Clinical UM Guideline
|Subject:||Clostridial Collagenase Histolyticum Injection|
|Guideline #:||CG-DRUG-27||Current Effective Date:||07/07/2015|
|Status:||Reviewed||Last Review Date:||05/07/2015|
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.
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, including Peyronie's disease, are considered not medically necessary.
Clostridial collagenase histolyticum injections are considered not medically necessary when the criteria above 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|
|ICD-9 Diagnosis||[For dates of service prior to 10/01/2015]|
|728.6||Contracture of palmar fascia (Dupuytren's contracture)|
|ICD-10 Diagnosis||[For dates of service on or after 10/01/2015]|
|M72.0||Palmar fascial fibromatosis (Dupuytren)|
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 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. 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.
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 (NCT 00954746). 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.
Another manufacturer sponsored study, the Safety and Effectiveness of AA4500 in Subjects With Peyronie's Disease, is a multicenter, Phase IIb, double-blind, randomized, placebo-controlled study intended to evaluate the safety/effectiveness and impact of collagenase treatment in Peyronie's disease. Although listed as completed, to date, nothing has been published regarding study results (NCT 00755222). Additional industry sponsored studies are ongoing or in stages of completion; however, no study results have been published yet.
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 endpoints 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. 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 8 injections of 0.58 mg collagenase C. histolyticum, that is 2 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 (Gelbard, 2013). 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).
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.
|Reviewed||05/07/2015||Medical Policy & Technology Assessment Committee (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.|