RELEASE-1: Effectiveness and Safety of EN3835 in the Treatment of EFP (Cellulite) in Women

• Sponsor: Endo Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03428750
• Collaborator: (none)
• Enrollment: 423
• Locations: 26
• Arms: 2
• Actual Duration (Months): 7.7
• Patients Per Site: 16.3
• Patients Per Site Per Month: 2.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Edematous Fibrosclerotic Panniculopathy (Cellulite)	Biological: EN3835; Biological: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 423 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of EN3835 In The Treatment Of Edematous Fibrosclerotic Panniculopathy (Cellulite)
• Actual Study Start Date: Feb 5, 2018
• Actual Primary Completion Date: Sep 26, 2018
• Actual Study Completion Date: Sep 26, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: EN3835 Active EN3835 0.84mg (Collagenase Clostridium Histolyticum)	Biological: EN3835; Collagenase clostridium histolyticum
Placebo Comparator: Placebo	Biological: Placebo; Placebo

Outcome Measures

Primary Outcome Measures

1. 2-level Composite Responders for the Target Buttock [Day 71]

   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.

Secondary Outcome Measures

1. 1-level PR-PCSS Responders of the Target Buttock [Day 71]

   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).

2. 2-level PR-PCSS Responders of the Target Buttock [Day 71]

   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).

3. 1-level Composite Responders of the Target Buttock [Day 71]

   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).

4. 2-level Composite Responder of the Non-target Buttock [Day 71]

   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).

5. 1-level SSRS Responders [Day 71]

   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.

6. Change From Baseline in PR-CIS Total Score [71 Days]

   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.

7. 1-level S-GAIS Responders of Target Buttock [Day 71]

   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.

8. 2-level S-GAIS Responders of Target Buttock [Day 71]

   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.

9. PR-PCSS Rating for the Target and Non-target Buttock by Visit [Day 1 to Day 71]

   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).

10. Subjects Satisfaction With Cellulite Treatment at Day 71 [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.

Other Outcome Measures

1. Serum Antibody Positivity by Visit [Day 1 - Day 71]

   Percent of participants that are seropositive. Percentages were based on the number of subjects who had immunogenicity lab samples analyzed at the visit.

2. Overall Antibody Titer Levels by Visit [Day 1 - Day 71]

   Descriptive statistics were based on log10 transformation of titer levels. Titer levels were imputed as 10 before the transformation if the reported level is "<10". Only seropositive participants are summarized.

3. Presence of Neutralizing Antibody (Seropositivity) at Day 71 (LOCF) by Antidrug Antibody Log Titer Quartiles [Day 71]

   Q1 and Q4 are based on the ADA titer levels.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Voluntarily sign and date an informed consent agreement

2. Be a female ≥18 years of age

3. At Screening visit, have 2 bilateral buttocks with each buttock having:

4. a score of 3 or 4 (moderate or severe) as reported by the subject (PR-PCSS), and

5. a score of 3 or 4 (moderate or severe) as reported by the Investigator (CR-PCSS)

6. At Day 1 visit, have 2 bilateral buttocks with each buttock having:

7. a score of 3 or 4 (moderate or severe) as reported by the subject (PR-PCSS), and

8. a score of 3 or 4 (moderate or severe) as reported by the Investigator (CR-PCSS)

9. 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)

10. Be judged to be in good health, based upon the results of a medical history, physical examination, and laboratory profile at Screening

11. 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

12. Be willing and able to cooperate with the requirements of the study

13. Be able to read, complete and understand the patient-reported outcomes rating instruments in English

Exclusion Criteria:

1. Has any of the following systemic conditions:

2. Coagulation disorder

3. Evidence or history of malignancy (other than excised basal-cell carcinoma) unless there has been no recurrence in at least 5 years

4. History of keloidal scarring or abnormal wound healing

5. 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

6. Evidence of clinically significant abnormalities on physical examination, vital signs, electrocardiogram (ECG), or clinical laboratory values

7. Has any of the following local conditions in the areas to be treated:

8. History of lower extremity thrombosis or post-thrombosis syndrome

9. Vascular disorder (eg, varicose veins, telangiectasia) in area to be treated

10. Inflammation or active infection

11. Severe skin laxity, flaccidity, and/or sagging

12. Active cutaneous alteration including rash, eczema, psoriasis, or skin cancer

13. Has a tattoo and/or a mole located within 2 cm of the site of injection

14. Requires the following concomitant medications before or during participation in the trial:

1. 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

1. 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:

