Adhesive Capsulitis, Frozen Shoulder
Conditions
Keywords
Adhesive Capsulitis, Frozen Shoulder, Shoulder Range of Motion limitation, Shoulder Pain
Brief summary
The objectives of this study are to assess the safety, effectiveness, and immunogenicity of AA4500 in the treatment of adhesive capsulitis.
Detailed description
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.
Interventions
OTHERPlacebo
Placebo injection
BIOLOGICALCollagenase Clostridium Histolyticum
Treatment of Adhesive Capsulitis
Sponsors
Endo Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Day 95 in Active Forward Flexion | Baseline, day 95 | Active range of motion (AROM) measurement using a goniometer to assess forward flexion in the affected shoulder |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Day 95 in Pain With Movement Using 11-point Numeric Rating Scale (NRS) | Baseline, day 95 | 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. |
| Change From Baseline to Day 95 in Active Abduction | Baseline, day 95 | AROM measurement using a goniometer to assess abduction in the affected shoulder |
| Change From Baseline to Day 95 in Passive Forward Flexion | Baseline, day 95 | Passive range of motion (PROM) measurement using a goniometer to assess forward flexion in the affected shoulder |
| Change From Baseline to Day 95 in Passive Abduction | Baseline, day 95 | PROM measurement using a goniometer to assess abduction in the affected shoulder |
| Change From Baseline to Day 95 in Active Internal Rotation | Baseline, day 95 | AROM measurement using a goniometer to assess internal rotation in the affected shoulder |
| Change From Baseline to Day 95 in Adapted American Shoulder and Elbow Surgeons (ASES) Function Subscale | Baseline, day 95 | 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). |
| Change From Baseline to Day 95 in Passive Internal Rotation | Baseline, day 95 | PROM measurement using a goniometer to assess internal rotation in the affected shoulder |
| Change From Baseline to Day 95 in Passive External Rotation | Baseline, day 95 | PROM measurement using a goniometer to assess external rotation in the affected shoulder |
| Change From Baseline to Day 95 in Adapted ASES Pain Subscale | Baseline, day 95 | 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 |
| Subject Satisfaction With Treatment at Day 95 | Day 95 | Participant assessment of satisfaction with treatment rated as very satisfied, quite satisfied, neither satisfied nor dissatisfied, quite dissatisfied, or very dissatisfied. |
| Investigator Assessment of Improvement With Treatment at Day 95 | 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. |
| Change From Baseline to Day 95 in Active External Rotation | Baseline, day 95 | AROM measurement using a goniometer to assess external rotation in the affected shoulder |
Countries
Australia, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AA4500 Up to 3 injections of 0.58 mg/1 mL AA4500, minimum of 21 days apart and home shoulder exercise | 237 |
| Placebo Up to three 1-mL injections of placebo, minimum of 21 days apart and home shoulder exercise | 84 |
| Total | 321 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Lost to Follow-up | 5 | 1 |
| Overall Study | Other/Unknown | 0 | 1 |
| Overall Study | Protocol Violation | 2 | 0 |
| Overall Study | Withdrawal by Subject | 10 | 2 |
Baseline characteristics
| Characteristic | AA4500 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 53.0 years | 51.0 years | 52.0 years |
| Age, Customized <45 | 30 Participants | 14 Participants | 44 Participants |
| Age, Customized 45-54 | 114 Participants | 44 Participants | 158 Participants |
| Age, Customized 55-64 | 75 Participants | 23 Participants | 98 Participants |
| Age, Customized 65-74 | 17 Participants | 3 Participants | 20 Participants |
| Age, Customized ≥75 | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 4 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 220 Participants | 80 Participants | 300 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 4 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 22 Participants | 7 Participants | 29 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 205 Participants | 72 Participants | 277 Participants |
| Sex: Female, Male Female | 162 Participants | 60 Participants | 222 Participants |
| Sex: Female, Male Male | 75 Participants | 24 Participants | 99 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 188 / 237 | 37 / 84 |
| serious Total, serious adverse events | 4 / 237 | 1 / 84 |
Outcome results
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
Time frame: Baseline, day 95
Population: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 | Change From Baseline to Day 95 in Active Forward Flexion | 41.0 degrees | Standard Deviation 28.89 |
| Placebo | Change From Baseline to Day 95 in Active Forward Flexion | 35.9 degrees | Standard Deviation 23.36 |
Secondary
Change From Baseline to Day 95 in Active Abduction
AROM measurement using a goniometer to assess abduction in the affected shoulder
Time frame: Baseline, day 95
Population: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 | Change From Baseline to Day 95 in Active Abduction | 49.0 degrees | Standard Deviation 33.1 |
| Placebo | Change From Baseline to Day 95 in Active Abduction | 43.8 degrees | Standard Deviation 30.71 |
Secondary
Change From Baseline to Day 95 in Active External Rotation
AROM measurement using a goniometer to assess external rotation in the affected shoulder
Time frame: Baseline, day 95
Population: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 | Change From Baseline to Day 95 in Active External Rotation | 28.6 degrees | Standard Deviation 21.3 |
| Placebo | Change From Baseline to Day 95 in Active External Rotation | 26.1 degrees | Standard Deviation 22.67 |
Secondary
Change From Baseline to Day 95 in Active Internal Rotation
AROM measurement using a goniometer to assess internal rotation in the affected shoulder
Time frame: Baseline, day 95
Population: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 | Change From Baseline to Day 95 in Active Internal Rotation | 23.1 degrees | Standard Deviation 25.21 |
| Placebo | Change From Baseline to Day 95 in Active Internal Rotation | 20.9 degrees | Standard Deviation 23.58 |
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).
