Dupuytren's Contracture
Conditions
Keywords
XIAFLEX, XIAPEX, Dupuytren's disease, contracture
Brief summary
The primary objective of this study is to assess the safety of two concurrent injections of AA4500 into the same hand in subjects with multiple Dupuytren's contractures with palpable cords followed 24 to 72 hours later by a finger extension procedure and compare the rate of occurrence of targeted serious adverse events (tendon rupture/ligament injury and anaphylaxis) to historical rates of the same in clinical studies and post-marketing commercial use. The secondary objective is to evaluate the efficacy of two concurrent injections of AA4500.
Detailed description
Methodology/Study Design: After all pre-injection procedures are completed on Day 1, eligible men and women will receive two concurrent injections AA4500 (AA4500/AA4500) into cord(s) affecting MP and/or PIP joints on the same or different fingers in the selected hand. A finger extension procedure to facilitate cord disruption will be performed (after administration of local anesthesia, if needed) 24 to 72 hours after injection in those subjects who do not have spontaneous disruption of their cord(s). Follow up visits for the evaluation of safety and efficacy will be required for all subjects 24 to 72 hours after injection, and on Days 15, 31, and 61. Upon completion of the day 61 follow-up visit (end of study visit), subjects who require additional treatment in the treated hand may receive up to three additional injections of AA4500 according to the XIAFLEX package insert. Subjects may receive up to a total of five injections and individual cords may receive up to a total of three injections. Subjects who require additional treatment will be followed for safety.
Interventions
BIOLOGICALXIAFLEX / XIAPEX
injection (0.58 mg after reconstitution with sterile diluent \[0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride\])
Sponsors
Endo Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Provide a signed and dated informed consent 2. Be a man or woman ≥ 18 years of age 3. Have a diagnosis of Dupuytren's disease and have at least 2 fixed-flexion contractures on the same hand that are ≥ 20º in PIP and/or MP joints in fingers, other than the thumbs, which are caused by palpable cord(s) suitable for treatment 4. Have a positive table top test defined as the inability to simultaneously place the affected finger(s) and palm flat against a table top 5. 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). 6. Be able to comply with the study visit schedule as specified in the protocol
Exclusion criteria
A subject will be excluded from study participation if he/she: 1. Received surgery (fasciectomy or surgical fasciotomy) and/or needle aponeurotomy/fasciotomy on the selected joints to be treated within 6 months before administration of study drug 2. Has a chronic muscular, neurological, or neuromuscular disorder that affects the hands 3. Has a known systemic allergy to collagenase or any other excipient of AA4500 4. 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 5. 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 6. 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 7. Received an investigational drug within 30 days before injection of study drug 8. Is pregnant or intends on becoming pregnant during the study or is breastfeeding a child 9. 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 10. Has jewelry on the hand to be treated that cannot be removed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Total Fixed Flexion | Baseline, Day 31 | Percent change from baseline in total fixed flexion = 100 \* (baseline total FFC - day 31 total FFC)/baseline total FFC, where total fixed flexion is defined as the sum of the fixed flexion contracture (FCC) of the 2 joints receiving treatment. Positive percent change from baseline indicates improvement. |
| Change From Baseline in Total Range of Motion | Baseline, Day 31 | The total range of motion (ROM) is the sum of the range of motion measurements of the 2 treated joints. ROM is defined as difference between full flexion angle and full extension expressed in degrees. A positive change from baseline indicates increased (improved) ROM. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Subject Assessment of Satisfaction With Treatment at Day 31 | Day 31 | Subject's were asked to rate satisfaction with treatment at the day 31 follow-up visit |
| Subject Assessment of Satisfaction With Treatment at Day 61 | Day 61 | Subject's were asked to rate satisfaction with treatment at the day 61 follow-up visit |
| Investigator Assessment of Improvement With Treatment at Day 31 | Day 31 | Investigator's determined the degree of improvement in the severity of the subject's treated finger(s) compared with screening at the day 31 follow-up visit. |