2. Liposuction in a buttock during the 12-month period before injection of study drug

3. 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

4. Any investigational treatment for EFP on a buttock during the 12-month period before the injection of study drug

5. Endermologie or similar treatments within a buttock during the 6-month period before injection of study drug

6. Massage therapy within a buttock during the 3-month period before injection of study drug

7. 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

8. Is presently nursing or providing breast milk

9. Intends to become pregnant during the study

10. Intends to initiate an intensive sport or exercise program during the study

11. Intends to initiate a weight reduction program during the study

12. Intends to use tanning spray or tanning booths during the study

13. Has received an investigational drug or treatment within 30 days before injection of study drug

14. Has a known systemic allergy to collagenase or any other excipient of study drug

15. Has received any collagenase treatments at any time prior to treatment

16. 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

17. Any other condition(s) that, in the Investigator's opinion, might indicate the subject to be unsuitable for the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Endo Clinical Trial Site #1	Scottsdale	Arizona	United States	85258
2	Endo Clinical Trial Site #2	Encinitas	California	United States	92024
3	Endo Clinical Trial Site #3	Long Beach	California	United States	90806
4	Endo Clinical Trial Site #4	Los Angeles	California	United States	90025
5	Endo Clinical Trial Site #5	Oceanside	California	United States	92056
6	Endo Clinical Trial Site #6	San Diego	California	United States	92121
7	Endo Clinical Trial Site #7	Boca Raton	Florida	United States	33486
8	Endo Clinical Trial Site #8	Largo	Florida	United States	33770
9	Endo Clinical Trial Site #9	Miami	Florida	United States	33185
10	Endo Clinical Trial Site #10	Snellville	Georgia	United States	30078
11	Endo Clinical Trial Site #11	Chicago	Illinois	United States	60654
12	Endo Clinical Trial Site #12	New Orleans	Louisiana	United States	70115
13	Endo Clinical Trial Site #13	Chestnut Hill	Massachusetts	United States	02467
14	Endo Clinical Trial Site #14	Quincy	Massachusetts	United States	02169
15	Endo Clinical Trial Site #15	Fridley	Minnesota	United States	55432
16	Endo Clinical Trial Site #16	Washington	Missouri	United States	63090
17	Endo Clinical Trial Site #17	Omaha	Nebraska	United States	68144
18	Endo Clinical Trial Site #18	Mount Kisco	New York	United States	10549
19	Endo Clinical Trial Site #21	New York	New York	United States	10022
20	Endo Clinical Trial Site #19	New York	New York	United States	10065
21	Endo Clinical Trial Site #20	New York	New York	United States	10075
22	Endo Clinical Trial Site #22	Cincinnati	Ohio	United States	45249
23	Endo Clinical Trial Site #23	Houston	Texas	United States	77056
24	Endo Clinical Trial Site #24	Pflugerville	Texas	United States	78660
25	Endo Clinical Trial Site #25	Sugar Land	Texas	United States	77497
26	Endo Clinical Trial Site #26	Charlottesville	Virginia	United States	22911

Sponsors and Collaborators

• Endo Pharmaceuticals

Investigators

• Study Director: Michael McLane, Endo Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 5, 2018

More Information

Publications

None provided.

• Responsible Party: Endo Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03428750
• Other Study ID Numbers: EN3835-302
• First Posted: Feb 12, 2018
• Last Update Posted: Oct 8, 2020
• Last Verified: Sep 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Cellulite; Edema

Study Results

Participant Flow

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)	Placebo
Arm/Group Description	CCH 0.84 mg/Buttock 1.68 mg Total Dose	Placebo-control
Period Title: Overall Study
STARTED	210	213
COMPLETED	186	192
NOT COMPLETED	24	21

