Phase 2, Double-blind, Randomized, Placebo-Controlled Study to Assess the Efficacy, Safety, and Tolerability of EN3835 vs Placebo in the Treatment of Plantar Fibromatosis
Phase: PHASE2
Conditions: Plantar Fibromatosis
Sponsor: Endo Pharmaceuticals

Endo Pharmaceuticals Inc. 
1400 Atwater Drive 
Malvern, PA 19355 USA 
COLLAGENASE CLOSTRIDIUM HISTOLYTICUM 
(EN3835) 
EN3835-222 
A PHASE 2, DOUBLE-BLIND, RANDOMIZED, PLACEBO-
CONTROLLED STUDY TO ASSESS THE EFFICACY, SAFETY, 
AND TOLERABILITY OF EN3835 VS PLACEBO IN THE 
TREATMENT OF PLANTAR FIBROMATOSIS 
Sponsor Name: Endo Pharmaceuticals Inc. 
Sponsor Legal Registered Address: 1400 Atwater Drive, Malvern, PA 19355 
Regulatory Agency Identifier Number: IND 129,719 
Original Protocol: 09 April 2021 
Amendment 01: 14 July 2021 
Amendment 02: 20 October 2021 
Amendment 03: 18 April 2022 
Amendment 04: 10 June 2022 
The sponsor of the Investigational New Drug Application (IND) is Auxilium Pharmaceuticals, LLC 
(Auxilium); however, Endo Pharmaceuticals Inc. (Endo) is authorized to act and to communicate on 
behalf of Auxilium. The sponsor is responsible for the conduct of the study, analysis of the data, and 
preparation of the clinical study report. 
Confidentiality Statement 
This document is the property of Endo Pharmaceuticals Inc. and may not—in full or part—be passed on, 
reproduced, published, distributed to any person, or submitted to any regulatory authority without the 
express written permission of Endo Pharmaceuticals Inc. 
NCT: NCT05152173

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SUMMARY OF CHANGES 
Rationale for Amendment 04 
The primary purpose for this amendment was to reduce the sample size for the study based on an 
85% statistical power and a lower dropout rate than expected. Major changes include: 
Section Name and Number 
Description of Change 
Section 6.1, Participant Inclusion 
Criteria 
Modify inclusion criterion #7, to able to read and understand the 
patient reported assessments in the local language of the country 
instead of limiting to English or Spanish 
Section 2.1, Synopsis, Overall 
Study Design and Number of 
Participants (Planned) 
Section 2.2, Study Schema 
Section 5.1, Overall Study Design 
Modified the expected number of participants from 216 to 172 to be 
enrolled in the study to account for the reduced dropout rate. 
Section 2.1, Synopsis, Objectives 
and Endpoints 
Section 4, Objectives and 
Endpoints 
Section 10.3.1.2.4, Other 
Secondary Endpoints and 
Exploratory Endpoints 
Changed exploratory objective and endpoint from the FFI total 
score to the FFI composite score 
Section 3.2.2, EN3835-106 
Indicated that the study is on hold. 
Section 10.1, Sample Size 
Determination 
Reduce the sample size for the study from 216 to 172 based on a 
statistical power of 85% (rather than 90%) and lower drop out rate 
(15%) than previously assumed (20%) 
Section 10.3.1.1.1, Primary 
Estimand 
Section 10.3.1.1.2, Method of 
Analysis 
Section 10.3.1.2.1, Key Secondary 
Endpoint 1 
Section 10.3.1.2.3, Key Secondary 
Endpoint 3 
Deleted the term “after 57 days of randomization” since this was 
redundant. 
Rationale for Amendment 03 
The primary purpose for this amendment was to incorporate changes after receiving FDA 
feedback on 22 December 2021. These changes included modifications to the statistical method 
of analysis and clarification that withdrawal only refers to withdrawal of consent. Changes 
included in Administrative Letter 02 were also incorporated with in. The major changes include: 

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Section Name and Number 
Description of Change 
Global 
Identified each study manual with better granularity. 
Section 2.2, Study Schema 
Section 2.3, Schedule of 
Assessments 
Section 8.1, Discontinuation of 
Study Intervention 
Section 9.3.1, Time Period and 
Frequency for Collecting AEs and 
SAE Information 
Added a 28-day follow-up safety visit for participants that 
discontinue study intervention to follow up for any ongoing 
adverse events (AEs) or serious adverse events (SAEs). 
Section 2.2, Study Schema, 
footnote “a”, Section 5.1, and 
Section 2.1, Synopsis  
Section 6.2.1, Participant Inclusion 
Criteria – Treatment 2 
Section 6.2.2, Participant Exclusion 
Criteria – Treatment 2 
Clarified that Treatment 2 (rather than inclusion/exclusion 
criteria) must be met on Day 29. 
Added separate sections for participant inclusion and exclusion 
criteria for Treatment 2. 
Section 2.3, Schedule of 
Assessments 
Footnote “c” on the foot examination on Day 29 was deleted. 
Modified footnote “p” to specify “that the second treatment visit 
should be administered only if the participant has a “previously 
treated” palpable nodule.” 
Added a separate entry in the Schedule of Assessments for 
Treatment 2 Criteria that must be met on Day 29.  
Switched contents of footnote “c” and footnote “p”. 
Section 3.1, Study Rationale 
Section 5.2, Scientific Rationale for 
Study Design 
Modified status of Study EN3835-105 from ongoing to 
completed, to reflect finalized clinical study report (CSR). 
Section 3.2.1, EN3835-105 Proof 
of Concept 
Section 3.2.2, EN3835-106 
Section 3.2.3, EN3835-306 
Updated background information to align with the current status 
of the development program. 
Section 3.3.1, Benefits of EN3835 
in Plantar Fibromatosis 
Section 13, References 
Added reference to Mahmoud et al, 2021. 
Section 5.1, Overall Design and 
Section 2.1, Synopsis 
Section 2.3, Schedule of 
Assessments, footnotes “c” and “l” 
Section 6.1, Participant Inclusion 
Criteria 
Section 6.2.1, Participant Inclusion 
Criteria – Treatment 2 
Section 7.1, Selection of Nodules 
Section 9.1.1.2, Consistency of the 
Selected Nodule 
Modified nodule consistency scale from hard, firm, or soft to 
hard, firm throughout, moderately firm, or soft.  
For initial treatment, participants must have hard, firm 
throughout or moderately firm nodules. 
For Treatment 2, participants must have previously treated 
nodule(s) that remains palpable (eg, hard, moderately firm, firm 
throughout or soft). 

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Section Name and Number 
Description of Change 
Section 5.1, Overall Design and 
Section 2.1, Synopsis 
Section 7.1, Section of Nodules 
Table 2, Dose of Study 
Intervention per Nodule 
Clarified that all hard and firm nodules on Day 1 will be treated. 
If all nodules on each foot are not hard or firm on Screening or 
Day 1, the participant will not be eligible for study inclusion. 
Section 5.2.1, Changes in the Study 
Design Due to COVID-19 
Section 6.4, Screen Failures 
Harmonize rescreening procedures, including situations of 
COVID-19. 
Indicated that participants may only be rescreened once prior to 
randomization.  
Section 5.2.4, Stopping Rules for 
the Study 
Removed reference to “probably” or “possibly” related, since 
investigators are blinded to study treatment. Added anaphylaxis 
reactions to the stopping rule. Harmonized text with 
Section 11.1.4. 
Section 5.3, End of Study 
Definition 
Added a definition for the overall end of study. 
Section 6.2, Participant Exclusion 
Criteria 
In Exclusion Criterion 1, added “affected” feet for further 
clarification. 
Added Exclusion Criterion 3, 4, 5, and 18. The numbering of 
other exclusion criteria have changed due to these additions. 
Section 7.3.1, Study Intervention 
Table 2 
Added additional clarification to the table footnotes on criteria 
for treatment. Added conversion from cm to mm as caliper 
measurements are in mm. 
Section 7.7.1, Prior Medications 
To capture potential impact on immunogenicity results, added 
that the use of a collagenase at any point in time must be 
captured in the electronic case report form (eCRF). 
Section 8.1, Discontinuation of 
Study Intervention and 
Discontinuation from the Study 
Section 2.3, Schedule of 
Assessments 
Added a 28-day post-treatment follow-up visit and early 
termination (ET) visit. 
Section 8.2, Participant Withdrawal 
from the Study 
Added further clarification that withdrawal refers to withdrawal 
of consent. 
Section 8.3, Lost to Follow-up 
Removed reference to the investigator in deciding to replace 
participants lost to follow-up. 
Section 9.1.1.2, Consistency of the 
Selected Nodule 
Clarified text. 
Section 10.3.1.1.1, Primary 
Estimand 
To meet the FDA request, added characteristics of the primary 
estimand. 
Section 10.3.1.1.2, Method of 
Analysis 
To meet the FDA request, updated the method of analysis to 
include a sensitivity analysis.  

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Section Name and Number 
Description of Change 
Section 10.3.1.2.1, Key Secondary 
Endpoint 
Section 10.3.1.2.2, Key Secondary 
Endpoint 2 
Section 10.3.1.2.3, Key Secondary 
Endpoint 3 
Section 10.3.1.2.4, Other 
Secondary Endpoints and 
Exploratory Endpoints 
The key secondary estimand was modified to align with the 
secondary endpoint defined in the protocol. 
To meet the FDA request, added characteristics of the key 
secondary endpoint 1, 2, and 3. Added characteristics of key 
secondary estimand 1, 2, and 3, method of calculation and 
sensitivity analysis. 
For Key Secondary Endpoint 3, removed reference to imputed 
data. 
Reorganized sections by endpoints and added exploratory 
analysis 
Section 10.3.2.1, Adverse Events 
To meet the FDA request, indicated that a confidence interval for 
the difference in the frequency of treatment-emergent adverse 
events (TEAEs) across treatments will be provided. 
Section 10.5, Handling of Missing 
Data 
Added reference to tipping point analysis. 
Section 10.7, Subgroup Analysis 
To meet the FDA request, added subgroup analyses. 
Section 11.1.2, Informed Consent 
Process 
Added that participants will need to sign a new informed consent 
form (ICF) if more than 28 days elapse between initial ICF 
signature and date of randomization. 
Section 11.1.5, Dissemination of 
Clinical Study Data 
Clarified that aggregate results will be disseminated for the 
study.  
Rationale for Amendment 02 
The primary purpose for this amendment was to incorporate changes after receiving FDA 
feedback on 22 September 2021 and 01 October 2021. The major changes include 1) limiting the 
dose to 1.8 mg in total per treatment visit; 2) removing pharmacokinetic (PK) assessments, PK 
endpoint, PK subgroups, and PK analysis; 3) removing photography subgroup and assessments; 
4) including the National Institute of Allergy and Infectious Disease (NIAID) definition for
assessing for anaphylaxis; 5) including the National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE) grading scale for assessing severity of
adverse events (AEs); 6) including a study specific grading scale for injection site reactions;
7) modifying the Intent-to-Treat (ITT) population definition and adding a modified Intent-to-
Treat (mITT) and a Full Analysis Sets (FAS) and 8) adding further details of statistical analysis
to be conducted. Relevant changes included in Administrative Change Letter 01 were also
incorporated into this amendment to the protocol.
Section Name and Number 
Description of Change 
Global 
Removed all references to PK assessments, endpoints, and 
statistical evaluation. PK will be assessed in another study. 
Global 
Removed all references to photography subgroup, assessments 
and photography visits. Photography will be assessed in another 
study. 

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Section Name and Number 
Description of Change 
Global 
Removed all references to high (2.7 mg) and low dose (1.8 mg) 
of study intervention. Capped maximum dose administered to 
1.8 mg in total and removed all references to the 2.7 mg dose.  
Indicated that the total number of injections across all nodules 
present shall not exceed 3 injections (1.35 mg) in a single foot 
when treating participants with unilateral plantar fibromatosis. 
When treating participants with bilateral plantar fibromatosis, the 
total number of injections across all nodules present shall not 
exceed 4 injections (1.8 mg) in total with each foot receiving a 
maximum dose of 0.9 mg. 
Section 2.2, Schedule of 
Assessments 
Included assessment of the Patient Global Impression of Severity 
(PGIS) and Pain Numerical Rating Scale (NRS) at screening to 
align with analysis conducted in the psychometric testing. 
Section 2.3, Schedule of 
Assessments, footnote “c” 
Section 9.2.2, Physical Examination 
In the Schedule of Assessments, modified footnote “c” and 
Section 9.2 to indicate that a foot examination will be conducted 
at the time points listed in the Schedule of Assessments. 
Section 2.3, Schedule of 
Assessments, footnote “l” 
Updated footnote “l” to reflect inclusion criterion related to 
nodule hardness on Treatment 2. 
Section 2.3, Schedule of 
Assessments 
Section 9.1.1.1, Anatomical 
Representation of Nodule Location 
Added assessment for Anatomic Representation of Nodule(s) at 
Screening and Day 57. Modified footnote “m” for harmonization. 
Section 2.3, Schedule of 
Assessments 
Section 6.2, Exclusion Criteria 
Section 9.2.5, Electrocardiogram 
Removed electrocardiogram (ECG) assessments and exclusion 
criterion pertaining to ECGs and assessments. 
Section 4, Objectives and 
Endpoints; Section 2.1, Synopsis 
Removed the term “over time” in the endpoints being assessed on 
Days 15, 29, 43, and 57. 
Section 4, Objectives and 
Endpoints; Section 2.1, Synopsis 
Modified PGIS endpoints from the difference in the mean change 
from Baseline to Day 57 to the difference in the PGIS scores 
between EN3835 and placebo at the assessed time points. 
Section 4, Objectives and 
Endpoints; Section 2.1, Synopsis 
Section 10.1, Sample Size 
Determination 
Section 10.3.1.1, Primary Analysis 
Removed “± 5 days” in endpoints being assessed at end of study 
(EOS) visit. 
Section 5.1, Overall Design 
Section 5.3, EOS Definition 
Clarified that all participants are expected to remain in the study 
until Day 57, regardless if they receive 1 or 2 treatments. 
Section 5.2.1, Changes in the Study 
Design due to COVID-19 
Section 9.2, Safety Assessments 
Updated date of the FDA COVID-19 guidance to 30 August 
2021. 
Section 5.2.2, Justification for Dose 
Added that the maximum dose has been limited to 1.8 mg since 
this was the dose studied in Study EN3835-105. 

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Section Name and Number 
Description of Change 
Section 5.2.4, Stopping Rules for 
the Study 
Per FDA recommendation, included stopping rules for enrollment 
into the study. 
Section 6.1, Inclusion Criteria 
Modified inclusion criteria to requiring ≤ 4 injections (1.8 mg 
maximum dose) per treatment visit. Indicated nodule 
configuration and maximum dose based on whether 1 or 2 feet 
are treated. 
Section 6.3, Lifestyle 
Considerations 
Added that participants should be encouraged to wear supportive 
footwear when on their feet during the study. 
Section 7.3.1, Study Intervention, 
Table 2, Dose of Study Intervention 
Per Nodule 
Indicated that maximum dose of study intervention is no more 
than 1.8 mg per foot in participants with bilateral plantar 
fibromatosis and no more than 1.35 mg per foot in participants 
with unilateral plantar fibromatosis. 
Section 7.3.1, Study Intervention, 
Table 3 Study Intervention Group 
Allocation Based on Count of 
Nodules and Nodule Sizes and 
Table 4 Total Count of Injections of 
Study Intervention Based on 
Nodule Size Combinations Present 
in Both Feet 
Removed Tables 3 and 4 since allocation to high-dose and low-
dose groups were linked to PK assessments which were removed 
during the amendment. 
Section 7.3.3, Care Procedures 
After Injection 
Removed reference to applying a gauze bandage or an adhesive 
dressing after injection.  
Section 7.5.1, Interactive Response 
Technology 
Indicated that the investigator will not have access to the 
participant’s treatment assignment. 
Section 8.1, Discontinuation of 
Study Intervention 
Indicated that participants that discontinue study intervention will 
be encouraged to remain in the study to complete all remaining 
evaluations. 
Indicated that participants that discontinue study intervention will 
not be replaced. 
Section 8.2, Participant Withdrawal 
from the Study 
Clarified procedures upon participant withdrawal from the study. 
Deleted text indicating that a participant can be withdrawn from 
the study due to AEs. 
Deleted text indicated that AE information must be collected after 
withdrawal of consent. 
Section 9.1.2.5, Subject Satisfaction 
with Treatment Scale 
Clarified instructions that the scale assessments will be 
completed for treated nodules on each foot, rather than per treated 
nodule. 
Section 9.3.7, Assessment of the 
Severity of Local Injection Site 
Reactions 
Per FDA recommendation, included a study specific grading 
scale for assessing injection site reactions. 
Section 9.3.9, Anaphylaxis 
Per FDA recommendation, included criteria for diagnosis of 
anaphylaxis according to the NIAID criteria. 
Section 10.2, Populations for 
Analysis 
Modified the definition of the ITT Population and added mITT 
and FAS Populations. 

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Section Name and Number 
Description of Change 
Section 10.3.1, Efficacy Analysis 
Summarized approach to the conduct of the efficacy analysis. 
Section 10.3.1.1, Primary Analysis 
Added definitions for the primary estimands. Included statistical 
methods to stratify for covariates.  
Section 10.3.1.2, Secondary and 
Exploratory Analyses 
Added estimands and method of analysis for key primary 
endpoints. 
Section 10.4, Multiplicity 
Adjustments 
Added testing hierarchy for key secondary endpoints. 
Section 10.5, Handling of Missing 
Data 
Added text to limit missing data for key analyses. 
Section 11.3.3, Intensity 
Assessment 
Modified the definition of intensity assessment to the NCI 
CTCAE. 
Rationale for Amendment 01 
The primary purpose for this amendment was to incorporate changes after receiving FDA 
feedback in the Type C Written Response (received 30 April 2021). These changes included 
modifying the Foot Function Index (FFI) and adding additional scales to measure the severity of 
pain, difficulty, and activity limitation of plantar fibromatosis. Study endpoints were updated to 
reflect these changes. To better assess the safety of the EN3835 doses administered, an 
independent unblinded Data Safety Monitoring Board (DSMB) will monitor pharmacokinetics 
and safety. Enrollment and procedures for the Photography and Pharmacokinetic Subgroup have 
been separated so that participants can enroll in either or both a Photography Subgroup or 
Pharmacokinetic Subgroup. Additionally, throughout the protocol, it was clarified that a 
maximum of 1.35 mg of study intervention can be injected into each foot and all nodules present 
on each foot on Day 1 must be treated. Major changes to the protocol and protocol synopsis are 
presented. Additional changes have been made for clarity and consistency. 
Section Name and Number 
Description of Change 
Section 2.1, Synopsis, Disclosure 
Statement  
Clarified that this is a safety and efficacy study. 
Section 2.2, Study Schema 
Harmonized the time points for scale assessments and 
pharmacokinetic sample collection with the Schedule of 
Assessments and modified for further clarification. 
Reduced syringe count in the study schema from 6 to 3 since 
each injection of study intervention (0.45 mg) will be 
administered as 2 aliquots of 0.225 mg each. 
Differentiated procedures for Pharmacokinetic and Photography 
Subgroup, into separate subgroups, the Pharmacokinetic 
Subgroup and the Photography Subgroup. 

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Section Name and Number 
Description of Change 
Section 2.3, Schedule of 
Assessments 
Added PGIS - Overall Plantar Fibromatosis (PF) and its 
subscales, Patient Global Impression of Change (PGIC) 
subscales, and the Pain Intensity NRS. 
Removed the Patient Global Impression of Bother (PGIB) Scale. 
Modified the name of the Investigator Assessment of 
Improvement Scale to the Clinician Global Impression of Change 
Scale. 
Differentiated procedures for Pharmacokinetic and Photography 
Subgroup, into separate subgroups, the Pharmacokinetic 
Subgroup and the Photography Subgroup. Added footnote “n”. 
Modified text in footnotes “l”, “m”, “t”. 
Specified the order of scale completion in footnote “k”.  
Section 3.1, Study Rationale 
Updated study rationale to reflect that an improved response in 
plantar fibromatosis symptoms on the FFI scale was observed 
with 2 injections of the higher strengths of EN3835. 
Section 3.3.2, Risks of EN3835 in 
Plantar Fibromatosis 
Included use of an independent DSMB to review safety and to 
mitigate risks. 
Section 3.3.3, Overall Assessment 
of Benefit Risks 
Specified a maximum dose of EN3835 1.35 mg per foot. 
Section 4, Objectives and 
Endpoints; Section 2.1, Synopsis 
The PGIC and Subject Satisfaction scales were recategorized as 
exploratory endpoints instead of secondary endpoints. 
Added objectives and endpoints related to PGIS– Overall PF and 
its subscales, PGIC pain, difficulty, and activity limitation 
subscales, and Pain Intensity NRS. 
Modified the name of the Investigator Assessment of 
Improvement Scale to the Clinician Global Impression of Change 
Scale. 
Removed the PGIB Scale. 
Added an exploratory objective and endpoint evaluating the FFI 
total score. 
Section 5.1, Overall Study Design; 
Section 2.1, Synopsis 
Deleted 300 participants to be screened as this is unknown. 
Added that all nodules present on each foot on Day 1 must be 
treated. 
Clarified that PK samples will be collected after the first 
treatment. 
Removed photography assessments after injection. 
Added additional scales. Removed the PGIB scale. Modified the 
name of the Investigator Assessment of Improvement Scale to the 
Clinician Global Impression of Change Scale. 
Differentiated procedures for Pharmacokinetic and Photography 
Subgroup, into separate subgroups, the Pharmacokinetic 
Subgroup and the Photography Subgroup. 
Clarified maximum dose of EN3835 as 1.35 mg/foot. 

