​​​Description
Clostridial collagenase is a bacterial collagenase, derived from Clostridium histolyticum, which has been evaluated for the treatment of fibroproliferative disorders such as Dupuytren's contracture, Peyronie's disease, and adhesive capsulitis.

Additional Information
Despite the important uncertainties that remain in the peer-reviewed scientific literature limiting determination of the effect of the technology on net health outcomes, the 2010 U.S. Food and Drug Administration (FDA) labeling and the 2015 American Urological Association guidelines identify a patient population for use of intralesional collagenase Clostridium histolyticum in combination with modeling in patients with stable Peyronie's disease, penile curvature greater than 30° and less than 90°, and intact erectile function.

Background
Fibroproliferative Disorders
Fibrotic tissue disorders, characterized by excessive collagen deposits, can affect the musculoskeletal system, causing pain and limiting movement and reducing joint range of motion. Examples of fibroproliferative disorders include Dupuytren's disease, Peyronie's disease, and adhesive capsulitis. The mechanisms that contribute to the pathology of fibroproliferative disorders are poorly understood, though likely the etiology is multifactorial and includes genetic, environmental and immunologic components.

Dupuytren's Disease
Dupuytren's disease is a progressive disorder of the palmar and digital fascia of the hand, leading to flexion deformity in up to 40% of those affected. Prevalence increases with age, from about 12% at age 55 years to 29% at 75 years.² Disease that has progressed to the point of limited hand function or digital flexion of 30 degrees or more is generally treated with surgery.

Peyronie's Disease
Peyronie's disease is characterized by deformities, including curvature, shortening, indentation and narrowing, in an erect penis.³ Men with Peyronie's disease may also have erectile dysfunction and penile pain, along with anxiety and depression. Peyronie's disease occurs most commonly in middle-aged men (45 – 60 years), although up to 10% of cases involve men younger than 40 years; prevalence is estimated to be 9%, though underreporting is likely. Comorbidities associated with Peyronie's disease include diabetes and cardiovascular disease. Patients with early stage disease may be managed medically, though the effectiveness of many non-surgical treatments is unclear. Later disease can be treated surgically.

Adhesive Capsulitis
The prevalence of adhesive capsulitis is estimated at 2% to 3% in the general population and increases with advancing age; additionally, adhesive capsulitis is more common in people with diabetes or thyroid disease and among women.⁴ Adhesive capsulitis is treated with physical therapy and mobilization in combination with analgesics or nonsteroidal anti-inflammatory drugs. Corticosteroid injection is used with caution. 

Clostridial Collagenase
Injection with clostridial collagenase is intended to provide a nonoperative treatment option for fibroproliferative disorders. 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 (XiaflexÒ; Auxilium Pharmaceuticals [Norristown, PA]) that have been approved by the U.S. Food and Drug Administration (FDA).

Table 1. FDA-Approved Indications for Clostridial Collagenase (Xiaflex)

Indication	Approved	Indications	Additional Information
Dupuytren's contracture	2010	Adults with Dupuytren's contracture with a palpable cord Up to 3 injections at 4-wk intervals into a palpable Dupuytren's cord with a contracture of a metacarpophalangeal or a proximal interphalangeal joint	Approval accompanied by REMS The manufacturer must: Evaluate and mitigate risks and serious adverse events Instruct health care providers on procedure to inject Xiaflex and perform finger extension procedures\ Inform patients of potential risks of treatment
	2014		Indication expanded: up to 2 joints in same hand may be treated during a treatment visit
Peyronie's disease	2013	Men with a palpable1 penile plaque and penile curvature > 30° A maximum of 4 cycles, each of which consists of 2 Xiaflex injection procedures	Approval accompanied by black box warning of corporal rupture and penile hematoma Only available through a restricted program (Xiaflex REMS), due to risk of corporal rupture. REMS requirements: Prescribers must enroll and complete training in administration of Xiaflex for treatment of Peyronie's disease Health care sites must be certified with the program and ensure that only certified prescribers administer Xiaflex

Adapted from Food and Drug Administration (2018).³
FDA: Food and Drug Administration; REMS: Risk Evaluation and Mitigation Strategy.

The discussion section of the 2015 American Urological Association guideline for use of clostridial collagenase in Peyronie's disease indicates that the exclusion criteria for the pivotal trials "included severe pain with penile palpation by the clinician, ED that was unresponsive to PDE5 inhibitors, and lack of full erectile response to prostaglandin E1 during curvature measurement."¹  

Policy
Injectable clostridial collagenase for the treatment of Dupuytren's contracture in adults with a palpable cord may be considered MEDICALLY NECESSARY, for up to 3 injections at intervals of at least 30 days (see the Policy Guidelines section).

Injectable clostridial collagenase for the treatment of Peyronie's disease in adults may be considered MEDICALLY NECESSARY for a maximum of 4 treatment cycles when the following criteria are met:

• Patient has a diagnosis of Peyronie’s disease with a palpable plaque; AND patient has a curvature deformity of at least 30 degrees at the start of therapy; AND the injections will be used in combination with a penile modeling procedure (1 – 3 days after injection).

Injectable clostridial collagenase is investigational/unproven therefore considered NOT MEDICALLY NECESSARY for all other indications including, but not limited to, adhesive capsulitis.

Policy Guidelines
Patient Subgroups
For individuals with Peyronie's Disease, the 2015 American Urological Association clinical practice guidelines¹ noted that clinicians should bear in mind that based on the inclusion and exclusion criteria for the IMPRESS trials, the use of collagenase treatment in certain patient subgroups or clinical situations has not been sufficiently evaluated. These subgroups are individuals with hourglass deformity, ventral curvature, calcified plaque, or plaque located proximal to the base of the penis.

