Clinical trial NCT04160091
Conditions: Osteoarthritis of the Shoulder Adhesive Capsulitis
Keywords: Osteoarthritis Adhesive Capsulitis Shoulder Pain Intra-articular Injection Steroid
Sponsor: Pacira Pharmaceuticals, Inc
Start date: 2019-11-07; Completion date: 2020-06-15
Enrollment: 19 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a double-blind study to evaluate the efficacy and safety of FX006 in patients with glenohumeral osteoarthritis (OA) or shoulder adhesive capsulitis (AC).

Detailed description:
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group study in separate cohorts of patients with a documented history of either glenohumeral OA or shoulder AC. Glenohumeral OA and shoulder AC patients will be randomized to receive a single intra-articular injection of either FX006 or placebo (saline) in a 1:1 ratio to the index shoulder with a 24-week Treatment Evaluation Period. Glenohumeral OA patients will be stratified by Baseline average daily shoulder pain with movement score according to the following classifications: 5.0 to \<7.0 or ≥7.0 to 9.0 (0 to 10 numeric rating scale \[NRS\]). Shoulder AC patients will be stratified by Baseline average daily shoulder pain with movement score according to the following classifications: 5.0 to \<7.0 or ≥7.0 to 9.0 (0 to 10 NRS), and by pain duration since onset (1 to 3 months, inclusive, or \>3 to ≤6 months). A Home Exercise Program will be implemented 3 days following injection for shoulder AC patients.

Arms: arm 1: Single intra-articular (IA) injection arm 2: Single intra-articular (IA) injection arm 3: Single intra-articular (IA) injection arm 4: Single intra-articular (IA) injection
Interventions: intervention 1: FX006 intervention 2: Normal Saline
Intervention descriptions: intervention 1: Single intra-articular injection intervention 2: Single intra-articular injection

Protocol documents:
Prot_SAP_002.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-
Group Study to Evaluate the Efficacy and Safety of FX006 in Patients 
With Glenohumeral Osteoarthritis or Shoulder Adhesive Capsulitis 
(RANGE) 
Investigational Product: FX006 
Protocol Number: FX006-2018-016 
 
 
 
Sponsor: 
Flexion Therapeutics, Inc. 
10 Mall Road, Suite 301 
Burlington, MA 01803 
United States of America 
Telephone: 781-305-7777 
 
DATE: 16 December 2019 
VERSION: Version 2.0 (Amendment 1) 
SUPERSEDES:  Version Number: 1.0 (22 July 2019) 
 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Flexion Therapeutics, Inc. except to the extent that disclosure would be required by 
law and for the purpose of evaluating and/or conducting a clinical study for Flexion 
Therapeutics, Inc. You are allowed to disclose the contents of this document only to your 
Institutional Review Board and study personnel directly involved with conducting this protocol. 
Persons to whom the information is disclosed must be informed that the information is 
confidential and proprietary to Flexion Therapeutics, Inc. and that it may not be further disclosed 
to third parties. 




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INVESTIGATOR AGREEMENT 
By signing below, I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Flexion Therapeutics, Inc. to study personnel under my supervision. I will discuss this material 
with them to ensure they are fully informed about the study medication and study procedures. I 
will let them know that this information is confidential and proprietary to Flexion Therapeutics, 
Inc. and that it may not be further disclosed to third parties. I understand that the study may be 
terminated, or enrollment suspended at any time by Flexion Therapeutics, Inc., with or without 
cause, or by me if it becomes necessary to protect the best interests of the study patients. 
I agree to conduct this study in full accordance with Food and Drug Administration Regulations, 
Institutional Review Board, and International Council for Harmonisation Guidelines for Good 
Clinical Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 


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SYNOPSIS 
TITLE:  A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to 
Evaluate the Efficacy and Safety of FX006 in Patients With Glenohumeral Osteoarthritis or 
Shoulder Adhesive Capsulitis 
PROTOCOL NUMBER:  FX006-2018-016 
INVESTIGATIONAL PRODUCT:  FX006 
PHASE:  2 
INDICATIONS:  Shoulder pain due to glenohumeral osteoarthritis (OA) and shoulder pain due 
to adhesive capsulitis (AC) 
OBJECTIVES: 
The primary objective of this study is to assess the efficacy of FX006 on pain following an 
intra-articular (IA) injection in patients with glenohumeral OA or shoulder AC. 
The secondary objectives of this study are to assess the efficacy of FX006 on pain, disability, 
function, and global impression of change in patients with glenohumeral OA or shoulder AC, and 
to assess the safety of FX006 in patients with glenohumeral OA or shoulder AC.  
The exploratory objectives of this study are to assess additional measures of pain, disability, 
function, QOL, rescue medication consumption, and proportion of responders at varying 
timepoints over the course of the study. 
POPULATIONS: 
The populations for this study are males or females, 35 to 80 years of age, inclusive, with painful 
symptoms associated with OA of the index glenohumeral joint for 3 months prior to the 
Screening Visit and X-ray confirmation of Grade 2 or 3 OA based on the Samilson-Prieto 
classification system; and male or females, 35 to 80 years of age, inclusive, with pain associated 
with shoulder AC of the index joint for 1 month but 6 months prior to the Screening Visit, more 
than 20% (25% if dominant shoulder is the index shoulder) loss of passive range of the rotation 
arc (external and internal rotation) of glenohumeral movement, measured with the patient in 
supine or sitting position and the shoulder elevated to 45 degrees, compared with the contralateral 
shoulder, and no X-ray evidence of OA.  
STUDY DESIGN AND DURATION: 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group study 
in separate cohorts of patients with a documented history of either glenohumeral OA or shoulder 
AC. Glenohumeral OA and shoulder AC patients will be randomized to 1 of 2 treatment groups 
within their shoulder condition in a 1:1 ratio to receive a single IA injection of either 32 mg 
FX006 or placebo (saline) to the index shoulder with a 24-week Treatment Evaluation Period. 
Glenohumeral OA patients will be stratified by Baseline average daily shoulder pain with 


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movement score according to the following classifications: 5.0 to <7.0 or 7.0 to 9.0 (0 to 
10 numeric rating scale [NRS]). Shoulder AC patients will be stratified by Baseline average daily 
shoulder pain with movement score according to the following classifications: 5.0 to <7.0 or 
7.0 to 9.0 (0 to 10 NRS), and by pain duration since onset at Screening (1 to 3 months, inclusive, 
or >3 to 6 months). A Home Exercise Program will be implemented 3 days following injection 
for shoulder AC patients.  
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
FX006 is an extended-release formulation of triamcinolone acetonide in 75:25 poly 
(lactic-co-glycolic acid) microspheres. FX006 will be supplied as a sterile, white to off-white 
powder in a single unit dose 5 mL vial and reconstituted in 5 mL of a diluent containing an 
isotonic, sterile aqueous solution of sodium chloride (NaCl; 0.9% weight by weight [w/w]) 
carboxymethylcellulose sodium (0.5% w/w), and polysorbate-80 (0.1% w/w) to form a suspension 
prior to IA injection. The placebo is sterile normal saline (NaCl). FX006 or placebo will be 
administered as a 5 mL IA injection into the index glenohumeral joint under ultrasound guidance 
per the injection procedure. 
EFFICACY VARIABLES AND ENDPOINTS:  
The efficacy variables include the average daily shoulder pain with movement (NRS score); the 
Shoulder Pain and Disability Index (SPADI) pain subscale, disability subscale, and total score; 
the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) 
subscales for pain, function, and total; the Patient Global Impression of Change (PGIC) score; 
active and passive ROM; the EuroQol 5 Dimensions 5 Levels questionnaire (EQ-5D-5L); and 
responder status. 
The primary efficacy endpoint for each of the shoulder conditions (glenohumeral OA and shoulder 
AC) in this study is the area under the curve (AUC) of the change from Baseline in the weekly 
mean of the average daily shoulder pain with movement score over 8 weeks for FX006 compared 
to placebo. 
The secondary efficacy endpoints comparing FX006 to placebo for each of the shoulder conditions 
(glenohumeral OA and shoulder AC) in this study include the following: 
• Change from Baseline in the weekly mean of the average daily shoulder pain with movement 
score at Week 12 
• Change from Baseline in the SPADI pain subscale at Week 12 
• Change from Baseline in the SPADI disability subscale at Week 12 
• The PGIC score at Week 12 
• Change from Baseline in the ROM of external rotation at Week 12 
The exploratory efficacy endpoints comparing FX006 to placebo for each of the shoulder 
conditions (glenohumeral OA and shoulder AC) in this study include the following: 
• AUC of change from Baseline in the weekly mean of the average daily shoulder pain with 
movement score over Weeks 4, 12, 16, 20, and 24 


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• AUC of change from Baseline in the SPADI pain subscale over Weeks 4, 8, 12, 16, 20, and 24 
• AUC of change from Baseline in the SPADI disability subscale over Weeks 4, 8, 12, 16, 20, 
and 24 
• Change from Baseline in the weekly mean of the average daily shoulder pain with movement 
score at Weeks 1, 4, 8, 16, 20, and 24 
• Change from Baseline in the SPADI pain subscale at Weeks 1, 4, 8, 16, 20, and 24 
• Change from Baseline in the SPADI disability subscale at Weeks 1, 4, 8, 16, 20, and 24 
• Change from Baseline in the SPADI total score at Weeks 1, 4, 8, 12, 16, 20, and 24 
• The PGIC score at Weeks 1, 4, 8, 16, 20, and 24 
• Change from Baseline in the ROM of external and internal rotation, abduction and flexion at 
Weeks 4, 8, 16, 20, and 24 
• Change from Baseline in the ROM of internal rotation, abduction and flexion at Week 12 
• Change from Baseline in the ASES pain subscale at Weeks 1, 4, 8, 12, 16, 20, and 24 
• Change from Baseline in the ASES disability subscale at Weeks 1, 4, 8, 12, 16, 20, and 24 
• Change from Baseline in the ASES total score at Weeks 1, 4, 8, 12, 16, 20, and 24 
• Percent of responders based on the SPADI at Weeks 1, 4, 8, 12, 16, 20, and 24 
• Proportion of patients experiencing a 20%, 30%, or 50% decrease in the weekly mean of 
the average daily shoulder pain with movement score at Weeks 1, 4, 8, 12, 16, 20, and 24 
• Change from Baseline in average weekly rescue medication use  
• Change from Baseline in the average weekly Sleep Interference score  
• Change from Baseline in the EQ-5D-5L at Weeks 1, 4, 8, 12, 16, 20, and 24 
SAFETY VARIABLES: 
The safety variables include adverse events, physical examinations, index shoulder examinations, 
vital signs, and clinical laboratory evaluations. 
STATISTICAL ANALYSES: 
Data collected in this study will be presented using summary tables, figures, and patient data 
listings. Summary tables will present data by treatment group and, if applicable, by time of 
collection. Continuous variables will be summarized using descriptive statistics, specifically the 
mean, median, standard deviation, minimum, and maximum. Categorical variables will be 
summarized by frequencies and percentages. Figures will be used to support the presentation of 
certain data. Sensitivity analyses may be performed to examine the effect of missing data, as well 
as the effect of Baseline imbalance, should it occur. 
All confidence intervals, statistical tests, and resulting p-values will be reported as 2-sided. 
Multiplicity will be addressed by analyzing the key secondary endpoints sequentially in the order 
presented in the protocol, testing each endpoint at the nominal α = 0.05, 2-sided level to ensure 


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overall type I error control at the 2-sided 0.05 level. Each shoulder condition will be analyzed 
completely separately. In general, the same analysis methods will be used for both shoulder 
conditions. 
For each shoulder condition, the following populations are planned for this study: 
• Full Analysis Set (FAS) Population: All patients who receive a complete dose of study 
medication and have Baseline and at least 1 post-dose efficacy endpoint assessment. The FAS 
Population will be used to examine efficacy for both the primary and secondary endpoints.  
• Safety Population: All patients who receive at least 1 dose of study medication. The Safety 
Population will be used to assess safety and tolerability. 
• Per Protocol Population: All patients in the FAS Population who complete the Week 24 visit 
with no major protocol deviations that may impact the evaluation of the primary efficacy 
endpoint based on blinded data prior to database lock. 
All study analyses will be completed using analysis data sets that are derived from the Study Data 
Tabulation Model and follow the Clinical Data Interchange Standards Consortium Analysis Data 
Model architecture. 
Covariates for efficacy analyses will include Baseline average daily shoulder pain with movement 
score, Baseline score for the endpoint, analysis site, and, for AC patients, pain duration since onset. 
Other covariates may also be explored. 
SAMPLE SIZE DETERMINATION: 
Approximately 250 patients will be randomized in a 1:1 ratio to either FX006 or placebo 
(approximately 136 patients with glenohumeral OA and approximately 114 patients with shoulder 
AC). Sample sizes were estimated to yield a statistically significant difference (α = 0.05, 2-sided) 
between the FX006 and placebo groups in the average daily shoulder pain with movement score 
at Week 12 (the first secondary endpoint for each shoulder condition). For glenohumeral OA, the 
true difference between the groups was assumed to be 1, with a standard deviation of 2, based on 
data observed in knee OA studies of FX006 and taking into consideration the clinical significance 
of a 1-point difference between the treatment groups. For shoulder AC, the true difference between 
the groups was assumed to be 1.2, with a standard deviation of 2.1, based on a review of the 
existing literature. The primary endpoint analyzing the AUC for the weekly mean of the average 
daily shoulder pain with movement score over 8 weeks should, therefore, have >80% power to 
show a significant difference between the FX006 and placebo groups. As the 2 shoulder conditions 
(glenohumeral OA and shoulder AC) are combined into 1 protocol strictly for ease of 
administration, all statistical testing will be performed separately for each shoulder condition and 
the overall type I error rate will be controlled at the α = 0.05 level within each shoulder condition. 
For each shoulder condition, a blinded interim analysis will occur when approximately 50% of the 
patients have completed Week 8 to determine the need for a potential adjustment to the sample 
sizes. Prior data suggest the standard deviation of the primary endpoint could range from 2 to 2.5. 
Therefore, the interim analyses will enable a sample size increase up to 150 in each shoulder 
condition to ensure the desired statistical power is obtained. 
SITES:  Approximately 35 study sites in the United States 


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SPONSOR: 
Flexion Therapeutics, Inc. 
10 Mall Road, Suite 301 
Burlington, MA 01803 
United States of America 
Telephone: 781-305-7777 


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TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents ............................................................................................................................ 9 
List of Tables ................................................................................................................................ 14 
List of Figures ............................................................................................................................... 15 
List of Abbreviations and Definition of Terms............................................................................. 16 
1 Introduction and Background Information ............................................................................. 18 
 
Rationale ........................................................................................................................ 18 
 
Overview of Nonclinical Studies with FX006 .............................................................. 18 
 
Overview of Clinical Studies with FX006 .................................................................... 19 
1.3.1 Systemic and Local Pharmacokinetics in Patients with Osteoarthritis of the 
Knee and Shoulder ............................................................................................ 19 
1.3.2 Pharmacodynamics in Patients with Osteoarthritis of the Knee ....................... 19 
1.3.3 Efficacy in Patients with Osteoarthritis of the Knee ......................................... 19 
1.3.4 Systemic and Local Safety in Patients with Osteoarthritis of the Knee ............ 20 
 
Risk/Benefit ................................................................................................................... 20 
2 Study Objectives ..................................................................................................................... 22 
 
Primary Objective ......................................................................................................... 22 
 
Secondary Objectives .................................................................................................... 22 
 
Exploratory Objectives .................................................................................................. 22 
3 Study Description.................................................................................................................... 23 
 
Summary of Study Design ............................................................................................ 23 
 
Study Indications ........................................................................................................... 24 
4 Selection and Withdrawal of Patients ..................................................................................... 25 
 