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Section Name and Number 
Description of Change 
Section 5.2, Scientific Rationale for 
Study Design 
Removed reference to placebo. Clarified maximum dose of 
EN3835 as 1.35 mg/foot. Indicated that PK samples will be 
collected after the first treatment 
Section 5.2.2, Justification for Dose 
Added supporting nonclinical data. 
Section 5.2.3, Justification of 
Measures 
Updated justification for the FFI-PF-May 2021 for further clarity. 
Added and included justification for the use of the PGIS, PGIC, 
and Pain Intensity NRS. 
Section 6.1, Participant Inclusion 
Criteria  
Revised Inclusion Criterion 4, to specify no more than 3 
injections of EN3835 (1.35 mg) per foot. 
Section 7.1, Selection of Nodules 
Indicated that all nodules present on each foot on Day 1 must be 
treated. Given that 1 injection will be administered as 2 aliquots, 
the injection count was modified to from 2 to 6 injections to 1 to 
3 injections per foot. 
Section 7.3, Study Intervention 
Administration 
Removed reference to the supine position and harmonized 
administration via the intralesional route. 
Section 7.3.1, Study Intervention 
In Table 1, decreased injection count from 6, 4, and 2 to 3, 2, and 
1, since each injection (0.45 mg) of study intervention will be 
administered as 2 aliquots of 0.225 mg each. 
In Table 2, simplified table and added a footnote to clarify that 
each injection of study intervention is administered as 2 aliquots 
of 0.225 mg each.  
Table 4, simplified table and added footnote to specify no more 
than 3 injections (1.35 mg) of study intervention per foot. Added 
a footnote to clarify that each injection of study intervention is 
administered as 2 aliquots of 0.225 mg each.  
Section 7.5, Measures to Minimize 
Bias  
Indicated that participants will complete clinical outcome 
measures before the Investigator completes outcome measures. 
Indicated that the Investigator will be blinded to the participant’s 
assessments. 
Section 7.7.2, Concomitant 
Medications 
Added vitamins, nutritional supplements, and vaccinations as 
examples of concomitant medications. 
Section 9, Study Assessments and 
Procedures 
Indicated that activities outlined in the Study Operations Manual 
must be followed or a protocol deviation will result. 
Included the order in which participant subscales should be 
completed. 
Removed the PGIB Scale. 
Added PGIS– Overall PF and its subscales, PGIC subscales, and 
Pain Intensity NRS. 
Modified the name of the Investigator Assessment of 
Improvement Scale to the Clinician Global Impression of Change 
Scale. 
Clarified text in the of the FFI Scale questions. Renamed this 
version FFI-PF-May-2021 (instead of FFI-PF–Feb-2021). 
Applies globally. 

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Section Name and Number 
Description of Change 
Section 9.1.1.2, Consistency of the 
Selected Nodule 
Indicated that all efforts should be made to ensure the same 
investigator is performing these assessments for a given 
participant. 
Section 9.1.2, Patient-Reported 
Outcome Assessments 
Revised to include measures to limit missing data. Included order 
of scale completion. 
Section 9.1.2.1, Foot Function 
Index 
Modified the FFI and FFI subscales to specify pain, difficulty, 
and activity limitations in the past week related to the feet.  
Section 9.1.2.2, Patient Global 
Impression of Severity  
Added details for the PGIS-PF Overall and subscales for foot 
pain, difficulty, and activity limitation. 
Section 9.1.2.3, Patient Global 
Impression of Change 
Modified the PGIC scale to describe the change in the overall 
severity of PF in the past week. Added subscales for foot pain, 
difficulty, and activity limitation. 
Section 9.1.2.4, Pain Numerical 
Rating Scale  
Added scale to describe the severity of foot pain on a Pain 
Intensity NRS. 
Section 9.1.2.5, Subject Satisfaction 
with Treatment Scale 
Modified scale from capturing satisfaction with treatment of each 
foot to satisfaction with treatment of each nodule. 
Section 9.1.3, Investigator 
Assessments 
Added that Investigators will be trained to complete the scales in 
a standardized manner. 
Section 9.1.3.1, Clinician Global 
Impression of Change Scale 
Modified the name of the Investigator Assessment of 
Improvement Scale to the Clinician Global Impression of Change 
Scale. 
Section 9.2.8, Foot Photography 
Section 9.5.1, Pharmacokinetic 
Sample Collection and Process 
Section 9.5.2, Pharmacokinetic 
Parameters 
Section 10.1, Sample Size 
Determination 
Differentiated procedures for Pharmacokinetic and Photography 
Subgroup, into separate subgroups, the Pharmacokinetic 
Subgroup and the Photography Subgroup. 
Section 9.3.5, Pregnancy 
Modified text to indicate that a participant who becomes pregnant 
will be removed from treatment but can continue in the study. 
Section 10.1, Sample Size 
Determination; Section 2.1, 
Synopsis, Number of Participants 
Planned 
Removed reference to 300 participants screened, as this is 
unknown. 
Section 10.2, Populations and 
Analysis 
Updated definition of the ITT Population to account for new 
scales added. 
Section 10.3.1.2, Secondary and 
Exploratory Analysis 
Updated analysis section to account for additional scales. 
Modified analysis to account for new exploratory endpoint (FFI-
total). 
Section 11.1.4, Data Safety 
Monitoring Board Committee 
Added text describing the DSMB. 
Section 11.1.7, Source 
Documentation 
Modified duration of document retention policy from 2 years to 3 
years to align with Endo policy. 

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Section Name and Number 
Description of Change 
Section 11.3.1, Definitions 
Clarified that any medical condition or laboratory abnormality 
present at screening or baseline should be reported as medical 
history. If the medical condition present at baseline changes in 
severity or seriousness at any time during the study, it should be 
reported as an AE. 
Clarified that AEs are considered concurrent diseases or medical 
occurrences. 
Clarified that an SAE is a congenital anomaly/birth defect in a 
participant “who received a study intervention” rather than “using 
a study intervention.” 

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TABLE OF CONTENTS 
1.
TITLE PAGE ................................................................................................................1 
2.
PROTOCOL SUMMARY ..........................................................................................19 
2.1. 
Synopsis ......................................................................................................................19 
2.2. 
Study Schema .............................................................................................................25 
2.3. 
Schedule of Assessments (Screening to End-of-Study) .............................................26 
3.
INTRODUCTION ......................................................................................................29 
3.1. 
Study Rationale ...........................................................................................................29 
3.2. 
Background .................................................................................................................30 
3.2.1. 
EN3835-105 (Proof of Concept) ................................................................................31 
3.2.2. 
EN3835-106 ................................................................................................................32 
3.2.3. 
EN3835-306 ................................................................................................................33 
3.3. 
Benefit/Risk Assessment ............................................................................................34 
3.3.1. 
Benefit of EN3835 in Plantar Fibromatosis ................................................................34 
3.3.2. 
Risks of EN3835 in Plantar Fibromatosis ..................................................................34 
3.3.3. 
Overall Assessment of Benefit and Risks ...................................................................35 
4.
OBJECTIVES AND ENDPOINTS ............................................................................36 
5.
STUDY DESIGN .......................................................................................................41 
5.1. 
Overall Design ............................................................................................................41 
5.2. 
Scientific Rationale for the Study Design ..................................................................41 
5.2.1. 
Changes in the Study Design Due to COVID-19 .......................................................42 
5.2.2. 
Justification for Dose ..................................................................................................42 
5.2.3. 
Justification of Measures ............................................................................................44 
5.2.3.1. 
Foot Function Index-PF-May 2021 ............................................................................44 
5.2.3.2. 
Patient Global Impression of Severity (PGIS) ............................................................44 
5.2.3.3. 
Patient Global Impression of Change (PGIC) ............................................................44 
5.2.3.4. 
Pain Intensity Numeric Rating Scale (NRS) ..............................................................44 
5.2.3.5. 
Durometer Use ............................................................................................................44 
5.2.4. 
Stopping Rules for the Study ......................................................................................45 
5.3. 
End of Study Definition ..............................................................................................45 
6.
SELECTION AND WITHDRAWAL OF PARTICIPANTS .....................................45 
6.1. 
Participant Inclusion Criteria ......................................................................................45 

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6.2. 
Participant Exclusion Criteria .....................................................................................46 
6.2.1. 
Participant Inclusion Criteria – Treatment 2...............................................................48 
6.2.2. 
Participant Exclusion Criteria – Treatment 2 .............................................................48 
6.3. 
Lifestyle Considerations .............................................................................................48 
6.4. 
Screen Failures ............................................................................................................49 
7. 
STUDY INTERVENTION ........................................................................................49 
7.1. 
Selection of Nodules ...................................................................................................49 
7.2. 
Topical Anesthetic ......................................................................................................50 
7.3. 
Study Intervention Administration .............................................................................50 
7.3.1. 
Study Intervention ......................................................................................................51 
7.3.2. 
Injection of Study Intervention ...................................................................................51 
7.3.3. 
Care Procedures After Injection .................................................................................51 
7.4. 
Study Intervention Preparation/Handling/Storage/Accountability .............................52 
7.5. 
Measures to Minimize Bias ........................................................................................52 
7.5.1. 
Interactive Response Technology ...............................................................................52 
7.5.2. 
Emergency Identification of Study Intervention ........................................................53 
7.6. 
Treatment Compliance ................................................................................................53 
7.7. 
Prior and Concomitant Medications and Procedures ..................................................53 
7.7.1. 
Prior Medications ........................................................................................................53 
7.7.2. 
Concomitant Medications ...........................................................................................53 
7.7.3. 
Prohibited Medications ...............................................................................................53 
7.8. 
COVID-19-Related Protocol Deviations ....................................................................54 
8. 
DISCONTINUATION FROM STUDY INTERVENTION AND 
PARTICIPANT WITHDRAWAL .............................................................................54 
8.1. 
Discontinuation of Study Intervention or from the Study ..........................................54 
8.2. 
Participant Withdrawal from the Study ......................................................................54 
8.3. 
Lost to Follow-up .......................................................................................................55 
9. 
STUDY ASSESSMENTS AND PROCEDURES......................................................55 
9.1. 
Efficacy Assessments .................................................................................................56 
9.1.1. 
Nodule Assessments ...................................................................................................56 
9.1.1.1. 
Anatomical Representation of Nodule Location ........................................................56 
9.1.1.2. 
Consistency of the Selected Nodule ...........................................................................56 
9.1.1.3. 
Caliper Measurements of the Selected Module ..........................................................56 

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9.1.1.4. 
Durometer Measurements ...........................................................................................57 
9.1.2. 
Patient-Reported Outcome Assessments ....................................................................57 
9.1.2.1. 
Foot Function Index ....................................................................................................57 
9.1.2.2. 
Patient Global Impression of Severity- Plantar Fibromatosis Overall .......................58 
9.1.2.3. 
Patient Global Impression of Change- PF Overall .....................................................59 
9.1.2.4. 
Pain Intensity Numerical Rating Scale .......................................................................60 
9.1.2.5. 
Subject Satisfaction with Treatment Scale .................................................................60 
9.1.3. 
Investigator Assessments ............................................................................................60 
9.1.3.1. 
Clinician Global Impression of Change Scale ............................................................60 
9.2. 
Safety Assessments .....................................................................................................60 
9.2.1. 
Medical and Surgical History .....................................................................................61 
9.2.2. 
Physical Examination .................................................................................................61 
9.2.3. 
Height and Weight ......................................................................................................61 
9.2.4. 
Vital Signs ..................................................................................................................61 
9.2.5. 
Clinical Laboratory Determinations ...........................................................................62 
9.2.6. 
Pregnancy Testing ......................................................................................................62 
9.3. 
Adverse Events and Serious Adverse Events .............................................................62 
9.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................63 
9.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events ...........................63 
9.3.3. 
Follow-up of Adverse Events and Serious Adverse Events .......................................63 
9.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events..............................63 
9.3.5. 
Pregnancy ...................................................................................................................64 
9.3.6. 
AEs/SAEs Experienced by Nonparticipants Exposed to Study Intervention .............64 
9.3.7. 
Assessment of the Severity of Local Injection Site Reactions ...................................65 
9.3.8. 
Adverse Events of Special Interest .............................................................................66 
9.3.9. 
Anaphylaxis ................................................................................................................66 
9.4. 
Treatment Overdose ....................................................................................................67 
9.4.1. 
Treatment Abuse/Misuse ............................................................................................67 
9.5. 
Pharmacodynamics .....................................................................................................67 
9.6. 
Genetics ......................................................................................................................68 
9.7. 
Biomarkers ..................................................................................................................68 
9.8. 
Immunogenicity Assessments ....................................................................................68 
10.
STATISTICAL CONSIDERATIONS AND METHODS .........................................68 

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10.1. 
Sample Size Determination ........................................................................................68 
10.2. 
Populations for Analysis .............................................................................................69 
10.3. 
Statistical Hypotheses and Analyses ..........................................................................69 
10.3.1. 
Efficacy Analysis ........................................................................................................69 
10.3.1.1. 
Primary Analysis ........................................................................................................69 
10.3.1.2. 
Secondary and Exploratory Analysis ..........................................................................71 
10.3.2. 
Safety Analyses ..........................................................................................................74 
10.3.2.1. 
Adverse Events ...........................................................................................................74 
10.3.2.2. 
Vital Sign, Laboratory Tests, and Other Safety Measures .........................................74 
10.3.2.3. 
Immunogenicity Analysis ...........................................................................................74 
10.4. 
Multiplicity Adjustment ..............................................................................................74 
10.5. 
Handling of Missing Data ...........................................................................................75 
10.6. 
Interim Analysis ..........................................................................................................75 
10.7. 
Subgroup Analysis ......................................................................................................75 
11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................76 
11.1. 
Appendix 1: Regulatory, Ethical and Study Oversight Considerations......................76 
11.1.1. 
Financial Disclosure ...................................................................................................77 
11.1.2. 
Informed Consent Process ..........................................................................................77 
11.1.3. 
Data Protection ...........................................................................................................78 
11.1.4. 
Data Safety Monitoring Board Committee .................................................................78 
11.1.5. 
Dissemination of Clinical Study Data ........................................................................78 
11.1.6. 
Data Quality Assurance ..............................................................................................78 
11.1.7. 
Source Documents ......................................................................................................79 
11.1.8. 
Study and Site Closure ................................................................................................80 
11.1.9. 
Publication Policy .......................................................................................................80 
11.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................81 
11.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting .........................................................................82 
11.3.1. 
Definitions ..................................................................................................................82 
11.3.2. 
Relationship to Study Intervention .............................................................................83 
11.3.3. 
Intensity Assessment ..................................................................................................83 
11.3.4. 
Method of Reporting Adverse Events and Serious Adverse Events ..........................84 

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11.3.4.1. 
Method of Reporting Adverse Events ........................................................................84 
11.3.4.2. 
Method of Reporting Serious Adverse Events ...........................................................84 
11.3.4.3. 
Follow-up Procedures for Serious Adverse Events ....................................................84 
11.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................85 
11.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ..............86 
11.6. 
Appendix 6: Abbreviations .........................................................................................87 
12. 
INVESTIGATOR’S STATEMENT ...........................................................................89 
13. 
REFERENCES ...........................................................................................................90 
 

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LIST OF TABLES 
Table 1: 
Study Intervention Administration .............................................................................50 
Table 2: 
Dose of Study Intervention per Nodule ......................................................................51 
Table 3: 
Assessment and Grading of the Severity of Injection Site Reactions.........................65 
Table 4: 
Clinical Criteria for Diagnosing Anaphylaxis ............................................................67 
 

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2. 
PROTOCOL SUMMARY 
2.1. 
Synopsis 
Name of Sponsor/Company: Endo Pharmaceuticals Inc. 
Name of Investigational Product: EN3835 (XIAFLEX) 
Name of Active Ingredient: Collagenase clostridium histolyticum 
Title of Study: A Phase 2, Double-blind, Randomized, Placebo-Controlled Study to Assess the Efficacy, 
Safety, and Tolerability of EN3835 vs Placebo in the Treatment of Plantar Fibromatosis 
Lead Principal Investigator: Not applicable 
Phase of development: 2 
Objectives and Endpoints: 
Objective 
Endpoint 
Primary 
• To assess the improvement with EN3835 vs 
placebo in the Foot Function Index (FFI)a 
pain subscale. 
• The difference between EN3835 and placebo in 
the mean change from Baseline (Day 1) to 
Day 57 on the foot pain subscale (total score on 
9 items) of the FFI ranging from 0 (“None”) to 
4 (“Extreme”). 
Secondary 
• To assess the improvement with EN3835 vs 
placebo in the FFI pain subscale over time. 
• The mean change from Baseline (Day 1) to 
Days 15, 29, 43, and 57 on the pain subscale of 
the FFI (total score on 9 items), ranging from 0 
(“None”) to 4 (“Extreme”) with EN3835 vs 
placebo.  
• To assess the overall improvement in the 
combined score of the FFI pain and 
difficulty subscales with EN3835 vs placebo  
• The difference between EN3835 and placebo in 
the mean change from Baseline (Day 1) to 
Day 57 on the total score of the FFI pain and 
difficulty subscales (combined).  
• The mean change from Baseline (Day 1) to 
Days 15, 29, 43, and 57 on the total score of the 
pain and difficulty subscales of the FFI with 
EN3835 vs placebo. 
• To assess investigator assessment of 
improvement with EN3835 treatment vs 
placebo. 
• The difference in the proportion of EN3835-
treated participants and those receiving only 
placebo reporting “Minimally Improved” (+1), 
“Much Improved” (+2), or “Very Much 
Improved” (+3) on the Clinician Global 
Impression of Change Scale, a 7-point scale 
ranging from −3 (“Very Much Worse”) to +3 
(“Very Much Improvement”) on Days 15, 29, 
43, and 57. 

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Name of Sponsor/Company: Endo Pharmaceuticals Inc. 
Name of Investigational Product: EN3835 (XIAFLEX) 
Name of Active Ingredient: Collagenase clostridium histolyticum 
•
To assess the change in nodule hardness
after administration of EN3835 vs placebo.
•
The difference between EN3835 and placebo in
the mean change from Baseline (Day 1) to the
Day 57 in the nodular hardness of the treated
nodules by durometer measurements.
•
The mean change from Baseline (Day 1) to
Days 15, 29, 43, 57 in the nodular hardness of
the treated nodules by durometer measurements
with EN3835 vs placebo
Safety 
•
To assess the safety and tolerability of
EN3835 in participants with plantar
fibromatosis.
•
Safety of EN3835 as assessed by incidence,
severity, and duration of treatment-emergent
adverse events (TEAEs), adverse events of
special interest (AESIs), and serious adverse
events (SAEs).
•
The change from baseline in vital signs and
clinical laboratory values at each visit where
these parameters are measured.
•
To assess the immunogenicity of EN3835 in
participants with plantar fibromatosis.
•
Presence of anti-AUX-I and anti-AUX-II
antibody titer levels in EN3835 treated-
participants at Day 1 and Day 57.
•
Presence of neutralizing antibodies to AUX-I
and AUX-II in EN3835 treated-participants at
Day 1 and Day 57.
Exploratory 
•
To assess the overall improvement in the
FFI composite score with EN3835 vs
placebo
•
The difference between EN3835 and placebo in
the mean change from Baseline (Day 1) to
Day 57 on the FFI composite score with the
score of each of the 21 items, ranging from 0 to
4, with 4 indicating higher severity.
•
The mean change from Baseline (Day 1) to
Days 15, 29, 43, and 57 on the FFI composite
score with EN3835 vs placebo.
•
To assess the overall improvement in
severity of plantar fibromatosis on the
Patient Global Impression of Severity
(PGIS) PF Overall scale.
•
The difference between EN3835 and placebo at
Day 57 on the PGIS PF Overall score.
•
The difference between EN3835 and placebo
Days 15, 29, 43, and 57 on the PGIS PF Overall
score with EN3835 vs placebo.

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Name of Sponsor/Company: Endo Pharmaceuticals Inc. 
Name of Investigational Product: EN3835 (XIAFLEX) 
Name of Active Ingredient: Collagenase clostridium histolyticum 
•
To assess the overall improvement in the
severity of foot pain with EN3835 vs
placebo in the PGIS foot pain subscale
•
The difference between EN3835 and placebo at
Day 57 on the foot pain subscale of the PGIS.
•
The difference between EN3835 and placebo at
Days 15, 29, 43, and 57 on the PGIS foot pain
subscale, ranging from 0 (“None”) to 4
(“Severe”) with EN3835 vs placebo.
•
To assess the overall improvement in the
severity of difficulty with EN3835 vs
placebo in the PGIS difficulty subscale
•
The difference between EN3835 and placebo at
Day 57 on the difficulty subscale of the PGIS.
•
The difference between EN3835 and placebo at
Days 15, 29, 43, and 57 on the PGIS difficulty
subscale, ranging from 0 (“None”) to 4
(“Severe”) with EN3835 vs placebo.
•
To assess the overall improvement in the
severity of difficulty with EN3835 vs
placebo in the PGIS activity limitation
subscale
•
The difference between EN3835 and placebo at
Day 57 on the activity limitation subscale of the
PGIS.
•
The difference between EN3835 and placebo at
Days 15, 29, 43, and 57 on the PGIS activity
limitation subscale, ranging from 0 (“None”) to
4 (“Severe”) with EN3835 vs placebo.
•
To assess the Patient Global Impression of
Change (PGIC) PF Overall with EN3835
treatment vs placebo.
•
The difference in the proportion of participants
treated with EN3835 or placebo reporting
“Minimal Improvement” (+1), “Much
Improvement” (+2), and “Very Much
Improvement” (+3) on the PGIC scale, a
7-point scale ranging from -3 (“Very Much
Worse”) to +3 (“Very Much Improvement”) on
Days 15, 29, 43, and 57.
•
To assess the change in the overall severity
of foot pain on the Foot Pain Subscale of the
PGIC.
•
The difference in the proportion of participants
treated with EN3835 or placebo reporting
“Minimal Improvement” (+1), “Much
Improvement” (+2), and “Very Much
Improvement” (+3) on the foot pain subscale of
the PGIC scale, a 7 point scale ranging from -3
(“Very Much Worse”) to +3 (“Very Much
Improvement”) on Days 15, 29, 43, and 57.