Multiple Injections
For patients with Dupuytren's contracture, physicians should treat no more than 2 joints per hand per treatment visit (this is consistent with U.S. Food and Drug Administration labeling).

Please see the Codes table for details. 

Benefit Application
Blue Card/National Account Issues
State or federal mandates (e.g., Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity. 

This is an office-based procedure, and general anesthesia is not required. 

Rationale 
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Dupuytren's Disease (Dupuytren's Contracture)
Clinical Context and Therapy Purpose
The purpose of administering local clostridial collagenase injection(s) in patients who have Dupuytren's contracture is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of local clostridial collagenase injection(s) improve the net health outcome in those with Dupuytren's contracture?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with Dupuytren's contracture. In Dupuytren's 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's disease is estimated at 3% to 6% in the general population and increases with advancing age. The disease is more common in people with diabetes or thyroid disease and among men.3,

Interventions
The therapy being considered is a local injection of clostridial collagenase.

Comparators
The following therapies and practices are currently being used to treat Dupuytren's contracture: observation and surgical therapy. The standard of care for Dupuytren's disease is surgery, most commonly open fasciectomy. Other surgical procedures are percutaneous fasciotomy and needle fasciotomy. Surgery is recommended in patients with functional impairment and metacarpophalangeal joint contractures of 30° or more. There is no effective pharmacotherapy.

Outcomes
The general outcomes of interest are recurrence rates, improvements in functional outcomes and quality of life, and treatment-related adverse events.

Short-term follow-up is up to 3 days after injections are administered; long-term follow-up to monitor for recurrence is over 1 to 5 years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Clostridial Collagenase Versus Surgery
Randomized Controlled Trials
Clostridial collagenase has been compared with percutaneous needle fasciotomy in 4 RCTs in individuals with Dupuytren's contracture.6,7,8,9,10, All the RCTs were conducted outside of the United States. Three RCTs were single-center and the fourth was a 2-center RCT. The RCTs were heterogenous in the types of joints involved and in the definitions of treatment success and recurrence. All the trials used similar treatment protocols, and 3 of the 4 trials explicitly included study participants with a palpable cord (Table 2). After 2 to 3 years follow-up, there were no statistically significant differences between treatment groups for any outcome measure (Table 3), suggesting that clostridial collagenase and surgery provide similar long-term benefits. It is notable that recurrence commonly occurred in both treatment groups. The studies had some methodological limitations, most notably not reporting outcome clinical significance a priori and lack of blinding (Tables 4 and 5).

Table 2. Summary of RCT Characteristics Comparing Clostridial Collagenase to Surgery

Study	Countries	Sites	Dates	Duration of follow-up	Participants	Interventions
						Clostridial collagenase injection	PNF
Abe (2020)6	Japan	1	2014 – 2016	3 years	Dupuytren’s disease of proximal interphalangeal joints with ≥ 30° total passive extension deficit in a single digital ray; presence or absence of a palpable cord not reported	N = 36 0.58 mg (0.20 to 0.25 ml) 1 session of 3 injections, if multiple joints were affected, a second injection session was scheduled for 1 month apart	N = 36 Repetitive penetrations of the pathologic cord with a 25-gauge needle from a distal portal to a proximal portal, until rupture and the finger was fully extended
Stromberg (2018)7	Sweden	1	2012 – 2014	2 years	Dupuytren's disease of the metacarpophalangeal joint with a palpable cord with an extension deficit of ≥ 20° in a single finger	N = 78 0.58 mg (0.39 ml) injected into the pretendinous cord at the MCP level in 3 portions; following injections a forced extension maneuver was performed to disrupt the cord and, if this was unsuccessful after 3 trials, the patient was scheduled for a second treatment in 1 month	N = 78 Injection of methylprednisolone and mepivacaine with a 25-gauge needle volarly and dorsally in relation to the pretendinous cord at the MCP level and, with the finger gently extended passively, the needle was passed through the cord repeatedly in various directions from the skin puncture site until the cord ruptured
Skov (2017)8	Denmark	1	2012 – 2013	2 years	Dupuytren's disease of proximal interphalangeal joints with ≤ 20° PIP joint passive extension deficit and a well-defined (palpable) cord	N = 29 0.58 mg (0.20 ml) injected into the palpable cord using a 27-gauge needle; manipulation was performed after approximately 1 day	N = 21 Repeated perforation of the cord with a 25-gauge needle while the finger was passively stretched to better visualize the cord and determine the perforation site. The finger was passively stretched to rupture the cord to complete the procedure
Scherman 20169 and Scherman 201810	Sweden	2	2012 – 2013	3 years	Dupuytren’s disease (excluding the thumb; primarily metacarpophalangeal joints) with a palpable cord, a total passive extension deficit between 30 and 135°, and a passive extension deficit ≤ 60° in the proximal interphalangeal joint.	N = 36 0.58 mg (0.20 ml) injected into the palpable cord; if needed, the joints were then manipulated up to 3 times	N = 40 Contracture released under simultaneous passive extension using 19 gauge needles through 1 to 4 (mean 1.8) portals along the cord

