A Randomized, Open-label, Parallel Group Study in Patients With Bilateral Knee Osteoarthritis Comparing the Systemic Exposure of Triamcinolone Acetonide Following Administration Into Both Knees of Either Extended-release FX006 or Immediate-release TAcs (Triamcinolone Acetonide Suspension)
Phase: PHASE2
Conditions: Bilateral Knee Osteoarthritis
Sponsor: Pacira Pharmaceuticals, Inc

 
CONFIDENTIAL INFORMATION 
CLINICAL STUDY PROTOCOL 
 
A Randomized, Open-label, Parallel Group Study in Patients with Bilateral Knee Osteoarthritis 
Comparing the Systemic Exposure of Triamcinolone Acetonide Following Administration into 
Both Knees of either Extended-release FX006 or Immediate-release TAcs (Triamcinolone 
Acetonide Suspension)  
 
PROTOCOL NUMBER:  FX006-2017-012 
 
 
PHASE:  2a 
 
STUDY MEDICATION(S): FX006 
 
INDICATION:  Osteoarthritis of the Knee  
 
  
MEDICAL MONITOR: Robert D. Arbeit, MD 
 
 
 
SPONSOR:  Flexion Therapeutics  
 
DATE:  10Nov17 
 
  
VERSION: 2.0 
 
 
SUPERCEDES: Version 1.0  
 

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SIGNATURE PAGE 
Clinical Study Protocol Version 2.0 (dated 10Nov2017) 
 
 
 
Sponsor Safety Officer Approval 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
Name (print): 
 
 
Neil Bodick, MD, PhD 
 
 
Title:                     
 
Chief Scientific Officer 
 
 
 
Principal Investigator Agreement:  I have read the protocol and agree to conduct the study as 
outlined herein. 
 
 
 
Signature: 
 
 
 
Date: 
 
 
 
Name (print): 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
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 ......................................................................................................18 
5.1. 
OSTEOARTHRITIS ...................................................................................................18 
5.2. 
Background .................................................................................................................18 
5.2.1. 
Investigational Medicinal Product:  FX006 ................................................................18 
5.2.2. 
Rationale for FX006 in OA of the Knee .....................................................................19 
5.2.3. 
Toxicology ..................................................................................................................19 
5.2.4. 
Systemic and Local PK in Patients with Osteoarthritis of the Knee ..........................20 
5.2.5. 
Pharmacodynamics in Patients with Osteoarthritis of the Knee .................................20 
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 .....................21 
5.2.8. 
Conclusion ..................................................................................................................22 
6. 
STUDY OBJECTIVES ..............................................................................................23 
6.1. 
Primary Objective .......................................................................................................23 
7. 
INVESTIGATIONAL PLAN .....................................................................................24 
7.1. 
Overall Study Design and Plan ...................................................................................24 
7.2. 
Site Staffing Requirements .........................................................................................24 
7.3. 
Discussion of Study Design ........................................................................................25 
7.3.1. 
Rationale for Study Population ...................................................................................25 
7.3.2. 
Rationale for Dose Selection ......................................................................................25 
7.3.3. 
Rationale for Study Design .........................................................................................25 
7.3.4. 
Rationale for Study Parameters ..................................................................................25 
7.3.5. 
Rationale for Control Type .........................................................................................26 

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7.4. 
Selection and Withdrawal of Study Patients ..............................................................26 
7.4.1. 
Number of Patients .....................................................................................................26 
7.4.2. 
Inclusion Criteria ........................................................................................................26 
7.4.3. 
Exclusion Criteria .......................................................................................................27 
7.4.4. 
Screen Failures ............................................................................................................29 
7.5. 
Treatment Administered .............................................................................................29 
7.5.1. 
Study Medication Treatment Arms ............................................................................29 
7.5.2. 
Identity of Investigational Product(s) .........................................................................29 
7.5.3. 
Identity of Reference Compound ................................................................................29 
7.5.4. 
Receipt, Dispensing, and Storage ...............................................................................30 
7.5.5. 
Packaging and Labeling of Study Medication ............................................................30 
7.5.6. 
Return of Study Medication ........................................................................................30 
7.5.7. 
Method of Assigning Patients to Treatment Groups ..................................................30 
7.5.8. 
Blinding ......................................................................................................................30 
7.5.9. 
Study Drug Administration Procedure .......................................................................30 
7.5.10. 
Treatment Compliance ................................................................................................31 
7.5.11. 
Removal of Patients from Therapy or Assessments ...................................................31 
7.6. 
Prior and Concomitant Therapy ..................................................................................31 
7.6.1. 
Allowable Medications ...............................................................................................32 
7.6.2. 
Restricted Medications ...............................................................................................32 
7.7. 
Study Variables ...........................................................................................................32 
7.7.1. 
Safety Variables ..........................................................................................................32 
7.7.2. 
Pharmacokinetic Variables .........................................................................................32 
7.7.3. 
Pharmacodynamic Variables ......................................................................................33 
7.8. 
Schedule of Study Assessments..................................................................................33 
7.9. 
Study Procedures ........................................................................................................35 
7.9.1. 
Informed Consent .......................................................................................................35 
7.9.2. 
Review of Eligibility, Medical History, Prior Treatment and Medications ...............35 
7.9.3. 
Physical Examination .................................................................................................35 
7.9.4. 
Knee X-rays ................................................................................................................35 
7.9.5. 
Knee Assessment ........................................................................................................35 
7.9.6. 
12-lead ECG ...............................................................................................................36 
7.9.7. 
Vital Signs ..................................................................................................................36 

