Conditions: Bilateral Knee Osteoarthritis
Keywords: Osteoarthritis Knee Corticosteroid Bilateral Pain Intra-articular Injection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: no

Brief summary:
This is a randomized, open-label, parallel group study to compare systemic exposure of triamcinolone acetonide following administration into both knees of either FX006 or TAcs.

Detailed description:
This is a randomized, open label, parallel group study that 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 screened to confirm the diagnosis of OA and eligibility based on the inclusion/exclusion requirements and will be randomized to treatment on Day 1. 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.

Arms:
arm 1: Two intra-articular (IA) injections of FX006 32 mg (total dose of 64 mg) arm 2: Two intra-articular (IA) injections of TAcs 40 mg (total dose of 80 mg)

Interventions: intervention 1: FX006 32 mg intervention 2: TAcs 40 mg
Intervention descriptions: intervention 1: Drug: Extended-release 32 mg FX006 IA injection into each knee (total 64 mg dose) intervention 2: Drug: Immediate-release 40mg TAcs IA injection into each knee (total 80 mg dose)

Protocol document:
Prot_000.pdf: 
 
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 
primary outcome data average daily pain (ADP) to evaluate durability and magnitude of 


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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. 

SAP_001.pdf: 
 
Document No.: STAT C002-TP01 v2.0 
 
Confidentiality 
This document is confidential and proprietary property of Flexion Therapeutics, Inc. and to be used only as 
authorized by Flexion Therapeutics, Inc..  No part is to be reproduced, disclosed to others, or quoted without prior 
written authorization from Flexion Therapeutics, Inc. 
STATISTICAL ANALYSIS PLAN 
Protocol FX006-2017-012 
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: 
(Version Date) 
FX006-2017-012 
Version 2.0 (10 November 2017) 
Name of Test Drug: 
FX006 
Phase: 
2a 
Methodology: 
Randomized, open label, parallel group, two intraarticular 
injections (one in each knee) study 
Sponsor: 
Flexion Therapeutics 
10 Mall Road, Suite 301 
Burlington, Massachusetts, USA  
Tel: 781-305-7777 
Sponsor Representative: 
Joelle Lufkin 
Vice President Clinical Operations 
Document Date: 
08 March 2018 
Document Version: 
Final Version 1.0  
 






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TABLE OF CONTENTS 
Section 
Page 
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS .......................................... 10 
1.1. 
Introduction ........................................................................................................ 10 
1.2. 
Objectives of Statistical Analysis ...................................................................... 11 
2. 
STUDY DESIGN ............................................................................................................ 12 
2.1. 
Synopsis of Study Design ................................................................................... 12 
2.2. 
Randomization Methodology ............................................................................ 12 
2.3. 
Stopping Rules and Unblinding ........................................................................ 12 
2.4. 
Study Procedures ............................................................................................... 12 
2.5. 
Safety, Pharmacodynamic and Pharmacokinetic (PK) Safety 
Variables ............................................................................................................. 15 
2.5.1. 
Safety Variables .................................................................................... 15 
2.5.2. 
Pharmacokinetic Variables ................................................................... 15 
2.5.3. 
Pharmacodynamic Variables ................................................................ 15 
3. 
PATIENT POPULATIONS .......................................................................................... 17 
3.1. 
Population Definitions ....................................................................................... 17 
3.2. 
Protocol Deviations ............................................................................................ 17 
4. 
STATISTICAL METHODS ......................................................................................... 18 
4.1. 
Sample Size Justification ................................................................................... 18 
4.1.1. 
Sample Size Considerations.................................................................. 18 
4.1.2. 
Sample Size Estimate............................................................................ 18 
4.2. 
General Statistical Methods and Data Handling ............................................ 18 
4.2.1. 
General Methods ................................................................................... 18 
4.2.2. 
Computing Environment....................................................................... 19 
4.2.3. 
Methods of Pooling Data ...................................................................... 19 
4.2.4. 
Adjustments for Covariates .................................................................. 19 
4.2.5. 
Multiple Comparisons/Multiplicity ...................................................... 19 
4.2.6. 
Subpopulations...................................................................................... 19 
4.2.7. 
Discontinuations and Loss to Follow-up .............................................. 19 
4.2.8. 
Missing, Unused, and Spurious Data .................................................... 20 
4.2.9. 
Visit Windows ...................................................................................... 20 


