Phase 2a Dose-Ranging Study to Evaluate Safety and Effectiveness of AA4500 in Treatment of Dupuytren's Disease Nodules
Sponsor
Endo Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT02193828
Collaborator
(none)
76
11
4
5
6.9
1.4
Study Details
Study Description
Brief Summary
The objectives of this study are to assess the safety and effectiveness of AA4500 in treating palmar Dupuytren's disease nodules.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
Approximately 13 sites in the United States and Australia, approximately 90 study subjects.
After all pre-injection procedures are completed on day 1, eligible men and women will be randomized in a 1:1:1 ratio to dose group and then in a 4:1 ratio to treatment group. Study drug will be administered into a palmar nodule located on the selected hand.
AA4500 (collagenase clostridium histolyticum) 3 doses (low, medium, and high) after reconstitution with sterile diluent (0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride). Each dose of study drug will be injected into the nodule. The injection will be administered in 3 different volumes according to randomization.
Placebo after reconstitution with sterile diluent (0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride). Each dose of study drug will be injected into the nodule. The injection will be administered in 3 different volumes according to randomization.
Follow up visits for the evaluation of safety and efficacy will be required for all subjects on days 8, 29, and 57.
Study Design
Study Type:
Interventional
Actual Enrollment
:
76 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
A Phase 2a, Double-blind, Randomized, Placebo-Controlled, Dose-Ranging Study to Evaluate the Safety and Effectiveness of AA4500 in the Treatment of Dupuytren's Disease Nodules
Study Start Date
:
Jul 1, 2014
Actual Primary Completion Date
:
Dec 1, 2014
Actual Study Completion Date
:
Dec 1, 2014
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: AA4500 0.25 mg Collagenase clostridium histolyticum, single 0.25 mg injection |
Biological: Collagenase clostridium histolyticum
Single injection into nodule
Other Names:
|
| Experimental: AA4500 0.40 mg Collagenase clostridium histolyticum, single 0.40 mg injection |
Biological: Collagenase clostridium histolyticum
Single injection into nodule
Other Names:
|
| Experimental: AA4500 0.60 mg Collagenase clostridium histolyticum, single 0.60 mg injection |
Biological: Collagenase clostridium histolyticum
Single injection into nodule
Other Names:
|
| Placebo Comparator: Placebo Placebo, single 0.25 mg, 0.40 mg, or 0.60 mg injection |
Biological: Placebo
Single injection into nodule
|
Outcome Measures
Primary Outcome Measures
- Percent Change From Baseline in Surface Area and Volume of the Treated Nodule at Day 57 Using Caliper Measurements [Baseline, Day 57]
Percent change from baseline in surface area and volume of the treated nodule was determined from hand-held caliper measurements of the length and width of the nodule. Percent change = 100*(Day 57 area [or volume] - baseline area [or volume])/baseline area [or volume]. A negative value represents the improvement from baseline (decreased size) while a positive value represents worsening.
Secondary Outcome Measures
- Percent Change From Baseline in Surface Area and Volume of the Treated Nodule at Day 57 Using Ultrasound [Baseline, Day 57]
Percent change from baseline in surface area and volume of the treated nodule was determined from ultrasound measurements of the length, width, and depth of the nodule. Percent change = 100*(Day 57 area [or volume] - baseline area [or volume])/baseline area [or volume]. A negative value represents the improvement from baseline (decreased size) while a positive value represents worsening.
- Change From Baseline in Consistency of the Treated Nodules at Day 57 [Baseline, Day 57]
Investigators determined the consistency of the nodule through palpitation using a 5-point scale: 5 = hard (solid), 4 = firm throughout, 3 = moderate firmness, 2 = soft, and 1 = non-palpable. The change scores could range from +4 (greatest worsening in consistency) to -4 (greatest improvement in consistency); a negative change from baseline value reflects improvement from baseline (softening) while a positive value reflects worsening.
- Percent Change From Baseline in Hardness of the Treated Nodule at Day 57 [Baseline, Day 57]
A durometer was used to assess nodule hardness on a scale of 0 (soft) to 100 (hard). Percent change = 100*(Day 57 hardness - baseline hardness)/baseline hardness. A negative value represents the improvement from baseline (softening) while a positive value represents worsening.
