourethrogram and visible 
with urethral ultrasonography will be included in the study. 
6) Must agree not to participate in a clinical study involving another 
investigational drug or device throughout the duration of this study 
7) Must be competent to understand the information given in IRB 
approved ICF and must sign the form prior to the initiation of any 
study procedure 
 
Exclusion 
Criteria 
1) Has not yet undergone proven non-invasive measures, including 
DVIU or balloon dilation. 
2) Multiple strictures or a single stricture larger than 2cm in size, 
measured with retrograde urethrogram, voiding cystourethrogram, 
or urethral ultrasonography. 
3) Corporal spongiosum tissues < 5 mm in depth at proposed injection 
site 
4) Grade 5 spongiofibrosis 
5) Age <18 
6) Females 
7) Prior urethroplasty 
8) Urethral fistula 
9) History of penile cancer, prostate cancer, or urinary tract 
malignancy (bladder, urethral, ureteral, or kidney). 
10) History of radiation (external or brachytherapy) to the pelvic 
organs, penis or groin.  
11) History of autoimmune or inflammatory bowel disease 
12) Contraindication to suprapubic tube placement  
13) Pre-procedure PVR >250mL 
14) Allergy or sensitivity to CHC 
15) Bleeding disorder or anticoagulant use other than aspirin up to 
150mg/day 


Protocol: CHC v6.0 01/25/2021 
 
6 
16) Untreated or recurrent urinary tract infection 
17) Inability to perform intermittent self-catheterization 
18) Participation in another clinical study or treatment with an 
investigational drug or device  
19) Serious or active medical or psychiatric condition which, in the 
opinion of the Investigator, may interfere with treatment, 
assessment, or compliance with the protocol 
 
Study Product, 
Dose, Route, 
Regimen 
Patients will first be identified and evaluated with fluoroscopic and 
ultrasound imaging. Based on the inclusion and exclusion criteria they will 
be counseled about eligibility for the study along with discussion of 
standard management options and possible risks of the investigation 
including full informed consent.  
On day of treatment, patients will undergo instillation of local anesthesia 
(20 mL of 2% urethral lidocaine jelly), the patient will undergo 
cystoscopy, transurethral injection (via a 70 cm 4.8 Fr flexible cystoscopic 
needle with a 23 gauge needle tip manufactured by Laborie®, Ontario, 
Canada) of 0.08ml of XIAFLEX® (0.58 mg of XIAFLEX® mixed with 
0.39 mL of sterile diluent) in a single location within the stricture, chased 
by an additional 0.25 mL of reconstituted XIAFLEX® to allow for 
clearance of the original 0.08 mL of reconstituted XIAFLEX® from the 
transurethral syringe into the urethral stricture. This is based on 0.25 mL 
residual fluid that remains within the lumen of the injeTAK syringe. Thus, 
by adding the additional 0.25 mL of XIAFLEX® as a chase, we are 
expecting the original total of 0.08 mL of XIAFLEX® to be injected into 
the area of scarring.  The depth and location of the needle will be 
determined pre-procedurally with urethral ultrasonography with the needle 
in a semi-parallel manner into the plaque as to avoid perforation into 
nearby structures. Injections will be performed at a single site identified on 
ultrasound as appropriate, and avoiding the 6 o’clock and 12 o’clock sites 
where potential perforation can lead to additional complications. The site 
of injection will be recorded accordingly for safety monitoring following 
treatment. The remaining 0.25 mL that remains in the injection syringe will 
be discarded per institutional policy for biohazard disposal.  
 
Statistical 
Methodology 
Data analysis will be conducted using de-identified data in SPSS or SAS 
statistical software.  
 
Study Population Analysis 
The distributions of the following characteristics will be tabulated and 
presented with descriptive statistics (i.e. mean, standard deviation, median, 
minimum, maximum, and patient count for continuous variables, and 
counts with percentages for categorical variables): 
- 
Demographics 
- 
Medical and surgical history 
- 
Final study exit classification (completed, discontinued, withdrew) 


Protocol: CHC v6.0 01/25/2021 
 
7 
     
Primary Safety Endpoint 
The primary safety variable will be complication rates following treatment 
(XIAFLEX®). Complications – specifically focus on pain, fever, genital 
lesions, or postoperative adverse events related to treatment (XIAFLEX®) 
 
Secondary Efficacy Endpoints 
The secondary endpoints will be evaluated with the following tests: 
 
- 
The percentage of subjects needing further intervention for 
treatment of urethral stricture during the 2 years follow-up. Further 
intervention – defined as any medical or surgical intervention for 
treatment of urethral stricture.  
- 
Incidence of urethral stricture recurrence within 2 years following 
initial treatment will be calculated and presented with descriptive 
statistics 
- 
Elapsed time to urethral stricture recurrence and elapsed time to 
additional intervention for urethral stricture treatment within 2 
years following initial treatment will be calculated and presented 
with descriptive statistics 
- 
Efficacy of XIAFLEX® treatment in improving obstructive 
voiding dysfunction will be analyzed using paired t-test for the 
difference in uroflow and post-void residual measurements before 
and after study treatment (collected at baseline, 6-week post 
treatment and follow-up visits) 
- 
Quality of life will be analyzed using paired t-test for the difference 
in AUA scores before and after study initial treatment (collected at 
baseline, 6-week post treatment and follow-up visits) 
 
Secondary Safety Endpoints 
The results of the following safety endpoints will be calculated and 
presented with descriptive statistics for all patients receiving study 
treatment. 
- 
Incidence of formation of spongiofibrosis or change in length and 
extent of spongiofibrosis 
- 
Incidence of change in normal urethra structure proximal to 
injected tissue 
- 
Incidence and severity of treatment-emergent AEs/SAEs during the 
study 
- 
Proportion of patients completing study treatment  
- 
Proportion of patients discontinuing due to treatment related 
complications 
 
 
 


Protocol: CHC v6.0 01/25/2021 
 
8 
2.0 Background 
 
2.1 Urethral Stricture Disease 
 
Urethral stricture disease can be difficult and expensive problem for urologists to 
manage.  The total cost of urethral stricture diseases in 2000 was approximately $200 million.  A 
diagnosis of urethral stricture increased health care expenditures by more than $6,000 per 
individual yearly1.  Conservative management involves frequent straight catheterization or 
management with an indwelling foley catheter; options that can decrease the patient’s quality of 
life and increase the patient's risk of urinary tract infections2.   
 
