Conditions: Edematous Fibrosclerotic Panniculopathy Cellulite Laxity; Skin
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 35
Healthy volunteers: yes

Brief summary:
This study is designed to investigate the safety and efficacy of collagenase clostridium histolyticum (CCH) for the treatment of mild to moderate edematous fibrosclerotic panniculopathy (cellulite) in participants with moderate to severe dermal laxity in the buttocks or thighs with comparison between two (2) different CCH injection techniques.

Detailed description:

Arms:
arm 1: Dose per participant per treatment visit = up to 1.68 milligrams (mg) of CCH (0.84 mg in each treatment area) arm 2: Dose per participant per treatment visit = up to 1.68 mg of CCH (0.84 mg in each treatment area) arm 3: Dose per participant per treatment visit = up to 1.68 mg of CCH (0.84 mg in each treatment area) arm 4: Dose per participant per treatment visit = up to 1.68 mg of CCH (0.84 mg in each treatment area)

Interventions: intervention 1: collagenase clostridium histolyticum
Intervention descriptions: intervention 1: Delivered via uniform grid injection techniques.

Protocol document:
Prot_000.pdf: 
Protocol 
 
 
Endo Pharmaceuticals Inc. 
1400 Atwater Drive 
Malvern, PA 19355 USA 
EN3835-224 
A PHASE 2 MULTICENTER, OPEN-LABEL, RANDOMIZED, 
PARALLEL-GROUP, MULTIPLE-DOSE STUDY TO ASSESS 
THE EFFECTIVENESS, SAFETY AND SATISFACTION 
WITH COLLAGENASE CLOSTRIDIUM HISTOLYTICUM 
GRID TECHNIQUE INJECTIONS OF BUTTOCK OR THIGH 
CELLULITE WITH LAXITY IN ADULT FEMALES 
Sponsor Name: Endo Pharmaceuticals Inc. 
Sponsor Legal Registered Address: 1400 Atwater Drive, Malvern, PA 19355 
Regulatory Agency Identifier Number(s): IND 110077 
Original Protocol: July 27, 2020 
Protocol Amendment 1: December 03, 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. 
NCT #NCT05249257


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TABLE OF CONTENTS 
1.
PROTOCOL SUMMARY ...........................................................................................12 
1.1. 
Synopsis ......................................................................................................................12 
1.2. 
Study Schema .............................................................................................................15 
1.3. 
Schedule of Activities .................................................................................................16 
2.
INTRODUCTION ......................................................................................................19 
2.1. 
Study Rationale ...........................................................................................................19 
2.2. 
Background .................................................................................................................20 
2.3. 
Risk/Benefit Assessment ............................................................................................20 
3.
OBJECTIVES AND ENDPOINTS ............................................................................22 
4.
STUDY DESIGN .......................................................................................................24 
4.1. 
Overall Design ............................................................................................................24 
4.2. 
Scientific Rationale for the Study Design ..................................................................25 
4.3. 
Justification for Dose ..................................................................................................26 
4.4. 
End of Study Definition ..............................................................................................26 
5.
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................26 
5.1. 
Subject Inclusion Criteria ...........................................................................................26 
5.2. 
Subject Exclusion Criteria ..........................................................................................27 
5.3. 
Lifestyle Considerations .............................................................................................29 
5.4. 
Screen Failures ............................................................................................................29 
6.
STUDY TREATMENT ..............................................................................................29 
6.1. 
Selecting the Treatment Region ..................................................................................30 
6.2. 
Treatment Administration ...........................................................................................30 
6.3. 
Selection of Treatment Regions and Treatment Intervals ..........................................32 
6.4. 
Study Treatment Preparation/Handling/Storage/Accountability ................................33 
6.5. 
Measures to Minimize Bias ........................................................................................34 
6.5.1. 
Interactive Response Technology ...............................................................................34 
6.6. 
Study Treatment Compliance .....................................................................................34 
6.7. 
Prior and Concomitant Medications and Procedures ..................................................34 
6.7.1. 
Prohibited Medications and Procedures .....................................................................34 
6.7.2. 
Rescue Medication ......................................................................................................35 
6.8. 
Study Treatment Modification ....................................................................................35 


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7. 
DISCONTINUATION FROM STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................36 
7.1. 
Discontinuation of Study Treatment ...........................................................................36 
7.2. 
Subject Discontinuation/Withdrawal from the Study .................................................36 
7.3. 
Lost to Follow-up .......................................................................................................37 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................37 
8.1. 
Eligibility Confirmation ..............................................................................................38 
8.2. 
Efficacy Assessments .................................................................................................38 
8.2.1. 
Subject and Investigator Cellulite Assessments .........................................................38 
8.2.1.1. 
Subject Global Aesthetic Improvement Scale ............................................................38 
8.2.1.2. 
Body-Q Appraisal of Cellulite ....................................................................................39 
8.2.1.3. 
Clinician-reported Photonumeric Cellulite Severity Scale - Buttock .........................39 
8.2.1.4. 
Clinician-reported Photonumeric Cellulite Severity Scale - Thigh ............................39 
8.2.1.5. 
Investigator Global Aesthetic Improvement Scale .....................................................39 
8.2.1.6. 
Hexsel Cellulite Severity Scale ..................................................................................40 
 
 
 
 
 
 
8.3. 
Safety Assessments .....................................................................................................40 
8.3.1. 
Medical and Cellulite History .....................................................................................40 
8.3.2. 
Physical Examination .................................................................................................41 
8.3.3. 
Height and Weight ......................................................................................................41 
8.3.4. 
Fitzpatrick Skin Type .................................................................................................41 
8.3.5. 
Vital Signs ..................................................................................................................41 
8.3.6. 
Electrocardiogram .......................................................................................................41 
8.3.7. 
Clinical Safety Laboratory Determinations ................................................................42 
8.3.8. 
Pregnancy Testing ......................................................................................................42 
8.4. 
Adverse Events and Serious Adverse Events .............................................................42 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................43 
8.4.2. 
Method of Detecting AEs and SAEs ..........................................................................43 
8.4.3. 
Follow-up of AEs and SAEs .......................................................................................43 
8.4.4. 
Regulatory Reporting Requirements for SAEs ...........................................................44 
8.4.5. 
Pregnancy ...................................................................................................................44 


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8.4.6. 
AEs/SAEs Experienced by Nonsubjects Exposed to Study Treatment ......................45 
8.4.7. 
Adverse Events of Special Interest .............................................................................45 
8.5. 
Treatment Overdose ....................................................................................................45 
8.6. 
Pharmacokinetics ........................................................................................................45 
8.7. 
Pharmacodynamics .....................................................................................................45 
8.8. 
Genetics ......................................................................................................................45 
8.9. 
Biomarkers ..................................................................................................................46 
8.9.1. 
Immunogenicity Assessments ....................................................................................46 
9. 
STATISTICAL CONSIDERATIONS AND METHODS .........................................47 
9.1. 
Sample Size Determination ........................................................................................47 
9.2. 
Populations for Analysis .............................................................................................47 
9.3. 
Statistical Hypotheses and Analyses ..........................................................................47 
9.3.1. 
Efficacy Analysis ........................................................................................................47 
9.3.1.1. 
Analyses of the Primary Efficacy Endpoint ...............................................................47 
9.3.1.2. 
Analyses of Secondary Efficacy Endpoints ................................................................47 
9.3.1.3. 
Analyses of Tertiary Efficacy Endpoints ....................................................................47 
9.3.2. 
Safety Analyses ..........................................................................................................48 
9.3.2.1. 
Adverse Events ...........................................................................................................48 
9.3.3. 
Other Analyses ............................................................................................................48 
9.4. 
Interim Analysis ..........................................................................................................48 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................49 
10.1. 
Appendix 1: Regulatory, Ethical and Study Oversight Considerations .....................49 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................49 
10.1.2. 
Financial Disclosure ...................................................................................................50 
10.1.3. 
Informed Consent Process ..........................................................................................50 
10.1.4. 
Data Protection ...........................................................................................................51 
10.1.5. 
Committee Structure ...................................................................................................51 
10.1.6. 
Dissemination of Clinical Study Data ........................................................................51 
10.1.7. 
Data Quality Assurance ..............................................................................................51 
10.1.8. 
Source Documents ......................................................................................................52 
10.1.9. 
Study and Site Closure ................................................................................................52 
10.1.10. 
Publication Policy .......................................................................................................52 


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10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................53 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting .........................................................................54 
10.3.1. 
Definitions ..................................................................................................................54 
10.3.2. 
Relationship to Study Drug ........................................................................................55 
10.3.3. 
Intensity Assessment ..................................................................................................55 
10.3.4. 
Reporting Adverse Events and Serious Adverse Events ............................................55 
10.3.4.1. 
Reporting Adverse Events ..........................................................................................55 
10.3.4.2. 
Reporting Serious Adverse Events .............................................................................56 
10.3.4.3. 
Follow-up Procedures for Serious Adverse Events ....................................................56 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................57 
10.5. 
Appendix 5: Genetics .................................................................................................57 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ..............57 
10.7. 
Appendix 7: Medical Device Incidents ......................................................................57 
10.8. 
Appendix 8: Country-specific Requirements .............................................................57 
10.9. 
Appendix 9: Abbreviations .........................................................................................58 
11. 
INVESTIGATOR’S STATEMENT ...........................................................................59 
12. 
REFERENCES ...........................................................................................................60 
 
 


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LIST OF TABLES 
Table 1: 
Schedule of Activities .................................................................................................16 
Table 2: 
Intended Distribution of Subject Treatment Area Characteristics and 
Locations .....................................................................................................................24 
Table 3: 
Study Treatment Administration ................................................................................31 
 
LIST OF FIGURES 
Figure 1: 
Study Design Overview ..............................................................................................15 
Figure 2:  Injection Techniques for Dosing for Cohorts A and B ...............................................32 
 
 
 




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At the Treatment Phase visits after Day 1 28 and Day 84 visits, the investigator has 
the option to skip treatment or proceed with a treatment session for a new sub-area.. 
• Text in Section 4.1 (Study Design: Overall Design) was revised from:  
The study is expected to enroll subjects over a 3-month period. The entire study is 
expected to require approximately 12 months to complete. 
to: 
The study is expected to enroll subjects over a period of approximately 3 months 
period. The entire study is expected to require approximately 12 months to complete, 
however, the duration of the study may be changed due to possible COVID-19 
impacts. 
• Text in Section 5.2 (Subject Exclusion Criteria), Criteria 1 was revised from:  
Has concurrent diseases that might interfere with the conduct of the study, confound 
the interpretation of the study results, or endanger the participant’s well-being, (eg, 
evidence or history of malignancy unless there has been no recurrence in at least 5 
years since treatment, or any significant hematological, endocrine, cardiovascular, 
respiratory, renal, hepatic, neurologic, psychiatric or gastrointestinal disease). 
to: 
Has concurrent diseases that might interfere with the conduct of the study, confound 
the interpretation of the study results, or endanger the participant’s well-being, (eg, 
evidence or history of malignancy, other than excised basal cell carcinoma and 
adequately treated squamous cell carcinoma of skin, unless there has been no 
recurrence in at least 5 years since treatment), or any significant hematological, 
endocrine, cardiovascular, respiratory, renal, hepatic, neurologic, psychiatric or 
gastrointestinal disease.  
• Text in Section 5.2 (Subject Exclusion Criteria), Criteria 10 was revised from:  
The sponsor’s medical monitor will be required to review the results for confirmation 
of eligibility in the case of any of the following: abnormalities in ECGs indicating 
corrected QT interval (QTc) prolongation of 470 ms or greater, ST-T wave 
abnormalities, or evidence of previous infarct, abnormalities in clinical laboratory 
values involving elevations above the normal range for alanine aminotransferase, 
total bilirubin, and aspartate aminotransferase. 
to: 
The sponsor’s medical monitor will be required to review the results for confirmation 
of eligibility in the case of any of the following: abnormalities in ECGs indicating 
corrected QT interval (QTc) prolongation of 470 ms or greater, ST T wave 
abnormalities, or evidence of previous infarct, abnormalities in clinical laboratory 
values involving elevations above the normal range for alanine aminotransferase, 
total bilirubin, and aspartate aminotransferase.   
• Text in the last sentence of the second paragraph of Section 5.4 (Screen Failures) was 
revised from:  
The period from the start of screening related procedures at the Screening Visit to the 
Day 1 Visit must not exceed 21◦days, inclusive of any repeat screening procedures. 








