Coverage Policy Manual
Policy #: 2010013
Category: Pharmacy
Initiated: March 2010
Last Review: April 2024
  Injection, Clostridial Collagenase for Fibroproliferative Disorders
Description:
Collagenases are enzymes that digest native collagen and are being evaluated for treatment of fibroproliferative disorders such as Dupuytren’s contracture and Peyronie’s disease. Clostridial collagenase is a bacterial collagenase derived from Clostridium histolyticum. Treatment of Dupuytren’s contracture consists of injection of collagenase into the cord followed by manipulation of the finger if contracture persists. Injection may be done up to 3 times at 4-week intervals.
 
Injection with clostridial collagenase is intended to provide a non-operative treatment option for fibroproliferative disorders. Fibrotic tissue disorders, characterized by excessive collagen deposits, can affect the musculoskeletal system causing pain and limitation of movement and reduction of joint range of motion. Dupuytren’s disease and adhesive capsulitis are such musculoskeletal disorders; Peyronie’s disease is another example.
 
The mechanisms that contribute to the pathology are poorly understood. In Dupuytren’s disease, collagen deposition results in nodules and cords in the palm and fingers resulting in pitting of the overlying cutis and flexion contractures. The standard of care for Dupuytren’s disease is surgery, most commonly open fasciectomy. Other surgical procedures are percutaneous fasciotomy and needle fasciotomy. Surgery is recommended in individuals with functional impairment and metacarpophalangeal-joint contractures of 30 degrees or more. There is no effective pharmacotherapy. Adhesive capsulitis or “frozen shoulder” is treated with physiotherapy and mobilization in combination with analgesics or nonsteroidal anti-inflammatory drugs. Corticosteroid injection is used with caution. The prevalence of Dupuytren’s disease and adhesive capsulitis is estimated at 3-6% and 2-3%, respectively, in the general population and increases with advancing age. Both conditions are more common in individuals with diabetes or thyroid disease. Dupuytren's disease is more common in men and adhesive capulitis more common in women.                                                                                                                                                                                                                       
 
Peyronie's disease is the development of abnormal scar tissue, or plaques, in the tunica albuginea layer of the penis causing distortion, curvature, and pain usually during erection. It occurs in 3-9% of men, most commonly between the ages of 45 and 60. In some cases, plaque does not cause severe pain or curvature, and the condition resolves on its own. In severe cases, erectile dysfunction can occur. The goal of treatment is to reduce pain and maintain sexual function. Treatments in early stages (before calcification) include vitamin E or para-aminobenzoate tablets (e.g., Potaba) although studies of oral therapies demonstrate inconsistent benefit. Intralesional injection therapy consisting of injection of interferon-alpha-2b or calcium channel-blockers (e.g., verapamil) is the current standard of therapy. Surgical procedures involve the excision (removal) of hardened tissue and skin graft, the removal or pinching (plication) of tissue opposite the plaque to reduce curvature (called the Nesbit procedure), a penile implant, or a combination of these.
 
Regulatory Status
 
In February 2010, the FDA approved Auxilium Pharmaceutical Inc.’s biologics license application for clostridial collagenase histolyticum (e.g., Xiaflex) for treatment of adult individuals with Dupuytren’s contracture with a palpable cord. The FDA labeling for Xiaflex states that up to 3 injections at 4-week intervals may be given into a palpable Dupuytren’s cord with a contracture of a metacarpophalangeal (MP) joint or a proximal interphalangeal (PIP) joint
 
In December 2013, the FDA approved Xiaflex for the treatment of Peyronie's disease (www.fda.gov, 2013). The FDA News Release on Dec. 6, 2013 included the following information:
 
In December 2013, FDA expanded the indications for Xiaflex to include Peyronie disease. Xiaflex is approved for men with a palpable penile plaque and penile curvature more than 30 degrees. FDA labelling states that a treatment course consists of a maximum of 4 cycles, each of which consists of 2 Xiaflex injection procedures. In clinical trials of Xiaflex for Peyronie disease, corporeal rupture was reported as an adverse event in 0.5% of Xiaflex-treated individuals. An additional 0.9% of Xiaflex-treated individuals experienced a combination of penile ecchymosis or hematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation, such that a diagnosis of corporal rupture could not be excluded. Severe penile hematoma was reported in 3.7% of individuals. Because of these complications, FDA required a boxed warning label for Xiaflex as a treatment for Peyronie disease. Xiaflex is available for the treatment of Peyronie disease only through a restricted program under a Risk Evaluation and Mitigation Strategy (the Xiaflex REMS Program). Required components of the REMS program are that prescribers are certified with the program by enrolling and completing training in the administration of Xiaflex for Peyronie disease and that healthcare sites are certified with the program and ensure that Xiaflex is only dispensed for use by certified prescribers (FDA News Release, 2013).
  
Coding
 
See CPT/HCPCS Code section below.
 
Policy/
Coverage:
Effective August 1, 2023, prior approval is required for Injectable Clostridial Collagenase for Fibroproliferative Disorders.
 
Effective September 1, 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Injectable clostridial collagenase meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
Dupuytren’s Contracture
 
INITIAL APPROVAL STANDARD REVIEW for up to 6 months:
 
    1. Individual has a diagnosis of Dupuytren’s contracture; AND
    2. Individual is 18 years of age or older; AND
    3. Individual will have no more than two joints in the same hand treated during a single treatment visit; AND
    4. Individual will not exceed three injections per cord per lifetime; AND
    5. Must be dosed in accordance with the FDA Label.
  
CONTINUED APPROVAL for up to 6 months:
 
    1. Individual has a diagnosis of Dupuytren’s contracture; AND
    2. Individual is 18 years of age or older; AND
    3. Individual has documentation of positive response to injectable clostridial collagenase (i.e., reduction of contractures and improvement of range of motion); AND
    4. Individual will have no more than two joints in the same hand treated during a single treatment visit; AND
    5. Individual will not exceed three injections per cord per lifetime; AND
6. Must be dosed in accordance with the FDA label.
 
Peyronie’s Disease
 
INITIAL APPROVAL STANDARD REVIEW for up to 6 months:
 
1. Individual has:
a. A diagnosis of Peyronie’s disease; AND
b. Disease is stable, quiescent, or unchanged for at least 3 months (See *stable disease under policy guidelines); AND
2. Individual is 18 years of age or older; AND
3. Individual must have a penile curvature greater than or equal to 30 degrees and less than or equal to 90 degrees; AND
4. Individual will not exceed a lifetime limit of two treatment courses (i.e., Up to 8 total treatment cycles or 16 injections); AND
5. Initial authorization will not exceed one treatment course (i.e., 4 treatment cycles or 8 injections); AND
6. Must be dosed in accordance with FDA Label.  
 
CONTINUED APPROVAL for up to 6 months:
 
1. Individual has:
a. A diagnosis of Peyronie’s disease; AND
b. Disease is stable, quiescent, or unchanged for at least 3 months (See *stable disease under policy guidelines); AND
2. Individual is 18 years of age or older; AND
3. Individual has documentation of positive response to injectable clostridial collagenase (i.e. improvement in curvature); AND
4. Individual has a remaining penile curvature greater than or equal to 15 degrees since last treatment course; AND
5. Individual will not exceed a lifetime limit of two treatment courses (i.e., Up to 8 total treatment cycles or 16 injections); AND
6. Continued authorization will not exceed one treatment course (i.e., 4 treatment cycles or 8 injections); AND
7. Must be dosed in accordance with FDA Label.  
 
Dosage and Administration
Dosing per FDA Guidelines
 
Dupuytren’s Contracture
The recommended dose of clostridial collagenase is 0.58 mg (0.25 mL for cords affecting a metacarpophalangeal joint or 0.20 mL for cords affecting a proximal interphalangeal joint) into each palpable Dupuytren’s cord with a contracture. Injections may be administered up to 3 times per cord at approximately 4-week intervals. Up to 2 injections in the same hand may be performed during a treatment visit.
 
Peyronie’s Disease
The recommended dose of clostridial collagenase is 0.58 mg (0.25 mL) into the target plaque. One treatment course consists of 4 treatment cycles (each cycle consists of 2 injection procedures with penile modeling for a total of 8 injections over a treatment course) separated by 6-week intervals.
 
Clostridial collagenase is available as a single use glass vial containing 0.9 mg of lyophilized powder for reconstitution.
 
Clostridial collagenase should be administered as an injection by a healthcare professional.  
  
