Effectiveness and Safety of EN3835 in the Treatment of EFP (Cellulite) in Women

Study Overview
=================
Brief Summary
-----------------
Subjects will be screened for study eligibility within 14 days prior to enrolling in this study. Subjects with 2 treatment areas (bilateral buttocks) with moderate or severe levels of cellulite as independently assessed by the subject using the Patient Reported Photonumeric Cellulite Severity Scale (PR-PCSS) and by the Investigator using the Clinician Reported Photonumeric Cellulite Severity Scale (CR-PCSS) will be eligible. The eligibility of the buttocks will be confirmed on Day 1. Once the eligibility of the buttocks is confirmed, subjects will be randomly assigned to a treatment group (EN3835 0.84 mg per buttock or placebo) in a 1:1 ratio within an investigational site. Each subject will receive a treatment course which consists of up to 3 treatment visits (sessions), separated by 21 days (ie, Days 1, 22, and 43). Each treatment visit will consist of 12 injections (0.3 mL per injection of EN3835 0.07 mg/injection or placebo; 0.84 mg in 3.6 mL per buttock) in each of the two buttocks for a total volume of 7.2 mL (1.68 mg). Selection of dimples to be treated in the buttocks will be at the discretion of the Investigator. End of study will occur at study day 71.

Official Title
-----------------
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of EN3835 In The Treatment Of Edematous Fibrosclerotic Panniculopathy (Cellulite)

Conditions
-----------------
Edematous Fibrosclerotic Panniculopathy (Cellulite)

