Phase 2a Dose-Ranging Study to Evaluate Safety and Effectiveness of AA4500 in Treatment of Dupuytren's Disease Nodules

Study Overview
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Brief Summary
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The objectives of this study are to assess the safety and effectiveness of AA4500 in treating palmar Dupuytren's disease nodules.

Detailed Description
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Approximately 13 sites in the United States and Australia, approximately 90 study subjects. After all pre-injection procedures are completed on day 1, eligible men and women will be randomized in a 1:1:1 ratio to dose group and then in a 4:1 ratio to treatment group. Study drug will be administered into a palmar nodule located on the selected hand. AA4500 (collagenase clostridium histolyticum) 3 doses (low, medium, and high) after reconstitution with sterile diluent (0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride). Each dose of study drug will be injected into the nodule. The injection will be administered in 3 different volumes according to randomization. Placebo after reconstitution with sterile diluent (0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride). Each dose of study drug will be injected into the nodule. The injection will be administered in 3 different volumes according to randomization. Follow up visits for the evaluation of safety and efficacy will be required for all subjects on days 8, 29, and 57.

Official Title
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A Phase 2a, Double-blind, Randomized, Placebo-Controlled, Dose-Ranging Study to Evaluate the Safety and Effectiveness of AA4500 in the Treatment of Dupuytren's Disease Nodules

Conditions
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Dupuytren's Disease

Intervention / Treatment
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* Biological: Collagenase clostridium histolyticum
* Biological: Placebo


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 one palmar nodule on the selected hand that is: Palpable Measures between 0.5 cm and 2.0 cm in length and between 0.5 cm and 2.0 cm in width using hand-held calipers n Not directly associated with a Dupuytren's cord 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: Received steroid injections (eg, tri-amcinolone acetonide) on the selected nodule within 3 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 Had surgery on the selected hand within 3 months before the screening visit 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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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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AA4500 0.25 mg<br>Collagenase clostridium histolyticum, single 0.25 mg injection | Biological: Collagenase clostridium histolyticum<br>* Single injection into nodule<br>* Other names: XIAPEX;|
| Experimental: AA4500 0.40 mg<br>Collagenase clostridium histolyticum, single 0.40 mg injection | Biological: Collagenase clostridium histolyticum<br>* Single injection into nodule<br>* Other names: XIAPEX;|
| Experimental: AA4500 0.60 mg<br>Collagenase clostridium histolyticum, single 0.60 mg injection | Biological: Collagenase clostridium histolyticum<br>* Single injection into nodule<br>* Other names: XIAPEX;|
| Placebo Comparator: Placebo<br>Placebo, single 0.25 mg, 0.40 mg, or 0.60 mg injection | Biological: Placebo<br>* Single injection into nodule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Surface Area and Volume of the Treated Nodule at Day 57 Using Caliper Measurements | Percent change from baseline in surface area and volume of the treated nodule was determined from hand-held caliper measurements of the length and width of the nodule. Percent change = 100*(Day 57 area [or volume] - baseline area [or volume])/baseline area [or volume]. A negative value represents the improvement from baseline (decreased size) while a positive value represents worsening. | Baseline, Day 57 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Surface Area and Volume of the Treated Nodule at Day 57 Using Ultrasound | Percent change from baseline in surface area and volume of the treated nodule was determined from ultrasound measurements of the length, width, and depth of the nodule. Percent change = 100*(Day 57 area [or volume] - baseline area [or volume])/baseline area [or volume]. A negative value represents the improvement from baseline (decreased size) while a positive value represents worsening. | Baseline, Day 57 | 
| Change From Baseline in Consistency of the Treated Nodules at Day 57 | Investigators determined the consistency of the nodule through palpitation using a 5-point scale: 5 = hard (solid), 4 = firm throughout, 3 = moderate firmness, 2 = soft, and 1 = non-palpable. The change scores could range from +4 (greatest worsening in consistency) to -4 (greatest improvement in consistency); a negative change from baseline value reflects improvement from baseline (softening) while a positive value reflects worsening. | Baseline, Day 57 | 
| Percent Change From Baseline in Hardness of the Treated Nodule at Day 57 | A durometer was used to assess nodule hardness on a scale of 0 (soft) to 100 (hard). Percent change = 100*(Day 57 hardness - baseline hardness)/baseline hardness. A negative value represents the improvement from baseline (softening) while a positive value represents worsening. | Baseline, Day 57 | 
| Change From Baseline in Nodular Pain of the Treated Nodule at Day 57 | After the nodule was squeezed using a dynamometer, subjects were asked to rate the amount of pain they felt on an 11-point visual analog scale (VAS) from 0 (no pain or discomfort) to 10 (extreme pain or discomfort). A negative change from baseline value reflects improvement from baseline (less pain) while a positive value reflects worsening. | Baseline, Day 57 | 
| Investigator Global Assessment of Improvement With Treatment | Investigators were asked to determine the degree of improvement in the subject's treated nodule compared with screening on a 7-point scale: 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. | Day 57 | 
| Subject Satisfaction With Treatment | Subjects were asked to rate their satisfaction with treatment on a 5-point scale: 1 = very satisfied, 2 = quite satisfied, 3 = neither satisfied nor dissatisfied, 4 = quite dissatisfied, and 5 = very dissatisfied. | Day 57 | 
| Composite Responder Analysis | A composite responder is a subject who had an improved assessment [values of 1 (very much improved), 2 (much improved), or 3 (minimally improved)] on the investigator global assessment and had a satisfied assessment [values of 1 (very satisfied) or 2 (quite satisfied)] on the subject assessment. | Day 57 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dupuytren's nodules