2.1.1 Treatment of Urethral Stricture 
 
Minimally invasive treatment options include direct vision internal urethrotomy (DVIU) 
and urethral dilation; these have been shown to be effective primarily on single, small bulbar 
strictures (<2cm), with repeated treatment being almost entirely ineffective3.  Other minimally 
invasive treatments including urethral stents, transurethral injection with Rapamycin, botulinum 
toxin, or glucocorticoids have shown limited efficacy or have fallen out of favor because of 
increased morbidity4, 5. The gold standard for treatment of anterior urethral strictures involves 
excision of the stricture with primary anastomosis of the urethra or urethroplasty. Both surgical 
options, however, require extensive anesthesia and are often poor options for elderly patients, 
patients with significant comorbidities, or patient who simply do not wish to undergo such 
extensive surgery. 
 
2.2 Clostridium Histolyticum Collagenase 
 
Clostridium histolyticum collagenase (CHC) is an injectable pharmacologic agent that 
works by hydrolyzing collagen under physiologic environments, with in vitro studies showing 
CHC to be specifically selective for collagen type I and III, the predominant types found in 
Peyronie’s plaque’s and Dupuytren’s contractures.  Additionally, CHC spares collagen type IV, 
which is present within connective tissue of surrounding arteries, large veins, and nerves, 
limiting surrounding nerve or vessel damage6.  CHC, marketed as XIAFLEX®, has been FDA 
approved for treatment of Dupuytren’s disease, as well as Peyronie’s disease.  Large double 
blind studies have shown a statistically significant improvement in penile deformity following 
CHC injections7.  Additionally, studies have shown significant improvement in curvature in 
patients who performed penile modeling with CHC. 
 
2.2.1 Animal Studies: Toxicity Data 
 
Based on a previously conducted study on local toxicity of Auxilium’s collagenase 
(AA4500) injected into various locations within the dogs penis, including the urethra, primary 
side effects were dose related and included discoloration of the penis/prepuce, persistence of 
swollen penis, and bruising.8 At a dose of 6.1 μg/kg, which corresponds to 1.1 fold on the mg/kg 
basis of the human dose, 4 out of 6 dogs were able to receive all three doses (total 3 dosing 
cycles). The primary toxicity findings at all dose levels were hemorrhage, edema, necrosis, 
inflammation, and neovascular proliferation with increasing severity based on dosing. 


Protocol: CHC v6.0 01/25/2021 
 
9 
Histopathology indicated resolution was in progress at the end of the 28-day treatment-free 
period. There was no significant systemic toxicity following intrapenile injections. Necrosis did 
not affect non-collagenous strictures within or adjacent to the injected tissue, nor was there any 
evidence of residual effects on these structures in recovery animals in all phases of the study. In 
particular, arteries, veins, nerves, and large veins were unaffected, with necrosis only seen in 
smaller veins comprised mostly of collagen and minimal smooth muscle.  
 
Antibodies to AA4500 were detected in all repeat-dose dogs following their last dose on 
Day 61. The consequence of antibody formation is unknown. However, the author did note that 
the presence of antibodies did not result in any apparent adverse systemic effects. Nor did the 
production of antibodies appear to alter the toxicokinetics or pharmacodynamics effects of 
aA4500.  
 
In another animal study, injecting clostridial collagenase (both 150 units and 300 units 
injected) into rats tail tendon showed local collagen lysis of injection at the site of injection only 
at 1 and 24 hours.9 At both doses, no adverse collagenase extravasation was seen at either time at 
the injection site or 0.5 cm proximal or distal to the injection site. 
 
2.3 Rationale for Urethral Stricture Treatment with XIAFLEX® 
 
Urethral strictures, like Dupuytren’s contractures and Peyronie’s disease, are associated 
with a total increase in type I and type III collagen smooth muscle10.   A recent study 
investigated injecting urethral strictures with high dose CHC in rats showed reduction in urethral 
fibrosis as well as a reduction in collagen type I and III expression in the rodents’ urethral 
strictures11.  We wish to investigate if CHC would have a similar impact on urethral strictures in 
men when administered in a similar fashion to the Peyronie’s disease algorithm.  
 
3.0 Study Objectives 
 
We hypothesize that XIAFLEX® (Endo Pharmaceuticals, Dublin, Ireland) injection is an 
effective treatment for urethral strictures.   
 
Primary Objectives 
The primary objective is to assess the safety of clostridium histolyticum collagenase 
(XIAFLEX®) in treating urethral strictures. 
Safety variable:  
o The primary safety variable will be complication rates following treatment 
(XIAFLEX®) 
Complications – specifically focus on pain, fever, genital lesions, or postoperative 
adverse events related to treatment (XIAFLEX®) 
  
Secondary Objectives 
The secondary objectives are to assess the efficacy of XIAFLEX® treatment in improving 
obstructive voiding dysfunction, safety of XIAFLEX® administration into urethral strictures via 
a transurethral approach and the quality of life following XIAFLEX® treatment. 
 
Secondary efficacy variables: 
o The primary efficacy variable will be the percentage of subjects needing further 
intervention for treatment of urethral stricture during the 2 years follow-up 


Protocol: CHC v6.0 01/25/2021 
 
10 
Further intervention – defined as any medical or surgical intervention for 
treatment of urethral stricture.  
o Urethral stricture recurrence during the 2 years follow-up 
o Elapsed time to urethral stricture recurrence during the 2 years follow-up 
o Elapsed time to additional intervention for urethral stricture treatment during the 2 
years follow-up 
o Improvement of obstructive voiding dysfunction – defined as change in uroflow 
and post-void residual measurements at baseline and 6-week post treatment and 
follow-up visits 
o    Quality of Life – change in AUA scores at baseline and 6-week post treatment 
and follow-up visits 
 
Secondary safety variables: 
o Spongiofibrosis - incidence of formation of spongiofibrosis or change in length 
and extent of spongiofibrosis between the baseline and follow-up visits 
o Normal urethra proximal to injected tissue – incidence of change in normal 
urethra structure proximal to injected tissue between baseline and follow-up visits  
4.0 Study Population 
 
Male patients receiving treatment at USF for obstructive voiding symptoms or catheter 
dependent because of urethral stricture disease.   
 
4.1 Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for participation in this 
study. 
1) Males 
2) Age ≥ 18 years 
3) Failed prior proven conservative measures, including DVIU or balloon dilation of the 
stricture will be included in this study 
4) Able and willing to undergo regular intervention as well as evaluation as described below 
will be included in the study 
5) With a single bulbar stricture <2cm in size that can be identified on retrograde 
urethrogram or voiding cystourethrogram and visible with urethral ultrasonography will 
be included in the study will be included in the study. 
6) Must agree not to participate in a clinical study involving another investigational drug or 
device throughout the duration of this study 
7) Must be competent to understand the information given in IRB approved ICF and must 
sign the form prior to the initiation of any study procedure 
 
4.2 Exclusion Criteria 
Patients who meet any of the following exclusion criteria are not eligible for participation in this 
study. 
1) Has not yet undergone proven non-invasive measures, including DVIU or balloon 
dilation. 