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Section 
Page 
4.2.10. 
Baseline definitions............................................................................... 20 
4.3. 
Interim Analyses ................................................................................................ 20 
4.4. 
Patient Disposition ............................................................................................. 20 
4.6. 
Demographic and Baseline Characteristics ..................................................... 21 
4.6.1. 
Demographic characteristics ................................................................. 21 
4.6.2. 
Osteoarthritis (OA) Medical History .................................................... 21 
4.6.3. 
Prior medication .................................................................................... 22 
4.7. 
Pharmacodynamics Evaluation ........................................................................ 22 
4.8. 
Study Drug Exposure and Pharmacokinetics Evaluation .............................. 23 
4.8.1. 
Study Drug Exposure ............................................................................ 23 
4.8.2. 
Plasma drug concentration analysis ...................................................... 23 
4.8.3. 
Handling of Concentration Data below the Limit of 
Quantification (BLOQ) ......................................................................... 23 
4.8.4. 
Pharmacokinetic analysis ...................................................................... 25 
4.8.5. 
Exploration of Bioequivalence between FX006 and TAcs .................. 27 
4.9. 
Safety Analyses ................................................................................................... 27 
4.9.1. 
Adverse Events ..................................................................................... 27 
4.9.2. 
Laboratory Data .................................................................................... 28 
4.9.3. 
Vital Signs and Physical Examinations and Knee 
Assessment............................................................................................ 29 
4.9.4. 
Electrocardiogram ................................................................................. 29 
4.9.5. 
Concomitant Medications ..................................................................... 29 
5. 
CHANGES TO PLANNED ANALYSES .................................................................... 31 
6. 
References ....................................................................................................................... 32 
7. 
CLINICAL STUDY REPORT APPENDICES ........................................................... 33 
7.1. 
Statistical Tables to be Generated .................................................................... 33 
7.2. 
Statistical Figures to be Generated .................................................................. 34 
7.3. 
Data Listings to be Generated .......................................................................... 35 
 
 
 
 


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LIST OF IN-TEXT TABLES 
Table 
Page 
Table 1 
Schedule of Assessments................................................................................................. 14 
Table 2 
PK Parameters ................................................................................................................. 26 
 


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ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse events 
ACR 
American College of Rheumatology 
ADaM 
Analysis Data Model 
ANOVA 
Analysis of variance 
ATC 
Anatomic Therapeutic Class  
AUC 
Area Under the Plasma Concentration Curve 
AUC(0-24) 
Area Under the Plasma Concentration Curve from 0 to 24 hours 
AUC(0-inf) 
Area Under the Plasma Concentration Curve from 0 extrapolated 
to infinity 
AUC(0-t) 
Area Under the Plasma Concentration Curve from 0 to last 
quantifiable concentration (t) 
BLOQ 
Below Limit of Quantification  
BMI 
Body Mass Index 
CI 
Confidence Interval 
Clast 
Last quantifiable plasma concentration 
CL 
Total Body Clearance 
Cmax 
Maximum Plasma Concentration 
CRF 
Case Report Form 
CSR 
Clinical study report 
CV 
Coefficient of variation 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
EULAR 
European League Against Rheumatism  
FDA 
Food and Drug Administration 
GM 
Geometric Mean 
HbA1c 
Hemoglobin A1C 
HIV 
Human Immunodeficiency Virus 
IA 
Intra-articular 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal product 
IxRS 
Interactive Voice/Web Response System 
kg 
Kilogram 
LSMD 
Least Square Mean Difference 


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Abbreviation 
Definition 
m 
Meter 
mg 
Milligram 
mL 
Milliliter 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean Residence Time 
ms 
millisecond 
NCA 
Non-Compartmental pharmacokinetic analysis 
OA 
Osteoarthritis 
OARSI 
Osteoarthritis Research Society International 
PK 
Pharmacokinetic 
PT 
Preferred Term 
Q1 
1st quartile 
Q3 
3rd quartile 
REML 
Residual Maximum Likelihood 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SE 
Standard Error 
SOC 
System Organ Class 
TA
1
 
Triamcinolone Acetonide   
TAcs
2
 
Triamcinolone Acetonide Injectable Suspension, Immediate-
Release (commercially available) (Reference Compound, 
Kenalog®-40) 
TEAE 
Treatment Emergent AE 
tlast 
Time of Last Quantifiable Plasma Concentration 
tmax 
Time from Dosing to Peak Exposure 
t1/2 
Terminal Half-Life 
US 
United States 
Vz_F 
Apparent volume of distribution during terminal phase after non-
intravenous administration, which approximates a steady state 
parameter estimate 
WHO 
World Health Organization 
WHO-DD 
World Health Organization-Drug Dictionary 
λz 
Terminal Elimination Rate Constant (aka: Lambda_z) 


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Protocol FX006-2017-012 
08 MAR 2018 
 
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9
1 Abbreviated in past protocols and documents as TCA 
2 Abbreviated in past protocols and documents as TCA-IR 


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1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1.1. 
Introduction 
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). 
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 OA 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)  
 
 


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1.2. 
Objectives of Statistical Analysis 
The primary objectives of this study are:  
• to compare the plasma pharmacokinetics (PK), including systemic exposure, of 
triamcinolone acetonide between extended-release (FX006) and immediate release 
(TAcs) formulations. 
• 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.  
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis 
of study data in order to answer the study objective(s). Populations for analysis, data handling 
rules, statistical methods, and formats for data presentation are provided.  The statistical 
analyses and summary tabulations described in this SAP will provide the basis for the results 
sections of the clinical study report (CSR) for this trial, as well as used for regulatory filings and 
manuscripts and presentations. 
This SAP also will outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol. 


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2. 
STUDY DESIGN 
2.1. 
Synopsis of Study Design 
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 single IA injections of either:  
1. extended-release FX006 64 mg total dose (approximately 12 patients) or  
2. 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.  
 
2.2. 
Randomization Methodology 
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). This is an open-label study 
design and no patients or study personnel are blinded to treatment assignment. 
 