Table 3. Summary of RCT Results Comparing Clostridial Collagenase to Surgery

Study	Treatment success	Recurrence	Function	Major adverse events
Abe (2020)6
Clostridial collagenase injection	At 30-days: MCP joint: 100% PIP joint, Stage 1: 89% PIP joint, Stage 2: 50%	MCP joint: 26% (8/31) PIP joint, Stage 1: 44% (4/9) PIP joint, Stage 2: 67% (4/6)	URAM score: 2.9	0% (0/36)
PNF	At 30-days: MCP joint: 100% PIP joint, Stage 1: 100% PIP joint, Stage 2: 67%	MCP joint: 29% (9/31) PIP joint, Stage 1: 38% (3/8) PIP joint, Stage 2: 67% (6/9)	URAM score: 3.9	5.9% (2/34)
p-value	MCP joint: p = NR PIP joint, Stage 1: p = NR PIP joint, Stage 2: p = NR	MCP joint: p > .05 PIP joint, Stage 1: p > .05 PIP joint, Stage 2: p > .05	p > .05	p > .05
Stromberg (2018)7
Clostridial collagenase injection	76% (58/76)	13% (10/76)	URAM score: data NR	NR
PNF	79% (60/76)	12% (9/76)	URAM: data NR	NR
p-value	p = .697	p = .806	p = .570	NR
Skov (2017)8
Clostridial collagenase injection	Clinical improvement ( ≥ 50% reduction in contracture): 7% (2/29)	83% (24/29)	NR	3% (1/29)
PNF	Clinical improvement ( ≥ 50% reduction in contracture): 29% (6/21)	68% (14/21)	NR	0% (0/21)
p-value	p = .05	p = .25	NR	p = .62
Scherman 201810
Clostridial collagenase injection	Retreatment rate: 11% (4/35)	33% (12/36)	URAM: 3 (IQR 8)	NR
PNF	Retreatment rate: 24% (11/45)	43% (17/40)	URAM: 1 (IQR 5)	NR
p-value	p = .09	p = .65	p > .05	NR

Table 4. Study Relevance Limitations in RCTs Comparing Clostridial Collagenase to Surgery

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Duration of Follow-upe
Abe (2020)6	3; presence or absence of palpable cord not reported			5
Stromberg (2018)7				3
Skov (2017)8
Scherman 20169 and Scherman 201810,				5

Table 5. Study Design and Conduct Limitations in RCTs Comparing Clostridial Collagenase to Surgery

Study	Allocation	Blinding	Selective Reporting	Data Completeness	Power	Statistical
Abe (2020)6		1, 2	1		1	3; only p-values reported
Stromberg (2018)7		1				3; only p-values reported
Skov (2017)8		1, 2
Scherman 20169 and Scherman 201810	3	2, 3	1			3; only p-values reported

The evidence limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated

Nonrandomized Studies
Clostridial collagenase has been compared to surgery other than percutaneous needle fasciotomy in 3 small, mostly short-term nonrandomized studies (N = 132) (Table 6).^11,12,13 Compared with surgery, findings from these studies suggest that clostridial collagenase may provide similar benefits and fewer adverse events at least in the short-term. However, their small sample sizes, lack of long-term follow-up, and limited data on the most clinically meaningful outcomes preclude reaching strong conclusions based on their findings.

Table 6. Summary of Nonrandomized Studies Comparing Collagenase Clostridium to Surgery

Study	Study Type	Country	Surgical Comparator	Follow-Up	N	Success	Major adverse events	Recurrence
Zhou (2015)11	Cohort	The Netherlands (7 sites)	Limited fasciectomy	3 months	66	NR	0% vs 6%	NR
Povlsen (2014)12	Prospective	UK (1 site)	Open fasciectomy	3 to 5 days	20	NR	NR	NR
Naam (2013)13	Retrospective	USA (1 site)	Fasciectomy	32 months	46	NR	NR	None

AE: adverse event; NR; not reported.

Clostridial Collagenase Versus Placebo
Systematic Reviews
In individuals with Dupuytren's contracture, for the comparison of collagenase injection to placebo and for long-term outcomes, the best available evidence comes from systematic reviews by Smeraglia et al. (2016)¹⁴ and Brazzelli et al. (2015)¹⁵ (Table 7). The review by Smeraglia et al. (2016) includes the largest number of studies to-date, but it did not include any quantitative analyses. Therefore, quantitative findings from the next largest and most recent review by Brazzelli et al. (2015) are also provided (Table 8). Both reviews included the 3 placebo-controlled RCTs^16,17,18 sponsored by Xiaflex manufacturer Auxilium Pharmaceuticals. The reviews also included numerous nonrandomized comparative studies^13,19 and noncomparative studies^{20,21,22,23,24,25,26} to address gaps in the RCTs for recurrence rates.

Table 7. Key Systematic Reviews & Meta-Analyses Characteristics

Study	Dates	Studies	Participants	N (Range)	Design	Duration
Smeraglia (2016) 14	2000 –2015	43	Dupuytren's contracture	6795 (4,715)	9 RCTs, 10 nonrandomized comparative studies; 24 case series and cost analyses	Mean follow-up = 15 months (range, 1 to 96 months)
Brazzelli et al. (2015) 15	2000 –2014	23a	Dupuytren's contracture	3737 (8,643)	5 RCTs; 2 non-randomized comparative studies; 16 case series	Range, 4 weeks to 8 years

a The health technology assessment by Brazzelli et al. (2015) included studies that focused only on comparing different surgical interventions and did not include a collagenase arm. We did not include those in our counts of numbers of studies, sample sizes, and durations as they do not provide information about collagenase. RCT: randomized controlled trial.

The reviews rated the RCTs as having low risk of important biases. Limitations included lack of blinding of outcome assessors. The RCTs were also industry sponsored. The Dupuytren's contracture selection criteria used in the RCTs included that participants have 1 cord, contracture between 20° and 100° for the metacarpophalangeal joint, and contracture between 20° and 80° for the proximal interphalangeal joint. Mean baseline contracture for the metacarpophalangeal and proximal interphalangeal joints ranged from 44° to 51° and from 43° to 53°, respectively.

