Pending Policies - Prescription Drugs


Clostridial Collagenase for Fibroproliferative Disorders

Number:RX501.073

Effective Date:04-15-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

Injectable clostridial collagenase may be considered medically necessary for the treatment of adult patients with Dupuytren’s contracture when ALL of the following criteria are met:

1. A palpable cord; AND

2. A contracture of a metacarpophalangeal (MP) joint or a proximal interphalangeal (PIP) joint.

NOTE 1: Treatment of up to 2 cords or 2 joints in the same hand may be allowed at a treatment visit. If a patient has more than 2 cords in the same hand, inject those cords at another visit. A finger extension procedure may be performed approximately 24 to 72 hours following an injection. Injection and finger extension procedures may be administered up to 3 times per cord at approximately 4-week intervals.

Injectable clostridial collagenase may be considered medically necessary for the treatment of adult patients with Peyronie’s disease when ALL of the following criteria are met:

1. Palpable penile plaque; AND

2. Objective documentation in the medical record of a penile curvature deformity of at least 30 degrees at start of therapy, as measured using intracavernosal injection (ICI) and goniometer; AND

3. Treatment will be administered in conjunction with a penile modeling procedure; AND

4. Treatment will be performed under the U.S. Food and Drug Administration (FDA)-mandated Risk Evaluation and Mitigation Strategy (REMS) program.

NOTE 2: A treatment course for Peyronie’s disease consists of a maximum of 4 treatment cycles (each separated by 6 weeks). Each treatment cycle consists of 2 clostridial collagenase injection procedures and 1 penile modeling procedure.

Injectable clostridial collagenase is considered experimental, investigational and/or unproven for all other indications including but not limited to adhesive capsulitis.

Description:

Injection with clostridial collagenase is intended to provide a nonoperative 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. Examples of fibroproliferative disorders include Dupuytren disease, adhesive capsulitis, and Peyronie’s disease.

The mechanisms that contribute to the pathology are poorly understood. In Dupuytren disease, collagen deposition in nodules and cords in the palm and fingers results in pitting of the overlying cutis and flexion contractures. The prevalence of Dupuytren disease is estimated at 3% to 6% in the general population and increases with advancing age. It is more common in people with diabetes or thyroid disease and among men. (2) The standard of care for Dupuytren disease is surgery, most commonly open fasciectomy. Other surgical procedures are percutaneous fasciotomy and needle fasciotomy. Surgery is recommended in patients with functional impairment and metacarpophalangeal (MCP) joint contractures of 30º 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 adhesive capsulitis is estimated 2% to 3% in the general population and increases with advancing age. It is more common in people with diabetes or thyroid disease and among women. (2)

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% to 9% of men, most commonly between the ages of 45 and 60 years. 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 have demonstrated inconsistent benefit. Intralesional injection therapy consisting of injection of interferon-a-2b or calcium channel-blockers (e.g., verapamil) is the current standard of therapy. (1) 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 (the Nesbit procedure), a penile implant, or a combination of these.

Clostridial collagenase histolyticum is an enzyme produced by the bacterium Clostridium histolyticum, which has the physiologic effect of breaking down collagen. It has been developed and marketed pharmacologically as a treatment for disorders associated with collagen overdevelopment.

REGULATORY STATUS

Table 1 lists indications for clostridial collagenase approved by the U.S. Food and Drug Administration (FDA).

Table 1. FDA-Approval History for Clostridial Collagenase (Xiaflex®) (3-6)

Indication

Approved

Initial Indication

Additional Information

Dupuytren contracture

2010

Adults with Dupuytren contracture with a palpable cord

Up to 3 injections at 4-week intervals into a palpable Dupuytren cord with a contracture of a metacarpophalangeal or a proximal interphalangeal joint

Approval accompanied by REMS

The manufacturer must:

o Evaluate and mitigate risks and serious adverse events

o Instruct health care providers on procedure to inject Xiaflex and perform finger extension procedures

o Inform patients of potential risks of treatment

Peyronie’s disease

2013

Men with a palpable penile plaque and penile curvature >30 degrees

A maximum of 4 cycles, each of which consists of 2 Xiaflex injection procedures

Approval accompanied by black box warning of corporal rupture

Only available through a restricted program, Xiaflex REMS, due to risk of corporal rupture. REMS requirements:

o Prescribers must enroll and complete training in administration of Xiaflex for treatment of Peyronie disease

o Health care sites must be certified with the program and ensure that only certified prescribers administer Xiaflex

Dupuytren contracture

2014

Indicated for the treatment of adult patients with Dupuytren’s contracture with a palpable cord

Indication expanded: up to 2 joints in same hand may be treated during a treatment visit

Peyronie’s disease

2016

To wait two weeks after the second injection of a treatment cycle before resuming sexual activity, provided pain and swelling have subsided

Patient counseling expanded: To not have sex between the first and second injections of a treatment cycle.

