Clinical trial NCT04496167
Conditions: Adhesive Capsulitis Frozen Shoulder
Sponsor: Endo Pharmaceuticals
Start date: 2020-07-29; Completion date: 2022-04-14
Enrollment: 198 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety and efficacy of EN3835 for the treatment of adhesive capsulitis of the shoulder (frozen shoulder).

Detailed description:

Arms: arm 1: EN3835 up to 1.74 mg arm 2: Placebo
Interventions: intervention 1: EN3835 intervention 2: Placebo
Intervention descriptions: intervention 1: Collagenase clostridium histolyticum intervention 2: Placebo comparator

Protocol documents:
Prot_000.pdf: 


EN3835-210 Protocol Amendment 4
22 October 2021
Endo Pharmaceuticals Inc.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Overall Rationale for Amendment 4:
The primary purpose of this amendment was to increase the total number of subjects for the 
study to 180 due to a higher than expected early termination rate.
Minor changes throughout the protocol amendment included wording changes for clarity and 
correction of minor typographical errors.
Amendment 4 was incorporated into the protocol on 23 October 2021.
Major updates to specific sections of the protocol that are affected are outlined below.
Section No. and Name
Description of Change
Brief Rationale
Protocol Amendment 
Summary of Changes
Summary of Changes updated.
Updated for Amendment 4.
Section 1.1 Synopsis
Estimated date of last subject 
completed updated from 
August 2021 to June 2022.
This update was made to reflect 
the increase in total number of 
subjects.
Section 1.1 Synopsis 
AND
Section 4.1 Overall Study 
Design 
AND
Section 9.1 Sample Size 
Determination 
Total number of subjects for the 
study increased from 160 to 180.
Due to a higher than expected 
early termination rate, sample size 
was increased to 180 subjects.
Section 1.1 Synopsis 
AND
Section 9.4 Interim Analysis
Specified the total number of 
subjects (86) who must have 
completed the Day 95/Early 
Termination (ET) Visit before 
interim analysis can be performed. 
Total number of subjects for 
interim analysis was 86.
Section 1.2 Schedule of 
Activities
Schedule of Activities Footnote b 
changed to: Treatment sessions 
should be at least 21 days apart.
Removed example of timing of 
treatment sessions to avoid 
confusion.


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Section No. and Name
Description of Change
Brief Rationale
Section 5.1 Subject Inclusion 
Criteria, Criterion #2
AND
Section 6.5.1 Prohibited 
Medications and Nondrug 
Therapies
Removed barbiturates and 
benzodiazepines from the pain 
medication list. Specified that 
nonsteroidal anti-inflammatory 
drugs (NSAIDs) (ibuprofen, etc) 
and Tylenol (acetaminophen) are 
allowed.
Barbiturates and benzodiazepines 
are not indicated for pain and 
should be available if necessary for 
subjects who experience anxiety 
during magnetic resonance 
imaging (MRI) scans.
Section 5.2 Subject Exclusion 
Criteria, Criterion #5, 4th 
bullet
Original Text: Uncontrolled 
thyroid disease defined as thyroid 
stimulating hormone (TSH) 
≥4 uIU/mL at the Screening Visit.
Note added: (Note: Uncontrolled 
thyroid disease is defined as a 
symptomatic medical condition not 
adequately controlled with 
medications.)
This change was made to clarify 
the definition of uncontrolled 
thyroid disease. 
Section 7.2 Subject 
Withdrawal from the Study
Rewritten to clarify the difference 
between subject discontinuation 
and subject withdrawal of consent.
Procedures performed after subject 
discontinuation and subject 
withdrawal of consent were 
clarified.
Overall Rationale for Amendment 3:
The primary purpose of this amendment was to clarify exclusion criteria regarding related to 
coagulation and bleeding disorders. In addition, the unit of measure for TSH was updated to 
reflect current practice. Furthermore, the storage of injection site photographs was defined. 
Photographs are to be stored in a database and not in the subject source documents. Text to 
clarify exclusion criterion #3 was added for the MRI review committee.
Minor changes throughout the protocol amendment included wording changes for clarity and 
correction of minor typographical errors.
Amendment 3 was incorporated into the protocol on 30 October 2020.
Major updates to specific sections of the protocol that are impacted are outlined below.
Section No. and Name
Description of Change
Brief Rationale
Protocol Amendment 
Summary of Changes
Summary of Changes updated.
Updated for Amendment 3.


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Section No. and Name
Description of Change
Brief Rationale
Section 5.2 Subject Exclusion 
Criteria, Criterion #3
Changed from:
Has any abnormalities/conditions 
in the affected shoulder that would 
be clinically significant or 
potentially confounding to the 
evaluations of safety and efficacy 
as determined by the investigator 
or central MRI review including 
but not limited to:
This change was made to remove 
responsibility from the 
investigators and to allow the MRI 
committee to determine eligibility 
based on their MRI grading 
criteria to ensure consistency.
Changed to:
Has any abnormalities/conditions 
in the affected shoulder that would 
be potentially confounding to the 
evaluations of efficacy as 
determined by the central MRI 
review committee grading criteria. 
The shoulder pathologies to be 
assessed include but are not 
limited to the following:
Section 5.2 Subject Exclusion 
Criteria, Criterion #5
Criterion #5, 2 bullet points were 
removed including:
‘Coagulation disorder’
and
‘A known bleeding disorder 
which, in the investigator’s 
opinion, would make the subject 
unsuitable for enrollment in the 
study.’
Bullet points were removed from 
Exclusion Criteria #5 to be 
included in the revised Exclusion 
Criteria #7 for clarity.
In addition, the unit of measure 
for TSH was changed from U/mL 
to uIU/mL.
To align with current practice.


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Section No. and Name
Description of Change
Brief Rationale
Section 5.2 Subject Exclusion 
Criteria, Criterion #7
Criterion #7 changed from: 
Requires anticoagulant or 
antiplatelet medication or has 
received anticoagulant or 
antiplatelet medication (except 
≤150 mg aspirin daily) within 
7 days prior to the first injection 
of study treatment.
To:
Has a known coagulation disorder 
and/ or is taking any medication 
(ie, anticoagulants or antiplatelet 
medications, except for ≤ 150 mg 
aspirin daily) that would increase 
the risk of bleeding within 7 days 
of the first injection of EN3835 
and for the duration of the study. 
Revised language for 
Coagulation/Bleeding disorders 
for clarity and to be more 
consistent with other ongoing 
studies.
Section 5.4 Screen Failures
Updated to:
Subjects will be allowed to repeat 
hematology, serum chemistry, 
urinalysis, or vital signs once, if 
necessary, if it is within the 
screening window.
Vital signs were added to the list 
of assessments to be repeated if 
the subject is retested.
Section 6.1 Study Treatment 
Administration
Updated to:
‘A screen capture/photograph of 
the injection will be taken at each 
injection visit and retained within
a database until the end of the 
study.’
Modified to reflect the location of 
archived images.
Overall Rationale for Amendment 2:
The primary purpose of this amendment was to clarify which pain medication would be 
considered exclusionary for the study, and to add clarity to the exclusion criteria or MRI 
contraindications for exclusion criterion #6 rationale to allow the technologist, radiologist, and 
investigator to determine whether or not a subject may undergo MRI.
Minor changes throughout the protocol amendment included wording changes for clarity and 
correction of minor typographical errors.
Amendment 2 was incorporated into the protocol on 31 July 2020.
Major updates to specific sections of the protocol that are impacted are outlined below.
Section No. and Name
Description of Change
Brief Rationale
Protocol Amendment 
Summary of Changes
Summary of Changes updated.
Updated for Amendment 2


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Section No. and Name
Description of Change
Brief Rationale
Section 5.1 Subject Inclusion 
Criteria, Criterion #2
and
Section 6.5.1 Prohibited 
Medications and Nondrug 
Therapies
New criterion #2 added to clarify 
the use of pain medication.
Text added to beginning of 
section to clarify the use of pain 
medication.
Added to indicate that narcotic 
pain medication will not be 
allowed during the study period 
and for 2 weeks prior to the start 
of study.
Section 5.2 Subject Exclusion 
Criteria, Criterion #3
Criterion #3 modified to add the 
exclusion of abnormalities/ 
conditions in the affected shoulder 
that would affect the evaluation of 
safety or efficacy evaluations.
Modified to clarify that conditions 
of the affected shoulder that are 
deemed clinically significant by 
the investigator and central MRI 
committee would be exclusionary 
for the study.
Section 5.2 Subject Exclusion 
Criteria, Criterion #6
Exclusion criterion #6 changed to: 
Has any of the following 
contraindications for MRI, as 
determined by the technologist, 
the radiologist, and/or the 
investigator (in accordance with 
the MHRA Safety Guidelines for 
Magnetic Resonance Imaging 
Equipment in Clinical Use, 
March 2015):
Note changed to: Any tattoo in the 
treated area will be exclusionary.
Modified to clarify that the 
technologist, radiologist, and 
investigator will determine subject 
eligibility for MRI, and that a 
tattoo in the treated area would 
exclude the subject from receiving 
and MRI.
Section 8.1.7 Magnetic 
Resonance Imaging
Added: A central MRI committee 
consisting of 2 blinded 
musculoskeletal radiologists who 
will serve as the primary readers 
and 1 blinded clinician who will 
serve as the adjudicator in 
discordant cases.
Text added to define the central 
MRI committee.
Overall Rationale for Amendment 1:
The primary purpose of this amendment was to align exclusion criteria on other shoulder 
pathologies seen on MRI with our MRI vendor to provide clarity and alignment for the MRI 
readers. The change was to clarify both the schedule of activities (SoA) and procedures detailed 
in the protocol. The other major reason for this amendment is to modify the protocol due to the 
potential interruption caused by the COVID-19 public health emergency. The COVID-19 public 
health emergency has disrupted the conduct of clinical research throughout the world. At Endo 
Pharmaceuticals Inc. (Endo), ensuring the safety of clinical study subjects is our primary 
concern. In addition, the integrity of data obtained from clinical trials must be ensured. 
In order to ensure subject safety and protect data integrity, Endo, in accordance with the FDA 
Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health 
Emergency (March 2020, updated 02 July 2020), will allow virtual visits for safety assessments. 
In addition, subjects impacted by the health emergency will be allowed to continue in the study 


EN3835-210 Protocol Amendment 4
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and complete remaining dosing and assessments when the investigational sites re-open as 
follows:
!
Subjects who were in screening (those who had completed or were in the process of
screening) for the study at the time of the COVID-19 interruption but who had not
been dosed with EN3835 may be rescreened. If a subject rescreens within 30 days of
their original screening MRI date and adhesive capsulitis (AC) was confirmed in the
affected shoulder by the MRI central review committee, and the unaffected shoulder
MRI was unremarkable, the subject will not need to have a repeat MRI of either
shoulder. Other adhesive capsulitis shoulder screening assessments will be
determined on a case by case basis as to whether or not the subject will need to
repeat. All repeat screening assessments must be completed within the screening
window.
Minor changes throughout the protocol amendment included wording changes for clarity and 
correction of minor typographical errors.
Amendment 1 was incorporated into the protocol on 10 July 2020.
Major updates to specific sections of the protocol that are impacted are outlined below.
Section No. and Name
Description of Change
Brief Rationale
Protocol Amendment 
Summary of Changes
Summary of Changes Added
Added with Amendment 1
Section 1.2 Schedule of 
Activities, Table 1
New footnote ‘e’ added to 
Adapted ASES of the affected 
shoulder.
Added to indicate that all patient-
reported outcomes (PROs) must 
be completed prior to study 
assessments/ beginning of visit.
Section 1.2 Schedule of 
Activities, Table 1
Footnote ‘g’ removed from pain 
upon movement (PUM)
assessment of the affected 
shoulder.
Removed as unnecessary.
New footnote ‘g’ added to active 
range of motion (AROM) and 
passive range of motion (PROM)
of the affected shoulder.
Added to indicate that all AROM 
measurements must be completed 
before PROM measurements.
Section 1.2 Schedule of 
Activities, Table 1
New footnote ‘h’ moved to 
Chemistry, hematology, 
urinalysis, HbA1c, TSH, serum 
pregnancy test Day 95 Visit.
Added to indicate that serum 
pregnancy testing is not to be 
done at the Day 95 Visit.
Section 1.2 Schedule of 
Activities, Table 1
Footnote ‘i’ updated.
Updated to indicate that the X-ray 
must be completed prior to MRI 
imaging. 
Section 8.1.7 Magnetic 
Resonance Imaging and X-rays
Text added.
Added text indicating that any 
X-ray of the affected shoulder
done within 30 days of Screening
is acceptable.


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Section No. and Name
Description of Change
Brief Rationale
Section 1.2 Schedule of 
Activities, Table 1
In the SoA, ‘X’ has been 
removed from concomitant 
medications and nondrug 
therapies for Treatment Session 
Day 1 and Treatment Sessions 
Day 22 and Day 43 in the post-
injection columns.
Procedure removed from 
postinjection time points listed in 
order to avoid repeating during a 
single visit.
Section 1.2 Schedule of 
Activities, Table 1
Remaining footnotes relettered.
Relettered to maintain footnote 
agreement.
Section 2.1 Study Rationale
The rationale for changes to the 
study due to the COVID-19 
public health emergency (as 
outlined above) has been added to 
the end of this section.


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Section No. and Name
Description of Change
Brief Rationale
Section 5.2 Subject Exclusion 
Criteria
Exclusion Criterion #3 updated as 
follows:
3. Has any of the following
conditions in the affected
shoulder:
•
AC as a result of traumatic
injury (ie, direct injury to the
shoulder such as fracture of the
humerus or clavicle immediately
preceding the onset of this
episode of AC). Traumatic events
in the past that are not temporally
related to the onset of this
episode of AC would not
necessarily exclude a subject
from participating in the study.
•
Active subacromial
impingement in the affected
shoulder
(subacromial/subdeltoid
bursitis, decreased subacromial
space, or bursal sided fraying).
•
Calcified tendonitis in the
affected shoulder.
•
Glenohumeral joint
arthrosisitis in the affected
shoulder.
•
Glenohumeral joint
inflammatory arthropathy.
•
Rotator cuff tears
(supraspinatus, infraspinatus,
teres minor, or subscapularis).
•
Fracture (humerus, glenoid,
or clavicle).
Arthrosis of the affected
shoulder.
•
Chondrolysis of the affected
shoulder.
•
Subscapularis tendon rupture
of the affected shoulder.
•
Acromioclavicular
arthropathy.
•
Rotator cuff pathologies of the
affected shoulder unrelated to
AC.
To align shoulder pathologies 
seen on MRI with our MRI 
vendor to ensure clarity for the 
MRI readers. 


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Section No. and Name
Description of Change
Brief Rationale
•
Biceps tendon pathologies.
•
Bursitis of the shoulder.
•
Labralum tears/suspected
labral tears.
•
Bone pathologies.
•
Polymyalgia rheumatica.
•
Any other abnormalities/
conditions as determined by the
central MRI review to be
potentially confounding to the
evaluation of safety and efficacy.
Section 5.2 Subject Exclusion 
Criteria
For Exclusion Criteria #6, bullet 
3, the following note has been 
added: Note: As determined by 
the technician performing the 
image and radiologist, with 
exemption of the area to be 
treated/reviewed. Any tattoo in 
this area will be exclusionary.
To clarify that the technician and 
radiologist can determine if the 
MRI can safely be performed in 
the presence of a tattoo not in the 
affected area.
Section 5.4 Screen Failures
An exception has been added for 
any rescreening process 
interrupted by COVID-19, 
subjects may be rescreened for a 
second time.
Section 6.6 Visits Affected by 
COVID-19 Interruption
Protocol deviations will be 
recorded for all subjects who 
have visits outside of the 
windows outlined in the SoA, 
regardless of reason (including all 
subjects who experienced the 
COVID-19 interruption). The 
reason for out of window visits 
will be recorded.
Section 8.2 Safety Assessments
Text was added to this section to 
allow virtual visits to assess 
safety during any COVID-19 
interruption in accordance with 
the FDA Guidance on Conduct of 
Clinical Trials of Medical 
Products during COVID-19 
Public Health Emergency (March
2020, updated 02 July 2020).


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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES .......................................................2
1.
PROTOCOL SUMMARY......................................................................................15
1.1.
Synopsis .................................................................................................................15
1.2.
Schedule of Activities.............................................................................................18
2.
INTRODUCTION..................................................................................................21
2.1.
Study Rationale ......................................................................................................21
2.2.
Background ............................................................................................................22
2.3.
Benefit/Risk Assessment ........................................................................................23
3.
OBJECTIVES AND ENDPOINTS.........................................................................25
3.1.
Objectives and Endpoints .......................................................................................25
4.
STUDY DESIGN...................................................................................................26
4.1.
Overall Design........................................................................................................26
4.2.
Scientific Rationale for the Study Design................................................................27
4.3.
Justification for Dose..............................................................................................27
4.4.
Justification for Magnetic Resonance Imaging........................................................27
4.5.
End of Study Definition..........................................................................................28
5.
SELECTION AND WITHDRAWAL OF SUBJECTS............................................28
5.1.
Subject Inclusion Criteria .......................................................................................28
5.2.
Subject Exclusion Criteria ......................................................................................29
5.3.
Lifestyle Considerations .........................................................................................32
5.4.
Screen Failures .......................................................................................................32
6.
STUDY TREATMENT..........................................................................................33
6.1.
Study Treatment Administration.............................................................................33
6.1.1.
Dose Interruption....................................................................................................34
6.2.
Study Treatment Preparation/Handling/Storage/Accountability ..............................34
6.3.
Measures to Minimize Bias.....................................................................................35
6.3.1.
Interactive Response Technology............................................................................35
6.3.2.
Emergency Identification of Study Treatment.........................................................35
6.4.
Study Treatment Compliance..................................................................................36
6.5.
Prior and Concomitant Medications and Nondrug Therapies...................................36
6.5.1.
Prohibited Medications and Nondrug Therapies......................................................36


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6.6.
Visits Affected by COVID-19 Interruption .............................................................37
7.
DISCONTINUATION FROM STUDY TREATMENT AND SUBJECT
WITHDRAWAL....................................................................................................37
7.1.
Discontinuation of Study Treatment........................................................................37
7.2.
Subject Withdrawal from the Study ........................................................................37
7.3.
Lost to Follow-up ...................................................................................................38
8.
STUDY ASSESSMENTS AND PROCEDURES ...................................................38
8.1.
Efficacy Assessments .............................................................................................39
8.1.1.
Adapted American Shoulder and Elbow Surgeons Standardized Shoulder 
Form.......................................................................................................................40
8.1.2.
Range of Motion.....................................................................................................40
8.1.3.
Pain Upon Movement.............................................................................................40
8.1.4.
Patient-reported Global Severity of Adhesive Capsulitis.........................................40
8.1.4.1.
Patient-reported Change in Severity of Adhesive Capsulitis....................................41
8.1.5.
Subject Satisfaction with Treatment........................................................................41
8.1.6.
Investigator Assessment of Improvement with Treatment .......................................41
8.1.7.
Magnetic Resonance Imaging and X-rays ...............................................................41
8.2.
Safety Assessments.................................................................................................42
8.2.1.
Demography...........................................................................................................42
8.2.2.
Medical and Surgical History..................................................................................42
8.2.3.
Adhesive Capsulitis History....................................................................................42
8.2.4.
Physical Examination .............................................................................................42
8.2.5.
Height and Weight..................................................................................................43
8.2.6.
Vital Signs..............................................................................................................43
8.2.7.
Electrocardiogram ..................................................................................................43
8.2.8.
Clinical Laboratory Determinations (Chemistry, Hematology, Urinalysis, 
HbA1c, TSH, Serum and Urine Pregnancy Test) ....................................................43
8.2.9.
Pregnancy Testing ..................................................................................................44
8.3.
Adverse Events and Serious Adverse Events...........................................................44
8.3.1.
Time Period and Frequency for Collecting AE and SAE Information......................44
8.3.2.
Method of Detecting AEs and SAEs .......................................................................45
8.3.3.
Follow-up of AEs and SAEs...................................................................................45
8.3.4.
Regulatory Reporting Requirements for SAEs........................................................45


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8.3.5.
Pregnancy...............................................................................................................46
8.3.6.
AEs/SAEs Experienced by Nonsubjects Exposed to Study Treatment.....................46
8.3.7.
Adverse Events of Special Interest..........................................................................46
8.4.
Overdose ................................................................................................................47
8.4.1.
Study Treatment Abuse/Misuse ..............................................................................47
8.5.
Pharmacokinetics....................................................................................................47
8.6.
Pharmacodynamics.................................................................................................47
8.7.
Genetics..................................................................................................................47
8.8.
Biomarkers .............................................................................................................47
8.8.1.
Immunogenicity Assessments.................................................................................47
8.9.
Medical Resource Utilization and Health Economics..............................................48
9.
STATISTICAL CONSIDERATIONS AND METHODS........................................48
9.1.
Sample Size Determination.....................................................................................48
9.2.
Populations for Analysis.........................................................................................48
9.3.
Statistical Hypotheses and Analyses .......................................................................49
9.3.1.
Efficacy Analysis....................................................................................................49
9.3.2.
Safety Analyses ......................................................................................................49
9.3.2.1.
Adverse Events.......................................................................................................49
9.3.2.2.
Vital Signs and Laboratory Evaluations ..................................................................50
9.3.3.
Other Analyses .......................................................................................................50
9.4.
Interim Analysis .....................................................................................................50
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS..............................................................................................51
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ...................51
10.1.1.
Regulatory and Ethical Considerations....................................................................51
10.1.2.
Financial Disclosure ...............................................................................................52
10.1.3.
Informed Consent Process ......................................................................................52
10.1.4.
Data Protection.......................................................................................................53
10.1.5.
Committee Structure...............................................................................................53
10.1.6.
Dissemination of Clinical Study Data .....................................................................53
10.1.7.
Data Quality Assurance ..........................................................................................53
10.1.8.
Source Documents..................................................................................................54
10.1.9.
Study and Site Closure............................................................................................54


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10.1.10.
Publication Policy...................................................................................................54
10.2.
Appendix 2: Clinical Laboratory Tests....................................................................55
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.....................................................................56
10.3.1.
Definitions..............................................................................................................56
10.3.2.
Relationship to Study Treatment.............................................................................57
10.3.3.
Intensity Assessment ..............................................................................................57
10.3.4.
Reporting Adverse Events and Serious Adverse Events ..........................................57
10.3.4.1.
Reporting Adverse Events ......................................................................................57
10.3.4.2.
Reporting Serious Adverse Events..........................................................................57
10.3.4.3.
Follow-up Procedures for Serious Adverse Events..................................................58
10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information.............................................................................................................58
10.5.
Appendix 5: Genetics .............................................................................................58
10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments.............58
10.7.
Appendix 7: Medical Device Incidents ...................................................................58
10.8.
Appendix 8: Abbreviations .....................................................................................59
11.
INVESTIGATOR’S STATEMENT........................................................................61
12.
REFERENCES.......................................................................................................62
LIST OF TABLES
Table 1:
Schedule of Activities.............................................................................................18
Table 2:
Study Treatment .....................................................................................................33


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Name of Sponsor/Company: Endo Pharmaceuticals Inc.
Name of Study Treatment: EN3835
Name of Active Ingredient: Collagenase clostridium histolyticum
Title of Study: A phase 2, randomized, double blind, placebo controlled study of the safety and 
efficacy of EN3835 for the treatment of adhesive capsulitis of the shoulder
Lead Principal Investigator: Not applicable 
Study period: 
Estimated date first subject enrolled: July 2020
Estimated date last subject completed: June 2022
Phase of development: 2
Objectives and Endpoints: 
Objectives
Endpoints
Primary
!
To assess the efficacy of EN3835 for the
treatment of AC of the shoulder using the
adapted American Shoulder and Elbow
Surgeons Standardized Shoulder Form
(ASES) composite score.
!
The change from baseline in the adapted
ASES composite score for the affected
shoulder at the Day 95 Visit.
Secondary
!
To assess the efficacy of EN3835 for the
treatment of AC of the shoulder using
passive range of motion (PROM).
!
The absolute and percent change from
baseline in PROM for forward flexion,
internal rotation, external rotation,
abduction, and shoulder extension in the
affected shoulder at the Day 22, 43, 64,
and 95 Visits compared to the contralateral
shoulder at baseline.
!
To assess the efficacy of EN3835 for the
treatment of AC of the shoulder using active
range of motion (AROM).
!
The absolute and percent change from
baseline in AROM for forward flexion,
internal rotation, external rotation,
abduction, and shoulder extension in the
affected shoulder at the Day 22, 43, 64,
and 95 Visits compared to the contralateral
shoulder at baseline.
!
To assess the efficacy of EN3835 for
treatment of AC of the shoulder using the
adapted ASES.
!
The change from baseline in the adapted
ASES composite score, the adapted ASES
function subscale, and the adapted ASES
pain subscale for the affected shoulder at
the Day 22, 43, 64, and 95 Visits.
!
To assess the impact of EN3835 on pain
upon movement (PUM) in subjects with AC
of the shoulder.
!
The change from baseline in the PUM
Scale for the affected shoulder at the Day
64 and Day 95 Visits.




