Clinical trial NCT03382262
Conditions: Osteoarthritis of the Shoulder Osteoarthritis of the Hip
Keywords: Osteoarthritis Shoulder Hip Pain Intra-articular Injection Corticosteroid
Sponsor: Pacira Pharmaceuticals, Inc
Start date: 2017-12-18; Completion date: 2018-10-09
Enrollment: 55 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open-label study to compare systemic exposure to triamcinolone acetonide following a dose of extended-release FX006 or immediate-release TAcs (triamcinolone acetonide suspension) in patients with osteoarthritis of the shoulder (glenohumeral joint) or hip

Detailed description:
This is a randomized, open-label, single dose study that will be conducted in male and female patients ≥40 years of age with OA of either the shoulder or the hip.

Approximately 24 patients with OA of the shoulder and approximately 24 patients with OA of the hip will be randomized to one of two treatment groups (1:1) and treated with a single IA injection of either:

* 32 mg FX006 (approximately 12 patients per joint) or
* 40 mg TAcs (approximately 12 patients per joint)

Each patient will be screened to confirm the diagnosis of OA of either the shoulder or hip and eligibility based on the other inclusion/exclusion requirements and will be randomized to treatment on Day 1. Each patient will be evaluated for a total of 12 weeks following the IA injection. Following screening, sampling for pharmacokinetics (PK) and safety will be completed at 10 out-patient visits scheduled on Study Days 1 \[calendar day of injection\], 2, 3, 5, 8, 15, 22, 29, 57, and 85.

Arms: arm 1: Single intra-articular (IA) injection of FX006 32 mg arm 2: Single intra-articular (IA) injection of TAcs 40 mg
Interventions: intervention 1: FX006 32 mg intervention 2: TAcs 40 mg
Intervention descriptions: intervention 1: Extended-release 32 mg FX006 IA injection intervention 2: Immediate-release 40mg TAcs IA injection

Protocol documents:
Prot_000.pdf: 
 
CONFIDENTIAL INFORMATION 
CLINICAL STUDY PROTOCOL 
 
A Randomized, Open-label Study Comparing the Systemic Exposure to Triamcinolone 
Acetonide Following a Single Intra-articular Dose of Extended-release FX006 or Immediate-
release TAcs (Triamcinolone Acetonide Suspension) in Patients with Osteoarthritis of the 
Shoulder (Glenohumeral Joint) or Hip 
 
PROTOCOL NUMBER:  FX006-2017-013 
 
 
PHASE:  2a 
 
 
STUDY MEDICATION(S): FX006 
 
INDICATION:  Osteoarthritis of the shoulder or hip 
 
 
  
MEDICAL MONITOR: Robert D. Arbeit, MD 
 
 
 
SPONSOR:  Flexion Therapeutics  
 
DATE:  05 April 2018 
 
  
VERSION: 3.0 
 
SUPERCEDES: Version 2.0 
 


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SIGNATURE PAGE 
Clinical Study Protocol Version 3.0 (dated 05Apr 2018) 
 
 
 
Sponsor Safety Officer Approval 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
Name (print): 
 
 
Scott Kelley MD 
 
 
Title: 
 
Chief Medical Officer 
 
 
 
Principal Investigator Agreement:  I have read the protocol and agree to conduct the study as 
outlined herein. 
 
 
 
Signature: 
 
 
 
Date: 
 
 
 
Name (print): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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


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


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


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10. 
DATA QUALITY ASSURANCE ..............................................................................44 
11. 
DATA HANDLING AND RECORDKEEPING .......................................................45 
11.1. 
Case Report Forms .....................................................................................................45 
11.2. 
Study Medication Accountability ...............................................................................45 
11.3. 
Confidentiality of Data ...............................................................................................45 
11.4. 
Retention of Records ..................................................................................................45 
11.5. 
Protocol Adherence ....................................................................................................46 
12. 
PUBLICATION POLICY ..........................................................................................47 
12.1. 
Sponsor’s Publication Policy ......................................................................................47 
12.2. 
Site publication ...........................................................................................................47 
13. 
REFERENCES ...........................................................................................................48 
14. 
APPENDICES ............................................................................................................50 
 
 
 
LIST OF TABLES 
Table 1: 
Schedule of Study Assessments..................................................................................32 
Table 2: 
BMI Calculations ........................................................................................................35 
Table 3: 
Clinical Laboratory Panel ...........................................................................................36 
 
 
 
 
 


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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 
KOOS  
Knee injury and Osteoarthritis Outcome Score  
LLOQ 
Lower Limit of Quantification 
LSM 
Least Square Mean  


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


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


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


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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 the index joint 
3. Clinical findings consistent with active infection or crystal disease in the index joint within 1 month of 
Screening 
4. History of fracture in the index limb within 12 months of Screening, or fracture with sequelae at any time 
5. Planned or anticipated surgery of the index joint during the study period 
6. Index joint instability or history of acute dislocation within 12 months of  Screening 
7. If shoulder is the index joint, history of full or partial rotator cuff tear or significantly compromised rotator 
cuff function that, in the opinion for the Investigator, increases the difficulty or risk of IA injection 
Previous or concomitant treatment-related criteria 
8. Presence of surgical hardware or other foreign body in the index joint 
9. Surgery or arthroscopy of the index joint within 12 months of Screening  
10. IA treatment of any joint with any of the following agents within 6 months of Screening:  
any corticosteroid preparation (investigational or marketed, including FX006), any biologic agent (e.g., 
platelet rich plasma (PRP) injection, stem cells, prolotherapy, amniotic fluid injection; investigational or 
marketed) 
11. IA treatment of the index joint with hyaluronic acid (investigational or marketed) within 6 months of 
Screening 
12. Parenteral or oral corticosteroids (investigational or marketed) within 3 months of Screening 
13. Inhaled, intranasal or topical corticosteroids (investigational or marketed) within 2 weeks of Screening 


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


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


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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 
• 
Cmax: Peak exposure, Maximum plasma concentration  
• 
Tmax: Time from dosing to peak exposure, time to maximum plasma concentration 
• 
Clast: Last quantifiable plasma concentration (last value observed above assay BLOQ) 
• 
Tlast: Time of last quantifiable plasma concentration 
• 
T1/2: Terminal half-life 
• 
AUC (0-last): Exposure: Area Under the Plasma Curve from time 0 to the last quantifiable concentration 
(Clast) 
• 
AUC(0-t): Exposure: Area Under the Plasma Curve from time 0 to tau post-IA injection, where tau is defined 
for partial AUC parameters from 0 to 24, and 0-96 hours.  
• 
AUC(0-inf): Exposure: Area Under the Plasma Curve from time 0 extrapolated to infinity. 
• 
MRT (Observed and Predicted): Mean residence time extrapolated to infinity 
Safety  
• 
AEs 
• 
Physical examinations 
• 
Index joint examinations 
• 
Vital signs 
• 
Clinical laboratory evaluations 
Sample Size Considerations: 
In this study, it is expected that the systemic exposure in plasma of TA from extended-release FX006 should not 
exceed that of the immediate-release TAcs formulation for the key parameters of Cmax, AUC (0-t), and AUC(0-inf).  
In a previous pharmacokinetic study with knee OA patients (FX006-2015-009) the ratio of the mean exposure 
parameters for 32 mg FX006 (N=60) and 40 mg TAcs (N=18) for Cmax was 0.10 with the upper limit of its 90% CI 
being 0.15 and for AUC(0-inf) was 0.52 with the upper limit of its 90% CI being 0.86. The pooled coefficients of 
variation for the parameters was between 0.53 (Cmax) and 0.68 (AUC0-inf).  
Sample Size Estimate: 
In this study, it is expected that the ratio of exposure means (FX006/TAcs) will be less than 1.0 when administered 
to treat either shoulder or hip OA. A sample size of 12 in each treatment arm (24 in total) is estimated for each joint 
cohort (hip and shoulder). Within each group the sample size of 24 achieves approximately 90% power, with a two-
sided alpha 0.05, to detect a ratio less than 1.0 of the exposure PK parameter means (FX006 / TAcs), with a pooled 
coefficient of variation estimate of 0.68 (PASS 15 Power Analysis and Sample Size Software (2017). NCSS, LLC. 
Kaysville, Utah, USA, ncss.com/software/pass). The sample size of 12 per treatment arm in each joint cohort 
assumes a 10% noncompliance sampling rate (a drop-out rate) for providing complete blood samples for PK 
analysis, and is sufficient to characterize the comparative pharmacokinetic of FX006 and TAcs in this study. The 
total sample size is estimated to be 48 patients (hip: 12 in each treatment arm, shoulder: 12 in each treatment arm) 
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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 study drug. The Safety Population will be used 
to assess safety and tolerability. 
• 
The PK Population will include patients who receive study drug and have sufficient plasma concentration 
data to allow calculation of PK parameters to be included in the PK population. Eligibility for inclusion 
into the PK Population will be determined by the pharmacokineticist for the study following review of 
plasma data. 
Pharmacokinetic (PK) parameters will be derived for each patient from plasma concentrations of TA using model-
independent non-compartmental analysis: (NCA) [Phoenix 7, WinNonlin® 7]. Individual elapsed sampling times 
(actual time) will be used in the PK calculations if significant deviations from the nominal sampling times are noted, 
otherwise nominal times will be used for analysis. Complete details on the calculation of PK parameters, and 
handling of concentration values below the Lower Limit of Quantification (LLOQ) will be fully specified in the 
SAP. 
Descriptive summaries of the TA plasma concentration levels (ng/mL) observed at each nominal time point will be 
provided for FX006 and TAcs treatments in each joint cohort (hip and shoulder). Descriptive summaries of the PK 
parameter estimates from each treatment group will also be completed for each joint cohort. Summary statistics for 
continuous variables will include n, mean, standard deviation, coefficient of variation (CV%), median, minimum, 
and maximum, geometric mean and standard error of the geometric mean. 
By patient plots (linear-linear, log-linear) of the plasma TA concentration data will be completed for each treatment 
group in each joint cohort. 
The PK parameters for Cmax, Tmax, AUC, and MRT PK parameters will be informative of the overall systemic 
exposure of TA from extended-release FX006 and immediate-release TAcs. A linear model will be used to compare 
the PK parameters from extended-release FX006 and immediate-release TAcs. Full details of the linear model will 
be specified in the SAP. 
Bioequivalence (BE) ratios between extended-release FX006 (Test) and immediate-release TAcs (Reference) for 
Cmax and AUC parameters will be explored.  Bioequivalence between Test and Reference will be evaluated using 
the average BE method for the mean ratio between test and reference products (μT/μR) as described in FDA 
guidance. Full details on the analysis of BE will be included in the SAP.  
 


