Purpose: Dupuytren’s disease affects 3% to 6% of adult Caucasians, and surgery is the standard of care. Injectable clostridial collagenase (AA4500) is an investigational, nonsurgical treatment alternative for joint contractures caused by advanced Dupuytren's disease. Two phase 3 trials (Collagenase Option for Reduction of Dupuytren’s [CORD] I and CORD II) evaluated the efficacy and safety of clostridial collagenase. These multicenter trials comprised randomized, double-blind, placebo-controlled phases and open-label extensions. Results of the double-blind phases are presented.
Methods: CORD I and II were conducted at 16 US and 5 Australian sites, respectively. Patients with metacarpophalangeal (MP) or proximal interphalangeal (PIP) joint contractures ≥20^o were enrolled. Patients’ primary joints (first joint treated in each patient) were stratified by baseline severity (low MP = ≤50^o; low PIP = ≤40^o) and randomized to receive up to 3 collagenase (0.58 mg) or placebo injections into affected cords at approximately 4-week intervals. One day postinjection, treated joints underwent a finger extension procedure. Primary endpoint was correction of primary joints to 0° to 5° of normal extension 30 days after last injection. In addition, 26 secondary endpoints and adverse events were evaluated.
Results: In CORD I, 306 primary joints were treated and evaluated: 133 MP and 70 PIP joints with collagenase, and 69 MP and 34 PIP joints with placebo. In CORD II, 66 primary joints were treated: 20 MP and 25 PIP joints with collagenase, and 11 MP and 10 PIP joints with placebo. Significantly (P<.001) more collagenase-treated than placebo-treated joints achieved primary endpoint: 64.0% vs 6.8% in CORD I and 44.4% vs 4.8% in CORD II. Contracted MP joints responded better than contracted PIP joints, and contracted joints with low baseline severity responded better than those with high baseline severity. At 56 to 57 days, median time to achieve primary endpoint was significantly (P<.001) shorter for collagenase-treated than placebo-treated primary joints. All 26 secondary endpoints were met with clinical significance in CORD I. Significantly (P<.001) more collagenase-treated than placebo-treated joints achieved a ≥50% reduction in joint contracture from baseline: 84.7% vs 11.7% in CORD I and 77.8% vs 14.3% in CORD II. Percent reduction in contracture from baseline after collagenase treatment was significantly (P<.001) greater than after placebo treatment—79.3% (50.2º to 12.2º) vs 8.6% (49.1º to 45.7º) in CORD I and 70.5% (53.2º to 16.7º) vs 13.6% (50.0º to 44.3º) in CORD II. Mean change in arc of motion from baseline to 30 days after the last injection was significantly (P<.001) greater for collagenase-treated than placebo-treated joints: 36.7º (43.9º to 80.7º) vs 4.0º (45.3º to 49.5º) in CORD I and 35.4º (40.3º to 75.8º) vs 7.6º (44.0º to 51.7º) in CORD II. No change was observed in full flexion or grip strength with either treatment. Most commonly reported adverse events were localized edema, pain, swelling, bruising, and pruritus at the injection site, and transient lymph node swelling and pain.
Conclusion: Injectable clostridial collagenase significantly reduced joint contractures caused by advanced Dupuytren’s disease and was generally well tolerated in 2 multicenter phase 3 trials.