Clinical Study for the Treatment of Adhesive Capsulitis of the Shoulder

Study Overview
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Brief Summary
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The objectives of this study are to assess the safety, effectiveness, and immunogenicity of AA4500 in the treatment of adhesive capsulitis.

Detailed Description
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Study is a Phase 2b, double-blind, placebo-controlled study of the safety and efficacy of AA4500 for the treatment of adhesive capsulitis of the shoulder. To be eligible for treatment, a subject must have unilateral idiopathic adhesive capsulitis of the shoulder with restricted range of motion in the affected shoulder for at least 3 months but not more than 12 months. Subjects will be screened for study eligibility within 28 days before injection of study drug. Approximately 300 adult women and men are to be enrolled in this study. Following screening and determination of study eligibility, subjects will be randomized 3:1 to receive 0.58 mg of AA4500 or placebo. Subjects will receive up to 3 injections of study drug. Each injection will be separated by a minimum of 21 days. Subjects will also be instructed in home shoulder exercises after the first injection.

Official Title
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A Randomized, Double-blind, Placebo-controlled Study of the Safety and Efficacy of AA4500 for the Treatment of Adhesive Capsulitis of the Shoulder

Conditions
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Adhesive Capsulitis, Frozen Shoulder

Intervention / Treatment
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* Biological: Collagenase Clostridium Histolyticum
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Unilateral idiopathic adhesive capsulitis of one shoulder for at least 3 months but not more than 12 months (Frozen Stage) Normal range of motion in the contralateral shoulder Restricted active range of motion (AROM) in the affected shoulder defined as: a deficit of at least 60 degrees in total AROM in the affected shoulder as compared with the total AROM in the contralateral shoulder and a deficit of at least 30 degrees in AROM in at least one of the following planes as compared with the contralateral shoulder: Forward flexion Abduction External rotation with the elbow up to 90 degrees abduction Internal rotation with the elbow up to 90 degrees abduction Exclusion Criteria: Has received treatment for adhesive capsulitis or is planning to receive treatment for adhesive capsulitis at any time during the study including but not limited to: physical therapy or acupuncture within 2 weeks before the first injection of study drug intra-articular or intrabursal injection(s) of lidocaine; suprascapular nerve blocks; corticosteroids, electroanalgesic and/or thermoanalgesic modalities within 1 month before the screening visit intra-articular or intrabursal injection(s) of sodium hyaluronate and/or glenohumeral distension arthrography within 3 months before the screening visit surgical intervention (including shoulder manipulation under anesthesia) at any time Has any of the following conditions, as determined by investigator to be potentially confounding to the evaluation of safety and efficacy: Adhesive capsulitis as a result of traumatic injury (ie, direct injury to the shoulder such as fracture of the humerus or clavicle immediately preceding the onset of this episode of adhesive capsulitis). Traumatic events in the past that are not temporally related to the onset of this episode of adhesive capsulitis would not necessarily exclude a subject from participating in the study. Active subacromial impingement in the affected shoulder Calcified tendonitis in the affected shoulder Glenohumeral joint arthritis in the affected shoulder Arthrosis of the affected shoulder Chondrolysis of the affected shoulder Subscapularis tendon rupture of the affected shoulder Other rotator cuff injuries of the affected shoulder Uncontrolled hypertension Uncontrolled diabetes Uncontrolled thyroid disease History of thrombosis or post-thrombosis syndrome Physical impairment that would preclude performing the protocol defined exercises Active infection in area to be treated Clinically significant neurological disease Bleeding disorder Chronic use of anticoagulation medications and the subject cannot be cleared medically to stop taking medication for 7 days prior to each injection. Less than or equal to 150 mg aspirin is allowed during the study. Known active hepatitis A, B, or C Other significant medical condition (eg, morbid obesity, cervical disc disease), which in the