Efficacy of a Novel CCH Protocol for PD Among Prior Non-responders

Study Overview
=================
Brief Summary
-----------------
Compare key clinical outcomes between controls and men treated with a novel CCH administration protocol among men previously unresponsive to CCH administration.

Detailed Description
-----------------
Beginning approximately 3 years ago, the investigators' team sought to achieve further improvements with CCH through the addition of more aggressive modeling therapies. Results from a comparison of CCH alone vs CCH and traction with RestoreX demonstrated a mean 33.8 degree (49%) curvature improvement with combined therapy compared to 19-20 degrees (30-31%) with CCH alone or CCH and other traction devices). These results currently represent the greatest improvements with CCH in published literature and further build upon phase IIb results which demonstrated that mechanical traction (via manual modeling in the phase IIb trial) represents a critical factor in achieving improvements with CCH. The investigators' team additionally published a survey of men who had experienced suspected penile fractures with CCH and demonstrated greater curvature improvements without any loss / worsening of erectile function. This critical study highlighted that conservative management of suspected fractures should not only be considered a standard of care in managing suspected fractures, but also that these men achieved better final outcomes (again highlighting the importance of the combination of mechanical curvature correction in addition to CCH management). Based on the above findings, the investigators' team began performing a more aggressive manual modeling protocol. This novel protocol included several notable innovations: dilution of the 0.9 mg of CCH in 0.7 ml of diluent, injection to the erect penis to assure accurate injection, repeat curvature assessments with each series (due to changing of the point of maximal curvature), incorporation of RestoreX traction therapy post injection, and 'aggressive' manual modeling (equivalent of 10-15 lbs of force) to achieve curvature correction. Preliminary (unpublished - abstract submitted to SMSNA 2021) results from these men demonstrated a median  60% curvature improvement. Importantly, several of the patients had previously undergone 8 CCH injections with outside providers and were able to similarly achieve a median 60% improvement with the investigators' injection / modeling protocol. These preliminary findings have several important ramifications for the treatment of PD: Men who have previously not achieved adequate curvature correction with 4 series of CCH injections may benefit from additional injections using a more aggressive traction protocol. A more aggressive traction protocol would benefit patients to achieve greater outcomes than with previously reported protocols. 1.2 Investigational Treatments The current study would randomize men 1:3 into one of two treatment cohorts: 1. Observation followed by CCH or 2. CCH followed by observation. This study design offers the benefits of a randomized, controlled trial (highest level of evidence). RCTs are particularly important in PD, where the disease changes over time in a percentage of men as a function of its natural history. This would also allow blinding of measurements using photographs (single-blinded assessments), which provides further study rigor. No treatment (control) followed by CCH. Men in this cohort would undergo baseline assessments followed by no treatment for 6 months and then repeat assessments. Men would then cross-over to CCH treatment and undergo up to 8 injections (or until curvature is <15 degrees). Interval assessments would be performed with the 1st injection of each series, and final assessments would then be performed 6 weeks following the final injection. CCH followed by no treatment. Men in this cohort would undergo baseline assessments followed by up to 8 injections of CCH (or until curvature is <15 degrees). Interval assessments would be performed with the 1st injection of each series and 6 weeks following completion of treatment. Men then would not undergo any additional treatments for 6 months, after which final assessments would then performed.

Official Title
-----------------
Efficacy of a Novel Collagenase Clostridium Histolyticum Protocol for Peyronie's Disease Among Prior Non-responders: A Randomized, Controlled, Single-Blinded Study

Conditions
-----------------
Peyronie's Disease

Intervention / Treatment
-----------------
* Drug: CCH administration
* Drug: Control - Crossover to CCH
* Device: RestoreX


