Clinical Trial Results:
Retreatment of recurrent contractures in joints effectively treated with AA4500 (collagenase clostridium histolyticum [XIAFLEX®/XIAPEX®]) in an Auxilium-sponsored Phase 3 Study in the United States, Australia, and Europe.
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Summary
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EudraCT number |
2011-005065-21 |
Trial protocol |
SE GB |
Global end of trial date |
07 Oct 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 |
09 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-862
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01498640 | ||
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
USA, 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
USA, 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 |
07 Oct 2013
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
07 Oct 2013
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Global end of trial reached? |
Yes
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Global end of trial date |
07 Oct 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 objectives of this study were to assess the safety and efficacy of AA4500 in the retreatment of recurrent contractures in joints that were effectively treated with AA4500 in a previous Auxilium-sponsored Phase 3 study.
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Protection of trial subjects |
Care After Injection
To evaluate the subject for possible immediate immunological AEs, the subject was to remain 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 could have been discharged from the study unit after a 60-minute observation period, provided:
• The subject exhibited no sign of an immunological or other significant systemic or local AE and
• The subject’s vital signs remained stable throughout the 60-minute observation period
Before discharge, subjects were instructed not to flex or extend the fingers on the treated hand for 12 hours after the 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 themselves.
Local Anesthesia
Before each finger extension procedure, the investigator could have administered local anesthesia according to the practice of his/her institution and the subject’s willingness to receive anesthesia. Local anesthesia was to be recorded as a concomitant medication.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
12 Mar 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 |
Australia: 21
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Country: Number of subjects enrolled |
United States: 21
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Country: Number of subjects enrolled |
Sweden: 6
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Country: Number of subjects enrolled |
United Kingdom: 4
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Worldwide total number of subjects |
52
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EEA total number of subjects |
10
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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) |
20
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From 65 to 84 years |
31
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85 years and over |
1
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Recruitment
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Recruitment details |
The recruitment period was March 2012 to October 2013. Recruitment took place in the Australia, Sweden, the United Kingdom and the United States, | ||||||||||||||
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Pre-assignment
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Screening details |
Subjects who had recurrence of contracture in a joint that was effectively treated with AA4500 in a Phase 3 Auxilium-sponsored study, were determined by the investigator as eligible and who provided informed consent were enrolled. | ||||||||||||||
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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: up to three 0.58 mg injections | ||||||||||||||
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 |
AA4500 was administered after reconstitution with diluent (0.9% NaCl containing 0.03% calcium chloride). The volume of injection was 0.25 mL for metacarpophalangeal (MP) joints and 0.20 mL for proximal interphalangeal (PIP) joints.
The investigator treated the recurrent cord affecting the joint with up to three injections of AA4500 until the outcome was deemed satisfactory by the investigator and/or the subject, or until the cord was no longer palpable. Injections of AA4500 were to be separated by approximately 28 days. Each subject in this study had only one recurrent contracture treated.
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Period 2
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Period 2 title |
XIAFLEX/XIAPEX Treatment
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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 |
Yes
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Arm title
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XIAFLEX/XIAPEX MP Joint | ||||||||||||||
Arm description |
Up to 3 injections of collagenase clostridium histolyticum 0.58 mg 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 |
Intracartilaginous use
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Dosage and administration details |
AA4500 was administered after reconstitution with diluent (0.9% NaCl containing 0.03% calcium chloride). The volume of injection was 0.25 mL for metacarpophalangeal (MP) joints and 0.20 mL for proximal interphalangeal (PIP) joints.
The investigator treated the recurrent cord affecting the joint with up to three injections of AA4500 until the outcome was deemed satisfactory by the investigator and/or the subject, or until the cord was no longer palpable. Injections of AA4500 were to be separated by approximately 28 days. Each subject in this study had only one recurrent contracture treated.
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Arm title
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XIAFLEX/XIAPEX PIP Joint | ||||||||||||||
Arm description |
Up to 3 injections of collagenase clostridium histolyticum 0.58 mg 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 |
Intracartilaginous use
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Dosage and administration details |
AA4500 was administered after reconstitution with diluent (0.9% NaCl containing 0.03% calcium chloride). The volume of injection was 0.25 mL for metacarpophalangeal (MP) joints and 0.20 mL for proximal interphalangeal (PIP) joints.
The investigator treated the recurrent cord affecting the joint with up to three injections of AA4500 until the outcome was deemed satisfactory by the investigator and/or the subject, or until the cord was no longer palpable. Injections of AA4500 were to be separated by approximately 28 days. Each subject in this study had only one recurrent contracture treated.
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Period 3
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Period 3 title |
Post-treatment
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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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Arm title
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XIAFLEX/XIAPEX | ||||||||||||||
Arm description |
XIAFLEX/XIAPEX: up to three 0.58 mg injections | ||||||||||||||
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 |
AA4500 was administered after reconstitution with diluent (0.9% NaCl containing 0.03% calcium chloride). The volume of injection was 0.25 mL for metacarpophalangeal (MP) joints and 0.20 mL for proximal interphalangeal (PIP) joints.
