A Randomized, Open-label Study Comparing the Systemic Exposure to Triamcinolone Acetonide Following a Single Intra-articular Dose of Extended-release FX006 or Immediate-release TAcs (Triamcinolone Acetonide Suspension) in Patients With Osteoarthritis of the Shoulder (Glenohumeral Joint) or Hip
Phase: PHASE2
Conditions: Osteoarthritis of the Shoulder, Osteoarthritis of the Hip
Sponsor: Pacira Pharmaceuticals, Inc

 
CONFIDENTIAL INFORMATION 
CLINICAL STUDY PROTOCOL 
 
A Randomized, Open-label Study Comparing the Systemic Exposure to Triamcinolone 
Acetonide Following a Single Intra-articular Dose of Extended-release FX006 or Immediate-
release TAcs (Triamcinolone Acetonide Suspension) in Patients with Osteoarthritis of the 
Shoulder (Glenohumeral Joint) or Hip 
 
PROTOCOL NUMBER:  FX006-2017-013 
 
 
PHASE:  2a 
 
 
STUDY MEDICATION(S): FX006 
 
INDICATION:  Osteoarthritis of the shoulder or hip 
 
 
  
MEDICAL MONITOR: Robert D. Arbeit, MD 
 
 
 
SPONSOR:  Flexion Therapeutics  
 
DATE:  05 April 2018 
 
  
VERSION: 3.0 
 
SUPERCEDES: Version 2.0 
 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 2 of 53 
SIGNATURE PAGE 
Clinical Study Protocol Version 3.0 (dated 05Apr 2018) 
 
 
 
Sponsor Safety Officer Approval 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
Name (print): 
 
 
Scott Kelley MD 
 
 
Title: 
 
Chief Medical Officer 
 
 
 
Principal Investigator Agreement:  I have read the protocol and agree to conduct the study as 
outlined herein. 
 
 
 
Signature: 
 
 
 
Date: 
 
 
 
Name (print): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 3 of 53 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................6 
1. 
ABBREVIATIONS AND DEFINITION OF TERMS ................................................7 
2. 
SYNOPSIS ...................................................................................................................9 
3. 
ETHICS ......................................................................................................................16 
3.1. 
Institutional Review Board/Ethics committee ............................................................16 
3.2. 
Ethical Conduct of Study ............................................................................................16 
3.3. 
Patient Information and Consent ................................................................................16 
4. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .................17 
4.1. 
Investigators ................................................................................................................17 
4.2. 
Study Administrative Structure ..................................................................................17 
5. 
INTRODUCTION ......................................................................................................17 
5.1. 
Osteoarthritis ...............................................................................................................17 
5.2. 
Background .................................................................................................................17 
5.2.1. 
Investigational Medicinal Product:  FX006 ................................................................17 
5.2.2. 
Rationale for FX006 in OA of the Shoulder and OA of the Hip ................................18 
5.2.3. 
Toxicology ..................................................................................................................18 
5.2.4. 
Systemic and Local PK in Patients with Osteoarthritis of the Knee ..........................19 
5.2.5. 
Pharmacodynamics in Patients with Osteoarthritis of the Knee .................................19 
5.2.6. 
Efficacy in Patients with Osteoarthritis of the Knee ..................................................20 
5.2.7. 
Systemic and Local Safety in Patients with Osteoarthritis of the Knee .....................20 
5.2.8. 
Conclusion ..................................................................................................................21 
6. 
STUDY OBJECTIVES ..............................................................................................21 
6.1. 
Primary Objective .......................................................................................................21 
7. 
INVESTIGATIONAL PLAN .....................................................................................22 
7.1. 
Overall Study Design and Plan ...................................................................................22 
7.2. 
Site Staffing Requirements .........................................................................................22 
7.3. 
Discussion of Study Design ........................................................................................23 
7.3.1. 
Rationale for Study Population ...................................................................................23 
7.3.2. 
Rationale for Dose Selection ......................................................................................23 
7.3.3. 
Rationale for Study Design .........................................................................................23 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 4 of 53 
7.3.4. 
Rationale for Study Parameters ..................................................................................23 
7.3.5. 
Rationale for Control Type .........................................................................................24 
7.4. 
Selection of Study Population ....................................................................................24 
7.4.1. 
Number of Patients .....................................................................................................24 
7.4.2. 
Inclusion Criteria ........................................................................................................24 
7.4.3. 
Exclusion Criteria .......................................................................................................25 
7.4.4. 
Screen Failures ............................................................................................................27 
7.5. 
Treatment Administered .............................................................................................27 
7.5.1. 
Study Medications by Treatment Arm .......................................................................27 
7.5.2. 
Identity of Investigational Product(s) .........................................................................28 
7.5.3. 
Identity of Reference Compound ................................................................................28 
7.5.4. 
Receipt, Dispensing and Storage ................................................................................28 
7.5.5. 
Packaging and Labeling of Study Medication ............................................................28 
7.5.6. 
Return of Study Medication ........................................................................................28 
7.5.7. 
Method of Assigning Patients to Treatment Groups ..................................................29 
7.5.8. 
Blinding ......................................................................................................................29 
7.5.9. 
Study Drug Administration Procedure .......................................................................29 
7.5.10. 
Treatment Compliance ................................................................................................30 
7.5.11. 
Removal of Patients from Therapy or Assessments ...................................................30 
7.6. 
Prior and Concomitant Therapy ..................................................................................30 
7.6.1. 
Allowable Medications ...............................................................................................30 
7.6.2. 
Restricted Medications ...............................................................................................31 
7.7. 
Study Variables ...........................................................................................................31 
7.7.1. 
Safety Variables ..........................................................................................................31 
7.7.2. 
Pharmacokinetic Variables .........................................................................................31 
7.8. 
Schedule of Study Assessments..................................................................................31 
7.9. 
Study Procedures ........................................................................................................33 
7.9.1. 
Informed Consent .......................................................................................................33 
7.9.2. 
Review of eligibility, medical history, prior treatment and medications ...................33 
7.9.3. 
Physical Examination .................................................................................................33 
7.9.4. 
Index Joint X-ray ........................................................................................................33 
7.9.5. 
Index Joint Assessment ...............................................................................................34 
7.9.6. 
12-lead ECG ...............................................................................................................34 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 5 of 53 
7.9.7. 
Vital Signs ..................................................................................................................34 
7.9.8. 
Height, Weight and BMI determination .....................................................................34 
7.9.9. 
Pharmacokinetic Evaluations ......................................................................................35 
7.9.10. 
Central Clinical Laboratory Evaluations ....................................................................35 
7.9.11. 
Treatment Administration ...........................................................................................36 
7.9.12. 
Review of adverse events and concomitant medications ...........................................36 
8. 
CLINICAL SAFETY ASSESSMENTS .....................................................................37 
8.1. 
Adverse Events ...........................................................................................................37 
8.1.1. 
Definitions ..................................................................................................................37 
8.1.2. 
Evaluating and Recording of Adverse Events ............................................................38 
8.1.3. 
Reporting of Serious Adverse Events .........................................................................40 
8.1.4. 
Safety Monitoring Roles .............................................................................................40 
8.1.5. 
Clinical Management of Index Joint Related Events .................................................40 
8.1.6. 
Pregnancy ...................................................................................................................41 
9. 
STATISTICAL CONSIDERATIONS .......................................................................41 
9.1. 
Statistical and Analytical Plans ..................................................................................41 
9.1.1. 
Final Analyses ............................................................................................................41 
9.2. 
General Considerations and Methods .........................................................................41 
9.2.1. 
Analysis Populations ..................................................................................................41 
9.2.2. 
Study Data ..................................................................................................................42 
9.2.3. 
Study Variables for Assessment .................................................................................42 
9.2.4. 
Sub-Groups and Covariates ........................................................................................42 
9.3. 
Determination of Sample Size ....................................................................................42 
9.3.1. 
Sample Size Considerations: ......................................................................................42 
9.3.2. 
Sample Size Estimate: ................................................................................................42 
9.4. 
General statistical Methods .........................................................................................43 
9.4.1. 
Demographics and Baseline Characteristics ...............................................................43 
9.4.2. 
Exposure .....................................................................................................................43 
9.4.3. 
Efficacy Analyses .......................................................................................................43 
9.4.4. 
Safety Analyses ..........................................................................................................43 
9.4.4.1. 
Analysis of Adverse Events ........................................................................................43 
9.4.4.2. 
Other Safety Analyses ................................................................................................43 
9.4.4.3. 
Pharmacokinetic Analyses ..........................................................................................43 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 6 of 53 
10. 
DATA QUALITY ASSURANCE ..............................................................................44 
11. 
DATA HANDLING AND RECORDKEEPING .......................................................45 
11.1. 
Case Report Forms .....................................................................................................45 
11.2. 
Study Medication Accountability ...............................................................................45 
11.3. 
Confidentiality of Data ...............................................................................................45 
11.4. 
Retention of Records ..................................................................................................45 
11.5. 
Protocol Adherence ....................................................................................................46 
12. 
PUBLICATION POLICY ..........................................................................................47 
12.1. 
Sponsor’s Publication Policy ......................................................................................47 
12.2. 
Site publication ...........................................................................................................47 
13. 
REFERENCES ...........................................................................................................48 
14. 
APPENDICES ............................................................................................................50 
 
 
 
LIST OF TABLES 
Table 1: 
Schedule of Study Assessments..................................................................................32 
Table 2: 
BMI Calculations ........................................................................................................35 
Table 3: 
Clinical Laboratory Panel ...........................................................................................36 
 
 
 
 
 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 7 of 53 
1. 
ABBREVIATIONS AND DEFINITION OF TERMS 
ACR 
American College of Rheumatology 
ADL 
Activities of Daily Living 
ADP 
Average Daily Pain 
AE 
Adverse Event 
AUC 
Area Under the Concentration-time Curve  
AUE 
Area Under the Effect Curve  
BE 
Bioequivalence  
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CGIC 
Clinical Global Impression of Change 
CI 
Confidence Interval 
CMC 
Carboxymethylcellulose Sodium 
CTCAE 
Common Terminology Criteria for Adverse Events 
CSR 
Clinical Study Report 
CV 
Coefficient of Variation 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EULAR 
European League Against Rheumatism 
FBR 
Foreign Body Response 
FDA 
Food and Drug Administration  
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B Surface Antigen 
HbA1c 
Hemoglobin A1c 
HCV 
Hepatitis C Virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HPA 
Hypothalamic-pituitary-adrenal 
IA 
Intra-articular 
IB 
Investigator’s Brochure 
IRB/EC 
Institutional Review Board/Ethics Committee 
IM 
Intramuscular 
IV 
Intravenous 
JSN 
Joint Space Narrowing 
kg 
Kilogram 
KOOS  
Knee injury and Osteoarthritis Outcome Score  
LLOQ 
Lower Limit of Quantification 
LSM 
Least Square Mean  

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 8 of 53 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
mmol/mol 
Millimoles per Mole 
MRT 
Mean Residence Time 
msec 
Millisecond 
n 
Number 
NaCl 
Sodium Chloride 
NRS 
Nuclear Rating Scale 
OA 
Osteoarthritis 
OARSI 
Osteoarthritis Research Society International 
PGIC 
Patients’ Global Impression of Change 
PLGA 
Poly[lactic-co-glycolic acid] 
PK 
Pharmacokinetic 
PRP 
Platelet Rich Plasma 
QOL 
Quality of Life 
QTc 
QT interval corrected for heart rate 
RBC 
Red Blood Cells 
RNA 
Ribonucleic Acid  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
S-P 
Samilson-Prieto 
TEAE 
Treatment-emergent Adverse Event 
TA1 
Triamcinolone Acetonide  
TAcs2 
Triamcinolone Acetonide Injectable Suspension, Immediate-Release 
(commercially available) 
US 
United States 
USP 
United States Pharmacopeia 
w/w 
weight by weight 
WBC 
White Blood Cells 
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 
                                                 