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men with Peyronie's Disease >18 years old Curvature ≥30 degrees Previously completed 6-8 CCH injections Prior minimal (<20% and/or <10 degrees) responsiveness to CCH administration Prior CCH injections must have been performed without use of a Restorex traction device and used the IMPRESS protocol Ability to achieve an erection satisfactory for intercourse with or without PDE5 inhibitors The patient exhibits a palpable plaque consistent with Peyronie's Disease Exclusion Criteria: Prior surgical treatment on the penis (other than circumcision) Any contraindications to CCH - as determined by the PI Inability to complete 8 additional CCH injections Severe plaque calcification (i.e. >1 cm shadowing)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients meeting criteria who have consented will be randomized to either control or CCH x 6 months, followed by a cross-over phase where controls will receive CCH. See Figure 1 for full study schema. Control. Men in this cohort would undergo baseline assessments followed by no treatment for 6 months and then repeat assessments. Men would then cross-over to the CCH treatment phase and undergo up to 8 injections (or until curvature is <15 degrees, whichever comes first). Final assessments would then be performed 6 weeks following the final injection. CCH followed by observation. Men in this cohort would undergo baseline assessments followed by up to 8 injections of CCH (or until curvature is <15 degrees). Assessments would then be performed 6 weeks after completion of treatment. Men then would not undergo any additional treatments for 6 months, after which they would have final assessments performed.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control - Crossover to CCH<br>Men in this cohort would undergo baseline assessments followed by no treatment for 6 months and then repeat assessments. Men would then cross-over to CCH treatment and undergo up to 8 injections (or until curvature is <15 degrees). Final assessments would then be performed 6 weeks following the final injection. | Drug: Control - Crossover to CCH<br>* Patients will be randomized 1:3 into the control arm. After undergoing baseline assessments, control men will not undergo treatments for 6 months. They will then have repeat assessments and receive up to 8 CCH injections. They will then have final assessments performed 6 weeks after treatment.<br>* Other names: Collagenase Clostridium Histolyticum;Device: RestoreX<br>* Both treatment arms will incorporate the use of RestoreX for 30-60 minutes daily during CCH administration and continued until 6 weeks after final injection administration.<br>|
| Experimental: Collagenase Clostridium Histolyticum<br>Men in this cohort would undergo baseline assessments followed by up to 8 injections of CCH (or until curvature is <15 degrees). Men would then undergo assessments 6 weeks later, followed by a 6-month no treatment phase and then final assessments. | Drug: CCH administration<br>* Patients will be randomized 3:1 into the CCH administration arm. After undergoing baseline assessments, this arm will receive up to 8 CCH injections, followed by final assessments 6 weeks later.<br>* Other names: Collagenase Clostridium Histolyticum;Device: RestoreX<br>* Both treatment arms will incorporate the use of RestoreX for 30-60 minutes daily during CCH administration and continued until 6 weeks after final injection administration.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Penile Curvature | Compare the change in degree of penile curvature from baseline (using a goniometer) between control and treatment groups at 6 months | 6 months | 
| Peyronie's Disease Questionnaire Outcomes | Compare Peyronie's Disease Questionnaire outcomes between control and treatment groups at 6 months using the Peyronie's Disease Questionnaire (15 items; subdomains - psychological and physical (Q1-6, 0-24), penile pain (Q7-9; 0-30), symptom bother (Q10-15; 0-16); 12 and 14 (Y/N q's); lower is better. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| International Index of Erectile Function Outcomes | Compare International Index of Erectile Function Outcomes between control and treatment groups at 6 months | 6 months | 
| Penile Curvature Compared to Baseline | Compare penile curvature changes (degrees) in control men at baseline and 12 months (i.e. prior to and following cross-over to CCH) - using goniometer | 12 months | 
| Penile Length Compared to Baseline | Compare penile length changes in control men at baseline and 12 months (i.e. prior to and following cross-over to CCH) | 12 months | 
| Compare Peyronie's Disease Questionnaire to Baseline | Compare PDQ changes in control men at baseline and 12 months (i.e. prior to and following cross-over to CCH) using the Peyronie's Disease Questionnaire (15 items; subdomains - psychological and physical (Q1-6, 0-24), penile pain (Q7-9; 0-30), symptom bother (Q10-15; 0-16); 12 and 14 (Y/N q's); lower is better. | 12 months | 
| Compare International Index of Erectile Function to baseline | Compare International Index of Erectile Function changes in control men at baseline and 12 months (i.e. prior to and following cross-over to CCH) | 12 months | 
| Penile Length Between Groups | Compare penile length changes between control and treatment groups at 6 months | 6 months | 
| Adverse events - 6 months - pain, sensation, swelling | Report adverse events at the 6-month time point | 6 months | 
| Adverse events - 12 months - pain, sensation, swelling | Report adverse events at the 12-month time point | 12 months | 
| Change in penile curvature durability | Report changes in penile curvature degree between the 6 and 12-month assessments for CCH men by goniometer. | 6 months |