Policy Guidelines
 
*Stable disease, Peyronie’s Disease:  In the individual with stable disease, symptoms have been clinically quiescent or unchanged for at least three months based on either individual report or clinician documentation. Pain with or without erection may be present but is less common. Stable disease means that the deformity is no longer progressive. Curvature may be uniplanar or biplanar and may not be dependent on the size and magnitude of the plaque. (AUA Guidelines for Peyronie’s 2015)
 
Treatment course, Peyronie’s Disease: A treatment course consists of 4 treatment cycles. If the curvature deformity is less than 15 degrees after the 1st, 2nd, or 3rd treatment cycle, or if further treatment is not clinically indicated, then subsequent treatment cycles should not be administered.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030)
for pharmacologic/biologic medications.  
  
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Injectable clostridial collagenase for any indication or circumstance not described above including but not limited to adhesive capsulitis, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
  
For members with contracts without primary coverage criteria, injectable clostridial collagenase for any indication or circumstance not described above including but not limited to, adhesive capsulitis is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective October 2020 to October 31, 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Dupuytren’s Contracture
 
Injectable clostridial collagenase for the treatment of Dupuytren’s contracture in adult individuals with a palpable cord meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes:
 
    1. Up to two joints in the same hand may be treated during a treatment visit.
    2. Inject 0.58 mg of clostridial collagenase into each palpable Dupuytren’s cord with a contracture.
    3. Injections and finger extension procedures may be administered up to 3 times per cord 4 week intervals.  (Limit: 3 injections per cord per lifetime).
  
Peyronie’s Disease
 
Injectable clostridial collagenase for the treatment of Peyronie’s disease (PD) in adult males meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when the following are met:
 
    1. Individual has:
a. A diagnosis of Peyronie’s disease AND
b. *Disease is stable, quiescent or unchanged for at least 3 months (See *stable disease below).
 2.  Must have a penile curvature greater than or equal to 30 degrees and less than or equal to 90 degrees.  
a. A treatment course consisting of 4 treatment cycles (2 injections per cycle with penile modeling for a total of 8 injections if required) will be approved.
b. Each treatment cycle may be repeated at 6 week intervals.  
c. If the curvature deformity is less than 15 degrees after the 1st, 2nd, or 3rd treatment cycle, or if  further treatment is not clinically indicated, then subsequent treatment cycles should not be administered
3. There will be a lifetime limit of 2 treatment courses (Up to 8 total treatment cycles).    
 
*Stable disease. In the individual with stable disease, symptoms have been clinically quiescent or unchanged for at least three months based on either individual report or clinician documentation. Pain with or without erection may be present but is less common. Stable disease means that the deformity is no longer progressive. Curvature may be uniplanar or biplanar and may not be dependent on the size and magnitude of the plaque. (AUA Guidelines for Peyronie’s 2015)
 
Dosage and administration
Dosing per FDA Guidelines
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030)
for pharmacologic/biologic medications.  
  
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Injectable clostridial collagenase for the treatment of any indication or circumstance other than those outlined above including but not limited to adhesive capsulitis, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
  
For members with contracts without primary coverage criteria, injectable clostridial collagenase for all other indications including, but not limited to, adhesive capsulitis is considered investigational.
  
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective June 2020
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Dupuytren’s Contracture
Injectable clostridial collagenase for the treatment of Dupuytren’s contracture in adult patients with a palpable cord meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
 
  1. Up to two joints in the same hand may be treated during a treatment visit.
  2. Inject 0.58 mg of clostridial collagenase into each palpable Dupuytren’s cord with a contracture.
  3. Injections and finger extension procedures may be administered up to 3 times per cord 4 week intervals.  (Limit: 3 injections per cord per lifetime).
 
Peyronie’s Disease
Injectable clostridial collagenase for the treatment of Peyronie’s disease (PD) in adult males meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness when the following are met:
 
  1. Individual has:
    • A diagnosis of Peyronie’s disease AND
    • Disease is stable, quiescent or unchanged for at least 3 months (Deformity no longer progressive).
2.  Must have a penile curvature greater than or equal to 30 degrees and less than or equal to 90 degrees.  
    •  A treatment course consisting of 4 treatment cycles (2 injections per cycle with penile modeling for a total of 8 injections if required) will be approved.
    • Each treatment cycle may be repeated at 6 week intervals.  
    • If the curvature deformity is less than 15 degrees after the 1st, 2nd, or 3rd treatment cycle, or if further treatment is not clinically indicated, then subsequent treatment cycles should not be administered
3. There will be a lifetime limit of 2 treatment courses (Up to 8 total treatment cycles).    
 
Dosage and administration:
    • Per FDA label guidelines
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Injectable clostridial collagenase for all other indications including, but not limited to adhesive capsulitis does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, injectable clostridial collagenase for all other indications including, but not limited to, adhesive capsulitis is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective February 2019
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Dupuytren’s Contracture
Injectable clostridial collagenase for the treatment of Dupuytren’s contracture in adult patients with a palpable cord meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
 
    1. Up to two joints in the same hand may be treated during a treatment visit.
    2. Inject 0.58 mg of clostridial collagenase into each palpable Dupuytren’s cord with a contracture.
    3. Injections and finger extension procedures may be administered up to 3 times per cord 4 week intervals.  (Limit: 3 injections per cord per lifetime).
 
Peyronie’s Disease
Injectable clostridial collagenase for the treatment of Peyronie’s disease (PD) in adult males meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness when the following are met:
 
    1.  Diagnosis of PD that has failed conservative treatment for at least 3 months prior to the initiation of clostridial collagenase treatment.
2.  Must have a penile curvature greater than or equal to 30 degrees and less than or equal to 90 degrees.  
 
        •  A treatment course consisting of 4 treatment cycles (2 injections per cycle with penile modeling for a total of 8 injections if required) will be approved.
        • Each treatment cycle may be repeated at 6 week intervals.  
        • If the curvature deformity is less than 15 degrees after the 1st, 2nd, or 3rd treatment cycle, or if further treatment is not clinically indicated, then subsequent treatment cycles should not be administered
 
3. There will be a lifetime limit of 2 treatment courses (Up to 8 total treatment cycles).    
 
Dosage and administration:
    • Per FDA label guidelines
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Injectable clostridial collagenase for all other indications including, but not limited to adhesive capsulitis does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, injectable clostridial collagenase for all other indications including, but not limited to, adhesive capsulitis is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective May 2014
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Injectable clostridial collagenase for the treatment of Dupuytren’s contracture in adult patients with a palpable cord meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for up to 3 injections per site, per lifetime at intervals of at least 4 weeks.  Injections may not exceed 0.58 mg per each individual injection.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Injectable clostridial collagenase for all other indications including, but not limited to, Peyronie’s disease, and adhesive capsulitis does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, injectable clostridial collagenase for all other indications including, but not limited to, Peyronie’s disease, and adhesive capsulitis is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Coverage Prior to Archival January 2013
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The injection of clostridial collagenase for the treatment of Dupuytren’s contracture does not meet primary coverage criteria for cost effectiveness.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The injection of clostridial collagenase for all other indications including, but not limited to, Peyronie’s disease, and adhesive capsulitis, does not meet primary coverage criteria for effectiveness.  Long term safety and effectiveness have not been reported.  Some members of the medical community have recommended additional clinical trials before this treatment is widely adopted.  
 
For contracts without primary coverage criteria the injection of clostridial collagenase for all other indications including, but not limited to, Dupuytren’s contracture, Peyronie’s disease, and adhesive capsulitis, is considered investigational.  Investigational services are an exclusion in the member benefit certificate.
 
Rationale:
A number of nonsurgical interventions for fibroproliferative disease have been studied. Investigations of a potential role for injectable clostridial collagenase have been ongoing over a period of 20 years. FDA approval has recently been granted for treatment of Dupuytren’s contracture with a palpable cord. Some authors include collagenase among standard injection therapies for Peyronie’s disease. Use of the material for treatment of conditions other than Dupuytren’s is an off-label application.
 