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Name of Sponsor/Company: Endo Pharmaceuticals Inc.
Name of Study Treatment: EN3835
Name of Active Ingredient: Collagenase clostridium histolyticum
up to 3 injections of study treatment (total dose: 1.74 mg) separated by a minimum of 21 days. 
Following each injection, subjects will remain under observation for at least 30 minutes. All subjects 
will undergo standardized, supervised, in-office physical therapy (PT) sessions after each treatment 
visit. In addition, subjects will complete standard home exercises starting 3 days after each injection of 
study treatment through the Day 95 Visit. Subjects will be evaluated for shoulder ROM, AC severity, 
function, and pain at each subsequent study visit. Dosing may be withheld at the Day 22 and 43 Visits 
if functional parameters are met. Subjects will be expected to complete all study visits, even if they do 
not receive study treatment at the Day 22 and/or Day 43 Visits. Follow-up visits will be conducted 
approximately 64 and 95 days after the first dose of EN3835 or placebo. 
An interim analysis for safety and futility is planned for when approximately 86 subjects have 
completed the Day 95/Early Termination Visit. Enrollment will continue during this analysis.
Disclosure Statement: This is a placebo-controlled safety and efficacy study with 2 blinded treatment 
cohorts.
Number of Study Subjects (planned): Approximately 180 subjects will be randomly assigned to 
EN3835 or placebo so that approximately 142 evaluable subjects will complete the study.
Treatment Groups and Duration: All subjects will receive up to 3 treatment sessions at least 21 days 
apart and consisting of 0.58 mg of EN3835 or placebo in the affected shoulder. The total amount of 
EN3835 to be administered per subject over the course of the study will not exceed 1.74 mg.
Independent Data and Safety Monitoring Committee: An interim analysis for safety and futility is 
planned for when approximately 86 subjects have completed the Day 95/Early Termination Visit. An 
independent unblinded data monitoring committee will review the interim data and provide 
recommendations for study continuation.


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1.2.
Schedule of Activities
Table 1:
Schedule of Activities
Activity
Screening Visit 
Day -28 to Day -1
Treatment Session 1
Day 1
Days 4-7
Days 8-21
Treatment Session 2a
Day 22 + 3 daysb
And
Treatment Session 3a
Day 43 + 3 daysb
Days 25-28 and
Days 46-49
Days 29-42 and
Days 50-63
Follow-up Day 64
(± 5 days)
End of Study Day 
95 (± 5 days)/Early 
Termination
Pre-
injection
Post-
injection
Pre-
injection
Post-
injection
Informed consentc
X
Inclusion/exclusion criteria review
X
Demography
X
Medical and surgical history
X
AC history
X
Prior medications and nondrug therapies
X
X
Complete physical examination
X
X
Height
X
Weight
X
X
Hand dominance
X
Vital signs (blood pressure, respiratory rate, 
pulse rate, body temperature)
X
Xd
Xd
Xd
Xd
X
X
12-lead ECG
X
Adapted ASES of the affected shouldere
Xe
X
X
X
X
Confirm external rotationf
Xe
Passive external rotation at 0°, 45°, and 90° of 
the affected shoulder
Xe
AROM and PROM of the contralateral shoulder
X
AROM and PROM of the affected shoulderg
X
X
X
X


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Table 1:
Schedule of Activities (Continued)
Activity
Screening Visit 
Day -28 to Day -1
Treatment Session 1
Day 1
Days 4-7
Days 8-21
Treatment Session 2a
Day 22 + 3 daysb
And
Treatment Session 3a
Day 43 + 3 daysb
Days 25-28 and
Days 46-49
Days 29-42 and
Days 50-63
Follow-up Day 64
(± 5 days)
End of Study Day 95 
(± 5 days)/Early 
Termination
Pre-
injection
Post-
injection
Pre-
injection
Post-
injection
PUM Assessment of the affected shoulder
X
X 
X
X
Patient-reported Global Severity of Adhesive 
Capsulitise
X
X
X
X
X
Patient-reported Change in Severity of Adhesive 
Capsulitise
X
X
X
Chemistry, hematology, urinalysis, HbA1c, 
TSH, serum pregnancy test
X 
Xh
Urine pregnancy test
X
X
Immunogenicity sample collection
X
X
X-ray of affected shoulder
Xi
MRI of affected shoulder
X
X
MRI of unaffected shoulder
X
Randomization
X
Ultrasound-guided study treatment injection and 
screen capture/photo of injection
X
X
Supervised in-office PTj
X
X
Train subjects on home exercise and diary use, 
distribute home exercise instructions and diary
X
X
Home exercisesk
X
X
Review diary (for home exercise compliance)
X
X
X
Investigator Assessment of Improvement with 
Treatment
X
X


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Table 1:
Schedule of Activities (Continued)
Activity
Screening Visit 
Day -28 to Day -1
Treatment Session 1
Day 1
Days 4-7
Days 8-21
Treatment Session 2a
Day 22 + 3 daysb
And
Treatment Session 3a
Day 43 + 3 daysb
Days 25-28 and
Days 46-49
Days 29-42 and
Days 50-63
Follow-up Day 64
(± 5 days)
End of Study Day 95 
(± 5 days)/Early 
Termination
Pre-
injection
Post-
injection
Pre-
injection
Post-
injection
Subject Satisfaction with Treatment
X 
X
Concomitant medications and nondrug therapies
X
X
X
X
X
X
X
Adverse eventsl
Monitored throughout study
a Subjects may receive up to a maximum of 3 treatment sessions. Treatment sessions (Day 22 and Day 43) should be determined based on the guidelines 
provided in Section 6.1.1. Subjects who are not eligible for treatment at the Day 22 and/or Day 43 Visits will continue in the study, completing all other 
activities and visits.
b Treatment sessions should be at least 21 days apart. 
c Performed prior to any study-related activities.
d On treatment session days, vital signs will be taken prior to the injection and at 15 and 30 minutes after the injection (except for body temperature which will be 
taken prior to the injection and 30 minutes after the injection). Vital signs must be stable for a period of at least 30 minutes before the subject can be discharged 
from the study site on treatment days.
e All patient-reported outcomes (PROs) must be completed prior to study assessments/ beginning of visit. Must be completed and criteria met prior to MRI.
f Subject must be able (in a supine position) to have the affected arm passively externally rotated to at least a neutral position within the subject’s level of pain 
tolerance with the elbow at the side (against the body) and flexed to 90°.
g AROM measurements must be completed before PROM measurements.
h Serum pregnancy assessment will not be done on the Day 95 Visit.
i Must be completed prior to MRI. Previous X-rays of the affected shoulder may be used if they were taken within 30 days of the Screening Visit.
j Subjects must complete supervised in-office PT 2 days per week for 2 weeks after each treatment session. Subjects must wait a minimum of 7 days after each 
treatment session prior to starting PT and there should be a minimum of 2 days between PT sessions.
k Home exercises will be completed at least 2 times per day and no more than 3 times per day, every day starting 3 days after each dose of study treatment 
through the Day 95 Visit. In-office PT will count as 1 of the home exercise sessions on PT days.
l AEs/SAEs will be captured from time of informed consent signature until the Day 95 Visit or for 28 days after last dose of study treatment for subjects who
discontinue early from the study. There is no time limit on collection of SAEs assessed as related to study treatment.
Note: Unless otherwise stated above, all assessments should be completed prior to dosing on treatment days (the Day 1, 22, and 43 Visits). 


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2.
INTRODUCTION
EN3835 is a parenteral lyophilized product comprised of 2 collagenases in an approximate 
1:1 mass ratio, Collagenase I (Clostridial class I collagenase [AUX-I]) and Collagenase II 
(Clostridial class II collagenase [AUX-II]). EN3835 (XIAFLEX®) is currently approved for use 
in adult patients 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.
2.1.
Study Rationale
The histopathology of adhesive capsulitis (AC) bears similarities to that seen in Dupuytren’s 
contracture (Bunker and Anthony, 1995; Bunker et al, 2000; Rodeo et al, 1997; Tamai et al, 
2014) with:
!
An initial phase of synovial hyperplasia that progresses to fibrosis of the synovium
and capsule, likely the result of increased fibroblast activity and cellular proliferation.
!
New and excessive collagen deposition within the capsule likely the result of
increased expression of multiple pro-inflammatory cytokines.
!
A residual stage in which fibroblast activity is diminished and reduced collagen
maturation and remodeling take place, culminating in a protracted stiffening of the
capsule.
Therefore, DC treatments such as EN3835 may be effective in other collagen mediated 
conditions such as AC. Based on the limitations of currently available treatments; there is an 
unmet need for a less invasive, cost effective treatment option that reduces the burden of illness 
due to AC. 
The COVID-19 public health emergency has disrupted the conduct of clinical research 
throughout the world. At Endo Pharmaceuticals Inc. (Endo), ensuring the safety of clinical study 
subjects is our primary concern. In addition, the integrity of data obtained from clinical trials 
must be ensured.
In order to ensure subject safety and protect data integrity, Endo, in accordance with the FDA 
Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health 
Emergency (March 2020, updated 02 July 2020), will allow virtual visits for safety assessments. 
In addition, subjects impacted by the health emergency will be allowed to continue in the study 
and complete remaining dosing and assessments when the investigational sites re-open as 
follows:
!
Subjects who were in screening (those who had completed or were in the process of
screening) for the study at the time of the COVID-19 interruption but who had not
been dosed with EN3835 may be rescreened. If a subject rescreens within 30 days of
their original screening MRI date and adhesive capsulitis was confirmed in the
affected shoulder by the MRI central review committee, and the unaffected shoulder
MRI was unremarkable, the subject will not need to have a repeat MRI of either
shoulder. Other adhesive capsulitis shoulder screening assessments will be


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determined on a case by case basis as to whether or not the subject will need to 
repeat. All repeat screening assessments must be completed within the screening 
window. 
2.2.
Background
EN3835, marketed as XIAFLEX, is currently approved for use in adults with DC and PD. These 
collagenases are proteinases that hydrolyze collagen in its native triple helical conformation 
under physiological conditions, which may result in lysis of collagen deposits in a Dupuytren’s 
cord and/or Peyronie’s plaque.
A description of the chemistry, pharmacology, efficacy, and safety of EN3835 is provided in the 
Investigators Brochure (Endo, 2020). 
AC is a prolonged, painful condition of the shoulder that is associated with loss of range of 
motion (ROM) in the glenohumeral joint. An American Shoulder and Elbow Society (ASES) 
consensus definition of AC is: “a condition characterized by functional restriction of both active 
and passive shoulder motion for which radiographs of the glenohumeral joint are essentially 
unremarkable” (Zuckerman and Rokito, 2011).
Management of AC is controversial and depends on the phase of the disease. Decision making is 
often based on quality of life and whether the patients are able to cope with the pain and/or 
stiffness until its eventual resolution. Treatment options include a range of conservative and 
surgical measures.
Both oral and intra-articular corticosteroids have been shown to have a benefit in reducing pain 
and increasing ROM in AC, but these benefits are short-lived and there are significant risks 
associated with long term systemic steroid use (Buchbinder et al, 2004; Buchbinder et al, 2006; 
Canbulat et al, 2015; Carette et al, 2003; Lorbach et al, 2010; Takase, 2010; Yoon et al, 2013).
Physical therapy (PT) to the limit of pain is widely accepted as part of the management of AC, at 
least in the early stages of the disease where it is thought to reduce pain and increase ROM 
(D’Orsi et al, 2012; Jain and Sharm, 2014; Russell et al, 2014; Struyf and Meeus, 2014; Wilson 
et al, 2015).
O’Kane et al (1999) reported that patients treated with home exercise alone improved in a 
self-assessed shoulder rating system, physical function, and pain after an average of 25 months 
of follow-up; however, 30% to 40% of these patients could not place an 8 pound object on a 
shelf or carry a 20 pound object at their side.
Studies of treatment with suprascapular nerve blocks, intra-articular hyaluronic acid, 
intra-articular injection of botulism toxin type A, hydrodilation (also known as distention 
arthrography), and manipulation under anesthesia (MUA) have found little difference in pain or 
ROM between these therapies and treatment with intra-articular corticosteroids and/or PT 
(Corbeil et al, 1992; Dahan et al, 2000; De Carli et al, 2012; Gam et al, 1998; Harris et al, 2011;
Jacobs et al, 1991; Jones and Chattopadhyay, 1999; Joo et al, 2013).
More recent nonrandomized studies have indicated that there may be some long term benefit to 
hydrodilation compared to corticosteroids (Ahn et al, 2015) or MUA (Clement et al, 2013; 
Simpson and Budge, 2004; Watson and Dalziel, 2000). However, there are significant risks 
associated with both procedures (D’Orsi et al, 2012; Loew et al, 2005; Magnussen and Taylor, 


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2011; Redler and Dennis, 2019; Vastamäki and Vastamäki, 2013). Complications from MUA 
include humeral fracture, subscapularis rupture, labral tears, and injury to the biceps tendon 
(Jacobs et al, 1991; Jacobs et al, 2009).
Arthroscopic capsular release has been used to treat AC effectively, particularly in patients who 
have been unresponsive to other treatments, by reducing pain and restoring ROM; however, risks 
associated with this procedure include postoperative pain, postoperative AC, and axillary nerve 
damage, as well as the risks associated with general anesthesia (Baums et al, 2007; Jerosch et al, 
2013; Le Lievre and Murrell, 2012; Smith et al, 2014; Walther et al, 2014; Watson et al, 2007).
AC remains a disease that is difficult to diagnose and there is little consensus in the literature 
regarding preferred treatment or the preferred time for treatment (D’Orsi et al, 2012; 
Georgiannos et al, 2017; Hannafin and Chiaia, 2000; Le et al, 2017; Manske and Prohaska, 2008; 
Nagy et al, 2013; Stupay and Neviaser, 2015). 
Three clinical studies with EN3835 have been conducted to date and results are outlined in 
Section 2.3, Section 4.2, and Section 4.3. Detailed information about these studies can be found 
in the Investigator’s Brochure (Endo, 2020).
2.3.
Benefit/Risk Assessment
Although a thorough benefit of EN3835 has not been fully established in the treatment of AC, 
the post hoc analyses from the previous phase 2b study (AUX-CC-871) and previous AC studies 
indicate that EN3835 should be further explored as a treatment. In addition, the lack of 
consensus regarding treatment of AC and the risks associated with surgical or drug treatment or 
with long-term corticosteroid use suggest that safe and effective treatments for this condition are 
needed.
In the most recent study of EN3835 in AC (AUX-CC-871), the most common (≥ 5% of subjects) 
treatment-related, treatment-emergent adverse events (TEAEs) were musculoskeletal pain 
(34.2%), contusion (28.7%), injection site pain (21.1%), ecchymosis (19.8%), injection site 
bruising (19.4%), localized edema (8.0%), and pruritus (5.1%). These events are similar to 
events reported in the clinical trials of EN3835 for the approved indications, and postmarketing 
safety data are consistent with the safety data reported in clinical trials. 
Use caution when administering EN3835 so as not to inject intra-articularly. A single animal 
study indicated significant adverse events associated with intra-articular injection of EN3835. 
While the effect in humans is not known, intra-articular injection (misapplication) of EN3835 
during treatment of AC must be avoided.
More information about the known and expected benefit, risks, and reasonably expected adverse 
events (AEs) can be found in the Investigator’s Brochure (Endo, 2020).
Risks associated with the use of a local anesthetic include bruising, pain, tingling, blurred vision, 
dizziness, headache, muscle twitching, weakness, and continuing numbness. Local anesthetics 
can sometimes cause allergic reactions including hives, itching, and difficulty breathing. In rare 
cases, cyanosis can occur at the site of injection; and very rarely, use of a local anesthetic can 
lead to depressed central nervous system syndrome.


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The baseline shoulder X-ray exposes subjects to a very low level of radiation. Extensive 
exposure to radiation can lead to cancer. Exposure to any radiation can harm an unborn fetus in a 
pregnant woman.
Risks associated with ultrasound are rare; however, subjects undergoing ultrasound may 
experience slight heating of tissues and the creation of cavitations (small pockets of gas) within 
the body. The long term effects of these events are unknown.
Due to the use of the strong magnet, magnetic resonance imaging (MRI) cannot be performed on 
subjects with any implant containing metal or those who have other internal or external metallic 
objects as it may cause these objects to move. 
All other procedures and activities in this study are generally accepted as standard of care for 
patients with AC and do not present any increased risk to the subjects.


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3.
OBJECTIVES AND ENDPOINTS
3.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
!
To assess the efficacy of EN3835 for the
treatment of AC of the shoulder using the
adapted American Shoulder and Elbow
Surgeons Standardized Shoulder Form
(ASES) composite score.
!
The change from baseline in the adapted
ASES composite score for the affected
shoulder at the Day 95 Visit.
Secondary
!
To assess the efficacy of EN3835 for the
treatment of AC of the shoulder using passive
range of motion (PROM).
!
The absolute and percent change from
baseline in PROM for forward flexion,
internal rotation, external rotation, abduction,
and shoulder extension in the affected
shoulder at the Day 22, 43, 64, and 95 Visits
compared to the contralateral shoulder at
baseline.
!
To assess the efficacy of EN3835 for the
treatment of AC of the shoulder using active
range of motion (AROM).
!
The absolute and percent change from
baseline in AROM for forward flexion,
internal rotation, external rotation, abduction,
and shoulder extension in the affected
shoulder at the Day 22, 43, 64, and 95 Visits
compared to the contralateral shoulder at
baseline.
!
To assess the efficacy of EN3835 for
treatment of AC of the shoulder using the
adapted ASES.
!
The change from baseline in the adapted
ASES composite score, the adapted ASES
function subscale, and the adapted ASES pain
subscale for the affected shoulder at the Day
22, 43, 64, and 95 Visits.
!
To assess the impact of EN3835 on pain upon
movement (PUM) in subjects with AC of the
shoulder.
!
The change from baseline in the PUM Scale
for the affected shoulder at the Day 64 and
Day 95 Visits.
!
To assess the impact of EN3835 on the
severity of AC in subjects with AC of the
shoulder.
!
The change from baseline in the
Patient-reported Global Severity of Adhesive
Capsulitis Scale at the Day 22, 43, 64 and 95
Visits.
!
The rating (response) in the Patient-reported
Change in Severity of Adhesive Capsulitis
Scale at the Day 22, 43, 64, and 95 Visits.
!
To assess subject satisfaction with treatment
and investigator assessment of improvement
with treatment of EN3835 for AC of the
shoulder.
!
Investigator assessment of improvement with
treatment at the Day 64 and Day 95 Visits.
!
Subject satisfaction with treatment at the
Day 64 and Day 95 Visits.




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The duration of the study from first subject first visit to last subject last visit will be dependent 
on the ability of the sites to identify and enroll eligible subjects. The study is expected to screen 
subjects over approximately 12 months. The entire study is expected to require approximately 
18 months to complete. 
4.2.
Scientific Rationale for the Study Design
A placebo-controlled, double-blind, parallel-arm study design was chosen in accordance with the 
FDA Guidance for Industry, E 10 Choice of Control Group and Related Issues in Clinical Trials. 
The use of a placebo control helps to prevent subjects from automatically thinking that all effects 
they experience are attributable to the active treatment since there is a 50% chance they are 
actually receiving inactive injection (placebo). In addition, no active control is used because 
there are no generally accepted pharmacologic treatments for AC.
4.3.
Justification for Dose
In a dose ranging study (AUX-CC-870) of EN3835 in AC, doses of 0.58 mg (at volumes of 
0.5 mL, 1 mL, and 2 mL) were well tolerated with most TEAEs occurring at the site of injection 
with a profile consistent with that observed in previous clinical trials of EN3835 in the treatment 
of DC and PD. Statistically significant improvements from baseline in AROM forward flexion, 
ASES composite score, and ASES pain and function subscale scores were seen at doses of 
0.58 mg/1 mL and 0.58 mg/2 mL compared to a home exercise alone group. In addition, the dose 
of 0.58 mg/1 mL had statistically significant improvement in AROM abduction, PROM forward 
flexion, PROM abduction, and PROM external rotation compared to the home exercise alone 
group. The dose of EN3835 0.58 mg/1 mL was equally well tolerated in the AUX-CC-871 study 
where results similar to those for AUX-CC-870 were observed. Based on these results, the 
EN3835 0.58 mg/1 mL dose was selected for the AC clinical development program.
4.4.
Justification for Magnetic Resonance Imaging
The diagnosis of AC is difficult to make on the basis of clinical findings and is usually a 
diagnosis of exclusion as other causes of shoulder pain and stiffness such as rotator cuff tear, 
impingement syndrome, calcific tendinitis, or osteoarthritis may mimic AC. Arthrography, 
ultrasonography, and MRI play an important role in identifying AC (Hsu et al, 2011; 
Zappia et al, 2016). 
Arthrography is not an optimal diagnostic tool for routine AC diagnosis as it is invasive and 
cannot be used to observe changes such as inflammation, thickening, or fibrosis in the 
glenohumeral joint capsule and synovium. While ultrasonography may aid in the diagnosis of 
AC, its role is still controversial (Zappia et al, 2016).
MRI is a noninvasive diagnostic tool that has been commonly used to help differentiate 
underlying disease that can mask the symptoms of AC (Hsu et al, 2011). MRI is capable of 
diagnosing AC early and can rule out confounding pathology through reliable imaging indicators 
including thickening of the CHL, the joint capsule in the rotator interval and axillary recess, as 
well as obliteration of the fat triangle under the coracoid process (Connell et al, 2002; Emig et al, 
1995; Gokalp et al, 2011; Harris et al, 2013; Jung et al, 2006; Mengiardi et al, 2004; Sofka et al, 
2008; Song et al, 2011).


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4.5.
End of Study Definition
A subject is considered to have completed the study if the subject has completed the Day 95 
Visit.
The end of the study is defined as the completion of the final assessment for the last subject 
enrolled in the trial.
5.
SELECTION AND WITHDRAWAL OF SUBJECTS
5.1.
Subject Inclusion Criteria
In order to be eligible to participate in the study, prior to randomization subjects must:
1. Be ≥18 years of age at the time of consent, and can be male or female.
2. Agree not to use pain medications for the duration of the study period and for 2 weeks
prior to the Screening Visit. Pain medications include but are not limited to: methadone,
buprenorphine, opioids (eg, codeine, heroin, hydrocodone, hydromorphone, morphine,
oxycodone), and cannabis.
Note: Nonsteroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, etc) and Tylenol
(acetaminophen) are allowed.
3. Have idiopathic unilateral AC defined as subjects with passive external rotation that
demonstrates at least a 30% loss of ROM tested at 0°, 45°, and 90° abduction in the
affected shoulder compared to the contralateral shoulder in the supine position. In the
event that 45° and 90° cannot be achieved due to pain or restriction, the amount of
external rotation available at maximum attainable abduction ROM is permissible as the
second and third measurements.
4. Have an adapted ASES function subscale score of < 35 in the affected shoulder at the
Screening and Day 1 Visits.
5. Have unaffected ROM in the contralateral shoulder as determined by the investigator.
6. Be able (in a supine position) to have the affected arm passively rotated to at least a
neutral position within their level of pain tolerance with the elbow at the side (against the
body) and flexed to 90°.
7. Be willing to undergo x-ray of the affected shoulder and MRI of the affected and
contralateral shoulder as required by the protocol.
8. Agree to participate in supervised, in-office PT sessions and to complete home exercises
at designated time points during the study.
9. Agree to avoid general lifting and carrying of no more than 10 pounds, and lifting of no
more than 5 pounds overhead for 21 days after each treatment, except during supervised
PT sessions.
10. Be able to read, understand, and independently complete PRO instruments in English.
11. If female, be of nonchildbearing potential (history of hysterectomy, bilateral
oophorectomy, bilateral tubal ligation, or postmenopausal with no history of menstrual


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flow in the 12 months prior to the Screening Visit); or, if of childbearing potential, be 
nonpregnant, nonlactating and agree to use effective contraception when with a male 
partner for the duration of the study (and for 28 days after any active treatment period for 
subjects who early terminate). Acceptable forms of contraception include hormonal 
measures (oral contraceptive pills, contraceptive patch, contraceptive ring, and 
injections), intrauterine devices, double barrier method (condom plus diaphragm, condom 
or diaphragm plus spermicidal gel or foam), surgical sterilization of the male partner, and 
abstinence. 
12. If male with reproductive potential, agree to use effective contraception (abstinence,
surgical sterilization [vasectomy], or condom with spermicide) with a female partner of
child-bearing potential for the duration of the study (and for 28 days after any active
treatment period for subjects who early terminate).
13. Be willing and able to comply with all protocol required visits and assessments.
14. Be adequately informed and understand the nature and risks of the study and be able to
provide consent as outlined in Section 10.1.3.
5.2.
Subject Exclusion Criteria
A subject is ineligible for study participation if, at the Screening Visit and/or on Day 1, the 
subject:
1. Has a known allergy to collagenase or any other excipient of EN3835 or any other
procedural medication (including local anesthetics).
2. Has received treatment for AC (in the timeframes outlined below) or is planning to
receive any treatment (other than study treatment) for AC at any time during the study in
the affected shoulder, including but not limited to:
!
PT or acupuncture within 2 weeks before the first injection of study treatment.
!
Intra-articular or intrabursal injections of lidocaine, suprascapular nerve blocks, or
electroanalgesic and/or thermoanalgesic modalities within 1 month before the
Screening Visit.
!
Intra-articular or intrabursal injections of corticosteroids within 8 weeks before the
Screening Visit.
!
Intra-articular or intrabursal injections of sodium hyaluronate and/or glenohumeral
distension arthrography within 3 months before the Screening Visit.
!
MUA at any time prior to the study.
!
Surgery (including arthroscopic or open capsular release, capsulectomy, or
capsulotomy) at any time prior to the study.