In the RCTs, the clinically meaningful outcome was ‘clinical success’, which was defined as a reduction in contracture to 0 to 5° of normal, within 30 days after the last injection. Pooled analyses from the review by Brazzelli et al. (2015) found greater rates of clinical success for clostridial collagenase (63%; range 44% to 91%) compared with placebo (6%; range 0% to 7%), which was a statistically significant difference (Table 8). The clinical success advantage for clostridial collagenase compared to placebo was greater for the metacarpophalangeal joints (relative risk [RR], 10.27; 95% confidence interval [CI], 4.88 to 21.65; N = 254) compared to the proximal interphalangeal joints (RR, 7.44; 95% CI, 2.44 to 22.62; N = 153)

Adverse events were significantly more frequent for participants receiving clostridial collagenase compared with placebo. In the RCTs, the proportions of participants experiencing at least 1 adverse event were 97% in the clostridial collagenase groups (range, 97% to 100%) and 28% in the placebo groups (range, 21% to 75%). Peripheral edema was the most frequent adverse event reported, which occurred in 73% of participants receiving clostridial collagenase compared with 5% in the placebo groups. The next most common mild and local adverse events included contusion, pain in extremity, and injection site pain. Serious adverse events were rare and not evaluated in a meta-analysis. Only 1.5% of participants who received clostridial collagenase (4/272) experienced a serious adverse event, including 1 case of complex regional pain syndrome and 2 cases of tendon rupture in CORD I and 1 case of flexion pulley rupture in CORD II.

Table 8. Key Results of Brazzelli et al. (2015) Systematic Review and Meta-Analysis

Study	Clinical success (residual contracture < 5°)	≥ 1 adverse event	Peripheral edema	Contusion	Pain in extremity	Injection site pain
Brazzelli et al. (2015)15
# RCTs; Total N	3; 407	3; 409	2; 374	2; 374	2; 374	3; 409
Range of N	25 to 306	35 to 308	66 to 308	66 to 308	66 to 308	35 to 308
Range of effect sizes: RR (95% CI)	9.33 (1.34, 64.98) to 23.29 (1.53, 354.07)	1.34 (0.96, 1.87) to 4.57 (3.15, 6.62)	8.17 (2.17, 30.80) to 18.86 (7.19, 49.49)	7.70 (2.04, 29.11) to 26.51 (6.68, 105.28)	5.13 (1.33, 19.83) to (5.13 (1.33, 19.83)	1.96 (1.13, 3.38) to 6.73 (2.80, 16.19)
Pooled effect (95% CI)	RR 10.21 (5.29, 19.69)	RR 2.49 (1.13, 5.50)	RR 15.23 (6.97, 33.29)	RR 14.09 (4.20, 47.30)	RR 6.26 (3.00, 13.09)	RR 3.49 (1.48, 8.27)
I2	0%	91%	3%	37%	0%	65%

CI: confidence interval; RCT: randomized controlled trial; RR: relative risk.

In the systematic review by Smeraglia et al. (2016), recurrence was typically defined as a decrease in passive extension that exceeded 20° and was reported in 12 studies (N = 2401) (Table 9). This included data from the RCTs with follow-up that ranged from 3 to 24 months,^17,16,18 as well as from an additional 9 nonrandomized studies with follow-up that extended to 88 months.^{20,21,22,23,24,25,26,13,19} Neither review performed meta-analyses on this outcome, but both reviews observed that recurrence rates tended to increase over time. Recurrence rates ranged from 0% to 4% in studies with follow-up from 3 to 12 months, from 0% to 28% in studies with follow-up of 15 to 24 months, and from 36% to 75% in studies with follow-up from 36 to 88 months. However, authors of the review by Smeraglia et al. (2016)¹⁴ and the nonrandomized, surgery-controlled study by Nydick et al. (2013)¹⁹ have raised questions about the clinical relevance of defining recurrence as a decrease in passive extension that exceeded 20°. For example, authors of Nydick et al. (2013)¹⁹ pointed out that although the recurrence rate of 75% is high in the longest-term, a very small case series by Watt et al. (2010) noted, "none of these patients had further intervention on the injected finger." Further, authors of the review by Smeraglia et al. (2016)¹⁴ proposed that a more clinically relevant definition of recurrence may be contracture greater than 30°, as this is the threshold for which surgery is indicated. In the Collagenase Option for Reduction of Dupuytren Long-Term Evaluation of Safety Study (CORDLESS) study, using the threshold of contracture greater than 30° led to a lower rate of 5-year recurrence of 32%.²¹

Table 9. Summary of Recurrence Results from the Smeraglia 2016 Review According to Duration of Follow-up¹⁴

Study	Design	Setting	N enrolled	Months of Follow-Up	Recurrence
Hurst (2009) CORD 17	RCT	USA (16 sites)	306	3	0/306 (0%)
Nydick (2013) 19	Nonrandomized comparative study	USA (1 site)	59	6	0/59 (0%)
Alberton (2014)22	Case series	Italy (1 site)	40	6	2/40 (3.8%)
Witthaut (2013) JOINT I/II 23	Case series	USA, Australia, UK, Switzerland, Sweden, Denmark, Finland (34 sites)	587	9	19/497 (4%)
Gilpin (2010) CORD II16	RCT	Australia (5 sites)	66	12	0/66 (0%)
McMahon (2013)24	Case series	USA (1 site)	48	15	13/48 (28%)
Badalamene (2000) 25	Case series	USA (sites NR)	35	20	3/35 (8.5%)
Naam (2013) 13	Nonrandomized comparative study	USA (1 site)	46	24	0/46 (0%)
Badalamene (2007) 18	RCT	USA (sites NR)	35	24	5/35 (14%)
Peimer (2013) CORDLESS 20	Case series	USA (10 sites)	643	36	217/623 (35%)
Peimer (2015) CORDLESS 21	Case series	USA (10 sites)	643	60	291/623 (47%)
Watt (2010)26	Case series	USA (1 site)	8	88	6/8 (75%)

