Conditions: Osteoarthritis of the Knee
Keywords: Osteoarthritis Knee Pain Steroid Intra-articular Injection
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 208
Healthy volunteers: no

Brief summary:
This is an Open-label Study to Assess the Safety of Repeat Dose of FX006 Administered to Patients with Osteoarthritis (OA) of the Knee

Detailed description:
This study is an open-label, repeat administration design of 32 mg FX006. The study will be conducted in male and female patients ≥ 40 years of age with symptomatic OA of the knee.

Eligible patients will be offered participation to receive an initial intra-articular (IA) injection of FX006 administered to the index knee at Day 1.

Patients who receive an initial injection of FX006 will return at Weeks 4 and 8 before being evaluated at 12, 16, 20 and 24 weeks for repeat administration. At the first evaluation where the patient has been determined to meet repeat administration eligibility criteria, the patient will be eligible to receive a second IA injection of FX006.

Patients who are eligible to receive a second injection will be evaluated for a total of 52 weeks post initial injection at: Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52, regardless of the time at which they receive their second injection. In addition, X-rays will be completed at Screening and Week 52 or End of Study (EOS) for assessment of safety.

Patients that do not benefit from the initial treatment as determined by evaluation at Week 12 will complete the study at the Week 12 follow-up visit.

Patients who are not eligible for a second injection of FX006 after evaluation at Weeks 12, 16, 20, and 24 will complete the study at the Week 24 follow-up visit.

Arms:
arm 1: Single intra-articular injection

Interventions: intervention 1: FX006 32 mg
Intervention descriptions: intervention 1: Single intra-articular injection

Protocol document:
Prot_000.pdf: 
 
CONFIDENTIAL INFORMATION 
CLINICAL STUDY PROTOCOL 
 
An Open-label Study to Assess the Safety of Repeat Administration of FX006 to Patients with 
Osteoarthritis of the Knee  
 
PROTOCOL NUMBER:   
FX006-2016-011 
 
 
PHASE:   
3b 
 
 
STUDY MEDICATION(S): FX006 
 
INDICATION:   
Osteoarthritis of the Knee  
 
  
MEDICAL MONITOR:  
Robert D. Arbeit, MD 
 
Chief Medical Officer 
 
Flexion Therapeutics 
Tel: 781-305-7717 
 
 
SPONSOR:   
Flexion Therapeutics 
 
           
10 Mall Road  
                       
Burlington, MA 01803 
Tel: 781-305-7777 
 
DATE:   
16 October 2017 
 
  
VERSION:  
2.0  
 
SUPERCEDES:  
Version 1.0; 14 September 2016 
 
 




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TABLE OF CONTENTS 
1. 
ABBREVIATIONS AND DEFINITION OF TERMS ................................................7 
2. 
SYNOPSIS ...................................................................................................................9 
3. 
ETHICS ......................................................................................................................16 
3.1. 
Institutional Review Board/Ethics committee ............................................................16 
3.2. 
Ethical Conduct of Study ............................................................................................16 
3.3. 
Patient Information and Consent ................................................................................16 
4. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .................17 
4.1. 
Investigators ................................................................................................................17 
4.2. 
Study Administrative Structure ..................................................................................17 
5. 
INTRODUCTION ......................................................................................................18 
5.1. 
Osteoarthritis ...............................................................................................................18 
5.2. 
Background .................................................................................................................18 
5.2.1. 
Investigational Medicinal Product:  FX006 ................................................................18 
5.2.2. 
Rationale for FX006 in OA of the Knee .....................................................................19 
5.2.3. 
Non-clinical ................................................................................................................19 
5.2.4. 
Clinical Experience .....................................................................................................19 
5.2.5. 
Clinical Pharmacokinetics ..........................................................................................21 
5.2.6. 
Clinical Pharmacodynamics .......................................................................................21 
5.2.7. 
Clinical Efficacy .........................................................................................................21 
5.2.7.1. 
Study FX006-2011-001 ..............................................................................................21 
5.2.7.2. 
Study FX006-2014-006 ..............................................................................................22 
5.2.7.3. 
Study FX006-2014-008 ..............................................................................................22 
5.2.8. 
Clinical Safety ............................................................................................................22 
5.2.9. 
Conclusion ..................................................................................................................23 
6. 
THESE DATA PROVIDE BASES FOR CONTINUED CLINICAL STUDY 
OF FX006.STUDY OBJECTIVES ............................................................................24 
6.1. 
Primary Objective .......................................................................................................24 
6.2. 
Exploratory Objective .................................................................................................24 
7. 
INVESTIGATIONAL PLAN .....................................................................................25 
7.1. 
Overall Study Design and Plan ...................................................................................25 
7.2. 
Site Staffing Requirements .........................................................................................25 
7.3. 
Discussion of Study Design ........................................................................................26 