- Change From Baseline in Nodular Pain of the Treated Nodule at Day 57 [Baseline, Day 57]
After the nodule was squeezed using a dynamometer, subjects were asked to rate the amount of pain they felt on an 11-point visual analog scale (VAS) from 0 (no pain or discomfort) to 10 (extreme pain or discomfort). A negative change from baseline value reflects improvement from baseline (less pain) while a positive value reflects worsening.
- Investigator Global Assessment of Improvement With Treatment [Day 57]
Investigators were asked to determine the degree of improvement in the subject's treated nodule compared with screening on a 7-point scale: 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse.
- Subject Satisfaction With Treatment [Day 57]
Subjects were asked to rate their satisfaction with treatment on a 5-point scale: 1 = very satisfied, 2 = quite satisfied, 3 = neither satisfied nor dissatisfied, 4 = quite dissatisfied, and 5 = very dissatisfied.
- Composite Responder Analysis [Day 57]
A composite responder is a subject who had an improved assessment [values of 1 (very much improved), 2 (much improved), or 3 (minimally improved)] on the investigator global assessment and had a satisfied assessment [values of 1 (very satisfied) or 2 (quite satisfied)] on the subject assessment.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Provide a signed and dated informed consent
-
Be a man or woman ≥ 18 years of age
-
Have a diagnosis of Dupuytren's disease AND have at least one palmar nodule on the selected hand that is:
-
Palpable
-
Measures between 0.5 cm and 2.0 cm in length and between 0.5 cm and 2.0 cm in width using hand-held calipers n
-
Not directly associated with a Dupuytren's cord
-
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)
-
Be able to comply with the study visit schedule as specified in the protocol
Exclusion Criteria:
-
Received steroid injections (eg, tri-amcinolone acetonide) on the selected nodule within 3 months before administration of study drug
-
Has a chronic muscular, neurological, or neuromuscular disorder that affects the hands
-
Has a known systemic allergy to collagenase or any other excipient of AA4500
-
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
-
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
-
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
-
Received an investigational drug within 30 days before injection of study drug
-
Is pregnant or intends on becoming pregnant during the study or is breastfeeding a child
-
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
-
Had surgery on the selected hand within 3 months before the screening visit
-
Has jewelry on the hand to be treated that cannot be removed
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Tucson Orthopaedic Institute | Tucson | Arizona | United States | 85712 |
| 2 | CORE Orthopaedic Medical Center | Encinitas | California | United States | 92024 |
| 3 | Marin Endocrine Care & Research, Inc. | Greenbrae | California | United States | 94904 |
| 4 | Brigid Freyne, MD, Inc. | Murrieta | California | United States | 92563 |
| 5 | Indiana Hand to Shoulder Center | Indianapolis | Indiana | United States | 46260 |
| 6 | State University of New York | Stony Brook | New York | United States | 11794 |
| 7 | OrthoCarolina Research Institute, Inc. | Charlotte | North Carolina | United States | 28207 |
| 8 | Orthopedic and Reconstructive Center | Oklahoma City | Oklahoma | United States | 73109 |
| 9 | Blair Orthopedic Associates, Inc. | Altoona | Pennsylvania | United States | 16602 |
| 10 | Brisbane Hand & Upper Limb Clinic | Brisbane | Queensland | Australia | 4000 |
| 11 | Houston Medical | Kippa Ring | Queensland | Australia | 4021 |
Sponsors and Collaborators
- Endo Pharmaceuticals
Investigators
- Study Director: Veronica Urdaneta, MD MPH, Endo Pharmaceuticals
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Endo Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT02193828
Other Study ID Numbers:
- AUX-CC-750
First Posted:
Jul 18, 2014
Last Update Posted:
Oct 5, 2017
Last Verified:
Sep 1, 2017
Keywords provided by Endo Pharmaceuticals
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | AA4500 0.60 mg | AA4500 0.40 mg | AA4500 0.25 mg | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Collagenase clostridium histolyticum (AA4500), single 0.60 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.40 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.25 mg injection into the nodule | Placebo, single 0.25 mg, 0.40 mg, or 0.60 mg injection into the nodule |
| Period Title: Overall Study | ||||
| STARTED | 18 | 18 | 23 | 17 |
| COMPLETED | 18 | 18 | 22 | 16 |
| NOT COMPLETED | 0 | 0 | 1 | 1 |
Baseline Characteristics