1 Abbreviated in past protocols and documents as TCA 
2 Abbreviated in past protocols and documents as TCA-IR 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 9 of 53 
2. 
SYNOPSIS 
Title of Study: A Randomized, Open-label Study Comparing the Systemic Exposure to Triamcinolone Acetonide 
Following a Single Intra-articular Dose of Extended-release FX006 or Immediate-release TAcs (Triamcinolone 
Acetonide Suspension) in Patients with Osteoarthritis of the Shoulder (Glenohumeral Joint) or Hip 
Study Centers:  Approximately 8 
Study Phase:  2a 
Objectives: 
The objectives of this study are to: 
• 
compare the plasma pharmacokinetics, including systemic exposure, of triamcinolone acetonide (TA) 
• 
assess the safety and general tolerability 
following a single intra-articular (IA) injection of 32 mg FX006 or 40 mg TAcs in patients with osteoarthritis (OA) 
of either the glenohumeral (also referred to herein as shoulder) or hip joint. 
Study Design and Methodology: 
This is a randomized, open-label, single dose study that will be conducted in male and female patients ≥40 years of 
age with OA of either the shoulder or the hip.  
Approximately 24 patients with OA of the shoulder and approximately  24 patients with OA of the hip will be 
randomized to one of two treatment groups (1:1) and treated with a single IA injection of either: 
• 
32 mg FX006 (approximately 12 patients per joint) or 
• 
40 mg TAcs (approximately 12 patients per joint) 
Each patient will be screened to confirm the diagnosis of OA of either the shoulder or hip and eligibility based on 
the other inclusion/exclusion requirements and will be randomized to treatment on Day 1. Each patient will be 
evaluated for a total of 12 weeks following the IA injection.  Following screening, sampling for pharmacokinetics 
(PK) and safety will be completed at 10 out-patient visits scheduled on Study Days 1 [calendar day of injection], 2, 
3, 5, 8, 15, 22, 29, 57, and 85.  The study is expected to enroll in approximately 3 months. 
Number of Patients: 
Approximately 24 patients with OA of the shoulder and approximately 24 patients with OA of the hip will be 
treated with a single IA injection of FX006 or TAcs. 
Test Product, Dose and Mode of Administration: 
FX006 – extended release formulation of TA in 75:25 poly(lactic-co-glycolic) acid (PLGA)  microspheres: Nominal 
32 mg TA, IA injection, administered as a 5 mL injection 
Reference Compound(s), Dose and Mode of Administration: 
Shoulder: Commercially available TAcs (Kenalog®) injectable suspension, 40 mg/mL, IA, administered as a 1 mL 
injection in the shoulder. 
Hip: Commercially available TAcs (Kenalog®) injectable suspension, 40 mg/mL, IA, (1 mL)  combined with 
normal saline, sodium chloride (0.9% NaCl) solution, IA (4 mL), administered as a 5 mL injection in the hip. 
Duration of Dosing: 
Single IA injection 
 