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7.3.1. 
Rationale for Study Population ...................................................................................26 
7.3.2. 
Rationale for Dose Selection ......................................................................................26 
7.3.3. 
Rationale for Study Design .........................................................................................26 
7.3.4. 
Rationale for Study Parameters ..................................................................................26 
7.4. 
Selection of Study Population ....................................................................................27 
7.4.1. 
Number of Patients .....................................................................................................27 
7.4.2. 
Screening Criteria .......................................................................................................27 
7.4.2.1. 
Screening Inclusion Criteria .......................................................................................27 
7.4.2.2. 
Screening Exclusion Criteria ......................................................................................28 
7.4.3. 
Repeat Administration Criteria ...................................................................................30 
7.4.3.1. 
Repeat Administration Inclusion Criteria ...................................................................30 
7.4.3.2. 
Repeat Administration Exclusion Criteria ..................................................................30 
7.4.4. 
Removal of Patients from Therapy or Assessments ...................................................31 
7.4.5. 
Screen Failures ............................................................................................................31 
7.5. 
Treatment Administered .............................................................................................32 
7.5.1. 
Study Medication Treatment Arms ............................................................................32 
7.5.2. 
Identity of Investigational Product(s) .........................................................................32 
7.5.3. 
Receipt, Dispensing, and Storage ...............................................................................32 
7.5.4. 
Packaging and Labeling of Study Medication ............................................................32 
7.5.5. 
Return of Study Medication ........................................................................................32 
7.5.6. 
Method of Assigning Patients to Treatment Groups ..................................................32 
7.5.7. 
Blinding ......................................................................................................................33 
7.5.8. 
Intra-articular Injection Procedure ..............................................................................33 
7.5.9. 
Treatment Compliance ................................................................................................33 
7.6. 
Prior and Concomitant Therapy ..................................................................................33 
7.6.1. 
Allowable Medications/Therapies ..............................................................................33 
7.6.2. 
Restricted Medications ...............................................................................................34 
7.7. 
Study Variables ...........................................................................................................34 
7.7.1. 
Safety Variables ..........................................................................................................34 
7.7.2. 
Exploratory Efficacy Variables ..................................................................................34 
7.7.3. 
Pharmacodynamic Variables ......................................................................................34 
7.8. 
Schedule of Study Assessments..................................................................................35 
7.9. 
Study Procedures ........................................................................................................37 


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7.9.1.1. 
Informed Consent .......................................................................................................37 
7.9.2. 
Review of Eligibility, Medical History, Prior Treatment, and Medications ..............37 
7.9.3. 
Physical Examination .................................................................................................37 
7.9.4. 
Index Knee X-ray .......................................................................................................37 
7.9.5. 
Index Knee Assessment ..............................................................................................38 
7.9.6. 
12-lead ECG ...............................................................................................................38 
7.9.7. 
Vital Signs ..................................................................................................................38 
7.9.8. 
Height, Weight, and BMI determination ....................................................................38 
7.9.9. 
Central Clinical Laboratory Evaluations ....................................................................39 
7.9.10. 
Patient Questionnaires ................................................................................................39 
7.9.11. 
Daily Activity .............................................................................................................39 
7.9.12. 
Synovial Fluid Aspiration ...........................................................................................40 
7.9.13. 
Treatment Administration ...........................................................................................40 
7.9.14. 
Review of Adverse Events and Concomitant Medications ........................................40 
8. 
CLINICAL SAFETY ASSESSMENTS .....................................................................41 
8.1. 
Adverse Events ...........................................................................................................41 
8.1.1. 
Definitions ..................................................................................................................41 
8.1.2. 
Evaluating and Recording of Adverse Events ............................................................42 
8.1.3. 
Reporting of Serious Adverse Events .........................................................................44 
8.1.4. 
Safety Monitoring Roles .............................................................................................44 
8.1.5. 
Clinical Management of Index Knee-related Events ..................................................45 
8.1.6. 
Pregnancy ...................................................................................................................45 
9. 
STATISTICAL CONSIDERATIONS .......................................................................46 
9.1. 
Statistical and Analytical Plans ..................................................................................46 
9.1.1. 
Interim Analysis ..........................................................................................................46 
9.1.2. 
Final Analyses ............................................................................................................46 
9.2. 
General Considerations and Methods .........................................................................46 
9.2.1. 
Analysis Populations ..................................................................................................47 
9.2.2. 
Study Data ..................................................................................................................47 
9.2.2.1. 
Clinical Data – CDISC Study Data Tabulation Model (SDTM) ................................47 
9.2.2.2. 
Analysis Data – CDISC Analysis Data Model (ADaM) ............................................47 
9.2.3. 
Study Variables for Assessment .................................................................................47 
9.2.4. 
Sub-Groups and Covariates ........................................................................................47 


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9.3. 
Determination of Sample Size ....................................................................................48 
9.4. 
General statistical Methods .........................................................................................48 
9.4.1. 
Demographics and Baseline Characteristics ...............................................................48 
9.4.2. 
Exposure .....................................................................................................................48 
9.4.3. 
Exploratory Efficacy Analyses ...................................................................................48 
9.4.4. 
Safety Analyses ..........................................................................................................49 
10. 
DATA QUALITY ASSURANCE ..............................................................................50 
11. 
DATA HANDLING AND RECORDKEEPING .......................................................51 
11.1. 
Case Report Forms .....................................................................................................51 
11.2. 
Study Medication Accountability ...............................................................................51 
11.3. 
Confidentiality of Data ...............................................................................................51 
11.4. 
Retention of Records ..................................................................................................51 
11.5. 
Protocol Adherence ....................................................................................................52 
12. 
PUBLICATION POLICY ..........................................................................................53 
12.1. 
Sponsor’s Publication Policy ......................................................................................53 
12.2. 
Site Publication ...........................................................................................................53 
13. 
REFERENCES ...........................................................................................................54 
14. 
APPENDICES ............................................................................................................56 
APPENDIX 1. KNEE OA DIAGNOSIS ASSESSMENTS .......................................................56 
APPENDIX 2. STUDY VISIT FLOW CHART .........................................................................57 
 