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Name of Sponsor/Company: Endo Pharmaceuticals Inc. 
Name of Investigational Product: EN3835 (XIAFLEX) 
Name of Active Ingredient: Collagenase clostridium histolyticum 
•
To assess the change in the overall severity
of difficulty on the Difficulty Subscale of
the PGIC.
•
The difference in the proportion of participants
treated with EN3835 or placebo reporting
“Minimal Improvement” (+1), “Much
Improvement” (+2), and “Very Much
Improvement” (+3) on the difficulty subscale of
the PGIC scale, a 7 point scale ranging from -3
(“Very Much Worse”) to +3 (“Very Much
Improvement”) on Days 15, 29, 43, and 57.
•
To assess the change in the overall severity
of activity limitation on the Activity
Limitation Subscale of the PGIC.
•
The difference in the proportion of participants
treated with EN3835 or placebo reporting
“Minimal Improvement” (+1), “Much
Improvement” (+2), and “Very Much
Improvement” (+3) on the activity limitation
subscale of the PGIC scale, a 7 point scale
ranging from -3 (“Very Much Worse”) to +3
(“Very Much Improvement”) on Days 15, 29,
43, and 57.
•
To assess the overall improvement in foot
pain with EN3835 vs placebo on the Pain
Intensity Numerical Rating Scale (NRS).
•
The difference between EN3835 and placebo in
the mean change from Baseline (Day 1) to
Day 57 on the Pain Intensity NRS.
•
The mean change from Baseline (Day 1) over
time (Days 15, 29, 43, and 57) on the Pain
Intensity NRS, ranging from 0 (“None”) to 10
(“Worst Pain Imaginable”) with EN3835 vs
placebo.
•
To assess participant satisfaction with
EN3835 treatment vs placebo.
•
The difference in the proportion of participants
treated with EN3835 or placebo reporting to be
“Quite Satisfied” (+1) and “Very Satisfied”
(+2) on the Subject Satisfaction With Treatment
Scale, a 5-point scale ranging from −2 (“Very
Dissatisfied”) to +2 (“Very Satisfied”) on
Days 15, 29, 43, and 57.
•
To assess the improvement with EN3835 vs
placebo in the FFI activity limitation
subscale in participants on the activity
limitation subscale at baseline.
•
The difference between EN3835 and placebo in
the mean change from Baseline (Day 1) to
Day 57 on the activity limitation subscale (total
score on 3 items) of the FFI, ranging from 0
(“Never”) to 4 (“Always”).
•
The mean change from Baseline (Day 1) to
Days 15, 29, 43, and 57 on the activity
limitation subscale (total score on 3 items) of
the FFI, ranging from 0 (“Never”) to 4
(“Always”) with EN3835 vs placebo.

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Name of Sponsor/Company: Endo Pharmaceuticals Inc. 
Name of Investigational Product: EN3835 (XIAFLEX) 
Name of Active Ingredient: Collagenase clostridium histolyticum 
•
To assess the improvement with EN3835 vs
placebo in the FFI difficulty subscale in
participants on the difficulty subscale at
baseline.
•
The difference between EN3835 and placebo in
the mean change from Baseline (Day 1) to
Day 57 on the difficulty subscale (total score on
9 items) of the FFI, ranging from 0 (“No
Difficulty”) to 4 (“A Lot of Difficulty”).
•
The mean change from Baseline (Day 1) to
Days 15, 29, 43, and 57 on the difficulty
subscale (total score on 9 items) of the FFI,
ranging from 0 (“No Difficulty”) to 4 (“A Lot
of Difficulty”) with EN3835 vs placebo.
•
To assess the change in nodule size after
administration of EN3835 vs placebo.
•
The difference between EN3835 and placebo in
the mean change from Baseline (Day 1) to
Day 57 in the size of the treated nodules by
caliper measurements.
•
The mean change from Baseline (Day 1) to
Days 15, 29, 43, and 57 in nodule size with
EN3835 vs placebo.
•
To assess the change in nodule consistency
(by palpation) after administration of
EN3835 vs placebo.
•
The difference between EN3835 and placebo in
the change in consistency from Baseline
(Day 1) to Day 57 as determined by the number
of participants with a soft or non-palpable
consistency at Day 57.
•
The change from Baseline (Day 1) to Days 15,
29, 43, and 57 in nodule consistency with
EN3835 vs placebo.
a For use in this study, the Foot Function Index has been adapted for plantar fibromatosis (FFI-PF-May 
2021), and will hereafter be referred to as the FFI. 
Overall Design: Participants will be screened to randomize approximately 172 participants into 
2 groups, an EN3835 group (n ~ 86) and a placebo group (n ~ 86) in a 1:1 ratio. Study intervention will 
be administered intralesionally to all nodules present based on the size of each nodule at the doses 
described in the dosage table. All nodules present on each foot on Day 1 must be treated. (If all nodules 
on each foot are not hard, firm throughout, moderately firm on Screening or on Day 1, the participant 
will not be eligible for study inclusion). Nodules will be measured using calipers and the largest width or 
length will be used to determine the number of injections to be administered in each nodule. The total 
number of study intervention injections across all nodules present shall not exceed 3 injections (1.35 mg) 
of study intervention in a single foot when treating participants with unilateral plantar fibromatosis. 
When treating participants with bilateral plantar fibromatosis, the total number of study intervention 
injections across all nodules present shall not exceed 4 injections (1.8 mg) in total with each foot 
receiving a maximum dose of 0.9 mg.  
After receiving study intervention, participants will be encouraged to resume normal daily activities 
including walking and bearing weight on the treated foot/feet. All participants will return to the clinic for 
3 follow-up visits, 2 weeks apart, on Days 15, 29, 43, and 57.  

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Name of Sponsor/Company: Endo Pharmaceuticals Inc. 
Name of Investigational Product: EN3835 (XIAFLEX) 
Name of Active Ingredient: Collagenase clostridium histolyticum 
At the Day 29 visit, if the participant has any previously treated nodule(s) that remains palpable and 
measurable by caliper with a consistency of hard, firm throughout, moderately firm, or soft that is/are 
deemed appropriate for treatment by the investigator, and the Treatment 2 criteria are met a second dose 
of the study intervention may be administered.  
For all participants, at the time points listed in the Schedule of Assessments, the efficacy of the study 
intervention will be assessed on the FFI (adapted for plantar fibromatosis; May 2021), the Subject 
Satisfaction with Treatment Scale, the PGIC PF Overall and individual PGIC subscales of pain, 
difficulty, and activity limitation, the Pain NRS, the PGIS PF Overall, and the individual PGIS subscales 
of pain, difficulty, and activity limitation, and the Clinician Global Impression of Change Scale. Safety 
will be assessed by evaluating the incidence and duration of TEAEs, AESIs, and SAEs, and changes in 
vital signs and clinical laboratory values. 
All participants will complete the study on Day 57 (EOS Visit), regardless of whether they receive 1 or 2 
treatments during the study. At the EOS visit, immunogenicity samples will be collected, safety will be 
assessed, and nodules will be measured. The maximum duration of participation is up to 85 days 
(Screening Period: 28 days, Treatment Period: 1 or 2 days, and a total Follow-up Period of 56 days). 
Disclosure Statement: This is a placebo-controlled efficacy and safety study with 2 blinded treatment 
groups. 
Number of Participants (planned): Participants will be screened to ensure that approximately 172 
participants are randomized into 2 treatment groups, an EN3835 group and a placebo group in a 1:1 ratio. 
Treatment Groups and Duration: There will be an active treatment group and a placebo treatment 
group of participants that receive up to 2 treatments of either EN3835 or placebo. 
Duration of the study:  
Screening Phase: Up to 28 days 
Study Intervention Administration: Up to 2 days  
Follow-Up Phase: from Intervention Administration 1 (End of Day 1) until Day 57 (± 5 days) 
Total Duration of the Study: Up to 85 Days (± 5 days) 
Independent Data Safety Monitoring Board: An independent unblinded data monitoring committee 
will review safety data periodically. 

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2.2. 
Study Schema 
a Based on the Day 29 examination of the nodule(s) and review of Treatment 2 Criteria.  
NOTE: The total number of injections across all nodules present shall not exceed 3 injections (1.35 mg) of study intervention in a single foot when treating 
participants with unilateral plantar fibromatosis. When treating participants with bilateral plantar fibromatosis, the total number of study intervention injections 
across all nodules present shall not exceed 4 injections (1.8 mg) in total with each foot receiving a maximum dose of 0.9 mg. 

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2.3. 
Schedule of Assessments (Screening to End-of-Study) 
Screening 
D −28 to D -1 
Treatment Visit 1 
D1 
Follow-up Visits 
EOS/ET 
D57 (±5)
Safety 
Follow-Ups 
D15 (±1)
Treatment Visit 2 
D29 (±1) 
D43 (±1)
28 days 
after the last dose 
(+5) 
Obtain signed informed consenta 
X 
Inclusion/exclusion criteria 
X 
Xb 
Treatment 2 criteria 
Xb,c 
Medical and surgical historyd 
X 
Prior medications and procedures 
X 
Serum pregnancy teste  
X 
X 
Urine pregnancy teste 
Xb 
Xb,c 
Physical examination 
Xf  
X 
Foot examination 
X 
Xb 
X 
Xb 
X 
X 
Clinical laboratory tests 
X 
X 
Immunogenicity sample collectiong 
Xb
X 
Vital signsh 
X 
Xb,i  
X 
Xb,i 
X 
X 
Examination and evaluation of the selected nodule(s): 
a) Caliper measurements
X 
Xb 
X 
Xb 
X 
X 
b) Foot Function Index (FFI)j,k
X 
Xb 
X 
Xb 
X 
X 
c) Nodular consistency (palpation)l
X 
Xb 
X 
Xb 
X 
X 
d) Nodular hardness measurement
using a durometer
X 
Xb 
X 
Xb 
X 
X 

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Screening 
D −28 to D -1 
Treatment Visit 1 
D1 
Follow-up Visits 
EOS/ET 
D57 (±5)
Safety 
Follow-Ups 
D15 (±1)
Treatment Visit 2 
D29 (±1) 
D43 (±1)
28 days 
after the last dose 
(+5) 
e) Anatomical representation of
nodule(s) locationm
X 
Xb 
X 
X 
Patient Global Impression of 
Severity (PGIS) PF Overall Scale 
Pain, Difficulty and Activity 
Limitation Subscalesk  
X 
X 
X 
X 
X 
X 
Patient Global Impression of 
Change (PGIC) PF Overall Scale 
Pain, Difficulty and Activity 
Limitation Subscalesk  
X 
Xb 
X 
X 
Pain Intensity Numerical Rating 
Scale (NRS)k  
X 
X 
X 
X 
X 
X 
Subject Satisfaction with 
Treatment Scalek  
X 
Xb
X 
X 
Clinician Global Impression of 
Change Scale 
X 
Xb 
X 
X 
Randomization 
Xn 
Study intervention administrationo  
X 
Xp 
Concomitant medications and 
proceduresq  
Throughout the study 
Adverse events (AEs)r  
Throughout the study 

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a Performed prior to any study-required assessments. 
b Before treatment. 
c The second treatment should be administered only if the participant has a previously treated palpable nodule measurable by caliper and the nodule (eg, hard, 
firm throughout, moderately firm or soft) is appropriate for a second treatment, according to the investigator. Women of childbearing potential must also have 
a negative urine pregnancy test (see Section 6.2.1). The participant must not have any significant medical conditions, which in the investigator’s opinion would 
preclude receiving a second treatment (see Section 6.2.2).  
d Any diagnostic, therapeutic, or surgical procedure performed within the past 10 years before the study, including those in the treatment area, should be 
recorded including the date, indication for, and description of the procedure. 
e For women of childbearing potential. 
f A complete physical examination, including height and weight at Screening. 
g Testing for neutralizing antibodies will be conducted if the participant tests positive for anti-AUX-I and anti-AUX-II antibodies.  
h Vital signs (ie, blood pressure, pulse, respiratory rate, and temperature) should be collected in a seated position after the participant has been sitting for 
5 minutes. 
i Vital signs should be collected in supine position prior to treatment and at 15 (±5) and 30 (±5) minutes post treatment. 
j Opioid analgesic use is prohibited during the study. Acetaminophen and over-the-counter (OTC) nonsteroidal anti-inflammatory drugs (NSAIDs) are permitted 
if the investigator deems it necessary. 
k Participants will complete the scale prior to evaluation by the investigator. The order of scale completion by the participant is as follows: FFI, PGIS Foot Pain 
Subscale, PGIC Foot Pain Subscale, PGIS Difficulty Subscale, PGIC Difficulty Subscale, PGIS Activity Limitation Subscale, PGIC Activity Limitation 
Subscale, PGIS PF Overall, PGIC PF Overall, Pain Intensity NRS, and Subject Satisfaction with Treatment Scale. 
l Palpation for nodular consistency. For Treatment 1, only hard, firm throughout, moderately firm nodules will be treated. For Treatment 2, palpable nodules that
are hard, firm throughout, moderately firm, or soft on clinical examination and measurable by caliper, that were previously treated, will be treated.
m The investigator will complete a graphic representation of the foot/feet and the location of the nodule(s) that are present. 
n Randomized in a 1:1 ratio to either EN3835 or placebo using an Interactive Response Technology (IRT) system. 
o Size of the nodule(s) will be determined by caliper and the largest width or length will be used to determine number of injections to be administered.
p On Visit Day 29, urine pregnancy testing will only be performed if the participant will receive a second treatment of study intervention.
q Including concomitant surgical and medical procedures for plantar fibromatosis and for conditions other than plantar fibromatosis.
r Serious adverse events (SAEs) and adverse events (AEs) will be collected by the investigator from the time of signing the informed consent through the
Day 57/EOS Visit. For participants who withdraw from the study early, SAEs and AEs will be collected for 28 days after the last dose of study intervention. 
s Participants are encouraged to remain in the study for follow-up until the Day 57 Visit (see Section 8.1). Participants who discontinue from the study or study 
intervention and do not agree to remain in the study for follow-up until Day 57, will be asked to complete an ET visit and if applicable the 28-day post-
treatment Safety Follow-up Visit (or phone call if a visit is not possible) to determine the status of any ongoing AEs/SAEs or the occurrence of any new 
AEs/SAEs (see Section 8.1). At the time of withdrawing from the study (withdraw consent), if possible an ET visit should be conducted as shown in the 
Schedule of Assessments (see Section 8.2).  
D = day(s); EOS = end of study; ET = early termination. 

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3.
INTRODUCTION
EN3835 is currently marketed in the United States as XIAFLEX® (collagenase clostridium 
histolyticum) and is indicated for the treatment of adults with Dupuytren’s contracture (DC) with 
a palpable cord and for the treatment of adult men with Peyronie’s disease (PD) with a palpable 
plaque and curvature deformity of at least 30 degrees at the start of therapy. A biologic license 
application (BLA) was submitted for a different formulation of EN3835 on 06 September 2019, 
and approved for the treatment of cellulite as QWO® (collagenase clostridium histolyticum-aaes) 
on 06 July 2020. 
EN3835 is being investigated for the treatment of plantar fibromatosis. 
3.1. 
Study Rationale 
Plantar fibromatosis is a rare pathology of the plantar aponeurosis characterized by disordered 
fibrous tissue and subsequent formation of nodules of the feet (Young et al, 2018). Specifically, 
the disease is characterized by slow-growing nodules in the medial or central plantar fascia, 
which are formed by excess collagen leading to fibrotic tissue. Plantar fibromatosis presents 
bilaterally in 25% of patients (Gudmundsson et al, 2013) with males predominantly affected 
(Allen et al, 1955). Symptoms range from local pressure and distention, to tender erythematous 
lesions that can affect the patient’s ability to bear weight and walk (Veith et al, 2013; Young 
et al, 2018). The primary symptom most patients experience is a slow-growing lump along the 
medial longitudinal arch, which becomes painful and causes swelling as it enlarges (Fuiano et al, 
2019). In rare cases, the fibromatosis leads to toe contractures, which potentially can lead to 
shrinkage and sclerosis of the fascia (Fuiano et al, 2019; Veith et al, 2013). The condition 
reduces quality of life and can cause functional disability, leading to severe impairment in some 
patients (Syed et al, 2012). 
Dupuytren’s disease has been reported to coexist in patients with plantar fibromatosis (Allen 
et al, 1955; Aviles et al, 1971; Fausto de Souza et al, 2010; Haedicke and Sturium, 1989; Wapner 
et al, 1995). Similar to Dupuytren’s disease, plantar fibromatosis has been reported to have a 
strong familial predisposition and the disease has been related to other forms of extra-palmar 
involvement (Gudmundsson et al, 2013). 
Plantar fibromatosis is also often referred to as “Dupuytren’s disease of the plantar fascia” based 
on immunohistological and ultrastructural analyses (Cavolo and Sherwood, 1982). The 
histopathology of plantar fibromatosis is the same as in the palmar fascia and the progression 
pattern of the disease follows the same 3 stages identified for Dupuytren’s disease (de Palma, 
et al 1999; Veith et al, 2013): 
1. A proliferative phase with increased fibroblast activity and cellular proliferation.
2. An active or involutional stage, where the nodules are formed and collagen is deposited.
3. A residual stage in which the fibroblast activity is diminished and reduced collagen
maturation and contracture take place.

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Based on the similar histopathology of Dupuytren’s disease and plantar fibromatosis, EN3835 
may be effective in the treatment of plantar fibromatosis. Furthermore, the collagenases 
comprising EN3835 are proteinases that can hydrolyze the triple-helical collagen polymer under 
physiological conditions at the site of injection (subdermal collagen as in Dupuytren’s 
cord/Peyronie’s plaque, and hypodermal septa in women with cellulite). As such, these 
collagenases have the potential to be effective in lysing subdermal collagen, such as that 
observed in the fibrous nodules of plantar fibromatosis. 
To date, since there is no available therapy that addresses the pathophysiology of plantar 
fibromatosis, disease progression cannot be prevented. The treatment of plantar fibromatosis is 
aimed at symptom relief and is adapted to the severity of the disease. Nonsurgical treatment 
options are available for the less painful stages of the disease. If pain reduction cannot be 
achieved and a stage of strong fibroblast activity has been reached, other therapeutic options 
such as X-ray irradiation and surgery are considered. The long-term safety of radiation therapy 
has not been established and the risk of malignant changes at the radiation site is not known. 
Surgical treatment is the only indicated treatment option in cases of persistent pain, however the 
recurrence rate is relatively high (between 60% and 100%), and the postsurgical burden to 
patients is significant due to tenderness and prolonged recovery (van der Veer et al, 2008). 
Because of the lack of effective therapies, there is an unmet need for a less invasive and more 
cost-effective treatment option for patients with persistent pain from plantar fibromatosis. 
Results of an interim analysis from a completed open-label Phase 1 study showed that 
participants who received 2 injections of either 1.2 mg/mL or 2.25 mg/mL had improvement in 
the severity of pain, difficulty and disability (activity limitation) in symptoms of plantar 
fibromatosis. A better treatment response was observed in the severity of pain, difficulty, and 
disability (activity limitation) in symptoms of plantar fibromatosis in participants who received 2 
injections of 2.25 mg/mL compared to those receiving 2 injections of 1.2 mg/mL. Both 
participants and investigators saw an improvement in nodule consistency by Day 57. All AEs 
reported were considered mild to moderate in severity and most AEs resolved within 21 days. 
The purpose of this double-blind, placebo-control Phase 2 study is to assess the efficacy, safety, 
tolerability, of EN3835 vs placebo.  
3.2. 
Background 
Collagenase clostridium histolyticum, or EN3835 (previously known as AA4500), comprises a 
mixture of 2 collagenases, Clostridial type I collagenase (AUX-I) and Clostridial type II 
collagenase (AUX-II) in an approximate 1:1 mass ratio. These collagenases are isolated and 
purified from the fermentation of the bacterium Clostridium histolyticum. Collagenase AUX-I is 
a single polypeptide chain consisting of approximately 1000 amino acids. It has an observed 
molecular weight of 114 kDa. It belongs to the Class I Clostridium histolyticum collagenases. 
Collagenase AUX-II is a single polypeptide chain consisting of approximately 1000 amino acids. 
It has an observed molecular weight of 113 kDa. It belongs to the Class II Clostridium 
histolyticum collagenases. These 2 collagenases are not immunologically cross-reactive and have 
different specificities, such that together they become synergistic, providing a very broad 
hydrolyzing reactivity toward collagen. 

