Clinical trial NCT04209530
Conditions: Cellulite Edematous Fibrosclerotic Panniculopathy (EFP)
Sponsor: Endo Pharmaceuticals
Start date: 2019-11-20; Completion date: 2020-10-05
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single center, open-label, Phase 2a study to assess the photonumeric scale, morphological, and histopathological changes associated with Collagenase Clostridium Histolyticum (CCH) in adult women with moderate or severe Edematous Fibrosclerotic Panniculopathy (EFP).

Detailed description:

Arms: arm 1: EN3835 up to 1.68 mg (Collagenase Clostridium Histolyticum)
Interventions: intervention 1: EN3835
Intervention descriptions: intervention 1: Collagenase Clostridium Histolyticum (CCH)

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
Endo Pharmaceuticals Inc. 
1400 Atwater Drive 
Malvern, PA 19355 USA 
 
EN3835-212 
A PHASE 2a, OPEN-LABEL STUDY TO ASSESS THE 
IMPACT OF CCH TREATMENT OF BUTTOCK AND 
THIGH CELLULITE IN ADULT FEMALES USING 
PHOTONUMERIC SCALES, MAGNETIC RESONANCE 
IMAGING, AND HISTOPATHOLOGY 
 
Sponsor Name: Endo Pharmaceuticals Inc. 
Sponsor Legal Registered Address:1400 Atwater Drive, Malvern, PA 19355 
Regulatory Agency Identifier Number(s): IND 110077 
 
Original Protocol: 22 October 2019 
Amendment 1: 16 January 2020 
Amendment 2: 04 March 2020 
Amendment 3: 08 May 2020 
 
The sponsor of the Investigational New Drug Application (IND) is Endo Global Aesthetics 
Limited (EGAL); however, Endo Pharmaceuticals Inc. (Endo) is authorized to act and to 
communicate on behalf of EGAL. The sponsor is responsible for the conduct of the study, 
analysis of the data, and preparation of the clinical study report. 
 
 
 
 
08 May 2020 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Protocol Amendment 3: 08 May 2020 
Amendment 3 was incorporated into the protocol on 08 May 2020. The major reason for this 
amendment is to modify the protocol due to the interruption caused by the COVID-19 public 
health emergency. The COVID-19 public health emergency has disrupted the conduct of clinical 
research throughout the world. At Endo Pharmaceuticals Inc. (Endo) ensuring the safety of 
clinical study participants is our primary concern. In addition, the integrity of data obtained from 
clinical trials must be ensured. 
Endo initiated Study EN3835-212 at a single investigational site in November 2019. The first 
subject was dosed with CCH on 26 December 2019. On 18 March 2020, the investigational site 
suspended Study EN3835-212 due to the COVID-19 public health emergency. At that time, 
7 subjects had received at least 1 dose of CCH in the study. Of those 7 subjects, 2 had completed 
the 3 doses required for the study and 1 subject had completed 2 doses. No subjects had 
completed all assessments required for the Day 71 Visit or beyond. 
On 15 April 2020, all 7 subjects were more than 1 week outside of the visit window for their next 
dose or for the Day 71 visit and there was no indication that the site would be able to re-open 
within the following 2 weeks. In order to ensure subject safety and protect data integrity, Endo, 
in accordance with the FDA Guidance on Conduct of Clinical Trials of Medical Products during 
COVID-19 Public Health Emergency (March 2020, updated 16 April 2020), decided to add 
additional subjects and modify the assessments required for current subjects when the 
investigational site re-opens as follows (and with subject consent): 
• Subjects who were in screening for the study at the time of interruption 
(18 March 2020) but who had not been dosed with CCH will repeat all screening 
assessments to determine eligibility, if willing to do so. All screening assessments 
must be repeated within the screening window. 
• Subjects who had received less than 3 doses of CCH prior to 18 March 2020 will be 
allowed to continue in the study and may receive any remaining doses with Sponsor 
approval. These subjects will complete all remaining visits and assessments EXCEPT 
biopsies and biopsy follow-up visits, if willing to do so. These subjects will be 
included in the safety assessments for the study, but will not be included in the 
efficacy assessments. Subjects who received less than 3 doses prior to 18 March 2020 
may elect to remain in the study without receiving additional doses. 
• Subjects who received all 3 doses of CCH prior to 18 March 2020, will be allowed to 
continue in the study and complete all remaining visits and assessments (including 
biopsies and biopsy follow-up visits), if willing to do so. These subjects will be 
included in the safety assessments for the study, but will not be included in the 
efficacy assessments. Subjects who received all 3 doses of CCH prior to 
18 March 2020 may elect to remain in the study without completing the biopsies and 
biopsy follow-up visits. 


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• An additional 12 subjects will be dosed in the study. These subjects will be included 
in the safety assessments, and all efficacy assessments will be based on the data for 
these 12 subjects. 
Major updates to specific sections of the protocol that are impacted are outlined below, other 
minor changes that do not impact study conduct or participant safety were also made: 
Section 1.1 Synopsis 
Study Period: The estimated date of last subject completion has been changed from 
November 2020 to October 2021. 
Overall Design: The number of subjects to be dosed in the study has been increased from 
12 to 19. The subject participation has been updated as outlined above. The approximate duration 
of the study has been increased from 12 months to 24 months. The per subject duration of 
participation has been modified to indicate approximately 305 days (10 months) plus any delays 
due to the COVID-19 public health emergency. 
Number of Subjects (planned): Wording has been modified to indicate that approximately 
19 subjects will receive study drug so that approximately 12 subjects who did not experience 
interruptions due to the COVID-19 public health emergency will complete the study. 
Section 1.2 Schedule of Activities 
Footnote “j” has been amended and added to indicate that subjects who had less than 3 doses of 
CCH prior to 18 March 2020 will not have the Day 71 or Day 251 biopsies. And footnote “k” 
was added to indicate subjects who had less than 3 doses of CCH prior to 18 March 2020 will 
not be required to have the Day 85 and Day 265 biopsy follow-up visits. 
Section 2.1 Study Rationale 
The rationale for changes to the study due to the COVID-19 public health emergency (as 
outlined above) has been added to the end of this section. 
Section 4.1 Overall Design 
The section has been updated with the modifications in design for subjects who were screened or 
dosed prior to 18 March 2020 as outlined above. 
Section 4.4 End of Study Definition 
This section has been modified as follows: A subject will be considered to have completed the 
study if the subject received their first dose of study drug after 18 March 2020 and completed the 
Day 265 visit. Subjects who received their first dose of study drug prior to 18 March 2020 and 
complete the Day 265 Visit (or the Day 251 Visit if they elect not to have biopsies) also will be 
considered to have completed the study. 
Section 5.4 Screen Failures 
The following text was added: Subjects who were screened prior to 18 March 2020 for the study 
but had not been dosed with CCH may be rescreened. All screening assessments must be 
repeated within the screening window (35 days). 


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Section 6.1 Selecting the Treatment Region 
The following text was added: For the 12 new subjects who receive their first dose of study drug 
after 18 March 2020, every attempt will be made to enroll an equal number of subjects across the 
2 severity levels in both buttocks and thighs (eg, 3 subjects with moderate buttock cellulite, 
3 subjects with severe buttock cellulite, 3 subjects with moderate thigh cellulite, and 3 subjects 
with severe thigh cellulite). 
Section 7.1 Discontinuation of Study Treatment, Section 7.2 Subject Discontinuation/ 
Withdrawal from Study, and Section 7.3 Lost to Follow-up 
These sections have been modified to indicate that all subjects dosed prior to 18 March 2020 will 
be replaced. In addition, subjects who receive their first dose of study drug after 18 March 2020 
and subsequently discontinue from study treatment and/or withdraw from the study and/or are 
lost to follow-up will not be replaced. 
Section 8.2.9 Biopsy Follow-up Examination 
This section was updated to indicate that the Day 85 and Day 265 Biopsy Follow-up Visits are 
not required for subjects who had less than 3 doses of study drug prior to 18 March 2020. 
Section 8.6.2 Double Punch Biopsy 
This section was updated to indicate that subjects who had less than 3 doses of study drug prior 
to 18 March 2020 will not have the Day 71 and Day 251 biopsies performed. In addition, 
subjects who completed 3 doses of CCH prior to 18 March 2020 will have Day 71 or Day 251 
biopsies, if willing to do so. 
Section 9.2 Populations for Analysis 
The Evaluable Population has been redefined to include all subjects in the Safety Population who 
received their first dose of CCH in this study after 18 March 2020 and who had a baseline and at 
least 1 postinjection PR-PCSS evaluation. 
Section 9.3.1 Efficacy Analysis 
This section has been updated to indicate that all secondary and tertiary PR-PCSS, CR-PCSS, 
and Hexsel efficacy endpoints will be summarized by treatment area (left or right) and region 
(buttock or thigh) using appropriate descriptive statistics using the Evaluable Population. 
Section 9.4 Interim Analysis 
This section has been modified to indicate that the interim analysis will be conducted when at 
least 4 of the 12 subjects who received their first dose of study drug after 18 March 2020 have 
completed their Day 71 visit. For all subjects who received their first dose of study drug after 
18 March 2020, analysis of all primary, secondary, and tertiary endpoints will be included in the 
interim analysis. For the subjects who received all three doses prior to 18 March 2020, their MRI 
and biopsy data, if available, will be assessed separately but included in interim analysis. The 
purpose of the interim analysis is to determine if changes in morphology and/or histology can be 
identified using MRI and biopsy. If the interim analysis does not indicate that such changes can 
be identified, subsequent or additional MRIs or biopsies will not be performed in this study. 


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Protocol Amendment 2: 04 March 2020 
Amendment 2 was incorporated into the protocol on 04 March 2020. The major reason for this 
amendment is that a slower than expected enrollment rate has made it unlikely that all subjects 
will complete the Day 71 visits before the earliest enrolled subjects are scheduled for additional 
MRI and biopsies. Therefore, the interim analysis will be conducted when the first 6 subjects 
complete their Day 71 Visit, rather than when all subjects complete that visit. Additional minor 
changes that do not impact study conduct or participant safety were also made. 
The major revision to the protocol is: 
• The interim analysis will be done when at least 6 subjects have completed their 
Day 71 visit (Section 9.4). 
 
Protocol Amendment 1: 16 January 2020 
Amendment 1 was incorporated into the protocol on 16 January 2020. The major reason for this 
amendment is to allow more time to obtain evaluable MRI images at screening and to permit 
repetition of MRIs during screening. Additional minor changes that do not impact study conduct 
or participant safety were also made. 
The major revisions to the protocol include: 
• Increasing the window for screening from 28 to 35 days. The screening period is now 
Day -35 to Day -1. This increases the duration of subject participation from 
approximately 298 Days to approximately 305 days (Section 1.1 Synopsis, 
Section 1.2 Schedule of Activities, and Section 4.1 Overall Design). 
• Increased the window for the Day 71 visit to 10 days (Section 1.2 Schedule of 
Activities). 
• Adding an additional inclusion criteria (Section 5.1, #13) requiring subjects to have 
evaluable MRI images of Dimples 1, 2, and 3 at screening. 
• Clarifying the wording in Section 5.4 Screen Failures to indicate that subjects can 
repeat any screening evaluation once with the exception of the Dimple 1, 2, and 3 
MRIs which may be repeated until an evaluable image is obtained, and to allow 
rescreening of subjects who do not have evaluable MRIs during the screening period. 
• As per Administrative Change Letter No. 1, the phrase “up to” was added to all 
references to the number of injections in Section 1.1 Synopsis, Section 6.2 Selecting 
and Marking Dimples for Treatment, and Table 2 Study Treatment. 
• Permitting the repetition of MRIs on Day 71 and Day 251 as often necessary to obtain 
an evaluable image (Section 1.2, footnote h and Section 8.6.1). 


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TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................... 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ...................................................... 2 
1. 
PROTOCOL SUMMARY ....................................................................................10 
1.1. 
Synopsis ...............................................................................................................10 
1.2. 
Schedule of Activities............................................................................................13 
2. 
INTRODUCTION................................................................................................16 
2.1. 
Study Rationale.....................................................................................................16 
2.2. 
Background ..........................................................................................................17 
2.3. 
Risk/Benefit Assessment.......................................................................................18 
3. 
OBJECTIVES AND ENDPOINTS .......................................................................19 
4. 
STUDY DESIGN .................................................................................................20 
4.1. 
Overall Design......................................................................................................20 
4.2. 
Scientific Rationale for the Study Design ...............................................................21 
4.3. 
Justification for Dose ............................................................................................21 
4.4. 
End of Study Definition .........................................................................................21 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS ...........................................21 
5.1. 
Subject Inclusion Criteria ......................................................................................21 
5.2. 
Subject Exclusion Criteria .....................................................................................23 
5.3. 
Lifestyle Considerations ........................................................................................25 
5.4. 
Screen Failures......................................................................................................25 
6. 
STUDY TREATMENT ........................................................................................26 
6.1. 
Selecting the Treatment Region .............................................................................26 
6.2. 
Selecting and Marking Dimples for Treatment .......................................................26 
6.3. 
Treatment Administration ......................................................................................26 
6.4. 
Study Treatment Preparation/Handling/Storage/Accountability ...............................28 
6.5. 
Measures to Minimize Bias ...................................................................................28 
6.5.1. 
Interactive Response Technology ...........................................................................28 
6.6. 
Study Treatment Compliance .................................................................................28 
6.7. 
Prior and Concomitant Medications and Procedures...............................................29 
6.7.1. 
Prohibited Medications and Procedures .................................................................29 
7. 
DISCONTINUATION FROM STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..............................................................30 


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7.1. 
Discontinuation of Study Treatment ......................................................................30 
7.2. 
Subject Discontinuation/Withdrawal from the Study ..............................................30 
7.3. 
Lost to Follow-up ..................................................................................................31 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................31 
8.1. 
Efficacy Assessments ...........................................................................................32 
8.1.1. 
Imaging for Efficacy Assessments.........................................................................32 
8.1.2. 
Subject and Investigator Cellulite Assessments ......................................................32 
8.1.2.1. 
Patient-reported Photonumeric Cellulite Severity Scale ..........................................32 
8.1.2.2. 
Clinician-reported Photonumeric Cellulite Severity Scale.......................................33 
8.1.2.3. 
Hexsel Cellulite Severity Scale..............................................................................33 
8.2. 
Safety Assessments ..............................................................................................33 
8.2.1. 
Medical and Surgical History ................................................................................33 
8.2.2. 
Physical Examination.............................................................................................34 
8.2.3. 
Height and Weight ................................................................................................34 
8.2.4. 
Fitzpatrick Skin Scale ...........................................................................................34 
8.2.5. 
Vital Signs ............................................................................................................34 
8.2.6. 
Electrocardiogram .................................................................................................35 
8.2.7. 
Clinical   Laboratory    Determinations    (Hematology,    Chemistry,    and 
Urinalysis) ............................................................................................................35 
8.2.8. 
Pregnancy Testing.................................................................................................35 
8.2.9. 
Biopsy Follow-up Examination ..............................................................................36 
8.3. 
Adverse Events and Serious Adverse Events..........................................................36 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information ......................36 
8.3.2. 
Method of Detecting AEs and SAEs ......................................................................36 
8.3.3. 
Follow-up of AEs and SAEs .................................................................................37 
8.3.4. 
Regulatory Reporting Requirements for SAEs .......................................................37 
8.3.5. 
Pregnancy ............................................................................................................37 
8.3.6. 
AEs/SAEs Experienced by Nonsubjects Exposed to Study Treatment .....................38 
8.3.7. 
Adverse Events of Special Interest ........................................................................38 
8.4. 
Treatment Overdose..............................................................................................38 
8.5. 
Pharmacokinetics ..................................................................................................39 
8.6. 
Pharmacodynamics ...............................................................................................39 
8.6.1. 
MRI .....................................................................................................................39 


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8.6.2. 
Double Punch Biopsy ............................................................................................39 
8.7. 
Genetics ...............................................................................................................40 
8.8. 
Biomarkers ...........................................................................................................40 
8.8.1. 
Immunogenicity Assessments ...............................................................................40 
8.9. 
Medical Resource Utilization and Health Economics ..............................................40 
9. 
STATISTICAL CONSIDERATIONS AND METHODS .......................................40 
9.1. 
Sample Size Determination ....................................................................................40 
9.2. 
Populations for Analysis........................................................................................40 
9.3. 
Statistical Hypotheses and Analyses ......................................................................41 
9.3.1. 
Efficacy Analysis ..................................................................................................41 
9.3.2. 
MRI and Biopsy Analyses.....................................................................................41 
9.3.3. 
Safety Analyses ....................................................................................................41 
9.3.3.1. 
Adverse Events.....................................................................................................41 
9.3.3.2. 
Vital Signs and Laboratory Evaluations ..................................................................41 
9.3.4. 
Other Analyses .....................................................................................................41 
9.4. 
Interim Analysis....................................................................................................41 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS............................................................................................42 
10.1. 
Appendix 1: Regulatory, Ethical and Study Oversight Considerations .....................42 
10.1.1. 
Regulatory and Ethical Considerations ...................................................................42 
10.1.2. 
Financial Disclosure ..............................................................................................43 
10.1.3. 
Informed Consent Process ....................................................................................43 
10.1.4. 
Data Protection .....................................................................................................44 
10.1.5. 
Committee Structure .............................................................................................44 
10.1.6. 
Dissemination of Clinical Study Data ....................................................................44 
10.1.7. 
Data Quality Assurance ........................................................................................44 
10.1.8. 
Source Documents ................................................................................................45 
10.1.9. 
Study and Site Closure ..........................................................................................45 
10.1.10. 
Publication Policy .................................................................................................45 
10.2. 
Appendix 2: Clinical Laboratory Tests ..................................................................46 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting .....................................................................46 
10.3.1. 
Definitions ............................................................................................................46 


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10.3.2. 
Relationship to Study Drug ................................................................................... 47 
10.3.3. 
Intensity Assessment ............................................................................................ 48 
10.3.4. 
Reporting Adverse Events and Serious Adverse Events ......................................... 48 
10.3.4.1. 
Reporting Adverse Events..................................................................................... 48 
10.3.4.2. 
Reporting Serious Adverse Events ........................................................................ 48 
10.3.4.3. 
Follow-up Procedures for Serious Adverse Events ................................................. 49 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .......................................................................................................... 49 
10.5. 
Appendix 5: Genetics ........................................................................................... 49 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ............. 49 
10.7. 
Appendix 7: Medical Device Incidents .................................................................. 49 
10.8. 
Appendix 8: Country-specific Requirements.......................................................... 49 
10.9. 
Appendix 9: Abbreviations ................................................................................... 50 
11. 
INVESTIGATOR’S STATEMENT ...................................................................... 51 
12. 
REFERENCES..................................................................................................... 52 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities............................................................................................13 
Table 2: 
Study Treatment ...................................................................................................27 
Table 3: 
Clinical Laboratory Tests ...................................................................................... 46 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
 
Name of Sponsor/Company: Endo Pharmaceuticals Inc. 
Name of Investigational Product: CCH 
Name of Active Ingredient: Collagenase clostridium histolyticum 
Title of Study: A Phase 2a open-label, study to assess the impact of CCH treatment of buttock and 
thigh cellulite in adult females using photonumeric scales, magnetic resonance imaging, and 
histopathology 
Lead Principal Investigator: Not applicable 
Study Period: 
Estimated date first subject enrolled: 
November 2019 
Estimated date last subject completed: October 2021 
Phase of Development: 2a 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
• 
To assess the subject reported impact of 
CCH in the treatment of cellulite in adult 
females. 
• 
The change from baseline (screening) in 
Patient-reported Photonumeric Cellulite 
Severity Scale (PR-PCSS) at Day 71. 
Secondary 
• 
To assess the subject and clinician 
reported impact of CCH in the treatment 
of cellulite in adult females. 
• 
The change from baseline (screening) in 
PR-PCSS at Days 22 and 43. 
• 
The change from baseline (screening) in 
Clinician-reported Photonumeric Cellulite 
Severity Scale (CR-PCSS) at Days 22, 43, 
and 71. 
• 
The change from baseline (screening) in 
Hexsel Cellulite Severity Scale (CSS) at 
Days 22, 43, and 71. 
• 
To radiologically assess the impact of 
treatment with CCH in adult females with 
cellulite. 
• 
Comparison of baseline (screening) MRI 
tissue morphology and septae under the 
treatment areas to images taken at Day 71. 
• 
To evaluate tissue histopathology to assess 
the impact of treatment with CCH in adult 
females with cellulite. 
• 
Comparison of baseline (screening) 
histopathology to the histopathology of 
samples taken at Day 71. 
• 
To assess the safety of CCH treatment of 
cellulite in adult females. 
• 
The proportion of subjects reporting each 
adverse event, treatment-emergent adverse 
event, adverse event of special interest, and 
serious adverse event. 
• 
The change from baseline in vital signs and 
clinical laboratory parameters at each visit 
where these parameters are measured. 
• 
The change from baseline in anti-AUX-I and 
anti-AUX-II antibodies and neutralizing 
antibodies at each visit where these 
parameters are measured. 


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Name of Sponsor/Company: Endo Pharmaceuticals Inc. 
Name of Investigational Product: CCH 
Name of Active Ingredient: Collagenase clostridium histolyticum 
Overall Design: 
This is a single-center, open-label, Phase 2a study to assess the photonumeric scale, morphological, and 
histopathological changes associated with CCH in adult women with moderate or severe edematous 
fibrosclerotic panniculopathy (EFP). Approximately 19 subjects with moderate or severe EFP in the 
posterolateral thighs will be dosed in this study. 
This study was suspended due to the COVID-19 public health emergency on 18 March 2020. When the 
study re-opens, subjects who had received less than 3 doses of CCH prior to 18 March 2020 will be 
allowed to continue in the study and may receive any remaining doses with Sponsor approval. These 
subjects will complete all remaining visits and assessments EXCEPT biopsies and biopsy follow-up 
visits, if willing to do so. These subjects will be included in the safety assessments for the study, but will 
not be included in the efficacy assessments. Subjects who received less than 3 doses prior to 
18 March 2020 may elect to remain in the study without receiving additional doses. 
Subjects who received all 3 doses of CCH prior to 18 March 2020, will be allowed to continue in the 
study and complete all remaining visits and assessments (including biopsies and biopsy follow-up 
visits), if willing to do so. These subjects will be included in the safety assessments for the study, but 
will not be included in the efficacy assessments. Subjects who received all 3 doses of CCH prior to 
18 March 2020 may elect to remain in the study without completing the biopsies and biopsy follow-up 
visits. 
An additional 12 subjects will be dosed in the study. These subjects will be included in the safety 
assessments, and all efficacy assessments will be based on the data for these 12 subjects. For the 
12 subjects who receive their first dose of study drug after 18 March 2020, every attempt will be made 
to enroll an equal number of subjects across the 2 severity levels in both buttocks and thighs (eg, 
3 subjects with moderate buttock cellulite, 3 subjects with severe buttock cellulite, 3 subjects with 
moderate thigh cellulite, and 3 subjects with severe thigh cellulite). 
Objectives 
Endpoints 
Tertiary 
• 
To assess the complete loss of patient 
reported impact after CCH treatment in 
adult females with cellulite. 
• 
The proportion of subjects with no change 
(or worsening) from baseline (screening) in 
PR-PCSS rating at Day 161 and at Day 251. 
• 
To assess the complete loss of clinician 
reported impact after CCH treatment in 
adult females with cellulite. 
• 
The proportion of subjects with no change 
(or worsening) from baseline (screening) in 
CR-PCSS rating at Day 161 and at Day 251. 
• 
The proportion of subjects with no change 
(or worsening) from baseline (screening) in 
Hexsel CSS total score at Day 161 and at 
Day 251. 
• 
To radiologically assess the long-term 
impact of treatment with CCH in adult 
females with cellulite. 
• 
Comparison of baseline (screening) 
magnetic resonance imaging (MRI) tissue 
morphology and septae under the treatment 
areas to images taken at Day 251. 
• 
To evaluate tissue histopathology to assess 
the long-term impact of treatment with 
CCH in adult females with cellulite. 
• 
Comparison of baseline (screening) 
histopathology to the histopathology of 
samples taken at Day 251. 