 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 10 of 53 
Inclusion Criteria:  
To be included in the trial, patients must fulfill the following criteria:  
Patient-related criteria 
1. Written consent to participate in the study 
2. Male or female ≥40 years of age 
3. Body mass index (BMI) ≤ 40 kg/m2 
4. Ambulatory and in good general health  
5. Willing and able to comply with the study procedures and visit schedules and able to follow verbal and written 
instructions 
6. Willing to abstain from use of the following protocol-restricted treatments from Screening through End-of-
Study visit: 
• 
Intravenous (IV), Intramuscular (IM), oral, inhaled, intranasal, or topical corticosteroids 
• 
IA corticosteroids in any joint 
• 
IA viscosupplementation (hyaluronic acid) in the index joint 
• 
Any investigational drug or device 
• 
Immunomodulators, immunosuppressives, or chemotherapeutic agents  
• 
Live or live-attenuated vaccines 
7. Sexually active males and females  of child-bearing potential (defined as not surgically sterile or post-
menopausal [defined as 12 consecutive months  with no menses without an alternative medical cause] for at 
least 1 year as documented in medical history) agree to use one of the following highly effective method 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). Females must agree to use such contraceptive measures for at 
least 30 days after the administration of the study drug. Males must agree to use contraceptives for at least 90 
days after administration of the study drug. 
Index Joint-related criteria  
For each patient, the index joint will meet the appropriate criteria as follows.  
8. Symptoms consistent with OA of the index joint for ≥ 6 months prior to Screening (patient reported is 
acceptable) 
9. Pain in the index joint for >15 days over the last month (as reported by the patient)  
10. (a)  Shoulder OA as defined by:  
• 
Radiologic findings of OA of the index shoulder meeting the Samilson-Prieto (S-P) Classification 
(Elsharkawi et al, 2013) Grades 2 or 3, defined as:  
o 
Grade 2, moderate (osteophytes 3 to 7 mm; with or without slight glenohumeral irregularity); 
o 
Grade 3, severe (osteophytes >7 mm, with or without glenohumeral joint narrowing and 
sclerosis). 
10. (b)  Hip OA as defined by: 
• 
ACR Criteria (clinical and radiological) for OA of the index hip (Altman et al, 1991):  
o 
Hip pain  
o 
at least 2 of the following 3 features: 
• 
ESR<20 mm/hour 
• 
Radiographic femoral or acetabular osteophytes 
• 
Radiographic joint space narrowing (superior, axial, and/or medial) 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 11 of 53 
Exclusion Criteria: 
Patients fulfilling at least one of the following criteria may not be included in the study: 
Disease-related criteria 
1. Reactive arthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or arthritis associated 
with inflammatory bowel disease  
2. History of infection in the index joint 
3. Clinical findings consistent with active infection or crystal disease in the index joint within 1 month of 
Screening 
4. History of fracture in the index limb within 12 months of Screening, or fracture with sequelae at any time 
5. Planned or anticipated surgery of the index joint during the study period 
6. Index joint instability or history of acute dislocation within 12 months of  Screening 
7. If shoulder is the index joint, history of full or partial rotator cuff tear or significantly compromised rotator 
cuff function that, in the opinion for the Investigator, increases the difficulty or risk of IA injection 
Previous or concomitant treatment-related criteria 
8. Presence of surgical hardware or other foreign body in the index joint 
9. Surgery or arthroscopy of the index joint within 12 months of Screening  
10. IA treatment of any joint with any of the following agents within 6 months of Screening:  
any corticosteroid preparation (investigational or marketed, including FX006), any biologic agent (e.g., 
platelet rich plasma (PRP) injection, stem cells, prolotherapy, amniotic fluid injection; investigational or 
marketed) 
11. IA treatment of the index joint with hyaluronic acid (investigational or marketed) within 6 months of 
Screening 
12. Parenteral or oral corticosteroids (investigational or marketed) within 3 months of Screening 
13. Inhaled, intranasal or topical corticosteroids (investigational or marketed) within 2 weeks of Screening 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 12 of 53 
Patient-related criteria 
14. Females who are pregnant or nursing or plan to become pregnant during the study; men who plan to 
conceive during the study 
15. Known hypersensitivity to any form of triamcinolone 
16. Use of anticoagulants (e.g., warfarin) at the time of Screening and for the duration of the study 
17. Skin breakdown at the index joint where the injection would take place 
18. Laboratory evidence of infection with human immunodeficiency virus (HIV), positive test for hepatitis B 
surface antigen (HBsAg) or positive serology for hepatitis C virus (HCV) with positive test for HCV RNA 
19. Uncontrolled diabetes as indicated by a hemoglobin A1c (HbA1c) of > 7.5% (> 59 mmol/mol) 
20. Any electrocardiogram (ECG) abnormality judged clinically significant by the Investigator 
21. A medical history suggesting the patient will or is likely to require a course of systemic corticosteroids 
during the study period  
22. History or evidence of active or latent systemic fungal or mycobacterial infection (including tuberculosis), 
or of ocular herpes simplex  
23. History of sarcoidosis or amyloidosis  
24. History of or active Cushing’s syndrome 
25. History of osteomyelitis of the index joint at any time, or of other areas within 5 years    
26. Use of immunomodulators, immunosuppressives, or chemotherapeutic agents within 5 years of Screening  
27. Active or history of malignancy within 5 years of Screening, with the exception of resected basal cell 
carcinoma, squamous cell carcinoma of the skin, or effectively managed cervical carcinoma 
28. Active substance abuse (drugs or alcohol) or history of substance abuse within the past 12 months of 
Screening 
29. Has received a live or live-attenuated vaccine within 3 months of Screening 
30. Use of any other investigational drug, biologic or device within 3 months of Screening. 
31. Any bacterial or viral infection requiring IV antibiotics within 4 weeks of Screening or oral antibiotics 
within 2 weeks of Screening  
32. Any other clinically significant acute or chronic medical conditions (e.g., bleeding disorder) 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 
Procedures and Assessments: 
Patients participating in this study will complete visit schedule as detailed in the Study Design, including the 
procedures indicated in the Schedule of Study Assessments. Those procedures include safety assessments, such as 
physical examinations, vital signs, blood collection for hematology and chemistry analyses, as well as adverse event 
monitoring and concomitant medication review.  
Blood samples for drug concentration measurements will be obtained from all patients on Day 1 prior to 
administration of study medication, and at 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours (± 10 min) after injection, on Day 2 at 
24 hours (± 2 hrs.) after the first injection of study medication, and at each of the subsequent scheduled visits.   
See Schedule of Study Assessments for full details. 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 13 of 53 
Blinding:  
Not applicable, this is an open-label study. 
Study Drug Administration Procedure:  
IA injections will be performed by the assigned injector. The injector may choose the numbing agent to be used 
based on standard of care. Sterile technique will be used.   
Prior to injection, the injection site should be thoroughly cleansed using a bactericidal solution.   
IA administration into the shoulder joint: 
Depending on randomization assignment either 5 mL of the reconstituted FX006 or 1 mL of TAcs will be injected 
into the shoulder joint. Refer to the Pharmacy Binder for detailed instructions on how to prepare FX006.   
Injection into the shoulder joint will be done with ultrasound guidance by the assigned injector. The injector may 
choose the approach for injection (e.g., anterior, posterior or lateral.)  
The injector will use a 21 gauge or larger needle for injection into the shoulder joint. 
Refer to Appendix 1 for detailed instructions on IA administration of study drug to the shoulder with ultrasound 
guidance. 
IA administration into the hip joint  
Depending on randomization assignment either 5 mL of the reconstituted FX006 or 5 mL of TAcs (1mL) and 
normal saline (4 mL) will be injected into the hip joint.  Refer to the Pharmacy Binder for detailed instructions on 
how to prepare FX006. 
Injection into the hip joint will be done with ultrasound guidance by the assigned injector. The injector may choose 
the position of the hip (e.g., supine position with lower extremity internally rotated) and the approach for injection 
(e.g., anterior.) 
The injector will use a 21 gauge or larger needle for injection into the hip joint. 
Refer to Appendix 1 for detailed instructions on IA administration of the study drug to the hip with ultrasound 
guidance. 
Post-Injection Care 
Patients should be advised to avoid strenuous activities or prolonged weight-bearing activities for approximately 24 
to 48 hours following the injection and to also maintain a stable lifestyle with regard to physical activity throughout 
the duration of the study. 
In the event that the patient has an immediate reaction (e.g., tenderness, increased pain, swelling, effusion, 
decreased mobility of the index joint), the patient should be treated according to local clinical guidelines and 
physician experience. 
Concomitant Medications: 
For the duration of the study, the following medications should not be taken by the patient:   
• 
IV, IM, oral, inhaled, intranasal or topical corticosteroids 
• 
IA corticosteroids in any joint 
• 
IA viscosupplementation (hyaluronic acid) or any IA intervention (IA injection, etc.) in the index joint 
• 
Any investigational drug, device or biologic 
• 
Immunomodulators, immunosuppressives, or chemotherapeutic agents  
• 
Live or live-attenuated vaccines 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 14 of 53 
Criteria for Evaluation: 
Extent and Duration of Exposure 
Drug concentration measurements in plasma (in ng/mL)  and the following derived pharmacokinetic parameters 
• 
Cmax: Peak exposure, Maximum plasma concentration  
• 
Tmax: Time from dosing to peak exposure, time to maximum plasma concentration 
• 
Clast: Last quantifiable plasma concentration (last value observed above assay BLOQ) 
• 
Tlast: Time of last quantifiable plasma concentration 
• 
T1/2: Terminal half-life 
• 
AUC (0-last): Exposure: Area Under the Plasma Curve from time 0 to the last quantifiable concentration 
(Clast) 
• 
AUC(0-t): Exposure: Area Under the Plasma Curve from time 0 to tau post-IA injection, where tau is defined 
for partial AUC parameters from 0 to 24, and 0-96 hours.  
• 
AUC(0-inf): Exposure: Area Under the Plasma Curve from time 0 extrapolated to infinity. 
• 
MRT (Observed and Predicted): Mean residence time extrapolated to infinity 
Safety  
• 
AEs 
• 
Physical examinations 
• 
Index joint examinations 
• 
Vital signs 
• 
Clinical laboratory evaluations 
Sample Size Considerations: 
In this study, it is expected that the systemic exposure in plasma of TA from extended-release FX006 should not 
exceed that of the immediate-release TAcs formulation for the key parameters of Cmax, AUC (0-t), and AUC(0-inf).  
In a previous pharmacokinetic study with knee OA patients (FX006-2015-009) the ratio of the mean exposure 
parameters for 32 mg FX006 (N=60) and 40 mg TAcs (N=18) for Cmax was 0.10 with the upper limit of its 90% CI 
being 0.15 and for AUC(0-inf) was 0.52 with the upper limit of its 90% CI being 0.86. The pooled coefficients of 
variation for the parameters was between 0.53 (Cmax) and 0.68 (AUC0-inf).  
Sample Size Estimate: 
In this study, it is expected that the ratio of exposure means (FX006/TAcs) will be less than 1.0 when administered 
to treat either shoulder or hip OA. A sample size of 12 in each treatment arm (24 in total) is estimated for each joint 
cohort (hip and shoulder). Within each group the sample size of 24 achieves approximately 90% power, with a two-
sided alpha 0.05, to detect a ratio less than 1.0 of the exposure PK parameter means (FX006 / TAcs), with a pooled 
coefficient of variation estimate of 0.68 (PASS 15 Power Analysis and Sample Size Software (2017). NCSS, LLC. 
Kaysville, Utah, USA, ncss.com/software/pass). The sample size of 12 per treatment arm in each joint cohort 
assumes a 10% noncompliance sampling rate (a drop-out rate) for providing complete blood samples for PK 
analysis, and is sufficient to characterize the comparative pharmacokinetic of FX006 and TAcs in this study. The 
total sample size is estimated to be 48 patients (hip: 12 in each treatment arm, shoulder: 12 in each treatment arm) 
for the study 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 15 of 53 
Statistical Methods: 
Complete details of the statistical and PK analyses will be specified in the statistical analysis plan (SAP).  Two 
analysis populations are planned for the study.  
• 
The Safety Population will include all patients who receive study drug. The Safety Population will be used 
to assess safety and tolerability. 
• 
The PK Population will include patients who receive study drug and have sufficient plasma concentration 
data to allow calculation of PK parameters to be included in the PK population. Eligibility for inclusion 
into the PK Population will be determined by the pharmacokineticist for the study following review of 
plasma data. 
Pharmacokinetic (PK) parameters will be derived for each patient from plasma concentrations of TA using model-
independent non-compartmental analysis: (NCA) [Phoenix 7, WinNonlin® 7]. Individual elapsed sampling times 
(actual time) will be used in the PK calculations if significant deviations from the nominal sampling times are noted, 
otherwise nominal times will be used for analysis. Complete details on the calculation of PK parameters, and 
handling of concentration values below the Lower Limit of Quantification (LLOQ) will be fully specified in the 
SAP. 
Descriptive summaries of the TA plasma concentration levels (ng/mL) observed at each nominal time point will be 
provided for FX006 and TAcs treatments in each joint cohort (hip and shoulder). Descriptive summaries of the PK 
parameter estimates from each treatment group will also be completed for each joint cohort. Summary statistics for 
continuous variables will include n, mean, standard deviation, coefficient of variation (CV%), median, minimum, 
and maximum, geometric mean and standard error of the geometric mean. 
By patient plots (linear-linear, log-linear) of the plasma TA concentration data will be completed for each treatment 
group in each joint cohort. 
The PK parameters for Cmax, Tmax, AUC, and MRT PK parameters will be informative of the overall systemic 
exposure of TA from extended-release FX006 and immediate-release TAcs. A linear model will be used to compare 
the PK parameters from extended-release FX006 and immediate-release TAcs. Full details of the linear model will 
be specified in the SAP. 
Bioequivalence (BE) ratios between extended-release FX006 (Test) and immediate-release TAcs (Reference) for 
Cmax and AUC parameters will be explored.  Bioequivalence between Test and Reference will be evaluated using 
the average BE method for the mean ratio between test and reference products (μT/μR) as described in FDA 
guidance. Full details on the analysis of BE will be included in the SAP.  
 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 16 of 53 
3. 
ETHICS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical 
Investigators (21 CFR 312). 
3.1. 
Institutional Review Board/Ethics committee  
This study will be conducted in compliance with current Good Clinical Practices (GCP) and 
Title 21 Part 56 of the United States of America Code of Federal Regulations (CFR) relating to 
Institutional Review Board (IRB)/Ethics Committee (EC). 
This study protocol and other related study documents will be submitted to the IRB/EC by the 
site or the Sponsor for review and approval as dictated by local regulations.  IRB/EC approval 
must be obtained before commencement of any study procedures. The study will be conducted 
only at sites where IRB/EC approval has been obtained. 
3.2. 
Ethical Conduct of Study 
This study will be conducted in accordance with the protocol, GCP guidelines and applicable 
national regulatory requirements. 
GCP is an international ethical and scientific quality standard for designing, conducting, 
recording, and reporting studies that involve the participation of human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study 
subjects are protected, consistent with the principles that have originated in the Declaration of 
Helsinki and that the clinical study data are credible. 
3.3. 
Patient Information and Consent 
Prior to initiation of any study related procedures, patients will give their written consent 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. 
An IRB/EC-approved informed consent document must be signed by the patient before his or her 
participation in the study.  A copy of the informed consent document must be provided to the 
patient.  If applicable, it will be provided in a certified translation of the local language. 
Signed informed consent forms must remain in each patient’s study file and must be available for 
verification by study monitors at any time. 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 17 of 53 
4. 
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE  
4.1. 
Investigators 
A Principal Investigator will be responsible for study conduct at each center and may delegate 
study-related activities to appropriately qualified and trained staff. This delegation will be 
documented in a study-specific Delegation of Responsibilities form. 
The contact information for all Principal Investigators participating in the trial will be kept in the 
Trial Master File. 
4.2. 
Study Administrative Structure 
The study will be managed by the Sponsor with specific responsibilities delegated to contract 
research organizations. 
5. 
INTRODUCTION 
5.1. 
Osteoarthritis 
Osteoarthritis (OA) is a painful and debilitating musculoskeletal disease that is characterized by 
intra-articular (IA) inflammation, deterioration of articular cartilage, and degenerative changes to 
peri-articular and subchondral bone (Creamer and Hochberg, 1997; Goldring and Goldring, 
2006).  Arthritis is the most common cause of disability in the United States (US) and OA is the 
most common joint disease, affecting 27 million Americans, with numbers expected to grow as a 
result of aging, obesity and sports injuries.  Recent data suggest that OA accounts for over $185 
billion of annual healthcare expenditures in the US, which does not include loss of productivity 
costs.  We estimate that by 2030, 45 million people will have OA.  OA commonly affect large 
weight-bearing joints like the knees and hips, but also occurs in the shoulders, hands, feet and 
spine.  Patients with OA suffer from joint pain, tenderness, stiffness and limited movement.  As 
the disease progresses, it becomes increasingly painful and debilitating, culminating, in many 
cases, in the need for total joint arthroplasty. 
Current Guidelines from the American College of Rheumatology (ACR), Osteoarthritis Research 
Society International (OARSI) and the European League against Rheumatism (EULAR) 
recommend the use of IA corticosteroids for short-term acute pain relief (Hochberg et al, 2012; 
Jordan et al, 2003; Menge et al, 2014). 
5.2. 
Background 
5.2.1. 
Investigational Medicinal Product:  FX006 
FX006 is an extended-release formulation of TA for IA administration. It is approved under the 
trade name ZILRETTA™ for the management of pain of osteoarthritis of the knee; however, 
shoulder and hip OA have not been studied and is an investigational use.  FX006 is intended to 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 18 of 53 
deliver TA to the synovial and peri-synovial tissues for a period of approximately 3 months 
depending on the dose administered.  (Bodick et al, 2013) 
FX006 contains TA, United States Pharmacopeia (Ph. Eur/USP), formulated in 75:25 
poly(lactic-co-glycolic acid) (PLGA) microspheres with a nominal drug load of 25% (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). 
5.2.2. 
Rationale for FX006 in OA of the Shoulder and OA of the Hip 
Available clinical and nonclinical data indicate that FX006 is safe and well tolerated when 
administered as a single injection into one knee and provides pain relief that is meaningfully 
better and more persistent than that provided by immediate release TAcs.   
The current clinical development program focuses on extending these studies to evaluate the 
therapeutic effects of FX006 in patients with OA of the shoulder and hip.  Although anatomy 
differs between the shoulder, hip and knee joints, the same histologic and cellular structures are 
present, the underlying pathophysiology is the same, and the injection volume of FX006 (5 mL) 
is appropriate to these large joints.  
5.2.3. 
Toxicology 
Overall, single or repeat administration of FX006 at the proposed clinical dose of 32 mg has no 
new safety liabilities compared to TAcs: 
• Systemic findings were similar among TAcs and FX006 groups following single and 
repeat dosing and were generally reversible.  Initial effects on clinical pathology 
parameters were more pronounced for the immediate-release form.  The incidence 
and/or intensity of steroid-associated systemic histopathological findings at the later 
time points were slightly higher for high dose FX006 than for TAcs at the same dose 
level of TA (18.75 mg/mL/joint), as expected based on the sustained release of TA.  
Microspheres were not detected in tissues outside of the synovial space. 
• Local findings were similar among TAcs and the FX006 groups and were reversible.  
The single and repeat dose dog toxicity studies recapitulated known effects of TA that 
had been previously published in normal animal joints following prolonged exposure.  
These include decreased Safranin O staining and changes in structure and cellularity 
of articular cartilage.   
• An expected, mild, reversible Foreign Body Response (FBR) was noted to the PLGA 
component of FX006 microspheres. 
− The local tissue response to the presence of blank microspheres as well as FX006 
microspheres consisted of an expected FBR of macrophage and multinucleated 
giant cell infiltration involving the synovium. Following a single dose, the FBR 
was evident at Day 4, peaked at approximately 6 weeks and was completely 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 19 of 53 
resolved by 6 months in all FX006 animals. Occasional lymphocyte and plasma 
cell infiltrates and sporadic focal-to-multifocal areas of minimal-to-slight fibrosis 
resolved by 9 months.  Following repeat IA dosing, a similar local, reversible 
FBR was noted.   
− Further, the dogs in these studies showed no local signs of inflammation on or 
around the joint and did not display pain, discomfort or difficulty.  
Information available for TA from the literature, corticosteroid product labels and clinical 
experience suggest that the potential of genetic toxicity, reproductive toxicity and carcinogenic 
potential of TA are 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. 
5.2.4. 
Systemic and Local PK in Patients with Osteoarthritis of the Knee 
Overall, FX006 displayed a favorable plasma PK profile relative to TAcs. 
PK 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.  TA 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.  
Relative to TAcs, 32 mg FX006 produced substantially lower peak plasma and systemic 
exposure to TA. FX006 performed as expected, prolonging the residence of TA in the joint while 
minimizing systemic exposure to TA. 
5.2.5. 
Pharmacodynamics in Patients with Osteoarthritis of the Knee 
In a Phase 2 PK/PD study evaluating three dose levels of FX006 (10 mg, 40 mg, 60 mg) 
administered as a 3 mL injection, suppression of cortisol in the days following injection 
produced by the 10 and 40 mg dose 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 Day 1-2 associated with all doses of FX006 would not be expected to be of clinical 
consequence in adult patients without otherwise comprised HPA 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 (70-180 mg/dL) 
(American Diabetes Association, 2016) was greater for FX006 as compared to TAcs over the 48 
hours post IA injection, providing another indication of the improvement in glycemic control. 
Over the entire time course of the 15-day post injection glucose monitoring period, blood 
glucose levels associated with FX006 remained at levels similar to or lower than those produced 
by TAcs. This observation is consistent with PK studies demonstrating low systemic exposure to 
TA associated with FX006. 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 20 of 53 
5.2.6. 
Efficacy in Patients with Osteoarthritis of the Knee 
Efficacy data from three studies provide substantial evidence supporting the effectiveness of 
32 mg FX006 in the management of OA pain. (Bodick et al, 2015; Conaghan et al, 2017) 
Results of the primary endpoint from the Phase 3, multi-center, adequate, and well-controlled 
trial, 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. 
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; (ADP) to evaluate durability and magnitude of 
response. These included least square mean (LSM) testing at each week and area under the effect 
curve (AUE) analyses for Weeks 1 through 12 and Weeks 1 through 24. Results demonstrated 
that the analgesic effect of 32 mg FX006 is significant at Week 1, increases through Week 7, and 
is sustained through at least Week 16. Responder analyses further suggested that FX006 provides 
clinically relevant improvement from Weeks 1 through 16 relative to placebo. 
Analyses utilizing data collected from other instruments or measures Western Ontario and 
McMaster Universities Osteoarthritis Index (WOMAC) Patients’ 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 effects on pain 
relief as well as physical function and global well-being.  FX006 32 mg provides 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, significant reduction of rescue 
medication utilization in patients treated with FX006 32 mg is of potential important clinical 
consequence and adds a meaningful element to the overall effectiveness profile of FX006 32 mg. 
Collectively, these results provide substantial evidence to support FX006 32 mg as an effective 
therapy for the management of OA knee pain.  
5.2.7. 
Systemic and Local Safety in Patients with Osteoarthritis of the Knee 
The evaluation of 687 patients treated with a single IA injection of FX006 at any dose in the 
FX006 clinical studies suggests that it was well tolerated with systemic and local safety profiles 
similar to those of TAcs and placebo.   
The safety data from the FX006 clinical studies are largely consistent.  
o The number of treatment-emergent adverse events (TEAEs) reported was similar across 
groups (FX006 46.0%; placebo 49.2%; TAcs 51.0%).   
o The majority of TEAEs in FX006-treated patients were mild or moderate (Grade 1 or 2). 
Severe or life-threatening events occurred in the FX006-treated patients at a rate of 3.0% 
as compared to 5.0% and 2.6% in the placebo and TAcs groups, respectively.  
o In the FX006-treated patients (n=687), the most common TEAEs were: 
− Arthralgia (in any joint) 9.8% (n=67) 
− Headache 5.4% (n=37) 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 21 of 53 
− Upper Respiratory Tract Infection 3.1% (n=21) 
− Joint swelling 2.8% (n=19) 
− Contusion and back pain 2.3% (n=16) 
− Nasopharyngitis 2.2% (n=15) 
• The rate of serious adverse events (SAEs) was low and consistent across groups 
(FX006 1.9%; placebo 1.1%; TAcs 2.3%); none were considered related to the study 
drug.  
• Across all studies there were no deaths.   
In the Phase 3 study, qualitative assessments based on X-rays of the index knee at 24 weeks post 
injection included joint space narrowing (JSN), subchondral bone changes, osteonecrosis, and 
insufficiency fracture. 
• The overall rate of JSN worsening of at least 1-grade between baseline and Week 24 
was low and similar among treatment groups (5.0% [7/140], 4.1% [6/148], and 3.5% 
[5/145] of patients with both baseline and Week 24 X-rays in the 32 mg FX006, 
placebo, and TAcs groups respectively); for all but 1 of these 18 patients, JSN 
worsened by 1 grade only. The remaining patient (in the placebo group) had a 2-grade 
worsening in JSN (from 0 at baseline to Grade 2 at Week 24).  
• No FX006-treated patient had X-ray evidence of treatment-emergent insufficiency 
fracture, subchondral bone changes, or osteonecrosis at Week 24. 
• Eighteen patients discontinued the study prior to Week 24 and completed a final X-
ray as part of early termination visit. Of these, 2 patients, 1 in the 32 mg FX006 group 
and 1 in the placebo group, had a 1-grade increase in JSN. There were no reports of 
insufficiency fracture, subchondral bone changes, or osteonecrosis. 
5.2.8. 
Conclusion 
These data provide bases for continued clinical study of FX006.   
6. 
STUDY OBJECTIVES 
6.1. 
Primary Objective 
The primary objectives of this study are to compare the plasma pharmacokinetics, including 
systemic exposure of TA and assess the safety and general tolerability following a single IA 
injection of 32 mg FX006 or 40 mg TAcs in patients with OA of either the glenohumeral (also 
referred to herein as shoulder) or hip joint.  

