Clinical UM Guideline
|Subject:||Clostridial Collagenase Histolyticum Injection|
|Guideline #:||CG-DRUG-27||Current Effective Date:||05/19/2016|
|Status:||Revised||Last Review Date:||05/05/2016|
This document addresses clostridial collagenase histolyticum which is a biologic that hydrolyzes native collagen. When injected into fibrous cords, the postulated mechanism of action is collagen lysis that results in enzymatic disruption of the cord, leading to a reduction in contracture and improvement in range of motion of the affected joints. An example of this type of biologic is Xiaflex® (Auxilium Pharmaceutical Inc., Malvern, PA).
Initial injection of clostridial collagenase histolyticum is considered medically necessary for treating Dupuytren's contracture when injected into a palpable palmar cord which has been documented to impair the individual's functional activities and which measures either:
Subsequent injection of clostridial collagenase histolyticum is considered medically necessary for treating Dupuytren's contracture up to 2 additional times per cord (total 3 injections per cord) at approximately 4-week intervals.
Clostridial collagenase histolyticum injections are considered medically necessary for treating Peyronie's disease when all of the following criteria are met:
Not Medically Necessary:
Repeat clostridial collagenase histolyticum injection of a previously treated cord within one year of a prior course is considered not medically necessary for treating Dupuytren's contracture.
Clostridial collagenase histolyticum injections for diagnoses other than Dupuytren's contracture and Peyronie's disease are considered not medically necessary.
Clostridial collagenase histolyticum injections are considered not medically necessary when the criteria are not met.
The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.
|20527||Injection, enzyme (eg, collagenase), palmar fascial cord (ie, Dupuytren's contracture)|
|26341||Manipulation, palmar fascial cord (ie, Dupuytren's cord), post enzyme injection (eg, collagenase), single cord|
|J0775||Injection, collagenase, clostridium histolyticum, 0.01 mg|
|M72.0||Palmar fascial fibromatosis (Dupuytren)|
|N48.6||Induration penis plastica (Peyronie's disease)|
Dupuytren's disease is a progressive fibroproliferative disorder of an unknown origin affecting the hands causing permanent flexion contracture of the fingers. Generally, the fourth and fifth digits (ring and pinky) are affected; however, the second and third digits (index and middle) can also be affected. Surgery (fasciectomy) has been the mainstay treatment for Dupuytren's. The procedure often requires a lengthy rehabilitation period.
An alternative to invasive surgery is injection of collagenase to break up the fibrous cord responsible for the contracture. Clostridial collagenase histolyticum (Xiaflex, Auxilium Pharmaceutical Inc., Malvern, PA) was approved by the U.S. Food and Drug Administration (FDA) through a biologics license application (BLA) in February 2010. The FDA labeling for Xiaflex states that this drug is injected into a palpable Dupuytren's cord with a contracture of a metacarpophalangeal (MP) joint or a proximal interphalangeal (PIP) joint up to 3 injections at 4 week intervals.
Hurst (2009) published the results of the Collagenase Optimal Reduction of Dupuytren's (CORD) I study, a double-blind, placebo controlled, multicenter trial of 308 subjects with Dupuytren's joint contractures of 20 degrees or more to receive up to three injections of a collagenase preparation (n=204) or placebo (n=104). Joints were stratified according to joint type (MP or PIP). Joints were manipulated one day after injection if necessary. The primary endpoint was reduction in contracture to 0-5 degrees of full extension 30 days after last injection. Recurrence of contracture was defined as an increase in joint contracture to greater than or equal 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 endpoint versus 7 of 103 (6.8%) placebo injected cords. More than half of the collagenase injected joints that did not meet the primary endpoint did not receive the maximum allowable number of injections, most commonly because a cord could not be palpated or the participant was satisfied with the result. Median time to reach the primary endpoint 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 endpoint. When analyzed by joint type, more collagenase treated joints achieved the primary endpoint than placebo (MP joint: 76.7% vs. 7.2% and PIP joint: 40.9% vs. 5.9%). The mean change in contracture from baseline to 30 days after last injection was 48.0 to 7.2 degrees in the collagen injected MP joints and 45.4 to 43.1 degrees in the placebo injected MP 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 MP joints than in the PIP joints; 94.0% versus 67.1% in the collagenase group and 11.6% versus 11.8% in the placebo group. Overall, 96.6% of participants who received collagenase reported at least one treatment-related adverse event (AE). They had significantly more injection and manipulation-related events, such as contusion, hemorrhage, injection-site pain, upper extremity pain, and lymphadenopathy, than those who received placebo injection. Most were mild or moderate in intensity; however, 20 participants in the collagenase group and 2 in the placebo group reported events that were severe in intensity. Severe adverse events considered to be treatment-related included 1 individual with complex regional pain syndrome and 2 others with tendon ruptures that required surgical procedures. While Xiaflex provides a less invasive option for the treatment of Dupuytren's contracture, pending additional studies, its use should be restricted to individuals with significant functional deficits.