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Name of Sponsor/Company: Endo Pharmaceuticals Inc. 
Name of Investigational Product: CCH 
Name of Active Ingredient: Collagenase clostridium histolyticum 
Following a screening period of up to 35 days, qualified subjects will receive 0.84 mg of CCH per 
treatment area (each buttock or each thigh) for a total dose of 1.68 mg in both buttocks or both thighs 
per treatment session × 3 treatment sessions (Day 1, Day 22, and Day 43). Buttock treated subjects will 
receive 0.84 mg of CCH administered as up to 12 injections (0.3 mL administered as three 0.1 mL 
aliquots per injection in each buttock). Thigh treated subjects will receive 0.84 mg of CCH administered 
as up to 12 injections (1.5 mL administered as five 0.3 mL aliquots per injection in each thigh). 
Subjects will have MRI and (except as noted above) double punch biopsies of 3 selected target dimples 
3 times during the study. All subjects will be followed for 265 days after the first dose of study 
treatment. 
Subjects will participate in the study for approximately 305 days (10 months) plus any delays caused by 
the COVID-19 public health emergency. The duration of the study from first subject first visit to last 
subject last visit will be dependent upon the ability of the site to identify and enroll subjects. The entire 
study is expected to require about 24 months to complete. 
Disclosure Statement: This is an open-label study. 
Number of Subjects (planned): Approximately 19 subjects will receive study drug so that 
approximately 12 subjects who did not experience COVID-19 public health emergency interruption will 
complete the study. 
Treatment Groups and Duration: Subjects will receive 3 treatment sessions 21 days apart and 
consisting of 0.84 mg of CCH in each treatment area (each buttock or each thigh for a total dose of 
1.68 mg). The total amount of CCH to be administered per subject over the course of the study will not 
exceed 5.04 mg. 
Data and Safety Monitoring Committee: No data and safety monitoring committee will be used for 
this study. 


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1.2. 
Schedule of Activities 
Table 1: 
Schedule of Activities 
 
Activities 
Screening 
(Day -35 to Day -1) 
Treatment Phase 
Extension Phase 
Before MRI 
Before biopsy 
Approximately Day -14 
Day 1 
Treatment Session I 
Day 22 (± 3 Days) 
Treatment Session II 
Day 43 (± 3 Days) 
Treatment Session III 
Day 71 (+10 Days) 
Day 85 (±5 Days)/ 
Biopsy Follow-up 
Day 161 (± 15 Days) 
Day 251 (±15 Days)/ 
Early Termination 
Day 265 (±5 Days)/ 
Biopsy Follow- up 
Informed consenta 
X 
Inclusion/exclusion criteria reviewb 
X 
X 
Medical and surgical history 
X 
EFP history 
X 
Prior medications (including all prior medications for cellulite) 
X 
Physical examination 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
Fitzpatrick Skin Type 
X 
Vital signs 
X 
Xc 
Xc 
Xc 
X 
X 
X 
ECG 
X 
Hematology, chemistry, and urinalysis 
X 
X 
X 
Serum pregnancy test 
X 
Urine pregnancy test 
X 
X 
X 
Xd 
X 
Xd 
HIV and Hepatitis B tests 
X 
Immunogenicity sample collection 
X 
X 
X 
X 
Selection of treatment region (both buttocks or both thighs) 
X 
Imaging for efficacy assessments (IntelliStudio) 
Xe 
Xf 
Xf 
Xf 
X 
X 
X 
PR-PCSS 
Xe 
X 
X 
X 
X 
X 
CR-PCSS 
Xe 
X 
X 
X 
X 
X 
Hexsel CSS 
Xe 
X 
X 
X 
X 
X 
Selection, marking, labeling, and/or photography of 3 dimples for 
MRI and Biopsy (Dimples 1, 2, and 3) 
X 


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Table 1: 
Schedule of Activities (Continued) 
 
Activities 
Screening 
(Day -35 to Day -1) 
Treatment Phase 
Extension Phase 
Before MRI 
Before biopsy 
Approximately Day -14 
Day 1 
Treatment Session I 
Day 22 (± 3 Days) 
Treatment Session II 
Day 43 (± 3 Days) 
Treatment Session III 
Day 71 (+10 Days) 
Day 85 (±5 Days)/ 
Biopsy Follow-up 
Day 161 (± 15 Days) 
Day 251 (±15 Days)/ 
Early Termination 
Day 265 (±5 Days)/ 
Biopsy Follow- up 
MRI 
Xg 
Dimples 
1, 2, and 3 
Xh 
Dimples 
2 and 3 
Xh 
Dimple 3 
Biopsy sample collection 
Xi 
Dimple 1 
Xj 
Dimple 2 
Xj 
Dimple 3 
Biopsy follow-up examination 
X 
Xk 
Xk 
Select and mark up to 12 dimples for CCH injection in each treatment 
area (including Dimples 2 and 3) 
X 
X 
X 
Study drug administration 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injections site reactions/local tolerability in areas treated 
X 
X 
X 
X 
X 
X 
All other AEsl 
Monitored throughout the study 
a Performed prior to any study-required assessments, unless exceptions granted for standard of care procedures. A separate informed consent may be used for HIV testing and 
must be signed before the sample is collected, if required. 
b Should be reassessed and verified prior to dosing. 
c Vital signs will be collected up to 4 hours prior to, and at 15 and 30 minutes after, study treatment administration on Days 1, 22, and 43. 
d Urine pregnancy test should be completed prior to the MRI. 
e At screening all 4 potential treatment areas (each buttock and each thigh) will be imaged; and CR-PCSS, PR-PCSS, and Hexsel CSS assessments will be done for each potential 
treatment area (each buttock and each thigh). 
f Before and after marking dimples for treatment. No manipulation of the treatment area should be done prior to the “before” photographs. 
g Screening MRIs will be performed after all other screening assessments (except the biopsy) have been completed. MRIs may be repeated within the screening window as often 
as necessary to obtain evaluable images. 
h The Day 71 and Day 251 MRIs may be performed up to 7 days prior to the indicated visit. The MRI must be completed before the biopsy required for these visits. The 
Day 251/Early Termination MRI is not required for subjects who withdraw from the study (early termination). The Day 71 and Day 251 MRIs may be repeated as often as 
necessary to obtain an evaluable image. 


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Table 1: 
Schedule of Activities (Continued) 
i The screening biopsy will be performed after all other screening assessments (including MRI) are completed. The screening biopsy will be performed at least 14 days prior to the 
Day 1 Treatment Visit. The investigator must examine and confirm sufficient healing of the biopsy site before dosing on Day 1. The timing of all subsequent visits will be based 
on the actual date that the first dose of CCH is administered. 
j   The Day 71 and Day 251 imaging for efficacy, PR-PCSS, and CR-PCSS must be completed prior to the biopsy sample collection required at those visits. The Day 251/Early 
Termination biopsy is not required for subjects who withdraw from the study (early termination). For subjects who received less than 3 doses of CCH prior to 18 March 2020, no 
Day 71 or Day 251 biopsy samples will be collected. 
k Visit not required for subjects who had less than 3 doses of CCH prior to 18 March 2020. 
l Adverse events (AE)/serious adverse events (SAE) will be captured from time of informed consent signature until the Day 265 Visit or until 28 days after last dose of study drug 
whichever is later. There is no time limit on collection of SAEs considered to be related to study treatment. 
Note: Unless otherwise stated above or outlined below (and with the exception of injection site reactions/local tolerability in the areas treated), all assessments should be 
completed prior to dosing on treatment days (Days 1, 22, and 43). 


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2. 
INTRODUCTION 
CCH is a parenteral lyophilized product comprised of 2 collagenases in an approximate 1:1 mass 
ratio, Collagenase I (Clostridial class I collagenase [AUX-I]) and Collagenase II (Clostridial 
class II collagenase [AUX-II]). CCH is a novel formulation of an existing product (XIAFLEX®) 
that is currently approved for use in adults with Dupuytren’s contracture and Peyronie’s disease. 
 
2.1. 
Study Rationale 
The results from Phase 2 (buttock and thigh) and Phase 3 (buttock) studies show CCH 0.84 mg 
given per treatment area (1 buttock or 1 thigh) is an effective treatment for edematous 
fibrosclerotic panniculopathy (EFP, commonly known as cellulite) based on improvement in the 
severity of cellulite as determined by the Investigator and the subject. There were no safety 
concerns following 3 doses of 0.84 mg of CCH per treatment area. The majority of adverse 
events (AEs) occurred at the site of injection and resolved before the next scheduled treatment in 
these studies. The immunogenicity profile of CCH has been consistent across all studies. 
The efficacy of CCH treatment on cellulite has been demonstrated in previous clinical studies 
using validated photonumeric scales. This study will capture the change from baseline after CCH 
treatment using the validated photonumeric scales and explore tissue level changes in the 
treatment areas (buttocks and thigh), both from histopathology and radiology perspectives. 
 
COVID-19 Public Health Emergency Impact 
The COVID-19 public health emergency has disrupted the conduct of clinical research 
throughout the world. At Endo Pharmaceuticals Inc. (Endo) ensuring the safety of clinical study 
participants is our primary concern. In addition, the integrity of data obtained from clinical trials 
must be ensured. 
Endo initiated study EN3835-212 at a single investigational site in November of 2019. The first 
subject was dosed with CCH on 26 December 2019. On 18 March 2020, the investigational site 
suspended Study EN3835-212 due to the COVID-19 public health emergency. At that time, 
7 subjects had received at least 1 dose of CCH in this study. Of those 7 subjects, 2 had completed 
the 3 doses required for the study and 1 subject had completed 2 doses. No subjects had 
completed all assessments required for the Day 71 Visit or beyond. 
On 15 April 2020, all 7 subjects were more than 1 week outside of the visit window for their next 
dose or for the Day 71 visit and there was no indication that the site would be able to re-open 
within the following 2 weeks. In order to ensure subject safety and protect data integrity, Endo, 
in accordance with the FDA Guidance on Conduct of Clinical Trials of Medical Products during 
COVID-19 Public Health Emergency (March 2020, updated 16 April 2020), decided to add 
additional subjects and modify the assessments required for current subjects when the 
investigational site re-opens as follows (and with subject consent): 
• Subjects who were in screening for the study at the time of interruption 
(18 March 2020) but who had not been dosed with CCH will repeat all screening 
assessments to determine eligibility, if willing to do so. All screening assessments 
must be repeated within the screening window. 


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• Subjects who had received less than 3 doses of CCH prior to 18 March 2020 will be 
allowed to continue in the study and may receive any remaining doses with Sponsor 
approval. These subjects will complete all remaining visits and assessments EXCEPT 
biopsies and biopsy follow-up visits, if willing to do so. These subjects will be 
included in the safety assessments for the study, but will not be included in the 
efficacy assessments. Subjects who received less than 3 doses prior to 18 March 2020 
may elect to remain in the study without receiving additional doses. 
• Subjects who received all 3 doses of CCH prior to 18 March 2020, will be allowed to 
continue in the study and complete all remaining visits and assessments (including 
biopsies and biopsy follow-up visits), if willing to do so. These subjects will be 
included in the safety assessments for the study, but will not be included in the 
efficacy assessments. Subjects who received all 3 doses of CCH prior to 
18 March 2020 may elect to remain in the study without completing the biopsies and 
biopsy follow-up visits. 
• An additional 12 subjects will be dosed in the study. These subjects will be included 
in the safety assessments and all efficacy assessments will be based on the data for 
these 12 subjects. 
 
2.2. 
Background 
EN3835 is a parenteral lyophilized product comprised of 2 collagenases in an approximate 1:1 
mass ratio (AUX-I and AUX-II). EN3835, marketed as XIAFLEX, is currently approved for use 
in adults with Dupuytren’s contracture and Peyronie’s disease. These collagenases are 
proteinases that hydrolyze collagen in its native triple helical conformation under physiological 
conditions, resulting in lysis of collagen deposits in a Dupuytren’s cord and/or Peyronie’s 
plaque. 
To investigate EN3835 in the treatment of EFP, commonly known as cellulite, Endo has 
developed a novel formulation of EN3835, referred to hereafter as CCH, with a different 
concentration and volume of the approved EN3835 formulation. 
Cellulite is an aesthetic condition that can be understood as an imbalance between the structural 
characteristics and biomechanical properties (ie, the delicate containment and extrusion forces) at 
the subdermal junction (Rudolph et al, 2019). As such, the goals of cellulite treatment are to 
strengthen the subdermal interface and/or to release the fibrous septae via various types of 
subcision (Rudolph et al, 2019). The fibrous septae has been recognized as a contributory 
underlying cause of cellulite and as a target of treatment for cellulite by anatomical and image 
analyses studies (Hexsel et al, 2009; Hexsel et al 2016; Mirrashed et al, 2004; Nürnberger and 
Müller, 1978; Piérard et al, 2000; Querleux et al, 2002). 
A number of therapies have been utilized in an attempt to treat cellulite, much of the evidence for 
their efficacy is anecdotal, subjective, or based only on patient self-assessment and many of the 
treatments have undesirable side effects (Avram, 2004; Collis et al, 1999; Khan et al, 2010; 
Hexsel and Mazzuco, 2000). Some of the historical treatments for EFP have included weight 
loss, pharmacological agents (eg, xanthines, retinoids, lactic acid, and herbals), Endermologie® 
or lipomassage, mesotherapy, radiofrequency, subcision (including powered subcision eg, 
Cellfina®), and laser (including Triactive® and CelluLaze™) (Boyce et al, 2005; 


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DiBernardo, 2011; Hexsel and Mazzuco, 2000; Khan et al, 2010). However, there remains an 
unmet need for safe and effective nonsurgical therapies to improve the aesthetic outcome in 
women with cellulite. CCH has the potential to effectively lyse the subdermally located fibrous 
septae, the underlying cause of the skin dimpling in women with cellulite, at the site of injection. 
The results from previous studies have shown improvement in the severity of cellulite, as 
determined by both the investigator and the subject, in subjects treated with CCH administered at 
a dose of 0.84 mg per treatment area (1 buttock or 1 thigh) every 21 days for 3 sessions. Across 
all previous studies, CCH has demonstrated an acceptable safety and immunogenicity profile. 
The majority of AEs occurred at the site of injection, were mild to moderate in nature, and often 
resolved within 2 to 3 weeks without any sequelae. 
A description of the chemistry, pharmacology, efficacy, and safety of CCH is provided in the 
current edition of the Investigator’s Brochure. 
The purpose of this study is to examine the impact of CCH on the tissue following administration 
of 0.84 mg per treatment area in the buttocks or thighs of adult women with EFP at 3 treatment 
sessions approximately 21 days apart using photonumeric scales, magnetic resonance imaging 
(MRI), and histopathology. 
 
2.3. 
Risk/Benefit Assessment 
Current treatments for EFP have limited efficacy and undesirable side effects. There remains an 
unmet need for safe and effective nonsurgical therapies to improve the aesthetic outcome in 
women with cellulite. 
The following AEs have been commonly observed in subjects treated with CCH for EFP: local 
injection site reactions including injection site bruising, injection site swelling, and injection site 
pain. These events are similar to events reported in the clinical trials of EN3835 for the approved 
indications. Postmarketing safety data are consistent with safety data reported in clinical trials. 
More detailed information about the known and expected benefit, risks, and reasonably expected 
AEs can be found in the current version of the Investigators Brochure. 
Due to the use of the strong magnet, MRI cannot be performed on subjects with any implant 
containing metal or those who have other internal or external metallic objects as it may cause 
these objects to move. MRI may potentially increase the temperature of amniotic fluid, so should 
not be used in pregnant women. The risks associated with punch biopsies include local bleeding 
and bruising, pain, infection, allergic reaction to the numbing medicine used in the procedure, 
damage to the structures beneath the skin site (such as an artery or a nerve), and permanent 
scarring. 
All other procedures and activities in this study are generally accepted as standard of care for 
patients with EFP and do not present any increased risk to the subjects. 


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3. 
OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Primary 
• 
To assess the subject reported impact of CCH 
in the treatment of cellulite in adult females. 
• 
The change from baseline (screening) in 
Patient Reported Photonumeric Cellulite 
Severity Scale (PR-PCSS) at Day 71. 
Secondary 
• 
To assess the subject and clinician reported 
impact of CCH in the treatment of cellulite in 
adult females. 
• 
The change from baseline (screening) in 
PR-PCSS at Days 22 and 43. 
• 
The change from baseline (screening) in 
Clinician-reported Photonumeric Cellulite 
Severity Scale (CR-PCSS) at Days 22, 43, and 
71. 
• 
The change from baseline (screening) in 
Hexsel Cellulite Severity Scale (CSS) at 
Days 22, 43, and 71. 
• 
To radiologically assess the impact of 
treatment with CCH in adult females with 
cellulite. 
• 
Comparison of baseline (screening) MRI tissue 
morphology and septae under the treatment 
areas to images taken at Day 71. 
• 
To evaluate tissue histopathology to assess the 
impact of treatment with CCH in adult females 
with cellulite. 
• 
Comparison of baseline (screening) 
histopathology to the histopathology of 
samples taken at Day 71. 
• 
To assess the safety of CCH treatment of 
cellulite in adult females. 
• 
The proportion of subjects reporting each AE, 
treatment-emergent adverse event (TEAE), 
adverse event of special interest (AESI), and 
serious adverse event (SAE). 
• 
The change from baseline in vital signs and 
clinical laboratory parameters at each visit 
where these parameters are measured. 
• 
The change from baseline in anti-AUX-I and 
anti-AUX-II antibodies and neutralizing 
antibodies at each visit where these parameters 
are measured. 
Tertiary 
• 
To assess the complete loss of patient reported 
impact after CCH treatment in adult females 
with cellulite. 
• 
The proportion of subjects with no change (or 
worsening) from baseline (screening) in 
PR-PCSS rating at Day 161 and at Day 251. 
• 
To assess the complete loss of clinician 
reported impact after CCH treatment in adult 
females with cellulite. 
• 
The proportion of subjects with no change (or 
worsening) from baseline (screening) in 
CR-PCSS rating at Day 161 and at Day 251. 
• 
The proportion of subjects with no change (or 
worsening) from baseline (screening) in Hexsel 
CSS total score at Day 161 and at Day 251. 


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Objectives 
Endpoints 
• 
To radiologically assess the long-term impact 
of treatment with CCH in adult females with 
cellulite. 
• 
Comparison of baseline (screening) MRI tissue 
morphology and septae under the treatment 
areas to images taken at Day 251. 
• 
To evaluate tissue histopathology to assess the 
long-term impact of treatment with CCH in 
adult females with cellulite. 
• 
Comparison of baseline (screening) 
histopathology to the histopathology of 
samples taken at Day 251. 
 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a single-center, open-label, Phase 2a study to assess the safety and efficacy of CCH in 
adult women with moderate or severe EFP of the buttocks or thighs using photonumeric scales, 
MRI, and histopathology of tissues from the treated area. Approximately 19 subjects will be 
dosed in this study. 
This study was suspended due to the COVID-19 public health emergency on 18 March 2020. 
When the study re-opens, subjects who had received less than 3 doses of CCH prior to 
18 March 2020 will be allowed to continue in the study and may receive any remaining doses 
with Sponsor approval. These subjects will complete all remaining visits and assessments 
EXCEPT biopsies and biopsy follow-up visits, if willing to do so. These subjects will be 
included in the safety assessments for the study, but will not be included in the efficacy 
assessments. Subjects who received less than 3 doses prior to 18 March 2020 may elect to 
remain in the study without receiving additional doses. 
Subjects who received all 3 doses of CCH prior to 18 March 2020, will be allowed to continue in 
the study and complete all remaining visits and assessments (including biopsies and biopsy 
follow-up visits), if willing to do so. These subjects will be included in the safety assessments for 
the study, but will not be included in the efficacy assessments. Subjects who received all 3 doses 
of CCH prior to 18 March 2020 may elect to remain in the study without completing the biopsies 
and biopsy follow-up visits. 
An additional 12 subjects will be dosed in the study. These subjects will be included in the safety 
assessments, and all efficacy assessments will be based on the data from these 12 subjects. For 
the 12 subjects who receive their first dose of study drug after 18 March 2020, every attempt will 
be made to enroll an equal number of subjects across the 2 severity levels in both buttocks and 
thighs (eg, 3 subjects with moderate buttock cellulite, 3 subjects with severe buttock cellulite, 
3 subjects with moderate thigh cellulite, and 3 subjects with severe thigh cellulite). 
Following a screening period of up to 35 days, qualified subjects will receive 0.84 mg of CCH 
per treatment area (each buttock or each thigh) for a total dose of 1.68 mg in both buttocks or 
both thighs per treatment session × 3 treatment sessions (Day 1, Day 22, and Day 43). Buttock 
treated subjects will receive 0.84 mg of CCH administered as up to 12 injections (0.3 mL 
administered as three 0.1 mL aliquots per injection in each buttock). Thigh treated subjects will 
receive 0.84 mg of CCH administered as up to 12 injections (1.5 mL administered as five 0.3 mL 
aliquots per injection in each thigh). 


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Page 21 
 
 
Subjects will have MRI and (except as noted above) double punch biopsies of 3 selected target 
dimples 3 times during the study. All subjects will be followed for 265 days after the first dose of 
study treatment. 
Subjects will participate in the study for approximately 305 days (10 months) plus any delays 
caused by the COVID-19 public health emergency. The duration of the study from first subject 
first visit to last subject last visit will be dependent upon the ability of the site to identify and 
enroll subjects. The entire study is expected to require about 24 months to complete. 
 
4.2. 
Scientific Rationale for the Study Design 
Although the visual impact and efficacy of CCH treatment on cellulite dimples has been studied 
using photographic images of buttocks and thighs, the subdermal impact has not been 
characterized and/or visualized. This study will use MRI and histopathology to attempt to 
visualize and/or characterize changes in subdermal tissue after treatment with CCH and to better 
understand the mechanism of action of CCH. 
 
4.3. 
Justification for Dose 
The results from a Phase 2b study (EN3835-201) suggested that CCH 0.84 mg per treatment area 
(1 buttock or 1 thigh) × 3 treatment sessions is safe and effective. The Phase 3 studies 
(EN3835-302 and EN3835-303) showed efficacy when using the same treatment in the buttocks 
with a similar safety profile where most AEs were mild to moderate in severity and transient. 
The immunogenicity profile of CCH has been consistent across all clinical studies to date. 
Therefore, the dose of 0.84 mg per treatment area (buttock or thigh - with a total dose of 1.68 mg 
of CCH for 2 buttocks or 2 thighs) administered at 3 treatment sessions approximately 21 days 
apart will be used in this study. 
 
4.4. 
End of Study Definition 
A subject will be considered to have completed the study if the subject received their first dose 
of study drug after 18 March 2020 and completed the Day 265 visit. Subjects who received their 
first dose of study drug prior to 18 March 2020 and complete the Day 265 Visit (or the Day 251 
Visit if they elect not to have biopsies) also will be considered to have completed the study. 
The end of the study is defined as the completion of the final assessment for the last subject 
enrolled in the trial. 
 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1. 
Subject Inclusion Criteria 
In order to be eligible to participate in the study, at the Screening Visit and on Study Day 1, 
subjects must: 
1. Be female and ≥ 18 and ≤ 50 years of age at the time of consent. 


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2. Have both buttocks or both posterolateral thighs with: 
a. A score of 3 or 4 (moderate or severe) as reported by the investigator using the 
CR-PCSS. 
b. A Hexsel CSS total score of ≤ 13. 
c. A Hexsel CSS Subsection A “Number of Evident Depressions” score of > 0. 
d. A Hexsel CSS Subsection B “Depth of Depressions” score of 2 (medium depth 
depressions) or 3 (deep depressions). 
3. Have a body mass index (BMI) score between 18.5 kg/m2 to 29.9 kg/m2 and intends to 
maintain stable body weight throughout the duration of the study (from the Screening 
Visit through the Day 251/Early Termination Visit). A variation of ≤ 10% from the Day 1 
Visit weight is permitted. 
4. Be willing and consent to undergo human immunodeficiency virus (HIV) and hepatitis B 
testing, as well as double punch biopsy and MRI procedures. 
5. Have a minimum of 2 well defined and isolated cellulite dimples that are considered 
moderate or deep in depth in each treatment area (each thigh or each buttock, for a total 
of 4 such dimples), of which 3 (Dimples 1, 2 and 3) will be selected for MRI and biopsy 
procedures. 
6. Be willing to apply sunscreen to the treatment area before each exposure to the sun for 
the duration of the study (from the Screening Visit through the Day 251/Early 
Termination Visit). 
7. Be judged by the investigator to be in good health, based upon the results of a medical 
history, physical examination, electrocardiogram (ECG), and laboratory profile at 
screening. 
8. Be of nonchildbearing potential (history of hysterectomy, bilateral oophorectomy, 
bilateral tubal ligation, or postmenopausal with no history of menstrual flow in the 
12 months prior to the Screening Visit); or, if of childbearing potential, be nonpregnant, 
nonlactating, and agree to use effective contraception when with a male partner at least 
1 menstrual cycle prior to the first dose of study treatment through the Day 251/Early 
Termination Visit. Acceptable forms of contraception include hormonal measures (oral 
contraceptive pills, contraceptive patch, contraceptive ring, injections, etc), intrauterine 
devices, double barrier methods (condom plus diaphragm, condom or diaphragm plus 
spermicidal gel or foam), surgical sterilization of the male partner, and abstinence. 
9. Have a negative serum pregnancy test at the Screening Visit and a negative urine 
pregnancy prior to dosing at each treatment session and prior to the Day 71 and Day 251 
MRIs. 
10. Be willing and able to comply with all protocol required visits and assessments. 
11. Be able to read, understand, and independently complete patient reported outcome 
instruments in English. 
12. Be adequately informed and understand the nature and risks of the study and be able to 
provide consent as outlined in Section 10.1.3. 