Inclusion Criteria ........................................................................................................... 25 
 
Exclusion Criteria .......................................................................................................... 26 
 
Withdrawal Criteria ....................................................................................................... 29 
4.3.1 Lost to Follow-Up ............................................................................................. 29 
4.3.2 Termination of Study ........................................................................................ 30 
4.3.3 Screening Failures ............................................................................................. 30 


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5 Study Treatments .................................................................................................................... 31 
 
Treatment Groups .......................................................................................................... 31 
 
Rationale for Dosing ..................................................................................................... 31 
 
Randomization and Blinding ......................................................................................... 31 
 
Breaking the Blind ........................................................................................................ 33 
 
Drug Supplies ................................................................................................................ 34 
5.5.1 Formulation and Packaging ............................................................................... 34 
5.5.2 Study Medication Preparation and Dispensing ................................................. 34 
5.5.3 Study Medication Administration ..................................................................... 34 
5.5.3.1 Index shoulder aspiration .................................................................... 35 
5.5.4 Treatment Compliance ...................................................................................... 35 
5.5.5 Storage and Accountability ............................................................................... 35 
5.5.6 Rescue Medication ............................................................................................ 35 
 
Prior and Concomitant Medications and/or Procedures ................................................ 36 
5.6.1 Excluded Medications and/or Procedures ......................................................... 36 
5.6.2 Restricted Medications and/or Procedures ........................................................ 37 
5.6.3 Allowed Medications and/or Procedures .......................................................... 37 
5.6.4 Documentation of Prior and Concomitant Medication Use .............................. 37 
6 Study Procedures .................................................................................................................... 38 
 
Informed Consent .......................................................................................................... 38 
 
Order of Questionnaires and Electronic Diary Entries .................................................. 38 
 
Screening Visit (Days -21 to -1) ................................................................................... 38 
 
Treatment Visit (Day 1) ................................................................................................ 39 
 
Treatment Evaluation Period (Weeks 1 to 24) .............................................................. 40 
6.5.1 Weeks 1 to 20 .................................................................................................... 40 
6.5.2 Week 24 (End of Study Visit) ........................................................................... 41 
 
Early Termination Visit and Withdrawal Procedures ................................................... 41 
7 Efficacy Assessments.............................................................................................................. 42 
 
Efficacy Endpoints ........................................................................................................ 42 
7.1.1 Primary Efficacy Endpoint ................................................................................ 42 
7.1.2 Secondary Efficacy Endpoints .......................................................................... 42 
7.1.3 Exploratory Efficacy Endpoints ........................................................................ 42 


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Efficacy Assessments .................................................................................................... 43 
7.2.1 Shoulder Pain with Movement Score ................................................................ 43 
7.2.2 Shoulder Pain and Disability Index ................................................................... 43 
7.2.3 American Shoulder and Elbow Surgeons Standardized Shoulder Assessment 
Form………………………………………………………………………….43 
7.2.4 Patient Global Impression of Change ................................................................ 43 
7.2.5 Active and Passive Ranges of Motion ............................................................... 43 
7.2.6 EuroQol 5 Dimensions 5 Levels Questionnaire ................................................ 43 
7.2.7 Responder Status ............................................................................................... 44 
7.2.8 Daily Sleep Interference Score .......................................................................... 44 
8 Safety Assessments ................................................................................................................. 45 
 
Adverse Events .............................................................................................................. 45 
8.1.1 Assessment of Adverse Events by the Investigator .......................................... 45 
 
Serious Adverse Events ................................................................................................. 47 
 
Serious Adverse Event Reporting − Procedures for Investigators ................................ 48 
 
Clinical Management of Index Shoulder-Related Events ............................................. 48 
 
Pregnancy Reporting ..................................................................................................... 49 
 
Expedited Reporting ...................................................................................................... 49 
 
Reporting Arthralgia in the Index Shoulder .................................................................. 49 
 
Clinical Laboratory Evaluations .................................................................................... 50 
 
Vital Signs ..................................................................................................................... 50 
 Height, Weight, and Body Mass Index Determination ................................................. 50 
 Physical Examinations .................................................................................................. 51 
 Electrocardiograms ........................................................................................................ 51 
 Index Shoulder Assessment .......................................................................................... 51 
 Placebo Response Reduction and Accurate Pain Reporting Trainings ......................... 51 
8.14.1 Placebo Response Reduction Training .............................................................. 51 
8.14.2 Accurate Pain Reporting Training ..................................................................... 52 
9 Statistics .................................................................................................................................. 53 
 
General Considerations and Methods ........................................................................... 53 
9.1.1 Demographics and Baseline Characteristics ..................................................... 53 
9.1.2 Exposure ............................................................................................................ 53 
 
Study Data ..................................................................................................................... 53 


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9.2.1 Clinical Data – Clinical Data Interchange Standards Consortium Study Data 
Tabulation Model .............................................................................................. 53 
9.2.2 Analysis Data – Clinical Data Interchange Standards Consortium Analysis 
Data Model ........................................................................................................ 54 
 
Analysis Populations ..................................................................................................... 54 
 
Statistical Methods ........................................................................................................ 54 
9.4.1 Analysis of Efficacy .......................................................................................... 54 
9.4.1.1 Primary efficacy analyses ................................................................... 54 
9.4.1.2 Secondary efficacy analyses ............................................................... 54 
9.4.1.3 Exploratory efficacy analyses ............................................................. 55 
9.4.2 Analysis of Safety ............................................................................................. 55 
9.4.2.1 Analysis of adverse events .................................................................. 55 
9.4.2.2 Other safety analyses .......................................................................... 55 
9.4.3 Interim Analyses ............................................................................................... 55 
9.4.4 Final Analyses ................................................................................................... 55 
9.4.5 Subgroups and Covariates ................................................................................. 55 
9.4.6 Sample Size Determination ............................................................................... 56 
10 Data Management and Record Keeping ................................................................................. 57 
 Data Management ......................................................................................................... 57 
10.1.1 Data Handling ................................................................................................... 57 
10.1.2 Computer Systems ............................................................................................. 57 
10.1.3 Data Entry ......................................................................................................... 57 
10.1.4 Medical Information Coding ............................................................................. 57 
10.1.5 Data Validation ................................................................................................. 57 
 Record Keeping ............................................................................................................. 57 
 End of Study Definition ................................................................................................ 58 
11 Investigator Requirements and Quality Control ..................................................................... 59 
 Ethical Conduct of the Study ........................................................................................ 59 
 Institutional Review Board ............................................................................................ 59 
 Informed Consent .......................................................................................................... 59 
 Study Monitoring Requirements ................................................................................... 59 
 Disclosure of Data ......................................................................................................... 60 
 Retention of Records ..................................................................................................... 60 


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 Study and Site Start and Closure ................................................................................... 60 
 Publication Policy ......................................................................................................... 61 
 Regulatory and Ethical Considerations ......................................................................... 61 
 Financial Disclosure ...................................................................................................... 62 
 Data Protection .............................................................................................................. 62 
 Insurance and Indemnity ............................................................................................... 62 
 Legal Aspects ................................................................................................................ 62 
12 Study Administrative Information .......................................................................................... 63 
 Protocol Amendments ................................................................................................... 63 
13 References ............................................................................................................................... 64 
Appendix A:  Schedule of Procedures .......................................................................................... 66 
Appendix B:  Clinical Laboratory Analytes ................................................................................. 71 
Appendix C:  Home Exercise Program for Patients With Shoulder Adhesive Capsulitis ............ 72 
Appendix D:  Instructions for Measuring Range of Motion of the Glenohumeral Joint With a 
Goniometer ............................................................................................................................. 75 
Appendix E:  Commonly Prescribed Antidepressants by Drug Class .......................................... 77 


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LIST OF TABLES 
Table 1. 
Schedule of Procedures ............................................................................................... 66 
Table 2. 
Entries to be Completed Daily by the Patient on the Electronic Diary ...................... 70 
Table 3.  Questionnaires to be Completed by the Patient at Study Site Visits .......................... 70 


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LIST OF FIGURES 
Figure 1. Study Flow Chart ........................................................................................................ 23 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
21 CFR 
Title 21 of the Code of Federal Regulations 
AC 
Adhesive capsulitis 
APR 
Accurate Pain Reporting 
ASES 
American Shoulder and Elbow Surgeons Standardized Shoulder 
Assessment Form 
AUC 
Area under the curve 
BMI 
Body mass index 
CDISC 
Clinical Data Interchange Standards Consortium 
CGIC 
Clinical Global Impression of Change 
CIs 
Confidence intervals 
CMC 
Carboxymethylcellulose sodium 
CRA 
Clinical research associate 
CSR 
Clinical Study Report 
CTA 
Clinical trial authorization 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eDiary 
Electronic diary 
EOS 
End of Study 
EQ-5D-5L 
EuroQol 5 Dimensions 5 Levels questionnaire 
ET 
Early Termination 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GAD-7 
General Anxiety Disorder 7-item scale 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen  
HCV 
Hepatitis C virus 
HEP 
Home Exercise Program 
HIV 
Human immunodeficiency virus  
IA 
Intra-articular 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IM 
Intramuscular 
IRB 
Institutional Review Board 
ISI 
Insomnia Severity Index 
IV 
Intravenous 


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Abbreviation 
Definition 
IxRS 
Interactive voice/web response system 
KOOS 
Knee Injury and Osteoarthritis Outcome Score 
LSM 
Least square mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NaCl 
Sodium chloride 
NRS 
Numeric rating scale 
NSAID 
Nonsteroidal anti-inflammatory drug 
OA 
Osteoarthritis 
PCS 
Pain Catastrophizing Scale 
PD-Q 
painDETECT Questionnaire 
PGIC 
Patient Global Impression of Change 
PHQ-9 
Patient Health Questionnaire-9 
PK 
Pharmacokinetic(s) 
PLGA 
Poly(lactic-co-glycol acid) 
PRP 
Platelet rich plasma 
PRR 
Placebo Response Reduction 
QOL 
Quality of Life 
ROM 
Ranges of motion 
SAE 
Serious adverse event  
SAP 
Statistical Analysis Plan 
SDTM 
Study Data Tabulation Model 
SI 
Sleep Interference 
SPADI 
Shoulder Pain and Disability Index 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TA 
Triamcinolone acetonide 
TAcs 
Triamcinolone acetonide injectable suspension, immediate-release 
TEAE 
Treatment-emergent adverse event 
TENS 
Transcutaneous electrical nerve stimulation  
USP 
United States Pharmacopeia 
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 
w/w 
Weight by weight 


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1 
INTRODUCTION AND BACKGROUND INFORMATION  
FX006 is an extended-release formulation of triamcinolone acetonide (TA) for intra-articular (IA) 
administration. It is approved in the United States under the trade name ZILRETTA® 
(TA extended-release injectable suspension) for the management of pain of osteoarthritis (OA) of 
the knee. FX006 is intended to deliver TA to the synovial and perisynovial tissues for a period of 
approximately 3 months.1 FX006 contains TA, United States Pharmacopeia (USP), formulated in 
75:25 poly(lactic-co-glycolic acid) (PLGA) microspheres with a nominal drug load of 25% 
(weight by weight [w/w]) and is provided as a sterile white to off-white powder for reconstitution. 
The drug product is reconstituted with diluent containing an isotonic, sterile aqueous solution of 
sodium chloride (NaCl; 0.9% w/w), carboxymethylcellulose sodium (CMC; 0.5% w/w), and 
polysorbate-80 (0.1% w/w) to form a suspension prior to IA injection. 
Further details of the physiochemical properties of FX006 can be found in the Investigator’s 
Brochure (IB).2 
 
Rationale 
Results of the primary endpoint from the Phase 3, multicenter, adequate, and well-controlled trial 
on pain secondary to OA of the knee showed that patients treated with 32 mg FX006 had a rapid, 
durable, and meaningful analgesic response that was statistically significantly better than placebo 
treated patients (p<0.0001). This finding was supported by a second, smaller Phase 2b study, where 
a highly similar pattern of response to 32 mg FX006 was demonstrated.3,4,5 Thus, one aspect of the 
current clinical development program focuses on evaluating the potential therapeutic effects of 
FX006 on pain in patients with OA of the shoulder where conventional steroid IA injection shows 
short-lived efficacy in shoulder OA patients,6 consistent with the efficacy observed in knee OA.7,8 
Likewise, FX006 is anticipated to have efficacy in the relief of pain due to OA in the synovial 
shoulder joint as it shares similar pathogenesis to knee OA.  
Shoulder adhesive capsulitis (AC) is a common painful and disabling disorder. The exact etiology 
is unknown, though the incidence is higher among patients with diabetes than observed in the 
general population. The disease pathogenesis is characterized by early synovial inflammation, 
hyperplasia, and hypervascularity, as well as fibroblastic proliferation and fibrosis in the late 
phase.9 Patients present with severe pain, limited ranges of motion (ROM), and frozen shoulder. 
Some patients end up with spontaneous recovery within 2 to 3 years, but up to 40% of patients 
may experience persistent symptoms with 7% to 15% having some degree of permanent functional 
loss.10 Intra-articular corticosteroid injection shows short-lived pain relief with a prolonged effect 
on passive ROM.11 It is hypothesized that an extended-release formulation of corticosteroid would 
provide long-lasting pain relief and functional improvement for patients with shoulder AC. 
The glenohumeral joint is a large synovial joint. The injection volume of FX006 (5 mL) is believed 
to be appropriate as such a volume has been routinely used in the combination of conventional 
corticosteroid with lidocaine. 
 
Overview of Nonclinical Studies with FX006 
Overall, toxicology studies showed that single or repeat IA administration of FX006 at the 
proposed clinical dose of 32 mg had no new safety liabilities compared to triamcinolone acetonide 
injectable suspension, immediate-release (TAcs), in healthy animals. 