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3. Has any abnormalities/conditions in the affected shoulder that would be potentially
confounding to the evaluations of efficacy as determined by the central MRI review
committee grading criteria. The shoulder pathologies to be assessed include but are not
limited to the following:
!
AC as a result of traumatic injury (ie, direct injury to the shoulder such as fracture of
the humerus or clavicle immediately preceding the onset of this episode of AC).
Traumatic events in the past that are not temporally related to the onset of this
episode of AC would not necessarily exclude a subject from participating in the
study.
!
Active subacromial impingement (subacromial/subdeltoid bursitis, decreased
subacromial space, or bursal sided fraying).
!
Calcified tendonitis.
!
Glenohumeral joint arthrosis.
!
Glenohumeral joint inflammatory arthropathy.
!
Rotator cuff tears (supraspinatus, infraspinatus, teres minor, or subscapularis).
!
Fracture (humerus, glenoid, or clavicle).
!
Acromioclavicular arthropathy.
!
Biceps tendon pathologies.
!
Bursitis.
!
Labral tears/suspected labral tears.
!
Bone pathologies.
4. Has a prosthesis or replacement of right or left shoulder, elbow, wrist, and/or hand.
5. Has any of the following systemic conditions:
!
Evidence or history of malignancy (other than excised basal-cell carcinoma) unless
there has been no recurrence in at least 5 years.
!
Uncontrolled hypertension, defined as a systolic blood pressure ≥ 160 mmHg or a
diastolic blood pressure ≥ 100 mmHg at the Screening Visit or before dosing on
Day 1.
!
Uncontrolled diabetes, defined as hemoglobin A1c (HbA1c) ≥ 8% at the Screening
Visit.
!
Uncontrolled thyroid disease defined as thyroid stimulating hormone (TSH)
≥4 uIU/mL at the Screening Visit. (Note: Uncontrolled thyroid disease is defined as a
symptomatic medical condition not adequately controlled with medications.)
!
History of thrombosis or post-thrombosis syndrome.
!
Physical impairment that would preclude performing the protocol defined exercises.
!
Active infection in the area to be treated.


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!
Any other significant medical condition (eg, morbid obesity, cervical disc disease),
which in the investigator’s opinion would make the subject unsuitable for enrollment
in the study.
6. Has any of the following contraindications for MRI, as determined by the technologist,
the radiologist, and/or the investigator (in accordance with the MHRA Safety Guidelines
for Magnetic Resonance Imaging Equipment in Clinical Use, March 2015):
!
An implant containing metal, including but not limited to intracranial aneurysm clips,
cochlear implants, prosthetic devices containing metal, implanted drug infusion
pumps, neurostimulators or bone growth stimulators, intrauterine contraceptive
devices containing metal, or any other type of iron based metal implant.
!
Internal metallic objects such as bullets or shrapnel, as well as surgical clips, pins,
plates, screws, metal sutures, or wire mesh.
!
Any tattoo or permanent cosmetics/make-up including but not limited to, permanent
lip liner or permanent eye liner.
Note: Any tattoo in the treated area will be exclusionary.
!
Severe claustrophobia.
!
A history of uncontrolled hypertension, epilepsy, asthma, anemia, or sickle cell
disease.
7. Has a known coagulation disorder and/or is taking any medication (ie, anticoagulants or
antiplatelet medications, except for ≤ 150 mg aspirin daily) that would increase the risk
of bleeding within 7 days of the first injection of EN3835 and for the duration of the
study.
8. Has received oral or parenteral steroids for any reason within 3 weeks before the
Screening Visit.
9. Has, at any time, received collagenase for the treatment of AC (including subjects who
received treatment in Study AUX-CC-870 or AUX-CC-871).
10. Has received treatment with an investigational product within 30 days (or 5 half-lives,
whichever is longer) of the first dose of study treatment.
11. Has received collagenase treatments (eg, Santyl® ointment and/or XIAFLEX/XIAPEX®)
for any other indication within 30 days prior to study treatment administration, or is
planning to be treated with collagenase (other than study treatment) at any time during
the study.
12. Has donated blood within 30 days prior to the Screening Visit or has plans to donate
blood during the study.
13. Has a corrected QT interval (QTc) of ≥ 450 ms for male subjects or ≥ 470 ms for female
subjects on the screening electrocardiogram (ECG).
14. 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


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the research staff conducting the study, or of the sponsor, or of the contract research 
organization, or of the IRB/IEC.
15. Has concurrent diseases that might interfere with the conduct of the study, confound the
interpretation of the study results, or endanger the subject’s well-being, (eg, evidence of
any significant hematological, endocrine, cardiovascular, respiratory, neurological, renal,
hepatic, or gastrointestinal disease). If there is a history of such disease but the condition
has been stable for more than 5 years and is judged by the investigator not to interfere
with the subject’s participation in the study, the subject may be included, with the
documented approval of the Medical Monitor.
16. Has any other conditions that, in the investigator’s opinion, might indicate that the
subject is unsuitable for the study.
5.3.
Lifestyle Considerations
From the signing of the informed consent through the Day 95/Early Termination Visit, subjects 
should refrain from any movements or activities that require pushing, pulling, running or 
jumping (except as directed in PT sessions or home exercises). Additionally, subjects should 
refrain from doing pushups, pull-ups, taking spin classes, and swimming. Purses should not be 
carried on the treated side.
Subjects who are avid exercisers may do lower body workouts that do not involve the arms 
and/or shoulders keeping in mind the weight lifting restrictions (see Section 5.1, Item 9). General 
stationary bike and treadmill walking are acceptable forms of cardiovascular strength training; 
however, subjects should refrain from road biking and the elliptical.
5.4.
Screen Failures
Screen failures are defined as subjects who consent to participate in this study but are not 
subsequently randomized.
Subjects will be allowed to repeat hematology, serum chemistry, urinalysis, and/or vital signs 
once, if necessary, if it is within the screening window. The subject will not be considered a 
screen failure unless the repeat assessment/procedure result does not meet eligibility criteria. The 
period from the start of screening related procedures at the Screening Visit to the Day 1 Visit 
must not exceed 28 days, inclusive of any repeat screening procedures. 
Subjects who do not meet all of the eligibility criteria will be deemed a screen failure and the 
following information must be recorded for all subjects who are screen failures:
!
Demography (age, gender, race/ethnicity).
!
Reason for screen failure.
!
Which eligibility criterion was not met.
!
Any AE/SAE experienced by the subject.
Subjects who were in screening (those who had completed or were in the process of screening) 
for the study at the time of any COVID-19 interruption but who had not been dosed with 
EN3835 may be rescreened. If a subject rescreens within 30 days of their original screening MRI 


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date and adhesive capsulitis was confirmed in the affected shoulder by the MRI central review 
committee, and the unaffected shoulder MRI was unremarkable, the subject will not need to have 
a repeat MRI of either shoulder. Other adhesive capsulitis shoulder screening assessments will be 
determined on a case by case basis as to whether or not the subject will need to repeat. All repeat 
screening assessments must be completed within the screening window.
6.
STUDY TREATMENT
Study treatment is defined as any investigational treatment, marketed product, placebo, or device 
intended to be administered to a study subject according to the study protocol. Table 2 provides 
general information regarding the treatments to be used in this study.
Table 2:
Study Treatment
Cohort Name
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
Vial
Vial
Unit Dose 
Strengths
0.9 mg per vial
NA
Dose Amount and 
Frequency
0.58 mg/mL given in each of up to 3 
treatment sessions at least 21 days apart
Volume matched placebo given in each 
of up to 3 treatment sessions at least 
21 days apart
Route of 
Administration
Pericapsular (periarticular) injection
Pericapsular (periarticular) injection
Sourcing
Provided centrally by the sponsor or 
designee
Provided centrally by the sponsor or 
designee
Packaging and 
Labeling
Product will be provided in kits 
containing 1 vial of EN3835 and 1 vial 
of diluent. Each kit will be labeled per 
country requirements
Product will be provided in kits 
containing 1 vial of placebo and 1 vial 
of diluent. Each kit will be labeled per 
country requirements
6.1.
Study Treatment Administration
EN3835 and its placebo are sterile lyophilized powders that are reconstituted with a sterile 
diluent made of 0.9% sodium chloride and 0.03% calcium chloride dihydrate in water. Subjects 
who qualify for the study will be given a dose of 0.58 mg of EN3835 or placebo per treatment 
administered in up to 3 treatment sessions at least 21 days apart (the Day 1, 22, and 43 Visits).
Treatment sessions should be at least 21 days apart. For example, if the Day 22 treatment session 
occurs late but within window (ie, on Day 24) the next treatment session should be 21 days later 
on Day 45 (+1 days) to maintain the minimum 21 days between doses.




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Reconstituted EN3835/placebo solution can be kept at room temperature (20°C to 25°C) for up 
to 1 hour or refrigerated (2°C to 8°C) for up to 4 hours prior to administration. If the 
reconstituted EN3835/placebo solution is refrigerated, allow the solution to return to room 
temperature for approximately 15 minutes before use.
The investigator or designee will confirm that appropriate temperature control conditions have 
been maintained during transit and while the study treatment is in the investigator’s possession 
for all study treatments received and that any discrepancies are reported and resolved prior to 
study treatment administration.
Only subjects enrolled in the study will receive study treatment and only authorized study staff 
can dispense study treatment.
In accordance with the International Council for Harmonisation (ICH) requirements, at all times 
the investigator must be able to account for all study treatment furnished to the study site. An 
accountability record must be maintained for this purpose. The investigator must maintain 
accurate records indicating dates and quantity of study treatment received, to whom it was 
administered (subject-by-subject accounting) and accounts of any study treatment accidentally or 
deliberately destroyed. 
Refer to the Pharmacy Manual for complete information regarding preparation, handling, 
storage, and accountability of study treatment.
6.3.
Measures to Minimize Bias
Subjects will be randomized according to a validated computer-generated allocation scheme to 
receive the study treatment described above in a 1:1 ratio using an interactive response 
technology (IRT) system. Subjects, investigators, site personnel, and Endo personnel (except 
clinical supplies personnel) will be blinded to treatment assignment. 
6.3.1.
Interactive Response Technology
The investigator or designee will utilize an IRT system to register subjects at screening. Each 
subject’s unique identification number (ID) will be assigned by the IRT system and will be used 
to identify the subject for the duration of the study within all systems and documentation. If the 
subject is not eligible to receive study treatment, or should withdraw from the study, the ID 
number will not be reassigned to another subject. Specific instructions for the use of the IRT 
system will be included in the Pharmacy Manual. 
The investigator must maintain a subject master log linking the subject ID to the subject’s name. 
The investigator must follow all applicable privacy laws in order to protect a subject’s privacy 
and confidentiality. Information that could identify a subject must be masked on material 
received by the sponsor.
6.3.2.
Emergency Identification of Study Treatment
The blind may be broken if, in the opinion of the investigator, it is in the subject’s best interest 
for the investigator to know the study treatment assignment. The sponsor must be notified before 
the blind is broken unless identification of the study treatment is required for a medical 
emergency in which the knowledge of the specific blinded study treatment will affect the 
immediate management of the subject’s condition. In this case, the sponsor must be notified 


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within 24 hours after breaking the blind. The date and time that the blind is broken must be 
recorded in the source documentation. Specific instructions for breaking the blind in the IRT 
system are provided in the Pharmacy Manual.
6.4.
Study Treatment Compliance
All subjects will receive study treatment administered by the investigator at the study site. All 
dosing information will be recorded for each subject visit. Study treatment inventory will be 
maintained in the IRT system, and all original containers of used and unused study treatment and 
diluent will be returned to the sponsor (or designee) at the end of the study. 
Accidental or intentional overdoses should be reported to the sponsor/designee promptly (see 
Section 8.4).
6.5.
Prior and Concomitant Medications and Nondrug Therapies
The start and stop date, dose, unit, frequency, route of administration, and indication for all prior 
(taken within the 90 days prior to the Screening Visit) and concomitant (taken from the 
Screening Visit through the Day 95 Visit) medications and nondrug therapies (eg, blood 
transfusions, oxygen supplementation, etc) received will be recorded.
In addition, all prior medications and nondrug therapies for AC will be recorded with start and 
stop date, dose, unit, frequency and route of administration.
6.5.1.
Prohibited Medications and Nondrug Therapies
To be eligible for the study, subjects will agree not to use pain medications for the duration of 
the study period and for 2 weeks prior to the Screening Visit. Pain medications include, but are 
not limited to: 
!
opioids (eg, codeine, heroin, hydrocodone, hydromorphone, morphine, oxycodone,
methadone, buprenorphine),
!
cannabis.
Note: NSAIDs (ibuprofen, etc) and Tylenol (acetaminophen) are allowed.
In addition, the following medications or nondrug therapies will not be permitted during the 
study (from the Screening Visit through the Day 95 Visit):
!
Anticoagulant or antiplatelet medication (except ≤ 150 mg aspirin daily).
!
Any other medications or nondrug therapies for the affected shoulder other than those
outlined in this protocol.
!
Any collagenase treatments (eg, Santyl ointment, XIAFLEX) other than study
treatment.
!
Any investigational product, device, or procedure administered as part of a research
study other than the treatment in this study.
If any prohibited medication/nondrug therapy 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 to continue the subject in the study.


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6.6.
Visits Affected by COVID-19 Interruption
Subjects who were in screening (those who had completed or were in the process of screening) 
for the study at the time of the COVID-19 interruption but who had not been dosed with EN3835 
may be rescreened. If a subject rescreens within 30 days of their original screening MRI date and 
adhesive capsulitis was confirmed in the affected shoulder by the MRI central review committee, 
and the unaffected shoulder MRI was unremarkable, the subject will not need to have a repeat 
MRI of either shoulder. Other adhesive capsulitis shoulder screening assessments will be 
determined on a case by case basis as to whether or not the subject will need to repeat. All repeat 
screening assessments must be completed within the screening window.
Protocol deviations will be recorded for all subjects who have visits outside of the windows 
outlined in the Schedule of Activities, regardless of reason (including all subjects who 
experienced a COVID-19 interruption). The reason for out-of-window visits will be recorded.
7.
DISCONTINUATION FROM STUDY TREATMENT AND
SUBJECT WITHDRAWAL
7.1.
Discontinuation of Study Treatment
Subjects who discontinue study treatment for any reason, will be encouraged to complete the 
remaining study visits and evaluations and provide any additional follow-up information as 
required by the study, unless the subject specifically indicates that they will not participate in any 
further evaluations. The date of and reason for study treatment discontinuation will be recorded.
Permanent study treatment discontinuation is required if:
!
The subject becomes pregnant during the study.
!
Discontinuation of study treatment for abnormal liver function should be considered
by the investigator when a subject meets the conditions outlined in Section 10.6.
!
If a clinically significant cardiac finding is identified (including but not limited to
changes from baseline in QTc after the start of study treatment), the investigator in
consultation with the medical monitor will determine if the subject can continue in
the study and if any change in management is needed.
Subjects who discontinue from study treatment at any time after the first dose of study treatment 
will not be replaced.
7.2.
Subject Withdrawal from the Study
Subjects may withdraw from the study at any time at their own request, or may be withdrawn at 
any time at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons. The date of withdrawal and the reason for withdrawal will be recorded.
If the subject withdraws consent for disclosure of future information, the sponsor may retain and 
continue to use any data collected before such withdrawal of consent. If a subject withdraws 
from the study, the subject may request destruction of any biological samples taken and not yet 
tested. The investigator must document this in the site study records.


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A subject may be discontinued from the study for the following medical or administrative 
reasons: 
• Withdrawal by subject (reason must be specified). 
• An AE. 
• Death. 
• A protocol violation (reason must be specified, for example: lack of compliance, use 
of a prohibited concomitant medication, etc). 
• The subject was lost to follow-up.  
• Other reasons (reason must be specified, for example: the subject moved, pregnancy, 
investigator decision, sponsor decision to terminate trial, etc). 
If a subject discontinues from the study, all early termination procedures should be conducted as 
detailed in the Schedule of Activities. The date a subject discontinues and the reason for 
discontinuation will be recorded in the source documentation and electronic case report form 
(eCRF). If, however, a subject withdraws consent, no additional procedures are required. This 
information should be recorded in the source documentation and the eCRF. 
7.3. 
Lost to Follow-up 
A subject will be considered lost to follow-up if the subject repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return for a required study visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and to ascertain whether or not the subject wishes to and/or should continue 
in the study. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls, and 
if necessary, a certified letter to the subject’s last known mailing address; or local 
equivalent methods). These attempts will be documented. 
• Should the subject continue to be unreachable, the subject will be considered to have 
withdrawn from the study. 
Subjects who have been lost to follow-up at any time after the first dose of study treatment will 
not be replaced. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedule of Activities (Section 1.2). 
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct. Protocol waivers or exemptions are not 


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allowed. Activities outlined in the Study Operations Manual must be followed or will result in a 
protocol deviation. 
Urgent safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the subject should continue study treatment and/or be withdrawn from 
the study.
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
subjects screened and to confirm eligibility or record reasons for screen failure, as applicable.
Passive External Rotation at 0°, 45°, and 90° of Abduction
Passive external rotation at 0°, 45°, and 90° of abduction will be measured in both shoulders 
using a goniometer at screening in the supine position. In the event that 45° and 90° cannot be 
achieved due to pain or restriction in the affected shoulder, the amount of external rotation 
available at maximum attainable abduction ROM is permissible as the second and third 
measurements.
Hand Dominance
The subject’s self-reported hand dominance will be recorded at screening.
Supervised In-office Physical Therapy
All subjects will undergo a standard supervised in-office PT regimen. The PT regimen will 
consist of 2 sessions per week for 2 weeks starting 7 days after each study treatment until the 
next scheduled injection and until the Day 64 Visit. In-office PT will last approximately 30 to 
60 minutes. Subjects will be provided with verbal and hands-on instructions for the exercises to 
be completed. Physical therapists will follow the standard PT regimen found in the Study 
Operations Manual. All subjects will continue the PT regimen regardless of dose interruption or 
withdrawal from the study.
Home Exercises
Study personnel will train each subject how to conduct a standard set of home exercises and 
provide each subject with a set of instructions and any necessary equipment (ie, pulleys) to 
complete the home exercises. These home exercises should be performed by each subject at least 
2 times per day and no more than 3 times a day. Home exercises will begin 3 days after each 
study treatment and will end at the Day 95 Visit. In office PT will count as 1 of the home 
exercise sessions on PT days. All subjects will continue the home exercises regardless of dose 
interruption or withdrawal from the study.
Subjects will document their home exercise completion and frequency using a diary. The site 
will train the subject on the use of the diary and will review the diary at visits specified in the 
Schedule of Activities to ensure compliance.
8.1.
Efficacy Assessments
Efficacy assessments will be evaluated at times specified in the Schedule of Activities. Below is 
a general description of each of these assessments. Specific instructions and questionnaires 


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and/or forms (where appropriate) will be provided in the Study Operations Manual. All PROs 
must be completed prior to any other assessments.
8.1.1.
Adapted American Shoulder and Elbow Surgeons Standardized Shoulder Form
The adapted ASES is a questionnaire to assess AC patient rated shoulder pain and function that 
has been modified from the ASES Standardized Shoulder Form (McClure and Michener, 2003; 
Michener, 2002). The adapted ASES is a self-administered PRO measure, divided into 2 
sections: a pain subscale and a function subscale. The pain subscale is a single item, numeric 
rating scale about pain in the affected shoulder on the day of assessment. The 11-point numeric 
rating scale ranges from 0 (No pain at all) to 10 (Pain as bad as it can be). The function subscale 
consists of 10 activities of daily living where the subject is asked to indicate on a 4 point ordinal 
scale their ability to do the activity with the affected arm (Evidera, 2016).
All subjects will complete the adapted ASES at times outlined in the Schedule of Activities. 
These data will be entered by the subject directly into an electronic clinical outcomes 
assessment (eCOA) instrument while the subject is alone with no study site personnel in the 
room. On treatment days (Days 1, 22 and 43), the adapted ASES must be completed prior to 
study treatment injection. 
8.1.2.
Range of Motion
PROM (for forward flexion, internal rotation, external rotation, abduction, and shoulder 
extension) and AROM (for forward flexion, internal rotation, external rotation, abduction, and 
shoulder extension) will be measured using a goniometer, and a spinal level (for internal 
rotation) at times specified in the Schedule of Activities for the affected and contralateral 
shoulder. These measurements will be completed with the subject in the supine position.
8.1.3.
Pain Upon Movement
The PUM Scale is a single item 11-point numerical rating scale of pain that asks subjects to rate 
the pain in their affected shoulder after AROM forward flexion, internal rotation, external 
rotation, abduction, and shoulder extension on a scale from 0 (No pain at all) to 10 (Pain as bad 
as it can be).
All subjects will complete the PUM at times outlined in the Schedule of Activities. The PUM 
data will be entered by the subject directly into an eCOA instrument while the subject is alone 
with no study site personnel in the room.
8.1.4.
Patient-reported Global Severity of Adhesive Capsulitis
The Patient-reported Global Severity of Adhesive Capsulitis is a single item 11-point numerical 
rating scale that asks subjects to rate the overall severity of their AC symptoms on a scale from 
0 (No symptoms) to 10 (Symptoms as bad as they can be).
All subjects will complete the Patient-reported Global Severity of Adhesive Capsulitis scale at 
times outlined in the Schedule of Activities. The Patient-reported Global Severity of Adhesive 
Capsulitis data will be entered by the subject directly into an eCOA instrument while the subject 
is alone with no study site personnel in the room.


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8.1.4.1.
Patient-reported Change in Severity of Adhesive Capsulitis
The Patient-reported Change in Severity of Adhesive Capsulitis is a questionnaire that asks 
subjects if their AC symptoms are “Better, About the Same, or Worse” since the last time the 
questionnaire was administered. Subjects who report that their symptoms are better or worse are 
then asked to rate the change in their symptoms on a 7-point ordinal scale.
All subjects will complete the Patient-reported Change in Severity of Adhesive Capsulitis 
questionnaire at times outlined in the Schedule of Activities. The Patient-reported Change in 
Severity of Adhesive Capsulitis questionnaire answers will be entered by the subject directly into 
an eCOA instrument while the subject is alone with no study site personnel in the room.
8.1.5.
Subject Satisfaction with Treatment
Subjects will rate their satisfaction with treatment on a 5-point Likert scale from Very 
Dissatisfied to Very Satisfied at times specified in the Schedule of Activities. The response will 
be entered directly into an eCOA instrument and completed while the subject is alone with no 
study site personnel in the room. The subject will be instructed to refrain from discussing their 
rating with the investigator and any other site personnel.
8.1.6.
Investigator Assessment of Improvement with Treatment
Investigators will provide their assessment of improvement with treatment for each subject using 
a 7-point Likert scale from Very Much Worse to Very Much Improved at times specified in the 
Schedule of Activities. The response will be entered directly into an eCOA instrument. The 
investigator will refrain from discussing their rating with the subject.
8.1.7.
Magnetic Resonance Imaging and X-rays
MRIs of the affected and contralateral shoulder will be performed for all subjects at times 
specified in the Schedule of Activities. Subjects should complete all other screening activities, 
including an X-ray of the affected shoulder, prior to the MRIs required at screening, and must 
meet the entry criteria of passive external rotation assessment at 0°, 45°, and 90° abduction and 
have an adapted ASES function subscale score (< 35) in the affected shoulder prior to the 
conduct of the screening MRIs. Previous X-rays of the affected shoulder may be used if they 
were taken within 30 days of the Screening Visit.
Additionally, subjects must be able (in a supine position) to have the affected arm passively 
externally rotated to at least a neutral position within the subject’s level of pain tolerance with 
the elbow at the side (against the body) and flexed to 90° prior to the MRI at screening.
A central MRI committee consisting of 2 blinded musculoskeletal radiologists who will serve as 
the primary readers and 1 blinded clinician who will serve as the adjudicator in discordant cases. 
All screening MRIs of the affected shoulder will be reviewed through a blinded central read, 
performed by specialists with expertise in musculoskeletal imaging to determine if the subject 
has any clinically significant confounding pathologies and to confirm subject eligibility. 
MRI-based determinations of eligibility made by the central MRI committee are final, and will 
supersede any previous MRI analyses made by investigational site personnel or MRI imaging 
center personnel. 