Time frame: Baseline, day 95
Population: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 | Change From Baseline to Day 95 in Adapted American Shoulder and Elbow Surgeons (ASES) Function Subscale | 17.0 units on a scale | Standard Deviation 11.65 |
| Placebo | Change From Baseline to Day 95 in Adapted American Shoulder and Elbow Surgeons (ASES) Function Subscale | 14.8 units on a scale | Standard Deviation 11.14 |
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
Time frame: Baseline, day 95
Population: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 | Change From Baseline to Day 95 in Adapted ASES Pain Subscale | 15.9 units on a scale | Standard Deviation 13.46 |
| Placebo | Change From Baseline to Day 95 in Adapted ASES Pain Subscale | 13.5 units on a scale | Standard Deviation 13.45 |
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.
Time frame: Baseline, day 95
Population: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 | Change From Baseline to Day 95 in Pain With Movement Using 11-point Numeric Rating Scale (NRS) | -4.4 units on a scale | Standard Deviation 2.83 |
| Placebo | Change From Baseline to Day 95 in Pain With Movement Using 11-point Numeric Rating Scale (NRS) | -3.9 units on a scale | Standard Deviation 2.93 |
Secondary
Change From Baseline to Day 95 in Passive Abduction
PROM measurement using a goniometer to assess abduction in the affected shoulder
Time frame: Baseline, day 95
Population: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 | Change From Baseline to Day 95 in Passive Abduction | 45.4 degrees | Standard Deviation 33.69 |
| Placebo | Change From Baseline to Day 95 in Passive Abduction | 42.8 degrees | Standard Deviation 32.12 |
Secondary
Change From Baseline to Day 95 in Passive External Rotation
PROM measurement using a goniometer to assess external rotation in the affected shoulder
Time frame: Baseline, day 95
Population: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 | Change From Baseline to Day 95 in Passive External Rotation | 24.8 degrees | Standard Deviation 22.31 |
| Placebo | Change From Baseline to Day 95 in Passive External Rotation | 24.4 degrees | Standard Deviation 26.16 |
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
Time frame: Baseline, day 95
Population: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 | Change From Baseline to Day 95 in Passive Forward Flexion | 39.3 degrees | Standard Deviation 29.47 |
| Placebo | Change From Baseline to Day 95 in Passive Forward Flexion | 34.1 degrees | Standard Deviation 22.37 |
Secondary
Change From Baseline to Day 95 in Passive Internal Rotation
PROM measurement using a goniometer to assess internal rotation in the affected shoulder
Time frame: Baseline, day 95
Population: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 | Change From Baseline to Day 95 in Passive Internal Rotation | 24.1 degrees | Standard Deviation 23.77 |
| Placebo | Change From Baseline to Day 95 in Passive Internal Rotation | 20.3 degrees | Standard Deviation 23.61 |
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.
Time frame: Day 95
Population: 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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AA4500 | Investigator Assessment of Improvement With Treatment at Day 95 | Minimally improved | 41 participants |
| AA4500 | Investigator Assessment of Improvement With Treatment at Day 95 | Minimally worse | 6 participants |
| AA4500 | Investigator Assessment of Improvement With Treatment at Day 95 | Much improved | 73 participants |
| AA4500 | Investigator Assessment of Improvement With Treatment at Day 95 | Much worse | 1 participants |
| AA4500 | Investigator Assessment of Improvement With Treatment at Day 95 | Very much worse | 1 participants |
| AA4500 | Investigator Assessment of Improvement With Treatment at Day 95 | No change | 13 participants |
| AA4500 | Investigator Assessment of Improvement With Treatment at Day 95 | Very much improved | 94 participants |
| Placebo | Investigator Assessment of Improvement With Treatment at Day 95 | Much worse | 0 participants |
| Placebo | Investigator Assessment of Improvement With Treatment at Day 95 | Very much improved | 27 participants |
| Placebo | Investigator Assessment of Improvement With Treatment at Day 95 | Much improved | 31 participants |
| Placebo | Investigator Assessment of Improvement With Treatment at Day 95 | Minimally improved | 16 participants |
| Placebo | Investigator Assessment of Improvement With Treatment at Day 95 | No change | 8 participants |
| Placebo | Investigator Assessment of Improvement With Treatment at Day 95 | Minimally worse | 0 participants |
| Placebo | Investigator Assessment of Improvement With Treatment at Day 95 | Very much worse | 0 participants |
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.
Time frame: Day 95
Population: 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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AA4500 | Subject Satisfaction With Treatment at Day 95 | Quite satisfied | 38 participants |
| AA4500 | Subject Satisfaction With Treatment at Day 95 | Quite dissatisfied | 10 participants |
| AA4500 | Subject Satisfaction With Treatment at Day 95 | Neither satisfied nor dissatisfied | 32 participants |
| AA4500 | Subject Satisfaction With Treatment at Day 95 | Very dissatisfied | 7 participants |
| AA4500 | Subject Satisfaction With Treatment at Day 95 | Very satisfied | 142 participants |
| Placebo | Subject Satisfaction With Treatment at Day 95 | Very dissatisfied | 6 participants |
| Placebo | Subject Satisfaction With Treatment at Day 95 | Very satisfied | 43 participants |
| Placebo | Subject Satisfaction With Treatment at Day 95 | Quite satisfied | 22 participants |
| Placebo | Subject Satisfaction With Treatment at Day 95 | Neither satisfied nor dissatisfied | 8 participants |
| Placebo | Subject Satisfaction With Treatment at Day 95 | Quite dissatisfied | 2 participants |