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Information available for TA from the literature, corticosteroid product labels, and clinical 
experience suggests that the potential of genetic toxicity, reproductive toxicity, and carcinogenicity 
of TA is well understood. Similarly, the biocompatibility and local safety of PLGA microspheres 
and genotoxic, reproductive toxicological, and carcinogenic potential of PLGA have been 
described in a combination of literature and product information packages. Therefore, no new risks 
relative to TAcs are presented by FX006 as intended for use. 
Further details of the nonclinical studies with FX006 can be found in the IB.2 
 
Overview of Clinical Studies with FX006 
1.3.1 
Systemic and Local Pharmacokinetics in Patients with Osteoarthritis of the Knee and 
Shoulder 
Overall, FX006 displayed a favorable plasma pharmacokinetic (PK) profile relative to that of 
TAcs. Pharmacokinetic observations resulted in a controlled and stable release of TA from PLGA 
microspheres into synovial tissues, where concentrations remained high relative to plasma 
concentrations for at least 12 weeks. Triamcinolone acetonide was absorbed systemically, with a 
plateau in plasma TA concentrations occurring in the first 24 hours post-dose, and slow elimination 
from the systemic circulation observed in the weeks thereafter.1,12  
Relative to TAcs, 32 mg FX006 produced substantially lower peak plasma concentrations. FX006 
performed as expected, prolonging the residence of TA in the knee joint while minimizing 
systemic peak exposure to TA. Similarly, the FX006 plasma PK profile in shoulder OA patients 
following IA administration was comparable to the plasma PK profile in knee OA patients. 
1.3.2 
Pharmacodynamics in Patients with Osteoarthritis of the Knee 
In a Phase 2 PK/pharmacodynamics study evaluating 3 dose levels of FX006 (10 mg, 40 mg, and 
60 mg) administered as a 3 mL injection, suppression of cortisol in the days following injection 
produced by the 10 mg and 40 mg doses of FX006 was less than that produced by injection of 
TAcs; the 60 mg dose of FX006 produced effects similar to 40 mg TAcs. Cortisol 
suppression subsequent to Days 1 to 2 associated with all doses of FX006 would not be expected 
to be of clinical consequence in adult patients without otherwise compromised 
hypothalamic-pituitary-adrenal axis function. In a Phase 2 study in diabetic patients with knee OA, 
treatment with 32 mg FX006 resulted in a statistically significant (p=0.0452) reduction in blood 
glucose elevation relative to TAcs over a 72-hour period following IA injection. The time in 
glycemic target range (70 to 180 mg/dL)13 was greater for FX006 as compared to TAcs over the 
48 hours post-IA injection, providing another indication of the improvement in glycemic control. 
This observation is consistent with PK studies demonstrating low systemic maximum plasma 
concentration for TA associated with FX006. 
1.3.3 
Efficacy in Patients with Osteoarthritis of the Knee 
Efficacy data from 3 studies provide substantial evidence supporting the effectiveness of 32 mg 
FX006 in the management of OA pain.3,4,5 Results of the primary endpoint from the Phase 3, 
multicenter, adequate, and well-controlled study showed that patients treated with 32 mg FX006 
had a rapid, durable, and meaningful analgesic response that was significantly better than 


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placebo-treated patients (p<0.0001). This finding was supported by a second smaller Phase 2b 
study where a highly similar pattern of response to 32 mg FX006 was demonstrated. 
Robustness of the primary outcome in the Phase 3 study was further supported by the internal 
consistency demonstrated in favor of 32 mg FX006 through secondary analyses utilizing the 
primary outcome data (average daily pain) to evaluate durability and magnitude of response. These 
included least square mean (LSM) testing at each week and area under the effect curve analyses 
for Weeks 1 through 12 and Weeks 1 through 24. Results demonstrated that the analgesic effect 
of 32 mg FX006 was significant at Week 1, increased through Week 7, and was sustained through 
at least Week 16. Responder analyses further suggested that FX006 provided clinically relevant 
improvement from Weeks 1 through 16 relative to placebo. 
Analyses utilizing data collected from other instruments or measures (i.e., Western Ontario and 
McMaster Universities Osteoarthritis Index [WOMAC], Patient Global Impression of 
Change [PGIC], Clinical Global Impression of Change [CGIC], and Knee Injury and Osteoarthritis 
Outcome Score [KOOS] Quality of Life [QOL]) provided additional insight into the effects on 
pain relief, as well as physical function and global well-being. At 32 mg, FX006 provided clinically 
relevant improvement relative to placebo through Week 12 for WOMAC and KOOS QOL and 
through at least Week 16 for PGIC and CGIC. Additionally, a significant reduction in rescue 
medication utilization in patients treated with 32 mg FX006 was of potential important clinical 
consequence and added a meaningful element to the overall effectiveness profile of 32 mg FX006. 
Collectively, these results provide substantial evidence to support 32 mg FX006 as an effective 
therapy for the management of OA knee pain. 
1.3.4 
Systemic and Local Safety in Patients with Osteoarthritis of the Knee 
The evaluation of 934 patients treated with a single or repeat IA injection(s) of FX006 at any dose 
in FX006 clinical studies suggested that it was well tolerated with systemic and local safety profiles 
similar to those of TAcs and placebo. In the Phase 3 study, qualitative assessments based on X-rays 
of the index knee at Baseline and 24 weeks post injection, including joint space narrowing, 
subchondral bone changes, osteonecrosis, and insufficiency fracture,5 showed no differences 
between the FX006, TAcs, and placebo groups. In the FX006 repeat dosing study, qualitative 
X-ray showed no clinically meaningful joint structure differences from Baseline up to 52 weeks 
post injection. 
 
Risk/Benefit 
FX006, an extended-release microsphere formulation of TA, demonstrated a comparable safety 
profile to TAcs in animals after single or repeated IA administration. Much lower peak plasma 
levels and much longer duration than TAcs after IA injection in knee OA patients contributed to a 
better systemic safety profile, as evidenced by decreased duration and magnitude in hyperglycemia 
of diabetic patients. Furthermore, FX006 demonstrated comparable local joint safety as compared 
to TAcs in patients with knee OA. Larger magnitude and longer duration of efficacy was observed 
with FX006 compared to TAcs, as demonstrated by WOMAC pain and function scores. Given the 
insufficient symptomatic management of glenohumeral OA and similar pathogenesis between 
knee and glenohumeral OA, it is anticipated that FX006 will provide a favorable risk/benefit 
profile to glenohumeral OA patients.  
Adhesive capsulitis is another painful shoulder condition that is commonly managed by IA 
conventional corticosteroids with short duration of pain relief but greater improvement in passive 


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ROM in both the short and long terms. Thus, it is hypothesized that an extended-release 
formulation of TA will provide meaningful benefits in both pain relief and functional improvement 
for patients with shoulder AC. 


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2 
STUDY OBJECTIVES 
 
Primary Objective 
The primary objective of this study is to assess the efficacy of FX006 on pain following an IA 
injection in patients with glenohumeral OA or shoulder AC. 
 
Secondary Objectives 
The secondary objectives of this study are the following: 
• To assess the efficacy of FX006 on pain, disability, function, and global impression of change 
in patients with glenohumeral OA or shoulder AC  
• To assess the safety of FX006 in patients with glenohumeral OA or shoulder AC 
 
Exploratory Objectives 
The exploratory objectives of this study are to assess additional measures of pain, disability, 
function, QOL, rescue medication consumption, and proportion of responders at varying 
timepoints over the course of the study. 
 


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3 
STUDY DESCRIPTION 
 
Summary of Study Design 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group study 
designed to evaluate the efficacy and safety of a single IA injection of either 5 mL of the 
reconstituted FX006 (32 mg) or 5 mL of placebo (sterile normal saline) in separate cohorts of 
patients with a documented history of glenohumeral OA or shoulder AC. 
This study will be conducted at approximately 35 study sites in the United States. Patients will be 
screened to confirm the diagnosis of OA or AC and eligibility based on the Inclusion and Exclusion 
Criteria. Eligible patients will be randomized to treatment on Day 1. Glenohumeral OA patients 
will be stratified by the Baseline average daily shoulder pain with movement score (0 to 
10 numeric rating scale [NRS]) (5.0 to <7.0 or 7.0 to 9.0). Shoulder AC patients will be stratified 
by the Baseline average daily shoulder pain with movement score (0 to 10 NRS) (5.0 to <7.0 or 
7.0 to 9.0), and pain duration since onset at Screening (1 to 3 months, inclusive, or >3 to 
6 months). 
Approximately 250 male or female patients, 35 to 80 years of age, inclusive (approximately 
136 glenohumeral OA patients and approximately 114 shoulder AC patients), will be enrolled in 
this study. The study duration is approximately 27 weeks, including a Screening Period of up to a 
maximum of 3 weeks and treatment on Day 1 followed by a 24-week Treatment Evaluation Period. 
The study design can be seen in Figure 1. 
Figure 1. Study Flow Chart 
AC = adhesive capsulitis; D = Day; EOS = End of Study; HEP = Home Exercise Program; OA = osteoarthritis; W = Week. 
For each shoulder condition, a blinded interim analysis will occur when approximately 50% of the 
patients have completed Week 8 to determine the need for potential adjustment to sample sizes. 
All final analyses will be completed following database lock once all patients complete Week 24. 
The study will involve a Screening Period (up to a maximum of 21 days), dosing on Day 1, and 
7 additional study site visits: during Week 1, and then every 4 weeks (Weeks 4, 8, 12, 16, 20, 
and 24) through Week 24. 


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At the times specified in Table 1, patients will undergo physical examinations, index shoulder 
assessments, and index shoulder X-rays; blood will be collected for clinical laboratory tests; and 
vital signs will be collected. A Home Exercise Program (HEP) will be implemented 3 days 
following injection for shoulder AC patients (see Appendix C). 
Information regarding adverse events and concomitant medications will be collected. Information 
regarding rescue medication usage, average daily shoulder pain with movement score, Sleep 
Interference (SI), and HEP compliance will be completed daily via an electronic diary (eDiary) 
and at each study site visit. At the Screening Visit, patients will be registered in the eDiary and 
receive instructions on its use. Questionnaires to be completed daily by the patient in the eDiary 
must follow the order defined in Table 2. 
Patients will complete the Accurate Pain Reporting (APR) and Placebo Response Reduction (PRR) 
trainings prior to completing the PainDETECT Questionnaire (PD-Q), Patient Health 
Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder 7-item scale (GAD-7), Pain 
Catastrophizing Scale (PCS), Insomnia Severity Index (ISI), EuroQol 5 Dimensions 5 Levels 
questionnaire (EQ-5D-5L), Shoulder Pain and Disability Index (SPADI) questionnaire, American 
Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), and PGIC 
questionnaire per the visit schedule in Table 3. Questionnaires competed at study site visits must 
follow the order defined in Table 3. 
 
Study Indications 
There are 2 shoulder conditions included in the study: shoulder pain due to glenohumeral OA and 
shoulder pain due to AC. 


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4 
SELECTION AND WITHDRAWAL OF PATIENTS  
 
Inclusion Criteria 
A patient who meets all of the following criteria will be eligible to participate in the study: 
1. Has 1 of the following diagnoses (can be diagnosed at the Screening Visit) and meets the 
following criteria: 
a. Glenohumeral OA: 
o Male or female, 35 to 80 years of age, inclusive, on the day of consent. 
o Painful symptoms associated with OA of the index glenohumeral joint for 3 months prior 
to the Screening Visit. 
o Grade 2 or 3 OA in the index glenohumeral joint based on the Samilson-Prieto 
classification system as confirmed by X-ray (axillary view and true anterior-posterior view) 
taken at the Screening Visit or within 6 weeks of the Screening Visit. 
b. Shoulder AC: 
o Male or female, 35 to 80 years of age, inclusive, on the day of consent. 
o Pain associated with AC of the index joint for 1 month but 6 months prior to the 
Screening Visit. 
o More than 20% (25% if dominant shoulder is the index shoulder) loss of passive range of 
the rotation arc (external and internal rotation) of glenohumeral movement, measured with 
the patient in supine or sitting position and the shoulder elevated to 45 degrees, compared 
with the contralateral shoulder. 
o No X-ray evidence of OA of the index shoulder (axillary view and true anterior-posterior 
view) at the Screening Visit or within 6 weeks of the Screening Visit. 
2. Is willing and able to sign the informed consent form (ICF), indicating that the patient 
understands the purpose of the study and procedures required for the study before the initiation 
of any study-specific procedures. Patients who are unable to provide informed consent will not 
be included in the study. 
3. Is willing and able to comply with the study procedures and visit schedules and able to follow 
verbal and written instructions. 
4. Has a body mass index (BMI) 40 kg/m2. 
5. Has an average daily mean shoulder pain with movement score 5.0 and 9.0 in the index 
shoulder (0 to 10 NRS) using the average daily ratings for at least 5 out of the 7 days prior to 
Day 1. 
Note: The required mean average daily shoulder pain with movement score will not be 
disclosed to the patient.  
6. Has shoulder pain present >15 days in the month prior to the Screening Visit. 
7. Is willing to complete a washout of protocol-specified excluded medications 7 days prior to 
Day 1 and abstain from use of protocol-specified excluded medications throughout the study 
(see Section 5.6.1). 


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8. Is willing to abstain from nonpharmacological therapies (e.g., physical therapy, acupuncture, 
transcutaneous electrical nerve stimulation (TENS), or bracing) for the index joint for 2 weeks 
prior to Day 1 and throughout the study. 
9. Shoulder AC patients only: Agrees to complete a standardized, protocol-specified shoulder 
HEP starting 3 days after injection until the End of Study (EOS) Visit. 
10. Sexually active males or females of childbearing potential (defined as not surgically sterile or 
postmenopausal [defined as 12 consecutive months with no menses without an alternative 
medical cause] for at least 1 year as documented in medical history)  must agree to use 1 of the 
following highly effective methods of contraception: abstinence; oral, injected, or implanted 
hormonal methods of contraception; intrauterine device or intrauterine system; 
condom or occlusive 
cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/suppository; or monogamous intercourse with a partner who is surgically 
sterile (post-vasectomy, post-hysterectomy, or tubal ligation). Such contraceptive measures 
should be used throughout the duration of the study.  
 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from participation in the study: 
1. Is unable to washout from excluded (see Section 5.6.1) or restricted medications (see 
Section 5.6.2). 
2. Has both glenohumeral OA and shoulder AC. 
3. Has bilateral AC. 
4. Has bilateral glenohumeral OA with glenohumeral OA pain of the shoulder contralateral to the 
index shoulder >3.0 (0 to 10 NRS) within 1 month prior to the Screening Visit (patient 
self-report acceptable). 
5. Has a history of symptomatic arthritis in other joints of the index shoulder (e.g., 
acromioclavicular joint or scapulothoracic joint), as confirmed by medical history and physical 
examination. 
6. Has a history or suspicion of full thickness rotator cuff tear in the index shoulder as assessed 
by the Investigator per medical history and physical examination, ultrasound, or magnetic 
resonance imaging (MRI) obtained within 6 months of the Screening Visit. 
7. Has symptomatic partial rotator cuff tear, tendinopathy, tendonitis, or bursitis in the index 
shoulder as assessed by Investigator per medical history and physical examination, ultrasound, 
or MRI obtained within 6 months of the Screening Visit. 
8. Has a subchondral bone insufficiency fracture or humeral head necrosis/collapse in the index 
shoulder based on X-ray used for study qualification. 
9. Shoulder AC patients only: Has a history of shoulder surgery in the index shoulder or 
radiotherapy (e.g., for breast, neck, or upper limb tumors). 
10. Glenohumeral OA patients only: Has a previous shoulder injury in the index shoulder with 
functional limitation 1 month (e.g., dislocation or fracture) or surgery in the index shoulder 
(including clavicle or scapula) within 52 weeks prior to the Screening Visit. 


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11. Has an index shoulder with major dysplasia or congenital abnormality, osteochondritis 
dissecans, 
acromegaly, 
ochronosis, 
hemochromatosis, 
Wilson’s 
disease, 
primary 
osteochondromatosis, or a history of avascular necrosis with secondary OA. 
12. Has current or history of infection (e.g., osteomyelitis) in the index shoulder or current skin 
infection at injection site. 
13. Has any concurrent chronic pain condition with a pain score >3.0 (0 to 10 NRS) within 1 month 
prior to the Screening Visit (patient self-report acceptable), including but not limited to, 
cervical spine conditions causing radicular pain or peripheral nerve injury/entrapment 
(e.g., brachial plexus injury or suprascapular nerve entrapment) that may affect sensation of 
the index shoulder; diabetic neuropathy; post-herpetic neuralgia; post-stroke pain; or 
fibromyalgia. 
14. Has a PD-Q score >18 during the Screening Visit. 
15. Has a history or current evidence of reactive arthritis, rheumatoid arthritis, psoriatic arthritis, 
ankylosing spondylitis, or arthritis associated with inflammatory bowel disease, systemic lupus 
erythematosus, calcium pyrophosphate dihydrate crystal deposition disease (CPPD) or other 
autoimmune diseases. 
16. Has any planned surgeries in the upper limbs during the study or any other surgery during the 
study that would require use of a restricted medication. 
17. Has surgical hardware or other foreign body present in the index shoulder. 
18. Has received an IA corticosteroid of any joint within 3 months of the Screening Visit 
(investigational or marketed, including FX006). 
19. Has received an IA treatment of the index shoulder with any of the following agents within 
6 months of the Screening Visit: any biologic agent (e.g., platelet rich plasma [PRP] injection, 
stem cells, prolotherapy, or amniotic fluid injection; investigational or marketed) or hyaluronic 
acid. 
20. Has received intravenous (IV), intrabursal, intratendinous, intramuscular (IM), or epidural 
corticosteroids (investigational or marketed) within 3 months of the Screening Visit.    
21. Has received oral corticosteroids (investigational or marketed) within 1 month of the 
Screening Visit. 
22. Has received inhaled, intranasal, or topical corticosteroids (investigational or marketed) within 
2 weeks of the Screening Visit. 
23. Has significant changes with regard to physical activity and lifestyle, within 1 month of the 
Screening Visit or any planned changes throughout the duration of the study. 
24. Has a total score 15 or score >0 on question #9 on the PHQ-9 at the Screening Visit. 
25. Has a score 15 on the GAD-7 at the Screening Visit. 
26. Has a clinically relevant level of pain catastrophizing, defined as a PCS score 30 at the 
Screening Visit. 
27. Has an ISI questionnaire score 15 (moderate severity) at the Screening Visit. 
28. Has known hypersensitivity to TA orPLGA. 