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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. 
5. 
INTRODUCTION 
5.1. 
Osteoarthritis 
Osteoarthritis (OA) is a painful and debilitating musculoskeletal disease that is characterized by 
intra-articular (IA) inflammation, deterioration of articular cartilage, and degenerative changes to 
peri-articular and subchondral bone (Creamer and Hochberg, 1997; Goldring and Goldring, 
2006).  Arthritis is the most common cause of disability in the United States (US) and OA is the 
most common joint disease, affecting 27 million Americans, with numbers expected to grow as a 
result of aging, obesity and sports injuries.  Recent data suggest that OA accounts for over $185 
billion of annual healthcare expenditures in the US, which does not include loss of productivity 
costs.  We estimate that by 2030, 45 million people will have OA.  OA commonly affect large 
weight-bearing joints like the knees and hips, but also occurs in the shoulders, hands, feet and 
spine.  Patients with OA suffer from joint pain, tenderness, stiffness and limited movement.  As 
the disease progresses, it becomes increasingly painful and debilitating, culminating, in many 
cases, in the need for total joint arthroplasty. 
Current Guidelines from the American College of Rheumatology (ACR), Osteoarthritis Research 
Society International (OARSI) and the European League against Rheumatism (EULAR) 
recommend the use of IA corticosteroids for short-term acute pain relief (Hochberg et al, 2012; 
Jordan et al, 2003; Menge et al, 2014). 
5.2. 
Background 
5.2.1. 
Investigational Medicinal Product:  FX006 
FX006 is an extended-release formulation of TA for IA administration. It is approved under the 
trade name ZILRETTA™ for the management of pain of osteoarthritis of the knee; however, 
shoulder and hip OA have not been studied and is an investigational use.  FX006 is intended to 


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deliver TA to the synovial and peri-synovial tissues for a period of approximately 3 months 
depending on the dose administered.  (Bodick et al, 2013) 
FX006 contains TA, United States Pharmacopeia (Ph. Eur/USP), formulated in 75:25 
poly(lactic-co-glycolic acid) (PLGA) microspheres with a nominal drug load of 25% (w/w) and 
is provided as a sterile white to off-white powder for reconstitution. The drug product is 
reconstituted with diluent containing an isotonic, sterile aqueous solution of sodium chloride 
(NaCl; 0.9% w/w), carboxymethylcellulose sodium (CMC; 0.5% w/w) and polysorbate-80 (0.1% 
w/w) to form a suspension prior to IA injection.   
Further details of the physiochemical properties of FX006 can be found in the Investigator’s 
Brochure (IB). 
5.2.2. 
Rationale for FX006 in OA of the Shoulder and OA of the Hip 
Available clinical and nonclinical data indicate that FX006 is safe and well tolerated when 
administered as a single injection into one knee and provides pain relief that is meaningfully 
better and more persistent than that provided by immediate release TAcs.   
The current clinical development program focuses on extending these studies to evaluate the 
therapeutic effects of FX006 in patients with OA of the shoulder and hip.  Although anatomy 
differs between the shoulder, hip and knee joints, the same histologic and cellular structures are 
present, the underlying pathophysiology is the same, and the injection volume of FX006 (5 mL) 
is appropriate to these large joints.  
5.2.3. 
Toxicology 
Overall, single or repeat administration of FX006 at the proposed clinical dose of 32 mg has no 
new safety liabilities compared to TAcs: 
• Systemic findings were similar among TAcs and FX006 groups following single and 
repeat dosing and were generally reversible.  Initial effects on clinical pathology 
parameters were more pronounced for the immediate-release form.  The incidence 
and/or intensity of steroid-associated systemic histopathological findings at the later 
time points were slightly higher for high dose FX006 than for TAcs at the same dose 
level of TA (18.75 mg/mL/joint), as expected based on the sustained release of TA.  
Microspheres were not detected in tissues outside of the synovial space. 
• Local findings were similar among TAcs and the FX006 groups and were reversible.  
The single and repeat dose dog toxicity studies recapitulated known effects of TA that 
had been previously published in normal animal joints following prolonged exposure.  
These include decreased Safranin O staining and changes in structure and cellularity 
of articular cartilage.   
• An expected, mild, reversible Foreign Body Response (FBR) was noted to the PLGA 
component of FX006 microspheres. 
− The local tissue response to the presence of blank microspheres as well as FX006 
microspheres consisted of an expected FBR of macrophage and multinucleated 
giant cell infiltration involving the synovium. Following a single dose, the FBR 
was evident at Day 4, peaked at approximately 6 weeks and was completely 


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resolved by 6 months in all FX006 animals. Occasional lymphocyte and plasma 
cell infiltrates and sporadic focal-to-multifocal areas of minimal-to-slight fibrosis 
resolved by 9 months.  Following repeat IA dosing, a similar local, reversible 
FBR was noted.   
− Further, the dogs in these studies showed no local signs of inflammation on or 
around the joint and did not display pain, discomfort or difficulty.  
Information available for TA from the literature, corticosteroid product labels and clinical 
experience suggest that the potential of genetic toxicity, reproductive toxicity and carcinogenic 
potential of TA are well understood.  Similarly, the biocompatibility and local safety of PLGA 
microspheres, and genotoxic, reproductive toxicological and carcinogenic potential of PLGA 
have been described in a combination of literature and product information packages.  Therefore, 
no new risks relative to TAcs are presented by FX006 as intended for use. 
5.2.4. 
Systemic and Local PK in Patients with Osteoarthritis of the Knee 
Overall, FX006 displayed a favorable plasma PK profile relative to TAcs. 
PK observations resulted in a controlled and stable release of TA from PLGA microspheres into 
synovial tissues, where concentrations remained high relative to plasma concentrations for at 
least 12 weeks.  TA was absorbed systemically, with a plateau in plasma TA concentrations 
occurring in the first 24 hours post-dose, and slow elimination from the systemic circulation 
observed in the weeks thereafter.  
Relative to TAcs, 32 mg FX006 produced substantially lower peak plasma and systemic 
exposure to TA. FX006 performed as expected, prolonging the residence of TA in the joint while 
minimizing systemic exposure to TA. 
5.2.5. 
Pharmacodynamics in Patients with Osteoarthritis of the Knee 
In a Phase 2 PK/PD study evaluating three dose levels of FX006 (10 mg, 40 mg, 60 mg) 
administered as a 3 mL injection, suppression of cortisol in the days following injection 
produced by the 10 and 40 mg dose of FX006 was less than that produced by injection of TAcs; 
the 60 mg dose of FX006 produced effects similar to 40 mg TAcs. Cortisol suppression 
subsequent to Day 1-2 associated with all doses of FX006 would not be expected to be of clinical 
consequence in adult patients without otherwise comprised HPA axis function. 
In a Phase 2 study in diabetic patients with knee OA, treatment with 32 mg FX006 resulted in a 
statistically significant (p=0.0452) reduction in blood glucose elevation relative to TAcs over a 
72-hour period following IA injection. The time in glycemic target range (70-180 mg/dL) 
(American Diabetes Association, 2016) was greater for FX006 as compared to TAcs over the 48 
hours post IA injection, providing another indication of the improvement in glycemic control. 
Over the entire time course of the 15-day post injection glucose monitoring period, blood 
glucose levels associated with FX006 remained at levels similar to or lower than those produced 
by TAcs. This observation is consistent with PK studies demonstrating low systemic exposure to 
TA associated with FX006. 