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Specific instructions for the MRI procedures will be provided in the Study Operations Manual. 
All MRIs from this study are the property of Endo and de-identified images may be utilized for 
clinical development, scientific communication, marketing, regulatory purposes, and/or legal 
applications as required/desired by Endo.
8.2.
Safety Assessments
All safety assessments will be performed at the times outlined in the Schedule of Activities. 
Additional (unscheduled) safety assessments may be performed as needed.
In order to ensure subject safety and protect data integrity, Endo, in accordance with the FDA 
Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health 
Emergency (March 2020, updated 02 July 2020), will allow virtual visits for safety assessments. 
In addition, subjects impacted by the health emergency will be allowed to continue in the study 
and complete remaining dosing and assessments when the investigational sites re-open.
8.2.1.
Demography
The subject’s birth date, gender, race, and ethnicity will be collected at screening.
8.2.2.
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 subjects, will be 
recorded. 
In addition, any history or current collagen mediated disorders (including but not limited to 
Garrod’s pads, Dupuytren’s nodules, plantar nodules, PD, AC of other joints, etc) will be 
recorded (excluding the current AC episode).
History of tobacco and alcohol use (never, current, former) will also be collected.
Surgical history will include a review of all surgical procedures completed in the prior 5 years 
and any surgery completed at any time in the affected shoulder.
8.2.3.
Adhesive Capsulitis History
A history of all past episodes of AC of the shoulder will be recorded at screening. Details of each 
past episode to be collected include: the affected shoulder (right or left), onset date, resolution 
date, and any procedures or medical treatments provided.
In addition, the history of the current AC episode including the affected shoulder (right or left), 
onset date of symptoms, and determination of idiopathic or traumatic AC will be recorded at 
screening.
8.2.4.
Physical Examination
The complete physical examination will include evaluation of the head, eyes, ears, nose, throat, 
neck (including thyroid), cardiovascular system (including assessment of heart, peripheral 


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pulses, presence or absence of edema), lungs, abdomen (including liver and spleen, bowel 
sounds), lymph nodes, musculoskeletal system (including spine, joints, muscles), neurological 
system (including cranial nerves, reflexes, sensation, strength), skin, extremities, and other 
conditions of note.
All examinations will be performed by a physician or health professional listed on the Form 
FDA 1572 and licensed to perform physical examinations. The investigator will review all 
physical exam findings for clinical significance. Any new, or change from the Screening Visit in, 
physical examination findings that is considered by the investigator to be clinically significant 
will be recorded as an AE (or SAE, if appropriate).
Any clinically significant physical exam finding will be recorded as medical history at screening. 
8.2.5.
Height and Weight
Height will be collected at screening only. Weight will be collected as outlined in the Schedule 
of Activities. Any change from the Screening Visit in subject weight that is considered by the 
investigator to be clinically significant will be recorded as an AE (or SAE, if appropriate).
8.2.6.
Vital Signs
Vital signs will be obtained after the subject has been seated for 5 minutes (minimum) and will 
include systolic and diastolic blood pressures, pulse rate, respiratory rate, and body temperature. 
The results, date, and time for all vital sign assessments will be recorded. 
On days that study treatment is administered (the Day 1, 22, and 43 Visits), vital signs will be 
taken up to 4 hours prior to dosing and at 15 and 30 minutes after dosing (body temperature is 
not required at the 15-minute postdose time point). The subject’s vital signs must be stable, or 
repeated until stable, before the subject can leave direct observation.
The investigator will review all vital sign values for clinical significance. Any change from the 
Screening Visit in vital signs that is considered by the investigator to be clinically significant will 
be recorded as an AE (or SAE, if appropriate).
8.2.7.
Electrocardiogram
A 12-lead ECG recording will be conducted at the Screening Visit. The subject should be in a 
supine position for at least 5 minutes before the recording is conducted. Lead position will be 
that of a standard 12-lead ECG; no additional or special lead placements will be necessary. 
If the ECG report shows QT prolongation (QTc ≥ 450 ms for males or QTc ≥ 470 ms for 
females), the investigator will exclude the subject from study participation.
The investigator will review all ECG results for clinical significance. Any ECG result meeting 
the investigator’s criteria for clinical significance will be recorded as an AE (or SAE, if 
appropriate).
8.2.8.
Clinical Laboratory Determinations (Chemistry, Hematology, Urinalysis, 
HbA1c, TSH, Serum and Urine Pregnancy Test)
Blood and urine samples will be collected for clinical laboratory testing at the time points 
outlined in the Schedule of Activities. Required clinical laboratory tests are outlined 


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in Section 10.2. 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. 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. Any additional testing will be 
performed by the designated central laboratory. 
8.2.9.
Pregnancy Testing
All female subjects of childbearing potential will have serum and/or urine pregnancy tests 
performed at the time points outlined in the Schedule of Activities. Results must be available 
prior to protocol mandated study treatment administration. Subjects with positive results at the 
Screening Visit or the Day 1 Visit will be ineligible for study entry. Any female subject that 
becomes pregnant during the study will be immediately discontinued from study treatment, but 
may continue in the study (see Section 7.1). All pregnancies will be reported as per 
Section 8.3.5. 
If applicable, the subject’s agreement to use contraception throughout their study participation 
(from Screening to the Day 95 Visit), or for 28 days after the last dose of study treatment for 
subjects who early terminate, will be documented.
8.3.
Adverse Events and Serious Adverse Events
The definitions of AEs and SAEs can be found in Section 10.3.
All AEs and SAEs, including both observed or volunteered problems, complaints, signs, or 
symptoms must be recorded, regardless of whether associated with the use of study treatment. 
This would include AEs resulting from concurrent illness, reactions to concurrent medication 
use, or progression of disease states (excluding the disease under study). A condition present at 
baseline that worsens after initiation of study treatment will be captured as an AE; the onset date 
will be the date the event worsened. The AE should be recorded in standard medical terminology 
when possible.
8.3.1.
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected by the investigator from the time of signing the informed 
consent form (ICF) through the Day 95 Visit, or for 28 days after the last dose of study treatment 
for those who early terminate. 
Investigators are not obligated to actively seek AEs and SAEs after conclusion of subject study 
participation. However, if the investigator learns of any SAE, including death, at any time after 
the subject has been discharged from the study, and the investigator considers the event to be
reasonably related to the study treatment or study participation, the investigator must notify the 
sponsor within 24 hours as described in Section 10.3.


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All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Section 10.3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and submitting SAE reports are provided in Section 10.3.
8.3.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and SAEs. Open-ended and 
nonleading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences. 
At each visit, subjects will be queried regarding any AEs that have occurred since the last visit. 
Subjects will be asked to volunteer information concerning AEs with a nonleading question such 
as, “How do you feel?” Study site personnel will then record all pertinent information. The study 
treatment compliance record should also be reviewed to detect potential intentional or 
unintentional overdoses.
Any AEs identified in the subject diaries will be reported in the appropriate electronic case report 
form (eCRF) module, and if SAEs, as described in Section 10.3.
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All nonserious AEs must be followed until resolution or until the last 
study visit whichever comes first; except for subjects who withdraw early from the study for 
whom nonserious AEs will be followed until resolution or for 28 days after the last 
administration of study treatment, whichever comes first. 
All SAEs and nonserious AESIs will be followed to resolution, stabilization, the event is 
otherwise explained, or until follow-up is no longer possible. Further information on follow-up 
procedures is provided in Section 10.3.
8.3.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities regarding the safety of the study treatment under clinical 
investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of the study treatment under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements regarding safety reporting to 
regulatory authorities, IRBs/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSARs) according to local regulatory requirements and sponsor policy, and forwarded to 
investigators as necessary. 
An investigator who receives 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 


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with the Investigator’s Brochure, and will notify the IRB/IEC, if appropriate according to local 
requirements.
8.3.5.
Pregnancy
All subject pregnancies that are identified during or after this study, where the estimated date of 
conception is determined to have occurred at any time during the study or (within 28 days of the 
last study treatment for those who terminate early) must be reported, followed to conclusion, and 
the outcome reported, even if the subject is withdrawn from the study. Pregnancies that occur in 
the partner of a treated subject (ie, female partner of male subject) also must be reported. The 
investigator must report (as outlined above) all pregnancies within 24 hours using the Pregnancy 
Report 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 
Report Forms. A Two-Month Follow-up Pregnancy Report Form detailing the status of the infant 
must also be submitted.
Pregnancy itself is not regarded as an AE unless there is suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Likewise, elective abortions without complications are not considered AEs. Any SAEs 
associated with pregnancy (eg, congenital abnormalities/birth defects, or any other serious 
events) must additionally be reported as such using the Serious Adverse Event (SAE)/Reportable 
Event Form (see Section 10.3). Spontaneous miscarriages should also be reported and handled as 
SAEs. 
Subjects will be instructed to immediately notify the investigator of any pregnancies. 
A subject who becomes pregnant must be immediately discontinued from study treatment but 
may remain in the study (see Section 7.1). Should a subject discontinue study treatment 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 subject withdraws from the study 
because of pregnancy.
8.3.6.
AEs/SAEs Experienced by Nonsubjects Exposed to Study Treatment
Nonsubjects are persons who are not enrolled in the study but have been exposed to study 
treatment, including instances of diversion of study treatment. Any AEs/SAEs occurring in 
nonsubjects from such exposure will be reported to the Endo PVRM Department (when the 
nonsubject agrees) on the Serious Adverse Event (SAE)/Reportable Event Form regardless of 
whether the event is serious or not. Instructions for completing the form for events experienced 
by nonsubjects will be provided. SAEs occurring in nonsubjects exposed to study treatment will 
be processed within the same SAE reporting timelines as described in Section 10.3. Additionally, 
the treatment accountability source documentation at the site should reflect this occurrence.
8.3.7.
Adverse Events of Special Interest 
AESIs for this study include:
!
Bruising, ecchymosis, hematomas, and contusions that occur remote to the site of
treatment administration.


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!
Any hypersensitivity reactions.
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 10.3.
8.4.
Overdose
Study treatment overdose is any accidental or intentional use of treatment in an amount higher 
than the dose indicated by the protocol for that subject. Study treatment compliance should be 
reviewed to detect potential instances of overdose (intentional or accidental).
Any treatment overdose during the study should be noted on the study treatment 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 10.3, even if the 
events do not meet seriousness criteria. If the AE associated with an overdose does not meet 
seriousness criteria, it must still be reported using the Endo Serious Adverse Event 
(SAE)/Reportable Event Form and in an expedited manner, but should be noted as nonserious on 
the form and the AE eCRF. 
8.4.1.
Study Treatment Abuse/Misuse
AEs associated with misuse or abuse will be appropriately reported as AEs or SAEs, and 
monitored per Section 10.3.
8.5.
Pharmacokinetics
Not applicable.
8.6.
Pharmacodynamics
Not applicable.
8.7.
Genetics
Not applicable.
8.8.
Biomarkers
8.8.1.
Immunogenicity Assessments
Serum samples will be collected at times outlined in the Schedule of Activities and will be tested 
for binding anti-AUX-I and anti-AUX-II antibody testing. When immunogenicity samples are 
required on a Treatment Day, the sample will be collected prior to study treatment 
administration. The antibody-positive samples also will be tested for neutralizing antibodies. 
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 Study Operations Manual.


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De-identified immunogenicity samples may be stored for a maximum of 5 years (or according to 
local regulations) following the last subject’s last visit for the study at a facility selected by the 
sponsor to enable further analysis of immune responses to study treatment; develop methods, 
assays, prognostics and/or companion diagnostics related to specify the treatment target, disease 
process, pathways associated with disease state, and/or mechanism of action of the study 
treatment.
8.9.
Medical Resource Utilization and Health Economics
Not applicable.
9.
STATISTICAL CONSIDERATIONS AND METHODS
9.1.
Sample Size Determination
A post hoc analysis was conducted using a subgroup of AUX-CC-871 subjects who were rated 
with moderate/severe AC based on baseline MRI images. This subgroup displayed a notable 
treatment effect (EN3835 vs placebo) on the pain and composite components of the adapted 
ASES questionnaire. This subgroup also displayed a treatment effect trend for the functional 
component of the adapted ASES. Given this result, the sample size calculation is based on the 
mean and SD found in this subgroup for the adapted ASES composite score on Day 95. Given a 
mean change from baseline value of 38.6 for the EN3835 group and 27.6 for the placebo group 
with an SD of 21.6, a sample size of approximately 142 subjects would be required given a 1:1 
randomization and a type I error of 0.05 with a power of 85%. With an expected drop-out rate of 
approximately 20%, 180 subjects (90 EN3835 and 90 placebo) should be dosed to ensure 
142 subjects complete the study.
9.2.
Populations for Analysis
For the purposes of analysis, the following populations are defined:
!
The Safety Population is defined as all randomized subjects who received at least 1
injection of study treatment (EN3835 or placebo). All safety analyses will be based
on this population.
!
The Intent-to-Treat (ITT) Population is defined as all randomized subjects who
received at least 1 injection of study treatment (EN3835 or placebo).
!
The Modified Intent-to-Treat (mITT) Population is defined as all ITT subjects who
have a valid baseline adapted ASES composite score in the affected shoulder and at
least 1 valid adapted ASES composite score after the injection of the study treatment.
All efficacy analyses will be based on this population.
!
The Per-Protocol (PP) Population is defined as those subjects in the mITT Population
who do not have any major protocol deviations. Determination of PP subjects will be
completed before the study database is closed and locked. If more than 10% of the
mITT Population is excluded from the PP Population, then all efficacy summaries
will be repeated using the PP Population for the sensitivity analysis.


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9.3.
Statistical Hypotheses and Analyses
This section provides a general summary of the statistical methods to be used in analyzing study 
data. A more detailed statistical analysis plan (SAP) will be developed and finalized prior to the 
interim analysis.
9.3.1.
Efficacy Analysis
The primary endpoint is the change from baseline to the Day 95 Visit in the adapted ASES 
composite score.
A mixed-model ANOVA with factors for treatment group and visit will be performed to compare 
active to placebo for the change from baseline to the Day 95 Visit in adapted ASES composite 
score. 
A mixed-model ANOVA with factors for treatment group and visit will be performed to compare 
active to placebo for the absolute and percent change from baseline to the Day 22, 43, 64, and 
Day 95 Visits in PROM, AROM, adapted ASES function subscale, and adapted ASES pain 
subscale.
For the Investigator Satisfaction with Treatment and Subject Satisfaction with Treatment at the 
Days 64 and Day 95 Visits, a Wilcoxon rank sum nonparametric test will be performed to 
compare active to placebo. A Wilcoxon rank sum nonparametric test will also be used to 
compare active to placebo for the change from baseline in Patient-reported Global Severity of 
Adhesive Capsulitis at the Day 22, 43, 64 and 95 Visits.
For Patient-reported Change in Severity of Adhesive Capsulitis at the Day 22, 43, 64, and 
95 Visits, a chi-square test will be performed to compare active to placebo.
Endpoints of the affected shoulder in the EN3835 group will be compared to the endpoints of the 
affected shoulder in the placebo group. 
The tertiary/exploratory analysis plan will be provided in the SAP.
9.3.2.
Safety Analyses
All subjects who receive at least 1 dose of study treatment will be included in the safety analyses. 
Subjects will be included in the safety analyses based on the actual treatment received.
Treatment comparisons for safety parameters will be performed using Fisher exact tests for 
categorical data such as event rates or Student t test for continuous data such as changes from 
baseline in the laboratory tests and vital signs using type 1 error rate of 0.05.
9.3.2.1.
Adverse Events
AEs will be coded using MedDRA by preferred term within system organ class (SOC). The
number of AEs and the number of subjects reporting AEs will be listed and summarized 
descriptively by SOC, preferred term, severity, and causality for each treatment group. Only 
TEAEs (events that are new in onset or aggravated in severity following treatment) will be 
included in all summaries. SAEs (including death) will be summarized. 


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9.3.2.2.
Vital Signs and Laboratory Evaluations
Descriptive statistics will be presented for actual and change from baseline at each visit for vital 
signs and for each clinical laboratory test parameter.
9.3.3.
Other Analyses
Descriptive statistics (percent of positive measurements and average antibody level) will be 
presented for anti-AUX-I and anti-AUX-II antibody levels at Day 1 and at the Day 95 Visit by 
treatment group. Average antibody levels will be summarized on logarithmically transposed titer 
values. In addition, by-treatment percentages of neutralizing anti-AUX-I and anti-AUX-II 
antibodies will be summarized at the Day 95 Visit.
9.4.
Interim Analysis
An interim analysis for safety and futility is planned for when approximately 86 subjects have 
completed the Day 95/Early Termination Visit. Details of the interim analysis will be provided in 
the SAP. The study will remain blinded to the subjects, investigators, site staff, and Endo 
personnel (with the exception of the drug supply personnel).
An independent unblinded data monitoring committee (DMC) will review the interim data and 
provide recommendations for study continuation.


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations
This clinical study is designed to comply with the ICH Guidance on General Considerations for 
Clinical Trials (62 FR 6611, December 17, 1997), Nonclinical Safety Studies for the Conduct of 
Human Clinical Trials for Pharmaceuticals (62 FR 62922, November 25, 1997), Good Clinical 
Practice: Consolidated Guidance (62 FR 25692, May 9, 1997) and 21 CFR parts 50, 54, 56, and 
312.
The study will be conducted in full compliance with ICH E6(R2), 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/IEC prior to the start of the study will be the responsibility of the 
investigator. A copy of approval documentation will be supplied to Endo along with a roster of 
IRB/IEC members that demonstrates appropriate composition or other documentation of 
assurance of appropriate composition per local and national regulations (eg, a Department of 
Health and Human Services Assurance Number will satisfy this requirement for IRBs in the 
United States). 
The study protocol, the ICF, advertisements, materials being provided to subjects, and 
amendments (if any) will be approved by IRB/IECs at each study site in conformance with ICH 
E6(R2), CFR Title 21 Part 56, and any other applicable local laws. The investigator is 
responsible for supplying the IRB/IEC with a copy of the current Investigator’s Brochure, 
Package Insert, or Summary of Product Characteristics, as well as any updates issued during the 
study. During the course of the study, the investigator will provide timely and accurate reports to 
the IRB/IEC on the progress of the study, at intervals not exceeding 1 year (or as appropriate), 
and will notify the IRB/IEC of SAEs or other significant safety findings, per the policy of the 
IRB/IEC. At the conclusion of the study, the investigator will submit a final report or close out 
report to the IRB/IEC and provide a copy to Endo.
Any amendment to this protocol will be provided to the investigator in writing by Endo. No 
protocol amendment may be implemented (with the exceptions noted below) before it has been 
approved by the IRB/IEC and the signature page, signed by the investigator, has been received 
by Endo. Where the protocol is amended to eliminate or reduce the risk to the subject, the 
amendment may be implemented before IRB/IEC review and approval. However, the IRB/IEC 
must be informed in writing of such an amendment and approval obtained within reasonable time 
limits. Deviating from the protocol is permitted only if absolutely necessary for the safety or 
clinical management of the subject, and must be immediately reported to Endo. 
The investigator will be responsible for supplying updated safety and/or study information to 
study subjects as it becomes available. 


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10.1.2.
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after the completion of the study.
10.1.3.
Informed Consent Process
The ICF must be approved by the sponsor and the IRB/IEC before any subject provides consent. 
The investigator will provide the sponsor with a copy of the IRB/IEC-approved ICF and a copy 
of the IRB/IEC’s written approval before the start of the study.
The ICF must contain all applicable elements of informed consent and the mandatory statements 
as defined by national and local regulations, including confidentiality. 
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 
subject the objectives of the exploratory research. Subjects will be told that they are free to 
refuse to participate and may withdraw their consent at any time and for any reason during the 
storage period. A separate signature will be required to document a subject’s agreement to allow 
any remaining specimens to be used for exploratory research. Subjects who decline to participate 
in this optional research will not provide this separate signature.
At the Screening Visit (and at other times as may be required by the study or when changes are 
made to the consent form), subjects will read the consent forms 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 forms and the privacy authorization form (if applicable), subjects will 
have an opportunity to ask questions about the study and discuss the contents of these forms with 
study site personnel. The consent/assent process shall be recorded in source documents.
Subjects must assent understanding of and voluntarily sign these forms in compliance with 
ICH GCP and all applicable national and international regulations, before participating in any 
study-related procedures. Subjects will be made aware that they may withdraw from the study at 
any time for any reason. 
All versions of each subject’s signed ICF must be kept on file by the site for possible inspection 
by regulatory authorities and the sponsor. Signed copies of the consent forms and the privacy 
authorization form, if applicable, will be given to the subject. 
The subjects will be made aware of their right to see and copy their records related to the study 
for as long as the investigator has possession of this information. If the subject withdraws 
consent and/or HIPAA authorization, the investigator can no longer disclose health information, 
unless it is needed to preserve the scientific integrity of the study.


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10.1.4.
Data Protection
Study subjects will be assigned a unique identifier by the sponsor or designee. Any subject 
records or datasets that are transferred to the sponsor will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be transferred. 
The subject must be informed that his/her personal study-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure (in accordance with local 
and/or national law) must also be explained to the subject. 
The subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.
10.1.5.
Committee Structure
A DMC will be used for the interim analysis. The DMC charter and composition are available 
upon request.
10.1.6.
Dissemination of Clinical Study Data
Aggregate results data will be provided to the sites that actively enrolled subjects into this study 
after the clinical study report is finalized.
Study results and de-identified individual subject data will be released as required by local and/or 
national regulation.
10.1.7.
Data Quality Assurance
Steps to assure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigators and associated 
personnel prior to start of the study, and periodic monitoring visits conducted by the sponsor or 
sponsor representative. Significant and/or repeated noncompliance will be investigated and 
remedial action instituted when appropriate. Failure to comply with remedial actions may result 
in investigator site termination and regulatory authority notification.
The sponsor or its designee will utilize qualified monitors to review and evaluate activities 
conducted at investigator sites.
The data will be entered into the clinical study database in a timely fashion and will be verified 
for accuracy, following procedures defined by the sponsor (or designee). Data will be processed 
and analyzed following procedures defined by the sponsor (or designee).
The study will be monitored and/or audited at intervals to ensure that the clinical study is 
conducted and data are generated, documented (recorded), and reported in compliance with the 
study protocol, ICH E6(R2) 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.


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


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10.2.
Appendix 2: Clinical Laboratory Tests
Hematology
Biochemistry
Urinalysis
Other
Hemoglobin
Hematocrit
Red blood cell
White blood cell (WBC)
Platelets
WBC with differential
Glucose
Sodium
Potassium
Calcium
Chloride
Carbon dioxide (CO2)
Inorganic phosphate
Blood urea nitrogen
Creatinine
Creatinine clearance (estimated)
Aspartate transaminase (AST)
Alanine transaminase (ALT)
Gamma-glutamyl transferase 
(GGT)
Total bilirubin (TBL) (direct 
bilirubin reflex if elevated)
Albumin
Alkaline phosphatase (ALP)
Uric acid
Glucose
Protein
Specific gravity
pH
Ketones
Bilirubin
Urobilinogen
Nitrite
Blooda
Leukocytesa
TSH
HbA1c
Human chorionic 
gonadotropin (hCG) 
(serum and urine 
pregnancy)
a Microscopic examination will be performed if blood or leukocytes are detected by dipstick.


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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definitions
An AE is any unfavorable or unintended change in body structure (signs), body function 
(symptoms), laboratory result (eg, chemistry, ECG, X-ray, etc), or worsening of a preexisting 
condition associated temporally with the use of the study treatment whether or not considered 
related to the study treatment. AEs will be captured once a subject has signed the informed 
consent. AEs include:
!
Changes in the general condition of the subject.
!
Participative symptoms offered by or elicited from the subject.
!
Objective signs observed by the investigator or other study personnel.
!
All concurrent diseases that occur after the start of the study, including any change in
severity or frequency of preexisting disease.
!
All clinically relevant laboratory abnormalities or physical findings that occur during
the study.
A TEAE is any condition that was not present prior to treatment with study treatment 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 treatment therapy does not constitute an SAE)
!
Results in permanent or substantial disability (permanent or substantial disruption of
one’s ability to conduct normal life functions)
!
Is a congenital anomaly/birth defect (in offspring of a subject using the study
treatment regardless of time to diagnosis)
!
Is considered an important medical event
Important medical events are defined as events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical treatment to prevent 1 of the 
other serious outcomes. Examples of important medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of treatment dependency or 
treatment abuse. 


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10.3.2.
Relationship to Study Treatment
The degree of “relatedness” of the AE to the study treatment must be described using the 
following scale: 
!
Not related indicates that the AE is definitely not related to the study treatment.
!
Unlikely related indicates that there are other, more likely causes and study
treatment is not suspected as a cause.
!
Possibly related indicates that a direct cause and effect relationship between study
treatment and the AE has not been demonstrated, but there is evidence to suggest
there is a reasonable possibility that the event was caused by the study treatment.
!
Probably related indicates that there is evidence suggesting a direct cause and effect
relationship between the AE and the study treatment.
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.
Causality assessments will be recorded on the eCRF and must indicate clearly the relationship 
being assessed. For example, an AE that appears during a placebo run-in phase would be 
assessed with respect to the placebo treatment received and/or study procedures conducted 
during this phase. If the AE continued into an active treatment phase, the relationship would be 
assessed for the active treatment phase only if the AE worsened.
10.3.3.
Intensity Assessment
The intensity (or severity) of AEs is characterized as mild, moderate, or severe:
!
Mild AEs are usually transient, requiring no special treatment, and do not interfere
with the subject’s daily activities.
!
Moderate AEs introduce a low level of inconvenience or concern to the subject and
may interfere with daily activities, but are usually ameliorated by simple therapeutic
measures.
!
Severe AEs interrupt a subject’s usual daily activity and typically require systemic
treatment therapy or other treatment.
10.3.4.
Reporting Adverse Events and Serious Adverse Events
10.3.4.1.
Reporting Adverse Events
Throughout the study, AEs will be documented on the source document and on the appropriate
page of the eCRF whether or not considered treatment related.
10.3.4.2.
Reporting Serious Adverse Events
Any SAE, including death resulting from any cause, which occurs to any subject 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 


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information collected for any initial report of an SAE must also be reported to the sponsor within 
24 hours of receipt by the investigator. 
All SAEs should be reported via email 
 or fax 
.
The sponsor will determine whether the SAE must be reported within 7 or 15 days to regulatory 
authorities in compliance with local and regional law. If so, the sponsor (or the sponsor’s 
representative) will report the event to the appropriate regulatory authorities. The investigator 
will report SAEs to the IRB/IEC per their IRB/IEC policy.
10.3.4.3.
Follow-up Procedures for Serious Adverse Events
To fully understand the nature of any SAE, obtaining follow-up information is important. 
Whenever possible, relevant medical records such as discharge summaries, medical 
consultations, and the like should be obtained. In the event of death, regardless of cause, all 
attempts should be made to obtain the death certificate and any autopsy report. These records 
should be reviewed in detail, and the investigator should comment on any event, lab abnormality, 
or any other finding, noting whether it should be considered a serious or nonserious AE, or 
whether it should be considered as part of the subject’s history. In addition, all events or other 
findings determined to be SAEs should be identified on the Serious Adverse Event (SAE)/ 
Reportable Event Form and the investigator should consider whether the event is related or not 
related to study treatment. All events determined to be nonserious should be reported on the 
eCRF.
10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
See Section 5 and Section 8.2.9.
10.5.
Appendix 5: Genetics
Not applicable.
10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments 
All events of alanine aminotransferase (ALT) ∀3 × upper limit of normal (ULN) and with total 
bilirubin ∀2 × ULN (> 35% direct bilirubin) or ALT ∀3 × ULN and international normalized 
ratio (INR) > 1.5 (if INR measured) which may indicate severe liver injury (possible Hy’s Law 
cases) must be reported as an SAE as outlined in Section 10.3.4 (excluding studies of hepatic 
impairment or cirrhosis).
Subjects with confirmed Hy’s Law liver injury will be immediately withdrawn from study 
treatment and no rechallenge will be allowed. 
10.7.
Appendix 7: Medical Device Incidents
Not applicable.