FDA: Food and Drug Administration; REMS: Risk Evaluation and Mitigation Strategy.

Rationale:

This policy was originally created in 2010 and was regularly updated with searches of the MEDLINE database. Following is a summary of the key findings through August 23, 2016.

Dupuytren Disease (Dupuytren Contracture)

Systematic Reviews

In 2016, Smeraglia et al. reported results of a systematic review of studies reporting on clostridial collagenase injections for Dupuytren contracture. (7) 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.

In 2015, Brazzelli et al. reported on a Health Technology Assessment including a systematic review and economic evaluation of clostridial collagenase for the treatment of Dupuytren contracture. (8) 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-randomized studies comparing collagenase and surgery (105 participants), five non-randomized 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.

Chen et al. published a systematic review in 2011 of various treatments for Dupuytren contracture. (9) 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 ranged from 13 to 261 patients. Reviewers found recurrence rates for collagenase injections (mean follow-up time range, 120 days to 4 years) ranged from 10% to 31%. Needle aponeurotomy had the highest recurrence rates of 50% to 58% (mean follow-up, 3-5 years), which were significantly higher than the open partial fasciectomy recurrence rates (12% - 39%; mean follow-up, 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. Reviewers concluded that 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 revision.

In 2015, Peimer et al. summarized the safety and tolerability of clostridial collagenase or surgical treatment (fasciectomy) for Dupuytren contracture. (10) The safety of clostridial collagenase was based on 11 clinical trials (n=1082 patients), while the safety of fasciectomy was based on 48 European studies (n=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%) all respectively. Pooled estimates and statistical comparisons were not reported.

Randomized Controlled Trials

We identified 5 publications from 3 unique double-blind, RCTs (including 2 follow-up RCT extension studies), all sponsored by the manufacturer (Auxilium Pharmaceuticals).

In 2009, Hurst et al. published results from the Collagenase Option for Reduction of Dupuytren’s I (CORD I) study, a randomized, double-blind placebo-controlled, multicenter trial (16 sites) of collagenase Clostridium histolyticum for Dupuytren contracture with 308 subjects with joint contractures of 20º or more. (11) This trial was included in the Chen review previously described. (9) Joints were stratified by type (MCP joints or proximal interphalangeal [PIP] joint) and severity of contracture; they were 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 1 day after injection if necessary. The primary end point was reduction in contracture to 0º to 5º 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 of 20 º or more and was considered an adverse event (AE). Efficacy results were based on 306 primary joints: 203 injected with collagenase and 103 injected with placebo. In the collagenase-treated group, 130 (64%) of 203 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 (MCP, 76.7% vs 7.2%; PIP joint, 40.9% vs 5.9%, both respectively; p<0.001 for both comparisons). Mean change in contracture from baseline to 30 days after last injection was 48.0º to 7.2 º in the collagen-injected MCP joints and 45.4º to 43.1º in the placebo-injected MCP 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 MCP joints than in PIP joints of in the collagenase group (94.0% vs 67.1%) than in the placebo group (11.6% vs 11.8%), all respectively. Overall, 96.6% of patients who received collagenase reported at least 1 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 AEs were considered to be treatment-related: a case of complex regional pain syndrome and 2 tendon ruptures, both requiring surgical procedures. The CORD I authors note that the trial timeframe was insufficient to assess recurrence. In 2011, Witthaut et al. reported on range of motion (ROM) outcomes from the CORD I study. (12) On day 30, mean ROM increased from 43.9º to 80.7 º in joints treated with collagenase. In the joints treated with placebo, mean ROM increased 45.3º to 49.5º on day 30. Using regression models to create a ROM severity classification, the authors reported that joints treated with collagenase had a significant mean increase in ROM of 36.7º (p<0.001), whereas joints treated with placebo did not (4.0º).

In a letter to the editor in response to publication of the study, Holzer and Holzer comment that successful treatment of Dupuytren disease correlates with the percentage of excised Dupuytren tissue and the extent of the intervention. (13) They cautioned that the value of collagenase injection must be confirmed in a long-term follow-up study that focuses on the recurrence rate.

