Dupuytren's Contracture
Conditions
Brief summary
This was a Phase 3, double-blind, randomized, placebo-controlled study conducted in the United States. Subjects with a diagnosis of Dupuytren's contracture in a metacarpophalangeal (MP) or proximal interphalangeal (PIP) joint that resulted in a fixed flexion deformity of at least one finger, other than the thumb, that was at least 20° as measured by finger goniometry and was suitable for injection were randomized 2:1 to receive AA4500 0.58 mg or placebo. This study was designed to be part of the larger clinical program, for adult patients with Dupuytren's contracture with a palpable cord, where the data from 2 pivotal Placebo-Controlled studies (AUX-CC-857 (NCT00528606) and AUX-CC-859 (NCT00533273)) and 7 non-pivotal studies were evaluated.
Interventions
BIOLOGICALcollagenase clostridium histolyticum
Subjects could have received up to three injections of AA4500 into the cord of the affected hand. Each injection was separated by at least 30 days. Individual cords may have received up to a maximum of three injections.
BIOLOGICALPlacebo
Subjects could have received up to three injections of placebo into the cord of the affected hand. Each injection was separated by at least 30 days. Individual cords may have received up to a maximum of three injections.
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
* Subjects with a diagnosis of Dupuytren's contracture, with a fixed flexion deformity of at least one finger, other than the thumb, that had a contracture at least 20°, but not greater than 100°, for MP (80° for PIP) joints, caused by a palpable cord that had never been treated with AA4500. * Had a positive table top test, defined as the inability to simultaneously place the affected finger(s) and palm flat against a table top. * Judged to be in good health.
Exclusion criteria
* Had a chronic muscular, neurological, or neuromuscular disorder that affected the hands. * Had received a treatment for Dupuytren's contracture, including surgery (fasciectomy or surgical fasciotomy), needle aponeurotomy/fasciotomy, or injection of verapamil and/or interferon on the selected primary joint within 90 days before the first dose of study drug. * Had a known recent history of stroke, bleeding, a disease process that affected the hands, or other medical condition, which in the investigator's opinion, would make the subject unsuitable for enrollment in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Success (Reduction in Contracture to 5° or Less) of the Primary Joint After the Last Injection | Within 30 days after the last injection | The Primary Outcome Measure for patients treated with AA4500 is the percentage of joints that were successfully treated where successfully treated was defined as reduction in contracture to within 0-5° of normal within 30 days of injection. The Primary Outcome Measure for placebo treated patients is the percentage of joints that were successfully treated where successfully treated was defined as reduction in contracture to within 0-5° of normal within 30 days of injection. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Reduction From Baseline Contracture After the Last Injection | Baseline; within 30 days after the last injection | Percent change in degree of contracture measured as 100\* (baseline contracture - last available post-injection contracture)/baseline contracture. |
| Change From Baseline Range of Motion After the Last Injection | Baselin; within 30 days after the last injection | Change in degree of motion measured as last available post-injection range of motion - baseline range of motion. |
| Time to First Achieve Success After the Last Injection | Last evaluation visit on which clinical success is achieved through the Day 30 evaluation | — |
| Clinical Improvement After the Last Injection | Baseline; within 30 days after the last injection | Clinical Improvement is defined as \>= 50% reduction from baseline in degree of contracture within 30 days of the injection. |
| Clinical Improvement After the First Injection | Baseline; within 30 days after the first injection | Clinical Improvement is defined as \>= 50% reduction from contracture within 30 days of the first injectionor greater of baseline contracture within 30 days of the injection. |
| Percent Reduction From Baseline Contracture After the First Injection | Baseline, within 30 days after the first injection | Percent change in degree of contracture measured as 100\* (baseline contracture - last available post-injection contracture)/baseline contracture. |
| Change From Baseline Range of Motion After the First Injection | Baseline; within 30 days after the first injection | Change in degree of motion measured as last available post-injection range of motion - baseline range of motion. |
| Clinical Success (Reduction in Contracture to 5° or Less) After the First Injection | Within 30 days after first injection | Clinical Success is defined as reduction in contracture to within 0-5 degrees of normal within 30 days of injection. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AA4500 0.58 mg collagenase clostridium histolyticum 0.58mg injected into metacarpophalangeal (MP) and/or proximal interphalangeal (PIP) joints | 204 |
| Placebo placebo injected into metacarpophalangeal (MP) and/or proximal interphalangeal (PIP) joints | 104 |
| Total | 308 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 |
| Overall Study | Lost to Follow-up | 4 | 1 |
| Overall Study | Other | 2 | 0 |
| Overall Study | Withdrew consent | 4 | 3 |
Baseline characteristics
| Characteristic | AA4500 0.58 mg | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 84 Participants | 47 Participants | 131 Participants |
| Age, Categorical Between 18 and 65 years | 120 Participants | 57 Participants | 177 Participants |
| Age, Continuous | 62.3 years STANDARD_DEVIATION 9.7 | 63.3 years STANDARD_DEVIATION 9.1 | 62.7 years STANDARD_DEVIATION 9.5 |
| Race/Ethnicity, Customized Hispanic | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 203 participants | 104 participants | 307 participants |
| Region of Enrollment United States | 204 participants | 104 participants | 308 participants |
| Sex: Female, Male Female | 33 Participants | 30 Participants | 63 Participants |
| Sex: Female, Male Male | 171 Participants | 74 Participants | 245 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 196 / 204 | 25 / 104 |
| serious Total, serious adverse events | 8 / 204 | 1 / 104 |
Outcome results
Primary
Clinical Success (Reduction in Contracture to 5° or Less) of the Primary Joint After the Last Injection
The Primary Outcome Measure for patients treated with AA4500 is the percentage of joints that were successfully treated where successfully treated was defined as reduction in contracture to within 0-5° of normal within 30 days of injection. The Primary Outcome Measure for placebo treated patients is the percentage of joints that were successfully treated where successfully treated was defined as reduction in contracture to within 0-5° of normal within 30 days of injection.