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Page 23 
 
 
13. Must have evaluable MRI images of Dimples 1, 2, and 3 at screening. An evaluable MRI 
is defined as an image that adheres to the protocol scanning parameters and is free from 
artifacts that could affect the analysis. 
 
5.2. 
Subject Exclusion Criteria 
A subject is ineligible for study participation if, at the Screening Visit and on Day 1, the subject: 
1. Is from a vulnerable population, as defined by the US Code of Federal Regulations (CFR) 
Title 45, Part 46, Section 46.111(b) and other local and national regulations, including 
but not limited to, employees (temporary, part-time, full-time, etc) or a family member of 
the research staff conducting the study, or of the sponsor, or of the contract research 
organization, or of the Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC). 
2. Has a history of sensitivity or allergy to collagenase or any other excipient of CCH. 
3. Has any of the following systemic conditions: 
a. Coagulation disorder. 
b. Evidence or history of malignancy (other than excised basal-cell carcinoma) unless 
there had been no recurrence in at least 5 years. 
c. History of keloidal scarring or abnormal wound healing. 
d. 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 will be discussed with the Medical Monitor. 
e. Evidence of clinically significant abnormalities on physical examination, vital signs, 
ECG, or clinical laboratory values. 
4. Has any of the following local conditions in the areas to be treated (both buttocks or both 
thighs): 
a. History of lower extremity thrombosis, deep vein thrombosis, or post-thrombosis 
syndrome. 
b. Vascular disorder (eg, varicose veins, telangiectasia). 
c. Inflammation or active infection. 
d. Active cutaneous alteration including rash, eczema, or psoriasis. 
e. A tattoo or other artificially inflicted body marker. 
f. A mole located within 2 cm of any injection site. 
5. Has a Hexsel CSS Subsection D “Grade of Laxity, Flaccidity, or Sagging Skin” score of 
≥2 or has linear undulations that can be effaced by lifting the skin in the areas to be 
treated (each buttock or each thigh). 
6. Requires anticoagulant or antiplatelet medication during the study or has received 
anticoagulant or antiplatelet medication (except for ≤ 150 mg aspirin daily) within 7 days 
before injection of study treatment. 


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7. Has used any of the following for the treatment of EFP on either thigh or either buttock 
within the timelines identified below or intends to use any of the following at any time 
during the course of the study: 
a. Liposuction during the 12-month period before injection of study treatment. 
b. Injections (eg, mesotherapy, dermal fillers, biostimulatory fillers); radiofrequency 
device treatments; laser treatment; buttock or thigh implant treatment; cryolipolysis; 
or surgery (including subcision and/or powered subcision) during the 12-month 
period before injection of study treatment. 
c. Any investigational treatment for EFP on a buttock or thigh during the 12-month 
period before the injection of study treatment. 
d. Endermologie or similar treatments during the 6-month period before injection of 
study treatment. 
e. Massage therapy during the 3-month period before injection of study treatment. 
f. Creams (eg, Celluvera™, TriLastin®) and/or home therapies to prevent or mitigate 
EFP during the 2-week period before injection of study treatment. 
8. Has used any form of artificial tanning (sprays, lotions, tanning booth, etc) within the 
30 days prior to the first injection of study drug or during the study (through the 
Day 265/Early Termination Visit). 
9. Has a positive HIV test and/or a positive Hepatitis B surface antigen (HBsAg) or 
Hepatitis B core antibody (HBcAb) test at screening. 
10. Has had any surgery, invasive procedure (eg, liposuction), injectable treatment 
(eg, KYBELLA®) or any similar treatment that could have destroyed fat cells and/or 
removed fat deposits in the treatment area. 
11. Has a history of keloids, hypertrophied scars, and/or other complications following 
biopsy. 
12. Has any contraindications for MRI including, but not limited to: 
a. Has an implant containing metal including but not limited to intracranial aneurysm 
clips, cochlear implants, prosthetic devices containing metal, implanted drug infusion 
pumps, neurostimulators, bone-growth stimulators, intrauterine contraceptive devices 
containing metal, or any other type of iron-based metal implants. 
b. Has an internal metallic object such as bullets or shrapnel, as well as surgical clips, 
pins, plates, screws, metal sutures, or wire mesh. 
c. Has any tattoo or permanent cosmetics/make-up including, but not limited to, 
permanent lip liner or permanent eye liner. 
d. Has severe claustrophobia. 
e. Has experienced “ceremonial” syncope (fainting while standing still). 
f. Has extremely low blood pressure, epilepsy, asthma, anemia, or sickle cell disease. 
13. Has received any collagenase treatments at any time prior to treatment in this study 
and/or has received EN3835 or CCH in a previous investigational study for cellulite. 
14. Has previously received treatment with CCH in this clinical study. 


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Page 25 
 
 
15. Has received treatment with an investigational product within 30 days (or 5 half-lives, 
whichever is longer) of the Screening Visit. 
16. Is pregnant and/or is providing breast milk or plans to become pregnant and/or to provide 
breast milk during the course of the study. 
17. Intends to initiate an intensive sport or exercise program during the study. 
18. Intends to initiate an intensive weight reduction program during the study. 
19. Has any other condition(s) that, in the investigator’s opinion, might indicate the subject to 
be unsuitable for the study. 
 
5.3. 
Lifestyle Considerations 
See Section 5.1 and Section 5.2. In addition, subjects should not donate blood while participating 
in this study and for 28 days after the last study treatment. 
 
5.4. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in this study but are not 
subsequently treated. 
Subjects will be allowed to repeat any screening assessment/procedure once; however, MRI(s) 
may be repeated as often as necessary to obtain an evaluable image, provided the repeat MRI(s) 
are within the screening window. The subject will not be considered a screen failure unless the 
repeat assessment/procedure result does not meet eligibility criteria. The period from the start of 
screening related procedures at the Screening Visit to the Day 1 Visit must not exceed 35 days, 
inclusive of any repeat screening procedures. 
Subjects who do not meet all of the eligibility criteria at the Screening or Day 1 Visits will be 
deemed a screen failure and the following information must be recorded for all subjects who are 
screen failures: 
• Demography (age, gender, race/ethnicity). 
• Reason for screen failure. 
• Which eligibility criterion was not met. 
• Any AEs (including SAEs) experienced by the subject. 
Subjects who were screened prior to 18 March 2020 for the study but had not been dosed with 
CCH may be rescreened. All screening assessments must be repeated within the screening 
window (35 days). 
For subjects screened after 18 March 2020, a subject who is a screen failure may not be 
rescreened, unless the reason for screen failure is the inability to obtain evaluable MRI(s) during 
the screening period. These subjects must repeat all screening activities. The period from the 
start of rescreening related activities to the first injection of study drug must not exceed 35 days. 
Subjects may be rescreened only once. 


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6. 
STUDY TREATMENT 
Study treatment is defined as any investigational treatment, marketed products, placebo, or 
device intended to be administered to a study subject according to the study protocol. 
 
6.1. 
Selecting the Treatment Region 
Selection of the treatment region (both buttocks or both thighs) will be at the discretion of the 
investigator at screening and in accordance with the distribution required for the study. 
Approximately 19 subjects will be dosed in this study. For the 12 new subjects who receive their 
first dose of study drug after 18 March 2020, every attempt will be made to enroll an equal 
number of subjects across the 2 severity levels in both buttocks and thighs (eg, 3 subjects with 
moderate buttock cellulite, 3 subjects with severe buttock cellulite, 3 subjects with moderate 
thigh cellulite, and 3 subjects with severe thigh cellulite). 
No subjects will be treated in both the buttocks and the thighs. 
 
6.2. 
Selecting and Marking Dimples for Treatment 
In each treatment area, cellulite dimples for CCH treatment will be selected at screening at the 
discretion of the investigator and must be well-defined, evident when the subject is standing, and 
suitable for treatment. An adequate number of dimples should be selected at each treatment area 
for administration of up to 12 subcutaneous CCH injections. The dimples selected for treatment 
must include Dimple 2 and Dimple 3 that were selected for MRI and biopsy and these dimples 
will be treated throughout the study (see Section 8.6). Dimple 1 will not be treated at any time 
during the study. 
For each dimple selected for treatment, the investigator or qualified designee will choose 
injection sites (injection sites within a dimple should be spaced approximately 2 cm apart, if a 
dimple requires more than 1 injection; locating at least one injection site at the nadir, if present, 
of the dimple). Each injection site will be marked with a “dot” using a surgical marker. For 
round dimples, the “dot” will be placed in the center of the dimple; for elongated dimples, “dots” 
will be spaced out approximately 2 cm along the longer axis of the dimple. The investigator or 
qualified designee will then use a surgical marker to circle each of the dimples selected for 
treatment. 
 
6.3. 
Treatment Administration 
CCH is a sterile lyophilized powder that is reconstituted with a sterile diluent made of 0.6% 
sodium chloride and 0.03% calcium chloride dihydrate in water. Subjects who qualify for the 
study will be given a maximum dose of 0.84 mg of CCH per treatment area (each buttock or 
each thigh) per treatment visit (total dose of 1.68 mg per treatment session), administered as up 
to 12 subcutaneous injections per buttock or thigh at 3 treatment sessions approximately 21 days 
apart (Days 1, 22, and 43). 
Buttock cellulite dimple injections will consist of administration of 0.3 mL of reconstituted 
CCH, administered in 3 aliquots of 0.1 mL each. For thighs, cellulite dimple injections will 
consist of 1.5 mL of reconstituted CCH, administered in 5 aliquots of 0.3 mL each (see Table 2). 


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In this study, the reconstitution volumes and angles of injection will be different for the buttocks 
and the posterolateral thighs. However, the total dose in each treatment area per treatment 
session will remain 0.84 mg of CCH. 
Specific instructions for CCH reconstitution and administration, including the injection 
techniques, will be provided in the Pharmacy Manual. 
Table 2: 
Study Treatment 
 
Number of 
Injections at 
Dose per 
Injection 
Each 
Injection Volume 
Treatment 
Each 
Volume per 
Treatment 
Dose (mg) at Each 
(mL) per Each 
Cumulative 
Area 
Injection 
Each Injection 
Visit 
Treatment Visit 
Treatment Visit 
EFP Dose 
Buttock 
CCH 0.07 mg 
0.3 mL (given 
12 per buttock 
0.84 mg per buttock 
3.6 mL per buttock 
5.04 mg 
as three 0.1 mL 
× 2 buttocks = 
× 2 buttocks = 
× 2 buttocks = 
(3 treatment 
aliquots) 
24 injections 
1.68 mg 
7.2 mL 
visits × 0.84 mg 
(up to 12 injections 
(24 injections × 
per buttock 
per buttock × 
0.3 mL) 
× 2 buttocks) 
0.07 mg/injection 
× 2 buttocks) 
Thigh 
CCH 0.07 mg 
1.5 mL (given 
12 per thigh 
0.84 mg per thigh 
18 mL per thigh 
5.04 mg 
as five 0.3 mL 
× 2 thighs = 
× 2 thighs = 
× 2 thighs = 
(3 treatment 
aliquots) 
24 injections 
1.68 mg 
36 mL 
visits × 0.84 mg 
(up to 12 injections 
(24 injections × 
per thigh 
per thigh × 
1.5 mL) 
× 2 thighs) 
0.07 mg/injection 
× 2 thighs) 
Treatment will consist of up to 12 injections per treatment area (1 buttock or 1 thigh) for a total 
of up to 24 injections in 2 buttocks or in 2 thighs per treatment visit. With the exception of 
Dimples 1, 2, and 3 (see Section 6.2), and because the goal of treatment is to improve the 
aesthetic appearance of each entire treatment area, the investigator will select dimples that in his 
or her opinion would most improve the aesthetic appearance of each entire treatment area. 
Therefore, the same dimples within a treatment area (each buttock or each thigh) or different 
dimples within a treatment area may be treated at each treatment visit, but injections must be 
administered within the selected treatment area (buttocks or thighs) for each of the 3 treatment 
visits. Dimple 1 will not be treated at any time during this study. Dimples 2 and 3 must be treated 
at each treatment session. 
Study treatment will be injected subcutaneously while the subject is in a prone position. Specific 
instructions outlining the injection techniques will be provided in the Pharmacy Manual. 
The investigator or qualified designee will then apply a sterile dressing to the injection areas with 
hypoallergenic tape. The subject will be instructed to remove the dressing in the evening. 
NOTE: CCH is a foreign protein and investigators must be prepared to address and manage an 
allergic reaction should it occur. At the time of each injection, a 1:1,000 solution of epinephrine 
for injection, 50-mg diphenhydramine injection or a suitable equivalent, and oxygen must be 
available and the investigator and site staff must be familiar with their use. To evaluate the 
subject for possible immediate immunological AEs, the subject will remain in direct observation 
of medical personnel who are skilled in the management of an allergic reaction for 30 minutes 
after receiving the injections of study treatment and until the subject exhibits no sign of an 
immunological or other clinically significant systemic or local AE. The subject’s vital signs 
should be stable before the subject can leave direct observation. 


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6.4. 
Study Treatment Preparation/Handling/Storage/Accountability 
CCH and its diluent will be supplied in bulk cartons of 10 vials each. Each vial of study 
treatment and diluent will minimally be labeled with contents, sponsor identification, storage, 
administration/use, and appropriate caution statements. CCH and the diluent must be stored in an 
appropriate, secure area. Study treatment must be kept in a temperature-monitored refrigerator 
(2°C to 8°C) with locked access until used or returned to Endo. 
The investigator or designee will confirm that appropriate temperature control conditions have 
been maintained for all study treatments received and that any discrepancies are reported and 
resolved prior to study treatment administration. 
Only subjects enrolled in the study will receive study treatment and only authorized study staff 
will dispense study treatment. 
In accordance with the International Council for Harmonisation (ICH) requirements, at all times 
the investigator will be able to account for all study treatment furnished to the study site. An 
accountability record will be maintained for this purpose. The investigator must maintain 
accurate records indicating dates and quantity of study treatment received, to whom it was 
administered (subject-by-subject accounting), and accounts of any study treatment accidentally 
or deliberately destroyed. All unused study treatment not involved in immediate subject 
treatment will be maintained under locked, temperature-controlled storage at the study site. 
Please refer to the Pharmacy Manual for complete information regarding preparation, handling, 
storage, and accountability of study treatment. 
 
6.5. 
Measures to Minimize Bias 
This is an open-label, nonrandomized study; measures to minimize bias using treatment blinding 
or randomization are not applicable to this study. 
 
6.5.1. 
Interactive Response Technology 
The investigator or designee will utilize an interactive response technology (IRT) system to 
register subjects at screening. Each subject’s unique identification (ID) number will be assigned 
by the IRT system and will be used to identify the subject for the duration of the study within all 
systems and documentation. If the subject is not eligible to receive study treatment, or should 
discontinue from the study, the subject ID number will not be reassigned to another subject. 
Specific instructions for the use of the IRT system will be included in the IRT User Manual. 
The investigator must maintain a subject master log linking the subject ID to the subject’s name. 
The investigator must follow all applicable privacy laws in order to protect a subject’s privacy 
and confidentiality. Information that could identify a subject will be masked on material received 
by the sponsor. 
 
6.6. 
Study Treatment Compliance 
All subjects will receive study treatment administered by the investigator at the study site. All 
dosing information will be recorded for each subject visit. Drug inventory will be maintained in 
the IRT system, and all original containers of used and unused study treatment and diluent will 
be returned to the sponsor (or designee) at the end of the study. 


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Accidental or intentional overdoses should be reported to the sponsor/designee promptly (see 
Section 8.4). 
 
6.7. 
Prior and Concomitant Medications and Procedures 
The start and stop date, dose, unit, frequency, route of administration, and indication for all prior 
(taken within the 90 days prior to the Screening Visit) and concomitant (taken from the 
Screening Visit through the Day 265 Visit) medications and nondrug therapies (eg, blood 
transfusions, oxygen supplementation, physical therapy, etc) received will be recorded. 
In addition, all prior treatments for EFP will be recorded with start and stop date, dose, unit, 
frequency and route of administration. 
 
6.7.1. 
Prohibited Medications and Procedures 
The following medications are prohibited for subjects during the study: 
• Anticoagulants (warfarin, heparin, direct thrombin inhibitors, Factor X inhibitors) and 
antiplatelet agents (aspirin > 150 mg/day and P2Y12 inhibitors, such as clopidogrel), 
which can cause additional bruising. However the use of aspirin at a dose level of 
≤ 150 mg per day will be permitted during study. 
The following procedures/treatments are not allowed in the selected treatment region (both 
buttocks or both thighs) during the course of the study (from the Screening Visit through the 
Day 265 Visit): 
• Liposuction. 
• Any injectable treatment (eg, KYBELLA) or any similar treatment that could destroy 
fat cells and/or remove fat deposits. 
• Injections (eg, mesotherapy); radiofrequency device treatments; laser treatment; 
buttock implant treatment; cryolipolysis; or surgery (including subcision and/or 
powered subcision). 
• Any investigational treatment for EFP (other than CCH as prescribed in this study). 
• Endermologie or similar treatments. 
• Massage therapy. 
• Creams (eg, Celluvera, TriLastin) and/or home therapies to prevent or mitigate EFP. 
If any prohibited medication or procedure is used during the study, all pertinent information will 
be recorded. The designated study Medical Monitor must be informed immediately so the 
sponsor may determine whether to continue the subject in the study. 


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7. 
DISCONTINUATION FROM STUDY TREATMENT AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment 
Subjects who receive at least 1 dose of study treatment and discontinue study treatment or who 
are withdrawn from the study will be encouraged to complete the remaining study visits and 
evaluations and provide any additional follow-up information as required by the study, unless the 
subject specifically indicates that they will not participate in any further evaluations. The date of, 
and reason for, study treatment discontinuation will be recorded. 
Permanent study treatment discontinuation is required for the following: 
• The subject becomes pregnant during the active treatment phase of the study (Day 1 
through Day 43). 
Discontinuation of study treatment for abnormal liver function should be considered by the 
investigator when a subject meets one of the conditions outlined in Section 10.6. 
If a clinically significant cardiac finding is identified (including but not limited to changes from 
baseline in corrected QT [QTc] interval) after the start of study treatment, the investigator or a 
qualified designee will determine if the subject can continue in the study and if any change in 
management is needed. 
All subjects dosed prior to 18 March 2020 will be replaced. Subjects who receive their first dose 
of study drug after 18 March 2020 and subsequently discontinue from study treatment will not be 
replaced. 
 
7.2. 
Subject Discontinuation/Withdrawal from the Study 
Subjects may withdraw from the study at any time at their own request, or may be withdrawn at 
any time at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons. The date of and reason for withdrawal from the study will be recorded. 
If the subject withdraws consent for disclosure of future information, the sponsor may retain and 
continue to use any data collected before such withdrawal of consent. If a subject withdraws 
from the study, the subject may request destruction of any samples taken and not tested and the 
investigator must document this in the site study records. 
Withdrawal from the study is required for any subject who becomes pregnant at any time during 
the study. 
A subject may also be withdrawn from the study for the following medical or administrative 
reasons: 
• Withdrawal by subject (reason must be specified). 
• An AE. 
• Death. 
• A protocol violation (reason must be specified, for example: lack of compliance, use 
of a prohibited concomitant medication, etc). 


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• The subject was lost to follow-up. 
• Other reasons (reason must be specified, for example: the subject moved, pregnancy, 
investigator decision, sponsor decision to terminate trial, etc). 
If a subject discontinues from the study, all Early Termination procedures should be conducted 
as detailed in the Schedule of Activities. The date a subject discontinues and the reason for 
discontinuation will be recorded in the source documentation and the electronic case report form 
(eCRF). If, however, a subject withdraws consent, no additional procedures are required except 
the collection of AE information. This information should be recorded in the source 
documentation and the eCRF. 
All subjects dosed prior to 18 March 2020 will be replaced. Subjects who receive their first dose 
of study drug after 18 March 2020 and subsequently withdraw from the study will not be 
replaced. 
 
7.3. 
Lost to Follow-up 
A subject will be considered lost to follow-up if the subject repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return for a required study visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and to ascertain whether or not the subject wishes to and/or should continue 
in the study. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls, and 
if necessary, a certified letter to the subject’s last known mailing address; or local 
equivalent methods). These attempts will be documented. 
• Should the subject continue to be unreachable, the subject will be considered to have 
withdrawn from the study. 
All subjects dosed prior to 18 March 2020 will be replaced. Subjects who receive their first dose 
of study drug after 18 March 2020 and are subsequently lost to follow-up will not be replaced. 
 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedule of Activities (Section 1.2). 
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct. Protocol waivers or exemptions are not 
allowed. Activities outlined in the Clinical Operations Study Manual must be followed or will 
result in a protocol deviation. 
Urgent safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the subject should continue study treatment and/or be withdrawn from 
the study. 


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All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
subjects screened and to confirm eligibility or record reasons for screen failure, as applicable. 
Procedures conducted as part of the subject’s routine clinical management and obtained before 
signing of the informed consent form (ICF) may be utilized for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the time 
frame defined in the Schedule of Activities. 
 
8.1. 
Efficacy Assessments 
Efficacy assessments will be evaluated at times specified in the Schedule of Activities. Below is 
a general description of each of these assessments. Specific instructions and questionnaires/forms 
(where appropriate) will be provided in the Clinical Operations Study Manual. 
 
8.1.1. 
Imaging for Efficacy Assessments 
Although digital photographs are not direct efficacy measurements, digital photography will be 
utilized in the assessment of certain efficacy measurements (ie, to assess certain cellulite severity 
parameters at specific intervals-see Section 1.2). At screening, the investigator or qualified 
designee will photograph each of the 2 potential treatment areas (both buttocks and both thighs) 
independently using a sponsor-supplied standardized digital camera in a standardized manner. 
For subsequent visits, only the areas receiving treatment (both buttocks or both thighs) will be 
photographed. The subject will be standing in a consistent, relaxed standing pose (ie, standing 
position with relaxed gluteus muscles) for each photography session and will be wearing a 
standardized photographic garment as described in the Photography Manual. These photographs 
will be taken before and after marking of the treatment area for dosing. 
All photographs from this study are the property of Endo and de-identified images may be 
utilized for clinical development, scientific communication, marketing, regulatory purposes, 
and/or legal applications as required/desired by Endo. 
8.1.2. 
Subject and Investigator Cellulite Assessments 
Investigator cellulite assessments are independent of the subject assessments. Therefore, all 
subject cellulite assessments must be completed before the investigator’s cellulite assessments 
are initiated. Subject assessments will occur while the subject is alone with no study site 
personnel in the room. Investigators will be instructed not to verbalize their ratings while in the 
presence of the subject and vice versa. 
 
8.1.2.1. 
Patient-reported Photonumeric Cellulite Severity Scale 
The PR-PCSS-Buttock and PR-PCSS-Thigh will be used to assess the severity of cellulite of 
both treatment areas (each buttock and each thigh, independently). The PR-PCSS-Buttock and 
PR-PCSS-Thigh are 5-level photonumeric scales developed specifically for patients and used by 
the subject to assess the severity of their cellulite in the buttocks and/or thighs by viewing digital 
images of each of their buttocks and/or thighs captured by photography at times outlined in the 
Schedule of Activities (Section 1.2). The ratings range from 0 (None) to 4 (Severe) with labels 
and descriptors to aid the subject in the assessments. 


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At screening, the subjects will use the appropriate PR-PCSS scale to assess the cellulite in all 
potential treatment areas (each buttock and each thigh) independently. For subsequent visits only 
the areas receiving treatment (each buttock or each thigh) will be assessed. 
Subjects will be trained/retrained on the use of the PR-PCSS prior to each assessment. 
 