The results of the CORD II study were reported by Gilpin in 2010. This study was a prospective, randomized, placebo controlled trial with 90day double-blind and 9month open-label phases involving 66 subjects with contractures affecting MP or PIP joints, Subjects were randomized 2:1 to receive treatment with either Xiaflex (0.58 mg, n=20 MP and 25 PIP) or placebo (n=11 MP and 10 PIP). Affected cords received a maximum of three injections, and cord disruption was attempted the day after injection using a standardized finger extension procedure. The primary endpoint was reduction in contracture to 0° to 5° of normal, 30 days after the last injection. The mean percentage decrease in degree of joint contracture from baseline to 30 days after last injection was 70.5% ± 29.2% in the collagenase group and 13.6% ± 26.1% in the placebo group (p<0.001). The mean increase in range of motion was significantly greater in the Xiaflex group (35.4° ± 17.8°) than in the placebo group (7.6° ± 14.9°; p<0.001). Efficacy after the open-label treatment was similar to that after the double-blind phase, with 50.7% of all joints achieving 0° to 5° of normal flexion. Flexion pulley rupture was reported in one subject and another underwent routine fasciectomy to address cord proliferation and sensory abnormality. There were no reports of recurrence, tendon ruptures or systemic allergic reactions. Most adverse events were related to the injection or finger extension procedure.
Watt (2010) reported on 8 individuals who completed an 8 year follow-up after treatment with Xiaflex. In this group, 6 had MP joint contractures averaging 57 degrees and 2 had PIP contractures averaging 45 degrees prior to treatment. Average contracture measurements at 1 year were 11 degrees in the MP group and 15 degrees in the PIP group. At the 8 year evaluation, the MP measurement average was 23 degrees while the PIP measurement average was 60 degrees. The long-term measurements suggested recurrence or progression of disease in 4 out of 6 MP participants and both PIP participants. However, 88% of the participants indicated that they would pursue further injections for the treatment of recurrent or progressive Dupuytren's disease.
The Collagenase Optimal Reduction of Dupuytren's - Long-term Evaluation of Success (CORDLESS) study is a manufacturer sponsored, observational study which was intended to assess the durability of treatment response for a collection of collagenase immunogenicity samples in the treatment of Dupuytren's disease in 600 subjects. This study was also intended to evaluate the long-term safety and progression of Dupuytren's disease in joints. In 2015, Peimer published 5 year safety and tolerability data for the CORDLESS study. Safety was evaluated for collagenase clostridial histolyticum (CCH) based on 11 clinical trials (n=1082) and compared with fasciectomy data in a structured literature review of 48 European studies (n=7727) for treatment of Dupuytren's contracture. The incidence of adverse events was numerically lower with CCH vs. equivalent complications from fasciectomy (median [range] incidence), including nerve injury (0% vs. 3.8% [0%-50%]); neurapraxia (4.4% vs. 9.4% [0%-51.3%]); complex regional pain syndrome (0.1% vs. 4.5% [1.3%-18.5%]); and arterial injury (0% vs. 5.5% [0.8%-16.5%]). Tendon injury (0.3% vs. 0.1% [0%-0.2%]); skin injury (16.2% vs. 2.8% [0%-25.9%]); and hematoma (77.7% vs. 2.0% [0%-25%]) occurred at a numerically higher incidence with CCH than surgery. Additional data from statistical comparisons were not reported, and the authors concluded that these results may support clinical decision-making for treatment of Dupuytren's contracture.