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7.9.8. 
Height, Weight, and BMI Determination ...................................................................36 
7.9.9. 
Pharmacokinetic Evaluations ......................................................................................37 
7.9.10. 
Central Clinical Laboratory Evaluations ....................................................................37 
7.9.11. 
Synovial Fluid Aspiration ...........................................................................................38 
7.9.12. 
Treatment Administration ...........................................................................................38 
7.9.13. 
Review of Adverse Events and Concomitant Medications ........................................38 
8. 
CLINICAL SAFETY ASSESSMENTS .....................................................................39 
8.1. 
Adverse Events ...........................................................................................................39 
8.1.1. 
Definitions ..................................................................................................................39 
8.1.2. 
Evaluating and Recording of Adverse Events ............................................................40 
8.1.3. 
Reporting of Serious Adverse Events .........................................................................42 
8.1.4. 
Safety Monitoring Roles .............................................................................................42 
8.1.5. 
Clinical Management of Knee-related Events ............................................................42 
8.1.6. 
Pregnancy ...................................................................................................................43 
9. 
STATISTICAL CONSIDERATIONS .......................................................................44 
9.1. 
Statistical and Analytical Plans ..................................................................................44 
9.1.1. 
Final Analyses ............................................................................................................44 
9.2. 
General Considerations and Methods .........................................................................44 
9.2.1. 
Analysis Populations ..................................................................................................44 
9.2.2. 
Study Data ..................................................................................................................44 
9.2.3. 
Study Variables for Assessment .................................................................................45 
9.2.4. 
Sub-Groups and Covariates ........................................................................................45 
9.3. 
Determination of Sample Size ....................................................................................45 
9.3.1. 
Sample Size Considerations .......................................................................................45 
9.3.2. 
Sample Size Estimate: ................................................................................................45 
9.4. 
General Statistical Methods ........................................................................................45 
9.4.1. 
Demographics and Baseline Characteristics ...............................................................45 
9.4.2. 
Exposure .....................................................................................................................45 
9.4.3. 
Efficacy Analyses .......................................................................................................46 
9.4.4. 
Safety Analyses ..........................................................................................................46 
9.4.4.1. 
Analysis of Adverse Events ........................................................................................46 
9.4.4.2. 
Other Safety Analyses ................................................................................................46 
9.4.5. 
Pharmacokinetic Analysis ..........................................................................................46 

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10. 
DATA QUALITY ASSURANCE ..............................................................................47 
11. 
DATA HANDLING AND RECORDKEEPING .......................................................48 
11.1. 
Case Report Forms .....................................................................................................48 
11.2. 
Study Medication Accountability ...............................................................................48 
11.3. 
Confidentiality of Data ...............................................................................................48 
11.4. 
Retention of Records ..................................................................................................48 
11.5. 
Protocol Adherence ....................................................................................................49 
12. 
PUBLICATION POLICY ..........................................................................................50 
12.1. 
Sponsor’s Publication Policy ......................................................................................50 
12.2. 
Site Publication ...........................................................................................................50 
13. 
REFERENCES ...........................................................................................................51 
 
 
LIST OF TABLES 
Table 1: 
Schedule of Study Assessments..................................................................................34 
Table 2: 
BMI Calculations ........................................................................................................36 
Table 3: 
Clinical Laboratory Panel ...........................................................................................37 
 
 
 
 

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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 
K-L 
Kellgren-Lawrence 
KOOS  
Knee injury and Osteoarthritis Outcome Score  

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LLOQ 
Lower Limit of Quantification 
LSM 
Least Square Mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
MRT 
Mean Residence Time 
msec 
Millisecond 
N 
Number 
NaCl 
Sodium Chloride 
NRS 
Numeric 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 
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 

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2. 
SYNOPSIS 
Title of Study: A Randomized, Open-label, Parallel Group Study in Patients with Bilateral Knee Osteoarthritis 
Comparing the Systemic Exposure of Triamcinolone Acetonide Following Administration into Both Knees of either 
Extended-release FX006 or Immediate-release TAcs (Triamcinolone Acetonide Suspension) 
Study Centers:  Approximately 4 
Study Phase:  2a 
Objectives: 
The objectives of this study are to: 
 
compare the plasma pharmacokinetics (PK), including systemic exposure, of triamcinolone acetonide (TA)  
 
assess the safety and general tolerability 
when FX006 is administered as two 5 mL IA injections (one to each knee) for a total dose of 64 mg or TAcs is 
administered as two 1 mL injections (one to each knee) for a total dose of 80 mg in patients with bilateral knee OA. 
Study Design and Methodology: 
This randomized, open label, parallel group study will be conducted in male and female patients ≥ 40 years of age 
with bilateral knee OA.  
Approximately 24 patients will be randomized to one of two treatment groups (1:1) and treated with IA injections to 
both knees of either: 
 