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29. Has laboratory evidence of infection with human immunodeficiency virus (HIV), a positive 
test for hepatitis B surface antigen (HBsAg), or positive serology for hepatitis C virus (HCV) 
with positive test for HCV ribonucleic acid. 
30. Has an electrocardiogram (ECG) abnormality judged clinically significant by the Investigator.  
31. Has a medical history suggesting the patient will or is likely to require a course of systemic 
corticosteroids during the study. 
32. Has uncontrolled diabetes as indicated by a hemoglobin A1c of >8% (>59 mmol/mol). 
33. Has a history or evidence of active or latent systemic fungal or mycobacterial infection 
(including tuberculosis), or of ocular herpes simplex. 
34. Has a history of sarcoidosis or amyloidosis. 
35. Has a history of or active Cushing’s syndrome. 
36. Has used chemotherapeutic agents, immunomodulators, or immunosuppressants other than 
corticosteroids within 5 years of the Screening Visit.  
Note: Restrictions pertinent to corticosteroid use specified in Exclusion Criteria 18, 20, 21, 
and 22. 
37. Has current or history of malignancy within 5 years prior to the Screening Visit, except for 
basal or squamous cell carcinoma of the skin or cervical carcinoma in situ that has been treated 
successfully. 
38. Has active substance use disorder (drugs or alcohol) or history of substance use disorder within 
12 months prior to the Screening Visit as per The Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition. 
39. Has received a live (e.g., measles, mumps, and rubella vaccine; chicken pox vaccine; or 
rotavirus vaccine) or live-attenuated vaccine (e.g., FluMist® or Zostavax®) within 3 months of 
the Screening Visit. 
40. Has used any other investigational drug, biologic, or device within 3 months of the 
Screening Visit. 
41. Has any infection requiring IV antibiotics 4 weeks prior to Day 1 or oral antibiotics 2 weeks 
prior to Day 1. 
42. Has any other clinically significant acute or chronic medical condition(s) that, in the judgment 
of the Investigator, would preclude the use of an IA corticosteroid or that could compromise 
patient safety, limit the patient’s ability to complete the study, and/or compromise the 
objectives of the study. 
43. Has a contraindication to the use of acetaminophen (allowed rescue pain medicine) per 
National Product Labeling and the Investigator's judgment. 
44. Is the Investigator or any sub-Investigator, research assistant, pharmacist, study coordinator, 
other staff, or relative thereof directly involved in the conduct of the study. 
45. Is a female that is pregnant or nursing or plans to become pregnant during the study; or is a 
male who plans to inseminate a partner or donate sperm during the study. 


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Withdrawal Criteria 
If a patient withdraws, he/she should continue to be followed for safety assessments up to 24 weeks 
after treatment. A patient may withdraw from the study at any time for any reason, without any 
consequences. In addition, a patient may be withdrawn from the study for the following reasons: 
• Adverse event (typically a serious adverse event [SAE]) 
• Patient choice (withdrawal of consent, Investigator will attempt to ascertain reason) 
• Protocol violation/noncompliance 
• Lack of efficacy (lack of expected or desired effect related to a therapy) 
• Physician decision (a position, opinion, or judgment reached after consideration by a physician 
with reference to the patient) 
• Progressive disease (a disease process that is increasing in extent or severity)  
• Study terminated by Sponsor 
• Technical problem (a problem with some technical aspect of a clinical study, usually related 
to an injection) 
• Other 
If a patient withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the study site records. 
If a patient withdraws prematurely from the study due to the above criteria or any other reason, 
study staff should make every effort to complete the full panel of assessments scheduled for the 
EOS Visit (Week 24) (see Section 6.6). The reason for patient withdrawal must be documented in 
the electronic case report form (eCRF). Those patients who withdraw from the study will be 
referred to a physician for follow-up care. 
Withdrawn patients will not be replaced.  
4.3.1 
Lost to Follow-Up 
A patient will be considered lost to follow-up if he/she 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 patient fails to return to the study site for a required study 
visit: 
• The study site must attempt to contact the patient and reschedule the missed visit as soon as 
possible, counsel the patient on the importance of maintaining the assigned visit schedule, and 
ascertain whether or not the patient wishes to and/or should continue in the study. 
• Before a patient is deemed lost to follow-up, the Investigator or designee must make every 
effort to regain contact with the patient (where possible, 3 telephone calls and, if necessary, a 
certified letter to the patient’s last known mailing address or local equivalent methods). These 
contact attempts should be documented in the patient’s medical record. 
Should the patient continue to be unreachable, he/she will be considered to be lost to follow-up. 


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4.3.2 
Termination of Study 
Although the Sponsor has every intention of completing the study, the Sponsor may terminate the 
study at any time for clinical or administrative reasons. 
4.3.3 
Screening Failures 
Screening failures are defined as patients who consent to participate in the clinical study but are 
not subsequently randomized into the study. A minimal set of screening failure information is 
required to ensure transparent reporting of screening failure patients to meet the Consolidated 
Standards of Reporting Trials publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screening failure details, eligibility 
criteria, and any SAE(s). 
Patients who do not meet criteria for participation in the study (screen failure) may be rescreened 
at the discretion of the Medical Monitor. The Medical Monitor will clearly document the rationale 
for any rescreening decision. Rescreened patients will be assigned a new screening number, be 
reconsented, and may have screening assessments repeated if necessary. 


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5 
STUDY TREATMENTS 
 
Treatment Groups 
Eligible patients with glenohumeral OA or shoulder AC will be randomized in a 1:1 ratio within 
their shoulder condition (OA or AC) and treated in the following arms: 
• Nominal 32 mg FX006 as a 5 mL IA injection to the index shoulder 
• Placebo (sterile normal saline) as a 5 mL IA injection to the index shoulder  
 
Rationale for Dosing 
FX006 at IA doses up to 60 mg has been tested in knee OA patients with an acceptable safety 
profile. FX006 has been approved to treat knee OA pain at a dose of 32 mg. The glenohumeral 
joint is also a large synovial joint. Similar doses of conventional corticosteroids have been used 
for the glenohumeral joint as in the knee joint. Likewise, the same dose of FX006 for the 
glenohumeral joint as for the knee joint is reasonable, particularly as the FX006 formulation results 
in much lower drug exposure to joint tissues. Therefore, a 32 mg IA dose has been selected for 
glenohumeral OA or shoulder AC. 
 
Randomization and Blinding 
Patients from each shoulder condition will be randomized on Day 1 to 1 of 2 treatment arms 
(FX006 or placebo) using centralized randomization accessed through an interactive voice/web 
response system randomization (IxRS) module. 
Glenohumeral OA patients will be stratified by the Baseline average daily shoulder pain with 
movement score (0 to 10 NRS) (5.0 to <7.0 or 7.0 to 9.0). Shoulder AC patients will be stratified 
by the Baseline average daily shoulder pain with movement score (0 to 10 NRS) (5.0 to <7.0 or 
7.0 to 9.0) and pain duration since onset at Screening (1 to 3 months, inclusive, or >3 to 
6 months). 
The blinded-assessor technique will be used in this study to maintain double-blind conditions. Key 
study site staff roles are defined below and a site-specific blinding plan will be developed to ensure 
the blind is maintained throughout the duration of the study. Treatments will be prepared by an 
unblinded pharmacist/coordinator who has experience with the preparation of study medication 
and who has been properly trained by the Sponsor or designee. Intra-articular injections will be 
performed by an unblinded injector. 
Overall unblinded team responsibilities may include the following: 
• Will have no other contact with the patient and will not have any blinded roles in the study (the 
only exception is that the unblinded injector may be delegated the role of obtaining informed 
consent at the Screening Visit). 
• Will not share treatment assignments with the blinded assessor, the patient, other blinded study 
personnel, or Sponsor personnel/representatives. 


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• Will make every effort to maintain the blind (e.g., reconstitute the study medication in an 
isolated room to prevent others from seeing and hearing tapping process). 
o If an adverse event occurs during the injection procedure, the unblinded injector will record 
the details of the adverse event in the patient’s chart and provide a full report of the event 
to the blinded assessor in a blinded manner. 
Detailed responsibilities for the unblinded study site staff may include the following: 
• Unblinded pharmacist/coordinator 
o Will receive the randomization notification of the patient’s study medication  
o Will dispense the appropriate prepared study medication and necessary materials for the 
injection  
o Will perform study medication reconstitution 
o Will transport the assigned treatment to the location where injection will take place  
o Will ensure that the FX006 investigational product is resuspended prior to injection  
o Will ensure the blind is maintained by following the site-specific blinding plan to ensure 
the patient is unaware of the treatment assignment prepared for injection 
o Will remain with the patient and unblinded injector until the injection is completed  
o Will record details of study medication preparation, transport (if applicable), and 
administration 
o Will store the used vials in the study medication storage location to be held until study 
medication accountability is performed by the unblinded monitor 
o Will complete the study medication accountability logs  
Note: Depending on site-specific requirements, the unblinded pharmacist/coordinator may be 
split into 2 roles. Details will be specified in the site-specific blinding plan. 
• Unblinded injector 
o Will perform study medication reconstitution (if not completed by the unblinded 
pharmacist/coordinator) 
o Will ensure that the FX006 investigational product is resuspended prior to injection  
o Will perform the aspiration and injection of the index shoulder using ultrasound in 
accordance with both his/her experience and the protocol-specified procedure 
The unblinded pharmacist/coordinator will report any product-related issues relating to 
reconstitution or administration of FX006 according to Sponsor instructions located in the 
Unblinded Pharmacy Manual.  


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All other study site and Sponsor personnel/representatives involved in the study at the study site 
will be blinded with regards to the study medication being administered with the following 
Sponsor/representative exceptions: 
• Unblinded monitor(s)  
o Will be responsible for unblinded study site monitoring  
o Will perform study medication accountability (used and unused vials) 
• Unblinded clinical trial manager 
o Will be responsible for oversight of unblinded study site monitoring 
o Will review unblinded monitoring visit reports and escalate unblinded study site issues to 
unblinded Sponsor representative 
• Unblinded Sponsor representative  
o Will be the point of escalation for the unblinded team 
o Will address any product-related issues 
o Will escalate, in a blinded manner, to the blinded study team, if necessary 
• Sponsor regulatory and pharmacovigilance personnel for safety assessment and 
reporting, if necessary 
Information regarding treatment assignments will be kept secure by the Sponsor or designee, per 
standard operating procedures. 
 
Breaking the Blind 
Investigators are not to break the study treatment blind except when information concerning the 
study medication is necessary for the medical treatment of the patient. If a medical emergency 
requiring unblinding occurs, the Investigator (or designated physician) is strongly encouraged to 
contact the medical or safety monitor to assess the necessity of breaking the study medication 
blind.  
If unblinding is warranted, the Investigator will obtain the treatment assignment information from 
the IxRS. Every effort is to be made to limit study site personnel unblinding only to those 
individuals providing direct care to that patient.  
Any intentional or unintentional breaking of the blind is to be reported immediately to the Sponsor 
that unblinding has occurred, without revealing the treatment. The other circumstances in which 
unblinding may be necessary are at the request of a patient who becomes pregnant during the study, 
or for regulatory reporting purposes.  
If the blind is broken, the date, time, and reason must be recorded in the patient’s eCRF, and any 
associated SAE report, if applicable. 


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Drug Supplies 
5.5.1 
Formulation and Packaging 
FX006 is an extended-release formulation of TA in 75:25 PLGA microspheres. FX006 will be 
supplied as a sterile, white to off-white powder in a single unit dose 5 mL vial with a butyl rubber 
stopper, aluminum seal, and plastic cap. FX006 will be reconstituted in diluent that will be supplied 
as a sterile aqueous solution in a 5 mL vial with a butyl rubber stopper, aluminum seal, and plastic 
cap.  
Placebo (NaCl injection, USP) is a sterile, nonpyrogenic, isotonic solution of NaCl and water for 
injection.  
Instructions for shipment, storage, accountability, reconciliation, and destruction of study 
medication are provided in the Unblinded Pharmacy Manual. 
5.5.2 
Study Medication Preparation and Dispensing 
Dispensing, preparation, and administration of investigational products will occur under the 
supervision of the Principal Investigator. The Principal Investigator may only delegate these 
activities in accordance with state licensing board requirements, local institutional policies, and 
applicable law. Before delegating this activity, the Principal Investigator should also ensure that 
the delegate is trained on and understands the requirements of the protocol. 
Immediately prior to IA injection, FX006 will be reconstituted in 5 mL of a diluent containing an 
isotonic, sterile aqueous solution of NaCl (0.9% w/w), CMC (0.5% w/w), and polysorbate-80 
(0.1% w/w) to form a suspension prior to IA injection. 
The reconstitution process should not be witnessed by any blinded study staff or by the patients. 
Refer to the Unblinded Pharmacy Manual for detailed instructions on study medication preparation 
and IA administration. 
5.5.3 
Study Medication Administration 
Only patients enrolled in the study may receive study medication and only authorized site staff 
may supply or administer study medication. 
Any difficulties with the study medication administration should not be reported to the blinded 
assessor unless it is a direct cause of an adverse event. In the event of difficulties during the 
procedure with administering the study medication, please proceed as follows: 
• Stop the procedure.  
• Do not attempt to reinject.  
• Report the event to the unblinded coordinators at the site and to the unblinded team at 
Flexion Therapeutics, Inc. via the Product Complaint Form.  
• The patient and blinded study personnel (coordinators and Investigators) should not be 
informed the procedure was stopped.  


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5.5.3.1 
Index shoulder aspiration 
Aspiration must be attempted prior to injection of study medication on Day 1. If effusion is 
detected by ultrasound guidance, the injector must withdraw to near dryness prior to the injection. 
Refer to the Unblinded Pharmacy Manual for detailed instructions on study medication preparation 
and IA administration. 
5.5.4 
Treatment Compliance 
Study medication will be administered by the unblinded injector in the clinic. Details regarding 
study medication administration will be documented in the eCRF. The receipt, dispensation, and 
return/destruction of any study medication will be properly documented. 
If for any reason the administration of study medication is stopped before the entire volume is 
injected, the injector should document the reason for stopping administration. 
5.5.5 
Storage and Accountability 
The packaged kits of FX006 must be stored under refrigeration at 2°C to 8°C in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to authorized, unblinded site staff.  
Placebo will be stored according to the commercial label and USP guidelines in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the authorized, unblinded site staff.  
The Investigator, or designee, must confirm appropriate temperature conditions have been 
maintained during transit for all study medications received and any discrepancies must be 
reported and resolved before the use of study medication. Any temperature excursions should be 
documented according to the Unblinded Pharmacy Manual instructions for Sponsor assessment 
and authorization for continued use. 
All study medication required for completion of this study will be provided by the Sponsor or 
designee.  
The Investigator, site, or the head of the site (where applicable) is responsible for study medication 
accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, and final 
disposition of records). 
In the event of a product complaint, complete the Product Complaint Form located in the 
Unblinded Pharmacy Manual. 
5.5.6 
Rescue Medication 
The study site will supply rescue pain medication (acetaminophen) that will be provided by the 
Sponsor. At the site, the rescue medication should be stored according to the commercial label. To 
standardize pain relief rescue medication across all patients, starting at the Screening Visit, patients 
will discontinue all excluded or restricted medications and observe the following procedures: 
• The designated rescue medication is acetaminophen 500 mg. The recommended dosing is 2 
tablets every 6 hours as needed, up to a maximum of 6 tablets (3000 mg) per 24-hour period. 