Baseline Characteristics

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)	Placebo	Total
Arm/Group Description	CCH 0.84 mg/Buttock 1.68 mg Total Dose	Placebo-control	Total of all reporting groups
Overall Participants	210	213	423
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.9 (10.33)	45.8 (9.84)	46.9 (10.13)
Sex: Female, Male (Count of Participants)
Female	210 100%	213 100%	423 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	31 14.8%	41 19.2%	72 17%
Not Hispanic or Latino	179 85.2%	172 80.8%	351 83%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.5%	2 0.9%	3 0.7%
Asian	0 0%	2 0.9%	2 0.5%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.5%	1 0.2%
Black or African American	47 22.4%	43 20.2%	90 21.3%
White	157 74.8%	161 75.6%	318 75.2%
More than one race	3 1.4%	4 1.9%	7 1.7%
Unknown or Not Reported	2 1%	0 0%	2 0.5%
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	31.04 (7.358)	30.97 (6.856)	31.00 (7.102)
Skin Category (Fitzpatrick Scale) (Count of Participants)
I (Pale White)	5 2.4%	4 1.9%	9 2.1%
II (Fair)	50 23.8%	48 22.5%	98 23.2%
III (Darker White)	69 32.9%	75 35.2%	144 34%
IV (Light Brown)	40 19%	35 16.4%	75 17.7%
V (Brown)	33 15.7%	27 12.7%	60 14.2%
VI (Dark Brown)	13 6.2%	24 11.3%	37 8.7%

Outcome Measures

1. Primary Outcome

Title	2-level Composite Responders for the Target Buttock
Description	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.
Time Frame	Day 71

Outcome Measure Data

Analysis Population Description

ITT Population includes all randomized participants who had at least 1 injection of study drug. All demographic and baseline characteristic summaries were based on this population. The primary and key secondary efficacy parameters were summarized based on this population.

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)	Placebo
Arm/Group Description	CCH 0.84 mg/Buttock	Placebo-control
Measure Participants	210	213
Yes: 2-Level Improvement	16 7.6%	4 1.9%
No: 2-Level Improvement	194 92.4%	209 98.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Collagenase Clostridium Histolyticum (CCH), Placebo
	Comments	CCH 0.84 mg/Buttock versus Placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusted for analysis center

2. Secondary Outcome

Title	1-level PR-PCSS Responders of the Target Buttock
Description	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).
Time Frame	Day 71

Outcome Measure Data

Analysis Population Description

ITT Population includes all randomized participants who had at least 1 injection of study drug. All demographic and baseline characteristic summaries were based on this population. The primary and key secondary efficacy parameters were summarized based on this population.

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)	Placebo
Arm/Group Description	CCH 0.84 mg/Buttock	Placebo-control
Measure Participants	210	213
Yes	114 54.3%	77 36.2%
No	96 45.7%	136 63.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Collagenase Clostridium Histolyticum (CCH), Placebo
	Comments	CCH 0.84 mg/Buttock versus Placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusted for analysis center

3. Secondary Outcome

Title	2-level PR-PCSS Responders of the Target Buttock
Description	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).
Time Frame	Day 71

Outcome Measure Data

Analysis Population Description

ITT Population includes all randomized participants who had at least 1 injection of study drug. All demographic and baseline characteristic summaries were based on this population. The primary and key secondary efficacy parameters were summarized based on this population.

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)	Placebo
Arm/Group Description	CCH 0.84 mg/Buttock	Placebo-control
Measure Participants	210	213
Yes	51 24.3%	26 12.2%
No	159 75.7%	187 87.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Collagenase Clostridium Histolyticum (CCH), Placebo
	Comments	CCH 0.84 mg/Buttock versus Placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusted for analysis center

4. Secondary Outcome

Title	1-level Composite Responders of the Target Buttock
Description	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).
Time Frame	Day 71

Outcome Measure Data

Analysis Population Description

ITT Population includes all randomized participants who had at least 1 injection of study drug. All demographic and baseline characteristic summaries were based on this population. The primary and key secondary efficacy parameters were summarized based on this population.

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)	Placebo
Arm/Group Description	CCH 0.84 mg/Buttock	Placebo-control
Measure Participants	210	213
Yes	78 37.1%	38 17.8%
No	132 62.9%	175 82.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Collagenase Clostridium Histolyticum (CCH), Placebo
	Comments	CCH 0.84 mg/Buttock versus Placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusted for analysis center

5. Secondary Outcome

Title	2-level Composite Responder of the Non-target Buttock
Description	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).
Time Frame	Day 71

Outcome Measure Data

Analysis Population Description

ITT Population includes all randomized participants who had at least 1 injection of study drug. All demographic and baseline characteristic summaries were based on this population. The primary and key secondary efficacy parameters were summarized based on this population.