investigator's opinion would make the subject unsuitable for enrollment in the study Has received oral or intravenous steroids for any reason within 3 weeks before the screening visit Has received an investigational drug or treatment within 30 days before the first dose of study drug. Has a known allergy to collagenase or any other excipient of AA4500 or any other procedural medication. Has, at any time, received collagenase for the treatment of adhesive capsulitis. Is unable to undergo an x-ray or MRI (contraindication) evaluation of the affected shoulder. Is planning to be treated with commercial XIAFLEX at any time during 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Collagenase Clostridium Histolyticum<br>Up to 3 injections of .58 mg/1 mL of collagenase clostridium histolyticum (CCH), minimum of 21 days apart and home shoulder exercise. | Biological: Collagenase Clostridium Histolyticum<br>* Treatment of Adhesive Capsulitis<br>* Other names: Xiapex;|
| Placebo Comparator: Placebo<br>Up to 3 1-mL injections of placebo, minimum of 21 days apart and home shoulder exercise. | Other: Placebo<br>* Placebo injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Day 95 in Active Forward Flexion | Active range of motion (AROM) measurement using a goniometer to assess forward flexion in the affected shoulder | Baseline, day 95 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Day 95 in Adapted American Shoulder and Elbow Surgeons (ASES) Function Subscale | Function subscale score ranging from 0-50, with 0 being most dysfunctional, derived from participant assessment of ability to do 10 activities with affected shoulder/arm where 0=unable to do to, 1=very difficult to do, 2=somewhat difficult, and 3=not difficult, and calculated as (cumulative total score for the 10 activity items) × (5/3); adapted from ASES Standardized Shoulder Assessment Form, Patient Self-Evaluation (United States adapted version). | Baseline, day 95 | 
| Change From Baseline to Day 95 in Pain With Movement Using 11-point Numeric Rating Scale (NRS) | Participant assessment of pain in response to How bad is the pain upon movement of your affected shoulder at its worst in the last 24 hours? using an 11-point NRS where 0=no pain at all and 10=pain as bad as it can be. | Baseline, day 95 | 
| Change From Baseline to Day 95 in Active Abduction | AROM measurement using a goniometer to assess abduction in the affected shoulder | Baseline, day 95 | 
| Change From Baseline to Day 95 in Passive Forward Flexion | Passive range of motion (PROM) measurement using a goniometer to assess forward flexion in the affected shoulder | Baseline, day 95 | 
| Change From Baseline to Day 95 in Passive Abduction | PROM measurement using a goniometer to assess abduction in the affected shoulder | Baseline, day 95 | 
| Change From Baseline to Day 95 in Active Internal Rotation | AROM measurement using a goniometer to assess internal rotation in the affected shoulder | Baseline, day 95 | 
| Change From Baseline to Day 95 in Active External Rotation | AROM measurement using a goniometer to assess external rotation in the affected shoulder | Baseline, day 95 | 
| Change From Baseline to Day 95 in Passive Internal Rotation | PROM measurement using a goniometer to assess internal rotation in the affected shoulder | Baseline, day 95 | 
| Change From Baseline to Day 95 in Passive External Rotation | PROM measurement using a goniometer to assess external rotation in the affected shoulder | Baseline, day 95 | 
| Change From Baseline to Day 95 in Adapted ASES Pain Subscale | Pain subscale score ranging from 0-50, with 0 being greatest pain, derived from participant overall assessment of pain in response to How bad is the pain in your affected shoulder today? using an 11-point NRS where 0=no pain at all and 10=pain as bad as it can be and calculated as (10 - NRS score) x 5; adapted from ASES Standardized Shoulder Assessment Form, Patient Self-Evaluation | Baseline, day 95 | 
| Subject Satisfaction With Treatment at Day 95 | Participant assessment of satisfaction with treatment rated as very satisfied, quite satisfied, neither satisfied nor dissatisfied, quite dissatisfied, or very dissatisfied. | Day 95 | 
| Investigator Assessment of Improvement With Treatment at Day 95 | Investigator assessment of degree of improvement in severity of the participant's treated shoulder compared with screening rated as very much improved, much improved, minimally improved, no change, minimally worse, much worse, or very much worse. | Day 95 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adhesive Capsulitis, Frozen Shoulder, Shoulder Range of Motion limitation, Shoulder Pain