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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 2 Multicenter, Open-label, Randomized, Parallel-group, Multiple-dose study to 
Assess the Effectiveness, Safety and Satisfaction with Collagenase Clostridium Histolyticum Grid 
Technique Injections of Buttock or Thigh Cellulite with Laxity in Adult Females 
Study period:  
Estimated date first subject enrolled: 01 October 2020 
Estimated date last subject completed: 01 June 2021 
Phase of development: Phase 2 
Objectives and Endpoints:  
Objectives 
Endpoints 
Primary 
 
• 
To assess the efficacy of CCH for the 
treatment of cellulite in the presence of 
dermal laxity using the Investigator 
Global Aesthetic Improvement Scale 
(I-GAIS) 
• 
Proportion of 1-level responders (+1 or 
better score) on the I-GAIS for either 
buttock or either thigh at Day 180 
Secondary 
 
• 
To assess the efficacy of CCH for the 
treatment of cellulite in the presence of 
dermal laxity using the I-GAIS  
• 
Proportion of 1-level responders (+1 or 
better score) on the I-GAIS for either 
buttock or either thigh at Study Days 28, 
56, 84, 112, and 140 
• 
I-GAIS ratings at Study Days 28, 56, 84, 
112, 140, and 180 
• 
To assess the efficacy of CCH for the 
treatment of cellulite in the presence of 
dermal laxity using subject assessments 
• 
Proportion of 1-level responders (+1 or 
better score) on the Subject Global 
Aesthetic Improvement Scale (S-GAIS) 
for either buttock or either thigh at Study 
Days 28, 56, 84, 112, 140, and 180 
• 
The change from baseline to Day 180 in 
the Body-Q Appraisal of the individual 
item cellulite scores and total score. 
• 
To assess the effectiveness of CCH for 
the treatment of cellulite in the presence 
of dermal laxity using Subsection D of 
the Hexsel Cellulite Severity Scale (CSS) 
• 
The change from baseline to each Study 
Visit (Day 28 through the Day 180 Visit) 
in Hexsel CSS Subsection D severity 
score.  






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1.2. 
Study Schema 
Figure 1: 
Study Design Overview 
 


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1.3. 
Schedule of Activities 
Table 1: 
Schedule of Activities 
Activities 
Screening 
Treatment Phasea 
Follow-up 
(Day -28 to 
Day -1) 
Day 1 
 
 
Visit 1 
Day 28 
(±3 day) 
 
Visit 2 
Day 56 
(±3 day) 
 
Visit 3 
Day 84 
(±3 days)  
 
Visit 4 
Day 112 
(±3 days)  
 
Visit 5 
Day 140 
(±3 days) 
 
Visit 6 
Day 180  
End of Study/ 
Early 
Termination 
Visit  
(±10 days) 
Informed consentb 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria review 
X 
Xc 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Imaging for eligibility confirmationd 
X 
 
 
 
 
 
 
 
Medical and cellulite history (including 
previous treatment) 
X 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
X 
Fitzpatrick skin type 
X 
 
 
 
 
 
 
 
Vital signse 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
X  
Clinical safety laboratories 
X 
 
 
 
 
 
 
X 
Anti-AUX-I/Anti-AUX-II antibody level 
sample 
 
X 
 
 
 
 
 
X 
Serum pregnancy test 
X 
 
 
 
 
 
 
X 
Urine pregnancy test 
 
X 
X 
X 
X 
X 
X 
  
CR-PCSS 
X 
 
 
 
 
 
 
 
I-GAISf 
 
 
X 
X 
X 
X 
X 
X 
S-GAISf 
 
 
X 
X 
X 
X 
X 
X 






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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.  
This study is designed to assess the safety and efficacy of CCH for the treatment of edematous 
fibrosclerotic panniculopathy (commonly known as cellulite) in the presence of dermal laxity. 
2.1. 
Study Rationale 
The results from the Phase 3 studies (EN3835-302 and EN3835-303) suggest that CCH 0.84 mg 
per treatment area (buttock) is an effective treatment of cellulite based on improvement in the 
severity of cellulite as determined by the investigator and the subject. There were no significant 
safety concerns following 3 doses of 0.84 mg per treatment area in the treatment of cellulite in 
the Phase 3 pivotal trials as well as other studies incorporating repeated dosing sessions. In Phase 
2 studies EN3835-201 and EN3835-202, 73 individual subjects received a total of 6 treatment 
sessions 21 to 56 days apart; and treatment-related adverse events (AEs) remained similar to 
those that received 3 treatment sessions approximately 21 days apart. No new safety signals were 
seen in these subjects who received a second treatment course consisting of 3 treatment sessions. 
The immunogenicity profile of CCH in the Phase 3 cellulite studies is similar to previous 
EN3835 studies and programs and has not been shown to impair efficacy. 
Dermal laxity and cellulite are interdependent pathologies, in that they are linked, and each 
aggravates the other (Hexsel et al, 2006). Women without cellulite are reported to have less 
dermal laxity. Both cellulite and dermal laxity are associated with findings of weaker connective 
tissue architecture. In the presence of dermal laxity, cellulite becomes more apparent (Dobke 
et al, 2002). It has been observed that dermal laxity frequently occurs in body areas characterized 
by thinner skin with potentially less retentive capacity over fat, such as the buttocks and thighs 
(Hexsel et al, 2001).  
To date, studies of the use of CCH in the treatment of cellulite have excluded subjects with 
significant dermal laxity. This exclusion was based on the presumed understanding of the 
mechanism of action of CCH. Our understanding of the mechanism of action of CCH 
(remodeling of subdermal architecture) has evolved and suggests that CCH treatment could be of 
benefit to subjects with both cellulite and moderate to severe dermal laxity.  
Endo Pharmaceuticals Inc. (Endo), with support from aesthetic medicine specialists, is proposing 
the current study to investigate CCH in the treatment of cellulite in subjects with moderate to 
severe dermal laxity in buttocks and thighs, and to compare 2 different CCH injection 
techniques. These injection techniques are intended to further elucidate improved methods to 
treat the deep dimpling that often occurs with cellulite in the presence of dermal laxity.  


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2.2. 
Background 
Collagenases are proteinases that hydrolyze collagen in its native triple helical conformation 
under physiological conditions. To investigate the use of collagenases in the treatment of 
cellulite, Endo has developed a novel formulation of AUX-I and AUX-II referred to as CCH. 
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 cellulite 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; 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 detailed description of the chemistry, pharmacology, efficacy, and safety of CCH for use in the 
treatment of cellulite is provided in the Qwo™ package insert (Qwo Prescribing Information). 
2.3. 
Risk/Benefit Assessment 
The results of all Phase 2 and 3 studies conducted demonstrated a consistent effect of CCH in 
reducing the severity of cellulite. The results of 2 Phase 3 pivotal efficacy studies (Studies 
EN3835-302 and EN3835-303) established the efficacy of CCH administration in the treatment 
of moderate to severe cellulite in the buttocks of adult women when injected subcutaneously at a 
dose of 0.84 mg per treatment area every 21 days for 3 treatment visits. A treatment area was 
defined as a single buttock receiving up to 12 injections, 0.3 mL each (up to a total of 3.6 mL), of 
CCH. Two treatment areas (2 buttocks) were treated at each visit; a reduction in the severity of 
cellulite was observed as assessed by validated assessment scales as early as 21 days after 
administration of the first treatment session of CCH and was sustained throughout the 71-day 
double-blind study period. Furthermore, overall patient-reported satisfaction, emotional impact, 


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and visual appearance measures showed a greater and statistically significant improvement in the 
CCH group over the placebo group. The treatment-emergent adverse events (TEAEs) observed 
were predominantly localized injection site reactions that were nonserious, primarily mild to 
moderate in severity, transient, and decreased in frequency with each subsequent treatment 
session. 
More detailed information about the known and expected risks and reasonably expected AEs can 
be found in the Qwo™ package insert (Qwo Prescribing Information). 
. 






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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 2, open-label, randomized, parallel-group, multiple-dose, safety and effectiveness 
study designed to evaluate 2 different CCH dose concentrations and aliquot volumes delivered 
via uniform grid injection techniques in female subjects presenting with both mild to moderate 
cellulite and moderate to severe dermal laxity of the buttocks, or thighs, and with a body mass 
index (BMI) of 18 to < 29.9kg/m2 (normal or overweight).  
The primary objective of the study is to assess the effectiveness of CCH for the treatment of 
cellulite in the presence of dermal laxity using investigator assessment of improvement as 
measured by I-GAIS (Investigator Global Aesthetic Improvement Scale). At screening, cellulite 
severity will be assessed by the investigator using the Clinician-reported Photonumeric Cellulite 
Severity Scale (CR-PCSS), and severity of dermal laxity will be measured by the Hexsel CSS 
scale (Subsection D). Only subjects with a CR-PCSS score of only 2 or 3 will be included in the 
study. Subjects with a dermal laxity severity score of greater than 3 will be excluded. (Note: A 
dermal laxity severity score greater than 3 is defined as an appearance significantly worse than 
exhibited in the Hexsel CSS Subsection D severe image [score = 3].) 
Following determination of eligibility based on photography and Inclusion/Exclusion 
assessments, the investigator will propose each eligible subject for treatment of either both 
buttocks, or both thighs. The sponsor will confirm subject eligibility for treatment of the thighs 
or buttocks based on review of screening images of areas to be treated. Prior to randomization 
each eligible subject’s buttocks and thighs will be categorized into the following characteristic 
groups: mild cellulite with moderate dermal laxity, mild cellulite with severe dermal laxity, 
moderate cellulite with moderate dermal laxity and moderate cellulite with severe dermal laxity.  
This pre-randomization process will be used in an attempt to fill the desired categories as 
depicted in Table 2.  
Table 2: 
Intended Distribution of Subject Treatment Area Characteristics and 
Locations 
Criteria 
CR-PCSS 2  
(mild cellulite) 
CR-PCSS 3  
(moderate cellulite) 
Hexsel CSS Subsection D 2  
(moderate laxity) 
8 Buttocks  
8 Buttocks 
8 Thighs 
8 Thighs 
Hexsel CSS Subsection D 3  
(severe laxity) 
8 Buttocks 
8 Buttocks 
8 Thighs 
8 Thighs 
Total 
32 treatment areas 
32 treatment areas 
Note: A total of 32 subjects are expected to contribute a total of 64 treatment areas. Each subject’s 2 treatment areas 
may be allocated to different categories according to the severity of cellulite and severity of dermal laxity. 
Subjects will then be randomized to treatment with either Cohort A (Uniform 0.1-mL 1-Aliquot 
GRID injection technique) or Cohort B (Uniform 0.3-mL 2-Aliquot GRID injection technique) 
in a 1:1 ratio. 




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Therefore Endo, with support from aesthetic medicine specialists, proposes to investigate CCH 
in the treatment of cellulite with moderate to severe dermal laxity in buttocks and thighs, and to 
compare 2 different methods of CCH administration which are intended to further evaluate 
improved methods to treat the deep dimpling that often occurs with cellulite in the presence of 
dermal laxity. 
4.3. 
Justification for Dose 
The dosage of CCH chosen for this study is based on the data and experience from several earlier 
studies as well as the completed Phase 3 clinical studies. The dose of 1.68 mg (0.84 mg per 
region) has been shown to be safe and well-tolerated. The multiple doses of up to 6 treatment 
sessions are supported by the safety profile generated in previous Phase 2 and 3 studies as 
described above. 
4.4. 
End of Study Definition 
A subject is considered to have completed the study if the subject has completed the Day 180 
End of Study Visit. 
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 ≥ 18 and ≤ 55 years of age at the time of consent. 
2. Have a BMI of 18 to < 29.9 kg/m2. 
3. At the Screening Visit, have either both buttocks or both posterolateral thighs with: 
a. A score of 2 or 3 (mild or moderate cellulite) as reported by the investigator using the 
CR-PCSS, and 
b. a Hexsel CSS Subsection D “Grade of Laxity, Flaccidity, or Sagging Skin” score of 2 
or 3 (moderate or severe) as determined by the investigator.  
4. 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 for the 
duration of the study and for 28 days after any active treatment period. Acceptable forms 
of contraception include hormonal measures (oral contraceptive pills, contraceptive 
patch, contraceptive ring, and injections), intrauterine devices, double barrier method 
(condom plus diaphragm, condom or diaphragm plus spermicidal gel or foam), surgical 
sterilization of the male partner, and abstinence. 