CORD: Collagenase Option for Reduction of Dupuytren; CORDLESS: Collagenase Option for Reduction of Dupuytren Long-Term Evaluation of Safety Study; JOINT I: clinicaltrials.gov title: "A Phase 3, Open-Label Study of the Safety and Efficacy of AA4500 in the Treatment of Subjects With Advanced Dupuytren's Disease"; JOINT II: Australian New Zealand Clinical Trials Registry Name, "An Open-Label Study of the Safety and Efficacy of AA4500 in the Treatment of Subjects With Dupuytren’s Contracture"; NR: not reported; RCT: randomized controlled trial. 

For functional outcomes, relevant findings were identified from only 1 open-label, single-arm study (JOINT I, acronym definition not found, clinicaltrials.gov title — "A Phase 3, Open-Label Study of the Safety and Efficacy of AA4500 in the Treatment of Subjects With Advanced Dupuytren's Disease") reported by Naam et al. (2013).¹³ This study retrospectively assessed patients who had Dupuytren's contracture affecting at least 1 joint with a palpable cord who underwent clostridial collagenase injections (n = 25) or fasciectomy (n = 21). 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 range of motion from baseline at the metacarpophalangeal and proximal interphalangeal joints did not differ significantly. Mean posttreatment range of motion at the metacarpophalangeal joint was significantly higher in the clostridial collagenase-treated patients (90.7° vs 83.3°, p = .02), while the posttreatment range of motion at the proximal interphalangeal joint was higher in the fasciectomy-treated patients, although the difference was not statistically significant (67.5° vs 88.8°, p = .06). Complication rates were similar in both groups, although patients who received clostridial collagenase returned more quickly to work and to normal daily activities.

No study has yet reported any quality of life outcomes.

Section Summary: Dupuytren's Contracture
For individuals with Dupuytren's contracture who receive clostridial collagenase, the evidence includes systematic reviews, RCTs, and nonrandomized comparative studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, and quality of life. Findings from randomized and nonrandomized studies comparing clostridial collagenase to surgery suggest similar benefits and harms. However, limited data on the most clinically meaningful outcomes preclude reaching strong conclusions based on their findings. Findings from systematic reviews of randomized, placebo-controlled trials, nonrandomized controlled studies, and noncomparative studies consistently demonstrated clinically important benefits for clostridial collagenase. However, data on quality of life have not yet emerged. Rates of mild local adverse events, including local swelling, contusion, and pain, are generally high, but serious adverse events have been rare. In comparative studies, the risk of contracture recurrence appears to increase over time regardless of treatment group. However, as recurrence rates vary by the definition of recurrence (contracture greater than 20° or 30°, and/or when further intervention is needed), standardization of definition is still needed. Although clostridial collagenase offers the potential benefit of less-invasive treatment for Dupuytren's contracture with clinically meaningful benefits and a low risk of major complications, important gaps in the evidence base exist related to treatment durability and impact on quality of life.

Peyronie's Disease
Clinical Context and Therapy Purpose
The purpose of administering local clostridial collagenase injection(s) in patients who have Peyronie's disease is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of local clostridial collagenase injection(s) improve the net health outcome in men with Peyronie's disease?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is men with Peyronie's disease. 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.

Interventions
The therapy being considered is a local injection of clostridial collagenase.

Comparators
The following therapies and practices are currently being used to treat Peyronie's disease: observation, oral medications, and other intralesional treatment (e.g., verapamil). 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 interferon-α-2b or calcium channel-blockers (e.g., verapamil) is the current standard of therapy.²⁷ Surgical procedures involve the excision of hardened tissue and skin graft, the removal or pinching (plication) of tissue opposite the plaque to reduce curvature (the Nesbit procedure), penile implant, or a combination of these.

Outcomes
The general outcomes of interest are improvements in functional outcomes and quality of life (e.g., sexual function) and treatment-related adverse events (e.g., rupture, hematoma).

Injections are administered in 1- to 3-day cycles at specific intervals over about 24 weeks depending on the degree of curvature, followed by manual modeling.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Carson et al. (2015) reported on a pooled analysis of 6 clinical studies to evaluate safety outcomes for clostridial collagenase for Peyronie's disease.²⁸ The review included phase 2 and 3 industry-sponsored trials of clostridial collagenase, including the Investigation for Maximal Peyronie’s Reduction Efficacy and Safety Studies (IMPRESS) I and II studies, discussed in the RCT section below. A total of 1,044 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.