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10.8.
Appendix 8: Abbreviations
Abbreviation
Explanation
AC
Adhesive capsulitis
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase 
AROM
Active range of motion
ASES
American Shoulder and Elbow Surgeons, American Shoulder and 
Elbow Surgeons Standardized Shoulder Form
AUX-I
Clostridial class I collagenase
AUX-II
Clostridial class II collagenase
CFR
Code of Federal Regulations
CHL
Coracohumeral ligament
DC
Dupuytren’s contracture
DMC
Data monitoring committee
ECG
Electrocardiogram
eCOA
Electronic clinical outcomes assessment
eCRF
Electronic case report form
HbA1c
Hemoglobin A1c
HIPAA
Health Insurance Portability and Accountability Act
ICF
Informed consent form
ICH
International Council for Harmonisation
ID
Identification number
INR
International normalized ratio
IRT
Interactive response technology
ITT
Intent-to-treat
MHRA
Medicines and Healthcare Products Regulatory Agency
mITT
Modified intent-to-treat
MRI
Magnetic resonance imaging
MUA
Manipulation under anesthesia
NSAID
Nonsteroidal anti-inflammatory drug
PD
Peyronie’s disease
PP
Per-protocol


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Abbreviation
Explanation
PRO
Patient-reported outcome
PROM
Passive range of motion
PT
Physical therapy
PUM
Pain upon movement
QTc
Corrected QT interval
ROM
Range of motion
SAE
Serious adverse event
SAP
Statistical analysis plan
SOC
System organ class
SUSAR
Suspected unexpected serious adverse reaction
TEAE
Treatment-emergent adverse event
TSH
Thyroid stimulating hormone


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


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12.
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Endo Pharmaceuticals Inc. EN3835 for Adhesive Capsulitis [Investigator’s Brochure]. Malvern, 
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SAP_001.pdf: 






Statistical Analysis Plan (SAP) Module 1 – Protocol EN3835-210 
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4.8.1. 
Adverse Events ...........................................................................................................35 
4.8.1.1. 
Treatment Emergent Adverse Events (TEAEs) ..........................................................35 
4.8.1.2. 
Intensity of Adverse Events ........................................................................................36 
4.8.1.3. 
Relationship to Study Drug ........................................................................................36 
4.8.1.4. 
Adverse Event Categorization by Treatment Session ................................................36 
4.8.2. 
Vital Signs and Clinical Laboratories .........................................................................36 
4.8.2.1. 
Laboratory Values ......................................................................................................36 
4.8.2.2. 
Vital Signs ..................................................................................................................37 
5. 
ANALYSIS POPULATIONS ....................................................................................37 
6. 
STATISTICAL METHODS .......................................................................................38 
6.1. 
General Methodology .................................................................................................38 
6.2. 
Derived Variables .......................................................................................................39 
6.3. 
Handling of Missing Data ...........................................................................................40 
6.3.1. 
Handling of Missing Data for Sensitivity Analysis of Primary Endpoint ..................41 
6.3.2. 
Imputation of Partial Dates .........................................................................................41 
6.3.2.1. 
TEAE Status for Completely Unknown Start Date ....................................................41 
6.3.2.2. 
Concomitant Status of Medication/Non-drug Therapy for Completely 
Unknown Start Date ...................................................................................................42 
6.3.2.3. 
Missing Last Menstrual Date ......................................................................................42 
6.4. 
Interim Analysis ..........................................................................................................42 
7. 
STATISTICAL ANALYSES .....................................................................................42 
7.1. 
Subject Disposition .....................................................................................................42 
7.2. 
Protocol Deviations ....................................................................................................43 
7.3. 
Demographics and Baseline Characteristics ...............................................................43 
7.4. 
Medical and Surgical History .....................................................................................43 
7.5. 
Adhesive Capsulitis History .......................................................................................43 
7.6. 
Prior/Concomitant Medications and Nondrug Therapies ...........................................43 
7.7. 
Hand Dominance ........................................................................................................44 
7.8. 
Passive External Rotation ...........................................................................................44 
7.9. 
Efficacy Analyses .......................................................................................................44 
7.9.1. 
Primary Analysis ........................................................................................................44 
7.9.1.1. 
Change from Baseline in Adapted ASES Composite Score .......................................44 
7.9.2. 
Secondary Analysis ....................................................................................................44 


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7.9.2.1. 
Absolute and Percent Change from Baseline in PROM .............................................44 
7.9.2.2. 
Absolute and Percent Change from Baseline in AROM ............................................45 
7.9.2.3. 
Change from Baseline in Adapted Pain and Function Subscale.................................46 
7.9.2.4. 
Change from Baseline in PUM Scale .........................................................................46 
7.9.2.5. 
Change from Baseline in Patient-reported Global Severity of Adhesive 
Capsulitis Scale ...........................................................................................................47 
7.9.2.6. 
Patient-reported Change in Severity of Adhesive Capsulitis Scale ............................47 
7.9.2.7. 
Investigator Assessment of Improvement with Treatment .........................................48 
7.9.2.8. 
Subject Satisfaction with Treatment ...........................................................................48 
7.9.3. 
Exploratory/Tertiary Analyses ....................................................................................48 
7.9.3.1. 
 
7.9.4. 
Sensitivity Analysis ....................................................................................................49 
7.9.4.1. 
Primary Endpoint Sensitivity Analysis with MMRM using Tipping Point 
Analysis (TPA) ...........................................................................................................49 
7.9.5. 
Supportive Analysis ....................................................................................................51 
7.9.5.1. 
Per-Protocol Population Analysis ...............................................................................51 
7.10. 
Safety Analyses ..........................................................................................................51 
7.10.1. 
Study Drug Exposure ..................................................................................................51 
7.10.2. 
Adverse Events ...........................................................................................................51 
7.10.3. 
Clinical Laboratory .....................................................................................................53 
7.10.4. 
Vital Signs ..................................................................................................................54 
7.10.5. 
12-Lead ECG ..............................................................................................................55 
7.10.6. 
Physical Examination .................................................................................................55 
7.10.7. 
Immunogenicity ..........................................................................................................55 
7.11. 
Other Analyses ............................................................................................................55 
7.11.1. 
X-Ray ..........................................................................................................................55 
7.11.2. 
Physical Therapy ........................................................................................................55 
7.11.3. 
Home Exercise ............................................................................................................55 
8.
CHANGE FROM PROTOCOL .................................................................................56 
9.
REVISION HISTORY ...............................................................................................56 
10.
REFERENCES ...........................................................................................................57 
11.
TABLES, LISTINGS, AND GRAPH SHELLS.........................................................58 


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LIST OF TABLES 
Table 1: 
Objectives and Endpoints .............................................................................................9 
Table 2: 
Schedule of Activities .................................................................................................12 
Table 3: 
Study Treatment ..........................................................................................................19 
Table 4: 
ASES: Pain Subscale ..................................................................................................22 
Table 5: 
ASES: Function Subscale ...........................................................................................23 
Table 6: 
PUM Scale ..................................................................................................................24 
Table 7: 
Patient-reported Global Severity of Adhesive Capsulitis Scale .................................24 
Table 8: 
Patient-reported Change in Severity of Adhesive Capsulitis Scale ............................25 
Table 9: 
Subject Satisfaction Prior to Receiving Treatment .....................................................26 
Table 10: Subject Satisfaction Compared to Better Shoulder ....................................................26 
Table 11: Investigator Assessment of Improvement with Treatment .........................................27 
Table 12: Clinical Safety Laboratory Parameters .......................................................................29 
Table 13: Potentially Clinically Important Laboratory Criteria .................................................37 
Table 14: Potentially Clinically Important Vital Sign Criteria ...................................................37 
Table 15: Analysis Populations ..................................................................................................38 
Table 16: Derived Variables and Definition ...............................................................................40 
Table 17: Changes from Protocol ...............................................................................................56 
Table 18: Revision History .........................................................................................................56 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
AC 
Adhesive capsulitis
AE 
Adverse event 
AESI 
Adverse event of special interest 
AROM 
Active range of motion 
ASES 
American Shoulder and Elbow Surgeons, American Shoulder and Elbow Surgeons 
Standardized Shoulder Form 
ATC 
Anatomical therapeutic chemical 
AUX-I 
Clostridial class I collagenase 
AUX-II 
Clostridial class II collagenase 
BMI 
Body mass index 
 
 
CI 
Confidence interval 
CRF 
Case report form 
DBP 
Diastolic blood pressure 
DMP 
Data Management Plan 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOS 
End of study 
ET 
Early termination 
HbA1c 
Hemoglobin A1c 
HBB 
Hand behind back 
ITT 
Intent-to-treat 
MAR 
Missing at random 
MCMC 
Markov chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
MI 
Multiple imputation 
mITT 
Modified intent-to-treat 
MMRM 
Mixed model with repeat measurements 
MRI 
Magnetic resonance imaging 
NSAID 
Nonsteroidal anti-inflammatory drug 


Statistical Analysis Plan (SAP) Module 1 – Protocol EN3835-210 
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Abbreviation 
Definition 
PCI 
Potentially clinically important 
PP 
Per-protocol 
PROM 
Passive range of motion 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SoA 
Schedule of activities 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TPA 
Tipping point analysis 
TSH 
Thyroid stimulating hormone 
WHO 
World Health Organization 
 


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1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned analyses to evaluate the safety and 
efficacy of EN3835 compared to placebo in adults for the treatment of adhesive capsulitis (AC) 
of the shoulder, also known as frozen shoulder. 
General information about the study is detailed in the EN3835-210 protocol; original protocol 
dated April 06, 2020, Amendment 1 dated July 10, 2020, Amendment 2 dated July 31, 2020, 
Amendment 3 dated November 06, 2020, and Amendment 4 on October 22, 2021.(1) 
2. 
STUDY OBJECTIVES 
The study objectives and corresponding endpoints are outlined in Table 1 below: 
Table 1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To assess the efficacy of EN3835 for the 
treatment of AC of the shoulder using the 
adapted American Shoulder and Elbow Surgeons 
Standardized Shoulder Form (ASES) composite 
score. 
• 
The change from baseline in the adapted ASES 
composite score for the affected shoulder at the 
Day 95 Visit. 
Secondary 
• 
To assess the efficacy of EN3835 for the 
treatment of AC of the shoulder using passive 
range of motion (PROM). 
• 
The absolute and percent change from baseline in 
PROM for forward flexion, internal rotation, 
external rotation, abduction, and shoulder 
extension in the affected shoulder at the Day 22, 
43, 64, and 95 Visits compared to the 
contralateral shoulder at baseline. 
• 
To assess the efficacy of EN3835 for the 
treatment of AC of the shoulder using active 
range of motion (AROM). 
• 
The absolute and percent change from baseline in 
AROM for forward flexion, internal rotation, 
external rotation, abduction, and shoulder 
extension in the affected shoulder at the Day 22, 
43, 64, and 95 Visits compared to the 
contralateral shoulder at baseline. 
• 
To assess the efficacy of EN3835 for treatment 
of AC of the shoulder using the adapted ASES. 
• 
The change from baseline in the adapted ASES 
composite score, the adapted ASES function 
subscale, and the adapted ASES pain subscale for 
the affected shoulder at the Day 22, 43, 64, and 95 
Visits. 
• 
To assess the impact of EN3835 on pain upon 
movement (PUM) in subjects with AC of the 
shoulder. 
• 
The change from baseline in the PUM Scale for 
the affected shoulder at the Day 64 and Day 95 
Visits. 
• 
To assess the impact of EN3835 on the severity 
of AC in subjects with AC of the shoulder. 
• 
The change from baseline in the Patient-reported 
Global Severity of Adhesive Capsulitis Scale at 
the Day 22, 43, 64 and 95 Visits. 




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case basis as to whether or not the subject will need to repeat. All repeat screening assessments 
must be completed within the screening window. 
Following screening, eligible subjects will be randomized 1:1 to receive EN3835 0.58 mg/1 mL 
or volume matched placebo.  
EN3835 or placebo will be administered by ultrasound-guided injection at the injection site 
 
 following the 
administration of a local anesthetic. Subjects will receive up to 3 injections of study treatment 
(total dose: 1.74 mg) separated by at least 21 days (on Day 1, Day 22, and Day 43). Following 
each injection, subjects will remain under observation for at least 30 minutes. All subjects will 
undergo standardized, supervised, in-office physical therapy (PT) sessions starting 7 days after 
each treatment session and will complete 2 sessions per week for 2 weeks with a minimum of 
2 days between each PT session. In addition, subjects will complete standard home exercises 
starting 3 days after each injection of study treatment through the Day 95 Visit.  
Subjects will be evaluated for shoulder ROM, AC severity, function, and pain at each subsequent 
study visit. Dosing may be withheld at the Day 22 and 43 Visits if functional parameters are met. 
Subjects will be expected to complete all study visits, even if they do not receive study treatment 
at the Day 22 and/or Day 43 Visits. Follow-up visits will be conducted approximately 64 and 
95 days after the first dose of EN3835 or placebo.  
An interim analysis for safety and futility is planned for when approximately 86 subjects 
(approximately 50% of subjects) have completed the Day 95/Early Termination (ET) Visit. 
Enrollment will continue during this analysis. 
The study is expected to screen subjects over approximately 12 months. The entire study is 
expected to require approximately 18 months to complete. 
3.1.1. 
End-of-Study Definition 
A subject is considered to have completed the study if the subject has completed the Day 95 
Visit. 
The end of the study visit is defined as the completion of the final assessment for the last subject 
enrolled in the trial. 
A subject is considered evaluable if the subject is randomized, received at least 1 injection of 
study treatment, and has a valid baseline ASES composite score in the affected shoulder and at 
least 1 valid adapted ASES composite score after administration of study treatment. This 
includes both completers and early terminated subjects. 
3.1.2. 
Schedule of Activities 
Table 2 below describes the schedule of events and assessments performed during the Screening 
Visit, Treatment visits, and Follow-up visits. 
 


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Table 2: 
Schedule of Activities  
Activity 
Screening Visit  
Day -28 to Day -1 
Treatment Session 1 
Day 1 
Days 4-7 
Days 8-21 
Treatment Session 2a  
Day 22 + 3 daysb 
and 
Treatment Session 3a  
Day 43 + 3 daysb 
Days 25-28 and  
Days 46-49 
Days 29-42 and  
Days 50-63 
Follow-up Day 64  
(± 5 days) 
End of Study Day 95  
(± 5 days)/Early  
Termination 
Pre-  
injection 
Post-  
injection 
Pre-  
injection 
Post-  
injection 
Informed consentc 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria review 
X 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
 
 
 
 
 
 
AC history 
X 
 
 
 
 
 
 
 
 
 
 
Prior medications and nondrug therapies 
X 
X 
 
 
 
 
 
 
 
 
 
Complete physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
X 
Hand dominance 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs (blood pressure, respiratory rate, 
pulse rate, body temperature) 
X 
Xd 
Xd 
 
 
Xd 
Xd 
 
 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
Adapted ASES of the affected shouldere 
Xe 
X 
 
 
 
X 
 
 
 
X 
X 
Confirm external rotationf 
Xe 
 
 
 
 
 
 
 
 
 
 
Passive external rotation at 0°, 45°, and 90° of 
the affected shoulder 
Xe 
 
 
 
 
 
 
 
 
 
 
AROM and PROM of the contralateral shoulder 
X 
 
 
 
 
 
 
 
 
 
 
AROM and PROM of the affected shoulderg 
X 
 
 
 
 
X 
 
 
 
X 
X 


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Table 2: 
Schedule of Activities (Continued) 
Activity 
Screening Visit  
Day -28 to Day -1 
Treatment Session 1 
Day 1 
Days 4-7 
Days 8-21 
Treatment Session 2a  
Day 22 + 3 daysb 
and 
Treatment Session 3a  
Day 43 + 3 daysb 
Days 25-28 and 
Days 46-49 
Days 29-42 and 
Days 50-63 
Follow-up Day 64 
(± 5 days) 
End of Study Day 95 
(± 5 days)/Early  
Termination 
Pre-  
injection 
Post-  
injection 
Pre-  
injection 
Post-  
injection 
PUM Assessment of the affected shoulder 
X 
X 
X 
X 
Patient-reported Global Severity of Adhesive 
Capsulitise 
X 
X 
X 
X 
X 
Patient-reported Change in Severity of Adhesive 
Capsulitise 
X 
X 
X 
Chemistry, hematology, urinalysis, HbA1c, 
TSH, serum pregnancy test 
X 
Xh 
Urine pregnancy test 
X 
X 
Immunogenicity sample collection 
X 
X 
X-ray of affected shoulder
Xi 
MRI of affected shoulder 
X 
X 
MRI of unaffected shoulder 
X 
Randomization 
X 
Ultrasound-guided study treatment injection and 
screen capture/photo of injection 
X 
X 
Supervised in-office PTj 
X 
X 
Train subjects on home exercise and diary use, 
distribute home exercise instructions and diary 
X 
X 
Home exercisesk 
X 
X 
Review diary (for home exercise compliance) 
X 
X 
X 


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Table 2: 
Schedule of Activities (Continued) 
Activity 
Screening Visit  
Day -28 to Day -1 
Treatment Session 1 
Day 1 
Days 4-7 
Days 8-21 
Treatment Session 2a  
Day 22 + 3 daysb 
and 
Treatment Session 3a  
Day 43 + 3 daysb 
Days 25-28 and  
Days 46-49 
Days 29-42 and  
Days 50-63 
Follow-up Day 64  
(± 5 days) 
End of Study Day 95  
(± 5 days)/Early  
Termination 
Pre-  
injection 
Post-  
injection 
Pre-  
injection 
Post-  
injection 
Investigator Assessment of Improvement with 
Treatment 
 
 
 
 
 
 
 
 
 
X 
X 
Subject Satisfaction with Treatment 
 
 
 
 
 
 
 
 
 
X 
X 
Concomitant medications and nondrug therapies 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
Adverse eventsl 
Monitored throughout study 
a  Subjects may receive up to a maximum of 3 treatment sessions. Treatment sessions (Day 22 and Day 43) should be determined based on the guidelines 
provided in Section 3.4 Subjects who are not eligible for treatment at the Day 22 and/or Day 43 visits will continue in the study, completing all other activities 
and visits. 
b  Treatment sessions should be at least 21 days apart.  
c  Performed prior to any study-related activities. 
d  On treatment session days, vital signs will be taken prior to the injection and at 15 and 30 minutes after the injection (except for body temperature which will be 
taken prior to the injection and 30 minutes after the injection). Vital signs must be stable for a period of at least 30 minutes before the subject can be discharged 
from the study site on treatment days. 
e  All patient-reported outcomes (PROs) must be completed prior to study assessments/ beginning of visit. Must be completed, and criteria met prior to MRI. 
f  Subject must be able (in a supine position) to have the affected arm passively externally rotated to at least a neutral position within the subject’s level of pain 
tolerance with the elbow at the side (against the body) and flexed to 90°. 
g  AROM measurements must be completed before PROM assessment. 
h  Serum pregnancy assessment will not be done on the Day 95 Visit. 
i  Must be completed prior to MRI. Previous X-rays of the affected shoulder may be used if they were taken within 30 days of the Screening Visit. 
j  Subjects must complete supervised in-office PT 2 days per week for 2 weeks after each treatment session. Subjects must wait a minimum of 7 days after each 
treatment session prior to starting PT and there should be a minimum of 2 days between PT sessions. 
k  Home exercises will be completed at least 2 times per day and no more than 3 times per day, every day starting 3 days after each dose of study treatment 
through the Day 95 visit. In-office PT will count as 1 of the home exercise sessions on PT days. 
l  AEs/SAEs will be captured from time of informed consent signature until the Day 95 visit or for 28 days after last dose of study treatment for subjects who 
withdraw early from the study. There is no time limit on collection of SAEs assessed as related to study treatment. 
Note: Unless otherwise stated above or outlined below, all assessments should be completed prior to dosing on treatment days (the Day 1, 22, and 43 visits).


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3.2. 
Eligibility Criteria for Subject Selection 
3.2.1. 
Inclusion Criteria 
In order to be eligible to participate in the study, prior to randomization subjects must: 
1. Be ≥ 18 years of age at the time of consent and can be male or female. 
2. Agree not to use pain medications for the duration of the study period and for 2 weeks 
prior to the Screening Visit. Pain medications include but are not limited to: methadone, 
buprenorphine, opioids (eg, codeine, heroin, hydrocodone, hydromorphone, morphine, 
oxycodone), and cannabis.  
Note: Nonsteroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, etc) and Tylenol 
(acetaminophen) are allowed. 
3. Have idiopathic unilateral AC defined as subjects with passive external rotation that 
demonstrates at least a 30% loss of ROM tested at 0°, 45°, and 90° abduction in the 
affected shoulder compared to the contralateral shoulder in the supine position. In the 
event that 45° and 90° cannot be achieved due to pain or restriction, the amount of 
external rotation available at maximum attainable abduction ROM is permissible as the 
second and third measurements. 
4. Have an adapted ASES function subscale score of < 35 in the affected shoulder at the 
Screening and Day 1 Visits. 
5. Have unaffected ROM in the contralateral shoulder as determined by the investigator. 
6. Be able (in a supine position) to have the affected arm passively rotated to at least a 
neutral position within their level of pain tolerance with the elbow at the side (against the 
body) and flexed to 90°. 
7. Be willing to undergo x-ray of the affected shoulder and MRI of the affected and 
contralateral shoulder as required by the protocol. 
8. Agree to participate in supervised, in-office PT sessions and to complete home exercises 
at designated time points during the study. 
9. Agree to avoid general lifting and carrying of no more than 10 pounds, and lifting of no 
more than 5 pounds overhead for 21 days after each treatment, except during supervised 
PT sessions. 
10. Be able to read, understand, and independently complete patient reported outcome 
instruments in English. 
11. If female, be of nonchildbearing potential (history of hysterectomy, bilateral 
oophorectomy, bilateral tubal ligation, or postmenopausal with no history of menstrual 
flow in the 12 months prior to the Screening Visit); or, if of childbearing potential, be 
nonpregnant, nonlactating and agree to use effective contraception when with a male 
partner for the duration of the study (and for 28 days after any active treatment period for 
subjects who early terminate). Acceptable forms of contraception include hormonal 
measures (oral contraceptive pills, contraceptive patch, contraceptive ring, and 


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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. 
12. If male with reproductive potential, agree to use effective contraception (abstinence, 
surgical sterilization [vasectomy], or condom with spermicide) with a female partner of 
child-bearing potential for the duration of the study (and for 28 days after any active 
treatment period for subjects who early terminate). 
13. Be willing and able to comply with all protocol required visits and assessments. 
14. Be adequately informed and understand the nature and risks of the study and be able to 
provide consent as outlined in Protocol Section 10.1.3. 
3.2.2. 
Exclusion Criteria 
A subject is ineligible for study participation if, at the Screening Visit and/or on Day 1, the 
subject: 
1. Has a known allergy to collagenase or any other excipient of EN3835 or any other 
procedural medication (including local anesthetics). 
2. Has received treatment for AC (in the timeframes outlined below) or is planning to 
receive any treatment (other than study treatment) for AC at any time during the study in 
the affected shoulder, including but not limited to: 
• PT or acupuncture within 2 weeks before the first injection of study treatment. 
• Intra-articular or intrabursal injection(s) of lidocaine, suprascapular nerve blocks, or 
electroanalgesic and/or thermoanalgesic modalities within 1 month before the 
Screening Visit. 
• Intra-articular or intrabursal injection(s) of corticosteroids within 8 weeks before the 
Screening Visit. 
• Intra-articular or intrabursal injection(s) of sodium hyaluronate and/or glenohumeral 
distension arthrography within 3 months before the Screening visit. 
• Manipulation under anesthesia (MUA) at any time prior to the study. 
• Surgery (including arthroscopic or open capsular release, capsulectomy, or 
capsulotomy) at any time prior to the study. 
3. Has any abnormalities/conditions in the affected shoulder that would be potentially 
confounding to the evaluations of efficacy as determined by the central MRI review 
committee grading criteria. The shoulder pathologies to be assessed include but are not 
limited to the following: 
• AC as a result of traumatic injury (ie, direct injury to the shoulder such as fracture of 
the humerus or clavicle immediately preceding the onset of this episode of AC). 
Traumatic events in the past that are not temporally related to the onset of this 
episode of AC would not necessarily exclude a subject from participating in the 
study.  


