Original Article
Injectable Collagenase Clostridium Histolyticum for Dupuytren's Contracture
N Engl J Med 2009; 361:968-979September 3, 2009
- Abstract
Background
Dupuytren's disease limits hand function, diminishes the quality of life, and may ultimately disable the hand. Surgery followed by hand therapy is standard treatment, but it is associated with serious potential complications. Injection of collagenase clostridium histolyticum, an office-based, nonsurgical option, may reduce joint contractures caused by Dupuytren's disease.
Methods
We enrolled 308 patients with joint contractures of 20 degrees or more in this prospective, randomized, double-blind, placebo-controlled, multicenter trial. The primary metacarpophalangeal or proximal interphalangeal joints of these patients were randomly assigned to receive up to three injections of collagenase clostridium histolyticum (at a dose of 0.58 mg per injection) or placebo in the contracted collagen cord at 30-day intervals. One day after injection, the joints were manipulated. The primary end point was a reduction in contracture to 0 to 5 degrees of full extension 30 days after the last injection. Twenty-six secondary end points were evaluated, and data on adverse events were collected.
Results
Collagenase treatment significantly improved outcomes. More cords that were injected with collagenase than cords injected with placebo met the primary end point (64.0% vs. 6.8%, P<0.001), as well as all secondary end points (P≤0.002). Overall, the range of motion in the joints was significantly improved after injection with collagenase as compared with placebo (from 43.9 to 80.7 degrees vs. from 45.3 to 49.5 degrees, P<0.001). The most commonly reported adverse events were localized swelling, pain, bruising, pruritus, and transient regional lymph-node enlargement and tenderness. Three treatment-related serious adverse events were reported: two tendon ruptures and one case of complex regional pain syndrome. No significant changes in flexion or grip strength, no systemic allergic reactions, and no nerve injuries were observed.
Conclusions
Collagenase clostridium histolyticum significantly reduced contractures and improved the range of motion in joints affected by advanced Dupuytren's disease. (ClinicalTrials.gov number, NCT00528606.)
Media in This Article
Figure 1
Dupuytren's Disease in a Study Patient.Figure 2
Administration of the Study Drug.Article Activity
- Article
Dupuytren's disease, a progressive genetic disorder of pathologic collagen production and deposition, begins with palpable nodules in the palm.1,2 Later, pathologic collagen cords form, extend longitudinally, thicken, and shorten, causing flexion contractures of the joints, which can severely limit hand function. Contractures typically affect the metacarpophalangeal joint, the proximal interphalangeal joint, or both. The ring and little fingers are most commonly affected. Dupuytren's disease occurs in all racial and ethnic groups, but the incidence of this disease is highest among people of northern European descent.3-5 The estimated global prevalence among whites is 3 to 6%.3,6 Dupuytren's disease is more common in men than in women,3-5 increases in incidence with advancing age,3-5 and has been associated with smoking,5,7 alcoholism,8 diabetes,9 epilepsy,3 and human immunodeficiency virus infection.10
The standard of care for Dupuytren's disease is surgery — open fasciectomy8,11-14 (the most common procedure),4 percutaneous or open fasciotomy,15 or needle fasciotomy.16,17 Surgery is recommended in patients with functional impairment and metacarpophalangeal-joint contractures of 30 degrees or more.18,19 For patients with proximal-interphalangeal-joint contractures, recommendations vary and are based on quantitative and qualitative assessments.18-20 No effective pharmacotherapy exists.21
Collagenase clostridium histolyticum, which lyses collagen and leads to disruption of contracted cords,22 is a new, office-based, minimally invasive, nonsurgical, investigational option for the treatment of advanced Dupuytren's disease. Treatment does not require anesthesia. Collagenase clostridium histolyticum is injected into the affected cord, and the next day, the treated joint is manipulated to attempt cord rupture.21 Extensive hand therapy after treatment is not required. In previous single-center studies, injectable collagenase clostridium histolyticum reduced contractures of the metacarpophalangeal and proximal interphalangeal joints to 0 to 5 degrees of full extension in approximately two thirds of treated joints.23-25 We conducted the Collagenase Option for Reduction of Dupuytren's (CORD) I study — a phase 3 clinical trial — to confirm the results of these studies in a larger patient population.