| Clinical Success | Within 30 days | Clinical success is defined as reduction of FFC of a treated joint to within 0-5 degrees of normal within 30 days of injection |
| Change From Baseline for Unité Rhumatologique Des Affections de la Main Scale at Day 31 | Baseline, Day 31 | The Unité Rhumatologique des Affections de la Main (URAM) scale is a patient-reported functional 9-item scale (total score 0-45) developed and validated to assess functional outcome of patients suffering from Dupuytren's disease with higher scores indicating greater difficulty using the hand.The estimated clinically important change of the URAM scale is 2.9 points. A decrease in total URAM score indicates improvement in hand function. |
| Change From Baseline for Unité Rhumatologique Des Affections de la Main Scale at Day 61 | Baseline, Day 61 | The URAM scale is a patient-reported functional 9-item scale (total score 0-45) developed and validated to assess functional outcome of patients suffering from Dupuytren's disease with higher scores indicating greater difficulty using the hand.The estimated clinically important change of the URAM scale is 2.9 points. A decrease in total URAM score indicates improvement in hand function. |
| Investigator Assessment of Improvement With Treatment at Day 61 | Day 61 | Investigator's determined the degree of improvement in the severity of the subject's treated finger(s) compared with screening at the day 61 follow-up visit. |
| Clinical Improvement | Within 30 days | Clinical improvement is defined as a reduction of FFC by 50% or greater of the baseline value within 30 days of injection |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| XIAFLEX/XIAPEX AA4500 (collagenase clostridium histolyticum): 2 concurrent 0.58 mg injections (1 injection per joint) in the same hand | 715 |
| Total | 715 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | XIAFLEX/XIAPEX |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 367 Participants |
| Age, Categorical Between 18 and 65 years | 348 Participants |
| Age, Continuous | 64.0 years STANDARD_DEVIATION 9.26 |
| Region of Enrollment Australia | 196 participants |
| Region of Enrollment Denmark | 87 participants |
| Region of Enrollment New Zealand | 70 participants |
| Region of Enrollment Sweden | 50 participants |
| Region of Enrollment United Kingdom | 34 participants |
| Region of Enrollment United States | 278 participants |
| Sex: Female, Male Female | 99 Participants |
| Sex: Female, Male Male | 616 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 680 / 715 |
| serious Total, serious adverse events | 15 / 715 |
Outcome results
Primary
Change From Baseline in Total Range of Motion
The total range of motion (ROM) is the sum of the range of motion measurements of the 2 treated joints. ROM is defined as difference between full flexion angle and full extension expressed in degrees. A positive change from baseline indicates increased (improved) ROM.
Time frame: Baseline, Day 31
Population: Efficacy analysis was based on the mITT population; all enrolled subjects who received both AA4500 injections and had a post-injection efficacy measure. Ten subjects were granted special re-enrollment and had an additional joint pair treated on the contralateral hand. Assessment is based on simultaneously treated joint pairs.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| XIAFLEX/XIAPEX | Change From Baseline in Total Range of Motion | 66.6 degrees |
Primary
Percent Change From Baseline in Total Fixed Flexion
Percent change from baseline in total fixed flexion = 100 \* (baseline total FFC - day 31 total FFC)/baseline total FFC, where total fixed flexion is defined as the sum of the fixed flexion contracture (FCC) of the 2 joints receiving treatment. Positive percent change from baseline indicates improvement.
Time frame: Baseline, Day 31
Population: Efficacy analysis was based on the modified intent-to-treat (mITT) population; all enrolled subjects who received both AA4500 injections and had a post-injection efficacy measure. Ten subjects were granted special re-enrollment and had an additional joint pair treated on contralateral hand. Assessment is based on simultaneously treated joint pairs.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| XIAFLEX/XIAPEX | Percent Change From Baseline in Total Fixed Flexion | 74.41 percentage of contracture change | Standard Deviation 24.83 |
Secondary
Change From Baseline for Unité Rhumatologique Des Affections de la Main Scale at Day 31
The Unité Rhumatologique des Affections de la Main (URAM) scale is a patient-reported functional 9-item scale (total score 0-45) developed and validated to assess functional outcome of patients suffering from Dupuytren's disease with higher scores indicating greater difficulty using the hand.The estimated clinically important change of the URAM scale is 2.9 points. A decrease in total URAM score indicates improvement in hand function.