2.3. 
Stopping Rules and Unblinding 
Unblinding is not applicable to this study since this is an open label-study. 
There will be no data review committee for this study. 
Furthermore, discontinuation from treatment is not applicable to this study as each treated 
patient receives study medication at a single study visit as two IA injections, one in each knee, 
except in the case in which only one knee is injected. 
 
2.4. 
Study Procedures 
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 (Day 1) and 5 outpatient visits following Day 1. At each visit 
following Screening, patients will provide blood samples for TA drug concentration 
measurements for PK 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 TA 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 
minutes) after the first knee injection, on Day 2 at 24 hours (± 2 hours) after the first injection of 
study medication, and at each of the subsequent scheduled visits: Day 8, 15, 29 and 43 (time as 


Flexion Therapeutics 
Protocol FX006-2017-012 
08 MAR 2018 
 
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13 
convenient during the scheduled visit). The date and time that each blood sample was obtained 
will be recorded. 
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. 
The schedule of assessments, as outlined in the study protocol, is provided in Table 1 
 
 


Flexion Therapeutics 
Protocol FX006-2017-012 
08 MAR 2018 
 
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Table 1 
Schedule of 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 & Medications5  
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 Concentrations 
 
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  


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Protocol FX006-2017-012 
08 MAR 2018 
 
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15 
9 Conduct for females of childbearing potential only. Serum pregnancy test to be performed via central laboratory 
at Screening and End-of-Study visit (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 prior to dosing 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.   
 
 
2.5. 
Safety, Pharmacodynamic and Pharmacokinetic (PK) Safety 
Variables 
 
2.5.1. 
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. 
 
2.5.2. 
Pharmacokinetic Variables 
Blood samples (4 mL per sample) for TA drug concentration measurements will be obtained 
from all patients at the following nominal, or planned, times:  
• On Day 1, within 1 hour prior to administration of study medication (Nominal Time -1), 
• On Day 1, at Hours 1, 2, 3, 4, 5, 6, 8, 10, and 12 (± 10 minutes) after injection of the first 
knee, 
• On Day 2, at 24 (± 2 hours) after injection of the first knee, 
• On Days 8, 15, 29, and 43 (time as convenient during the scheduled visit). 
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. 
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. 
PK parameter endpoints are described in section 4.8.4. 
 
2.5.3. 
Pharmacodynamic Variables 
Blood samples for serum cortisol levels will be collected between 7 am and 9 am at Screening, 
prior to administration of the study medication on Day 1, and on Study Days 1, 2, 15, 29, 43. 


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16 
Synovial fluid samples will be preserved for a maximum of 5 years for potential future analyses 
of biomarkers that may have utility in defining pathogenesis of OA and/or be associated with 
responsiveness to FX006 treatment. No analysis is planned at this time.  
 


Flexion Therapeutics 
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3. 
PATIENT POPULATIONS 
3.1. 
Population Definitions 
The following patient populations will be evaluated and used for presentation and analysis of 
the data: 
Safety population: 
All patients who received study medication (injection in at least one knee). Patients will be 
analyzed according to the treatment they have received (“analyses as treated”). 
Pharmacokinetic Population: 
All patients from safety population who receive two IA injections (one to each knee), complete 
scheduled sampling, and have sufficient plasma concentration data to allow calculation of PK 
parameters will be included in the PK population. Review of the plasma drug concentration data 
and eligibility for inclusion into the PK population will be completed by the study 
Pharmacokineticist. The rationale for inclusion or exclusion in the PK population will be 
documented and listed. Patients will be analyzed according to the treatment they have received 
(“analyses as treated”). 
 
3.2. 
Protocol Deviations 
All protocol deviations will be presented in the data listings. 


Flexion Therapeutics 
Protocol FX006-2017-012 
08 MAR 2018 
 
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4. 
STATISTICAL METHODS 
4.1. 
Sample Size Justification 
4.1.1. 
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 PK 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). 
4.1.2. 
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 PK 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. 
 
4.2. 
General Statistical Methods and Data Handling 
4.2.1. 
General Methods 
All output will be incorporated into Microsoft Excel or Word files, sorted and labeled according 
to the International Conference on Harmonization (ICH) recommendations, and formatted to the 
appropriate page size(s). 
Tabulations will be produced for appropriate demographic, baseline, pharmacodynamics, PK 
and safety parameters.  Summary tables will present data by treatment arm. 
For categorical variables, summary tabulations of the number and percentage within each 
category (with a category for missing data) of the parameter will be presented. 
For continuous variables, the number of non-missing values (n), the mean, median, standard 
deviation (SD), minimum and maximum values will be presented. 95% Confidence Intervals 
(CI) may be provided.  In addition, for concentration-based parameters, the coefficient of 
variation (CV %), the geometric mean (GM) and log-scale standard deviation will be provided. 
Additional statistics may be presented for certain endpoints as described below. 
All collected data will be presented in by-patient listings sorted by treatment arm and patient 
number. 