Methods
Trial Design
CORD I is a prospective, multicenter, phase 3 clinical trial comprising a 90-day, randomized, double-blind, placebo-controlled phase and an ongoing open-label extension. The trial was conducted under the auspices of the institutional review board at each of the 16 participating centers throughout the United States. The study was conducted according to the ethical principles of Good Clinical Practices, the International Conference on Harmonisation Guidelines, and the Code of Federal Regulations title 21. Auxilium Pharmaceuticals financially supported the trial, which was designed by Auxilium and the CORD I Study Group investigators. Data were collected by the investigators and analyzed by Auxilium. Data management was performed by Kendle International. The authors had full access to the data and made the decision to submit the manuscript for publication. All authors contributed to the content of the manuscript, reviewed the data, and vouch for the completeness and accuracy of the data and data analyses.
Study Population
Patients with Dupuytren's disease and fixed-flexion contractures of the metacarpophalangeal joint or proximal interphalangeal joint of 20 degrees or more in one finger (excluding the thumb) were enrolled. The patients were in good health, were 18 years of age or older, had metacarpophalangeal-joint contractures between 20 degrees and 100 degrees or proximal-interphalangeal-joint contractures between 20 degrees and 80 degrees, and were unable to simultaneously place the affected finger and palm flat on a table. Women included in the study were postmenopausal or used contraception. Exclusion criteria were breast-feeding or pregnancy, a bleeding disorder, a recent stroke, previous treatment of the primary joint within 90 days before the beginning of the study, collagenase treatment or treatment with any investigational drug within 30 days before the beginning of the study, the use of a tetracycline derivative within 14 days before the beginning of the study, the use of an anticoagulant within 7 days before the beginning of the study, an allergy to collagenase, and a chronic muscular, neurologic, or neuromuscular disorder affecting the hands. All patients provided written informed consent.
Treatment
Before initiating treatment, the investigators identified a primary joint for treatment in each patient (Figure 1Figure 1
Dupuytren's Disease in a Study Patient.). Secondary and tertiary joints were also identified for possible subsequent injections. Primary joints were stratified according to type (two metacarpophalangeal joints to one proximal interphalangeal joint) and according to the severity of joint contracture (metacarpophalangeal joint, ≤50 degrees or >50 degrees, and proximal interphalangeal joint, ≤40 degrees or >40 degrees) and then randomly assigned in a 2:1 ratio to either injectable collagenase clostridium histolyticum or placebo. Randomization was achieved with the use of a permuted-block design (block size of 6) with random assignment within each stratum for each study site.Collagenase clostridium histolyticum (0.58 mg per injection) was reconstituted in 0.25 ml of sterile diluent (for metacarpophalangeal joints) or 0.20 ml of sterile diluent (for proximal interphalangeal joints) and injected directly into the affected cords (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Placebo (10 mM TRIS per 60 mM sucrose reconstituted in diluent) was administered in a similar manner. If needed, the joints were then manipulated up to three times with the use of a standardized procedure (Supplementary Appendix) the day after injection (Figure 1) in an effort to rupture the cords. Patients were given a splint to wear nightly for up to 4 months. They did not undergo physical therapy. Follow-up visits occurred 1, 7, and 30 days after injection. A treatment cycle comprised injection, manipulation, and 30-day follow-up (Figure 2Figure 2
Administration of the Study Drug.). Each affected cord that was contracting the joint could undergo a maximum of three treatment cycles, and each patient could receive a maximum of three injections during the double-blind phase. If the primary joint met the primary end point with one or two injections, a secondary joint could be treated. If the primary joint and a secondary joint met the primary end point with one injection each, a tertiary joint could be treated (Figure 2).Efficacy End Points and Assessments
The primary end point was a reduction in primary-joint contracture to 0 to 5 degrees of full extension 30 days after the last injection. Twenty-six secondary end points were evaluated in a fixed-sequence serial testing procedure with an a priori ordered hypothesis based on two time points: 30 days after the last injection and 30 days after the first injection. Recurrence of contracture, defined as an increase in joint contracture to 20 degrees or more in the presence of a palpable cord at any time during the study, was evaluated in primary joints that reached the primary end point and was recorded as an adverse event.
