Clinical UM Guideline


Subject:Clostridial Collagenase Histolyticum Injection
Guideline #:  CG-DRUG-27Current Effective Date:  10/08/2013
Status:ReviewedLast Review Date:  08/08/2013

Description

Clostridial collagenase histolyticum 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).

Clinical Indications

Medically Necessary:

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 are considered not medically necessary.

Clostridial collagenase histolyticum injections are considered not medically necessary when the criteria above are not met.

Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes.  A draft of future ICD-10 Coding (effective 10/01/2014) related to this document, as it might look today, is included below for your reference.  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.

CPT 
20527Injection, enzyme (eg, collagenase), palmar fascial cord (ie,Dupuytren's contracture)
26341Manipulation, palmar fascial cord (ie, Dupuytren's cord), post enzyme injection (eg, collagenase), single cord 
  
HCPCS 
J0775Injection, collagenase, clostridium histolyticum, 0.01 mg
  
ICD-9 Diagnosis 
728.6Contracture of palmar fascia (Dupuytren's contracture)
  
ICD-10 DiagnosisICD-10-CM draft codes; effective 10/01/2014:
M72.0Palmar fascial fibromatosis (Dupuytren)
  
Discussion/General Information

Dupuytren'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 double-blind placebo-controlled, multicenter trial of 308 subjects with Dupuytren's joint contractures of 20 degrees or more to receive up to 3 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 one individual with complex regional pain syndrome and two others with tendon ruptures that required surgical procedures. While Xiaflex provides a less invasive option for the treatment of Dupuytren's contracture, its use should be restricted to individuals with significant functional deficits pending additional studies.

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, ongoing observational study which is 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 will also evaluate the long-term safety and progression of Dupuytren's disease in joints.  Although the original estimated completion date was May 2013, this trial is listed as ongoing but no longer recruiting participants.  Thus far, nothing has been published about the trial results (NCT 00954746).  Another manufacturer sponsored study, the Safety and Effectiveness of AA4500 in Subjects With Peyronie's Disease, is a multi-center, 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):
Gelbard and colleagues (2012) reported phase II trial results using collagenase clostridium histolyticum for the treatment of Peyronie's disease (PD) in a randomized controlled double blind study. One hundred forty-seven 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 plus or minus 15.1 degrees for subjects randomized to the treatment group and 50.6 plus or minus 15.1 degrees for the placebo group. A mean change in penile curvature of -16.3 plus or minus 14.6 degrees was observed for the  treatment group,  or a 29.7% (mean) improvement, compared with the mean change of -5.4 plus or minus 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. Phase III studies are ongoing to provide further safety and efficacy data.

Definitions

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.

References

Peer Reviewed Publications:

  1. Badalamente MA, Hurst LC. Efficacy and safety of injectable mixed collagenase subtypes in the treatment of Dupuytren's contracture. J Hand Surg Am. 2007; 32(6):767-774.
  2. Gelbard M, Lipshultz LI, Tursi J, et al. Phase 2b study of the clinical efficacy and safety of collagenase clostridium histolyticum in patients with peyronie disease. J Urol. 2012; 187(6):2268-2274.
  3. Hurst LC, Badalamente MA, Hentz VR, et al.  CORD I Study Group. Injectable collagenase clostridium histolyticum for Dupuytren's contracture.  N Engl J Med. 2009; 361(10):968-979.
  4. Watt AJ, Curtin CM, Hentz VR. Collagenase injection as nonsurgical treatment of Dupuytren's disease: 8-year follow-up. J Hand Surg Am. 2010; 35(4):534-539.

Government Agency, Medical Society, and Other Authoritative Publications: 

  1. Auxilium Pharmaceuticals. Long-term Observational Evaluation of Subjects Treated With AA4500 in Studies AUX-CC-854, AUX-CC-856, AUX-CC-857/AUX-CC-858 and AUX-CC-859. NLM Identifier: NCT00954746. Last Updated on March 19, 2013. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00954746?term=xiaflex&rank=14. Accessed on July 10, 2013.   
  2. Auxilium Pharmaceuticals. The Safety and Effectiveness of AA4500 in Subjects With Peyronie's Disease. NLM Identifier: NCT00755222.  Last Updated on January 24, 2012   http://www.clinicaltrials.gov/ct2/show/NCT00755222?term=injectable+AND+clostridial+collagenase&rank=5  Accessed on July 10, 2013.
  3. Collagenase Clostridium Histolyticum Monograph. February 2010. American Hospital Formulary Service®. Available at: http://www.ashp.org/ahfs/. Accessed on July 10, 2013.   
  4. Collagenase, Clostridium histolyticum (systemic). In: DrugPoints® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated periodically. Available at: http://www.thomsonhc.com. Accessed on July 10, 2013.
  5. Hatzimouratidis K, Eardley I, Giuliano F, et al. European Association of Urology (EAU) Guidelines on Penile Curvature. Eur Urol. 2012; 62(3):543-552.
  6. U.S. Food and Drug Administration (FDA). Xiaflex®   (clostridial collagenase histolyticum) approval. February 2, 2010. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed on July 10, 2013.
Web Sites for Additional Information
  1. American Academy Orthopedic Surgeons (AAOS). Dupuytren's Contracture. Available at: http://orthoinfo.aaos.org/topic.cfm?topic=A00008.  Accessed on July 10, 2013.
  2. Dupuytrens Foundation. Available at: http://www.dupuytrenfoundation.org/. Accessed on July 10, 2013.
Index

Clostridial collagenase histolyticum
Duyputren's
Peyronie's disease
Xiaflex

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.

History
StatusDateAction
Reviewed08/08/2013Medical Policy & Technology Assessment Committee (MPTAC) review.  No change to criteria.  The Discussion section and References were updated.
Reviewed08/09/2012MPTAC review. Discussion/General Information, Definitions and References updated.
 01/01/2012Updated Coding section with 01/01/2012 CPT changes.
Revised08/18/2011MPTAC review. Medically necessary contracture criteria for the metacarpophalangeal (MP) joint changed to 20 degrees. Discussion/General Information and References updated.
 01/01/2011Updated Coding section with 01/01/2011 HCPCS changes; removed C9266 deleted 12/31/2010.
New08/19/2010MPTAC review. Initial guideline development.