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)	Placebo
Arm/Group Description	CCH 0.84 mg/Buttock	Placebo-control
Measure Participants	210	213
Yes	16 7.6%	2 0.9%
No	194 92.4%	211 99.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Collagenase Clostridium Histolyticum (CCH), Placebo
	Comments	CCH 0.84 mg/Buttock versus Placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusted for analysis center

6. Secondary Outcome

Title	1-level SSRS Responders
Description	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.
Time Frame	Day 71

Outcome Measure Data

Analysis Population Description

ITT Population includes all randomized participants who had at least 1 injection of study drug. All demographic and baseline characteristic summaries were based on this population. The primary and key secondary efficacy parameters were summarized based on this population.

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)	Placebo
Arm/Group Description	CCH 0.84 mg/Buttock (1.68 mg Total Dose)	Placebo-control
Measure Participants	210	213
Count of Participants [Participants]	102 48.6%	48 22.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Collagenase Clostridium Histolyticum (CCH), Placebo
	Comments	CCH 0.84 mg/Buttock versus Placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusted for analysis center

7. Secondary Outcome

Title	Change From Baseline in PR-CIS Total Score
Description	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.
Time Frame	71 Days

Outcome Measure Data

Analysis Population Description

ITT Population includes all randomized participants who had at least 1 injection of study drug. All demographic and baseline characteristic summaries were based on this population. The primary and key secondary efficacy parameters were summarized based on this population.

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)	Placebo
Arm/Group Description	CCH 0.84 mg/Buttock (1.68 mg Total Dose)	Placebo-control
Measure Participants	210	213
Baseline (Day 1)	51.1 (8.86)	51.6 (9.77)
Day 71	40.2 (13.27)	45.7 (12.93)
Change from Baseline	-10.9 (12.51)	-5.9 (11.62)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Collagenase Clostridium Histolyticum (CCH), Placebo
	Comments	CCH 0.84 mg/Buttock versus Placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments	With factors of treatment group and analysis center adjusted for baseline values in the model

8. Secondary Outcome

Title	1-level S-GAIS Responders of Target Buttock
Description	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.
Time Frame	Day 71

Outcome Measure Data

Analysis Population Description

ITT Population includes all randomized participants who had at least 1 injection of study drug. All demographic and baseline characteristic summaries were based on this population. The primary and key secondary efficacy parameters were summarized based on this population.

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)	Placebo
Arm/Group Description	CCH 0.84 mg/Buttock	Placebo-control
Measure Participants	210	213
Count of Participants [Participants]	135 64.3%	82 38.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Collagenase Clostridium Histolyticum (CCH), Placebo
	Comments	CCH 0.84 mg/Buttock versus Placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusted for analysis center

9. Secondary Outcome

Title	2-level S-GAIS Responders of Target Buttock
Description	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.
Time Frame	Day 71

Outcome Measure Data

Analysis Population Description

ITT Population includes all randomized participants who had at least 1 injection of study drug. All demographic and baseline characteristic summaries were based on this population. The primary and key secondary efficacy parameters were summarized based on this population.

Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)	Placebo
Arm/Group Description	CCH 0.84 mg/Buttock	Placebo-control
Measure Participants	210	213
Count of Participants [Participants]	49 23.3%	13 6.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Collagenase Clostridium Histolyticum (CCH), Placebo
	Comments	CCH 0.84 mg/Buttock versus Placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusted for analysis center

10. Secondary Outcome

Title	PR-PCSS Rating for the Target and Non-target Buttock by Visit
Description	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).
Time Frame	Day 1 to Day 71

Outcome Measure Data

Analysis Population Description

mITT Population includes all ITT participants with a baseline and at least 1 post-injection evaluation of both the CR-PCSS and PR-PCSS for both the target and nontarget buttocks. All secondary and supportive efficacy evaluations were based on the mITT Population.

