Edematous Fibrosclerotic Panniculopathy (EFP)
Conditions
Keywords
cellulite, dimple, orange peel, cottage cheese, mattress texture
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.
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.
Interventions
BIOLOGICALCollagenase Clostridium Histolyticum
injectible intervention
BIOLOGICALPlacebo
Sponsors
Endo Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
No
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. \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Investigator Global Assessment of Aesthetic Improvement | 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
| Measure | Time frame | Description |
|---|---|---|
| Subject Cellulite Severity Item (CSI)-Change From Baseline | 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. |
| Subject Global Bother Assessment (SGBA)- Change From Baseline | 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. |
| Subject-reported Cellulite Impact Scale (SR-CIS)-Change From Baseline | 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. |
| Investigator Cellulite Severity Score (CSS) Total Score- Change From Baseline | 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. |
| Subject Global Assessment Cellulite (SGA-C) | 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 |
| Subject Global Assessment of Aesthetic Improvement (C-GAIS) | 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). |
| Subject Satisfaction With Treatment Assessment (SCTA) | 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) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Collagenase Clostridium Histolyticum: injectible intervention | 43 |
| 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.
Collagenase Clostridium Histolyticum: injectible intervention | 43 |
| 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.
Collagenase Clostridium Histolyticum: injectible intervention | 40 |
| Placebo Placebo
Each subject could receive up to three treatment sessions. Each treatment session was separated by approximately 21 days.
Placebo | 24 |
| Total | 150 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 2 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | AA4500 0.06 mg (Low Dose) | AA4500 0.48 mg (Mid-dose) | AA4500 0.84 mg (High Dose) | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 37.7 years STANDARD_DEVIATION 5.78 | 36.8 years STANDARD_DEVIATION 7.07 | 36.1 years STANDARD_DEVIATION 5.62 | 37.3 years STANDARD_DEVIATION 8.08 | 36.9 years STANDARD_DEVIATION 6.5 |
| Age, Customized <25 | 2 Participants | 3 Participants | 2 Participants | 1 Participants | 8 Participants |
| Age, Customized 25-34 | 6 Participants | 11 Participants | 12 Participants | 6 Participants | 35 Participants |
| Age, Customized 35-44 | 33 Participants | 23 Participants | 25 Participants | 13 Participants | 94 Participants |
| Age, Customized >=45 | 2 Participants | 6 Participants | 1 Participants | 4 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 13 Participants | 9 Participants | 4 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants | 30 Participants | 31 Participants | 20 Participants | 114 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 3 Participants | 4 Participants | 2 Participants | 11 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 40 Participants | 40 Participants | 36 Participants | 20 Participants | 136 Participants |
| Region of Enrollment United States | 43 participants | 43 participants | 40 participants | 24 participants | 150 participants |
| Sex: Female, Male Female | 43 Participants | 43 Participants | 40 Participants | 24 Participants | 150 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 43 | 0 / 43 | 0 / 40 | 0 / 24 |
| other Total, other adverse events | 28 / 43 | 31 / 43 | 31 / 40 | 7 / 24 |
| serious Total, serious adverse events | 1 / 43 | 0 / 43 | 0 / 40 | 0 / 24 |
Outcome results
Primary
Investigator Global Assessment of Aesthetic Improvement
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).
Time frame: Baseline, Day 73
Population: All subjects who received at least one injection of study drug and had at least one post-injection efficacy measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 0.06 mg (Low Dose) | Investigator Global Assessment of Aesthetic Improvement | 0.7 units on a scale | Standard Deviation 0.82 |
| AA4500 0.48 mg (Mid-dose) | Investigator Global Assessment of Aesthetic Improvement | 0.9 units on a scale | Standard Deviation 0.93 |
| AA4500 0.84 mg (High Dose) | Investigator Global Assessment of Aesthetic Improvement | 1.1 units on a scale | Standard Deviation 0.91 |
| Placebo | Investigator Global Assessment of Aesthetic Improvement | 0.5 units on a scale | Standard Deviation 0.72 |
Other Pre-specified
Investigator Cellulite Severity Score (CSS) Total Score- Change From Baseline
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.
Time frame: Baseline, Day 73
Population: All subjects who received at least one injection of study drug and had at least one post-injection efficacy measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 0.06 mg (Low Dose) | Investigator Cellulite Severity Score (CSS) Total Score- Change From Baseline | -1.1 units on a scale | Standard Deviation 1.74 |
| AA4500 0.48 mg (Mid-dose) | Investigator Cellulite Severity Score (CSS) Total Score- Change From Baseline | -1.3 units on a scale | Standard Deviation 1.7 |
| AA4500 0.84 mg (High Dose) | Investigator Cellulite Severity Score (CSS) Total Score- Change From Baseline | -1.9 units on a scale | Standard Deviation 2.37 |
| Placebo | Investigator Cellulite Severity Score (CSS) Total Score- Change From Baseline | -0.7 units on a scale | Standard Deviation 1.52 |
Other Pre-specified
Subject Cellulite Severity Item (CSI)-Change From Baseline
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.