extended-release FX006 64 mg total dose (approximately 12 patients) or 
 
immediate-release TAcs 80 mg total dose (approximately 12 patients) 
Each patient will be evaluated for a total of 6 weeks following the two IA injections.  Following screening, 
pharmacokinetics (PK) and safety will be evaluated at 6 out-patient visits scheduled on Study Days 1 [calendar day 
of injection], 2, 8, 15, 29, and 43.  The study is expected to enroll in approximately 1 month. 
Number of Patients: 
Approximately 24 patients with bilateral knee OA (approximately 12 per treatment arm) will be treated with two IA 
injections (one to each knee) of either 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: Total dose of 64 mg administered following an IA 
injection in each knee. 
Reference Compound(s), Dose and Mode of Administration: 
Commercially available TAcs (Kenalog®-40) injectable suspension, 40 mg/mL, IA, administered as a 1 mL 
injection.  Total dose of 80 mg administered following an IA injection in each knee. 
Duration of Dosing: 
Two single IA injections (one to each knee) 

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Inclusion Criteria:  
To be included in the trial, patients must fulfill the following criteria:  
1. Written consent to participate in the study 
2. Male or female  40 years of age 
3. Symptoms consistent with OA in both knees for ≥ 6 months prior to Screening (patient reported is acceptable) 
4. Currently meets ACR Criteria (clinical and radiological) for OA in both knees (Altman et al, 1986) as follows:  
 
Knee pain 
 
at least 1 of the following: 
o 
Age > 50 years 
o 
Stiffness < 30 minutes 
o 
Crepitus 
 
Osteophytes  
5. Knee pain in both knees for >15 days over the last month (as reported by the patient)  
6. Body mass index (BMI) ≤ 40 kg/m2 
7. Morning serum cortisol result within normal range at Screening (5-23 mcg/dL or 138-635 nmol/dL) 
8. Ambulatory and in good general health  
9. Willing and able to comply with the study procedures and visit schedules and able to follow verbal and written 
instructions 
10. Willing to abstain from use of the following protocol-restricted medications during the study: 
 
Intravenous (IV), Intramuscular (IM), oral, inhaled, intranasal or topical corticosteroids 
 
IA corticosteroids in any joint 
 
IA viscosupplementation (hyaluronic acid) in either knee 
 
Any investigational drug or device 
 
Immunomodulators, immunosuppressives, or chemotherapeutic agents  
 
Live or live attenuated vaccines 
11. 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. 
 

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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 either knee joint 
3. Clinical signs and symptoms of active knee infection or crystal disease in either knee within 1 month of 
Screening 
4. Unstable joint (such as a torn anterior cruciate ligament) in either knee within 12 months of Screening  
Previous or concomitant treatment-related criteria 
5. Presence of surgical hardware or other foreign body in either knee 
6. Surgery or arthroscopy of either knee within 12 months of Screening 
7. IA treatment of any joint with any of the following agents within six (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) 
8. IA treatment in either knee with hyaluronic acid (investigational or marketed) within 6 months of 
Screening 
9. Parenteral or oral corticosteroids (investigational or marketed) within 3 months of Screening 
10. Inhaled, intranasal, or topical corticosteroids (investigational or marketed) within 2 weeks of Screening 

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Patient-related criteria 
11. Females who are pregnant or nursing or plan to become pregnant during the study; men who plan to 
conceive during the study 
12. Known hypersensitivity to any form of triamcinolone 
13. Skin breakdown at either knee where the injection would take place 
14. 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 
15. Currently using insulin and/or oral medication for the treatment of diabetes (Type I or Type II) or a 
hemoglobin A1c (HbA1c) of >7.5 %(>59 mmol/mol) 
16. Any electrocardiogram (ECG) abnormality judged clinically significant by the Investigator 
17. A medical history suggesting the patient will or is likely to require a course of systemic corticosteroids 
during the study period 
18. History or evidence of active or latent systemic fungal or mycobacterial infection (including tuberculosis), 
or of ocular herpes simplex  
19. History of sarcoidosis or amyloidosis  
20. History of or active Cushing’s syndrome 
21. History of osteomyelitis of either leg at any time, or of other areas within 5 years 
22. Use of immunomodulators, immunosuppressives, or chemotherapeutic agents within 5 years of Screening  
23. Active or history of malignancy within the last 5 years, with the exception of resected basal cell carcinoma, 
squamous cell carcinoma of the skin, or effectively managed cervical carcinoma 
24. Active substance abuse (drugs or alcohol) or history of substance abuse within the past 12 months 
25. Has received a live or live attenuated vaccine within 3 months of Screening 
26. Use of any other investigational drug, biologic or device within 3 months of Screening 
27. Any bacterial or viral infection requiring IV antibiotics within 4 weeks of Screening or oral antibiotics 
within 2 weeks of Screening 
28. 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 7 scheduled visits for a total study duration of up to 8 weeks 
(including Screening period). The study will involve a Screening period (up to 14 days), a Baseline/Day 1 visit and 
5 outpatient visits following Day 1. At each visit following Screening, subjects will provide plasma samples for 
pharmacokinetic analysis. 
At specified times throughout the study, patients will undergo safety assessments such as physical examinations, 
vital signs, hematology and chemistry blood collection for analyses and adverse event and concomitant medication 
review.  
Blood samples for drug concentration measurements will be obtained from all patients prior to administration of 
study medication on Day 1, and at hours 1, 2, 3, 4, 5, 6, 8, 10, and 12 (± 10 min) after the first knee injection, on 
Day 2 at 24 hours (± 2 hrs) after the first injection of study medication, and at each of the subsequent scheduled 
visits.   
Blood samples for morning cortisol levels will be obtained between 7-9 am from all patients at Screening, prior to 
administration of the study medication on Day 1, and then at each of the subsequent scheduled visits.  
See Schedule of Study Assessments for full details.  
Blinding: 
Not applicable, this is an open-label study 