Protocol: CHC v6.0 01/25/2021 
 
11 
2) Multiple strictures or a single stricture larger than 2cm in size, measured with retrograde 
urethrogram, voiding cystourethrogram, or urethral ultrasonography. 
3) Corporal spongiosum tissues < 5 mm in depth at proposed injection site 
4) Grade 5 spongiofibrosis 
5) Age <18 
6) Females 
7) Prior urethroplasty 
8) Urethral fistula 
9) History of penile cancer, prostate cancer, or urinary tract malignancy (bladder, urethral, 
ureteral, or kidney). 
10) History of radiation (external or brachytherapy) to the pelvic organs, penis or groin.  
11) History of autoimmune or inflammatory bowel disease 
12) Contraindication to suprapubic tube placement  
13) Pre-procedure PVR >250mL  
14) Allergy or sensitivity to CHC 
15) Bleeding disorder or anticoagulant use other than aspirin up to 150mg/day 
16) Untreated or recurrent urinary tract infection 
17) Inability to perform intermittent self-catheterization 
18) Participation in another clinical study or treatment with an investigational drug or device  
19) Serious or active medical or psychiatric condition which, in the opinion of the 
Investigator, may interfere with treatment, assessment, or compliance with the protocol 
 
5.0 Study Drug and Device 
 
5.1 Study Agent 
XIAFLEX® is a combination of bacterial collagenases indicated for the treatments of adult 
patients with Dupuytren’s contracture with a palpable cord and adult men with Peyronie’s 
disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of 
therapy. XIAFLEX® contains purified collagenase clostridium histolyticum, consisting of two 
microbial collagenases in a defined mass ratio, Collagenase AUX-I and Collagenase AUX-II, 
which are isolated and purified from the fermentation of Clostridium histolyticum bacteria. The 
dosing used for this study is based on recommendations for Peyronie’s disease treatment with 
XIAFLEX®.  
 
5.2 Dose Rationale 
A recently published comprehensive review of recent clinical trials and in vivo studies 
examining CHC in the treatment of Peyronie’s disease reported that the clinical trials have 
demonstrated the efficacy and tolerability of CHC in treating Peyronie’s disease and an in vivo 
study showed that CHC also could be applied to urethral stricture disease without serious adverse 
complications.12 A recent urethral injection of rat model (300-350g) used 0.05 - 0.1mg CCH per 
subject. This showed no urethral or voiding complication and no urinary retention or urethral 
fistulas11. This dosing would equal 0.14-0.33mg/kg. A dose of 0.119mg (0.08ml of 0.58mg 
XIAFLEX in 0.39ml) in a 70kg patient would be 0.0017mg/kg.  
 


Protocol: CHC v6.0 01/25/2021 
 
12 
5.3 Risks/Benefits 
Urethral stricture disease can be difficult and expensive problem for urologists to manage. As 
observed with this patient population, conservative management involves frequent straight 
catheterization or management with an indwelling foley catheter that can decrease the patient’s 
quality of life and increase the patient's risk of urinary tract infections. Other minimally invasive 
treatments have shown limited efficacy or have increased morbidity. Surgical options that are 
effective, however, involves higher risks, require extensive anesthesia and are often poor options 
for elderly patients, patients with significant comorbidities, or patient who simply do not wish to 
undergo such extensive surgery. Therefore, treatments with injections may provide sufficient 
potential benefit and an acceptable potential for risk for this study population.  
 
5.4 Dosage and Administration 
On day of treatment, prior to study drug administration, photographic evidence captured with 
urethral ultrasound will be used to confirm eligibility criterion: < Grade 5 spongiofibrosis. If the 
patient’s urethral ultrasound for Baseline/Screening was performed more than 30 days prior to 
the treatment day (Day 0), it will be performed again on the treatment day (Day 0) prior to study 
drug administration to re-confirm the patient’s study eligibility and to allow for proper 
procedural planning for study treatment. 
 
On day of treatment, patients will undergo instillation of local anesthesia (20 mL of 2% urethral 
lidocaine jelly), the patient will undergo cystoscopy, transurethral injection (via a 70 cm 4.8 Fr 
flexible cystoscopic needle with a 23 gauge needle tip manufactured by Laborie®, Ontario, 
Canada) of 0.08ml of XIAFLEX® (0.58 mg of XIAFLEX® mixed with 0.39 mL of sterile 
diluent) in a single location within the stricture, chased by an additional 0.25 mL of reconstituted 
XIAFLEX® to allow for clearance of the original 0.08 mL of reconstituted XIAFLEX® from the 
transurethral syringe into the urethral stricture. This is based on 0.25 mL residual fluid that 
remains within the lumen of the injeTAK syringe. Thus, by adding the additional 0.25 mL of 
XIAFLEX® as a chase, we are expecting the original total of 0.08 mL of XIAFLEX® to be 
injected into the area of scarring.  The depth and location of the needle will be determined pre-
procedurally with urethral ultrasonography with the needle in a semi-parallel manner into the 
plaque as to avoid perforation into nearby structures. Injections will be performed at a single site 
identified on ultrasound as appropriate, and avoiding the 6 o’clock and 12 o’clock sites where 
potential perforation can lead to additional complications.  The site of injection will be recorded 
accordingly for safety monitoring following treatment. The remaining 0.25 mL that remains in 
the injection syringe will be discarded per institutional policy for biohazard disposal.  
 
Reconstitution of the Lyophilized Powder for Peyronie’s Disease (taken from XIAFLEX® package insert) 
1. Before use, remove the vial containing the lyophilized powder of XIAFLEX® and the 
vial containing the diluent for reconstitution from the refrigerator and allow the two vials 
to stand at room temperature for at least 15 minutes and no longer than 60 minutes. 
Visually inspect the vial containing XIAFLEX®. The cake of lyophilized powder should 
be intact and white in color.  
2. After removal of the flip-off cap from each vial, using aseptic technique swab the rubber 
stopper and surrounding surface of the vial containing XIAFLEX® and the vial 
containing the diluent for reconstitution with sterile alcohol (no other antiseptics should 
be used). 


Protocol: CHC v6.0 01/25/2021 
 
13 
3. Use on the supplied diluent for reconstitution. The diluent contains calcium which is 
required for the activity of XIAFLEX®. 
4. Using a 1 mL syringe with 0.01 mL graduations with a 27-gauge ½-inch needle, 
withdraw a volume of 0.39 mL of the diluent supplied. 
5. Inject the diluent slowly into the sides of the vial containing the lyophilized powder of 
XIAFLEX®. Do not invert the vial or shake the solution. Slowly swirl the solution to 
ensure that all of the lyophilized powder has gone into solution. 
6. The reconstituted XIAFLEX® solution can be kept at room temperature (20º to 25ºC/68º 
to 77ºF) for up to one hour or refrigerated at 2º to 8ºC (36º to 46ºF) for up to 4 hours prior 
to administration. If the reconstituted XIAFLEX® solution is refrigerated, allow this 
solution to return to room temperature for approximately 15 minutes before use. 
7. Discard the syringe and needle used for reconstitution and the diluent vial. 
 