| Arm/Group Title | AA4500 0.60 mg | AA4500 0.40 mg | AA4500 0.25 mg | Placebo | Total |
|---|---|---|---|---|---|
| Arm/Group Description | Collagenase clostridium histolyticum (AA4500), single 0.60 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.40 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.25 mg injection into the nodule | Placebo, single 0.25 mg, 0.40 mg, or 0.60 mg injection into the nodule | Total of all reporting groups |
| Overall Participants | 18 | 18 | 22 | 17 | 75 |
| Age (Count of Participants) | |||||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
13
72.2%
|
12
66.7%
|
16
72.7%
|
11
64.7%
|
52
69.3%
|
| >=65 years |
5
27.8%
|
6
33.3%
|
6
27.3%
|
6
35.3%
|
23
30.7%
|
| Age (years) [Median (Full Range) ] | |||||
| Median (Full Range) [years] |
62.0
|
60.0
|
57.0
|
58.0
|
58.0
|
| Sex: Female, Male (Count of Participants) | |||||
| Female |
6
33.3%
|
10
55.6%
|
11
50%
|
7
41.2%
|
34
45.3%
|
| Male |
12
66.7%
|
8
44.4%
|
11
50%
|
10
58.8%
|
41
54.7%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||||
| Hispanic or Latino |
1
5.6%
|
1
5.6%
|
1
4.5%
|
1
5.9%
|
4
5.3%
|
| Not Hispanic or Latino |
17
94.4%
|
17
94.4%
|
21
95.5%
|
16
94.1%
|
71
94.7%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |||||
| American Indian or Alaska Native |
0
0%
|
1
5.6%
|
0
0%
|
0
0%
|
1
1.3%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| White |
18
100%
|
17
94.4%
|
22
100%
|
17
100%
|
74
98.7%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | |||||
| United States |
12
66.7%
|
10
55.6%
|
14
63.6%
|
12
70.6%
|
48
64%
|
| Australia |
6
33.3%
|
8
44.4%
|
8
36.4%
|
5
29.4%
|
27
36%
|
Outcome Measures
| Title | Percent Change From Baseline in Surface Area and Volume of the Treated Nodule at Day 57 Using Caliper Measurements |
|---|---|
| Description | Percent change from baseline in surface area and volume of the treated nodule was determined from hand-held caliper measurements of the length and width of the nodule. Percent change = 100*(Day 57 area [or volume] - baseline area [or volume])/baseline area [or volume]. A negative value represents the improvement from baseline (decreased size) while a positive value represents worsening. |
| Time Frame | Baseline, Day 57 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis based on Modified Intent-to-Treat (mITT) population; all randomized subjects who received study medication and had pre- and post-baseline nodule measurements for ultrasound and calipers. Analytical outliers (subjects whose percent change in ultrasound volume was greater than the 75th percentile + 3× the interquartile range) were excluded. |
| Arm/Group Title | AA4500 0.60 mg | AA4500 0.40 mg | AA4500 0.25 mg | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Collagenase clostridium histolyticum (AA4500), single 0.60 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.40 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.25 mg injection into the nodule | Placebo, single 0.25 mg, 0.40 mg, or 0.60 mg injection into the nodule |
| Measure Participants | 17 | 18 | 20 | 15 |
| Surface Area |
-81.61
(20.251)
|
-80.11
(21.459)
|
-58.30
(29.849)
|
-41.76
(32.445)
|
| Volume |
-89.03
(15.016)
|
-87.58
(16.372)
|
-68.15
(33.859)
|
-49.13
(36.736)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.60 mg, AA4500 0.40 mg, AA4500 0.25 mg, Placebo |
|---|---|---|
| Comments | For surface area | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.60 mg, Placebo |
|---|---|---|
| Comments | For surface area | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.40 mg, Placebo |
|---|---|---|
| Comments | For surface area | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.25 mg, Placebo |
|---|---|---|
| Comments | For surface area | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0713 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.60 mg, AA4500 0.40 mg, AA4500 0.25 mg, Placebo |
|---|---|---|
| Comments | For volume | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0002 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.60 mg, Placebo |
|---|---|---|
| Comments | For volume | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0001 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
Statistical Analysis 7
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.40 mg, Placebo |
|---|---|---|
| Comments | For volume | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0001 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
Statistical Analysis 8
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.25 mg, Placebo |
|---|---|---|
| Comments | For volume | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0446 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