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5.2.6. 
Efficacy in Patients with Osteoarthritis of the Knee 
Efficacy data from three studies provide substantial evidence supporting the effectiveness of 
32 mg FX006 in the management of OA pain. (Bodick et al, 2015; Conaghan et al, 2017) 
Results of the primary endpoint from the Phase 3, multi-center, adequate, and well-controlled 
trial, showed that patients treated with 32 mg FX006 had a rapid, durable, and meaningful 
analgesic response that was statistically significantly better than placebo treated patients 
(P < 0.0001). This finding was supported by a second smaller Phase 2b study, where a highly 
similar pattern of response to 32 mg FX006 was demonstrated. 
Robustness of the primary outcome in the Phase 3 study was further supported by the internal 
consistency demonstrated in favor of 32 mg FX006 through secondary analyses utilizing the 
primary outcome data average daily pain; (ADP) to evaluate durability and magnitude of 
response. These included least square mean (LSM) testing at each week and area under the effect 
curve (AUE) analyses for Weeks 1 through 12 and Weeks 1 through 24. Results demonstrated 
that the analgesic effect of 32 mg FX006 is significant at Week 1, increases through Week 7, and 
is sustained through at least Week 16. Responder analyses further suggested that FX006 provides 
clinically relevant improvement from Weeks 1 through 16 relative to placebo. 
Analyses utilizing data collected from other instruments or measures Western Ontario and 
McMaster Universities Osteoarthritis Index (WOMAC) Patients’ Global Impression of Change 
(PGIC), Clinical Global Impression of Change (CGIC), and Knee injury and Osteoarthritis 
Outcome Score (KOOS) Quality of Life (QOL) provided additional insight into effects on pain 
relief as well as physical function and global well-being.  FX006 32 mg provides clinically 
relevant improvement relative to placebo through Week 12 for WOMAC and KOOS QOL and 
through at least Week 16 for PGIC and CGIC. Additionally, significant reduction of rescue 
medication utilization in patients treated with FX006 32 mg is of potential important clinical 
consequence and adds a meaningful element to the overall effectiveness profile of FX006 32 mg. 
Collectively, these results provide substantial evidence to support FX006 32 mg as an effective 
therapy for the management of OA knee pain.  
5.2.7. 
Systemic and Local Safety in Patients with Osteoarthritis of the Knee 
The evaluation of 687 patients treated with a single IA injection of FX006 at any dose in the 
FX006 clinical studies suggests that it was well tolerated with systemic and local safety profiles 
similar to those of TAcs and placebo.   
The safety data from the FX006 clinical studies are largely consistent.  
o The number of treatment-emergent adverse events (TEAEs) reported was similar across 
groups (FX006 46.0%; placebo 49.2%; TAcs 51.0%).   
o The majority of TEAEs in FX006-treated patients were mild or moderate (Grade 1 or 2). 
Severe or life-threatening events occurred in the FX006-treated patients at a rate of 3.0% 
as compared to 5.0% and 2.6% in the placebo and TAcs groups, respectively.  
o In the FX006-treated patients (n=687), the most common TEAEs were: 
− Arthralgia (in any joint) 9.8% (n=67) 
− Headache 5.4% (n=37) 


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


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


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


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


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intrauterine system; condom or occlusive cap (diaphragm or cervical/vault caps) with 
spermicidal foam/gel/film/cream/suppository; or monogamous intercourse with a partner 
who is surgically sterile (post-vasectomy, post-hysterectomy, or tubal ligation.).  Females 
must agree to use such contraceptive measures for at least 30 days after the 
administration of the study drug.  Men must agree to use contraceptives for at least 90 
days after administration of the study drug. 
Index Joint-related criteria  
• For each patient, the index joint will meet the appropriate criteria as follows.  
8. Symptoms consistent with OA of the index joint for ≥ 6 months prior to Screening 
(patient reported is acceptable) 
9. Pain in the index joint for >15 days over the last month (as reported by the patient)  
10. 
(a) Shoulder OA as defined by: 
• Radiologic findings of OA of the shoulder meeting the Samilson-Prieto (S-P) 
Classification (Elsharkawi et al, 2013) Grades 2 or 3, defined as:  
o Grade 2, moderate (osteophytes 3 to 7 mm; with or without 
slight glenohumeral irregularity); 
o Grade 3, severe (osteophytes >7 mm, with or without glenohumeral joint 
narrowing and sclerosis). 
10. 
(b) Hip OA as defined by:   
• ACR Criteria (clinical and radiological) for OA of the hip (Altman et al, 1991):  
− Hip pain  
• at least 2 of the following 3 features: 
• 
ESR<20 mm/hour 
• 
Radiographic femoral or acetabular osteophytes 
• 
Radiographic joint space narrowing (superior, axial, and/or medial) 
7.4.3. 
Exclusion Criteria 
Patients fulfilling at least one of the following criteria may not be included in the study: 
Disease-related criteria 
1. Reactive arthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or 
arthritis associated with inflammatory bowel disease  
2. History of infection in the index joint 
3. Clinical findings consistent with active infection or crystal disease in the index joint 
within 1 month of Screening 
4. History of fracture in the index limb within 12 months of Screening, or fracture with 
sequelae at any time. 


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


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


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7.5.2. 
Identity of Investigational Product(s) 
FX006 is supplied as a sterile, white to off white powder in a single unit dose 5 mL vial with a 
butyl rubber stopper, aluminum seal and plastic cap.  FX006 is reconstituted in diluent 
containing an isotonic, sterile aqueous solution of sodium chloride (NaCl; 0.9% w/w), 
carboxymethylcellulose sodium (CMC; 0.5% w/w) and polysorbate-80 (0.1% w/w) to form a 
suspension prior to IA injection.  Diluent will be supplied as a sterile liquid in a 5 mL vial with a 
butyl rubber stopper, aluminum seal and plastic cap.  FX006 will be reconstituted in 5.0 mL of 
diluent to form a suspension immediately prior to IA injection.  FX006 will be administered as a 
single 5 mL IA injection. 
7.5.3. 
Identity of Reference Compound  
TAcs (e.g., Kenalog®-40) is a synthetic glucocorticoid corticosteroid with anti-inflammatory 
action.  Each mL of the sterile aqueous suspension provides 40 mg triamcinolone acetonide, with 
sodium chloride for isotonicity, carboxymethylcellulose sodium, and polysorbate 80.  A 
preservative, benzyl alcohol may also be present.  Sodium hydroxide or hydrochloric acid may 
be present to adjust pH to 5.0 to 7.5.  At the time of manufacture, the air in the container is 
replaced by nitrogen. 
For hip injections only: Normal saline (0.9% sodium chloride injection is a sterile, nonpyrogenic, 
isotonic solution of sodium chloride and water for injection. Each mL contains sodium chloride 
9 mg. 
7.5.4. 
Receipt, Dispensing and Storage 
Study medication will be shipped to the site from the drug supply distribution center. Receipt and 
dispensation of study medication will be properly documented on the drug accountability form in 
the Pharmacy Binder. Any temperature excursions should be documented and will require 
Sponsor assessment and authorization for continued use.  
The packaged kits of FX006 will be stored in a secure area and will be stored refrigerated at 2 to 
8 °C. 
TAcs and normal saline will be stored in a secure area at room temperature. 
7.5.5. 
Packaging and Labeling of Study Medication 
The packaged kit of FX006 will contain one (1) vial of FX006, one (1) vial of Diluent, and a vial 
adapter.  The FX006 and diluent vials will be labelled with their respective unique lot numbers 
within the packaged kit, which will be affixed with its own label and kit number.   
TAcs will be supplied as commercially available Kenalog®-40 Injection.  
Normal saline will be supplied locally by the investigative sites.  
7.5.6. 
Return of Study Medication 
All study medications (packaged kits/used and unused vials) will be returned to the drug supply 
distribution center.  Return of study medications will be properly documented. 