Dupuytren’s Disease (Dupuytren’s Contracture)
In 2009, Hurst and colleagues published a randomized, double-blind placebo-controlled, multicenter trial (16 sites) of collagenase clostridium histolyticum for Dupuytren’s contracture with 308 subjects with joint contractures of 20 degrees or more.  Joints were stratified according to type (metacarpophalangeal joints or proximal interphalangeal joint [PIP]) and severity of contracture and randomly assigned in a 2:1 ratio to receive up to 3 injections of either collagenase or placebo in the contracted collagen cord at 30-day intervals. Secondary and tertiary joints were identified for possible subsequent injections. Joints were manipulated one day after injection if necessary. The primary end point was reduction in contracture to 0-5 degrees of full extension 30 days after last injection. Twenty-six secondary end points were also evaluated. Recurrence of contracture was defined as an increase in joint contracture to >/= 20 degrees and was considered an adverse event. Efficacy results were based on 306 primary joints: 203 injected with collagenase and 103 injected with placebo. In the collagenase treated group, 130 of 203 (64%) cords met the primary end point versus 7 of 103 (6.8%) placebo injected cords (P<0.001). More than half of the collagenase injected joints that did not meet the primary end point did not receive the maximum allowable number of injections, most commonly because a cord could not be palpated or the patient was satisfied with the result. Median time to reach the primary end point for collagenase treated joints was 56 days. At the 90-day visit, there was no recurrence of contracture in collagenase treated primary joints that had reached the primary end point. When analyzed by joint type, more collagenase treated joints achieved the primary end point than placebo (metacarpophalangeal 76.7% vs. 7.2% and proximal interphalangeal joint 40.9% vs. 5.9%) (P<0.001 for both comparisons). The mean change in contracture from baseline to 30 days after last injection was 48.0 to 7.2 degrees in the collagen-injected metacarpophalangeal joints and 45.4 to 43.1 degrees in the placebo-injected metacarpophalangeal joints. Thirty days after last injection 84.7% of collagenase injected joints versus 11.7% of placebo injected joints showed clinical improvement. Results were better in metacarpophalangeal joints than in interphalangeal joints: 94.0% versus 67.1% in the collagenase group and 11.6% versus 11.8% in the placebo group. Overall, 96.6% of patients who received collagenase reported at least one treatment related adverse event. They had significantly more injection- and manipulation-related events, such as contusion, hemorrhage, injection-site pain, upper extremity pain, and lymphadenopathy (P</=0.02), than patients who received placebo injection. Most were mild or moderate in intensity, however 20 patients in the collagenase group and 2 in the placebo group reported events that were severe in intensity. Three severe adverse events were considered to be treatment related: a case of complex regional pain syndrome and 2 tendon ruptures, both requiring surgical procedures. The authors note that the timeframe of this study was insufficient to assess recurrence, and they could not make any claims about this outcome.
 
In a letter to the editor in response to publication of the study, Holzer and Holzer (2009) comment that successful treatment of Dupuytren’s disease correlates with the percentage of excised Dupuytren’s tissue and the extent of the intervention.  They caution that the value of collagenase injection must be confirmed in a long-term follow-up study that focuses on the recurrence rate.
 
Peyronie’s Disease
Russell and colleagues, 2007, authored a systematic review of plaque injection therapy that included 2 studies of collagenase in their analysis.  Both papers reported positive treatment outcomes. One study was rated, according to the Oxford Centre for Evidence-Based Medicine criteria, as level 2 (randomized controlled trial [RCT] with low power or <80% follow-up/retention or good-quality, randomized prospective cohort study) and the other level 4 (case series or poor-quality cohort or case-control study). These 2 studies are noted below.  Agents used in the other 19 studies reviewed were corticosteroid, verapamil, and interferon. In a 1985 paper Gelbard reported a series of 31 men treated, 20 showed improvement.  Pain was eliminated in 13 of 14 patients who experienced pain before treatment. One small corporeal rupture at the injection site was reported in one patient. No significant adverse events were reported in 9.8 months of follow-up. In a 1993 randomized placebo-controlled double-blind study with 49 subjects reported by the same author, the effects of collagenase and placebo on plaque size and penile deformity were investigated. For the group as a whole, treatment with collagenase was significantly more effective (p<0.007). Patients with lesser deformity responded more favorably to treatment.  In 2008, Jordan reported on a series of 25 patients with well-defined plaque treated with 3 intralesional injections of clostridial collagenase over 7-10 days with repeat treatment at 3 months. (8) Primary end points were changes from baseline in deviation angle and plaque size. Significant decreases from baseline were achieved in the mean deviation angle at months 3 (P = 0.0001) and 6 (P = 0.0012), plaque width at months 3 (P = 0.0052), 6 (P =0.0239), and 9 (P = 0.0484), and plaque length at months 3 (P =0.0018) and 6 (P = 0.0483). More than 50% of patients in this series considered themselves "very much improved" or "much improved" at all time points in the study, and the drug was generally well tolerated. An industry sponsored placebo controlled trial is underway - NCT00755222.
 
No studies including patients with adhesive capsulitis were identified in the literature search but there is an ongoing trial of collagenase in frozen shoulder - NCT00261196.
 
In summary, the evidence from one large clinical trial suggests that injectable clostridial collagenase provides short-term release of contracture in Dupuytren’s disease. However, longer term recurrence rates are not reported. A comparison of overall outcomes compared to surgical intervention may also be useful. Potentially serious adverse events also warrant further investigation. Small trials demonstrated short-term improvement in patients with Peyronie’s disease. Larger trials directly comparing outcomes with current treatment options are required.
 
Within the 2015 American Urological Association guidelines for Peyronie’s disease, it states that:
“ Clinicians may administer intralesional collagenase clostridium histolyticum in combination with modeling by the clinician and by the patient for the reduction of penile curvature in patients with stable Peyronie's disease, penile curvature >30° and <90°, and intact erectile function (with or without the use of medications). (Moderate Recommendation; Evidence Strength Grade B)”  
 
Discussion. The Panel emphasizes that the use of intralesional collagenase + clinician/patient modeling is appropriate only in the patient with stable disease with curvature > 30 degrees and < 90 degrees who has intact erectile function with or without the use of medications. In addition, the Panel notes that, to-date, clinical trials have not evaluated the use of collagenase in patients with hourglass deformity, ventral curvature, calcified plaque, or plaque located proximal to the base of the penis; outcomes for these patient subgroups are unknown. Further, the Panel notes that intralesional collagenase is a therapy for curvature; it does not treat pain or ED.
 
2011 Update
The policy was updated with a search of the MEDLINE database through January 2011.
 
This search found no new studies of collagenase for treatment of Peyronie’s Disease. Recruitment is under way for several studies at centers in the US (Clinicaltrials.gov).  
 
Two papers reporting long-term outcomes (recurrences) of treatment of Dupuytren’s contracture were identified in the search. Badalamente and Hurst reported on patients who participated in a double-blind phase III randomized controlled trial comparing collagenase and placebo injections (Badalamente, 2007). During the double-blind and open-label phases 62 joints (31 MCP and 31 PIP) were treated in 35 patients. Fifty-four (87%) were clinical successes. Twenty-seven joints were followed up for 24 months. Over the 24 months following the last injection, 5 joints had recurrences (1 MCP and 4 PIP), 1 before 12 months, 2 at 12 months, and 2 at 24 months after treatment. Three of these patients subsequently underwent fasciectomy. The most common adverse events were local reactions to injections. The limited patient follow-up makes it difficult to reach conclusions from this study.
 
In the second report, 23 patients who participated in a phase II clinical trial were contacted; eight patients completed 8-year follow-up (Watt, 2010). In the isolated metacarpophalangeal (MCP) group (n=6), average contracture was 57 degrees before treatment, 9 degrees at 1 week, 11 degrees at 1 year, and 23 degrees at 8-year follow-up. Four of 6 patients experienced recurrence by the 8 year follow-up. In the isolated proximal interphalangeal (PIP) joint group (n-2), both patients had recurrence by 8-year follow-up. Outcomes at specific intervals between 1 year and 8 years were not reported. Potential bias in patient selection and the small number of patients precludes drawing conclusions from this report.
 
In a recent review, Desai and Hentz make several observations regarding the role of collagenase in the treatment for Dupuytren’s contracture (Desai, 2010). They recommend caution when treating the small finger; all three tendon ruptures seen across all studies reported to the FDA and adverse events of boutonniere deformity and pulley injury occurred in the small finger. An active immune-response was seen in patients after injection of collagen in the clinical trials which suggests the possibility that effectiveness of subsequent injects might be impacted. The authors also note that long term effects of repeat injections and contracture recurrence have yet to be studied and direct comparisons with the current gold standard, palmar fasciectomy, have not been made.
 
No studies that will report on long-term outcomes were found in a search of the National Institutes of Health clinical trials database. Several industry-sponsored studies of collagenase injection for residual Dupuytren’s contracture are underway (Clinicaltrials.gov).
 
2012 Update
A literature search was conducted in PubMed through September 2012.  Chen and colleagues published a systematic review in 2011 of various treatments for Dupuytren’s contracture.  Studies published through December 2010 were examined and included 4 prospective studies (including 2 randomized studies) on collagenase injections, 6 studies on open partial fasciotomy (including 2 randomized studies) and 3 studies on needle aponeurotomy. Sample sizes for all of the studies included in the review ranged from 13–261 patients. The authors found recurrence rates for collagenase injections (mean follow-up times of 120 days to 4 years) ranged from 10–31%. Needle aponeurotomy had the highest recurrence rates of 50-58% (mean follow-up of 3-5 years), which were significantly higher than the open partial fasciectomy recurrence rates of 12–39% (mean follow-up time of 1.5–7.3 years). Additionally, open partial fasciectomy recurrence rates were significantly higher than collagenase injection. Complications occurred most often with open partial fasciectomy, although 2 cord ruptures were reported with collagenase injection. The authors concluded further studies are needed to understand the long–term outcomes of these interventions and how to address contracture recurrence. It was also noted that it is unclear whether collagenase injection can be used for Dupuytren’s revision.
 