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5. Be willing and able to comply with all protocol required visits and assessments, including 
eligibility photographs of the mid-back to mid- posterolateral-thigh taken during 
screening that will be submitted to a sponsor-designated reviewer to confirm eligibility 
(Section 8.1).  
6. Be willing to apply sunscreen to the treatment areas before each exposure to the sun for 
the duration of the study (from the Screening Visit through the Day 180/Early 
Termination Visit).  
7. 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.  
5.2. 
Subject Exclusion Criteria 
A subject is ineligible for study participation if, at the Screening Visit and on Study Day 1, the 
subject: 
1. Has a history of hypersensitivity or allergy to collagenase or any other excipient of CCH. 
Has concurrent diseases that might interfere with the conduct of the study, confound the 
interpretation of the study results, or endanger the participant’s well-being, (eg, evidence 
or history of malignancy, other than excised basal cell carcinoma and adequately treated 
squamous cell carcinoma of skin, unless there has been no recurrence in at least 5 years 
since treatment), or any significant hematological, endocrine, cardiovascular, respiratory, 
renal, hepatic, neurologic, psychiatric or gastrointestinal disease. If there is a history of 
such disease but the condition has been stable for more than 5 years and is judged by the 
investigator not to interfere with the participant’s participation in the study, the 
participant may be included, with the documented approval of the Medical Monitor. 
2. At the Screening Visit has a CR-PCSS score of less than 2 or greater than 3 for the area 
to be treated (buttocks or thighs) and/or has a Hexsel CSS Subsection D “Grade of 
Laxity, Flaccidity, or Sagging Skin” score of less than 2 or greater than 3 (severe) for the 
area to be treated (buttocks or thighs).  
3. Has a coagulation disorder which requires anticoagulant or antiplatelet medication during 
the study (except for ≤ 150 mg aspirin daily), or has taken anticoagulant or antiplatelet 
medication within 14 days before injection of study treatment (except for ≤ 150 mg 
aspirin daily).  
4. Is a prisoner, an individual with impaired decision making capacity, 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), or in the 
judgment of the investigator the subject is disadvantaged and vulnerable to coercion due 
to lack of education, or due to poor economic circumstances. 
5. Has participated in a previous investigational study of CCH, received any collagenase 
treatments at any time prior to treatment in this study and/or has received previous 
treatment with CCH for cellulite, or received treatment with an investigational product 
within 30 days (or 5 half-lives, whichever is longer) of the Screening Visit. 


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6. Is pregnant and/or is breast-feeding or plans to become pregnant and/or to breast-feed 
during the course of the study, or for 28 days after the last dose of study intervention. 
7. Has a history of scarring due to keloids or abnormal wound healing. 
8. Has any of the following local conditions in the areas to be treated (both buttocks or both 
thighs): 
a. History of lower extremity thrombosis or post-thrombosis syndrome. 
b. A current vascular disorder (eg, vasculitis, varicose veins, telangiectasia). 
c. Inflammation or active infection (including lesions that indicate an active infection).  
d. Active cutaneous alteration including but not limited to rash, eczema or psoriasis. 
e. A tattoo or other artificially inflicted body marker within 2 cm of any injection site. 
f. Has a mole located within 2 cm of any injection site.  
9. Has history of drug or alcohol abuse within the 5 years prior to the Screening Visit. 
10. Has evidence of clinically significant abnormalities, as judged by the investigator, in any 
of the following: physical examination findings, electrocardiogram (ECG), clinical 
laboratory values, or vital signs. The sponsor’s medical monitor will be required to 
review the results for confirmation of eligibility in the case of any of the following: 
abnormalities in ECGs indicating corrected QT interval (QTc) prolongation of 470 ms or 
greater, abnormalities in clinical laboratory values involving elevations above the normal 
range for alanine aminotransferase, total bilirubin, and aspartate aminotransferase.  
11. Has used any of the following for the treatment of cellulite on either thigh or either 
buttock within the specified timelines, 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 dosing with study treatment. 
b. Injections (eg, mesotherapy, dermal 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 cellulite 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 
cellulite during the 2-week period before injection of study treatment. 
12. Intends to initiate an intensive sport or exercise program during the study. 
13. Intends to initiate an intensive weight reduction program during the study.  
14. Has any other condition(s) that, in the investigator’s opinion, might indicate the 
participant to be unsuitable for the study. 


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15. For the subset of subjects participating in the collection of ultrasound data, the following 
exclusions will apply: subjects will be excluded who have: a history of a spinal 
laminectomy, a previous history or presence of vascular abnormalities (eg, deep vein 
thrombosis, thrombophlebitis), a healing fracture, an impaired sensation within, or near, 
the planned treatment area, or any implants within, or near, the planned treatment area. 
5.3. 
Lifestyle Considerations 
See Section 5.1 and Section 5.2. 
5.4. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in this study but are not 
subsequently treated. Eligibility confirmation by the sponsor or designee is required for this 
study (see Section 8.1). 
Subjects will be allowed to repeat any single screening assessment/procedure once, if necessary, 
if it is 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 can last up to 28 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(ia) was not met 
• Any AEs (including serious adverse events [SAEs]) experienced by the subject  
A subject who is a screen failure at the Screening Visit may be rescreened with approval from 
the sponsor. The subject must repeat all screening procedures. The period from the start of 
rescreening related procedures to the study treatment can last up to 28 days. Subjects may be 
rescreened only once; however subjects whose rescreening process was interrupted by 
COVID-19 related delays may be rescreened for a second time. 
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. 










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Additional information on preparation, handling, storage, and accountability of the study 
treatment is described in the Pharmacy Binder. 
6.5. 
Measures to Minimize Bias 
This is an open label study; however, the specific treatment taken by each subject will be 
randomly assigned using IRT.  
6.5.1. 
Interactive Response Technology 
The investigator or designee will utilize the 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. The 
IRT service provider will generate the randomization code and manage the implementation of 
randomization using the IRT system. Endo, the investigators and the subjects are not blinded to 
treatment assignment. 
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 for each site, 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.  
Accidental or intentional overdoses should be reported to the sponsor/designee promptly (see 
Section 8.5). 
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 30 days prior to the Screening Visit) and concomitant (taken from the 
Screening Visit through the End of Study Visit) medications and nondrug therapies (eg, blood 
transfusions, oxygen supplementation, physical therapy, etc) received will be recorded.  
In addition, all prior treatments for the disease/condition under study 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), 


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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 180 End of Study/Early Termination 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 cellulite (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 
cellulite. 
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. 
6.7.2. 
Rescue Medication 
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 must 
be stable before the subject can leave direct observation. 
6.8. 
Study Treatment Modification 
At any visit after Day 1, the investigator can choose not to continue treatment if there are 
moderate or severe ongoing injection site reactions in the overall treatment area or if there are no 
new areas to treat, or if the cellulite and laxity have sufficiently resolved. 


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7. 
DISCONTINUATION FROM STUDY TREATMENT AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment 
Subjects who discontinue from study treatment for any reason after the Day 1 dosing 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 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 140). 
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 QTc 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. 
If implications from COVID-19 cause subjects to miss study visits during the Treatment Phase 
additional subjects may be enrolled, at the discretion of the sponsor, in order to obtain a 
minimum of 24 subjects with sufficient efficacy assessments for overall objective and endpoint 
analysis purposes. 
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 yet tested. The 
investigator must document this in the site study records. 
A subject may 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). 
• The subject was lost to follow-up.  


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• 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.  
If implications from COVID-19 cause subjects to miss study visits during the Treatment Phase 
additional subjects may be enrolled, at the discretion of the sponsor, in order to obtain a 
minimum of 24 subjects with sufficient efficacy assessments for overall objective and endpoint 
analysis purposes. 
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. 
Subjects who have been lost to follow-up at any time after the first dose of study drug will not be 
replaced. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedule of Activities (Table 1). 
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. The details of activities outlined in the Study Operations 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. 
8.1. 
Eligibility Confirmation 
As part of eligibility confirmation investigators will submit photographs of either the thighs, or 
the buttocks, to the sponsor for consideration as an overall treatment area. The sponsor-
designated central reviewer will only review for the submitted treatment area. If the subject is 
determined to be ineligible by the central reviewers for the selected treatment area, the 
investigator may submit photographs of the other treatment area from the same subject for 
reconsideration of eligibility. The sponsor can provide additional clarification for reconsideration 
of eligibility of a subject. 
For these eligibility confirmation photographs, the subject will be in a consistent, standardized 
relaxed standing pose (ie, standing position with relaxed gluteus muscles), and will be wearing a 
standardized photographic garment. Specific instructions for taking the eligibility confirmation 
photographs as well as for providing them to, and receiving confirmation (or lack thereof) from 
the sponsor-designated reviewer will be provided in the Study Operations Manual.  
Inclusion/exclusion criteria will be re-reviewed at Visit 1 prior to dosing on Day 1. Only subjects 
deemed eligible by the sponsor-designated reviewer will be allowed to proceed with screening 
activities and receive study treatment. Subjects deemed ineligible in the overall submitted 
treatment area(s) by the sponsor-designated reviewer will be considered screen failures (note that 
at least 1 submitted treatment area must be determined as eligible for a subject to be enrolled). 
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.  
8.2. 
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 Study Operations Manual. During any COVID-19 
interruption remote efficacy assessments (I-GAIS, S-GAIS, Hexsel CSS Subsection D, Body-Q 
Appraisal of Cellulite, CR-PCSS-Buttock, CR-PCSS-Thigh, and 
 
are not allowed due to potential bias. 
8.2.1. 
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.  
8.2.1.1. 
Subject Global Aesthetic Improvement Scale  
The S-GAIS is a 7-level scale ranging from 3 (very much improved) to −3 (very much worse). 
Subjects will use the S-GAIS to determine the degree of improvement of each buttock or thigh 


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by comparing the cellulite from the Day 1 pretreatment (baseline) image of each buttock or each 
thigh to the images taken at the subsequent visits specified in the Schedule of Activities.  
8.2.1.2. 
Body-Q Appraisal of Cellulite 
The Body-Q Appraisal of Cellulite is a subset of questions from the Body-Q questionnaire that 
was developed to measure patient perceptions of weight loss and/or body contouring 
(Scott et al, 2012). The Body-Q Appraisal of Cellulite will be conducted at Days 1 and 180. 
8.2.1.3. 
Clinician-reported Photonumeric Cellulite Severity Scale - Buttock 
The CR-PCSS-Buttock will be used to assess the severity of cellulite of both treatment areas 
(each buttock, independently) at Screening to determine study eligibility. The CR-PCSS-Buttock 
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 each buttock 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. 
Investigators who are physicians will be trained and qualified on the use of the 
CR-PCSS-Buttock prior to assessing any subjects. 
8.2.1.4. 
Clinician-reported Photonumeric Cellulite Severity Scale - Thigh 
The CR-PCSS-Thigh will be used to assess the severity of cellulite of both treatment areas (each 
thigh, independently) at Screening to determine study eligibility. The CR-PCSS-Thigh 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 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. 
Investigators who are physicians will be trained and qualified on the use of the CR-PCSS-Thigh 
prior to assessing any subjects. 
8.2.1.5. 
Investigator Global Aesthetic Improvement Scale  
The I-GAIS is a 7-level scale ranging from 3 (very much improved) to −3 (very much worse). 
Investigators who are physicians will use the I-GAIS to determine the degree of improvement of 
each buttock or thigh by comparing the cellulite from the Day 1 pretreatment (baseline) image of 
each buttock or each thigh to the images taken at the subsequent visits specified in the Schedule 
of Activities.  
The I-GAIS assessments will be based on digital photographs, are performed separately for each 
of 2 treatment areas and must be completed before study intervention administration on those 
visits. At treatment visits, the photographs taken before marking the treatment areas will be used.  




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8.3.2. 
Physical Examination 
The complete physical examination will 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, extremities, and other 
systems or organs 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 examination findings for clinical significance. Any physical examination finding 
meeting the investigator’s or sponsor’s criteria for clinical significance will be recorded as an AE 
or SAE as appropriate. 
8.3.3. 
Height and Weight 
Height will be collected at screening only. Weight will be collected as outlined in the Schedule 
of Activities. 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). 
8.3.4. 
Fitzpatrick Skin Type 
The Fitzpatrick Skin Scale is a 6-level scale (levels I-VI) for assessment of skin color and 
propensity for tanning to categorize skin types. 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. 
8.3.5. 
Vital Signs 
Vital signs will be obtained 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, 28, 56, 84, 112, and 140), 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. It will not be necessary to 
measure the 15 and 30 minute vital signs time points from subjects who do not receive treatment 
during a treatment visit. 
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). 
8.3.6. 
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 


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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 a QTc prolongation of 470 ms or greater, the investigator should repeat 
the ECG within 1 hour. If the initial findings are confirmed, the investigator should 
exclude/withdraw the subject from study participation. The finding will be recorded as an AE 
and the subject will be withdrawn due to the AE. 
The investigator will review ECG results for clinical significance. Any ECG result meeting the 
investigator’s or sponsor’s criteria for clinical significance will be recorded as an AE (or SAE, if 
appropriate). 
8.3.7. 
Clinical Safety Laboratory Determinations 
Clinical safety laboratory tests will be conducted according to the Schedule of Activities. 
Required clinical laboratory tests are outlined in Section 10.2. Clinical safety laboratory tests 
will be performed by a designated central laboratory. Each site will be provided with instructions 
on specimen collection, preparation, packaging and transport. The results of the tests will be 
returned to the investigational sites.  
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. 
8.3.8. 
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. Results must be available prior to protocol 
mandated study treatment. 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 any further treatment and will have the pregnancy reported as per 
Section 8.4.5.  
For all female subjects of childbearing potential, the subject’s agreement to use contraception 
throughout their study participation (Screening Visit through the Day 180 Visit, or for a 
minimum of 28 days after the last dose of study treatment for subjects who terminate early) will 
be documented.  
8.4. 
Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Section 10.3. 