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Nonclinical primary pharmacology studies were conducted during the development of XIAFLEX 
for the DC and PD indications. The relevance of the results of these studies as applicable to 
plantar fibromatosis is summarized in the current edition of the investigator brochure (IB). 
During clinical pharmacology studies of EN3835 conducted in participants with DC and 
cellulite, there were no quantifiable plasma levels of AUX-I and AUX-II after single and 
concurrent injections of EN3835. In participants with PD, following each of 2 intralesional 
injections of EN3835 0.58 mg into the penile plaque, separated by 24 hours, plasma levels of 
AUX-I and AUX-II in participants with quantifiable levels were minimal and short-lived. All 
plasma levels were below the limits of quantification within 30 minutes following dosing. There 
was no evidence of accumulation following 2 sequential injections of EN3835 administered 
24 hours apart. 
The results of 14 completed studies conducted in over 1100 participants worldwide formed the 
basis of the efficacy and safety data supporting the approval of XIAFLEX in adult patients with 
DC with a palpable cord. Since the approval of XIAFLEX for the treatment of DC, 8 additional 
studies have been completed in participants with DC. The safety profile of XIAFLEX in DC is 
summarized in the prescribing information (XIAFLEX Prescribing Information). 
The efficacy and safety of EN3835 was also demonstrated in participants with palmar 
Dupuytren’s disease nodules. The results of the study suggested that single injections of EN3835 
0.60 mg and EN3835 0.40 mg may be effective in the treatment of Dupuytren’s disease nodules. 
Most AEs reported were local to the injection site and resolved within a median of 14 days. 
Because EN3835 contains foreign proteins, severe allergic reactions can occur. Anaphylaxis was 
reported in a postmarketing clinical study in 1 patient who had previous exposure to EN3835 in 
the treatment of DC. 
A detailed description of the chemistry, nonclinical and clinical pharmacology, efficacy, and 
safety of EN3835 is provided in the current edition of the IB of EN3835 for plantar fibromatosis. 
3.2.1. 
EN3835-105 (Proof of Concept) 
Study EN3835-105 is a completed Phase 1, open-label, randomized, dose-ranging proof of 
concept study. The safety, immunogenicity, PK, and effect of EN3835 on nodule size in 24 
participants with plantar fibromatosis were assessed. The effect of EN3835 on investigator and 
patient-reported outcome measures were also evaluated,  
The study randomized 24 participants into 3 treatment groups (8 participants per treatment 
group). On Day 1, participants were randomized in a 1:1:1 ratio to 3 treatment concentrations of 
EN3835. Based on the maximum diameter of the nodule collected on ultrasound, participants 
received either 1 (for nodules ≤ 1.5 cm) or 2 (for nodules > 1.5 cm) injections of EN3835 per 
nodule. The total dose per nodule ranged from 0.12 to 0.45 mg for nodules ≤ 1.5 cm and 0.24 to 
0.9 mg for nodules > 1.5 cm. Blood samples were drawn for PK analysis on Day 1 before dosing 
and at 10, 20, 30, 60 minutes and 2, 4, 8, 12, and 24 hours following injection. 
During the Initial Treatment Period, participants returned to the clinic for 4 follow-up visits, 
1 week apart, on Days 8, 15, 22, and 29. On each visit day, the nodules were palpated, caliper 
measurements of the treated nodules were collected, and an ultrasound was conducted. At each 
visit, the participants completed the Foot Function Index-Short Form-23 (FFI-SF-23) and the 
Participant Satisfaction with Treatment Scale. In addition, the Investigator Assessment of 

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Improvement with Treatment Scale was completed at each visit. Safety was assessed by the 
incidence, severity, and duration of treatment-emergent adverse events (TEAEs). Nodule size 
was assessed from baseline to the end of study (EOS) visit (Day 57 ± 5 days). 
A Retreatment Period was added to the EN3835-105 study to allow for retreatment of treated 
nodules and to assess the safety, tolerability, and efficacy of multiple doses of EN3835 in the 
treatment of plantar fibromatosis. Based on the result of an interim analysis, the concentration 
and dose of EN3835 selected for use in the Retreatment Period, was EN3835 2.25 mg/mL 
ranging from 0.45 mg (for nodules ≤ 2 cm) to 0.9 mg per nodule (for nodules >2 cm) . 
After the Initial Treatment Period, almost all (90%) nodules improved by at least 1-level in 
nodular consistency in the EN3835 2.25 mg/mL and 1.2 mg/mL treatment groups, and in the 
EN3835 0.6 mg/mL treatment group, 72.7% of nodules had at least a 1-level improvement. All 
(100%) participants in the EN3835 2.25 mg/mL and almost all (87.5%) participants in the 
1.2 mg/mL treatment groups had at least a 1-level improvement in nodular consistency, There 
was an overall improvement in the FFI-SF-23 composite score in the EN3835 of -48.7%, with a 
negative change representing an improvement. On a nodular level, 73.3% of nodules improved 
by at least 1-level in nodular consistency. There was an incremental improvement of -9.3% in the 
FFI-SF-23 mean (SD) composite score by Day 57. On a nodular level, in all treatment groups, 
≥ 72.7% of nodules were responders on the Subject Satisfaction with Treatment Scale. On a 
participant level, in all treatment groups ≥ 75% of participants were responders on the Subject 
Satisfaction with Treatment Rating Scale and the Investigator Assessment of Improvement Scale. 
There were small and inconsistent changes in nodule size (with increases and decreases) as 
measured by calipers, However, ultrasound measurements remained relatively unchanged and 
therefore did not correlate with other measures of improvement. There was no quantifiable 
systemic exposure of AUX-II following intralesional EN3835 injection of up to 2 injections of 
0.9 mg in the foot and up to 1.8 mg per total dose 
During the Retreatment Period, by Day 57, after administration of 1 or 2 treatments of EN3835 
2.25 mg/mL, almost all participants (81.8%) had nodules that improved by at least 1 level in 
consistency. Additionally, 63.6% of participants were responders on the Subject Satisfaction 
with Treatment Rating Scale. On a nodular level, on, 66.7% of nodules were responders on the 
Subject Satisfaction with Treatment Rating Scale. 
EN3835 was well tolerated. During the Initial Treatment and Retreatment Periods, there were no 
serious adverse events (SAEs), and no TEAEs leading to death, EN3835 discontinuation, or 
study withdrawal. Common TEAEs included: injection site pain, injection site swelling, and 
injection site bruising, with the majority resolving within 21 days. On Day 57 of the Retreatment 
Period, all participants tested (10/10; 100%) had detectable neutralizing AUX-I antibodies and 
almost all participants (8/10; 80%) tested had detectable neutralizing AUX-II antibodies. There 
were no clinically relevant findings in participants with detectable anti-AUX-I, anti-AUX-II, or 
neutralizing AUX-I and AUX-II antibodies. 
3.2.2. 
EN3835-106 
Study EN3835-106 is a Phase 1, open-label study to assess the safety, tolerability, and PK of 
EN3835, administered intralesionally at total doses of either 1.8 mg, 2.7 mg, or 3.6 mg in 
participants with complex configurations of their plantar fibromatosis nodules. The effect of 
EN3835 on foot function, nodule hardness, nodule consistency, and nodule size will also be 

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assessed. To be eligible for treatment participants must have unilateral or bilateral palpable hard 
or firm plantar fibromatosis nodules with a nodule configuration requiring 4 (1.8 mg), 6 (2.7 mg) 
or 8 (3.6 mg) injections of EN3835. Based on the total count, distribution, and size of the 
nodules to be treated, participants will be allocated into a low dose (1.8 mg total dose), medium 
dose (2.7 mg total dose), or high dose (3.6 mg total dose) cohort.  
Depending on the size of the nodule, each nodule will be treated with intralesional EN3835 
0.45 mg (for nodules ≤ 2 cm), 0.9 mg (for nodules >2 - ≤4 cm), 1.35 mg (for nodules > 4 - 
≤ 6 cm), or 1.8 mg (for nodules > 6 cm). PK and immunogenicity samples will be collected 
throughout the study.  
After the first dose of EN3835, participants will return for a total of 8 outpatient follow-up visits, 
on Days 2 (24 hours after injection), 3 (48 hours after injection), 8 (168 hours after injection) and 
22 (504 hours after injection) for collection of PK samples (collected within 10% of nominal 
time point). Biweekly on Days 15, 29, 43, and 57 nodules will be measured using calipers, 
nodule hardness will be assessed via a durometer, nodular consistency by palpation, participant 
assessments of foot function (pain, difficulty, and activity limitation) and treatment satisfaction, 
and clinician assessments of improvement. Treated feet will be photographed through Day 22 to 
document bruising, ecchymosis, and any other similarly related visible local reactions post 
injection. 
Participants will complete the study on Day 57 (EOS Visit) during which immunogenicity 
samples will be collected, safety will be assessed and the nodules will be measured. The 
maximum duration of study participation is up to 85 days (Screening Period: 28 days, Dosing 
Period: 1 day, and a total Follow-up Period of 56 days). 
To date, the study is on hold. 
3.2.3. 
EN3835-306 
Study EN3835-306 is an ongoing Phase 3, multi-center, open-label extension study to assess the 
long-term safety and efficacy of EN3835 in participants who have participated in a parent 
placebo-controlled study of EN3835. Enrolled participants will have the option of:  
1. observation only,
2. treated or retreated with up to 2 treatments of EN3835, or
3. having new nodules treated with up to 2 treatments of EN3835 and agree to either be
treated or retreated during this study.
EN3835 will be administered intralesionally based on the size of the nodule to all nodules 
present. The total number of EN3835 injections across all nodules present shall not exceed 3 
injections (1.35 mg) per treatment in a single foot when treating participants with unilateral 
plantar fibromatosis. When treating participants with bilateral plantar fibromatosis, the total 
number of EN3835 injections across all nodules present shall not exceed 4 injections (1.8 mg) in 
total per treatment with each foot receiving a maximum dose of 0.9 mg.  
Participants will include those who have been treated with EN3835 or placebo as part of a 
sponsored clinical study and are observed and not retreated in the study are expected to enroll in 
the study for approximately 15 months (Day 450).  

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For participants that are retreated/treated on Day 180, the study design allows for evaluation of 
long-term efficacy or safety of up to approximately 417 days (up to approximately 14 months). 
For participants retreated/treated on Day 270, the study design allows evaluation of long-term 
efficacy and safety for approximately 507 days (approximately 17 months). 
3.3. 
Benefit/Risk Assessment 
3.3.1. 
Benefit of EN3835 in Plantar Fibromatosis 
There are 4 case reports of off-label use of EN3835 in patients with recurrent plantar 
fibromatosis. Hammoudeh (2014) reported unsuccessful treatment of a 72-year-old male with 
recurrent bilateral plantar fibromatosis after a single dose of EN3835 0.58 mg. Lehrman et al 
(2019) reported successful treatment of a 22-year-old white female with recurrent plantar 
fibromatosis after a single dose of EN3835 0.58 mg and foot extension and massage. De Vitis 
et al (2020) reported successful treatment of a 59-year-old male with recurrent bilateral nodules 
due to Ledderhose disease (a type of plantar fibromatosis) after single doses of EN3835 0.58 mg 
in each foot without foot extension or massage. Mahmoud et al (2021) reported successful 
treatment of plantar fibromatosis in a 13-year-old female who had recurrent plantar fibromatosis 
after surgical treatment. As early as 3 weeks after treatment the nodule decreased in size and 
there was no tenderness upon palpation. One year after treatment with EN3835 symptoms had 
resolved. 
This study will be conducted in otherwise healthy participants with plantar fibromatosis. To date, 
there is no available therapy to treat the pathophysiology of plantar fibromatosis and prevent 
disease progression. 
3.3.2. 
Risks of EN3835 in Plantar Fibromatosis 
Safety information for EN3835 is derived from the broad experience in participants with DC, 
PD, and cellulite. The preponderance of evidence suggests that XIAFLEX is safe and well 
tolerated, but can result in AEs. In studies of participants with DC, the majority of AEs were 
local, mild, or moderate in severity, confined to the treated extremity, and generally resolved 
within 21 days. As outlined in the prescribing information and in the IB, common AEs observed 
in supporting clinical trials in approved indications and reported in postmarketing safety data 
included local injection site reactions, injection site bruising, injection site swelling, and 
injection site pain.  
SAEs reported in studies of DC included flexor tendon ruptures that occurred after EN3835 
injection into the injected finger/hand and manipulation of the tendon (XIAFLEX Prescribing 
Information). Other EN3835-associated serious local adverse reactions in the treatment of DC 
included pulley rupture, ligament injury, complex regional pain syndrome, sensory abnormality 
of the hand, and skin laceration (tear). There is risk that similar events may occur when EN3835 
is injected into nodules of plantar fibromatosis. To mitigate these risks, participants with 
complicated plantar nodules (eg, encapsulating the nerves, tendons and/or vascular structures) 
that in the investigator’s opinion would make the participant unsuitable for the study will be 
excluded from the study. Examination of the nodule will be conducted at the follow-up visits and 
can be used to assess for the risk of tendon ruptures. Investigators will be encouraged to provide 
necessary medical care to all participants experiencing local adverse reactions. 

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Additionally, investigators will be trained to inject study intervention only into the nodules 
resulting from plantar fibromatosis, and take precautions to avoid injecting into tendons, nerves, 
blood vessels, or other collagen-containing structures of the foot. Investigators will be trained to 
recognize signs or symptoms that may reflect serious injury to the area injected, which should be 
promptly evaluated for any required surgical intervention. 
Because EN3835 contains foreign proteins, severe allergic reactions to EN3835 can occur, 
including anaphylaxis. Participants with a known systemic allergy to collagenase or any other 
excipient of EN3835 will be excluded from the study. The protocol instructs healthcare providers 
to be prepared to address severe allergic reactions following EN3835 injections with 
interventions that may include epinephrine, diphenhydramine (or a suitable equivalent), and 
oxygen. 
AEs of injection site bruising, ecchymosis/contusion, or injection site hemorrhages were 
commonly observed during clinical studies of EN3835 for DC and for other indications 
(cellulite). To mitigate this risk, participants with coagulation disorders and participants currently 
receiving or planning on receiving anticoagulant or antiplatelet medications (except aspirin 
≤ 150 mg) within 7 days before injection of study intervention will be excluded. Use of 
anticoagulants and antiplatelet medications (except aspirin ≤ 150 mg) will be prohibited 
throughout the study. 
Safety monitoring will occur throughout the study to assess the risks of treatment. An 
independent DSMB will periodically review safety data to mitigate risks. 
3.3.3. 
Overall Assessment of Benefit and Risks 
The assessment of the likelihood of these AEs occurring in participants with plantar fibromatosis 
was evaluated while taking into consideration the range of doses of EN3835 to be administered 
in this study. Based on the overall benefit-risk assessment and the precautions taken into account 
in this protocol, it is concluded that EN3835 administered as doses ranging from 0.45 mg to 
1.35 mg per nodule per foot (for participants with unilateral plantar fibromatosis) for up to 2 
treatment visits with a maximum total dose of 1.8 mg per treatment visit (for participants with 
bilateral plantar fibromatosis) has an acceptable benefit-risk ratio. 
Strict inclusion and exclusion criteria, safety monitoring, and clinician training on injection 
technique will ensure appropriate use of EN3835. In summary, the potential risks to participants 
with plantar fibromatosis in this study are outweighed by the potential benefits that may result 
from the clinical development of EN3835 for patients with symptomatic nodules due to plantar 
fibromatosis. 

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4.
OBJECTIVES AND ENDPOINTS
Objective 
Endpoint 
Primary 
•
To assess the improvement with EN3835 vs
placebo in the Foot Function Index (FFI)a pain
subscale.
•
The difference between EN3835 and placebo
in the mean change from Baseline (Day 1) to
Day 57 on the foot pain subscale (total score
on 9 items) of the FFI ranging from 0 (“None”)
to 4 (“Extreme”).
Secondary 
•
To assess the improvement with EN3835 vs
placebo in the FFI pain subscale over time.
•
The mean change from Baseline (Day 1) to
Days 15, 29, 43, and 57 on the pain subscale of
the FFI (total score on 9 items), ranging from 0
(“None”) to 4 (“Extreme”) with EN3835 vs
placebo.
•
To assess the overall improvement in the
combined score of the FFI pain and difficulty
subscales with EN3835 vs placebo.
•
The difference between EN3835 and placebo
in the mean change from Baseline (Day 1) to
Day 57 on the total score of the FFI pain and
difficulty subscales (combined).
•
The mean change from Baseline (Day 1) to
Days 15, 29, 43, and 57 on the total score of
the pain and difficulty subscales of the FFI
with EN3835 vs placebo.
•
To assess investigator assessment of
improvement with EN3835 treatment vs placebo.
•
The difference in the proportion of EN3835-
treated participants and those receiving only
placebo reporting “Minimally Improved” (+1),
“Much Improved” (+2), or “Very Much
Improved” (+3) on the Clinician Global
Impression of Change Scale, a 7-point scale
ranging from −3 (“Very Much Worse”) to +3
(“Very Much Improvement”) on Days 15, 29,
43, and 57.
•
To assess the change in nodule hardness after
administration of EN3835 vs placebo.
•
The difference between EN3835 and placebo
in the mean change from Baseline (Day 1) to
Day 57 in the nodular hardness of the treated
nodules by durometer measurements.
•
The mean change from Baseline (Day 1) to
Days 15, 29, 43, 57 in the nodular hardness of
the treated nodules by durometer
measurements with EN3835 vs placebo

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Objective 
Endpoint 
Safety 
•
To assess the safety and tolerability of EN3835
in participants with plantar fibromatosis.
•
Safety of EN3835 as assessed by incidence,
severity and duration of treatment-emergent
adverse events (TEAEs), adverse events of
special interest (AESIs), and serious adverse
events (SAEs).
•
The change from baseline in vital signs and
clinical laboratory values at each visit where
these parameters are measured.
•
To assess the immunogenicity of EN3835 in
participants with plantar fibromatosis.
•
Presence of anti-AUX-I and anti-AUX-II
antibody titer levels in EN3835 treated-
participants at Day 1 and Day 57.
•
Presence of neutralizing antibodies to AUX-I
and AUX-II in EN3835 treated-participants at
Day 1 and Day 57.
Exploratory 
•
To assess the overall improvement in the FFI
composite score with EN3835 vs placebo.
•
The difference between EN3835 and placebo
in the mean change from Baseline (Day 1) to
Day 57 on the FFI composite score, with the
score of each of the 21 items ranging from 0 to
4, with 4 indicating higher severity.
•
The mean change from Baseline (Day 1) to
Days 15, 29, 43, and 57 on the FFI composite
score with EN3835 vs placebo.
•
To assess the overall improvement in severity of
plantar fibromatosis on the Patient Global
Impression of Severity (PGIS) PF Overall scale.
•
The difference between EN3835 and placebo
at Day 57 on the PGIS PF Overall score.
•
The difference between EN3835 and placebo
Days 15, 29, 43, and 57 on the PGIS PF
Overall score with EN3835 vs placebo.
•
To assess the overall improvement in the
severity of foot pain with EN3835 vs placebo in
the PGIS foot pain subscale.
•
The difference between EN3835 and placebo
at Day 57 on the foot pain subscale of the
PGIS.
•
The difference between EN3835 and placebo
at Days 15, 29, 43, and 57 on the PGIS foot
pain subscale, ranging from 0 (“None”) to 4
(“Severe”) with EN3835 vs placebo.
•
To assess the overall improvement in the
severity of difficulty with EN3835 vs placebo in
the PGIS difficulty subscale.
•
The difference between EN3835 and placebo
at Day 57 on the difficulty subscale of the
PGIS.
•
The difference between EN3835 and placebo
at Days 15, 29, 43, and 57 on the PGIS
difficulty subscale, ranging from 0 (“None”) to
4 (“Severe”) with EN3835 vs placebo.

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Objective 
Endpoint 
•
To assess the overall improvement in the
severity of difficulty with EN3835 vs placebo in
the PGIS activity limitation subscale.
•
The difference between EN3835 and placebo
at Day 57 on the activity limitation subscale of
the PGIS.
•
The difference between EN3835 and placebo
at Days 15, 29, 43, and 57 on the PGIS activity
limitation subscale, ranging from 0 (“None”)
to 4 (“Severe”) with EN3835 vs placebo.
•
To assess the Patient Global Impression of
Change (PGIC) PF Overall with EN3835
treatment vs placebo.
•
The difference in the proportion of participants
treated with EN3835 or placebo reporting
“Minimal Improvement” (+1), “Much
Improvement” (+2), and “Very Much
Improvement” (+3) on the PGIC scale, a
7-point scale ranging from -3 (“Very Much
Worse”) to +3 (“Very Much Improvement”)
on Days 15, 29, 43, and 57.
•
To assess the change in the overall severity of
foot pain on the Foot Pain Subscale of the PGIC.
•
The difference in the proportion of participants
treated with EN3835 or placebo reporting
“Minimal Improvement” (+1), “Much
Improvement” (+2), and “Very Much
Improvement” (+3) on the foot pain subscale
of the PGIC scale, a 7 point scale ranging from
-3 (“Very Much Worse”) to +3 (“Very Much
Improvement”) on Days 15, 29, 43, and 57.
•
To assess the change in the overall severity of
difficulty on the Difficulty Subscale of the PGIC.
•
The difference in the proportion of participants
treated with EN3835 or placebo reporting
“Minimal Improvement”(+1), “Much
Improvement” (+2), and “Very Much
Improvement” (+3) on the difficulty subscale
of the PGIC scale, a 7 point scale ranging from
-3 (“Very Much Worse”) to +3 (“Very Much
Improvement”) on Days 15, 29, 43, and 57.
•
To assess the change in the overall severity of
activity limitation on the Activity Limitation
Subscale of the PGIC.
•
The difference in the proportion of participants
treated with EN3835 or placebo reporting
“Minimal Improvement” (+1), “Much
Improvement” (+2), and “Very Much
Improvement” (+3) on the activity limitation
subscale of the PGIC scale, a 7 point scale
ranging from -3 (“Very Much Worse”) to +3
(“Very Much Improvement”) on Days 15, 29,
43, and 57.

