A Phase 2, Randomized, Double-blind, Placebo Controlled Dose Ranging Study of Repeat Doses of AA4500 for the Treatment of Edematous Fibrosclerotic Panniculopathy

• ClinicalTrials.gov Identifier: NCT01987986
• Recruitment Status: Completed
• First Posted: November 20, 2013
• Results First Posted: July 2, 2017
• Last Update Posted: October 5, 2017
• Sponsor: Endo Pharmaceuticals
• Information provided by (Responsible Party): Endo Pharmaceuticals

Study Description

Brief Summary:

To assess the safety and effectiveness of repeat doses of AA4500 in the treatment of edematous fibrosclerotic panniculopathy (EFP) commonly known as cellulite in adult women.

Condition or disease	Intervention/treatment	Phase
Edematous Fibrosclerotic Panniculopathy (EFP)	Biological: Collagenase Clostridium Histolyticum; Biological: Placebo	Phase 2

Detailed Description:

The Phase 2a study is a randomized, double-blind multiple-dose study that is expected to enroll approximately 144 women between the ages of 18 and 45 in the United States. Treatment effectiveness will be evaluated by investigator and patient assessments, as well as 3-D photographic imaging techniques. Once the safety and local tolerability profile from the first stage has been found to be acceptable subjects will be enrolled in stage 2. After an interim safety and local tolerability review was completed of all subjects in stage 1, it was determined that enrollment in stage 2 is acceptable and has been initiated.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 150 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Double-blind and Placebo Dose Ranging Study of Repeat Doses of AA4500 for the Treatment of Edematous Fibrosclerotic Panniculopathy
• Study Start Date: October 2013
• Actual Primary Completion Date: August 2014
• Actual Study Completion Date: August 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: AA4500 0.06 mg (low dose); AA4500 (Collagenase Clostridium Histolyticum) Each subject could receive up to three treatment sessions. Each treatment session was separated by approximately 21 days.	Biological: Collagenase Clostridium Histolyticum; injectible intervention; Other Names: AA4500; Xiaflex; Xiapex
Experimental: AA4500 0.48 mg (mid-dose); AA4500 (Collagenase Clostridium Histolyticum) Each subject could receive up to three treatment sessions. Each treatment session was separated by approximately 21 days.	Biological: Collagenase Clostridium Histolyticum; injectible intervention; Other Names: AA4500; Xiaflex; Xiapex
Experimental: AA4500 0.84 mg (high dose); AA4500 (Collagenase Clostridium Histolyticum) Each subject could receive up to three treatment sessions. Each treatment session was separated by approximately 21 days.	Biological: Collagenase Clostridium Histolyticum; injectible intervention; Other Names: AA4500; Xiaflex; Xiapex
Placebo Comparator: Placebo; Placebo Each subject could receive up to three treatment sessions. Each treatment session was separated by approximately 21 days.	Biological: Placebo

Outcome Measures

Primary Outcome Measures :

1. Investigator Global Assessment of Aesthetic Improvement [ Time Frame: Baseline, Day 73 ]
   Investigators assessment of aesthetic improvement (I-GAIS) scores ranged from 3 to -1 as follows: 3 (very much improved), 2 (much improved), 1 (improved), 0 (no change), -1 (worse).

Other Outcome Measures:

1. Investigator Cellulite Severity Score (CSS) Total Score- Change From Baseline [ Time Frame: Baseline, Day 73 ]
   The CSS is a photonumeric scale that was used to evaluate 5 morphologic features of cellulite; (A) number of evident depressions, (B) depth of depressions, (C) morphological appearance of skin surface alterations, (D) laxity, flaccidity or sagging of skin, and (E) current classification scale based on medical literature including Nuernberger and Mueller. The severity of each feature is rated on a scale from 0 (none) to 3 (most severe). The CSS total score is the sum of the 5 cellulite features (range: 0 to 15, with higher scores corresponding to more severe cellulite). Change is Day 73 study visit rating minus baseline rating; negative values indicate improvement in cellulite.
2. Subject Cellulite Severity Item (CSI)-Change From Baseline [ Time Frame: Baseline, Day 73 ]
   CSI scores ranged from 0 (no cellulite present), 1 (very mild), 2 (mild), 3 (moderate), 4 (severe) to 5 (very severe). Change is Day 73 study visit rating minus baseline rating; negative values indicate a lessening in cellulite severity.
3. Subject Global Bother Assessment (SGBA)- Change From Baseline [ Time Frame: Baseline, Day 73 ]
   Subjects rated their cellulite on a scale from 0 (not at all bothered) to 4 (extremely bothered). Change from baseline is Day 73 study visit value minus baseline value; negative change reflects an improvement in the amount the subject was bothered by cellulite; positive change reflects a worsening in the amount the subject is bothered by cellulite.
4. Subject-reported Cellulite Impact Scale (SR-CIS)-Change From Baseline [ Time Frame: Baseline, Day 73 ]
   Subjects were asked to answer 6 exploratory questions regarding the appearance of their cellulite on a scale of 0 to 10 with 0 representing "not at all" and 10 representing "extremely." A SR-CIS total score was derived from these 6 questions with values varying from 0 (No negative impact) to 60 (Extreme negative impact). Change from baseline is Day 73 value minus baseline value; negative change reflects an improvement.
5. Subject Satisfaction With Treatment Assessment (SCTA) [ Time Frame: Day 73 ]
   Subjects rated their treatment satisfaction at the Day 73 visit on a 5-point scale ranging from -2 (very dissatisfied) to +2 (very satisfied)
6. Subject Global Assessment Cellulite (SGA-C) [ Time Frame: Day 73 ]
   Subjects assessed their cellulite based on a 5-point scale from -1 (slightly worse), 0 (same), 1 (slightly improved), 2 (moderately improved), to 3 (much improved) on Day 73
7. Subject Global Assessment of Aesthetic Improvement (C-GAIS) [ Time Frame: Day 73 ]
   Subjects's assessment of aesthetic improvement (C-GAIS) scores ranged from 3 to -1 as follows: 3 (very much improved), 2 (much improved), 1 (improved), 0 (no change), -1 (worse).