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All AEs, including both observed or volunteered problems, complaints, signs or symptoms 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. 
8.4.1. 
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 180/End of Study Visit or for 28 days after the last study treatment for 
those who early terminate. 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, 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. 
8.4.2. 
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.  
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. 
8.4.3. 
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. 


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8.4.4. 
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 
according to local regulatory requirements and sponsor policy, and forwarded to investigators as 
necessary.  
An investigator who receives an investigator safety report describing an 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. 
8.4.5. 
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 
dose of 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 Initial Pregnancy Report Form. Monitoring of the pregnancy should 
continue until conclusion of the pregnancy and follow-up information detailing the progress and 
outcome should be submitted on one or more Pregnancy Form(s). A Two Month Follow-Up 
Pregnancy Report form detailing the status of the infant should also 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.  
Subjects will be instructed to immediately notify the investigator of any pregnancies.  
A subject who becomes pregnant must immediately be discontinued from study treatment but 
may remain in the study if the investigator judges that the potential benefit to the subject 
outweighs any potential risk to the subject and/or the fetus, and the subject continues to give 
informed consent for further participation. The investigator should counsel the subject and 
discuss the risks of continuing with the pregnancy and the possible effects on the fetus.  
Attempts to obtain the pregnancy follow-up and pregnancy outcome information detailed above 
are necessary even if a subject discontinues treatment or withdraws from the study because of 
pregnancy. 


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8.4.6. 
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. 
8.4.7. 
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. 
8.5. 
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.  
8.6. 
Pharmacokinetics 
Not applicable. 
8.7. 
Pharmacodynamics 
Not applicable. 
8.8. 
Genetics 
Not applicable.  


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8.9. 
Biomarkers 
8.9.1. 
Immunogenicity Assessments 
Anti-AUX-I and anti-AUX-II antibodies and anti-AUX-I and anti-AUX-II neutralizing 
antibodies will be evaluated in samples (4-mL tubes of blood) collected from all subjects at times 
outlined in the Schedule of Activities. These samples will be tested by the sponsor or sponsor’s 
designee. The titer of confirmed positive samples will be reported. Other analyses may be 
performed to verify the stability of antibodies and/or further characterize the immunogenicity of 
study treatment. 
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 a separate document. 
De-identified immunogenicity samples may be stored for a maximum of 2 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 
treatment. 


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9. 
STATISTICAL CONSIDERATIONS AND METHODS 
9.1. 
Sample Size Determination 
The sample size for this exploratory Phase 2 study was based on the minimum number of 
treatment area assessments (N=64 treatment areas, among 32 subjects) that could contribute to an 
initial clinical evaluation of tolerability and response to CCH treatment in a population of 
subjects with both mild to moderate cellulite and moderate to severe dermal laxity. This 
population will also allow a comparison across the 2 randomized treatment arms that utilize a 
grid pattern for dosing. This study is not statistically powered to detect a difference in response 
across the 2 treatment cohorts. 
9.2. 
Populations for Analysis 
For the purposes of analysis, the following populations are defined: 
• The Safety Population is defined as all enrolled participants who received at least 1 
injection of CCH. All safety analyses will be based on this population. 
• The Intent-to-Treat (ITT) Population is defined as all enrolled participants who 
received at least 1 injection of CCH. 
• The Modified Intent-to-Treat (mITT) Population is defined as all ITT participants 
who have at least 1 valid I-GAIS assessment after an injection of CCH. All 
efficacy/effectiveness analysis will be based on this population.  
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 database 
lock. 
9.3.1. 
Efficacy Analysis 
Refer to the Statistical Analysis Plan for details of the efficacy analyses. 
9.3.1.1. 
Analyses of the Primary Efficacy Endpoint  
The proportion of subjects with improved (+1 or better) score on the I-GAIS for either buttock or 
either thigh at Day 180 will be summarized and its 95% CI will be provided. 
9.3.1.2. 
Analyses of Secondary Efficacy Endpoints 
For responder endpoints, the proportion of responders at each scheduled visit and its 95% CI at 
Day 180 will be provided. For change from baseline parameters, descriptive statistics (n, mean, 
SD, median, minimum and maximum) at each scheduled visit and 95% CI of the mean at 
Day 180 will be provided. 
9.3.1.3. 
Analyses of Tertiary Efficacy Endpoints 
All exploratory efficacy/effectiveness endpoints will be summarized using appropriate 
descriptive statistics by time point and treatment area. 


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9.3.2. 
Safety Analyses 
All subjects who receive at least 1 dose of study drug will be included in the safety analyses.  
Refer to the Statistical Analysis Plan for details of the Safety Analyses. 
9.3.2.1. 
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 TEAE events 
that are new in onset or aggravated in severity following treatment) will be included in all 
summaries. SAEs (including death) will be summarized. AESI incidence will be summarized.  
9.3.3. 
Other Analyses 
The incidence of subjects meeting specific potentially clinically important (PCIs) criteria for 
both vital signs and clinical safety laboratory results will be summarized. 
Anti-AUX-I and anti-AUX-II antibody levels and neutralizing antibody levels will be 
summarized using descriptive statistics for the actual value at the visit.  
9.4. 
Interim Analysis 
No interim analysis is planned for this study. 


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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 Code of Federal 
Regulations (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 practice (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 Pharmaceuticals Inc. 
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 Assurance Number will satisfy this requirement for 
IRBs in the United States).  
The study protocol, the informed consent form (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 Pharmaceuticals Inc. 
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 
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.  


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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.  
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. 


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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 may 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 
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. 


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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 Pharmaceuticals Inc. 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 Pharmaceuticals Inc. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
Hematology 
Biochemistry 
Urinalysis 
Hemoglobin 
Hematocrit 
Red blood cells 
White blood cells 
Platelets 
White blood cell differential 
Prothrombin time 
Glucose 
Sodium 
Potassium 
Calcium 
Chloride 
CO2 
Inorganic phosphate 
Blood urea nitrogen 
Creatinine 
Creatinine clearance (estimated)  
Aspartate transaminase (AST) 
Alanine transaminase (ALT) 
Gamma-glutamyl transferase (GGT) 
Total bilirubin (direct bilirubin reflex if elevated) 
Albumin 
Alkaline phosphatase (ALP) 
Uric acid 
Glucose 
Protein 
Specific gravity 
pH 
Ketones 
Bilirubin 
Urobilinogen 
Nitrite 
Blooda 
Leukocytesa 
a Microscopic examination will be performed if blood or leukocytes are detected by dipstick. 


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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 preexisting 
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 preexisting disease. 
• All clinically relevant laboratory abnormalities or physical findings that occur during 
the study. 
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). 
An 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: any form of cancer, 
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.  


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See Section 10.6 for laboratory tests that indicate severe liver injury (possible Hy’s Law) must be 
reported as an SAE. 
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. 
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 


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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 Day 180/End of study 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 180/End of 
Study Visit or until 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 the 
day 180/End of Study Visit or until 28 days after the last dose of study treatment for those who 
terminate early. SAEs that occur within 28 days, following cessation of the study treatment, or 
within 28 days, following premature discontinuation 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 sent via email (
) or fax (
).  
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 follow-up SAE 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. 


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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
See Section 5 and Section 8.3.8. 
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. 


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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  
ECG  
Electrocardiogram 
eCRF 
Electronic case report form 
FDA 
Food and Drug Administration 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed consent form 
ICH  
International Council for Harmonisation 
ID 
Identification 
IEC 
Independent Ethics Committee 
I-GAIS 
Investigator Global Aesthetic Improvement Scale  
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-treat 
mITT 
Modified intent-to-treat 
QTc 
Corrected QT interval 
SAE 
Serious adverse event 
S-GAIS 
Subject Global Aesthetic Improvement Scale  
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 Name of Investigator 
 


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12. 
REFERENCES 
Avram MM. Cellulite: a review of its physiology and treatment. J Cosmet Laser Ther. 
2004;6(4):181-185. 
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):233-237. 
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):1110-1114. 
DiBernardo BE. Treatment of cellulite using a 1440-nm pulsed laser with one-year follow-up. 
Aesthet Surg J. 2011;31(3):328-341. 
Dobke MK, Dibernardo B, Thompson RC, Usal H. Assessment of biomechanical skin 
properties: is cellulitic skin different? Aesthet Surg J. 2002; 22(3):260-6. 
doi:10.1067/maj.2002.124711 
Hexsel D, DalʹForno T, Hexsel C, et al. Magnetic Resonance Imaging of Cellulite Depressed 
Lesions Successfully Treated by Subcision. Dermatol Surg. 2016;42(5):693-696.  
Hexsel D, de Oliveira DalʹForno T, Cignachi S. Definition, clinical aspects, associated 
conditions, and differential diagnosis. In: Goldman MP, Bacci PA, Leibashoff G, Hexsel D, 
Angelini F, eds. Cellulite: Pathophysiology and Treatment. 1st ed. New York, NY: Taylor & 
Francis Group; 2006:7-28. 
Hexsel D. Body repair. In: Parish LC, Brenner S, Ramos-e-Silva M, eds. Women’s 
Dermatology: from Infancy to Maturity. 1st ed. New York: Parthenon Publishing Group; 
2001:586-595. 
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):1471-1477. 
Hexsel DM, Mazzuco R. Subcision: a treatment for cellulite. Int J Dermatol. 2000;39(7):539-
544. 
Khan MH, Victor F, Rao B, Sadick NS. Treatment of cellulite: Part II. Advances and 
controversies. J Am Acad Dermatol. 2010;62(3):373-384. 
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;10(3):161-168.  
Nürnberger F, Müller G. So-called cellulite: an invented disease. J Dermatol Surg Oncol. 
1978;4(3):221-229.  
Piérard GE, Nizet JL, Piérard-Franchimont C. Cellulite: from standing fat herniation to 
hypodermal stretch marks. Am J Dermatopath. 2000;22(1):34-37. 
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):118-124. 


EN3835-224 Protocol Amendment 1 
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Qwo [Prescribing Information]. Endo Aesthetics LLC: Malvern, PA; 2020. Accessed 
23 July 2020. https://d1skd172ik98el.cloudfront.net/48a33315-f594-4269-8043-
8853d10fb7bf/072f2aa5-dab8-4d49-91db-ec03748af061/072f2aa5-dab8-4d49-91db-
ec03748af061_source__v.pdf 
Rudolph C, Hladik C, Hamade H, et 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 
Scott AM, Pusic AL, Cano SJ, et al. The BODY-Q: A new patient reported outcome (PRO) 
measure for body contouring patients. Qual Life Res. 2012;20(suppl 1):74–75. 
 

