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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Collagenase Clostridium Histolyticum | Experimental | Up to 3 injections of .58 mg/1 mL of collagenase clostridium histolyticum (CCH), minimum of 21 days apart and home shoulder exercise. |
|
| Placebo | Placebo Comparator | Up to 3 1-mL injections of placebo, minimum of 21 days apart and home shoulder exercise. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Collagenase Clostridium Histolyticum | Biological | Treatment of Adhesive Capsulitis |
|
| 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 |
| 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). |
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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:
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:
Has any of the following conditions, as determined by investigator to be potentially confounding to the evaluation of safety and efficacy:
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.
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| Name | Affiliation | Role |
|---|---|---|
| Neil H Schusterman, MD FACP | Endo USA Inc., a Keenova Therapeutics Company | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Alabama Orthopaedic Center-Research | Birmingham | Alabama | 35209 | United States | ||
| Coastal Clinical Research |
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| ID | Title | Description |
|---|---|---|
| FG000 | AA4500 | Up to 3 injections of 0.58 mg/1 mL collagenase clostridium histolyticum (AA4500), minimum of 21 days apart and home shoulder exercise |
| FG001 | Placebo | Up to three 1-mL injections of placebo, minimum of 21 days apart and home shoulder exercise |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Placebo | Other | Placebo injection |
|
| 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 |
| Mobile |
| Alabama |
| 36608 |
| United States |
| Arizona Research Center, Inc. | Phoenix | Arizona | 85023 | United States |
| Advance Med Clinical Research | Carlsbad | California | 92008 | United States |
| Triwest Research Associates | El Cajon | California | 92020 | United States |
| Core Orthopedic Medical Center | Encinitas | California | 92024 | United States |
| Temecula Rheumatology & Internal Medicine | Murrieta | California | 92563 | United States |
| Clearview Medical Research | Santa Clarita | California | 91350 | United States |
| Colorado Orthopedic Consultants, PC | Englewood | Colorado | 80110 | United States |
| Florida Research Associates | DeLand | Florida | 32720 | United States |
| Shrock Orthopedic Research, LLC | Fort Lauderdale | Florida | 33316 | United States |
| Jewett Orthopedic Clinic | Orlando | Florida | 32822 | United States |
| Clinical Research of West Florida | Tampa | Florida | 33603 | United States |
| Non-Surgical Orthopedics, P.C. / Georgia Institute for Clinical Research, LLC | Marietta | Georgia | 30060 | United States |
| Injury Care Medical Center | Boise | Idaho | 83713 | United States |
| Rockford Orthopedic Associates | Rockford | Illinois | 61107 | United States |
| Rockford Orthopedics Associates | Rockford | Illinois | 61114 | United States |
| Indiana Hand to Shoulder Center | Indianapolis | Indiana | 46260 | United States |
| PRN of Kansas | Wichita | Kansas | 67203 | United States |
| Central Kentucky Research Associates | Lexington | Kentucky | 40509 | United States |
| Bone and Joint Clinic | Gretna | Louisiana | 70056 | United States |
| MedPharmics, LLC | Metairie | Louisiana | 70006 | United States |
| Arthritis and Rheumatism Associates, PC | Wheaton | Maryland | 20902 | United States |
| Great Falls Clinic | Great Falls | Montana | 59405 | United States |
| Nevada Orthopedic & Spine Center | Las Vegas | Nevada | 89128 | United States |
| Stony Brook University Medical Center (SUNY) | Stony Brook | New York | 11794 | United States |
| Triangle Orthopedic Associates, PA | Durham | North Carolina | 27704 | United States |
| Wake Research Associates | Raleigh | North Carolina | 27612 | United States |
| The Neuromusculoskeletal Center of the Cascades d.b.a. The Center | Bend | Oregon | 97701 | United States |
| Blair Orthopedic Associates, Inc. | Altoona | Pennsylvania | 16602 | United States |
| University of Pennsylvania Penn Orthopaedics | Philadelphia | Pennsylvania | 19087 | United States |
| Texas Orthopedic Specialist | Bedford | Texas | 76021 | United States |
| Centex Studies | Houston | Texas | 77062 | United States |
| Commonwealth Orthopaedics & Rehabilitation | Arlington | Virginia | 22205 | United States |
| Danville Orthopedic Clinic, Inc. | Danville | Virginia | 24541 | United States |
| Sports Medicine Professionals | Richmond | Victoria | 3121 | Australia |
| Hunter Clinical Research | NSW | Australia |
| Royal Prince Alfred | NSW | Australia |
| St George Hospital | NSW | Australia |
| Peninsula Private Hospital | Queensland | Australia |
| QPharm | Queensland | Australia |
| Menzies Research Institute | Tasmania | Australia |
| Emeritus Research | VIC | Australia |
| Epworth Hospital | VIC | Australia |
| Repatriation Hospital | VIC | Australia |
| Hand and Upper Limb Centre | WA | Australia |
| COMPLETED |
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| NOT COMPLETED |
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All participants who received at least 1 administration of study drug (1 participant excluded)
