Clinical Trial Results:
A Phase 3b open-label, historically-controlled study to assess the safety and efficacy of two concurrent injections of AA4500 in adult subjects with multiple Dupuytren’s contractures with palpable cords
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Summary
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EudraCT number |
2012-004091-19 |
Trial protocol |
SE GB DK |
Global end of trial date |
12 Jul 2013
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Results information
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Results version number |
v1(current) |
This version publication date |
10 Feb 2016
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First version publication date |
12 Jul 2015
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
AUX-CC-867
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01674634 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Auxilium Pharmaceuticals, Inc.
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Sponsor organisation address |
1400 Atwater Drive, Malvern, United States, PA 19355
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Public contact |
Veronica Urdaneta, MD, MPH, Auxilium Pharmaceuticals, Inc
1400 Atwater Drive
Malvern, PA 19355, 001 4842167721, Urdaneta.Veronica@endo.com
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Scientific contact |
Veronica Urdaneta, MD, MPH, Auxilium Pharmaceuticals, Inc
1400 Atwater Drive
Malvern, PA 19355, 001 4842167721, Urdaneta.Veronica@endo.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
12 Jul 2013
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
12 Jul 2013
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Jul 2013
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this study was to assess the safety of two concurrent injections of AA4500 0.58 mg (one injection per joint) 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 SAEs (tendon rupture/ligament injury and anaphylaxis) to historical rates of the same in clinical studies and post-marketing commercial use (ie, historical controls).
The secondary objective was to evaluate the efficacy of two concurrent injections of AA4500 0.58 mg (one injection per joint) into the same hand.
An additional objective was to evaluate the efficacy and safety of two concurrent injections of AA4500 0.58 mg (one injection per joint) in the same hand based upon the time between injection and finger extension procedure (ie, 24 hours, 48 hours or 72 hours).
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Protection of trial subjects |
Care After Injection
In order to evaluate the subject for possible immediate immunological AEs, the subject remained in direct observation of medical personnel who were skilled in the management of acute allergic reactions for the first 20 minutes after receiving an injection of study drug. A subject may have been discharged from the study unit after a 60-minute observation provided:
• The subject exhibited no sign of an immunological or other significant systemic or local AE.
• The subject’s vital signs remained stable throughout the 60-minute observation period.
Subjects were instructed not to flex or extend the fingers on the treated hand for 12 hours after injection to prevent extravasation of AA4500 out of the cord. A soft bulky gauze dressing was applied to the treated hand. The dressing served as a reminder to the subject not to move the treated hand. Subjects were instructed when to remove the dressing and to inspect the treated hand for edema, sensation, and movement. The subject was instructed to contact the investigator immediately if any problems were noticed. Subjects were instructed not to manipulate the injected finger(s) themselves.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
12 Sep 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Sweden: 50
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Country: Number of subjects enrolled |
United Kingdom: 34
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Country: Number of subjects enrolled |
Denmark: 87
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Country: Number of subjects enrolled |
Australia: 196
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Country: Number of subjects enrolled |
New Zealand: 70
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Country: Number of subjects enrolled |
United States: 278
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Worldwide total number of subjects |
715
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EEA total number of subjects |
171
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
348
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From 65 to 84 years |
360
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85 years and over |
7
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Recruitment
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Recruitment details |
The recruitment period was September 2012 to April 2013. Patients were recruited in Europe (Sweden, Denmark and United Kingdom) , Australia, New Zealand and the United States. | ||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Provide a signed and dated informed consent. Male or female ≥18 years of age. Diagnosis of Dupuytren’s disease with at least two fixed flexion contractures on the same hand that were ≥20º in PIP and/or MP joints in fingers, other than the thumbs, which were caused by palpable cord(s) suitable for treatment. Have a positive “table top test”. | ||||||||||||||||||||||||
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Period 1
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Period 1 title |
Baseline
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||
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Arms
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Arm title
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XIAFLEX/XIAPEX | ||||||||||||||||||||||||
Arm description |
XIAFLEX / XIAPEX injection (0.58 mg after reconstitution with sterile diluent [0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride]) | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
XIAFLEX/XIAPEX
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Investigational medicinal product code |
AA4500
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Other name |
Collagenase Clostridium histolyticum
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Pharmaceutical forms |
Injection
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Routes of administration |
Intracartilaginous use
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Dosage and administration details |
XIAFLEX / XIAPEX injection (0.58 mg after reconstitution with sterile diluent [0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride]).