Arm/Group Title	Day 1: CCH	Day 1: Placebo	Day 22: CCH	Day 22: Placebo	Day 43: CCH	Day 43: Placebo	Day 71: CCH	Day 71: Placebo	Day 71: CCH (LOCF)	Day 71: Placebo (LOCF)
Arm/Group Description	Baseline (Day 1) for CCH Treated Group	Baseline (Day 1) for Placebo Group	Day 22 for CCH Treated Group	Day 22 for Placebo Group	Day 43 for CCH Treated Group	Day 43 for Placebo Group	Day 71 for CCH Treated Group	Day 71 for Placebo Group	Day 71 for CCH Treated Group (Last observation carried forward)	Day 71 for Placebo Group (Last observation carried forward)
Measure Participants	201	205	201	205	201	205	201	205	201	205
None (0)	0 0%	0 0%	0 0%	0 NaN	0 NaN	1 NaN	0 NaN	2 NaN	0 NaN	2 NaN
Almost None (1)	0 0%	0 0%	1 0.2%	0 NaN	13 NaN	4 NaN	25 NaN	5 NaN	25 NaN	5 NaN
Mild (2)	0 0%	0 0%	29 6.9%	7 NaN	50 NaN	24 NaN	54 NaN	38 NaN	58 NaN	40 NaN
Moderate (3)	84 40%	82 38.5%	79 18.7%	95 NaN	75 NaN	95 NaN	65 NaN	77 NaN	72 NaN	81 NaN
Severe (4)	117 55.7%	123 57.7%	78 18.4%	100 NaN	50 NaN	71 NaN	40 NaN	67 NaN	46 NaN	77 NaN
None (0)	0 0%	0 0%	0 0%	0 NaN	1 NaN	1 NaN	1 NaN	2 NaN	1 NaN	2 NaN
Almost None (1)	0 0%	0 0%	2 0.5%	0 NaN	12 NaN	4 NaN	20 NaN	7 NaN	21 NaN	7 NaN
Mild (2)	0 0%	0 0%	27 6.4%	9 NaN	50 NaN	33 NaN	55 NaN	34 NaN	59 NaN	35 NaN
Moderate (3)	81 38.6%	83 39%	81 19.1%	89 NaN	80 NaN	82 NaN	63 NaN	88 NaN	70 NaN	93 NaN
Severe (4)	120 57.1%	122 57.3%	77 18.2%	104 NaN	45 NaN	75 NaN	45 NaN	59 NaN	50 NaN	68 NaN

11. Secondary Outcome

Title	Subjects Satisfaction With Cellulite Treatment at Day 71
Description	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.
Time Frame	Day 71

Outcome Measure Data

Analysis Population Description

mITT Population includes all ITT participants with a baseline and at least 1 post-injection evaluation of both the CR-PCSS and PR-PCSS for both the target and nontarget buttocks. All secondary and supportive efficacy evaluations were based on the mITT Population.

Arm/Group Title	Day 71: CCH	Day 71: Placebo	Day 71: CCH (LOCF)	Day 71: Placebo (LOCF)
Arm/Group Description	CCH	Placebo	Last Observation Carried Forward - CCH	Last Observation Carried Forward - Placebo
Measure Participants	184	190	195	191
Very Satisfied (+2)	24 11.4%	7 3.3%	24 5.7%	7 NaN
Satisfied (+1)	76 36.2%	42 19.7%	80 18.9%	42 NaN
Neither Satisfied Nor Dissatisfied (0)	46 21.9%	56 26.3%	52 12.3%	56 NaN
Dissatisfied (-1)	23 11%	42 19.7%	23 5.4%	42 NaN
Very Dissatisfied (-2)	15 7.1%	43 20.2%	16 3.8%	44 NaN

12. Other Pre-specified Outcome

Title	Serum Antibody Positivity by Visit
Description	Percent of participants that are seropositive. Percentages were based on the number of subjects who had immunogenicity lab samples analyzed at the visit.
Time Frame	Day 1 - Day 71

Outcome Measure Data

Analysis Population Description

Safety Population includes all participants who received at least 1 dose of CCH in this study. All safety parameters were summarized based on this population.

