Study Number: AUX-CC-862 Title of Study: Retreatment of Recurrent Contractures in Joints Effectively Treated with AA4500 (Collagenase Clostridium Histolyticum [XIAFLEX /XIAPEX ]) in an Auxilium-Sponsored Phase 3 Study in the United States, Australia, and Europe Investigators: Multicenter Study center(s): 12 investigative sites in the United States, Australia, and Europe enrolled subjects in the study. Publications (reference): None. Studied period: 12 months Date first subject enrolled: 12 March 2012 Date last subject completed: 07 October 2013 Phase of development: Phase 4 Objectives: The objectives of this study were to assess the safety and efficacy of AA4500 in the retreatment of recurrent contractures in joints that were effectively treated with AA4500 in a previous pre-approval Auxilium-sponsored Phase 3 study in Dupuytren's contracture. Methodology: This was an open-label, Phase 4 study in subjects who were participating in the long-term follow-up study (AUX-CC-860) and who had recurrence of contracture (ie, joint contracture increased by at least 20 compared with the Day 30 value after the last injection in a Phase 3 Auxilium-sponsored study and a palpable cord was present) in a joint that was effectively treated with AA4500 (ie, reduction in contracture to 5 or less 30 days after the last injection) in a Phase 3 Auxilium-sponsored study. Subjects in Study AUX-CC-860 who experienced recurrence of contracture in one or more effectively treated joints could be enrolled in this retreatment study after the investigator determined subject eligibility and after informed consent was obtained. Once informed consent was obtained for participation in this study, the investigator withdrew the subject from Study AUX-CC-860. If a subject had more than one recurrent contracture, the investigator designated the joint to be treated. The investigator treated the recurrent cord affecting the joint with up to three injections. Only one recurrent contracture was to be treated in this study. Injections of AA4500 were to be separated by approximately 28 days. Approximately 24 hours after each injection the investigator performed a finger extension procedure on the treated finger in an attempt to disrupt the cord. Additionally, there was a Day 365 follow-up visit for the determination of safety and immunogenicity. The efficacy evaluation of AA4500 included finger goniometry with ROM of the recurrent joint. Physician determination of improvement in contracture and subject satisfaction with treatment of the recurrent joint was also evaluated 30 days after the last injection of AA4500. The safety of AA4500 was evaluated through the reporting of adverse events (AEs), including injection site reactions, local tolerability, and vital sign assessments. The immunogenicity of AA4500 was also evaluated 30 days after the last injection and at the Day 365 follow-up visit. Number of subjects (planned and analyzed): There was no planned sample size; 52 subjects were treated and analyzed. 1
Diagnosis and main criteria for inclusion: Subjects enrolled in AUX-CC-860 with a joint that was effectively treated (had a correction to 5 or less at the Day 30 evaluation after the last injection of AA4500) in a previous Auxilium Phase 3 study, had an effectively treated joint that had an increase in contracture of at least 20 compared with the Day 30 value after the last injection of AA4500 in a previous Auxilium Phase 3 study, and had a palpable cord present in the joint to be treated were eligible. Test product, dose and mode of administration, batch number: AA4500 0.58 mg injected directly into the cord, after reconstitution with sterile diluent (0.9% sodium chloride containing 0.03% calcium chloride). The volume of injection was 0.25 ml for metacarpophalangeal (MP) joints and 0.20 ml for proximal interphalangeal (PIP) joints. Lot numbers for AA4500 were C0527 in the United States and Australia and 1000189 in Europe; lot numbers for sterile diluent were C0568 in the United States and Australia and 1000205 in Europe. Duration of treatment: Only the cord affecting the recurrent joint was treated with up to three injections of AA4500. Injections of AA4500 were separated by approximately 28 days. The end of study was when the last subject completed the Month 12 follow-up visit. Reference therapy, dose and mode of administration, batch number: None Criteria for evaluation: Efficacy: The following parameters were measured in order to establish clinical effectiveness of AA4500: reduction in contracture to 5 or less, category of time to reach reduction in contracture to 5 or less, clinical improvement, percentage change from baseline contracture, range of motion (ROM), physician and subject global assessments, and investigator-determined recurrence. Safety: Safety was evaluated through the monitoring of adverse events (AEs), clinical laboratory evaluation, vital signs Immunogenicity: Immunogenicity was evaluated through collection of blood samples for the determination of anti-drug antibodies, neutralizing antibodies to AUX-I and AUX-II, and matrix metalloproteinases (MMP) cross reactivity. Statistical Methods: The modified intent-to-treat (mitt) population was defined as all ITT subjects who had a recurrent joint retreated in the current study. If the joint treated in the current study did not meet the definition of a recurrent joint then the subject was not included in the mitt population. All efficacy parameters were based on this population. The safety population was defined as all enrolled subjects who had at least one AA4500 injection. All safety parameters were based on this population. Efficacy: The treated joints that succeeded and reached clinical improvement were summarized by joint type (MP or PIP) and by joint type/baseline severity. These summaries were done by injection number and for all subjects after the last injection to the joint. The average number of injections given and the average number of injections necessary to reach success were summarized on the clinical success summary. Joints that reached clinical success but received additional injections after reaching success were to be noted; the success was only counted at the last injection. Clinical success at Day 30 after the last injection was also summarized by joint type and finger and by joint type and investigator. A 95% confidence interval (CI) around the rate of success and rate of improvement at the Day 30 visit after the last injection was computed by joint type. 2
Baseline fixed-flexion contracture (FFC) measurements, FFC measurements at Day 30 after the last injection, change from baseline in FFC measurements, and percentage change from baseline in FFC measurements were summarized by joint type and by joint type/baseline severity for the treated joint. This summary was done by injection number and for all subjects after the last injection to the joint. A 95% CI around the average percentage change from baseline was computed for the summary by joint type. Baseline ROM measurements, ROM measurements at Day 30, and change from baseline in ROM measurements were summarized by joint type and by joint type/baseline severity for the treated joint. This summary was done by injection number and for all subjects after the last injection to the joint. A 95% CI around the average change from baseline was computed for the summary by joint type. Subject satisfaction with treatment and the Investigator s assessment of improvement were summarized by joint type and overall. For recurrent contractures, all treated joints that recurred again at the Day 365 visit were listed. Safety: All treatment-emergent AEs (TEAEs) and serious AEs (SAEs) were summarized overall, by treatment phase, and post-treatment phase (regardless of causality and relationship to study drug). For each of these parameters, TEAEs were presented overall, by body system, preferred term, and severity. Clinical laboratory data (chemistry and hematology) were summarized for actual value and change from baseline. Vital sign measurements and change from baseline were summarized by injection on the injection day (Day 1) across the different time points (pre-injection, 15 minutes, 30 minutes, 45 minutes, and last injection day values). Vital signs taken at each visit were summarized across visit day (Day 1 [pre-injection], Day 2, Day 30 for each injection, and Day 365). The count and percentage of subjects with Sponsor-defined clinically significant laboratory and vital signs values at any time during the study were also presented. Anti-clostridial type I collagenase (AUX-I) and anti-clostridial type II collagenase (AUX-II) antibody levels, neutralizing potential of antibodies to AUX-I and AUX-II, and matrix metalloproteinase (MMP) cross-reactivity were summarized. Descriptive statistics were used to summarize the proportion of subjects with positive titers and log titer levels at the Day 30 visit after the last injection and at the Day 365 follow-up visit. The percentage of subjects with cross-reactivity to MMPs was summarized at the Day 30 visit after the last injection and at the Day 365 follow-up visit. SUMMARY EFFICACY RESULTS: The findings from this retreatment study are similar to those observed among the 1082 subjects who received at least one injection of AA4500 in the Dupuytren s Phase 3 clinical program. Key findings from this study were as follows: When