Flexion Therapeutics 
Protocol FX006-2017-012 
08 MAR 2018 
 
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19 
All data listings that contain an evaluation date will contain relative analysis day (Rel Day). Pre-
treatment and post treatment analysis days are numbered relative to the day of the first dose of 
study treatment (i.e., injection in the first knee), which is designated as Day 1. The preceding 
day is Day-1; the day before that is Day-2, etc. 
For data listings relative to PK assessments where several assessments are made on the same 
day, there will be also a relative study day and time. 
The sections below describe the intended analysis of the endpoints. Additional sensitivity 
analysis may be employed in the event of any unforeseen data anomalies or data issues not 
known at the time of writing this analysis plan. 
 
4.2.2. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS® statistical software 
(Version 9.4 or higher), unless otherwise noted. 
Non-compartmental PK analyses (NCA) will be conducted using Phoenix 7, WinNonlin® 
Version 7 or higher (Certara Corporation). 
Adverse events will be coding using Medical Dictionary for Regulation Activity (MedDRA) 
Version 20.1 (or higher).  
Concomitant medications will be coded using World Health Organization (WHO) Drug 
Dictionary (DD) (Version B3 Mar 2014 or Higher).  
 
4.2.3. 
Methods of Pooling Data 
Not applicable to the present study. 
 
4.2.4. 
Adjustments for Covariates 
No formal statistical analysis that adjusts for possible covariate effects is planned. 
 
4.2.5. 
Multiple Comparisons/Multiplicity 
Not applicable. 
 
4.2.6. 
Subpopulations 
Not applicable to the present study.   
4.2.7. 
Discontinuations and Loss to Follow-up 
Each treated patient from this study receives study medication as two single IA injections. 
Therefore, discontinuation from treatment is not applicable. Whether or not patients may receive 
the entire content of study drug injection will be considered in the study drug exposure analyses. 


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08 MAR 2018 
 
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20 
Each patient may only discontinue from the study for further assessments and study visits. Data 
collected from discontinued patients will be included in the CSR. Patients who discontinue from 
the study may be replaced at the discretion of the sponsor.  
 
4.2.8. 
Missing, Unused, and Spurious Data 
Missing values will not be imputed and data will be analyzed “as observed”. 
 
4.2.9. 
Visit Windows 
Visit windows will be calculated based on the schedule of assessments. 
All endpoints will be summarized and presented according to the nominal visit (and hour, if 
applicable) as recorded on the Case Report Form (CRF). 
 
4.2.10. 
Baseline definitions 
For all endpoints, for exposed patients, baseline is the Baseline/Day 1 assessment prior to study 
drug administration date and time, in the first knee. If baseline result is missing, the first non-
missing result prior to study drug administration may be used from the Screening period. For 
randomized and not exposed patients the latest assessment during the screening period will be 
used. 
 
4.3. 
Interim Analyses 
An interim analysis is not planned for this study. 
 
4.4. 
Patient Disposition 
All patients who are enrolled will be accounted for in this study.  
Patient disposition will be tabulated and include the number randomized, treated and completed; 
the number in each patient population for analysis; and the number who discontinued prior to 
completing the study and reason(s) for discontinuation.   
Summary data will be presented by treatment arm and overall. 
A by-patient data listing of study completion information including the reason for early study 
discontinuation, if applicable, will be presented. 
A listing of patients by analysis population will also be provided, including reason for exclusion 
from an analysis population. 
 
4.5. 
Protocol Deviations 
All protocol deviations will be presented in a data listing.  


Flexion Therapeutics 
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21 
 
4.6. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized on the safety population and will 
be presented by treatment group.  
No formal statistical comparisons will be performed. 
All collected demographic, baseline characteristic, bilateral knee assessment and medical 
history data will be provided on the safety population.  
All collected demographic, baseline characteristic, and medical history data will be provided in 
data listings.   
4.6.1. 
Demographic characteristics 
The following baseline parameters will be described: 
• Age (year) at consent - Age will be calculated as the years between date of birth and date 
of informed consent, and will be rounded down to the nearest year. 
• Weight (kg); 
• Height (cm); 
• Gender (Male/Female); 
• Body mass index (BMI) (kg/m²); 
• BMI category: 
o Underweight: <18.0 kg/m² 
o Normal: 18.0 to <25.0 kg/m² 
o Overweight: 25.0 to <30.0 kg/m2 
o Obesity Class I:  30.0 to <35.0 kg/m2 
o Obesity Class II: 35.0 to <40.0 kg/m2 
o Obesity Class III: >=40.0 kg/m2 
• Ethnicity (Hispanic or Latino / Not Hispanic or Latino); 
• Race (White, Asian / Black or African American / American Indian or Alaska Native / 
Native Hawaiian or Other Pacific Islander); 
• Country. 
Age, height, weight, and body mass index (BMI) will be summarized using descriptive statistics 
(number of patients, mean, standard deviation, median, minimum, and maximum). The number 
and percentage of patients in each gender, ethnicity, race and BMI category will also be 
presented.  
 
4.6.2. 
Osteoarthritis (OA) Medical History 
General OA and knee OA medical history data as collected on the CRF will also be tabulated 
for the Safety Population. 