In 2010, Gilpin et al. published results of the CORD II study. (14) 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, that within 30 days, collagenase injections resulted in significantly more cord contracture improvement from baseline to within 0 º to 5º 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 ≥20º) 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 1 patient while rapid thickening of the treated cord and sensory abnormalities occurred in another patient.

In 2014, McGrouther et al. 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. (15) Of the subgroup, 82% met the primary end point of clinical success, defined as a reduction in contracture to within 5º of full extension 30 days after the last injection. Recurrence of the contracture (defined as an increase in joint contracture to ≥20º 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 treatment-related adverse events, all of which were considered mild (e.g., pain and swelling at the injection site).

In 2007, Badalamente and Hurst reported on patients who participated in a double-blind phase 3 RCT comparing collagenase and placebo injections. (16) During the double-blind and open-label phases, 62 joints (31 MCP, 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, 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 AEs were local reactions to injections. Limited patient follow-up makes drawing conclusions difficult.

In 2014, Raven et al. published a subgroup analysis of data pooled from the previously described 3 RCTs (CORD I, CORD II, Badalamente and Hurst) of collagenase treatment of Dupuytren-related contractures. (17) This analysis included 271 patients with MCP (n=167) or PIP (n=104) joint contractures of 20º or more treated with collagenase injections (0.58 mg collagenase per injection). Subgroups included age, sex, and diabetes status. End points included rate of clinical success (reduction in contracture to 0º-5º of normal) and percentage of AEs. There were no significant difference in clinical success by age, diabetes status, or sex, with 63% of cases reaching the end point. In addition, there were no difference in complication rates among the subgroups, with peripheral edema, contusion, and injection-site hemorrhage being most common.

Nonrandomized Comparative Studies

Since the publication of the RCTs previously described, several smaller nonrandomized studies have compared clostridial collagenase to surgical procedures for the treatment of Dupuytren contracture.

Naam et al. retrospectively compared patients with Dupuytren contracture affecting at least 1 joint with a palpable cord who underwent clostridial collagenase injections (n=25) or fasciectomy (n=21). (18) Some patients who received clostridial collagenase injections were enrolled in the JOINT 1 study, described below. Over an average follow-up of 32 months for patients treated with clostridial collagenase and 39 months for those treated with fasciectomy, mean posttreatment contracture, decrease in contracture from baseline, and increase in ROM from baseline at the MCP and PIP joints did not significantly differ. Mean posttreatment ROM at the MCP joint was significantly higher in the clostridial collagenase-treated patients (90.7° vs 83.3°, p=0.02), while the posttreatment ROM at the PIP was higher in the fasciectomy-treated patients, although the difference did not reach statistical significance (67.5° vs 88.8°, 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 et al. prospectively assessed outcomes for patients with single-digit Dupuytren contraction who underwent open fasciectomy (n=10) or clostridial collagenase injection followed by manipulation (n=10). (19) 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<0.025, respectively) in the short term (i.e., days) after the procedure. Longer term follow-up is not reported.

Zhou et al. compared outcomes for patients who underwent clostridial collagenase injection or limited fasciectomy for Dupuytren contracture at 7 sites in the Netherlands. (20) 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 6 to 12 weeks postprocedure, the residual contracture for affected MCP joints did not differ significantly between groups (13º for clostridial collagenase vs 6º for limited fasciectomy, p=0.095), while affected PIP joints had significantly worse residual contracture in the collagenase group (25º vs 15º, p=0.010). Fewer adverse events occurred among clostridial collagenase?treated subjects.

Noncomparative Studies

Noncomparative studies are discussed to provide data on adverse event rates after clostridial collagenase injections. 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.

In 2013, Witthaut et al. 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 contracture at 9 months of follow-up. (21) The primary end point was clinical success, defined as a reduction in contracture to within 0º to 5º of full extension 30 days after the last injection. A secondary end point was clinical improvement, defined as 50% or more reduction from baseline contracture. Dupuytren cords affecting 879 joints (531 MCP, 348 PIP) in 587 patients were administered collagenase injections at 14 American (JOINT I) and 20 Australian/European (JOINT II) sites. Similar results were reported in both studies. Seventy-one percent (n=625) of joints 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 (SD=0.5) collagenase injections per cord. More MCP than PIP joints achieved clinical success (70% and 37%, respectively) and clinical improvement (89% and 58%, respectively). For joints not achieving clinical success and not receiving the maximum 3 injections (128 MCP, 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 satisfaction with response (MCP joint, 8%; PIP joint, 9%). When data from JOINT I and 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 better responses 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. (21)

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 previously reviewed.