5.5 Formulation 
XIAFLEX® will be supplied in single-use glass vials containing 0.9 mg of collagenase 
clostridium histolyticum as a sterile, lyophilized powder for reconstitution. Sterile diluent for 
reconstitution will be provided in a package in a single-use glass vial containing 3 mL of 0.3 
mg/mL calcium chloride dehydrate in 0.9% sodium chloride. 
 
5.6 Packaging and Labeling 
Study drugs packaging and labeling will be provided as marketed. No modifications to the 
packaging and labeling will be made. A single-use package will consist of one carton containing 
a single-use vial for XIAFLEX® and a single-use vial of sterile diluent. 
 
5.7 Storage and Handling 
Prior to reconstitution, the vials of XIAFLEX® and diluent should be stored in a refrigerator at 
2ºC to 8ºC (36º to 46ºF). The reconstituted XIAFLEX® solution can be kept at room temperature 
(20º to 25ºC/68º to 77ºF) for up to one hour or refrigerated at 2º to 8ºC (36º to 46ºF) for up to 4 
hours prior to administration. The Clinical Research Center’s personnel at USF Health South 
Tampa Center for Advanced Healthcare will be monitoring study drug storage integrity (i.e. 
refrigerator temperature monitoring). Records and notifications of temperature excursions will be 
provided to the Principal Investigator and study coordinator accordingly. The Principal 
Investigator and study coordinator will ensure the integrity and monitoring of the drug prior to 
use. The time of each step in the process (i.e. removal from refrigerator, reconstitution, re-
refrigeration and/or administration) will be recorded accordingly. Study drug will not be used of 
the integrity of study drug is compromised.  
 
5.8 Drug Accountability 
The Principal Investigator and study coordinator will maintain records of product’s delivery and 
receipt from Endo Pharmaceuticals, Inc. to the drug storage site (USF Health South Tampa 
Center for Advanced Healthcare, Clinical Research Center at 2 Tampa General Circle,  Room 
4064, Tampa, FL 33606 – only accessible to Clinical Research Center’s personnel), the 
inventory at the site, the use by each patient, and disposal of unused products.   These records 
will include dates, quantities, log/batch/serial numbers, expiration or use-by dates, and unique 
code numbers assigned to the study drugs and study patients.  


Protocol: CHC v6.0 01/25/2021 
 
14 
 
At each treatment visit, the drugs will be obtained by the study coordinator and will be 
transported to USF Health South Tampa Center for Advance Healthcare (storage and clinic are in 
same area), where the treatment will occur. 
 
5.9 Concomitant and Prohibited Medications 
XIAFLEX® should be used with caution in patients receiving concomitant anticoagulants 
(except for low-dose aspirin). For this study, patients with bleeding disorder or anticoagulant use 
(up to 150 mg/day) other than aspirin are excluded. 
 
5.10 Injection Device 
The injection device will be the 70 cm 4.8 Fr flexible injeTAK® cystoscopic needle with a 23 
Gauge needle tip manufactured by Laborie®, Ontario, Canada. The 4.8 Fr allows for use with 
smaller working channels. The black indicator tip provides visual proximity to tissue for accurate 
placement, safe penetration and gauged puncture depth. The angle and 3-bevel tip is engineered 
to minimize puncture force. The cannula design also provides easy injection and flexibility while 
maintaining structural integrity. The needle tip can be adjusted to 0, 2, 3, 4, and 5 mm to 
accommodate thickness. For this study, the depth of the needle will be set based on pre-operative 
urethral ultrasound to determine needle location and depth. The needle will be injected in a semi-
parallel manner into the plaque as to avoid perforation into nearby structures.  
6.0 Methods 
 
6.1 Subject Identification 
Potential subjects will be identified through physician referrals (internal/external physicians will 
only share availability of trial, same information as that already shared with the public on 
clinicaltrials.gov, to their patients and provide USF urology clinic or research member’s contact 
information for further evaluation – all study recruitment will still occur at the USF urology 
clinic) and USF urology clinic at the USF Health South Tampa Center for Advanced Healthcare. 
 
6.2 Limited Waiver of Consent 
Potential subjects will be identified through physician referrals (internal/external physicians will 
only share availability of trial, same information as that already shared with the public on 
clinicaltrials.gov, to their patients and provide USF urology clinic or research member’s contact 
information for further evaluation – all study recruitment will still occur at the USF urology 
clinic) and USF urology clinic at the USF Health South Tampa Center for Advanced Healthcare 
– the PI’s and sub-investigator’s clinic. If the patient has urethral stricture, the PI/sub-
investigator will consider the patient for recruitment for the study. The PI/sub-investigator will 
discuss the study with the patient first, then the research coordinator will be introduced to the 
patient to complete the informed consent process. During the initial conversation between the 
investigator/research staff and the patient, the patient may be asked to provide certain health 
information that is necessary to the recruitment and enrollment process. The 
investigator/research staff may also review portions of their medical records in order to further 
assess eligibility prior to study consent – the investigators have a treatment relationship with the 
potential subjects and the study coordinators do not. They will use the information provided by 


Protocol: CHC v6.0 01/25/2021 
 
15 
the patient and/or medical record (USF EPIC electronic medical record system) to confirm that 
the patient is eligible and to approach the patient regarding study enrollment. Record review for 
screening purposes will be completed prior to receiving signed consent. If the patient turns out to 
be ineligible for the research study, the research staff will destroy all information collected on the 
patient during the initial conversation and medical records review, except for any information 
that must be maintained for screening log purposes.  
 
In most cases, the initial contact with the prospective subject will be conducted either by the 
treatment team, investigator or the research staff working in consultation with the treatment 
team. The recruitment process presents no more than minimal risk to the privacy of the patients 
who are screened and minimal PHI will be used as part of a screening process. For these reasons, 
we seek a (partial) limited waiver of authorization for the purposes of 1) reviewing medical 
records to identify potential research subjects and obtain information relevant to the enrollment 
process; 2) conversing with patients regarding possible enrollment; 3) handling of PHI contained 
within those records and provided by the potential subjects. 
 
6.3 Consent Process 
Patients who meet the inclusion and exclusion criteria will be considered for the study and will 
be asked to sign an informed consent form.  
In order to provide ample opportunity for the patient to consider participation, a copy of the 
consent form will be provided to all patients that verbally express interest to participate in the 
study. All study discussions will take place in a private exam room.  
 