8.1.2.2. 
Clinician-reported Photonumeric Cellulite Severity Scale 
The CR-PCSS-Buttock and CR-PCSS-Thigh will be used to assess the severity of cellulite of 
both treatment areas (each buttock and each thigh, independently). The CR-PCSS-Buttock and 
CR-PCSS-Thigh are 5-level photonumeric scales developed specifically for clinicians and used 
by the investigator to assess the severity of the subject’s cellulite in each buttock or each thigh by 
live assessments. The ratings range from 0 (None) to 4 (Severe) with labels and descriptors to aid 
the investigator in the assessments. This assessment should be made while the subject is in the 
standing position with relaxed gluteus muscles at times outlined in the Schedule of Activities 
(Section 1.2). Each treatment area (each buttock and/or each thigh) will be assessed 
independently. 
At screening, an Investigator who is a physician will use the appropriate CR-PCSS scale to 
assess the cellulite in all potential treatment areas (each buttock and each thigh) independently 
For subsequent visits only the areas receiving treatment (each buttock or each thigh) will be 
assessed. 
Investigators who are physicians will be trained and qualified on the use of each CR-PCSS scale 
prior to assessing any subjects. 
 
8.1.2.3. 
Hexsel Cellulite Severity Scale 
The Hexsel CSS is a photonumeric scale that looks at 5 key 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 (Hexsel et al, 2009; Nürnberger and Müller, 1978). Each of 
these features is evaluated on a 4-point scale from a low of 0 to a high of 3. 
At screening, an Investigator who is a physician will use the Hexsel CSS to assess the cellulite in 
all potential treatment areas (each buttock and each thigh) independently. For subsequent visits 
only the areas receiving treatment (each buttock or each thigh) will be assessed. This assessment 
should be made while the subject is in the standing position with relaxed gluteus muscles. 
 
8.2. 
Safety Assessments 
All safety assessments will be performed at the times outlined in the Schedule of Activities 
(Section 1.2). Additional (unscheduled) safety assessments may be performed as needed. 
 
8.2.1. 
Medical and Surgical History 
Medical and surgical history will be obtained at the Screening Visit. Medical history will include 
a review of the following systems: general, dermatological, respiratory, cardiovascular, 
gastrointestinal, genitourinary, gynecological, endocrine, musculoskeletal, hematological, 
neuropsychological, immune (allergies), and head, eyes, ears, nose, and throat. Historical and 


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current medical conditions including date of last menstrual period for female subjects will be 
recorded. History of tobacco and alcohol use (never, current, former) will also be collected. 
Surgical history will include a review of all surgical procedures completed in the prior 5 years 
and any surgery completed at any time in the treatment area. 
EFP history will include the start date of the condition and any family history of EFP. 
 
8.2.2. 
Physical Examination 
The complete physical examination should include evaluation of the head, eyes, ears, nose, 
throat, neck (including thyroid), cardiovascular system (including assessment of heart, peripheral 
pulses, presence or absence of edema), lungs, abdomen (including liver and spleen, bowel 
sounds), lymph nodes, musculoskeletal system (including spine, joints, muscles) neurological 
system (including cranial nerves, reflexes, sensation, strength), skin (excluding cellulite), 
extremities, and other conditions of note. 
All examinations will be performed by a physician or health professional listed on the Form 
FDA 1572 and licensed to perform physical examinations. The investigator will review all 
physical exam findings for clinical significance. Any physical exam finding meeting the 
investigator’s or sponsor’s criteria for clinical significance will be recorded as an AE or SAE as 
appropriate. 
 
8.2.3. 
Height and Weight 
Height will be collected at screening only. Weight will be collected as outlined in the Schedule 
of Activities (Section 1.2). Any change from the Screening Visit in subject weight that is 
considered by the investigator to be clinically significant will be recorded as an AE (or SAE, if 
appropriate). 
 
8.2.4. 
Fitzpatrick Skin Scale 
The Fitzpatrick Skin Scale is a 6-level scale (Levels I-VI) for assessment of skin color and 
propensity for tanning. The skin types range from Level I: “Pale white skin, blue/hazel eyes, 
blond/red hair, always burns, does not tan” to Level VI: “Dark brown or black skin, never burns, 
always tans darkly”. The investigator (or designee) will determine the Fitzpatrick Skin Type for 
all subjects at screening. 
 
8.2.5. 
Vital Signs 
Vital signs will be obtained at times outlined in the Schedule of Events and after the subject has 
been seated for 5 minutes (minimum) and will include systolic and diastolic blood pressures, 
pulse rate, respiratory rate, and body temperature. The results, date, and time for all vital sign 
assessments will be recorded. 
On study treatment days (Days 1, 22, and 43), vital signs will be taken up to 4 hours prior to 
dosing and at 15 minutes and 30 minutes after dosing (body temperature is not required at the 
15 minute postdose time point). The subject’s vital signs must be stable, or repeated until stable 
before the subject can leave direct observation. 


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The investigator will review all vital sign values for clinical significance. Any vital sign value 
meeting the investigator’s or sponsor’s criteria for clinical significance will be recorded as an AE 
(or SAE, if appropriate). 
8.2.6. 
Electrocardiogram 
A 12-lead ECG recording will be conducted at the Screening Visit. The subject should be in a 
supine position for at least 5 minutes before the recording is conducted. Lead position will be 
that of a standard 12-lead ECG; no additional or special lead placements will be necessary. The 
ECG record should include a minimum of 5 heart cycles (beats). 
If the ECG report shows QT prolongation with QTc ≥ 450 ms, the investigator should repeat the 
ECG within 1 hour. If the initial findings are confirmed, the investigator should exclude the 
subject from study participation. 
The investigator will review all other ECG results for clinical significance. Any ECG result 
meeting the investigator’s criteria for clinical significance will be recorded as an AE (or SAE, if 
appropriate). 
8.2.7. 
Clinical Laboratory Determinations (Hematology, Chemistry, and Urinalysis) 
Clinical laboratory tests will be conducted according to the Schedule of Activities (Section 1.2). 
Required clinical laboratory tests are outlined in Section 10.2. Clinical laboratory tests will be 
performed by a designated central laboratory. The site will be provided with instructions for 
specimen collection, preparation, packaging and transport. The results of the tests will be 
returned to the investigational site. 
Samples for laboratory testing may be collected under fasted or nonfasted conditions. Fasting 
early morning samples are preferred, but a random daytime sample is acceptable. The date and 
time of the sample collection must be documented on the laboratory report. Investigators must 
review and sign laboratory reports and document the clinical significance of each laboratory 
abnormality. New clinically significant laboratory abnormalities or clinically significant changes 
in laboratory values will be reported as AEs (or SAEs, if appropriate). 
Clinical laboratory test data will be reviewed by the investigator, or designee, and additional 
clinical laboratory tests may be ordered at his/her discretion (eg, if the results of any clinical 
laboratory test falls outside the reference range or clinical symptoms necessitate additional 
testing to ensure safety). Any additional testing will be performed by the designated central 
laboratory (or local laboratory, if needed to ensure subject safety). 
 
8.2.8. 
Pregnancy Testing 
All female subjects of childbearing potential will have serum and/or urine pregnancy tests at the 
time points outlined in the Schedule of Activities (Section 1.2). Results must be available prior to 
protocol mandated study treatment and prior to MRIs. Subjects with positive results at the 
Screening Visit or on Day 1 will be ineligible for study entry. Any female subject that becomes 
pregnant during the study will be immediately withdrawn from the study and will have the 
pregnancy reported as per Section 8.3.5. 
For all female subjects of childbearing potential, the subject’s agreement to use contraception 
throughout their study participation (Screening Visit through Day 265, or for a minimum of 


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28 days after the last dose of study treatment for subjects who early terminate) will be 
documented. 
 
8.2.9. 
Biopsy Follow-up Examination 
The investigator will examine the biopsy site for evidence of ongoing AEs related to the biopsy 
and to determine if the biopsy site has healed at times specified in the Schedule of Activities 
(Section 1.2). The Day 85 and Day 265 Biopsy Follow-up Visits are not required for subjects 
who had less than 3 doses of study drug prior to 18 March 2020. 
 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Section 10.3. 
All AEs, including both observed or volunteered problems, complaints, signs or symptoms, and 
medically significant laboratory values must be recorded, regardless of whether associated with 
the use of study treatment. This would include AEs resulting from concurrent illness, reactions to 
concurrent medication use, or progression of disease states (excluding the disease under study). 
A condition present at baseline that worsens after initiation of study treatment will be captured as 
an AE; the onset date will be the date the event worsened. The AE should be recorded in 
standard medical terminology when possible. 
 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All SAEs and AEs will be collected by the investigator from the time of signing the informed 
consent through the Day 265 visit or for 28 days after the last study treatment for those who early 
terminate. For subjects who undergo the screening biopsy and are not subsequently dosed, AEs 
will be followed for 28 days after the biopsy. This will include any AEs that are ongoing at the 
time of completion/termination of the study. All ongoing AEs must be followed until resolution 
or for 28 days after the subject’s last study treatment, whichever comes first. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Section 10.3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available. 
Investigators are not obligated to actively seek AEs and SAEs after conclusion of subject study 
participation. However, if the investigator learns of any SAE, including death, at any time after 
the subject has been discharged from the study, and the investigator considers the event to be 
reasonably related to the study treatment or study participation, including all medically 
significant and grade 4 labs, the investigator must promptly notify the sponsor. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and submitting SAE reports are provided in Section 10.3. 
 
8.3.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and SAEs. Open-ended and 
nonleading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences. 


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At each visit, subjects will be queried regarding any AEs that have occurred since the last visit. 
Subjects will be asked to volunteer information concerning AEs with a nonleading question such 
as, “How do you feel?”. Study site personnel will then record all pertinent information. The 
study drug compliance record should also be reviewed to detect potential intentional or 
unintentional overdoses. 
 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs and nonserious AESIs will be followed to resolution, 
stabilization, the event is otherwise explained, or the subject is lost to follow-up. Further 
information on follow-up procedures is provided in Section 10.3. 
 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities regarding the safety of the study treatment under clinical 
investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of the study treatment under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements regarding safety reporting to 
regulatory authorities, IRBs/IECs, and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSARs) according to local regulatory requirements and sponsor policy, and forwarded to 
investigators as necessary. 
An investigator who receives an investigator safety report describing and SAE or other specific 
safety information (ie, summary or listing of SAEs) from the sponsor will review and then file it 
with the Investigators Brochure, and will notify the IRB/IEC, if appropriate according to local 
requirements. 
 
8.3.5. 
Pregnancy 
All subject pregnancies that are identified during or after this study, where the estimated date of 
conception is determined to have occurred during study drug therapy or within 28 days of the last 
study treatment need to be reported, followed to conclusion, and the outcome reported, even if 
the subject is discontinued from the study. The investigator should report all pregnancies within 
24 hours using the Pregnancy Form. Monitoring of the pregnancy should continue with 1 or 
more Pregnancy Form(s) detailing progress, and a Two-Month Follow-up Pregnancy Report 
Form detailing the outcome, should be submitted. 
Pregnancy itself is not regarded as an AE unless there is suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Likewise, elective abortions without complications are not considered AEs. Any SAEs 
associated with pregnancy (eg, congenital abnormalities/birth defects, or any other serious 
events) must additionally be reported as such using the Serious Adverse Event (SAE)/Reportable 
Event Form (see Section 10.3). Spontaneous miscarriages should also be reported and handled as 
SAEs. 


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Subjects will be instructed to immediately notify the investigator of any pregnancies. 
A subject who becomes pregnant must immediately be discontinued from study treatment and 
withdrawn from the study. 
Attempts to obtain the pregnancy follow-up and pregnancy outcome information detailed above 
are necessary even if a subject discontinues treatment and withdraws from the study because of 
pregnancy. 
8.3.6. 
AEs/SAEs Experienced by Nonsubjects Exposed to Study Treatment 
Nonsubjects are persons who are not enrolled in the study but have been exposed to study 
treatment, including instances of diversion of study treatment. All such AEs/SAEs occurring in 
nonsubjects from such exposure will be reported to Endo (when the nonsubject agrees) on the 
Serious Adverse Event (SAE)/Reportable Event Form regardless of whether the event is serious 
or not. Instructions for completing the form for events experienced by nonsubjects will be 
provided. SAEs occurring in nonsubjects exposed to study medication will be processed within 
the same SAE reporting timelines as described in Section 10.3. Additionally, the drug 
accountability source documentation at the site should reflect this occurrence. 
 
8.3.7. 
Adverse Events of Special Interest 
AESIs for this study include: 
• Bruising, ecchymosis, hematomas, and contusions that occur remote to the site of 
drug administration. 
• Any hypersensitivity reactions. 
• Local AEs associated with the injection site, including bruising, pain, nodules/mass, 
ulceration, erythema, pruritus, swelling, and/or induration. 
These events will be reported as AEs in the eCRF. All AEs will be evaluated for seriousness and 
severity. If any of these events meet the criteria for an SAE, they will also be reported as such 
using the procedure outlined in Section 10.3. 
 
8.4. 
Treatment Overdose 
Study treatment overdose is any accidental or intentional use of treatment in an amount higher 
than the dose indicated by the protocol for that subject. Study treatment compliance should be 
reviewed to detect potential instances of overdose (intentional or accidental). 
Any treatment overdose during the study should be noted on the study medication eCRF. 
An overdose is not an AE per se, however all AEs associated with an overdose should both be 
entered on the Adverse Event eCRF and reported using the procedures detailed in Section 10.3, 
even if the events do not meet seriousness criteria. If the AE associated with an overdose does 
not meet seriousness criteria, it must still be reported using the Endo Serious Adverse Event 
(SAE)/Reportable Event Form and in an expedited manner, but should be noted as nonserious on 
the form and the Adverse Event eCRF. 


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8.5. 
Pharmacokinetics 
Not applicable. 
 
8.6. 
Pharmacodynamics 
Prior to the first MRI and biopsy, the investigator will select 3 dimples from the 2 treatment 
areas (both buttocks or both thighs) for MRI and biopsy evaluation from the 4 well-defined, 
isolated dimples that are considered moderate or deep in depth identified at screening (see 
Section 5.1, Item 5). The 3 selected dimples should be distributed across both regions of the 
treatment area (eg, 1 dimple on the left thigh [or buttock] and 2 dimples on the right thigh [or 
buttock], or vice versa). The investigator or designee will mark and label these 3 dimples in a 
manner that will allow them to be relocated for subsequent MRIs and biopsies (see the Clinical 
Operations Study Manual for specific instructions). To ensure proper healing, the dimple 
biopsied at screening (Dimple 1) will not receive treatment with CCH. Dimple 2 and Dimple 3 
will receive the entire CCH treatment course in this study. 
 
8.6.1. 
MRI 
MRIs of each of the 3 dimples selected for MRI and biopsy (Dimples 1, 2, and 3) will be 
performed on all subjects at times outlined in the Schedule of Activities (Section 1.2). Screening, 
Day 71, and Day 251 MRIs may be repeated as often as necessary to obtain an evaluable image. 
Repeat screening MRIs must take place within the screening window. MRIs must be completed 
prior to the required biopsies. Specific instructions for the MRI procedures will be provided in 
the Clinical Operations Study Manual. 
All MRIs from this study are the property of Endo and de-identified images may be utilized for 
clinical development, scientific communication, marketing, regulatory purposes, and/or legal 
applications as required/desired by Endo. 
8.6.2. 
Double Punch Biopsy 
Subjects will have a total of three 8 mm double punch biopsies done, 1 in each of the 3 dimples 
selected for MRI and biopsy (Dimples 1, 2, and 3) at the times outlined in the Schedule of 
Activities (Section 1.2). Detailed directions of the collection, processing, storage, handling and 
shipment of the biopsy samples will be provided in the Clinical Operations Study Manual. The 
investigator must examine and confirm sufficient healing of the biopsy site before dosing on 
Day 1. 
Subjects who received all 3 doses of study drug prior to 18 March 2020 will have Day 71 and 
251 biopsies, if willing to do so. Subjects who received less than 3 doses of study drug prior to 
18 March 2020 will not have the Day 71 and Day 251 biopsies performed. 
De-identified biopsy samples may be stored for a maximum of 5 years (or according to local 
regulations) following the last sample collection from the last subject last visit for the study at a 
facility selected by the sponsor to enable further analysis including to develop methods, assays, 
prognostics and/or companion diagnostics related to specify the intervention target, disease 
process, pathways associated with disease state, and/or mechanism of action of the study 
intervention. 


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8.7. 
Genetics 
Not applicable 
 
8.8. 
Biomarkers 
8.8.1. 
Immunogenicity Assessments 
Serum samples will be collected at times outlined in the Schedule of Activities (Section 1.2) and 
will be tested for binding anti-AUX-I and anti-AUX-II antibody testing. When immunogenicity 
samples are required on a Treatment Day, the sample will be collected prior to study treatment 
administration. The samples also will be tested for neutralizing antibodies at times to be 
determined by the sponsor. 
The serum samples obtained will be processed, stored and then shipped frozen on dry ice to 
Endo’s appointed laboratory for the determination of anti-AUX-I and anti-AUX-II antibodies. 
Specific instructions for the collection, processing, storage, handling and shipment of the 
immunogenicity samples will be provided in the Clinical Operations Study Manual. 
De-identified immunogenicity samples may be stored for a maximum of 5 years (or according to 
local regulations) following the last subject’s last visit for the study at a facility selected by the 
sponsor to enable further analysis of immune responses to study treatment; develop methods, 
assays, prognostics and/or companion diagnostics related to specify the intervention target, 
disease process, pathways associated with disease state, and/or mechanism of action of the study 
the study treatment. 
 
8.9. 
Medical Resource Utilization and Health Economics 
Not applicable 
 
9. 
STATISTICAL CONSIDERATIONS AND METHODS 
9.1. 
Sample Size Determination 
There was no formal sample size calculation for this study. A total of 12 subjects is considered 
sufficient to determine if biopsy will demonstrate changes in histopathology associated with 
CCH treatment while exposing the minimum number of subjects possible to the risks associated 
with this invasive procedure. 
 
9.2. 
Populations for Analysis 
For the purposes of analysis, the following populations are defined: 
• The Safety Population will include all subjects who have undergone the first 
(screening) biopsy. 
• The Evaluable Population will include all subjects in the Safety Population who 
received their first dose of CCH in this study after 18 March 2020 and who had a 
baseline and at least 1 postinjection PR-PCSS evaluation. 


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9.3. 
Statistical Hypotheses and Analyses 
This section provides a general summary of the statistical methods to be used in analyzing study 
data. A more detailed statistical analysis plan will be developed and finalized prior to the interim 
analysis. 
9.3.1. 
Efficacy Analysis 
The primary endpoint of change from baseline in PR-PCSS at Day 71 will be summarized by 
treatment area (left or right) and region (buttock or thigh) using appropriate descriptive statistics 
using the Evaluable Population. 
All secondary and tertiary PR-PCSS, CR-PCSS, and Hexsel efficacy endpoints will be 
summarized by treatment area (left or right) and region (buttock or thigh) using appropriate 
descriptive statistics using the Evaluable Population. 
9.3.2. 
MRI and Biopsy Analyses 
A descriptive summary of changes from baseline seen in MRI and biopsy results will be 
provided for the Evaluable Population. 
 
9.3.3. 
Safety Analyses 
All subjects who have undergone the first biopsy during screening will be included in the safety 
analyses. 
 
9.3.3.1. 
Adverse Events 
AEs will be coded using MedDRA by preferred term within system organ class. The number of 
AEs and the number of subjects reporting AEs will be listed and summarized descriptively by 
body system, preferred term, severity, and causality for each treatment group. Only TEAEs 
(events that are new in onset or aggravated in severity following treatment) will be included in 
all summaries. SAEs (including death) will be summarized. 
 
9.3.3.2. 
Vital Signs and Laboratory Evaluations 
Descriptive statistics will be presented for actual and change from baseline at each visit for vital 
signs and for each clinical laboratory test parameter. 
 
9.3.4. 
Other Analyses 
Anti-AUX-I and anti-AUX-II antibody levels will be summarized using descriptive statistics for 
the actual value at the visit. Samples from Day 1, Day 71, Day 161, and Day 251 visits will be 
analyzed for anti-AUX-I and anti-AUX-II antibodies and a subset of samples will be analyzed 
for neutralizing antibodies. Neutralizing antibody results, if tested, will be summarized as 
percentage of positive/negative. 
 
9.4. 
Interim Analysis 
An interim analysis will be conducted when at least 4 of the 12 subjects who received their first 
dose of study drug after 18 March 2020 have completed their Day 71 visit. For all subjects who 
received their first dose of study drug after 18 March 2020, analysis of all primary, secondary, 


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and tertiary endpoints will be included in the interim analysis. For the subjects who received all 
three doses prior to 18 March 2020, their MRI and biopsy data, if available, will be assessed 
separately but included in interim analysis. The purpose of the interim analysis is to determine if 
changes in morphology and/or histology can be identified using MRI and biopsy. If the interim 
analysis does not indicate that such changes can be identified, subsequent or additional MRIs or 
biopsies will not be performed in this study. 
 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This clinical study is designed to comply with the ICH Guidance on General Considerations for 
Clinical Trials (62 FR 6611, December 17, 1997), Nonclinical Safety Studies for the Conduct of 
Human Clinical Trials for Pharmaceuticals (62 FR 62922, November 25, 1997), Good Clinical 
Practice: Consolidated Guidance (62 FR 25692, May 9, 1997) and 21 CFR parts 50, 54, 56 and 
312. 
The study will be conducted in full compliance with ICH E6, the Food and Drug administration 
(FDA) guidelines for good clinical practices (GCP) and in accordance with the ethical principles 
that have their origins in the Declaration of Helsinki defined in 21 CFR, 312.120. 
Approval by the IRB/IEC prior to the start of the study will be the responsibility of the 
investigator. A copy of approval documentation will be supplied to Endo. along with a roster of 
IRB/IEC members that demonstrates appropriate composition or other documentation of 
assurance of appropriate composition per local and national regulations (eg, a Department of 
Health and Human Services [DHHS] Assurance Number will satisfy this requirement for IRBs in 
the United States). 
The study protocol, the ICF, advertisements, materials being provided to subjects, and 
amendments (if any) will be approved to IRB/IECs at each study center in conformance with 
ICH E6, CFR Title 21 Part 56, and any other applicable local laws. The investigator is 
responsible for supplying the IRB/IEC with a copy of the current Investigator’s Brochure, 
Package Insert, or Summary of Product Characteristics, as well as any updates issued during the 
study. During the course of the study, the investigator will provide timely and accurate reports to 
the IRB/IEC on the progress of the study, at intervals not exceeding 1 year (or as appropriate), 
and will notify the IRB/IEC of SAEs or other significant safety findings, per the policy of the 
IRB/IEC. At the conclusion of the study, the investigator will submit a final report or close out 
report to the IRB/IEC and provide a copy to Endo. 
Any amendment to this protocol will be provided to the investigator in writing by Endo. No 
protocol amendment may be implemented (with the exceptions noted below) before it has been 
approved by the IRB/IEC and the signature page, signed by the investigator, has been received 
by Endo. Where the protocol is amended to eliminate or reduce the risk to the subject, the 
amendment may be implemented before IRB/IEC review and approval. However, the IRB/IEC 


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must be informed in writing of such an amendment and approval obtained within reasonable time 
limits. Deviating from the protocol is permitted only if absolutely necessary for the safety or 
clinical management of the subject, and must be immediately reported to Endo. 
The investigator will be responsible for supplying updated safety and/or study information to 
study subjects as it becomes available. 
 
10.1.2. 
Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after the completion of the study. 
 
10.1.3. 
Informed Consent Process 
The ICF must be approved by the sponsor and the IRB/IEC before any subject provides consent. 
The investigator will provide the sponsor with a copy of the IRB/IEC-approved ICF and a copy 
of the IRB/IEC’s written approval before the start of the study. 
The ICF must contain all applicable elements of informed consent and the mandatory statements 
as defined by national and local regulations, including confidentiality. 
If appropriate, the ICF will contain a separate section that addresses the use of remaining 
mandatory samples for optional exploratory research. The investigator or authorized designee 
will explain to each participant the objectives of the exploratory research. Participants will be 
told that they are free to refuse to participate and may withdraw their consent at any time and for 
any reason during the storage period. A separate signature will be required to document a 
subject’s agreement to allow any remaining specimens to be used for exploratory research. 
Subjects who decline to participate in this optional research will not provide this separate 
signature. 
At the Screening Visit (and at other time as may be required by the study or when changes are 
made to the consent form), subjects will read the consent form(s) and any privacy authorization 
as required by local and national regulations (such as the Health Insurance Portability and 
Accountability Act [HIPAA] authorization form), after being given an explanation of the study. 
Before signing the consent form(s) and the privacy authorization form (if applicable), subjects 
will have an opportunity to ask questions about the study and discuss the contents of these forms 
with study site personnel. The consent/assent process shall be recorded in source documents. 
Subjects must assent understanding of and voluntarily sign these forms in compliance with ICH 
GCP and all applicable national and international regulations, before participating in any 
study-related procedures. Subjects will be made aware that they may withdraw from the study at 
any time for any reason. 
All versions of each subject’s signed ICF must be kept on file by the site for possible inspection by 
regulatory authorities and the sponsor. Signed copies of the consent form(s) and the privacy 
authorization form, if applicable, will be given to the subject. 