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| ID | Title | Description |
|---|---|---|
| BG000 | AA4500 | Up to 3 injections of 0.58 mg/1 mL AA4500, minimum of 21 days apart and home shoulder exercise |
| BG001 | Placebo | Up to three 1-mL injections of placebo, minimum of 21 days apart and home shoulder exercise |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median | Full Range | years |
| |||||||||||||||
| Age, Customized | Count of Participants | Participants |
| ||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 | All participants who have a baseline AROM measurement of the affected shoulder and at least 1 measurement of AROM of the affected shoulder following the first administration of study drug (1 participant excluded); 25 participants missing either baseline or day 95 active forward flexion measurement also excluded | Posted | Mean | Standard Deviation | degrees | Baseline, day 95 |
|
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| ||||||||||||||||||||||||||||
| Secondary | 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). | All participants who have a baseline AROM measurement of the affected shoulder and at least 1 measurement of AROM of the affected shoulder following the first administration of study drug (1 participant excluded); 34 participants missing either baseline or day 95 function subscale scores also excluded | Posted | Mean | Standard Deviation | units on a scale | Baseline, day 95 |
|
| |||||||||||||||||||||||||||||
| Secondary | 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. | All participants who have a baseline AROM measurement of the affected shoulder and at least 1 measurement of AROM of the affected shoulder following the first administration of study drug (1 participant excluded); 33 participants missing either baseline or day 95 pain with movement scores also excluded | Posted | Mean | Standard Deviation | units on a scale | Baseline, day 95 |
|
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| Secondary | Change From Baseline to Day 95 in Active Abduction | AROM measurement using a goniometer to assess abduction in the affected shoulder | All participants who have a baseline AROM measurement of the affected shoulder and at least 1 measurement of AROM of the affected shoulder following the first administration of study drug (1 participant excluded); 25 participants missing either baseline or day 95 active abduction measurement also excluded | Posted | Mean | Standard Deviation | degrees | Baseline, day 95 |
|
| |||||||||||||||||||||||||||||
| Secondary | 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 | All participants who have a baseline AROM measurement of the affected shoulder and at least 1 measurement of AROM of the affected shoulder following the first administration of study drug (1 participant excluded); 25 participants missing either baseline or day 95 active forward flexion measurement also excluded | Posted | Mean | Standard Deviation | degrees | Baseline, day 95 |
|
| |||||||||||||||||||||||||||||
| Secondary | Change From Baseline to Day 95 in Passive Abduction | PROM measurement using a goniometer to assess abduction in the affected shoulder | All participants who have a baseline AROM measurement of the affected shoulder and at least 1 measurement of AROM of the affected shoulder following the first administration of study drug (1 participant excluded); 25 participants missing either baseline or day 95 passive abduction measurement also excluded | Posted | Mean | Standard Deviation | degrees | Baseline, day 95 |
|
| |||||||||||||||||||||||||||||
| Secondary | Change From Baseline to Day 95 in Active Internal Rotation | AROM measurement using a goniometer to assess internal rotation in the affected shoulder | All participants who have a baseline AROM measurement of the affected shoulder and at least 1 measurement of AROM of the affected shoulder following the first administration of study drug (1 participant excluded); 25 participants missing either baseline or day 95 active internal rotation measurement also excluded | Posted | Mean | Standard Deviation | degrees | Baseline, day 95 |
|
| |||||||||||||||||||||||||||||
| Secondary | Change From Baseline to Day 95 in Active External Rotation | AROM measurement using a goniometer to assess external rotation in the affected shoulder | All participants who have a baseline AROM measurement of the affected shoulder and at least 1 measurement of AROM of the affected shoulder following the first administration of study drug (1 participant excluded); 25 participants missing either baseline or day 95 active external rotation measurement also excluded | Posted | Mean | Standard Deviation | degrees | Baseline, day 95 |
|
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| Secondary | Change From Baseline to Day 95 in Passive Internal Rotation | PROM measurement using a goniometer to assess internal rotation in the affected shoulder | All participants who have a baseline AROM measurement of the affected shoulder and at least 1 measurement of AROM of the affected shoulder following the first administration of study drug (1 participant excluded); 25 participants missing either baseline or day 95 passive internal rotation measurement also excluded | Posted | Mean | Standard Deviation | degrees | Baseline, day 95 |