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Objective 
Endpoint 
•
To assess the overall improvement in foot pain
with EN3835 vs placebo on the Pain Intensity
Numerical Rating Scale (NRS).
•
The difference between EN3835 and placebo
in the mean change from Baseline (Day 1) to
Day 57 on the Pain Intensity NRS.
•
The mean change from Baseline (Day 1) to
Days 15, 29, 43, and 57 on the Pain Intensity
NRS, ranging from 0 (“None”) to 10 (“Worst
Pain Imaginable”) with EN3835 vs placebo.
•
To assess participant satisfaction with EN3835
treatment vs placebo.
•
The difference in the proportion of participants
treated with EN3835 or placebo reporting to be
“Satisfied” (+1) and “Very Satisfied” (+2) on
the Subject Satisfaction With Treatment Scale,
a 5-point scale ranging from −2 (“Very
Dissatisfied”) to +2 (“Very Satisfied”) on
Days 15, 29, 43, and 57.
•
To assess the improvement with EN3835 vs
placebo in the FFI activity limitation subscale in
participants on the activity limitation subscale at
baseline.
•
The difference between EN3835 and placebo
in the mean change from Baseline (Day 1) to
Day 57 on the activity limitation subscale
(total score on 3 items) of the FFI, ranging
from 0 (“Never”) to 4 (“Always”).
•
The mean change from Baseline (Day 1) to
Days 15, 29, 43, and 57 on the activity
limitation subscale (total score on 3 items) of
the FFI, ranging from 0 (“Never”) to 4
(“Always”) with EN3835 vs placebo.
•
To assess the improvement with EN3835 vs
placebo in the FFI difficulty subscale in
participants on the difficulty subscale at baseline.
•
The difference between EN3835 and placebo
in the mean change from Baseline (Day 1) to
Day 57 on the difficulty subscale (total score
on 9 items) of the FFI, ranging from 0 (“No
Difficulty”) to 4 (“A Lot of Difficulty”).
•
The mean change from Baseline (Day 1) to
Days 15, 29, 43, and 57 on the difficulty
subscale (total score on 9 items) of the FFI,
ranging from 0 (“No Difficulty”) to 4 (“A Lot
of Difficulty”) with EN3835 vs placebo.
•
To assess the change in nodule size after
administration of EN3835 vs placebo.
•
The difference between EN3835 and placebo
in the mean change from Baseline (Day 1) to
Day 57 in the size of the treated nodules by
caliper measurements.
•
The mean change from Baseline (Day 1) to
Days 15, 29, 43, and 57 in nodule size with
EN3835 vs placebo.

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Objective 
Endpoint 
•
To assess the change in nodule consistency (by
palpation) after administration of EN3835 vs
placebo.
•
The difference between EN3835 and placebo
in the change in consistency from Baseline
(Day 1) to Day 57 as determined by the
number of participants with a soft or non-
palpable consistency at Day 57.
•
The change from Baseline (Day 1) to Days 15,
29, 43, and 57 in nodule consistency with
EN3835 vs placebo.
a. For use in this study, the Foot Function Index has been adapted for plantar fibromatosis (FFI-PF-May 2021), and
will hereafter be referred to as FFI.

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5.
STUDY DESIGN
5.1. 
Overall Design 
Participants will be screened to randomize approximately 172 participants into 2 groups, an 
EN3835 group (n ~86) and a placebo group (n ~86) in a 1:1 ratio. Study intervention will be 
administered intralesionally to all nodules present based on the size of each nodule at the doses 
described in the dosage table (Table 2). All nodules present on each foot on Day 1 must be 
treated. (If all nodules on each foot are not hard, firm throughout, moderately firm on Screening 
and Day 1, the participant will not be eligible for study inclusion). Nodules will be measured 
using calipers and the largest width or length will be used to determine the number of injections 
to be administered in each nodule. The total number of study intervention injections across all 
nodules present, shall not exceed 3 injections (1.35 mg) in a single foot when treating 
participants with unilateral plantar fibromatosis. When treating participants with bilateral plantar 
fibromatosis, the total number of study intervention injections across all nodules present shall not 
exceed 4 injections (1.8 mg) in total with each foot receiving a maximum dose of 0.9 mg. After 
receiving study intervention, participants will be encouraged to resume normal daily activities 
including walking and bearing weight on the treated foot/feet. All participants will return to the 
clinic for 4 follow-up visits, 2 weeks apart, on Days 15, 29, 43, and 57.  
At the Day 29 visit, if the participant has any previously treated nodule(s) that remains palpable 
and measurable by caliper with a consistency of hard, firm throughout, moderately firm, or soft 
that is/are deemed appropriate for treatment by the investigator, and the Treatment 2 Criteria are 
met, a second dose of the study intervention may be administered.  
For all participants, at the time points listed in the Schedule of Assessments, the efficacy of the 
study intervention will be assessed on the FFI (adapted for plantar fibromatosis; May 2021), the 
Subject Satisfaction with Treatment Scale, the PGIC PF Overall and individual PGIC subscales 
of pain, difficulty, and activity limitation, the Pain Intensity NRS, the PGIS PF Overall, and the 
individual PGIS subscales of pain, difficulty, and activity limitation, and the Clinician Global 
Impression of Change Scale. Safety will be assessed by evaluating the incidence and duration of 
TEAEs, AESIs, SAEs, and changes in vital signs and clinical laboratory values. 
All participants will complete the study on EOS (Day 57) Visit, regardless of whether they 
receive 1 or 2 treatments during the study. At the EOS visit, immunogenicity samples will be 
collected, safety will be assessed, and nodules will be measured. The maximum duration of 
participation is up to 85 days (Screening Period: 28 days, Treatment Periods: 1 or 2 days, and a 
total Follow-up Period of 56 days). 
5.2. 
Scientific Rationale for the Study Design 
Study EN3835-105 is a completed, open-label study conducted to assess the safety, tolerability, 
and PK of EN3835 in the treatment of plantar fibromatosis. The effect of EN3835 on nodule size 
was assessed and a validated assessment tool (ie, Foot Function Index-Short Form-23 
[FFI-SF-23]) was used to obtain a preliminary assessment of the treatment with EN3835 on 
multiple functional domains (eg, foot pain, disability, and difficulty) considered representative of 
clinically meaningful endpoints in the treatment of plantar fibromatosis. Results of an interim 
analysis from this study showed that participants receiving EN3835 showed improvement in the 

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severity of their plantar fibromatosis symptoms of pain, difficulty, and disability (activity 
limitation) with improvements more prominent with the 1.2 mg/mL or 2.25 mg/mL doses. Both 
participants and investigators saw an improvement in nodule consistency by Day 57. All AEs in 
this study were considered mild to moderate in severity and most were TEAEs related to the 
injection site. Most AEs resolved within 21 days. 
Study EN3835-222 is a randomized, double-blind, placebo-controlled study will evaluate the 
efficacy and safety of up to 2 doses of EN3835 vs placebo in participants with plantar 
fibromatosis. Participants will receive a maximum dose of up to 1.8 mg per treatment for up to 2 
treatments based on the configuration of their nodules. For participants with bilateral plantar 
fibromatosis, no more than 2 injections (0.9 mg) per foot can be administered. For participants 
with unilateral plantar fibromatosis, no more than 3 injections (1.35 mg) may be administered in 
the single foot. Multiple nodules may be treated on the same foot.  
Efficacy and safety data will be collected throughout the study. 
5.2.1. 
Changes in the Study Design Due to COVID-19 
The COVID-19 public health emergency has disrupted the conduct of clinical research 
throughout the world. At Endo, ensuring the safety of clinical study participants is our primary 
concern. In addition, the integrity of data obtained from clinical studies must be ensured. 
To ensure participant safety and protect data integrity with Endo’s approval, Endo may allow 
remote visits for certain safety assessments. This is aligned with the FDA Guidance on Conduct 
of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency 
(March 2020, updated 30 August 2021). 
Additionally, participants impacted by the health emergency will be allowed to continue in the 
study and complete assessments when the investigational sites re-open as follows: 
•
A participant who had received any dose of EN3835 in the study prior to an
interruption will be allowed to continue in the study.
5.2.2. 
Justification for Dose 
EN3835-105 was a randomized dose-ranging study during which in the initial phase, the safety 
and effectiveness of 3 different concentrations of EN3835: 0.6, 1.2, and 2.25 mg/mL, were 
studied. In addition, nodules which were 1.5 cm or smaller in diameter received 1 injection while 
nodules that exceeded 1.5 cm received 2 injections. Once all participants completed the initial 
study phase, an interim analysis was done to compare the 3 concentrations and select the optimal 
concentrations for use in the retreatment phase of EN3835-105 and EN3835-222 overall. 
In EN3835-105, at the time of the interim analysis, there were an insufficient number of 
participants with at least a 50% score on the pain subscale to evaluate the 2.25 mg/mL cohort 
treatment effect. To evaluate this population participants who had a baseline total FFI-SF-23 
score of at least 34 were selected to evaluate the treatment effect. 
The following criteria were to be collected throughout the study and used to evaluate the dose 
selection: safety (incidence and severity of AEs), nodular consistency, nodule size (area), and 
FFI-SF-23 response in subdomains of Pain, Difficulty, and Disability. 

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Safety data along with a combination of observed change in nodule characteristics (size and 
consistency) in addition to participant-reported responses to the FFI-SF-23 were used to evaluate 
the response to 0.6, 1.2, and 2.25 mg/mL of EN3835. 
The combination of responses to each of the 3 categories were assigned levels of treatment 
response (Very good, Good, Some, No, and Poor) as below: 
Very good treatment response was defined as a non-palpable nodule (no measurable size or 
consistency) and reduction in FFI-SF-23 score.  
Good treatment response was defined as a reduction in all 3 categories. 
Some treatment response was defined as a reduction in 2 of the 3 categories. 
No treatment response was defined as a reduction in 1 category and no change in the other 2. 
Poor treatment response was defined as no reduction in any category. 
Worsening (significant increase in size, increase in hardness or increase in composite 
FFI-SF-23 response) in any category was considered a Poor treatment response.  
At the time of the interim analysis of EN3835-105 there were 24 total treatment-related AEs in 
the 0.6 mg/mL group, 16 treatment-related AEs in the 1.2 mg/mL group, and 15 treatment-
related AEs in the 2.25 mg/mL group. All AEs were of mild to moderate intensity and most 
resolved within 21 days. The safety profiles, including the type (injection site reactions, 
including pain, bruising, swelling, and ecchymosis), intensity, and duration of the treatment 
related AEs were similar among treatment groups. It was concluded that all concentrations were 
equally safe and well tolerated. 
Dose Selection 
Rodent studies assessed the effects of intravenous injection of EN3835 directly into the systemic 
circulation. Dose-dependent liver toxicity was noted at exposures greater than or equal to 
13 times the 2.7 mg of the maximum recommended human dose on a mg/kg basis (Study LAB 
1007-1671). Since the proposed maximum total dose of EN3835 recommended for intralesional 
injection per treatment visit will be much lower than the intravenous injection administered in 
rodent studies, Endo considers the proposed dose will have no risk of systemic toxicity. 
Based on the aforementioned data, it was concluded that in the interim analysis of Study 
EN3835-105, both the 1.2 and 2.25 mg/mL concentrations had a better treatment effect versus 
the lowest concentration, 0.6 mg/mL. Participants who received 2 injections of either 1.2 mg/mL 
or 2.25 mg/mL had a better treatment effect compared to those receiving 1 injection. A better 
treatment response on the FFI was observed in participants who received 2 injections of 
2.25 mg/mL compared to those receiving 2 injections of 1.2 mg/mL. Overall, participants in the 
2.25 mg/mL group had the best treatment responses as defined above. Paired with the nearly 
equivalent safety profile between the 2 concentrations, the 2.25 mg/mL concentration was 
selected to be used in the retreatment phase of Studies EN3835-105 and EN3835-222. The 
maximum total dose of EN3835 to be administered during this study when both feet are treated is 
1.8 mg, and the maximum dose administered to a single foot is 1.35 mg when only 1 foot is 
treated, given that these were the maximum doses evaluated in Study EN3835-105.  

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5.2.3. 
Justification of Measures 
5.2.3.1. 
Foot Function Index-PF-May 2021 
The Foot Function Index (FFI) scale for use in Study EN3835-105 was an adapted from the Foot 
Function Index-Short Form-23 (FFI-SF-23) for use in plantar fibromatosis. The FFI-SF-23 is a 
total foot function assessment instrument (Budiman-Mak et al, 1991; Budiman-Mak et al, 2013) 
comprising 23 items used to assess foot pain, disability, and difficulty in participants with ankle 
and foot disorders.  
Concept elicitation and cognitive interviews were conducted with participants with plantar 
fibromatosis (n=19) using the FFI-SF-23 to confirm content validity and to confirm that the 
measure was understandable and relevant in this population. The feedback from the interviews, 
in combination with FDA feedback resulted in minor revisions to the instrument, which 
produced a 21-item version, the FFI-PF-May 2021, referred to as the FFI, which will be used in 
this study. This pain subscale of the FFI will be used in this study in the assessment of the 
primary endpoint. Additional cognitive interviews (n=7) were conducted, focused specifically on 
the changes present in the FFI, to confirm content validity and comprehension of the FFI. Based 
on the second round of cognitive interviews, participants felt that the FFI applied to them and did 
not recommend changes to the items or response options, therefore no additional changes were 
made to the FFI. 
5.2.3.2. 
Patient Global Impression of Severity (PGIS) 
A single global item PGIS scale will be used for overall severity of plantar fibromatosis. 
Additional PGIS subscales will measure the overall severity of foot pain, difficulty, and activity 
limitation  
5.2.3.3. 
Patient Global Impression of Change (PGIC) 
A single global item PGIC scale will be used for overall impression of change in plantar 
fibromatosis. Additional PGIC subscales will measure the overall impression of change in the 
severity of foot pain, difficulty with the foot/feet, and activity limitation due to the feet.  
5.2.3.4. 
Pain Intensity Numeric Rating Scale (NRS) 
A single item NRS will be used to capture the intensity for foot pain related to plantar 
fibromatosis.  
5.2.3.5. 
Durometer Use 
Based on the interim data available from Study EN3835-105, after administration of EN3835, 
most nodules become softer upon palpation and scores on the FFI-SF-23 improve during the 
weeks after treatment. In order to quantify nodule consistency and to standardize the 
interpretation of nodule consistency, a durometer will be used to measure changes in nodules 
during the study. 

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5.2.4. 
Stopping Rules for the Study 
During the conduct of the study, AEs and SAEs will be reported to identify any safety concerns 
(Section 9.3.1). These events are continuously reviewed by the medical monitor at the frequency 
established in the medical monitoring plan. 
The sponsor may decide to stop enrollment early due to recommendations from the external, 
independent DSMB (Section 11.1.4). The DSMB will meet at an appropriate frequency, as 
described in the DSMB charter. The DSMB will also convene if ≥3% of study participants have 
developed a TEAE of CTCAE ≥ Grade 3 due to serious injuries to the foot caused by local 
complications of the injection, or if ≥3% of study participants have experienced anaphylaxis after 
the study treatment. In that setting, the DSMB will conduct an independent assessment and make 
a recommendation regarding study continuation based upon their overall assessment of risks and 
benefits to study participants based upon a review of unblinded data.  
This study may be terminated by the sponsor for any reason at any time. This can include new 
safety concerns that can invalidate the earlier positive risk-benefit assessment. 
5.3. 
End of Study Definition 
A participant is considered to have completed the study if the participant has completed the EOS 
(Day 57) Visit.  
The end of study is defined as the completion of the final assessment for the last participant. All 
participants are expected to remain in the study until Day 57, regardless if they receive 1 or 2 
treatments. 
The study completion date is defined as date the final participant was examined or received an 
intervention for purposes of final collection of data for the primary and secondary outcome 
measures and adverse events (e.g., last participant's last visit or 28-day follow-up Safety Visit), 
as shown in the Schedule of Assessments (Section 2.3). This study completion date applies 
whether the study concluded according to the pre-specified protocol or was terminated. 
6.
SELECTION AND WITHDRAWAL OF PARTICIPANTS
6.1. 
Participant Inclusion Criteria
Diagnosis and Inclusion Criteria 
To be eligible to participate in the study, the participant must meet the following criteria: 
Age and Sex: 
1. Be an ambulatory male or female ≥18 years of age.
Disease Characteristics: 
2. Has a diagnosis of plantar fibromatosis AND have at least 1 hard, firm throughout, or
moderately firm, palpable fibrous nodule on clinical examination and measurable by
caliper.

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3. Has a score of at least 50% on the pain subscale of the FFI (maximum score of 28
[without orthotics] or 36 [with orthotics] as applicable).
4. Requires ≤ 4 injections (1.8 mg maximum total dose) per treatment visit.
a.
For participants with bilateral plantar fibromatosis, has a nodule configuration
requiring ≤ 2 injections per foot (0.9 mg maximum dose per foot) based on the total
count and size of all plantar nodules present.
b. For participants with unilateral plantar fibromatosis, has a nodule configuration
requiring ≤ 3 injections (1.35 mg maximum dose per foot), based on the total count
and size of plantar nodules.
5. Has no significant medical history or examination findings related to the participant’s
plantar nodule (s), which in the investigator’s opinion, would make the participant
unsuitable for study intervention administration.
Type of Participant: 
6. Willing and able to comply with all protocol required visits and assessments.
7. Able to read and understand the patient reported assessments in the local language of the
country.
8. Agree not to use opioids (eg, codeine, heroin, hydrocodone, hydromorphone, morphine,
oxycodone) during the study period and has not used opioids 2 weeks before the
Screening Visit.
9. Agree to not initiate or change use of orthotics or inserts designed to relieve symptoms of
plantar fibromatosis during the study period.
10. If female, be of non-childbearing 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
non-pregnant, non-lactating 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, 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.
Informed Consent: 
11. Capable of providing consent, are adequately informed, and understand the nature and
risks of the study.
6.2. 
Participant Exclusion Criteria 
A participant is ineligible for study participation if the participant meets any of the following 
criteria: 

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Medical Conditions: 
1. Has the presence of non-plantar fibromatosis-related nodules on the affected foot/feet
(eg, neurofibroma, rhabdomyosarcoma, liposarcoma, neurilemmomas, rheumatoid
nodules, desmoid tumors, or malignant soft tissue lesions of the foot or ankle).
2. Has any musculoskeletal, neuromuscular, neurosensory, other neurological or related
disorder that affects the participant's use of his or her feet and/or would impair his/her
completion of study assessments as determined by the investigator.
3. Has the presence of soft (or not hard/firm) plantar fibromatosis nodule on either foot.
4. Has ≥ 5 plantar fibromatosis nodules (for bilateral and unilateral plantar fibromatosis).
5. For bilateral plantar fibromatosis:
−
Has > 2 nodules per foot OR
−
Has any nodules > 4 cm
6. For unilateral plantar fibromatosis:
−
Has >3 nodules OR
−
Has ≥2 nodule that are >2 cm each.
7. Has a known systemic allergy to collagenase or any other excipient of EN3835.
8. Has a known bleeding disorder which would make the participant unsuitable for
enrollment in the study (see Exclusion Criterion #16).
9. Has a clinically significant laboratory abnormality or any laboratory test results meeting
any of the following criteria:
a.
alanine aminotransferase (ALT) ≥ 3 × upper limit of normal (ULN)
b. total bilirubin (TBL) ≥ 2 × ULN (> 35% direct bilirubin)
c.
aspartate aminotransferase (AST) ≥ 3 × ULN
d. international normalized ratio (INR) >1.5
10. 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) or any significant
hematological, endocrine, cardiovascular, respiratory, renal, hepatic, or gastrointestinal
disease). If there is a history of such disease but the condition has been stable (defined as
not requiring significant change in therapy or hospitalization for worsening disease) for
more than 1 year and is judged by the investigator not to interfere with participation in
the study, the participant may be included, with the documented approval of the medical
monitor.
11. Any other significant medical condition(s), which in the investigator’s opinion would
make the participant unsuitable for enrollment in the study.
12. Is pregnant or plans to become pregnant.
13. Is breastfeeding, or is providing or plans to provide breast milk in any manner during the
study.