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• Starting at the Screening Visit, each patient will be provided with a sufficient quantity of rescue 
medication for the interval to the next scheduled study site visit.  
• Patients will record their dosage regimen of the rescue medication over the past 24 hours daily 
in their eDiary. 
At each visit, patients will return any unused rescue medication provided at the previous visit for 
rescue medication accountability and be issued a new supply. 
As with FX006/placebo, the Investigator, site, or the head of the site (where applicable) is 
responsible for rescue medication accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition of records). 
 
Prior and Concomitant Medications and/or Procedures 
Prior therapy is defined as all medications taken by or administered to the patient prior to providing 
informed consent. Concomitant therapy is defined as all medications taken by or administered to 
the patient from providing informed consent to the EOS Visit. Review of any concomitant 
medications should be performed and documented in the source documentation. 
5.6.1 
Excluded Medications and/or Procedures 
The following medications are excluded for the duration of the study. If a patient is taking any of 
these excluded medications, they must, after signing the ICF, complete a washout consisting of a 
period of 5 half-lives of the excluded drug 7 days prior to Day 1. 
• Oral nonsteroidal anti-inflammatory drugs (NSAIDs). 
• Aspirin (>325 mg/day). 
• Centrally-acting pain medications (e.g., pregabalin, gabapentin, duloxetine, and/or 
milnacipran) unless specifically allowed, or allowed with restriction, in the protocol. 
• Opioids. 
• Topical therapies (e.g., NSAIDs, capsaicin, lidocaine patches, CBD products, or other local 
treatments) applied to the index shoulder. 
• Anesthetic medications injected locally in the index shoulder (other than the selected anesthetic 
if used for the IA injection procedure). 
• Muscle relaxants (e.g., cyclobenzaprine, tetrazepam, and/or diazepam). 
The following medications and/or procedures should not be taken and/or performed throughout 
the study: 
• IV or IM corticosteroids within 3 months of the Screening Visit.  
• Oral corticosteroids within 1 month of the Screening Visit.  
• Inhaled, intranasal, or topical corticosteroids within 2 weeks of the Screening Visit. 
• IA corticosteroids in any joint within 3 months of the Screening Visit. 
• IA viscosupplementation (hyaluronic acid) or any IA intervention (e.g., IA injection) in the 
index shoulder within 6 months of the Screening Visit. 


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• Any investigational drug, biologic, or device within 3 months of the Screening Visit. 
• Chemotherapeutic agents, 
immunomodulators, or immunosuppressants 
other than 
corticosteroids within 5 years of the Screening Visit.  
• Live or live-attenuated vaccines within 3 months of the Screening Visit. 
• Significant changes with regard to physical activity and lifestyle, within 1 month prior to the 
Screening Visit and changes throughout the duration of the study. 
5.6.2 
Restricted Medications and/or Procedures 
The following medications/nonpharmacologic therapies may be taken or used throughout the study 
with the following restrictions: 
• Aspirin for cardioprotection at a maximum dose of 325 mg/day provided the dose has been 
stable over the 3 months prior to study entry.  
• Medical therapy for depression, including selective serotonin reuptake inhibitors, 
non-selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, 
and tricyclic antidepressants provided the dose has been stable over the 3-month period prior 
to the Screening Visit (see Appendix E). 
5.6.3 
Allowed Medications and/or Procedures 
The following medications/nonpharmacologic therapies may be taken or used throughout the 
study: 
• Any treatment for a pre-existing condition or for an adverse event, outside of the study 
indication, that is not listed as excluded or restricted. 
• Study-allocated rescue medication. 
• Patients should be advised to maintain a stable lifestyle with regard to physical activity 
throughout the duration of the study. Patients treated for shoulder AC will begin the HEP (see 
Appendix C) beginning 3 days post injection. 
5.6.4 
Documentation of Prior and Concomitant Medication Use 
During the study, prior medications, changes to concomitant medications, and/or the addition of 
new medications and the associated reasons for use and/or changes will be documented and 
recorded on the applicable eCRF. 


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6 
STUDY PROCEDURES 
 
Informed Consent 
Prior to initiation of any study related procedures, patients will review and sign the study’s ICF to 
participate in the study after having been informed about the nature and purpose of the study, 
participation and termination conditions, and risks and benefits. Patients who are unable to provide 
informed consent will not be included in the study. 
 
Order of Questionnaires and Electronic Diary Entries 
Entries to be completed daily in the eDiary must follow the order defined in Table 2. 
Questionnaires to be completed during study site visits must follow the order defined in Table 3. 
 
Screening Visit (Days -21 to -1) 
The study will include a Screening Period of a maximum of 21 days. The following procedures 
will be performed at the Screening Visit: 
• Obtain informed consent. 
• Confirm eligibility based on Inclusion and Exclusion Criteria (see Sections 4.1 and 4.2, 
respectively). 
• Complete APR and PRR trainings prior to patient questionnaires. 
• Administer the PD-Q, PHQ-9, GAD-7, PCS, and ISI. 
• Record medical history, including OA medical history and AC medical history.  
o For glenohumeral OA patients, OA medical history will include American College of 
Rheumatology diagnosis details; OA diagnosis date (if available); number of days with 
index shoulder pain in the last month; previous IA corticosteroid, PRP, or hyaluronic 
injections; presence of OA in other joints; and prior procedures or surgeries for index 
shoulder OA. 
o For AC patients, AC diagnosis date (if available); pain duration since onset at Screening; 
previous IA corticosteroid, PRP, or hyaluronic injections; presence of OA in other joints; 
and prior procedures or surgeries for index shoulder AC. 
• Record patient demographics. 
• Record prior treatments and medications. 
• Record the average daily shoulder pain with movement score (0 to 10 NRS), SI question, and 
rescue medication usage in the eDiary. 
• Record the pain with duration since onset (AC patients only). 
• Perform physical examination. 
• Perform shoulder assessment, including active and passive ROM, on the index and 
contralateral shoulder. 


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• Perform index shoulder X-ray. 
o X-ray of the index shoulder will include axillary view and true anterior-posterior view. 
o For glenohumeral OA patients, the Screening Visit X-ray will be read centrally to confirm 
Grade 2 or 3 OA in the index glenohumeral joint based on the Samilson-Prieto 
classification system. 
o For shoulder AC patients, the Screening Visit X-ray will be read centrally to confirm there 
is no evidence of OA in the index shoulder. 
o An x-ray acquired within 6 weeks of the Screening Visit may be used for study 
qualification if the specified imaging protocol was followed.  The x-ray will be read 
centrally to confirm there is no evidence of OA in the index shoulder.  
• Obtain vital signs. 
• Perform ECG. 
• Record height and weight and calculate BMI. 
• Collect blood samples for hematology and chemistry, including hemoglobin A1c. 
• Perform HIV, HBsAg, and HCV screens. 
• Perform serum pregnancy test (for women of childbearing potential only). Follicle-
stimulating hormone in perimenopausal women who have not had a menstrual period for 1 
year will be measured at the Screening Visit. 
• Begin washout of excluded medications. 
• Register patients in eDiary and provide instructions on its use. 
• Dispense rescue medication. 
• Assess adverse events and concomitant medications. 
• Review HEP video with AC patients to ensure agreement to be compliant.  
 
Treatment Visit (Day 1) 
The following procedures will be performed at the Treatment Visit (Day 1): 
• Confirm eligibility based on Inclusion and Exclusion Criteria (see Sections 4.1 and 4.2, 
respectively) prior to administration of study medication.  
o Review the average daily shoulder pain with movement (0 to 10 NRS) to ensure at least 
5 out of the 7 days prior to Day 1 have been recorded. 
• Complete APR and PRR trainings prior to patient questionnaires and administration of study 
medication. 
• Administer the EQ-5D-5L, SPADI, and ASES after completion of APR and PRR training, but 
prior to any other assessments.  
• Review and update medical history prior to administration of study medication. 


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• Review and update prior treatments and medications prior to administration of study 
medication. 
• Review SI question and rescue medication usage in the eDiary. 
• Perform index shoulder assessment including active and passive ROM prior to administration 
of study medication. 
• Obtain vital signs prior to administration of study medication. 
• Perform urine pregnancy test prior to administration of study medication (for women of 
childbearing potential). 
• Perform randomization prior to administration of study medication. 
• Perform index shoulder aspiration prior to administration of study medication. 
• Administer study medication following standard of care procedure. 
• Dispense/return rescue medication as needed. 
• Assess adverse events and concomitant medications (post injection). 
• For shoulder AC patients only, a Home Exercise Program (HEP) will be implemented 3 days 
following injection and performed twice daily (see Appendix C). 
 
Treatment Evaluation Period (Weeks 1 to 24) 
Following the Treatment Visit, patients will return to the study site for visits that will occur within 
±3 days of the scheduled time.  
6.5.1 
Weeks 1 to 20 
The following procedures will be performed on Weeks 1, 4, 8, 12, 16, and 20: 
• Complete APR and PRR trainings prior to patient questionnaires. 
• Administer the EQ-5D-5L, SPADI, and ASES after completion of APR and PRR training, but 
prior to any other assessments.  
• Review the average daily shoulder pain with movement score (0 to 10 NRS), SI question, and 
rescue medication usage in the eDiary. 
• Perform index shoulder assessment including active and passive ROM. 
• Obtain vital signs. 
• Dispense/return rescue medication as needed. 
• Record HEP compliance in the eDiary (AC patients only). 
• Administer the PGIC. 
• Assess adverse events and concomitant medications. 
• For shoulder AC patients only, a Home Exercise Program (HEP) will be implemented 3 days 
following injection and performed twice daily (see Appendix C). 


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•  
6.5.2 
Week 24 (End of Study Visit)  
The following procedures will be performed at the EOS Visit (Week 24): 
• Complete APR and PRR trainings prior to patient questionnaires. 
• Administer the EQ-5D-5L, SPADI, and ASES after completion of APR and PRR training, but 
prior to any other assessments.  
• Review the average daily shoulder pain with movement score (0 to 10 NRS), SI question, and 
rescue medication usage in eDiary. 
• Perform physical examination. 
• Perform index shoulder assessment including active and passive ROM. 
• Obtain vital signs. 
• Perform ECG. 
• Record weight and calculate BMI. 
• Collect blood samples for hematology and chemistry. 
• Perform urine pregnancy test (for women of childbearing potential). 
• Return rescue medication as needed. 
• Record HEP compliance in eDiary (AC patients only). 
• Administer the PGIC. 
• Assess adverse events and concomitant medications. 
 
Early Termination Visit and Withdrawal Procedures 
The end of treatment for patients completing the study is the EOS Visit (Week 24). For patients 
who withdraw from the study prior to completion (Early Termination [ET]), all EOS Visit 
procedures will be performed at the corresponding visit. See Section 6.5.2 for the procedures that 
will be performed.  


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7 
EFFICACY ASSESSMENTS 
 
Efficacy Endpoints 
7.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint for each of the shoulder conditions (glenohumeral OA and shoulder 
AC) in this study is the area under the curve (AUC) of the change from Baseline in the weekly 
mean of the average daily shoulder pain with movement score over 8 weeks for FX006 compared 
to placebo. 
7.1.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints comparing FX006 to placebo for each of the shoulder conditions 
(glenohumeral OA and shoulder AC) in this study include the following: 
• Change from Baseline in the weekly mean of the average daily shoulder pain with movement 
score at Week 12 
• Change from Baseline in the SPADI pain subscale at Week 12 
• Change from Baseline in the SPADI disability subscale at Week 12 
• The PGIC score at Week 12 
• Change from Baseline in the ROM of external rotation at Week 12 
7.1.3 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints comparing FX006 to placebo for each of the shoulder 
conditions (glenohumeral OA and shoulder AC) in this study include the following: 
• AUC of change from Baseline in the weekly mean of the average daily shoulder pain with 
movement score over Weeks 4, 12, 16, 20, and 24 
• AUC of change from Baseline in the SPADI pain subscale over Weeks 4, 8, 12, 16, 20, and 24 
• AUC of change from Baseline in the SPADI disability subscale over Weeks 4, 8, 12, 16, 20, 
and 24 
• Change from Baseline in the weekly mean of the average daily shoulder pain with movement 
score at Weeks 1, 4, 8, 16, 20, and 24 
• Change from Baseline in the SPADI pain subscale at Weeks 1, 4, 8, 16, 20, and 24 
• Change from Baseline in the SPADI disability subscale at Weeks 1, 4, 8, 16, 20, and 24 
• Change from Baseline in the SPADI total score at Weeks 1, 4, 8, 12, 16, 20, and 24 
• The PGIC score at Weeks 1, 4, 8, 16, 20, and 24 
• Change from Baseline in the ROM of external and internal rotation, abduction and flexion at 
Weeks 4, 8, 16, 20, and 24  
• Change from Baseline in the ROM of internal rotation, abduction and flexion at Week 12 
• Change from Baseline in the ASES pain subscale at Weeks 1, 4, 8, 12, 16, 20, and 24 


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• Change from Baseline in the ASES disability subscale at Weeks 1, 4, 8, 12, 16, 20, and 24 
• Change from Baseline in the ASES total score at Weeks 1, 4, 8, 12, 16, 20, and 24 
• Percent of responders based on the SPADI at Weeks 1, 4, 8, 12, 16, 20, and 24 
• Proportion of patients experiencing a 20%, 30%, or 50% decrease in the weekly mean of 
the average daily shoulder pain with movement score at Weeks 1, 4, 8, 12, 16, 20, and 24 
• Change from Baseline in average weekly rescue medication use  
• Change from Baseline in the average weekly SI score  
• Change from Baseline in the EQ-5D-5L at Weeks 1, 4, 8, 12, 16, 20, and 24 
 
Efficacy Assessments 
Efficacy variables include the following: 
7.2.1 
Shoulder Pain with Movement Score 
The average shoulder pain with movement (NRS score) experienced in the previous 24 hours will 
be recorded daily in the eDiary. 
7.2.2 
Shoulder Pain and Disability Index 
The SPADI will be administered at the study visits indicated in Appendix A. 
The SPADI will include the pain subscale, disability subscale, and total score.14,15 
7.2.3 
American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form 
The ASES will be administered at the study visits indicated in Appendix A. 
The ASES will include subscales for pain, function, and total.14 
7.2.4 
Patient Global Impression of Change 
The PGIC will be administered at the study visits indicated in Appendix A. 
The PGIC will be scored on a 7-point scale.16,17,18 
7.2.5 
Active and Passive Ranges of Motion 
Active and passive ROM will be assessed with a goniometer per standardized measurement 
protocol, as outlined in Appendix D at the study visits indicated in Appendix A.  
7.2.6 
EuroQol 5 Dimensions 5 Levels Questionnaire 
The EQ-5D-5L will be administered at the study visits indicated in Appendix A. 
The EQ-5D-5L consists of 2 pages (the EuroQol 5 Dimensions descriptive system and the EuroQol 
visual analogue scale19). 


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7.2.7 
Responder Status  
Responder status will be defined by: 
• Proportion of patients experiencing either a 20%, 30%, or 50% decrease (improvement) in 
pain (minimum, at least moderate, and substantial clinically important differences, 
respectively, as defined by Dworkin et al20) 
7.2.8 
Daily Sleep Interference Score 
The degree to which index shoulder pain has interfered with sleep during the previous 24 hours 
will be recorded daily in the eDiary. 