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 45 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Be a female between 18 to 45 years of age.
2. Have at least one well defined dimple that is at least 1 cm but not more than 2 cm along the long axis and that is evident when the subject is standing
3. Have a photonumeric cellulite severity scale (CSS) score between 6 and 12
4. Have a Body Mass Index (BMI) >19 and <30 kg/m2, and intends to maintain stable body weight throughout the duration of the study
5. Be willing to apply appropriate sunscreen to the selected quadrant before each exposure to the sun while participating in the study
6. Be judged to be in good health, based upon the results of a medical history, physical examination, and laboratory profile at screening.
7. Have a negative urine pregnancy test at screening and before injection of AA4500 and be using an effective contraception method (ie, 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.
8. Be willing and able to cooperate with the requirements of the study.
9. Voluntarily sign and date an informed consent agreement approved by the Institutional Review Board/Independent Ethics Committee/Human Research Ethics Committee (IRB/IEC/HREC).
10. Be able to read, complete and understand the Patient Reported Outcomes rating instruments in English.

Exclusion Criteria:

1. Thyroid disease, unless controlled with medication for ≥ 6 months
2. Uncontrolled diabetes mellitus, as determined by the investigator
3. Uncontrolled hypertension, as determined by the investigator
4. Vascular disorder (eg, phlebitis or varicose veins) in area to be treated
5. Lipedema or a lymphatic disorder
6. Cushing's disease and/or use of systemic corticosteroids
7. History of lower extremity thrombosis or post-thrombosis syndrome
8. Documented autoimmune disorder such as lupus erythematosus, rheumatoid arthritis
9. Inflammation or active infection in area to be treated
10. Cutaneous alteration in area to be treated
11. Rash, eczema, psoriasis, or skin cancer in the area to be treated
12. History of keloidal scarring or abnormal wound healing
13. Coagulation disorder
14. Taking a medication for chronic anticoagulation (except for ≤ 150 mg aspirin daily)
15. Known active hepatitis A, B or C
16. Known immune deficiency disease or a positive test for human immunodeficiency virus (HIV)
17. Other significant conditions including body dysmorphic disorder, which in the investigator's opinion would make the subject unsuitable for enrollment in the study
18. Is menopausal defined as 12 months of amenorrhea in the absence of other biological or physiological causes, as determined by the investigator

19. Has used any of the following for the treatment of EFP on the legs or buttock within the timelines identified below or intends to use any of the following at any time during the course of the study:

    • Liposuction on the side of the body selected for treatment during the 12-month period before injection of AA4500
    • Injections (eg, mesotherapy); radiofrequency device treatments; laser treatment; or surgery (including subcision) within the selected treatment quadrant during the 12-month period before injection of AA4500
    • Endermologie or similar treatments within the selected treatment quadrant during the 6-months period before injection of AA4500
    • Massage therapy within the selected treatment quadrant during the 3-month period before injection of AA4500
    • Creams (eg, Celluvera™, TriLastin®) to prevent or mitigate EFP within the selected treatment quadrant during the 2-week period before injection of AA4500
20. Has a tattoo located within 2 cm of the site of injection
21. Is presently nursing a baby or providing breast milk for a baby.
22. Intends to become pregnant during the study.
23. Intends to initiate an intensive sport or exercise program during the study.
24. Has received an investigational drug or treatment within 30 days before injection of AA4500.
25. Has a known systemic allergy to collagenase or any other excipient of AA4500.

26. Has received any collagenase treatments within 30 days before treatment.

    -

Contacts and Locations

Locations

United States, California

Dermatology Cosmetic Laser Medical Associates of La Jolla

San Diego, California, United States, 92121

ATS Clinical Research

Santa Monica, California, United States, 90404

United States, Florida

Dermatology Research Institute

Coral Gables, Florida, United States, 33146

Kenneth Beer, MD PA

West Palm Beach, Florida, United States, 33401

United States, Missouri

Mercy Health Research

Washington, Missouri, United States, 63090

United States, New York

Sadick Research Group

New York, New York, United States, 10075

Stony Brook University Medical Center

Stony Brook, New York, United States, 11794

United States, Tennessee

Tennessee Clinical Research Center

Nashville, Tennessee, United States, 37215

United States, Virginia

Charlottesville Dermatology

Charlottesville, Virginia, United States, 22911

United States, Washington

Premier Clinical Research

Spokane, Washington, United States, 99204

Sponsors and Collaborators

Endo Pharmaceuticals

Investigators

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

More Information

• Responsible Party: Endo Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01987986
• Other Study ID Numbers: AUX-CC-831
• First Posted: November 20, 2013
• Results First Posted: July 2, 2017
• Last Update Posted: October 5, 2017
• Last Verified: September 2017

Keywords provided by Endo Pharmaceuticals:

cellulite; dimple; orange peel; cottage cheese; mattress texture

Additional relevant MeSH terms:

Edema