Randomized Controlled Trials
Gelbard et al. (2013) published the results of 2 double-blind, placebo-controlled randomized trials (IMPRESS I and II), which examined the clinical efficacy and safety of collagenase injections in subjects with Peyronie's disease.²⁹ These RCTs were sponsored by the manufacturer (Auxilium Pharmaceuticals), the findings of which were submitted to the FDA in support of their biologics license application. These 2 trials 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). Men were stratified by baseline penile curvature (30° to 60°vs. 61° to 90°) and randomized to collagenase injections or placebo in a 2:1 ratio. The primary outcomes were the percent change in the penile curvature abnormality, as well as the change in the Peyronie’s Disease Questionnaire (PDQ; developed by the manufacturer; see discussion at the end of this section on PDQ validation) 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. The change in curvature and the percent improvement in the collagenase group were significantly greater in the injection group (each p < .001). The mean change in the PDQ symptom bother domain score was significantly improved in the collagenase group (-2.8) compared with the placebo group (-1.8; p = .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 corpor al rupture (3 cases) and penile hematoma (3 cases). All corpor al ruptures and 1 hematoma were successfully repaired surgically. Of the other 2 penile hematomas, 1 case resolved successfully without intervention, and the other ended with aspiration.

Lipshultz et al. (2015) reported post hoc subgroup analyses from combined data from the IMPRESS I and II studies.³⁰ This analysis included a modified intention-to-treat population of 612 subjects who had a penile curvature deformity measurement, 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 the duration of illness, the degree of plaque calcification, and the 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 30° to 60° and 61° to 90°, disease duration over 2 years, no calcification, and IIEF severity score of 17 or greater. PDQ symptom bother score reductions were significantly greater with clostridial collagenase than with placebo for those with penile curvature 30° to 60°, disease duration over 4 years, no calcification, and IIEF scores 1 to 5 (no sexual activity) and 17 or greater. However, a generalization of this analysis is limited by its post hoc design and small subgroups.

The development and validation of the PDQ have been described by Hellstrom et al. (2013) using data from IMPRESS I and II studies.³¹ Investigators developed the PDQ to assess quantitatively the symptoms and psychosexual consequences of Peyronie's disease by 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 different degrees of curvature abnormality. Coyne et al. (2015) assessed the responsiveness of the PDQ to changes in Peyronie's disease symptoms in men from the IMPRESS I and II trials.³² 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)³³ 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.

Goldstein et al. (2020) reported noncomparative 5-year outcomes in men treated with clostridial collagenase.³⁴ The study included 280 men previously enrolled in the IMPRESS I and II trials or in the AUX-CC 802 or 806 open-label studies. After a mean 4.6 years of follow-up, in 180 men with data, there was a 9.1% improvement in mean penile curvature relative to their final measure in their original study enrollment. Mean PDQ bother (N = 123; p = .0003), psychological and physical symptoms (N = 119; p = .0004), and pain (N = 52; p = .04) were all significantly improved compared with the last measure of their previous study. Serious adverse events occurred in 2.1% (6/280) of the population. Due to the high number of participants with missing follow-up data (27%) and the lack of a comparison group, these study results should be interpreted with caution.

A single-arm, open-label trial reported by Levine et al. (2015) described outcomes for 238 subjects with Peyronie's 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).³⁵ 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 a 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 on 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 in their degree of bothersomeness related to the disease. However, it is not clear that these improvements in curvature or in the degree of symptom bothersomeness translate into differences in patient outcomes or whether the benefit of treatment exceeds the risks.

Adhesive Capsulitis
Clinical Context and Therapy Purpose
The purpose of administering local clostridial collagenase injection(s) in patients who have adhesive capsulitis is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of local clostridial collagenase injection(s) improve the net health outcome in those with adhesive capsulitis?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is people with adhesive capsulitis, which is also commonly referred to as "frozen shoulder."

Interventions
The therapy being considered is a local injection of clostridial collagenase.

Comparators
The following therapies and practices are currently being used to treat adhesive capsulitis: physical therapy and mobilization in combination with analgesics or nonsteroidal anti-inflammatory drugs.

Outcomes
The general outcomes of interest are improvements in symptoms , functional outcomes, quality of life, and treatment-related adverse events

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Evidence on the use of clostridial collagenase for treatment of adhesive capsulitis is extremely limited. Fitzpatrick et al. (2020)³⁶ reported results from 11 participants enrolled at a single center comparing clostridial collagenase injection (n = 9) with placebo (n = 2). There was no statistically significant difference between clostridial collagenase and placebo in shoulder function based on measures of range of motion after 3 months of follow up. Adverse events that included bruising and swelling occurred in 100% (9/9) of participants receiving clostridial collagenase injection and no (0/2) placebo participants. These results are part of a larger randomized trial of 322 participants at 46 sites which was completed in 2014 (NCT02006719). Complete results for the trial remain unpublished although Fitzpatrick et al. note that their findings were consistent with those of the full trial population.

Section Summary: Adhesive Capsulitis
Evidence on the use of clostridial collagenase for treatment of adhesive capsulitis is extremely limited. One small substudy of a larger, unpublished RCT found no benefit of clostridial collagenase injection over placebo in functional outcomes, with increased adverse events.

Summary of Evidence
For individuals with Dupuytren's contracture who receive clostridial collagenase, the evidence includes systematic reviews, RCTs, and nonrandomized comparative studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, and quality of life. Findings from randomized and nonrandomized studies comparing clostridial collagenase to surgery suggest similar benefits and harms. However, limited data on the most clinically meaningful outcomes preclude reaching strong conclusions based on their findings. Findings from systematic reviews of randomized, placebo-controlled trials, nonrandomized controlled studies, and noncomparative studies consistently demonstrated clinically important benefits for clostridial collagenase. However, data on quality of life have not yet emerged. Rates of mild local adverse events, including local swelling, contusion and pain, are generally high, but, serious adverse events have been rare. In comparative studies, the risk of contracture recurrence appears to increase over time regardless of treatment group. However, as recurrence rates vary by the definition of recurrence (contracture greater than 20° or 30°, and/or when further intervention is needed), standardization of the definition is still needed. Although clostridial collagenase offers the potential benefit of less-invasive treatment for Dupuytren's contracture with clinically meaningful benefits and a low risk of major complications, important gaps in the evidence base exist related to treatment durability and impact on quality of life. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have Peyronie's 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 reductions in self-reported distress from symptoms related to Peyronie's disease. However, evidence demonstrating improvements in health outcomes is lacking, as are studies comparing clostridial collagenase with other therapies for Peyronie's disease. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have adhesive capsulitis who receive local clostridial collagenase injection(s), evidence is lacking. Relevant outcomes are symptoms, change in disease status, functional outcomes, and quality of life. One small substudy of an RCT found no benefit of clostridial collagenase injection over placebo in functional outcomes, with increased adverse events. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2011 Input
In response to 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's 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, another reviewer noted that injectable clostridial collagenase for Dupuytren's 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's contracture might 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's contracture.