Flexion Therapeutics 
Protocol FX006-2017-012 
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22 
For each knee, time from primary diagnosis of OA in the knee to Day 1 of the study in days 
(first dose date – date of diagnosis + 1), will be computed and presented descriptively.  If only 
month and year of initial diagnosis is available, day will be imputed as 1 for calculations.  If 
month and day are missing, the time from primary diagnosis will be computed as year of first 
dose minus year of diagnosis. If year is missing, time from diagnosis will not be computed. 
Knee OA history data will be summarized by knee injected (first injection and second injection 
separately).  
4.6.3. 
Prior medication  
All prior medications will be presented in the concomitant medication data listing with a flag 
identifying which medications are prior medications (refer to Section  4.9.4 for details on 
defining prior and concomitant medications). 
 
4.7. 
Pharmacodynamics Evaluation 
The actual value and change from baseline (Day 1 or Screening if Day 1 is missing) will be 
summarized for serum cortisol levels by actual treatment arm. In the event of repeat values, the 
last non-missing value per study day/time will be used.  
All serum cortisol data will be provided in tables and listings. Results falling outside of the 
expected collection time of 7:00am to 9:00 am will be flagged” 
 
 


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4.8. 
Study Drug Exposure and Pharmacokinetics Evaluation 
4.8.1. 
Study Drug Exposure 
Details of study drug administration will be tabulated and presented by actual treatment arm and 
knee injected (first injection and second injection separately) for the Safety Population. 
Specifically, the position of the knee during injection, the approach during injection, the 
numbing agent to be used, whether or not the entire contents of the syringe was injected, and 
whether a 21 gauge or larger needle was used will be presented. 
The time between the first knee IA injection and second knee IA injection will be included in 
listings. 
All dosing data will be presented in a data listing. 
 
4.8.2. 
Plasma drug concentration analysis 
 
Tabular summaries of mean TA plasma concentrations, by treatment for each nominal sampling 
time will be presented for the PK population. 
Visit date and times are calculated relative to the Baseline/Day 1 visit. The reference time point 
is Day 1 time of 1st study drug administration in the first knee (Time 0). Of note, the pre-dose 
sample is only relevant if a quantifiable concentration of TA is present. 
All data collected will be summarized and presented in individual plots. However, all data will 
be presented in data listings with those results falling outside of the visit window flagged. Both 
nominal (planned) and actual sampling time will be presented. 
 
Descriptive statistics (n, mean, SD, geometric mean, log-scale SD, 95% CI, median, minimum, 
maximum) will be calculated by time point for plasma drug concentration levels. Frequencies of 
patients with values identified as BLOQ will be presented by time point.  
 
4.8.3. 
Handling of Concentration Data below the Limit of Quantification (BLOQ) 
The bioanalytical assay sensitivity for TA will be noted in the table and listings. Values assayed 
below these limits will be identified as BLOQ. Concentrations that are not detected will be 
identified as “Not Detected” and recorded as BLOQ.   
For the PK analysis and individual concentration vs. time plots, a concentration that is BLOQ is 
assigned a value of zero if it occurs in a profile before the first measurable concentration.  If a 
BLOQ value occurs after a measurable concentration in a profile and is followed by a value 
above the lower limit of quantification, then the BLOQ is treated as missing data.  If a BLOQ 
value occurs at the end of the collection interval (after the last quantifiable concentration) it is 
set to zero. If two BLOQ values occur in succession after Cmax, the profile is deemed to have 


Flexion Therapeutics 
Protocol FX006-2017-012 
08 MAR 2018 
 
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24 
terminated at the first BLOQ value and any subsequent concentrations are set to zero for PK 
calculations.   
 
 


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25 
 
4.8.4. 
Pharmacokinetic analysis 
 
PK analysis will be performed on the PK population.  PK parameter estimates will be completed 
by the study pharmacokineticist and results provided for incorporation into study datasets.  
PK parameters will be derived using model-independent methods (non-compartmental analysis 
(NCA)) as implemented in Phoenix 7, WinNonlin® (version 7) and will be based on TA plasma 
concentrations from patients in the PK Population. Mean concentration profiles will be 
computed for each treatment arm: FX006 64 mg and TAcs 80 mg. 
Actual sampling times will be used for the estimation of the PK parameters if significant 
deviations from the nominal sampling time are noted in data review by the study 
pharmacokineticist. All descriptive summary tables and figures will be presented with the 
nominal (planned) sampling times. 
All blood samples will be assayed for concentration levels of TA using a validated High 
Performance Liquid Chromatographic Method with Tandem Mass Spectrometry Detection 
method (LC/MS-MS), each matrix with a validated assay range in pg/mL. Bioanalytical 
methods for the assay of TA will be provided in a separate bioanalytical report that will include 
information on calibration standards for the assay. 
Each PK parameter will be estimated for each patient with NCA methodology. 
The PK endpoints to be computed on plasma TA concentration measurements will be either 
observed from those concentration measurements or estimated by WinNonlin® (version 7) 
using the trapezoidal rule for calculation of the AUC estimates to the last measureable 
concentration. Additional estimates of the half-life clearance, residence time, volume of 
distribution and the extrapolated area for the AUC0-inf and related parameters will be estimated 
using the slope estimate for the terminal elimination rate constant for each patient with 
WinNonlin® (version 7). 
 