Fixed-flexion angles were measured with the use of finger goniometry after the fingers had been passively extended until a firm end point was reached. Full flexion was measured with maximum contraction of the treated fingers. Angles of extension and flexion were measured during screening, during each treatment cycle, and at the 90-day visit. Grip strength was assessed with the use of a dynamometer at the screening visit, immediately before injection, 7 and 30 days after injection, and at the 90-day visit.
Safety Assessments
A 60-minute observation period followed each injection. Patients were monitored for systemic and local adverse events. Vital signs were assessed before injection, for 60 minutes after injection, and on days 1, 7, 30, and 90. Blood and urine samples for laboratory testing were obtained at screening, 30 days after injection, and at the 90-day visit. Adverse events, assessed for severity and relationship to the treatment, were recorded from the first injection until 30 days after completion of the study. Investigators used their own terminology to describe adverse events.
Statistical Analysis
Sample-size calculations for efficacy analyses (Table 1 in the Supplementary Appendix) were based on estimated response rates of 80% for metacarpophalangeal joints and 70% for proximal interphalangeal joints in the active-treatment group and a response rate of 10% in the placebo group, with a type 1 error of 0.05 and a power of 80% with the use of two-sided tests. The resulting sample sizes for efficacy were 14 patients receiving active treatment and 7 patients receiving placebo for metacarpophalangeal joints and 18 patients receiving active treatment and 9 patients receiving placebo for proximal interphalangeal joints. The primary efficacy analysis was performed with the use of the Cochran–Mantel–Haenszel test, with adjustment for the type of joint and the severity of contracture at baseline. Clinical improvement (defined as ≥50% reduction in joint contracture relative to baseline 30 days after the last injection) was analyzed with the use of the Cochran–Mantel–Haenszel test. The percent reduction in contracture and the change from baseline in the range of motion were analyzed with the use of analysis of variance, with factors for study group, severity of baseline contracture, and type of joint. Kaplan–Meier survival analyses were used to compare the time to the primary end point in the two study groups. Simultaneous hypothesis testing for efficacy analyses was accomplished by applying a fixed-sequence serial testing procedure with a priori ordered hypotheses that strongly controlled the 5% type 1 error.26 With this standard procedure, all hypotheses that followed the first nonsignificant hypothesis (P>0.05) were not tested. Adverse events in the two study groups were compared with the use of Fisher's exact test. Vital signs, laboratory assessments, and grip strength were summarized with descriptive statistics. All reported P values are two-sided and have not been adjusted for multiple comparisons. In addition, the 95% confidence interval for the treatment difference is provided for the primary end point, and 99% confidence intervals are provided for the secondary end points. No interim analyses were planned or carried out before the completion of the trial.