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• Active subacromial impingement (subacromial/subdeltoid bursitis, decreased 
subacromial space, or bursal sided fraying). 
• Calcified tendonitis.  
• Glenohumeral joint arthritis. 
• Glenohumeral joint inflammatory arthropathy. 
• Rotator cuff tears (supraspinatus, infraspinatus, teres minor, or subscapularis). 
• Fracture (humerus, glenoid, or clavicle). 
• Acromioclavicular arthropathy. 
• Biceps tendon pathologies. 
• Bursitis. 
• Labral tears/suspected labral tears. 
• Bone pathologies. 
4. Has a prosthesis or replacement of right or left shoulder, elbow, wrist, and/or hand. 
5. Has any of the following systemic conditions: 
• Evidence or history of malignancy (other than excised basal-cell carcinoma) unless 
there has been no recurrence in at least 5 years. 
• Uncontrolled hypertension, defined as a systolic blood pressure ≥ 160 mmHg or a 
diastolic blood pressure ≥ 100 mmHg at the Screening Visit or before dosing on 
Day 1. 
• Uncontrolled diabetes, defined as hemoglobin A1c (HbA1c) ≥ 8% at the Screening 
Visit. 
• Uncontrolled thyroid disease defined as thyroid stimulating hormone (TSH) 
≥ 4 uIU/mL at the Screening Visit. (Note: Uncontrolled thyroid disease is defined as a 
symptomatic medical condition not adequately controlled with medications.) 
• History of thrombosis or post-thrombosis syndrome. 
• Physical impairment that would preclude performing the protocol defined exercises. 
• Active infection in the area to be treated. 
• Any other significant medical condition (eg, morbid obesity, cervical disc disease), 
which in the investigator’s opinion would make the subject unsuitable for enrollment 
in the study. 
6. Has any of the following contraindications for MRI, as determined by the technologist, 
the radiologist, and/or the investigator (in accordance with the MHRA Safety Guidelines 
for Magnetic Resonance Imaging Equipment in Clinical Use, March 2015): 
• An implant containing metal, including but not limited to intracranial aneurysm clips, 
cochlear implants, prosthetic devices containing metal, implanted drug infusion 


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pumps, neurostimulators or bone growth stimulators, intrauterine contraceptive 
devices containing metal, or any other type of iron based metal implant. 
• Internal metallic object(s) such as bullets or shrapnel, as well as surgical clips, pins, 
plates, screws, metal sutures, or wire mesh. 
• Any tattoo or permanent cosmetics/make-up including but not limited to, permanent 
lip liner or permanent eye liner. 
Note: Any tattoo in the treated area will be exclusionary.  
• Severe claustrophobia. 
• A history of uncontrolled hypertension, epilepsy, asthma, anemia, or sickle cell 
disease. 
7. Has a known coagulation disorder and/or is taking any medication (ie, anticoagulants or 
antiplatelet medications, except for ≤ 150 mg aspirin daily) that would increase the risk 
of bleeding within 7 days of the first injection of EN3835 and for the duration of the 
study. 
8. Has received oral or parenteral steroids for any reason within 3 weeks before the 
Screening Visit. 
9. Has, at any time, received collagenase for the treatment of AC (including subjects who 
received treatment in Study AUX-CC-870 or AUX-CC-871). 
10. Has received treatment with an investigational product within 30 days (or 5 half-lives, 
whichever is longer) of the first dose of study treatment. 
11. Has received collagenase treatments (eg, Santyl® ointment and/or XIAFLEX/XIAPEX®) 
for any other indication within 30 days prior to study treatment administration, or is 
planning to be treated with collagenase (other than study treatment) at any time during the 
study. 
12. Has donated blood within 30 days prior to the Screening Visit or has plans to donate 
blood during the study. 
13. Has a corrected QT interval (QTc) of ≥ 450 ms for male subjects or ≥ 470 ms for female 
subjects on the screening electrocardiogram (ECG). 
14. Is from a vulnerable population, as defined by the US Code of Federal Regulations (CFR) 
Title 45, Part 46, Section 46.111(b) and other local and national regulations, including 
but not limited to, employees (temporary, part-time, full-time, etc) or a family member of 
the research staff conducting the study, or of the sponsor, or of the contract research 
organization, or of the IRB/IEC. 
15. Has concurrent diseases that might interfere with the conduct of the study, confound the 
interpretation of the study results, or endanger the subject’s well-being, (eg, evidence of 
any significant hematological, endocrine, cardiovascular, respiratory, neurological, renal, 
hepatic, or gastrointestinal disease). If there is a history of such disease but the condition 
has been stable for more than 5 years and is judged by the investigator not to interfere 
with the subject’s participation in the study, the subject may be included, with the 
documented approval of the Medical Monitor. 


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16. Has any other conditions that, in the investigator’s opinion, might indicate that the 
subject is unsuitable for the study. 
3.3. 
Study Treatment  
Subjects will be given a dose of 0.58 mg of EN3835 or placebo per treatment session for up to 3 
treatment sessions at least 21 days apart (the Day 1, 22, and 43 Visits). 
The injection concentration for each treatment visit is outlined in Table 3 below.  
Table 3: 
Study Treatment 
Cohort 
Route of Administration 
Number of 
Injections 
at Each 
Treatment 
Visit 
Dose at Each 
Treatment 
visit 
(mg) 
Number of 
Treatment 
Visits 
Total Dose  
Administered 
(mg) 
EN3835 
Pericapsular 
(periarticular) Injection 
1 
0.58 
3 
1.74 
Placebo 
Pericapsular 
(periarticular) Injection 
1 
-- 
3 
-- 
3.4. 
Dose Interruption 
All eligible subjects will receive their first dose of study treatment on Day 1. At each subsequent 
treatment visit (the Day 22 and 43 Visits) each subject will be evaluated to determine if they can 
continue treatment. 
Subjects that have all 5 measurements of AROM and PROM (forward flexion, internal rotation, 
external rotation, abduction, and shoulder extension) of the affected shoulder that are > 90% of 
the baseline contralateral shoulder ROM and have an adapted ASES function subscale score of 
> 40 in the affected shoulder should not be dosed unless the investigator believes that the clinical 
benefit outweighs the risk. 
Subjects who are not treated at the Day 22 Visit will continue in the study and will be reassessed 
at the Day 43 Visit and may be treated based on these assessments and investigator discretion. 
Subjects who are not treated at the Day 22 and/or Day 43 Visits will complete all other activities 
required for those visits and are also expected to complete the Day 64 and Day 95 Visits. 
3.5. 
Determination of Sample Size  
A post hoc analysis was conducted using a subgroup of AUX-CC-871 subjects who were rated 
with moderate/severe AC based on baseline MRI images. This subgroup displayed a notable 
treatment effect (EN3835 vs placebo) on the pain and composite components of the adapted 
ASES questionnaire. This subgroup also displayed a treatment effect trend for the functional 
component of the adapted ASES. Given this result, the sample size calculation is based on the 
mean and SD found in this subgroup for the adapted ASES composite score on Day 95. Given a 
mean change from baseline value in adapted ASES composite score at Day 95 of 38.6 for the 
EN3835 group and 27.6 for the placebo group with an SD of 21.6, a sample size of 
approximately 142 subjects would be required given a 1:1 randomization and a type I error of 


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0.05 with a power of 85%. With an expected drop-out rate of approximately 20%, 180 subjects 
(90 EN3835 and 90 placebo) should be dosed to ensure 142 complete the study. 
3.6. 
Medical and Surgical History 
A medical and surgical history of the subject will be taken during the Screening Visit. Medical 
history will include relevant diagnoses and procedures/therapies with onset/resolutions dates. 
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 subjects, with onset/resolutions dates will be recorded. 
In addition, any history or current collagen mediated disorders (including but not limited to 
Garrod’s pads, Dupuytren’s nodules, plantar nodules, Peyronie’s disease, AC of other joints, etc) 
will be recorded (the current AC episode will not be recorded on the medical history case report 
form [CRF] - see next section). 
Surgical history will include a review of all surgical procedures completed in the prior 5 years 
and any surgery completed at any time in the affected shoulder. 
3.7. 
Adhesive Capsulitis History 
A history of all past episodes of AC of the shoulder will be recorded at the Screening Visit. 
Details of each past episode to be collected include: the affected shoulder (right or left), onset 
date, resolution date, and any procedures or medical treatments provided. 
In addition, the history of the current AC episode in the affected shoulder (right or left), onset 
date of symptoms, and determination of idiopathic or traumatic AC will be recorded at screening. 
3.8. 
Substance Use 
History of tobacco and alcohol use will also be taken during screening and the following 
information will be recorded: 
• Type of substance (Alcohol/Tobacco). 
• History of usage (Never/Currently/Former). 
• Number of years the product was used (for current or former users). 
• Stop date of using the product (for former users). 
3.9. 
Prior and Concomitant Medications and Nondrug Therapies 
Any medications and nondrug therapies (eg, blood transfusions, oxygen supplementation, 
physical therapy, etc) taken during the study or within 90 days prior to the Screening Visit will 
be recorded. 
In addition, all prior medications and nondrug therapies for AC will be recorded. 


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3.10. 
Prohibited Medications 
To be eligible for the study, subjects will agree not to use pain medications for the duration of 
the study period and for 2 weeks prior to the Screening Visit. Pain medications include, but are 
not limited to: 
• opioids (eg, codeine, heroin, hydrocodone, hydromorphone, morphine, oxycodone, 
methadone, buprenorphine), 
• cannabis. 
Note: NSAIDs (ibuprofen, etc) and Tylenol (acetaminophen) are allowed. 
In addition, the following medications or nondrug therapies will not be permitted during the 
study (from the Screening Visit through the Day 95 Visit): 
• Anticoagulant or antiplatelet medication (except ≤ 150 mg aspirin daily). 
• Any other medications or nondrug therapies for the affected shoulder other than those 
outlined in this protocol. 
• Any collagenase treatments (eg, Santyl ointment, XIAFLEX) other than study 
treatment. 
• Any investigational product, device, or procedure administered as part of a research 
study other than the treatment in this study. 
If any prohibited medication is taken during the study, all pertinent information will be recorded. 
3.11. 
Passive External Rotation at 0°, 45°, and 90° of Abduction 
Passive external rotation at 0°, 45°, and 90° of abduction will be measured in both shoulders 
using a goniometer at screening in the supine position. In the event that 45° and 90° cannot be 
achieved due to pain or restriction in the affected shoulder, the amount of external rotation 
available at maximum attainable abduction ROM is permissible as the second and third 
measurements. 
3.12. 
Hand Dominance 
The subject’s self-reported hand dominance will be recorded at screening.  
3.13. 
Supervised In-office Physical Therapy 
All subjects will undergo a standard supervised in-office physical therapy regimen. The physical 
therapy regimen will consist of 2 sessions per week for 2 weeks with a minimum of 2 days 
between each session starting 7 days after each study treatment until the next scheduled injection 
and until the Day 64 Visit. In-office physical therapy will last approximately 30 to 60 minutes. 
Subjects will be provided with verbal and hands-on instructions for the exercises to be 
completed. Physical therapists will follow the standard physical therapy regimen found in the 
Study Operations Manual. 


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3.14. 
Home Exercises 
Study personnel will train each subject how to conduct a standard set of home exercises and 
provide each subject with a set of instructions and any necessary equipment (ie, pulleys) to 
complete the home exercises. These home exercises should be performed by each subject at least 
2 times per day and no more than 3 times a day. Home exercises will begin 3 days after each 
study treatment and will end at the Day 95/ET Visit. In-office PT will count as 1 of the home 
exercise sessions on PT days. 
Subjects will document their home exercise completion and frequency using a diary. The site 
will train the subject on the use of the diary and will review the diary at visits specified in the 
Schedule of Activities (SoA) (Table 2) to ensure compliance. 
3.15. 
Efficacy Assessments 
3.15.1. 
Adapted American Shoulder and Elbow Surgeons Standardized Shoulder Form 
(ASES) 
The adapted ASES is a questionnaire to assess AC patient rated shoulder pain and function that 
has been modified from the ASES Standardized Shoulder Form.(2,3) All subjects will complete 
the adapted ASES at times outlined in the SoA (Table 2). 
The adapted ASES is a self-administered patient reported outcome measure, comprised of 2 
subscales: pain subscale and function subscale. 
Pain subscale: Numeric rating scale about pain in the affected shoulder on the day of 
assessment. Scale ranges from 0 (No pain at all) to 10 (Pain as bad as it can be). 
Table 4: 
ASES: Pain Subscale 
Question 
Responses 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
How bad is the pain in your affected 
shoulder today? 
 
 
 
 
 
 
 
 
 
 
 
Function subscale: This scale consists of 10 activities of daily living where the subject is asked 
to indicate on a 4 point ordinal scale their ability to do the activity with the affected arm.(4) 
Scale ranges from 0 to 3.  
The responses are: 0 = Unable to do; 1 = Very difficult; 2 = Somewhat difficult; 3 = Not 
difficult. 


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Table 5: 
ASES: Function Subscale 
No. 
Question 
Is it difficult for you to ... 
Responses for Affected Shoulder 
0 
1 
2 
3 
1 
Put on a coat 
 
 
 
 
2 
Sleep on your painful or affected side 
 
 
 
 
3 
Wash back/do-up bra in back 
 
 
 
 
4 
Manage toileting 
 
 
 
 
5 
Comb hair 
 
 
 
 
6 
Reach a high shelf 
 
 
 
 
7 
Lift 10 lbs. (4.5kg) above shoulder 
 
 
 
 
8 
Throw a ball overhand 
 
 
 
 
9 
Do usual work 
 
 
 
 
10 
Do usual sport/leisure activities 
 
 
 
 
3.15.2. 
Range of Motion (ROM) 
PROM and AROM will be measured for the affected and contralateral shoulder at times 
specified in the SoA (Table 2) using a goniometer. The below range of motion measurements 
will be recorded: 
• Forward flexion. 
• Internal rotation.  
• External rotation.  
• Abduction.  
• Shoulder extension.  
The unit to measure PROM and AROM is degrees (°).  
In addition, Hand Behind the Back (HBB) assessment will be performed for active internal 
rotation. The response for HBB assessment will be free text with no unit. 
3.15.3. 
Pain Upon Movement (PUM) 
The PUM Scale is a single item 11-point numerical rating scale of pain that asks subjects to rate 
the pain in their affected shoulder after AROM forward flexion, internal rotation, external 
rotation, abduction, and shoulder extension on a scale from 0 (No pain at all) to 10 (Pain as bad 
as it can be).  


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Table 6: 
PUM Scale 
Question 
Responses 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
When you move your arm to the point where pain limits your 
movement in the affected shoulder (forward and backwards 
circles keeping elbow straight, lifting arms out to the side, 
reaching your arm behind your back as if you were getting 
something out of your pocket, positioning your arms as if you 
were carrying serving trays keeping your elbows glued to your 
sides, and extending your arms straight behind you) please rate 
your worst pain on a scale of 0-10 when you do these 
movements with your affected shoulder.  
 
 
 
 
 
 
 
 
 
 
 
All subjects will complete the PUM at times outlined in the SoA (Table 2).  
3.15.4. 
Patient-reported Global Severity of Adhesive Capsulitis 
The Patient-reported Global Severity of Adhesive Capsulitis is a single item 11-point numerical 
rating scale that asks subjects to rate the overall severity of their AC symptoms on a scale from 
0 (No severity) to 10 (Severe as can be). 
Table 7: 
Patient-reported Global Severity of Adhesive Capsulitis Scale 
Question 
Responses 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
What is the severity of your frozen shoulder in the last 
24 hours? 
 
 
 
 
 
 
 
 
 
 
 
All subjects will complete the Patient-reported Global Severity of Adhesive Capsulitis scale at 
times outlined in the SoA (Table 2). 
3.15.4.1. Patient-reported Change in Severity of Adhesive Capsulitis 
The Patient-reported Change in Severity of Adhesive Capsulitis is a questionnaire that asks 
subjects if their AC symptoms are “Better, About the Same, or Worse” since the last time the 
questionnaire was administered.  
Subjects who report that their symptoms are better or worse are then asked to rate the change in 
their symptoms on a 7-point ordinal scale. 


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Table 8: 
Patient-reported Change in Severity of Adhesive Capsulitis Scale 
No. 
Question 
Responses 
Numeric 
Description 
1 
Have there been any changes in overall severity of 
your frozen shoulder since you started the study? 
-1 
Worse (Complete Question 2) 
0 
About the same (Stop) 
1 
Better (Complete Question 3) 
2 
How much worse would you say the overall severity of 
your frozen shoulder is since you started the study? 
0 
Almost the same, hardly worse at all 
-1 
A little worse 
-2 
Somewhat worse 
-3 
Moderately worse 
-4 
A good deal worse 
-5 
A great deal worse 
-6 
A very great deal worse 
3 
How much better would you say the overall severity of 
your frozen shoulder is since you started the study? 
0 
Almost the same, hardly better at all 
1 
A little better 
2 
Somewhat better 
3 
Moderately better 
4 
A good deal better 
5 
A great deal better 
6 
A very great deal better 
All subjects will complete the Patient-reported Change in Severity of Adhesive Capsulitis 
questionnaire at times outlined in the SoA (Table 2). 
3.15.5. 
Subject Satisfaction with Treatment 
Subjects will rate their satisfaction with treatment on a 7-point Likert scale from Very 
Dissatisfied to Very Satisfied at times specified in the SoA (Table 2). 


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Table 9: 
Subject Satisfaction Prior to Receiving Treatment 
No. 
Question 
Responses 
Numeric 
Description 
1 
In your treated shoulder, how satisfied are you with the 
relief of pain now compared to the pain prior to 
treatment? 
3 
Very Satisfied 
2 
Satisfied 
1 
Somewhat Satisfied 
0 
Neither Satisfied nor Dissatisfied 
-1 
Somewhat Dissatisfied 
-2 
Dissatisfied 
-3 
Very Dissatisfied 
2 
In your treated shoulder, how satisfied are you with the 
relief of stiffness now compared to the stiffness prior to 
treatment?  
3 
Very Satisfied 
2 
Satisfied 
1 
Somewhat Satisfied 
0 
Neither Satisfied nor Dissatisfied 
-1 
Somewhat Dissatisfied 
-2 
Dissatisfied 
-3 
Very Dissatisfied 
Table 10: 
Subject Satisfaction Compared to Better Shoulder 
No. 
Question 
Responses 
Numeric 
Description 
1 
Compared to your better shoulder, overall how satisfied 
are you with the relief of pain in your treated shoulder? 
3 
Very Satisfied 
2 
Satisfied 
1 
Somewhat Satisfied 
0 
Neither Satisfied nor Dissatisfied 
-1 
Somewhat Dissatisfied 
-2 
Dissatisfied 
-3 
Very Dissatisfied 
2 
Compared to your better shoulder, overall how satisfied 
are you with the relief of stiffness in your treated 
shoulder?  
3 
Very Satisfied 
2 
Satisfied 
1 
Somewhat Satisfied 
0 
Neither Satisfied nor Dissatisfied 
-1 
Somewhat Dissatisfied 
-2 
Dissatisfied 
-3 
Very Dissatisfied 


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3.15.6. 
Investigator Assessment of Improvement with Treatment 
Investigators will provide their assessment of improvement with treatment for each subject using 
a 7-point Likert scale from Very Much Worse to Very Much Improved at times specified in the 
SoA (Table 2). 
Table 11: 
Investigator Assessment of Improvement with Treatment 
No. 
Question 
Responses 
Numeric 
Description 
1 
At the follow-up visit, please rate the degree of change 
in the severity of the subject’s treated shoulder 
compared with screening 
3 
Very Much Improved 
2 
Much Improved 
1 
Minimally Improved 
0 
No Change 
-1
Minimally Worse 
-2
Much Worse 
-3
Very Much Worse 
3.15.7. 
Magnetic Response Imaging (MRI) and X-rays 
An X-ray of the affected shoulder is required at screening unless there is a historic X-ray of the 
affected shoulder that was taken within 30 days of the Screening Visit. 
MRIs of the affected shoulder will be performed for all subjects at Screening and Day 95 and of 
the contralateral shoulder at the Screening Visit only. 
 
Subjects should complete all other screening activities prior 
to the MRIs required at screening and must meet the entry criteria. 
3.16. 
Safety Assessments 
Virtual visits are allowed to assess safety during any COVID-19 interruption. 
3.16.1. 
Adverse Events 
All adverse events (AEs) will be recorded from the time informed consent is signed through the 
Day 95/ET Visit, or for 28 days after the last dose of study treatment for those who early 
terminate. 
Conditions existing prior to screening will be recorded as part of subject’s medical history. 
3.16.1.1. Adverse Events (AE) 
An AE is any unfavorable or unintended change in body structure (signs), body function 
(symptoms), laboratory result (eg, chemistry, ECG, X-ray, etc), or worsening of a pre-existing 
condition associated temporally with the use of the study medication whether or not considered 
related to the study medication. This would include AEs resulting from concurrent illness, 
reactions to concurrent medication use, or progression of disease states (excluding the disease 
under study). A condition present at baseline that worsens after initiation of study treatment will 
be captured as an AE; the onset date will be the date the event worsened.  


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3.16.1.2. Serious Adverse Events (SAEs) 
SAEs are those AEs that meet any of the following criteria: 
• Results in death.  
• Life-threatening event.  
• Results in or prolongs an inpatient hospitalization.  
• Results in permanent or substantial disability. 
• Is a congenital anomaly or birth defect.  
• Any important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
3.16.1.3. Adverse Events of Special Interest (AESI) 
AESIs for this study include: 
• Bruising, ecchymosis, hematomas, and contusions that occur remote to the site of 
treatment administration. 
• Any hypersensitivity reactions. 
These events will be reported as AEs in the electronic case report form (eCRF). All AESIs will 
be evaluated for seriousness and severity. AESIs will be sponsor-defined by the AE preferred 
term prior to database lock. 
3.16.2. 
Clinical Laboratory Determinations 
Blood and urine samples will be collected for testing the clinical laboratory parameters in 
Table 12 below at the time points outlined in the SoA.  


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Table 12: 
Clinical Safety Laboratory Parameters 
Hematology 
Biochemistry 
Urinalysis 
Other 
Hemoglobin 
Hematocrit 
Red blood cell 
White blood cell (WBC) 
Platelets 
WBC Differential 
Glucose 
Sodium 
Potassium 
Calcium 
Chloride 
Carbon dioxide (CO2) 
Inorganic phosphate 
Blood urea nitrogen  
Creatinine 
Creatinine clearance (estimated) 
Aspartate transaminase (AST) 
Alanine transaminase (ALT) 
Gamma-glutamyl transferase (GGT) 
Total bilirubin (TBL) (direct bilirubin 
reflex if elevated) 
Albumin 
Alkaline phosphatase (ALP) 
Uric acid 
Glucose 
Protein 
Specific gravity 
pH 
Ketones 
Bilirubin 
Urobilinogen 
Nitrite 
Blooda 
Leukocytesa 
TSH 
HbA1c 
Human chorionic 
gonadotropin (hCG) 
(serum and urine 
pregnancy) 
a Microscopic examination will be performed if blood or leukocytes are detected by dipstick. 
Any clinically significant laboratory abnormality observed will be considered as an AE or SAE 
as appropriate. 
3.16.3. 
Pregnancy Test 
All female subjects of childbearing potential must have a negative pregnancy test at Screening to 
be enrolled in the study. Female subjects of childbearing potential will undergo a serum 
pregnancy test at the Screening Visit and urine pregnancy tests before injection on treatment 
visits (Day 1, 22 and 43).  
3.16.4. 
Height and Weight 
Height will be collected at screening only. Weight will be obtained at the Screening and 
Day 95/ET Visit.  
Any clinically significant abnormality in weight compared to the screening value, will be 
considered as an AE or SAE as appropriate. 
3.16.5. 
Vital Signs 
Vital sign measurements will include systolic blood pressure (SBP), diastolic blood pressure 
(DBP), pulse rate, respiratory rate, and body temperature and will be taken at Screening, 
treatment visits (Day 1, 22 and 43), Day 64 and Day 95/ET Visits.  
On days that study treatment is administered, vital signs will be taken up to 4 hours prior to 
dosing and at 15 and 30 minutes after dosing (body temperature is not required at the 15-minute 


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post dose time point). The subject’s vital signs must be stable, or repeated until stable, before the 
subject can leave direct observation. 
Any clinically significant abnormality in vital signs observed will be considered as an AE or 
SAE as appropriate. 
3.16.6. 
Electrocardiogram 
A 12-lead ECG recording will be performed during the Screening Visit. The subject should be in 
a supine position for at least 5 minutes before the recording is conducted. 
If the ECG report shows QT prolongation with QTc ≥ 450 ms for males or QTc ≥ 470 ms for 
females, the investigator will exclude the subject from study participation. 
ECGs will be assessed by the Investigator and graded as: 
•
Normal.
•
Abnormal, not clinically significant.
•
Abnormal, clinically significant.
Any clinically significant abnormality in ECG observed will be considered as an AE or SAE as 
appropriate. 
3.16.7. 
Physical Examination 
The complete physical examination (by body system) on each subject will be performed at the 
Screening and Day 95/ET Visits. Physical examination will include: evaluation of the head, eyes, 
ears, nose, throat, neck (including thyroid), cardiovascular system (including assessment of heart, 
peripheral pulses, presence or absence of edema), lungs, abdomen (including liver and spleen, 
bowel sounds), lymph nodes, musculoskeletal system (including spine, joints, muscles), 
neurological system (including cranial nerves, reflexes, sensation, strength), skin, extremities, 
and other conditions of note. 
The investigator will assess the physical examination findings as normal or abnormal. If physical 
examination findings meet the Investigator’s criteria for clinical significance, then it will be 
reported as an AE or SAE as appropriate. 
3.17. 
Immunogenicity 
Immunogenicity variables include anti-AUX-I /anti-AUX-II binding antibodies (ie, anti-drug 
antibodies) and neutralizing antibody results. Serum samples will be collected at the Day 1 Visit 
(prior to study treatment administration) and at the Day 95/ET Visit for the determination of 
serum anti-AUX-I and anti-AUX-II antibody levels and neutralizing antibodies to AUX-I and 
AUX-II. 


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4. 
STUDY PARAMETERS 
4.1. 
Subject Disposition 
A subject will be considered to have completed the study if the subject has completed the Day 95 
Visit.  
Subjects who discontinue or are withdrawn from the study treatment for any reason will be 
encouraged to complete the remaining study visits and evaluations and provide any additional 
follow-up information as required by the study unless the subject specifically indicates that they 
will not participate in any further evaluations. The reason and date for study treatment 
discontinuation will be recorded in the eCRF. 
If a subject withdraws from the study, all early termination procedures will be conducted as 
detailed in the SoA (Table 2). The reason and date for early withdrawal will be recorded in the 
eCRF for subjects who do not complete the study. If, however, a subject withdraws consent, no 
additional procedures are required except the collection of AE information. This information will 
be recorded in the source documentation and the eCRF.  
Subjects who have been withdrawn from the study at any time after the first dose of study 
treatment will not be replaced. The reason for screen failure will also be recorded in the eCRF 
for subjects who consent to participate in this study but are not subsequently randomized. 
4.2. 
Protocol Deviations 
Potential deviations will be identified prior to database lock. Protocol deviations will be derived 
from the eCRF data, electronic vendor data and will be obtained from the clinical monitoring 
reports. All deviations from these sources will be reconciled and duplicate deviations will be 
removed. 
Possible protocol deviations include, but are not restricted to the following deviation types:  
• Ineligible subject/study entry criteria not satisfied.  
• Informed consent not completed correctly.  
• Non-compliance of study treatment. 
• Prohibited medications/procedure.  
• Visit/procedure missing or out of window. 
The Endo study team will approve all final protocol deviation assignments and classify them as 
either major or minor during ongoing protocol deviation review meetings held throughout the 
study and a final meeting prior to the database lock.  
4.3. 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics include the following parameters: 
• Age. 
• Height (at Screening). 