In 2013, Peimer et al. 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). (22) Of 1080 collagenase-treated joints, 623 (451 MCP, 172 PIP) had achieved 0º to 5º 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. (22) Five-year follow-up from the CORDLESS registry were reported in 2015. (23) 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. (24) 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 (0º-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. (25) 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 postbaseline 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.

A number of other smaller single-arm studies have been published, with sample sizes ranging from 23 to 254 patients, and generally with shorter term follow-up (≈6 to 15 months). (26-32) One study, by Watt et al., reported on 23 patients, 8 of whom had long-term follow-up to 8 years. (26) Among those with isolated MCP contracture (n=6), 4 experienced recurrence by 8 years, while both patients with isolated PIP contracture experienced recurrence by 8 years.

Section Summary: Dupuytren Contracture

The most direct evidence related to the use of clostridial collagenase for Dupuytren contractures comes from several RCTs that compared clostridial collagenase with placebo injections, and generally showed high rates of contracture resolution. This evidence is supported by nonrandomized comparative studies comparing clostridial collagenase to surgery. Some studies have reported similar outcomes with faster return-to-work and return-to-usual activities rates with clostridial collagenase, but 1 study reported poorer contraction improvement but lower adverse event rates with clostridial collagenase. Rates of local adverse event s, including local swelling, pain, and ecchymosis, are generally high.

Peyronie’s Disease

Systematic Reviews

In 2015, Carson et al. reported a pooled analysis of 6 clinical studies to evaluate safety outcomes for clostridial collagenase for Peyronie’s disease. (33) 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.

In 2007, Russell et al. conducted a systematic review of plaque injection therapy for Peyronie’s disease, which included 2 studies of collagenase. (34) Both papers, 1 RCT and 1 rated as lower level study and published in 1985 and 1993, (35, 36) reported positive treatment outcomes. However, more recent RCT evidence is available that provides more direct evidence on the efficacy on clostridial collagenase injections for Peyronie’s disease.

Randomized Controlled Trials

A 1993 randomized, placebo-controlled, double-blind study with 49 subjects reported by Gelbard et al. compared the effects of collagenase and placebo on plaque size and penile deformity. (36) 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 2012, Gelbard et al. (37) completed the phase 2b study of the clinical efficacy and safety of collagenase clostridium histolyticum in patients with Peyronie’s disease. In this double-blind, randomized, placebo controlled study the goal was to determine the safety and efficacy of collagenase clostridium histolyticum and evaluate the patient reported outcome questionnaire. A total of 147 subjects were randomized into 4 groups to receive collagenase clostridium histolyticum or placebo (3:1) with or without penile plaque modeling (1:1). Two injections of collagenase clostridium histolyticum (0.58 mg) were given 24 to 72 hours apart (per treatment cycle). Subjects received a maximum of 3 cycles at 6-week intervals. When designated, investigator modeling was done 24 to 72 hours after the second injection of each cycle. The penile curvature was assessed by goniometer measurement, patient reported outcomes and adverse event profiles. After collagenase histolyticum treatment significant improvements in penile curvature (29.7% vs 11.0%, p=0.001) and patient reported outcome symptom bother scores (p=0.05) were observed compared to placebo. In modeled subjects 32.4% improvement in penile curvature was observed in those on collagenase clostridium histolyticum compared to 2.5% worsening of curvature in those on placebo (p<0.001). Those treated with collagenase clostridium histolyticum who underwent modeling also showed improved symptom bother scores (p=0.004). In subjects without modeling there were minimal differences between the active and placebo cohorts. Most adverse events in the collagenase clostridium histolyticum group occurred at the injection site and were mild or moderate in severity. No treatment related serious adverse events were reported and the treatment was well tolerated. There was significant improvement in penile curvature and patient reported outcome symptom bother scores, suggesting that this may be a safe, nonsurgical alternative for Peyronie’s disease.