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The subjects will be made aware of their right to see and copy their records related to the study 
for as long as the investigator has possession of this information. If the subject withdraws 
consent and/or HIPAA authorization, the investigator can no longer disclose health information, 
unless it is needed to preserve the scientific integrity of the study. 
 
10.1.4. 
Data Protection 
Study subjects will be assigned a unique identifier by the sponsor or designee. Any subject 
records or datasets that are transferred to the sponsor will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be transferred. 
The subject must be informed that his/her personal study-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure (in accordance with local 
and/or national law) must also be explained to the subject. 
The subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Committee Structure 
No monitoring committees will be used for this study. 
 
10.1.6. 
Dissemination of Clinical Study Data 
Aggregate results data will be provided to the sites that actively enrolled subjects into this study 
after the clinical study report is finalized. 
Study results and de-identified individual subject data will be released as required by local and/or 
national regulation. 
 
10.1.7. 
Data Quality Assurance 
Steps to assure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study centers, review of protocol procedures with the investigators and 
associated personnel prior to start of the study, and periodic monitoring visits conducted by the 
sponsor or sponsor representative. Significant and/or repeated noncompliance will be 
investigated and remedial action instituted when appropriate. Failure to comply with remedial 
actions may result in investigator site termination and regulatory authority notification. 
The sponsor or its designee will utilize qualified monitors to review and evaluate activities 
conducted at investigator sites. 
The data will be entered into the clinical study database in a timely fashion and will be verified 
for accuracy, following procedures defined by the sponsor (or designee). Data will be processed 
and analyzed following procedures defined by the sponsor (or designee). 
The study will be monitored and/or audited at intervals to ensure that the clinical study is 
conducted and data are generated, documented (recorded), and reported in compliance with the 
study protocol, ICH E6 consolidated guidelines, and other applicable regulations. The extent, 
nature, and frequency of monitoring and/or audits will be based on such considerations as the 
study objectives and/or endpoints, the purpose of the study, study design complexity, and 


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enrollment rate. At the conclusion of a program, a compliance statement will be generated by the 
sponsor (or designee) listing all audit activities performed during the clinical study. 
All data recordings and source documentation (including electronic health records) must be made 
available to the sponsor (or designee), FDA and any other regulatory agencies that request access 
to study records for inspection and copying, in keeping with national and local regulations. 
The investigator shall permit audits and inspections by the sponsor, its representatives, and 
members of regulatory agencies. The investigator should immediately notify the sponsor of an 
upcoming FDA or other regulatory agency inspection. 
 
10.1.8. 
Source Documents 
All subject information recorded in the eCRF will be attributable to source data from the 
investigational site unless otherwise outlined in this protocol. 
Source documents include but are not limited to original documents, data and records such as 
hospital/medical records (including electronic health records), clinic charts, lab results, subject 
diaries, data recorded in automated instruments, microfilm or magnetic media, and pharmacy 
records, etc. At a minimum, all data required to be collected by the protocol should have 
supporting source documentation for entries in the eCRF, unless the protocol specifies that data 
can be recorded directly on/in the eCRF or other device. 
The investigator shall retain and preserve 1 copy of all data collected or databases generated in 
the course of the study, specifically including but not limited to those defined by GCP as 
essential. Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational medicinal product. These documents should be 
retained for a longer period, however, if required by the applicable regulatory requirements or by 
an agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. Prior to 
destruction of any study essential documents, the investigator must first obtain written approval 
from the sponsor. 
 
10.1.9. 
Study and Site Closure 
The sponsor has the right to suspend or terminate the study at any time. The study may be 
suspended or terminated for any reason. 
 
10.1.10. 
Publication Policy 
All data generated in this study are the property of Endo. An integrated clinical and statistical 
report will be prepared at the completion of the study. 
Publication of the results by the investigator will be subject to mutual agreement between the 
investigator and Endo. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
Table 3: 
Clinical Laboratory Tests 
 
Hematology 
Biochemistry 
Urinalysis 
Hemoglobin 
Glucose 
Glucose 
Hematocrit 
Sodium 
Protein 
Red blood cell 
Potassium 
Specific gravity 
White blood cell (WBC) 
Calcium 
pH 
Platelets 
Chloride 
Ketones 
WBC Differential 
Carbon dioxide (CO2) 
Bilirubin 
Inorganic phosphate 
Urobilinogen 
Blood urea nitrogen 
Nitrite 
Creatinine 
Blooda 
Creatinine clearance (estimated) 
Aspartate transaminase (AST) 
Leukocytesa 
Alanine transaminase (ALT) 
Gamma-glutamyl transferase (GGT) 
Total bilirubin (TBL) (direct bilirubin reflex if elevated) 
Albumin 
Alkaline phosphatase (ALP) 
Uric acid 
a Microscopic examination will be performed if blood or leukocytes are detected by dipstick. 
 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting 
10.3.1. 
Definitions 
An AE is any unfavorable or unintended change in body structure (signs), body function 
(symptoms), laboratory result (eg, chemistry, ECG, X-ray, etc), or worsening of a pre-existing 
condition associated temporally with the use of the study medication whether or not considered 
related to the study medication. AEs will be captured once a subject has signed the informed 
consent. AEs include: 
• Changes in the general condition of the subject. 
• Subjective symptoms offered by or elicited from the subject. 
• Objective signs observed by the investigator or other study personnel. 
• All concurrent diseases that occur after the start of the study, including any change in 
severity or frequency of pre-existing disease. 
• All clinically relevant laboratory abnormalities or physical findings that occur during 
the study. 
A treatment-emergent AE (TEAE) is any condition that was not present prior to treatment with 
study medication but appeared following treatment, was present at treatment initiation but 
worsened during treatment, or was present at treatment initiation but resolved and then 
reappeared while the individual was on treatment (regardless of the intensity of the AE when the 
treatment was initiated). 


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A SAE is defined as an AE that: 
• Results in death 
• Is immediately life-threatening (there is an immediate risk of death from the AE as it 
occurred; this does not include an AE that had it occurred in a more serious form may 
have caused death) 
• Results in or prolongs an inpatient hospitalization (Note: a hospitalization for elective 
or preplanned surgery, procedure, or drug therapy does not constitute an SAE) 
• Results in permanent or substantial disability (permanent or substantial disruption of 
one’s ability to conduct normal life functions) 
• Is a congenital anomaly/birth defect (in offspring of a subject using the study 
medication regardless of time to diagnosis) 
• Is considered an important medical event 
Important medical events are defined as events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
other serious outcomes. Examples of important medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
 
10.3.2. 
Relationship to Study Drug 
The degree of “relatedness” of the AE to the study medication must be described using the 
following scale: 
• Not related indicates that the AE is definitely not related to the study medication. 
• Unlikely related indicates that there are other, more likely causes and study 
medication is not suspected as a cause. 
• Possibly related indicates that a direct cause and effect relationship between study 
medication and the AE has not been demonstrated, but there is evidence to suggest 
there is a reasonable possibility that the event was caused by the study medication. 
• Probably related indicates that there is evidence suggesting a direct cause and effect 
relationship between the AE and the study medication. 
It is the sponsor’s policy to consider “Probably related” and “Possibly related” causality 
assessments as positive causality. “Not related” and “Unlikely related” causality assessments are 
considered as negative causality. 
Assessments will be recorded on the eCRF and must indicate clearly the relationship being 
assessed. For example, an AE that appears during a placebo run-in phase would be assessed with 
respect to the placebo treatment received and/or study procedures conducted during this phase. If 
the AE continued into an active treatment phase, the relationship would be assessed for the active 
treatment phase only if the AE worsened. 


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10.3.3. 
Intensity Assessment 
The intensity (or severity) of AEs is characterized as mild, moderate, or severe: 
• Mild AEs are usually transient, requiring no special treatment, and do not interfere 
with the subject’s daily activities. 
• Moderate AEs introduce a low level of inconvenience or concern to the subject and 
may interfere with daily activities, but are usually ameliorated by simple therapeutic 
measures. 
• Severe AEs interrupt a subject’s usual daily activity and typically require systemic 
drug therapy or other treatment. 
 
10.3.4. 
Reporting Adverse Events and Serious Adverse Events 
 
10.3.4.1. Reporting Adverse Events 
Throughout the study, AEs will be documented on the source document and on the appropriate 
page of the eCRF whether or not considered treatment-related. This includes any new signs, 
symptoms, injury or illness, including increased severity of previously existing signs, symptoms, 
injury, or illness. Conditions existing prior to screening will be recorded as part of the subject’s 
medical history. The investigator is responsible for assessing the relationship of AEs to the study 
medication; relationship will be classified as not related, unlikely related, possibly related, or 
probably related. 
All AEs will be collected by the investigator from the time of signing the informed consent 
through the Day 265 Visit or for 28 days after the last study treatment in subjects who terminate 
early. All ongoing AEs must be followed until resolution or until the Day 265 Visit, or 28 days 
after the last dose of study medication for subjects who terminate early, whichever comes first. 
 
10.3.4.2. Reporting Serious Adverse Events 
Any SAE, including death resulting from any cause, which occurs to any subject participating in 
this study, must be reported via email or fax by the investigator using the Endo Serious Adverse 
Event (SAE)/Reportable Event Form within 24 hours of first becoming aware of the SAE. SAEs 
will be collected by the investigator from the time of signing the informed consent through Day 
265 or 28 days after the last dose of study medication in subjects who early terminate. SAEs that 
occur within 28 days following study treatment discontinuation, or within 28 days following 
withdrawal from the study for any reason, must also be reported within the same timeframe. Any 
SAE that is felt by the investigator to be related to the study medication must be reported 
regardless of the amount of time since the last dose received. Follow-up information collected 
for any initial report of an SAE must also be reported to the sponsor within 24 hours of receipt 
by the investigator. 
All SAEs will be followed until resolution, stabilization of condition, or until follow-up is no 
longer possible. 
All SAEs should be reported via email (safety@endo.com) or fax (610-968-7135). 


EN3835-212 Protocol Amendment 3 
08 May 2020 
Endo Pharmaceuticals Inc. 
 
Page 49 
 
 
The sponsor will determine whether the SAE must be reported within 7 or 15 days to regulatory 
authorities in compliance with local and regional law. If so, the sponsor (or the sponsor’s 
representative) will report the event to the appropriate regulatory authorities. The investigator 
will report SAEs to the IRB/IEC per their IRB/IEC policy. 
 
10.3.4.3. Follow-up Procedures for Serious Adverse Events 
To fully understand the nature of any SAE, obtaining follow-up information is important. 
Whenever possible, relevant medical records such as discharge summaries, medical 
consultations, and the like should be obtained. In the event of death, regardless of cause, all 
attempts should be made to obtain the death certificate and any autopsy report. These records 
should be reviewed in detail, and the investigator should comment on any event, lab abnormality, 
or any other finding, noting whether it should be considered a serious or non-serious AE, or 
whether it should be considered as part of the subject’s history. In addition, all events or other 
findings determined to be SAEs should be identified on the Serious Adverse Event 
(SAE)/Reportable Event Form and the investigator should consider whether the event is related 
or not related to study drug. All events determined to be nonserious should be reported on the 
eCRF. 
 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
See Section 5 and Section 8.2.8. 
 
10.5. 
Appendix 5: Genetics 
Not applicable. 
 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments 
All events of alanine aminotransferase (ALT) ≥ 3 × upper limit of normal (ULN) and with total 
bilirubin ≥ 2 × ULN (> 35% direct bilirubin) or ALT ≥ 3 × ULN and international normalized 
ratio (INR) >1.5 (if INR measured) which may indicate severe liver injury (possible Hy’s Law) 
must be reported as an SAE as outlined in Section 10.3.4 (excluding studies of hepatic 
impairment or cirrhosis). 
Subjects with confirmed Hy’s Law liver injury will be immediately withdrawn from study 
treatment and no rechallenge will be allowed. 
 
10.7. 
Appendix 7: Medical Device Incidents 
Not applicable. 
 
10.8. 
Appendix 8: Country-specific Requirements 
Not applicable. 


EN3835-212 Protocol Amendment 3 
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Endo Pharmaceuticals Inc. 
 
Page 50 
 
 
10.9. 
Appendix 9: Abbreviations 
 
Abbreviation 
Explanation 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AUX-I 
Clostridial class I collagenase 
AUX-II 
Clostridial class II collagenase 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CR-PCSS 
Clinician-reported Photonumeric Cellulite Severity Scale 
CSS 
Cellulite Severity Scale 
DHHS 
Department of Health and Human Services 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EFP 
Edematous fibrosclerotic panniculopathy 
EGAL 
Endo Global Aesthetics Limited 
FDA 
Food and Drug Administration 
GCP 
Good clinical practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ID 
Identification 
IEC 
Independent ethics committee 
IND 
Investigational new drug 
INR 
International normalized ratio 
IRB 
Institutional review board 
IRT 
Interactive response technology 
MRI 
Magnetic resonance imaging 
PR-PCSS 
Patient-reported Photonumeric Cellulite Severity Scale 
QTc 
Corrected QT interval 
SAE 
Serious adverse event 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 


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11. 
INVESTIGATOR’S STATEMENT 
I agree to conduct the study in accordance with the protocol, and with all applicable government 
regulations and Good Clinical Practice guidance. 
 
 
  
/ 
/  
 
Investigator’s Signature 
Date 
 
 
 
Typed/Printed Name of Investigator 


EN3835-212 Protocol Amendment 3 
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Page 52 
 
 
 
12. 
REFERENCES 
Avram MM. Cellulite: a review of its physiology and treatment. J Cosmet Laser Ther. 
2004;6(4):181-5. 
Boyce S, Pabby A, Chuchaltkaren P, Brazzini B, Goldman MP. Clinical Evaluation of a Device 
for the Treatment of Cellulite: Triactive. Am J Cosmet Surg. 2005;22(4):233-7. 
Collis N, Elliot LA, Sharpe C, Sharpe DT. Cellulite treatment: a myth or reality: a prospective 
randomized, controlled trial of two therapies, Endermologie and aminophylline cream. Plast 
Reconstr Surg. 1999;104(4):1110-4. 
DiBernardo BE. Treatment of cellulite using a 1440-nm pulsed laser with one-year follow-up. 
Aesthet Surg J. 2011;31(3):328-41. 
Food and Drug Administration. Guidance for Industry, Investigators, and Institutional Review 
Boards. FDA Guidance on Conduct of Clinical Trials of Medical Products During COVID-10 
Public Health Emergency. March 2020 (updated 16 April 2020). Available at 
https://www.fda.gov/media/136238/download. Accessed 16 April 2020. 
Hexsel DM, Abreu M, Rodrigues TC, Soirefmann M, do Prado DZ, Gamboa MM. Side-by-side 
comparison of areas with and without cellulite depressions using magnetic resonance imaging. 
Dermatol Surg. 2009;35(10):1471-7. 
Hexsel D, DalʹForno T, Hexsel C, Schilling-Souza J, Naspolini Bastos F, Siega C. Magnetic 
Resonance Imaging of Cellulite Depressed Lesions Successfully Treated by Subcision. Dermatol 
Surg. 2016; 42(5):693-6. 
Hexsel DM, Mazzuco R. Subcision: a treatment for cellulite. Int J Dermatol. 2000;39(7):539-44. 
Khan MH, Victor F, Rao B, Sadick NS. Treatment of cellulite: Part II. Advances and 
controversies. J Am Acad Dermatol. 2010;62(3):373-84. 
Mirrashed F, Sharp JC, Krause V, Morgan J, Tomanek B. Pilot study of dermal subcutaneous fat 
structures by MRI in individuals who differ in gender, BMI, and cellulite grading. Skin Res 
Technol. 2004(3);10:161-8. 
Nürnberger F, Müller G. So-called cellulite: an invented disease. J Dermatol Surg Oncol. 
1978;4(3):221-9. 
Piérard GE, Nizet JL, Piérard-Franchimont C. Cellulite: from standing fat herniation to 
hypodermal stretch marks. Am J Dermatopath. 2000;22(1):34-7. 
Querleux B, Cornillon C, Jolivet O, Bittoun J. Anatomy and physiology of subcutaneous adipose 
tissue by in vivo magnetic resonance imaging and spectroscopy: relationships with sex and 
presence of cellulite. Skin Res Technol. 2002;8(2):118-24. 
Rudolph C, Hladik C, Hamade H, Frank K, Kaminer MS, Hexsel D, at al. Structural Gender 
Dimorphism and the Biomechanics of the Gluteal Subcutaneous Tissue: Implications for the 
Pathophysiology of Cellulite. Plast Reconstr Surg. 2019;143(4):1077–1086. 
doi: 10.1097/PRS.0000000000005407 

SAP_001.pdf: 
Statistical Analysis Plan (SAP) Module 1 – Protocol EN3835-212 
20-Feb-2020 
Endo Pharmaceuticals Inc. 
 
Page 1 
 
 
 
SAP MODULE 1 – DETAILED STATISTICAL METHODOLOGY 
 
Protocol EN3835-212; October 22, 2019 
Amendment 1: January 16, 2020 
 
A PHASE 2A, OPEN-LABEL STUDY TO ASSESS THE IMPACT 
OF CCH TREATMENT OF BUTTOCK AND THIGH CELLULITE 
IN ADULT FEMALES USING PHOTONUMERIC SCALES, 
MAGNETIC RESONANCE IMAGING, AND HISTOPATHOLOGY 
 
Version 1.0 
February 20, 2020 
 
Endo Pharmaceuticals Inc. 
1400 Atwater Drive 
Malvern, PA 19355 
USA 


Statistical Analysis Plan (SAP) Module 1 – Protocol EN3835-212 
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Endo Pharmaceuticals Inc. 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................7 
1. 
INTRODUCTION ..................................................................................................8 
2. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................8 
3. 
STUDY DESIGN AND MEASURES .....................................................................9 
3.1. 
Study Design ..........................................................................................................9 
3.2. 
Eligibility Criteria for Subject Selection ................................................................ 14 
3.2.1. 
Inclusion Criteria .................................................................................................. 14 
3.2.2. 
Exclusion Criteria ................................................................................................. 15 
3.3. 
Treatment Region ................................................................................................. 17 
3.4. 
Selection and Marking of Dimples ........................................................................ 17 
3.5. 
Study Drug Administration ................................................................................... 17 
3.6. 
Determination of Sample Size ............................................................................... 18 
3.7. 
Blinding and Randomization ................................................................................. 19 
3.8. 
Medical, Surgical and EFP History........................................................................ 19 
3.9. 
Alcohol/Tobacco Use ........................................................................................... 19 
3.10. 
Prior/Concomitant Medications and Procedures ..................................................... 19 
3.11. 
Prohibited Medications and Therapies ................................................................... 19 
3.12. 
Efficacy Assessments ........................................................................................... 20 
3.12.1. 
Imaging for Efficacy Assessments......................................................................... 20 
3.12.2. 
Subject and Investigator Cellulite Assessments ...................................................... 20 
3.12.2.1. 
Patient Reported Photonumeric Cellulite Severity Scale (PR-PCSS) ....................... 20 
3.12.2.2. 
Clinician Reported Photonumeric Cellulite Severity Scale (CR-PCSS) ................... 21 
3.12.2.3. 
Hexsel Cellulite Severity Scale (CSS) ................................................................... 21 
3.13. 
Safety Assessments .............................................................................................. 22 
3.13.1. 
Adverse Events..................................................................................................... 22 
3.13.1.1. 
Adverse Events..................................................................................................... 22 
3.13.1.2. 
Serious Adverse Events (SAEs) ............................................................................ 23 
3.13.1.3. 
Adverse Events of Special Interest (AESI)............................................................. 23 
3.13.2. 
Clinical Safety Laboratory Tests ........................................................................... 23 
3.13.2.1. 
Pregnancy Test ..................................................................................................... 24 
3.13.3. 
Vital Signs ........................................................................................................... 24 


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3.13.4. 
12-Lead Electrocardiogram (ECG) ........................................................................ 25 
3.13.5. 
Physical Examination ........................................................................................... 25 
3.13.6. 
Height and Weight................................................................................................ 25 
3.13.7. 
Fitzpatrick Skin Scale ........................................................................................... 25 
3.13.8. 
Immunogenicity Samples...................................................................................... 26 
3.13.9. 
Follow-up Biopsy ................................................................................................. 26 
3.14. 
Pharmacodynamics ............................................................................................... 26 
3.14.1. 
MRI ..................................................................................................................... 26 
3.14.2. 
Double Punch Biopsy ........................................................................................... 27 
4. 
STUDY PARAMETERS ...................................................................................... 27 
4.1. 
Subject Disposition............................................................................................... 27 
4.1.1. 
Discontinuation of Study Treatment ...................................................................... 27 
4.1.2. 
Subject Withdrawal from the Study ....................................................................... 27 
4.2. 
Protocol Deviations .............................................................................................. 28 
4.3. 
Prior/Concomitant Medications and Procedures ..................................................... 28 
4.4. 
Prior EFP Treatment ............................................................................................. 28 
4.5. 
Efficacy Parameters .............................................................................................. 29 
4.5.1. 
Change from Baseline in PR-PCSS Rating (Primary Endpoint) .............................. 29 
4.5.2. 
Change from Baseline in PR-PCSS Rating (Secondary Endpoint) .......................... 29 
4.5.3. 
Change from Baseline in CR-PCSS Rating (Secondary Endpoint) .......................... 29 
4.5.4. 
Change from Baseline in Hexsel CSS Total Score (Secondary Endpoint)................ 29 
4.5.5. 
Proportion of Subjects with No Change (or Worsening) from Baseline 
(Tertiary Endpoints) ............................................................................................. 29 
4.6. 
Safety Parameters ................................................................................................. 29 
4.6.1. 
Adverse Events..................................................................................................... 29 
4.6.1.1. 
Treatment Emergent Adverse Events..................................................................... 30 
4.6.1.2. 
Intensity of Adverse Events .................................................................................. 30 
4.6.1.3. 
Relationship to Study Drug ................................................................................... 30 
4.6.2. 
Potentially Clinically Important Laboratory Values................................................ 30 
4.6.3. 
Potentially Clinically Important Vital Sign Values ................................................. 30 
4.6.4. 
Immunogenicity ................................................................................................... 31 
4.7. 
Pharmacodynamics ............................................................................................... 31 
4.7.1. 
Comparison of Baseline (Screening) MRI Tissue Morphology and Septae .............. 31 


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4.7.2. 
Comparison of Baseline (Screening) Histopathology ............................................. 31 
5. 
ANALYSIS POPULATIONS ............................................................................... 32 
6. 
STATISTICAL METHODS ................................................................................. 32 
6.1. 
General Methodology ........................................................................................... 32 
6.2. 
Derived Variables ................................................................................................. 33 
6.3. 
Handling of Missing Data ..................................................................................... 34 
6.3.1. 
Imputation of Partial Dates ................................................................................... 34 
6.3.1.1. 
Concomitant Status of Medication for Unknown Start Date.................................... 34 
6.3.1.2. 
TEAE Status When Start Date Is Unknown ........................................................... 35 
6.3.1.3. 
Missing EFP Onset Date ....................................................................................... 35 
6.4. 
Interim Analyses .................................................................................................. 35 
7. 
STATISTICAL ANALYSES ................................................................................ 35 
7.1. 
Subject Disposition............................................................................................... 35 
7.2. 
Protocol Deviations .............................................................................................. 36 
7.3. 
Demographics and Baseline Characteristics ........................................................... 36 
7.4. 
Medical and Surgical History ................................................................................ 36 
7.5. 
Prior/Concomitant Medications and Procedures ..................................................... 36 
7.6. 
Efficacy Analyses ................................................................................................. 36 
7.6.1. 
Primary Endpoint ................................................................................................. 37 
7.6.1.1. 
Change from Baseline in PR-PCSS Rating at Day 71 ............................................. 37 
7.6.2. 
Secondary Endpoints ............................................................................................ 37 
7.6.2.1. 
Change from Baseline in PR-PCSS Rating at Days 22 and 43 ................................ 37 
7.6.2.2. 
Change from Baseline in CR-PCSS Rating at Days 22, 43, and 71 ......................... 37 
7.6.2.3. 
Changes in the Hexsel CSS Total Score from Baseline at Days 22, 43, 
and 71 .................................................................................................................. 38 
7.6.3. 
Tertiary Endpoints ................................................................................................ 38 
7.6.3.1. 
Proportion of Subjects with No Change (or Worsening) from Baseline in 
PR-PCSS Rating on Days 161 and 251 .................................................................. 38 
7.6.3.2. 
Proportion of Subjects with No Change (or Worsening) from Baseline in 
CR-PCSS Rating on Days 161 and 251 ................................................................. 38 
7.6.3.3. 
Proportion of Subjects with No Change (or Worsening) from Baseline in 
Hexsel CSS Total Score on Days 161 and 251 ....................................................... 38 
7.7. 
Safety Analyses .................................................................................................... 38 
7.7.1. 
Study Drug Exposure............................................................................................ 38 