 
LIST OF TABLES 
Table 1: 
Schedule of Study Assessments..................................................................................36 
Table 2: 
BMI Calculations ........................................................................................................38 
Table 3: 
Clinical Laboratory Panel ...........................................................................................39 
 
 
 
 
 


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1. 
ABBREVIATIONS AND DEFINITION OF TERMS 
ACR 
American College of Rheumatology 
ADL 
Activities of daily living 
ADaM 
Analysis Data Model 
ADP 
average daily pain 
ADRG 
Analysis Data Reviewer’s Guide 
AE 
adverse event 
ANOVA 
analysis of variance 
AUC 
area under the concentration-time curve  
BMI 
Body Mass Index 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
Code of Federal Regulations 
CGIC 
Clinical Global Impression of Change 
CI 
confidence interval 
CMC 
Carboxymethylcellulose sodium 
CTCAE 
Common Terminology Criteria for AEs 
CSR 
Clinical Study Report 
CV 
coefficient of variation 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EULAR 
European League Against Rheumatism 
GCP 
Good Clinical Practice 
GPAQ 
Global Physical Activity Questionnaire 
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 
K-L 
Kellgren-Lawrence 
KM 
Kaplan-Meier 
KOOS 
Knee injury and Osteoarthritis Outcome Score 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures 
NaCl 
sodium chloride 
OA 
osteoarthritis 


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OARSI 
Osteoarthritis Research Society International 
PGIC 
Patients’ Global Impression of Change 
PLGA 
poly[lactic-co-glycolic acid] 
PK 
pharmacokinetic 
PRP 
platelet rich plasma 
PTOA 
post-traumatic osteoarthritis 
QOL 
Quality of Life 
QTc 
QT interval corrected for heart rate 
RBC 
red blood cells 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDRG 
Study Data Reviewer’s Guide 
SDTM 
Study Data Tabulation Model 
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/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: An Open-label Study to Assess the Safety of Repeat Administration of FX006 to Patients with 
Osteoarthritis of the Knee 
Study Centers:  Approximately 20 centers 
Study Phase:  3b 
Objectives: 
The primary objective of this study is to assess the overall safety and general tolerability of repeat administration of 
FX006 (two doses of 32 mg FX006) in patients with symptomatic osteoarthritis (OA) of the knee. 
Exploratory objectives of this study include the following: 
 
examine efficacy signals for sustained pain reduction following two doses of 32 mg FX006. 
 
collect synovial fluid samples to enable potential future examination of synovial fluid biomarkers that may 
contribute to the pathogenesis of OA and/or be associated with responsiveness to FX006 treatment. 
Study Design and Methodology: 
This study is an open-label, repeat administration design of 32 mg FX006. The study will be conducted in male and 
female patients ≥ 40 years of age with symptomatic OA of the knee. 
Eligible patients will be offered participation to receive an initial IA injection of FX006 administered to the index 
knee at Day 1. 
Patients who receive an initial injection of FX006 will return at Weeks 4 and 8 before being evaluated at 12, 16, 20, 
and 24 weeks following the initial administration of FX006 for repeat administration.  At the first visit where the 
patient has been determined to meet repeat administration eligibility criteria described in Section 7.4.3, the patient 
will be eligible to receive a second IA injection of FX006 administered to the index knee. 
Patients who are eligible to receive a second injection will be evaluated for a total of 52 weeks post initial injection 
at: Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52, regardless of the visit at which they receive their 
second injection. 
Patients that do not benefit from the initial treatment as determined by evaluation at Week 12 will complete the 
study at the Week 12 follow-up visit.  These patients will be evaluated for a total of 12 weeks post initial injection 
at: Weeks 4, 8, 12. 
Patients who are not eligible for a second injection of FX006 after evaluation at Weeks 12, 16, 20, and 24 will 
complete the study at the Week 24 follow-up visit.  These patients will be evaluated for a total of 24 weeks post 
initial injection at: Weeks 4, 8, 12, 16, 20, and 24.   
Refer to Appendix 2 Study Visit Flow Chart. 
The study is expected to enroll over approximately 6 months. 
Number of Patients: 
Approximately 200 patients will be enrolled to ensure that at least 100 patients receive two doses of 32 mg FX006 
and complete the study through Week 52. 
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, administered as a single 5 mL injection 
Reference Compound(s), Dose and Mode of Administration: 
Not applicable 


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Duration of Dosing: 
Single IA injection for all enrolled patients at Day 1/Baseline, and a second IA injection for those meeting repeat 
administration requirements at either Week 12, 16, 20, or 24. 
Screening Inclusion Criteria:  
To be included in the trial, patients must fulfill the following criteria to participate in the study 
1. Written consent to participate in the study 
2. Willingness and ability to comply with the study procedures and visit schedules and ability to follow verbal 
and written instructions 
3. Male or female 40 years of age 
4. Symptoms associated with OA of the index knee for ≥ 6 months prior to Screening (patient self-report is 
acceptable)   
5. Currently meets ACR Criteria (clinical and radiological) for OA (Altman et al, 1986) as follows:  
 