PK variables consist of PK parameters identified in Table 2. 
 
 


Flexion Therapeutics 
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Table 2 
PK Parameters 
PK Parameter 
Description (Computation Method) 
Cmax 
Peak exposure, Maximum plasma concentration observed. 
tmax 
Time from dosing to peak exposure, time to maximum plasma 
concentration observed. 
Clast 
Last quantifiable plasma concentration (last value observed above assay 
BLOQ) 
tlast 
Time of last quantifiable plasma concentration 
λz 
Terminal elimination rate constant (lambda_z) 
t1/2 
Terminal half-life: Computed as t1/2=
𝐿𝐿𝐿𝐿(2)
λz  
AUC(0-t) 
Exposure: Area Under the Plasma Curve from time 0 to the last 
quantifiable concentration (t). Calculated using the linear trapezoidal rule. 
AUC(0-24) 
Exposure: Area Under the Plasma Curve from time 0 to 24 hours post IA 
injection. Calculated using the linear trapezoidal rule 
AUC(0-∞) 
Exposure: Area Under the Plasma Curve from time 0 extrapolated to 
infinity. Calculated as follows: 
𝐴𝐴𝐴𝐴𝐴𝐴𝑖𝑖𝑖𝑖𝑖𝑖= 𝐴𝐴𝐴𝐴𝐴𝐴(0−𝑡𝑡) + C𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙
λ𝑧𝑧 where Clast is the last quantifiable 
concentration. 
CL 
Total Body Clearance, computed as Dose/ AUC(0-∞) 
MRT 
Mean residence time extrapolated to infinity, computed as 
𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴(0−∞) 𝐴𝐴𝐴𝐴𝐴𝐴(0−∞)
⁄
 
Vz_F  
Volume of Distribution, based on terminal phase, computed as : 
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷
λ𝑧𝑧. 𝐴𝐴𝐴𝐴𝐴𝐴(0−∞)
 
 
Descriptive summaries of the individual patient PK parameters and population summaries over 
all patients will be presented. Individual linear-linear and log-linear concentration profiles will 
be completed for each patient. Graphical display (plasma drug concentration curves) will be 
used to present geometric mean with 95% CIs for plasma drug concentrations (linear-linear and 
log-linear plots) for each treatment arm.  
All PK parameters and data will be presented in a data listing. Results from the PK analysis will 
be included in the CSR. Along with the bioanalytical report from the assay laboratory, model 
output from the NCA analysis will be provided in a separate document. 
A linear model will be used to compare the PK parameters from extended-release FX006 and 
immediate-release TAcs for each Cmax, Tmax, Clast, MRT, and AUC parameters. The model will 
include treatment as a single fixed effect. The least square mean difference (LSMD) between the 
two treatments will be explored to examine the magnitude of difference in exposure PK 
parameters between FX006 and TAcs. All p-values will be considered informative. 


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4.8.5. 
Exploration of Bioequivalence between FX006 and TAcs 
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 for the assessment of 
bioequivalence (FDA, 2013). 
The FDA Guidance on the assessment of Bioequivalence recommends that bioequivalence 
measures of AUC and Cmax be log-transformed. In this study, the natural log will be used to 
transform the values for the model, and the Cmax, AUC0-24, and AUC0-∞. PK parameters will be 
exponentiated from a mixed effects model to examine bioequivalence. 
In this study bioequivalence is not expected for the ratio of FX006 / TAcs. The properties of 
FX006 suggest that a reduced Cmax (reduced maximum exposure) is evident due to slower 
release of TA into systemic circulation. The potential shift in Tmax and potential decay in Cmax, 
both of which would be associated with corresponding differences in AUC will be explored. 
A linear mixed effects model may be used for this study to average bioequivalence with PK 
parameters of log-transformed AUC0-24, AUC0-∞, and Cmax. In the initial model fixed effects for 
treatment and site will be included, with a random effect for patient. 
GM with 95% CIs will be presented for each treatment group. BE ratio with standard error (SE) 
and 90% CIs will be presented for Cmax, AUC0-24, and AUC0-∞. 
 
4.9. 
Safety Analyses 
Safety analyses will be conducted using the Safety Population.   
4.9.1. 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and displayed in tables and listings using System Organ Class (SOC) and Preferred 
Term. 
Analyses of adverse events will be performed for those events that are considered treatment 
emergent, where treatment emergent is defined as any adverse event with onset after the 
administration of study medication in the first knee through the end of the study or any event 
that was present at baseline but worsened in intensity through the end of the study.   
If the start date/time of an AE is partially or completely missing, the date/time will be compared 
as far as possible with the date/time of the start of administration of study drug.  The AE will be 
assumed to be treatment emergent if it cannot be definitively shown that the AE did not occur or 
worsen during the treatment-emergent period (worst case approach).  The following general 
rules will be used: 
• If the start time of an AE is missing but the start date is complete, an AE will only be 
excluded as being treatment emergent if the start date is before the date of study drug 
administration or if the stop date/time is before study drug administration. 
• If the start time and day are missing but the start month and year are complete, an AE 
will only be excluded as being treatment emergent if the start month/year is before the 