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7.7.2. 
Adverse Events..................................................................................................... 39 
7.7.3. 
Clinical Laboratory............................................................................................... 40 
7.7.4. 
Vital Signs and Body Weight ................................................................................ 40 
7.7.5. 
12-Lead ECG ....................................................................................................... 41 
7.7.6. 
Physical Examination ........................................................................................... 41 
7.7.7. 
Immunogenicity ................................................................................................... 41 
7.8. 
Pharmacodynamics ............................................................................................... 41 
7.8.1. 
Comparison of Baseline (Screening) MRI Tissue Morphology and Septae .............. 41 
7.8.2. 
Comparison of Baseline (Screening) Histopathology ............................................. 41 
8. 
CHANGE FROM PROTOCOL ............................................................................ 41 
9. 
REVISION HISTORY ......................................................................................... 41 
10. 
REFERENCES..................................................................................................... 42 
11. 
TABLES, LISTINGS, AND GRAPH SHELLS ..................................................... 42 


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LIST OF TABLES 
Table 1: 
Objectives and Endpoints........................................................................................ 8 
Table 2: 
Schedule of Activities............................................................................................11 
Table 3: 
Study Treatment ...................................................................................................18 
Table 4: 
PR-PCSS for Buttocks or Thighs ...........................................................................21 
Table 5: 
CR-PCSS for Buttocks or Thighs ...........................................................................21 
Table 6: 
Hexsel CSS ..........................................................................................................22 
Table 7: 
Clinical Safety Laboratory Parameters ..................................................................24 
Table 8: 
Fitzpatrick Skin Scale ...........................................................................................26 
Table 9: 
Potentially Clinically Important Laboratory Criteria ...............................................30 
Table 10: 
Potentially Clinically Important Vital Sign Criteria ................................................31 
Table 11: 
Analysis Population ...............................................................................................32 
Table 12: 
Derived Variables and Definition ...........................................................................33 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate transaminase 
ATC 
Anatomical therapeutic chemical 
AUX-I 
Clostridial class I collagenase 
AUX-II 
Clostridial class II collagenase 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CRF 
Case report form 
CR-PCSS 
Clinician-reported Photonumeric Cellulite Severity Scale 
CSS 
Cellulite Severity Scale 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EFP 
Edematous fibrosclerotic panniculopathy 
FDA 
United States Food and Drug Administration 
HBsAg 
Hepatitis B surface antigen 
HBcAb 
Hepatitis B core antibody 
HIV 
Human immunodeficiency virus 
IEC 
Independent ethics committee 
IRB 
Institutional review board 
MedDRA 
Medical Dictionary for Regulatory Activities 
Max 
Maximum 
Min 
Minimum 
MRI 
Magnetic resonance imaging 
PCI 
Potentially clinically important 
PR-PCSS 
Patient-reported Photonumeric Cellulite Severity Scale 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the planned analyses to assess the impact of CCH 
treatment on buttock and thigh cellulite using photonumeric scales, magnetic resonance imaging 
(MRI), and histopathology in adult women. 
Specific information about the study is described in the EN3835-212 protocol. 
 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
The primary, secondary, and tertiary objectives and corresponding endpoints are outlined in 
Table 1 below. 
Table 1: 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
To assess the subject reported impact of 
CCH in the treatment of cellulite in adult 
females. 
 
The change from baseline (screening) in Patient- 
reported Photonumeric Cellulite Severity Scale 
(PR-PCSS) at Day 71. 
Secondary 
 
To assess the subject and clinician reported 
impact of CCH in the treatment of cellulite 
in adult females. 
 
The change from baseline (screening) in PR- 
PCSS at Days 22 and 43. 
 
The change from baseline (screening) in 
Clinician-reported Photonumeric Cellulite 
Severity Scale (CR-PCSS) at Days 22, 43, 
and 71. 
 
The change from baseline (screening) in Hexsel 
Cellulite Severity Scale (CSS) at Days 22, 43, 
and 71. 
 
To radiologically assess the impact of 
treatment with CCH in adult females with 
cellulite. 
 
Comparison of baseline (screening) MRI tissue 
morphology and septae under the treatment areas 
to images taken at Day 71. 
 
To evaluate tissue histopathology to assess 
the impact of treatment with CCH in adult 
females with cellulite. 
 
Comparison of baseline (screening) 
histopathology to the histopathology of samples 
taken at Day 71. 
 
To assess the safety of CCH treatment of 
cellulite in adult females. 
 
The proportion of subjects reporting each adverse 
event (AE), treatment-emergent adverse event 
(TEAE), adverse event of special interest (AESI), 
and serious adverse event (SAE). 


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Objectives 
Endpoints 
 
The change from baseline in vital signs and 
clinical laboratory parameters at each visit where 
these parameters are measured.
 
The change from baseline in anti-AUX-I and 
anti-AUX-II antibodies and neutralizing 
antibodies at each visit where these parameters 
are measured.
Tertiary 
 
To assess the complete loss of patient 
reported impact after CCH treatment in 
adult females with cellulite. 
 
The proportion of subjects with no change (or 
worsening) from baseline (screening) in 
PR-PCSS rating at Day 161 and at Day 251. 
 
To assess the complete loss of clinician 
reported impact after CCH treatment in 
adult females with cellulite. 
 
The proportion of subjects with no change (or 
worsening) from baseline (screening) in 
CR-PCSS rating at Day 161 and at Day 251. 
 
The proportion of subjects with no change (or 
worsening) from baseline (screening) in Hexsel 
CSS total score at Day 161 and at Day 251. 
 
To radiologically assess the long-term 
impact of treatment with CCH in adult 
females with cellulite. 
 
Comparison of baseline (screening) MRI tissue 
morphology and septae under the treatment areas 
to images taken at Day 251. 
 
To evaluate tissue histopathology to assess 
the long-term impact of treatment with CCH 
in adult females with cellulite. 
 
Comparison of baseline (screening) 
histopathology to the histopathology of samples 
taken at Day 251. 
 
3. 
STUDY DESIGN AND MEASURES 
3.1. 
Study Design 
This is a single center, open-label, Phase 2a study to assess the safety and efficacy of CCH in 
adult women with moderate or severe edematous fibrosclerotic panniculopathy (EFP) of the 
buttocks or thighs using photonumeric scales, MRI, and histopathology of tissues from the 
treated area. Approximately 18 subjects will be screened in order to dose approximately 12 
subjects. Every attempt will be made to enroll an equal number of subjects across the 2 severity 
levels in both buttocks and thighs (eg, 3 subjects with moderate buttock cellulite, 3 subjects with 
severe buttock cellulite, 3 subjects with moderate thigh cellulite, and 3 subjects with severe thigh 
cellulite). 
Following a screening period of approximately 35 days, qualified subjects will receive 0.84 mg 
of CCH per treatment area (buttock or thigh) for a total dose of 1.68 mg in both buttocks or both 
thighs per treatment session for 3 sessions. Treatment sessions will occur approximately 21 days 
apart (Day 1, Day 22, and Day 43). Following treatment and assessments at Day 71, subjects will 
be assessed and followed for an additional 194 days. 


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Subjects will have MRIs and double punch biopsies of 3 selected target dimples 3 times during 
the study (Screening, Day 71, and Day 251). 
Subjects will participate in the study for up to approximately 305 days (approximately 
10 months). The duration of the study from first subject first visit to last subject last visit will be 
dependent upon the ability of the site to identify and enroll subjects. The entire study is expected 
to require approximately 12 months to complete. 
Table 2 below describes the schedule of activities and assessments performed during screening, 
the treatment phase, and the extension phase of the study. 


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Table 2: 
Schedule of Activities 
 
Activities 
Screening 
(Day -35 to Day -1) 
Treatment Phase 
Extension Phase 
Before MRI 
Before biopsy 
Approximately Day -14 
Day 1 
Treatment Session I 
Day 22 (± 3 Days) 
Treatment Session II 
Day 43 (± 3 Days) 
Treatment Session III 
Day 71 (+10 Days) 
Day 85 (±5 Days)/ 
Biopsy Follow-up 
Day 161 (± 15 Days) 
Day 251 (±15 Days)/ 
Early Termination 
Day 265 (±5 Days)/ 
Biopsy Follow- up 
Informed consent a 
X 
Inclusion/exclusion criteria review b 
X 
X 
Medical and surgical history 
X 
EFP history 
X 
Prior medications (including all prior medications 
for cellulite) 
X 
Physical examination 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
Fitzpatrick Skin Type 
X 
Vital signs 
X 
X c 
X c 
X c 
X 
X 
X 
ECG 
X 
Hematology, chemistry, and urinalysis 
X 
X 
X 
Serum pregnancy test 
X 
Urine pregnancy test 
X 
X 
X 
X d 
X 
X d 
HIV and Hepatitis B tests 
X 
Immunogenicity sample collection 
X 
X 
X 
X 
Selection of treatment region (both buttocks or both 
thighs) 
X 
Imaging for efficacy assessments (IntelliStudio) 
X e 
X f 
X f 
X f 
X 
X 
X 
PR-PCSS 
X e 
X 
X 
X 
X 
X 
CR-PCSS 
X e 
X 
X 
X 
X 
X 
Hexsel CSS 
X e 
X 
X 
X 
X 
X 
Selection, marking, labeling, and/or photography of 
3 dimples for MRI and biopsy (Dimples 1, 2, and 3) 
X 


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Table 2: 
Schedule of Activities (Continued) 
 
Activities 
Screening 
(Day -35 to Day -1) 
Treatment Phase 
Extension Phase 
Before MRI 
Before biopsy 
Approximately Day -14 
Day 1 
Treatment Session I 
Day 22 (± 3 Days) 
Treatment Session II 
Day 43 (± 3 Days) 
Treatment Session III 
Day 71 (+10 Days) 
Day 85 (±5 Days)/ 
Biopsy Follow-up 
Day 161 (± 15 Days) 
Day 251 (±15 Days)/ 
Early Termination 
Day 265 (±5 Days)/ 
Biopsy Follow- up 
MRI 
X g 
Dimples 
1, 2,and 3 
X h 
Dimples 
2 and 3 
X h 
Dimple 3 
Biopsy sample collection 
X i 
Dimple 1 
X j 
Dimple 2 
X j 
Dimple 3 
Biopsy follow-up examination 
X 
X 
X 
Select and mark up to 12 dimples for CCH injection 
in each treatment area (including Dimples 2 and 3) 
X 
X 
X 
Study drug administration 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injections site reactions/local tolerability in areas 
treated 
X 
X 
X 
X 
X 
X 
All other AEs k 
Monitored throughout the study 
a Performed prior to any study-required assessments, unless exceptions granted for standard of care procedures. A separate informed consent may be used for 
HIV testing and must be signed before the sample is collected, if required. 
b Should be reassessed and verified prior to dosing. 
c Vital signs will be collected up to 4 hours prior to, and at 15 and 30 minutes after, study treatment administration on Days 1, 22, and 43. 
d Urine pregnancy test should be completed prior to the MRI. 
e At screening all 4 potential treatment areas (each buttock and each thigh) will be imaged; and CR-PCSS, PR-PCSS, and Hexsel CSS assessments will be done 
for each potential treatment area (each buttock and each thigh). 
f Before and after marking dimples for treatment. No manipulation of the treatment area should be done prior to the "before" photographs. 
g Screening MRIs will be performed after all other screening assessments (except the biopsy) have been completed. 
h The Day 71 and Day 251 MRIs may be performed up to 7 days prior to the indicated visit. MRI must be completed before the biopsy required for this visit. The 
Day 251/Early Termination MRI is not required for subjects who withdraw from the study (early termination). The Day 71 and Day 251 MRIs may be repeated 
as often as necessary to obtain an evaluable image. 


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i The screening biopsy will be performed after all other screening assessments (including MRI) are completed. The screening bio psy will be performed at least 14 
days prior to the Day 1 Treatment Visit. The investigator must examine and confirm sufficient healing of the biopsy site before dosing on Day 1. The timing of 
all subsequent visits will be based on the actual date that the first dose of CCH is administered. 
j The Day 71 and Day 251 imaging for efficacy, PR-PCSS, and CR-PCSS must be completed prior to the biopsy sample collection required at those visits. The 
Day 251/Early Termination biopsy is not required for subjects who withdraw from the study (early termination). 
k Adverse events (AE)/serious adverse events (SAE) will be captured from time of informed consent signature until the Day 265 Visit or until 28 days after last 
dose of study drug whichever is later. There is no time limit on collection of SAEs considered to be related to study treatment. 
Note: unless otherwise stated above or outlined below (and with the exception of injection site reactions/local tolerability in the areas treated), all assessments 
should be completed prior to dosing on treatment days (Days 1, 22, and 43). 


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3.2. 
Eligibility Criteria for Subject Selection 
3.2.1. 
Inclusion Criteria 
In order to be eligible to participate in the study, at the Screening Visit and on Study Day 1, 
subject must: 
1. Be female and ≥18 and ≤50 years of age at the time of consent. 
2. Have both buttocks or both posterolateral thighs with: 
a. A score of 3 or 4 (moderate or severe) as reported by the investigator using the 
CR-PCSS. 
b. A Hexsel Cellulite Severity Scale (CSS) total score of ≤13. 
c. A Hexsel CSS Subsection A “Number of Evident Depressions” score of >0. 
d. A Hexsel CSS Subsection B “Depth of Depressions” score of 2 (medium depth 
depressions) or 3 (deep depressions). 
3. Have a body mass index (BMI) score between 18.5 kg/m2 to 29.9 kg/m2 and intends to 
maintain stable body weight throughout the duration of the study (from the Screening 
Visit through the Day 251/Early Termination Visit). A variation of ≤10% from the Day 1 
Visit weight is permitted. 
4. Be willing and consent to undergo human immunodeficiency virus (HIV) and hepatitis B 
testing, as well as double punch biopsy and MRI procedures. 
5. Have a minimum of 2 well defined and isolated cellulite dimples that are considered 
moderate or deep in depth in each treatment area (each thigh or each buttock, for a total 
of 4 such dimples), of which 3 will be selected for MRI and biopsy procedures. 
6. Be willing to apply sunscreen to the treatment area before each exposure to the sun for 
the duration of the study (from the Screening Visit through the Day 251/Early 
Termination Visit). 
7. Be judged by the investigator to be in good health, based upon the results of a medical 
history, physical examination, electrocardiogram (ECG), and laboratory profile at 
screening. 
8. Be of nonchildbearing potential (history of hysterectomy, bilateral oophorectomy, 
bilateral tubal ligation, or postmenopausal with no history of menstrual flow in the 12 
months prior to the Screening Visit); or, if of childbearing potential, be nonpregnant, 
nonlactating, and agree to use effective contraception when with a male partner at least 1 
menstrual cycle prior to the first dose of study treatment through the Day 251/Early 
Termination Visit. Acceptable forms of contraception include hormonal measures (oral 
contraceptive pills, contraceptive patch, contraceptive ring, injections, etc), intrauterine 
devices, double barrier methods (condom plus diaphragm, condom or diaphragm plus 
spermicidal gel or foam), surgical sterilization of the male partner, and abstinence. 
9. Have a negative serum pregnancy test at the Screening Visit and a negative urine 
pregnancy prior to dosing at each treatment session and prior to the Day 71 and Day 251 
MRIs. 


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10. Be willing and able to comply with all protocol required visits and assessments. 
11. Be able to read, understand, and independently complete patient reported outcome 
instruments in English. 
12. Be adequately informed and understand the nature and risks of the study and be able to 
provide consent as per Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC). 
13. Must have evaluable MRI images of Dimples 1, 2, and 3 at screening. An evaluable MRI 
is defined as an image that adheres to the protocol scanning parameters and is free from 
artifacts that could affect the analysis. 
3.2.2. 
Exclusion Criteria 
A subject is ineligible for study participation if, at the Screening Visit and on Day 1, the subject: 
1. Is from a vulnerable population, as defined by the US Code of Federal Regulations (CFR) 
Title 45, Part 46, Section 46.111(b) and other local and national regulations, including 
but not limited to, employees (temporary, part-time, full time, etc) or a family member of 
the research staff conducting the study, or of the sponsor, or of the contract research 
organization, or of the IRB/IEC. 
2. Has a history of sensitivity or allergy to collagenase or any other excipient of CCH. 
3. Has any of the following systemic conditions: 
a. Coagulation disorder. 
b. Evidence or history of malignancy (other than excised basal-cell carcinoma) unless 
there had been no recurrence in at least 5 years. 
c. History of keloidal scarring or abnormal wound healing. 
d. 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 will be discussed with the Medical Monitor. 
e. Evidence of clinically significant abnormalities on physical examination, vital signs, 
ECG, or clinical laboratory values. 
4. Has any of the following local conditions in the areas to be treated (both buttocks or both 
thighs): 
a. History of lower extremity thrombosis, deep vein thrombosis, or post-thrombosis 
syndrome. 
b. Vascular disorder (eg, varicose veins, telangiectasia). 
c. Inflammation or active infection. 
d. Active cutaneous alteration including rash, eczema, or psoriasis. 
e. A tattoo or other artificially inflicted body marker. 
f. A mole located within 2 cm of any injection site. 


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5. Has a Hexsel CSS Subsection D “Grade of Laxity, Flaccidity, or Sagging Skin” score of 
≥2 or has linear undulations that can be effaced by lifting the skin in the areas to be 
treated (each buttock or each thigh). 
6. Requires anticoagulant or antiplatelet medication during the study or has received 
anticoagulant or antiplatelet medication (except for ≤150 mg aspirin daily) within 7 days 
before injection of study treatment. 
7. Has used any of the following for the treatment of EFP on either thigh or either buttock 
within the timelines identified below or intends to use any of the following at any time 
during the course of the study: 
a. Liposuction during the 12-month period before injection of study treatment. 
b. Injections (eg, mesotherapy, dermal fillers, biostimulatory fillers); radiofrequency 
c. device treatments; laser treatment; buttock or thigh implant treatment; cryolipolysis; 
or surgery (including subcision and/or powered subcision) during the 12-month 
period before injection of study treatment. 
d. Any investigational treatment for EFP on a buttock or thigh during the 12-month 
period before the injection of study treatment. 
e. Endermologie or similar treatments during the 6 month period before injection of 
study treatment. 
f. Massage therapy during the 3-month period before injection of study treatment. 
g. Creams (eg, Celluvera™, TriLastin®) and/or home therapies to prevent or mitigate 
EFP during the 2-week period before injection of study treatment. 
8. Has used any form of artificial tanning (sprays, lotions, tanning booth, etc) within the 30 
days prior to the first dose of study treatment or plans to use any form of artificial tanning 
during the study (through the Day 251/Early Termination Visit). 
9. Has a positive HIV test and/or a positive hepatitis B surface antigen (HBsAg) or 
hepatitis B core antibody (HBcAb) test at screening. 
10. Has had any surgery, invasive procedure (eg, liposuction), injectable treatment (eg, 
KYBELLA®) or any similar treatment that could have destroyed fat cells and/or removed 
1fat deposits in the treatment area. 
11. Has a history of keloids, hypertrophied scars, and/or other complications following 
biopsy. 
12. Has any contraindications for MRI including, but not limited to: 
a. Has an implant containing metal including but not limited to intracranial aneurysm 
clips, cochlear implants, prosthetic devices containing metal, implanted drug infusion 
pumps, neurostimulators, bone-growth stimulators, intrauterine contraceptive devices 
containing metal, or any other type of iron-based metal implants. 
b. Has an internal metallic object such as bullets or shrapnel, as well as surgical clips, 
pins, plates, screws, metal sutures, or wire mesh. 
c. Has any tattoo or permanent cosmetics/make-up including, but not limited to, 
permanent lip liner or permanent eye liner. 


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d. Has severe claustrophobia. 
e. Has experienced “ceremonial” syncope (fainting while standing still). 
f. Has extremely low blood pressure, epilepsy, asthma, anemia, or sickle cell disease. 
13. Has received any collagenase treatments at any time prior to treatment in this study 
and/or has received EN3835 or CCH in a previous investigational study for cellulite. 
14. Has previously received treatment with CCH in this clinical study. 
15. Has received treatment with an investigational product within 30 days (or 5 half-lives, 
whichever is longer) of the Screening Visit. 
16. Is pregnant and/or is providing breast milk or plans to become pregnant and/or to provide 
breast milk during the course of the study. 
17. Intends to initiate an intensive sport or exercise program during the study. 
18. Intends to initiate an intensive weight reduction program during the study. 
19. Has any other condition(s) that, in the investigator’s opinion, might indicate the subject to 
be unsuitable for the study. 
 
3.3. 
Treatment Region 
Treatment region is defined as both buttocks or both thighs. Approximately 12 subjects will be 
dosed in this study, thus 6 subjects will be treated in the buttocks and 6 subjects will be treated in 
the thighs. 
No subjects will be treated in both the buttocks and the thighs. 
 
3.4. 
Selection and Marking of Dimples 
In each treatment area, cellulite dimples for CCH treatment will be selected at screening at the 
discretion of the investigator and must be well-defined, evident when the subject is standing, and 
suitable for treatment. An adequate number of dimples should be selected at each treatment area 
for administration of up to 12 subcutaneous CCH injections. The dimples selected for treatment 
must include Dimple 2 and Dimple 3 that were selected for MRI and biopsy and these dimples 
will be treated throughout the study. Dimple 1 will not be treated at any time during the study. 
For each dimple selected for treatment, the investigator or qualified designee will choose 
injection sites (injection sites within a dimple should be spaced approximately 2 cm apart, if a 
dimple requires more than 1 injection; locating at least 1 injection site at the nadir, if present, of 
the dimple). Each injection site will be marked with a “dot” using a surgical marker. For round 
dimples, the “dot” will be placed in the center of the dimple; for elongated dimples, “dots” will 
be spaced out approximately 2 cm along the longer axis of the dimple. The investigator or 
qualified designee will then use a surgical marker to circle each of the dimples selected for 
treatment. 
 
3.5. 
Study Drug Administration 
Each qualified subject will receive up to 24 subcutaneous injections (up to 12 injections per 
buttock or thigh) for a maximum total of 1.68 mg (0.84 mg per treatment area) at each treatment 


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session. Each subject will receive study drug on Day 1, Day 22, and Day 43. The maximum 
cumulative CCH dose will be 5.04 mg for each subject who completes the 3 treatment visits  
(total maximum dose of 1.68 mg per treatment session × 3 treatment sessions). 
Study treatment will be injected subcutaneously while the subject is in a prone position. In this 
study, the reconstitution volumes and angles of injection will be different for the buttocks and the 
posterolateral thighs. However, the total dose in each treatment area (each buttock or each thigh) 
will be no more than 0.84 mg of CCH per treatment session. 
Buttock cellulite dimple injections will consist of administration of 0.3 mL of reconstituted 
CCH, administered in 3 aliquots of 0.1 mL each. For thighs, cellulite dimple injections will 
consist of 1.5 mL of reconstituted CCH, administered in 5 aliquots of 0.3 mL each. 
The injection volume and concentration for each treatment area are outlined in Table 3 below. 
Table 3:         Study Treatment 
 
Number of 
Injection 
Injections 
Dose per 
Volume per 
at Each 
Dose (mg) at 
Injection Volume 
Treatment 
Each 
Each 
Treatment 
Each Treatment 
(mL) per Each 
Cumulative 
Area 
Injection 
Injection 
Visit 
Visit 
Treatment Visit 
EFP Dose 
Buttock 
CCH 0.07 mg 
0.3 mL 
12 per buttock 
0.84 mg per buttock 
3.6 mL per buttock 
5.04 mg 
(given as 
× 2 buttocks = 
× 2 buttocks = 
× 2 buttocks = 
(3 treatment 
three 0.1-mL 
24 injections 
1.68 mg 
7.2 mL 
visits 
aliquots) 
(up to 12 injections 
(24 injections × 
× 0.84 mg per 
per buttock × 
0.3 mL) 
buttock 
0.07 mg/injection 
× 2 buttocks) 
× 2 buttocks) 
Thigh 
CCH 0.07 mg 
1.5 mL 
12 per thigh 
0.84 mg per thigh 
18 mL per thigh 
5.04 mg 
(given as 
× 2 thighs = 
× 2 thighs = 
× 2 thighs = 
(3 treatment 
five 0.3-mL 
24 injections 
1.68 mg 
36 mL 
visits 
aliquots) 
(up to 12 injections 
(24 injections × 
× 0.84 mg per 
per thigh × 
1.5 mL) 
thigh 
0.07 mg/injection 
× 2 thighs) 
× 2 thighs) 
Since the goal of treatment is to improve the aesthetic appearance of each entire treatment area, 
the investigator will select dimples that in his or her opinion would most improve the aesthetic 
appearance of each entire treatment area. Therefore, the same dimples within a treatment area 
(each buttock or each thigh) or different dimples within a treatment area may be treated at each 
treatment visit, but injections must be administered within the selected treatment area (buttocks 
or thighs) for each of the 3 treatment visits. Dimple 1 will not be treated at any time during this 
study. Dimples 2 and 3 must be treated at each treatment session. 
 