Knee pain 
 
at least 1 of the following: 
o 
Age > 50 years 
o 
Stiffness < 30 minutes 
o 
Crepitus 
 
Osteophytes  
6. Kellgren-Lawrence (KL) Grade 2, 3 or 4 in the index knee based on X-ray performed during Screening 
(locally read) 
7. WOMAC A total sum score of ≥ 6 at Screening and Day 1/Baseline 
8. Index knee pain for >15 days over the last month (as reported by the patient) 
9. If bilateral OA exists, pain in the contralateral knee must be less than pain in the index knee as reported by 
the patient 
10. Body mass index (BMI) ≤ 40 kg/m2s 
11. Ambulatory and in good general health  
12. Willingness to abstain from use of the following protocol-restricted medications during the study: 
 
Intravenous (IV), intramuscular (IM) and oral corticosteroids (Note: inhaled, intranasal and topical 
corticosteroids are allowed) 
 
IA corticosteroids in any joint 
 
IA viscosupplementation (hyaluronic acid) or any IA intervention (IA injection, IA aspiration, etc.) in 
the index knee 
 
Opiates  
 
Any investigational drug, device or biologic 
 
Immunomodulators, immunosuppressives, or chemotherapeutic agents  
 
Live or live attenuated vaccines 


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Screening 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 knee joint 
3. Clinical signs and symptoms of active knee infection or crystal disease of the index knee within 1 month of 
Screening 
4. Presence of surgical hardware or other foreign body in the index knee 
5. Unstable index knee joint (such as a torn anterior cruciate ligament) within 12 months of Screening 
Previous or concomitant treatment-related criteria 
6. IA corticosteroid (investigational or marketed) in index knee within 3 months of Screening  
7. IA hyaluronic acid (investigational or marketed) in the index knee within 6 months of Screening 
8. IV or IM corticosteroids (investigational or marketed) within 3 months of Screening 
9. Oral corticosteroids (investigational or marketed) within 1 month of Screening 
10. Any other IA drug/biologic use within 6 months of Screening or 5 half-lives (whichever is longer) (e.g., 
platelet rich plasma (PRP) injection, stem cells, prolotherapy and amniotic fluid injection) 
11. Prior administration of FX006  
12. Prior arthroscopic or open surgery of the index knee within 12 months of Screening 
13. Planned/anticipated surgery of the index knee during the study period 
Patient-related criteria 
14. Known hypersensitivity to any form of triamcinolone 
15. History of sarcoidosis or amyloidosis  
16. Active or history of malignancy within the last 5 years, with the exception of resected basal cell carcinoma, 
squamous cell carcinoma of the skin, or effectively managed cervical carcinoma 
17. Known active or quiescent systemic fungal, bacterial, mycobacterial (including tuberculosis), viral or 
parasitic infections, or, shingles, herpes zoster and ocular herpes simplex  
18. Any infection requiring IV antibiotics within 4 weeks of Screening or oral antibiotics within 2 weeks of 
Screening 
19. History of osteomyelitis 
20. Known or clinically suspected infection with human immunodeficiency virus (HIV), hepatitis B or C 
viruses 
21. Any clinically significant electrocardiogram (ECG) abnormality as judged by the Investigator 
22. Patients requiring or likely to require chronic treatment with corticosteroids during the study period based 
on patient medical history 
23. History of, or active Cushing’s syndrome 
24. Active substance abuse (drugs or alcohol), history of chronic substance abuse within the past year, or prior 
chronic substance abuse judged by the investigator as likely to recur during the study 
25. Skin breakdown at the knee where the injection would take place 
26. Women who are pregnant or nursing or plan to become pregnant during the study; men who plan to 
conceive during the study 
27. Women of child-bearing potential (not surgically sterile or post-menopausal for at least 1 year as 
documented in medical history) not using a 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 male sterilization (vasectomy)] 
 


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28. Use of immunomodulators, immunosuppressives, or chemotherapeutic agents within 5 years of Screening  
29. Has received a live or live attenuated vaccine within 3 months of Screening 
30. Use of any other investigational drug or device within 30 days of Screening or within 5 half-lives 
(whichever is longer) or an investigational biologic within 60 days of Screening or within 5 half-lives 
(whichever is longer) 
31. 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 
Repeat Administration Inclusion Criteria:  
To be eligible to receive a repeat administration, patients must fulfill the following criteria: 
1. Benefit from the initial dose of FX006 in the opinion of both the patient and the Investigator 
2. No major safety concerns during the initial dose period as assessed by the Investigator 
3. Clinically indicated to receive a second dose of FX006 in the opinion of both the patient and the 
Investigator 
4. WOMAC A total sum score of ≥ 6 or a clinical rationale as to why a second dose is indicated 
5. Compliant with study procedures and visit schedules through at least Week 12 and the willingness and 
ability to continue to comply through Week 52  
6. Willingness to abstain from use of protocol-restricted medications during the study  
Repeat Administration Exclusion Criteria:  
Patients fulfilling at least one of the following are not eligible to receive a repeat administration: 
1. Clinical signs and symptoms of active knee infection or crystal disease of the index knee  
2. Received a non-protocol specified IA intervention (IA injection, IA aspiration, etc.) in index knee during 
study participation 
3. Use of immunomodulators, immunosuppressives, or chemotherapeutic agents during study participation 
4. Received a live or attenuated vaccine during study participation 
5. Use of any other investigational drug, device or biologic during study participation 
6. Allergic reaction to initial dose of 32 mg FX006 
7. Any infection requiring IV antibiotics within 4 weeks or oral antibiotics within 2 weeks of second dose of 
FX006 
8. Skin breakdown at the knee where the injection would take place 
9. Women who are pregnant or nursing or plan to become pregnant during the study; men who plan to 
conceive during the study 
10. Women of child-bearing potential (not surgically sterile or post-menopausal for at least 1 year as 
documented in medical history) not using a 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 male sterilization (vasectomy)] 
11. 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 