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| Secondary | Change From Baseline to Day 95 in Passive External Rotation | PROM measurement using a goniometer to assess external rotation in the affected shoulder | All participants who have a baseline AROM measurement of the affected shoulder and at least 1 measurement of AROM of the affected shoulder following the first administration of study drug (1 participant excluded); 25 participants missing either baseline or day 95 passive external rotation measurement also excluded | Posted | Mean | Standard Deviation | degrees | Baseline, day 95 |
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| Secondary | 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 | All participants who have a baseline AROM measurement of the affected shoulder and at least 1 measurement of AROM of the affected shoulder following the first administration of study drug (1 participant excluded); 33 participants missing either baseline or day 95 pain subscale scores also excluded | Posted | Mean | Standard Deviation | units on a scale | Baseline, day 95 |
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| Secondary | 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. | All participants who have a baseline AROM measurement of the affected shoulder and at least 1 measurement of AROM of the affected shoulder following the first administration of study drug (1 participant excluded); 11 participants not completing questionnaire also excluded | Posted | Number | participants | Day 95 |
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| Secondary | 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. | All participants who have a baseline AROM measurement of the affected shoulder and at least 1 measurement of AROM of the affected shoulder following the first administration of study drug (1 participant excluded); 10 participants also excluded for incomplete questionnaire | Posted | Number | participants | Day 95 |
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130 days (up to 28 day screening period and 95±7 day study period)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | AA4500 | Up to 3 injections of 0.58 mg/1 mL AA4500, minimum of 21 days apart and home shoulder exercise | 4 | 237 | 188 | 237 | ||
| EG001 | Placebo | Up to three 1-mL injections of placebo, minimum of 21 days apart and home shoulder exercise | 1 | 84 | 37 | 84 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Atrial fibrilation | Cardiac disorders | MedDRA (16.1) | Non-systematic Assessment |
| |
| Glioblastoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (16.1) | Non-systematic Assessment |
| |
| Overdose | Injury, poisoning and procedural complications | MedDRA (16.1) | Non-systematic Assessment |
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| Post procedural bile leak | Injury, poisoning and procedural complications | MedDRA (16.1) | Non-systematic Assessment |
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| Procedural pain | Injury, poisoning and procedural complications | MedDRA (16.1) | Non-systematic Assessment |
| |
| Gastric ulcer | Gastrointestinal disorders | MedDRA (16.1) | Non-systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA (16.1) | Non-systematic Assessment |
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| Contusion | Injury, poisoning and procedural complications | MedDRA (16.1) | Non-systematic Assessment |
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| Injection site bruising | General disorders | MedDRA (16.1) | Non-systematic Assessment |
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| Injection site pain | General disorders | MedDRA (16.1) | Non-systematic Assessment |
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| Ecchymosis | Skin and subcutaneous tissue disorders | MedDRA (16.1) | Non-systematic Assessment |
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| Localised oedema | General disorders | MedDRA (16.1) | Non-systematic Assessment |
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| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA (16.1) | Non-systematic Assessment |
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| Pruritus | Skin and subcutaneous tissue disorders | MedDRA (16.1) | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Trial Coordinator | Endo Pharmaceuticals Inc. | clinicalsite.inquiries@endo.com |
| ID | Term |
|---|---|
| D002062 | Bursitis |
| D020069 | Shoulder Pain |
| ID | Term |
|---|---|
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D018771 | Arthralgia |
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D003012 | Microbial Collagenase |
| C570746 | xiapex |
| ID | Term |
|---|---|
| D017364 | Collagenases |
| D008666 | Metalloendopeptidases |
| D010450 | Endopeptidases |
| D010447 | Peptide Hydrolases |
| D006867 | Hydrolases |
| D004798 | Enzymes |
| D045762 | Enzymes and Coenzymes |
| D045726 | Metalloproteases |
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| 45-54 |
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| 55-64 |
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| 65-74 |
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| ≥75 |
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| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Participants |
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