3.6. 
Determination of Sample Size 
The sample size for this study is not based on a formal sample size calculation. A total of 12 
subjects are considered sufficient to determine if biopsy will demonstrate changes in 
histopathology associated with CCH treatment while exposing the minimum number of subjects 
possible to the associated risks. 


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3.7. 
Blinding and Randomization 
This is an open-label and non-randomized study. Treatment blinding and randomization are not 
applicable to this study. 
 
3.8. 
Medical, Surgical and EFP History 
The medical, surgical, and EFP history of the subjects will be taken at screening. Medical history 
will include relevant diagnoses and/or procedures/therapies with onset/resolutions dates. 
Historical and current medical conditions including date of last menstrual period will be 
recorded. 
If onset date is unknown, then whether it occurred within 5 years or more than 5 years ago will 
be recorded on the electronic case report form (eCRF). 
Surgical history will include a review of all surgical procedures completed in the prior 5 years 
and any surgery during the study. 
EFP history will be obtained from the subject at screening. EFP history will include the 
following: 
 Family history of cellulite (answered as yes, no, or unknown). 
 Onset date of EFP symptoms. 
 Previous treatments used for EFP. 
3.9. 
Alcohol/Tobacco Use 
History of tobacco and alcohol use will also be obtained at screening and the following 
information will be recorded: 
 Type of substance (Alcohol/Tobacco). 
 History of usage (Never/Currently/Former). 
 Number of years the product was used (for current or former users). 
 Stop date of using the product (for former users). 
3.10. 
Prior/Concomitant Medications and Procedures 
Any prior medications taken within the 90 days prior to the Screening Visit or any concomitant 
medications taken from the Screening Visit through the Day 265 Visit and nondrug therapies (eg, 
blood transfusions, oxygen supplementation, physical therapy, etc) will be recorded. 
In addition, all prior treatments (including medications and procedures) for EFP will be recorded 
with start and stop date; and, where appropriate dose, unit, frequency and route of administration. 
 
3.11. 
Prohibited Medications and Therapies 
The following medications are prohibited for subjects during the study: 
 Anticoagulants (warfarin, heparin, direct thrombin inhibitors, Factor X inhibitors) and 
antiplatelet agents (aspirin >150 mg/day and P2Y12 inhibitors, such as clopidogrel), 


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which can cause additional bruising. However, the use of aspirin at a dose level of 
≤150 mg per day will be permitted during study. 
The following procedures/treatments are not allowed in the selected treatment region (both 
buttocks or both thighs) during the course of the study (from the Screening Visit through the 
Day 265 Visit): 
 Liposuction. 
 Any injectable treatment (eg, KYBELLA) or any similar treatment that could destroy 
fat cells and/or remove fat deposits. 
 Injections (eg, mesotherapy); radiofrequency device treatments; laser treatment; 
buttock implant treatment; cryolipolysis; or surgery (including subcision and/or 
powered subcision). 
 Any investigational treatment for EFP (other than CCH as prescribed in this study). 
 Endermologie or similar treatments. 
 Massage therapy. 
 Creams (eg, Celluvera, TriLastin) and/or home therapies to prevent or mitigate EFP. 
3.12. 
Efficacy Assessments 
3.12.1. 
Imaging for Efficacy Assessments 
The digital photographs are not direct efficacy measurements; however, digital photographs will 
be utilized in the assessment of certain efficacy measurements. At screening each of the 2 
potential treatment areas (both buttocks and both thighs) will be photographed, using a Sponsor- 
supplied standardized digital camera in a standardized manner as per the Photography Manual. 
For subsequent visits, only the areas receiving treatment (both buttocks or both thighs) will be 
photographed. These photographs will be taken before and after marking of the treatment areas 
for dosing. 
 
3.12.2. 
Subject and Investigator Cellulite Assessments 
Investigator cellulite assessments are independent of the subject assessments. All subject cellulite  
assessments must be completed before the investigator cellulite assessments are initiated. Subject 
assessments will occur while the subject is alone with no study site personnel in the room. 
Investigators will be instructed not to verbalize their rating while in the presence of the subject 
and vice versa. 
 
3.12.2.1. Patient Reported Photonumeric Cellulite Severity Scale (PR-PCSS) 
The PR-PCSS-Buttock and PR-PCSS-Thigh will be used to assess the severity of cellulite of 
both treatment areas (each buttock and each thigh) independently. 
The scale is a 5-level photonumeric scale developed specifically for patients and used by the 
subject to assess the severity of their cellulite in the buttocks or thighs by viewing digital images 
of each of their buttocks and/or thighs at Screening, Day 22, Day 43, Day 71, Day 161, and 
Day 251. 


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The ratings range from 0 (None) to 4 (Severe) with labels and descriptors to aid the subject in the 
assessments (Table 4). 
Table 4: 
PR-PCSS for Buttocks or Thighs 
 
Rating 
Level of Severity 
Description 
0 
None 
No evident cellulite 
1 
Almost None 
A few superficial dimples or ridges 
2 
Mild 
Several dimples or ridges of which most are superficial 
3 
Moderate 
Many dimples or ridges of which most are somewhat deep 
4 
Severe 
A lot of dimples or ridges of which many are deep covering most of the skin 
area 
 
3.12.2.2. Clinician Reported Photonumeric Cellulite Severity Scale (CR-PCSS) 
The CR-PCSS-Buttock and CR-PCSS-Thigh will be used to assess the severity of cellulite of 
both treatment areas (each buttock and each thigh) independently. 
The scale is a 5-level photonumeric scale developed specifically for clinicians and used by the 
investigator to assess the severity of the subject’s cellulite in buttocks or thighs by live 
assessments at Screening, Day 22, Day 43, Day 71, Day 161, and Day 251. 
The ratings range from 0 (None) to 4 (Severe) with labels and descriptors to aid the investigator 
in the assessments (Table 5). 
Table 5: 
CR-PCSS for Buttocks or Thighs 
 
Rating 
Level of Severity 
Description 
0 
None 
No dimples or evident cellulite 
1 
Almost None 
Few dimples that are mostly superficial in depth 
2 
Mild 
Several dimples of which most are shallow in depth 
3 
Moderate 
Many dimples of which most are moderate in depth 
4 
Severe 
A lot of dimples with some of more severe depth 
 
3.12.2.3. Hexsel Cellulite Severity Scale (CSS) 
The Hexsel CSS (Hexsel et al, 2009; Nürnberger and Müller, 1978) is a photonumeric scale that 
looks at 5 key 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. 
 E: Current classification scale based on medical literature. 


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The investigator will access the cellulite using the Hexsel CSS for each buttock and each thigh, 
independently at Screening. For Day 22, Day 43, Day 71, Day 161, and Day 251, only the areas 
receiving treatment (each buttock or each thigh) will be assessed. This assessment should be 
made while the subject is in a standing position with relaxed gluteus muscles. 
Each feature of the Hexsel CSS is evaluated on a 4-point scale, ranging from 0 to 3 as outlined in 
Table 6 below. 
Table 6: 
Hexsel CSS 
 
Morphologic Features 
Severity Grade 
0 
1 
2 
3 
Number of Evident 
Depressions 
None/No 
depressions 
A small amount: 
1 – 4 depressions 
are visible 
A moderate amount: 
5 – 9 depressions 
are visible 
A large amount: 
10 or more 
depressions are 
visible 
Depth of depressions 
No depressions 
Superficial 
depressions 
Medium depth 
depressions 
Deep depressions 
Morphological 
Appearance of Skin 
Surface Alterations 
No raised areas 
Orange peel 
appearance 
Cottage cheese 
appearance 
Mattress 
appearance 
Grade of Laxity, 
Flaccidity or Sagging 
Skin 
Absence of laxity, 
flaccidity, or 
sagging skin 
Slight draped 
appearance 
Moderate draped 
appearance 
Severe draped 
appearance 
Classification Scale by 
Nurnberger and Muller 
Zero grade 
First grade 
Second grade 
Third grade 
 
3.13. 
Safety Assessments 
3.13.1. 
Adverse Events 
Adverse events will be collected from the time of signing informed consent through the Day 265 
Visit, or for 28 days after the last study treatment for subjects who terminate early. 
 
3.13.1.1. Adverse Events 
An AE is any unfavorable or unintended change in body structure (signs), body function 
(symptoms), laboratory result (eg, chemistry, ECG, X-ray, etc), or worsening of a preexisting 
condition associated temporally with the use of the study medication whether or not considered 
related to the study medication. AEs include: 
 Changes in the general condition of the subject. 
 Subjective symptoms offered by or elicited from the subject. 
 Objective signs observed by the investigator or other study personnel. 
 All concurrent diseases that occur after the start of the study, including any change in 
severity or frequency of preexisting disease. 


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 All clinically relevant laboratory abnormalities or physical findings that occur during 
the study. 
 
3.13.1.2. Serious Adverse Events (SAEs) 
Serious adverse events are those AEs that meet any of the following criteria: 
 Results in death. 
 Life-threatening event. 
 Results in or prolongs an inpatient hospitalization. 
 Results in permanent or substantial disability. 
 Is a congenital anomaly or birth defect. 
 Any important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
 
3.13.1.3. Adverse Events of Special Interest (AESI) 
AEs such as bruising, ecchymosis, hematomas, and contusions that occur remote to the site of 
drug administration, or any hypersensitivity reactions, including anaphylaxis, will be recorded as 
AESIs. 
In addition, local AEs associated with the injection site, including bruising, pain, nodules/mass, 
ulceration, erythema, pruritus, swelling, and/or induration will be recorded as AESIs. 
 
3.13.2. 
Clinical Safety Laboratory Tests 
Blood and urine samples will be collected for testing of the following clinical laboratory 
parameters during Screening, Day 71, and Day 251 (Table 7). Serology tests for HIV and 
hepatitis B will be performed at Screening. 


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Table 7: 
Clinical Safety Laboratory Parameters 
 
Hematology 
Biochemistry 
Urinalysis 
Hemoglobin 
Glucose 
Glucose 
Hematocrit 
Sodium 
Protein 
Red blood cell 
Potassium 
Specific gravity 
White blood cell (WBC) 
Calcium 
pH 
Platelets 
Chloride 
Ketones 
WBC Differential 
Carbon dioxide (CO2) 
Bilirubin 
Inorganic phosphate 
Urobilinogen 
Blood urea nitrogen (BUN) 
Nitrite 
Creatinine 
Blooda 
Creatinine clearance (estimated) 
Leukocytesa 
Aspartate transaminase (AST) 
 
Alanine transaminase (ALT) 
 
Gamma-glutamyl transferase (GGT) 
 
Total bilirubin (TBL) (direct bilirubin reflex if 
elevated) 
 
Albumin 
 
Alkaline phosphatase (ALP) 
 
Uric acid 
 
a Microscopic examination will be performed if blood or leukocytes are detected by dipstick. 
Any clinically significant laboratory abnormality observed will be considered as an AE or SAE 
as appropriate. The clinical laboratory performing the testing will provide the reference ranges 
for all clinical laboratory parameters. 
3.13.2.1. Pregnancy Test 
All subjects of childbearing potential must have a negative pregnancy test at Screening and 
Day 1 to be enrolled in the study. All subjects of childbearing potential will undergo a serum 
pregnancy test at Screening and urine pregnancy tests at Day 1, Day 22, Day 43, Day 71, 
Day 161, and Day 251. Results must be available prior to study treatment and prior to MRIs. A 
subject who becomes pregnant must immediately be discontinued from study treatment and be  
withdrawn from the study. 
3.13.3. 
Vital Signs 
Vital signs (systolic and diastolic blood pressure, respiratory rate, pulse rate, body temperature) 
will be collected at Screening, Day 1, Day 22, Day 43, Day 71, Day 161, and Day 251, after the 
subject has been seated for 5 minutes (minimum). 
On study treatment days (Days 1, 22, and 43), vital signs will be taken up to 4 hours prior to 
dosing and at 15 minutes and 30 minutes after dosing (body temperature is not required at the 
15-minute post dose time point). The subject’s vital signs must be stable or repeated until stable 
before the subject can leave direct observation. 
Any clinically significant abnormality in vital sign observed, will be considered as an AE or SAE 
as appropriate. 


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3.13.4. 
12-Lead Electrocardiogram (ECG) 
A 12-lead ECG will be performed at Screening while the subject is in the supine position for at 
least 5 minutes. 
The ECG recording should include a minimum of 5 heart cycles (beats). If the ECG report shows 
QT prolongation with QTc ≥ 450 ms, the investigator should repeat the ECG within 1 hour. If 
the initial findings are confirmed, the investigator should exclude the subject from study 
participation. 
The ECG will be interpreted by the investigator and graded as: 
 Normal. 
 Abnormal, not clinically significant. 
 Abnormal, clinically significant. 
Any clinically significant abnormality in ECG observed, will be considered as an AE or SAE as 
appropriate. 
 
3.13.5. 
Physical Examination 
A complete physical examination (by body system) will be performed at Screening. A complete 
physical evaluation will include an examination of head, eyes, ears, nose, throat, neck (including 
thyroid), cardiovascular system (including assessment of heart, peripheral pulses, presence or 
absence of edema), lungs, abdomen (including liver and spleen, bowel sounds), lymph nodes, 
musculoskeletal system (including spine, joints, muscles) neurological system (including cranial 
nerves, reflexes, sensation, strength), skin (excluding cellulite), extremities, and any other 
conditions of note. 
Physical examination findings will be recorded as normal or abnormal. 
If physical examination findings meet the investigator’s criteria for clinical significance, then it 
will be reported as an AE or SAE as appropriate. 
 
3.13.6. 
Height and Weight 
Height will be collected at Screening. Weight will be collected at Screening, Day 1, Day 22, 
Day 43, Day 71, Day 161, and Day 251. If change in subject weight from Screening to 
subsequent visits meets the investigator’s criteria for clinical significance, then it will be reported 
as an AE or SAE as appropriate. 
 
3.13.7. 
Fitzpatrick Skin Scale 
The Fitzpatrick Skin Scale is used for assessment of skin color and propensity for tanning. 
Fitzpatrick skin type for all subjects will be determined at Screening. 
The Fitzpatrick Skin Scale is a 6-level scale (Types I-VI) ranging from 1 to 6 as mentioned in 
Table 8 below. 


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Table 8: 
Fitzpatrick Skin Scale 
 
Level 
Description 
1 
Type I: Pale white skin, blue/hazel eyes, blond/red hair; Always burns, does not tan 
2 
Type II: Fair skin, blue eyes; Burns easily, tans poorly 
3 
Type III: Darker white skin; Tans after initial burn 
4 
Type IV: Light brown skin; Burns minimally, tans Easily 
5 
Type V: Brown Skin; Rarely burns, tans darkly easily 
6 
Type VI: Dark brown or black skin; Never burns, always tans darkly 
 
3.13.8. 
Immunogenicity Samples 
Immunogenicity variables include anti-AUX-I /anti-AUX-II (anti-drug antibodies) and 
neutralizing antibody results. Serum samples will be collected at Day 1 (prior to study treatment 
administration), Day 71, Day 161, and Day 251 for all subjects for the determination of serum 
anti-AUX-I and anti-AUX-II antibody levels and neutralizing antibodies to AUX-I and AUX-II. 
 
3.13.9. 
Follow-up Biopsy 
The investigator will examine the biopsy site for evidence of ongoing AEs related to the biopsy 
and will determine if the biopsy site has healed. The follow-up biopsy examination will be 
conducted at the Day 1, Day 85 and Day 265 visits. The investigator will examine and confirm 
sufficient healing of the biopsy site before dosing on Day 1. 
 
3.14. 
Pharmacodynamics 
Prior to the first MRI and biopsy, the investigator will select 3 dimples from the 2 treatment 
areas (both buttocks or both thighs) for MRI and biopsy evaluation from the 4 well-defined, 
isolated dimples that are considered moderate or deep in depth identified at Screening. The 3 
selected dimples should be distributed across both regions of the treatment area (eg, 1 dimple on 
the left thigh [or buttock] and 2 dimples on the right thigh [or buttock], or vice versa). The 
investigator or designee will mark and label these 3 dimples for MRI and biopsies. The MRI 
technician or designee will locate the marked dimples and place an MRI coil appropriately on the 
dimple and photograph each dimple with the coil in place in a manner that will allow them to be 
relocated for subsequent MRIs. 
 
3.14.1. 
MRI 
MRI will be performed at Screening, Day 71 and Day 251. The Screening MRI will be 
performed after all other screening assessments, except the biopsy, are completed. Screening, 
Day 71, and Day 251 MRIs may be repeated as often as necessary to obtain an evaluable image. 
Repeat screening MRIs must take place within the screening window. The Day 71 and Day 251 
MRI may be performed up to 7 days prior to the Day 71 and Day 251 visits respectively. The 
MRI must be completed before the biopsy at each visit. The Screening MRI will be done on all 3 
selected dimples whereas the Day 71 and Day 251 MRI will be done on Dimple 2 & 3 and 
Dimple 3 respectively. 


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The Day 251/Early Termination MRI is not required for subjects who withdraw from the study 
(early termination). 
 
3.14.2. 
Double Punch Biopsy 
Biopsies will be performed at Screening, Day 71 and Day 251. The Screening biopsy will be 
performed on Dimple 1 after all other screening assessments, including MRI, are completed. The 
Screening biopsy will be performed at least 14 days prior to the Day 1 Visit. 
The Day 71 biopsy will be performed on Dimple 2 and the Day 251 biopsy will be performed on 
Dimple 3 after completion of imaging for efficacy, PR-PCSS, and CR-PCSS at Day 71 and 
Day 251 respectively. 
The Day 251/Early Termination biopsy is not required for subjects who withdraw from the study 
(early termination). 
 
4. 
STUDY PARAMETERS 
4.1. 
Subject Disposition 
4.1.1. 
Discontinuation of Study Treatment 
Subjects will be considered as completing the treatment phase if they complete Day 71 visit. 
Subjects discontinued from study treatment are those who discontinued the study at any time 
before completing all treatment phase visits. The date of, and reason for, study treatment 
discontinuation will be recorded in the eCRF. 
If a subject becomes pregnant during the active treatment phase of the study (Day 1 through 
Day 43) then the study treatment will be permanently discontinued for that subject. Study 
treatment will also be discontinued if abnormal liver function is observed. 
Subjects who discontinue from study treatment at any time after the first dose of study drug will 
not be replaced. 
 
4.1.2. 
Subject Withdrawal from the Study 
Subjects will be considered as completing the study if they complete the Day 265 visit. 
Withdrawn subjects are those who withdrew the study at any time before study end. The 
withdrawal date and reason will be recorded in the eCRF. 
Subjects who withdrew from the study should undergo all early termination assessments. A 
subject who becomes pregnant at any time during the study will be permanently withdrawn.  
Subjects who have been withdrawn from the study will not be replaced. 
The reason for early discontinuation will be recorded in the eCRF for the subjects who do not 
complete the study. The reason for screen failure will also be recorded in the eCRF for subjects 
who are not enrolled and are considered screen failures. 


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4.2. 
Protocol Deviations 
Potential deviations will be identified and documented prior to database lock. Protocol deviations 
will be derived from the eCRF data, electronic vendor data, and will be obtained from the 
clinical monitoring reports. All deviations from these sources will be reconciled and duplicate 
deviations will be removed. 
Possible deviations include, but are not restricted to the following deviation types: 
 Ineligible subject/study entry criteria not satisfied. 
 Informed consent not completed correctly. 
 Non-compliance with study treatment. 
 Prohibited medications/procedure. 
 Visit/procedure missing or out of window. 
 The Endo study team will approve all final protocol deviation assignments and 
classify them as either major or minor during ongoing protocol deviation review 
meetings, with the final meeting held prior to the database lock. 
 
4.3. 
Prior/Concomitant Medications and Procedures 
All medications will be coded using the World Health Organization (WHO) Drug Dictionary by 
active ingredient and anatomical therapeutic chemical (ATC) classification of ingredients. The 
dictionary version used is defined in the Data Management Plan. 
Any medications/procedures within 90 days prior to the Screening Visit will be classified as 
prior medications/procedures. 
Any medications/procedures from the Screening Visit through the Day 265 Visit will be 
classified as concomitant medications/procedures. 
 
4.4. 
Prior EFP Treatment 
Prior EFP treatment will be obtained from the prior/concomitant medication and/or 
prior/concomitant procedure pages of the eCRF. If on either of these pages a medication or 
procedure is reported with the indication ‘EFP/Cellulite’ and the start date is prior to the 
Screening Visit, then the medication or procedure will be considered a prior EFP treatment. 
All medications will be classified as EFP Drug. All procedures will be classified into one of the 
following groups: 
 Liposuction. 
 Laser. 
 Massage. 
 Radiofrequency. 
 Mesotherapy. 
 Cream. 


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 Other. 
The classification will be reviewed and approved by the study medical monitor. Any EFP 
treatment used after the Day 1 visit will be noted and reported as a protocol violation. 
 
4.5. 
Efficacy Parameters 
Cellulite assessments using the PR-PCSS, CR-PCSS and Hexsel CSS will be performed at 
Screening, Days 22, 43, 71, 161, and 251. 
 
4.5.1. 
Change from Baseline in PR-PCSS Rating (Primary Endpoint) 
To assess the subject reported impact of CCH in the treatment of cellulite in adult females, the 
change from Baseline (Screening) in PR-PCSS will be determined for treatment region (both 
buttocks or both thighs) on Day 71. 
4.5.2. 
Change from Baseline in PR-PCSS Rating (Secondary Endpoint) 
To assess the subject reported impact of CCH in the treatment of cellulite in adult females, the 
change from Baseline (Screening) in PR-PCSS will be determined for treatment region (both 
buttocks or both thighs) on Days 22 and 43. 
4.5.3. 
Change from Baseline in CR-PCSS Rating (Secondary Endpoint) 
To assess the clinician reported impact of CCH in the treatment of cellulite in adult females, the 
change from Baseline (Screening) in CR-PCSS will be determined for treatment region (both 
buttocks or both thighs) on Days 22, 43, and 71. 
4.5.4. 
Change from Baseline in Hexsel CSS Total Score (Secondary Endpoint) 
To assess the clinician reported impact of CCH in the treatment of cellulite in adult females, the 
change from Baseline (Screening) in Hexsel CSS total score will be determined for treatment 
region (both buttocks or both thighs) on Days 22, 43, and 71. 
4.5.5. 
Proportion of Subjects with No Change (or Worsening) from Baseline (Tertiary 
Endpoints) 
Complete loss of Response at Days 161 and 251 is defined as worsening of cellulite severity 
improvement on PR-PCSS/CR-PCSS /Hexsel CSS total score ratings at Days 161 and 251 
compared to the score at Day 71, where cellulite severity returns to baseline levels or worse. 
Tertiary endpoints will be analyzed for each scale separately. 
 
4.6. 
Safety Parameters 
4.6.1. 
Adverse Events 
AE verbatim terms as reported by the investigator will be mapped to system organ class (SOC) 
and preferred term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA). The 
dictionary version is defined in the Data Management Plan. 


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4.6.1.1. 
Treatment Emergent Adverse Events 
TEAEs are defined as any AEs that occur or worsen (increase in severity) on the same day or 
after the study drug administration on Day 1. 
Refer to Section 6.3.1.2 to identify TEAE status when start date of an AE is unknown. 
 
4.6.1.2. 
Intensity of Adverse Events 
Intensity (or severity) of AEs will be graded as “Mild”, “Moderate” or “Severe”. For AEs with 
missing severity, the most severe assessment will be imputed for analyses, following worst case 
principle. If the intensity of an AE changes, then the most severe intensity during the continuous 
episode will be recorded. 
 