Patients will be recruited from physician referrals (internal/external physicians will only share 
availability of trial, same information as that already shared with the public on clinicaltrials.gov, 
to their patients and provide USF urology clinic or research member’s contact information for 
further evaluation – all study recruitment will still occur at the USF urology clinic) and within 
our urology practice by the PI and sub-investigators. Recruitment may occur in the clinic at USF. 
After identifying a patient who meets minimum eligibility criteria and before collecting any 
study data, the study will be explained in detail to the participant including: (1) that the study 
represents a research effort, (2) that participation is voluntary, and there is no penalty for 
withdrawal, (3) any anticipated costs to the patient for participation, (4) potential risks and 
benefits for participation, (5) the procedures to ensure privacy of their medical information, and 
(6) contact information for addressing additional concerns. Patients will be informed of the 
purpose of the study. Only with the full and complete understanding of the study, and signed 
informed consent, will the evaluation of the potential participant continue. The subject will be 
given sufficient time to read the consent and ask any questions. Once the informed consent is 
signed, the subject will be given a copy of the document. 
 
6.4 Duration of Study Participation 
Study participation will require up to 2 years involvement. 
 
6.5 Study Visits 
This is a prospective, single-center, open-label study. Patients eligible for the study will undergo 
informed consent. Once consented, patients will be enrolled and treated with an approved open-
label treatment – XIAFLEX® injection.  


Protocol: CHC v6.0 01/25/2021 
 
16 
 
6.5.1 Baseline/Screening  
The following procedures will be performed at the Baseline/Screening visit: 
- 
Screen inclusion/exclusion criteria 
- 
Obtain informed consent 
- 
Record demographics and medical and surgical history 
- 
Evaluate and record concomitant medications 
- 
Administer American Urological Association (AUA) questionnaire 
- 
Perform physical exam (as occur per standard of care) 
- 
Perform retrograde urethrogram (RUG), voiding cystourethrogram (VCUG), post-void 
residual (PVR), uroflow, and cystoscopy to evaluate and document the anatomy and 
length and extent of spongiofibrosis at baseline related to the urethral stricture (as occur 
per standard of care). 
- 
Perform clinic urethral ultrasound to grade urethral stricture based on previously 
described grading system. (Figure 1)  
 
 
Figure 1. Urethral stricture grading scale based on urethral ultrasound  
 
6.5.2 Treatment (Day 0)  
The following procedures will be performed on day of XIAFLEX® injection treatment: 
- 
Evaluate and record concomitant medications 
- 
Perform study treatment 
- 
Assess for adverse events. Patients will be kept in clinic with vitals at 60min following 
injection to ensure no allergic reaction. Patients will be kept on campus until they have 
voided twice with a PVR <250ml or no more than 20% greater than their pre-procedural 
PVR.   
Treatment Group – XIAFLEX® injection 
On day of treatment, patients will undergo instillation of local anesthesia (20 mL of 2% urethral 
lidocaine jelly), the patient will undergo cystoscopy, transurethral injection (via a 70 cm 4.8 Fr 
flexible cystoscopic needle with a 23 gauge needle tip manufactured by Laborie®, Ontario, 
Canada) of 0.08ml of XIAFLEX® (0.58 mg of XIAFLEX® mixed with 0.39 mL of sterile 
diluent) in a single location within the stricture, chased by an additional 0.25 mL of reconstituted 
XIAFLEX® to allow for clearance of the original 0.08 mL of reconstituted XIAFLEX® from the 
transurethral syringe into the urethral stricture. This is based on 0.25 mL residual fluid that 
remains within the lumen of the injeTAK syringe. Thus, by adding the additional 0.25 mL of 
XIAFLEX® as a chase, we are expecting the original total of 0.08 mL of XIAFLEX® to be 
injected into the area of scarring.  The depth and location of the needle will be determined pre-
procedurally with urethral ultrasonography with the needle in a semi-parallel manner into the 


Protocol: CHC v6.0 01/25/2021 
 
17 
plaque as to avoid perforation into nearby structures. Injections will be performed at a single site.  
The remaining 0.25 mL that remains in the injection syringe will be discarded per institutional 
policy for biohazard disposal.  
 
 
 
Figure 2: Illustration of transurethral injection method for CCH injection. Note: the insertion of 
the needle, parallel to the direction of the urethra, to decrease the likelihood of injury to 
structures adjacent to the urethra.  
 
6.5.3 Post-treatment (Days 2 or 3) 
The patient will be instructed to return to clinic within 2-3 days of the injection  
- 
Perform physical exam 
- 
Perform uroflow, post-void residual (PVR) measurements 
- 
Administer AUA questionnaire  
- 
Evaluate and record concomitant medications 
- 
Assess for adverse events  
 
6.5.4 Post-treatment (Days 14, 28, 42, 56, 70, 84 ± 3 days) 
The patient will be instructed to return to clinic every 2 weeks following treatment.  
 
The following procedures will be performed at this visit:  


Protocol: CHC v6.0 01/25/2021 
 
18 
- 
Perform physical exam 
- 
Perform uroflow, post-void residual (PVR) measurements, and evaluate and document 
length and extent of spongiofibrosis every 2 weeks 
- 
Cystoscopy and urethral ultrasonography will be performed every 4 weeks   
- 
Administer AUA questionnaire  
- 
Evaluate and record concomitant medications and post treatment interventions, if any 
- 
Assess for adverse events  
- 
Test for antibodies to AUX I and AUX II at 6 weeks and neutralizing antibodies at 12 
weeks.  
 
6.5.5 Follow-up (6, 9, 12, 18 and 24 months (± 7 days))  
The patient will have follow-up evaluations in clinic at 6, 9, 12, 18, and 24 (± 7 days) months 
following the first treatment visit.   
 
The following procedures will be performed at these visits: 
- 
Perform physical exam 
- 
Perform cystoscopy, urethral ultrasound, uroflow, PVR measurements, and evaluate 
length and extent of spongiofibrosis. 
- 
Administer AUA questionnaire 
- 
Evaluate and record concomitant medications and post treatment interventions, if 
anyAssess for adverse events 
 
6.5.6 Unscheduled Visits 
If there is any medical or safety concern, the patient will be brought in earlier for re-evaluation in 
clinic. 
 