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


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


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


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


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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 
provided, they will be asked to sign the study’s informed consent form in order to participate in 
the study. 
7.9.2. 
Review of eligibility, medical history, prior treatment and medications 
Eligibility criteria (inclusion and exclusion criteria), medical history (including OA history), and 
prior treatment and medications are reviewed during screening and again at Day 1. 
OA medical history includes details to support the inclusion criteria for OA of the shoulder or 
hip.  
7.9.3. 
Physical Examination 
The physical exam will assess the following body systems:  
1. General Appearance 
2. Skin 
3. Lymphatics 
4. HEENT (head, ears, eyes, nose, throat) 
5. Cardiovascular 
6. Respiratory 
7. Abdominal 
8. Musculoskeletal 
9. Neurological  
Any clinically significant findings, outside of the typical disease state,  must be documented in 
the source and added to the medical history if found at Screening or recorded as an AE if new or 
worsened from pre-dosing on Day 1.    
7.9.4. 
Index Joint X-ray 
If an index joint X-ray performed within 6 months prior to Screening or during the Screening 
period is not available, then a plain radiograph of the index joint must be obtained at Screening 
to confirm the diagnosis of OA.  
• The recommended view of the hip is an anterior-posterior pelvic weight-bearing 
radiograph of the pelvis with the lower limbs in 15° internal rotation with a size ratio 
of 1:1. 


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


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


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


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


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


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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 
Within 24 hours of becoming aware of an SAE, the Investigator or appropriate designee must 
complete the SAE form and submit to the Sponsor according to the SAE form instructions.  
When the Investigator becomes aware of additional follow up information on an SAE, this 
should also be reported on an SAE form within 24 hours.  
All SAEs that occur at your site should also be reported to the responsible IRB, if applicable, 
according to IRB requirements. 
During the conduct of the study, the Sponsor will provide expedited safety reports (AEs 
classified as serious, unexpected and at least possibly related to investigational product) to the 
investigative sites as notification of new safety findings.  If this occurs, the investigative site 
must report the information to their IRB per local guidelines (may be submitted by the Sponsor 
or designee for sites that use a central IRB). 
8.1.4. 
Safety Monitoring Roles 
The site personnel will carefully monitor each patient throughout the study for possible AEs.  All 
AEs will be documented on the eCRF designed specifically for this purpose, and will be 
followed until either resolved, returned to baseline, or until a stable chronic outcome is 
determined by the Principal Investigator.   
The Medical Monitor must promptly review all information relevant to the safety of an 
investigational new product received from any source including adverse event data individually 
and in aggregate throughout the course of the study.  The Medical Monitor will also review alert 
laboratory results in real time and will contact Investigators as needed to ensure that issues are 
managed in an appropriate manner. 
8.1.5. 
Clinical Management of Index Joint Related Events  
In the event that the patient has an immediate reaction following administration of study 
medication or returns to the clinic with an acute exacerbation (e.g., tenderness, increased pain, 
swelling, effusion, decreased mobility of the index joint), the patient should be treated according 
to local clinical guidelines and physician experience.   
If the index joint is aspirated at any time after administration of study medication for any reason, 
the volume of synovial fluid aspirated must be documented, synovial fluid should be (1) 
cultured, (2) evaluated for presence of crystals and (3) assessed for white cell count at a local 
laboratory, and the results should be documented.   


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


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


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


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


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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 to the study 
site should be maintained per instructions in the Pharmacy Binder. 
In the event of a temperature excursion, refer to the Pharmacy Binder for instructions. 
In the event of a product complaint, complete the Product Complaint Form located in the 
Pharmacy Binder and send to the assigned monitor or clinical manager who will coordinate with 
the Sponsor for further guidance.  
11.3. 
Confidentiality of Data 
Patient medical information obtained by this study is confidential, and disclosure to third parties 
other than those noted below is prohibited. 
Upon the patient’s permission, medical information may be given to his or her personal 
physician or other appropriate medical personnel responsible for his or her welfare. 
Data generated by this study must be available for inspection by representatives of Competent 
Authorities, the Sponsor or their representative, and the IRB/EC. 
To maintain patient privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the patient by initials where permitted and/or by the assigned 
patient number.  The patient’s confidentiality will be maintained and will not be made publicly 
available to the extent permitted by the applicable laws and regulations. 
11.4. 
Retention of Records 
In accordance with US federal regulations (21 CFR 312.62[c]), the Sponsor requires that records 
and documents pertaining to the conduct of this study and the distribution of study medications, 
including eCRFs, consent forms, laboratory test results, glucose source data, and medical 
inventory records, must be retained by the Principal Investigator for 2 years after marketing 
application approval.  If no application is filed, these records must be kept 2 years after the 
investigation is discontinued and the regulatory authorities are notified.  The Sponsor or their 


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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, Alarcon G, Appelrouth D, Bloch D, Borenstein D, Brandt K, et al. The American 
College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hip. 
Arthritis Rheum 1991;34:505-514 
American Diabetes Association, Position Statement 5. Glycemic Targets. Diabetes Care. 
2016;39(Supplement 1), S39-S46. doi:10.2337/dc16-S008. 
Bodick N, Lufkin J, Willwerth C, Blanks R, Inderjeeth C, Kumar A, Clayman M. 
FX006 prolongs the residency of triamcinolone acetonide in the synovial tissues 
of patients with knee osteoarthritis. Osteoarthritis Cartilage. 2013;21:(Suppl); 
S144-5. 
Bodick N, Lufkin J, Willwerth C, Kumar A, Bolognese J, Schoonmaker C, Ballal R, Hunter D, 
Clayman, M.  An Intra-Articular, Extended-Release Formulation of Triamcinolone Acetonide 
Prolongs and Amplifies Analgesic Effect in Patients with Osteoarthritis of the Knee, A 
Randomized Clinical Trial. J Bone Joint Surg Am. 2015;97:877-88 
Conaghan, PG, Cohen, SB, Berenbaum, F, Lufkin, J, Johnson, J.R and Bodick, N. Phase 2b trial 
of a novel extended-release microsphere formulation of triamcinolone acetonide for intra-
articular injection in knee osteoarthritis. Arthritis Rheumatol. Accepted Author Manuscript. 
doi:10.1002/art.40364 
Creamer P, Hochberg MC.  Osteoarthritis.   Lancet 1997;350(906):503–508. 
Elsharkawi M, Cakir B, Reichel H, Kappe T. Reliability of radiologic glenohumeral 
osteoarthritis classifications. J Shoulder Elbow Surg. 2013; 22: 1063-1067. 
Goldring SR, Goldring MB.  Clinical aspects, pathology and pathophysiology of osteoarthritis.   
J Musculoskelet Neuronal Interact 2006;6(4):376–378. 
Habib GS.  Systemic effects of intra-articular corticosteroids. Clin Rheumatol 2009;28:749–756. 
Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, Towheed T, Welch 
V, Wells G, Tugwell P.  American College of Rheumatology 2012 Recommendations for the 
Use of Nonpharmacologic and Pharmacologic Therapies in Osteoarthritis of the Hand, Hip, and 
Knee.   Arthritis Care & Research 2012; 64:465-474. 
Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, Gunther K, 
Hauselmann H, Herrero-Beaumont, Kaklamanis P, Lohmander S, Leeb B, Lequesne M, 
Mazieres B, Martin-Mola E, Pavelka K, Pendleton A, Punzi L, Serni U, Swoboda B, Verbruggen 
G, Zimmerman-Gorska I, Dougados M.  EULAR Recommendations 2003: an evidence based 
approach to the management of knee osteoarthritis: Report of a Task Force of the Standing 
Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT).  Ann 
Rheum Dis 2003;62(12):1145–1155. 