Time frame: Within 30 days after the last injection
Population: Modified-Intent-to-Treat population (Intent-to-treat subjects were excluded from this population if they did not have fixed-flexion measurements after the first injection or had both screening and Treatment 1, Day 0 fixed-flexion measurements between 0 and 5 degrees)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AA4500 0.58 mg | Clinical Success (Reduction in Contracture to 5° or Less) of the Primary Joint After the Last Injection | 64 Percentage of Joints |
| Placebo | Clinical Success (Reduction in Contracture to 5° or Less) of the Primary Joint After the Last Injection | 6.8 Percentage of Joints |
Comparison: p-value based on Cochran-Mantel-Haenszel test comparing treatment groups, stratified by baseline severity group and joint type.p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Change From Baseline Range of Motion After the First Injection
Change in degree of motion measured as last available post-injection range of motion - baseline range of motion.
Time frame: Baseline; within 30 days after the first injection
Population: Modified ITT population (Change in degree of motion measured as last available post-injection range of motion - baseline range of motion)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 0.58 mg | Change From Baseline Range of Motion After the First Injection | 28.30 degrees | Standard Deviation 20.23 |
| Placebo | Change From Baseline Range of Motion After the First Injection | 1.50 degrees | Standard Deviation 11.03 |
Secondary
Change From Baseline Range of Motion After the Last Injection
Change in degree of motion measured as last available post-injection range of motion - baseline range of motion.
Time frame: Baselin; within 30 days after the last injection
Population: Modified ITT Population (Intent-to-treat subjects were excluded from this population if they did not have fixed-flexion measurements after the first injection or had both screening and Treatment 1, Day 0 fixed-flexion measurements between 0 and 5 degrees)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 0.58 mg | Change From Baseline Range of Motion After the Last Injection | 36.70 degrees | Standard Deviation 21.01 |
| Placebo | Change From Baseline Range of Motion After the Last Injection | 4.0 degrees | Standard Deviation 14.77 |
Secondary
Clinical Improvement After the First Injection
Clinical Improvement is defined as \>= 50% reduction from contracture within 30 days of the first injectionor greater of baseline contracture within 30 days of the injection.
Time frame: Baseline; within 30 days after the first injection
Population: Modified ITT population (Intent-to-treat subjects were excluded from this population if they did not have fixed-flexion measurements after the first injection or had both screening and Treatment 1, Day 0 fixed-flexion measurements between 0 and 5 degrees)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AA4500 0.58 mg | Clinical Improvement After the First Injection | 67.5 Percentage of Joints |
| Placebo | Clinical Improvement After the First Injection | 2.9 Percentage of Joints |
Secondary
Clinical Improvement After the Last Injection
Clinical Improvement is defined as \>= 50% reduction from baseline in degree of contracture within 30 days of the injection.
Time frame: Baseline; within 30 days after the last injection
Population: Modified ITT population( Intent-to-treat subjects were excluded from this population if they did not have fixed-flexion measurements after the first injection or had both screening and Treatment 1, Day 0 fixed-flexion measurements between 0 and 5 degrees)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AA4500 0.58 mg | Clinical Improvement After the Last Injection | 84.7 Percentage of Joints |
| Placebo | Clinical Improvement After the Last Injection | 11.7 Percentage of Joints |
Secondary
Clinical Success (Reduction in Contracture to 5° or Less) After the First Injection
Clinical Success is defined as reduction in contracture to within 0-5 degrees of normal within 30 days of injection.
Time frame: Within 30 days after first injection
Population: Modified ITT population (Intent-to-treat subjects were excluded from this population if they did not have fixed-flexion measurements after the first injection or had both screening and Treatment 1, Day 0 fixed-flexion measurements between 0 and 5 degrees)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AA4500 0.58 mg | Clinical Success (Reduction in Contracture to 5° or Less) After the First Injection | 38.9 Percentage of Joints |
| Placebo | Clinical Success (Reduction in Contracture to 5° or Less) After the First Injection | 1.0 Percentage of Joints |
Secondary
Percent Reduction From Baseline Contracture After the First Injection
Percent change in degree of contracture measured as 100\* (baseline contracture - last available post-injection contracture)/baseline contracture.
