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
Phase: PHASE2
Conditions: Edematous Fibrosclerotic Panniculopathy, Cellulite, Laxity; Skin
Sponsor: Endo Pharmaceuticals

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

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 2 
 
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 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 3 
 
 
 
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 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 4 
 
 
 
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 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 5 
 
 
 
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 
 
 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 6 
 
 
 
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 
 
 
 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 8 
 
 
 
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. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 12 
 
 
 
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.  

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 15 
 
 
 
1.2. 
Study Schema 
Figure 1: 
Study Design Overview 
 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 16 
 
 
 
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 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 19 
 
 
 
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.  

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 20 
 
 
 
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, 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 21 
 
 
 
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). 
. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 24 
 
 
 
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. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 26 
 
 
 
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. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 27 
 
 
 
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. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 28 
 
 
 
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. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 29 
 
 
 
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. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 34 
 
 
 
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), 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 35 
 
 
 
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. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 36 
 
 
 
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.  

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 37 
 
 
 
• 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. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 38 
 
 
 
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 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 39 
 
 
 
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.  

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 41 
 
 
 
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 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 42 
 
 
 
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. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 43 
 
 
 
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. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 44 
 
 
 
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. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 45 
 
 
 
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.  

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 46 
 
 
 
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. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 47 
 
 
 
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. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 48 
 
 
 
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. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 49 
 
 
 
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.  

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 50 
 
 
 
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. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 51 
 
 
 
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. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 52 
 
 
 
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. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 53 
 
 
 
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. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 54 
 
 
 
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.  

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 55 
 
 
 
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 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 56 
 
 
 
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. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 57 
 
 
 
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. 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 58 
 
 
 
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 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 59 
 
 
 
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 
 

EN3835-224 Protocol Amendment 1 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 60 
 
 
 
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 
03 December 2020 
Endo Pharmaceuticals Inc. 
Page 61 
 
 
 
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.