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 22 of 53 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
This randomized, open-label, single dose study will be conducted in male and female patients 
≥ 40 years of age with OA of either the shoulder or hip.  
Approximately 24 patients with OA of the shoulder and approximately 24 patients with OA of 
the hip will be randomized to one of two treatment groups (1:1) and treated with a single IA 
injection of either: 
• 32 mg FX006 (approximately 12 patients per joint) or 
• 40 mg TAcs (approximately 12 patients per joint) 
Each patient will be screened to confirm the diagnosis of OA of either the shoulder or hip and 
other eligibility requirements and will be randomized to treatment on Day 1.  Each patient will 
be evaluated for a total of 12 weeks following the IA injection.  Following screening, sampling 
for PK and safety will be completed at 10 out-patient visits scheduled on Study Days 1 [calendar 
day of injection], 2, 3, 5, 8, 15, 22, 29, 57, and 85.  The study is expected to enroll in 
approximately 3 months. 
7.2. 
Site Staffing Requirements 
The Principal Investigator is responsible for overseeing the conduct of the study at his/her site, 
ensuring that sufficient and appropriately experienced staff are available to conduct the trial, and 
ensuring that activities are appropriately delegated and documented  Any delegation of 
responsibilities will be documented in a study-specific Clinical Site Responsibilities and 
Signature log.  The term ‘Principal Investigator’ is used throughout this protocol to refer to the 
actual Principal Investigator and/or his/her delegated team member(s) for the specific 
responsibility being described.  
Pharmacist/coordinator  
• Must be a registered pharmacist or an individual with the qualifications and training 
required to handle and prepare study medications 
• Is responsible for handling and preparing all study medications and maintaining 
investigational product accountability records 
Injector  
• Must be a medical doctor, a physician’s assistant, or nurse practitioner experienced in 
administering IA injections of the index joint using ultrasound guidance 
• Is responsible for performing IA injections of study medication of the index joint 
using ultrasound guidance 
Assessor  
• Must be a medical doctor, a physician’s assistant, or nurse practitioner 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 23 of 53 
• Must have relevant OA experience 
• Is responsible for performing the physical examination and index joint assessments 
• Assessing causality of an adverse event (AE) or SAE 
− Must be either the PI or physician sub-investigator  
The same individual may serve in multiple roles (e.g., a physician sub-investigator may serve as 
both the Injector and/or Assessor).  
7.3. 
Discussion of Study Design 
7.3.1. 
Rationale for Study Population 
Patients with pain associated with OA of either the shoulder or hip as defined by clinical and 
radiologic criteria that are otherwise in good health or that have chronic conditions (for example, 
hypertension) that are well controlled are eligible.  In general this population tolerates IA 
injections of commercially available corticosteroids (Habib 2009).  In prior clinical studies of 
FX006 in this population, single injections of up to 60 mg of FX006 were well tolerated. 
7.3.2. 
Rationale for Dose Selection 
The 32 mg dose of FX006 was selected for study in hip and shoulder based on the safety and 
efficacy seen for this dose in the knee.  In a Phase 2b study (FX006-2014-006) comparing 16 mg 
and 32 mg doses, both dose levels of FX006 achieved maximal analgesic effect based on the 
ADP intensity score using an NRS of similar magnitude at Week 5 post-injection. However, a 
dose effect was evident in the maintenance of maximal effect, which persisted through Week 9 
with 16 mg FX006 and through Week 13 with 32 mg FX006. The durability of the treatment 
effect seen with the 32 mg dose was reproduced in the Phase 3 Study FX006-2014-008.  
Thus, based on the collective clinical evidence (a) there is a dose response effect and (b) the 
32 mg dose of FX006 appears to be the most effective of those doses studied in OA of the knee. 
Further, across several trials, a single IA administration of 32 mg FX006 in the knee has been 
shown to be well-tolerated and in PK studies a single 5 mL IA injection of 32 mg FX006 resulted 
in substantial and sustained joint residency of TCA in adults with OA of the knee.  The approved 
dose of FX006 as an approved treatment for pain associated with OA of the knee is 32 mg; 
therefore this dose was selected for further study in investigational uses. 
7.3.3. 
Rationale for Study Design 
The current trial design is substantially similar to PK studies conducted in OA of the knee. The 
randomized, parallel group design applied in this protocol has proved reliable for comparing the 
plasma PK profiles for these two different formulations.  
7.3.4. 
Rationale for Study Parameters 
Plasma drug concentration measurements directly support the assessment of systemic exposure 
of TA following IA administration of FX006 and TAcs, and the sampling schedule, and PK 
analyses are substantially similar to those conducted for assessment of knee OA. 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 24 of 53 
The clinical safety parameters to be assessed (adverse events, physical examinations, index joint 
examinations, vital signs, and clinical laboratory evaluations) are standard safety and tolerability 
assessments and support the clinical monitoring necessary based on the safety profile for FX006. 
7.3.5. 
Rationale for Control Type 
The active control (TAcs) Kenalog®-40 Injection, is commonly used in the treatment of OA of 
the hip and shoulder, and differences in systemic exposure are informative to clinicians and may 
be extrapolated to other corticosteroids.  
7.4. 
Selection of Study Population 
7.4.1. 
Number of Patients 
Approximately 24 patients with OA of the shoulder and approximately24 patients with OA of the 
hip will be treated with one IA injection of FX006 or TAcs.  
7.4.2. 
Inclusion Criteria 
To be included in the trial, patients must fulfill the following criteria:  
Patient-related criteria 
1. Written consent to participate in the study 
2. Male or female ≥40 years of age 
3. Body mass index (BMI) ≤ 40 kg/m2 
4. Ambulatory and in good general health  
5. Willing and able to comply with the study procedures and visit schedules and able to 
follow verbal and written instructions 
6. Willing to abstain from use of the following protocol-restricted treatments from 
Screening through End-of-Study visit: 
• Intravenous (IV), Intramuscular (IM), oral, inhaled, intranasal, or topical 
corticosteroids 
• IA corticosteroids in any joint 
• IA viscosupplementation (hyaluronic acid) in the index joint 
• Any investigational drug or device 
• Immunomodulators, immunosuppressives, or chemotherapeutic agents  
• Live or live-attenuated vaccines 
7. Sexually active males and females of child-bearing potential (defined as not surgically 
sterile or post-menopausal [defined as 12 consecutive months with no menses without an 
alternative medical cause] for at least 1 year as documented in medical history) agree to 
use one of the following highly effective method of contraception: abstinence; oral, 
injected or implanted hormonal methods of contraception; intrauterine device or 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 25 of 53 
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.).  Females 
must agree to use such contraceptive measures for at least 30 days after the 
administration of the study drug.  Men must agree to use contraceptives for at least 90 
days after administration of the study drug. 
Index Joint-related criteria  
• For each patient, the index joint will meet the appropriate criteria as follows.  
8. Symptoms consistent with OA of the index joint for ≥ 6 months prior to Screening 
(patient reported is acceptable) 
9. Pain in the index joint for >15 days over the last month (as reported by the patient)  
10. 
(a) Shoulder OA as defined by: 
• Radiologic findings of OA of the shoulder meeting the Samilson-Prieto (S-P) 
Classification (Elsharkawi et al, 2013) Grades 2 or 3, defined as:  
o Grade 2, moderate (osteophytes 3 to 7 mm; with or without 
slight glenohumeral irregularity); 
o Grade 3, severe (osteophytes >7 mm, with or without glenohumeral joint 
narrowing and sclerosis). 
10. 
(b) Hip OA as defined by:   
• ACR Criteria (clinical and radiological) for OA of the hip (Altman et al, 1991):  
− Hip pain  
• at least 2 of the following 3 features: 
• 
ESR<20 mm/hour 
• 
Radiographic femoral or acetabular osteophytes 
• 
Radiographic joint space narrowing (superior, axial, and/or medial) 
7.4.3. 
Exclusion Criteria 
Patients fulfilling at least one of the following criteria may not be included in the study: 
Disease-related criteria 
1. Reactive arthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or 
arthritis associated with inflammatory bowel disease  
2. History of infection in the index joint 
3. Clinical findings consistent with active infection or crystal disease in the index joint 
within 1 month of Screening 
4. History of fracture in the index limb within 12 months of Screening, or fracture with 
sequelae at any time. 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 26 of 53 
5. Planned or anticipated surgery of the index joint during the study period. 
6. Index joint instability or history of acute dislocation within 12 months of Screening 
7. If shoulder is the index joint, history of full or partial rotator cuff tear or significantly 
compromised rotator cuff function that, in the opinion for the Investigator, increases the 
difficulty or risk of IA injection.  
Previous or concomitant treatment-related criteria 
8. Presence of surgical hardware or other foreign body in the index joint 
9. Surgery or arthroscopy of the index joint within 12 months of Screening  
10. IA treatment of any joint with any of the following agents within 6 months of Screening: 
any corticosteroid preparation (investigational or marketed, including FX006), any 
biologic agent (e.g., platelet rich plasma (PRP) injection, stem cells, prolotherapy, 
amniotic fluid injection; investigational or marketed) 
11. IA treatment of the index joint with hyaluronic acid (investigational or marketed) within 
6 months of Screening 
12. Parenteral or oral corticosteroids (investigational or marketed) within 3 months of 
Screening 
13. Inhaled, intranasal or topical corticosteroids (investigational or marketed) within 2 weeks 
of Screening 
Patient-related criteria 
14. Females who are pregnant or nursing or plan to become pregnant during the study; men 
who plan to conceive during the study 
15. Known hypersensitivity to any form of triamcinolone 
16. Use of anticoagulants (e.g., warfarin) at the time of Screening and for the duration of the 
study.  
17. Skin breakdown at the index joint where the injection would take place 
18. Laboratory evidence of infection with human immunodeficiency virus (HIV), positive 
test for hepatitis B surface antigen (HBsAg) or positive serology for hepatitis C virus 
(HCV) with positive test for HCV RNA. 
19. Uncontrolled diabetes as indicated by a hemoglobin A1c (HbA1c) of > 7.5% 
(> 59 mmol/mol) 
20. Any electrocardiogram (ECG) abnormality judged clinically significant by the 
Investigator. 
21. A medical history suggesting the patient will or is likely to require a course of systemic 
corticosteroids during the study period  
22. History or evidence of active or latent systemic fungal or mycobacterial infection 
(including tuberculosis), or of ocular herpes simplex  