Results
Between September and December 2007, a total of 352 patients were screened and 308 patients were enrolled: 204 joints received collagenase and 104 received placebo. All 308 patients with primary joints that were randomly assigned to receive at least one dose of a study drug composed the intention-to-treat and safety populations. Baseline characteristics of the patients were similar between the two study groups, with the exception of sex (P=0.01) (Table 1Table 1
Baseline Characteristics of the Patients.). Efficacy results were based on 306 primary joints: 203 that were injected with collagenase and 103 that were injected with placebo. The analysis excluded two primary joints that were injected: one joint in the placebo group was not evaluated after injection, and one joint in the collagenase group had a baseline contracture of 0 degrees before treatment.Efficacy
The proportions of joints that met the primary end point and all 26 secondary end points were significantly higher when injected with collagenase than when injected with placebo (P≤0.002) (Table 2Table 2
Treatment Outcomes, According to a Modified Intention-to-Treat Analysis.). Contractures were reduced to 0 to 5 degrees of full extension 30 days after the last injection in 64.0% of joints injected with collagenase, as compared with 6.8% of those injected with placebo. An example of a collagenase-treated joint that met the primary end point is shown in Figure 1. More than half of the collagenase-treated joints that did not meet the primary end point did not receive the maximum allowable number of collagenase injections (three per cord), most commonly because investigators could not palpate a cord or patients were satisfied with the result. The median time to reach the primary end point for collagenase-treated joints was 56 days. At the 90-day visit, there was no recurrence of contracture in any collagenase-treated primary joint that had reached the primary end point. The mean change in contracture from baseline to 30 days after the last injection was a reduction from 50.2 to 12.2 degrees in collagenase-injected joints and from 49.1 to 45.7 degrees in placebo-injected joints. More collagenase-injected than placebo-injected joints also met the end point of a reduction in contracture to 0 to 5 degrees of full extension 30 days after the first injection (38.9% vs. 1.0%, P<0.001).When analyzed according to type of joint, more collagenase-injected than placebo-injected joints met the primary end point (metacarpophalangeal joint, 76.7% vs. 7.2%; proximal interphalangeal joint, 40.0% vs. 5.9%; P<0.001 for both comparisons). The median time to the primary end point was 36 days for the collagenase-injected metacarpophalangeal joints. The mean change in contracture from baseline to 30 days after the last injection was 48.0 to 7.2 degrees in the collagenase-injected metacarpophalangeal joints and 45.4 to 43.1 degrees in the placebo-injected metacarpophalangeal joints. When analyzed according to type of joint and baseline severity, 88.9% of collagenase-injected metacarpophalangeal joints with a baseline contracture of 50 degrees or less met the primary end point, as compared with 57.7% of such joints with a baseline contracture of more than 50 degrees. Similarly, 80.9% of the collagenase-injected proximal interphalangeal joints with a baseline contracture of 40 degrees or less met the primary end point, as compared with 22.4% of such joints with a baseline contracture of more than 40 degrees.
Significantly more collagenase-injected joints than placebo-injected joints showed clinical improvement 30 days after the last injection. Among all joints that were injected with collagenase, 84.7% showed improvement (94.0% of metacarpophalangeal joints and 67.1% of proximal interphalangeal joints). Among all joints that were injected with placebo, 11.7% showed improvement (11.6% of metacarpophalangeal joints and 11.8% of proximal interphalangeal joints). As compared with placebo-injected joints, collagenase-injected joints showed a significantly greater percent reduction in contracture from baseline to 30 days after the last injection: 79.3% (87.1% of metacarpophalangeal joints and 64.5% of proximal interphalangeal joints), versus 8.6% for placebo-injected joints (7.2% of metacarpophalangeal joints and 11.4% of proximal interphalangeal joints).
Collagenase-injected primary joints showed greater improvement in range of motion than placebo-injected joints. The mean change in range of motion from baseline to 30 days after the last injection was an increase from 43.9 to 80.7 degrees (mean, 36.7 degrees) in collagenase-injected joints and from 45.3 to 49.5 degrees (mean, 4.0 degrees) in placebo-injected joints. The findings were similar when these data were analyzed according to type of joint. The mean change in range of motion from baseline to 30 days after the last injection was an increase from 42.6 to 83.7 degrees (mean, 40.6 degrees) in the collagenase-injected metacarpophalangeal joints (Figure 3AFigure 3
Mean Changes in Range of Motion.), from 46.4 to 74.9 degrees (mean, 29.0 degrees) in the collagenase-injected proximal interphalangeal joints (Figure 3B), from 45.7 to 49.7 degrees (mean, 3.7 degrees) in the placebo-injected metacarpophalangeal joints, and from 44.4 to 49.1 degrees (mean, 4.7 degrees) in the placebo-injected proximal interphalangeal joints.Adverse Effects