The JOINT I and JOINT II studies were two open-label studies that evaluated the efficacy and safety of Xiaflex for the treatment of Dupuytren's contracture. These studies enrolled subjects with fixed-flexion contractures of MP (20° to 100°) or PIP joints (20° to 80°) who received up to three 0.58-mg injections per cord (up to five total injections per subject). Witthaut (2013) reported on the 1, 2, 6, and 9 month results of these studies. The primary endpoint was reduction in contracture to within 0° to 5° of full extension 30 days after the last injection. Clinical improvement was defined as 50% or more reduction from baseline contracture. The report includes data from 879 joints (531 MCP and 348 PIP) in 587 subjects treated at 14 U.S. (JOINT I) and 20 Australian/European (JOINT II) sites. Similar outcomes were reported in both studies. Clinical success was achieved in 497 (57%) treated joints. More MP than PIP joints achieved clinical success (70% and 37%, respectively) and clinical improvement (89% and 58%, respectively). Less severely contracted joints responded better than those more severely contracted. Mean change in contracture was 55° for MP joints and 25° for PIP joints. The physician-rated change from baseline was "very much improved" in 47% of subjects or "much improved" in 35%. Injections were well tolerated with no tendon ruptures or systemic reactions reported.
In 2015, Badalamente published the results of a safety and efficacy meta-analysis using data from the CORD I and II and JOINT I and II studies. A total of 506 adults received 1165 injections of Xiaflex in 644 PIP joint cords. Most subjects (60%) received one injection, with 24%, 16%, and 1% receiving two, three, and four injections, respectively. Clinical success and clinical improvement occurred in 27% and 49% of PIP joints after one injection and in 34% and 58% after the last injection. Subjects with lower baseline severity showed greater improvement, and response was comparable between fingers, as were improvements in range of motion. Adverse events occurring in more than 10% of subjects included peripheral edema (58%), contusion (38%), injection site hemorrhage (23%), injection site pain (21%), injection site swelling (16%), and tenderness (13%). Two tendon ruptures occurred. No further ruptures occurred after a modified injection technique was adopted.
Retreatment of Dupuytren's contracture with Xiaflex was addressed in a small unpublished study detailed in the Xiaflex package insert. "Study 5" was a follow-up study of a prior trial reported to the FDA, known as "Study 4." Study 5 was a case series study that involved 52 subjects with recurrent disease following prior Xiaflex treatment in Study 4. A clinical response rate of 65% for MP joints and 45% for PIP joints was reported. No new "safety signals" were identified in this study and immunogenicity results were not different that those reported for Study 4. No timeframes were provided for retreatment. However, expert opinion is that retreatment within 1 year is not warranted.
Peyronie's disease (PD)
PD is a connective tissue disorder which involves the growth of fibrous plaque in the soft tissue of the penis. This plaque, or scar tissue, forms in the tunica albuginea, the thick sheath of tissue surrounding the corpora cavernosa, causing pain, abnormal curvature, erectile dysfunction, indentation, loss of girth and shortening of the penis. While 12% of men with PD will undergo spontaneous improvement, 40-48% will continue to experience a worsening of the curvature; the remaining men experience stable disease. For 94% of men, pain related to PD will resolve within 12-24 months. On December 6, 2013, the FDA-approved indications for collagenase clostridium histolyticum were expanded to add, "Treatment of adult men with Peyronie's disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy." A Black Box Warning is noted from the FDA for corporal rupture (penile fracture) or other serious penile injury in the treatment of Peyronie's disease. According to the FDA prescribing information:
Corporal rupture (penile fracture) was reported as an adverse reaction in 5 of 1044 (0.5%) XIAFLEX-treated patients in clinical studies. In other XIAFLEX-treated patients (9 of 1044; 0.9%), a combination of penile ecchymosis or hematoma, sudden penile detumescence, and/or a penile 'popping' sound or sensation was reported, and in these cases, a diagnosis of corporal rupture cannot be excluded. Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 (3.7%) XIAFLEX-treated patients… Because of the risks of corporal rupture or other serious penile injury, XIAFLEX is available for the treatment of Peyronie's disease only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), called the XIAFLEX REMS Program.