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 27 of 53 
23. History of sarcoidosis or amyloidosis  
24. History of or active Cushing’s syndrome 
25. History of osteomyelitis of the index joint at any time, or of other areas within 5 years    
26. Use of immunomodulators, immunosuppressives, or chemotherapeutic agents within 5 
years of Screening  
27. Active or history of malignancy within 5 years of Screening, with the exception of 
resected basal cell carcinoma, squamous cell carcinoma of the skin, or effectively 
managed cervical carcinoma 
28. Active substance abuse (drugs or alcohol) or history of substance abuse within 12 months 
of Screening 
29. Has received a live or live-attenuated vaccine within 3 months of Screening 
30. Use of any other investigational drug, biologic or device within 3 months of Screening. 
31. Any bacterial or viral infection requiring IV antibiotics within 4 weeks of Screening or 
oral antibiotics within 2 weeks of Screening 
32. Any other clinically significant acute or chronic medical conditions (e.g., bleeding 
disorder) 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. 
7.4.4. 
Screen Failures 
Minimal data for patients who fail screening such as demographic information and the reason for 
screen failure will be collected. 
Patients that fail to meet eligibility criteria may be re-screened at the discretion of the Medical 
Monitor.  The Medical Monitor will clearly document the rationale for any re-screening decision.  
Patients that are allowed to re-screen will be assigned a new screening number, re-consented and 
may have screening assessments repeated if necessary.   
7.5. 
Treatment Administered 
7.5.1. 
Study Medications by Treatment Arm 
Investigation Medicinal Product Arm: 
• FX006: an extended-release formulation of TA in 75:25 PLGA microspheres. 
Nominal 32 mg TA, administered as a single 5 mL IA injection. 
Reference Compound:   
• Shoulder: Commercially available TAcs (Kenalog®) injectable suspension, 
40 mg/mL, IA, administered as a 1 mL injection in the shoulder. 
• Hip: Commercially available TAcs (Kenalog®) injectable suspension, 40 mg/mL, IA 
(1 mL) combined with normal saline, sodium chloride (0.9% NaCl) solution, IA 
(4 mL), administered as a 5 mL total injection in the hip. 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 28 of 53 
7.5.2. 
Identity of Investigational Product(s) 
FX006 is 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 is reconstituted in 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.  Diluent will be supplied as a sterile liquid in a 5 mL vial with a 
butyl rubber stopper, aluminum seal and plastic cap.  FX006 will be reconstituted in 5.0 mL of 
diluent to form a suspension immediately prior to IA injection.  FX006 will be administered as a 
single 5 mL IA injection. 
7.5.3. 
Identity of Reference Compound  
TAcs (e.g., Kenalog®-40) is a synthetic glucocorticoid corticosteroid with anti-inflammatory 
action.  Each mL of the sterile aqueous suspension provides 40 mg triamcinolone acetonide, with 
sodium chloride for isotonicity, carboxymethylcellulose sodium, and polysorbate 80.  A 
preservative, benzyl alcohol may also be present.  Sodium hydroxide or hydrochloric acid may 
be present to adjust pH to 5.0 to 7.5.  At the time of manufacture, the air in the container is 
replaced by nitrogen. 
For hip injections only: Normal saline (0.9% sodium chloride injection is a sterile, nonpyrogenic, 
isotonic solution of sodium chloride and water for injection. Each mL contains sodium chloride 
9 mg. 
7.5.4. 
Receipt, Dispensing and Storage 
Study medication will be shipped to the site from the drug supply distribution center. Receipt and 
dispensation of study medication will be properly documented on the drug accountability form in 
the Pharmacy Binder. Any temperature excursions should be documented and will require 
Sponsor assessment and authorization for continued use.  
The packaged kits of FX006 will be stored in a secure area and will be stored refrigerated at 2 to 
8 °C. 
TAcs and normal saline will be stored in a secure area at room temperature. 
7.5.5. 
Packaging and Labeling of Study Medication 
The packaged kit of FX006 will contain one (1) vial of FX006, one (1) vial of Diluent, and a vial 
adapter.  The FX006 and diluent vials will be labelled with their respective unique lot numbers 
within the packaged kit, which will be affixed with its own label and kit number.   
TAcs will be supplied as commercially available Kenalog®-40 Injection.  
Normal saline will be supplied locally by the investigative sites.  
7.5.6. 
Return of Study Medication 
All study medications (packaged kits/used and unused vials) will be returned to the drug supply 
distribution center.  Return of study medications will be properly documented. 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 29 of 53 
7.5.7. 
Method of Assigning Patients to Treatment Groups 
Patients will be assigned to treatment groups by randomization using a central system accessed 
directly by the sites after the patient is assessed as eligible. Randomization will be stratified by 
joint cohort (hip or shoulder). 
7.5.8. 
Blinding 
This is an open-label study.  
7.5.9. 
Study Drug Administration Procedure 
IA injections will be performed by the assigned injector. The injector may choose the numbing 
agent to be used based on standard of care. Sterile technique will be used.   
Prior to injection, the injection site should be thoroughly cleansed using a bactericidal solution.   
IA administration into the shoulder joint: 
Depending on randomization assignment either 5 mL of the reconstituted FX006 or 1 mL of 
TAcs will be injected into the shoulder joint. Refer to the Pharmacy Binder for detailed 
instructions on how to prepare FX006.   
Injection into the shoulder joint will be done with ultrasound guidance by the assigned injector. 
The injector may choose the approach for injection (e.g., anterior, posterior or lateral).  
The injector will use a 21 gauge or larger needle for injection into the shoulder joint. 
Refer to Appendix 1 for detailed instructions on IA administration of study drug to the shoulder 
with ultrasound guidance. 
IA administration into the hip joint  
Depending on randomization assignment either 5 mL of the reconstituted FX006 or 5 mL of 
TAcs (1mL) and normal saline (4 mL) will be injected into the hip joint.  Refer to the Pharmacy 
Binder for detailed instructions on how to prepare FX006. 
Injection into the hip joint will be done with ultrasound guidance by the assigned injector. The 
injector may choose the position of the hip (e.g., supine position with lower extremity internally 
rotated) and the approach for injection (e.g., anterior). 
The injector will use a 21 gauge or larger needle for injection into the hip joint. 
Refer to Appendix 1 for detailed instructions on IA administration of the study drug to the hip 
with ultrasound guidance. 
Post-Injection Care 
Patients should be advised to avoid strenuous activities or prolonged weight-bearing activities for 
approximately 24 to 48 hours following the injection and to also maintain a stable lifestyle with 
regard to physical activity throughout the duration of the study. 
In the event that the patient has an immediate reaction (e.g., tenderness, increased pain, swelling, 
effusion, decreased mobility of the index joint), the patient should be treated according to local 
clinical guidelines and physician experience.  

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 30 of 53 
7.5.10. 
Treatment Compliance 
Study medication will be administered by the injector in the clinic.  Details regarding study 
medication administration will be documented in the electronic Case Report Form (eCRF).  The 
receipt, dispensation and return/destruction of any study medication will be properly documented 
per the instructions in the Pharmacy Binder. 
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 and record the 
volume delivered. 
7.5.11. 
Removal of Patients from Therapy or Assessments 
Each patient in this study receives study medication as a single IA injection. Therefore, 
discontinuation from treatment is not applicable. Each patient may only discontinue from the 
study for further assessments and study visits.  
Each patient will be informed of his/her right to discontinue from the study at any time for any 
reason and without prejudice to alternative treatment.  The Principal Investigator may also 
discontinue a patient from the study at any time if, for example, he/she considers the patient’s 
health to be compromised by remaining in the study, or the study is prematurely terminated.  In 
these cases the Principal Investigator will: 
1. Attempt to arrange for a formal Early Termination Visit and complete the study 
assessments specified for the End-of-Study scheduled for Day 85.   
2. Determine whether the patient is willing to be contacted to follow ongoing or new AEs 
through Day 85 (if reason for discontinuation is not “subject withdrew consent”). 
3. Document patient consent in the source document for continued follow-up.  
4. Contact the patient as necessary (via phone or in-person) to follow ongoing or new AEs 
through Day 85 (concomitant medications associated with any AE will also be captured). 
Data collected from discontinued patients will be included in the clinical study report. Patients 
who discontinue from the study may be replaced at the discretion of the Sponsor. 
7.6. 
Prior and Concomitant Therapy  
Prior therapy is defined as all medications taken by or administered to the patient prior to 
obtaining informed consent. Concomitant therapy is defined as all medications from obtaining 
consent to End of Study visit.  
7.6.1. 
Allowable Medications 
The following medications may be taken or used throughout the study: 
• Any treatment for a pre-existing condition or for an AE, including the study 
indication (e.g., analgesic medications), that is not listed below as restricted  
• Physical therapy for index joint 
• Bracing of index joint 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 31 of 53 
7.6.2. 
Restricted Medications 
Per the exclusion criteria, a patient is not eligible for this study if he/she has received any of the 
indicated treatments within the specified windows detailed in the Exclusion criteria (Section 
7.4.3).  In addition the following medications should not be taken or used from the time of 
obtaining consent to the End of Study visit:   
• IV, IM, oral, inhaled, intranasal or topical corticosteroids 
• IA corticosteroids in any joint 
• Any IA intervention in the index joint including aspiration or the injection of any 
approved or investigational agent, including viscosupplementation (hyaluronic acid)  
• Any investigational drug, device or biologic 
• Immunomodulators, immunosuppressives, or chemotherapeutic agents  
• Live or live-attenuated vaccines 
7.7. 
Study Variables 
7.7.1. 
Safety Variables  
Safety and tolerability will be evaluated on the basis of AEs spontaneously reported by the 
patient or discovered by the Investigator and findings from the following assessments: physical 
examinations, index joint assessments, vital signs, and clinical laboratory evaluations.  
7.7.2. 
Pharmacokinetic Variables 
Blood samples (4 mL per sample) for drug concentration measurements will be obtained from all 
patients at the following times: 
• On Day 1, within 1 hour prior to administration of study medication 
• On Day 1, at Hours (±10 minutes) 1, 2, 3, 4, 5, 6, 8, 10, and 12 post-injection  
• On Day 2, at 24 (±2) hours post-injection 
• On Days 3, 5, 8, 15, 22, 29, 57, and 85 (time as convenient) 
These represent a total of 19 samples from each patient, each sample representing 4 mL of blood 
for a maximum estimated total volume of 76 mL of blood collected from each patient for drug 
concentration measurement. 
Procedures for sample collection, handling, storage and shipment will be described in the 
Laboratory Manual. Plasma TA concentrations will be measured using an established validated 
LC-MS/MS method.  
7.8. 
Schedule of Study Assessments 
A summary of the schedule of study assessments is provided in Table 1.  Refer to Section 7.9 for 
details of each assessment.   