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• Weight (at Screening). 
• Body Mass Index (BMI) in kg/m2 (at Screening) (refer to Table 16). 
• Gender.  
• Race. 
• Ethnicity. 
• Time since last menstrual period for female subjects. 
• Report of tobacco and alcohol use 
− Alcohol use (Never, Current, and Former). 
− Tobacco use (Never, Current, and Former). 
4.4. 
Prior and Concomitant Medications 
All medications will be coded using World Health Organization (WHO) Drug Dictionary, by 
active ingredient and WHO anatomical therapeutic chemical (ATC) classification of ingredients. 
The dictionary version to be used will be defined in the Data Management Plan (DMP). 
A prior medication (or non-drug therapy) is defined as any medication (or non-drug therapy) 
taken prior to the Screening Visit and stopped before the Screening Visit.  
A concomitant medication (or non-drug therapy) is any medication (or non-drug therapy) taken 
on or after the Screening Visit through the Day 95/ET Visit or taken prior to the Screening Visit 
and continuing during the study. 
4.4.1. 
Prior Adhesive Capsulitis (AC) Treatment  
Prior AC treatment will be obtained from the prior/concomitant medication and/or prior 
concomitant non-drug therapy pages of the eCRF. If on either of these pages a medication or 
nondrug therapy is reported with the indication ‘Adhesive capsulitis’ prior to the Screening Visit, 
then the medication or procedure will be considered a prior AC treatment. 
All AC treatment medications will be classified as an “AC drug”. All AC treatment procedures 
will also be classified. The classification will be reviewed and approved by the study medical 
monitor. Any AC treatment used after the Day 1 Visit will be noted and reported as a protocol 
deviation. 
4.5. 
Passive External Rotation at 0°, 45°, and 90° of Abduction 
Degrees and percent deficit of the affected shoulder compared to the contralateral shoulder will 
be calculated as: 
Let  
PS: Measurement from affected shoulder 
PC: Measurement from contralateral unaffected shoulder  


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then 
Degrees deficit = PS - PC 
Percent deficit = (PS - PC) / PC) * 100 
4.6. 
Home Exercise Compliance 
The compliance to home exercise will be calculated as: 
Compliance (%) = (No. of days with at least 2 home exercises / total number of days 
required home exercises) * 100 
In-office physical therapy will count as 1 of the home exercise sessions when attended and 
completed. 
4.7. 
Efficacy Parameters 
4.7.1. 
Adapted American Shoulder and Elbow Surgeons Standardized Shoulder Form 
(ASES) 
4.7.1.1. 
Pain Subscale 
The adapted ASES pain subscale score is calculated as: 
Pain subscale score = (10 - Pain Raw score) * 5 
The score range for pain subscale is 0-50 representing the worst pain (0) to no pain (50).  
Change from baseline in the adapted ASES pain subscale for the affected shoulder at the Day 22, 
43, 64, and 95 Visits will be analyzed. 
4.7.1.2. 
Function Subscale 
The adapted ASES function subscale score is calculated by multiplying the total score for 10 
items by 5 and then dividing it by 3. The calculation is: 
Function subscale score = [(Sum of scores of 10 items) * 5]/3 
If the responses to 1 or 2 items in the ASES function subscale are missing, the ASES function 
subscale score will be calculated as = 10 × (mean of the scores for the non-missing activity 
items) × 5/3. If more than 2 items of the responses to the ASES function subscale are missing, 
then the ASES function subscale score will be considered as missing.  
The score range for function subscale is 0-50 representing no function (0) to full function (50).  
Change from baseline in the adapted ASES function subscale for the affected shoulder at the 
Day 22, 43, 64, and 95 Visits will be analyzed. 
4.7.1.3. 
Composite Score  
The adapted ASES composite score is the sum of the pain subscale score (50% of the composite 
score) and the function subscale score (50% of the composite score). The calculation is: 
Composite score = Pain subscale score + Function subscale score 


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The range for the composite score is 0-100, where 0 is the worst pain and least functional and 
100 is least pain and most functional. If either of the pain subscale or function subscale score is 
missing, then the ASES composite score will be considered as missing. 
Change from baseline in the adapted ASES composite score for the affected shoulder at the Day 
22, 43, 64, and 95 Visits will be analyzed. Positive change from baseline score means an 
improvement in pain and/or shoulder function from baseline. 
4.7.2. 
Passive Range of Motion (PROM) and Active Range of Motion (AROM) 
The PROM and AROM in affected shoulder at Day 22, 43, 64 and 95 will be analyzed for the 
following motions: 
• Forward flexion. 
• Internal Rotation. 
• External rotation. 
• Abduction. 
• Shoulder extension. 
The PROM and AROM will be analyzed at Day 22, 43, 64 and 95 using the following endpoints: 
• Absolute change from baseline in affected shoulder  
• Absolute and percent change from baseline in affected shoulder compared to the 
contralateral shoulder. The calculation is as below: 
Let  
ASi: Measurement from affected shoulder at visit i 
CS1: Measurement from contralateral unaffected shoulder at baseline 
then 
Di = ASi - CS1 
D1 (Baseline value) = AS1 - CS1 
Absolute change = Di - D1 
Percent change from baseline at Visit i = ((Di - D1) / D1) * 100 
In addition, the HBB values will be ordinal ranked based on the level a subject can reach behind 
the back. The higher ranked assessment value signifies the ability to reach higher up behind the 
back. The lower the ranked value signifies the ability to reach behind the back low. A value of 0 
will be assigned to subjects that cannot reach behind the back at all (the lowest rank possible).  
The observed and change from baseline in HBB values will be analyzed at the Day 22, 43, 64 
and 95 Visits. 
4.7.3. 
Pain Upon Motion (PUM) Scale 
The change from baseline in the PUM scale for the affected shoulder at the Day 64 and Day 95 
Visits will analyzed. 


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4.7.4. 
Patient-reported Global Severity of Adhesive Capsulitis Scale 
The change from baseline in the Patient-reported Global Severity of Adhesive Capsulitis Scale at 
the Day 22, 43, 64 and 95 Visits will be analyzed. 
4.7.5. 
Patient-reported Change in Severity of Adhesive Capsulitis Scale 
The rating (response) in the Patient-reported Change in Severity of Adhesive Capsulitis Scale at 
the Day 22, 43, 64, and 95 Visits will be analyzed. 
4.7.6. 
Investigator Assessment of Improvement with Treatment 
Investigator assessment of improvement with treatment at the Day 64 and Day 95 Visits will be 
analyzed. 
A responder is defined as a response of “Very Much Improved”, “Much Improved” or 
“Minimally Improved” in the investigator assessment of improvement with treatment. 
4.7.7. 
Subject Satisfaction with Treatment 
Subject satisfaction with treatment at the Day 64 and Day 95 Visits will be analyzed separately 
for individual questions of subject satisfaction prior to receiving treatment and subject 
satisfaction compared to better shoulder. 
A responder is defined as a subject with a response of “Very Satisfied”, “Satisfied” or 
“Somewhat Satisfied” in the subject satisfaction with treatment. 
 
 
 
 
4.8. 
Safety Parameters 
4.8.1. 
Adverse Events 
Adverse event verbatim terms as reported by the investigator will be mapped to system organ 
class (SOC) and preferred term (PT) using the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary. The dictionary version to be used will be defined in the DMP. 
4.8.1.1. 
Treatment Emergent Adverse Events (TEAEs) 
TEAEs are defined as any AEs that occur or worsen (increase in severity) on the same day or 
after the treatment initiation. 
The following rules will apply in cases where the start date of an AE is known: 
•
If the AE onset date is prior to first administration of the study drug, then the AE will
not be considered a TEAE.
•
If the AE onset date or date of AE worsening is equal to or later than first
administration of the study drug, then the AE will be considered a TEAE.
Refer to section 6.3.2.1 to identify TEAE status when start date of an AE is unknown. 


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4.8.1.2. 
Intensity of Adverse Events 
Intensity (or severity) of AEs will be graded as “Mild”, “Moderate” or “Severe”. For AEs with 
missing severity, the most severe assessment will be imputed for analyses as “Severe”, following 
worst case principle. 
4.8.1.3. 
Relationship to Study Drug 
Causal relationship of AEs to study drug will be classified by the Investigator and will be 
reported as follows: 
• Not related. 
• Unlikely related. 
• Possibly related. 
• Probably related. 
Related adverse events are AEs with the relationship described by the investigator as “Probably 
related” or “Possibly related”. “Not related” or “Unlikely related” causality assessments are 
considered as negative causality. 
Any AE with a missing relationship to study drug will be considered as related to study drug for 
the analyses, following worst case principle.  
4.8.1.4. 
Adverse Event Categorization by Treatment Session 
• The AEs will be associated with the treatment session based on the start date of the 
AE compared to injection date, as below: 
• Treatment session 1: First injection date until start of second injection. 
• Treatment session 2: Second injection date until start of third injection. 
• Treatment session 3: Third injection date until start of Day 64 Visit. 
4.8.2. 
Vital Signs and Clinical Laboratories 
4.8.2.1. 
Laboratory Values 
Clinical laboratory data (hematology and chemistry only) will be analyzed for observed value 
and change from baseline at Day 95/ET Visit. Refer to Table 16 for definition of baseline. 
In addition, subjects reporting any sponsor-defined potentially clinically important (PCI) 
laboratory values during the study will be analyzed. 
PCI laboratory values are presented in Table 13 below. 


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Table 13: 
Potentially Clinically Important Laboratory Criteria 
Parameter 
PCI Low: Less than or equal to 
PCI High: Greater than or equal to 
Hemoglobin (g/L) 
100 
190 
Hematocrit (%) 
30 
60 
Platelets (109/L) 
100 
650 
ALT (U/L) 
 
3×ULN 
AST (U/L) 
 
3×ULN 
Creatinine (μmol/L) 
 
200 
BUN (mmol/L) 
 
14 
ALT=Alanine transaminase; AST=Aspartate transaminase; BUN=Blood urea nitrogen; PCI=Potentially clinically 
significant; ULN=Upper limit of normal 
4.8.2.2. 
Vital Signs  
Vital signs will be analyzed for observed value and change from baseline separately for vital 
signs on injection days and vital signs at each visit (excluding post injection time points on 
injection days). Refer to Table 16 for the definition of baseline. 
In addition, subjects reporting any sponsor-defined PCI vital sign values during the study will be 
analyzed. 
Vital sign values are PCI if they meet both the observed value criteria and the change from 
baseline criteria. The PCI vital sign values are presented in Table 14 below. 
Table 14: 
Potentially Clinically Important Vital Sign Criteria 
Parameter 
PCI Low 
PCI High 
Systolic blood pressure 
≤90 mm Hg and decrease ≥20 mm Hg 
from baseline 
≥140 mm Hg and increase ≥20 mm Hg 
from baseline 
Diastolic blood pressure 
≤60 mm Hg and decrease ≥15 mm Hg 
from baseline 
≥100 mm Hg and increase ≥15 mm Hg 
from baseline 
Pulse rate 
≤50 bpm and decrease ≥15 bpm from 
baseline 
≥125 bpm and increase ≥15 bpm from 
baseline 
Respiratory rate 
≤12 brpm and decrease ≥7 brpm from 
baseline 
≥25 brpm and increase ≥7 brpm from 
baseline 
Temperature 
 
≥38.3°C and increase ≥1.1°C from 
baseline 
bpm=Beats per minute; brpm=Breaths per minute; PCI=Potentially clinically significant 
5. 
ANALYSIS POPULATIONS 
The study will use the following analysis populations for data summaries.  


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Table 15: 
Analysis Populations 
Population 
Definition 
Displays 
Safety 
Population 
The Safety Population is defined as all randomized 
subjects who received at least 1 injection of study 
treatment (EN3835 or placebo). 
Subjects will be included in the Safety Population 
based on the actual treatment received. 
All demographic, baseline characteristics 
and safety parameters will be summarized 
based on this population. 
Intent-to-Treat 
(ITT) 
Population 
The ITT Population is defined as all randomized 
subjects who received at least 1 injection of study 
treatment (EN3835 or placebo). 
Subjects will be included in the ITT Population 
based on the planned treatment. 
 
Modified 
Intent-to-Treat 
(mITT) 
Population 
The mITT Population is defined as all ITT subjects 
who have a valid baseline adapted ASES 
composite score in the affected shoulder and at 
least 1 valid adapted ASES composite score after 
administration of study treatment. 
Subjects will be included in the mITT Population 
based on the planned treatment. Any subjects in the 
mITT Population are considered evaluable 
subjects, including early terminated subjects and/or 
completers. 
All efficacy analyses will be based on this 
population. 
Per-Protocol 
(PP) Population  
The PP Population is defined as those subjects in 
the mITT Population who do not have any major 
protocol deviations which have a significant effect 
on the primary endpoint. 
If more than 10% of the mITT Population 
is excluded from the PP Population, then 
select efficacy summaries will be repeated 
using the PP Population for the sensitivity 
analysis. 
6. 
STATISTICAL METHODS 
6.1. 
General Methodology 
All statistical tests, summary tables and data listings will be prepared using SAS version 9.3 or 
higher. 
All statistical tests of efficacy parameters will be 2-sided with a significance level of =0.05, 
unless specified otherwise. Statistical tests will be supported by presenting estimates and 95% 
confidence intervals (CI) for each treatment group.  
Continuous data will be summarized using descriptive statistics (number of subjects [n], mean, 
SD, median, minimum, and maximum). Discrete data will be summarized using frequency 
counts and percentages. The denominator will be based on the number of subjects in the 
appropriate population.  
For the purpose of display, the summary results will be rounded as follows:  
• Minimum and maximum: Same number of decimal places as the raw data.  
• Mean and Median: One more decimal place than the raw data.  


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• SD: Two more decimal places than the raw data.  
• Percentages will be displayed with 1 decimal place precision. A zero count will be 
left blank. 
• The standard form of a percentage change variable is 0 decimal places. 
For categorical variables with missing values, a category documenting the frequency of missing 
values will be displayed in the summary tables.  
Summary tables, subject listings, graphs and any supportive SAS output will include footnotes 
that will indicate: 
• Date of data extraction. 
• Date and time of output generation. 
• SAS program name, including the path that generated the output. 
When calculating percentages, the denominator will be based on the number of subjects with 
non-missing values. If the denominator is expected to change over time, then the denominator 
used to calculate the percentage will be based on the number of subjects with non-missing values 
at each visit. Any subject removed from an analysis will be noted at the bottom of the table along 
with the reason the subject was removed.  
Empty summary tables will be presented with a note stating that “No Subjects Met Criteria.” 
Subject listings of all data from the eCRFs as well as any derived variables will be presented. 
6.2. 
Derived Variables 
Table 16 defines the derived variables for study parameters. 


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Table 16: 
Derived Variables and Definition 
Variable 
Definition 
Height (cm) 
If height is recorded in inches, then height is equal to the recorded value 
multiplied by 2.54 and then rounded to 1 decimal place. 
Weight (kg) 
If weight is recorded in pounds, then weight is equal to the recorded value 
multiplied by 0.454 and then rounded to 1 decimal place. 
Body Mass Index (BMI) 
BMI will be computed using height and body weight measured at Screening 
as, BMI (kg/m2) = Weight (kg) / Height (m)2 
Relative Day 1 
The day of first injection of study drug will be considered as relative Day 1. 
Study Day (for assessment on or 
after Day 1) 
Study Day will be computed as, Date of Assessment – Date of Day 1 + 1 
Study Day (for assessment before 
Day 1) 
Study Day will be computed as, Date of Assessment – Date of Day 1 
Baseline 
Baseline is defined as the last non-missing measurement/assessment prior to 
the first dose of study drug.  
The assessments made in unscheduled visits will be considered in calculation 
of baseline, if the unscheduled assessment is the closest value preceding the 
first dose of study drug. 
Baseline for Vital Signs on 
Injection Days 
For vital signs on injection days, the baseline value will be the vital sign 
measure immediately prior to the first dose of study drug.  
Change from Baseline 
Change from baseline will be derived as, post-baseline visit/time point 
value – the baseline value. 
Last Date in Study 
Last date in study is defined as:  
• 
The date of End of Study (EOS) Visit (Day 95) if the subject 
completes the study 
• 
The date of early termination visit if the subject is terminated early 
from study at a non-scheduled visit 
• 
The date of the latest scheduled visit if the subject is terminated early 
from study at a scheduled visit or lost to follow-up. 
Duration of AE 
AE end date – AE start date + 1 
AE Onset Day (for AE onset date 
on or after date Day 1) 
AE start date – Date of Day 1 + 1 
AE Onset Day (for AE onset date 
before date of Day 1) 
AE start date – Date of Day 1 
6.3. 
Handling of Missing Data 
Subjects who withdraw from the study after the initiation of the study drug will not be replaced 
and available data for these subjects until the point of withdrawal will be summarized.  
Any missing baseline assessments (last assessment prior to initial study drug treatment) will not 
be imputed. 
For categorical variables with missing values, a category documenting the frequency of missing 
values will be displayed in the summary tables. 


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Subjects who withdraw early from study will be encouraged to have all EOS procedures and 
assessments completed at an early termination visit.  
For ASES function subscale, if the responses to 1 or 2 items are missing, the ASES function 
subscale score will be calculated as = 10 × (mean of the scores for the non-missing activity 
items) × 5/3. If more than 2 items of the responses to the ASES function subscale are missing, 
then the ASES function subscale score will be considered as missing. If either of the pain 
subscale or function subscale score is missing, then the ASES composite score will be 
considered as missing. 
There will be no imputation of missing values for safety data, however missing relationship 
between AE and study drug will be considered as related to study drug following worst case 
principle. Missing severity of an AE will be summarized as a severe AE. Duration of an AE will 
be classified in the “> 21 Days” category if an AE is ongoing for more than 21 days by the time 
of the last visit of the subject in the study. 
Immunogenicity samples with a positive titer value will undergo a log transformation for 
analyses. Samples with titer level less than 10 will be assigned or imputed as a log transformed 
titer of 1 for analyses.  
6.3.1. 
Handling of Missing Data for Sensitivity Analysis of Primary Endpoint 
The primary endpoint is the change from baseline in the adapted ASES composite score for the 
affected shoulder at Day 95.  This value could be missing if the subject has missing data due to 
discontinuation from the study prior to Day 95, due to a missed assessment, lost to follow-up, or 
other. 
A sensitivity analysis using a mixed model with repeat measurements (MMRM) with imputation 
using a tipping point analysis (refer to section 7.9.4.1) will be performed on the primary endpoint 
to assess the impact of missing values. If the primary analysis result is not significant (p-value 
greater than 0.05), no sensitivity analysis (tipping point) will be completed. 
6.3.2. 
Imputation of Partial Dates 
6.3.2.1. 
TEAE Status for Completely Unknown Start Date 
The following rules will apply in cases where start date of an AE is completely unknown:  
• If the AE onset date is unknown and the end date is after first injection on Day 1 or 
ongoing, then the AE will be considered a TEAE.  
• If the AE onset date is unknown and the end date is before first injection on Day 1, 
then the AE will not be considered a TEAE.  
• If both the start and end dates are unknown (or end date is ongoing), then the AE will 
be considered a TEAE, following the worst-case principle.  
If the AE onset date is partly present and month/year is prior to the first injection on Day 1, then 
the AE will not be considered a TEAE. 


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6.3.2.2. 
Concomitant Status of Medication/Non-drug Therapy for Completely Unknown 
Start Date 
The following rules will apply in cases where start date of medication is completely unknown:  
• If the medication onset date is unknown and the end date is after the date of screening 
but before the Day 95/ET Visit or medication is ongoing, then the medication will be 
considered as concomitant.  
• If the medication onset date is unknown and the end date is before the date of 
screening, then the medication will not be considered as concomitant.  
• If both the start and end dates are unknown, then the medication will be considered as 
concomitant. This approach is considered to be the most conservative following the 
worst-case principle.  
If the medication onset date or end date is partly present and month/year is prior to the date of 
screening, then the medication will not be considered as concomitant. If the medication onset 
date or end date is partly present and month/year is after to the date of screening or medication is 
ongoing, then the medication will be considered as concomitant. 
6.3.2.3. 
Missing Last Menstrual Date 
Missing date of last menstrual period will be imputed with the last day of the month and missing 
onset month will be imputed with December. 
6.4. 
Interim Analysis 
An interim analysis for safety and futility is planned for when approximately 86 subjects 
(approximately 50% of subjects) have completed the Day 95/Early Termination Visit. 
Enrollment will continue during this analysis. Details of the interim analysis will be provided in 
a separate document.  
An independent unblinded data monitoring committee will review the interim data and provide 
recommendations for study continuation. 
7. 
STATISTICAL ANALYSES 
7.1. 
Subject Disposition 
The number of subjects included in each study population will be summarized by treatment 
group and overall. Subjects excluded from the safety, ITT, mITT, or PP populations will be 
listed. 
The frequency counts and percentages of subjects screened, enrolled, completed and/or 
withdrawn from the study, as well as the reason for withdrawal from study will be summarized 
by treatment group and overall.  
A listing of disposition data will be provided. Screen failure reasons will also be listed. In 
addition, a listing for inclusion/exclusion criteria will be presented. 


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7.2. 
Protocol Deviations 
Protocol deviations will be summarized by deviation classification (major/minor), and by 
treatment group and overall. A listing of all protocol deviations will be presented.  
7.3. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment group and overall, 
for the safety, mITT, and PP populations.  
Age, height (at baseline), body weight (at baseline), BMI in kg/m2, and time since last menstrual 
period for female subjects will be summarized as continuous variables using descriptive 
statistics.  
Age group, gender, race, and ethnicity will be summarized as categorical variables using 
frequency counts and percentages.  
History of tobacco and alcohol use will be summarized using frequency counts and percentages 
as: 
• Alcohol use (Never, Current or Former). 
• Tobacco use (Never, Current or Former). 
All demographic and baseline characteristics will be presented in by subject listings. 
7.4. 
Medical and Surgical History 
Medical history will be coded using the MedDRA dictionary. The version to be used will be 
defined in the DMP. Medical and surgical history data will not be summarized; however, a 
subject listing for medical history will be provided for subjects in the Safety Population. 
A separate listing for surgical history of the affected shoulder will also be provided. 
7.5. 
Adhesive Capsulitis History 
A listing for history of all past episodes of AC of the shoulder will be provided. 
A separate listing for AC current symptomatology will also be provided. 
7.6. 
Prior/Concomitant Medications and Nondrug Therapies 
Prior and concomitant medication use will be summarized by treatment group and overall using 
frequency counts and percentages for subjects in the Safety Population, by active ingredient 
within each ATC, with ATC and active ingredients ordered alphabetically. Prior and concomitant 
non-drug therapies (procedures) will be summarized by treatment group and overall using 
frequency counts and percentages with name of the procedures ordered alphabetically. Multiple 
use of the same medication/nondrug therapy by a subject will be counted only once.  
Listings of prior and concomitant medications and nondrug therapies will be provided for all 
subjects in the Safety Population. Similarly, a separate listing of prior medications and non-drug 
therapies for AC will also be provided.  


