Non-US Study of AA4500 (XIAFLEX™, Proposed Name) in the Treatment of Advanced Dupuytren's Disease

Study Overview
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Brief Summary
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This 12-month study had two phases: a 90-day double-blind, randomized, placebo-controlled phase and a nine-month open-label extension phase. Before treatment, eligible subjects were stratified by the primary joint type (30 metacarpophalangeal [MP] joints and 30 proximal interphalangeal [PIP] joints) and by severity of the primary joint contracture (ie, up to 50° or >50° for MP joints and up to 40° or >40° for PIP joints) and then randomized in a 2:1 ratio to either AA4500 0.58 mg or placebo. Upon completion of the double-blind phase (ie, 90-day evaluation after the first injection), all subjects were eligible to enter the open-label extension phase of the study in which they were followed for an additional nine months. Subjects who required further treatment because they either did not achieve reduction in contracture to 5° or less, the cord affecting the primary joint received placebo, another cord received less than three injections of AA4500, or they had untreated cords that were affecting other joints had the option to receive up to five additional injections of AA4500 0.58 mg in the open-label extension phase, with individual cords receiving up to three injections of AA4500. This study was designed to be part of the larger clinical program, for adult patients with Dupuytren's contracture with a palpable cord, where the data from 2 pivotal Placebo-Controlled studies (AUX-CC-857 [NCT00528606] and AUX-CC-859 [NCT00533273]) and 7 non-pivotal studies were evaluated.

Official Title
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A Phase 3, Double-Blind, Randomized, Placebo-Controlled Study of the Safety and Efficacy of AA4500 in the Treatment of Subjects With Advanced Dupuytren's Disease Followed by an Open-Label Extension Phase

Conditions
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Advanced Dupuytren's Disease

Intervention / Treatment
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* Biological: collagenase clostridium histolyticum


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with a diagnosis of advanced Dupuytren's disease, with a fixed flexion deformity of at least one finger, other than the thumb, that had a contracture at least 20°, but not greater than 100°, for MP (80° for PIP) joints, caused by a palpable cord. Had a positive table top test, defined as the inability to simultaneously place the affected finger(s) and palm flat against a table top. Were naive to AA4500 treatment Were judged to be in good health, based upon the results of a medical history, physical examination, and safety laboratory profile. Exclusion Criteria: Had a chronic muscular, neurological, or neuromuscular disorder that affected the hands. Had received a treatment for advanced Dupuytren's disease, including surgery (fasciectomy or surgical fasciotomy), needle aponeurotomy/fasciotomy, or injection of verapamil and/or interferon on the selected primary joint within 90 days before the first dose of study drug. Had a known recent history of stroke, bleeding, a disease process that affected the hands, or other medical condition, which in the investigator's opinion, would make the subject unsuitable for enrollment in the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AA4500 0.58 mg<br> | Biological: collagenase clostridium histolyticum<br>* Subjects could have received up to three injections of AA4500 0.58 mg/placebo into the cord of the affected hand in the double-blind phase. In the open-label extension phase, subjects could have received up to five additional injections of AA4500, with each injection separated by at least 30 days. Individual joints could have received up to a maximum of three AA4500 injections.<br>* Other names: AA4500;|
| Placebo Comparator: Placebo<br> | Biological: collagenase clostridium histolyticum<br>* Subjects could have received up to three injections of AA4500 0.58 mg/placebo into the cord of the affected hand in the double-blind phase. In the open-label extension phase, subjects could have received up to five additional injections of AA4500, with each injection separated by at least 30 days. Individual joints could have received up to a maximum of three AA4500 injections.<br>* Other names: AA4500;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in Primary Joint Contracture to 5° or Less | Successfully treated or clinical success in primary joint defined as reduction in contracture to within 0-5° of normal within 30 days of injection. | Within 30 days after last injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Improvement in Primary Joint After the Last Injection | Clinical improvement in primary joint defined as ≥50% reduction from baseline in the degree of contracture within 30 days after injection | Baseline, Within 30 days after last injection | 
| Percent Reduction From Baseline Contracture of Primary Joint After the Last Injection | Percent change in degree of contracture of primary joint measured as 100 * (baseline contracture - last available post-injection contracture)/baseline contracture | Baseline, Day 30 after last injection | 
| Change From Baseline Range of Motion in Primary Joint After the Last Injection | Change in degree of range of motion in primary joint measured as last available post-injection range of motion - baseline range of motion | Baseline, Day 30 after last injection | 
| Time to Reach Clinical Success in Primary Joint | Clinical success in primary joint defined as reduction in contracture to within 0-5° of normal within 30 days of injection, displayed in post injection time point categories | Within 30 days after last injection | 
| Clinical Success in Primary Joint After the First Injection | Clinical success in primary joint defined as reduction in contracture to within 0-5° of normal within 30 days of injection. | Within 30 days after first injection | 
| Clinical Improvement in Primary Joint After the First Injection | Clinical improvement in primary joint defined as ≥50% reduction from baseline in the degree of contracture within 30 days after injection | Baseline, Within 30 days after first injection | 
| Percent Reduction From Baseline Contracture of Primary Joint After the First Injection | Percent change in degree of contracture of primary joint measured as 100 * (baseline contracture - last available post-injection contracture prior to next injection)/baseline contracture | Baseline, Day 30 after first injection | 
| Change From Baseline Range of Motion in Primary Joint After the First Injection | Change in degree of range of motion in primary joint measured as last available post-injection range of motion prior to the next injection - baseline range of motion | Baseline, Day 30 after first injection | 
| Reduction in Non-primary Joint Contracture to 5° or Less After the Last Injection | Successfully treated or clinical success in non-primary joint defined as reduction in contracture to within 0-5° of normal within 30 days of injection. | Within 30 days after last injection | 
| Clinical Improvement in Non-Primary Joint After the Last Injection | Clinical improvement in non-primary joint defined as ≥50% reduction from baseline in the degree of contracture within 30 days after injection | Baseline, Within 30 days after last injection | 
| Percent Reduction From Baseline Contracture of Non-Primary Joint After the Last Injection | Percent change in degree of contracture of non-primary joint measured as 100 * (baseline contracture - last available post-injection contracture)/baseline contracture | Baseline, Day 30 after last injection | 
| Change From Baseline Range of Motion in Non-Primary Joint After the Last Injection | Change in degree of range of motion in non-primary joint measured as last available post-injection range of motion - baseline range of motion | Baseline, Day 30 after last injection | 
| Time to Reach Clinical Success in Non-Primary Joint | Clinical success in non-primary joint defined as reduction in contracture to within 0-5° of normal within 30 days of injection, displayed in post injection time point categories | Within 30 days after last injection | 
| Clinical Success in Non-Primary Joint After the First Injection | Clinical success in non-primary joint defined as reduction in contracture to within 0-5° of normal within 30 days of injection. | Within 30 days after first injection | 
| Clinical Improvement in Non-Primary Joint After the First Injection | Clinical improvement in non-primary joint defined as ≥50% reduction from baseline in the degree of contracture within 30 days after injection | Baseline, Within 30 days after first injection | 
| Percent Reduction From Baseline Contracture of Non-Primary Joint After the First Injection | Percent change in degree of contracture of non-primary joint measured as 100 * (baseline contracture - last available post-injection contracture prior to next injection)/baseline contracture | Baseline, Day 30 after first injection | 
| Change From Baseline Range of Motion in Non-Primary Joint After the First Injection | Change in degree of range of motion in non-primary joint measured as last available post-injection range of motion prior to the next injection - baseline range of motion | Baseline, Day 30 after first injection |