Time frame: Baseline, within 30 days after the first injection
Population: Modified ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 0.58 mg | Percent Reduction From Baseline Contracture After the First Injection | 64.8 Percent reduction from baseline | Standard Deviation 34.6 |
| Placebo | Percent Reduction From Baseline Contracture After the First Injection | 4.7 Percent reduction from baseline | Standard Deviation 20.81 |
Secondary
Percent Reduction From Baseline Contracture After the Last Injection
Percent change in degree of contracture measured as 100\* (baseline contracture - last available post-injection contracture)/baseline contracture.
Time frame: Baseline; within 30 days after the last injection
Population: Modified ITT population (Intent-to-treat subjects were excluded from this population if they did not have fixed-flexion measurements after the first injection or had both screening and Treatment 1, Day 0 fixed-flexion measurements between 0 and 5 degrees)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 0.58 mg | Percent Reduction From Baseline Contracture After the Last Injection | 79.3 Percent reduction from baseline | Standard Deviation 32.58 |
| Placebo | Percent Reduction From Baseline Contracture After the Last Injection | 8.6 Percent reduction from baseline | Standard Deviation 30.78 |
Secondary
Time to First Achieve Success After the Last Injection
Time frame: Last evaluation visit on which clinical success is achieved through the Day 30 evaluation
Population: Modified ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AA4500 0.58 mg | Time to First Achieve Success After the Last Injection | Injection 1, Day 1 | 12.8 percentage of joints |
| AA4500 0.58 mg | Time to First Achieve Success After the Last Injection | Injection 2, Day 7 | 5.4 percentage of joints |
| AA4500 0.58 mg | Time to First Achieve Success After the Last Injection | Injection 1, Day 30 | 14.3 percentage of joints |
| AA4500 0.58 mg | Time to First Achieve Success After the Last Injection | Injection 2, Day 30 | 6.4 percentage of joints |
| AA4500 0.58 mg | Time to First Achieve Success After the Last Injection | Injection 3, Day 1 | 2.0 percentage of joints |
| AA4500 0.58 mg | Time to First Achieve Success After the Last Injection | Injection 3, Day 7 | 2.5 percentage of joints |
| AA4500 0.58 mg | Time to First Achieve Success After the Last Injection | Injection 2, Day 0 | 0.5 percentage of joints |
| AA4500 0.58 mg | Time to First Achieve Success After the Last Injection | Injection 3, Day 30 | 2.5 percentage of joints |
| AA4500 0.58 mg | Time to First Achieve Success After the Last Injection | Injection 1, Day 7 | 12.3 percentage of joints |
| AA4500 0.58 mg | Time to First Achieve Success After the Last Injection | Day 90 | 0.5 percentage of joints |
| AA4500 0.58 mg | Time to First Achieve Success After the Last Injection | Injection 2, Day 1 | 4.9 percentage of joints |
| AA4500 0.58 mg | Time to First Achieve Success After the Last Injection | Did not reach clinical success by last injection | 36.0 percentage of joints |
| AA4500 0.58 mg | Time to First Achieve Success After the Last Injection | Injection 3, Day 0 | 0.0 percentage of joints |
| Placebo | Time to First Achieve Success After the Last Injection | Did not reach clinical success by last injection | 93.2 percentage of joints |
| Placebo | Time to First Achieve Success After the Last Injection | Injection 3, Day 0 | 0.0 percentage of joints |
| Placebo | Time to First Achieve Success After the Last Injection | Injection 3, Day 1 | 0.0 percentage of joints |
| Placebo | Time to First Achieve Success After the Last Injection | Injection 1, Day 1 | 0.0 percentage of joints |
| Placebo | Time to First Achieve Success After the Last Injection | Injection 1, Day 7 | 0.0 percentage of joints |
| Placebo | Time to First Achieve Success After the Last Injection | Injection 1, Day 30 | 1.0 percentage of joints |
| Placebo | Time to First Achieve Success After the Last Injection | Injection 2, Day 0 | 0.0 percentage of joints |
| Placebo | Time to First Achieve Success After the Last Injection | Injection 2, Day 1 | 0.0 percentage of joints |
| Placebo | Time to First Achieve Success After the Last Injection | Injection 2, Day 7 | 0.0 percentage of joints |
| Placebo | Time to First Achieve Success After the Last Injection | Injection 2, Day 30 | 1.0 percentage of joints |
| Placebo | Time to First Achieve Success After the Last Injection | Injection 3, Day 7 | 0.0 percentage of joints |
| Placebo | Time to First Achieve Success After the Last Injection | Injection 3, Day 30 | 4.9 percentage of joints |
| Placebo | Time to First Achieve Success After the Last Injection | Day 90 | 0.0 percentage of joints |