In 2010, Gilpin and colleagues published results of the CORD II study.  In this study, 66 patients were randomized to receive collagenase injection (45 cords) or placebo (21 cords) in the 90-day, double-blind phase followed by an open label phase of 9 months. The authors reported, within 30 days, collagenase injections resulted in significantly more cord contracture improvement from baseline to within 0-5 degrees of normal than placebo (44.4% vs. 4.8%, respectively). Results after the open-label treatment were reported to be similar to the double-blind phase. Recurrence of contracture (defined as increase of contracture to 20 degrees or more) did not occur during the 12-month follow-up. All study participants experienced mild adverse events (e.g., swelling and pain at injection site). Three serious adverse effects related to the treatment were reported. A flexion pulley rupture of the left small finger occurred in one patient while rapid thickening of the treated cord and sensory abnormalities occurred in another patient.
 
Ongoing Clinical Trials
Several studies were identified on injectable clostridial collagenase injections in a search of the National Institutes of Health clinical trials database online at clinicaltrials.gov, including industry-sponsored studies of collagenase injections for Dupuytren’s contracture. In the CORDLESS observational study (Collagenase Optimal Reduction of Dupuytren's - Long-term Evaluation of Success Study), the long-term durability and safety of clostridial collagenase injections for Dupuytren’s contracture will be evaluated yearly in 600 patients (NCT00954746). This trial began in July 2009, is currently enrolling by invitation only and is expected to be completed in March 2013. In a Phase IV, randomized trial, the effects of delayed manipulation of digits following collagenase injections for the treatment of Dupuytren's contracture will be examined in 60 patients (NCT01226121). Collagenase injections to the thumb for Dupuytren’s contracture treatment will be studied in 10 patients in NCT01265420. Outcomes after collagenase injection for Dupuytren’s contracture will be studied in a Phase III study of 250 patients followed for 11 months (NCT01229436). This trial is expected to be completed in September 2010. The safety and efficacy of 2 injections of clostridial collagenase into the same hand of 60 patients with multiple Dupuytren’s contractures will be evaluated in an open-label, Phase III study. (NCT01407068).
 
Three Phase III studies were identified to evaluate clostridial collagenase injections for patients with Peyronie’s disease that are expected to be completed in March 2012 (NCT01243411, NCT01221623, and NCT01221597). No studies were identified on collagenase injections for adhesive capsulitis.
 
2014 Update
This policy is being reactivated with a literature search through April 2014 using the MEDLINE database. Following archival, the FDA approved the used of Xiaflex for the treatment of Peyronie’s disease. The available literature on the use of clostridial collagenase for Peyronie’s Disease, Dupuytren’s Disease and other indications are summarized below.
 
Dupuytren’s Disease (Dupuytren’s Contracture)
In 2013, Witthaut and colleagues published the findings from 2 concurrent open-label, single-arm studies (JOINT I and JOINT II) designed to evaluate the efficacy and safety of collagenase injections (0.58 mg collagenase per injection) used to reduce the degree of contracture in patients with advanced Dupuytren’s contracture at 9 months of follow-up (Witthaut, 2013). The primary endpoint was clinical success, defined as a reduction in contracture to within 0 to 5 degrees of full extension 30 days after the last injection. A secondary endpoint was clinical improvement, defined as 50% or more reduction from baseline contracture. Dupuytren cords affecting 879 joints (531 MCP and 348 PIP) in 587 patients were administered collagenase injections at 14 American (JOINT I) and 20 Australian/European sites (JOINT II). Similar results were reported in both studies. Seventy-one percent of joints (n=625) did not require a second injection, and 89% of joints did not require a third injection. Clinical success was achieved in 497 (57%) of treated joints using 1.2 ± 0.5 (mean ± standard deviation) collagenase injections per cord. More MCP than PIP joints achieved clinical success (70% and 37%, respectively) or clinical improvement (89% and 58%, respectively). For joints not achieving clinical success and not receiving the maximum 3 injections (128 MCP and 173 PIP joint), reasons included no palpable cord (MCP joint, 52%; PIP joint, 44%); injections in other cords reached the protocol-specified per-patient maximum of 5 per patient (MCP joint, 19%; PIP joint, 21%); and satisfied with response (MCP joint, 8%; PIP joint, 9%). When data from JOINT I and JOINT II were pooled to evaluate clinical success by contracture severity, the MCP and PIP joints with lesser contracture severity (i.e., ≤50° and ≤40°, respectively) showed a better response than more severely contracted joints. After 9 months of follow-up, 71% of patients were “very satisfied” and 21% “quite satisfied” with collagenase treatment, using a 5-point Likert-type scale. For physician ratings of improvement, 47% rated change from baseline as “very much improved,” and 35% as “much improved” using a 7-point scale (Witthaut, 2013).
 
The relatively short-term (9-month) follow-up period in these 2 JOINT studies limits the ability to make conclusions regarding long-term outcomes, including the likelihood of recurrence. Patients who achieved clinical success in these 2 JOINT studies had the option to enroll in a 5-year follow-up study, which also included patients from the 2 CORD studies reviewed above. In 2013, Peimer and colleagues published interim data after the third year of the above-mentioned 5-year follow-up study, Collagenase Option for Reduction of Dupuytren Long-Term Evaluation of Safety Study (CORDLESS) (Peimer, 2013).  Of 1,080 collagenase-treated joints, 623 (451 MCP, 172 PIP) had achieved 0 to 5 degrees contracture in the original studies. Recurrence occurred in 35% of the successfully treated joints over the 3-year follow-up period. No long-term complications attributed to collagenase injections were reported during this follow-up period (Peimer, 2013).
 
In 2013, Raven and colleagues published a subgroup analysis of data pooled from the above 3 RCTs (CORD I, CORD II, and Badalamente and Hurst) of collagenase treatment of Dupuytren-related contractures (Raven, 2013). This analysis included 271 patients with MCP (n=167) or PIP (n=104) joint contractures greater than or equal to 20 degrees treated with collagenase injections (0.58 mg collagenase per injection). Subgroups included age, sex, and diabetes status. Endpoints included rate of clinical success (reduction in contracture to 0-5 degrees of normal) and percentage of adverse events. There was no significant difference in clinical success by age, diabetes status, or sex, with 63% of cases reaching the endpoint. In addition, there was no difference in complication rates among the subgroups, with peripheral edema, contusion, and injection-site hemorrhage being most common (Raven, 2013).
 
Peyronie’s Disease
In 2013, Gelbard and colleagues published the results of 2 double-blind, placebo-controlled RCTs, IMPRESS (Investigation for Maximal Peyronie’s Reduction Efficacy and Safety Studies) I and II, which examined the clinical efficacy and safety of collagenase injections in subjects with Peyronie’s disease (Gelbard, 2013). These RCTs were sponsored by the manufacturer (Auxilium Pharmaceuticals), the findings of which were submitted to the FDA in support of their biologics license application. These 2 studies examined collagenase injections in 417 and 415 participants, respectively, through a maximum of 4 treatment cycles, each separated by 6 weeks (for up to 8 injections of 0.58 mg collagenase). Men were stratified by baseline penile curvature (30 to 60 vs. 61 to 90 degrees) and randomized to collagenase injections or placebo in a 2:1 ratio. The primary outcomes were the percent change in the penile curvature abnormality and the change in the Peyronie’s Disease Questionnaire (PDQ, developed by the manufacturer) “symptoms bother” score from baseline to 52 weeks. Data from the IMPRESS I and II studies were combined. Participants treated with collagenase injections showed a mean percent improvement in penile curvature abnormality of 34%, compared to 18% improvement in penile curvature in the placebo group; this change in curvature and the percent improvement in the collagenase group were significantly greater than in the placebo group (each p <0.0001). The mean change in the PDQ symptom bother domain score was significantly improved in the collagenase group vs. the placebo group (-2.8 ± 3.8 vs. -1.8 ± 3.5, p=0.0037). The most frequently reported complications (≥45%) in the collagenase-treated group included penile ecchymosis, penile swelling and penile pain. Six participants experienced treatment-related serious adverse events, including corporeal rupture in 3 cases and penile hematoma in the other 3 cases. The 3 corporeal ruptures and one hematoma were successfully repaired surgically. Of the 2 remaining penile hematomas, one case was successfully resolved without intervention and the other resolved with aspiration (Gelbard, 2013).
 