Study drug was administered in a volume of 0.25 mL for MP joints and 0.20 mL for PIP joints. Study drug was injected directly into the cord using a 26 or 27 gauge ½ inch (13 mm) needle.
On Day 1 of this study, each subject received two concurrent injections of AA4500 0.58 mg (one injection per joint) into the same hand (selected hand). After completing the Day 61 follow-up visit, 10 subjects with bilateral disease were granted special permission to re-enroll into the study and receive a second series of two injections in their contralateral hand.
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Period 2
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Period 2 title |
Treatment/Assessment/Follow up
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Is this the baseline period? |
No | ||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
No
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Arm title
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XIAFLEX/XIAPEX | ||||||||||||||||||||||||
Arm description |
XIAFLEX / XIAPEX injection (0.58 mg after reconstitution with sterile diluent [0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride]) | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
XIAFLEX/XIAPEX
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Investigational medicinal product code |
AA4500
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Other name |
Collagenase Clostridium histolyticum
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Pharmaceutical forms |
Injection
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Routes of administration |
Intracartilaginous use
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Dosage and administration details |
XIAFLEX / XIAPEX injection (0.58 mg after reconstitution with sterile diluent [0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride]).
Study drug was administered in a volume of 0.25 mL for MP joints and 0.20 mL for PIP joints. Study drug was injected directly into the cord using a 26 or 27 gauge ½ inch (13 mm) needle.
On Day 1 of this study, each subject received two concurrent injections of AA4500 0.58 mg (one injection per joint) into the same hand (selected hand). After completing the Day 61 follow-up visit, 10 subjects with bilateral disease were granted special permission to re-enroll into the study and receive a second series of two injections in their contralateral hand.
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Arm title
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XIAFLEX/XIAPEX MP Joint | ||||||||||||||||||||||||
Arm description |
AA4500 (collagenase clostridium histolyticum); 0.58 mg injection in the metacarpophalangeal (MP) joint cord. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
XIAFLEX/XIAPEX
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Investigational medicinal product code |
AA4500
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Other name |
Collagenase Clostridium histolyticum
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
XIAFLEX / XIAPEX injection (0.58 mg after reconstitution with sterile diluent [0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride]).
Study drug was administered in a volume of 0.25 mL for MP joints and 0.20 mL for PIP joints. Study drug was injected directly into the cord using a 26 or 27 gauge ½ inch (13 mm) needle.
On Day 1 of this study, each subject received two concurrent injections of AA4500 0.58 mg (one injection per joint) into the same hand (selected hand). After completing the Day 61 follow-up visit, 10 subjects with bilateral disease were granted special permission to re-enroll into the study and receive a second series of two injections in their contralateral hand.
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Arm title
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XIAFLEX/XIAPEX PIP Joint | ||||||||||||||||||||||||
Arm description |
AA4500 (collagenase clostridium histolyticum); 0.58 mg injection in the proximal interphalangeal (PIP) joint cord. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
XIAFLEX/XIAPEX
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Investigational medicinal product code |
AA4500
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Other name |
Collagenase Clostridium histolyticum
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
XIAFLEX / XIAPEX injection (0.58 mg after reconstitution with sterile diluent [0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride]).
Study drug was administered in a volume of 0.25 mL for MP joints and 0.20 mL for PIP joints. Study drug was injected directly into the cord using a 26 or 27 gauge ½ inch (13 mm) needle.
On Day 1 of this study, each subject received two concurrent injections of AA4500 0.58 mg (one injection per joint) into the same hand (selected hand). After completing the Day 61 follow-up visit, 10 subjects with bilateral disease were granted special permission to re-enroll into the study and receive a second series of two injections in their contralateral hand.
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Baseline characteristics reporting groups
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Reporting group title |
Baseline
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
XIAFLEX/XIAPEX
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Reporting group description |
XIAFLEX / XIAPEX injection (0.58 mg after reconstitution with sterile diluent [0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride]) | ||
Reporting group title |
XIAFLEX/XIAPEX
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Reporting group description |
XIAFLEX / XIAPEX injection (0.58 mg after reconstitution with sterile diluent [0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride]) | ||
Reporting group title |
XIAFLEX/XIAPEX MP Joint
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Reporting group description |
AA4500 (collagenase clostridium histolyticum); 0.58 mg injection in the metacarpophalangeal (MP) joint cord. | ||
Reporting group title |
XIAFLEX/XIAPEX PIP Joint
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Reporting group description |
AA4500 (collagenase clostridium histolyticum); 0.58 mg injection in the proximal interphalangeal (PIP) joint cord. | ||
Subject analysis set title |
Safety Population
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The safety population was defined as all enrolled subjects who had at least one AA4500 injection. All safety parameters were summarized based on this population.