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Menge TJ, Boykin RE, Byram IR, Bushnell BD. A Comprehensive Approach to Glenohumeral 
Arthritis. So. Med. J. 2014;107(9):567-573 


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


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


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


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

SAP_001.pdf: 
Flexion Therapeutics 
Protocol FX006-2017-013 
SAP, Final Version 1.0 
17 OCT 2018 
 
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 FX006-2017-013 
A Randomized, Open-label Study Comparing the Systemic Exposure to 
Triamcinolone Acetonide Following a Single Intra-articular Dose of Extended-
release FX006 or Immediate-release TAcs (Triamcinolone Acetonide Suspension) 
in Patients with Osteoarthritis of the Shoulder (Glenohumeral Joint) or Hip 
Protocol Number: 
(Version Date) 
FX006-2017-013 
Version 3.0 (05 April 2018) 
Name of Test Drug: 
FX006 
Phase: 
2a 
Methodology: 
Randomized, open label, parallel group, single intraarticular 
injection study 
Sponsor: 
Flexion Therapeutics 
10 Mall Road, Suite 301 
Burlington, Massachusetts, USA  
Tel: 781-305-7777 
Sponsor Representative: 
Amy Cinar, PhD 
Director, Biostatistics 
Document Date: 
17 October 2018 
Document Version: 
Final Version 1.0 
 






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CONFIDENTIAL - 4 - 
TABLE OF CONTENTS 
Section 
Page
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS...................... 9
1.1. 
Introduction .................................................................................... 9 
1.2. 
Objectives of Statistical Analysis ................................................ 10 
2. 
STUDY DESIGN ...................................................................................... 11 
2.1. 
Synopsis of Study Design ............................................................. 11 
2.2. 
Randomization Methodology ...................................................... 11 
2.3. 
Stopping Rules and Unblinding .................................................. 11 
2.4. 
Study Procedures ......................................................................... 11 
2.5. 
Safety and Pharmacokinetic (PK) Variables ............................. 14 
2.5.1. 
Safety Variables .............................................................. 14 
2.5.2. 
Pharmacokinetic Variables ............................................. 14 
3. 
PATIENT POPULATIONS .................................................................... 15 
3.1. 
Population Definitions ................................................................. 15 
3.2. 
Protocol Deviations ...................................................................... 15 
4. 
STATISTICAL METHODS ................................................................... 16 
4.1. 
Sample Size Justification ............................................................. 16 
4.1.1. 
Sample Size Considerations ............................................ 16 
4.1.2. 
Sample Size Estimate ...................................................... 16 
4.2. 
General Statistical Methods and Data Handling ...................... 16 
4.2.1. 
General Methods ............................................................. 16 
4.2.2. 
Computing Environment ................................................. 17 
4.2.3. 
Methods of Pooling Data ................................................ 17 
4.2.4. 
Adjustments for Covariates ............................................. 17 
4.2.5. 
Multiple Comparisons/Multiplicity ................................ 17 
4.2.6. 
Subpopulations ................................................................ 17 
4.2.7. 
Discontinuations and Loss to Follow-up ........................ 18 
4.2.8. 
Missing, Unused, and Spurious Data .............................. 18 
4.2.9. 
Visit Windows ................................................................ 18 
4.2.10. 
Baseline definitions ......................................................... 18 
4.3. 
Interim Analyses .......................................................................... 18 


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CONFIDENTIAL - 5 - 
Section 
Page
4.4. 
Patient Disposition ....................................................................... 18
4.6. 
Demographic and Baseline Characteristics ............................... 19 
4.6.1. 
Demographic characteristics ........................................... 19 
4.6.2. 
OA Medical History ........................................................ 20 
4.6.3. 
Prior medication .............................................................. 20 
4.7. 
Study Drug Exposure and Pharmacokinetics Evaluation ........ 20 
4.7.1. 
Study Drug Exposure ...................................................... 20 
4.7.2. 
Plasma drug concentration analysis ................................ 20 
4.7.3. 
Handling of Concentration Data below the Limit of 
Quantification ................................................................. 21 
4.7.4. 
Pharmacokinetic analysis ................................................ 22 
4.7.5. 
Exploration of Bioequivalence between FX006 and 
TAcs ................................................................................ 24 
4.8. 
Safety Analyses ............................................................................. 25 
4.8.1. 
Adverse Events ............................................................... 25 
4.8.2. 
Laboratory Data .............................................................. 27 
4.8.3. 
Vital Signs and Physical Examinations and Index Joint 
Assessment ...................................................................... 27 
4.8.4. 
Electrocardiogram ........................................................... 27 
4.8.5. 
Concomitant Medications ............................................... 27 
5. 
CHANGES TO PLANNED ANALYSES .............................................. 29 
6. 
References ................................................................................................. 30 
7. 
CLINICAL STUDY REPORT APPENDICES ..................................... 31 
7.1. 
Statistical Tables to be Generated .............................................. 31 
7.2. 
Statistical Figures to be Generated ............................................. 32 
7.3. 
Data Listings to be Generated ..................................................... 32 
 
 
 
 


Flexion Therapeutics 
Protocol FX006-2017-013 
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17 OCT 2018 
 
CONFIDENTIAL - 6 - 
LIST OF IN-TEXT TABLES 
Table 
Page 
Table 1 
Schedule of Assessments ................................................................................................. 13 
Table 2 
Plasma Pharmacokinetic Parameters ............................................................................... 23 
 


Flexion Therapeutics 
Protocol FX006-2017-013 
SAP, Final Version 1.0 
17 OCT 2018 
 
CONFIDENTIAL - 7 - 
 
ABBREVIATIONS 
 
 
Abbreviation 
Definition 
AE 
Adverse event 
ACR 
American College of Rheumatology 
AUC 
Area Under the Plasma Concentration Curve 
AUC(0-last) 
Area Under the Plasma Curve from time 0 to the last quantifiable 
concentration (t). 
AUC(0-inf) 
Area Under the Plasma Concentration Curve from 0 extrapolated 
to infinity 
AUC(0-t) 
Area Under the Plasma Curve from time 0 to tau post-IA 
injection, where tau is defined for partial AUC parameters from 0 
to 24, and 0-96 hours 
BE 
Bioequivalence 
BLOQ 
Below Limit of Quantification  
BMI 
Body Mass Index 
CI 
Confidence Interval 
Clast 
Last quantifiable plasma concentration 
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 
kg 
Kilogram 
LC/MS-MS 
Liquid Chromatographic Method with Tandem Mass 
Spectrometry Detection 
LSMD 
Least Square Mean Difference 
m 
Meter 
MedDRA 
Medical Dictionary for Regulatory Activities 


Flexion Therapeutics 
Protocol FX006-2017-013 
SAP, Final Version 1.0 
17 OCT 2018 
 
CONFIDENTIAL - 8 - 
Abbreviation 
Definition 
mg 
Milligram 
MRT 
Mean Residence Time 
NCA 
Non-Compartmental pharmacokinetic analysis 
OA 
Osteoarthritis 
OARSI 
Osteoarthritis Research Society International 
PDF 
Portable Document Format 
pg/mL 
Picograms per Milliliter 
PK 
Pharmacokinetic 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
t1/2 
Terminal Half-Life 
TA1 
Triamcinolone Acetonide 
TAcs2 
Triamcinolone Acetonide Injectable Suspension, Immediate-
Release (commercially available) (Reference Compound, 
Kenalog®-40) 
tlast 
Time of last quantifiable plasma concentration 
tmax 
Time from Dosing to Peak Exposure 
TEAE 
Treatment Emergent AE 
US 
United States 
WHO 
World Health Organization 
λz 
Terminal Elimination Rate Constant (aka: Lambda_z) 
1 Abbreviated in past protocols and documents as TCA 
2 Abbreviated in past protocols and documents as TCA-IR 


Flexion Therapeutics 
Protocol FX006-2017-013 
SAP, Final Version 1.0 
17 OCT 2018 
 
CONFIDENTIAL - 9 - 
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 
affects large weight-bearing joints like the knees and hips, but also occurs in the shoulders, 
hands, feet and spine.  Patients with OA suffer from joint pain, tenderness, stiffness and limited 
movement.  As the disease progresses, it becomes increasingly painful and debilitating, 
culminating, in many cases, in the need for total joint arthroplasty. 
Current Guidelines from the American College of Rheumatology (ACR), Osteoarthritis 
Research Society International (OARSI) and the European League against Rheumatism 
(EULAR) recommend the use of IA corticosteroids for short-term acute pain relief (Hochberg et 
al, 2012; Jordan et al, 2003; Menge et al, 2014).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 TA for IA administration. It is approved under the 
trade name ZILRETTA™ for the management of pain of osteoarthritis of the knee; however, 
shoulder and hip OA have not been studied and are investigational uses.  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) 
 


Flexion Therapeutics 
Protocol FX006-2017-013 
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17 OCT 2018 
 
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1.2. 
Objectives of Statistical Analysis 
Following a single IA injection of 32 milligram (mg) FX006 or 40 mg TAcs in patients with OA 
of either the glenohumeral (also referred to herein as shoulder) or hip joint, the primary 
objectives of this study are to:  
 Compare the plasma pharmacokinetics (PK), including systemic exposure, of 
triamcinolone acetonide (TA) between extended-release (FX006) and immediate release 
(TAcs) formulations, and 
 Assess the safety and general tolerability.  
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. 