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Procedures and Assessments: 
The study will involve a Screening period (a minimum of 7 days, up to 21 days), dosing at Day 1/Baseline and up to 
13 additional outpatient visits (Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52) depending if the patient is 
eligible for and receives a second injection.    
At specified times throughout the study, patients will undergo physical examinations, index knee assessments and 
index knee X-rays; blood samples will be collected for laboratory safety tests and vital signs will be collected or 
measured.  Information regarding AEs and concomitant medications will be collected.  
Patients will have index knee synovial fluid collected at baseline and the week at which the second dose is 
administered (if the patient is eligible to receive a second dose).  Patients that are not eligible to receive a second 
dose will not have synovial fluid drawn at their final study visit.  These samples will be preserved for potential 
future OA biomarker analyses. 
Steps per day will be captured using a measured function device.  Patients will be provided with a device at the 
Screening visit to be worn for at least 7 days prior to Baseline/Day 1 through Week 12. The site will confirm patient 
compliance with wearing the device to capture steps per day data at each patient visit from Day 1 through Week 12.  
As well, patients will complete the Global Physical Activity Questionnaire (GPAQ) at Screening and at Week 12. 
During out-patient visits, patients will complete the Western Ontario and McMaster Universities (WOMAC®) 
Osteoarthritis Index Likert (LK) 3.1 and the Knee injury and Osteoarthritis Outcome Score (KOOS) Quality of Life 
(QOL) Subscale. 
Blinding:  
This is an open-label study.  
IP Administration Procedure:  
IA injections will be performed by the assigned injector.  The injector may choose the position of the knee (e.g., 
extended or flexed), the approach for the injection (e.g., medial or lateral) and the numbing agent to be used (e.g., 
ethyl chloride, subcutaneous lidocaine; IA anesthetics are not allowed) based on standard of care. Sterile technique 
should be used.   
Prior to injection, the index knee should be thoroughly cleansed using a bactericidal solution.  The index knee will 
be aspirated in all cases prior to administration of study medication.  Following attempted aspiration, 5 mL of the 
reconstituted FX006 will be injected into the synovial space.  Refer to the Pharmacy Binder for detailed instructions 
on how to prepare FX006.  
The same needle used for IA injection of the study medication may also be used for synovial fluid aspiration, 
thereby allowing for a single injection with syringe replacement.  The injector will use a 21 gauge or larger needle 
for injection and aspiration of fluid. 
Patients should be advised to avoid strenuous activities or prolonged weight-bearing activities for approximately 24 
to 48 hours following the injection and to also maintain a stable lifestyle with regard to physical activity throughout 
the duration of the study. 
In the event that the patient has an immediate reaction (e.g., tenderness, increased pain, swelling, effusion, 
decreased mobility of the index knee), the patient should be treated according to local clinical guidelines and 
physician experience 


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Concomitant Medications: 
The exclusion criteria indicate that a patient may not be enrolled if he/she has used any of the following within the 
specified windows.  In addition these medications should not be taken or used throughout the study:   
 
IV, IM or oral corticosteroids 
 
IA corticosteroids in any joint 
 
IA viscosupplementation (hyaluronic acid) or any IA intervention (IA injection, IA aspiration, etc.) in the 
index knee 
 
Opiates  
 
Any investigational drug, device or biologic 
 
Immunomodulators, immunosuppressives, or chemotherapeutic agents  
 
Live or live attenuated vaccines 
Criteria for Evaluation: 
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 knee assessments, vital 
signs, and clinical laboratory evaluations. In addition the index knee will be evaluated by X-ray and assessed by a 
central imaging vendor for joint space narrowing, chondrolysis, subchondral bone changes, bone infarcts, avascular 
necrosis, joint swelling, and insufficiency fracture. 
Exploratory Efficacy Variables 
 
Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index (Likert (LK) 3.1, 5-point 
scale): pain, stiffness and function domains independently and collectively (Bellamy et al, 1988).  
 
Knee injury and Osteoarthritis Outcome Score (KOOS) Quality of Life (QOL) Subscale  
 
Daily activity measured as steps per day 
 
Global Physical Activity Questionnaire (GPAQ) domains for Occupational physical activity, Transport-
related physical activity, and Physical activity during discretionary or leisure time)  
Sample Size Considerations: 
A sample size of approximately 100 patients who receive two doses of 32 mg FX006 is considered a reasonable 
sample size in order to assess the safety profile of repeat administration of FX006.  No formal power and sample 
size calculations have been made as the analysis of the efficacy data collected from this study will be considered 
exploratory and hypothesis-generating for future multiple dose studies of FX006. In order to ensure at least 100 
patients who receive two doses of 32 mg FX006 are enrolled and followed for 52 weeks, approximately 200 patients 
will be enrolled based on an estimate that approximately 66% of patients enrolled will be eligible to receive a 
second dose of 32 mg FX006 and approximately 75% of subjects who receive a second dose will complete the study 
through Week 52. 