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Study Drug Administration Procedure:  
IA injections will be performed by the assigned injector.  The injector may choose the position of the knees (e.g., 
extended or flexed), the approach for the injection (e.g., medial or lateral) and the numbing agent to be used based 
on standard of care. Sterile technique will be used.   
Prior to injection, each knee should be thoroughly cleansed using a bactericidal solution.  Each knee will be 
aspirated in all cases prior to administration of study medication.  Following attempted aspiration, 5 mL of the 
reconstituted FX006 or 1 mL of TAcs will be injected into the synovial space. Refer to the Pharmacy Binder for 
detailed instructions on how to prepare FX006. The injection into the second knee should be given within 15 
minutes of the injection in the first knee.   
The same needle used for synovial fluid aspiration may also be used for IA injection of the study medication, 
thereby allowing for a single injection with syringe replacement.  The injector will use a 21 gauge or larger needle 
for injection and aspiration of fluid. 
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 either knee), 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 prescribed by the investigator or taken by the 
patient from another source:   
 
IV, IM, oral, inhaled, intranasal, or topical corticosteroids 
 
IA corticosteroids in any joint 
 
IA viscosupplementation (hyaluronic acid) or any IA intervention (IA injection, IA aspiration, etc.) in 
either knee 
 
Any investigational drug, device, or biologic 
 
Immunomodulators, immunosuppressives, or chemotherapeutic agents  
 
Live or live-attenuated vaccines 

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Criteria for Evaluation: 
Extent and Duration of Exposure 
 
Drug concentration measurements in plasma (in ng/mL) and the following derived pharmacokinetic 
parameters 
o 
Cmax: Peak exposure, Maximum plasma concentration 
o 
Tmax: Time from dosing to peak exposure, time to maximum plasma concentration 
o 
Clast: Last quantifiable plasma concentration (last value observed above assay BLOQ) 
o 
Tlast: Time of last quantifiable plasma concentration 
o 
T1/2: Terminal half-life 
o 
AUC (0-last): Exposure: Area Under the Plasma Curve from time 0 to the last quantifiable 
concentration (Clast) 
o 
AUC(0-24h): Exposure: Area Under the Plasma Curve from time 0 to 24 hours post IA injection 
o 
AUC(0-inf): Exposure: Area Under the Plasma Curve from time 0 extrapolated to infinity. 
o 
MRT (Observed and Predicted): Mean residence time extrapolated to infinity 
 
Morning Serum Cortisol measurements 
Safety  
 
AEs 
 
Physical examinations 
 
Bilateral knee 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 FX006 32 mg (N=60) and TAcs 40 mg (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).  
In this study, it is expected that the ratio of exposure means (FX006/TAcs) will be less than 1.0 when administered 
to treat bilateral knees. A sample size of 12 in each treatment arm (24 in total) is estimated. 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 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 24 patients (12 in each treatment arm) for the study. 

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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 at least one dose of study drug.  
 
The PK Population will include patients who receive two IA injections (one to each knee), complete 
scheduled sampling, 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. Descriptive summaries of the PK parameter estimates from each 
treatment group will also be completed. 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. 
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.  
Safety analyses will be performed on the Safety Population.  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.  Incidences of TEAEs will also be presented by maximum severity and relationship to study medication. 
Clinical laboratory data and vital sign information will be summarized by treatment group as summary statistics for 
value and change from baseline 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. 
 

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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. 

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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. 

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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). 
While historically OA has been considered a non-inflammatory disease, it is increasingly being 
recognized that chronic synovitis occurs in all stages of knee OA (Benito et al, 2005; Sellam and 
Berenbaum, 2010; Wenham and Conaghan, 2010).  As synovial inflammation is correlated with 
clinical symptoms and joint degeneration, it should be an important target for therapeutic 
intervention.  The inflamed synovium may well be the target for IA corticosteroids which are 
widely used in knee OA (Ayral et al, 2005). 
5.2. 
Background 
5.2.1. 
Investigational Medicinal Product:  FX006 
FX006 is an extended-release formulation of triamcinolone acetonide (TA) for IA 
administration. It is approved under the trade name ZILRETTA™ for the management of pain of 
osteoarthritis of the knee, however, injection in both knees has not been studied and is an 
investigational use.    FX006 is intended to 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.   