Arm/Group Title	Anti-AUX-I: CCH	Anti-AUX-I: Placebo	Anti-AUX-II: CCH	Anti-AUX-II: Placebo
Arm/Group Description	CCH	Placebo	CCH	Placebo
Measure Participants	209	212	209	212
Seropositive	12 5.7%	5 2.3%	11 2.6%	9 NaN
Seronegative	197 93.8%	207 97.2%	198 46.8%	203 NaN
Seropositive	97 46.2%	5 2.3%	49 11.6%	9 NaN
Seronegative	90 42.9%	195 91.5%	138 32.6%	191 NaN
Seropositive	186 88.6%	6 2.8%	180 42.6%	10 NaN
Seronegative	2 1%	188 88.3%	8 1.9%	184 NaN
Seropositive	185 88.1%	10 4.7%	185 43.7%	12 NaN
Seronegative	0 0%	182 85.4%	0 0%	180 NaN

13. Other Pre-specified Outcome

Title	Overall Antibody Titer Levels by Visit
Description	Descriptive statistics were based on log10 transformation of titer levels. Titer levels were imputed as 10 before the transformation if the reported level is "<10". Only seropositive participants are summarized.
Time Frame	Day 1 - Day 71

Outcome Measure Data

Analysis Population Description

Safety Population includes all participants who received at least 1 dose of CCH in this study. All safety parameters were summarized based on this population.

Arm/Group Title	Anit-AUX-I: CCH	Anti-AUX-I: Placebo	Anti-AUX-II: CCH	Anti-AUX-II: Placebo
Arm/Group Description	CCH	Placebo	CCH	Placebo
Measure Participants	209	212	209	212
Day 1 positive	4.396 (2.2644)	3.682 (2.2514)	4.366 (2.1658)	2.478 (1.6280)
Day 22 positive	2.561 (1.7812)	3.428 (2.3377)	2.599 (2.1305)	2.693 (1.7244)
Day 43 positive	4.639 (0.9961)	2.597 (1.5802)	3.706 (1.2138)	2.052 (1.3049)
Day 71 positive	6.011 (0.6758)	1.845 (1.3931)	5.266 (0.7549)	1.927 (1.3274)

14. Other Pre-specified Outcome

Title	Presence of Neutralizing Antibody (Seropositivity) at Day 71 (LOCF) by Antidrug Antibody Log Titer Quartiles
Description	Q1 and Q4 are based on the ADA titer levels.
Time Frame	Day 71

Outcome Measure Data

Analysis Population Description

Safety Population includes all participants who received at least 1 dose of CCH in this study. All safety parameters were summarized based on this population.

Arm/Group Title	CCH: Q1	CCH: Q4	CCH: Total
Arm/Group Description	Quartile 1	Quartile 4	Total
Measure Participants	24	24	48
Negative	16 7.6%	0 0%	16 3.8%
Positive	8 3.8%	24 11.3%	32 7.6%
Negative	10 4.8%	0 0%	10 2.4%
Positive	13 6.2%	23 10.8%	36 8.5%

Adverse Events

Time Frame	All (serious and nonserious) AEs, from Day 1 to Day 71
Adverse Event Reporting Description	All (serious and nonserious) AEs, whether elicited or observed during study visits or spontaneously reported by the participant, including events that occurred from the time the participant signed the study-specific consent form until completion of or discharge from the study.
Arm/Group Title	Collagenase Clostridium Histolyticum (CCH)		Placebo
Arm/Group Description	CCH 0.84 mg/Buttock 1.68 mg Total Dose		Placebo-control
All Cause Mortality
	Collagenase Clostridium Histolyticum (CCH)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/210 (0%)		0/213 (0%)
Serious Adverse Events
	Collagenase Clostridium Histolyticum (CCH)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/210 (0%)		1/213 (0.5%)
Gastrointestinal disorders
Colitis ischaemic	0/210 (0%)		1/213 (0.5%)
Other (Not Including Serious) Adverse Events
	Collagenase Clostridium Histolyticum (CCH)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	166/210 (79%)		55/213 (25.8%)
General disorders
Injection site bruising	137/210 (65.2%)		42/213 (19.7%)
Injection site pain	76/210 (36.2%)		11/213 (5.2%)
Injection stie nodule	38/210 (18.1%)		0/213 (0%)
Injection site pruritus	29/210 (13.8%)		1/213 (0.5%)
Injection site haemorrhage	25/210 (11.9%)		5/213 (2.3%)
Injection site mass	18/210 (8.6%)		1/213 (0.5%)
Injection site swelling	15/210 (7.1%)		0/213 (0%)
Injection site discolouration	12/210 (5.7%)		0/213 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.