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Prior/Concomitant Therapy: 
14. Received surgical or non-surgical treatment(s) (eg, steroid injection,
transdermal/intralesional verapamil, radiation therapy, extracorporeal shock wave
therapy) on the foot or nodule(s) to be treated within 3 months before administration of
study intervention.
15. Has received any collagenase treatment (eg, Santyl® ointment, XIAFLEX®/XIAPEX®,
EN3835, or CCH) within 30 days prior to Day 1.
16. Is currently receiving, has received (within 7 days of the first treatment of study
intervention, or plans to receive any anticoagulant or antiplatelet medication (except for
≤150 mg aspirin daily) that would increase the risk of bleeding during the study.
Prior/Concurrent Clinical Study Experience: 
17. Participation in other studies involving an investigational drug within 30 days before
treatment with study intervention and/or during study participation.
18. Has previously participated in clinical studies of EN3835 in plantar fibromatosis.
Other Considerations: 
19. Is from a vulnerable population, as defined by the US Code of Federal Regulations (CFR)
Title 45, Part 46, Section 46.111(b) and other local and national regulations, including
but not limited to, employees (temporary, part-time, full-time, etc) or a family member of
the research staff conducting the study, or of the sponsor, or of the contract research
organization, or of the Institutional Review Board (IRB).
6.2.1. 
Participant Inclusion Criteria – Treatment 2 
To be eligible to receive the second treatment, on Day 29, the participant must meet the 
following criteria: 
Disease Characteristics: 
1. The participant may receive additional treatment if the participant has a previously
treated nodule(s) that remains palpable (eg, hard, moderately firm, firm throughout or
soft) on clinical examination and measurable by caliper.
2. Women of childbearing potential must have a negative urine pregnancy test.
6.2.2. 
Participant Exclusion Criteria – Treatment 2 
Medical Conditions: 
1. The participant must not have any significant medical conditions, which in the
investigator’s opinion would preclude receiving a second treatment.
6.3. 
Lifestyle Considerations 
After receiving study intervention, participants will be encouraged to resume normal daily 
activities including weight bearing and walking on the treated foot/feet. Participants should be 

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encouraged to wear supportive footwear (such as sneakers or tennis shoes) when on their feet 
during the study. Participants must agree to not initiate or change the use of orthotics or inserts 
designed to relieve symptoms of plantar fibromatosis during the study period. 
6.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in this study but are not 
randomized. 
A participant who is a screen failure at the Screening Visit or Day 1 may be rescreened with 
approval of the sponsor. The period from the start of rescreening related procedures to injection 
of study intervention must not exceed 28 days. Participants may be rescreened only once; this 
includes any rescreening due to COVID-19 interruption.  
If the day of rescreening is > 28 days from the day the participant was initially screened, the 
participant will need to repeat all procedures and be reconsented. If the day of rescreening is 
< 28 days from the day the participant was initially screened, the need to repeat other screening 
assessments will be determined on an individual basis. 
Participants who do not meet all of the eligibility criteria at the Screening and Day 1 visits will 
be deemed a screen failure and the following information must be recorded for all participants 
who are screen failures: 
•
Demography (age, gender, race/ethnicity).
•
Reason for screen failure.
•
Which inclusion criteria not met or exclusion criteria met.
•
Any AE/SAE experienced by the participant.
7.
STUDY INTERVENTION
Study intervention is defined as any investigational treatment, marketed products, placebo, or 
device intended to be administered to a study participant according to the study protocol. In this 
protocol, study intervention refers to EN3835 and placebo. 
7.1. 
Selection of Nodules 
During the Screening and Day 1 Visits, the investigator will examine and evaluate the nodules on 
the affected foot/feet, by conducting caliper measurements, measuring nodule hardness using a 
durometer, palpating the nodule for consistency, and assessing the FFI. Only hard, firm 
throughout, moderately firm fibrous nodules that are palpable on clinical examination and 
measurable on calipers are eligible for treatment on Day 1. All hard, firm throughout, moderately 
firm nodules present on each foot on Day 1 must be treated. (If all nodules on each foot are not 
hard, moderately firm or firm throughout on Screening and Day 1, the participant will not be 
eligible for study inclusion). Study intervention will be administered intralesionally to nodules 
present meeting eligibility criteria based on the size of each nodule at the doses described in 
Table 2. 

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Based on the largest diameter of width or length of the nodule determined by calipers, 
participants will receive 1 to 3 injections of study intervention per foot. Participants with nodules 
of ≤ 2 cm will receive 1 intralesional injection of study intervention per nodule. Participants with 
nodules of > 2 cm to ≤ 4 cm will receive 2 intralesional injections of study intervention per 
nodule. Participants with nodules of > 4 cm will receive 3 intralesional injections of study 
intervention per nodule. 
Nodules treated on Day 1 that remain palpable on Day 29 clinical examination and have 
consistency of hard, firm throughout, moderately firm, or soft are eligible for a second treatment 
on Day 29. 
7.2. 
Topical Anesthetic 
Topical anesthetics (ie, cream, ointment, gel, spray) may be administered before intralesional 
injection of study intervention provided it does not interfere with proper identification of the 
nodule or with administration of the study intervention. The topical anesthetic used should be 
captured as a concomitant medication. 
7.3. 
Study Intervention Administration 
Details of the study intervention and administration are presented in Table 1. Specific 
instructions for EN3835/placebo reconstitution and preparation of administration syringes will be 
provided in the Pharmacy Manual. Study intervention will be injected intralesionally. Specific 
instructions outlining the injection techniques will be provided in the Study Operations Manual. 
Table 1: 
Study Intervention Administration 
Treatment Concentrations 
EN3835 
Placebo 
Product Name 
EN3835 (0.9 mg of collagenase 
clostridium histolyticum with 0.5 mg of 
hydrochloric acid, 18.5 mg of sucrose 
and 1.1 mg of tromethamine) plus 
diluent 
Placebo (0.5 mg of hydrochloric acid, 
18.5 mg of sucrose and 1.1 mg of 
tromethamine) plus diluent 
Type 
Biologic 
NA 
Dose Formulation 
Injectable liquid 
Injectable liquid 
Unit Dose Strengths 
2.25 mg/mL 
NA 
Dose Amount and 
Frequencya 
0.45 mg administered as 1 injection  
0.9 mg administered as 2 injections 
1.35 mg administered as 3 injections 
Volume matched placebo administered 
as 1 injection, 2 injections, or 
3 injections per nodule depending on 
nodule size 
Route of Administration 
Intralesional injection 
Intralesional injection 
Sourcing 
Provided centrally by the sponsor 
Provided centrally by the sponsor 
Packaging and Labeling 
Product will be provided in vials. Each 
vial will be labeled per country 
requirement. 
Product will be provided in vials. Each 
vial will be labeled per country 
requirement. 
aEach injection (0.45 mg) of study intervention will be administered as 2 aliquots of 0.225 mg each. 

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7.3.1. 
Study Intervention 
The dose of study intervention that will be administered per nodule based on nodule size is 
presented in Table 2. The total dose received by a participant is determined by size of nodule and 
number of injections. Each injection (0.45 mg) of study intervention will be administered as 2 
aliquots of 0.225 mg each.  
Table 2: 
Dose of Study Intervention per Nodule 
Palpable Nodule Size 
Injections 
Total Volume (mL) 
Total Dose Administered/ 
Nodule (mg) 
Up to 2 cm 
1 
0.2 
0.45 
>2 cm to ≤4 cm
2 
0.4 
0.9 
>4 cm
3 
0.6 
1.35 
•
Size of each nodule will be determined by caliper and the largest width or length will be used to determine
number of injections/aliquots to be administered.
•
Each injection of study intervention (0.45 mg) is administered as 2 aliquots of 0.225 mg each.
•
Maximum dose at 1 treatment visit not to exceed 1.8 mg in total (with maximum of 0.9 mg/per foot) when
treating bilateral plantar fibromatosis. When treating unilateral plantar fibromatosis, the maximum dose at 1
treatment should not exceed 1.35 mg in the affected foot. All hard, firm throughout, or moderately firm nodules
present on each foot on Day 1 must be treated. If all nodules on each foot are not hard, firm throughout,
moderately firm on Screening and on Day 1, the participants are not eligible for inclusion.
•
1 cm = 10 mm
7.3.2. 
Injection of Study Intervention 
Study intervention will be injected intralesionally directly into the nodule using a 27-gauge, 
0.5-inch needle. Instructions are provided in the Injection Guide in the Study Operations Manual. 
NOTE: As EN3835 is a foreign protein, investigators must be prepared to address a severe 
allergic reaction should it occur. At the time of injection, a 1:1000 solution of epinephrine for 
injection, 50 mg diphenhydramine injection or a suitable equivalent, and oxygen should be 
available to the investigator and site staff familiar with their use.  
7.3.3. 
Care Procedures After Injection 
Care procedures after the injection are provided in the Study Operations Manual. 
To evaluate the participant for possible immediate immunological AEs, the participant will 
remain in direct observation of medical personnel who are skilled in the management of acute 
allergic reactions for the first 30 minutes after receiving an injection of study intervention (see 
Section 7.3.2). Participants may leave direct observation after the 30-minute period provided: 
•
The participant exhibits no sign of an immunological or other clinically significant
systemic or local AE.
•
The participant’s vital signs have remained stable throughout the 30-minute
observation period (see Section 9.2.4).
Participants will be instructed when to inspect the treated foot for edema, sensation, movement, 
and when they will be allowed to walk bearing their full weight as tolerable.  

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7.4. 
Study Intervention Preparation/Handling/Storage/Accountability 
EN3835, placebo, and the diluent will be supplied in glass vials, which will be shipped and 
stored at 2°C to 8°C.  
The investigator or designee will confirm that appropriate temperature control conditions have 
been maintained during transit and while in the investigator's possession for all study 
interventions received and any discrepancies are reported and resolved prior to study intervention 
administration. 
The study intervention will be maintained in a monitored, environmentally controlled (in 
accordance with treatment labeling), secure, locked area with restricted access at the study site. 
Only participants enrolled in the study will receive study intervention and only authorized study 
staff will dispense study intervention. 
In accordance with the International Council for Harmonisation (ICH) requirements, at all times 
the investigator will be able to account for all study intervention furnished to the study site. An 
accountability record will be maintained for this purpose. The investigator must maintain 
accurate records indicating dates and quantity of study intervention received, to whom it was 
administered (participant-by-participant accounting) and accounts of any study intervention 
accidentally or deliberately destroyed. All unused study intervention not involved in immediate 
participant treatment will be maintained under locked, temperature-controlled storage at the 
study site. Please refer to the Pharmacy Manual for complete information regarding preparation, 
handling, storage, and accountability of study intervention. 
7.5. 
Measures to Minimize Bias 
This is a double-blind, placebo-controlled study. Participants will be randomized according to a 
validated, computer generated allocation scheme to receive the study interventions described in a 
1:1 ratio. Participants will complete their assessment scales before the investigator scales will be 
completed to avoid bias. Precautions will be in place to ensure that investigators are blinded to 
participant assessments on the COA scales. 
7.5.1. 
Interactive Response Technology 
The investigator or designee will utilize interactive response technology (IRT) system to register 
participants at screening. Each participant’s unique identification (ID) number will be assigned 
by the IRT system and will be used to identify the participant for the duration of the study within 
all systems and documentation. If the participant is not eligible to receive study intervention, or 
should discontinue from the study, the participant ID number will not be reassigned to another 
participant. Specific instructions for the use of the IRT system will be included in the IRT User 
Manual. 
The investigator must maintain a participant master log linking the participant ID to the 
participant’s name. The investigator will not have access to the participant’s treatment 
assignment. The investigator must follow all applicable privacy laws in order to protect a 
participant’s privacy and confidentiality. Information that could identify a participant will be 
masked on material received by the sponsor.  

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7.5.2. 
Emergency Identification of Study Intervention 
The blind may be broken if, in the opinion of the investigator, it is in the participant’s best 
interest for the investigator to know the study intervention assignment. The sponsor must be 
notified before the blind is broken unless identification of the study intervention is required for a 
medical emergency in which the knowledge of the specific blinded treatment will affect the 
immediate management of the participant’s condition (eg, antidote available). In this case, the 
sponsor must be notified within 24 hours after breaking the blind. The date and time that the 
blind was broken must be recorded in the source documentation. 
7.6. 
Treatment Compliance 
All participants will receive study intervention administered by a qualified health care 
professional at the study site. Study intervention will be administered according to the 
instructions provided in the Study Operations Manual. 
Accidental or intentional overdoses should be reported to the sponsor/designee promptly (see 
Section 9.4). 
7.7. 
Prior and Concomitant Medications and Procedures 
7.7.1. 
Prior Medications 
The start and stop date, dose, unit, frequency, route of administration, and indication for all prior 
medications (taken within the 30 days prior to the Screening Visit) and nondrug therapies 
(eg, blood transfusions, oxygen supplementation, physical therapy, etc) received will be 
recorded.  
In addition, all prior treatments administered for the disease/condition under study will be 
recorded with start and stop date, dose, unit, frequency and route of administration. The use of a 
collagenase at any point in time must be captured in the electronic case report form (eCRF). 
7.7.2. 
Concomitant Medications 
The start and stop date, dose, unit, frequency, route of administration, and indication for all 
concomitant medications taken from the Screening Visit through the EOS (Day 57) Visit, 
including oral and topical analgesics/anesthetics before study intervention injection, and nondrug 
therapies (eg, blood transfusions, oxygen supplementation, physical therapy, nutritional 
supplements, vitamins, vaccinations, etc) received will be recorded. 
7.7.3. 
Prohibited Medications 
The following medications are prohibited during the study: 
•
Opioids (eg, codeine, heroin, hydrocodone, hydromorphone, morphine, oxycodone)
2 weeks prior to the screening visit and during the study period.
•
Anticoagulants (warfarin, heparin, direct thrombin inhibitors, Factor Xa inhibitors)
and antiplatelet agents (aspirin > 150 mg/day and P2Y12 inhibitors, such as
clopidogrel) from 7 days before the Day 1 Visit through the EOS (Day 57) Visit as

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these medications can cause additional bruising. However, the use of aspirin 
≤ 150 mg per day will be permitted.  
•
Injectable anesthetic use in or around the plantar nodule targeted for treatment is
prohibited from the Day 1 Visit through the EOS (Day 57) Visit.
•
Use of an investigational drug during the study
If any prohibited medication is taken during the study, all pertinent information will be recorded. 
The designated study medical monitor must be informed immediately so the sponsor may 
determine whether the participant can continue in the study. 
7.8. 
COVID-19-Related Protocol Deviations 
All study assessments conducted outside of the allowed windows outlined in the Schedule of 
Assessments due to a COVID-19 interruption will be documented as a protocol deviation. 
COVID-19 will be recorded as the reason for these out-of-window assessments. 
8.
DISCONTINUATION FROM STUDY INTERVENTION AND
PARTICIPANT WITHDRAWAL
8.1. 
Discontinuation of Study Intervention or from the Study
In rare instances, it may be necessary for a participant to be permanently discontinued from study 
intervention by the investigator or the sponsor for safety, behavioral, or compliance reasons. 
Participants who request to discontinue from the study intervention or discontinue from the study 
prior to the Day 57 visit will be encouraged to complete the remaining study visits and 
evaluations and provide any additional follow-up information as required by the study. 
Participants who discontinue from the study intervention and do not agree to remain in the study 
for follow-up until Day 57, will be requested to complete an ET visit and if applicable the 28-day 
post-treatment Safety Follow-up Visit (or phone call if a visit is not possible) to determine the 
status of any ongoing AEs/SAEs or the occurrence of any new AEs/SAEs. The date of and 
reason for discontinuation of study intervention will be recorded. 
Discontinuation of study intervention for abnormal liver function will be considered by the 
investigator when a participant meets one of the conditions outlined in Section 11.5. 
If a clinically significant finding is identified after the start of study intervention, the investigator 
or a qualified designee will discuss with the sponsor to determine if the participant can continue 
in the study and if any change in management is needed.  
Participants who discontinue study intervention will not be replaced according to the discretion 
of the sponsor and discussion as needed with investigator. 
8.2. 
Participant Withdrawal from the Study 
A participant may withdraw from the study (withdraw consent) at any time at his/her own 
request. 

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•
At the time of withdrawing from the study, if possible, an ET visit should be
conducted, as shown in the Schedule of Assessments
•
The participant will be permanently discontinued from the study intervention, and the
study, at the time of withdrawal of consent.
•
If the participant withdraws consent for the sponsor may retain and continue to use
any data collected before the withdrawal of consent.
•
If a participant withdraws from the study, he/she may request destruction of any
samples taken and not tested, and the investigator must document this in the site study
records.
The date a participant withdraws and the reason for withdrawal will be recorded in the source 
documentation and the electronic case report form (eCRF). When a participant withdraws 
consent and does not agree to an ET visit, then no procedures are required.  
8.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if the participant 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 participant fails to return for a required study visit: 
•
The site must attempt to contact the participant and reschedule the missed visit as
soon as possible and counsel the participant on the importance of maintaining the
assigned visit schedule and to ascertain whether or not the participant wishes to
and/or should continue in the study.
•
Before a participant is deemed lost to follow-up, the investigator or designee must
make every effort to regain contact with the participant (where possible, 3 telephone
calls, and if necessary, a certified letter to the participant’s last known mailing
address; or local equivalent methods). These attempts will be documented.
•
Should the participant continue to be unreachable, the participant will be considered
to have withdrawn from the study.
Participants who have been lost to follow-up may be replaced according to the discretion of the 
sponsor. 
9.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the Schedule of Assessments (Section 2.3). 
Adherence to the study design requirements, including those specified in the Schedule of 
Assessments, is essential and required for study conduct. Protocol waivers or exemptions are not 
allowed. Activities outlined in the Study Operations Manual must be followed or a protocol 
deviation will result. 
Urgent safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue study intervention and/or be 
discontinued from the study. 

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All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screen failure, as applicable. 
9.1. 
Efficacy Assessments 
Examination and evaluation of the selected nodule(s) will be performed at the time points 
specified in the Schedule of Assessments. A general description of each of these assessments 
follows. Specific instructions and questionnaires/forms (where appropriate) will be provided in 
the Study Operations Manual. 
9.1.1. 
Nodule Assessments 
9.1.1.1. 
Anatomical Representation of Nodule Location 
At Screening, Days 1, 29, and 57 Visits, the investigator will complete a graphic representation 
of the foot/feet and the location(s) of the nodule(s) treated. 
Additional information is provided in the Study Operations Manual. 
9.1.1.2. 
Consistency of the Selected Nodule 
At the time points listed in the Schedule of Assessments, the investigator or qualified designee 
will palpate the selected nodule, determine the consistency of the nodule, and classify the nodule. 
For the first treatment, only hard, firm throughout, or moderately firm, palpable fibrous nodules 
will be treated. For the second treatment, nodules previously treated on Day 1 that remain 
palpable and are either hard, firm throughout, moderately firm, or soft) are eligible for Treatment 
2. All efforts should be made to ensure the same investigator is performing these assessments for
each participant. The nodule consistency scale is classified as,
4: Hard 
3: Firm Throughout 
2: Moderately Firm 
1: Soft  
0: Non-palpable.  
Additional information on the classification of the nodule is provided in the Study Operations 
Manual. 
9.1.1.3. 
Caliper Measurements of the Selected Module 
At the time points listed in the Schedule of Assessments, the investigator or qualified designee 
will use a surgical marker to outline the circumference of the selected nodule.  
After the nodule has been marked, the investigator or qualified designee will use handheld 
calipers to measure the length and width of the selected nodule, and nodule measurements will 
be recorded. 
Gross observations will be solicited from the investigator from the investigator at each time of 
examination. 

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Additional information is provided in the Study Operations Manual. 
9.1.1.4. 
Durometer Measurements 
At the time points listed in the Schedule of Assessments, the investigator or qualified designee 
will use the Type OO Shore Durometer provided to measure the hardness of each of the selected 
nodule, on a scale ranging from 0 to 100, and the nodule hardness measurements will be 
recorded.  
Additional information is provided in the Study Operations Manual. 
9.1.2. 
Patient-Reported Outcome Assessments 
To limit missing data from the clinical outcome assessments (COA) scales the following 
measures will be implemented: 
•
Participants and site staff will be trained on the purpose of collecting COAs to encourage
compliance with completing these assessments.
•
COA scales will be completed electronically. Furthermore, completion of each COA
scale will be required to proceed to the subsequent COA scale.
The order of scale completion by the participant is as follows: FFI-PF-May 2021, PGIS Foot 
Pain Subscale, PGIC Foot Pain Subscale, PGIS Difficulty Subscale, PGIC Difficulty Subscale, 
PGIS Activity Limitation Subscale, PGIC Activity Limitation Subscale, PGIS-PF Overall, PGIC 
PF Overall, Pain Intensity NRS, and Subject Satisfaction with Treatment Scale. 
9.1.2.1. 
Foot Function Index 
At the time points included in the Schedule of Assessments, each participant will be asked to 
complete the FFI-PF-May 2021, otherwise known as the FFI, which assesses the impact of foot 
pathology on 3 domains of pain, difficulty, and activity limitation. The participant will complete 
the scale prior to evaluation by the investigator. 
The activity limitation subscale consists of 3 items and measures limitations in activities because 
of your feet in the past week, such as staying off one foot or both feet. It is scored on a 5-point 
verbal rating scale as follows: 
0 - Never 
1 - Rarely 
2 - Sometimes 
3 - Often 
4 - Always 
The difficulty subscale consists of 9 items and measures difficulty performing various functional 
activities because of your feet in the past week, such as difficulty climbing stairs. It is scored on 
a 5-point verbal rating scale as follows: 

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0 - No difficulty 
1 - A little difficulty 
2 - Some difficulty 
3 - Much difficulty 
4 - A lot of difficulty 
The pain subscale consists of 9 items and measures the severity of foot pain during the past week 
in different situations, such as walking barefoot versus walking with shoes. For the pain 
subscale, if the participant marks “does not wear orthotics” items pertaining to orthotics are not 
scored and are not included in the total score. It is scored on a 5-point verbal rating scale as 
follows: 
0 - None 
1 - Mild 
2 - Moderate 
3 - Severe 
4 - Extreme 
9.1.2.2. 
Patient Global Impression of Severity- Plantar Fibromatosis Overall 
At the time points included in the Schedule of Assessments (prior to evaluation by the 
investigator), each participant will be asked to describe the severity of plantar fibromatosis in the 
past week on a 5 point scale ranging from 0 (“None”) to 4 (“Severe”). 
0 None 
1 Minimal 
2 Mild 
3 Moderate 
4 Severe 
9.1.2.2.1. Patient Global Impression of Severity – Foot Pain 
At the time points included in the Schedule of Assessments (prior to evaluation by the 
investigator), each participant will be asked to describe the overall severity of foot pain in the 
past week on a 5 point scale ranging from 0 (“None”) to 4 (“Severe”).  
9.1.2.2.2. Patient Global Impression of Severity -Difficulty 
At the time points included in the Schedule of Assessments (prior to evaluation by the 
investigator), each participant will be asked to describe the overall difficulty had with your foot 
or feet doing physical activities (eg, walking, running, going up and down stairs and curbs) in the 
past week on a 5 point scale ranging from 0 (“None”) to 4 (“Severe”). 