SAP_001.pdf: 


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TABLE OF CONTENTS
1.
INTRODUCTION....................................................................................................8
2.
STUDY OBJECTIVES AND ENDPOINTS.............................................................8
3.
STUDY DESIGN AND MEASURES ......................................................................9
3.1.
Study Design ............................................................................................................9
3.1.1.
End-of-Study Definition .........................................................................................10
3.1.2.
Schedule of Activities.............................................................................................10
3.2.
Subject Inclusion Criteria .......................................................................................14
3.3.
Subject Exclusion Criteria ......................................................................................14
3.4.
Treatment Region and Treatment Area ...................................................................16
3.5.
Pre-Randomization of Samples into Four Groups ...................................................16
3.6.
Study Drug Administration.....................................................................................17
3.6.1.
Determination of Sample Size.................................................................................18
3.6.2.
Blinding and Randomization...................................................................................18
3.7.
Efficacy Assessments .............................................................................................18
3.7.1.
Subject and Investigator Cellulite Assessments.......................................................18
3.7.2.
Subject Global Aesthetic Improvement Scale (S-GAIS)..........................................19
3.7.3.
Investigator Global Aesthetic Improvement Scale (I-GAIS)....................................19
3.7.4.
Body-Q Appraisal of Cellulite ................................................................................20
3.7.5.
Clinician Reported Photonumeric Cellulite Severity Scale (CR-PCSS) –
Buttock...................................................................................................................20
3.7.6.
Clinician Reported Photonumeric Cellulite Severity Scale (CR-PCSS) –
Thigh......................................................................................................................21
3.7.7.
Hexsel Cellulite Severity Scale ...............................................................................21
3.7.8.
3.8.
Medical and Cellulite History.................................................................................24
3.9.
Substance Use ........................................................................................................24
3.10.
Prior/Concomitant Medications and Procedures......................................................24
3.10.1.
Prohibited Medications and Procedures ..................................................................24
3.11.
Adverse Events.......................................................................................................25
3.11.1.
Adverse Events (AE)..............................................................................................25


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3.11.2.
Serious Adverse Events (SAE) ...............................................................................25
3.11.3.
Adverse Events of Special Interest (AESI)..............................................................26
3.12.
Clinical Safety Laboratory Tests.............................................................................26
3.13.
Pregnancy Test .......................................................................................................26
3.14.
Body Height, Body Weight and BMI......................................................................27
3.15.
Vital Signs..............................................................................................................27
3.16.
Electrocardiogram ..................................................................................................27
3.17.
Physical Examination .............................................................................................27
3.18.
Immunogenicity......................................................................................................28
4.
STUDY PARAMETERS........................................................................................28
4.1.
Subject Disposition.................................................................................................28
4.2.
Demographics and Baseline Characteristics ............................................................29
4.3.
Protocol Deviations ................................................................................................29
4.4.
Prior/Concomitant Medications ..............................................................................29
4.5.
Prior Cellulite Treatment ........................................................................................30
4.6.
Efficacy Parameters................................................................................................30
4.6.1.
I-GAIS ...................................................................................................................30
4.6.1.1.
I-GAIS Ratings.......................................................................................................30
4.6.1.2.
One-Level I-GAIS Responder.................................................................................30
4.6.2.
S-GAIS...................................................................................................................31
4.6.2.1.
S-GAIS Ratings......................................................................................................31
4.6.2.2.
One-Level S-GAIS Responder for Either Buttock or Either Thigh ..........................31
4.6.3.
Body-Q Appraisal of Cellulite ................................................................................31
4.6.3.1.
Individual Item Ratings ..........................................................................................31
4.6.3.2.
Total Scores............................................................................................................31
4.6.4.
Hexsel CSS Subsection D Severity .........................................................................31
4.6.5.
4.7.
Safety Parameters ...................................................................................................32
4.7.1.
Adverse Events.......................................................................................................32
4.7.1.1.
Treatment Emergent Adverse Events......................................................................32
4.7.1.2.
Intensity of Adverse Events ....................................................................................32


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4.7.1.3.
Relationship to study drug ......................................................................................32
4.7.1.4.
Adverse Event Categorization by Treatment Session ..............................................33
4.7.2.
Vital Signs and Clinical Laboratories......................................................................33
4.7.2.1.
Laboratory Values ..................................................................................................33
4.7.2.2.
Vital Signs..............................................................................................................34
4.8.
Immunogenicity......................................................................................................34
5.
ANALYSIS POPULATIONS.................................................................................35
6.
STATISTICAL METHODS...................................................................................35
6.1.
General Methodology.............................................................................................35
6.2.
Derived Variables...................................................................................................36
6.3.
Handling of Missing Data.......................................................................................38
6.3.1.
Imputation of Partial Dates .....................................................................................38
6.3.1.1.
TEAE Status for Completely Unknown Start Date..................................................38
6.3.1.2.
Concomitant Status of Medication for Completely Unknown Start Date .................38
6.3.1.3.
Missing Cellulite Onset Date ..................................................................................39
6.3.1.4.
Missing Last Menstrual Date ..................................................................................39
6.4.
Interim Analysis .....................................................................................................39
7.
STATISTICAL ANALYSES..................................................................................39
7.1.
Subject Disposition.................................................................................................39
7.2.
Protocol Deviations ................................................................................................39
7.3.
Demographics and Baseline Characteristics ............................................................40
7.4.
Medical and Surgical History..................................................................................40
7.5.
Cellulite History .....................................................................................................40
7.6.
Prior/Concomitant Medications and Procedures......................................................41
7.7.
Efficacy Analyses...................................................................................................41
7.7.1.
Primary Efficacy Endpoint......................................................................................41
7.7.1.1.
One-level I-GAIS Responders ................................................................................41
7.7.2.
Secondary Efficacy Endpoints ................................................................................41
7.7.2.1.
One-level I-GAIS Responders by Visit ...................................................................41
7.7.2.2.
One-level S-GAIS Responders by Visit ..................................................................41
7.7.2.3.
Change from baseline in Body-Q -Appraisal of Cellulite Total Score by Visit ........42
7.7.2.4.
Change from baseline in Hexsel CSS Subsection D Score by Visit .........................42
7.7.3.
Exploratory Efficacy Endpoints ..............................................................................42






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LIST OF ABBREVIATIONS
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine transaminase
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
CCH
Collagenase clostridium histolyticum
CI
Confidence Interval
CR-PCSS
Clinician-reported Photonumeric Cellulite Severity Scale
CSS
Cellulite Severity Scale
ECG
Electrocardiogram
eCRF
Electronic case report form
ET
Early Termination
I-GAIS
Investigator Global Aesthetic Improvement Scale
S-GAIS
Subject Global Aesthetic Improvement Scale
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
MedDRA
Medical Dictionary for Regulatory Activities
PCI
Potentially Clinically Important
PT
Preferred Term
QTc
Corrected QT interval
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
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 safety and 
efficacy of collagenase clostridium histolyticum (CCH) in adult women with mild or moderate 
cellulite and moderate to severe dermal laxity. 
General information about the study is described in the EN3835-224 Clinical Study Protocol, 
protocol amendment dated December 3, 2020.(1)
2.
STUDY OBJECTIVES AND ENDPOINTS
The primary, secondary, and exploratory objectives and corresponding endpoints are outlined in
Table 1 below.
Table 1:
Objectives and Endpoints
Objectives
Endpoints
Primary

To assess the efficacy of CCH for the treatment of 
cellulite in the presence of dermal laxity using the 
Investigator Global Aesthetic Improvement Scale 
(I-GAIS).

Proportion of one-level responders (+1 or better 
score) on the I-GAIS for either buttock or either 
thigh at Day 180.
Secondary

To assess the efficacy of CCH for the treatment of 
cellulite in the presence of dermal laxity using the I-
GAIS.

Proportion of one-level responders (+1 or better 
score) on the I-GAIS for either buttock or either 
thigh at Study Days 28, 56, 84, 112, and 140.

I-GAIS ratings at Study Days 28, 56, 84, 112, 
140, and 180.

To assess the efficacy of CCH for the treatment of 
cellulite in the presence of dermal laxity using subject 
assessments.

Proportion of one-level responders (+1 or better 
score) on the Subject Global Aesthetic 
Improvement Scale (S-GAIS) for either buttock or 
either thigh at Study Days 28, 56, 84, 112, 140, 
and 180.

The Change from baseline to Day 180 in the 
Body-Q Appraisal of the individual item cellulite 
scores and total score.

To assess the effectiveness of CCH for the treatment 
of cellulite in the presence of dermal laxity using 
Subsection D of the Hexsel Cellulite Severity Scale 
(CSS).

The Change from baseline to each Study Visit 
(Day 28 through the Day 180 Visit) in Hexsel 
CSS Subsection D severity score.

To assess the safety and tolerability of CCH for the 
treatment of cellulite in the presence of dermal laxity.

Proportion (incidence) of subjects reporting each 
adverse event (AE), treatment-emergent adverse 
event (TEAE), treatment-related AE, and adverse 
event of special interest (AESI). Change from 
baseline reported at each visit for vital signs, 
potentially clinically important vital signs, clinical 
laboratory tests, and potentially clinically 
important laboratory tests.












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3.2.
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 ≥ 18 and ≤ 55 years of age at the time of consent.
2. Have a body mass index (BMI) of 18 to < 29.9 kg/m2.
3. At the Screening Visit, have either both buttocks or both posterolateral thighs with:
a.
A score of 2 or 3 (mild or moderate cellulite) as reported by the investigator using the 
CR-PCSS, and
b. a Hexsel CSS Subsection D “Grade of Laxity, Flaccidity, or Sagging Skin” score of 2 
or 3 (moderate or severe) as determined by the investigator.
4. 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 for the 
duration of the study and for 28 days after any active treatment period. Acceptable forms 
of contraception include hormonal measures (oral contraceptive pills, contraceptive 
patch, contraceptive ring, and injections), intrauterine devices, double barrier method 
(condom plus diaphragm, condom or diaphragm plus spermicidal gel or foam), surgical 
sterilization of the male partner, and abstinence.
5. Be willing and able to comply with all protocol required visits and assessments, including 
eligibility photographs of the mid-back to mid- posterolateral-thigh taken during 
screening that will be submitted to a sponsor designated reviewer to confirm eligibility.
6. Be willing to apply sunscreen to the treatment areas before each exposure to the sun for 
the duration of the study (from the Screening Visit through the Day 180/early termination 
[ET] Visit).
7. Be adequately informed and understand the nature and risks of the study and be able to 
provide consent.
3.3.
Subject Exclusion Criteria
A subject is ineligible for study participation if, at the Screening Visit and on Study Day 1, the 
subject:
1. Has a history of hypersensitivity or allergy to collagenase or any other excipient of CCH. 
Has concurrent diseases that might interfere with the conduct of the study, confound the 
interpretation of the study results, or endanger the participant’s well-being, (eg, evidence 
or history of malignancy, other than excised basal cell carcinoma and adequately treated 
squamous cell carcinoma of skin, unless there has been no recurrence in at least 5 years 
since treatment, or any significant hematological, endocrine, cardiovascular, respiratory, 
renal, hepatic, neurologic, psychiatric or gastrointestinal disease). If there is a history of 
such disease but the condition has been stable for more than 5 years and is judged by the 


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investigator not to interfere with the participant’s participation in the study, the 
participant may be included, with the documented approval of the Medical Monitor.
2. At the Screening Visit has a CR-PCSS score of less than 2 or greater than 3 for the area 
to be treated (buttocks or thighs) and/or has a Hexsel CSS Subsection D “Grade of 
Laxity, Flaccidity, or Sagging Skin” score of less than 2 or greater than 3 (severe) for the 
area to be treated (buttocks or thighs).
3. Has a coagulation disorder which requires anticoagulant or antiplatelet medication during 
the study (except for ≤ 150 mg aspirin daily), or has taken anticoagulant or antiplatelet 
medication within 14 days before injection of study treatment (except for ≤ 150 mg 
aspirin daily).
4. Is a prisoner, an individual with impaired decision making capacity, 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), or in the 
judgment of the investigator the subject is disadvantaged and vulnerable to coercion due 
to lack of education, or due to poor economic circumstances.
5. Has participated in a previous investigational study of CCH, received any collagenase 
treatments at any time prior to treatment in this study and/or has received previous 
treatment with CCH for cellulite, or received treatment with an investigational product 
within 30 days (or 5 half-lives, whichever is longer) of the Screening Visit.
6. Is pregnant and/or is breast-feeding or plans to become pregnant and/or to breast-feed 
during the course of the study, or for 28 days after the last dose of study intervention.
7. Has a history of scarring due to keloids or abnormal wound healing.
8. Has any of the following local conditions in the areas to be treated (both buttocks or both 
thighs):
a.
History of lower extremity thrombosis or post-thrombosis syndrome.
b. A current vascular disorder (eg, vasculitis, varicose veins, telangiectasia).
c.
Inflammation or active infection (including lesions that indicate an active infection).
d. Active cutaneous alteration including but not limited to rash, eczema or psoriasis.
e.
A tattoo or other artificially inflicted body marker within 2 cm of any injection site.
f.
Has a mole located within 2 cm of any injection site.
9. Has history of drug or alcohol abuse within the 5 years prior to the Screening Visit.
10. Has evidence of clinically significant abnormalities, as judged by the investigator, in any 
of the following: physical examination findings, electrocardiogram (ECG), clinical 
laboratory values, or vital signs. The sponsor’s medical monitor will be required to 
review the results for confirmation of eligibility in the case of any of the following: 
abnormalities in ECGs indicating corrected QT interval (QTc) prolongation of 470 ms or 
greater, abnormalities in clinical laboratory values involving elevations above the normal 
range for alanine aminotransferase, total bilirubin, and aspartate aminotransferase.