Flexion Therapeutics 
Protocol FX006-2017-013 
SAP, Final Version 1.0 
17 OCT 2018 
 
CONFIDENTIAL - 11 - 
2. 
STUDY DESIGN 
2.1. 
Synopsis of Study Design 
This is a randomized, open-label, single dose study that will be conducted in male and female 
patients ≥40 years of age with OA of either the shoulder or the hip.  
Approximately 24 patients with OA of the shoulder and approximately 24 patients with OA of 
the hip will be randomized to one of two treatment groups (1:1) and treated with a single IA 
injection of either: 
 32 mg FX006 (approximately 12 patients per joint) or 
 40 mg TAcs (approximately 12 patients per joint) 
Each patient will be screened to confirm the diagnosis of OA of either the shoulder or hip and 
eligibility based on the other inclusion/exclusion requirements and will be randomized to 
treatment on Day 1. Each patient will be evaluated for a total of 12 weeks following the IA 
injection.  Following screening, sampling for PK and safety will be completed at 10 out-patient 
visits scheduled on Study Days 1 [calendar day of injection], 2, 3, 5, 8, 15, 22, 29, 57, and 85.   
 
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 stratified by 
joint cohort (hip or shoulder). 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 a single IA injection. 
 
2.4. 
Study Procedures 
Patients participating in this study will complete visit schedule as detailed in the Study Design, 
including the procedures indicated in the Schedule of Study Assessments. Those procedures 
include safety assessments, such as physical examinations, vital signs, blood collection for 
hematology and chemistry analyses, as well as adverse event (AE) monitoring and concomitant 
medication review.  
Blood samples for drug concentration measurements will be obtained from all patients on Day 1 
prior to administration of study medication, and at 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours (± 10 min) 
after injection, on Day 2 at 24 hours (± 2 hrs.) after the first injection of study medication, and at 
each of the subsequent scheduled visits.   


Flexion Therapeutics 
Protocol FX006-2017-013 
SAP, Final Version 1.0 
17 OCT 2018 
 
CONFIDENTIAL - 12 - 
See Schedule of Study Assessments for full details. The schedule of assessments, as outlined in 
the study protocol, is provided in Table 1. 
 
 


Flexion Therapeutics 
Protocol FX006-2017-013 
SAP, Final Version 1.0 
17 OCT 2018 
 
CONFIDENTIAL - 13 - 
Table 1 
Schedule of Assessments 
Procedures 
Screening1
Day  
1 
Days 
2, 3, 5 
Day 
82 
 
Days  
15, 223 
(Weeks 2,3)
Day  
293 
 (Week 4) 
Day  
573 
(Week 8) 
Day  
853 
(Week 12) 
(End of Study) 
Informed consent 
X4 
 
 
 
 
 
 
 
Inclusion/Exclusion Review 
X 
X5 
 
 
 
 
 
 
Medical History/Update 
X 
X5
 
 
 
 
 
 
OA Medical History 
X 
X5
 
 
 
 
 
 
Prior Treatment & Medications6 
X 
X5
 
 
 
 
 
 
Physical Examination 
X 
X5
 
 
 
 
 
X 
Index Joint X-ray7 
X 
 
 
 
 
 
 
 
Vital Signs 
X 
X5
 
X 
 
X 
 
X 
12-Lead ECG 
X 
 
 
 
 
 
 
 
Index Joint Assessments8 
X 
X5
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
Weight and BMI  
X  
 
 
 
 
 
 
X 
Hematology & Chemistry9 
X 
X5
 
 
 
X 
 
X 
HIV, Hepatitis B/C, HbA1c9 
X 
 
 
 
 
 
 
 
Pregnancy Test10 
X 
X5
 
 
 
 
 
X 
Blood for Drug Concentrations 
 
X11 
X12 
X 
X 
X 
X 
X 
Treatment Administration13 
 
X 
 
 
 
 
 
 
Adverse Event Monitoring14 
 
---------------------------------------------X-------------------------------------------------- 
Concomitant Medications14 
 
---------------------------------------------X-------------------------------------------------- 
                                                     
1 Screening may occur up to 14 days prior to Day 1 
2 Visit should be conducted +/- 1 day from scheduled date. 
3 Visits should be conducted +/- 2 days from scheduled date. 
4 Consent must be obtained prior to performing any study-specific procedures 
5 Complete assessment prior to dosing. 
6 Record any medications received within 30 days prior to Screening. 
7 Obtain new x-ray if >6 months since prior x-ray. Screening X-ray will be read locally for radiological findings of OA (S-P 
Classification for the shoulder and ACR criteria for the hip). 
8 For all patients, the index joint (shoulder or hip) will be assessed for evidence of inflammation including tenderness, heat/ 
redness, swelling, and effusion. Clinically significant findings (new or worsening from baseline) should be recorded as 
AEs. 
9 Via Central Laboratory. 
10 Conduct for females of childbearing potential only.  Serum pregnancy test to be performed via central laboratory at Screening 
and End-of-Study visit; urine pregnancy test to be performed locally on Day 1 and results available prior to dosing.   
11 On Day 1, blood for plasma drug concentration measurements will be collected at Time 0 (prior to administration) and at 
Hours 1, 2, 3, 4, 5, 6, 8, 10, and 12 post-injection (±10 minutes). 
12 On Day 2, blood for plasma drug concentration will be collected at 24 hours post-injection (+/- 2 hours). 
13 To be performed under continuous ultrasound guidance. 
14 AEs and Concomitant Medications will be captured from Day 1 (post-injection) to End of Study Visit. 
 


Flexion Therapeutics 
Protocol FX006-2017-013 
SAP, Final Version 1.0 
17 OCT 2018 
 
CONFIDENTIAL - 14 - 
2.5. 
Safety and Pharmacokinetic (PK) 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, index joint assessments, vital signs, and clinical laboratory evaluations.  
 
2.5.2. 
Pharmacokinetic Variables 
Blood samples (4 mL per sample) for drug concentration measurements will be obtained from 
all patients at the following times: 
 On Day 1, within 1 hour prior to administration of study medication 
 On Day 1, at Hours (±10 minutes) 1, 2, 3, 4, 5, 6, 8, 10, and 12 post-injection  
 On Day 2, at 24 (±2) hours post-injection 
 On Days 3, 5, 8, 15, 22, 29, 57, and 85 (time as convenient) 
These represent a total of 19 samples from each patient, each sample representing 4 mL of blood 
for a maximum estimated total volume of 76 mL of blood collected from each patient for drug 
concentration measurement. 
Procedures for sample collection, handling, storage and shipment will be described in the 
Laboratory Manual. Plasma TA concentrations will be measured using an established validated 
LC-MS/MS method.  
 
PK parameter endpoints are described in Section 4.7.4. 
 