In summary, these two manufacturer-sponsored double-blind, placebo-controlled randomized trials, have demonstrated short-term improvement in patients with Peyronie’s disease. Larger trials directly comparing outcomes with current treatment options; assessing the long-term durability and safety; and the assessment of meaningful clinical outcomes are required.
 
Adhesive Capsulitis
No studies including patients with adhesive capsulitis were identified in the literature search.
 
Ongoing Clinical Trials
Several studies on injectable clostridial collagenase injections for were identified in a search of online site ClinicalTrials.gov in May 2014:
 
Dupuytren’s contractures
 
  • In a randomized study of 50 patients, collagenase injections will be compared to percutaneous needle fasciotomy for Dupuytren’s contracture (NCT01538017); this study is active but not currently recruiting participants with an estimated completion date of January 2015.
  • In the CORDLESS observational study (Collagenase Optimal Reduction of Dupuytren's - Long-term Evaluation of Success Study), the long-term durability and safety of clostridial collagenase injections for Dupuytren’s contracture will be evaluated yearly in 600 patients (NCT00954746); this is a 5-year follow-up study of which interim data after the third-year by Peimer and colleagues have been reported above. This study is active but not recruiting.
  • Outcomes after collagenase injection for Dupuytren’s contracture has been studied in a Phase III study of 254 patients followed for 11 months (NCT01229436); this study has been completed, but no results have been published.
  • The safety and efficacy of 2 injections of clostridial collagenase into the same hand of 60 patients with multiple Dupuytren’s contractures has been evaluated in a Phase III study (NCT01407068); this study has been completed, but no results have been published.
  • Retreatment with collagenase injections for recurrent Dupytren’s contracture will be evaluated in a nonrandomized study of 100 patients (NCT01498640); this study is ongoing, but not recruiting participants with an estimated completion date of September 2013.
 
Adhesive capsulitis
  • Injectable collagenase has been evaluated in a randomized study of 50 subjects for adhesive capsulitis of the shoulder (NCT01483963); this study has been completed, but no results have been published.
 
Peyronie’s disease
  • Three Phase III studies were identified to evaluate clostridial collagenase injections for patients with Peyronie’s disease (NCT01243411, NCT01221623, and NCT01221597); the latter 2 studies are the double-blind, placebo-controlled RCTs, IMPRESS I and II by Gelbard and colleagues reported above. All three studies are reported as completed.
 
2015 Update
A literature search conducted through February 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2014, Peimer and colleagues summarized the safety and tolerability of clostridial collagenase or surgical treatment (fasciectomy) for Dupuytren contracture (Peimer, 2014). The safety of clostridial collagenase was based on 11 clinical trials, including 1082 patients, while the safety of fasciectomy was based on 48 European studies, including 7727 patients. Compared with rates reported after fasciectomy, clostridial collagenase-treated patients had lower rates of nerve injury (median 0% vs 3.8%), neurapraxia (4.4% vs 9.4%), complex regional pain syndrome (0.1% vs 4.5%) and arterial injury (0% vs 5.5%), but higher reported rates of tendon injury (0.3% vs 0.1%), skin injury (16.2% vs 2.8%), and hematoma (77.75 vs 2%). Pooled estimates and statistical comparisons are not reported.
 
Randomized Controlled Trials
In 2014, McGrouther and colleagues reported results from a post hoc subgroup analysis of the randomized and open label phases CORD I and CORD II studies to evaluate the efficacy and safety of clostridial collagenase in the subgroup of 58 Dupuytren contracture patients (67 joints) with up to 2 joints affected and moderate disease according to British Society of Surgery of the Hand classification (McGrouther, 2014).  Of the subgroup, 82% met the primary endpoint of clinical success, defined as a reduction in contracture to within 5 degrees of full extension 30 days after the last injection. Recurrence of the contracture (defined as an increase n joint contracture to ≥20° in the presence of a palpable cord in joints that had previously had clinical success) occurred in 3.8% of joints treated. Fifty-five patients (94.8%) developed a treatment related adverse events, all of which were considered milk (eg, pain and swelling at the injection site.
 
Nonrandomized, Comparative Studies
Since the publication of the RCTs described above, several smaller nonrandomized studies have compared clostridial collagenase to surgical procedures for the treatment of Dupuytren contracture. Naam and colleagues conducted a retrospective comparison of patients with Dupuytren contracture affecting at least 1 joint with a palpable cord who underwent clostridial collagenase injections (N=25) or fasciectomy (N=21) (Naam, 2013). Some patients who received clostridial collagenase injections were enrolled in the JOINT 1study, described below. Over an average follow up of 32 months for patients treated with clostridial collagenase and 39 months for those treated with fasciectomy, the mean post-treatment contracture, decrease in contracture from baseline, and increase in range of motion from baseline at the MP and PIP joints did not significantly differ. The mean post-treatment range of motion at the MP joint was significantly higher in the clostridial collagenase-treated patients (90.7 degrees vs 83.3 degrees, P=0.02), while the post-treatment range of motion at the PIP was higher in the fasciectomy-treated patients, although the difference did not reach statistical significance (67.5 degrees vs 88.8 degrees, P=0.06). Complication rates were similar in both groups, although patients who received clostridial collagenase returned more quickly to work and to normal daily activities.
 
In a small study from a single United Kingdom center, Povlsen and colleagues prospectively compared outcomes for patients with single-digit Dupuytren contraction who underwent open fasciectomy (N=10) or clostridial collagenase injection followed by manipulation (N=10) (Povlsen, 2014). Total active movement at the PIP joint and at the MCP and PIP joints combined were statistically better in the clostridial collagenase group (P=0.01 and P=0.0258, respectively) in the short term (i.e., days) after the procedure. Longer term follow up is not reported.
 
Noncomparative Studies
A number of single-arm studies have reported outcomes after clostridial collagenase injections for Dupuytren contracture, the largest of which were the JOINT I, JOINT II, and CORDLESS studies. Other smaller single arm studies are summarized below:
 
Watt and colleagues reported on collagenase injection as nonsurgical treatment of Dupuytren's disease: 8-year follow-up on 23 subjects (8 with long-term); overview of findings – in patients with isolated metacarpophalangeal (MCP) contracture (N=6), 4 experienced recurrence by 8 years (Watt, 2010).
 
Alberton and colleagues reported on the efficacy and safety of collagenase Clostridium histolyticum injection for Dupuytren contracture: report of 40 cases; 40 subjects (32 with MCP and 8 with PIP contracture); follow up period of 6 months; overview of findings - in patients with isolated PIP contracture (N=2), both experienced recurrence by 8 years (Alberton, 2013).
 
Warwick and colleagues reported on Collagenase Clostridium histolyticum in patients with Dupuytren's contracture: results from POINT X, an open-label study of clinical and patient reported Outcomes; 254 subjects; the follow up is at 6 months; overview of findings – at follow up, 87% of patients and 86% of physicians were very satisfied or satisfied with treatment. Treatment-related AEs occurred in 88% of patients, most commonly peripheral edema (44%), extremity pain (26%), and injection site pain (21%) (Warwick, 2014).
 
Verheyden and colleagues reported on Early outcomes of a sequential series of 144 patients with Dupuytren's contracture treated by collagenase injection using an increased dose, multi-cord technique; 144 subjects; follow up period mean 35 days for patients with pretendinous cords; 38 days for patients with spiral cords; overview of findings - demonstrated the feasibility of a novel technique: patients were treated with the entire bottle of enzyme, approximately 0.78 mg, along with use of a novel slow intracord multi-cord injection; % achieving complete correction for MCP pretendinous cords: 83%, for PIP spiral cords: 58%; adverse events all patients developed swelling, pain, and ecchymosis at the injection site, 35 skin lacerations were noted (Verheyden, 2014).
 
McMahon and colleagues reported on Examining the efficacy and maintenance of contracture correction after collagenase clostridium histolyticum treatment for Dupuytren's disease; 102subjects treated (48 with  follow up available); follow up at 15  months; overview of findings – After cord rupture, contracture decreased from 48° (± 21°) to 7 (±11°) in 64 joints treated, at latest follow up, mean contracture was 15° (±19°), Recurrence rates: 11/46 (24%) of MCP joints treated; 7/18 (39%) of PIP joints treated (McMahon, 2013).
 