analyzed by joint type, 64.5% of MP joints (20/31) and 45.0% of PIP joints (9/20) achieved clinical success achieved clinical success 30 days after the last injection of AA4500. In addition to the 29 joints that achieved clinical success, 15 additional joints (MP, 7; PIP 8) had a positive outcome. For these 15 joints, there was either no palpable cord to inject after the first or second injection of AA4500 or the subject was satisfied with the improvement achieved after the first or second injection and chose not to receive any additional injections. Taken together, 87.1% of MP joints (27/31) and 85.0% of PIP joints (17/20) achieved a positive outcome after retreatment with up to three injections of AA4500. 3
The majority of MP joints (66.7%) and PIP joints (66.7%) of low severity achieved clinical success after the last injection of AA4500. Most (57.1%) MP joints and 12.5% of PIP joints of high severity were also successful after retreatment with AA4500. Although fewer PIP joints of high severity achieved clinical success, retreatment with AA4500 was efficacious in the treatment of these joints. On average, contracture in PIP joints of high severity was reduced from 66.9 at baseline to 24.4 after the last injection of AAA4500, which represents a 62.2% reduction from baseline contracture. The majority of MP (90.3%) and PIP (70.0%) joints showed clinical improvement within 30 days after the last injection of AA4500. Within 30 days after the last injection of AA4500, the reduction in degree of contracture from baseline was 83.24% for MP joints and 69.10% for PIP joints. Within 30 days after the final injection of AA4500, the improvement (increase) from baseline was 31.4 for MP joints and 26.8 for PIP joints. At the end of treatment, Dupuytren s contracture was very much improved or much improved in the majority of subjects (92.0%), as determined by the investigator. At the end of treatment, the majority of subjects (91.7%) were very satisfied or quite satisfied with their treatment. Six (MP, 3; PIP, 3) of the 29 successfully treated joints in this study developed recurrence of contracture at the Day 365 visit. For five of these recurrent joints, the degree of contracture at the time of recurrence was less than (n=4) or equal to (n=1) the baseline contracture measurement at the start of this study. SAFETY RESULTS: Treatment-emergent AEs reported by 10.0% of subjects overall were oedema peripheral (61.5%), contusion (44.2%), pain in extremity (30.8%), injection site pain (19.2%), pruritus (19.2%), lymphadenopathy (15.4%), injection site haematoma (15.4%), and skin laceration (13.5%). Most subjects had TEAEs that were related to study drug, as assessed by the investigator. The majority of subjects had TEAEs or treatment-related TEAEs that were at most mild or moderate in severity, as assessed by the investigator. One subject died during the study due to cerebellar infarction; this event was considered by the investigator to be not related to study drug. Four subjects experienced treatment-emergent SAEs during the study. All SAEs were considered by the investigator to be not related to study drug. No subject prematurely discontinued due to a TEAE. No clinically concerning trends were observed with regard to hematology and chemistry laboratory parameter results, vital sign results, or immunogenicity results. IMMUNOGENICITY RESULTS: Most subjects continued to have antibodies to AUX-I and AUX-II at the AUX-CC-862 baseline visit. Thirty days following retreatment with AA4500, mean log anti-drug antibody titers increased from 3.8 to 5.8 for anti-aux-i, and from 3.4 to 5.8 for anti-aux-ii. - Anti-AUX-I and anti-aux-ii titers remained increased (mean log titers 5) through the Day 365 visit. The presence of neutralizing antibodies to AUX-I and/or AUX-II did not negatively impact the efficacy of AA4500. 4
There were no reports of systemic hypersensitivity reactions in this current study, despite antidrug antibody titers being elevated at the start of treatment. By Day 365, the percentage of subjects who were neutralizing antibody positive decreased among subjects who continued to have mean log anti-drug antibody titers 5. This finding suggests that neutralizing antibodies do not remain persistent despite the presence of high ADA titers. Persistence of neutralizing antibodies 30 days after the last injection of AA4500 and at Day 365 did not negatively impact the efficacy of AA4500. - The improvement in fixed-flexion contracture was maintained through Day 365 in subjects who had persistent neutralizing antibodies. Anti-AUX-I and anti-aux-ii did not show any cross- reactivity with any of the five human MMPs that were tested; all were negative. 5