| Title | Percent Change From Baseline in Surface Area and Volume of the Treated Nodule at Day 57 Using Ultrasound |
|---|---|
| Description | Percent change from baseline in surface area and volume of the treated nodule was determined from ultrasound measurements of the length, width, and depth of the nodule. Percent change = 100*(Day 57 area [or volume] - baseline area [or volume])/baseline area [or volume]. A negative value represents the improvement from baseline (decreased size) while a positive value represents worsening. |
| Time Frame | Baseline, Day 57 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis based on mITT population; all randomized subjects who received study medication and had pre- and post-baseline nodule measurements for ultrasound and calipers. Analytical outliers (subjects whose percent change in ultrasound volume was greater than the 75th percentile + 3× the interquartile range) were excluded. |
| Arm/Group Title | AA4500 0.60 mg | AA4500 0.40 mg | AA4500 0.25 mg | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Collagenase clostridium histolyticum (AA4500), single 0.60 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.40 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.25 mg injection into the nodule | Placebo, single 0.25 mg, 0.40 mg, or 0.60 mg injection into the nodule |
| Measure Participants | 17 | 18 | 20 | 15 |
| Surface Area |
-34.23
(41.353)
|
-19.37
(39.658)
|
-10.30
(41.696)
|
-4.54
(54.784)
|
| Volume |
-40.99
(46.612)
|
-13.01
(68.804)
|
-9.52
(60.156)
|
-7.19
(69.877)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.60 mg, AA4500 0.40 mg, AA4500 0.25 mg, Placebo |
|---|---|---|
| Comments | For surface area | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .2431 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.60 mg, Placebo |
|---|---|---|
| Comments | For surface area | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0625 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.40 mg, Placebo |
|---|---|---|
| Comments | For surface area | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .3409 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.25 mg, Placebo |
|---|---|---|
| Comments | For surface area | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .7040 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.60 mg, AA4500 0.40 mg, AA4500 0.25 mg, Placebo |
|---|---|---|
| Comments | For volume | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.3556 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.60 mg, Placebo |
|---|---|---|
| Comments | For volume | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .1275 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
Statistical Analysis 7
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.40 mg, Placebo |
|---|---|---|
| Comments | For volume | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .7883 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
Statistical Analysis 8
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.25 mg, Placebo |
|---|---|---|
| Comments | For volume | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .9123 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
| Title | Change From Baseline in Consistency of the Treated Nodules at Day 57 |
|---|---|
| Description | Investigators determined the consistency of the nodule through palpitation using a 5-point scale: 5 = hard (solid), 4 = firm throughout, 3 = moderate firmness, 2 = soft, and 1 = non-palpable. The change scores could range from +4 (greatest worsening in consistency) to -4 (greatest improvement in consistency); a negative change from baseline value reflects improvement from baseline (softening) while a positive value reflects worsening. |
| Time Frame | Baseline, Day 57 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis based on mITT population; all randomized subjects who received an injection of study medication and had pre- and post-baseline nodule measurements for both ultrasound and calipers. Subjects with an incomplete assessment (not done) on Day 57 were excluded. |
| Arm/Group Title | AA4500 0.60 mg | AA4500 0.40 mg | AA4500 0.25 mg | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Collagenase clostridium histolyticum (AA4500), single 0.60 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.40 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.25 mg injection into the nodule | Placebo, single 0.25 mg, 0.40 mg, or 0.60 mg injection into the nodule |
| Measure Participants | 16 | 17 | 22 | 15 |
| Mean (Standard Deviation) [units on a scale] |
-1.9
(0.93)
|
-1.9
(1.05)
|
-1.2
(1.10)
|
-0.3
(0.96)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.60 mg, AA4500 0.40 mg, AA4500 0.25 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0002 |
| Comments | ||