Sood and colleagure reported on treatment of dupuytren disease with injectable collagenase in a veteran population: a case series at the department of veterans affairs new jersey health care system; 16  subjects; follow up 12.3 months; overview of findings – of 27 joints treated, 74.1% had ≥51% reduction of the original extension deficit, Recurrence rates: of 18 MCP joints treated, recurrence to ≥50% occurred, on 0%, but recurrence to 5-50° occurred in 33.3%; of 9 proximal interphalangeal (PIP) joints treated, recurrence to ≥40° occurred in 18.5% and to 5-40° occurred in 7.4%, most patients (93.8%) experienced local AEs (eg, ecchymosis, skin laceration, injection-site swelling or hemorrhage) (Sood, 2014).
 
In summary the most direct evidence related to the use of clostridial collagenase for Dupuytren contractures comes from several RCTs which compare clostridial collagenase to placebo injections, and generally show high rates of contracture resolution. This evidence is supported by nonrandomized comparative studies comparing clostridial collagenase to surgery, the largest of which, with 46 patients, reported similar outcomes with faster return-to-work and return-to-usual activities rates with clostridial collagenase. Rates of local adverse effects, including local swelling, pain, and ecchymosis, are generally high.
 
Peyronie Disease
 
Randomized, Controlled Trials
The development and validation of the PDQ was described by Hellstrom and colleagues (Hellstrom, 2013). Investigators developed the PDQ to quantitatively assess the symptoms and psychosexual consequences of Peyronie disease by provided 3 subscale domain scores, including psychological/physical symptoms (6 items), penile pain (3 items), and symptom bother (4 scored items and 2 yes/no questions). Questions were evaluated based on baseline data for 679 patients in IMPRESS I and II who had been sexually active in the last 3 months (81% of the total 836 enrolled). PDQ domain scores did not significantly differentiate between patients with a different extent of curvature abnormality.
 
Noncomparative Studies
Several case series report outcomes from the treatment of clostridial collagenase for Peyronie disease.
 
The most direct evidence related to the use of clostridial collagenase injections to treat Peyronie disease comes from 2 industry-sponsored RCTs that compared clostridial collagenase to placebo. Clostridial collagenase-treated subjects demonstrated significant improvements in penile curvature (absolute percentage improvement 16%) and reported improvements their degree of bother related to their Peyronie disease. However, it is not clear that these improvements in curvature or in the degree of symptom bother translated to differences in patient outcomes, and whether the benefit of treatment exceeds the risks.
 
Ongoing and Unpublished Clinical Trials
The following studies on injectable clostridial collagenase injections for fibroproliferative disorders were identified in a search of the online site ClinicalTrials.gov in September 2014.
 
Dupuytren Contractures
  • Injectable Collagenase and Percutaneous Needle Fasciotomy for Dupuytren's Contracture (NCT01538017) – This is a randomized, open-label trial to compare clostridial collagenase with percutaneous needle fasciotomy in patients with Dupuytren contraction. Enrollment is planned for 50 subjects; the estimated study completion date is January 2015.
  • Phase 2a Dose-ranging Study to Evaluate Safety and Effectiveness of AA4500 in Treatment of Dupuytren's Disease Nodules (NCT02193828) – This is a double blinded RCT to compare the safety and efficacy of clostridial collagenase to placebo in the treatment of Dupuytren disease with at least 1 palmar nodule in the affected hand. Enrollment is planned for 90 subjects; the estimated study completion date is February 2015.
 
Adhesive Capsulitis
  • A Phase 2a, Open-label, Dose-ranging Study of the Safety and Effectiveness of AA4500 for the Treatment of Adhesive Capsulitis of the Shoulder (NCT01483963) – This is a randomized, unblinded trail to evaluate clostridial collagenase in the treatment of shoulder adhesive capsulitis. Enrollment was planned for 50 subjects. The study is listed as completed, but no results have been published.
  • Clinical Study for the Treatment of Adhesive Capsulitis of the Shoulder (AC) (NCT02006719) – This is a double blinded RCT to compare clostridial collagenase to placebo in the treatment of adhesive capsulitis. The primary outcome is the change (degrees) from baseline to the Day 95 follow-up in active forward flexion in the affected shoulder. Enrollment is planned for 300 subjects;the estimated study completion date is January 2015.
 
For other disorders, there is less evidence. Five studies, including 2 manufacturer-sponsored doubl-blind, placebo-controlled randomized trials, have demonstrated short-term improvement in penile curvature and self-reported distress from Peyronie-related symptoms in patients with Peyronie disease. However, evidence demonstrating health outcome improvements are lacking, as are comparisons with current treatments. Clostridial collagenase treatment for Peyronie plaques is associated with relatively high rates of risk for significant local adverse effects. No published literature that addressed the treatment of adhesive capsulitis with clostridial collagenase was identified. Based on the available evidence and clinical input, injection of clostridial collagenase is considered investigational for all other treatment indications, including Peyronie disease and adhesive capsulitis.
 
2016 Update
A literature search through April 2016 did not reveal any new information that would prompt a change in the coverage statement. Below is a summary of the key identified literature.
 
Dupuytren Disease (Dupuytren Contracture)
 
Nonrandomized Comparative Studies
Zhou et al compared outcomes for patients who underwent clostridial collagenase injection or limited fasciectomy for Dupuytren contracture at 7 sites in the Netherlands (Zhou, 2015).  A total of 218 subjects met inclusion criteria (104 treated with clostridial collagenase, 114 treated with limited fasciectomy). After propensity score matching, the final analysis group included 66 subjects with each treatment. At last follow-up at 6 to 12 weeks postprocedure, the residual contracture for affected MCP joints did not differ significantly between groups (13° for clostridial collagenase vs 6° for limited fasciectomy, p=0.095), while affected PIP joints had significantly worse residual contracture in the collagenase group (25° vs 15°, p=0.010). Fewer adverse events occurred among clostridial collagenase‒treated subjects.
 
Noncomparative Studies
Five-year follow-up from the CORDLESS registry (discussed in a previous update) were reported in 2015 (Peimer, 2015). Recurrence occurred in 47% (291/623) of successfully treated joints.
 
Badalamente et al published a pooled analysis of data from the CORD I and II trials (described in Randomized Controlled Trials section above) and the JOINT I and II trials reporting on outcomes for clostridial collagenase for PIP contractures (Badalamente, 2015). The pooled analysis included 644 PIP joints in 506 patients, of which 60% (384 joints), 24% (154 joints), and 16% (100 joints) were treated with 1, 2, and 3 injections, respectively. Clinical success (0°-5° of full extension) occurred in 27% of joints after 1 injection and 34% after the last injection. Clinical improvement occurred in 49% of joints after 1 injection and 585 after the last injection. Six treatment-related serious adverse events occurred, including 2 tendon ruptures and 1 case each of tendon injury, complex regional pain syndrome, finger deformity, and tendonitis.
 
In 2015, Gaston et al reported safety and efficacy outcomes of a phase 3b, open-label study of the concurrent administration of 2 clostridial collagenase injections into cords in the same hand to treat 2 joints with Dupuytren contractures (Gaston, 2015). The study enrolled 715 patients with 725 joint pairs treated; 3 patients were lost to follow-up, 3 patients withdrew consent, and 1 patient did not have a post-baseline efficacy assessment. Seven hundred fourteen patients with 724 joint pairs were included in a modified intention-to-treat efficacy analysis. Joint pairs treated included MCP and PIP joints on the same finger, 2 MCP joints on different fingers, 2 PIP joints on different fingers, and 1 MCP and 1 PIP joint on different fingers in 48%, 34%, 10%, and 8% of subjects, respectively. The percent improvement in fixed flexion contracture was 72%, 84%, 60%, and 68% in patients who had treatment of the MCP/PIP joints (same finger), 2 MCP joints (different fingers), 2 PIP joints (different fingers), and MCP/PIP joints (different fingers), respectively. At least 1 treatment-related adverse event occurred in 95% of subjects, most of which were mild or moderate. Six patients had treatment-related or possibly treatment-related serious adverse events.
 
Peyronie Disease
 
Randomized Controlled Trials
In 2015, Lipshultz et al reported post hoc subgroup analyses from the combined data from the IMPRESS I and II studies (Lipshultz, 2015). This analysis included a modified intention-to-treat population of 612 subjects who had both a penile curvature deformity measurement and a PDQ response at baseline and at least 1 subsequent time point after the first injection of clostridial collagenase. Subgroups included those stratified based on duration of illness, degree of plaque calcification, and International Index of Erectile Function (IIEF) severity score. Reductions in penile curvature deformity occurred in all groups; penile curvature deformity reductions were significantly greater with clostridial collagenase than with placebo for those with baseline penile curvature 30° to 60° and 61° to 90°, disease duration over 2 years, no calcification, and IIEF severity score of 17 or greater. Peyronie disease symptom bother reductions were
significantly greater with clostridial collagenase than with placebo for those with penile curvature 30° to 60°, disease duration over 4 years, no calcification, and IIEF scores 1 to 5 (no sexual activity) and 17 or greater. However, generalization of this analysis is limited by its post hoc design and small subgroups.
 