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 32 of 53 
Table 1: 
Schedule of Study Assessments 
Procedures 
Screening1 
Day  
1 
Days  
2, 3, 5 
Day  
82 
 
Days  
15, 223 
(Weeks 2,3) 
Day  
293 
 (Week 4) 
Day  
573 
(Week 8) 
Day  
853 
(Week 12) 
(End of Study) 
Informed consent 
X4 
 
 
 
 
 
 
 
Inclusion/Exclusion Review 
X 
X5 
 
 
 
 
 
 
Medical History/Update 
X 
X5 
 
 
 
 
 
 
OA Medical History 
X 
X5 
 
 
 
 
 
 
Prior Treatment & 
Medications6 
X 
X5 
 
 
 
 
 
 
Physical Examination 
X 
X5 
 
 
 
 
 
X 
Index Joint X-ray7 
X 
 
 
 
 
 
 
 
Vital Signs 
X 
X5 
 
X 
 
X 
 
X 
12-Lead ECG 
X 
 
 
 
 
 
 
 
Index Joint Assessments8 
X 
X5 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
Weight and BMI  
X  
 
 
 
 
 
 
X 
Hematology & Chemistry9 
X 
X5 
 
 
 
X 
 
X 
HIV, Hepatitis B/C, HbA1c9 
X 
 
 
 
 
 
 
 
Pregnancy Test10 
X 
X5 
 
 
 
 
 
X 
Blood for Drug Concentrations 
 
X11 
X12 
X 
X 
X 
X 
X 
Treatment Administration13 
 
X 
 
 
 
 
 
 
Adverse Event Monitoring14 
 
---------------------------------------------X-------------------------------------------------- 
Concomitant Medications14 
 
---------------------------------------------X-------------------------------------------------- 
 
                                                 
1 Screening may occur up to 14 days prior to Day 1 
2 Visit should be conducted +/- 1 day from scheduled date. 
3 Visits should be conducted +/- 2 days from scheduled date. 
4 Consent must be obtained prior to performing any study-specific procedures 
5 Complete assessment prior to dosing. 
6 Record any medications received within 30 days prior to Screening. 
7 Obtain new x-ray if >6 months since prior x-ray. Screening X-ray will be read locally for radiological findings of OA (S-P 
Classification for the shoulder and ACR criteria for the hip). 
8 For all patients, the index joint (shoulder or hip) will be assessed for evidence of inflammation including tenderness, heat/ 
redness, swelling, and effusion. Clinically significant findings (new or worsening from baseline) should be recorded as AEs. 
9 Via Central Laboratory. 
10 Conduct for females of childbearing potential only.  Serum pregnancy test to be performed via central laboratory at Screening 
and End-of-Study visit; urine pregnancy test to be performed locally on Day 1 and results available prior to dosing.   
11 On Day 1, blood for plasma drug concentration measurements will be collected at Time 0 (prior to administration) and at 
Hours 1, 2, 3, 4, 5, 6, 8, 10, and 12 post-injection (±10 minutes). 
12 On Day 2, blood for plasma drug concentration will be collected at 24 hours post-injection (+/- 2 hours). 
13 To be performed under continuous ultrasound guidance. 
14 AEs and Concomitant Medications will be captured from Day 1 (post-injection) to End of Study Visit. 
 
 
 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 33 of 53 
7.9. 
Study Procedures 
7.9.1. 
Informed Consent 
Prior to initiation of any study related procedures, patients will be informed about the nature and 
purpose of the study, participation and termination conditions, and risks and benefits.  Patients 
will be given the opportunity to ask questions of site personnel and to discuss with family or 
friends if they wish.  After a patient has had ample opportunity to consider the information 
provided, they will be asked to sign the study’s informed consent form in order to participate in 
the study. 
7.9.2. 
Review of eligibility, medical history, prior treatment and medications 
Eligibility criteria (inclusion and exclusion criteria), medical history (including OA history), and 
prior treatment and medications are reviewed during screening and again at Day 1. 
OA medical history includes details to support the inclusion criteria for OA of the shoulder or 
hip.  
7.9.3. 
Physical Examination 
The physical exam will assess the following body systems:  
1. General Appearance 
2. Skin 
3. Lymphatics 
4. HEENT (head, ears, eyes, nose, throat) 
5. Cardiovascular 
6. Respiratory 
7. Abdominal 
8. Musculoskeletal 
9. Neurological  
Any clinically significant findings, outside of the typical disease state,  must be documented in 
the source and added to the medical history if found at Screening or recorded as an AE if new or 
worsened from pre-dosing on Day 1.    
7.9.4. 
Index Joint X-ray 
If an index joint X-ray performed within 6 months prior to Screening or during the Screening 
period is not available, then a plain radiograph of the index joint must be obtained at Screening 
to confirm the diagnosis of OA.  
• The recommended view of the hip is an anterior-posterior pelvic weight-bearing 
radiograph of the pelvis with the lower limbs in 15° internal rotation with a size ratio 
of 1:1. 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 34 of 53 
• The recommended views for the shoulder are (a) axillary radiograph and 
(b) anteroposterior with the arm actively held at 45°of abduction.   
The X-rays of the index joint will be read locally at Screening for radiological findings of OA 
(S-P classification for the shoulder and ACR criteria for the hip).   
7.9.5. 
Index Joint Assessment  
The index joint assessment will be performed by the designated assessor at the days indicated in 
the Schedule of Study Assessments.  The index joint will be assessed for tenderness, 
heat/redness, swelling, and effusion.  If there is a clinically significant finding at the Screening or 
Day 1 Visit (pre-injection), add to the Medical History.  At time points post-injection, if there are 
new clinically significant findings or findings that worsen for the patient’s baseline condition, 
record as AEs. 
7.9.6. 
12-lead ECG 
At Screening, a 12-lead ECG will be obtained in the supine position.   Measures of heart rate, PR 
interval, RR interval, QT interval, QTc (corrected for Bazett’s or Fridericia’s) interval and QRS 
duration will be obtained.  If QTc > 450 msec for male patients or > 470 msec for female 
patients on the first 10-second 12-lead ECG recording, two additional 10-second 12-lead ECG 
recordings must be collected 1 to 2 minutes apart.  ECGs will be locally read and a copy of each 
recording will be kept with the patient’s source documentation. 
7.9.7. 
Vital Signs 
Vital signs are to be taken at the days indicated in the Schedule of Study Assessments. The 
following measurements will be taken: sitting blood pressure, heart rate, respiration rate, and 
temperature.  
7.9.8. 
Height, Weight and BMI determination 
Height and weight are to be taken at the days indicated in the Schedule of Study Assessments.  
Height will be measured in centimeters or inches. Weight will be measured in kilograms or 
pounds. BMI will be calculated using the formulas in Table 2 (reference: www.cdc.gov): 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 35 of 53 
Table 2: 
BMI Calculations 
Measurement Units 
Formula and Calculation 
Kilograms and meters 
(or centimeters)  
Formula: weight (kg) / [height (m)]2 
With the metric system, the formula for BMI is weight in kilograms 
divided by height in meters squared.  
If, as common, height is measured in centimeters, divide height in 
centimeters by 100 to obtain height in meters. 
Example: Weight = 68 kg, Height = 165 cm (1.65 m) 
Calculation: 68 ÷ (1.65)2 = 24.98 
Pounds and inches 
Formula: weight (lb) / [height (in)]2 x 703  
Calculate BMI by dividing weight in pounds (lbs) by height in inches 
(in) squared and multiplying by a conversion factor of 703. 
Example: Weight = 150 lbs, Height = 5'5" (65") 
Calculation: [150 ÷ (65)2] x 703 = 24.96 
7.9.9. 
Pharmacokinetic Evaluations 
Blood samples will be taken at the time points indicated in the Schedule of Study Assessments. 
Follow the Central Laboratory Manual for detailed sample collection, handling, storage, and 
shipping instructions.   
7.9.10. 
Central Clinical Laboratory Evaluations 
Blood samples will be taken at the days indicated in the Schedule of Study Assessments.  The 
specific laboratory panels to be run can be found in Table 3.  Follow the Central Laboratory 
Manual for detailed sample collection, handling, storage, and shipping instructions. 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 36 of 53 
Table 3: 
Clinical Laboratory Panel 
Hematology 
Clinical Chemistry  
Hemoglobin 
Sodium  
Hematocrit  
Potassium  
Erythrocyte count (RBC) 
Bicarbonate  
Mean cell volume 
Chloride  
Leukocytes (WBC)  
Calcium   
Absolute counts of:  
Total bilirubin  
• 
Neutrophils  
Alkaline phosphatase  
• 
Lymphocytes  
Alanine aminotransferase  
• 
Monocytes  
Aspartate aminotransferase  
• 
Eosinophils  
Blood urea nitrogen 
• 
Basophils  
Creatinine  
• 
Platelets 
Uric acid  
 
Glucose 
Infectious diseases  
Total protein  
Hepatitis B Surface Antigen 
Albumin  
Hepatitis C Virus Antibody1 
Total cholesterol  
HIV2 
Triglycerides 
 
 
Other  
 
HBA1C 
 
 
 
Pregnancy tests (females of child-bearing potential only) 
Serum: submitted to and performed by Central Laboratory 
Urine: test provided by central laboratory but performed and read at the site 
1. Patients positive for HCV Antibody will have reflex testing for circulating HCV RNA. 
2. HIV screening will use a current 4th generation test for both antibody and viral antigen. 
7.9.11. 
Treatment Administration 
At Day 1, and completion of all required assessments, the following will occur: 
• Study medication will be prepared by the pharmacist/coordinator.  Refer to the 
Pharmacy Binder for FX006 dose preparation instructions. The injector will perform 
the IA injection of the study medication (refer to Section 7.5.9 for instructions).   
7.9.12. 
Review of adverse events and concomitant medications 
After receiving assigned study medication, the patient will be monitored for any AEs.  Review of 
any Concomitant Medications will also be performed and documented in source documentation.  
Refer to Section 8.1.3 for further information in regard to reporting of AEs.  Refer to Section 7.6 
for further information in regards to allowed and restricted concomitant medication. 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 37 of 53 
8. 
CLINICAL SAFETY ASSESSMENTS   
Adverse events will be collected starting with administration of study medication (Day 1) 
through the Final Visit (Week 12/Day 85). Results of clinical safety assessments are to be 
recorded in the patient’s medical records and transcribed to the appropriate eCRF, including the 
AE eCRF for clinically significant findings. 
8.1. 
Adverse Events 
8.1.1. 
Definitions 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.   
An AE can therefore be:   
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) 
product.  
• Any clinically significant abnormality found on an ECG, laboratory test or physical 
examination. 
• Any worsening (i.e., any clinical significant adverse change in frequency and/or 
intensity) of a preexisting condition, which is temporally associated with the use of 
the medicinal (investigational) product, is also an AE. 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death, 
• Is life-threatening, 
• This serious criterion refers to an event in which the patient was at substantial risk 
of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe.   
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• This serious criterion applies if the reported AE requires at least a 24-hour 
inpatient hospitalization or, if in the opinion of the Principal Investigator, 
prolongs an existing hospitalization.  A hospitalization for an elective procedure 
or a routinely scheduled treatment is not an SAE by this criterion because a 
“procedure” or a “treatment” is not an untoward medical occurrence. 
• Results in permanent or significant disability/incapacity. 
• This serious criterion applies if the “disability” caused by the reported AE results 
in a substantial disruption of the patient’s ability to carry out normal life 
functions. 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 38 of 53 
• Is a congenital anomaly/birth defect. 
• This serious criterion applies if a patient exposed to a medicinal (investigational) 
product gives birth to a child with congenital anomaly or birth defect. 
• Is, in the judgement of the PI, an important medical event.  
• Medical and scientific judgment should be exercised in deciding that a medical 
event, although not immediately life-threatening, resulting in hospitalization, or in 
death is, nevertheless, clinically important and serious based on because the 
patient was in jeopardy of or require intervention to prevent one of the other 
outcomes listed above. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; convulsions that do not 
result in hospitalization; or development of drug dependency or drug abuse. 
8.1.2. 
Evaluating and Recording of Adverse Events 
At each visit all AEs that occur from the time of treatment and throughout a patient’s study 
participation that are observed, elicited by the site personnel, or reported by the patient, will be 
recorded in the source documentation and appropriate section of the AE eCRF and evaluated by 
the Principle Investigator or Sub-Investigator.  
Minimum information required for each AE includes type of event, duration (start and end 
dates), severity, seriousness, causality to investigational medicinal product, action taken, and 
outcome. 
Severity of AEs will be graded by the Principal Investigator using the Common Terminology 
Criteria for AEs (CTCAE) version 4.0 (refer to the Study Manual or 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).   
For AEs not listed in the CTCAE, the following definitions should be used: 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 39 of 53 
Grade 1 
Mild 
Symptomatic or mild symptoms 
Clinical or diagnostic observations only 
Intervention not indicated 
Grade 2 
Moderate 
Minimal, local or noninvasive intervention indicated 
Limiting age-appropriate instrumental activities of daily living (ADL)* 
Grade 3 
Severe or medically significant but not immediately life-threatening 
Hospitalization or prolongation of hospitalization indicated 
Disabling 
Limiting self-care ADL** 
Grade 4 
Life-threatening consequences 
Urgent intervention indicated 
Grade 5 
Death related to AE 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
The relationship of the AE to the investigational medicinal product should be specified by the 
Principal Investigator, using the following definitions: 
1.  Not Related: 
Concomitant illness, accident or event with no reasonable association 
with treatment. 
2.  Unlikely: 
The reaction has little or no temporal sequence from administration of 
the investigational medicinal product, and/or a more likely alternative 
etiology exists. 
3.  Possibly Related: 
The reaction follows a reasonably temporal sequence from 
administration of the investigational medicinal product and follows a 
known response pattern to the suspected drug; the reaction could have 
been produced by the study medication or could have been produced by 
the subject’s clinical state or by other modes of therapy administered to 
the subject. 
4.  Probably Related: 
The reaction follows a reasonable temporal sequence from 
administration of study medication; is confirmed by discontinuation of 
the study medication or by rechallenge; and cannot be reasonably 
explained by the known characteristics of the subject’s clinical state. 
5.  Definitely Related: The reaction follows a reasonable temporal sequence from 
administration of study medication; that follows a known or expected 
response pattern to the study medication; and that is confirmed by 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 40 of 53 
improvement on stopping or reducing the dosage of the study 
medication, and reappearance of the reaction on repeated exposure. 
If discernible at the time of completing an AE eCRF, a specific disease or syndrome rather than 
individual associated signs and symptoms should be identified by the Investigator and recorded 
on the appropriate AE eCRF.  However, if an observed or reported sign, symptom, or clinically 
significant laboratory anomaly is not considered by the Investigator to be a component of a 
specific disease or syndrome, then it should be recorded as a separate AE on the appropriate AE 
eCRF. 
8.1.3. 
Reporting of Serious Adverse Events 
Within 24 hours of becoming aware of an SAE, the Investigator or appropriate designee must 
complete the SAE form and submit to the Sponsor according to the SAE form instructions.  
When the Investigator becomes aware of additional follow up information on an SAE, this 
should also be reported on an SAE form within 24 hours.  
All SAEs that occur at your site should also be reported to the responsible IRB, if applicable, 
according to IRB requirements. 
During the conduct of the study, the Sponsor will provide expedited safety reports (AEs 
classified as serious, unexpected and at least possibly related to investigational product) to the 
investigative sites as notification of new safety findings.  If this occurs, the investigative site 
must report the information to their IRB per local guidelines (may be submitted by the Sponsor 
or designee for sites that use a central IRB). 
8.1.4. 
Safety Monitoring Roles 
The site personnel will carefully monitor each patient throughout the study for possible AEs.  All 
AEs will be documented on the eCRF designed specifically for this purpose, and will be 
followed until either resolved, returned to baseline, or until a stable chronic outcome is 
determined by the Principal Investigator.   
The Medical Monitor must promptly review all information relevant to the safety of an 
investigational new product received from any source including adverse event data individually 
and in aggregate throughout the course of the study.  The Medical Monitor will also review alert 
laboratory results in real time and will contact Investigators as needed to ensure that issues are 
managed in an appropriate manner. 
8.1.5. 
Clinical Management of Index Joint Related Events  
In the event that 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, decreased mobility of the index joint), the patient should be treated according 
to local clinical guidelines and physician experience.   
If the index joint is aspirated at any time after 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 presence of crystals and (3) assessed for white cell count at a local 
laboratory, and the results should be documented.   