The following procedures will be performed at these visits: 
- 
Perform physical exam 
- 
Perform cystoscopy, urethral ultrasound, uroflow, PVR measurements, and evaluate 
length and extent of spongiofibrosis, if applicable 
- 
Evaluate and record concomitant medications and post treatment interventions, if any 
- 
Assess for adverse events 
 
6.5.7 Early Termination 
 
Early Discontinuation 
Reasons for discontinuation of treatment may include, but are not limited to, the following: 
- 
Patient withdrawal of consent 
- 
Any medical condition that the Investigator determines may jeopardize the patient’s 
safety if he continues in the study 
- 
Investigator determines it is in the best interest of the patient 
- 
Patient noncompliance, such as missing scheduled visits, non-adherence with 
concomitant medications, etc. 
- 
Lost to follow-up 
- 
If patients have no clinical response to the intervention and have persistent clinical 
manifestations of their stricture disease they may elect to undergo definite management in 


Protocol: CHC v6.0 01/25/2021 
 
19 
the form of urethral dilation, urethrectomy, or urethral reconstruction. They will still be 
followed per above protocol and included in all statistical analysis.  
 
After study treatment is discontinued, patient will be asked to remain in the study whenever 
possible and complete all study visits according to the planned schedule of assessments (except 
for patients who have withdrawn consent and are lost to follow-up). The primary reason for 
premature discontinuation of study treatment should be documented appropriately. If a patient 
chooses to discontinue study treatment and withdraw from the study, then the patient will be 
asked to return to the clinic for the early termination (ET) visit and complete all assessments. 
 
Patients who prematurely discontinue study treatment will not be replaced. 
 
Early Withdrawal 
All patients have the right to withdraw from study participation without prejudice at any time 
during the study. If a patient terminates participation in the study, the Investigator will make a 
reasonable effort to determine the cause of study withdrawal. If, for whatever reason, a patient 
withdraws from the study or the study is terminated while the patient is receiving study 
treatment, an early termination (ET) visit will be performed.  
 
Patients who prematurely withdraw from the study will not be replaced. 
 
The following procedures will performed at the ET visit if allowed by patient: 
- 
Perform physical exam 
- 
Perform cystoscopy, urethra ultrasound, uroflow, PVR measurements, and evaluate 
length and extent of spongiofibrosis 
- 
Administer AUA questionnaire 
- 
Evaluate and record concomitant medications, medical and surgical history 
- 
Assess for adverse events 
 
6.6 Sample Size Justification 
Sample size selection was based on the feasibility of completing a small number of subjects in a 
pilot study for safety assessments. A total of 5 patients will be enrolled in this study.  
 
6.7 Statistical Analysis Plan 
Data analysis will be conducted using de-identified data in SPSS or SAS statistical software. 
 
Study Population Analysis 
The distributions of the following characteristics will be tabulated and presented with descriptive 
statistics (i.e. mean, standard deviation, median, minimum, maximum, and patient count for 
continuous variables, and counts with percentages for categorical variables): 
- 
Demographics 
- 
Medical and surgical history 
- 
Final study exit classification (completed, discontinued, withdrew) 
     
Primary Safety Endpoint 


Protocol: CHC v6.0 01/25/2021 
 
20 
The primary safety variable will be complication rates following treatment (XIAFLEX®). 
Complications – specifically focus on pain, fever, genital lesions, or postoperative AEs related to 
treatment (XIAFLEX®) 
 
Secondary Efficacy Endpoints 
The secondary endpoints will be evaluated with the following tests: 
- 
The percentage of subjects needing further intervention for treatment of urethral stricture 
during the 2 years follow-up. Further intervention – defined as any medical or surgical 
intervention for treatment of urethral stricture.  
- 
Incidence of urethral stricture recurrence within 2 years following initial treatment will be 
calculated and presented with descriptive statistics 
- 
Elapsed time to urethral stricture recurrence and elapsed time to additional intervention 
for urethral stricture treatment within 2 years following initial treatment will be 
calculated and presented with descriptive statistics 
- 
Efficacy of XIAFLEX® treatment in improving obstructive voiding dysfunction will be 
analyzed using paired t-test for the difference in uroflow and post-void residual 
measurements before and after study treatment (collected at baseline, 6-week post 
treatment and follow-up visits) 
- 
Quality of life will be analyzed using paired t-test for the difference in AUA scores 
before and after study initial treatment (collected at baseline, 6-week post treatment and 
follow-up visits) 
 
Secondary Safety Endpoints 
The results of the following safety endpoints will be calculated and presented with descriptive 
statistics for all patients receiving study treatment. 
- 
Complication rates following treatment – specifically pain, fever, genital lesions, or 
postoperative complaints secondary to treatment 
- 
Incidence of formation of spongiofibrosis or change in length and extent of 
spongiofibrosis 
- 
Incidence of change in normal urethra structure proximal to injected tissue 
- 
Incidence and severity of treatment-emergent AEs/SAEs during the study 
- 
Proportion of patients completing study treatment  
- 
Proportion of patients discontinuing due to treatment related complications 
 
7.0 Benefits 
This study may not directly benefit participants but may provide information that may accede a 
larger study that will benefit future clinical practice and patients.  
 
8.0 Risks 
 
The following adverse reactions have been associated with XIAFLEX® in treatment of 
Peyronie’s disease: 
- 
Penile hematoma (includes injection site hematoma and penile hematoma) 


Protocol: CHC v6.0 01/25/2021 
 
21 
- 
Penile swelling (includes injection site swelling, penile edema, penile swelling, local 
swelling, scrotal swelling, and injection site edema) 
- 
Penile pain (includes injection site pain, penile pain, and injection site discomfort) 
- 
Penile ecchymoses (includes contusion, ecchymoses, penile hemorrhage, and injection 
site hemorrhage) 
- 
Blood blister 
- 
Penile blister 
- 
Pruritus genital 
- 
Painful erection 
- 
Erectile dysfunction 
- 
Skin discoloration 
- 
Procedural pain 
- 
Injection site vesicles 
- 
Localized edema 
- 
Dyspareunia 
- 
Injection site pruritus 
- 
Nodule 
- 
Suprapubic pain 
- 
Corporal rupture (penile fracture) 
- 
Penile “popping” sounds or sensations 
 
These adverse reactions were reported in XIAFLEX® clinical trials in patients with Peyronie’s 
disease, from which most adverse reactions were reported as local events of the penis and groin 
and the majority of these events were of mild or moderate severity, and most (79%) resolved 
within 14 days of injection. The adverse reaction profile was similar after each injection, 
regardless of the number of injections administered 10.  
 