Required components of the REMS Program include:
Prior to the expanded FDA approval of Xiaflex (collagenase clostridium histolyticum) for PD, Gelbard and colleagues (2012) had reported phase II trial results using collagenase clostridium histolyticum for the treatment of PD in a randomized controlled (RCT) double-blind study. A total of 147 men were stratified by degree of penile curvature (30 to 60 or greater than 60 degrees) and randomized in a 3 to 1 treatment or placebo group, with or without plaque modeling (1 to 1). Primary efficacy end-points were the curvature change and percent change from baseline to week 36. Mean penile curvature at baseline was 54.4 ± 15.1 degrees for subjects randomized to the treatment group and 50.6 ± 15.1 degrees for the placebo group. A mean change in penile curvature of -16.3 ± 14.6 degrees was observed for the treatment group, or a 29.7% (mean) improvement, compared with the mean change of -5.4 ± 13.8 degrees for the placebo group or an 11% (mean) improvement. The authors noted that spontaneous improvement in PD is rare and an unexpected study outcome was a high placebo response in the group without modeling. However, greater improvement was seen in the treatment group without modeling, though not statistically significant. The authors concluded that the study results suggest that collagenase clostridium histolyticum for the treatment of PD is an option.
In 2013, results of the IMPRESS (Investigation for Maximal Peyronie's Reduction Efficacy and Safety Studies) I and II trials were published which formed the basis for the FDA approval for PD (Gelbard, 2013). The IMPRESS studies were double-blinded, randomized, placebo controlled, phase III studies which examined the clinical efficacy and safety of collagenase clostridium histolyticum intralesional injections in subjects with PD. Co-primary outcomes in these identical phase III RCTs included the percent change in the penile curvature abnormality and the change in the PD questionnaire "Symptom bother" score from baseline to 52 weeks. Collagenase C. histolyticum intralesional injections were given to 417 and 415 subjects, respectively; through a maximum of 4 treatment cycles, each separated by 6 weeks. Men received up to eight injections of 0.58 mg collagenase C. histolyticum; that is two injections per cycle separated by approximately 24 to 72 hours with the second injection of each followed 24 to 72 hours later by penile plaque modeling. Subjects were stratified by baseline penile curvature (30 to 60 vs. 61 to 90 degrees) and randomized to collagenase C. histolyticum or placebo, 2:1 in favor of the former. Post hoc meta-analysis of the IMPRESS I and II data revealed that men treated with collagenase C. histolyticum showed a mean 34% improvement in penile curvature, representing a mean ± SD (standard deviation) of -17.0 ± 14.8 degree change per subject, compared with a mean 18.2% improvement in placebo treated men, representing a mean -9.3 ± 13.6 degree change per subject (p<0.0001). The mean change in PD symptom "Bother score" was significantly improved in treated men vs. men on placebo (-2.8 ± 3.8 vs. -1.8 ± 3.5, p=0.0037). Three serious adverse events (corporeal rupture) were reported which required surgical repair. Although these trials demonstrated clinical safety and efficacy for use of collagenase C. histolyticum in PD and were the basis for the 2013 FDA approval, study limitations and inconsistencies were also noted (Jain, 2013).
A subgroup analysis of the IMPRESS I and II studies by Lipshultz (2015) evaluated the efficacy of Xiaflex within specific subgroups of subjects according to several factors. The first factor was penile curvature at baseline, either 30-60° [n=492] or 61-90° [n=120]. The second factor was duration of disease (1 to ≤ 2 years [n=201], > 2 to ≤ 4 years [n=212] and > 4 years [n=199]). The third factor was the degree of plaque calcification (no calcification [n=447], non-contiguous stippling [n=103] and contiguous calcification that did not interfere with injection [n=62]). The final factor was baseline erectile function (International Index of Erectile Function [IIEF] scores 1-5 [n=22], 6-16 [n=106] and ≥ 17 [n=480]). The authors reported that reductions in penile curvature deformity and symptom bother were observed in all subgroups. Penile curvature deformity reductions were significantly greater in the Xiaflex group vs. placebo for the following subgroups: baseline penile curvature 30-60° and 61-90°; disease duration > 2 to ≤ 4 years and > 4 years; no calcification; and IIEF score ≥ 17 (high IIEF-erectile function score; p<0.05 for all comparisons). Symptom bother reductions were significantly greater in the Xiaflex group for subjects with penile curvature 30-60°, disease duration > 4 years, no calcification, and IIEF score 1-5 (no sexual activity) and ≥ 17 (p<0.05 for all).