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 41 of 53 
Any event that is a change from the patient’s baseline status (new or worsening case) should be 
reported as an AE and those meeting the definition of serious must be reported in accordance 
with Section 8.1.3. 
8.1.6. 
Pregnancy 
All pregnancies occurring during the study will be reported in the same timeframe as SAEs. All 
reports of pregnancy, including male patients who conceive, must be followed for information 
regarding the course of the pregnancy and delivery, as well as the condition of the newborn.  
Follow-up information concerning the outcome of the pregnancy should be provided to the 
Sponsor in a timely manner.  Additional follow-up is not needed when a newborn baby is 
healthy.  
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical and Analytical Plans 
Key aspects of the proposed statistical analyses are summarized below. A comprehensive 
statistical analysis plan will be written and approved prior to database lock for this study. If, after 
the study has been completed, changes are made to the statistical analysis plan referenced below, 
these deviations to the plan will be listed in the Clinical Study Report (CSR), along with an 
explanation as to why they occurred.  
9.1.1. 
Final Analyses 
All final analyses specified in the statistical analysis plan (SAP) will be completed following 
database lock and reported in the trial CSR. Post-hoc, exploratory analyses, may also be 
performed to further understand and elucidate study results; these analyses will be clearly 
identified as such in the CSR.  
9.2. 
General Considerations and Methods 
Data collected in this study will be presented using summary tables, figures, and 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, including the mean, 
median, standard deviation, minimum and maximum.  Categorical variables will be summarized 
by frequencies and percentages.  Confidence intervals may also be provided.  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 any baseline imbalance. 
All confidence intervals (CIs), statistical tests, and resulting p values will be reported as 2-sided.  
Significance will be assessed at α = 0.05 level and the significance level will not be adjusted for 
the secondary endpoint analyses. 
9.2.1. 
Analysis Populations 
Complete details of the statistical and PK analyses will be specified in the SAP.  Two analysis 
populations are planned for this study as follows: 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 42 of 53 
o The Safety Population will include all patients who receive study drug. The Safety 
Population will be used to assess safety and tolerability. 
o The PK Population will include patients who receive study drug and have sufficient 
plasma concentration data to allow calculation of PK parameters to be included in the PK 
population. Eligibility for inclusion into the PK Population will be determined by the 
Pharmacokineticist for the study following review of plasma data. 
9.2.2. 
Study Data 
Study data identified in this protocol are collected, and source verified, on electronic Case 
Record Forms (eCRF) at sites completing the study.  All study data will be formulated into data 
sets to provide transparency, traceability, and integrity of trial analysis results from collection 
source.  
9.2.3. 
Study Variables for Assessment 
Please refer to Section 7.7 for study variables.  
9.2.4. 
Sub-Groups and Covariates 
No pre-planned sub-groups are identified for each joint cohort of this study. Sub-groups may be 
defined and explored after all pre-planned analyses have been completed to further elucidate 
study results. 
9.3. 
Determination of Sample Size 
9.3.1. 
Sample Size Considerations: 
In this study, it is expected that the systemic exposure in plasma of TA from extended-release 
FX006 should not exceed that of the immediate-release TAcs formulation for the key parameters 
of Cmax, AUC(0-t), and AUC(0-inf).  
In a previous pharmacokinetic study with knee OA patients (FX006-2015-009) the ratio of the 
mean exposure parameters for 32 mg  FX006 (N=60) and  40 mg  TAcs (N=18) for Cmax was 
0.10 with the upper limit of its 90% CI being 0.15 and for AUC(0-inf) was 0.52 with the upper 
limit of its 90% CI being 0.86. The pooled coefficients of variation for the parameters was 
between 0.53 (Cmax) and 0.68 (AUC0-inf).  
9.3.2. 
Sample Size Estimate: 
In this study, it is expected that the ratio of exposure means (FX006/TAcs) will be less than 1.0 
when administered to treat either shoulder or hip OA. A sample size of 12 in each treatment arm 
(24 in total) is estimated for each joint cohort (hip and shoulder). Within each group the sample 
size of 24 achieves approximately 90% power, with a two-sided alpha 0.05, to detect a ratio less 
than 1.0 of the exposure PK parameter means (FX006 / TAcs), with a pooled coefficient of 
variation estimate of 0.68 (PASS 15 Power Analysis and Sample Size Software (2017). NCSS, 
LLC. Kaysville, Utah, USA, ncss.com/software/pass). The sample size of 12 per treatment arm 
in each joint cohort assumes a 10% noncompliance sampling rate (a drop-out rate) for providing 
complete blood samples for PK analysis, and is sufficient to characterize the comparative 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 43 of 53 
pharmacokinetic of FX006 and TAcs in this study. The total sample size is estimated to be 48 
patients (hip: 12 in each treatment arm, shoulder: 12 in each treatment arm) for the study. 
9.4. 
General statistical Methods 
9.4.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be listed by joint cohort, treatment, study site and 
patient, and will be summarized by treatment for each joint cohort.  Frequencies and proportions 
will be presented for the categorical variables and descriptive statistics will be presented for 
continuous variables. 
9.4.2. 
Exposure 
Treatment exposure will be listed by joint cohort, treatment, study site and patient, and will be 
summarized by treatment for each joint cohort. 
9.4.3. 
Efficacy Analyses 
Not Applicable. 
9.4.4. 
Safety Analyses 
9.4.4.1. 
Analysis of Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary.  
Incidences (number and percent) of treatment-emergent adverse events (TEAEs; those events 
that started after dosing or worsened after dosing), will be presented by treatment group for each 
joint cohort. Additional analyses of incidences of TEAEs will also be presented by maximum 
severity and by relationship to study medication. Similar presentations will be provided for 
serious AEs, AEs leading to death, AEs leading to withdrawal from the study, and for AEs 
related to the index joint. 
9.4.4.2. 
Other Safety Analyses 
Clinical laboratory data and vital sign information will be summarized by treatment group for 
each joint cohort as summary statistics for value and change from Day 1 at each individual time 
point.  Summary statistics will include n, mean, median, standard deviation, minimum, and 
maximum. 
Details for the additional safety endpoints will be provided in the SAP. 
9.4.4.3. 
Pharmacokinetic Analyses 
PK parameters will be derived for each patient from plasma concentrations of TA using model-
independent non-compartmental analysis: (NCA) [Phoenix 7, WinNonlin® 7]. Individual 
elapsed sampling times (actual time) will be used in the PK calculations if significant deviations 
from the nominal sampling times are noted, otherwise nominal times will be used for analysis. 
Complete details on the calculation of PK parameters, and handling of concentration values 
below the LLOQ will be fully specified in the SAP. 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 44 of 53 
Descriptive summaries of the TA plasma concentration levels (ng/mL) observed at each nominal 
time point will be provided for FX006 and TAcs treatments in each joint cohort (hip and 
shoulder). Descriptive summaries of the PK parameter estimates from each treatment group will 
also be completed for each joint cohort. Summary statistics for continuous variables will include 
n, mean, standard deviation, coefficient of variation (CV%), median, minimum, and maximum, 
geometric mean and standard error of the geometric mean. 
By patient plots (linear-linear, log-linear) of the plasma TA concentration data will be completed 
for each treatment group in each joint cohort. 
The PK parameters for Cmax, Tmax, AUC, and MRT PK parameters will be informative of the 
overall systemic exposure of TA from extended-release FX006 and immediate-release TAcs. A 
linear model will be used to compare the PK parameters from extended-release FX006 and 
immediate-release TAcs. Full details of the linear model will be specified in the SAP. 
Bioequivalence (BE) ratios between extended-release FX006 (Test) and immediate-release TAcs 
(Reference) for Cmax and AUC parameters will be explored.  Bioequivalence between Test and 
Reference will be evaluated using the average BE method for the mean ratio between test and 
reference products (μT / μR) as described in FDA guidance. Full details on the analysis of BE 
will be included in the SAP.  
10. 
DATA QUALITY ASSURANCE 
At the time the study is initiated, the clinical study monitor will thoroughly review the final 
protocol and the eCRF with the Principal Investigator and staff.  During the course of the study, 
the clinical study monitor will visit the clinical site regularly to check the completeness of the 
patient records, the accuracy of entries into the eCRF, the adherence to the final protocol and to 
International Conference on Harmonisation GCP, the progress of enrollment, and the storage, 
dispensing and accountability of study medication. The Principal Investigator and key study 
personnel should be available to assist the clinical study monitor during these visits.   
The Principal Investigator will give the monitor, auditor(s), Sponsor, Sponsor designee and 
regulatory authorities direct access to relevant clinical records. No information in these records 
about the identity of the patients will leave the clinical site.  The Sponsor will maintain the 
confidentiality of all patient records. 
Source data is all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained in source documents 
(original records or certified copies). 
Independent clinical quality assurance audits may be performed at any time during or following 
completion of the Study by the Sponsor, or its authorized agents, and Competent Authorities 
and/or the IRB/EC. 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 45 of 53 
11. 
DATA HANDLING AND RECORDKEEPING 
11.1. 
Case Report Forms 
The eCRF will be supplied by the Sponsor or designee and should be handled in accordance with 
the instructions provided. All study data should initially be documented in source documents 
(e.g., patient charts, notes, laboratory reports, ECG recordings, etc.) and then subsequently 
entered from the source into the eCRF.  All eCRFs should be filled out completely by examining 
personnel or the study coordinator.  The eCRF is reviewed, signed, and dated electronically by 
the Principal Investigator. 
11.2. 
Study Medication Accountability 
All study medication required for completion of this study will be provided by the Sponsor or 
designee.  Study medication will be acknowledged upon receipt indicating shipment content and 
condition.  Damaged supplies will be replaced. 
Accurate records of all study medications received by, dispensed from or returned to the study 
site should be maintained per instructions in the Pharmacy Binder. 
In the event of a temperature excursion, refer to the Pharmacy Binder for instructions. 
In the event of a product complaint, complete the Product Complaint Form located in the 
Pharmacy Binder and send to the assigned monitor or clinical manager who will coordinate with 
the Sponsor for further guidance.  
11.3. 
Confidentiality of Data 
Patient medical information obtained by this study is confidential, and disclosure to third parties 
other than those noted below is prohibited. 
Upon the patient’s permission, medical information may be given to his or her personal 
physician or other appropriate medical personnel responsible for his or her welfare. 
Data generated by this study must be available for inspection by representatives of Competent 
Authorities, the Sponsor or their representative, and the IRB/EC. 
To maintain patient privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the patient by initials where permitted and/or by the assigned 
patient number.  The patient’s confidentiality will be maintained and will not be made publicly 
available to the extent permitted by the applicable laws and regulations. 
11.4. 
Retention of Records 
In accordance with US federal regulations (21 CFR 312.62[c]), the Sponsor requires that records 
and documents pertaining to the conduct of this study and the distribution of study medications, 
including eCRFs, consent forms, laboratory test results, glucose source data, and medical 
inventory records, must be retained by the Principal Investigator for 2 years after marketing 
application approval.  If no application is filed, these records must be kept 2 years after the 
investigation is discontinued and the regulatory authorities are notified.  The Sponsor or their 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 46 of 53 
representative will notify the Principal Investigator of these events.  In the event that local 
regulations are more stringent than that specified above, the local regulations will be adhered to.   
11.5. 
Protocol Adherence 
The Principal Investigator must adhere to the protocol as detailed in this document and agrees 
that any changes to the protocol must be approved by the Sponsor or their representative prior to 
seeking approval from the IRB/EC.  When the changes involved are only logistical and 
administrative in nature to the trial this may not require prior approval by the IRB/EC. The 
Principal Investigator will be responsible for enrolling only those patients who have met protocol 
eligibility criteria. 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 47 of 53 
12. 
PUBLICATION POLICY 
12.1. 
Sponsor’s Publication Policy 
Sponsor or its designee shall have the right to publish or otherwise publicly disclose the 
information contained in or related to the Study Drug, the Study Data, or other Confidential 
Information in any form without the written consent of Site, the Principal Investigator or any 
other person.  Each of Site and Principal Investigator further agrees that Sponsor shall have the 
exclusive right to commercialize any products or services that are based upon, or derived from 
the Study Drug, the Study Data, or other Confidential Information. 
12.2. 
Site publication 
After the Study is completed, which means that all completed eCRFs have been received by 
Sponsor, and the database has been locked at all participating sites and Study closeout visits have 
taken place at all participating sites, then Site shall have the right, subject to the HIPAA Rules, to 
publish or otherwise make public data resulting from the conduct of the Study at the Site upon 
the earlier of (a) the date of publication of a multi-center publication coordinated by Sponsor 
with respect to the data resulting from the Study, and (b) the date of submission of the data 
resulting from the Study by Sponsor to the FDA for regulatory approval; provided that Site shall 
furnish Sponsor with a copy of any proposed publication or release at least 90 days in advance of 
the proposed submission or presentation date.  Within this 90-day period, the Sponsor shall 
review such proposed publication or release to determine whether it contains any Confidential 
Information (other than Study Data), or whether Sponsor desires to file patent applications on 
subject matter contained therein, and to ensure the accuracy of the information contained in the 
publication or release. Upon receiving any notification from Sponsor requesting deletion of 
Confidential Information (other than Study Data), requesting correction of inaccuracies, or 
requesting a delay in publication of up to 90 days to allow the filing of patent applications before 
publication or release, Site shall take the requested action.  The parties acknowledge and agree 
that Site shall be solely responsible for the editorial content of any such publication or release.  
In a manner consistent with customary practice, Site shall acknowledge the support and 
contributions of Sponsor, if requested by Sponsor, in connection with the Study, in any and all 
publications and presentations reporting and data resulting from the Study.  Site and the Principal 
Investigator shall comply with all applicable federal and state laws and other applicable rules and 
requirements regarding disclosure of industry support (financial or otherwise) in connection with 
such publications and presentations. 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 48 of 53 
13. 
REFERENCES 
Altman R, Alarcon G, Appelrouth D, Bloch D, Borenstein D, Brandt K, et al. The American 
College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hip. 
Arthritis Rheum 1991;34:505-514 
American Diabetes Association, Position Statement 5. Glycemic Targets. Diabetes Care. 
2016;39(Supplement 1), S39-S46. doi:10.2337/dc16-S008. 
Bodick N, Lufkin J, Willwerth C, Blanks R, Inderjeeth C, Kumar A, Clayman M. 
FX006 prolongs the residency of triamcinolone acetonide in the synovial tissues 
of patients with knee osteoarthritis. Osteoarthritis Cartilage. 2013;21:(Suppl); 
S144-5. 
Bodick N, Lufkin J, Willwerth C, Kumar A, Bolognese J, Schoonmaker C, Ballal R, Hunter D, 
Clayman, M.  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;97:877-88 
Conaghan, PG, Cohen, SB, Berenbaum, F, Lufkin, J, Johnson, J.R and Bodick, N. Phase 2b trial 
of a novel extended-release microsphere formulation of triamcinolone acetonide for intra-
articular injection in knee osteoarthritis. Arthritis Rheumatol. Accepted Author Manuscript. 
doi:10.1002/art.40364 
Creamer P, Hochberg MC.  Osteoarthritis.   Lancet 1997;350(906):503–508. 
Elsharkawi M, Cakir B, Reichel H, Kappe T. Reliability of radiologic glenohumeral 
osteoarthritis classifications. J Shoulder Elbow Surg. 2013; 22: 1063-1067. 
Goldring SR, Goldring MB.  Clinical aspects, pathology and pathophysiology of osteoarthritis.   
J Musculoskelet Neuronal Interact 2006;6(4):376–378. 
Habib GS.  Systemic effects of intra-articular corticosteroids. Clin Rheumatol 2009;28:749–756. 
Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, Towheed T, Welch 
V, Wells G, Tugwell P.  American College of Rheumatology 2012 Recommendations for the 
Use of Nonpharmacologic and Pharmacologic Therapies in Osteoarthritis of the Hand, Hip, and 
Knee.   Arthritis Care & Research 2012; 64:465-474. 
Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, Gunther K, 
Hauselmann H, Herrero-Beaumont, Kaklamanis P, Lohmander S, Leeb B, Lequesne M, 
Mazieres B, Martin-Mola E, Pavelka K, Pendleton A, Punzi L, Serni U, Swoboda B, Verbruggen 
G, Zimmerman-Gorska I, Dougados M.  EULAR Recommendations 2003: an evidence based 
approach to the management of knee osteoarthritis: Report of a Task Force of the Standing 
Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT).  Ann 
Rheum Dis 2003;62(12):1145–1155. 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 49 of 53 
Menge TJ, Boykin RE, Byram IR, Bushnell BD. A Comprehensive Approach to Glenohumeral 
Arthritis. So. Med. J. 2014;107(9):567-573 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 50 of 53 
14. 
APPENDICES 
APPENDIX 1. STUDY DRUG ADMINISTRATION PROCEDURE WITH 
ULTRASOUND GUIDANCE 
All IA injections will be performed by the assigned injector. The injector may choose the 
numbing agent to be used based on standard of care.  
Aseptic technique will be used study drug preparation. Sterile technique will be used for 
injection.   
General Guidance for IA Hip injection   
The injector may choose the position of the hip and the approach of the injection. 
Preferred Patient position:  Patient is positioned supine with the hip neutral or slightly 
internally rotated. 
Preferred Approach: Antero- inferior longitudinal approach.  
Ultrasound Probe position: Longitudinal to femoral neck. With probe positioned parallel to the 
femoral neck; sonoanatomy of the hip should show clear image of the femoral head, acetabulum, 
iliopsoas muscle and iliac bone.] 
Supplies: Needle gauge must be 21 gauge or larger.  Recommended needle length 3.5”.   
General Guidance for IA Shoulder (glenohumeral) Injection 
Patient position: Sitting positon with ipsilateral hand resting on opposite shoulder 
Preferred Approach: Posterior 
Ultrasound Probe Position:  Placed just below the acromion at humeral head 
Supplies:  Needle gauge must be 21 gauge or larger.  Recommended needle length 2.5” or 3.5”. 
 