A total of 741 injections (444 collagenase and 297 placebo) were administered in 308 patients. Overall, 96.6% of the patients who received collagenase reported at least one treatment-related adverse event, as compared with 21.2% of the patients who received placebo (Table 3Table 3
Treatment-Related Adverse Events in 2% or More of Patients in Either Study Group.). Patients who received collagenase had significantly more injection- and manipulation-related events (e.g., contusion, injection-site hemorrhage, injection-site pain, pain in the upper extremity, tenderness, ecchymosis, injection-site swelling, pruritus, skin laceration, lymph-node enlargement and tenderness on palpation, lymphadenopathy, erythema, blister, injection-site pruritus, and axillary pain) than patients who received placebo (P≤0.02). Most treatment-related adverse events were mild or moderate in intensity and resolved without intervention within a median of 10 days. Twenty patients in the collagenase group and two patients in the placebo group reported adverse events related to the study drug that were severe in intensity (Table 2 in the Supplementary Appendix). All events were deemed to be related to the study drug except for one report each of contact dermatitis, muscle spasms, and myocardial infarction in the collagenase group and one report each of acute cholecystitis, nasopharyngitis, and radius fracture in the placebo group. Seven patients who received collagenase had a serious adverse event, of which three were deemed to be treatment-related: one case of complex regional pain syndrome and two tendon ruptures, both of which required surgical procedures; one tendon rupture was treated by excision of the ruptured tendon and tenolysis of the remaining tendon and the other underwent tendon reconstruction (Table 2 in the Supplementary Appendix). Two patients in the collagenase group discontinued treatment because of adverse events: severe injection-site pain after the first injection in one patient and mild dizziness 28 days after the first injection in the other. Mean changes in hematologic and biochemical variables from baseline to day 30 and day 90 were not considered to be clinically meaningful in either study group. No deaths, clinically meaningful changes in grip strength, or nerve injuries were reported.There were no clinically meaningful systemic allergic reactions (Supplementary Appendix). Most patients (≥85.8%) tested positive for antibodies against type I collagenase clostridium histolyticum (AUX-I), type II collagenase clostridium histolyticum (AUX-II), or both 30 days after the first injection. After a third injection, all patients tested positive for antibodies against both AUX-I and AUX-II. An analysis of treatment outcome according to antibody titer was not conducted.
Discussion
The results of this double-blind, placebo-controlled, randomized trial show that injectable collagenase clostridium histolyticum is an effective nonsurgical treatment option in patients with advanced Dupuytren's disease. This condition often limits hand function and activities of daily living, including hair brushing, face washing, hand holding, and the ability to reach into a pocket and to shake hands, and it leads many patients to seek treatment, which is currently limited to surgery. Many patients cannot undergo surgery, however, because of advanced age, a coexisting condition, or both.18,27 Other patients (particularly those with early-stage disease) delay surgery or are unwilling to undergo surgery because of the surgical process and its associated risks, the long period of recovery, and the need for extensive hand therapy.21 Most patients with advanced Dupuytren's disease would be candidates for treatment with injectable collagenase clostridium histolyticum.
In this study, injectable collagenase clostridium histolyticum was significantly superior to placebo in reducing contractures and improving the range of motion in affected joints. The primary end point was a reduction of contracture to within 5 degrees of full extension in the primary joint 30 days after the last injection. Overall, 64% of primary joints — 77% of metacarpophalangeal joints and 40% of proximal interphalangeal joints — treated with collagenase met this end point. Furthermore, joints with less severe contractures were more likely to respond to treatment with collagenase than were joints with more severe contractures, indicating that early intervention may be the most effective treatment approach. Similar observations have also been reported in the surgical literature. Delaying treatment makes surgical correction more difficult.11
After collagenase treatment, 92% of contractures of the metacarpophalangeal joint were 30 degrees or less; thus, these contracted joints no longer met the accepted criteria for surgery. In addition, 85% of collagenase-treated joints had a reduction of 50% or more in contracture from baseline to 30 days after the last injection and showed significant improvement in range of motion, which is critical for hand function.
Surgery for Dupuytren's disease is often successful, but surgery is not the best option for all patients. After surgery, recuperation is long and requires substantial postoperative hand therapy, restricting the ability of patients to return to work or resume daily activities and athletic pursuits.21,27-29 In contrast, hand therapy is not required after treatment with injectable collagenase clostridium histolyticum. In this study, patients were advised to wear a custom-fitted splint at night for up to 4 months, although compliance and the effectiveness of splinting were not assessed.
