OREF Clinical Research Award Winners aim to make life easier
It isn’t easy for people with Dupuytren’s contracture to open a door or hold a football. Nor can individuals with adhesive capsulitis (frozen shoulder) easily reach for items on a shelf or sleep soundly without pain.
Lawrence C. Hurst, MD
Fibroproliferative disorders such as Dupuytren’s contracture are characterized by a progressive accumulation of collagen that can limit movement, reduce range of motion, and negatively affect quality of life. In Dupuytren’s contracture, the accumulation of collagen causes Dupuytren’s cords to form, leading to a progressive flexion of the fingers. The research conducted by Dr. Hurst and his colleagues focuses on the use of injectable Clostridial collagenase as an alternative to surgery in treating Dupuytren’s contracture.
“The collagenase preparation consists of multiple collagenase subtypes that are not immunologically cross reactive, have different specificities, and act synergistically,” explained the researchers in their paper. “Delivery of the preparation directly into the cord by injection is intended to lyse collagen and subsequently disrupt the contracted cord.”
Preclinical studies test the theory
Using a rat tail tendon model, researchers first tested whether the preparation would have any effect on the collagen bundles without damage to adjacent nerves, arteries, and veins. In comparing three groups (two of which received different doses of purified Clostridial collagenase, and one that served as a control), researchers found evidence of collagen lysis as early as an hour after the injection. “Most importantly, in all animals receiving Clostridial collagenase, no extravasation of collagenase to adjacent tissues was noted,” they wrote.
These preclinical tests were followed by an in vitro biomechanical study and phase 2 clinical trials involving patients with Dupuytren’s contracture.
Normal within 30 days
Using a dose-escalation protocol, researchers tested the efficacy of various doses of collagenase and found that 10,000 units (0.58 mg) was the most effective dose. Of the 29 patients treated with this dose, 30 of 34 metacarpophalangeal (MP) joints and 4 of 9 proximal interphalangeal (PIP) joints treated were fully corrected or improved to within 5° of normal joint extension within 30 days after the injection. Fifteen patients required a second injection; the condition recurred in three MP joints 2 years postinjection, and in 1 PIP joint 3 months postinjection.
In a single-center, ramdomized, placebo-controlled, double-blind study, “more joints with cords treated with collagenase than placebo achieved correction of deformity within 0° to 5° of normal and within a shorter time.” In most cases, this correction was achieved after only a single injection.
A second, multicenter, randomized, double-blind, placebo-controlled, dose-response study confirmed that 10,000 units was the minimum safe and effective dose. Additional studies found that the therapy was well-tolerated, with few mild adverse events (injection-site pain, hand ecchymosis, edema) that quickly resolved. Some patients, primarily those with a severe (greater than 80º) contracture over many years, sustained skin lacerations that effectively healed with dressing change treatment only.
“Encouragingly, clinical efficacy appears to be durable,” wrote the authors, “with long-term follow-up of patients from the first phase 3 clinical trial indicating that recurrence rates are low (about 10 percent for MP joints and about 20 percent for PIP joints at 5-year follow-up).”
Unfreezing the shoulder
Although most patients with Dupuytren’s contracture are male, frozen shoulder affects primarily females. Theorizing that the lysis resulting from the injectable Clostridial collagenase treatment might loosen the collagenous adhesion(s) often present in frozen shoulder, investigators have recently begun testing the procedure.
After cadaver studies verified the safety of the injection technique, a phase 2, placebo-controlled, double-blind randomized clinical trial was begun. Although it is a small study (60 patients), “assessment of shoulder joint movement 1 month after injection revealed statistically significant improvements in functional score, shoulder motion, and pain among patients receiving collagenase compared to those receiving saline (P<.05),” noted the authors.>
Although injectable Clostridial collagenase may be a potential new, nonsurgical treatment for frozen shoulder, the authors call for further studies in this area to confirm preliminary observations and suitability of the treatment.
A new treatment alternative?
“At present, surgery represents the only treatment option [for Dupuytren’s contracture],” concluded the authors, “but widespread evidence suggests that fasciectomy has several important limitations. … This translational research, starting with preclinical animal and in vitro experiments through to phase 2 and phase 3 clinical trials, presents injectable Clostridial collagenase as a rationally researched and strong clinical candidate for the treatment of Dupuytren’s contracture.”
Drs. Badalamente, Hurst, and Wang received grant support from Auxilium Pharmaceuticals, Inc.; Biospecifics Technologies Corp.; and the National Institutes of Health (M01RR10710) and are consultants for Auxilium Pharmaceuticals, Inc.