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8 
SAFETY ASSESSMENTS 
 
Adverse Events 
Patients will be monitored for adverse events from the time of informed consent through the end 
of their participation in the study. 
An adverse event is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An adverse event can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational medicinal product, whether or not related to the investigational medicinal 
product. 
Patients should be instructed to report any adverse event that they experience to the Investigator, 
whether or not they think the event is due to study medication. Beginning at the time of informed 
consent, Investigators should make an assessment for adverse events at each visit and record the 
event on the appropriate adverse event eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF. For 
example, a diagnosis of ‘influenza’ should be reported as an adverse event instead of the symptoms 
of fever, fatigue, malaise, and positive flu test. Additionally, the condition that led to a medical or 
surgical procedure (e.g., surgery, endoscopy, tooth extraction, or transfusion) should be recorded 
as an adverse event, not the procedure itself.  
Any medical condition already present at the time of informed consent should be recorded as 
medical history and not be reported as an adverse event unless the medical condition or signs or 
symptoms present at Baseline changes in severity, frequency, or seriousness at any time during the 
study. In this case, it should be reported as an adverse event. 
Clinically significant abnormal laboratory or other examination findings that are detected or 
significantly worsen during the study should be reported as adverse events, as described below. 
The Investigator will exercise his/her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant. Abnormal test 
results that are determined to be an error should not be reported as an adverse event.  
8.1.1 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each adverse event and its potential 
relationship to study medication. 
Assessment of Severity 
Each adverse event should be evaluated for severity or intensity. This is not the same as “serious,” 
which is based on patient/event outcome or action criteria usually associated with events that pose 


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a threat to a patient’s life or functioning. The severity of adverse events will be assessed according 
to the following definitions: 
• Mild – The adverse event is noticeable to the patient and/or the Investigator but does not 
interfere with routine activity. 
• Moderate – The adverse event interferes with routine activity but responds to symptomatic 
therapy or rest. 
• Severe – The adverse event significantly limits the patient’s ability to perform routine 
activities despite symptomatic therapy. 
Causality Assessment 
A medically qualified Investigator must assess the relationship of any adverse events (including 
SAEs) to the use of the investigational product, as related or not related, based on clinical 
judgment and using all available information according to the following definitions: 
• Not related – Temporal relationship is lacking (e.g., the event did not occur within a 
reasonable time frame following administration of the study medication), or other causative 
factors more likely explain the event (e.g., a pre-existing condition or other concomitant 
treatments). 
• Related – There is a positive temporal relationship (e.g., the event occurred within a 
reasonable time frame following administration of study medication), and the adverse event 
is more likely explained by the investigational product than by another cause (e.g., the 
adverse event shows a pattern consistent with previous knowledge of the investigational 
product or the class of the investigational product). 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study medication. This means that there are facts (evidence) or arguments to suggest a causal 
relationship. 
The following factors should also be considered: 
• The temporal sequence from study medication administration- 
The event should occur after the study medication is given. The length of time from study 
medication exposure to event should be evaluated in the clinical context of the event. 
• Underlying, concomitant, intercurrent diseases- 
Each report should be evaluated in the context of the natural history and course of the disease 
being treated and any other disease the patient may have. 
• Concomitant drug- 
The other drugs the patient is taking or the treatment the patient receives should be examined 
to determine whether any of them might be recognized to cause the event in question. 
• Known response pattern for this class of study medication- 
Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 


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• Exposure to physical and/or mental stresses- 
The exposure to stress might induce adverse changes in the recipient and provide a logical and 
better explanation for the event. 
• The pharmacology and PK of the study medication- 
The known pharmacologic properties (absorption, distribution, metabolism, and excretion) of 
the study medication should be considered. 
 
Serious Adverse Events 
An adverse event or adverse reaction is considered serious if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes: 
• Death. 
• A life-threatening adverse event. 
Note: An adverse event or adverse reaction is considered “life-threatening” if, in view of either 
the Investigator or Sponsor, its occurrence places the patient at immediate risk of death. It does 
not include an event that, had it occurred in a more severe form, might have caused death. 
• Requires hospitalization or prolongation of existing hospitalizations. 
Note: Any hospitalization over 24 hours will be considered an inpatient hospitalization. An 
emergency room or urgent care visit without hospital admission will not be recorded as an SAE 
under this criterion, nor will hospitalization for a procedure scheduled or planned before 
signing of informed consent, or elective treatment of a pre-existing condition that did not 
worsen from Baseline. However, unexpected complications and/or prolongation of 
hospitalization that occur during elective surgery should be recorded as adverse events and 
assessed for seriousness. Admission to the hospital for social or situational reasons (i.e., no 
place to stay, live too far away to come for hospital visits, or respite care) will not be considered 
inpatient hospitalizations.  
• A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• A congenital anomaly/birth defect. 
• An important medical event. 
Note: Important medical events that do not meet any of the above criteria may be considered 
an SAE when, based upon appropriate medical judgment, they may jeopardize the patient and 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such 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 hospitalizations, or the development of drug dependency. 


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Serious Adverse Event Reporting − Procedures for Investigators 
Initial Reports 
All SAEs occurring from the time of informed consent until the EOS/ET Visit must be entered 
into the electronic data capture (EDC) system within 24 hours of the knowledge of the occurrence. 
To report the SAE, complete the SAE form electronically in the EDC system for the study. When 
the form is completed, Medpace Safety personnel will be notified electronically by the EDC 
system and will retrieve the form. Flexion Pharmacovigilance will also receive notification. If the 
event meets serious criteria and it is not possible to access the EDC system, send an email to 
Medpace Safety at medpace-safetynotification@medpace.com or call the Medpace SAE 
Reporting Line (phone number listed below), and fax/email the completed paper SAE form to 
Medpace (fax number listed below) within 24 hours of awareness. When the EDC system becomes 
available, the SAE information must be entered within 24 hours of the system becoming available. 
Safety Contact Information: Medpace Clinical Safety 
Medpace SAE reporting line – USA: 
Telephone: +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3 
Fax: +1-866-336-5320 or +1-513-579-0444 
E-mail: medpace-safetynotification@medpace.com 
Follow-Up Reports 
The Investigator is required to follow SAEs until resolution or withdrawal of consent. Resolution 
is defined as: 
• A return to Baseline for a pre-existing condition. 
• Resolved with or without residual effects. 
• The Investigator does not expect any further improvement or worsening of the event. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any requested documentation 
(e.g., patient discharge summary or autopsy reports) to the Sponsor via e-mail. If it is not possible 
to access the EDC system, refer to the procedures outlined above for initial reporting of SAEs. 
Fatal Outcomes 
If an autopsy is performed on a deceased patient, the autopsy report should be provided to the 
Medical Monitor and Flexion Pharmacovigilance as soon as it is available. 
 
Clinical Management of Index Shoulder-Related Events 
In the event the patient has an immediate reaction following administration of study medication or 
returns to the clinic with an acute exacerbation (e.g., tenderness, increased pain, swelling, effusion, 
or decreased mobility of the index shoulder), the patient should be treated according to local 
clinical guidelines and physician experience. 
If the index shoulder is aspirated at any time other than administration of study medication for any 
reason, the volume of synovial fluid aspirated must be documented, synovial fluid should be 
(1) cultured, (2) evaluated for the presence of crystals, and (3) assessed for white cell count at a 
local laboratory, and the results should be documented. 


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Any event that is a change from the patient’s Baseline status (new or worsening case) should be 
reported as an adverse event and those meeting the definition of an SAE must be reported in 
accordance with Section 8.3. 
 
Pregnancy Reporting 
A pregnancy is not considered to be an adverse event or SAE; however, it must be reported to 
Medpace Clinical Safety within 24 hours of knowledge of the event.  Medpace Clinical Safety will 
then provide the Investigator/site the Exposure In Utero (EIU) form for completion. The 
Investigator/site must complete the EIU form and fax or e-mail it back to Medpace Clinical Safety.  
If the female partner of a male patient becomes pregnant during the study, the Investigator should 
notify Medpace Clinical Safety as described above.  
The pregnancy should be followed until the outcome of the pregnancy, whenever possible. Once 
the outcome of the pregnancy is known, the Exposure In Utero form should be completed and 
emailed to Medpace Clinical Safety. If the outcome of the pregnancy meets the criteria for 
immediate classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, 
neonatal death, or congenital anomaly), the Investigator should follow the procedures for reporting 
an SAE. Additional subsequent follow-up is not needed when a newborn baby is healthy. 
 
Expedited Reporting 
The Sponsor/designee will report all relevant information about Suspected Unexpected Serious 
Adverse Reactions (SUSAR) that are fatal or life-threatening as soon as possible to the Food and 
Drug Administration (FDA), and in any case no later than 7 days after knowledge by the 
Sponsor/designee of such a case. Relevant follow-up information will subsequently be 
communicated according to the required regulatory timelines.  
All other SUSAR will be reported to the FDA as soon as possible but within a maximum of 15 days 
of first knowledge by the Sponsor/designee.  
The Sponsor/designee will also report any additional expedited safety reports required in 
accordance with the timelines outlined by the FDA.  
The Sponsor/designee will also inform all Investigators as required per local regulation. 
The requirements above refer to the requirements relating to an investigational medicinal product. 
 
Reporting Arthralgia in the Index Shoulder 
Since all enrolled patients are required to have a certain level of arthralgia in the index shoulder 
before they receive study medication, the Investigator must take care to fully assess any patient 
reports of index shoulder arthralgia that occur during the study. Incremental return of pre-existing 
index shoulder arthralgia following postinjection pain relief does not meet the criteria for an 
adverse event unless the arthralgia is clinically significantly worse from Baseline (before study 
medication administration).  
Changes in the patient’s typical average daily shoulder pain with movement, which serves as the 
primary efficacy outcome measure, will be assessed utilizing the NRS scale via the daily eDiary 
and would not meet the criteria for an adverse event of arthralgia unless the pain has clearly 
worsened relative to Baseline. However, any new arthralgia, including any new type of arthralgia 
in the index shoulder joint, should be recorded as an adverse event. 


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Clinical Laboratory Evaluations 
See Appendix B for the list of clinical laboratory tests to be performed and to the Schedule of 
Procedures in Appendix A for the timing and frequency. See the Central Laboratory Manual for 
detailed sample collection, handling, storage, and shipping instructions. 
The Investigator must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the adverse event section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the patient’s condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values return to normal or Baseline or are no longer 
considered clinically significant by the Investigator or Medical Monitor. 
• If such values do not return to normal/Baseline within a period of time judged reasonable by 
the Investigator, the etiology should be identified, and the Sponsor notified. 
• All protocol required laboratory assessments, as defined in Appendix B, must be conducted in 
accordance with the Central Laboratory Manual and the Schedule of Procedures. 
• If laboratory values from non-protocol specified laboratory assessments performed at the site’s 
local laboratory require a change in patient management or are considered clinically significant 
by the Investigator (e.g., SAE or adverse event), then the results must be recorded in the eCRF. 
 
Vital Signs 
Vital signs will be measured as indicated in Appendix A. The following measurements will be 
obtained: sitting blood pressure, heart rate, respiratory rate, and oral temperature.  
• Temperature, blood pressure, respiratory rate, and heart rate measurements will be assessed in 
a seated position. Blood pressure will be measured with a completely automated device. 
Manual techniques will be used only if an automated device is not available. 
• Blood pressure, heart rate, and respiratory rate measurements should be preceded by at least 
5 minutes of rest for the patient in a quiet setting without distractions (e.g., television or cell 
phones). 
• Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 heart rate 
and 1 blood pressure measurement and recorded on the eCRF. 
 
Height, Weight, and Body Mass Index Determination 
Height and weight will be assessed as indicated in Appendix A. 
• Height will be recorded in centimeters. Weight will be recorded in kilograms. Body mass index 
will be calculated using the following formula:21 
o Kilograms and centimeters. 
▪ With the metric system, the formula for BMI is weight in kilograms divided by height 
in meters squared. Since height is commonly measured in centimeters, divide height in 
centimeters by 100 to obtain height in meters. 


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Physical Examinations 
A complete physical examination will be performed as indicated in Appendix A. A physical 
examination will be performed at the Screening Visit and Week 24.  
The physical exam will assess the following body systems: 
• General appearance 
• Skin 
• Lymphatics 
• Head, ears, eyes, nose, and throat 
• Cardiovascular 
• Respiratory 
• Abdominal 
• Musculoskeletal 
• Neurological 
Any clinically significant findings must be documented in the source and added to the medical 
history if found at the Screening Visit or recorded as an adverse event if new or worsened from 
Baseline at one of the post-Baseline visits. 
 
Electrocardiograms 
A single 12-lead ECG will be obtained as indicated in Appendix A using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. Results will 
be recorded in the eCRF. 
 
Index Shoulder Assessment 
The index shoulder assessment will be performed by the blinded assessor at the days indicated in 
Appendix A. The index shoulder will be assessed for tenderness, heat/redness, swelling, and 
effusion. The index shoulder assessment will also include a measurement of active and passive 
ROM. Ranges of motion will be measured with a goniometer and include glenohumeral joint 
flexion, glenohumeral joint abduction, glenohumeral external rotation, and glenohumeral internal 
rotation in 45° or comfort abduction as defined in Appendix D. Ranges of motion assessments will 
be performed bilaterally (on the index and contralateral shoulder) at the Screening Visit. 
 
Placebo Response Reduction and Accurate Pain Reporting Trainings 
8.14.1 
Placebo Response Reduction Training  
The PRR training22 consists of a set of patient and staff educational materials for training on 
appropriate expectations of personal benefit while participating in a clinical trial. The purpose is 
to provide patients truthful information that will neutralize the typically excessive expectations 
that drive high placebo responses in clinical studies. Patients will receive training as indicated in 
Appendix A. The training video is approximately 10 minutes and must be completed prior to any 
patient questionnaires. 


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8.14.2 
Accurate Pain Reporting Training 
The APR training23 consists of a set of patient and staff educational materials and instructions on 
how to accurately and reliably report pain scores and on the proper use of pain intensity scales, 
with the aim of increasing patients’ pain reporting accuracy. Patients will receive training as 
indicated in Appendix A. The training video is approximately 10 minutes and must be completed 
prior to any patient questionnaires. 


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9 
STATISTICS 
A comprehensive Statistical Analysis Plan (SAP) will be written and approved prior to database 
lock for this study. Each shoulder condition will be analyzed completely separately. In general, the 
same analysis methods will be used for both shoulder conditions, and any differences in analyses 
between the shoulder conditions will be detailed in the SAP. 
 
General Considerations and Methods 
Data collected in this study will be presented using summary tables, figures, and patient data 
listings. Summary tables will present data by treatment group and, if applicable, by time of 
collection. Continuous variables will be summarized using descriptive statistics, specifically the 
mean, median, standard deviation, minimum, and maximum. Categorical variables will be 
summarized by frequencies and percentages. Figures will be used to support the presentation of 
certain data. Sensitivity analyses may be performed to examine the effect of missing data, as well 
as the effect of Baseline imbalance, should it occur. 
All confidence intervals (CIs), statistical tests, and resulting p-values will be reported as 2-sided. 
Multiplicity will be addressed by analyzing the key secondary endpoints sequentially in the order 
presented in the protocol, testing each endpoint at the nominal α = 0.05, 2-sided level to ensure 
overall type I error control at the 2-sided 0.05 level. 
9.1.1 
Demographics and Baseline Characteristics 
Demographic and Baseline characteristics will be listed by study site and patient and will be 
summarized by treatment. 
9.1.2 
Exposure 
Treatment exposure will be listed by study site and patient and will be summarized by treatment. 
 