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Statistical Methods: 
A comprehensive statistical analysis plan (SAP) will be written and approved prior to database lock for this study 
that describes the final analyses to be completed for safety and exploratory efficacy endpoints. 
No formal interim analysis is planned for the primary safety endpoints in this open-label study to assess the safety 
and tolerability of FX006 after repeat administration.  However, interim analysis may be conducted with exploratory 
endpoints to examine efficacy signals following administration of one or two doses of 32mg FX006. These interim 
analyses on exploratory endpoints may be completed for data review, regulatory updates, and/or publication (or 
presentation at congresses) for this open-label study. Any interim analysis completed will have an interim analysis 
plan written and approved to describe the purpose and analytical objectives of the interim analysis.  Final analyses, 
described in the protocol and statistical analysis plan, will be conducted after completion of the study, when all 
subjects have either discontinued the study early (prior to Week 52) or completed the study through Week 52. 
Demographic and baseline characteristics will be listed by study site and patient, and will be summarized by 
treatment.  Frequencies and proportions will be presented for the categorical variables and descriptive statistics will 
be presented for continuous variables. 
Treatment exposure will be listed by study site and patient, and will be summarized by treatment and dose. 
The examination of efficacy is exploratory in this study. Data from the WOMAC® questionnaire will be presented in 
by-patient listings with summary presentation of the data and exploratory analyses.  
Analysis of the magnitude of pain relief observed with WOMAC A (pain), stiffness (WOMAC B), and function 
(WOMAC C) will be explored between patients who receive one dose and those receiving a second following the 
first and second doses of 32 mg FX006 will be explored with a mixed model for repeated measures (MMRM) with 
fixed effects of number of doses (1 or 2) received, and a dose by time interaction. Model covariates will include 
study site, and potentially other variables.  Subject will be a random effect in the model.  Time points of interest for 
this analysis are those when a subject is eligible for a second dose. 
A second within subject analysis will be completed for subjects who receive two doses of FX006 to examine the 
improvement in WOMAC scores within a subject after receiving the second dose: WOMAC after the first dose, 
compared to WOMAC following the second dose. The change from baseline to the last WOMAC score for the first 
dose will be compared to the change from the last score prior to the second dose to the last WOMAC score following 
the second dose. The increment difference in the overall change for the first dose compared to second dose will be 
explored with a linear model. 
Evaluation of dose-response will be assessed descriptively with an examination of WOMAC A responses at the time 
(in weeks) of second dose administration to assess the magnitude of scores at each week that a second dose may be 
administered. The time to maximal pain relief response with WOMAC A following the first and second doses of 
32 mg FX006 will be examined using a Kaplan-Meier (KM) procedure. 
Questionnaire data from the Global Physical Activity Questionnaire (GPAQ) domains (occupational physical 
activity, transport-related physical activity, and physical activity during discretionary or leisure time) will be 
described descriptively at the two time points collected (Screening and Week 12). The change in GPAQ domain 
scores and total score will be examined with an analysis of variance (ANOVA) model with summaries comparing 
patients who receive one dose to those receiving two doses of 32 mg FX006. GPAQ information collected at 
Screening will be utilized to normalize steps per day based on lifestyles activity.  GPAQ information will be a model 
covariate in subsequent analyses. 
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 in severity after dosing, will be presented by treatment group.  Incidences of TEAEs will also be presented 
by maximum severity and relationship to study medication. 
Similar presentations will be provided for serious AEs, AEs leading to withdrawal from the study, or AEs leading to 
death. Analysis of AE data will include examination of the incidence rates of TEAEs and index knee related TEAEs 
following the first dose and second dose, as well as the cumulative incidence of TEAEs after all doses of 32 mg 
FX006. Both the number of events and the number of patients experiencing an event will be examined to assess the 
by patient cumulative incidence of TEAEs associated with repeat administration. 
Clinical laboratory data and vital sign information will be presented as descriptive summary statistics for value and 
change from Baseline at each individual time point. 


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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/IEC 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 patients. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study 
patients 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, 
conditions of participation and termination, and risks and benefits. 
An IRB/EC-approved informed consent document must be signed by the patient or the patient’s 
legal guardian before his or her participation in the study.  A copy of the informed consent 
document must be provided to the patient or the patient’s legal guardian.  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 Clinical Site Responsibilities and Signature log. 
The contact information for all Principal Investigators participating in the trial will be kept in the 
Trial Master File. 
4.2. 
Study Administrative Structure 
The study will be managed by the Sponsor with specific responsibilities delegated to contract 
research organizations. 