4.6.1.3. 
Relationship to Study Drug 
Causal relationship of an AE with study drug will be classified by the investigator and will be 
reported as “Not related”, “Unlikely related”, “Probably related” or “Possibly related”. The 
sponsor will classify “Probably related” and “Possibly related” causality assessments as positive 
causality and “Not related” and “Unlikely related” causality assessments as negative causality. 
Any missing relationship of an AE to study drug will be considered as related to study drug for 
the analyses, following worst case principle. 
 
4.6.2. 
Potentially Clinically Important Laboratory Values 
Potentially clinically important (PCI) laboratory values are presented in Table 9 below. 
Table 9: 
Potentially Clinically Important Laboratory Criteria 
 
Parameter 
PCI Low: Less than or equal to 
PCI High: Greater than or equal to 
Hemoglobin (g/L) 
100 
190 
Hematocrit 
0.3 
0.6 
Platelets (109/L) 
100 
650 
ALT (U/L) 
3×ULN 
AST (U/L) 
3×ULN 
Creatinine (μmol/L) 
300 
BUN (mmol/L) 
12 
ALT=Alanine Aminotransferase; AST=Aspartate Aminotransferase; BUN=Blood urea nitrogen; ULN=Upper limit 
of normal 
 
4.6.3. 
Potentially Clinically Important Vital Sign Values 
Vital sign values are PCI if they meet either or both of the observed value criteria and the change 
from baseline criteria. The PCI vital sign values are presented in Table 10 below. 


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Table 10: 
Potentially Clinically Important Vital Sign Criteria 
 
Parameter 
PCI Low 
PCI High 
Systolic Blood Pressure 
≤90 mmHg and/or decrease ≥20 mmHg 
from baseline 
≥180 mmHg and/or increase ≥20 mmHg 
from baseline 
Diastolic Blood Pressure ≤50 mmHg and/or decrease ≥15 mmHg 
from baseline 
≥105 mmHg and/or increase ≥15 mmHg 
from baseline 
Pulse Rate 
≤50 bpm and/or decrease ≥15 bpm from 
baseline 
≥120 bpm and/or increase ≥15 bpm from 
baseline 
Respiratory Rate 
≤8 brpm and/or decrease ≥7 brpm from 
baseline 
≥25 brpm and/or increase ≥7 brpm from 
baseline 
Temperature 
≥38.3°C and/or increase ≥1.1°C from 
baseline 
bpm=Beats per minute; brpm=Breaths per minute 
 
4.6.4. 
Immunogenicity 
Serum samples will be collected and will be tested for binding anti-AUX-I and anti-AUX-II 
antibodies. When immunogenicity samples are required on Day 1, the samples will be collected 
prior to study treatment administration. The samples also will be tested for neutralizing 
antibodies at times to be determined by the sponsor. 
 
4.7. 
Pharmacodynamics 
4.7.1. 
Comparison of Baseline (Screening) MRI Tissue Morphology and Septae 
To radiologically assess the impact of treatment with CCH in adult females with cellulite, 
Baseline (Screening) MRI tissue morphology and septae will be compared to images taken at 
Day 71. 
The long-term impact of treatment with CCH in adult females with cellulite will be assessed by 
comparing the changes in MRI tissue morphology and septae at Day 251 to Baseline 
(Screening). 
4.7.2. 
Comparison of Baseline (Screening) Histopathology 
The evaluation of tissue histopathology in assessing the impact of treatment with CCH in adult 
females with cellulite will be done by comparing Baseline (Screening) histopathology to the 
sample taken at Day 71. 
The evaluation of tissue histopathology in assessing the long-term impact of treatment with CCH 
in adult females with cellulite will be done by comparing Baseline (Screening) histopathology to 
the sample taken at Day 251. 


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5. 
ANALYSIS POPULATIONS 
The study will use the following analysis populations for data summarization. 
Table 11: 
Analysis Population 
 
Population 
Definition 
Displays 
Safety Population 
The Safety Population will include all 
subjects who have undergone any MRI 
or biopsy at Screening. 
All demographic and baseline 
characteristics as well as safety 
parameters will be summarized based on 
this population. 
Evaluable Population 
The Evaluable Population will include 
all subjects in the Safety Population who 
have a baseline and at least 1 post- 
injection PR-PCSS evaluation. 
All efficacy analyses will be based on 
this population. 
 
6. 
STATISTICAL METHODS 
6.1. 
General Methodology 
All statistical analysis, summary tables and data listings will be prepared using version 9.3 or 
later of SAS software. 
All statistical tests of efficacy parameters will be 2-sided with a significance level of α=0.05, 
unless specified otherwise. 
Continuous data will be summarized using descriptive statistics (number of subjects [n], mean, 
standard deviation [SD] or standard error [SE], median, minimum [min], and maximum [max]) 
and discrete data will be summarized using frequency counts and percentages, the denominator 
will be based on the number of subjects in the appropriate population. For the purpose of display, 
the summary results will be rounded as follows: 
 Min and max: same number of decimal places as the raw data. 
 Mean and median: 1 more decimal place than the raw data. 
 SD/SE: 2 more decimal places than the raw data. 
 Percentages will be displayed with 1 decimal precision. A zero count will not have 
the associated percentage presented on the table (ie, no 0%). 
 The standard form of a percentage change variable is 0 decimal places. 
For categorical variables with missing values, a category documenting the frequency of missing 
values will be displayed in the summary tables. 
Summary tables, subject listings and any supportive SAS output will include a “footer” of 
explanatory notes that will indicate, when applicable: 
 Date of data extraction 
 Date and time of output generation 
 SAS program name, including the path, that generates the output 


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When calculating percentages, the denominator will be based on the number of subjects with 
non-missing values. If the denominator is expected to change over time, then the denominator 
used to calculate the percentage should be based on the number of subjects with non-missing 
values at each visit. Any subject removed from an analysis will be noted at the bottom of the 
table along with the reason the subject was removed. 
Null summary tables will be presented with a note stating that “No Subjects Met Criteria”. 
Subject listings of all data from the eCRFs as well as any derived variables will be presented. 
6.2. 
Derived Variables 
Refer to Table 12 below for derived variables and their definitions for various study parameters. 
Table 12: 
Derived Variables and Definition 
 
Variable 
Definition 
Height (cm) 
If height is recorded in inches, then height is equal to the recorded value multiplied 
by 2.54 and then rounded to 1 decimal place. 
Weight (kg) 
If weight is recorded in pounds, then weight is equal to the recorded value multiplied 
by 0.454 and then rounded to 1 decimal place. 
Baseline 
Baseline is defined as the last non-missing measurement/assessment prior to the 
CCH injections given at Day 1. 
Any assessments performed at an unscheduled visit will be considered in the 
calculation of baseline, if the unscheduled assessment is the closest value preceding 
the study drug injection. 
Study Day 
Study Day will be computed as Date of Assessment – Date of Day 1 + 1 for 
assessments on or after Day 1, else study day will be computed as Date of 
Assessment – Date of Day 1. 
Change from Baseline 
Change from baseline will be derived as post-baseline visit/time point value – the 
baseline value. 
Last Date in the Study 
Last date in study is defined as: 
 The date of Day 265 (Biopsy follow-up visit) if the subject completes the study 
 The date of early termination visit if the subject is terminated early from study at 
a non-scheduled visit 
 The date of the latest scheduled visit if the subject is terminated early from study 
at a scheduled visit or lost to follow-up. 
Age (Years) at EFP 
Symptom Onset 
Date of EFP symptoms reported – Date of Birth/365.25. 
See Section 6.3.1.3 for handling of partial or unknown EFP symptom onset dates. 
Time (Years) Since Last 
EFP Treatment 
Date of most recent EFP treatment – Date of informed consent/365.25. 
See Section 6.3.1.3 for handling of partial or unknown EFP treatment dates. 
Duration (Minutes) of 
Exposure at Each Visit 
Date/Time of Last Injection – Date/Time of First Injection 
Duration of AE (Days) 
AE end date – AE start date + 1 
AE Onset Day 
AE start date – Date of Day 1 + 1. 


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6.3. 
Handling of Missing Data 
Subjects who discontinue the study any time after the initiation of the study drug will not be 
replaced and available data of these subjects until the point of discontinuation will be 
summarized. The missing baseline assessment will not be imputed. 
For categorical variables with missing values, a category documenting the frequency of missing 
values will be displayed in the summary tables. 
Subjects who discontinue early will be encouraged to complete all end of study (EOS) 
procedures and assessments at an early termination visit. 
There will be no imputation of missing values for safety data, however missing relationship 
between AE and study drug will be considered as related to study drug following worst case 
principle. Missing severity of an AE will be summarized as a severe AE. 
Immunogenicity samples with a positive titer value will undergo a log transformation for 
analyses. Samples with titer levels less than 1 will be assigned or imputed as a log transformed 
titer of 0 for analyses. 
 
6.3.1. 
Imputation of Partial Dates 
The following rules will apply in cases of partial dates in concomitant medications and 
procedures: 
 If the start date is partial with month and year present, then missing day will be 
imputed with the first day of the month. Whereas if the end date is partial with month 
and year present then missing day will be imputed with the last day of the month. 
 If only year is present in the start date, then missing day and month will be imputed 
with first day of January. Whereas if only year is present then missing day and month 
will be imputed with the last day of December. 
 
6.3.1.1. 
Concomitant Status of Medication for Unknown Start Date 
The following rules will apply in cases where the start date of a concomitant medication is 
completely unknown: 
 If the medication onset date is unknown and the end date is on or after the Screening 
Visit date or medication is ongoing, then the medication will be considered as 
concomitant. 
 If the medication onset date is unknown and the end date is before the Screening Visit 
date, then the medication will not be considered as concomitant. 
 If both the start and end dates are unknown, then the medication will be considered as 
concomitant. This approach is considered to be the most conservative following the 
worst-case principle. 
 If the medication onset date is partly present and month/year is before informed 
consent date, then the medication will not be considered as concomitant. 


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6.3.1.2. 
TEAE Status When Start Date Is Unknown 
The following rules will apply in cases where start date of an AE is unknown: 
 If the AE onset date is unknown and the end date is after the date of CCH injection on 
Day 1 or ongoing, then the AE will be considered a TEAE. 
 If the AE onset date is unknown and the end date is before the date of CCH injection 
on Day 1, then the AE will not be considered a TEAE. 
 If both the start date and end date are unknown (or ongoing), then the AE will be 
considered a TEAE, following the worst-case principle. 
 
6.3.1.3. 
Missing EFP Onset Date 
Missing EFP onset day will be imputed as the first day of the month and missing onset month 
will be imputed as January. If the EFP onset date is indicated as completely unknown but starting 
less than 5 years ago, the EFP onset date will be imputed as the informed consent date minus 
5 years. If the EFP onset date is indicated as completely unknown but starting more than 5 years 
ago, the EFP onset date will not be imputed. Missing EFP medication/treatment end days will be 
imputed with the last day of the month and missing end months will be imputed with December, 
except if the end year is equal to the date of injection year and then the EFP medication/ 
treatment end date will be imputed with the first injection date. 
6.4. 
Interim Analyses 
An interim analysis will be conducted when all subjects have completed their Day 71 visit. 
Analysis of all primary and secondary endpoints will be included in the interim analysis. 
The purpose of the interim analysis is to determine if changes in morphology and/or histology 
can be identified using MRI and biopsy. If the interim analysis does not indicate that such 
changes can be identified, subsequent or additional MRIs or biopsies will not be done in this 
study. 
 
7. 
STATISTICAL ANALYSES 
7.1. 
Subject Disposition 
The number of subjects included in each study population will be summarized by treatment 
region (ie, buttocks, thighs) and overall. Subjects excluded from the Safety Population or 
Evaluable Population will be listed. 
The frequency counts and percentages of subjects screened, screen failed, treated, not treated 
completed, and discontinued from study treatment and/or withdrawn from the study, as well as 
the reason for discontinuation from study and reason for discontinuation of study drug will be 
summarized by treatment region and overall. 
A listing of disposition for all subjects will be provided. Screen failure reasons will also be listed. 
In addition, a listing for inclusion/exclusion criteria will also be presented. 


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7.2. 
Protocol Deviations 
A listing of all protocol deviations will be presented. 
 
7.3. 
Demographics and Baseline Characteristics 
Demographic and other baseline characteristics will be summarized by treatment region, not 
treated and overall using the Safety and Evaluable Population. 
Age, height (at screening), body weight (at screening) and BMI in kg/m2 will be summarized by 
treatment region and overall as continuous variables using descriptive statistics. Gender, race, 
ethnicity, skin category based on the Fitzpatrick scale assessment, PR-PCSS, CR-PCSS, Hexsel 
CSS total score and report of tobacco and alcohol use (never, current, and former) will be 
summarized by treatment region, not treated and overall as categorical variables using frequency 
counts and percentages. 
All demographic and baseline characteristics will be presented in a listing for all subjects. 
 
7.4. 
Medical and Surgical History 
Medical history will be coded using the MedDRA dictionary (version is defined in the Data 
Management Plan). Medical, surgical and EFP history data will not be summarized; however, a 
subject listing will be provided for all subjects. 
 
7.5. 
Prior/Concomitant Medications and Procedures 
Prior and concomitant medications, procedures and EFP treatments will be summarized by 
treatment region, not treated and overall using frequency counts and percentages for subjects in 
the Safety Population, by active ingredient within each ATC, with ATC and active ingredients 
ordered alphabetically. Multiple use of the same medication by a subject will be counted only 
once. 
A listing of prior and concomitant medications and procedures will be provided for all subjects. 
Similarly, a separate listing of medications and procedures for EFP/Cellulite will also be 
presented. 
 
7.6. 
Efficacy Analyses 
Efficacy parameters will be summarized by treatment area (left or right) and treatment region 
(buttock or thigh) using the Evaluable Population. 
PR-PCSS, CR-PCSS and Hexsel CSS total score ratings and the level of change from baseline 
will be summarized as per below sections. 
A listing for digital photography will be provided with date and time for photos taken and 
reasons for photos not taken per protocol. 
Individual listings will be provided for PR-PCSS ratings, CR-PCSS ratings and Hexsel CSS 
ratings and total scores. 


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7.6.1. 
Primary Endpoint 
 
7.6.1.1. 
Change from Baseline in PR-PCSS Rating at Day 71 
The baseline PR-PCSS ratings and the level of change in PR-PCSS ratings from Baseline 
(Screening) at Day 71 will be summarized using frequency counts and percentages for each 
severity rating and with mean and SD. 
To assess the impact of CCH at Day 71, the PR-PCSS ratings at Day 71 will be compared with 
Baseline ratings using paired t test. The normality assumption of the difference of assessment 
will be evaluated using Shapiro-Wilk test and Q-Q plot. 
Two-sided p value with 5% level of significance will be used to check if normality is achieved or 
not. Normality will be concluded if the p value > 0.05. 
In case normality assumption is not met then Wilcoxon Signed Rank Pratt Lehmann test 
(adjusted for the correction factor for ties and zeros, if present) will be used. 
The result of the analysis will be presented as: 
SAS appendix will be presented detailing the test of normality of differences in Day 71 and 
Baseline PR-PCSS ratings. 
Paired t test: Mean difference between Baseline and Day 71 ratings and associated 95% CI, SE, 
and p value. The negative mean difference indicates improvement in cellulite severity at Day 71. 
Wilcoxon Signed Rank Pratt Lehmann test: Sum of positive ranks, sum of negative ranks and 
p value will be presented. If the sum of the negative rank is greater than the sum of positive rank, 
then it indicates improvement in cellulite severity at Day 71. 
 
7.6.2. 
Secondary Endpoints 
 
7.6.2.1. 
Change from Baseline in PR-PCSS Rating at Days 22 and 43 
The baseline PR-PCSS ratings and the level of change in PR-PCSS ratings from Baseline 
(Screening) at Day 22 and 43 will be summarized using frequency counts and percentages for 
each severity rating and with mean and SD. 
In addition, the PR-PCSS ratings at Day 22 and 43 will be compared with Baseline ratings using 
similar analysis as mentioned for primary endpoint. Refer to Section 7.6.1.1 for more details. 
 
7.6.2.2. 
Change from Baseline in CR-PCSS Rating at Days 22, 43, and 71 
The baseline CR-PCSS ratings and the level of change in CR-PCSS ratings from Baseline 
(Screening) at Days 22, 43, and 71 will be summarized using frequency counts and percentages 
for each severity rating and with mean and SD. 
In addition, the CR-PCSS ratings at Days 22, 43, and 71 will be compared with Baseline ratings 
using similar analysis as mentioned for primary endpoint. Refer to Section 7.6.1.1 for more 
details. 


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7.6.2.3. 
Changes in the Hexsel CSS Total Score from Baseline at Days 22, 43, and 71 
The baseline Hexsel CSS scores and the level of change in Hexsel CSS scores from Baseline 
(Screening) at Days 22, 43, and 71 will be summarized using frequency counts and percentages 
for each severity scores and with mean and SD. 
In addition, the Hexsel CSS total score ratings at Days 22, 43, and 71 will be compared with 
Baseline using similar analysis as mentioned for the primary endpoint. Refer to Section 7.6.1.1 
for more details. 
7.6.3. 
Tertiary Endpoints 
 
7.6.3.1. 
Proportion of Subjects with No Change (or Worsening) from Baseline in 
PR-PCSS Rating on Days 161 and 251 
The proportion of subjects with complete loss of response as provided in Section 4.5.5 in 
PR-PCSS rating will be summarized using frequency counts and percentages. 
 
7.6.3.2. 
Proportion of Subjects with No Change (or Worsening) from Baseline in 
CR-PCSS Rating on Days 161 and 251 
The proportion of subjects with complete loss of response as provided in Section 4.5.5 in 
CR-PCSS rating will be summarized using frequency counts and percentages. 
 
7.6.3.3. 
Proportion of Subjects with No Change (or Worsening) from Baseline in Hexsel 
CSS Total Score on Days 161 and 251 
The proportion of subjects with complete loss of response as provided in Section 4.5.5 in Hexsel 
CSS total score will be summarized using frequency counts and percentages. 
 
7.7. 
Safety Analyses 
Safety data will be summarized using the Safety Population. 
 
7.7.1. 
Study Drug Exposure 
The following will be summarized at each treatment session by treatment area for each treatment 
region using descriptive statistics: 
 Number of injections given. 
 Number of dimples treated. 
 Average number of injections per dimple. 
 Duration of exposure (refer to Table 12 for computation of exposure duration). 
 Total dose administered. 
The number of subjects treated at each treatment session will be summarized using frequency 
counts and percentages by treatment area for each treatment region. 
A subject listing of overall exposure and injection status will be provided. 


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7.7.2. 
Adverse Events 
All AE summary tables will include TEAEs and the AEs before the first injection. 
AEs will be summarized by SOC and PT and by treatment region and overall as frequency 
counts and percentages of subjects with AEs and number of AEs (total events), unless otherwise 
specified. 
A subject will only be counted once per SOC and PT. 
For AEs by severity grade (mild, moderate, severe), if a subject has multiple events occurring in 
the same SOC or same PT, then the event with the maximum intensity (ie, severe) will be 
counted. 
For AEs by relationship to study drug, if a subject has multiple events occurring in the same 
SOC or same PT, the event with the highest association (ie, related) to study drug will be 
summarized. 
AEs will be presented in decreasing order of the incidences at SOC level and within each SOC, 
in decreasing order of the incidences at the PT level. 
An overall summary of AEs and AEs related to study drug will be presented and will include: 
 Any AE. 
 Any mild, moderate and severe AE. 
 Any study drug related AE. 
 Any serious AEs. 
 Any study drug related serious AE. 
 Any AEs leading to study drug interruption/discontinuation. 
 Any study drug related AEs leading to study drug interruption/discontinuation. 
 Any AEs leading to study withdrawal. 
 Any study drug related AEs leading to study withdrawal. 
 Any AEs resulting in death. 
 Any study drug related AEs resulting in death. 
 Any AESIs. 
The following summary tables will be presented by SOC and PT: 
 All AEs. 
 AEs by Severity. 
 TEAEs by Relationship to Study Drug. 
 Serious AEs. 
 Serious study drug related TEAEs. 
 TEAEs leading to study drug interruption/discontinuation. 


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 Study drug related TEAEs leading to study drug interruption/discontinuation. 
 AEs leading to study withdrawal. 
 Study drug related TEAEs leading to study withdrawal. 
 AEs resulting in death. 
 Study drug related TEAEs resulting in death. 
 AESIs. 
Most common non-serious AEs by order of frequency (most frequent, 2nd most frequent, and 3rd 
most frequent) will be summarized by PT. Most common non-serious AEs are any PT that at 
least 5% of the subjects reported at least once. 
The following listings will be presented by subject: 
 All AEs. 
 Serious AEs. 
 AEs resulting in drug interruption/discontinuation. 
 AEs resulting in study withdrawal. 
 AEs resulting in deaths. 
 AESIs. 
Refer to Table 12 for computation of duration of AEs. 
 
7.7.3. 
Clinical Laboratory 
Laboratory parameters (hematology and chemistry) results will be summarized by treatment 
region, not treated and overall using descriptive statistics for observed and change from baseline 
values at Baseline (Screening), Day 71, and Day 251. 
PCI laboratory values will be summarized by frequency counts and percentages. Refer to Table 9 
for PCI criteria. 
Individual laboratory results including hematology, chemistry, urinalysis, blood serology, serum 
and urine pregnancy test results will be listed. 
 
7.7.4. 
Vital Signs and Body Weight 
Vital signs parameters (blood pressure, pulse rate, respiratory rate, and body temperature) and 
body weight will be summarized by treatment region, not treated and overall using descriptive  
statistics for observed and change from baseline values for all visits/time points. 
PCI vital sign values will be summarized by frequency counts and percentages. Refer to Table 10 
for PCI criteria. 
Individual vital sign measurements including pulse rate, systolic blood pressure, diastolic blood 
pressure, respiratory rate, and body temperature will be listed. 


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7.7.5. 
12-Lead ECG 
A subject listing will be presented for the investigator interpretation. 
 
7.7.6. 
Physical Examination 
A subject listing will be presented for the physical examination (by body system) for Screening 
results. 
 
7.7.7. 
Immunogenicity 
Binding anti-AUX-I and anti-AUX-II antibody data will be summarized using the number of 
subjects with an immunogenicity sample, the frequency counts and percentages of subjects with 
a positive sample, and a descriptive summary of the average titer level of the positive samples at 
Day 1, Day 71, Day 161, and Day 251. The titer levels will be logarithmically transformed prior 
to being summarized descriptively. 
The frequency counts and percentages of assayed serum samples that will detect the presence or 
absence of neutralizing antibodies (positive/negative) to AUX-I and AUX-II will be summarized 
by treatment region and overall using frequency counts and percentages at all visits. 
Listings of immunogenicity data will be presented for all subjects. 
 
7.8. 
Pharmacodynamics 
Pharmacodynamic parameters, if available, will be summarized by treatment region (buttock or 
thigh) using the Safety Population. 
 
7.8.1. 
Comparison of Baseline (Screening) MRI Tissue Morphology and Septae 
A summary table and a listing will be provided based on Safety population if the data are 
available. 
 
7.8.2. 
Comparison of Baseline (Screening) Histopathology 
A summary table and a listing will be provided based on Safety population if the data are 
available. 
 
8. 
CHANGE FROM PROTOCOL 
This SAP is prepared primarily based on the study protocol; original version dated 
October 22, 2019 and protocol amendment 1 dated January 16, 2020. 
 
9. 
REVISION HISTORY 
This SAP is the first version. 


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10. 
REFERENCES 
A Phase 2a Open-Label, Study to Assess the Impact of CCH Treatment of Buttock and Thigh 
Cellulite in Adult Females Using Photonumeric Scales, Magnetic Resonance Imaging, and 
Histopathology [EN3835-212 Clinical Study Protocol, Amendment 1]. Endo Pharmaceuticals 
Inc.; January 16, 2020. 
Hexsel DM, Abreu M, Rodrigues TC, Soirefmann M, do Prado DZ, Gamboa MM. Side-by-side 
comparison of areas with and without cellulite depressions using magnetic resonance imaging. 
Dermatol Surg. 2009;35(10):1471-7. 
Nürnberger F, Müller G. So-called cellulite: an invented disease. J Dermatol Surg Oncol. 
1978;4(3):221-9. 
 
11. 
TABLES, LISTINGS, AND GRAPH SHELLS 
The layouts of the summary tables, subject listings, and graphs are presented in SAP Module 2. 
These layouts incorporate all the appropriate table titles, table numbers, and footnotes.