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month/year of study drug administration or if the stop date/time is before study drug 
administration. 
• If the start day and month are missing but the start year is complete, an AE will only be 
excluded as being treatment emergent if start year is before the year of study drug 
administration or if the stop date/time is before study drug administration. 
• If the start date is completely missing, an AE will be considered treatment-emergent 
unless the stop date/time is before study drug administration. 
Adverse events are summarized by patient incidence rates; therefore, in any tabulation, a patient 
contributes only once to the count for a given SOC or preferred term. 
Adverse events tables and listings will be presented by actual treatment arm. 
The number and percentage of patients with any treatment-emergent AE (TEAE), with any 
serious TEAE, with any TEAE leading to study discontinuation (related or serious), with any 
TEAE by maximum severity and with any TEAE by relationship will be tabulated.   
Similar data presentations will be made for knee related TEAEs. In these tabulations, related is 
defined as any TEAE deemed possibly, probably or definitely related to study drug by the 
investigator. 
Tabulations presented in SOC internal agreed order and PT in alphabetical order within each 
SOC will also be produced for:  
• all treatment-emergent AEs 
• related TEAEs   
• TEAEs by maximum severity   
• for serious TEAEs  
Knee related TEAEs will be tabulated in a similar manner. Knee related TEAEs that occur in 
both knees will be provided in a separate listing.  
No formal hypothesis-testing analysis of AE incidence rates will be performed. 
All AEs occurring on-study will be provided in data listings. 
By-patient listings will also be provided for the following:  patient deaths, Serious Adverse 
Events (SAE), and AEs leading to discontinuation. 
 
4.9.2. 
Laboratory Data 
Clinical laboratory values will be expressed in SI units. 
The actual value and change from baseline (Day 1 or Screening if Day 1 is missing) will be 
summarized for each hematology and clinical chemistry laboratory parameter by actual 
treatment arm. In the event of repeat values, the last non-missing value per study day/time will 
be used.  
All laboratory data will be provided in data listings. 


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4.9.3. 
Vital Signs and Physical Examinations and Knee Assessment 
The actual value and change from baseline (Day 1) at each time point will be summarized for 
vital signs by actual treatment arm. Vital sign measurements will be presented for each patient 
in a data listing. 
All physical examination abnormalities will be presented in a data listing. 
The incidence of inflammation, as determined from the knee assessment, will be tabulated for 
each visit. For those patients experiencing inflammation, the details of the inflammation will 
also be tabulated. In these tabulations, percentages will be based on those patients who have a 
non-missing knee assessment at a given visit. In addition, a shift table displaying shifts in knee 
assessments from baseline over time will be presented. Knee assessment as well as knee 
aspiration data will be presented in a data listing.  Inflammation data will be summarized 
separately for each knee with the first and second knee defined as stated previously.  
 
4.9.4. 
Electrocardiogram  
ECG data will be provided in patient data listing.  
 
4.9.5. 
Concomitant Medications 
Concomitant medications will be defined as those medications that were initiated after first dose 
of treatment or those that were ongoing at the time of first study drug administration.  If the start 
date or stop date of a medication is partially missing, the date will be compared as far as 
possible with the date of the start of administration of study drug.  The medication will be 
assumed to be prior medication if it cannot be definitively shown that the medication did not 
start or continue during the treatment period.  The following approach will be taken: 
• If the start date of medication is complete and occurs on or after the day of the first dose, 
the medication will be assumed concomitant.  If the start date occurs prior to the first 
dose date but the end date is on or after the first dose date or the medication is recorded 
as ongoing, the medication will be considered concomitant. 
• If the start day is missing but the start month and year are complete, a medication will 
only be excluded as being concomitant if the start month/year is before the month/year 
of study drug administration and if the stop date (full date, month and year if missing 
day, or year if missing month and day) is before study drug administration. 
• If the start day and month are missing but the start year is complete, a medication will 
only be excluded as concomitant if the start year is before the year of study drug 
administration and if the stop date (full date, month and year if missing day, or year if 
missing month and day) is before study drug administration.  
• If the start date is completely missing and the stop date is prior to first dose or 
completely missing, the medication will be assumed to be a prior medication. 


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The use of concomitant medications and pain/restricted medications will be included in a by-
patient data listing.  Pain/restricted medications are specifically identified in the CRF and will 
be noted in the listing. 


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5. 
CHANGES TO PLANNED ANALYSES 
Although the protocol states that listings will be provided by study site and patient, per this 
SAP, by-patient listings will be sorted by treatment arm and then patient number. 


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6. 
REFERENCES 
 
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. 
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. 
EMA (2010) – Guidance on investigation bioequivalence, CPMP/EWP/QWP/1404/98 Rev. 1/ Corr, 
Committee for medicinal products for Human Use. 
FDA (2001) – Guidance for industry – Statistical approaches to Establish Bioequivalence, U.S. 
Department of Health and Human Services, Food and Drug administration, Center for drug Evaluation 
and Research, BP. 
FDA (2013) – Guidance for industry – Bioequivalence study with Pharmacokinetic Endpoints for drug 
Submitted Under ANDA, U.S., Department of Health and Human Services, Food and Drug 
Administration, Center for drug evaluation and Research, Biopharmaceutics 
Goldring SR, Goldring MB.  Clinical aspects, pathology and pathophysiology of osteoarthritis.   J 
Musculoskelet Neuronal Interact 2006;6(4):376–378. 
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. 
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. 