| Method | Kruskal-Wallis | |
| Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.60 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | Wilcoxon (Mann-Whitney) | |
| Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.40 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0002 |
| Comments | ||
| Method | Wilcoxon (Mann-Whitney) | |
| Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.25 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0139 |
| Comments | ||
| Method | Wilcoxon (Mann-Whitney) | |
| Comments | ||
| Title | Percent Change From Baseline in Hardness of the Treated Nodule at Day 57 |
|---|---|
| Description | A durometer was used to assess nodule hardness on a scale of 0 (soft) to 100 (hard). Percent change = 100*(Day 57 hardness - baseline hardness)/baseline hardness. A negative value represents the improvement from baseline (softening) while a positive value represents worsening. |
| Time Frame | Baseline, Day 57 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis based on mITT population; all randomized subjects who received an injection of study medication and had pre- and post-baseline nodule measurements for both ultrasound and calipers. Subjects with an incomplete assessment (not done) on Day 57 were excluded. |
| Arm/Group Title | AA4500 0.60 mg | AA4500 0.40 mg | AA4500 0.25 mg | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Collagenase clostridium histolyticum (AA4500), single 0.60 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.40 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.25 mg injection into the nodule | Placebo, single 0.25 mg, 0.40 mg, or 0.60 mg injection into the nodule |
| Measure Participants | 16 | 17 | 22 | 15 |
| Mean (Standard Deviation) [percentage of change] |
-17.05
(15.584)
|
-30.40
(24.930)
|
-17.87
(22.265)
|
4.80
(23.959)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.60 mg, AA4500 0.40 mg, AA4500 0.25 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0004 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.60 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0075 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.40 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.25 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0031 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
| Title | Change From Baseline in Nodular Pain of the Treated Nodule at Day 57 |
|---|---|
| Description | After the nodule was squeezed using a dynamometer, subjects were asked to rate the amount of pain they felt on an 11-point visual analog scale (VAS) from 0 (no pain or discomfort) to 10 (extreme pain or discomfort). A negative change from baseline value reflects improvement from baseline (less pain) while a positive value reflects worsening. |
| Time Frame | Baseline, Day 57 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis based on mITT population; all randomized subjects who received an injection of study medication and had pre- and post-baseline nodule measurements for both ultrasound and calipers. Subjects with an incomplete assessment (not done) on Day 57 were excluded. |
| Arm/Group Title | AA4500 0.60 mg | AA4500 0.40 mg | AA4500 0.25 mg | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Collagenase clostridium histolyticum (AA4500), single 0.60 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.40 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.25 mg injection into the nodule | Placebo, single 0.25 mg, 0.40 mg, or 0.60 mg injection into the nodule |
| Measure Participants | 16 | 17 | 22 | 15 |
| Mean (Standard Deviation) [units on a scale] |
-0.8
(1.97)
|
-1.6
(2.21)
|
-1.7
(2.57)
|
-0.5
(1.77)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.60 mg, AA4500 0.40 mg, AA4500 0.25 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .3135 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.60 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .7249 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.40 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .1573 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.25 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .1234 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
| Title | Investigator Global Assessment of Improvement With Treatment |
|---|---|
| Description | Investigators were asked to determine the degree of improvement in the subject's treated nodule compared with screening on a 7-point scale: 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. |
| Time Frame | Day 57 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis based on mITT population; all randomized subjects who received an injection of study medication and had pre- and post-baseline nodule measurements for both ultrasound and calipers. |