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11. Has used any of the following for the treatment of cellulite on either thigh or either 
buttock within the specified timelines, 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 dosing with study treatment.
b. Injections (eg, mesotherapy, dermal 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 cellulite 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 
cellulite during the 2-week period before injection of study treatment.
12. Intends to initiate an intensive sport or exercise program during the study.
13. Intends to initiate an intensive weight reduction program during the study.
14. Has any other condition(s) that, in the investigator’s opinion, might indicate the 
participant to be unsuitable for the study.
15. For the subset of subjects participating in the collection of ultrasound data, the following 
exclusions will apply: subjects will be excluded who have: a history of a spinal 
laminectomy, a previous history or presence of vascular abnormalities (eg, deep vein 
thrombosis, thrombophlebitis), a healing fracture, an impaired sensation within, or near, 
the planned treatment area, or any implants within, or near, the planned treatment area.
3.4.
Treatment Region and Treatment Area
Treatment region is defined as either 2 buttocks or 2 thighs. Treatment area is defined as each 
buttock or thigh. None of the subjects will be treated in both buttock and thigh areas.
3.5.
Pre-Randomization of Samples into Four Groups
All subjects must have the following:

a cellulite score of 2 (mild) or 3 (moderate) on the CR-PCSS assessment and

a dermal laxity score of 2 (moderate) or 3 (severe) on the Hexsel CSS Subsection D 
assessment.
Once a subject’s treatment areas are classified to the defined categories, pre-randomization will 
be performed with the interactive response technology (IRT) cohort management module. Pre-
randomization will be used to manage recruitment such that approximately equivalent numbers 
of subjects are enrolled for treatment of buttocks vs thighs, mild vs moderate cellulite, and 
moderate vs severe dermal laxity.






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personnel in the room. Investigators will be instructed not to verbalize their ratings while in the 
presence of the subject and vice versa.
3.7.2.
Subject Global Aesthetic Improvement Scale (S-GAIS)
The S-GAIS is a 7-level scale (Table 5) ranging from +3 (very much improved) to -3 (very much 
worse). Subjects will use the S-GAIS to determine the degree of improvement of each buttock or 
thigh by comparing the cellulite from the Day 1 pretreatment (baseline) image of each buttock or 
each thigh to the images taken at the subsequent visits (Days 28, 56, 84, 112, 140 and 180/ET) 
specified in the Schedule of Activities (Table 2). 
S-GAIS assessments, which will be based on digital photographs and will be performed 
separately for each of 2 treatment areas and must be completed before study intervention 
administration on the scheduled visits. At treatment visits, the photographs taken before marking 
the treatment areas will be used.
Table 5:
S-GAIS Scale
Rating
Response Option
Description
+3
Very much improved
My treated cellulite looks very much better.
+2
Much improved
My treated cellulite looks much better, but additional treatment would 
slightly improve the result.
+1
Improved
My treated cellulite looks better, but additional treatment is necessary. 
  0
No change
My treated cellulite looks essentially the same as it did originally. 
-1
Worse
My treated cellulite looks worse than it did originally.
-2
Much worse
My treated cellulite looks much worse than it did originally.
-3
Very much worse
My treated cellulite looks very much worse than it did originally. 
3.7.3.
Investigator Global Aesthetic Improvement Scale (I-GAIS)
The I-GAIS is a 7-level scale (Table 6) ranging from +3 (very much improved) to -3 (very much 
worse). Investigators who are physicians will use the I-GAIS to determine the degree of 
improvement of each buttock or thigh by comparing the cellulite from the Day 1 pretreatment 
(baseline) image of each buttock or each thigh to the images taken at the subsequent visits 
(Days 28, 56, 84, 112, 140 and 180/ET) specified in the Schedule of Activities (Table 2).
The I-GAIS assessments will be based on digital photographs, are performed separately for each 
of 2 treatment areas and must be completed before study intervention administration on those 
visits. At treatment visits, the photographs taken before marking the treatment areas will be used.


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Table 6:
I-GAIS Scale
Rating
Response Option
Description
+3
Very Much Improved
Optimal cosmetic result from treatment of the treated dimples.
+2
Much Improved
Marked improvement in the treated area appearance from before treatment, 
but not completely optimal.
+1
Improved
Obvious improvement in the treated area appearance from before treatment, 
but additional treatment is indicated.
  0
No Change
The treated area appearance is essentially the same as before treatment.
-1
Worse
The treated area appearance is worse than before treatment.
-2
Much Worse
Marked worsening in appearance from the initial condition.
-3
Very Much Worse
Obvious worsening in appearance from the initial condition.
3.7.4.
Body-Q Appraisal of Cellulite
The Body-Q Appraisal of Cellulite is a subset of questions from the Body-Q questionnaire that 
was developed to measure patient perceptions of weight loss and/or body contouring.(2) The 
Body-Q Appraisal of Cellulite in this study consists of 11 questions (see Table 7) which are 
based on how subjects are bothered by their cellulite, and the responses will be collected using a 
4-level scale. The ratings range from 1 (Extremely bothered) to 4 (Not at all bothered). Subjects 
will complete this questionnaire at Day 1 and Day 180/ET Visits.
The Body-Q Appraisal of Cellulite will be completed prior to any investigator cellulite 
assessments (CR-PCSS, I-GAIS, 
Table 7:
Body-Q Appraisal of Cellulite Questions and Responses
Extremely 
bothered
Moderately 
bothered
A little 
bothered
Not at all 
bothered
1. Having to dress in a way to hide your cellulite?
1
2
3
4
2. How deep the dimpling in your cellulite looks?
1
2
3
4
3. Not being able to wear certain clothes because of 
your cellulite?
1
2
3
4
4. How noticeable your cellulite is?
1
2
3
4
5. How lumpy your cellulite looks?
1
2
3
4
6. The amount of dimpling in your cellulite?
1
2
3
4
7. The amount of cellulite you have?
1
2
3
4
8. How the skin where you have cellulite looks (not as 
smooth as you would like)?
1
2
3
4
9. People seeing your cellulite?
1
2
3
4
10. How your cellulite looks up close?
1
2
3
4
11. How your cellulite looks when you are naked?
1
2
3
4
3.7.5.
Clinician Reported Photonumeric Cellulite Severity Scale (CR-PCSS) – Buttock
The CR-PCSS-Buttock will be used to assess the severity of cellulite of both buttocks (each 
buttock, independently) at Screening to determine study eligibility. The CR-PCSS-Buttock is a 


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5-level photonumeric scale developed specifically for clinicians and used by the investigator to 
assess the severity of the subject’s cellulite in each buttock by live assessments (Table 8). 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.
Investigators who are physicians will be trained and qualified on the use of the CR-PCSS-
Buttock prior to assessing any subjects.
Table 8:
CR-PCSS - Buttock
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.
3.7.6.
Clinician Reported Photonumeric Cellulite Severity Scale (CR-PCSS) – Thigh
The CR-PCSS-Thigh will be used to assess the severity of cellulite of both thighs (each thigh, 
independently) at Screening to determine study eligibility. The CR-PCSS-Thigh 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 each thigh by live assessments (Table 9). 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.
Investigators who are physicians will be trained and qualified on the use of the CR-PCSS-Thigh 
prior to assessing any subjects.
Table 9:
CR-PCSS - Thigh
Rating
Level of Severity
Description
0
None
No depressions or raised area.
1
Almost None
A few depressions or undulations that are mostly superficial in depth.
2
Mild
Several undulations that are shallow in depth with areas of slight 
Protuberances.
3
Moderate
Many undulations with alternating areas of protuberances and depressions, 
of which most are moderate in depth.
4
Severe
A lot of undulations with alternating areas of protuberances and
depressions, some of more severe depth.
3.7.7.
Hexsel Cellulite Severity Scale
The Hexsel CSS is a photonumeric scale that looks at 5 key morphologic features of cellulite (3):
A - Number of evident depressions.
B - Depth of depressions.






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3.8.
Medical and Cellulite History
A medical and cellulite history of the subject will be taken during 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 of medical history 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 completed at any time in the treatment areas.
3.9.
Substance Use
History of tobacco and alcohol use will also be taken during the Screening period and the 
following information will be recorded:

Type of substance (Alcohol/Tobacco/Illegal Drug).

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 medications and nondrug therapies (eg, blood transfusions, oxygen supplementation, 
physical therapy, etc) taken prior to the Screening Visit or any concomitant medications or 
nondrug therapies received from the Screening Visit through the End of Study (EOS) Visit will 
be recorded.
In addition, all prior treatments (including medications and procedures) for cellulite 
disease/condition under study will be recorded with start and stop date; and, where appropriate 
dose, unit, frequency and route of administration.
3.10.1.
Prohibited Medications and Procedures
The following medications and procedures are not allowed during the course of the study (from 
the Screening Visit through the Day 180 Visit):

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 180 /ET Visit):

Liposuction.

Any injectable treatment (eg, KYBELLA) or any similar treatment that could destroy 
fat cells and/or remove fat deposits.


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
Injections (eg, mesotherapy); radiofrequency device treatments; laser treatment; 
buttock implant treatment; cryolipolysis; or surgery (including subcision and/or 
powered subcision).

Any investigational treatment for cellulite (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 
cellulite.
3.11.
Adverse Events
All AEs and serious adverse events (SAEs) will be collected by the investigator from the time of 
signing the informed consent through the Day 180 Visit or for 28 days after the last study 
treatment for those who terminate early.
3.11.1.
Adverse Events (AE)
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 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.

Conditions present at baseline that worsen after initiation of study treatment will be 
captured as an AE; the onset date will be the date the event worsened.

All clinically relevant laboratory abnormalities or physical findings that occur during 
the study.
3.11.2.
Serious Adverse Events (SAE)
Serious adverse event 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. 


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
Any important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above.
3.11.3.
Adverse Events of Special Interest (AESI)
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.
3.12.
Clinical Safety Laboratory Tests
Blood and urine samples will be collected for testing the following clinical laboratory parameters 
at Screening, and Day 180/ET Visit.
Table 14:
Clinical Laboratory parameters
Hematology
Biochemistry
Urinalysis
Hemoglobin
Hematocrit
Red blood cells
White blood cells
Platelets
White blood cell differential
Prothrombin time
Glucose
Sodium
Potassium
Calcium
Chloride
CO2
Inorganic phosphate
Blood urea nitrogen
Creatinine
Creatinine clearance (estimated)
Aspartate transaminase (AST)
Alanine transaminase (ALT)
Gamma-glutamyl transferase (GGT)
Total bilirubin (direct bilirubin 
reflex if elevated)
Albumin
Alkaline phosphatase (ALP)
Uric acid
Glucose
Protein
Specific gravity
pH
Ketones
Bilirubin
Urobilinogen
Nitrite
Blooda
Leukocytesa
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.
3.13.
Pregnancy Test
All female subjects of childbearing potential must have a negative pregnancy test at Screening 
and Day 1 to be enrolled in the study. Female subjects of child bearing potential will undergo a 


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serum pregnancy test at the Screening Visit and 180/ET Visit and urine pregnancy tests at 
Days 1, 28, 56, 84, 112, and 140 visits. Any female subject that becomes pregnant during the 
study will be immediately withdrawn from treatment and will have the pregnancy reported.
3.14.
Body Height, Body Weight and BMI
Height and body weight measurements will be taken at screening. Body weight will also be 
measured at the Days 1 and 180/ET Visits. BMI will be calculated using the height at screening 
and weight at respective visits. Refer to Table 19 for BMI derivation.
3.15.
Vital Signs
Vital signs measurements include systolic and diastolic blood pressure, respiratory rate, pulse 
rate, and body temperature. Vital signs measurements will be taken at the Screening, Days 1, 28, 
56, 84, 112, 140 and 180/ET Visits. On treatment visits (Days 1, 28, 56, 84, 112, and 140), vital 
signs will be assessed at 4 hours prior to, and at 15 and 30 minutes after study drug 
administration (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.
The investigator will review all vital sign values for clinical significance. Any clinically
significant abnormality in vital sign observed will be considered as an AE or SAE as appropriate.
3.16.
Electrocardiogram
A 12-Lead ECG will be recorded during screening while the subject is in a supine position for at 
least 5 minutes before the recording is conducted.
ECGs will be assessed 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.
3.17.
Physical Examination
The complete physical examination (by body system) will be performed at the Screening and 
Day 180/ET Visit. Physical examination will 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, extremities, and other 
systems or organs of note. Physical examination findings will be recorded as normal, abnormal 
or not done as not standard of care.
Any clinically significant abnormality in physical examination observed will be considered as an
AE or SAE as appropriate.