Risks related to lidocaine injections include, but are not limited to: 
- 
Hypotension 
- 
Edema 
- 
Redness at injection site 
- 
Small red or purple spots on skin 
- 
Skin irritation 
- 
Constipation 
- 
Nausea 
- 
Vomiting 
- 
Confusion 
- 
Tremors 
- 
Dizziness 
- 
Headache 
- 
Numbness and tingling 
- 
Drowsiness 
- 
Severe allergic reactions 
- 
Dark urine 
- 
Sudden feeling of warmth with muscle stiffness and pain 
- 
Feeling hot or cold 


Protocol: CHC v6.0 01/25/2021 
 
22 
- 
Anxiety 
 
Other risks related to the injections include, but are not limited to: 
- 
Bleeding 
- 
Infection 
- 
Fistula 
- 
New stricture or scar tissue 
- 
Inefficacy 
- 
Incontinence 
- 
Need for surgical intervention 
- 
Lymphadenopathy 
- 
Lymph Node Pain 
- 
Inguinal Pain 
- 
Need for suprapubic tube 
- 
Need for extensive reconstruction in the future  
- 
Fistula (urethrocutaneous)   
- 
Periuretheral abscess 
- 
Urethral diverticulum  
- 
Acute urinary retention 
- 
Need for urethral catheterization  
 
Risk related to breach of confidentiality 
The risks of participants in this project involve the use of PHI for the initial access to study-
related data. Anytime such data is accessed and stored by handlers outside the domain of clinical 
routine, the risk of breached data security is increased, however all means necessary have been 
inputted to secure the information. Medical record numbers and patient names will be used to 
access the patient’s medical record. Once the data collection is complete, the medical record 
numbers, patient names, and any other PHI will be destroyed.  
 
Risks related to completing the surveys 
The cognitive assessments ask about disease and health.  Thinking about these things may make 
the patient uncomfortable. The patient may also feel a loss of privacy by answering the 
questions. The responses will be kept confidential and the patient may skip any questions he does 
not want to answer. 
 
9.0 Safety Monitoring 
A Data and Safety Monitoring Board (DSMB) will be established to monitor adverse reactions 
and the safety of the study. The DSMB will consist of experts in the relevant biomedical fields of 
urology and biostatistics. The members will have no direct relationship to the study (will not 
involve in any study related activities but may have their inputs in the study design and changes). 
The DSMB will review the protocol of the study and periodically monitor the progress, data, 
outcomes and safety during the study. An analysis will be performed after 5 patients have 
completed their study treatment and 6-week post treatment visits. All adverse events and 
reactions will be tabulated and presented to the DSMB. Further safety analysis will be performed 
by the biostatistician on the DSMB as necessary.  


Protocol: CHC v6.0 01/25/2021 
 
23 
 
9.1 Adverse Events 
Adverse events (AE) will be monitored and collected by the study team from the point of signed 
consent to the end of patient’s participation in the study. For each AE, a detailed explanation will 
be obtained from the patient and patient’s medical record. All AEs are to be recorded on the case 
report forms located in the patient’s study binder and master database maintained by the 
principal investigator.  
 
Definition of Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence associated with the use of 
a drug in humans, whether or not considered drug-related. All adverse events, including observed 
or volunteered problems, complaints, or symptoms, are to be recorded. Subjects will be 
instructed to report any adverse event they experience to the investigator/study staff. 
Investigators will assess for adverse events at each visit and record accordingly. Any medical 
condition that is present when a subject is screened or present at baseline that does not worsen or 
deteriorate will not be reported as an adverse event. However, medical conditions present at 
baseline that change in severity at any time during the study will be reported as an adverse event.  
The investigator will exercise his medical and scientific judgment in deciding whether an 
abnormal assessment is clinically significant. The investigator will rate the severity of and clarify 
each adverse event based on the definitions below. 
Assess of Severity of Adverse Event: 
- 
Mild – transient in nature and generally does not interfere with normal activities 
- 
Moderate – sufficiently discomforting to interfere with normal activities 
- 
Severe – incapacitating, causing inability to perform normal activities 
Assessment of Adverse Event and Study Drug Relatedness: 
No related – definitely not related to study drug and is judged clearly due to causes other than 
study drug 
Unlikely related – follows a temporal sequence from study drug administration, such that a 
relationship is not likely and could be reasonably explained by the subject’s current medical 
condition or other standard of care treatment the subject is receiving 
Possibly related – follows a temporal sequence from study drug administration, but may be due 
to another cause and could also be reasonable explained by the subject’s current medical 
condition or other standard of care treatment the subject is receiving 
Definitely related – clearly related to study drug administration 
 
9.2 Serious Adverse Events 
An adverse event is considered serious if it results in any of the following: 
- 
Death 
- 
Life-threatening adverse event – subject is at immediate risk of death due to adverse 
event occurrence 
- 
Requires inpatient hospitalization or prolongs existing hospitalization 
- 
Results in persistent or significant disability/incapacity 
- 
Significant medical event that may require medical/surgical intervention to prevent one 
of the outcomes above 
 


Protocol: CHC v6.0 01/25/2021 
 
24 
9.3 Unanticipated Adverse Events 
The following are examples of adverse events considered to be unanticipated adverse events that 
must be reported to the USF Institutional Review Board (IRB) promptly, or within five (5) 
calendar days: 
• A single occurrence of a serious, unexpected event that is uncommon and strongly 
associated with drug exposure (such as angioedema, agranulocytosis, hepatic injury, or 
Stevens-Johnson syndrome; 
• A single occurrence, or more often a small number of occurrences, of a serious, unexpected 
event that is not commonly associated with drug exposure, but uncommon in the study 
population (e.g., tendon rupture, progressive multifocal leukoencephalopathy); 
• Multiple occurrences of an AE that, based on aggregate analysis, is determined to be an 
unanticipated problem. There should be a determination that the series of AEs represents a 
signal that the AEs were not just isolated occurrences and involve risk to human subjects; 
• An AE that is described or addressed in the investigator’s brochure, protocol, or informed 
consent documents, but occurs at a frequency or severity that is inconsistent with prior 
observations.  
• A serious AE that is described or addressed in the investigator’s brochure, protocol, or 
informed consent documents, but for which the rate of occurrence in the study represents a 
clinically significant increase in the expected rate of occurrence (ordinarily, reporting would 
only be triggered if there were a credible baseline rate for comparison).  
• Any other AE or safety finding that would cause the sponsor to modify the investigator’s 
brochure, study protocol, or informed consent documents, or would prompt other action by 
the IRB to ensure the protection of human subjects.  
• Any breaches in confidentiality that would place the participant or others at risk; 
• Any change in FDA labeling or withdrawal from marketing of a drug, device, or biologic 
used in a research protocol; 
• Any change to the protocol that was taken without prior IRB approval to eliminate apparent 
immediate hazard to a research participant; 
• Incarceration of a participant when enrolled on a study not approved under Subpart C 
provisions; or 
• Breach of privacy or confidentiality including the loss of data on a computer or any 
electronic device which holds private or confidential information. 
 
A comprehensive list of all adverse and serious adverse events will be submitted with each 
continuing review application to the USF IRB. 
 
