Safety and Efficacy of Two Concurrent Injections of AA4500 in Adult Subjects With Multiple Dupuytren's Contractures

Study Overview
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Brief Summary
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The primary objective of this study is to assess the safety of two concurrent injections of AA4500 into the same hand in subjects with multiple Dupuytren's contractures with palpable cords followed 24 to 72 hours later by a finger extension procedure and compare the rate of occurrence of targeted serious adverse events (tendon rupture/ligament injury and anaphylaxis) to historical rates of the same in clinical studies and post-marketing commercial use. The secondary objective is to evaluate the efficacy of two concurrent injections of AA4500.

Detailed Description
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Methodology/Study Design: After all pre-injection procedures are completed on Day 1, eligible men and women will receive two concurrent injections AA4500 (AA4500/AA4500) into cord(s) affecting MP and/or PIP joints on the same or different fingers in the selected hand. A finger extension procedure to facilitate cord disruption will be performed (after administration of local anesthesia, if needed) 24 to 72 hours after injection in those subjects who do not have spontaneous disruption of their cord(s). Follow up visits for the evaluation of safety and efficacy will be required for all subjects 24 to 72 hours after injection, and on Days 15, 31, and 61. Upon completion of the day 61 follow-up visit (end of study visit), subjects who require additional treatment in the treated hand may receive up to three additional injections of AA4500 according to the XIAFLEX package insert. Subjects may receive up to a total of five injections and individual cords may receive up to a total of three injections. Subjects who require additional treatment will be followed for safety.

Official Title
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A Phase 3b Open-label, Historically-controlled Study to Assess the Safety and Efficacy of Two Concurrent Injections of AA4500 in Adult Subjects With Multiple Dupuytren's Contractures With Palpable Cords

Conditions
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Dupuytren's Contracture

Intervention / Treatment
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* Biological: XIAFLEX / XIAPEX


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide a signed and dated informed consent Be a man or woman ≥ 18 years of age Have a diagnosis of Dupuytren's disease and have at least 2 fixed-flexion contractures on the same hand that are ≥ 20º in PIP and/or MP joints in fingers, other than the thumbs, which are caused by palpable cord(s) suitable for treatment Have a positive table top test defined as the inability to simultaneously place the affected finger(s) and palm flat against a table top Have a negative urine pregnancy test at screening and before injection of study drug and be using a highly effective (ie, < 1% failure rate) contraception method as judged by the investigator (eg, abstinence, intrauterine device [IUD], hormonal [estrogen/progestin] contraceptives, or barrier control) for at least one menstrual cycle prior to study enrollment and for the duration of the study or be surgically sterile (if female of childbearing potential); or be a postmenopausal female (no menses for at least 1 year or hysterectomy). Be able to comply with the study visit schedule as specified in the protocol Exclusion Criteria: A subject will be excluded from study participation if he/she: Received surgery (fasciectomy or surgical fasciotomy) and/or needle aponeurotomy/fasciotomy on the selected joints to be treated within 6 months before administration of study drug Has a chronic muscular, neurological, or neuromuscular disorder that affects the hands Has a known systemic allergy to collagenase or any other excipient of AA4500 Has received any collagenase treatments (eg, Santyl® ointment and/or XIAFLEX®/XIAPEX®) within 30 days before injection of study drug in the hand selected for treatment Is currently receiving or plans to receive anticoagulant medication or has received anticoagulant medication (except for ≤ 150 mg aspirin daily) within 7 days before injection of study drug Has a known recent history of stroke, bleeding, or other medical condition, which in the investigator's opinion would make the subject unsuitable for enrollment in the study Received an investigational drug within 30 days before injection of study drug Is pregnant or intends on becoming pregnant during the study or is breastfeeding a child Has any clinically significant medical history or condition(s), including conditions that affect the hands, that would, in the opinion of the investigator, substantially increase the risk associated with the subject's participation in the protocol or compromise the scientific objectives of the study Has jewelry on the hand to be treated that cannot be removed

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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: XIAFLEX / XIAPEX<br>AA4500 (collagenase clostridium histolyticum) | Biological: XIAFLEX / XIAPEX<br>* injection (0.58 mg after reconstitution with sterile diluent [0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride])<br>* Other names: AA4500 (collagenase clostridium histolyticum);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Total Fixed Flexion | Percent change from baseline in total fixed flexion = 100 * (baseline total FFC - day 31 total FFC)/baseline total FFC, where total fixed flexion is defined as the sum of the fixed flexion contracture (FCC) of the 2 joints receiving treatment. Positive percent change from baseline indicates improvement. | Baseline, Day 31 | 
| Change From Baseline in Total Range of Motion | The total range of motion (ROM) is the sum of the range of motion measurements of the 2 treated joints. ROM is defined as difference between full flexion angle and full extension expressed in degrees. A positive change from baseline indicates increased (improved) ROM. | Baseline, Day 31 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Success | Clinical success is defined as reduction of FFC of a treated joint to within 0-5 degrees of normal within 30 days of injection | Within 30 days | 
| Clinical Improvement | Clinical improvement is defined as a reduction of FFC by 50% or greater of the baseline value within 30 days of injection | Within 30 days | 
| Subject Assessment of Satisfaction With Treatment at Day 31 | Subject's were asked to rate satisfaction with treatment at the day 31 follow-up visit | Day 31 | 
| Subject Assessment of Satisfaction With Treatment at Day 61 | Subject's were asked to rate satisfaction with treatment at the day 61 follow-up visit | Day 61 | 
| Investigator Assessment of Improvement With Treatment at Day 31 | Investigator's determined the degree of improvement in the severity of the subject's treated finger(s) compared with screening at the day 31 follow-up visit. | Day 31 | 
| Investigator Assessment of Improvement With Treatment at Day 61 | Investigator's determined the degree of improvement in the severity of the subject's treated finger(s) compared with screening at the day 61 follow-up visit. | Day 61 | 
| Change From Baseline for Unité Rhumatologique Des Affections de la Main Scale at Day 31 | The Unité Rhumatologique des Affections de la Main (URAM) scale is a patient-reported functional 9-item scale (total score 0-45) developed and validated to assess functional outcome of patients suffering from Dupuytren's disease with higher scores indicating greater difficulty using the hand.The estimated clinically important change of the URAM scale is 2.9 points. A decrease in total URAM score indicates improvement in hand function. | Baseline, Day 31 | 
| Change From Baseline for Unité Rhumatologique Des Affections de la Main Scale at Day 61 | The URAM scale is a patient-reported functional 9-item scale (total score 0-45) developed and validated to assess functional outcome of patients suffering from Dupuytren's disease with higher scores indicating greater difficulty using the hand.The estimated clinically important change of the URAM scale is 2.9 points. A decrease in total URAM score indicates improvement in hand function. | Baseline, Day 61 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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XIAFLEX, XIAPEX, Dupuytren's disease, contracture