Time frame: Baseline, Day 31
Population: Efficacy analysis was based on the mITT population; all enrolled subjects who received both AA4500 injections and had a post-injection efficacy measure. Ten subjects were granted special re-enrollment and had an additional joint pair treated on the contralateral hand. Assessment is based on simultaneously treated joint pairs.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| XIAFLEX/XIAPEX | Change From Baseline for Unité Rhumatologique Des Affections de la Main Scale at Day 31 | -11.3 units on a scale | Standard Deviation 9.19 |
Secondary
Change From Baseline for Unité Rhumatologique Des Affections de la Main Scale at Day 61
The URAM scale is a patient-reported functional 9-item scale (total score 0-45) developed and validated to assess functional outcome of patients suffering from Dupuytren's disease with higher scores indicating greater difficulty using the hand.The estimated clinically important change of the URAM scale is 2.9 points. A decrease in total URAM score indicates improvement in hand function.
Time frame: Baseline, Day 61
Population: Efficacy analysis was based on the mITT population; all enrolled subjects who received both AA4500 injections and had a post-injection efficacy measure. Ten subjects were granted special re-enrollment and had an additional joint pair treated on the contralateral hand. Assessment is based on simultaneously treated joint pairs.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| XIAFLEX/XIAPEX | Change From Baseline for Unité Rhumatologique Des Affections de la Main Scale at Day 61 | -12.3 units on a scale | Standard Deviation 9.75 |
Secondary
Clinical Improvement
Clinical improvement is defined as a reduction of FFC by 50% or greater of the baseline value within 30 days of injection
Time frame: Within 30 days
Population: Efficacy analysis was based on the mITT population; all enrolled subjects who received both AA4500 injections and had a post-injection efficacy measure. Ten subjects were granted special re-enrollment and had an additional joint pair treated on the contralateral hand. This assessment is based on individual treated joints by joint type.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| XIAFLEX/XIAPEX | Clinical Improvement | No | 96 Joints |
| XIAFLEX/XIAPEX | Clinical Improvement | Yes | 800 Joints |
| XIAFLEX/XIAPEX PIP Joint | Clinical Improvement | No | 157 Joints |
| XIAFLEX/XIAPEX PIP Joint | Clinical Improvement | Yes | 395 Joints |
Secondary
Clinical Success
Clinical success is defined as reduction of FFC of a treated joint to within 0-5 degrees of normal within 30 days of injection
Time frame: Within 30 days
Population: Efficacy analysis was based on the mITT population; all enrolled subjects who received both AA4500 injections and had a post-injection efficacy measure. Ten subjects were granted special re-enrollment and had an additional joint pair treated on the contralateral hand. This assessment is based on individual treated joints by joint type.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| XIAFLEX/XIAPEX | Clinical Success | No | 317 Joints |
| XIAFLEX/XIAPEX | Clinical Success | Yes | 579 Joints |
| XIAFLEX/XIAPEX PIP Joint | Clinical Success | No | 394 Joints |
| XIAFLEX/XIAPEX PIP Joint | Clinical Success | Yes | 158 Joints |
Secondary
Investigator Assessment of Improvement With Treatment at Day 31
Investigator's determined the degree of improvement in the severity of the subject's treated finger(s) compared with screening at the day 31 follow-up visit.
Time frame: Day 31
Population: Efficacy analysis was based on the mITT population; all enrolled subjects who received both AA4500 injections and had a post-injection efficacy measure. Ten subjects were granted special re-enrollment and had an additional joint pair treated on the contralateral hand. Assessment is based on simultaneously treated joint pairs.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| XIAFLEX/XIAPEX | Investigator Assessment of Improvement With Treatment at Day 31 | Very much improved | 375 Joint Pairs |
| XIAFLEX/XIAPEX | Investigator Assessment of Improvement With Treatment at Day 31 | Much improved | 271 Joint Pairs |
| XIAFLEX/XIAPEX | Investigator Assessment of Improvement With Treatment at Day 31 | Minimally improved | 51 Joint Pairs |
| XIAFLEX/XIAPEX | Investigator Assessment of Improvement With Treatment at Day 31 | No change | 4 Joint Pairs |
| XIAFLEX/XIAPEX | Investigator Assessment of Improvement With Treatment at Day 31 | Minimally worse | 3 Joint Pairs |
| XIAFLEX/XIAPEX | Investigator Assessment of Improvement With Treatment at Day 31 | Much worse | 0 Joint Pairs |
| XIAFLEX/XIAPEX | Investigator Assessment of Improvement With Treatment at Day 31 | Very much worse | 0 Joint Pairs |
| XIAFLEX/XIAPEX | Investigator Assessment of Improvement With Treatment at Day 31 | Not done | 20 Joint Pairs |
Secondary
Investigator Assessment of Improvement With Treatment at Day 61
Investigator's determined the degree of improvement in the severity of the subject's treated finger(s) compared with screening at the day 61 follow-up visit.