Study Data 
Study data identified in this protocol will be collected and source verified at the study sites 
completing the study visits. All study data will be formulated into data sets to provide transparency, 
traceability, and integrity of study analysis results from collection sources. Observed study data 
will be mapped to the Clinical Data Interchange Standards Consortium (CDISC) Study Data 
Tabulation Model (SDTM) and serve as the source data from the study. All study analyses will be 
completed using analysis data sets that are derived from the SDTM and follow the CDISC Analysis 
Data Model (ADaM) architecture. 
9.2.1 
Clinical Data – Clinical Data Interchange Standards Consortium Study Data 
Tabulation Model 
Clinical data will be mapped to CDISC SDTM using implementation guide version 3.2. No derived 
data required for analyses will be included in the SDTM domains. All SDTM domains will be fully 
documented with define documents (DEFINE.XML) and a Study Data Reviewer’s Guide after 
database lock and final analyses are completed. 


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9.2.2 
Analysis Data – Clinical Data Interchange Standards Consortium Analysis Data 
Model 
All planned and exploratory analyses will be completed using CDISC compliant ADaM data sets 
derived from the SDTM domains for this study. Analysis data sets will contain all derived study 
endpoints required for analysis. All ADaM analysis data sets will be fully documented with define 
documents (DEFINE.XML) and an Analysis Data Reviewer’s Guide after database lock and final 
analyses are completed. 
 
Analysis Populations 
For each shoulder condition, the following populations are planned for this study: 
• Full Analysis Set (FAS) Population: All patients who receive a complete dose of study 
medication and have Baseline and at least 1 post-dose efficacy endpoint assessment. The FAS 
Population will be used to examine efficacy for both the primary and secondary endpoints. 
• Safety Population: All patients who receive at least 1 dose of study medication. The Safety 
Population will be used to assess safety and tolerability. 
• Per Protocol Population: All patients in the FAS Population who complete the Week 24 visit 
with no major protocol deviations that may impact the evaluation of the primary efficacy 
endpoint based on blinded data prior to database lock. 
 
Statistical Methods 
9.4.1 
Analysis of Efficacy 
9.4.1.1 
Primary efficacy analyses 
For each shoulder condition, the primary AUC endpoint will be calculated and comparisons will 
be estimated from an Analysis of Covariance model with parameters for treatment group, Baseline 
average daily shoulder pain with movement score, and analysis site. In addition, the model for 
shoulder AC will also include a covariate for pain duration since onset. Full details of the AUC 
analyses will be detailed in the SAP. 
9.4.1.2 
Secondary efficacy analyses 
The key secondary change from Baseline endpoints will be analyzed with longitudinal mixed 
models for repeated measures with fixed effects for treatment group, study week, 
treatment-by-week interaction, analysis site, and Baseline score. Patient will be the random effect. 
Treatment differences from control will be estimated via LSMs from the analysis model along 
with 95% CIs and associated 2-sided p-values. This model assumes data are missing at random 
and includes only observed data. In addition, the model for shoulder AC will also include a 
covariate for pain duration since onset. 
Multiplicity will be addressed by analyzing the key secondary endpoints sequentially in the order 
presented in the protocol, testing each endpoint at the nominal α = 0.05, 2-sided level to ensure 
overall type I error control at the 2-sided 0.05 level. 


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9.4.1.3 
Exploratory efficacy analyses 
Area under the curve and continuous exploratory efficacy endpoints will be analyzed similarly to 
the primary and key secondary endpoints for each shoulder condition. Categorical endpoints will 
be compared via chi-square or exact tests depending on incidence rates. No adjustments will be 
made for multiplicity for exploratory efficacy endpoints.  
9.4.2 
Analysis of Safety 
9.4.2.1 
Analysis of adverse events 
Safety analyses will be performed on the Safety Population. Adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Incidences (number and percent) of 
treatment-emergent adverse events (TEAEs), those events that start after dosing or worsened in 
severity after dosing, will be presented by treatment. Incidences of TEAEs will also be presented 
by maximum severity and relationship to study medication. 
Similar presentations will be provided for SAEs, adverse events leading to withdrawal from the 
study, or adverse events leading to death. Analysis of adverse event data will include examination 
of the incidence rates of index shoulder-related TEAEs. 
9.4.2.2 
Other safety analyses 
Laboratory data and vital sign information will be summarized by treatment and will be presented 
as descriptive summary statistics for value and change from Baseline at each individual time point. 
9.4.3 
Interim Analyses 
For each shoulder condition, a blinded interim analysis will occur when approximately 50% of the 
patients have completed Week 8 to determine the need for a potential adjustment to the sample 
sizes. Prior data suggest the standard deviation of the primary endpoint could range from 2 to 2.5. 
Therefore, the interim analyses will enable a sample size increase up to 150 in each shoulder 
condition to ensure the desired statistical power is obtained. 
9.4.4 
Final Analyses 
All final analyses will be completed following database lock for each shoulder condition. Final 
analyses specified in the protocol and SAP will be completed and reported in the Clinical Study 
Report (CSR). Post-hoc, exploratory analyses may be completed to further understand and 
elucidate study results. Any post-hoc, exploratory analyses completed will be clearly identified as 
such in the final CSR. 
9.4.5 
Subgroups and Covariates 
Preplanned subgroup analyses including aspiration status, OA grade based on the Samilson-Prieto 
classification system, gender, and Baseline average daily shoulder pain with movement score will 
be detailed in the SAP. In addition, subgroups of pain duration since onset are preplanned for 
shoulder AC patients. Further subgroups may be defined and explored after all preplanned analyses 
have been completed to further elucidate study results. 


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Covariates for efficacy analyses will include Baseline average daily shoulder pain with movement 
score, Baseline score for the endpoint, analysis site, and, for AC patients, pain duration since onset. 
Other covariates may be explored and will be fully defined in the SAP. 
9.4.6 
Sample Size Determination 
Approximately 250 patients will be randomized in a 1:1 ratio to either FX006 or placebo 
(approximately 136 patients with glenohumeral OA and approximately 114 patients with 
shoulder AC). Sample sizes were estimated to yield a statistically significant difference (α = 0.05, 
2-sided) between the FX006 and placebo groups in the average daily shoulder pain with movement 
score at Week 12 (the first secondary endpoint for each shoulder condition). For glenohumeral 
OA, the true difference between the groups was assumed to be 1, with a standard deviation of 2, 
based on data observed in knee OA studies of FX006 and taking into consideration the clinical 
significance of a 1-point difference between the treatment groups. For shoulder AC, the true 
difference between the groups was assumed to be 1.2, with a standard deviation of 2.1, based on a 
review of the existing literature. The primary endpoint analyzing the AUC for the weekly mean of 
the average daily shoulder pain with movement score over 8 weeks should, therefore, have >80% 
power to show a significant difference between the FX006 and placebo groups. As the 2 shoulder 
conditions (glenohumeral OA and shoulder AC) are combined into 1 protocol strictly for ease of 
administration, all statistical testing will be performed separately for each shoulder condition and 
the overall type I error rate will be controlled at the α = 0.05 level within each shoulder condition. 
 


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10 
DATA MANAGEMENT AND RECORD KEEPING 
 
Data Management 
10.1.1 
Data Handling 
Data will be recorded at the study site on eCRFs and reviewed by the clinical research associate 
(CRA) during monitoring visits. The CRAs will verify data recorded in the EDC system with 
source documents. All corrections or changes made to any study data must be appropriately tracked 
in an audit trail in the EDC system. An eCRF will be considered complete when all missing, 
incorrect, and/or inconsistent data has been accounted for. 
10.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
10.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All study site personnel 
must log into the system using their secure username and password in order to enter, review, or 
correct study data. These procedures must comply with Title 21 of the Code of Federal Regulations 
(21 CFR) Part 11 and other appropriate international regulations. All passwords will be strictly 
confidential. 
10.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
• MedDRA (latest) for adverse events 
• World Health Organization Drug Dictionary for prior and concomitant medications 
10.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the study site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
 
Record Keeping 
Records of patients, source documents, monitoring visit logs, eCRFs, inventory of study 
medication, regulatory documents, and other Sponsor correspondence pertaining to the study must 
be kept in the appropriate study files at the study site. Source data are defined as all information in 
original records and certified copies of original records of clinical findings, observations, or other 
activities in a clinical study necessary for the evaluation and reconstruction of the clinical study. 
Source data are contained in source documents (original records or certified copies). Data entered 
in the eCRF that are transcribed from source documents must be consistent with the source 
documents or the discrepancies must be explained. The Investigator may need to request previous 
medical records. Current medical records must be available. These records will be retained in a 


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secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  
 
End of Study Definition 
A patient is considered to have completed the study if he/she has completed all phases of the study 
through Week 24.  
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment for the last patient in the study.  


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11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
 
Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human patients. Compliance 
with this standard provides public assurance that the rights, safety, and wellbeing of study patients 
are protected, consistent with the principles that have their origin in the Declaration of Helsinki, 
and that the clinical study data are credible. 
 
Institutional Review Board 
The Institutional Review Board (IRB) will review all appropriate study documentation in order to 
safeguard the rights, safety, and well-being of patients. The study will only be conducted at sites 
where IRB approval has been obtained. The protocol, IB, ICF, advertisements (if applicable), 
written information given to the patients, safety updates, annual progress reports, and any revisions 
to these documents will be provided to the IRB by the Investigator. 
Federal regulations and International Council for Harmonisation (ICH) Guidelines require that 
approval be obtained from an IRB prior to participation of patients in research studies. Prior to 
study onset, the protocol, any protocol amendments, ICFs, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to a patient or 
patient’s legal guardian must be approved by the IRB. 
No study medication will be released to the study site for dosing until written IRB authorization 
has been received by the Sponsor. 
 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB prior to its use and must be in compliance with all ICH GCP, 
local regulatory requirements, and legal requirements.   
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
patient has been informed of his/her rights to privacy. The Investigator will obtain written informed 
consent from each patient before any study-specific activity is performed and should document in 
the source documentation that consent was obtained prior to enrollment in the study. Patients must 
be reconsented to the most current version of the ICF(s) during their participation in the study. The 
original signed copy of the ICF and any updates to the ICF must be maintained by the Investigator 
and are subject to inspection by the Sponsor, their representatives, auditors, the IRB, and/or 
regulatory agencies. A copy of all signed ICFs will be given to the patient. 
Patients who are rescreened will be required to sign a new ICF. 
 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, Declaration of Helsinki, ICH GCP, and applicable regulatory requirements, and that 
valid data are entered into the eCRFs. 


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To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well organized and easily retrievable data. Before 
the enrollment of any patient in this study, the Sponsor or their designee will review with the 
Investigator and study site personnel the following documents: protocol, IB, eCRFs and 
procedures for their completion, informed consent process, and the procedure for reporting SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data are 
entered by the study site, the CRA will review the data for safety information, completeness, 
accuracy, and logical consistency. Computer programs that identify data inconsistencies may be 
used to help monitor the clinical study. If necessary, requests for clarification or correction will be 
sent to Investigators. The Investigator and his/her staff will be expected to cooperate with the 
monitor and provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the study site by signature and date on the study-specific monitoring log. 
 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Patients or their legal 
representatives may request their medical information be given to their personal physician or other 
appropriate medical personnel responsible for their welfare. 
Patient medical information obtained during the study is confidential and disclosure to third parties 
other than those noted above is prohibited. 
 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating patients (sufficient information to link 
records, e.g., eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE 
forms, source documents, and detailed records of treatment disposition. The records should be 
retained by the Investigator according to specifications in the ICH guidelines, local regulations, or 
as specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor. 
 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of patients. 
The first act of recruitment is the first site opening (site activation) and will be the study start date. 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 


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completion. A study site is considered closed when all required documents and study supplies have 
been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are not 
limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB or local 
health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of patients by the Investigator 
• Discontinuation of further study medication development 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IRBs, the regulatory authorities, and any contract research organization(s) used 
in the study of the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The Investigator shall promptly inform the patients and should assure appropriate 
patient therapy and/or follow-up. 
 
Publication Policy 
The results of this study may be published or presented at scientific meetings. Each Investigator is 
obligated to keep data pertaining to the study confidential. The Investigator must consult with the 
Sponsor before any study data are submitted for publication. The Sponsor reserves the right to 
deny publication rights until mutual agreement on the content, format, interpretation of data in the 
manuscript, and journal selected for publication are achieved. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a coordinating 
Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences International 
Ethical Guidelines 
• Applicable ICH GCP Guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., advertisements) 
must be submitted to the IRB by the Investigator and reviewed and approved by the IRB before 
the study is initiated. 


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Any amendments to the protocol will require IRB approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to study 
patients. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB annually, or more frequently 
in accordance with the requirements, policies, and procedures established by the IRB. 
• Notifying the IRB of SAEs or other significant safety findings as required by IRB procedures. 
• Providing oversight of the conduct of the study at the site and adherence to requirements of 
21 CFR, ICH guidelines, the IRB, and all other applicable local regulations. 
 
Financial Disclosure 
Investigators and sub-Investigators 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 to fulfill its 
obligations under 21 CFR Part 54. In addition, Investigators must commit to promptly updating 
this information if any relevant changes occur during the study and for a period of 1 year after the 
completion of the study. 
 
Data Protection 
Patients will be assigned a unique identifier by the Sponsor. Any patient records or datasets that 
are transferred to the Sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred. 
Patients must be informed that their personal study-related data will be used by the Sponsor in 
accordance with local data protection law(s). The level of disclosure must also be explained to the 
patient who will be required to give consent for their data to be used as described in the ICF.  
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate IRB 
members, and by inspectors from regulatory authorities. 
 
Insurance and Indemnity 
In accordance with the relevant national regulations, the Sponsor has taken out patient liability 
insurance for all patients who have given their consent to the clinical study. This cover is designed 
for the event that a fatality, physical injury, or damage to health occurs during the clinical study’s 
execution. 
 
Legal Aspects 
The clinical study is submitted to the relevant national competent authorities in all participating 
countries to achieve a clinical trial authorization (CTA). 
The study will commence (i.e., initiation of study sites) when the CTA and favorable Ethics 
opinion have been received.  


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12 
STUDY ADMINISTRATIVE INFORMATION 
 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by Medpace or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB, unless immediate implementation of the change is necessary for patient safety. In this case, 
the situation must be documented and reported to the IRB within 5 working days. 