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The subject’s skin type and propensity for tanning will be assessed at screening using the
Fitzpatrick scale (6-level scale [levels I-VI]) shown below:
Table 15:
Fitzpatrick Scale
Level
Description
I
Pale white skin, blue/hazel eyes, blond/red hair; Always burns, does not tan
II
Fair skin, blue eyes; Burns easily, tans poorly
III
Darker white skin; Tans after initial burn
IV
Light brown skin; Burns minimally, tans easily
V
Brown skin; Rarely burns, tans darkly easily
VI
Dark brown or black skin; Never burns, always tans darkly
3.18.
Immunogenicity
Immunogenicity variables include anti-AUX-I /anti-AUX-II binding antibodies (ie, anti-drug 
antibodies) and neutralizing antibody results. Serum samples will be collected at the Day 1 Visit 
(prior to study treatment administration) and at the Day 180/ET Visit for the determination of 
serum anti-AUX-I and anti-AUX-II antibody levels and neutralizing antibodies to AUX-I and 
AUX-II.
4.
STUDY PARAMETERS
4.1.
Subject Disposition
A subject will be considered to have completed the study if they complete the Day 180 Visit. 
Subjects who discontinue from study treatment or withdraw from the study for any reason after 
the Day 1 dosing 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. 
If a subject withdraws from the study, all ET procedures should be conducted as detailed in the 
Schedule of Activities. The reason and date for early withdrawal will be recorded in the eCRF 
for subjects who do not complete the study. 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. 
Subjects who have been withdrawn from the study at any time after the first dose of study 
treatment will not be replaced. The reason for screen failure will also be recorded in eCRF for 
subjects who sign consent but do not receive any dose of study treatment.
If implications from COVID-19 cause subjects to miss study visits during the Treatment Phase 
additional subjects may be enrolled, at the discretion of the sponsor, in order to obtain a 
minimum of 24 subjects with sufficient efficacy assessments for overall objective and endpoint 
analysis purposes.


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4.2.
Demographics and Baseline Characteristics
Demographics and baseline characteristics include the following parameters:

Age.

Height (at Screening).

Body weight (at Screening).

BMI in kg/m2 (at Screening).

Gender.

Race.

Ethnicity.

Time since last menstrual period.

CR-PCSS cellulite severity ratings for thigh and buttock at Screening.

Hexsel CSS Section D (laxity, flaccidity or sagging of skin) scores at Screening.

Skin category based on Fitzpatrick scale assessment.

Report of substance use

Alcohol use (Never, Current, and Former).

Tobacco use (Never, Current, and Former).

Illegal Drug use (Never, Current, and Former).
4.3.
Protocol Deviations
Protocol deviations will be identified and documented prior to database lock. Protocol deviations 
may be derived from the eCRF data, electronic vendor data, and from the clinical monitoring 
reports. All deviations from these sources will be reconciled and duplicate deviations will be 
removed. 
Possible protocol 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 of 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.
4.4.
Prior/Concomitant Medications
All medications will be coded using World Health Organization (WHO) Drug Dictionary, by 
active ingredient and WHO anatomical therapeutic chemical (ATC) classification of ingredients.
A prior medication is defined as any medication taken prior to the Screening Visit.


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A concomitant medication (or non-drug therapy) is any medication (or therapy) taken on or after 
the Screening Visit through the Day 180 Visit or the medication is reported as ongoing.
Please note that if a medication started prior to Screening and end date is after 
Screening/ongoing it will be counted as both prior and concomitant medication.
4.5.
Prior Cellulite Treatment
Prior cellulite 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’ prior to the Screening Visit, then the
medication or procedure will be considered a prior cellulite treatment.
All cellulite treatment medications will be classified as cellulite Drug. All cellulite treatment 
procedures will be classified into one of the following groups:

Liposuction.

Surgery (including subcision and/or powered subcision).

Laser.

Massage.

Radiofrequency.

Mesotherapy.

Cream.

Other.
The classification will be reviewed and approved by the study medical monitor. Any cellulite 
treatment used after the Day 1 visit will be noted and reported as a protocol deviation.
4.6.
Efficacy Parameters
4.6.1.
I-GAIS
4.6.1.1.
I-GAIS Ratings
The I-GAIS rating is directly obtained from the investigator’s assessments at an analysis visit 
(Day 28, Day 56, Day 84, Day 112, Day 140, Day 180 and Last [see the definition of Last in
Table 19]).
4.6.1.2.
One-Level I-GAIS Responder 
One-level I-GAIS Responder for a treatment area (left buttock, right buttock, left thigh, or right 
thigh) is defined as any subject with an improved (+1, +2 or +3) score on the I-GAIS at an 
analysis visit for that treatment area.
One-level I-GAIS Responder for either buttock is defined as any buttock-treated subject with an 
improved (+1, +2 or +3) score on the I-GAIS for at least one buttock at an analysis visit.
One-level I-GAIS Responder for either thigh is defined as any thigh-treated subject with an 
improved (+1, +2 or +3) score on I-GAIS for at least one thigh at an analysis visit.






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Any missing relationship of an AE to study drug will be considered as related to study drug for 
the analyses, following worst-case principle.
4.7.1.4.
Adverse Event Categorization by Treatment Session
The AEs will be associated with the treatment session based on the start date of the AE 
compared to date of treatment sessions, as below:

Treatment session 1: First injection date until start of next treatment session or end of 
study visit if no treatment after treatment session 1.

Treatment session 2: Date of second treatment session until start of next treatment 
session or end of study visit if no treatment after treatment session 2.

Treatment session 3: Date of third treatment session until start of next treatment 
session or end of study visit if no treatment after treatment session 3.

Treatment session 4: Date of fourth treatment session until start of next treatment 
session or end of study visit if no treatment after treatment session 4.

Treatment session 5: Date of fifth treatment session until start of sixth treatment 
session or end of study visit if no treatment after treatment session 5.

Treatment session 6: Sixth injection date until start of Day 180/ET Visit.
Note: For adverse events by treatment session, Treatment Session y, where y denotes 1, 2, 3, 4, 
5, 6 refers to a period of time from the start date of the study drug given at that treatment session 
to the end of the day before the next treatment session, or the end of study if no study drug was 
given after Treatment Session y. Therefore, Treatment Session y varies among subjects in study.
4.7.2.
Vital Signs and Clinical Laboratories
4.7.2.1.
Laboratory Values
Clinical laboratory data (hematology and chemistry only) will be analyzed for observed value 
and change from baseline to Last. Refer to Table 19 for definition of baseline and Last.
In addition, subjects reporting any sponsor-defined Potentially Clinically Important (PCI) 
laboratory values during the study will be analyzed.
PCI laboratory values are presented in Table 16 below.


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Table 16:
Potentially Clinically Important Laboratory values
Parameter
PCI Low: Less than or equal to
PCI High: Greater than or equal to
Hemoglobin (g/L)
100
190
Hematocrit (%)
30
60
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 transaminase; AST=Aspartate transaminase; BUN=Blood urea nitrogen; ULN=Upper limit of 
normal.
4.7.2.2.
Vital Signs 
Vital signs will be analyzed for observed value and change from baseline separately for vital 
signs on injection days and vital signs at each visit (excluding post injection time points on 
injection days). Refer to Table 19 for the definition of baseline.
In addition, subjects reporting any sponsor-defined PCI vital sign values during the study will be 
analyzed.
Vital sign values are PCI if they meet both the observed value criteria and the change from 
baseline criteria. The PCI vital sign values are presented in Table 17 below.
Table 17:
Potentially Clinically Important Vital Sign Criteria
Parameter
PCI Low
PCI High
Systolic blood pressure
≤90 mmHg and decrease ≥20 mmHg 
from baseline
≥180 mmHg and increase ≥20 mm Hg 
from baseline
Diastolic blood pressure
≤50 mmHg and decrease ≥15 mmHg 
from baseline
≥105 mmHg and increase ≥15 mmHg 
from baseline
Pulse rate
≤50 bpm and decrease ≥15 bpm from 
baseline
≥120 bpm and increase ≥15 bpm from 
baseline
Respiratory Rate
≤8 brpm and decrease ≥7 brpm from 
baseline
≥25 brpm and increase ≥7 brpm from 
baseline
Temperature
≥38.3°C and increase ≥1.1°C from 
baseline
bpm=Beats per minute; brpm=Breaths per minute.
4.8.
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.


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5.
ANALYSIS POPULATIONS
The study will use the following analysis populations for data summaries.
Table 18:
Analysis Populations
Population
Definition
Analysis
Safety Population
Safety Population is defined as all 
enrolled participants who received 
at least 1 injection of CCH. 
All demographic, baseline 
characteristics and safety 
parameters will be summarized 
based on this population.
Intent-to-Treat (ITT)
The Intent-to-Treat (ITT) 
Population is defined as all enrolled 
participants who received at least 1 
injection of CCH.
Modified Intent-to-Treat (mITT)
The Modified Intent-to-Treat 
(mITT) Population is defined as all 
ITT participants who have at least 1 
valid I-GAIS assessment after an 
injection of CCH.
All efficacy/effectiveness analysis 
will be based on this population.
6.
STATISTICAL METHODS
6.1.
General Methodology
All statistical tests, summary tables and data listings will be prepared using SAS version 9.3 or 
higher.
All statistical tests will be performed with a significance level of α=0.05, unless specified 
otherwise and will be supported by presenting estimates and 95% confidence intervals (CI). 
Continuous data will be summarized using descriptive statistics. Discrete data will be 
summarized using frequency counts and percentages. The denominator will be based on the 
number of evaluable subjects in the appropriate population. 
For the purpose of display, the summary results will be rounded as follows:

Minimum and maximum: same number of decimal places as the raw data.

Mean and Median: one decimal place more than the raw data.

Standard deviation (SD): Two decimal places more than the raw data.

Percentages will be displayed with one decimal place precision.
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, graphs and any supportive SAS output will include footnotes 
that will indicate:

Date of data extraction.

Date and time of output generation.

SAS program name, including the path, which generated 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 will 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.
Empty 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
Table 19 defines the derived variables for study parameters.


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Table 19:
Derived Variables and Definition
Variable
Definition
Age Group
18 – <35 years
5 – <45 years
45 – 55 years
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.
Body Mass Index (BMI)
BMI will be computed using height measured at screening and body weight 
measured at respective visits as, BMI (kg/m2) = Weight (kg) / Height (m)2
Relative Day
The day of first injection of study drug will be considered as relative Day 1.
Study Day (for assessment on or 
after Day 1)
Study Day will be computed as: Date of Assessment – Date of Day 1 + 1
Study Day (for assessment before 
Day 1)
Study Day will be computed as: Date of Assessment – Date of Day 1
Baseline
Baseline is defined as the last non-missing measurement/assessment prior to 
the first dose of study drug. 
For clinical laboratories this will be the screening value. 
The assessments made in unscheduled visits will be considered in 
calculation of baseline, if the unscheduled assessment is the closest value 
preceding the first dose of study drug.
Baseline for Vital Signs on 
Injection Days
For vital signs on injection days, the baseline value will be the vital sign 
measure immediately prior to the first dose of study drug. 
Change from baseline
Change from baseline will be derived as: post baseline visit/time point
value – the baseline value.
Last (analysis)
Last is defined as the last non-missing measurement/assessment post the first 
dose of study drug. 
Last Date in Study
Last date in study is defined as:

The date of Day 180 Visit if the subject completes the study.

The date of ET 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 cellulite Onset
(Date of cellulite symptoms reported – Date of Birth)/365.25. See Section 
6.3.1.3 for handling of partial or unknown Cellulite symptom onset dates.
Time (Years) since last cellulite 
treatment
(Date of informed consent – Date of most recent cellulite treatment)/365.25. 
See Section 6.3.1.3 for handling of partial or unknown treatment dates.
Duration (Minutes) of Exposure 
at each visit
Date/Time of Last Injection – Date/Time of First Injection
Duration (Days) of AE
AE end date – AE start date + 1
AE Start Day
AE start date – Date of Day 1 + 1
AE Stop Day
AE end date – Date of Day 1 + 1


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6.3.
Handling of Missing Data
Subjects who withdraw from the study after the initiation of the study drug will not be replaced 
and available data for these subjects until the point of withdrawal 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.
For Body Q- Appraisal of Cellulite, if missing data at a visit is less than 50% of the scale’s items, 
the mean of the completed items multiplied by 11 will be used to determine total score. Also, if 
the missing data at a visit is more than 50% then for that subject raw sum score will be 
considered as missing.
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. Duration of the AE is 
classified in the ‘>21 Days” category if an AE is ongoing for more than 21 days by the last visit 
of the subject in the study.
Immunogenicity samples with a positive titer value will undergo a log transformation for 
analyses. Samples with titer level less than 10 will be assigned or imputed as a log transformed 
titer of 1 for analyses.
6.3.1.
Imputation of Partial Dates
6.3.1.1.
TEAE Status for Completely Unknown Start Date
The following rules will apply in cases where start date of an AE is completely unknown:

If the AE onset date is unknown and the end date is on or after first 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 first injection on Day 1, 
then the AE will not be considered a TEAE.