Noncomparative Studies
A single-arm, open-label trial reported by Levine et al described outcomes for 238 subjects with Peyronie disease treated with clostridial collagenase with both a penile curvature measurement and a PDQ response at baseline and at least 1 subsequent time point (of 347 total subjects treated) (Levine, 2015). The degree of penile curvature improved from baseline to week 36 (34.4%; 95% CI, 31.2 to 37.6%) and PDQ Symptom Bother score (mean change, 3.3; 95% CI, 2.8 to 3.7). However, the lack of comparison group and exclusion of a high proportion of subjects missing follow-up data limit conclusions that can be drawn.
 
Carson et al reported serious and nonserious adverse events after clostridial collagenase for Peyronie disease in a pooled analysis of clostridial collagenase recipients from 6 trials (N=1044) (Carson, 2015). Of treated patients, 85.8% (n=896) reported at least 1 treatment-related adverse event, most frequently penile hematoma in more than 25.0% of patients. Nine patients (0.9%) had a treatment-related serious adverse event involving significant penile hematoma or corporal rupture.  
 
2017 Update
A literature search conducted through April 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Smeraglia and colleagues reported results of a systematic review of studies reporting on clostridial collagenase injections for Dupuytren contracture (Smeraglia, 2016). The review included 43 studies (total N=6795 patients) published from 2000 to 2015, with some overlap across studies in terms of patient populations. Mean follow-up was 15 months (range, 1-96 months). Eighteen studies reported on primary outcomes of clinical satisfaction of patients and residual contracture of less than 5°, and 9 studies reported on patient satisfaction.
 
Brazzelli and coleagues reported on a Health Technology Assessment including a systematic review and economic evaluation of clostridial collagenase for the treatment of Dupuytren contracture (Brazzelli, 2015). The review included randomized controlled trials (RCTs), nonrandomized comparative studies, and observational studies with collagenase and/or surgical interventions, in patients with a palpable Dupuytren cord. The reviewers included the following studies: “Five RCTs comparing collagenase with placebo (493 participants), three RCTs comparing surgical techniques (334 participants), two non-randomised studies comparing collagenase and surgery (105 participants), five non-randomised comparative studies assessing various surgical procedures (3571 participants) and 15 collagenase case series (3154 participants).” No head-to-head RCTs of clostridial collagenase compared with surgery were identified by meta-analysis. Of the 5 RCTs comparing collagenase with placebo, 3 were included in a meta-analysis. In pooled analysis, the proportion of all first, first metacarpophalangeal (MCP), first proximal interphalangeal (PIP) joints achieving clinical success favored clostridial collagenase (relative risk [RR], 10.21; 95% confidence interval [CI], 5.29 to 19.69; I2=0%; RR=10.27; 95% CI, 4.88 to 21.65; I2=0%; RR=6.90; 95% CI, 4.28 to 11.12; I2=0%, respectively). However, rates of local adverse events were higher in clostridial collagenase-treated patients.
 
Carson and colleagues reported a pooled analysis of 6 clinical studies to evaluate safety outcomes for clostridial collagenase for Peyronie disease (Carson, 2015). Studies included were phase 2 and 3 industry-sponsored trials of clostridial collagenase, which are included in the Randomized Controlled Trials section below. A total of 1044 patients were included in the pooled safety analysis, of whom 85.8% had a treatment-related adverse event, most of which (75.2%) were mild or moderate in severity. Approximately 1% (n=9) of patients had a treatment-related serious adverse event, including 5 cases of penile hematoma and 4 cases of corporal rupture.
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2018. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
National Institute for Health and Care Excellence  
In 2017, the National Institute for Health and Care Excellence recommended the use of collagenase Clostridium histolyticum to treat adults with Dupuytren contracture in cases of moderate disease where percutaneous needle fasciotomy is not an option (NICE, 2017). The Institute advised that the decision to use collagenase clostridium rather than limited fasciectomy should be made only after thorough discussion between the patient and caregiver; the Institute further defined appropriate outpatient treatment as consisting of a single injection at a time, and administered by a qualified hand surgeon.
 
2019 Update
A literature search conducted through April 2019 did not reveal any new information that would prompt a change in the coverage statement.
 
2020 Update
A literature search was conducted through March 2020.  There was no new information identified that would prompt a change in the coverage statement.  
 
Peyronie's Disease
The 2015 American Urological Association guidelines for Peyronie’s disease, states that:“Clinicians may administer intralesional collagenase clostridium histolyticum in combination with modeling by the clinician and by the patient for the reduction of penile curvature in patients with stable Peyronie's disease, penile curvature >30° and <90°, and intact erectile
function (with or without the use of medications).” (Moderate Recommendation; Evidence Strength Grade B)”  
Discussion. The Panel emphasizes that the use of intralesional collagenase + clinician/patient modeling is appropriate only in the patient with stable disease with curvature > 30 degrees and < 90 degrees who has intact erectile function with or without the use of medications. In addition, the Panel notes that, to-date, clinical trials have not evaluated the use of collagenase in patients with hourglass deformity, ventral curvature, calcified plaque, or plaque located proximal to the base of the penis; outcomes for these patient subgroups are unknown. Further, the Panel notes that intralesional collagenase is a therapy for curvature; it does not treat pain or ED.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2023. No new literature was identified that would prompt a change in the coverage statement.
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2024. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
20527Injection, enzyme (eg, collagenase), palmar fascial cord (ie, Dupuytren's contracture)
20550Injection(s); single tendon sheath, or ligament, aponeurosis (eg, plantar &quot;fascia&quot;)
26341Manipulation, palmar fascial cord (ie, Dupuytren's cord), post enzyme injection (eg, collagenase), single cord
54200Injection procedure for Peyronie disease;
J0775Injection, collagenase, clostridium histolyticum, 0.01 mg
J3590Unclassified biologics
References: Abe Y.(2020) Comparison of Treatment Outcomes after Collagenase Injection and Percutaneous Needle Fasciotomy for Dupuytren's Contracture: Objective and Subjective Comparisons with a 3-Year Follow-Up. Plast Reconstr Surg. Jun 2020; 145(6): 1464-1474. PMID 32459776

Alberton F, Corain M, Garofano A, et al.(2013) Efficacy and safety of collagenase Clostridium histolyticum injection for Dupuytren contracture: report of 40 cases. Musculoskelet Surg. Nov 20 2013. PMID 24254968

Atroshi I, Nordenskjold J, Lauritzson A, et al.(2015) Collagenase treatment of Dupuytren's contracture using a modified injection method: a prospective cohort study of skin tears in 164 hands, including short-term outcome. Acta Orthop. Jun 2015;86(3):310-315. PMID 25695745

Badalamente MA, Hurst LC, Benhaim P, et al.(2015) Efficacy and safety of collagenase clostridium histolyticum in the treatment of proximal interphalangeal joints in dupuytren contracture: combined analysis of 4 phase 3 clinical trials. The Journal of hand surgery. May 2015;40(5):975-983. PMID 25843533

Badalamente MA, Hurst LC.(2007) Efficacy and safety of injectable mixed collagenase subtypes in the treatment of Dupuytren’s contracture. J Hand Surg 2007; 32A(6):767-74.

Brazzelli M, Cruickshank M, Tassie E, et al.(2015) Collagenase clostridium histolyticum for the treatment of Dupuytren's contracture: systematic review and economic evaluation. Health Technol Assess. Oct 2015;19(90):1-202. PMID 26524616

Carson CC, 3rd, Sadeghi-Nejad H, Tursi JP, et al.(2015) Analysis of the clinical safety of intralesional injection of collagenase Clostridium histolyticum (CCH) for adults with Peyronie's disease (PD). BJU Int. Nov 2015;116(5):815-822. PMID 25818264

Carson CC, 3rd, Sadeghi-Nejad H, Tursi JP, et al.(2015) Analysis of the clinical safety of intralesional injection of collagenase Clostridium histolyticum (CCH) for adults with Peyronie's disease (PD). BJU Int. Nov 2015;116(5):815-822. PMID 25818264

Chen NC, Srinivasan RC, Shauver MJ et al.(2011) A systematic review of outcomes of fasciotomy, aponeurotomy, and collagenase treatments for Dupuytren’s contracture. Hand 2011; 6(3):250-5. Available online at: http://www.springerlink.com/content/ak764w413n378314/fulltext.pdf .