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5. 
INTRODUCTION 
5.1. 
Osteoarthritis 
Osteoarthritis (OA) is a painful and debilitating musculoskeletal disease that is characterized by 
intra-articular (IA) inflammation, deterioration of articular cartilage, and degenerative changes to 
peri-articular and subchondral bone (Creamer and Hochberg, 1997; Goldring and Goldring, 
2006).  Arthritis is the most common cause of disability in the United States (US) and OA is the 
most common joint disease, affecting 27 million Americans, with numbers expected to grow as a 
result of aging, obesity and sports injuries.  Recent data suggest that OA accounts for over $185 
billion of annual healthcare expenditures in the US, which does not include loss of productivity 
costs.  We estimate that by 2030, 45 million people will have OA.  OA commonly affect large 
weight-bearing joints like the knees and hips, but also occurs in the shoulders, hands, feet and 
spine.  Patients with OA suffer from joint pain, tenderness, stiffness and limited movement.  As 
the disease progresses, it becomes increasingly painful and debilitating, culminating, in many 
cases, in the need for total joint arthroplasty. 
Current Guidelines from the American College of Rheumatology (ACR), Osteoarthritis Research 
Society International (OARSI) and the European League against Rheumatism (EULAR) 
recommend the use of IA corticosteroids for short-term acute pain relief (ACR Subcommittee 
2000; Hochberg et al, 2012; Jordan et al, 2003). 
While historically OA has been considered a non-inflammatory disease, it is increasingly being 
recognized that chronic synovitis occurs in all stages of knee OA (Benito et al, 2005; Sellam and 
Berenbaum, 2010; Wenham and Conaghan, 2010).  As synovial inflammation is correlated with 
clinical symptoms and joint degeneration, it should be an important target for therapeutic 
intervention.  The inflamed synovium may well be the target for IA corticosteroids which are 
widely used in knee OA (Ayral et al, 2005). 
5.2. 
Background 
5.2.1. 
Investigational Medicinal Product:  FX006 
FX006 is an extended-release formulation of triamcinolone acetonide (TA) for IA administration 
that is being developed for the treatment of patients with pain attributed to OA of the knee.  
FX006 is intended to deliver TA to the synovial and peri-synovial tissues for a period of 
approximately 3 months depending on the dose administered (Bodick et al, 2013). 
FX006 contains TA, United States Pharmacopeia (Ph. Eur/USP), formulated in 75:25 
poly(lactic-co-glycolic acid) (PLGA) microspheres with a nominal drug load of 25% (w/w) and 
is provided as a sterile white  to off-white powder for reconstitution. The drug product is 
reconstituted with diluent containing an isotonic, sterile aqueous solution of sodium chloride 
(NaCl; 0.9% w/w), carboxymethylcellulose sodium (CMC; 0.5% w/w) and polysorbate-80 (0.1% 
w/w) to form a suspension prior to IA injection.   
Further details of the physiochemical properties of FX006 can be found in the Investigator’s 
Brochure (IB). 


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5.2.2. 
Rationale for FX006 in OA of the Knee 
Available clinical and nonclinical data indicate that FX006 is likely to be safe and well tolerated 
and has the potential to provide pain relief that is meaningfully better and more persistent than 
that provided by immediate release triamcinolone acetonide (TAcs).  Nonclinical data and the 
literature suggest that this potential could extend to limiting structural progression in patients 
with inflammatory joint disorders. The near term clinical development program for FX006 
focuses on the analgesic effects in patients with OA of the knee. 
5.2.3. 
Non-clinical  
The safety of FX006 was evaluated following single IA injection in one non-GLP rat toxicity 
study and two GLP-compliant dog toxicity studies, and following repeated IA injection in one 
GLP-compliant dog toxicity study.  In the repeat dose study, dogs were dosed once every 3 
months (1Q3M) for a total of 3 doses, or once every month (1Q1M) for a total of 3 doses); local 
and systemic (steroid target tissues) toxicity were assessed. 
The systemic effects of repeat IA administration of FX006 containing up to 18.75 mg of TA and 
75 mg of PLGA microspheres were consistent with known TA/corticosteroid affects and were 
similar for the 1Q3M and 1Q1M dose regimens.  Regarding local toxicity, at 1 month after the 
last dose following I.A. administration every 3 months (1Q3M), the only effect on cartilage 
observed at 1-month post-dose was loss of Safranin-O staining, reflecting reduced levels of 
glycosaminoglycan.  At 6-months post-dose, there were additional changes in the structure and 
cellularity of articular cartilage in both the TAcs and FX006 groups (in males only).  These 
effects are consistent with the known effects of corticosteroids in normal joints.  Occasional 
FX006-treated animals show slower recovery for cartilage changes compared to TAcs-treated 
animals, as expected based on the longer exposure to TA in the joints of these animals.  After 
monthly dosing (Q1M), small changes in structure and cellularity were present at 1-month post-
dose in both FX006 and TAcs groups, in addition to loss of Safranin-O staining.  This is 
consistent with the more intensive dosing regimen. By 6 months after the cessation of dosing 
there was clear evidence of recovery. Again, these effects are consistent with the known effects 
of corticosteroids in normal joints. 
A local foreign body tissue response was observed 1-month following repeated IA injection of 
FX006 or blank microspheres.  This effect was characterized by macrophage and multinucleated 
giant cell infiltration to the presence of the microspheres in the synovium.  The local foreign 
body response was partially or fully reversed by 6 months post dosing.  An increased incidence 
and/or intensity of lymphocyte and plasma cells, and minimal fibrosis were also observed in the 
blank microsphere and FX006 groups at 1 and 6 months post dosing.  Overall, these changes 
suggest a host tissue response, which is an expected reaction to PLGA products and is consistent 
with a foreign body response.  
Additional details on non-clinical pharmacology, pharmacokinetics (PK) and pharmacodynamics 
in animals and toxicology information for TA, PLGA, and FX006 can be found in Section 4 of 
the IB. 
5.2.4. 
Clinical Experience 
The clinical development of FX006 to date consists of eight completed studies (FX006-2011 
001, FX006-2011-002, FX006-2013-005, FX006-2014-006, FX006-2014-007, FX006-2014-008, 