Flexion Therapeutics 
Protocol FX006-2017-013 
SAP, Final Version 1.0 
17 OCT 2018 
 
CONFIDENTIAL - 15 - 
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 drug. Patients will be analyzed according to the treatment they 
have received (“analyses as treated”). 
Pharmacokinetic Population: 
All patients from safety population who receive a full dose of study drug, 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 FX006-2017-013 
SAP, Final Version 1.0 
17 OCT 2018 
 
CONFIDENTIAL - 16 - 
4. 
STATISTICAL METHODS 
4.1. 
Sample Size Justification 
4.1.1. 
Sample Size Considerations 
Sample size is based on the PK primary endpoint. In this study, it is expected that the systemic 
exposure in plasma of TA from extended-release FX006 should not exceed that of the 
immediate-release TAcs formulation for the key parameters of Cmax, AUC(0-t), and AUC(0-inf).  
In a previous pharmacokinetic study with knee OA patients (FX006-2015-009) the ratio of the 
mean exposure parameters for 32 mg  FX006 (N=60) and  40 mg  TAcs (N=18) for Cmax was 
0.10 with the upper limit of its 90% CI being 0.15 and for AUC(0-inf) was 0.52 with the upper 
limit of its 90% CI being 0.86. The pooled coefficients of variation for the parameters was 
between 0.53 (Cmax) and 0.68 (AUC0-inf).  
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 either shoulder or hip OA. A sample size of 12 in each treatment arm 
(24 in total) is estimated for each joint cohort (hip and shoulder). Within each group the sample 
size of 24 achieves approximately 90% power, with a two-sided alpha 0.05, to detect a ratio less 
than 1.0 of the exposure PK parameter means (FX006/TAcs), with a pooled coefficient of 
variation estimate of 0.68 (PASS 15 Power Analysis and Sample Size Software (2017), NCSS, 
LLC. Kaysville, Utah, USA, ncss.com/software/pass). The sample size of 12 per treatment arm 
in each joint cohort assumes a 10% noncompliance sampling rate (a drop-out rate) for providing 
complete blood samples for PK analysis, and is sufficient to characterize the comparative 
pharmacokinetic of FX006 and TAcs in this study. The total sample size is estimated to be 48 
patients (hip: 12 in each treatment arm, shoulder: 12 in each treatment arm) for the study. 
 
4.2. 
General Statistical Methods and Data Handling 
4.2.1. 
General Methods 
All output will be incorporated into Portable Document Format (PDF) 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 and safety parameters.  
Summary tables will present data by joint cohort (hip and shoulder) and 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. 


Flexion Therapeutics 
Protocol FX006-2017-013 
SAP, Final Version 1.0 
17 OCT 2018 
 
CONFIDENTIAL - 17 - 
All collected data will be presented in by-patient listings sorted by joint cohort, treatment arm 
and patient number. 
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 which is designated as Day 1. The preceding day is Day-1; the day before that is 
Day-2, etc. 
For PK assessments, when several assessments are made on the same day, both relative study 
day and hour will be presented. 
The sections below describe the intended analysis of the endpoints. Additional sensitivity 
analyses 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 WinNonlin® 
Version 8 or higher (Certara Corporation). 
AEs will be coding using Medical Dictionary for Regulatory Activities (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 
No pre-planned subpopulations are identified for this study. Subgroup tables and figures may be 
completed that are not identified in the list of planned tables and figures if needed to further 
explain results.  


Flexion Therapeutics 
Protocol FX006-2017-013 
SAP, Final Version 1.0 
17 OCT 2018 
 
CONFIDENTIAL - 18 - 
4.2.7. 
Discontinuations and Loss to Follow-up 
Each treated patient from this study receives study medication as a single IA injection. 
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. 
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.  
Data collected at unscheduled visits will be mapped to the closest scheduled visit, but only if 
that data is not already available in that visit. For assessments that are not collected at every 
visit, data will be mapped to the next scheduled visit where that assessment is to be performed 
(e.g., Hematology and Chemistry collected at Day 15 would be mapped to Week 4 since 
Hematology and Chemistry is not a planned assessment at Day 15). 
 
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. If baseline result is missing, the last 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 joint cohort (hip or shoulder).  Each joint cohort will be 
presented by treatment arm and overall.  


Flexion Therapeutics 
Protocol FX006-2017-013 
SAP, Final Version 1.0 
17 OCT 2018 
 
CONFIDENTIAL - 19 - 
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.  
 
4.6. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized for the Safety Population and will 
be presented by joint cohort (hip or shoulder).  Each joint cohort will be presented by treatment 
arm and overall.  
No formal statistical comparisons will be performed. 
All collected demographic, baseline characteristic, bilateral joint 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 (kilogram (kg)); 
 Height (cm); 
 Gender (Male/Female); 
 Body mass index (BMI) (kg/meter (m)2); 
 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); 


Flexion Therapeutics 
Protocol FX006-2017-013 
SAP, Final Version 1.0 
17 OCT 2018 
 
CONFIDENTIAL - 20 - 
Age, height, weight, and BMI will be summarized using descriptive statistics (number of 
patients, mean, SD, 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. 
OA Medical History 
General OA and joint OA medical history data as collected on the CRF will be tabulated for the 
Safety Population. 
General and joint OA medical history will be presented in separate tables (one for each joint 
cohort).  Each table will be presented by treatment group and overall. Time from primary 
diagnosis of OA in the index joint 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. 
   
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 4.8.5 for details on 
defining prior and concomitant medications). 
 
4.7. 
Study Drug Exposure and Pharmacokinetics Evaluation 
4.7.1. 
Study Drug Exposure 
Details of study drug administration will be tabulated and presented for the Safety Population 
and will be presented by joint cohort (hip or shoulder).  Each joint cohort will be presented by 
treatment arm and overall.  
Index joint injected (left or right), injection approach, needle gauge and length, numbing agent 
used, whether or not the entire contents of the syringe were injected, total amount injected, and 
whether ultrasound guidance was used will be presented. Synovial fluid aspiration (yes/no and 
volume) will also be presented. 
All dosing data will be presented in a data listing. 
 
4.7.2. 
Plasma drug concentration analysis 
Tabular summaries of mean TA plasma concentrations for each nominal sampling time will be 
presented for the PK population. Each joint cohort (hip and shoulder) will be presented 
separately by treatment arm.  
Visit date and times are calculated relative to the Baseline/Day 1 visit. The reference time point 
is Day 1 time of study drug administration (Time 0). Of note, the pre-dose sample is only 
relevant if a quantifiable concentration of TA is present. 


Flexion Therapeutics 
Protocol FX006-2017-013 
SAP, Final Version 1.0 
17 OCT 2018 
 
CONFIDENTIAL - 21 - 
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 below the limit of quantification (BLOQ) will be presented by 
time point.  
 
4.7.3. 
Handling of Concentration Data below the Limit of Quantification 
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 
terminated at the first BLOQ value and any subsequent concentrations are set to zero for PK 
calculations.  If sufficient data are missing for a given subject, that subject may be considered 
non-evaluable for pharmacokinetic analysis and will not be included in the PK Population. 
 
 


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4.7.4. 
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 WinNonlin® (version 8 or higher) and will be based on TA 
plasma concentrations from patients in the PK Population. Mean concentration profiles will be 
computed. Each joint cohort (hip and shoulder) will be presented separately by treatment arm.  
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.  
The following pharmacokinetic parameters will be calculated for Plasma TA (Table 2). 
 
 


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Table 2 
Plasma Pharmacokinetic Parameters 
PK Parameter 
Definition 
Method of Determination 
Cmax 
Peak exposure, Maximum plasma 
concentration observed. 
Observed value 
tmax 
Time from dosing to peak exposure, 
time to maximum plasma concentration 
observed. 
First occurrence of observed 
Cmax 
Clast 
Last quantifiable plasma concentration 
(last value observed above assay 
BLOQ) 
Observed value 
tlast 
Time of last quantifiable plasma 
concentration 
Observed value 
λz 
Terminal elimination rate constant  
lambda_z 
t1/2 
Apparent terminal elimination half-life 
ln(2)/λz,  
AUC(0-last) 
Area Under the Plasma Curve from 
time 0 to the last quantifiable 
concentration (t).  
Will be calculated using the 
linear up/log down variant of 
the trapezoidal rule 
AUC(0-t) 
Area Under the Plasma Curve from 
time 0 to tau post-IA injection, where 
tau is definedfor partial AUC 
parameters from 0 to 24, and 0-96 hours
Will be calculated using the 
linear up/log down variant of 
the trapezoidal rule 
AUC(0-∞) 
Area under concentration vs time curve 
from 0 to infinity after dosing. 
Will be calculated using the 
linear up/log down variant of 
the trapezoidal rule using the 
following formula AUC(0-last) 
+ Clast/λz 
CL 
Total Body Clearance  
Dose/ AUC(0-∞) 
MRT 
Mean residence time extrapolated to 
infinity 
ܣܷܯܥሺ଴ିஶሻܣܷܥሺ଴ିஶሻ
⁄
 