9.4 Study Stopping Criteria 
Study termination may be recommended for any perceived safety concern based on clinical 
judgment, including by not limited to a higher than anticipated rate of ≥ 1% for any component 
resulting in an unanticipated SAEs. Subjects will also be withdrawn from the study if benefits are 
outweighed by the risks. 
 
The study will be stopped altogether if there is one case of study treatment adversely affecting 
other post treatment intervention and/or urethroplasty in patients with recurrence of urethral 
stricture as determined by the principal investigator and DSMB to be related to study treatment. 


Protocol: CHC v6.0 01/25/2021 
 
25 
 
10.0 Data Handling and Monitoring 
Data will be monitored by the PI and coordinator on a regular basis. The collection of personal 
patient information will be limited to the amount necessary to achieve the aims of the research, 
so that no unneeded sensitive information is being collected.  
Only study personnel will collect data.  All hard copy documents will be kept in a locked room 
in the research coordinator’s office for the duration of the study. Data entry will be completed in 
the REDCap secured database. REDCap data will be exported into Excel or other file format for 
data analysis. Only de-identified data will be used for data analysis. Collected data will be sent to 
a biostatistician consultant for statistical analysis.  
 
Data will be kept secure for at least 5 years after the final study report has been submitted to the 
IRB. Data will ultimately be destroyed by shredding physical documents and discarding them in 
the HIPAA labeled bins at USF. Electronic documents will be completely removed from any 
databases used. 
 
11.0 Conflicts of Interest 
There are no financial conflicts of interest. 
 
12.0 References 
 
1. 
Santucci RA, Joyce GF, Wise M. Male urethral stricture disease. The Journal of urology. 
2007;177:1667-1674. 
2. 
Chenoweth CE, Saint S. Urinary tract infections. Infectious disease clinics of North 
America. 2011;25:103-115. 
3. 
Heyns CF, Steenkamp JW, De Kock ML, Whitaker P. Treatment of male urethral 
strictures: is repeated dilation or internal urethrotomy useful? The Journal of urology. 
1998;160:356-358. 
4. 
Hussain M, Greenwell TJ, Shah J, Mundy A. Long-term results of a self-expanding 
wallstent in the treatment of urethral stricture. BJU international. 2004;94:1037-1039. 
5. 
Zhang K, Qi E, Zhang Y, Sa Y, Fu Q. Efficacy and safety of local steroids for urethra 
strictures: a systematic review and meta-analysis. Journal of endourology / 
Endourological Society. 2014;28:962-968. 
6. 
Peak TC, Mitchell GC, Yafi FA, Hellstrom WJ. Role of collagenase clostridium 
histolyticum in Peyronie's disease. Biologics : targets & therapy. 2015;9:107-116. 
7. 
Gelbard M, Goldstein I, Hellstrom WJ, et al. Clinical efficacy, safety and tolerability of 
collagenase clostridium histolyticum for the treatment of peyronie disease in 2 large 
double-blind, randomized, placebo controlled phase 3 studies. The Journal of urology. 
2013;190:199-207. 
8.  
Brown P. Center for Drug Evaluation and Research. Application Number 125338. 2009. 
9. 
Badalamente MA, Hurst LC. Enzyme injection as a nonoperative treatment for 
Dupuytren's disease. Drug Delivery. 1996;3:34-40. 


Protocol: CHC v6.0 01/25/2021 
 
26 
10. 
Cavalcanti AG, Costa WS, Baskin LS, McAninch JA, Sampaio FJ. A morphometric 
analysis of bulbar urethral strictures. BJU international. 2007;100:397-402. 
11. 
Sangkum P, Yafi FA, Kim H, et al. Collagenase Clostridium histolyticum (XIAFLEX®) 
for the Treatment of Urethral Stricture Disease in a Rat Model of Urethral Fibrosis. 
Urology. 2015;86:647.e641-646. 
12. 
Gabrielson AT, Spitz JT, Hellstrom WJG. Collagenase Clostridium Histolyticum in the 
Treatment of Urologic Disease: Current and Future Impact. Sex Med Rev. 2017 Apr 25. 
pii: S2050-0521(17)30035-5. 
13. 
XIAFLEX® [package insert]. Auxilium Pharmaceuticals, LLC, Malvern, PA; August 
2016. 
http://www.endo.com/File%20Library/Products/Prescribing%20Information/XIAFLEX®
_prescribing_information.pdf. Accessed Oct 21, 2016. 
 


Protocol: CHC v6.0 01/25/2021 
 
27 
13.0 Schedule of Assessments 
 
Visit 
Screening 
/ Baseline 
Treatment 
(Day 0) 
2-Day 
 
Q2wk3 
(0-84 days) 
Q4wk 
(0-84 days)  
6-Mo 
9-Mo 
12-Mo 
18-Mo 
Visit Window 
- 
+14 days from 
Control Visit 
±1 day 
±3 day 
±1 days 
±7 
days 
±7 days ±7 days 
±7 
days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Demographics and Medical 
History 
X 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
Concomitant Meds 
X 
X 
X 
X 
 
X 
X 
X 
X 
AUA questionnaire 
X 
 
X 
X 
 
X 
X 
X 
X 
Retrograde urethrogram 
X1 
 
 
 
 
 
 
 
 
Voiding cystourethrogram 
X1 
 
 
 
 
 
 
 
 
Physical exam 
X1 
 
X 
X 
 
X 
X 
X 
X 
Post-void residual 
X1 
 
X 
X 
 
X1 
X1 
X 
X 
Uroflowmetry 
X1 
 
X 
X 
 
X1 
X1 
X 
X 
Cystoscopy 
X1 
 
 
 
X 
X1 
X1 
X 
X 
Urethral ultrasound including 
evaluation of length and 
extent of spongiofibrosis 
X 
 
 
 
X 
X 
X 
X 
X 
AE assessment 
 
X 
X 
X 
 
X 
X 
X 
X 
Study treatment 
 
XIAFLEX® 
injection 
 
 
 
 
 
 
 
 


Protocol: CHC v6.0 01/25/2021 
 
28 
Visit 
24-Mo 
Unscheduled 
Early Termination 
Visit Window 
±7 days 
- 
- 
Concomitant Meds 
X 
X 
X 
AUA questionnaire 
X 
X 
X 
Retrograde urethrogram 
 
 
 
Voiding cystourethrogram 
 
 
 
Physical exam 
X 
X 
 
Post-void residual 
X1 
X2 
X 
Uroflowmetry 
X1 
X2 
X 
Cystoscopy 
X1 
X2 
X 
Urethral ultrasound including evaluation of 
length and extent of spongiofibrosis 
X 
X2 
X 
AE assessment 
X 
X 
X 
 
1. Collected as occurred as standard of care 
2. Perform if applicable 
3. Test for antibodies to AUX I and AUX II at 6 weeks and neutralizing antibodies at 12 weeks