In 2013, Gelbard et al. 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. (38) These RCTs were sponsored by the manufacturer (Auxilium Pharmaceuticals), the findings of which were submitted to the Food and Drug Administration 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 collagenase 0.58 mg). Men were stratified by baseline penile curvature (30º to 60º vs 61º to 90º) 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 pooled. Participants treated with collagenase injections showed a mean percent improvement in penile curvature abnormality of 34%, compared with 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 <0.001). The mean change in the PDQ symptom bother domain score was significantly improved in the collagenase group (-2.8±3.8) than in the placebo group (-1.8±3.5, p=0.004). 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 (3 cases) and penile hematoma (3 cases). All corporeal ruptures and 1 hematoma were successfully repaired surgically. Of the other 2 penile hematomas, 1 case resolved successfully without intervention and the other resolved with aspiration. (38)

In 2015, Lipshultz et al. reported post hoc subgroup analyses from the combined data from the IMPRESS I and II studies. (39) 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, though the reductions were significantly greater with clostridial collagenase than with placebo for those with baseline penile curvature 30º to 60° and 61º to 90°, disease duration over 2 years, no calcification, and IIEF severity score of 17 or greater. PDQ symptom bother reductions were significantly greater with clostridial collagenase than with placebo for those with penile curvature 30º 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.

The development and validation of the PDQ was described by Hellstrom et al. in 2013. (40) Investigators developed the PDQ to quantitatively assess the symptoms and psychosexual consequences of Peyronie’s disease by provided 3 subscale domain scores, including psychological and physical symptoms (6 items), penile pain (3 items), and symptom bother (4 scored items and 2 yes/no questions). Questions were evaluated using baseline data for 679 (81% of the total 836 enrolled) patients in IMPRESS I and II who had been sexually active in the last 3 months. PDQ domain scores did not significantly differentiate between patients with a different extent of curvature abnormality. Coyne et al. assessed the responsiveness of the PDQ to changes in Peyronie disease symptoms in men from the IMPRESS I and II trials. (41) In this group, PDQ psychological and physical symptoms and symptom bother subscales significantly discriminated patient improvement in responses to a global assessment of the PDQ and degree of penile curvature at weeks 24 and 52.

Noncomparative Studies

Case series have reported Peyronie’s disease outcomes after treatment with clostridial collagenase. Many series are small (e.g., ≈ 20 patients) (42) or from earlier treatment eras (e.g., 1985), which limit their utility. However, some larger studies provide data on adverse events after clostridial collagenase treatment for Peyronie’s disease.

Carson et al. (discussed above) reported serious and nonserious adverse events after clostridial collagenase for Peyronie disease in a pooled analysis of clostridial collagenase recipients from 6 trials (total N=1044 patients). (33) Of treated patients, 85.8% (n=896) reported at least 1 treatment-related adverse event, most frequently penile hematoma (>25% of patients). Nine (0.9%) patients had a treatment-related serious adverse event involving significant penile hematoma or corporal rupture.

A single-arm, open-label trial reported by Levine et al. described outcomes for 238 subjects with Peyronie disease treated with clostridial collagenase who had both a penile curvature measurement and a PDQ response at baseline and at least 1 subsequent time point (of 347 total subjects treated). (43) The degree of penile curvature improved from baseline to week 36 (34.4%; 95% CI, 31.2 to 37.6%) as did 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.

Section Summary: Peyronie’s Disease

The most direct evidence related to the use of clostridial collagenase injections to treat Peyronie’s disease comes from 2 industry-sponsored RCTs that compared clostridial collagenase with placebo. Clostridial collagenase-treated subjects demonstrated significant improvements in penile curvature (absolute percentage improvement, 16%) and reported improvements related to their Peyronie’s disease.

Adhesive Capsulitis

No studies including patients with adhesive capsulitis were identified that would change the coverage position of this medical policy.

Summary of Evidence

For individuals who have Dupuytren contracture who receive local clostridial collagenase injection(s), the evidence includes several placebo-controlled, randomized trials, nonrandomized comparative studies, and single-arm studies, along with systematic reviews of these studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, and quality of life. The evidence from clinical trials has suggested that injectable clostridial collagenase provides short-term release of contracture. A comparison of overall outcomes compared with surgical intervention may be useful; however, randomized studies with direct comparisons are not available. Some nonrandomized studies comparing clostridial collagenase with surgery have reported similar outcomes with faster return-to-work and return-to-usual activities rates with clostridial collagenase, but 1 study reported poorer contraction improvement though lower adverse event rates. Evidence on long-term recurrence rates is somewhat limited, but 3- and 5-year follow-ups from 1 large registry reported high recurrence rates (47% at 5 years). Although clostridial collagenase offers the potential benefit of less-invasive treatment for Dupuytren contracture, gaps in the evidence base related to treatment durability exist.

For individuals who have Peyronie disease who receive local clostridial collagenase injection(s), the evidence includes 2 randomized trials and several noncomparative studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, and quality of life. The available double-blind, placebo-controlled randomized trials have demonstrated short-term improvement in penile curvature and self-reported distress from symptoms related to Peyronie’s disease.