Coyne KS, Currie BM, Thompson CL, et al.(2015) Responsiveness of the Peyronie's Disease Questionnaire (PDQ). The journal of sexual medicine. Apr 2015;12(4):1072-1079. PMID 25664497

Desai SS, Hentz VR.(2010) Collagenase clostridium histolyticum for Dupuytren’s contracture. Expert Opin Biol Ther 2010; 10(9):1395-404.

FDA News Release. Dec. 6, 2013.(2013) FDA approves first drug treatment for Peyronie’s disease. Accessed at www.fda.gov.

Gaston RG, Larsen SE, Pess GM, et al.(2015) The Efficacy and Safety of Concurrent Collagenase Clostridium Histolyticum Injections for 2 Dupuytren Contractures in the Same Hand: A Prospective, Multicenter Study. The Journal of hand surgery. Oct 2015;40(10):1963-1971. PMID 26216077

Gelbard M, Goldstein I, Hellstrom WJ et al.(2013) 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. J Urol 2013; 190(1):199-207.

Gelbard MK, James K, et al.(1993) Collagenase versus placebo in the treatment of Peyronie's disease: a double-blind study. J Urol, 1993; 149(1):56-8.

Gelbard MK, Lindner A, Kaufman JJ.(1985) The use of collagenase in the treatment of Peyronie's disease. J Urol, 1985; 134(2)280-3.

Gilpin D, Coleman S, Hall S et al.(2010) Injectable collagenase Clostridium histolyticum: a new nonsurgical treatment for Dupuytren's disease. J Hand Surg Am 2010; 35(12):2027-38 e1.

Hellstrom WJ, Feldman R, Rosen RC, et al.(2013) Bother and distress associated with Peyronie's disease: validation of the Peyronie's disease questionnaire. J Urol. Aug 2013;190(2):627-634. PMID 23376705

Hellstrom WJ.(2009) Medical management of Peyronie's disease. J Anrol, 2009; 30(4):397-405.

Holzer LA, Holzer G.(2009) Injectable collagenase clostridium histolyticum for Dupuytren's contracture. NEJM, 2009; 361(26):2579.

Hurst LC, Badalamente MA, et al.(2009) Injectable collagenase clostridium histolyticum for Dupuytren's contracture. NEJM, 2009; 361(10):968-79.

Hurst LC, Badalamente MA, Wang ED.(2009) Injectable clostridial collagenase: striving toward non-operative treatment options for fibroproliferative disorders. http://www.aaos.org/research/committee/research/Kappa/KD2009_Hurst.pdf

Jordan GH.(2008) The use of intralesional clostridial collagenase injection therapy for Peyronie's disease: a prospsective, single-center, non-placebo-controlled study. J Sex Med, 2008; 5(1):180-7.

Levine LA, Cuzin B, Mark S, et al.(2015) Clinical safety and effectiveness of collagenase clostridium histolyticum injection in patients with Peyronie's disease: a phase 3 open-label study. The journal of sexual medicine. Jan 2015;12(1):248-258. PMID 25388099

Lipshultz LI, Goldstein I, Seftel AD, et al.(2015) Clinical efficacy of collagenase Clostridium histolyticum in the treatment of Peyronie's disease by subgroup: results from two large, double-blind, randomized, placebo-controlled, phase III studies. BJU Int. Oct 2015;116(4):650-656. PMID 25711400

McGrouther DA, Jenkins A, Brown S, et al.(2014) The efficacy and safety of collagenase clostridium histolyticum in the treatment of patients with moderate Dupuytren's contracture. Curr Med Res Opin. Apr 2014;30(4):733-739. PMID 24397625

McMahon HA, Bachoura A, Jacoby SM, et al.(2013) Examining the efficacy and maintenance of contracture correction after collagenase clostridium histolyticum treatment for Dupuytren's disease. Hand (N Y). Sep 2013;8(3):261-266. PMID 24426932

Naam NH.(2013) Functional outcome of collagenase injections compared with fasciectomy in treatment of Dupuytren's contracture. Hand (N Y). Dec 2013;8(4):410-416. PMID 24426958

National Institute for Health and Care Excellence (NICE).(2017) Collagenase clostridium histolyticum for treating Dupuytren’s contracture: Technology appraisal guidance [TA459]. https://www.nice.org.uk/guidance/TA459/chapter/1-Recommendations. Accessed November 26, 2017.

National Institutes of Health. Clinical Trails Database. Available at http://clinicaltrials.gov/ct2/results?term=collagenase+AND+dupuytren%27s. Assessed February 2011.

National Institutes of Health. Clinical Trials Database. Available online at http://clinicaltrials.gov/ct2/results?term=collagenase+AND+peyronie%27s Last accessed February 2011.

Nehra A, Alterowitz R, Culkin DJ, et al.(2015) Peyronie's Disease: AUA Guideline. 2015 Accessed March, 2020.

Nehra A, Alterowitz R, Culkin DJ, et al:(2015) American Urological Association Education and Research, Inc., Peyronie's Disease: AUA Guideline. J Urol. 2015; 194(3):745-753.

Peimer CA, Blazar P, Coleman S et al.(2013) Dupuytren contracture recurrence following treatment with collagenase clostridium histolyticum (CORDLESS study): 3-year data. J Hand Surg Am 2013; 38(1):12-22.

Peimer CA, Blazar P, Coleman S, et al.(2015) Dupuytren contracture recurrence following treatment with Collagenase Clostridium histolyticum (CORDLESS [Collagenase Option for Reduction of Dupuytren Long-Term Evaluation of Safety Study]): 5-year data. The Journal of hand surgery. Aug 2015;40(8):1597-1605. PMID 26096221

Peimer CA, Wilbrand S, Gerber RA, et al.(2014) Safety and tolerability of collagenase Clostridium histolyticum and fasciectomy for Dupuytren's contracture. J Hand Surg Eur Vol. Apr 29 2014. PMID 24698851

Povlsen B, Povlsen SD.(2014) What is the better treatment for single digit Dupuytren's contracture: surgical release or collagenase clostridium histolyticum (Xiapex) injection? Hand Surg. Aug 25 2014:1-4. PMID 25155703

Raven RB, 3rd, Kushner H, Nguyen D et al.(2013) Analysis of efficacy and safety of treatment with collagenase clostridium histolyticum among subgroups of patients with Dupuytren contracture. Ann Plast Surg 2013.

Russell S, Steers W, McVary KT.(2007) Systematic evidence-based analysis of plaque injection therapy of Peyronie's disease. Eur Urol, 2007; 51(3):640-7.

Smeraglia F, Del Buono A, Maffulli N.(2016) Collagenase clostridium histolyticum in Dupuytren's contracture: a systematic review. Br Med Bull. Jun 2016;118(1):149-158. PMID 27151958

Sood A, Therattil PJ, Paik AM, et al.(2014) Treatment of dupuytren disease with injectable collagenase in a veteran population: a case series at the department of veterans affairs new jersey health care system. Eplasty. 2014;14:e13. PMID 24741384

US Food and Drug Administration (FDA).(2013) Highlights of prescribing information: Xiaflex. 2013; http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125338s0061lbl.pdf. Accessed August, 2014.

Verheyden JR.(2014) Early outcomes of a sequential series of 144 patients with Dupuytren's contracture treated by collagenase injection using an increased dose, multi-cord technique. J Hand Surg Eur Vol. Apr 2 2014. PMID 24698852

Warwick D, Arner M, Pajardi G, et al.(2014) Collagenase Clostridium histolyticum in patients with Dupuytren's contracture: results from POINT X, an open-label study of clinical and patient reported outcomes. J Hand Surg Eur Vol. Mar 18 2014. PMID 24470559

Watt AJ, Curtin CM, Hentz VE.(2010) Collagenase injection as nonsurgical treatment of Dupuytren’s disease: 8-year follow-up. J Hand Surg Am 2010; 35(4):534-9, 539.e1.

Watt AJ, Curtin CM, Hentz VR.(2010) Collagenase injection as nonsurgical treatment of Dupuytren's disease: 8-year follow-up. J Hand Surg Am. Apr 2010;35(4):534-539, 539 e531. PMID 20353858

Witthaut J, Jones G, Skrepnik N et al.(2013) Efficacy and safety of collagenase clostridium histolyticum injection for Dupuytren contracture: short-term results from 2 open-label studies. J Hand Surg Am 2013; 38(1):2-11.

Zhou C, Hovius SE, Slijper HP, et al.(2015) Collagenase Clostridium histolyticum versus limited fasciectomy for dupuytren's contracture: outcomes from a multicenter propensity score matched study. Plast Reconstr Surg. Jul 2015;136(1):87-97. PMID 25829153
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