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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 Knee 
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 triamcinolone acetonide 
(TAcs).  Nonclinical data and the literature suggest that this potential could extend to limiting 
structural progression in patients with inflammatory joint disorders. The near term clinical 
development program for FX006 focus on analgesics effects in patient with OA (bilateral knee, 
hip, and shoulder) as well as other shoulder maladies. 
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 
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 

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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, FX006 32 mg 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 (10mg, 40mg, 60mg) 
administered as a 3mL 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 TAcs 40 mg. 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 FX006 32 mg 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. 
5.2.6. 
Efficacy in Patients with Osteoarthritis of the Knee 
Efficacy data from three studies provide substantial evidence supporting the effectiveness of 
FX006 32 mg 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 FX006 32 mg 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 FX006 32 mg was demonstrated. 
Robustness of the primary outcome in the Phase 3 study was further supported by the internal 
consistency demonstrated in favor of FX006 32 mg through secondary analyses utilizing the 
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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 FX006 32 mg 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.  
 The number of treatment-emergent adverse events (TEAEs) reported was similar 
across groups (FX006 46.0%; placebo 49.2%; TAcs 51.0%).   
 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.  
 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) 
 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.   

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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 FX006 32 mg, 
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 FX006 32 mg 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.   

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6. 
STUDY OBJECTIVES 
6.1. 
Primary Objective 
The primary objectives of this study are (a) to compare the systemic exposure to triamcinolone 
acetonide from extended-release FX006 and immediate release TAcs and (b) to assess the safety 
and general tolerability, when FX006 is administered as two 5 mL IA injections (one to each 
knee) for a total dose of 64 mg or TAcs is administered as two 1 mL injections (one to each 
knee) for a total dose of 80 mg in patients with bilateral knee OA.  

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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
This randomized, parallel group study will be conducted in male and female patients ≥ 40 years 
of age with bilateral knee OA.  
Approximately 24 patients will be randomized to one of two treatment groups (1:1) and treated 
with two IA injections of either: 
 extended-release FX006 64 mg total dose (approximately 12 patients) or 
 immediate-release TAcs 80 mg total dose (approximately 12 patients) 
Each patient will be evaluated for a total of 6 weeks following the two IA injections.  Following 
screening, PK and safety will be evaluated at 6 out-patient visits scheduled on Study Days 1 
[calendar day of injection], 2, 8, 15, 29, and 43.  The study is expected to enroll in approximately 
1 month. 
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/Aspirator  
 must be a medical doctor, a physician’s assistant, or nurse practitioner experienced in 
administering IA injections and performing synovial fluid aspirations of the knee 
 is responsible for performing IA injections of study medication and synovial fluid 
aspirations of the knee 
Assessor  
 must be a medical doctor, a physician’s assistant, or nurse practitioner 
 must have relevant OA experience 
 responsible for performing the physical examination and knee assessments  

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 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/Aspirator and/or Assessor).  
7.3. 
Discussion of Study Design 
7.3.1. 
Rationale for Study Population 
Patients with pain associated with OA of the knee 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 included.  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. It is expected that 
plasma levels will increase secondary to simultaneous injections in the knee. This study is to 
establish the safety with these increased levels. 
7.3.2. 
Rationale for Dose Selection 
The 32 mg dose of FX006 was selected for this study 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 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 is 32 mg, therefore this dose was selected for further study in investigational uses. 
7.3.3. 
Rationale for Study Design 
The current trial is design is substantially similar to PK studies previously conducted in OA of 
the knee. The randomized, open label, 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 objective of the study to 
characterize the systemic PK and local extent and duration of exposure of TA from FX006 and 
TAcs. 

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The clinical safety parameters to be assessed (adverse events, physical examinations, knee 
examinations, vital signs, and clinical laboratory evaluations) are standard safety and tolerability 
assessments and support the clinical monitoring necessary based on the toxicology profile for 
FX006. 
7.3.5. 
Rationale for Control Type  
The active control (TAcs) Kenalog®-40 Injection is commonly used in treatment of OA of the 
knee, and differences in systemic exposure are informative to clinicians and may be extrapolated 
to other corticosteroids.    
7.4. 
Selection and Withdrawal of Study Patients 
7.4.1. 
Number of Patients 
Approximately 24 patients with bilateral knee OA (up to 12 per treatment arm) will be treated 
with two IA injections (one to each knee) of FX006 or TAcs.    
7.4.2. 
Inclusion Criteria 
To be included in the trial, patients must fulfill the following criteria:  
1. Written consent to participate in the study 
2. Male or female  40 years of age 
3. Symptoms consistent with OA in both knees for  6 months prior to Screening (patient 
reported is acceptable) 
4. Currently meets ACR Criteria (clinical and radiological) for OA in both knees (Altman et 
al, 1986) as follows:  
 Knee pain 
 at least 1 of the following: 
o Age > 50 years 
o Stiffness < 30 minutes 
o Crepitus 
 Osteophytes  
5. Knee pain in both knees for >15 days over the last month (as reported by the patient)  
6. Body mass index (BMI) ≤ 40 kg/m2 
7. Morning serum cortisol result within normal range at Screening (5-23 mcg/dL or 
138-635 nmol/dL) 
8. Ambulatory and in good general health  
9. Willing and able to comply with the study procedures and visit schedules and able to 
follow verbal and written instructions. 