If both the start and end dates are unknown (or end date is ongoing), then the AE will 
be considered a TEAE, following the worst-case principle. 

If the AE onset date is partly present and month/year is prior to the first injection 
date, then the AE will not be considered a TEAE.
6.3.1.2.
Concomitant Status of Medication for Completely Unknown Start Date
The following rules will apply in cases where start date of concomitant medication is completely 
unknown:

If the medication onset date is unknown and the end date is after the screening date 
but before the Day 180 visit date or the 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 date, 
then the medication will not be considered as concomitant.


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
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 prior to the first 
injection date, then the medication will not be considered as concomitant.
6.3.1.3.
Missing Cellulite Onset Date
Missing cellulite onset days will be imputed with the first day of the month and missing onset 
month will be imputed with January. 
If the onset date is indicated as completely unknown but starting less than 5 years ago, the onset 
date will be imputed as the informed consent date minus 5 years.
If the onset date is indicated as completely unknown but starting more than 5 years ago, the onset 
date will not be imputed.
Missing cellulite 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 cellulite medication/treatment end date will be imputed with 
the first injection date.
6.3.1.4.
Missing Last Menstrual Date
Missing date of last menstrual period will be imputed with the last day of the month and missing 
onset month will be imputed with December.
6.4.
Interim Analysis
No interim analysis is planned for this study.
7.
STATISTICAL ANALYSES
7.1.
Subject Disposition
The number of subjects included in each study population will be summarized by treatment 
regimen and overall. Subjects excluded from the safety, ITT, or mITT populations will be listed.
The frequency counts and percentages of subjects screened, enrolled, completed, and/or 
withdrawn from the study, as well as the reason for withdrawal from study will be summarized 
by treatment regimen and overall.
A listing of disposition data will be provided. Screen failure reasons will also be listed. In 
addition, listing for inclusion/exclusion criteria will also be presented.
7.2.
Protocol Deviations
Protocol deviations will be summarized by deviation classification (major/minor), and by 
treatment regimen and overall. A listing of all protocol deviations will be presented. 


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7.3.
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized by treatment regimen and overall 
using the Safety Population. Age, height (at Screening), body weight (at Screening), BMI in 
kg/m2 (at Screening) and time since last menstrual period will be summarized as continuous 
variables using descriptive statistics.
Gender, race and ethnicity will be summarized as categorical variables using frequency counts 
and percentages.
Refer to Table 19 for descriptions of age categories.
The following baseline characteristics will be summarized using frequency counts and 
percentages:

CR-PCSS cellulite severity ratings for thigh and buttock at screening (mean and SD 
will also be provided).

Hexsel CSS Section D (laxity, flaccidity or sagging of skin) scores at screening (mean 
and SD will also be provided).

Skin category based on Fitzpatrick scale assessment.

Report of substance use

Alcohol use (Never, Current or Former).

Tobacco use (Never, Current or Former).

Illegal Drug use (Never, Current or Former).
All demographic and baseline characteristics will be presented in subject listings.
7.4.
Medical and Surgical History
Medical history will be coded using MedDRA. Medical and surgical history data will not be 
summarized; however, a subject listing will be provided.
7.5.
Cellulite History
Cellulite history will be summarized by treatment regimen and overall using frequency counts 
and percentages which will include:

Age (years) at cellulite symptom onset (summarized descriptively).

Prior treatments for cellulite including liposuction, laser, massage, radiofrequency, 
drug, mesotherapy, cream, other, or none. Subjects can report more than 1 prior 
cellulite treatment.

Number of prior cellulite treatments (0, 1, 2, or ≥3).

Time (years) since most recent cellulite treatment (summarized descriptively).
Refer to Table 19 for computation of “age at cellulite onset” and “time since last cellulite 
treatment.” Cellulite history will be listed.


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7.6.
Prior/Concomitant Medications and Procedures
Prior and concomitant medications will be summarized by treatment regimen and overall using 
frequency counts and percentages by active ingredient within each ATC, with ATC and active 
ingredients ordered alphabetically. Prior and concomitant procedures (nondrug therapies) will be 
summarized by treatment regimen and overall using frequency counts and percentages with 
name of the procedures ordered alphabetically. Multiple uses of the same medication/procedure 
by a subject will be counted only once.
A subject listing of medications indicating prior and concomitant medications and procedures 
will be provided. Similarly, a separate listing of medications and procedures for cellulite will 
also be presented.
7.7.
Efficacy Analyses
Efficacy parameters will be summarized for each treatment areas (buttock or thigh), treatment 
regimen and overall using the mITT Population.
7.7.1.
Primary Efficacy Endpoint
7.7.1.1.
One-level I-GAIS Responders 
The 1-level I-GAIS responders will be summarized by treatment regimen and overall using 
frequency counts, proportion and corresponding 95% CI based on the Clopper-Pearson method 
for 1-level I-GAIS responders at Day 180 and Last for each treatment area and either buttock or 
either thigh.
The definition of a one-level responder is provided in Section 4.6.1.2.
7.7.2.
Secondary Efficacy Endpoints
7.7.2.1.
One-level I-GAIS Responders by Visit
The 1-level I-GAIS responders will also be summarized by treatment regimen and overall using 
frequency counts, proportion and corresponding 95% CI based on the Clopper-Pearson method
for 1-level I-GAIS responders at Day 28, Day 56, Day 84, Day 112, Day 140, and Last for each 
treatment area and either buttock or either thigh.
Additionally, I-GAIS ratings will also be summarized at Day 28, Day 56, Day 84, Day 112, 
Day 140, Day 180, and Last for each treatment area.
7.7.2.2.
One-level S-GAIS Responders by Visit
The 1-level S-GAIS responders will also be summarized by treatment regimen and overall using
frequency counts, proportion and corresponding 95% CI based on the Clopper-Pearson method
for 1-level S-GAIS responders at Day 28, Day 56, Day 84, Day 112, Day 140, Day 180 and Last 
for each treatment area and for either buttock or either thigh.
The definition of a one-level responder is provided in Section 4.6.2.2.
Additionally, S-GAIS ratings will also be summarized at Day 28, Day 56, Day 84, Day 112, 
Day 140, Day 180 and Last for each treatment area. 




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7.8.
Safety Analyses
Safety data will be summarized by treatment regimen and overall using the Safety Population.
7.8.1.
Study Drug Exposure
The following will be summarized at each treatment visit by treatment regimen for each 
treatment region (thigh or buttock) and each treatment area (left or right) using descriptive 
statistics:

Total number of injections given.

Number of sub-area under each treatment area treated.

Number of additional sub-area under each treatment area treated.

Number of treatment region treated.

Average number of injections per sub-area under each treatment area.

Duration of exposure (refer to Table 19 for computation of exposure duration).
The number of subjects treated at each treatment visit will be summarized using frequency 
counts and percentages by treatment area for each treatment region and treatment regimen.
A subject listing of drug exposure information will be provided.
7.8.2.
Adverse Events
All AE summary tables will include only TEAEs, unless otherwise specified. TEAEs will be 
summarized by SOC and PT. A subject will only be counted once per SOC and PT.
For TEAEs 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 TEAEs 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.
An overall summary of TEAEs and TEAEs related to study drug will be presented and will 
include:

Total number of TEAEs reported.

Total number of TEAEs reported by severity.

Total number of TEAEs of special interest.

Subjects with any TEAE.

Subjects with any TEAE of special interest.

Subjects with any serious TEAE.

Subjects with any severe TEAE.

Subjects with no severe TEAEs, but at least one moderate TEAE.

Subjects with no severe TEAEs, but at least one mild TEAE.

Subjects with any TEAEs leading to drug interruption/discontinuation.


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
Subjects with any TEAEs leading to withdrawal from study.

Subjects with any TEAEs resulting in death.
The following summary tables will be presented by SOC and PT:

All TEAEs.

Study drug related TEAEs.

TEAEs by severity.

Study drug related TEAEs by severity.

TEAEs by treatment session.

Duration of study drug related TEAEs (1 – 7 days, 8 – 14 days, 15 – 21 days, 
>21 days).

Serious TEAEs. 

TEAEs of special interest.

TEAEs of special interest by severity.
The most common non-serious TEAEs by order of frequency (most frequent, 2nd most frequent, 
and 3rd most frequent) will be summarized by PT. The most common non-serious AEs are those 
with any PT that at least 5% of the subjects reported at least once.
The following listings will be presented by subject:

All AEs.

Fatal AEs.

Non-fatal serious AEs.

Non-fatal non-serious AEs leading to study discontinuation.

Non-fatal non-serious AEs resulting in drug interruption/withdrawn.
Refer to Table 19 for computation of duration of AEs.
7.8.3.
Clinical Laboratory
Hematology and chemistry results will be summarized by treatment regimen and overall using 
descriptive statistics for observed and change from baseline to Last.
The PCI laboratory values will be summarized by treatment regimen and overall using frequency 
counts and percentages. Refer to Table 16 for PCI criteria.
A subject listing (including urinalysis results) will be presented for all laboratory parameters. 
Serum and urine pregnancy test results will also be listed.
7.8.4.
Body Height, Body Weight and BMI
Body height, weight and BMI at Screening will be summarized by treatment regimen and overall 
and listed as baseline characteristics as mentioned in Section 7.3.
Body weight will be summarized by treatment regimen and overall using descriptive statistics for 
observed and change from baseline values for all visits.


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7.8.5.
Vital Signs
Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, and body 
temperature) will be summarized by treatment regimen and overall using descriptive statistics for 
observed and change from baseline values for all assessments visits. Baseline (study baseline) 
will be the vital sign value taken at Day 1 predose for the by-visit analyses.
Vital signs will additionally be summarized by treatment regimen and overall for observed and 
change from baseline values for all time points on each injection day. For each injection day, 
baseline (injection day baseline) will be a predose value taken on that day.
The PCI vital signs values will be summarized by treatment regimen and overall using frequency 
counts and percentages. Refer to Table 17 for PCI criteria.
A subject listing will be presented for vital sign results.
7.8.6.
12-Lead ECG
The investigator interpretation of ECG results (normal, abnormal not clinically significant or 
abnormal clinically significant) will be summarized by treatment regimen and overall using 
frequency counts and percentages.
A subject listing will be presented for the investigator interpretation with other details.
7.8.7.
Physical Examination
Physical examination results (by body system) at baseline and Last will be presented by 
treatment regimen and overall using frequency counts and percentages.
A subject listing will be presented for the physical examination result (by body system).
7.8.8.
Immunogenicity
The immunogenicity analysis of binding and neutralizing anti-AUX-I and anti-AUX-II 
antibodies will summarize the number of subjects with an immunogenicity sample, the 
percentage of subjects with a positive sample, and the average titer level of the positive samples 
at Day 1 and Last by total number of treatment sessions received. The titer levels will be 
logarithmically transformed prior to being summarized.
Neutralizing antibody results will be summarized by total number of treatment sessions as 
percentage of positive/negative.
A listing of immunogenicity results by subject will be provided.
Note: For immunogenicity table “x treatment sessions” presents a cohort of subjects who 
received a total of x treatment sessions during the study.


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8.
CHANGE FROM PROTOCOL
This SAP is prepared based on Protocol Amendment 1: December 3, 2020. Table 20 lists any 
significant changes in the SAP from what is proposed in the protocol.
Table 20:
Changes from Protocol
Text in Protocol
Change in SAP
Justification
N/A
9.
REVISION HISTORY
Non-editorial changes made to any of the modules of this SAP will be recorded in Table 21.
Table 21:
Revision History
Version
Date
Revision Author
Comments
1.0
09-Nov-2020
Original
1.1
24-Jun-2021
SAP updated as per Protocol Amendment 1
10.
REFERENCES
1. Protocol Amendment 1: A Phase 2 Multicenter, Open-Label, Randomized, Parallel-
Group, Multiple-Dose Study to Assess The Effectiveness, Safety And Satisfaction With 
Collagenase Clostridium Histolyticum Grid Technique Injections Of Buttock Or Thigh 
Cellulite With Laxity In Adult Females. Dated: December 3, 2020.
2. Scott AM, Pusic AL, Cano SJ, et al. The BODY-Q: A new patient reported outcome 
(PRO) measure for body contouring patients. Qual Life Res. 2012;20:74-5.
3. Hexsel DM, Dal’Forno T, Hexsel CL. A validated photonumeric cellulite severity scale. 
J Eur Acad Dermatol Venereol. 2009;23 (5):523-8.