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Subject analysis set title |
mITT
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
The mITT population was defined as all enrolled subjects who had both AA4500 injections and had at least one post-injection efficacy measurement of either fixed flexion contracture or a global assessment. All efficacy parameters were summarized based on this population.
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Subject analysis set title |
Per-Protocol Population
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The PP population was defined as all safety subjects who did not have any major protocol deviation.
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End point title |
Percent Change From Baseline in Total Fixed Flexion [1] | ||||||||
End point description |
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.
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End point type |
Primary
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End point timeframe |
Baseline, Day 31
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The statistical methods were composed entirely of summary tables with descriptive statistics. There were no explicit hypotheses being tested in this study. |
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| Notes [2] - Number of Treated Joint Pairs Analysed =724 |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Total Range of Motion [3] | ||||||||
End point description |
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.
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End point type |
Primary
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End point timeframe |
Baseline, Day 31
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The statistical methods were composed entirely of summary tables with descriptive statistics. There were no explicit hypotheses being tested in this study. |
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| Notes [4] - Number of Treated Joint Pairs Analysed = 724 |
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| No statistical analyses for this end point | |||||||||
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End point title |
Clinical Success | |||||||||||||||
End point description |
Clinical success is defined as reduction of FFC of a treated joint to within 0-5 degrees of normal within 30 days of injection
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End point type |
Secondary
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End point timeframe |
Within 30 days.
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| Notes [5] - Number of treated joints analysed=896 [6] - Number of treated joints analysed = 552 |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Clinical Improvement | |||||||||||||||
End point description |
Clinical improvement is defined as a reduction of FFC by 50% or greater of the baseline value within 30 days of injection.
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End point type |
Secondary
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End point timeframe |
Within 30 days.
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| Notes [7] - Number of treated joints analysed = 896 [8] - Number of treated joints analysed = 552 |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Subject Assessment of Satisfaction With Treatment at Day 31 | ||||||||||||||||||
End point description |
Subject's were asked to rate satisfaction with treatment at the day 31 follow-up visit
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End point type |
Secondary
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End point timeframe |
Day 31
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| Notes [9] - Number of Treated Joint Pairs Analysed =724 |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Subject Assessment of Satisfaction With Treatment at Day 61 | ||||||||||||||||||
End point description |
Subject's were asked to rate satisfaction with treatment at the day 61 follow-up visit
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End point type |
Secondary
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End point timeframe |
Day 61
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| Notes [10] - Number of Treated Joint Pairs Analysed =724 |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Investigator Assessment of Improvement With Treatment at Day 31 | ||||||||||||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Day 31
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| Notes [11] - Number of Treated Joint Pairs Analysed=724 |
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Investigator Assessment of Improvement With Treatment at Day 61 | ||||||||||||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Day 61
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| Notes [12] - Number of Treated Joint Pairs Analysed= 724 |
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Change From Baseline for Unité Rhumatologique Des Affections de la Main Scale at Day 31 | ||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 31
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| Notes [13] - Number of Treated Joint Pairs Analysed=724 |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline for Unité Rhumatologique Des Affections de la Main Scale at Day 61 | ||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 61
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| Notes [14] - Number of Treated Joint Pairs Analysed =724 |
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From screening visit to end of study.
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Adverse event reporting additional description |
AA4500 (collagenase clostridium histolyticum): 2 concurrent 0.58 mg injections (1 injection per joint) in the same hand
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15.1
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Reporting groups
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Reporting group title |
XIAFLEX/XIAPEX
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Reporting group description |
XIAFLEX / XIAPEX injection (0.58 mg after reconstitution with sterile diluent [0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride]) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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14 Dec 2012 |
Clarified that the study period of 60 days for the core study was followed by an optional 90-day additional treatment period.
Added that subjects who required additional treatment in the treated hand may have received up to three additional injections of AA4500 according to the XIAFLEX package insert.
Updated that the end of the core study occurred when the last subject completed the Day 61 follow-up visit. The end of the completed study occurred when the last subject completed the Day 30 visit after the last additional injection.
Added that AEs, including targeted AEs, were to be captured on the eCRF. In addition, the date of each additional injection and the finger and joint treated were to be recorded on the eCRF. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