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10. Willing to abstain from use of the following protocol-restricted medications during the 
study: 
 Intravenous (IV), Intramuscular (IM), oral, inhaled, intranasal or topical 
corticosteroids 
 IA corticosteroids in any joint 
 IA viscosupplementation (hyaluronic acid) in either knee 
 Any investigational drug or device 
 Immunomodulators, immunosuppressives, or chemotherapeutic agents  
 Live or live attenuated vaccines 
11. 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. 
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 either knee joint 
3. Clinical signs and symptoms of active knee infection or crystal disease in either knee 
within 1 month of Screening 
4. Unstable joint (such as a torn anterior cruciate ligament) in either knee within 12 months 
of Screening  
Previous or concomitant treatment-related criteria 
5. Presence of surgical hardware or other foreign body in either knee  
6. Surgery or arthroscopy of either knee within 12 months of Screening 
7. IA treatment of any joint with any of the following agents within six (6) months of 
Screening: any corticosteroid preparation (investigational or marketed, including FX006), 

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any biologic agent (e.g., platelet rich plasma (PRP) injection, stem cells, prolotherapy, 
amniotic fluid injection; investigational or marketed). 
8. IA treatment in either knee with hyaluronic acid (investigational or marketed) within 6 
months of Screening 
9. Parenteral or oral corticosteroids (investigational or marketed) within 3 months of 
Screening 
10. Inhaled, intranasal or topical corticosteroids (investigational or marketed) within 2 weeks 
of Screening 
Patient-related criteria 
11. Females who are pregnant or nursing or plan to become pregnant during the study; men 
who plan to conceive during the study 
12. Known hypersensitivity to any form of triamcinolone 
13. Skin breakdown at either knee where the injection would take place 
14. 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. 
15. Currently using insulin and/or oral medication for the treatment of diabetes (Type I or 
Type II) or a hemoglobin A1c (HbA1c) of >7.5% (>59 mmol/mol) 
16. Any electrocardiogram (ECG) abnormality judged clinically significant by the 
Investigator. 
17. A medical history suggesting the patient will or is likely to require a course of systemic 
corticosteroids during the study period. 
18. History or evidence of active or latent systemic fungal or mycobacterial infection 
(including tuberculosis), or of ocular herpes simplex  
19. History of sarcoidosis or amyloidosis  
20. History of or active Cushing’s syndrome 
21. History of osteomyelitis of either leg at any time, or of other areas within 5 years.    
22. Use of immunomodulators, immunosuppressives, or chemotherapeutic agents within 5 
years of Screening  
23. Active or history of malignancy within the last 5 years, with the exception of resected 
basal cell carcinoma, squamous cell carcinoma of the skin, or effectively managed 
cervical carcinoma 
24. Active substance abuse (drugs or alcohol) or history of substance abuse within the past 12 
months 
25. Has received a live or live attenuated vaccine within 3 months of Screening 
26. Use of any other investigational drug, biologic or device within 3 months of Screening 

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27. Any bacterial or viral infection requiring IV antibiotics within 4 weeks of Screening or 
oral antibiotics within 2 weeks of Screening 
28. 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 Medication Treatment Arms 
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 to each knee for a 
total dose of 64 mg. 
Reference Compound:   
 Commercially available TAcs (Kenalog®-40) injectable suspension, 40 mg/mL, IA, 
administered as a 1 mL injection to each knee for a total dose of 80 mg.  
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 (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. 

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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 refrigerated at 2 to 8 °C. 
TAcs 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.   
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. 
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 continuous 
across the study (i.e., no stratification), using a block size of 4 (four). See Statistics Section 9 for 
further details.   
7.5.8. 
Blinding 
This is an open-label study.  
7.5.9. 
Study Drug Administration Procedure 
IA injections of study drug will be performed by the assigned injector.  The injector may choose 
the position of the knee (e.g., extended or flexed), the approach for the injection (e.g., medial or 
lateral) and the numbing agent to be used  based on standard of care. Sterile technique will be 
used. 
Prior to injection, each knee should be thoroughly cleansed using a bactericidal solution. Each 
knee will be aspirated in all cases prior to administration of study medication. Following 
aspiration, 5 mL of the reconstituted FX006 or 1 mL of TAcs will be injected into the synovial 
space. Refer to the Pharmacy Binder for detailed instructions on how to prepare FX006. The 
injection into the second knee should be given within 15 minutes of the injection in the first 
knee. 
The same needle used for fluid aspiration may also be used for IA injection of study medication, 
thereby allowing for a single injection with syringe replacement.   

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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 knee), the patient should be treated according to local clinical 
guidelines and physician experience (see also Protocol Section 8.1.5). 
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 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 treated 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 Visit (Day 43). 
2. Determine whether the patient is willing to be contacted to follow ongoing or new AEs 
through Day 43 (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 43 (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.  

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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 either knee 
 Bracing of either knee 
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 either knee 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, knee 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 1, 2, 3, 4, 5, 6, 8, 10, and 12 after injection of the first knee  
 On Day 2, at 24 (± 2) hours after the first injection of study drug 
 On Days 8, 15, 29, and 43 (time as convenient) 
These represent a total of 15 samples from each patient, each sample representing 4 mL of blood, 
for a maximum estimated total volume of 60 mL of blood collected from each patient for drug 
concentration measurement. 