For individuals who have adhesive capsulitis who receive local clostridial collagenase injection(s), the evidence is very limited. Relevant outcomes are symptoms, change in disease status, functional outcomes, and quality of life. No published literature addressing the treatment of adhesive capsulitis with clostridial collagenase was identified. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical Input from Physician Specialty Societies and Academic Medical Centers

2011 Input

In response to Blue Cross Blue Shield Association’s requests, input was received from 2 physician specialty societies (2 reviews) and 5 academic medical centers (6 reviews) while this policy was under review in 2011. Two reviewers indicated injectable clostridium collagenase is investigational for the treatment of Dupuytren contracture, noting lack of long-term data and head-to-head trials comparing collagenase with surgical options. However, despite considering this treatment investigational due to insufficient long-term evidence of effectiveness, 1 reviewer noted that injectable clostridial collagenase for Dupuytren contracture is approved by the U.S. Food and Drug Administration, and there is evidence of short- to medium-term effectiveness. Five reviewers indicated injectable clostridial collagenase for Dupuytren contracture may be considered medically necessary. They noted it is a treatment alternative to surgery. This recommendation was considered to be near-uniform support for the medical necessity of injectable clostridial collagenase for the treatment of Dupuytren contracture.

Four reviewers agreed that injectable clostridium collagenase is investigational for the treatment of Peyronie disease. One of these reviewers also commented that, while this treatment is considered investigational, it may be indicated for Peyronie disease when it is bothersome, noting that surgery is intrusive. Four reviewers also agreed injectable clostridium collagenase is investigational for the treatment of adhesive capsulitis. Finally, 6 reviewers agreed injectable clostridium collagenase is investigational for all other indications.

Practice Guidelines and Position Statements

Ralph et al. developed guidelines for the treatment of Peyronie’s disease in 2010. (44) These guidelines stated that surgery is the treatment of choice, although conservative management is an appropriate option.

American Urological Association (AUA)

In 2015, the AUA issued a guideline for the diagnosis and treatment of Peyronie disease. (45) For patients with stable Peyronie disease, penile curvature greater than 30° and less than 90°, and intact erectile function (with or without the use of medications), AUA recommended intralesional collagenase Clostridium histolyticum in combination with modeling (Moderate recommendation; Evidence Strength Grade B).

European Association of Urology (EAU)

The 2012 EAU guideline on penile curvature have indicated injectable collagenase as a treatment option for Peyronie’s disease based on evidence rated as level 2b (“Evidence obtained from at least one other type of well-designed quasi-experimental study”) and grade C (“Made despite the absence of directly applicable clinical studies of good quality”). (46) The EAU guideline was updated in 2015 and included injectable collagenase as a treatment option for Peyronie’s disease based on evidence rated as level 1b (“Evidence obtained from at least one randomized trial”) and grade B (Based on well-conducted clinical studies, but without randomized clinical trials. (47)

National Institute for Health Research

In 2012, the National Institute for Health Research published a Health Technology Assessment (HTA) on the management of adhesive capsulitis. (48) In this HTA, collagenase injections were not included in the treatments considered for adhesive capsulitis.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 2.

Table 2. Summary of Key Trials

NCT No.

Trial Name

Planned enrollment

Completion Date

Unpublished

NCT01538017

Comparing Injectable Collagenase (CI) and Percutaneous Needle Fasciotomy (PNF) for Dupuytren's Contracture (DC) Affecting Proximal Interphalangeal Joints (PIP). A Randomised Controlled Trial

50

Oct 2016 (completed)

NCT01483963a

A Phase 2a, Open-label, Dose-ranging Study of the Safety and Effectiveness of AA4500 for the Treatment of Adhesive Capsulitis of the Shoulder

50

Feb 2013 (completed)

NCT02193828a

A Phase 2a, Double-blind, Randomized, Placebo-Controlled, Dose-Ranging Study to Evaluate the Safety and Effectiveness of AA4500 in the Treatment of Dupuytren's Disease Nodules

76

Mar 2014 (completed)

NCT02006719a

A Randomized, Double-blind, Placebo-controlled Study of the Safety and Efficacy of AA4500 for the Treatment of Adhesive Capsulitis of the Shoulder

322

Dec 2014 (completed)

NCT02267460a

A Phase 3b, Open-label Pilot Study to Evaluate the Safety and Effectiveness of up to Four Treatment Cycles of AA4500 in Combination With the ErecAid® Esteem® Manual Vacuum Therapy System in Men With Peyronie's Disease

30

Mar 2016 (completed)

NCT: national clinical trial.

a Denotes industry-sponsored or cosponsored trial.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

20527, 20550, 20551, 26341, 54200, 54205, 54235

HCPCS Codes

J0775, J3590

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

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6. US Food and Drug Administration (FDA). Highlights of prescribing information: Xiaflex (2016). Available at <https://www.accessdata.fda.gov> (accessed - 2017 May 18).