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13 
REFERENCES 
1. 
Bodick N, Lufkin J, Willwerth C, et al. FX006 prolongs the residency of triamcinolone 
acetonide in the synovial tissues of patients with knee osteoarthritis. Osteoarthritis 
Cartilage. 2013;21(Supplement):S144-S145. 
2. 
Investigator’s Brochure for Flexion Therapeutics, Inc. FX006. Edition 7.1, 
13 November 2018. 
3. 
Bodick N, Lufkin J, Willwerth C, et al. An intra-articular, extended-release formulation 
of triamcinolone acetonide prolongs and amplifies analgesic effect in patients with 
osteoarthritis of the knee: a randomized clinical trial. J Bone Joint Surg Am. 
2015;97(11):877-888. 
4. 
Conaghan PG, Hunter DJ, Cohen SB, et al. Effects of a single intra-articular injection of 
a microsphere formulation of triamcinolone acetonide on knee osteoarthritis pain: a 
double-blinded, randomized, placebo-controlled, multinational study. J Bone Joint Surg 
Am. 2018;100(8):666-677. 
5. 
Conaghan PG, Cohen SB, Berenbaum F, et al. Brief report: a phase IIb trial of a novel 
extended-release microsphere formulation of triamcinolone acetonide for intraarticular 
injection in knee osteoarthritis. Arthritis Rheumatol. 2018;70(2):204-211. 
6. 
Merolla G, Sperling JW, Paladini P, et al. Efficacy of Hylan G-F 20 versus 
6-methylprednisolone acetate in painful shoulder osteoarthritis: a retrospective controlled 
trial. Musculoskelet Surg. 2011;95(3):215-224.  
7. 
Zhang W, Nuki G, Moskowitz RW, et al. OARSI recommendations for the management 
of hip and knee osteoarthritis: part III: changes in evidence following systematic 
cumulative update of research published through January 2009. Osteoarthritis Cartilage. 
2010;18(4):476-499. 
8. 
Jüni P, Hari R, Rutjes AW, et al. Intra-articular corticosteroid for knee osteoarthritis. 
Cochrane Database Syst Rev. 2015;(10):CD005328. 
9. 
Rodeo SA, Hannafin JA, Tom J, et al. Immunolocalization of cytokines and their 
receptors in adhesive capsulitis of the shoulder. J Orthop Res. 1997;15(3):427-436. 
10. 
Koh KH. Corticosteroid injection for adhesive capsulitis in primary care: a systematic 
review of randomised clinical trials. Singapore Med J. 2016;57(12):646-657.  
11. 
Wang W, Shi M, Zhou C, et al. Effectiveness of corticosteroid injections in adhesive 
capsulitis of shoulder: a meta-analysis. Medicine (Baltimore). 2017;96(28):e7529. 
12. 
Kraus VB, Conaghan PG, Aazami HA, et al. Synovial and systemic pharmacokinetics 
(PK) of triamcinolone acetonide (TA) following intra-articular (IA) injection of an 
extended-release microsphere-based formulation (FX006) or standard crystalline 
suspension in patients with knee osteoarthritis (OA). Osteoarthritis Cartilage. 
2018;26(1):34-42. 
13. 
American Diabetes Association. Glycemic targets. Sec. 5. In Standards of Medical Care 
in Diabetes–2016. Diabetes Care. 2016;39(Supplement 1):S39-S46. 
14. 
Kelley MJ, Shaffer MA, Kuhn JE, et al. Shoulder pain and mobility deficits: adhesive 
capsulitis. J Orthop Sports Phys Ther. 2013;43(5):A1-A31.  
15. 
Williams JW Jr, Holleman DR Jr, Simel DL. Measuring shoulder function with the 
Shoulder Pain and Disability Index. J Rheumatol. 1995;22(4):727-732. 
 
 


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16. 
Farrar JT, Young JP Jr, LaMoreaux L, et al. Clinical importance of changes in chronic 
pain intensity measured on an 11-point numerical pain rating scale. Pain. 
2001;94(2):149-158. 
17. 
Guy W. ECDEU assessment manual for psychopharmacology. Rockville, MD: United 
States Department of Health, Education, and Welfare, Public Health Service, Alcohol, 
Drug Abuse, and Mental Health Administration, National Institute of Mental Health, 
Psychopharmacology Research Branch, Division of Extramural Research Programs; 
1976. 
18. 
Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical 
trials: IMMPACT recommendations. Pain. 2005;113(1-2):9-19.  
19. 
EuroQol Research Foundation. EQ-5D. https://euroqol.org. Accessed 10 June 2019. 
20. 
Dworkin RH, Turk DC, Wyrwich KW, et al. Interpreting the clinical importance of 
treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain. 
2008;9(2):105-121.  
21. 
Centers for Disease Control and Prevention. Healthy Weight: About Adult BMI. 
https://www.cdc.gov/healthyweight/assessing/bmi/adult_bmi/index.html. Accessed 
10 June 2019.  
22. 
“Participating in a Research Study, What you need to know,” Analgesic Solutions, 
Wayland, MA  
23. 
“Reporting Your Pain,” Analgesic Solutions, Wayland, MA 
 


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APPENDIX A:  SCHEDULE OF PROCEDURES 
Table 1. Schedule of Procedures 
Visit/Period 
Screening Visit 
Treatment Visit 
Treatment Evaluation Period 
Time Point 
Days -21 to -1 
Day 1 
Weeks 1, 4, 8, 12, 16, & 20 
Week 24 (EOS/ET)1 
Window  
±3 Days 
Assessment 
 
Informed consent 
X2 
 
 
 
Inclusion/exclusion review 
X 
X3 
 
 
APR and PRR trainings4 
X 
X3 
X 
X 
PD-Q, PHQ-9, GAD-7, PCS, and ISI 
X 
 
 
 
SPADI, ASES, and EQ-5D-5L5 
 
X3 
X 
X 
PGIC 
 
 
X 
X 
Medical history 
X 
X3 
 
 
OA medical history 
X 
 
 
 
Patient demographics 
X 
 
 
 
Prior treatment and medications 
X 
X3 
 
 
Shoulder pain with movement, SI, and 
rescue medication (eDiary)6 
X 
X 
X 
X 
Pain duration since onset (shoulder 
AC patients only) 
X 
 
 
 
Physical examination 
X 
 
 
X 
Index shoulder assessment7 
X 
X3 
X 
X 
Contralateral shoulder assessment7 
X 
 
 
 
Index shoulder X-ray8 
X 
 
 
 
Vital signs 
X 
X3 
X 
X 
12-lead ECG 
X 
 
 
X 
Height 
X 
 
 
 
Weight and BMI 
X 
 
 
X 
Hematology and chemistry9 
X 
 
 
X 
Hemoglobin A1c 
X 
 
 
 
HIV, HBsAg, and HCV 
X 
 
 
 
Serum pregnancy test and FSH10 
X 
 
 
 
Urine pregnancy test10 
 
X3 
 
X 
Washout of excluded medications11 
X 
 
 
 
Randomization 
 
X3 
 
 


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Index shoulder aspiration12 
 
X3 
 
 


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Table 1.  Schedule of Procedures (Continued) 
Visit/Period 
Screening Visit 
Treatment Visit 
Treatment Evaluation Period 
Time Point 
Days -21 to -1 
Day 1 
Weeks 1, 4, 8, 12, 16, & 20 
Week 24 (EOS/ET)1 
Window  
±3 Days 
Assessment 
 
Study medication administration 
 
X 
 
 
eDiary registration13 
X 
 
 
 
Rescue medication (dispense/return)14 
X 
X 
X 
X15 
HEP compliance (shoulder 
AC patients only)16 
 
 
X 
X 
Adverse event assessment17 
X 
X 
X 
X 
Concomitant medications18 
X 
X 
X 
X 
1. 
For patients who are withdrawn from the study prior to completion, all EOS Visit procedures will be performed at the corresponding visit. 
2. 
Written informed consent must be obtained prior to performing any study-specific procedures. 
3. 
Must be collected or assessed prior to administration of study medication. 
4. 
To be completed prior to questionnaires completed at study site visits. 
5. 
To be completed after APR and PRR training, but prior to any other assessments. 
6. 
These assessments will be collected daily each evening in the eDiary and reviewed (not completed) at site visits. 
7. 
To include assessment of active and passive ranges of motion per standardized measurement protocol. Performed bilaterally (index and contralateral) at the Screening Visit.   
8. 
X-ray of shoulder will include axillary view and true anterior-posterior view to be taken at the Screening Visit (or within 6 weeks of the Screening Visit) and read centrally 
to confirm eligibility criteria are met. 
9. 
To be analyzed by the Central Laboratory. 
10. Pregnancy tests will be performed in women of childbearing potential only. Follicle-stimulating hormone in perimenopausal women who have not had a menstrual period 
for 1 year will be measured at the Screening Visit. 
11. After signing the ICF, patients must stop taking excluded medications (see Section 5.6.1). Excluded medication washout should be for 5 half-lives of the medication and be 
completed 7 days prior to Day 1. 
12. Aspiration must be attempted prior to the injection. If effusion is detected by ultrasound guidance, injector must withdraw to near dryness prior to the injection. 
13. Patients will be registered in the eDiary and provided instructions on its use.  
14. Rescue medication will be dispensed to patients at the Screening Visit. At each subsequent visit, rescue medication accountability will be performed and additional rescue 
medication will be returned/dispensed as needed. 
15. Rescue medication will be returned but not dispensed at the EOS/ET Visit. 
16. Shoulder AC patients will follow a HEP beginning 3 days postinjection through the EOS/ET Visit and record their compliance daily via eDiary. 
17. Adverse events will be assessed from the time of informed consent until the end of patient participation in the study. 
18. Concomitant medication(s) will be captured from the time of informed consent until the end of patient participation in the study. 
AC = adhesive capsulitis; APR = Accurate Pain Reporting; ASES = American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form; BMI = body mass index; 
ECG = electrocardiogram; eDiary = electronic diary; EOS = End of Study; EQ-5D-5L = EuroQol 5 Dimensions 5 Levels; ET = Early Termination; FSH = follicle-stimulating 
hormone; GAD-7 = General Anxiety Disorder 7-item scale; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HEP = Home Exercise Program; HIV = human 
immunodeficiency virus; ICF = informed consent form; ISI = Insomnia Severity Index; OA = osteoarthritis; PCS = Pain Catastrophizing Scale; PD-Q = painDETECT 
Questionnaire; PGIC = Patient Global Impression of Change; PHQ-9 = Patient Health Questionnaire-9; PRR = Placebo Response Reduction; SI = Sleep Interference; 
SPADI = Shoulder Pain and Disability Index. 


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Table 2. Entries to be Completed Daily by the Patient on the Electronic Diary 
Sequence of Completion 
Daily 
1 
Shoulder pain with movement 
2 
SI question 
3 
HEP compliance1 
4 
Rescue medication usage  
1. 
Only shoulder AC patients.  
AC = adhesive capsulitis; HEP = Home Exercise Program; SI = Sleep Interference. 
 
Table 3.  Questionnaires to be Completed by the Patient at Study Site Visits 
Visit 
Screening Visit 
Day 1 
Weeks 1, 4, 8, 12, 16, & 20 
Week 24 (EOS) 
Sequence at Visit 
 
1 
PD-Q 
SPADI 
SPADI 
SPADI 
2 
PHQ-9 
ASES 
ASES 
ASES 
3 
GAD-7 
EQ-5D-5L 
EQ-5D-5L 
EQ-5D-5L 
4 
PCS 
 
PGIC 
PGIC 
5 
ISI 
 
 
 
ASES = American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form; EOS = End of Study; EQ-5D-5L = EuroQol 5 Dimensions 5 Levels; GAD-7 = General 
Anxiety Disorder 7-item scale; ISI = Insomnia Severity Index; PCS = Pain Catastrophizing Scale; PD-Q = painDETECT Questionnaire; PGIC = Patient Global Impression of 
Change; PHQ-9 = Patient Health Questionnaire-9; SPADI = Shoulder Pain and Disability Index. 
 
 


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APPENDIX B:  CLINICAL LABORATORY ANALYTES 
Standard Safety Chemistry Panel 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatinine 
Glucose 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Uric acid 
 
 
Endocrinology 
Follicle-stimulating hormone [1] 
Serum pregnancy test 
Urine pregnancy test 
 
1. Follicle-stimulating hormone in perimenopausal women who have not had a menstrual period 
for 1 year will be measured at the Screening Visit. 
 
Hematology 
Hematocrit 
Hemoglobin 
Hemoglobin A1c  
Mean cell volume 
Platelet cell count 
Red blood cell count 
White blood cell count and differential [2] 
 
2. Manual microscopic review is performed only if white blood cell count and/or 
differential values are out of reference range. 
 
Virology 
Hepatitis B surface antigen 
Hepatitis C antibody [3] 
Human immunodeficiency virus [4] 
 
3. Patients positive for hepatitis C virus (HCV) antibody will have reflex testing for circulating 
HCV ribonucleic acid. 
4. Human immunodeficiency virus screening will use a current fourth generation test for both 
antibody and viral antigen. 


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APPENDIX C:  HOME EXERCISE PROGRAM FOR PATIENTS WITH 
SHOULDER ADHESIVE CAPSULITIS 


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APPENDIX D:  INSTRUCTIONS FOR MEASURING RANGE OF 
MOTION OF THE GLENOHUMERAL JOINT WITH A GONIOMETER1 
Instrument: Goniometer (Medigauge® electronic digital goniometer for orthopedics, chiropractic, 
sports medicine, animal science, occupational therapy, physical therapy, and research) 
 
Patient position: Sitting or supine position 
Scapular position: Stabilize the scapula by grasping the coracoid process and the spine of the 
scapula posteriorly (2 people may be needed to fully inhibit scapular motion). 
Glenohumeral joint flexion  
To measure flexion range of motion (ROM), the patient must be in sitting or supine position with 
the arm comfortably by the side.  
• The patient will be asked to actively flex the shoulder with his/her palm facing medially to end 
range in the sagittal plane (with no compensatory movements from the thorax or the lumbar 
spine). Range of motion will be measured by placing the axis of the goniometer over the 
humeral head. The stationary arm will be aligned with the midline of the trunk. The movable 
arm will be aligned with the lateral epicondyle.  
• For passive ROM, the examiner will passively flex the shoulder with the patient’s palm facing 
medially until end range is reached and measures as above.  
 
1. 
Magee D. Orthopedic Physical Assessment. 6th edition. Saunders. 2013 


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Glenohumeral joint abduction  
To measure abduction ROM, the patient must be in a sitting or supine position with the arm 
comfortably by his/her side. 
• The patient will be asked to actively abduct the shoulder in external rotation position (palm 
facing up) to end range (shoulder must remain in the frontal plane). Range of motion will be 
measured by placing the axis of the goniometer over the anterior aspect of the acromion 
process.. The stationary arm will be aligned parallel with the midline of the sternum. The 
movable arm will be aligned with the midshaft of the humerus.  
• For passive ROM, the examiner will passively abduct the shoulder with the patient’s palm 
facing up until end range is reached and measures as above. 
Glenohumeral external rotation  
To measure external rotation ROM with the shoulder in the adduction position, the patient must 
be in a sitting or supine position. Place a folded towel under the humerus to keep the shoulder and 
elbow level with the elbow flexed to 90° (palm facing medially) and the forearm perpendicular to 
the floor. 
• The patient will be asked to actively externally rotate the shoulder to end range. Range of 
motion will be measured by placing the axis of the goniometer on the olecranon process. The 
stationary arm will be perpendicular to the floor. The movable arm will be aligned with the 
ulnar styloid process. 
• For passive ROM, the examiner will passively externally rotate the glenohumeral joint until 
end range is reached and measures as above. 
Glenohumeral internal rotation in 45°or comfortable abduction  
Internal rotation ROM must be measured with the patient in a sitting or supine position, the 
shoulder abducted to 45° or comfortable position, and the elbow flexed to 90°. Place a folded towel 
under the humerus to keep the shoulder and elbow level.   
• The patient will be asked to actively internally rotate the shoulder with his/her palm facing 
medially to end range without scapular compensation. Range of motion will be measured by 
placing the axis of the goniometer on the olecranon process. The stationary arm will be 
perpendicular to the floor. The movable arm will be aligned with the ulnar styloid process.  
• For passive ROM, the examiner will passively internally rotate the glenohumeral joint until 
end range is reached, ensuring that there is no scapular compensation. 
 


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APPENDIX E:  COMMONLY PRESCRIBED ANTIDEPRESSANTS BY 
DRUG CLASS 
Class 
Generic Name 
Brand Name(s) 
Selective serotonin reuptake 
inhibitors 
Citalopram  
Celexa®  
Escitalopram 
Lexapro®, Cipralex® 
Fluoxetine 
Prozac®, Sarafem® 
Fluvoxamine 
Luvox®  
Paroxetine 
Paxil®, Seroxat® 
Sertraline  
Zoloft®  
Serotonin-norepinephrine reuptake 
inhibitors 
 
 
Venlafaxine  
Effexor®  
Tricyclic antidepressants 
Amitriptyline  
Elavil®  
Doxepin  
Sinequan®  
Imipramine 
Tofranil® 
Nortriptyline  
Aventyl®, Noritren®, Pamelor® 
Norepinephrine-dopamine reuptake 
inhibitors 
Bupropion 
Wellbutrin®, Zyban®