Levine (2015) reported on the results of a Phase 3 open-label study involving 347 subjects treated with Xiaflex. Full data for analysis were available for 238 subjects. The authors reported that there were statistically significant mean improvements from baseline to week 36 in both penile curvature deformity (34.4%) and PD symptom bother score (3.3). Most adverse events (AEs) were mild or moderate in severity and local to the penis. There were three serious treatment-related AEs, two penile hematomas and one corporal rupture; all resolved with additional treatment.
Carson (2015) conducted a meta-analysis addressing the safety of Xiaflex when used to treat Peyronie's disease. The study included 1044 subjects from six clinical studies who had received at least one dose of 0.58 mg of Xiaflex. The results indicated that overall, 92.5% of subjects (966 of 1044) reported at least one treatment-emergent adverse event, defined as all AEs with a start date on or after the date of the first injection of collagenase clostridium histolyticum (CCH) up to the last study visit. The most frequently reported treatment-related AEs included penile hematoma (50.2%), penile pain (33.5%), and penile swelling (28.9%). Most subjects (75.2%) had mild or moderate severity treatment-related AEs; 14.2% had no treatment-related AEs. Of the pooled population, 5.7% (60/1044) of the CCH-treated subjects had at least one treatment-emergent serious adverse event (SAE). The authors reported no association between AEs and anti-AUX-I or anti-AUX-II antibody levels across treatment cycles, and no systemic hypersensitivity reactions occurred. The authors concluded that, "This pooled safety analysis shows that, although non-serious and serious treatment-related AEs can occur after CCH treatment for PD, most were non-serious and the SAEs were manageable."
In mid-2015, The American Urological Association (AUA) published a new guideline addressing the treatment of Peyronie's Disease (Nehra, 2015). In this document they state:
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).
This recommendation is based on the findings of the IMPRESS studies (discussed above), and was given a "Moderate Recommendation" with an "Evidence Strength Grade B," indicating moderate quality evidence and moderate certainty.
Collagen: A fibrous protein found in connective tissue, bone, and cartilage.
Collagenase: Enzymes that break the peptide bonds in collagen.
Fascia: A sheet of fibrous tissue that envelops the body beneath the skin; it also encloses muscles and groups of muscles and separates their several layers or groups.
Fasciectomy: Surgical removal of the fibrous tissue beneath the skin.
Fibroproliferative: Producing new fibrous tissue.
Metacarpophalangeal (MP) joint: Commonly called the knuckle, is attached to the proximal first phalanges.
Peyronie disease (PD): The formation of fibrous scar tissue (plaques) on the upper or lower side of the penis resulting in mild to severe curvature.
Proximal interphalangeal (PIP) joint: The second joint of the finger.
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
|Websites for Additional Information|
Clostridial collagenase histolyticum
The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
|Revised||05/05/2016||Medical Policy & Technology Assessment Committee (MPTAC) review. The medically necessary indications for use of clostridial collagenase histolyticum injections were expanded to include Peyronie's disease when criteria are met. The Discussion section and References were updated. Updated Coding section and removed ICD-9 codes.|
|Reviewed||05/07/2015||MPTAC review. The Discussion section and References were updated.|
|Revised||05/15/2014||MPTAC review. Addition of Peyronie's disease to the indications considered not medically necessary. The Discussion section and References were updated.|
|Reviewed||08/08/2013||MPTAC review. The Discussion section and References were updated.|
|Reviewed||08/09/2012||MPTAC review. Discussion/General Information, Definitions and References updated.|
|01/01/2012||Updated Coding section with 01/01/2012 CPT changes.|
|Revised||08/18/2011||MPTAC review. Medically necessary contracture criteria for the metacarpophalangeal (MP) joint changed to 20 degrees. Discussion/General Information and References updated.|
|01/01/2011||Updated Coding section with 01/01/2011 HCPCS changes; removed C9266 deleted 12/31/2010.|
|New||08/19/2010||MPTAC review. Initial guideline development.|