Intervention / Treatment
-----------------
* Biological: EN3835
* Biological: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Voluntarily sign and date an informed consent agreement Be a female ≥18 years of age At Screening visit, have 2 bilateral buttocks with each buttock having: a score of 3 or 4 (moderate or severe) as reported by the subject (PR-PCSS), and a score of 3 or 4 (moderate or severe) as reported by the Investigator (CR-PCSS) At Day 1 visit, have 2 bilateral buttocks with each buttock having: a score of 3 or 4 (moderate or severe) as reported by the subject (PR-PCSS), and a score of 3 or 4 (moderate or severe) as reported by the Investigator (CR-PCSS) Be willing to apply sunscreen to the buttocks before each exposure to the sun while participating in the study (ie, Screening through end of study) Be judged to be in good health, based upon the results of a medical history, physical examination, and laboratory profile at Screening Have a negative serum pregnancy test at Screening and a negative urine pregnancy test before injection of study drug and be using a stable and effective contraception method (eg, abstinence, intrauterine device [IUD], hormonal [estrogen/progestin] contraceptives, or double barrier method) for at least 1 menstrual cycle prior to study enrollment and for the duration of the study; or be menopausal defined as 12 months of amenorrhea in the absence of other biological or physiological causes, as determined by the Investigator; or post-menopausal for at least 1 year; or be surgically sterile Be willing and able to cooperate with the requirements of the study Be able to read, complete and understand the patient-reported outcomes rating instruments in English Exclusion Criteria: Has any of the following systemic conditions: Coagulation disorder Evidence or history of malignancy (other than excised basal-cell carcinoma) unless there has been no recurrence in at least 5 years History of keloidal scarring or abnormal wound healing Concurrent diseases or conditions that might interfere with the conduct of the study, confound the interpretation of the study results, or endanger the subject's well-being. Any questions about concurrent diseases should be discussed with the Medical Monitor Evidence of clinically significant abnormalities on physical examination, vital signs, electrocardiogram (ECG), or clinical laboratory values Has any of the following local conditions in the areas to be treated: History of lower extremity thrombosis or post-thrombosis syndrome Vascular disorder (eg, varicose veins, telangiectasia) in area to be treated Inflammation or active infection Severe skin laxity, flaccidity, and/or sagging Active cutaneous alteration including rash, eczema, psoriasis, or skin cancer Has a tattoo and/or a mole located within 2 cm of the site of injection Requires the following concomitant medications before or during participation in the trial: a. Anticoagulant or antiplatelet medication or has received anticoagulant or antiplatelet medication (except for ≤150 mg aspirin daily) within 7 days before injection of study drug Has used any of the following for the treatment of EFP on a buttock within the timelines identified below or intends to use any of the following at any time during the course of the study: Liposuction in a buttock during the 12-month period before injection of study drug Injections (eg, mesotherapy); radiofrequency device treatments; laser treatment; buttock implant treatment; cryolipolysis; or surgery (including subcision and/or powered subcision) within a buttock during the 12-month period before injection of study drug Any investigational treatment for EFP on a buttock during the 12-month period before the injection of study drug Endermologie or similar treatments within a buttock during the 6-month period before injection of study drug Massage therapy within a buttock during the 3-month period before injection of study drug Creams (eg, Celluvera™, TriLastin®) and/or home therapies to prevent or mitigate EFP within a buttock during the 2-week period before injection of study drug Is presently nursing or providing breast milk Intends to become pregnant during the study Intends to initiate an intensive sport or exercise program during the study Intends to initiate a weight reduction program during the study Intends to use tanning spray or tanning booths during the study Has received an investigational drug or treatment within 30 days before injection of study drug Has a known systemic allergy to collagenase or any other excipient of study drug Has received any collagenase treatments at any time prior to treatment Was a subject in a previous cellulite clinical trial of CCH: AUX-CC-830, AUX-CC-831, EN3835-102, EN3835-104, EN3835-201, EN3835-202, and/or EN3835-205 Any other condition(s) that, in the Investigator's opinion, might indicate the subject to be unsuitable for the study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: EN3835 Active<br>EN3835 0.84mg (Collagenase Clostridium Histolyticum) | Biological: EN3835<br>* Collagenase clostridium histolyticum<br>|
| Placebo Comparator: Placebo<br> | Biological: Placebo<br>* Placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-level Composite Responders for the Target Buttock | Number of of 2-level Clinician-Reported Photonumeric Cellulite Severity Scale (CR-PCSS) / Patient-Reported Photonumeric Cellulite Severity Scale (PR-PCSS) composite responders in the target buttock at Day 71. CR-PCSS and PR-PCSS is a 5-level scale ranging from 0 (None) to 4 (Severe). A participant who missed one or two assessments of CR-PCSS and PR-PCSS at Day 71 was defined as a non-responder. A 2-level composite responder is defined as a participant with an improvement from baseline of at least 2-levels of severity in the CR-PCSS and an improvement from baseline of at least 2-levels of severity in the PR-PCSS of the target buttock. | Day 71 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1-level PR-PCSS Responders of the Target Buttock | Improvement in cellulite severity of the Target Buttock from baseline of at least 1-level of severity in Patient-Reported Photonumeric Cellulite Severity Scale (PR-PCSS). PR-PCSS is a 5-level scale ranging from 0 (None) to 4 (Severe). | Day 71 | 
| 2-level PR-PCSS Responders of the Target Buttock | Improvement in cellulite severity of the Target Buttock from baseline of at least 2-level of severity in Patient-Reported Photonumeric Cellulite Severity Scale (PR-PCSS). PR-PCSS is a 5-level scale ranging from 0 (None) to 4 (Severe). | Day 71 | 
| 1-level Composite Responders of the Target Buttock | Improvement in cellulite severity of the Target Buttock from baseline of at least 1-level of severity in Patient-Reported Photonumeric Cellulite Severity Scale (PR-PCSS) / Clinician-Reported Photonumeric Cellulite Severity Scale (CR-PCSS). PR-PCSS and CR-PCSS is a 5-level scale ranging from 0 (None) to 4 (Severe). | Day 71 | 
| 2-level Composite Responder of the Non-target Buttock | Improvement in cellulite severity of the Non-target Buttock from baseline of at least 2-levels of severity in Patient-Reported Photonumeric Cellulite Severity Scale (PR-PCSS) / Clinician-Reported Photonumeric Cellulite Severity Scale (CR-PCSS). PR-PCSS and CR-PCSS is a 5-level scale ranging from 0 (None) to 4 (Severe). | Day 71 | 
| 1-level SSRS Responders | Subject Self-Rating Scale (SSRS) is a measure that assesses participant satisfaction with appearance in association with cellulite on the buttocks using whole numbers on a 7-level scale that ranges from 0 (Extremely Dissatisfied) to 6 (Extremely Satisfied). A 1-level SSRS responder is defined as a participant who is at least slightly satisfied (Slightly Satisfied [4], Very Satisfied [5], or Extremely Satisfied [6]) with the appearance of the cellulite on her buttocks at Day 71. | Day 71 | 
| Change From Baseline in PR-CIS Total Score | Patient Reported Cellulite Impact Scale (PR-CIS) is a 6-item static questionnaire, each item is answered by a participant on a 11-level numerical rating scale that ranges from 0 (Not at all) to 10 (Extremely). The PR-CIS total score is the sum of individual item scores and can range from 0 to 60 with higher numbers reflecting a more negative impact from the cellulite. A responder was defined as a participant with a reduction in the PR-CIS total score of at least 12 from baseline at an evaluation time point. A negative change from baseline indicates an improvement in cellulite severity. | 71 Days | 
| 1-level S-GAIS Responders of Target Buttock | Subject Global Aesthetic Improvement Scale (S-GAIS) is a measure that assesses participant rating of cellulite appearance after treatment. This scale has 7-levels ranging from +3 (Very Much Improved) to -3 (Very Much Worse). Responders are defined as participants with at least ≥ 1-level improvement (Improved, Much Improved or Very Much Improved) in S-GAIS assessment of the Target Buttock. | Day 71 | 
| 2-level S-GAIS Responders of Target Buttock | Subject Global Aesthetic Improvement Scale (S-GAIS) is a measure that assesses participant rating of cellulite appearance after treatment. This scale has 7-levels ranging from +3 (Very Much Improved) to -3 (Very Much Worse). Responders are defined as participants with at least ≥ 2-level improvement (Much Improved or Very Much Improved) in S-GAIS assessment of the Target Buttock. | Day 71 | 
| PR-PCSS Rating for the Target and Non-target Buttock by Visit | The Patient-Reported Photonumeric Cellulite Severity Scale (PR-PCSS) is a 5-level photonumeric scale used by the patient (participant) to assess the severity of the participant's cellulite. The scale ratings range from 0 (None) to 4 (Severe). | Day 1 to Day 71 | 
| Subjects Satisfaction With Cellulite Treatment at Day 71 | A 1-level Subject Satisfaction responder is defined as a participant who is at least Satisfied (Satisfied [+1], or Very Satisfied [+2]) with the appearance of the cellulite on her buttocks at the Day 71 visit. A positive change indicates an improvement in cellulite. | Day 71 |