Surgery is also associated with complications, including injury to the tendon, digital nerve, or artery with the potential loss of a finger; infection; loss of flexion or grip strength; recurrence of contracture; complex regional pain syndrome; skin necrosis; and wound-healing complications.4,8,11,17,19,30-33 Reported complication rates among patients undergoing surgery are 0.2% for tendon ruptures, 1.7 to 7.8% for digital-nerve injury, 1.9 to 9.7% for digital-artery injury, and 1.0 to 10.6% for infection.4,8,11,14 In the present study, collagenase treatment resulted in two tendon ruptures. Collagenase injections were also associated with mild-to-moderate adverse events related to injection or manipulation, such as bruising, pain, and swelling. Treatment with collagenase did not affect flexion or grip strength, and no nerve injuries were reported.
Extension of disease to previously unaffected areas, recurrence of contracture, or both occur in 26 to 80% of patients after surgery, depending on the patient's diathesis and the type of surgery performed.21 Repeat surgery, when indicated, is usually more challenging.8,11 In this study, patients who had a reduction in contracture to 0 to 5 degrees were monitored for 30 days after the last injection. This time frame was insufficient to assess recurrence, and we cannot make any claims about this outcome.
In conclusion, this study demonstrated the efficacy and safety of injectable collagenase clostridium histolyticum in patients with advanced Dupuytren's disease. Our data on 30-day outcomes indicate that this office-based procedure effectively reduced contractures and improved range of motion, thus providing an alternative to surgery.
Dr. Hurst reports receiving consulting and advisory-board fees and grant support from Auxilium Pharmaceuticals and grant support from BioSpecifics Technologies (and may receive royalty fees pending Food and Drug Administration [FDA] approval); Dr. Badalamente, receiving consulting and advisory-board fees from Auxilium Pharmaceuticals and grant support from BioSpecifics Technologies (and may receive royalty fees pending FDA approval); Dr. Kaplan, receiving consulting and advisory-board fees from Auxilium Pharmaceuticals; Drs. Rodzvilla and Smith, being employees of and holding stock options with Auxilium Pharmaceuticals; and Drs. Meals, Hentz, and Hotchkiss, receiving consulting fees from Auxilium Pharmaceuticals.
We thank Catherine Curtin, M.D., for her contribution to the study, Maribeth Bogush, Ph.D., for her editorial assistance with an earlier version of the manuscript, and Heather Sailer for her contributions to an earlier version of the figures.
Source Information
From the State University of New York (SUNY) at Stony Brook, Stony Brook (L.C.H., M.A.B.); Stanford Hospitals and Clinics, Palo Alto, CA (V.R.H.); the Hospital for Special Surgery, New York (R.N.H.); the Indiana Hand Center, Indianapolis (F.T.D.K.); Los Angeles (R.A.M.); and Auxilium Pharmaceuticals, Malvern, PA (T.M.S., J.R.).
Address reprint requests to Dr. Hurst at the Department of Orthopaedics, SUNY at Stony Brook, Health Science Center, Level 18, Rm. 020, Stony Brook, NY 11794-8181, or at lhurst@notes.cc.sunysb.edu.
Members of the Collagenase Option for Reduction of Dupuytren's (CORD) I Study Group are listed in the Supplementary Appendix, available with the full text of this article at NEJM.org.
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Citing Articles
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Michael Worrell. (2012) Dupuytren’s Disease. Orthopedics 35:1, 52-60
CrossRef2
Larisa Kristine Vartija, Leslie L. McKnight, Achilleas Thoma. 2011. Dupuytren's Disease. , 1029-1038.
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Johann Beaudreuil, Jean-Luc Lermusiaux, Jean-Pierre Teyssedou, Sophie Lahalle, Sandra Lasbleiz, Brigitte Bernabé, Henri Lellouche, Philippe Orcel, Thomas Bardin. (2011) Multi-needle aponeurotomy for advanced Dupuytren's disease: Preliminary results of safety and efficacy (MNA 1 Study). Joint Bone Spine 78:6, 625-628
CrossRef4
Spencer J. Stanbury, Warren C. Hammert. (2011) Dupuytren Contracture. The Journal of Hand Surgery 36:12, 2038-2040
CrossRef5
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