Four reviewers agreed that injectable clostridium collagenase is investigational for the treatment of Peyronie's disease. One of these reviewers also commented that, while this treatment is considered investigational, it may be indicated for Peyronie's 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
Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

Peyronie's Disease
American Urological Association
In 2015, the American Urological Association (AUA) issued guidelines based on a systematic review on the diagnosis and treatment of Peyronie's disease.⁵ For patients with stable Peyronie's disease, penile curvature greater than 30° and less than 90°, and intact erectile function (with or without the use of medications), the Association recommended intralesional collagenase Clostridium histolyticum in combination with modeling (moderate recommendation; evidence strength grade B). The AUA panel discussion indicated that their recommendation was based primarily on the IMPRESS I and II RCTs discussed above. They acknowledge that some uncertainty remains about the long-term durability of curvature improvements, replication by another group of investigators, and generalizability to other patient subgroups such as those with hourglass deformity, ventral curvature, calcified plaque, or plaque located proximal to the base of the penis. Ultimately, their moderate recommendation for clostridial collagenase was because of the modest curvature reductions obtained and the low risk of serious adverse events in IMPRESS I and II.

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 10.

Table 10. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
	Dupuytren's Interventions: Surgery vs. Collagenase Trial (DISC)	710	July 2022
Unpublished
NCT03000114	Comparison of Collagenase Injection and Percutaneous Needle Aponeurotomy for Treatment of Dupuytren’s Disease	334	Jan. 2021 (status: unknown)
NCT02725528	A Multi-Center, Randomized Controlled Trial Comparing The Clinical Effectiveness and Cost-Effectiveness of Collagenase Injection (Xiaflex) and Palmar Fasciectomy in the Management of Dupuytren’s Disease	128	Nov. 2019 (status: completed)
NCT02301078	Comparing Short-term Function and Pain After Treatment With Collagenase Clostridium Histolyticum or Percutaneous Needle Aponeurotomy for Dupuytren’s Disease	60	Nov. 2017 (status: unknown)
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 (status: completed)b
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	Dec. 2014 (status: completed)

ISRCTN: International Standard Randomised Controlled Trials Number; NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.
b Results from one center (of 46) reported in Fitzpatrick et al. (2020)

References:  