Time frame: Baseline, Day 73
Population: All subjects who received at least one injection of study drug and had at least one post-injection efficacy measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 0.06 mg (Low Dose) | Subject Cellulite Severity Item (CSI)-Change From Baseline | -0.7 units on a scale | Standard Deviation 1.22 |
| AA4500 0.48 mg (Mid-dose) | Subject Cellulite Severity Item (CSI)-Change From Baseline | -1.1 units on a scale | Standard Deviation 1.07 |
| AA4500 0.84 mg (High Dose) | Subject Cellulite Severity Item (CSI)-Change From Baseline | -1.3 units on a scale | Standard Deviation 1.34 |
| Placebo | Subject Cellulite Severity Item (CSI)-Change From Baseline | -0.8 units on a scale | Standard Deviation 1.35 |
Other Pre-specified
Subject Global Assessment Cellulite (SGA-C)
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
Time frame: Day 73
Population: All subjects who at least one injection of study drug and had at least one post-injection efficacy measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 0.06 mg (Low Dose) | Subject Global Assessment Cellulite (SGA-C) | 0.9 units on a scale | Standard Deviation 1.23 |
| AA4500 0.48 mg (Mid-dose) | Subject Global Assessment Cellulite (SGA-C) | 1.6 units on a scale | Standard Deviation 0.85 |
| AA4500 0.84 mg (High Dose) | Subject Global Assessment Cellulite (SGA-C) | 1.5 units on a scale | Standard Deviation 1.04 |
| Placebo | Subject Global Assessment Cellulite (SGA-C) | 0.8 units on a scale | Standard Deviation 0.96 |
Other Pre-specified
Subject Global Assessment of Aesthetic Improvement (C-GAIS)
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).
Time frame: Day 73
Population: All subjects who received at least one injection of study medication and had at least one post injection efficacy measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 0.06 mg (Low Dose) | Subject Global Assessment of Aesthetic Improvement (C-GAIS) | 0.9 units on a scale | Standard Deviation 1.14 |
| AA4500 0.48 mg (Mid-dose) | Subject Global Assessment of Aesthetic Improvement (C-GAIS) | 1.6 units on a scale | Standard Deviation 0.88 |
| AA4500 0.84 mg (High Dose) | Subject Global Assessment of Aesthetic Improvement (C-GAIS) | 1.4 units on a scale | Standard Deviation 1.03 |
| Placebo | Subject Global Assessment of Aesthetic Improvement (C-GAIS) | 0.7 units on a scale | Standard Deviation 0.91 |
Other Pre-specified
Subject Global Bother Assessment (SGBA)- Change From Baseline
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.
Time frame: Baseline, Day 73
Population: All subjects who received at least one injection of study drug and had at least one post-injection efficacy measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 0.06 mg (Low Dose) | Subject Global Bother Assessment (SGBA)- Change From Baseline | -0.9 units on a scale | Standard Deviation 1.33 |
| AA4500 0.48 mg (Mid-dose) | Subject Global Bother Assessment (SGBA)- Change From Baseline | -1.0 units on a scale | Standard Deviation 1.23 |
| AA4500 0.84 mg (High Dose) | Subject Global Bother Assessment (SGBA)- Change From Baseline | -1.0 units on a scale | Standard Deviation 1.12 |
| Placebo | Subject Global Bother Assessment (SGBA)- Change From Baseline | -1.0 units on a scale | Standard Deviation 1.33 |
Other Pre-specified
Subject-reported Cellulite Impact Scale (SR-CIS)-Change From Baseline
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.
Time frame: Baseline, Day 73
Population: All subjects who received at least one injection and who had at least one post-injection efficacy measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 0.06 mg (Low Dose) | Subject-reported Cellulite Impact Scale (SR-CIS)-Change From Baseline | -15.0 units on a scale | Standard Deviation 18.9 |
| AA4500 0.48 mg (Mid-dose) | Subject-reported Cellulite Impact Scale (SR-CIS)-Change From Baseline | -18.0 units on a scale | Standard Deviation 15.7 |
| AA4500 0.84 mg (High Dose) | Subject-reported Cellulite Impact Scale (SR-CIS)-Change From Baseline | -17.7 units on a scale | Standard Deviation 14.61 |
| Placebo | Subject-reported Cellulite Impact Scale (SR-CIS)-Change From Baseline | -11.9 units on a scale | Standard Deviation 13.97 |
Other Pre-specified
Subject Satisfaction With Treatment Assessment (SCTA)
Subjects rated their treatment satisfaction at the Day 73 visit on a 5-point scale ranging from -2 (very dissatisfied) to +2 (very satisfied)
Time frame: Day 73
Population: All subjects who received at least one injection of study drug and had at least one post -injection efficacy measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 0.06 mg (Low Dose) | Subject Satisfaction With Treatment Assessment (SCTA) | 0.0 units on a scale | Standard Deviation 1.31 |
| AA4500 0.48 mg (Mid-dose) | Subject Satisfaction With Treatment Assessment (SCTA) | 0.9 units on a scale | Standard Deviation 0.89 |
| AA4500 0.84 mg (High Dose) | Subject Satisfaction With Treatment Assessment (SCTA) | 0.7 units on a scale | Standard Deviation 0.93 |
| Placebo | Subject Satisfaction With Treatment Assessment (SCTA) | 0.1 units on a scale | Standard Deviation 1.33 |