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7.7. 
Hand Dominance 
Hand dominance will be summarized by treatment group and overall using frequency count and 
percentages for subjects in the Safety Population. 
A listing for hand dominance will be provided. 
7.8. 
Passive External Rotation 
Passive external rotation at 0°, 45°, and 90° of abduction at screening will be summarized by 
treatment group and overall using absolute degrees, degrees and percent deficit of the affected 
shoulder compared to the contralateral shoulder for subjects in the Safety Population. 
A listing for passive external rotation at 0°, 45°, and 90° of abduction will be provided. 
7.9. 
Efficacy Analyses 
Efficacy parameters will be summarized and analyzed by treatment group using the mITT 
Population.  
For primary and secondary analysis, endpoints of the affected shoulder in the EN3835 treatment 
group will be compared to those in the placebo group.  
7.9.1. 
Primary Analysis  
7.9.1.1. 
Change from Baseline in Adapted ASES Composite Score 
The primary endpoint is the change from baseline to the Day 95 Visit in the adapted ASES 
composite score. 
MMRM will be performed to estimate change from baseline treatment effect at Day 64 and Day 
95 Visits comparing active to placebo for the adapted ASES composite score in the affected 
shoulder. MMRM will be performed to estimate the least square (LS) means of change from 
baseline for EN3835 and placebo treatment. P values and 95% CIs for the treatment difference 
(EN3835 – Placebo) will be calculated by MMRM for the visits with treatment, visit, and an 
interaction of treatment and visit as fixed effected and repeated with visit/subject. Autoregressive 
covariance structure will be used in the model.  
Observed values and change from baseline in the adapted ASES composite score in the affected 
shoulder for each treatment group will be summarized at Day 22, 43, 64 and 95 Visits using 
descriptive statistics. 
A listing of adapted ASES scores will be provided. 
7.9.2. 
Secondary Analysis  
7.9.2.1. 
Absolute and Percent Change from Baseline in PROM 
MMRM will be performed to estimate change from baseline treatment effect at Day 22, 43, 64 
and Day 95 Visits comparing active to placebo for PROM for forward flexion, internal rotation, 
external rotation, abduction, and shoulder extension in the affected shoulder. MMRM will be 
performed to estimate the LS means of absolute change from baseline for EN3835 and placebo 
treatment. P values and 95% CIs for the treatment difference (EN3835 – Placebo) will be 


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calculated by MMRM for the visits with treatment, visit, and an interaction of treatment and visit 
as fixed effected and repeated with visit/subject. Autoregressive covariance structure will be 
used in the model.  
MMRM will be performed to estimate absolute and percent change from baseline treatment 
effect compared to baseline of the contralateral shoulder at Day 22, 43, 64 and Day 95 Visits 
comparing active to placebo for PROM for forward flexion, internal rotation, external rotation, 
abduction, and shoulder extension in the affected shoulder. MMRM will be performed to 
estimate the LS means of absolute and percent change from baseline for EN3835 and placebo 
treatment. P values and 95% CIs for the treatment difference (EN3835 – Placebo) will be 
calculated by MMRM for the visits with treatment, visit, and an interaction of treatment and visit 
as fixed effected and repeated with visit/subject. Autoregressive covariance structure will be 
used in the model.  
Observed values and change from baseline in PROM for forward flexion, internal rotation, 
external rotation, abduction, and shoulder extension in the affected shoulder for each treatment 
group at Day 22, 43, 64, and 95 Visits compared to the affected shoulder at baseline will be 
summarized using descriptive statistics. 
Observed values, absolute and percent change from baseline in PROM for forward flexion, 
internal rotation, external rotation, abduction, and shoulder extension in affected shoulder for 
each treatment group at Day 22, 43, 64, and 95 Visits compared to the contralateral shoulder at 
baseline will be summarized using descriptive statistics. 
A listing of PROM will be provided. 
7.9.2.2. 
Absolute and Percent Change from Baseline in AROM 
MMRM will be performed to estimate change from baseline treatment effect at Day 22, 43, 64 
and Day 95 Visits comparing active to placebo for AROM for forward flexion, internal rotation, 
external rotation, abduction, and shoulder extension in the affected shoulder. MMRM will be 
performed to estimate the LS means of absolute change from baseline for EN3835 and placebo 
treatment. P values and 95% CIs for the treatment difference (EN3835 – Placebo) will be 
calculated by MMRM for the visits with treatment, visit, and an interaction of treatment and visit 
as fixed effected and repeated with visit/subject. Autoregressive covariance structure will be 
used in the model.  
MMRM will be performed to estimate absolute and percent change from baseline treatment 
effect compared to baseline of the contralateral shoulder at Day 22, 43, 64 and Day 95 Visits 
comparing active to placebo for AROM for forward flexion, internal rotation, external rotation, 
abduction, and shoulder extension in the affected shoulder. MMRM will be performed to 
estimate the LS means of absolute and percent change from baseline for EN3835 and placebo 
treatment. P values and 95% CIs for the treatment difference (EN3835 – Placebo) will be 
calculated by MMRM for the visits with treatment, visit, and an interaction of treatment and visit 
as fixed effected and repeated with visit/subject. Autoregressive covariance structure will be 
used in the model.  
Observed values and change from baseline in AROM for forward flexion, internal rotation, 
external rotation, abduction, and shoulder extension in the affected shoulder for each treatment 


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group at Day 22, 43, 64, and 95 Visits compared to the affected shoulder at baseline will be 
summarized using descriptive statistics. 
Observed values, absolute and percent change from baseline in AROM for forward flexion, 
internal rotation, external rotation, abduction, and shoulder extension in the affected shoulder for 
each treatment group at Day 22, 43, 64, and 95 Visits compared to the contralateral shoulder at 
baseline will be summarized using descriptive statistics. 
A Wilcoxon rank sum nonparametric test will be used to compare EN3835 to placebo for the 
HBB change from baseline values for active internal rotation in affected shoulder at the Day 22, 
43, 64 and 95 Visits.  
The null and alternative hypotheses for this test will be as below: 
H0: There is no difference in the change in baseline HBB values for active internal rotation in 
the 2 treatment groups. 
Vs 
H1: The change in baseline HBB values for active internal rotation differs in the 2 treatment 
groups. 
The Wilcoxon scores (Rank Sums) for treatment groups and test statistics along with p value for 
the test of significance will be presented. 
Responses for HBB assessment for internal rotation will be summarized for each treatment group 
using frequency counts and percentages. 
A listing of AROM will be provided. 
7.9.2.3. 
Change from Baseline in Adapted Pain and Function Subscale 
MMRM will be performed to estimate change from baseline treatment effect at Day 22, 43, 64 
and Day 95 Visits comparing active to placebo for adapted pain subscale and adapted function 
subscale in the affected shoulder. MMRM will be performed to estimate the LS means of change 
from baseline for EN3835 and placebo treatment. P values and 95% CIs for the treatment 
difference (EN3835 – Placebo) will be calculated by MMRM for the visits with treatment, visit, 
and an interaction of treatment and visit as fixed effected and repeated with 
visit/subject. Autoregressive covariance structure will be used in the model.  
Observed values and change from baseline in adapted pain subscale and adapted function 
subscale in the affected shoulder for each treatment group will be summarized at Day 22, 43, 64, 
and 95 Visits using descriptive statistics. 
In addition, score and change from baseline for each of the individual questions will be 
summarized for adapted function subscale for each treatment group using frequency counts and 
percentages with mean and SD. 
7.9.2.4. 
Change from Baseline in PUM Scale 
MMRM will be performed to estimate change from baseline treatment effect at Day 64 and 
Day 95 Visit comparing active to placebo for PUM scale in the affected shoulder. MMRM will 
be performed to estimate the LS means of change from baseline for EN3835 and placebo 
treatment. P values and 95% CIs for the treatment difference (EN3835 – Placebo) will be 


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calculated by MMRM for the visits with treatment, visit, and an interaction of treatment and visit 
as fixed effected and repeated with visit/subject. Autoregressive covariance structure will be 
used in the model. 
Observed values and change from baseline in the PUM scale in the affected shoulder for each 
treatment group will be summarized at Day 64 and Day 95 Visits using descriptive statistics. 
A listing of PUM scale scores will be provided. 
7.9.2.5. 
Change from Baseline in Patient-reported Global Severity of Adhesive 
Capsulitis Scale 
A Wilcoxon rank sum nonparametric test will be used to compare EN3835 to placebo for the 
change from baseline in Patient-reported Global Severity of Adhesive Capsulitis Scale in the 
affected shoulder at the Day 22, 43, 64 and 95 Visits.  
The null and alternative hypotheses for this test will be as below: 
H0: There is no difference in the change in severity in the 2 treatment groups. 
Vs 
H1: The change in severity differs in the 2 treatment groups. 
The Wilcoxon scores (Rank Sums) for treatment groups and test statistics along with p value for 
the test of significance will be presented. 
Observed values and change from baseline in Patient-reported Global Severity of Adhesive 
Capsulitis Scale in the affected shoulder for each treatment group will be summarized at the 
Day 22, 43, 64 and 95 Visits using descriptive statistics. 
A listing of Patient-reported Global Severity of Adhesive Capsulitis Scale scores will be 
provided. 
7.9.2.6. 
Patient-reported Change in Severity of Adhesive Capsulitis Scale 
Reponses for Patient-reported Change in Severity of Adhesive Capsulitis Scale at the Day 22, 43, 
64, and 95 Visits will be compared between EN3835 to placebo using a chi-square test (or 
Fisher’s exact test based on expected frequencies).  
The null and alternative hypotheses for this test will be as below: 
H0: The distribution of responses is independent of the treatment groups. 
Vs 
H1: The distribution of responses is dependent on the treatment group (ie, there is a 
difference in distribution of responses among the treatment groups). 
Reponses for Patient-reported Change in Severity of Adhesive Capsulitis Scale will be 
summarized by each treatment group using frequency counts and percentages and in addition 
chi-square (or Fisher’s exact) test statistics along with p value for the test of significance will be 
presented.  
The change in the symptoms will be summarized by each treatment group using frequency 
counts and percentages with mean and SD. 


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A listing of Patient-reported Change in Severity of Adhesive Capsulitis Scale scores will be 
provided. 
7.9.2.7. 
Investigator Assessment of Improvement with Treatment 
A Wilcoxon rank sum nonparametric test will be used to compare EN3835 to placebo for the 
Investigator Assessment of Improvement with Treatment in the affected shoulder at the Day 64 
and 95 Visits.  
The null and alternative hypotheses for this test will be as below: 
H0: There is no difference in the Investigator Assessment of Improvement with Treatment in 
the 2 treatment groups. 
Vs 
H1: The Investigator Assessment of Improvement with Treatment differs in the 2 treatment 
groups. 
Wilcoxon scores (Rank Sums) for treatment group and test statistics along with p value for the 
test of significance will be presented. 
Reponses for Investigator Assessment of Improvement with Treatment in the affected shoulder 
and responders will be summarized by treatment group using frequency counts and percentages 
with mean and SD. 
A listing of Investigator Assessment of Improvement with Treatment scores will be provided. 
7.9.2.8. 
Subject Satisfaction with Treatment 
A Wilcoxon rank sum nonparametric test will be used to compare EN3835 to placebo for all the 
individual questions of Subject Satisfaction prior to receiving treatment and Subject Satisfaction 
compared to better shoulder for the affected shoulder at the Day 64 and 95 Visits. The null and 
alternative hypotheses for this test will be as below: 
H0: There is no difference in the Subject Satisfaction with Treatment in the 2 treatment 
groups. 
Vs 
H1: Subject Satisfaction with Treatment differs in the 2 treatment groups. 
Wilcoxon scores (Rank Sums) for treatment group and test statistics along with p value for the 
test of significance will be presented. 
Reponses for Subject Satisfaction with Treatment in the affected shoulder and responders will be 
summarized by treatment group using frequency counts and percentages with mean and SD. 
A listing of Subject Satisfaction with Treatment scores will be provided. 
7.9.3. 
Exploratory/Tertiary Analyses  
7.9.3.1. 
 
r
 
  


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7.9.4. 
Sensitivity Analysis 
7.9.4.1. 
Primary Endpoint Sensitivity Analysis with MMRM using Tipping Point 
Analysis (TPA)  
A sensivity analysis will be performed to assess the impact of missing data with MMRM using 
tipping point analysis as described in section 7.9.1. Note that if the primary analysis result is not 
significant (p-value greater than 0.05), no sensitivity analysis will be perfomed. 
To evaluate the impact of deviations from the missing at random (MAR) assumption, a delta-
adjustment multiple imputation (MI) method will be used to find the tipping point where the 
result is no longer statistically significant.  
There are three steps to be followed for this sensivity analysis. 
Step 1: Generate Pattern of Missing Data 
Before various MI methods are applied, the different types of missing data patterns will be 
checked using NIMPUTE=0 in SAS PROC MI. This will generate the pattern of missing data 
and will not generate any imputed values for missing data.  
PROC MI DATA=INPUT NIMPUTE=0; 
VAR VAR1 VAR2 VAR3...(variables in order the missing patterns are created for); 
 
RUN; 
 
Step 2: Imputation of data for non-monotone and monotone missing data  
• Intermittent missing values: If there are subjects with intermittent missing values (ie. 
non-monotone missing data), the intermittent missing values will be imputed based on 
Markov Chain Monte Carlo (MCMC) methods.  SAS PROC MI will be utilized with 
MCMC to generate datasets with monotone missing pattern. The number of imputations 
will be set to n (20 is the default value). 
 
PROC MI DATA=INPUT NIMPUTE=n SEED=234 OUT=IN_MCMC; 
VAR …; (treatment group, baseline covariates, and the preceding non-missing values in 
the order of clinical visits: baseline, Visit X, ..., Visit Y) 
MCMC CHAIN=SINGLE NBITER=1000 NITER=1000 IMPUTE=MONOTONE; 
RUN; 
 


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• If all subjects have a monotone missing data pattern (either directly from the study or 
created by the previous step), the MAR-based multiple imputation with the regression 
option will be used to impute missing values, the imputed values will then be adjusted 
accordingly. Delta-adjustment will be generated for different combinations of δP an δA 
values as defined below: 
• Active-only adjustment analysis:  δP = 0 and δA = 0 to Δ1 (Δ1 is the effect size 
reported in the primary analysis)  
• Analysis with a control adjustment that is half of the active adjustment: δP = δA /2 
and δA = 0 to Δ1 
• All arms with identical adjustment: δP = δA and δA = 0 to Δ1 
 
• The imputation will be performed using SAS PROC MI with the MONOTONE statement 
and the REGRESSION option with the following specifications: 
 
PROC MI DATA=IN_MCMC NIMPUTE=1 (see note) SEED=234 OUT=OUTPUT; 
 VAR …; (treatment group, baseline covariates, and the preceding non-missing values in 
the order of clinical visits: baseline, Visit X, ..., Visit Y) 
 CLASS…; (treatment group)  
 MONOTONE REG (/details); 
 MNAR ADJUST (Visit X / SHIFT=delta_a ADJUSTOBS=(TRT01PN ='1'));  
 MNAR ADJUST (Visit Y / SHIFT=delta_a ADJUSTOBS=(TRT01PN ='1'));  
 MNAR ADJUST (…        / SHIFT=delta_a ADJUSTOBS=(TRT01PN ='1')); 
 MNAR ADJUST (Visit X / SHIFT=delta_p ADJUSTOBS=(TRT01PN ='0'));  
 MNAR ADJUST (Visit Y / SHIFT=delta_p ADJUSTOBS=(TRT01PN ='0'));  
 MNAR ADJUST (…       / SHIFT=delta_p ADJUSTOBS=(TRT01PN ='0’)); 
RUN; 
 
Note: NIMPUTE=n if MCMC was NOT applied at the previous step.  
 
Step 3: Analysis and Pooling 
For each value of δP and δA, MMRM described in section 7.9.1 will be performed for each of the 
n adjusted fully imputed datasets. The analysis results obtained will be combined into a single 
estimation using PROC MIANALYZE to produce final inferences. 
The following estimates will be presented in the sensitivity analysis table: 
1. LSM estimate for the mean change from baseline at the visit where primary 
endpoint is measured for each treatment. 
2. LSM estimate for treatment difference of the mean change from baseline at the 
visit where primary endpoint is measured and the corresponding 2-sided 95% CI 
and p-value for change from baseline in the primary endpoint will be provided. 
Shift parameters will begin with active-only adjustment, followed by a control adjustment that is 
half of the active adjustment, followed by all arms with identical shift adjustments, as stated in 
Step 2. 
 


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All steps above are repeated with different values of the shift parameter until the tipping point is 
reached or all possible values are explored. The tipping point can be identified when the result is 
no longer statistically significant (p-value >0.05). It is possible a tipping point is not reached if 
little to no data is missing. 
 
Once tipping point is reached, if implausible departure from MAR is needed to change the results 
from statistically significant to insignificance, the results of the primary endpoint are considered 
to be robust. If the tipping point obtained for overturning the primary endpoint result is clinically 
plausible, the conclusion can be questioned and viewed with caution. 
7.9.5. 
Supportive Analysis 
7.9.5.1. 
Per-Protocol Population Analysis 
If more than 10% of the mITT Population is excluded from the PP Population, then select 
efficacy summaries will be repeated using the PP Population for the supportive analysis. 
7.10. 
Safety Analyses 
Safety data will be summarized by each treatment group and overall using the Safety Population. 
Subjects will be included in the safety analyses based on the actual treatment received. 
7.10.1. 
Study Drug Exposure 
The study drug exposure will be summarized at each treatment visit and by each treatment group. 
The following will be summarized descriptively: 
• Number of injections received. 
• Total dose administered (mg). 
A subject listing of overall exposure will be provided. 
7.10.2. 
Adverse Events 
Proportion of subjects reporting at least 1 adverse event, treatment-emergent adverse event, 
adverse event of special interest, and serious adverse event will be compared for EN3835 to 
placebo treatment group using Fisher’s exact test.  
The null and alternative hypotheses for this test will be as below: 
H0: p1 = p2 (Proportion of subjects having an adverse event are equal in treatment groups) 
Vs 
H1: p1 ≠ p2 (Proportion of subjects having an adverse event are unequal in treatment groups) 
Where, 
p1: Proportion of subjects having adverse event in EN3835 treatment group. 
p2: Proportion of subjects having adverse event in placebo treatment group. 


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Number and proportion of subjects with at least 1 adverse event, treatment-emergent adverse 
event, adverse event of special interest, and serious adverse will be summarized by treatment 
groups and in addition p value for treatment comparison will also be presented. 
All AE summary tables will include only TEAEs, unless otherwise specified.  
AEs will be summarized by SOC and PT. A subject will only be counted once per SOC and PT. 
For AEs by severity grade (mild, moderate, severe), if a subject has multiple events occurring in 
the same SOC or same PT, then the event with the maximum intensity (ie, severe) will be 
counted.  
For AEs by relationship to study drug, if a subject has multiple events occurring in the same 
SOC or same PT, the event with the highest association (ie, related) to study drug will be 
summarized. 
AEs will be presented in decreasing order of the incidences at SOC level and within each SOC, 
in decreasing order of the incidences at the PT level. 
An overall summary of AEs and AEs related to study drug will be presented and will include:  
• Total number of TEAEs reported. 
• Total number of TEAEs reported by severity. 
• Total number of TEAEs of special interest. 
• Subjects with any TEAE.  
• Subjects with any TEAE of special interest. 
• Subjects with any serious TEAE.  
• Subjects with any severe TEAE.  
• Subjects with no severe TEAEs, but at least 1 moderate TEAE. 
• Subjects with no severe TEAEs, but at least 1 mild TEAE. 
• Subjects with any TEAEs leading to drug interruption/withdrawal.  
• Subjects with any TEAEs leading to study discontinuation.  
• Subjects with any TEAEs resulting in death.  
The following summary tables will be presented by SOC and PT:  
• All TEAEs.  
• Study drug related TEAEs.  
• TEAEs by severity. 
• Study drug related TEAEs by severity.  
• Study drug related TEAEs by treatment session 
• Duration (1-7 days, 8-14 days, 15-21 days, > 21 days) of study drug related TEAEs. 
• Serious TEAEs.  


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• TEAE of special interest.  
• TEAE of special interest by severity. 
Most common non-serious TEAEs by order of frequency (Most frequent, 2nd most frequent, and 
3rd most frequent) will be summarized by PT. Most common non-serious AEs are those that at 
least 5% of the subjects reported at least once (using PT).  
The following listings will be presented by subject:  
• All AEs. 
• AEs resulting in death.  
• Non-fatal serious AEs.  
• AEs resulting in drug interruption/withdrawal. 
• AEs resulting in study discontinuation. 
Refer to Table 16 for computation of duration of AEs.  
7.10.3. 
Clinical Laboratory 
Student t test (2-sample t test) will be used to compare EN3835 to placebo for change from 
baseline in the laboratory parameters (hematology and chemistry) at the Day 95 Visit.  
The null and alternative hypotheses for this test will be as below: 
H0: There is no significant difference in mean change in laboratory parameters for 2 
treatment groups. 
Vs 
H1: There is significant difference in mean change in laboratory parameters for 2 treatment 
groups. 
Hematology and chemistry results will be summarized by each treatment group using descriptive 
statistics for observed and change from baseline values along with p value at Day 95/EOS Visit.  
Proportion of subjects reporting with PCI laboratory values will be compared for EN3835 to the 
placebo treatment group using Fisher’s exact test. Refer to Table 13 for PCI criteria. 
The null and alternative hypotheses for this test will be as below: 
H0: p1 = p2 (Proportion of subjects having PCI laboratory values are equal in treatment 
groups) 
Vs 
H1: p1 ≠ p2 (Proportion of subjects having PCI laboratory values are unequal in treatment 
groups) 
Where, 
p1: Proportion of subjects having PCI laboratory values in EN3835 treatment group. 
P2: Proportion of subjects having PCI laboratory values in placebo treatment group. 


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The PCI laboratory values will be summarized by treatment groups. In addition, the p value for 
treatment comparison will be presented. 
A subject listing will be presented for all laboratory parameters (hematology, biochemistry, 
urinalysis, TSH and HbA1c). Serum and urine pregnancy test results will be listed separately. 
7.10.4. 
Vital Signs 
Student t test (2-sample t test) will be used to compare EN3835 to placebo for change from 
baseline in the vital signs (SBP, DBP, pulse rate, respiratory rate, body temperature, and body 
weight) at Day 1, 22, 43, 64, and 95 Visits.  
The null and alternative hypotheses for this test will be as below: 
H0: There is no significant difference in mean change in vital sign parameters between the 2 
treatment groups. 
Vs 
H1: There is a significant difference in mean change in vital sign parameters between the 2 
treatment groups. 
Vital signs (SBP, DBP, pulse rate, respiratory rate, body temperature) taken on the injection days 
will be summarized across the required measurement time points (15 minutes and 30 minutes 
post injection) for each treatment group using descriptive statistics for observed and change from 
baseline values.  
Vital signs taken at each visit will be summarized across study visits not including the post 
injection time points for each treatment group and overall using descriptive statistics for 
observed and change from baseline values along with p value. 
Proportion of subjects reporting with PCI vital sign values will be compared for EN3835 to the 
placebo treatment group using Fisher’s exact test. Refer to Table 14 for PCI criteria. 
The null and alternative hypotheses for this test will be as below: 
H0: p1 = p2 (Proportion of subjects having PCI vital sign values are equal in treatment 
groups) 
Vs 
H1: p1 ≠ p2 (Proportion of subjects having PCI vital sign values are unequal in treatment 
groups) 
Where, 
p1: Proportion of subjects having PCI vital sign values in EN3835 treatment group. 
p2: Proportion of subjects having PCI vital sign values in placebo treatment group. 
The PCI vital sign values will be summarized by treatment groups. In addition, the p value for 
treatment comparison will be presented. 
A listing will be presented for vital signs results. 


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7.10.5. 
12-Lead ECG 
The investigator interpretation of ECG results (normal, abnormal not clinically significant, or 
abnormal clinically significant) will be summarized by each treatment group and overall using 
frequency counts and percentages. 
A listing of investigator interpretation of ECG results will be presented. 
7.10.6. 
Physical Examination 
Physical examination results (by body system) at baseline and at Day 95/ET will be presented by 
each treatment group and overall using frequency counts and percentages. 
A listing will be presented for the physical examination results (by body system). 
7.10.7. 
Immunogenicity 
The immunogenicity analysis of binding and neutralizing anti-AUX-I and anti-AUX-II 
antibodies will be summarized by the number of subjects with an immunogenicity sample, the 
percentage of subjects with a positive sample, and the average titer level of the positive samples 
at Screening and Day 95/ET along with summary statistics if antibody assays are conducted. 
The titer levels will be logarithmically transformed prior to being summarized. Samples from 
Screening and Day 95/ET will be analyzed for anti-AUX-I and anti-AUX-II antibodies and only 
positive samples will be analyzed for neutralizing antibodies. Neutralizing antibody results will 
be summarized as percentage of samples tested by positive/negative results. 
A listing of immunogenicity results by subject will be provided. 
7.11. 
Other Analyses 
7.11.1. 
X-Ray 
A listing for x-ray will be provided. 
7.11.2. 
Physical Therapy 
A listing for physical therapy will be provided. 
7.11.3. 
Home Exercise  
The compliance of home exercises at all study days (starting 3 days after each study treatment up 
to the Day 95/ET Visit) will be summarized for each treatment group and overall using 
descriptive statistics. 
A listing for home exercise will be provided. 


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8. 
CHANGE FROM PROTOCOL 
This SAP is prepared based on the study protocol; original version dated April 06, 2020, 
Amendment 1 dated July 10, 2020, Amendment 2 dated July 31, 2020, Amendment 3 on 
November 06, 2020, and Amendment 4 on October 22, 2021.  
Table 17 lists any significant changes in the SAP from what is proposed in the protocol. 
Table 17: 
Changes from Protocol 
Text in Protocol 
Change in SAP 
Justification 
The Per-Protocol (PP) Population is 
defined as those subjects in the 
mITT Population who do not have 
any major protocol deviations. 
The PP Population is defined as 
those subjects in the mITT 
Population who do not have any 
major protocol deviations which 
have a significant effect on the 
primary endpoint. 
Change the PP Population to 
emphasize only subjects with major 
PDs that effect the primary endpoint to 
be excluded. This allows subjects with 
major PDs related to safety only (and 
no effect on primary endpoint) to be 
included in PP Population. 
N/A 
Added a tipping point sensitivity 
analysis (section 7.9.4) 
Tipping point analysis checks if the 
missing data effects the primary 
analysis conclusions by checking 
severity of missing data. Identify the 
tipping poing where treatment effect in 
subjects with missing data overturns 
the significant treatment effect 
otbtained in the missing at random 
primary analysis.   
9. 
REVISION HISTORY 
Non-editorial changes made to any of the modules of this SAP will be recorded in Table 18. 
Table 18: 
Revision History 
Version 
Date 
Revision Author 
Comments 
v1.0 
Aug 12, 2020 
 
Original version 
v2.0 
April 25, 2022 
 
Protocol amendment updates, prior/concomitant 
definition, adverse events of special interest, tipping 
point sensitivity analysis 


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10. 
REFERENCES 
1. Endo Pharmaceuticals Inc. A Phase 2, Randomized, Double Blind, Placebo Controlled 
Study of the Safety and Efficacy of EN3835 for the Treatment of Adhesive Capsulitis of 
the Shoulder [EN3835-210 Clinical Study Protocol, Amendment 2]. Malvern, PA; 
31 July 2020. 
2. McClure P, Michener L. Measures of adult shoulder function: the American Shoulder and 
Elbow Surgeons Standardized Shoulder Form patient self-reported section (ASES), 
Disabilities of the Arm, Shoulder, and Hand (DASH), Shoulder Disability Questionnaire, 
Shoulder Pain and Disability Index (SPADI), and Simple Shoulder Test. Arthritis Rheum. 
2003;49(5S):S50-S58. doi:10.1002/art.11404 
3. Michener LA, McClure PW, Sennett BJ. American Shoulder and Elbow Surgeons 
Standardized Shoulder Assessment Form, patient self-report section: reliability, validity, 
and responsiveness. J Shoulder Elbow Surg. 2002;11(6):587-594. 
doi:10.1067/mse.2002.127096 
4. Evidera. Evaluation of Test-Retest Reliability of the Standardized Shoulder Assessment 
Form Adapted from the ASES and a Pain Upon Movement Question. Version 1.0. 
Bethesda, MD; 22 January 2016. 


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11. 
TABLES, LISTINGS, AND GRAPH SHELLS 
The layouts of the summary tables, subject listings, and graphs are presented in SAP Module 2.  
These layouts incorporate all the appropriate table titles, table numbers, and footnotes.