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9. Chen NC, Srinivasan RC, Shauver MJ, et al. A systematic review of outcomes of fasciotomy, aponeurotomy, and collagenase treatments for Dupuytren's contracture. Hand (N Y). Sep 2011; 6(3):250-255. PMID 22942847

10. Peimer CA, Wilbrand S, Gerber RA, et al. Safety and tolerability of collagenase Clostridium histolyticum and fasciectomy for Dupuytren's contracture. J Hand Surg Eur Vol. Feb 2015; 40(2):141-149. PMID 24698851

11. Hurst LC, Badalamente MA, Hentz VR, et al. Injectable collagenase clostridium histolyticum for Dupuytren's contracture. N Engl J Med. Sep 3 2009; 361(10):968-979. PMID 19726771.

12. Witthaut J, Bushmakin AG, Gerber RA, et al. Determining clinically important changes in range of motion in patients with Dupuytren's Contracture: secondary analysis of the randomized, double-blind, placebo-controlled CORD I study. Clin Drug Investig. Nov 1 2011; 31(11):791-798. PMID 21967070.

13. Holzer LA, Holzer G. Injectable collagenase clostridium histolyticum for Dupuytren's contracture. N Engl J Med. Dec 24 2009; 361(26):2579; author reply 2579-2580. PMID 20050321.

14. Gilpin D, Coleman S, Hall S, et al. Injectable collagenase Clostridium histolyticum: a new nonsurgical treatment for Dupuytren's disease. J Hand Surg Am. Dec 2010; 35(12):2027-2038 e2021. PMID 21134613.

15. McGrouther DA, Jenkins A, Brown S, et al. 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.

16. Badalamente MA, Hurst LC. Efficacy and safety of injectable mixed collagenase subtypes in the treatment of Dupuytren's contracture. J Hand Surg Am. Jul-Aug 2007; 32(6):767-774. PMID 17606053.

17. Raven RB, 3rd, Kushner H, Nguyen D, et al. Analysis of efficacy and safety of treatment with collagenase Clostridium histolyticum among subgroups of patients with Dupuytren contracture. Ann Plast Surg. Sep 2014; 73(3):286-290. PMID 23511746

18. Naam NH. 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.

19. Povlsen B, Povlsen SD. What is the better treatment for single digit Dupuytren's contracture: surgical release or collagenase clostridium histolyticum (Xiapex) injection? Hand Surg. 2014; 19(3): 389-92. PMID 25155703.

20. Zhou C, Hovius SE, Slijper HP, et al. 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

21. Witthaut J, Jones G, Skrepnik N, et al. Efficacy and safety of collagenase clostridium histolyticum injection for Dupuytren contracture: short-term results from 2 open-label studies. J Hand Surg Am. Jan 2013; 38(1):2-11. PMID 23218556.

22. Peimer CA, Blazar P, Coleman S, et al. Dupuytren contracture recurrence following treatment with collagenase clostridium histolyticum (CORDLESS study): 3-year data. J Hand Surg Am. Jan 2013; 38(1):12-22. PMID 23200951.

23. Peimer CA, Blazar P, Coleman S, et al. 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. J Hand Surg. Aug 2015; 40(8):1597-1605. PMID 26096221

24. Badalamente MA, Hurst LC, Benhaim P, et al. 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. J Hand Surg. May 2015; 40(5):975-983. PMID 25843533

25. Gaston RG, Larsen SE, Pess GM, et al. efficacy and safety of concurrent collagenase clostridium histolyticum injections for 2 Dupuytren contractures in the same hand: a prospective, multicenter study. J Hand Surg. Oct 2015; 40(10):1963-1971. PMID 26216077

26. Watt AJ, Curtin CM, Hentz VR. 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.

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

28. Warwick D, Arner M, Pajardi G, et al. 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.

29. Verheyden JR. 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.

30. McMahon HA, Bachoura A, Jacoby SM, et al. 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.

31. Sood A, Therattil PJ, Paik AM, et al. Treatment of dupuytren disease with injectable collagenase in a veteran population: a case series at the department of veteran’s affairs New Jersey health care system. Eplasty. 2014; 14:e13. PMID 24741384.