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9.1.2.2.3. Patient Global Impression of Severity- Activity Limitation Subscale 
At the time points included in the Schedule of Assessments (prior to evaluation by the 
investigator), each participant will be asked to describe the activity limitation had with your foot 
or feet doing physical activities (eg. staying off one foot or both feet) in the past week on a 5 
point scale ranging from 0 (“None”) to 4 (“Severe”). 
9.1.2.3. 
Patient Global Impression of Change- PF Overall 
At the time points included in the Schedule of Assessments (prior to evaluation by the 
investigator), each participant will be asked to describe the change in the overall severity of 
plantar fibromatosis in the past week on a 7-point scale, ranging from -3 (“Very Much Worse”) 
to +3 (“Very Much Improvement”) as follows: 
−3 Very Much Worse
−2 Much Worse
−1 Minimally Worse
0 No Change
+1 Minimal Improvement
+2 Much Improvement
+3 Very Much Improvement
9.1.2.3.1. Patient Global Impression of Change- Foot Pain Subscale 
At the time points included in the Schedule of Assessments (prior to evaluation by the 
investigator), each participant will be asked to describe the change in the overall severity of foot 
pain experienced in the past week on a 7-point scale, ranging from -3 (“Very Much Worse”) to 
+3 (“Very Much Improvement”).
9.1.2.3.2. Patient Global Impression of Change- Difficulty Subscale 
At the time points included in the Schedule of Assessments (prior to evaluation by the 
investigator), each participant will be asked to describe the change in the overall difficulty with 
the foot or feet doing physical activities (eg, walking, running, going up and down stairs and 
curbs) in the past week on a 7-point scale, ranging from -3 (“Very Much Worse”) to +3 (“Very 
Much Improvement”). 
9.1.2.3.3.  Patient Global Impression of Change- Activity Limitation Subscale 
At the time points included in the Schedule of Assessments (prior to evaluation by the 
investigator), each participant will be asked to describe the change in the overall limitations in 
the daily activities experienced in the past week on a 7-point scale, ranging from -3 (“Very Much 
Worse”) to +3 (“Very Much Improvement”).  

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9.1.2.4. 
Pain Intensity Numerical Rating Scale 
At the time points included in the Schedule of Assessments (prior to evaluation by the 
investigation), each participant will be asked to describe the worst severity of foot pain in the 
past week, ranging from 0 (No Pain) to 10 (Worst Pain Imaginable). 
9.1.2.5. 
Subject Satisfaction with Treatment Scale 
At the time points included in the Schedule of Assessments (prior to evaluation by the 
investigator), each participant will be asked to rate his/her satisfaction with treatment of their 
nodule(s) per treated foot on a 5-point scale ranging from -2 (“Very Dissatisfied”) to +2 (“Very 
Satisfied”) as follows: 
−2 Very Dissatisfied
−1 Quite Dissatisfied
0 Neither Satisfied nor Dissatisfied
+1 Quite Satisfied
+2 Very Satisfied
9.1.3. 
Investigator Assessments 
Training will be provided to ensure that investigators complete the Clinician Global Impression 
of Change Scale in a standardized manner. 
9.1.3.1. 
Clinician Global Impression of Change Scale 
At the time points included in the Schedule of Assessments, the investigator will determine the 
degree of improvement with treatment per each foot on a 7-point scale ranging from -3 (“Very 
Much Worse”) to +3 (“Very Much Improvement”) as follows: 
−3 Very Much Worse
−2 Much Worse
−1 Minimally Worse
0 No Change
+1 Minimal Improvement
+2 Much Improvement
+3 Very Much Improvement
9.2. 
Safety Assessments 
All safety assessments will be performed at the time outlined in the Schedule of Activities. 
Additional (unscheduled) safety assessments may be performed as needed. 
To ensure participant safety and protect data integrity, Endo, in accordance with the FDA 
Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health 
Emergency (March 2020, updated 30 August 2021), will allow remote visits for certain safety 
assessments. Additionally, participants impacted by the health emergency will be allowed to 
continue in the study and complete remaining assessments when the investigational sites re-open. 

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9.2.1. 
Medical and Surgical History 
Medical and surgical history will be obtained at the Screening Visit. Medical history will include 
a review of the following systems: general, dermatological, respiratory, cardiovascular, 
gastrointestinal, genitourinary, gynecological, endocrine, musculoskeletal, hematological, 
neuropsychological, immune (allergies), and head, eyes, ears, nose, and throat. Historical and 
current medical conditions including date of last menstrual period for female participants will be 
recorded.  
History of tobacco use, and alcohol use (never, current, former) and drug abuse (both illegal and 
prescription) will be collected. 
Any diagnostic, therapeutic, or surgical procedure performed ≤ 10 years before the study, 
including those in the treatment area, should be recorded including the date, indication for, and 
description of the procedure. 
Note: Any medical condition or laboratory abnormality already present at screening or baseline 
should be reported as medical history. If the medical condition present at baseline changes in 
severity or seriousness at any time during the study, it should be reported as an AE. 
9.2.2. 
Physical Examination 
At the time points listed in the Schedule of Assessments, a physical examination will be 
conducted. The physical examination should be conducted per standard of care and may 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, particularly of the feet, and other conditions of note. 
At the time points listed in the Schedule of Assessments, a foot examination will be conducted. 
All examinations will be performed by a physician or health professional listed on the Form 
FDA 1572 and licensed to perform physical examinations. The investigator will review all 
physical exam findings for clinical significance. Any physical examination finding meeting the 
investigator’s or sponsor’s criteria for clinical significance will be recorded as an AE or SAE as 
appropriate. 
9.2.3. 
Height and Weight  
Height and weight will be evaluated at Screening. 
9.2.4. 
Vital Signs 
At the time points listed in the Schedule of Assessments, vital signs will be obtained after the 
participant has been sitting 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 the day that study intervention will be administered, 
vital signs should be collected in supine position prior to injection and at 15 (±5) and 30 (±5) 
minutes post injection. 

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The investigator will review all vital sign values for clinical significance. Any vital sign value 
meeting the investigator’s or sponsor’s criteria for clinical significance will be recorded as an AE 
(or SAE, if appropriate). 
9.2.5. 
Clinical Laboratory Determinations 
At the time points listed in the Schedule of Assessments, clinical laboratory tests will be 
conducted. Required clinical laboratory tests are outlined in Section 11.2. Clinical 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 if needed to ensure participant safety. 
Urine dipsticks will be provided by the central laboratory to the sites. 
9.2.6. 
Pregnancy Testing 
All female participants of childbearing potential will have serum and/or urine pregnancy tests at 
the time points outlined in the Schedule of Assessments. Results must be available prior to 
protocol mandated study intervention. Participants with positive results at the Screening Visit 
will be ineligible for study entry. A positive urine pregnancy test at any time will be confirmed 
with a serum pregnancy test. Any female participant that becomes pregnant during the study will 
immediately be discontinued from study intervention but may continue in the study. Pregnancy 
will be reported as described in Section 9.3.5. 
For all female participants of childbearing potential, the participant’s agreement to use 
contraception throughout their study participation (Screening Visit through the Day 57/EOS 
Visit), if eligible, will be documented. 
9.3. 
Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs are provided in Section 11.3. 
All AEs, including both observed or volunteered problems, complaints, signs or symptoms must 
be recorded, regardless of whether associated with the use of study intervention. 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 intervention will be captured as an AE; the onset date will 

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be the date the event worsened. The AE should be recorded in standard medical terminology 
when possible. 
9.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
The investigator will collect all SAEs and AEs from the time of signing the informed consent 
form (ICF) through the EOS (Day 57) Visit. This will include any AEs that are ongoing at the 
time of completion/termination of the study. Participants who request to discontinue from the 
study will be asked to complete the 28-day post treatment Safety Follow-up Visit (or phone call 
if a visit is not possible) to determine the status of any ongoing AEs/SAEs or the occurrence of 
any new AEs/SAEs. 
Investigators are not obligated to actively seek AEs and SAEs after conclusion of participant 
study participation. However, if the investigator learns of any SAE, including death, at any time 
after the participant has been discharged from the study, and the investigator considers the event 
to be reasonably related to the study intervention or study participation, the investigator must 
notify the sponsor within 24 hours as described in Section 11.3.4.2. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 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 11.3. 
9.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences.  
At each visit, participants will be queried regarding any AEs that have occurred since the last 
visit. Study site personnel will then record all pertinent information. The study medication 
compliance record should also be reviewed to detect potential intentional or unintentional 
overdoses. 
9.3.3. 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All ongoing AEs must be followed until they have resolved, or for 
28 days after the participant’s last study intervention, whichever comes first. All SAEs will be 
followed until they resolved or the condition stabilizes, the event is otherwise explained, or until 
follow-up is no longer possible. Further information on follow-up procedures is provided in 
Section 11.3. 
9.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events 
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 intervention 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 intervention under clinical investigation. The 

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sponsor will comply with country-specific regulatory requirements regarding safety reporting to 
regulatory authorities, IRBs, and investigators. 
Investigator safety reports must be prepared for suspected, unexpected serious adverse reactions 
(SUSARs) according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary.  
An investigator who receives a SUSAR (IND) 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 IB, and will notify the IRB, if appropriate according to local requirements. 
9.3.5. 
Pregnancy 
All pregnancies in participants identified during or after this study, where the estimated date of 
conception is determined to have occurred during the study or within 28 days of the last study 
intervention must be reported, followed to conclusion, and the outcome reported, even if the 
participant is discontinued from the study. Pregnancies that occur in the partner of a treated 
participant (ie, female partner of male participant) must also be reported. The investigator should 
report (as outlined above) all pregnancies within 24 hours using the Pregnancy Form. Monitoring 
of the pregnancy should continue until conclusion and follow-up information detailing the 
progress and outcome must be submitted on 1 or more Pregnancy Forms. A Two-Month 
Follow-up Pregnancy 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 11.3). Spontaneous miscarriages should also be reported and handled as 
SAEs.  
Participants will be instructed to notify the investigator immediately of any pregnancies. 
A participant who becomes pregnant while participating in the study will discontinue study 
intervention, but can continue in the study. Should a participant discontinue study intervention 
due to pregnancy, alternative treatment (if available) should be arranged according to standard of 
care, as determined by the investigator. Attempts to obtain the pregnancy follow-up and 
pregnancy outcome information detailed above are necessary even if a participant discontinues 
study intervention because of pregnancy. 
9.3.6. 
AEs/SAEs Experienced by Nonparticipants Exposed to Study Intervention 
Nonparticipants are persons who are not enrolled in the study but have been exposed to study 
intervention, including instances of diversion of study intervention. All AEs/SAEs occurring in 
nonparticipants from such exposure will be reported to the Endo Pharmacovigilance and Risk 
Management Department 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 nonparticipants will be provided. SAEs occurring in nonparticipants exposed to 
study intervention will be processed within the same SAE reporting timelines as described 

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in Section 11.3. Additionally, the drug accountability source documentation at the site should 
reflect this occurrence. 
9.3.7. 
Assessment of the Severity of Local Injection Site Reactions 
Based on clinical assessments, investigators should classify and assess the severity of local 
injection site reactions during the study according to Table 3. The table does not comprise a 
comprehensive list of injection site reactions. For TEAEs not included, refer to the CTCAE 
Version 5 for a more comprehensive list of events. Local injection site reactions will be reported 
as TEAEs in the eCRF. 
Table 3: 
Assessment and Grading of the Severity of Injection Site Reactions 
Local Reaction to 
Study Intervention 
Mild (Grade 1) 
Moderate (Grade 2) Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain/Pain in 
extremity 
Mild Pain 
Moderate pain; 
limiting instrumental 
ADL 
Severe pain; limiting 
self-care ADL 
Tenderness 
Mild discomfort to 
touch  
Discomfort with 
movement  
Significant 
discomfort at rest 
Erythema/Redness 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling 
2.5 – 5 cm and does 
not interfere with 
activity 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or prevents
daily activity
Necrosis 
Pruritus, itchiness 
Mild or localized; 
topical intervention 
indicated 
Widespread and 
intermittent; skin 
changes from 
scratching (eg, 
edema, papulation, 
excoriations, 
lichenification, 
oozing/crusts); oral 
intervention 
indicated; limiting 
instrumental ADL 
Widespread and 
constant; limiting 
self-care ADL or 
sleep; systemic 
corticosteroid or 
immunosuppressive 
therapy indicated 
Localized edema 
Localized to 
dependent areas, no 
disability or 
functional 
impairment 
Moderate localized 
edema and 
intervention 
indicated; limiting 
instrumental ADL 
Severe localized 
edema and 
intervention 
indicated; limiting 
self-care ADL 
Bruising, Contusion, 
Ecchymosis 
Localized or in a 
dependent area 
Generalized 
Hemorrhage 
Mild symptoms; 
intervention not 
indicated 
Moderate 
symptoms; 
intervention 
indicated 
Transfusion 
indicated; invasive 
intervention 
indicated; 
hospitalization 
Life-threatening 
consequences; 
urgent intervention 
indicated 

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Table 3: 
Assessment and Grading of the Severity of Injection Site Reactions 
(Continued) 
Local Reaction to 
Study Intervention 
Mild (Grade 1) 
Moderate (Grade 2) Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Hematoma 
Mild symptoms; 
intervention not 
indicated 
Minimally invasive 
evacuation or 
aspiration indicated 
Transfusion; 
invasive intervention 
indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Skin laceration 
Observation only; 
topical intervention 
indicated 
Bedside local care 
indicated 
Operative 
intervention 
indicated 
Life-threatening 
consequences 
Injection site 
lymphadenopathy 
Local lymph node 
enlargement 
Localized 
ulceration; 
generalized lymph 
node enlargement 
Injection site 
reaction
Tenderness with or 
without associated 
symptoms (eg, 
warmth, erythema, 
itching) 
Pain; lipodystrophy; 
edema; phlebitis 
Ulceration or 
necrosis; severe 
tissue damage; 
operative 
intervention 
indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Plantar fascial 
tear/rupture 
Asymptomatic or 
mild symptoms; 
clinical or diagnostic 
observations only; 
intervention not 
indicated 
Moderate; Minimal 
or noninvasive 
intervention 
indicated 
Severe or medically 
significant but not 
immediately life-
threatening; Invasive 
intervention 
indicated 
Source: Adapted from the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5 and FDA Guidance for Industry Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials September 1997. 
ADL = activities of daily living 
9.3.8. 
Adverse Events of Special Interest 
AESIs for this study include: 
•
Any severe hypersensitivity reactions.
•
Plantar fascial tears.
These events will be reported as AEs in the eCRF. All AESIs 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 11.3. 
9.3.9. 
Anaphylaxis 
Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death. To identify 
participants experiencing such a reaction, use the criteria provided by Sampson et al (2006) in 
Table 4. Anaphylaxis will be reported as an SAE in the eCRF. 

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Table 4: 
Clinical Criteria for Diagnosing Anaphylaxis 
Anaphylaxis is highly likely when any 1 of the following 3 criteria are fulfilled: 
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or
both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING
a.
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory
flow, hypoxemia)
b.
Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, hypotonia
[collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to collagenase or any other excipient
of EN3835 for that participant (minutes to several hours):
a.
Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-tongue-
uvula)
b.
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory
flow, hypoxemia)
c.
Reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope,
incontinence)
d.
Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3.
Reduced blood pressure after exposure to collagenase or any other excipient of EN3835 for that
participant (minutes to several hours):
a.
Adults: systolic blood pressure of less than 90 mm Hg or greater than 30% decrease from that
person’s baseline
9.4. 
Treatment Overdose 
Study intervention overdose is any accidental or intentional use of treatment in an amount higher 
than the dose indicated by the protocol for that participant. Study intervention 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 intervention eCRF. 
An overdose is not an AE per se, however all AEs associated with an overdose should both be 
entered on the AE eCRF and reported using the procedures detailed in Section 11.3, 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 AE eCRF.  
9.4.1. 
Treatment Abuse/Misuse 
Not applicable. 
9.5. 
Pharmacodynamics 
Not applicable. 

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9.6. 
Genetics 
Not applicable. 
9.7. 
Biomarkers 
Not applicable. 
9.8. 
Immunogenicity Assessments 
Serum samples will be collected at the time points listed in the Schedule of Assessments and will 
be tested for binding anti-AUX-I and anti-AUX-II antibodies. If the participant tests positive for 
anti-AUX-I and anti-AUX-II antibodies, testing for neutralizing antibodies will be conducted. 
The serum samples obtained will be processed, stored, and then shipped frozen on dry ice to 
Endo’s appointed laboratory for the determination of anti-AUX-I and anti-AUX-II antibodies. 
Specific instructions for the collection, processing, storage, handling, and shipment of the 
immunogenicity samples will be provided in the Laboratory Manual. 
De-identified immunogenicity samples may be stored for a maximum of 5 years (or according to 
local regulations) following the last participant last visit for the study at a facility selected by the 
sponsor. This will enable further analysis of immune responses; develop methods, assays, 
prognostics, and/or companion diagnostics related to specify the intervention target, disease 
process, pathways associated with disease state, and/or mechanism of action, of the study 
intervention. 
10.
STATISTICAL CONSIDERATIONS AND METHODS
10.1. 
Sample Size Determination
The primary endpoint is the difference between EN3835 and placebo in the mean change from 
Baseline (Day 1) to Day 57 on the foot pain subscale (total score on 9 items) of the FFI ranging 
from 0 (“None”) to 4 (“Extreme”).  
The sample size was estimated based on an interim analysis of the Day 57 data from Study 
EN3835-105, a dose-finding Phase 1 study. Assuming a difference in the mean change from 
Baseline to Day 57 in the pain subscale of FFI between EN3835 and placebo of 5.0 with a 10 
standard deviation and 85% statistical power using a 2-sided test (α = 0.05), 73 participants per 
treatment group (146 in total) will be needed to detect this difference between the 2 treatment 
groups. Assuming a dropout rate of 15%, the total sample size will be 172, eighty-six per 
treatment group for the study.  
Participants will be screened to ensure that approximately 172 participants are randomized into 2 
treatment groups, an EN3835 group and a placebo group in a 1:1 ratio.  

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10.2. 
Populations for Analysis 
For the purposes of analysis, the following populations are defined: 
•
The Safety Population will include all participants who receive at least 1 injection of
EN3835 or placebo. All safety and immunogenicity analyses will be based on the
Safety Population.
•
The ITT Population will include all randomized participants. Treatment group
assignment will be based on the randomized treatment. The ITT population will be
used for analysis of the primary and secondary endpoints.
•
The FAS Population will include all ITT participants who receive at least 1 injection
of EN3835 or placebo and have at least 1 post injection FFI pain subscale measures.
Treatment group assignment will be based on the randomized treatment. This
population will be used for analysis of the primary and secondary endpoints.
•
The mITT Population will include all ITT participants who receive at least 1 injection
of EN3835 or placebo and have both baseline and at least 1 post injection FFI pain
subscale measures. The treatment group assignment will be based on the randomized
treatment. This population will be used for analysis of the primary, secondary, and
exploratory endpoints.
10.3. 
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 (SAP) will be developed and finalized prior to 
database lock. 
10.3.1. 
Efficacy Analysis 
The ITT population will be the primary population for the efficacy analysis. Efficacy analyses 
will also be performed for the FAS and mITT populations as supportive analyses. 
For the data collected at nodule level, the analyses will be performed at participant level and 
nodule level. The data interpretation will be based on participant level results. The nodule level 
results will be supportive. The details of how to map the data from nodule level to participant 
level will be specified in the SAP. 
10.3.1.1. Primary Analysis 
10.3.1.1.1. Primary Estimand 
Primary Endpoint: 
The difference between EN3835 and placebo in the mean change from Baseline (Day 1) to 
Day 57 on the foot pain subscale (total score on 9 items) of the FFI ranging from 0 (“None”) 
to 4 (“Extreme”). 