| Arm/Group Title | AA4500 0.60 mg | AA4500 0.40 mg | AA4500 0.25 mg | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Collagenase clostridium histolyticum (AA4500), single 0.60 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.40 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.25 mg injection into the nodule | Placebo, single 0.25 mg, 0.40 mg, or 0.60 mg injection into the nodule |
| Measure Participants | 18 | 18 | 22 | 16 |
| Mean (Standard Deviation) [units on a scale] |
1.7
(0.84)
|
1.7
(0.75)
|
2.5
(1.10)
|
3.0
(1.15)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.60 mg, AA4500 0.40 mg, AA4500 0.25 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0006 |
| Comments | ||
| Method | Kruskal-Wallis | |
| Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.60 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0014 |
| Comments | ||
| Method | Wilcoxon (Mann-Whitney) | |
| Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.40 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0012 |
| Comments | ||
| Method | Wilcoxon (Mann-Whitney) | |
| Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.25 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .1298 |
| Comments | ||
| Method | Wilcoxon (Mann-Whitney) | |
| Comments | ||
| Title | Subject Satisfaction With Treatment |
|---|---|
| Description | Subjects were asked to rate their satisfaction with treatment on a 5-point scale: 1 = very satisfied, 2 = quite satisfied, 3 = neither satisfied nor dissatisfied, 4 = quite dissatisfied, and 5 = very dissatisfied. |
| Time Frame | Day 57 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis based on mITT population; all randomized subjects who received an injection of study medication and had pre- and post-baseline nodule measurements for both ultrasound and calipers. |
| Arm/Group Title | AA4500 0.60 mg | AA4500 0.40 mg | AA4500 0.25 mg | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Collagenase clostridium histolyticum (AA4500), single 0.60 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.40 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.25 mg injection into the nodule | Placebo, single 0.25 mg, 0.40 mg, or 0.60 mg injection into the nodule |
| Measure Participants | 18 | 18 | 22 | 16 |
| Mean (Standard Deviation) [units on a scale] |
1.5
(0.79)
|
1.6
(0.85)
|
2.3
(1.17)
|
2.8
(1.34)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.60 mg, AA4500 0.40 mg, AA4500 0.25 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0048 |
| Comments | ||
| Method | Kruskal-Wallis | |
| Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.60 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0034 |
| Comments | ||
| Method | Wilcoxon (Mann-Whitney) | |
| Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.40 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0079 |
| Comments | ||
| Method | Wilcoxon (Mann-Whitney) | |
| Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.25 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .3216 |
| Comments | ||
| Method | Wilcoxon (Mann-Whitney) | |
| Comments | ||
| Title | Composite Responder Analysis |
|---|---|
| Description | A composite responder is a subject who had an improved assessment [values of 1 (very much improved), 2 (much improved), or 3 (minimally improved)] on the investigator global assessment and had a satisfied assessment [values of 1 (very satisfied) or 2 (quite satisfied)] on the subject assessment. |
| Time Frame | Day 57 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis based on mITT population; all randomized subjects who received an injection of study medication and had pre- and post-baseline nodule measurements for both ultrasound and calipers. |
| Arm/Group Title | AA4500 0.60 mg | AA4500 0.40 mg | AA4500 0.25 mg | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Collagenase clostridium histolyticum (AA4500), single 0.60 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.40 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.25 mg injection into the nodule | Placebo, single 0.25 mg, 0.40 mg, or 0.60 mg injection into the nodule |
| Measure Participants | 18 | 18 | 22 | 16 |
| Responder: Yes |
14
77.8%
|
16
88.9%
|
12
54.5%
|
6
35.3%
|
| Responder: No |
4
22.2%
|
2
11.1%
|
10
45.5%
|
10
58.8%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.60 mg, AA4500 0.40 mg, AA4500 0.25 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0065 |
| Comments | ||
| Method | Fisher Exact | |
| Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.60 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0349 |
| Comments | ||
| Method | Fisher Exact | |
| Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.40 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .0033 |
