Phase 2a Dose-Ranging Study to Evaluate Safety and Effectiveness of AA4500 in Treatment of Dupuytren's Disease Nodules

• Sponsor: Endo Pharmaceuticals
• Information provided by (Responsible Party): Endo Pharmaceuticals

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
Dupuytren's Disease	Biological: Collagenase clostridium histolyticum; Biological: Placebo	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 (Clinical Trial)
• 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: July 2014
• Actual Primary Completion Date: December 2014
• Actual Study Completion Date: December 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: AA4500; XIAFLEX; XIAPEX
Experimental: AA4500 0.40 mg; Collagenase clostridium histolyticum, single 0.40 mg injection	Biological: Collagenase clostridium histolyticum; Single injection into nodule; Other Names: AA4500; XIAFLEX; XIAPEX
Experimental: AA4500 0.60 mg; Collagenase clostridium histolyticum, single 0.60 mg injection	Biological: Collagenase clostridium histolyticum; Single injection into nodule; Other Names: AA4500; XIAFLEX; XIAPEX
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 :

1. Percent Change From Baseline in Surface Area and Volume of the Treated Nodule at Day 57 Using Caliper Measurements [ Time Frame: 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 :

1. Percent Change From Baseline in Surface Area and Volume of the Treated Nodule at Day 57 Using Ultrasound [ Time Frame: 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.
2. Change From Baseline in Consistency of the Treated Nodules at Day 57 [ Time Frame: 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.
3. Percent Change From Baseline in Hardness of the Treated Nodule at Day 57 [ Time Frame: 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.
4. Change From Baseline in Nodular Pain of the Treated Nodule at Day 57 [ Time Frame: 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.
5. Investigator Global Assessment of Improvement With Treatment [ Time Frame: 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.
6. Subject Satisfaction With Treatment [ Time Frame: 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.
7. Composite Responder Analysis [ Time Frame: 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

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

Criteria

Inclusion Criteria:

1. Provide a signed and dated informed consent
2. Be a man or woman ≥ 18 years of age

3. Have a diagnosis of Dupuytren's disease AND have at least one palmar nodule on the selected hand that is:

   1. Palpable
   2. 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
   3. Not directly associated with a Dupuytren's cord
4. 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)
5. Be able to comply with the study visit schedule as specified in the protocol

Exclusion Criteria:

1. Received steroid injections (eg, tri-amcinolone acetonide) on the selected nodule within 3 months before administration of study drug
2. Has a chronic muscular, neurological, or neuromuscular disorder that affects the hands
3. Has a known systemic allergy to collagenase or any other excipient of AA4500
4. Has received any collagenase treatments (eg, Santyl® ointment and/or XIAFLEX®/XIAPEX®) within 30 days before injection of study drug in the hand selected for treatment
5. Is currently receiving or plans to receive anticoagulant medication or has received anticoagulant medication (except for ≤ 150 mg aspirin daily) within 7 days before injection of study drug
6. Has a known recent history of stroke, bleeding, or other medical condition, which in the investigator's opinion would make the subject unsuitable for enrollment in the study
7. Received an investigational drug within 30 days before injection of study drug
8. Is pregnant or intends on becoming pregnant during the study or is breastfeeding a child
9. Has any clinically significant medical history or condition(s), including conditions that affect the hands, that would, in the opinion of the investigator, substantially increase the risk associated with the subject's participation in the protocol or compromise the scientific objectives of the study
10. Had surgery on the selected hand within 3 months before the screening visit
11. Has jewelry on the hand to be treated that cannot be removed

Contacts and Locations

Locations

United States, Arizona

Tucson Orthopaedic Institute

Tucson, Arizona, United States, 85712

United States, California

CORE Orthopaedic Medical Center

Encinitas, California, United States, 92024

Marin Endocrine Care & Research, Inc.

Greenbrae, California, United States, 94904

Brigid Freyne, MD, Inc.

Murrieta, California, United States, 92563

United States, Indiana

Indiana Hand to Shoulder Center

Indianapolis, Indiana, United States, 46260

United States, New York

State University of New York

Stony Brook, New York, United States, 11794

United States, North Carolina

OrthoCarolina Research Institute, Inc.

Charlotte, North Carolina, United States, 28207

United States, Oklahoma

Orthopedic and Reconstructive Center

Oklahoma City, Oklahoma, United States, 73109

United States, Pennsylvania

Blair Orthopedic Associates, Inc.

Altoona, Pennsylvania, United States, 16602

Australia, Queensland

Brisbane Hand & Upper Limb Clinic

Brisbane, Queensland, Australia, 4000

Houston Medical

Kippa Ring, Queensland, Australia, 4021

Sponsors and Collaborators

Endo Pharmaceuticals

Investigators

• Study Director: Veronica Urdaneta, MD MPH; Endo Pharmaceuticals

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Costas B, Coleman S, Kaufman G, James R, Cohen B, Gaston RG. Efficacy and safety of collagenase clostridium histolyticum for Dupuytren disease nodules: a randomized controlled trial. BMC Musculoskelet Disord. 2017 Aug 30;18(1):374. doi: 10.1186/s12891-017-1713-z.

• Responsible Party: Endo Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02193828 History of Changes
• Other Study ID Numbers: AUX-CC-750
• First Posted: July 18, 2014
• Results First Posted: July 7, 2015
• Last Update Posted: October 5, 2017
• Last Verified: September 2017

Keywords provided by Endo Pharmaceuticals:

Dupuytren's nodules

Additional relevant MeSH terms:

Dupuytren Contracture; Fibroma; Neoplasms, Fibrous Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Contracture; Muscular Diseases; Musculoskeletal Diseases; Connective Tissue Diseases