Time frame: Day 61
Population: Efficacy analysis was based on the mITT population; all enrolled subjects who received both AA4500 injections and had a post-injection efficacy measure. Ten subjects were granted special re-enrollment and had an additional joint pair treated on the contralateral hand. Assessment is based on simultaneously treated joint pairs.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| XIAFLEX/XIAPEX | Investigator Assessment of Improvement With Treatment at Day 61 | Very much improved | 382 Joint Pairs |
| XIAFLEX/XIAPEX | Investigator Assessment of Improvement With Treatment at Day 61 | Much improved | 263 Joint Pairs |
| XIAFLEX/XIAPEX | Investigator Assessment of Improvement With Treatment at Day 61 | Minimally improved | 62 Joint Pairs |
| XIAFLEX/XIAPEX | Investigator Assessment of Improvement With Treatment at Day 61 | No change | 7 Joint Pairs |
| XIAFLEX/XIAPEX | Investigator Assessment of Improvement With Treatment at Day 61 | Minimally worse | 2 Joint Pairs |
| XIAFLEX/XIAPEX | Investigator Assessment of Improvement With Treatment at Day 61 | Much worse | 0 Joint Pairs |
| XIAFLEX/XIAPEX | Investigator Assessment of Improvement With Treatment at Day 61 | Very much worse | 0 Joint Pairs |
| XIAFLEX/XIAPEX | Investigator Assessment of Improvement With Treatment at Day 61 | Not done | 8 Joint Pairs |
Secondary
Subject Assessment of Satisfaction With Treatment at Day 31
Subject's were asked to rate satisfaction with treatment at the day 31 follow-up visit
Time frame: Day 31
Population: Efficacy analysis was based on the mITT population; all enrolled subjects who received both AA4500 injections and had a post-injection efficacy measure. Ten subjects were granted special re-enrollment and had an additional joint pair treated on the contralateral hand. Assessment is based on simultaneously treated joint pairs.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| XIAFLEX/XIAPEX | Subject Assessment of Satisfaction With Treatment at Day 31 | Very satisfied | 461 Joint Pairs |
| XIAFLEX/XIAPEX | Subject Assessment of Satisfaction With Treatment at Day 31 | Quite satisfied | 198 Joint Pairs |
| XIAFLEX/XIAPEX | Subject Assessment of Satisfaction With Treatment at Day 31 | Neither satisfied nor dissatisfied | 38 Joint Pairs |
| XIAFLEX/XIAPEX | Subject Assessment of Satisfaction With Treatment at Day 31 | Quite dissatisfied | 9 Joint Pairs |
| XIAFLEX/XIAPEX | Subject Assessment of Satisfaction With Treatment at Day 31 | Very dissatisfied | 6 Joint Pairs |
| XIAFLEX/XIAPEX | Subject Assessment of Satisfaction With Treatment at Day 31 | Not done | 12 Joint Pairs |
Secondary
Subject Assessment of Satisfaction With Treatment at Day 61
Subject's were asked to rate satisfaction with treatment at the day 61 follow-up visit
Time frame: Day 61
Population: Efficacy analysis was based on the mITT population; all enrolled subjects who received both AA4500 injections and had a post-injection efficacy measure. Ten subjects were granted special re-enrollment and had an additional joint pair treated on the contralateral hand. Assessment is based on simultaneously treated joint pairs.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| XIAFLEX/XIAPEX | Subject Assessment of Satisfaction With Treatment at Day 61 | Very dissatisfied | 8 Joint Pairs |
| XIAFLEX/XIAPEX | Subject Assessment of Satisfaction With Treatment at Day 61 | Neither satisfied nor dissatisfied | 38 Joint Pairs |
| XIAFLEX/XIAPEX | Subject Assessment of Satisfaction With Treatment at Day 61 | Very satisfied | 496 Joint Pairs |
| XIAFLEX/XIAPEX | Subject Assessment of Satisfaction With Treatment at Day 61 | Quite satisfied | 167 Joint Pairs |
| XIAFLEX/XIAPEX | Subject Assessment of Satisfaction With Treatment at Day 61 | Quite dissatisfied | 11 Joint Pairs |
| XIAFLEX/XIAPEX | Subject Assessment of Satisfaction With Treatment at Day 61 | Not done | 4 Joint Pairs |