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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.  
7.7.3. 
Pharmacodynamic Variables 
Blood samples for morning serum cortisol levels will be collected between 7 am and 9 am at 
Screening and on Study Days 1, 2, 8, 15, 29, 43. Levels observed in the two treatment arms will 
be compared using descriptive statistics. There is no statistical hypothesis or objective for this 
parameter.  
Synovial fluid samples will be preserved for a maximum of 5 years for potential future analyses 
of biomarkers that may contribute to the pathogenesis of OA and/or be associated with 
responsiveness to FX006 treatment. No genomic analyses (gene sequencing studies) will be 
performed using these samples. Patients will be able to withdraw consent throughout the duration 
of storage. Once analysis has begun, consent will no longer be able to be withdrawn.  
7.8. 
Schedule of Study Assessments 
A summary of the schedule of study assessments is provided in Table 1.  All visits will be 
conducted on an out-patient basis.  
Refer to Section 7.9 for details of each assessment.   
 
 

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Table 1: 
Schedule of Study Assessments 
Procedures 
Screening1 
Day  
1 
Day  
2 
Day  
82 
Day 
152 
Day 
292 
Day 432 
(End of Study) 
Informed consent 
X3 
 
 
 
 
 
 
Inclusion/Exclusion Review 
X 
X4 
 
 
 
 
 
Medical History/Update 
X 
X4 
 
 
 
 
 
OA Medical History 
X 
 
 
 
 
 
 
Prior Treatment & Meds5  
X 
X4 
 
 
 
 
 
Physical Examination 
X 
X4 
 
 
 
 
X 
Bilateral Knee X-rays 
X6 
 
 
 
 
 
 
Bilateral Knee Assessments7 
X 
X4 
 
 
 
 
X 
12-Lead ECG 
X 
 
 
 
 
 
 
Vital Signs 
X 
X4 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
Weight and BMI  
X 
 
 
 
 
 
X 
Hematology & Chemistry8 
X 
X4 
 
 
 
 
X 
HIV, Hepatitis B/C, HbA1c8 
X 
 
 
 
 
 
 
Pregnancy Test9 
X 
X4 
 
 
 
 
X 
Blood for Drug Conc. 
 
X10 
X11 
X 
X 
X 
X 
Blood for Morning Serum 
Cortisol12 
X 
X4 
X 
X 
X 
X 
X 
Knee Aspiration and Collection of 
Synovial Fluid 
 
X4 
 
 
 
 
 
Treatment Administration13 
 
X 
 
 
 
 
 
Adverse Event Monitoring14 
 
------------------------------------- X----------------------------------- 
Concomitant Medications14 
 
------------------------------------- X----------------------------------- 
                                                 
1 Screening may occur up to 14 days prior to Day 1 (calendar day of dosing). 
2 Visit should be conducted +/- 2 days from scheduled date 
3 Consent must be obtained prior to performing any study-specific procedures. 
4 Complete assessment prior to dosing. 
5 Record any medications received within 30 days prior to Screening. 
6 Obtain new x-rays if >6 months since prior x-ray. 
7 Both knees will be assessed for tenderness, heat/redness, swelling, effusion, and Baker’s cyst. Clinically significant findings 
(new or worsening from baseline) should be recorded as AEs. 
8 Via Central Laboratory 
9 Conduct for female of childbearing potential only.  Serum pregnancy test to be performed via central laboratory at Screening 
and End-of-Study visits (scheduled for Day 43); urine pregnancy test to be performed locally on Day 1 and results available 
prior to dosing.   
10 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 of the first knee (±10 minutes). 
11 On Day 2, blood for plasma drug concentration measurements will be collected at 24 hours post-injection of the first knee (± 2 
hours), and on subsequent visits as convenient. 
12 Blood for morning cortisol measurements will be collected between 7 and 9 am. 
13 The injection of the second knee should take place within 15 minutes of the first knee injection. 
14 AEs and Concomitant Medications will be captured from Day 1 (post-injection) to End of Study Visit. 

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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 
provide, 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 pre-dosing on Day 1. 
OA medical history includes ACR diagnosis details, OA diagnosis date (if available), number of 
days with pain in both knees in the last month, and previous IA steroid or hyaluronic injections.  
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 to any time point post-dosing to final study visit.  
7.9.4. 
Knee X-rays  
An X-ray is required for each knee within 6 months prior to Screening or during the Screening 
period. It is recommended that the anterior-posterior view, weight bearing and extended be used.  
If possible, the X-ray will be read locally for K-L grading at Screening.   
7.9.5. 
Knee Assessment 
The knee assessment will be performed on both knees by the designated assessor at the days 
indicated in the Schedule of Study Assessments.  The knee will be assessed for tenderness, 

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heat/redness, swelling, effusion, and Baker’s cyst. If there is a clinically significant finding 
outside of the patient’s typical disease state at the Screening or Baseline Visit, add to the Medical 
History.  At time points post-injection, if there are new clinically significant findings outside of 
the patient’s typical disease state or findings that worsen from 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): 
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 

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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. 
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 Antibody1 
Total cholesterol  
HIV2 
Triglycerides 
 
 
Other  
 
HbA1c 
 
Morning Serum Cortisol 
 
 
 
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 fourth generation test for both antibody and viral antigen. 