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7. 
CLINICAL STUDY REPORT APPENDICES 
7.1. 
Statistical Tables to be Generated 
 
Table 14.1.1 
Patient Enrollment and Disposition 
Table 14.1.2 
Demographic and Baseline Characteristics (Safety Population) 
Table 14.1.3 
Osteoarthritis History and Bilateral Knee Characteristics (Safety 
Population) 
Table 14.1.4 
Summary of Protocol Deviations (Safety Population) 
Table 14.1.5 
Study Drug Exposure Summary (Safety Population) 
Table 14.1.6 
Summary and Change from Baseline for Serum Cortisol (nmol/L) by 
Visit (Safety Population) 
Table 14.1.7 
Plasma Drug Concentrations (pg/mL) by Time Point (PK Population) 
Table 14.2.1 
Plasma Pharmacokinetic Parameters (PK Population) 
Table 14.2.2 
Summary of Bioequivalence Geometric Mean Ratios (PK Population) 
Table 14.3.1.1 
Summary of Treatment-Emergent Adverse Events (Safety Population) 
Table 14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.1.3 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term - Related to Study Drug (Safety Population) 
Table 14.3.1.4 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term by Maximum Severity (Safety Population) 
Table 14.3.1.5 
Knee-Related Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term (Safety Population) 
Table 14.3.1.6 
Knee Related Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term- Related to Study Drug (Safety Population) 
Table 14.3.1.7 
Knee Related Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term by Maximum Severity (Safety Population) 
Table 14.3.1.8 
Serious Adverse Events by System Organ Class and Preferred Term 
(Safety Population) 
Table 14.3.2.1 
Patient Listing of Deaths 
Table 14.3.2.2 
Patient Listing of Serious Adverse Events 
Table 14.3.2.3 
Patient Listing of Discontinuations Due to Adverse Events 
Table 14.4.1.1 
Summary and Change from Baseline for Hematology Parameters by 
Visit (Safety Population) 
Table 14.4.1.2 
Summary and Change from Baseline for Chemistry Parameters by Visit 
(Safety Population) 
Table 14.4.2 
Summary and Change from Baseline for Vital Signs by Visit (Safety 
Population) 
Table 14.4.3 
Summary of Bilateral Knee Assessments (Safety Population) 


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7.2. 
Statistical Figures to be Generated 
 
Figure 14.1.7 
GM with 95% CI for Plasma Drug Concentration Curve (Plasma Drug 
Concentration) 
Figure 14.2.1 
Individual Patient Linear-Linear and Log-Linear Plasma Drug 
Concentration Profiles (PK Population) 
 
 


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7.3. 
Data Listings to be Generated 
 
Listing 16.2.1 
Patient Disposition 
Listing 16.2.2.1 
Inclusion/Exclusion Criteria Not Met 
Listing 16.2.2.3 
Protocol Deviations 
Listing 16.2.3.1 
Analysis Populations 
Listing 16.2.4.1 
Demographics and Baseline Characteristics 
Listing 16.2.4.2 
Medical History 
Listing 16.2.4.3 
Medical History - Knee Osteoarthritis 
Listing 16.2.4.4 
Medical History - Prior Treatment of Knee Osteoarthritis 
Listing 16.2.4.5 
Medical History - Other Osteoarthritis 
Listing 16.2.4.6 
Medical History - Other Osteoarthritis Procedures or Surgeries 
Listing 16.2.4.7 
Knee X-ray/Kellgren-Lawrence Grade 
Listing 16.2.5.1 
Study Drug Exposure 
Listing 16.2.5.2 
Plasma Sampling Times and Plasma Drug Concentration 
Measurements 
Listing 16.2.5.3 
Plasma PK Parameters 
Listing 16.2.6 
Serum Cortisol (nmol/L) 
Listing 16.2.7.1 
Adverse Events – Sorted By Patient and Onset Date 
Listing 16.2.7.2 
Adverse Events Occurring in Both Knees – Sorted By Patient and 
Onset Date 
Listing 16.2.7.3 
Adverse Events – Sorted by System Organ Class, Preferred Term, 
Treatment, Patient, and Onset Date 
Listing 16.2.7.4 
Adverse Events – Glossary by MedDRA SOC, Preferred Term and 
Verbatim 
Listing 16.2.8.1 
Laboratory Assessment – Hematology 
Listing 16.2.8.2 
Laboratory Assessment – Chemistry 
Listing 16.2.8.3 
Screening Laboratory Assessments and Urine/Serum Pregnancy Test 
Results 
Listing 16.2.8.4 
Bilateral Knee Assessments 
Listing 16.2.9.1 
Vital Signs 
Listing 16.2.9.2 
Physical Examination Findings 
Listing 16.2.9.3 
Electrocardiograms Results 
Listing 16.2.9.4 
Prior and Concomitant Medications 
Listing 16.2.9.5 
Knee Aspiration 
Listing 16.2.9.6 
Surgical Procedures