 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 51 of 53 
Guidance for FX006 Injection Under Continuous Ultrasound Guidance (hip or shoulder) 
Step 1: Prepare FX006 and utilize the 5 mL syringe to draw up suspended FX006 into the 
syringe via the vial adapter as per the Instructions for Use located in the Pharmacy Manual  
Step 2: Prior to injection, the injection site should be thoroughly cleansed using a bactericidal 
solution. 
Step 3: Connect the needle to an empty syringe or if using a spinal needle, only the needle with 
stylet inserted, and advance in-plane under real time ultrasound guidance to the joint space.   
• Obtain ultrasound image when the needle tip is clearly visualized in the joint space and 
correct intra-articular needle placement is established. Retain the ultrasound image.  
Step 4: Re-suspend solution of FX006 in syringe   
• To ensure the powder is suspended, gently invert the syringe containing FX006 several 
times just prior to administration. Grip the syringe firmly and turn it so the syringe 
plunger is pointing straight down. Then turn the syringe gently, 180 degrees, until the 
plunger is pointing straight up. Invert the syringe several times to ensure a properly 
mixed suspension as shown below. 
INCORRECT         CORRECT 
• 
 
Step 5: Detach the empty syringe or remove the spinal needle stylet.  Connect the syringe to the 
needle previously placed in joint. 
Step 6: Inject 1-2 ml of FX006 solution into the joint  
• Obtain a second ultrasound image demonstrating a hyperechoic area near the needle tip in 
the joint space.  Retain the ultrasound image. 
Step 7: Administer remaining volume of FX006 solution into the joint.  
• Obtain third ultrasound image demonstrating distention of the capsule after FX006 
deposition. Retain the ultrasound image.  
Note: If the entire contents of the syringe cannot be injected easily into the joint space, stop the 
injection and obtain an ultrasound image demonstrating tip location.  Then remove the needle 
and record the estimated volume that was injected.  Do not re-attempt the injection. 
 
 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 52 of 53 
Guidance for TAcs Injection Under Continuous Ultrasound Guidance (hip only):  
Step 1: Utilize the 5 mL syringe to draw 1 mL of TAcs and 4 mL of normal saline into the 
syringe. 
Step 2: Prior to injection, the injection site should be thoroughly cleansed using a bactericidal 
solution. 
Step 3: Connect the needle to an empty syringe or if using a spinal needle, only the needle with 
stylet inserted, and advance in-plane under real time ultrasound guidance to the joint space.  
• Obtain ultrasound image when the needle tip is clearly visualized in the joint space and 
correct intra-articular needle placement is established. Retain the ultrasound image.  
Step 4:  Detach the empty syringe or remove the spinal needle stylet.  Connect the syringe to the 
needle previously placed in joint. Inject 1-2 ml of TAcs/normal saline solution into the joint.  
• Obtain a second ultrasound image demonstrating a hyperechoic area near the needle tip in 
the joint space. Retain the ultrasound image. 
Step 5: Administer remaining volume of injection. 
• Obtain third ultrasound image confirming distention of the capsule after TAcs/normal 
saline deposition. Retain the ultrasound image. 
NOTE: If the entire contents of the syringe cannot be injected easily into the joint space, stop the 
injection and obtain an ultrasound image demonstrating tip location.  Then remove the needle 
and record the estimated volume that was injected.  Do not re-attempt the injection. 
 
 

Flexion Therapeutics, Inc. 
Protocol FX006-2017-013 
FX006 
Version 3.0 (05Apr2018) 
 
CONFIDENTIAL 
Page 53 of 53 
Guidance for TAcs Injection Under Continuous Ultrasound Guidance (shoulder only):  
Step 1: Utilize the 5 mL syringe to draw 1 mL of TAcs into the syringe. 
Step 2: Prior to injection, the injection site should be thoroughly cleansed using a bactericidal 
solution. 
Step 3: Connect the needle to an empty syringe or if using a spinal needle, only the needle with 
stylet inserted and advance in-plane under real time ultrasound guidance to the joint space.  
• Obtain ultrasound image when the needle tip is clearly visualized in the joint space and 
correct intra-articular needle placement is established. Retain the ultrasound image. 
Step 4: Detach the empty syringe or remove the spinal needle stylet.  Connect the syringe to the 
needle previously placed in joint. Inject the total volume of TAcs solution into the joint.  
• Obtain second ultrasound image confirming distention of the capsule after TAcs 
deposition. Retain the ultrasound image. 
NOTE: If the entire contents of the syringe cannot be injected into the joint space, remove the 
needle and record the estimated volume that was injected.  Do not re-attempt the injection.