1. Layton T, Nanchahal J. Recent advances in the understanding of Dupuytren's disease. F1000Res. 2019; 8. PMID 30854193
2. Hussein AA, Alwaal A, Lue TF. All about Peyronie's disease. Asian J Urol. Apr 2015; 2(2): 70-78. PMID 29264123
3. Dias R, Cutts S, Massoud S. Frozen shoulder. BMJ. Dec 17 2005; 331(7530): 1453-6. PMID 16356983
4. Food and Drug Administration (FDA). Xiaflex: collagenase clostridium histolyticum. 2018; http://www.endo.com/File%20Library/Products/Prescribing%20Information/Xiaflex_prescribing_information.html# LINK_a7d1f7e8-79cf-49aa-8e76-3ddc035530db. Accessed January 26, 2022.
5. Nehra A, Alterowitz R, Culkin DJ, et al. Peyronie's Disease: AUA Guideline. 2015; http://www.auanet.org/guidelines/peyronies-disease-(2015). Accessed January 26, 2022.
6. Abe Y. Comparison of Treatment Outcomes after Collagenase Injection and Percutaneous Needle Fasciotomy for Dupuytren's Contracture: Objective and Subjective Comparisons with a 3-Year Follow-Up. Plast Reconstr Surg. Jun 2020; 145(6): 1464-1474. PMID 32459776
7. Stromberg J, Ibsen Sorensen A, Friden J. Percutaneous Needle Fasciotomy Versus Collagenase Treatment for Dupuytren Contracture: A Randomized Controlled Trial with a Two-Year Follow-up. J Bone Joint Surg Am. Jul 05 2018; 100(13): 1079-1086. PMID 29975270
8. Skov ST, Bisgaard T, Sondergaard P, et al. Injectable Collagenase Versus Percutaneous Needle Fasciotomy for Dupuytren Contracture in Proximal Interphalangeal Joints: A Randomized Controlled Trial. J Hand Surg Am. May 2017; 42(5): 321-328.e3. PMID 28473158
9. Scherman P, Jenmalm P, Dahlin LB. One-year results of needle fasciotomy and collagenase injection in treatment of Dupuytren's contracture: A two-centre prospective randomized clinical trial. J Hand Surg Eur Vol. Jul 2016; 41(6): 577-82. PMID 26631343
10. Scherman P, Jenmalm P, Dahlin LB. Three-year recurrence of Dupuytren's contracture after needle fasciotomy and collagenase injection: a two-centre randomized controlled trial. J Hand Surg Eur Vol. Oct 2018; 43(8): 836-840. PMID 30012049
11. Zhou C, Hovius SER, 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
12. 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
13. Naam NH. Functional outcome of collagenase injections compared with fasciectomy in treatment of Dupuytren's contracture. Hand (N Y). Dec 2013; 8(4): 410-6. PMID 24426958
14. Smeraglia F, Del Buono A, Maffulli N. Collagenase clostridium histolyticum in Dupuytren's contracture: a systematic review. Br Med Bull. Jun 2016; 118(1): 149-58. PMID 27151958
15. Brazzelli M, Cruickshank M, Tassie E, et al. Collagenase clostridium histolyticum for the treatment of Dupuytren's contracture: systematic review and economic evaluation. Health Technol Assess. Oct 2015; 19(90): 1-202. PMID 26524616
16. 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): 2027-38.e1. PMID 21134613
17. Hurst LC, Badalamente MA, Hentz VR, et al. Injectable collagenase clostridium histolyticum for Dupuytren's contracture. N Engl J Med. Sep 03 2009; 361(10): 968-79. PMID 19726771
18. 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): 767-74. PMID 17606053
19. Nydick JA, Olliff BW, Garcia MJ, et al. A comparison of percutaneous needle fasciotomy and collagenase injection for dupuytren disease. J Hand Surg Am. Dec 2013; 38(12): 2377-80. PMID 24060510
20. 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
21. 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 Am. Aug 2015; 40(8): 1597-605. PMID 26096221
22. 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. Dec 2014; 98(3): 225-32. PMID 24254968
23. 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
24. 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): 261-6. PMID 24426932
25. Badalamente MA, Hurst LC. Enzyme injection as nonsurgical treatment of Dupuytren's disease. J Hand Surg Am. Jul 2000; 25(4): 629-36. PMID 10913202
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): 534-9, 539.e1. PMID 20353858
27. Hellstrom WJ. Medical management of Peyronie's disease. J Androl. Jul-Aug 2009; 30(4): 397-405. PMID 18974422
28. Carson CC, 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): 815-22. PMID 25818264
29. 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
30. 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): 650-6. PMID 25711400
31. 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): 627-34. PMID 23376705
32. Coyne KS, Currie BM, Thompson CL, et al. Responsiveness of the Peyronie's Disease Questionnaire (PDQ). J Sex Med. Apr 2015; 12(4): 1072-9. PMID 25664497
33. 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): 180-7. PMID 18173766
34. Goldstein I, Lipshultz LI, McLane M, et al. Long-Term Safety and Curvature Deformity Characterization in Patients Previously Treated with Collagenase clostridium Histolyticum for Peyronie's Disease. J Urol. Jun 2020; 203(6): 1191-1197. PMID 31922462
35. 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): 248-58. PMID 25388099
36. Fitzpatrick J, Richardson C, Klaber I, et al. Clostridium histolyticum (AA4500) for the Treatment of Adhesive Capsulitis of the Shoulder: A Randomised Double-Blind, Placebo-Controlled Study for the Safety and Efficacy of Collagenase - Single Site Report. Drug Des Devel Ther. 2020; 14: 2707-2713. PMID 32764872

Coding Section

Codes	Number	Description
CPT	20527	Injection, enzyme (eg, collagenase), palmar fascial cord (i.e., Dupuytren’s contracture)
	26341	Manipulation, palmar fascial cord (i.e., Dupuytren’s cord), post enzyme injection (e.g., collagenase), single cord
	54200	Injection procedure for Peyronie disease
	54235	Injection of corpora cavernosa with pharmacologic agent(s) (e.g., papaverine, phentolamine) — this part of the service is to induce an erection so that the location of the clostridial collagenase injection can be determined. If the penis does not detumesce, code 96372 might also be reported for administration of a medication to pharmacologically detumesce the penis.
HCPCS	J0775	Injection, collagenase clostridium histolyticum, 0.01 mg
ICD-10-CM	M72.0	Palmar fascial fibromatosis (Dupuytren)
	M75.00 – M75.02	Adhesive capsulitis of shoulder code range
	N48.6	Induration penis plastica (Peyronie’s disease)
ICD-10-PCS		ICD-10-PCS codes are only for use on inpatient services
	3E0U33Z	Introduction, joints, percutaneous, anti-inflammatory
Type of service	Therapy
Place of Service	Outpatient/Inpatient

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. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology^© American Medical Association. All Rights Reserved" 

History From 2013 Forward     

01/12/2023	Annual review, no change to policy intent. Updating rationale and references.)
01/06/2022	Annual review, no change to policy intent. Updating description, background, rationale and references.
01/19/2021	Annual review, no change to policy intent.
08/13/2020	Interim review, adding coverage for the following:Injectable clostridial collagenase for the treatment of Peyronie's disease in adults may be considered medically necessary for a maximum of 4 treatment cycles when the following criteria are met:
01/02/2020	Annual review, no change to policy intent.
02/01/2019	Annual review, no change to policy intent. Updating background, description, rationale and references.
02/13/2018	Updating policy to move injectable clostridial collagenase to not medically necessary (previously considered investigational). No other changes made.
02/12/2018	Annual review, no change to policy intent. Updating rationale and references.
12/13/2016	Annual review, no change to policy intent. Updating background, description, regulatory status, rationale and references.
01/20/2016	Annual review, no change to policy intent. Updating background, description, rationale, references, regulatory status and guidelines.
01/13/2015	Annual review, no change to policy intent. Updated description, background, regulatory status, rationale and references. Added guidelines and coding.
01/14/2014	Annual review, updated rationale and references. No change to policy intent.