AA4500 (XIAFLEX™, Proposed Name) in the Treatment of Dupuytren's Contracture (CORD-I)

A Phase 3, Double-Blind, Randomized, Placebo-Controlled Study of the Safety and Efficacy of AA4500 in the Treatment of Subjects With Dupuytren's Contracture

This was a Phase 3, double-blind, randomized, placebo-controlled study conducted in the United States. Subjects with a diagnosis of Dupuytren's contracture in a metacarpophalangeal (MP) or proximal interphalangeal (PIP) joint that resulted in a fixed flexion deformity of at least one finger, other than the thumb, that was at least 20° as measured by finger goniometry and was suitable for injection were randomized 2:1 to receive AA4500 0.58 mg or placebo.

This study was designed to be part of the larger clinical program, for adult patients with Dupuytren's contracture with a palpable cord, where the data from 2 pivotal Placebo-Controlled studies (AUX-CC-857 (NCT00528606) and AUX-CC-859 (NCT00533273)) and 7 non-pivotal studies were evaluated.

Study Overview

• Status: Completed
• Conditions: Dupuytren's Contracture
• Intervention / Treatment: Biological: collagenase clostridium histolyticum; Biological: Placebo

• Study Type: Interventional
• Enrollment (Actual): 308
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • 100 UCLA Medical Plaza, Suite 305
    • Palo Alto, California, United States, 94304
      • Hand Surgery Clinic
  • Colorado
    • Denver, Colorado, United States, 80210
      • Hand Surgery Associates, PC
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • The Hand and Upper Extremity Center of Georgia, P.C.
  • Illinois
    • Rockford, Illinois, United States, 61107
      • Rockford Orthopedic Associates, Ltd.
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • The Indiana Hand Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital, Department of Orthopedic Surgery
    • Newton, Massachusetts, United States, 02462
      • Newton-Wellesley Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55431
      • TRIA Orthopaedic Center
  • New York
    • New York, New York, United States, 10021
      • Hospital for Special Surgery
    • Stony Brook, New York, United States, 11794
      • SUNY Stony Brook - Department of Orthopedics
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73109
      • Health Research Institute
  • Pennsylvania
    • Erie, Pennsylvania, United States, 16550
      • Hand Microsurgery & Reconstructive Orthopaedics
    • State College, Pennsylvania, United States, 16801
      • University Orthopedics Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Department of Orthopaedics, Brown University, Rhode Island Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects with a diagnosis of Dupuytren's contracture, with a fixed flexion deformity of at least one finger, other than the thumb, that had a contracture at least 20°, but not greater than 100°, for MP (80° for PIP) joints, caused by a palpable cord that had never been treated with AA4500.
• Had a positive "table top test," defined as the inability to simultaneously place the affected finger(s) and palm flat against a table top.
• Judged to be in good health.

Exclusion Criteria:

• Had a chronic muscular, neurological, or neuromuscular disorder that affected the hands.
• Had received a treatment for Dupuytren's contracture, including surgery (fasciectomy or surgical fasciotomy), needle aponeurotomy/fasciotomy, or injection of verapamil and/or interferon on the selected primary joint within 90 days before the first dose of study drug.
• Had a known recent history of stroke, bleeding, a disease process that affected the hands, or other medical condition, which in the investigator's opinion, would make the subject unsuitable for enrollment in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Biological: Placebo; Subjects could have received up to three injections of placebo into the cord of the affected hand. Each injection was separated by at least 30 days. Individual cords may have received up to a maximum of three injections.
Experimental: AA4500 0.58 mg	Biological: collagenase clostridium histolyticum; Subjects could have received up to three injections of AA4500 into the cord of the affected hand. Each injection was separated by at least 30 days. Individual cords may have received up to a maximum of three injections.; Other Names: XIAFLEX®; AA4500

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Success (Reduction in Contracture to 5° or Less) of the Primary Joint After the Last Injection	The Primary Outcome Measure for patients treated with AA4500 is the percentage of joints that were successfully treated where "successfully treated" was defined as reduction in contracture to within 0-5° of normal within 30 days of injection. The Primary Outcome Measure for placebo treated patients is the percentage of joints that were successfully treated where "successfully treated" was defined as reduction in contracture to within 0-5° of normal within 30 days of injection.	Within 30 days after the last injection

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Improvement After the Last Injection	Clinical Improvement is defined as >= 50% reduction from baseline in degree of contracture within 30 days of the injection.	Baseline; within 30 days after the last injection
Percent Reduction From Baseline Contracture After the Last Injection	Percent change in degree of contracture measured as 100* (baseline contracture - last available post-injection contracture)/baseline contracture.	Baseline; within 30 days after the last injection
Change From Baseline Range of Motion After the Last Injection	Change in degree of motion measured as last available post-injection range of motion - baseline range of motion.	Baselin; within 30 days after the last injection
Time to First Achieve Success After the Last Injection		Last evaluation visit on which clinical success is achieved through the Day 30 evaluation
Clinical Success (Reduction in Contracture to 5° or Less) After the First Injection	Clinical Success is defined as reduction in contracture to within 0-5 degrees of normal within 30 days of injection.	Within 30 days after first injection
Clinical Improvement After the First Injection	Clinical Improvement is defined as >= 50% reduction from contracture within 30 days of the first injectionor greater of baseline contracture within 30 days of the injection.	Baseline; within 30 days after the first injection
Percent Reduction From Baseline Contracture After the First Injection	Percent change in degree of contracture measured as 100* (baseline contracture - last available post-injection contracture)/baseline contracture.	Baseline, within 30 days after the first injection
Change From Baseline Range of Motion After the First Injection	Change in degree of motion measured as last available post-injection range of motion - baseline range of motion.	Baseline; within 30 days after the first injection

Collaborators and Investigators

• Sponsor: Endo Pharmaceuticals
• Investigators: Study Director: Veronica Urdaneta, MD, Endo Pharmaceuticals

Publications and helpful links

General Publications

• Witthaut J, Bushmakin AG, Gerber RA, Cappelleri JC, Le Graverand-Gastineau MP. Determining clinically important changes in range of motion in patients with Dupuytren's Contracture: secondary analysis of the randomized, double-blind, placebo-controlled CORD I study. Clin Drug Investig. 2011 Nov 1;31(11):791-8. doi: 10.1007/BF03256918.
• Hurst LC, Badalamente MA, Hentz VR, Hotchkiss RN, Kaplan FT, Meals RA, Smith TM, Rodzvilla J; CORD I Study Group. Injectable collagenase clostridium histolyticum for Dupuytren's contracture. N Engl J Med. 2009 Sep 3;361(10):968-79. doi: 10.1056/NEJMoa0810866.

Helpful Links

• XIAFLEX Prescribing Information

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2007
• Primary Completion (Actual): April 1, 2008
• Study Completion (Actual): April 1, 2008

Study Registration Dates

• First Submitted: September 11, 2007
• First Submitted That Met QC Criteria: September 11, 2007
• First Posted (Estimate): September 12, 2007

Study Record Updates

• Last Update Posted (Actual): December 2, 2017
• Last Update Submitted That Met QC Criteria: October 26, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Joint Diseases; Musculoskeletal Diseases; Connective Tissue Diseases; Muscular Diseases; Neoplasms, Connective Tissue; Neoplasms, Fibrous Tissue; Fibroma; Contracture; Dupuytren Contracture
• Other Study ID Numbers: AUX-CC-857