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The primary estimand is defined as follows: 
In participants with plantar fibromatosis, what is the difference in mean change from baseline 
(Day 1) to Day 57 in foot pain score (as measured with the FFI pain subscale) between EN3835 
and placebo regardless of discontinuation of study intervention?  
The primary estimand includes the following components: 
•
Treatment of interest: The randomized study intervention (EN3835 or placebo)
•
Target Population: Adult participants with plantar fibromatosis who are included in
the ITT Population.
•
Variable (Endpoint) of interest: Change from Baseline (Day 1) to Day 57 in FFI
pain subscale score.
•
Treatments being compared: The mean change from Baseline (Day 1) to Day 57 in
FFI pain subscale score will be compared between EN3835 and placebo.
•
Intercurrent Event: The treatment policy strategy will be adopted for primary
analysis.
−
Any new or change in concomitant treatment will not be adjusted for in the
primary analysis.
−
Early discontinuation from the study or loss to follow up: If participants do not
have a FFI pain subscale score at Day 57, the missing values will be imputed
before the analysis using a multiple imputation washout model. In multiple
imputation washout model, all participants who are randomized and have a
baseline assessment will be considered.
•
Population Level-Summary measure: Least square mean (LSM) estimates for
treatment difference between EN3835 and placebo.
10.3.1.1.2. Method of Analysis 
The primary estimand will be based on the data at Baseline and Day 57. Therefore participants 
who discontinue study intervention or discontinue from the study will be encouraged to complete 
the remaining study visits and evaluations, and provide any additional follow-up information as 
required by the study. In cases where the participants do not have an FFI pain subscale score at 
Day 57 due to early study discontinuation, the missing values will be imputed before the analysis 
using a multiple imputation washout model. The details of the model will be specified in the 
SAP. 
After imputation, the changes from Baseline to Day 57 will be analyzed using an ANCOVA 
model with treatment group as fixed effect, FFI pain subscale at baseline, the nodule size and the 
number of nodules as covariates. The summary measure, least squares (LS) mean estimate for 
treatment difference between EN3835 and placebo and their corresponding 95% confidence 
intervals (CIs) will be reported. 
A sensitivity analysis with tipping-point approach will be implemented, the details of this 
approach will be specified in the SAP. In addition, another sensitivity analysis will be performed 
based all observed data up to Day 57. The changes from Baseline will be analyzed using a mixed 

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effect model for repeated measures (MMRM). This MMRM model will include treatment group, 
study visit, treatment by visit interaction as fixed effects, and the covariates of the baseline score, 
nodule size and the number of nodules. The repeated measure is the participant visits. The 
dependent variable will be the change from the Baseline at each visit. The summary measure, 
LSM estimate for treatment difference at Day 57 between EN3835 and placebo and their 
corresponding 95% CIs will be reported. 
The FFI pain subscales, and their changes from Baseline will be summarized by study visit (if 
applicable) and treatment group using appropriate descriptive statistics. 
10.3.1.2. Secondary and Exploratory Analysis 
All secondary and exploratory endpoints will be summarized by study visit (if applicable) and 
treatment group using appropriate descriptive statistics.  
10.3.1.2.1. Key Secondary Endpoint 1 
Key Secondary Endpoint 1: 
The difference of mean change from baseline to Day 57 for FFI Pain and Difficulty 
combined score between EN3835 and placebo 
Key Secondary Estimand 1: In participants with plantar fibromatosis, what is the difference in 
mean change from baseline to Day 57 in foot pain and difficulty combined score (as measured 
with combined score of the FFI pain subscale and the FFI difficulty subscale) between EN3835 
and placebo, regardless of discontinuation of study intervention?  
The key secondary estimand 1 includes the following components: 
•
Treatment of interest: The randomized study treatment (EN3835 or placebo)
•
Target Population: Adult participants with plantar fibromatosis who are included in
the ITT Population.
•
Variable (Endpoint) of interest: Change from Baseline (Day 1) to Day 57 in FFI
pain and difficulty combined score.
•
Treatments being compared: The mean change from Baseline (Day 1) to Day 57
FFI pain and difficulty combined score will be compared between EN3835 and
placebo.
•
Intercurrent Event: The treatment policy strategy will be adopted for primary
analysis.
−
Any new or change in concomitant treatment will not be adjusted for primary
analysis.
−
Early discontinuation from the study or loss to follow up: If participants do not
have FFI pain and difficulty combined score at Day 57, the missing values will be
imputed before the analysis using a multiple imputation washout model. In
multiple imputation washout model, all participants who are randomized and have
a baseline assessment will be considered.

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•
Population Level-Summary measure: LSM estimate for treatment difference
between EN3835 and placebo.
The method of analysis (including sensitivity analysis) for key secondary endpoint #1 will follow 
the same method of analysis for primary endpoint. 
10.3.1.2.2. Key Secondary Endpoint 2 
Key Secondary Endpoint 2: The difference in the proportion of participants treated with 
EN3835 or placebo reporting “Minimally Improved” (+1), “Much Improved” (+2), or “Very 
Much Improved” (+3) on the Clinician Global Impression of Change Scale at Day 57.  
Key Secondary Estimand 2: In participants with plantar fibromatosis, what is the difference in 
the proportion of participants with an improvement (as assessed by the investigators with rating 
of “Minimally Improved” (+1), “Much Improved” (+2), or “Very Much Improved” (+3) on the 
Clinician Global Impression of Change Scale) between EN3835 and placebo at Day 57, 
regardless of study withdrawal? 
The key secondary estimand 2: includes the following components: 
•
Treatment of interest: The randomized study treatment (EN3835 or placebo)
•
Target Population: Adult participants with plantar fibromatosis who are included in
the ITT Population.
•
Variable (Endpoint) of interest: Difference in the proportion of Clinician Global
Impression of Change (CGIC), a 7-point scale ranging from −3 (“Very Much
Worse”) to +3 (“Very Much Improvement”) at Day 57.
•
Treatments being compared: The difference in proportion at Day 57 in CGIC will
be compared between EN3835 and placebo.
•
Intercurrent Event: The treatment policy strategy will be adopted for primary
analysis.
−
Any new or change in concomitant treatment will not be adjusted for primary
analysis.
−
Early discontinuation from the study or loss to follow up: All participants with
early discontinuation or loss to follow up will be considered as non-responders.
The responder is defined as a participant for whom the investigator reports a score
to be “Minimal Improvement”, “Much Improvement” or “Very Much
Improvement” on the Clinician Global Impression of Change Scale at Day 57.
•
Population Level-Summary measure: The stratum adjusted risk difference,
associated 95% CI and p value will be presented separately for each visit between
EN3835 and placebo.
The proportions (response rates) will be compared between treatment groups using the Cochran-
Mantel-Haenszel method. 
A sensitivity analysis with tipping-point approach will be implemented for key secondary 
endpoint #2. The details of this approach will be specified in the SAP. 

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10.3.1.2.3. Key Secondary Endpoint 3 
Key Secondary Endpoint 3: The difference of mean changes from Baseline to Day 57 for 
hardness measurements between EN3835 and placebo. 
Key Secondary Estimand 3: In participants with plantar fibromatosis, what is the difference in 
mean change from baseline to Day 57 in hardness measurements (as measured by durometer) 
between EN3835 and placebo, regardless of discontinuation of study intervention?  
The key secondary estimand 3: includes the following components: 
•
Treatment of interest: The randomized study treatment (EN3835 or placebo)
•
Target Population: Adult participants with plantar fibromatosis who are included in
the ITT Population.
•
Variable (Endpoint) of interest: Mean change from Baseline (Day 1) to Day 57 in
nodular hardness.
•
Treatments being compared: The mean change from Baseline (Day 1) to Day 57
nodular hardness will be compared between EN3835 and placebo.
•
Intercurrent Event: The treatment policy strategy will be adopted for primary
analysis.
−
Any new or change in concomitant treatment will not be adjusted for primary
analysis.
−
Early discontinuation from the study or loss to follow up. If participants do not
have nodular hardness at Day 57, the missing values will be imputed before the
analysis using a multiple imputation washout model. In multiple imputation
washout model, all participants who are randomized and have a baseline
assessment will be considered.
•
Population Level-Summary measure: LSM estimate for treatment difference
between EN3835 and placebo.
This estimand will be based on the data at Baseline and Day 57. The imputation and the analysis 
methods (including sensitivity analysis) are similar to the primary estimand. The summary 
measure, LSM estimates for treatment difference between EN3835 and placebo, and the 
corresponding 95% CIs will be reported. 
10.3.1.2.4. Other Secondary Endpoints and Exploratory Endpoints 
The other secondary endpoints and exploratory endpoints including the mean changes from 
Baseline (Day 1) to study visits (Days 15, 29, 43 and 57) for FFI- Pain and Difficulty combined 
score, FFI- pain subscale, FFI- difficulty subscale, and FFI-activity limitation subscale, FFI-
composite score, Pain intensity NRS, nodule size, and hardness measurement will be analyzed 
using the MMRM method based on observed data. The LSM estimates for the treatment 
difference at each visit and their corresponding 95% CIs will be reported. 
The PGIS (overall, pain, difficulty, and activity limitation subscales) scores at each study visit 
(Days 15, 29, 43, and 57) will be compared between treatment groups using a rank based 

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analysis. The Hodges-Lehmann estimator and its 95% CIs will be provided to represent the 
median difference/location shift between the treatment groups.  
In addition, response rates for the PGIC for PF overall and each individual subscale, participant 
satisfaction with treatments, Clinician Global Impression of Change Scale, and nodule 
consistency will be compared between treatment groups using the Cochran-Mantel-Haenszel 
method. The responder definition for each assessment will be detailed in the SAP. 
Psychometric properties of the FFI will be assessed under a separate SAP. A series of tests are 
proposed to validate the FFI in the plantar fibromatosis patient population. Upon completion of 
the analyses, an overall impression and conclusion regarding the psychometric properties of the 
FFI instrument will be made, based on the analysis results. 
10.3.2. 
Safety Analyses 
All participants who receive at least 1 injection of study intervention will be included in the 
safety analyses. Participants will be included in the safety analyses based on the actual treatment 
received. 
10.3.2.1. Adverse Events 
AE analysis by treatment group will include the incidence of AEs, AEs resulting in drug 
discontinuation, AEs leading to study discontinuation, SAEs, and AESIs. Summaries of AEs will 
be provided including the number and percentage of participants who experienced at least 1 AE. 
These summaries will be presented by system organ class (SOC) and preferred term (PT). The 
occurrence of AEs will also be tabulated by severity. A confidence interval for the difference in 
frequency of TEAEs across treatment groups will be provided. SAEs and AEs resulting in study 
discontinuation will be summarized separately by treatment group. 
10.3.2.2. Vital Sign, Laboratory Tests, and Other Safety Measures 
All vital sign measurements, laboratory tests, and other safety variables and their changes (if 
applicable) from Baseline will be summarized by treatment group, study visit/days using 
appropriate descriptive statistics. 
10.3.2.3. Immunogenicity Analysis 
Anti-AUX-I and anti-AUX-II antibody results (titer levels) and neutralizing antibodies to AUX-I 
and AUX-II will be summarized using descriptive statistics. 
10.4. 
Multiplicity Adjustment 
The significance tests for key secondary endpoints will be conducted in sequential order to 
preserve the overall type-I error rate < 0.05 according to the following order: 
1. Key secondary endpoint 1
2. Key secondary endpoint 2
3. Key secondary endpoint 3

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Testing of the first key secondary endpoint will be conducted if the results of the primary 
endpoint are statistically significant. Testing of these key secondary endpoints will be conducted 
in a hierarchical manner until p value > 0.05.  
No multiplicity adjustment will be made on other secondary endpoints and exploratory 
endpoints. The nominal p values will be reported for those endpoints. 
10.5. 
Handling of Missing Data 
Before the primary efficacy analysis, the missing values due to participant discontinuation from 
the study or loss to follow up will be imputed using a multiple imputation washout model. The 
washout model will be performed on actual values, ie, FFI pain subscale. The changes from 
baseline are calculated after the imputation. The full details of the multiple imputation washout 
model will be provided in the SAP. 
In addition, sensitivity analyses using MMRM without multiple imputation and tipping point 
analysis (see details in the SAP) will be performed on the primary and key secondary efficacy 
endpoints (if applicable) to assess the impact of missing values.  
No imputation will be performed for all non-specified secondary and exploratory endpoints. The 
analyses for those endpoints will be based on observed data. 
10.6. 
Interim Analysis 
Not applicable. 
10.7. 
Subgroup Analysis 
Analysis for primary endpoint, key secondary endpoints, and frequency of TEAEs will be 
performed in the following subgroups. 
1. Number of injections (1 vs 2 vs 3 vs 4)
2. Baseline FFI pain subscale score: Group 1 vs Group 2
a.
Group 1: subscale score ≤20 for participants without orthotics or subscale score ≤26
for participants with orthotics
b. Group 2: subscale score ≥21 for participants without orthotics or subscale score ≥27
for participants with orthotics
Subgroups maybe be combined with adjacent groups if the number of participants in that group 
is less than 10.  

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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
11.1. 
Appendix 1: Regulatory, Ethical and Study Oversight 
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 (GCP), Consolidated Guidance (62 FR 25692, May 9, 1997); and 21 CFR parts 50, 54, 
56 and 312. 
The study will be conducted in full compliance with ICH E6, the FDA guidelines for 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 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 members that demonstrates appropriate composition or other documentation of 
assurance of appropriate composition per local and national regulations (eg, a Department of 
Health and Human Services [DHHS] Assurance Number will satisfy this requirement for IRBs in 
the United States).  
The study protocol, the ICF, advertisements, materials being provided to participants, and 
amendments (if any) will be approved by the IRB at the 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 with a copy of the current IB, 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 on the progress of the 
study, at intervals not exceeding 1 year (or as appropriate), and will notify the IRB of SAEs or 
other significant safety findings, per the policy of the IRB. At the conclusion of the study, the 
investigator will submit a final report or close out report to the IRB and provide a copy to Endo. 
Any amendment to this protocol will be provided to the investigator in writing by Endo. No 
protocol amendment may be implemented (with the exceptions noted below) before it has been 
approved by the IRB 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 participant, the 
amendment may be implemented before IRB review and approval. However, the IRB 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 participant, and must be immediately reported to Endo.  
The investigator will be responsible for supplying updated safety and/or study information to 
study participants as it becomes available.  

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11.1.1. 
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. 
11.1.2. 
Informed Consent Process 
The ICF must be approved by the sponsor and the IRB before any participant provides consent. 
The investigator will provide the sponsor with a copy of the IRB approved ICF and a copy of the 
IRB’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 
participant’s agreement to allow any remaining specimens to be used for exploratory research. 
Participants 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), participants 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), participants 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. Participants will need to sign a new ICF if more than 28 days 
elapse between initial ICF signature and date of randomization. 
Participants 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. Participants will be made aware that they may withdraw from the study 
at any time for any reason.  
All versions of each participant’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 participant.  
The participants 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 participant 
withdraws consent and/or HIPAA authorization, the investigator can no longer disclose health 
information, unless it is needed to preserve the scientific integrity of the study. 

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11.1.3. 
Data Protection 
Study participants will be assigned a unique identifier by the sponsor or designee. Any 
participant records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information, which would make the participant identifiable, will not be 
transferred.  
The participant 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 participant.  
The participant 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 members, and by inspectors from regulatory authorities. 
11.1.4. 
Data Safety Monitoring Board Committee 
To supplement the routine study monitoring outlined in this protocol, an independent, unblinded 
DSMB will be used to monitor safety data on an ongoing basis. The voting members of the 
DSMB are external to the Sponsor. The members of the DSMB must not be involved with the 
study in any other way (eg, they cannot be study investigators) and must have no competing 
interests that could affect their roles with respect to the trial. 
The DSMB will make recommendations to the Sponsor regarding steps to ensure participant 
safety and the continued ethical integrity of the study. The DSMB will evaluate the accumulated 
safety data, consider the overall risk and benefit to study participants, and provide 
recommendations for continuation of dosing and any necessary steps to ensure participant safety. 
Specific details regarding composition, responsibilities, and governance, including the roles and 
responsibilities of the various members; meeting facilitation; the trial governance structure; and 
requirements for and proper documentation of DSMB reports, minutes and recommendations 
will be described in a separate charter that is reviewed and approved by the DSMB. The DSMB 
will monitor the study at an appropriate frequency, as described in the detailed DSMB charter. 
The DSMB will also provide recommendations to the Sponsor regarding steps to ensure 
participant safety and the continued ethical integrity of the study. 
11.1.5. 
Dissemination of Clinical Study Data 
Aggregate results for the study will be provided to the sites that actively enrolled participants 
into this study after the clinical study report is finalized. 
Study results and de-identified individual participant data will be released as required by local 
and/or national regulation. 
11.1.6. 
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 

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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. 
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. 
11.1.7. 
Source Documents 
All participant 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, 
participant diaries, and 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 for at least 3 years after the last approval of a 
marketing application in an ICH region, until there are no pending or contemplated marketing 
applications in an ICH region, or at least 3 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. 

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11.1.8. 
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. 
11.1.9. 
Publication Policy 
All data generated in this study are the property of Endo. An integrated clinical and statistical 
report will be prepared at the completion of the study. 
Publication of the results by the investigator will be participant to mutual agreement between the 
investigator and Endo. 

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11.2. 
Appendix 2: Clinical Laboratory Tests 
Hematology 
Biochemistry 
Urinalysis 
Hemoglobin 
Hematocrit 
Red blood cell 
White blood cell (WBC) 
Platelets 
WBC Differential 
Prothrombin Time (PT)/ 
International Normalized 
Ratio (INR)  
Glucose 
Sodium 
Potassium 
Calcium 
Chloride 
Carbon dioxide (CO2) 
Blood urea nitrogen  
Creatinine 
AST 
ALT 
Gamma-glutamyl transferase (GGT) 
TBL (direct bilirubin reflex if elevated) 
Albumin 
Alkaline phosphatase (ALP) 
Total protein 
Glucose 
Protein 
Specific gravity 
pH 
Ketones 
Bilirubin 
Urobilinogen 
Nitrite 
Blooda 
Leukocytesa 
a Microscopic examination will be performed if blood or leukocytes are detected by dipstick. 

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11.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting 
11.3.1. 
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 intervention whether or not considered 
related to the study intervention. Note: Any medical condition or laboratory abnormality already 
present at screening or baseline should be reported as medical history. If the medical condition 
present at baseline changes in severity or seriousness at any time during the study, it should be 
reported as an AE. AEs will be captured once a participant has signed the informed consent. AEs 
include: 
•
Changes in the general condition of the participant.
•
Subjective symptoms offered by or elicited from the participant.
•
Objective signs observed by the investigator or other study personnel.
•
All concurrent diseases and/or medical occurrences that occur after the start of the
study, including any change in severity or frequency of pre-existing disease.
•
All clinically relevant laboratory abnormalities or physical findings that occur during
the study.
A TEAE is any condition that was not present prior to treatment with study intervention 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 participant who received study
intervention 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 participant and may require medical or surgical intervention to prevent one of 
the other serious outcomes. Examples of important medical events include any cancer, allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 

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or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.  
11.3.2. 
Relationship to Study Intervention 
The degree of “relatedness” of the AE to study intervention must be described using the 
following scale:  
•
Not related indicates that the AE is definitely not related to study intervention.
•
Unlikely related indicates that there are other, more likely causes and study
intervention is not suspected as a cause.
•
Possibly related indicates that a direct cause and effect relationship between study
intervention and the AE has not been demonstrated, but there is evidence to suggest
there is a reasonable possibility that the event was caused by study intervention
•
Probably related indicates that there is evidence suggesting a direct cause and effect
relationship between the AE and EN3835.
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 clearly indicate 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. 
11.3.3. 
Intensity Assessment 
The intensity (or severity) of AEs is characterized as Grades 1 to 5 according to the CTCAE 
Version 5.0. For the AEs not directly referenced in CTCAE, the investigator should use clinical 
judgment in assessing the intensity of such events using the below categories as a guide: 
•
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations
only; intervention not indicated.
•
Grade 2 Moderate; minimal, local, or noninvasive intervention indicated; limiting
age-appropriate instrumental activities of daily living (ADL).*
•
Grade 3 Severe or medically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.†
•
Grade 4 Life-threatening consequences; urgent intervention indicated
•
Grade 5 Death related to AE.
* Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing
money, etc.
† Self-care-ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not
bedridden.

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11.3.4. 
Method of Reporting Adverse Events and Serious Adverse Events 
11.3.4.1. Method of 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.  
11.3.4.2. Method of Reporting Serious Adverse Events 
Any SAE, including death resulting from any cause, which occurs to any participant 
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. 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 Endo Serious Adverse Event (SAE)/Reportable Event Forms should be sent to 
safety@endo.com or faxed to 610-968-7135.  
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 per their IRB policy. 
11.3.4.3. 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 nonserious AE, or 
whether it should be considered as part of the participant’s history. In addition, all events or other 
findings determined to be SAEs should be identified on the Serious Adverse Event 
(SAE)/Reportable Event Form and the investigator should consider whether the event is related 
or not related to study intervention. All events determined to be nonserious should be reported on 
the eCRF. 

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11.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
See Section 6, Section 9.2.6, and Section 9.3.5. 

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11.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments  
All events, which may indicate severe liver injury (possible Hy’s Law), meeting the following 
criteria: 
•
ALT ≥ 3 × ULN or AST ≥ 3 × ULN and TBL ≥ 2 × ULN (> 35% direct bilirubin),
OR
•
ALT ≥ 3 × ULN or AST ≥ 3 × ULN and INR >1.5
must be reported as an SAE as outlined in Section 11.3.4. 
Participants with confirmed Hy’s Law liver injury will be immediately withdrawn from study 
intervention and no rechallenge will be allowed. 

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11.6. 
Appendix 6: Abbreviations 
Abbreviation 
Definition 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUX-I 
Clostridial type I collagenase 
AUX-II 
Clostridial type II collagenase 
BLA 
Biologics license application 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
COA 
Clinical Outcome Assessment 
CTCAE 
Common Terminology Criteria for Adverse Events 
DC 
Dupuytren’s contracture 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOS 
End of study 
FAS 
Full Analysis Set 
FFI 
Foot Function Index 
FFI-SF-23 
Foot Function Index-Short Form 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ITT 
Intent-to-Treat 
LS 
Least squares 
LSM 
Least squares mean 

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Abbreviation 
Definition 
mITT 
Modified Intent-to-Treat Population 
MMRM 
Mixed effect model for repeated measures 
NCI 
National Cancer Institute 
NIAID 
National Institute of Allergy and Infectious Disease 
NRS 
Numerical Rating Scale 
PD 
Peyronie’s disease 
PF 
Plantar fibromatosis 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
System Organ Class 
SUSAR 
Suspected, unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 

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12.
INVESTIGATOR’S STATEMENT
I agree to conduct the study in accordance with the protocol, and with all applicable government 
regulations and Good Clinical Practice guidance. 
_____/_____/______ 
Investigator’s Signature 
Date 
Typed Name of Investigator 

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13.
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