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7.9.11. 
Synovial Fluid Aspiration 
Synovial fluid samples for potential future biomarker evaluation will be obtained from all 
patients via aspiration on  Day 1 prior to study medication administration. The injector/aspirator 
will attempt to aspirate synovial fluid from the knee using sterile technique.  The volume of the 
synovial fluid obtained will be recorded in the eCRF. If no synovial fluid is obtained then 0 mLs 
should be recorded.  Procedures for sample collection, handling, storage and shipment will be 
described in the Laboratory Manual.  The synovial fluid samples will be preserved for potential 
future analyses of biomarkers that may contribute to the pathogenesis of OA and/or be associated 
with responsiveness to FX006 treatment.       
7.9.12. 
Treatment Administration 
On Day 1, after completing all the 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.)   
 Synovial fluid will be aspirated from each knee just prior to administration of study 
medication (refer to Section 7.9.10 for more details of the synovial fluid aspiration).   
 The injector/aspirator will perform the IA injection of the study medication (refer to 
Section 7.5.9 for instructions).   
7.9.13. 
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 for further information in regards to reporting of AEs.  Refer to Section 7.6 
for further information in regards to allowed and restricted concomitant medication. 

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8. 
CLINICAL SAFETY ASSESSMENTS 
Safety evaluations will be based on the assessment of AEs occurring after the administration of 
study medication on Day 1 through the Final Visit (scheduled for Day 43).  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, 
o 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, 
o 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, or 
o 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. 

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 Is a congenital anomaly/birth defect. 
o 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: 

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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 

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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 
When an SAE occurs, the Investigator or designee, must log into the electronic data capture 
(EDC) system and complete the SAE report form within 24 hours of first becoming aware of the 
SAE. The SAE will automatically be reported to the Medical Monitor, or designee, 
electronically. 
Follow up information relating to an SAE must be reported to the Medical Monitor, or designee, 
within 24 hours of receipt by the Investigator by entering new information into the electronic 
SAE form. The updated SAE will be automatically reported to the Medical Monitor or designee 
electronically.  
If one is unable to log into the EDC system, the SAE hotline may be contacted (information 
located in the Investigator Site File in the Study Contact List).  
All SAEs that occur at your site should, in addition, be reported by the Investigators to the 
responsible IRB/EC without undue delay, if applicable according to IRB/EC 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/EC 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 completely resolved or until a stable chronic outcome is determined by the 
Principal Investigator.  SAEs will be reported in accordance with Section 8.1.3. 
The Medical Monitor must promptly review all information relevant to the safety of an 
investigational new product received from any source.  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 Knee-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, 

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swelling, effusion, decreased mobility of the knee), the patient should be treated according to 
local clinical guidelines and physician experience.   
If the knee 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.   
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. 

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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 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; there 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 patent 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 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 statistical analysis 
plan (SAP). Two analysis populations are planned for this study as follows: 
 The Safety Population will include all subjects who received at least one dose of 
study drug. The Safety Population will be used to assess safety and tolerability. 
 The PK Population will include subjects who receive two IA injections (one to each 
knee), complete scheduled sampling, 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 

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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 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 FX006 32 mg (N=60) and TAcs 40 mg (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 bilateral knee OA. A sample size of 12 in each treatment arm (24 in 
total) is estimated. 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 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 24 patients (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 study site and patient, and will be 
summarized by treatment.  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 study site and patient, and will be summarized by treatment.   

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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.  
Incidences of TEAEs will also be presented by maximum severity and relationship to study 
medication. Similar presentations will be provided for serious AEs, AEs leading to withdrawal 
from the study, or AEs leading to death. Analysis of AE data will include examination of the 
incidence rates of TEAEs and index knee related TEAEs.  
9.4.4.2. 
Other Safety Analyses 
Clinical laboratory data and vital sign information will be summarized by treatment group as 
summary statistics for value and change from pre-dose at each individual time point.  Summary 
statistics will include n, mean, median, standard deviation, minimum, and maximum. 
9.4.5. 
Pharmacokinetic Analysis 
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 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. Descriptive summaries of the PK 
parameter estimates from each treatment group will also be completed. 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. 
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.  

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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. 

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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 by 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 

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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. 

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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. 
 

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13. 
REFERENCES 
Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, et al. The American College of 
Rheumatology criteria for the classification and reporting of osteoarthritis of the knee. Arthritis 
Rheum 1986;29:1039-1049 
Ayral X, Pickering EH, Woodworth TG, Mackillop N, Dougados M. Synovitis: a potential 
predictive factor of structural progression of medial tibiofemoral knee osteoarthritis -- results of 
a 1 year longitudinal arthroscopic study in 422 patients. Osteoarthritis Cartilage 2005;13:361-7. 
Benito MJ, Veale DJ, FitzGerald O, van den Berg WB, Bresnihan B.  Synovial tissue 
inflammation in early and late osteoarthritis.  Ann Rheum Dis 2005;64:1263-1267.  
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, P. G., Cohen, S. B., 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. 
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. 

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Sellam J and Berenbaum F.  The role of synovitis in pathophysiology and clinical symptoms of 
osteoarthritis.  Nature Reviews Rheumatology  2010;6:625-635. 
Wenham CYJ and Conaghan PG.  The role of synovitis in osteoarthritis.  Ther Adv Musculoskel 
Dis  2010;2:349-359.