The investigator treated the recurrent cord affecting the joint with up to three injections of AA4500 until the outcome was deemed satisfactory by the investigator and/or the subject, or until the cord was no longer palpable. Injections of AA4500 were to be separated by approximately 28 days. Each subject in this study had only one recurrent contracture treated.
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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: up to three 0.58 mg injections | ||
Reporting group title |
XIAFLEX/XIAPEX MP Joint
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Reporting group description |
Up to 3 injections of collagenase clostridium histolyticum 0.58 mg in the metacarpophalangeal (MP) joint cord | ||
Reporting group title |
XIAFLEX/XIAPEX PIP Joint
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Reporting group description |
Up to 3 injections of collagenase clostridium histolyticum 0.58 mg in the proximal interphalangeal (PIP) joint cord | ||
Reporting group title |
XIAFLEX/XIAPEX
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Reporting group description |
XIAFLEX/XIAPEX: up to three 0.58 mg injections | ||
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 ITT subjects who had a recurrent joint contracture retreated in the current study. If the joint treated in the current study did not meet the definition of a recurrent joint then the subject was not included in the mITT population.
All efficacy parameters were summarized using this population.
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End point title |
Clinical Success [1] | ||||||||||||
End point description |
Clinical success defined as reduction in fixed-flexion contracture to less than or equal to 5 degrees 30 days after the last injection of AA4500.
Efficacy assessment based on modified intent-to-treat (mITT) population which includes all enrolled subjects who received at least 1 AA4500 injection to the treated joint and had at least 1 post-injection efficacy measure.
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End point type |
Primary
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End point timeframe |
30 days after last injection
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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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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percent Change from Baseline in Degree of Contracture [2] | ||||||||||||
End point description |
Change in fixed-flexion contracture measured in degrees where a decrease of 100% would correspond to a reduction in contracture to 0 degrees.
Efficacy assessment based on modified intent-to-treat (mITT) population which includes all enrolled subjects who received at least 1 AA4500 injection to the treated joint and had at least 1 post-injection efficacy measure.
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End point type |
Primary
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End point timeframe |
Baseline and 30 days after last injection
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| Notes [2] - 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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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in Range of Motion [3] | ||||||||||||
End point description |
Range of motion defined as difference between full flexion angle and full extension angle expressed in degrees.
Efficacy assessment based on modified intent-to-treat (mITT) population which includes all enrolled subjects who received at least 1 AA4500 injection to the treated joint and had at least 1 post-injection efficacy measure.
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End point type |
Primary
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End point timeframe |
Baseline and 30 days after last injection
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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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| No statistical analyses for this end point | |||||||||||||
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End point title |
Physician Global Assessment of Improvement | ||||||||||||||||||||||||||||||||||||
End point description |
Physician global assessment of change (improvement) in subject's Dupuytren's contracture.
Efficacy assessment based on modified intent-to-treat (mITT) population which includes all enrolled subjects who received at least 1 AA4500 injection to the treated joint and had at least 1 post-injection efficacy measure.
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End point type |
Secondary
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End point timeframe |
30 days after last injection
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
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End point title |
Subject Global Assessment of Satisfaction | ||||||||||||||||||||||||||||||
End point description |
Subject global assessment of overall treatment satisfaction.
Efficacy assessment based on modified intent-to-treat (mITT) population which includes all enrolled subjects who received at least 1 AA4500 injection to the treated joint and had at least 1 post-injection efficacy measure.
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End point type |
Secondary
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End point timeframe |
30 days after last injection
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Recurrence of Contracture | ||||||||||||
End point description |
Recurrence of contracture in the joint at day 365 that was successfully treated 30 days after last injection assessed. Recurrence was defined as 20 degree or greater increase of contracture of the treated joint at day 365 or medication intervention of the treated joint between the 2 time points.
Efficacy assessment based on mITT population which includes all enrolled subjects who received at least 1 AA4500 injection to the treated joint and had at least 1 post-injection efficacy measure; only joints that were successfully treated (reduction in contracture to 5 degrees or less) 30 days after last injection were assessed
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End point type |
Secondary
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End point timeframe |
Day 365
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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 |
1 year
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Adverse event reporting additional description |
XIAFLEX/XIAPEX: up to three 0.58 mg injections
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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 |
11.1
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Reporting groups
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Reporting group title |
XIAFLEX/XIAPEX
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Reporting group description |
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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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01 Nov 2011 |
The following change was made throughout the protocol:
WAS: Injections of AA4500 should be separated by a minimum of 28 days. The maximum interval between the first and last injection should be less than or equal to 6 months.
Changed to: Injections of AA4500 are to be separated by approximately 28 days.
Section 9.4 was added.
9.4 Interim Analysis
An interim analysis of data will be performed after the last subject completes the Day 30 follow-up visit after the last injection. The final analysis of data will be performed after the last subject completes the Day 365 follow-up visit. |
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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 | |||