32. Atroshi I, Nordenskjold J, Lauritzson A, et al. 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

33. Carson CC, 3rd, Sadeghi-Nejad H, Tursi JP, et al. 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

34. Russell S, Steers W, McVary KT. Systematic evidence-based analysis of plaque injection therapy for Peyronie's disease. Eur Urol. Mar 2007; 51(3):640-647. PMID 17092631.

35. Gelbard MK, Lindner A, Kaufman JJ. The use of collagenase in the treatment of Peyronie's disease. J Urol. Aug 1985; 134(2):280-283. PMID 2991611.

36. Gelbard MK, James K, Riach P, et al. Collagenase versus placebo in the treatment of Peyronie's disease: a double-blind study. J Urol. Jan 1993; 149(1):56-58. PMID 8417217.

37. Gelbard M et al., Phase 2b study of the clinical efficacy and safety of collagenase clostridium histolyticum in patients with Peyronie’s disease. J Urol. Jun 2012; 187(6):2268-74. PMID 22503048

38. Gelbard M, Goldstein I, Hellstrom WJ, et al. Clinical efficacy, safety and tolerability of collagenase clostridium histolyticum for the treatment of Peyronie disease in 2 large double-blind, randomized, placebo controlled phase 3 studies. J Urol. Jul 2013; 190(1):199-207. PMID 23376148.

39. Lipshultz LI, Goldstein I, Seftel AD, et al. 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

40. Hellstrom WJ, Feldman R, Rosen RC, et al. 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.

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

42. Jordan GH. The use of intralesional clostridial collagenase injection therapy for Peyronie's disease: a prospective, single-center, non-placebo-controlled study. J Sex Med. Jan 2008; 5(1):180-187. PMID 18173766.

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

44. Ralph D, Gonzalez-Cadavid N, Mirone V, et al. The management of Peyronie's disease: evidence-based 2010 guidelines. J Sex Med. Jul 2010; 7(7):2359-2374. PMID 20497306.

45. American Urological Association (AUA). Peyronie's Disease: AUA Guideline (2015). Available at <https://www.auanet.org> (accessed - 2017 May 25).

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49. Injectable Clostridial Collagenase for Fibroproliferative Disorders. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2016 October) Prescription Drug 5.01.19.

Policy History:

Date Reason
4/15/2018 Reviewed. No changes.
7/15/2017 Document updated with literature review. The following editorial change was made to coverage: adhesive capsulitis was added to the EIU coverage statement.
3/15/2016 Reviewed. No changes.
8/1/2015 Document updated with literature review. The following was added to Coverage for the treatment of Dupuytren’s contracture: 1) A contracture of a metacarpophalangeal (MCP) joint or a proximal interphalangeal (PIP) joint. 2) A note was added to describe the FDA approved treatment course to include a) Treatment of up to 2 cords or 2 joints in the same hand may be allowed at a treatment visit. b) If a patient has more than 2 cords in the same hand, inject those cords at another visit. c) A finger extension procedure may be performed approximately 24 to 72 hours following an injection. d) Injection and finger extension procedures may be administered up to 3 times per cord at approximately 4-week intervals.
8/1/2014 Document updated with literature review. The following was added to coverage: Injectable clostridial collagenase may be considered medically necessary in adult patients with a diagnosis of Peyronie’s disease when ALL of the following criteria is met: 1) Palpable plaque; and 2) Objective documentation in the medical record of a penile curvature deformity of at least 30 degrees at start of therapy, as measured using intracavernosal injection (ICI) and goniometer; and 3) Treatment will be used in combination with penile modeling procedure; and 5) Administered under the Risk Evaluation and Mitigation Strategy (REMS) program. Note: A treatment course for Peyronie’s disease consists of a maximum of 4 treatment cycles (each separated by 6 weeks). Each treatment cycle consists of 2 Clostridial Collagenase injection procedures and 1 penile modeling procedure. Injectable clostridial collagenase is considered experimental, investigational and/or unproven for all other indications.
7/15/2012 Document updated with literature review. Coverage unchanged.
12/15/2010 New medical document. Injectable Clostridial collagenase may be considered medically necessary for treatment of adult patients with Dupuytren’s contracture with a palpable cord. Injectable Clostridial collagenase is considered experimental, investigational and unproven for all other indications including, but not limited to, Peyronie’s disease and adhesive capsulitis.

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