 
The AUC parameters will be calculated using the linear trapezoidal method for ascending 
concentrations and the log trapezoidal method for descending concentrations ('linear up, log 
down') calculation method option in WinNonlin. 
Onset of the apparent terminal log-linear phase used in the calculation of λz will be determined 
using WinNonlin Auto Selection and will be reviewed by the pharmacokineticist for 
reasonableness. No values for AUC(0-) or Apparent Terminal t1/2 will be reported for cases that 
do not exhibit a terminal log-linear phase in the concentration versus time profile. 
In determining the individual Apparent Terminal t1/2 and AUC(0-) values, the parameters 
"Rsq_adjusted” (adjusted R2), AUC(0-last), and “AUC%extrap_predicted” (predicted percent 
extrapolated AUC(0-)) will be used.  However, these values will only be referenced in the CSR 


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in cases where the extrapolated AUC(0-) is ≥ 25% of predicted, when it will be starred with 
added footnote in the text with justification for inclusion/exclusion and percent extrapolated. 
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 mean with SE and geometric mean with 95% CIs for plasma drug concentrations 
(linear-linear and log-linear plots) for each treatment arm. The distribution of plasma drug 
concentrations by time point will be displayed using box plots. 
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. 
Hip patients in the TAcs group received an injection volume of 1.0 mL or 5.0 mL depending on 
which version of the protocol was in use at the time of injection. If different PK profiles are 
observed within the hip cohort for subjects receiving TAcs, either due to differences in volume 
or due to other reasons, exploratory analyses may be performed to investigate potential sources 
of the difference. 
4.7.5. 
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. BE 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). Each joint cohort (hip and shoulder) will be tested for BE 
separately.  
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, AUC(0-24), AUC(0-t), and AUC(0-∞). 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 AUC(0-24), AUC(0-t), AUC(0-∞), 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, AUC(0-24), AUC(0-t), and AUC(0-∞). 
 
 


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4.8. 
Safety Analyses 
Safety analyses will be conducted using the Safety Population by joint cohort (hip and 
shoulder). Each joint cohort will be presented by treatment arm, according to the treatment that 
was received.   
 
4.8.1. 
Adverse Events 
AEs will be coded using MedDRA and displayed in tables and listings using System Organ 
Class (SOC) and Preferred Term (PT). 
Analyses of AEs will be performed for those events that are considered treatment emergent, 
where treatment emergent is defined as any AE with onset after the administration of study 
treatment, 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 
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. 
AEs will be summarized by patient incidence rates; therefore, in any tabulation, a patient 
contributes only once to the count for a given SOC or PT. 
Summary tables will display the number and percentage of patients who experienced at least 
one treatment emergent AE (TEAE) in each of the following categories: 
 Any TEAE 
 Any Serious AE (SAE) 
 Any TEAE leading to study discontinuation 


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 Any TEAE by severity (grade 1-5) 
 Any TEAE by relationship 
 Any index-joint related TEAE 
 Any index- joint related SAE 
 Any index- joint related TEAE leading to study discontinuation  
 Any index- joint related TEAE by severity (grade 1-5) 
 Any index- joint related TEAE by relationship  
 Any TEAE related to injection procedure 
Separate tabulations will be produced for each of following categories: 
 All TEAEs by SOC and PT  
 All SAEs by SOC and PT  
 All TEAEs related to study drug by SOC and PT 
 All TEAEs related to injection procedure by SOC and PT 
 All TEAEs by maximum severity by SOC and PT 
 All TEAEs leading to study discontinuation 
 All TEAEs leading to death 
 All index-joint related TEAEs by SOC and PT 
 All index-joint related TEAEs related to study drug by SOC and PT 
 All index-joint related TEAEs by maximum severity by SOC and PT 
 
In the summary table for "Any TEAE by SOC and PT", an additional row with the number of 
events observed will be presented. A patient will be counted once for the number of patients if 
they have multiple events. The total number of events will be the absolute number of events 
observed, and a patient will be counted more than once for the event totals if they have multiple 
events.  
In these tabulations, related is defined as any TEAE deemed possibly, probably or definitely 
related to study drug by the investigator. If relationship is missing, it will be imputed as related 
and flagged in the listings. 
No formal hypothesis-testing analysis of AE incidence rates will be performed. 
By-patient listings of all AEs occurring on-study will be provided as well as for the following, 
for all patients:  patient deaths, SAEs and AEs leading to discontinuation. 
 
 


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Protocol FX006-2017-013 
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4.8.2. 
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. 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. 
 
4.8.3. 
Vital Signs and Physical Examinations and Index Joint Assessment 
The actual value and change from baseline (Day 1) at each time point will be summarized. 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 index joint 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 index joint assessment at a given visit. Index joint assessment as well as index joint 
aspiration data will be presented in data listings.  
 
4.8.4. 
Electrocardiogram  
ECG data will be provided in patient data listing.  
 
4.8.5. 
Concomitant Medications 
Concomitant medications will be defined as those medications that were initiated after study 
drug administration or those that were ongoing at the time of 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 
administration of study treatment, the medication will be assumed concomitant. If the 
start date occurs prior to administration of study treatment but the end date is on or after 
the administration of study treatment 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 (either full date, month and year if 
missing day, or year if missing month and day) is before study drug administration. 


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 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 (either 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 administration of study 
treatment or completely missing, the medication will be assumed to be a prior 
medication.  
All prior and concomitant medications (CM) will be presented in a data listing with flags 
indicating whether each medication was prior and/or concomitant. The listings will include type 
of medication (general or restrictive) and whether the CM was used for treatment of an AE. 
 


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Protocol FX006-2017-013 
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5. 
CHANGES TO PLANNED ANALYSES 
Although the protocol states that listings will be provided by joint cohort, treatment, study site 
and patient, per this SAP, by-patient listings will be sorted by joint cohort, treatment arm and 
then patient number. 
The protocol states that a linear model will be used to compare the PK parameters from 
extended-release FX006 and immediate-release TAcs. This analysis will not be performed, since 
comparison of the PK parameters will be accomplished via the BE testing. 
 


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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. 
Creamer P, Hochberg MC. Osteoarthritis. Lancet 1997;350(906):503–508. 
FDA (2013) – Guidance for industry – Bioequivalence studies with Pharmacokinetic Endpoints for 
Drugs Submitted Under ANDA, U.S., Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), 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. 
Menge TJ, Boykin RE, Byram IR, Bushnell BD. A Comprehensive Approach to Glenohumeral Arthritis. 
So. Med. J. 2014;107(9):567-573 
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 14.1.3.1 
Osteoarthritis Medical History and Index Joint Characteristics of the 
Shoulder (Safety Population) 
Table 14.1.3.2 
Osteoarthritis Medical History and Index Joint Characteristics of the 
Hip (Safety Population) 
Table 14.1.3.3 
Other Osteoarthritis Medical History (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 
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 
Index-Joint-Related Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term (Safety Population) 
Table 14.3.1.6 
Index-Joint-Related Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term- Related to Study Drug (Safety 
Population) 
Table 14.3.1.7 
Index-Joint-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 Index Joint Assessments (Safety Population) 
 


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7.2. 
Statistical Figures to be Generated 
Figure 14.1.6.1 
Distribution of Plasma Drug Concentrations (pg/mL) by Time Point (PK 
Population) 
Figure 14.1.6.2 
Mean and GM 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) 
 
7.3. 
Data Listings to be Generated 
 
Listing 16.2.1 
Patient Disposition 
Listing 16.2.2.1 
Inclusion/Exclusion Criteria Not Met 
Listing 16.2.2.2 
Protocol Deviations 
Listing 16.2.3 
Analysis Populations 
Listing 16.2.4.1 
Demographics and Baseline Characteristics 
Listing 16.2.4.2 
Medical History 
Listing 16.2.4.3.1 
Medical History - Shoulder Osteoarthritis 
Listing 16.2.4.3.2 
Medical History - Hip Osteoarthritis 
Listing 16.2.4.4 
Medical History - Prior Treatment of Osteoarthritis Under Study 
Listing 16.2.4.5 
Medical History - Other Osteoarthritis 
Listing 16.2.4.6 
Medical History - Other Osteoarthritis Procedures or Surgeries 
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 16.2.7.1 
Adverse Events – Sorted By Patient and Onset Date 
Listing 16.2.7.2 
Adverse Events – Sorted by System Organ Class, Preferred Term, 
Treatment, Patient, and Onset Date 
Listing 16.2.7.3 
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 
Index Joint 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 


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Listing 16.2.9.5 
Index Joint Aspiration 
Listing 16.2.9.6 
Surgical Procedures