| Comments | ||
| Method | Fisher Exact | |
| Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | AA4500 0.25 mg, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .3423 |
| Comments | ||
| Method | Fisher Exact | |
| Comments | ||
Adverse Events
| Time Frame | Adverse events were collected from enrollment through the end of the study (Day 57). | |||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Adverse events are reported for the Safety population; all randomized subjects who received an injection of study medication. | |||||||
| Arm/Group Title | AA4500 0.60 mg | AA4500 0.40 mg | AA4500 0.25 mg | Placebo | ||||
| Arm/Group Description | Collagenase clostridium histolyticum (AA4500), single 0.60 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.40 mg injection into the nodule | Collagenase clostridium histolyticum (AA4500), single 0.25 mg injection into the nodule | Placebo, single 0.25 mg, 0.40 mg, or 0.60 mg injection into the nodule | ||||
All Cause Mortality |
||||||||
| AA4500 0.60 mg | AA4500 0.40 mg | AA4500 0.25 mg | Placebo | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | / (NaN) | ||||
Serious Adverse Events |
||||||||
| AA4500 0.60 mg | AA4500 0.40 mg | AA4500 0.25 mg | Placebo | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/18 (0%) | 0/18 (0%) | 0/22 (0%) | 0/17 (0%) | ||||
Other (Not Including Serious) Adverse Events |
||||||||
| AA4500 0.60 mg | AA4500 0.40 mg | AA4500 0.25 mg | Placebo | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 17/18 (94.4%) | 18/18 (100%) | 21/22 (95.5%) | 7/17 (41.2%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Lymphadenopathy | 1/18 (5.6%) | 0/18 (0%) | 0/22 (0%) | 0/17 (0%) | ||||
| Gastrointestinal disorders | ||||||||
| Nausea | 0/18 (0%) | 1/18 (5.6%) | 0/22 (0%) | 0/17 (0%) | ||||
| General disorders | ||||||||
| Axillary pain | 4/18 (22.2%) | 1/18 (5.6%) | 6/22 (27.3%) | 0/17 (0%) | ||||
| Injection site bruising | 6/18 (33.3%) | 4/18 (22.2%) | 5/22 (22.7%) | 0/17 (0%) | ||||
| Injection site haemorrhage | 1/18 (5.6%) | 0/18 (0%) | 2/22 (9.1%) | 0/17 (0%) | ||||
| Injection site hypoaesthesia | 1/18 (5.6%) | 0/18 (0%) | 0/22 (0%) | 0/17 (0%) | ||||
| Injection site oedema | 2/18 (11.1%) | 0/18 (0%) | 2/22 (9.1%) | 0/17 (0%) | ||||
| Injection site pain | 2/18 (11.1%) | 4/18 (22.2%) | 4/22 (18.2%) | 0/17 (0%) | ||||
| Injection site pruritus | 2/18 (11.1%) | 3/18 (16.7%) | 2/22 (9.1%) | 1/17 (5.9%) | ||||
| Injection site swelling | 0/18 (0%) | 4/18 (22.2%) | 5/22 (22.7%) | 0/17 (0%) | ||||
| Local swelling | 10/18 (55.6%) | 7/18 (38.9%) | 8/22 (36.4%) | 3/17 (17.6%) | ||||
| Localised oedema | 1/18 (5.6%) | 1/18 (5.6%) | 0/22 (0%) | 0/17 (0%) | ||||
| Pain | 0/18 (0%) | 0/18 (0%) | 0/22 (0%) | 1/17 (5.9%) | ||||
| Tenderness | 1/18 (5.6%) | 0/18 (0%) | 1/22 (4.5%) | 0/17 (0%) | ||||
| Injury, poisoning and procedural complications | ||||||||
| Contusion | 9/18 (50%) | 9/18 (50%) | 13/22 (59.1%) | 1/17 (5.9%) | ||||
| Injection related reaction | 1/18 (5.6%) | 0/18 (0%) | 1/22 (4.5%) | 0/17 (0%) | ||||
| Investigations | ||||||||
| Liver function test abnormal | 1/18 (5.6%) | 0/18 (0%) | 0/22 (0%) | 0/17 (0%) | ||||
| Musculoskeletal and connective tissue disorders | ||||||||
| Arthralgia | 0/18 (0%) | 0/18 (0%) | 0/22 (0%) | 1/17 (5.9%) | ||||
| Arthritis | 0/18 (0%) | 0/18 (0%) | 0/22 (0%) | 1/17 (5.9%) | ||||
| Dupuytren's contracture | 1/18 (5.6%) | 0/18 (0%) | 0/22 (0%) | 0/17 (0%) | ||||
| Joint range of motion decreased | 0/18 (0%) | 1/18 (5.6%) | 0/22 (0%) | 0/17 (0%) | ||||
| Musculoskeletal pain | 0/18 (0%) | 0/18 (0%) | 0/22 (0%) | 1/17 (5.9%) | ||||
| Pain in extremity | 7/18 (38.9%) | 10/18 (55.6%) | 10/22 (45.5%) | 1/17 (5.9%) | ||||
| Pain in jaw | 1/18 (5.6%) | 0/18 (0%) | 0/22 (0%) | 0/17 (0%) | ||||
| Nervous system disorders | ||||||||
| Headache | 0/18 (0%) | 0/18 (0%) | 0/22 (0%) | 1/17 (5.9%) | ||||
| Skin and subcutaneous tissue disorders | ||||||||
| Blister | 0/18 (0%) | 1/18 (5.6%) | 0/22 (0%) | 0/17 (0%) | ||||
| Blood blister | 1/18 (5.6%) | 1/18 (5.6%) | 0/22 (0%) | 0/17 (0%) | ||||
| Night sweats | 1/18 (5.6%) | 0/18 (0%) | 0/22 (0%) | 0/17 (0%) | ||||
| Pruritus | 1/18 (5.6%) | 2/18 (11.1%) | 2/22 (9.1%) | 0/17 (0%) | ||||
| Rash | 0/18 (0%) | 1/18 (5.6%) | 0/22 (0%) | 0/17 (0%) | ||||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Results Point of Contact
| Name/Title | Clinical Trial Coordinator |
|---|---|
| Organization | Endo Pharmaceuticals, Inc. |
| Phone | |
| clinicalsite.inquiries@endo.com |
Responsible Party:
Endo Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT02193828
Other Study ID Numbers:
- AUX-CC-750
First Posted:
Jul 18, 2014
Last Update Posted:
Oct 5, 2017
Last Verified:
Sep 1, 2017