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FX006-2015-009 and FX006-2015-010) conducted in patients with pain associated with OA of 
the knee. A brief summary of each study and data from the completed and fully analyzed studies 
is presented below. 
NOTE TO REVIEWER:  Subsequent to completion of the human pharmacology, efficacy, and 
safety studies reported herein (as of September 2017), extensive in-house testing was performed 
to assess the actual FX006 dose removed and delivered under the conditions of the dose 
preparation procedure.  This in-house testing determined that the FX006 delivered dose to the 
patient from an FX006 40 mg vial is 32 mg.  Hence, past clinical studies using a FX006 40 mg 
dose under the current resuspension conditions (5 mL of diluent) should be considered to have 
delivered a 32 mg dose of TA.  All future studies performed with FX006 from the date of 
Investigator’s Brochure Version 7.0 forward will reflect a 32 mg dose. 
Completed studies 
Study FX006-2011-001 was a Phase 2b, multi-center, randomized, double-blind, dose-ranging, 
active comparator study.  The primary objectives of this study were to assess the magnitude and 
duration of pain relief of a single 3 mL IA injection of FX006 (10, 40, or 60 mg) relative to 
40 mg of TAcs and assess the general tolerability of FX006.   
Study FX006-2011-002 was a Phase 2, double-blind, randomized, parallel-group, active 
comparator study.  The primary objectives of this study were to assess the safety and tolerability 
of a single 3 mL IA injection of FX006 (10, 40, or 60 mg), characterize the systemic PK profile 
of TA from FX006 relative to 40 mg of TAcs, and characterize the effects on the hypothalamic-
pituitary-adrenal (HPA) axis of FX006 relative to 40 mg of TAcs.   
Study FX006-2013-005 was a Phase 2, open-label, single administration study.  The objectives 
of this study were to characterize the local duration of exposure of TA and to assess the safety 
and general tolerability of a single 3 mL IA injection of FX006 (10 or 32 mg) relative to 40 mg 
of TAcs.   
Study FX006-2014-006 was a Phase 2b, multi-center, randomized, parallel group, dose-ranging 
study.  The primary objectives of this study were to assess the magnitude and duration of pain 
relief of a single 5 mL IA injection of FX006 (20 mg or 32 mg) relative to placebo (normal 
saline) and assess the safety and general tolerability of FX006.   
FX006-2014-007 was a prospective, double-blind, randomized, parallel-group, proof of concept, 
active comparator-controlled study. The primary objective of this study was to assess the 
analgesic effect of a single 5 mL IA injection of FX006 (32 mg) relative to 40 mg of TAcs 
(active control) in patients with moderately symptomatic post-traumatic osteoarthritis (PTOA) of 
the knee.  Due to the challenges of enrolling military personnel with PTOA, this study was 
discontinued early. 
Study FX006-2014-008 was a Phase 3, multi-center, double-blind, randomized, placebo- and 
active comparator-controlled study. The primary objective of this study was to assess the 
magnitude and duration of pain relief of a single 5 mL IA injection of FX006 (32 mg), relative to 
normal saline (placebo control) and 40 mg of TAcs (active comparator).   
Study FX006-2015-009 was a Phase 2, open-label, single administration study.  The objectives 
of this study were to characterize the local extent and duration of exposure of TA from FX006 
and TAcs, characterize the systemic PK of FX006 and TAcs, and assess the safety and general 


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tolerability of a single 5 mL IA injection of 32 mg FX006 relative to 40 mg of TAcs in patients 
with OA of the knee. 
Study FX006-2015-010 was a Phase 2, multi-center, double blind, randomized, parallel group 
study.  The primary objective of this study was the assessment of the effects of a single 5 mL IA 
injection of FX006 (32 mg) on blood glucose levels in patients with type 2 diabetes mellitus, 
relative to 40 mg of TAcs. 
5.2.5. 
Clinical Pharmacokinetics 
Overall, FX006 displayed a favorable plasma PK profile relative to TAcs. 
The PK observations in Study FX006-2015-009 resulted in a controlled and stable release of TA 
from PLGA microspheres into synovial tissues, where concentrations remained high relative to 
plasma concentrations for at least 12 weeks.  TA was absorbed systemically, with a plateau in 
plasma TA concentrations occurring in the first 24 hours post-dose, and slow elimination from 
the systemic circulation observed in the weeks thereafter.  
Relative to TAcs, FX006 32 mg produced substantially lower peak plasma and systemic 
exposure to TA. FX006 performed as expected, prolonging the residence of TA in the joint while 
minimizing systemic exposure to TA. 
5.2.6. 
Clinical Pharmacodynamics 
In Study FX006-2011-002, suppression of cortisol in the days following injection produced by 
the 10 and 40 mg dose of FX006 was less than that produced by injection of TAcs; the 60 mg 
dose of FX006 produced effects similar to TAcs 40 mg. Cortisol suppression subsequent to Day 
1-2 associated with all doses of FX006 would not be expected to be of clinical consequence in 
adult patients without otherwise comprised HPA axis function. 
In Study FX006-2015-010, treatment with FX006 32 mg resulted in a statistically significant 
(p=0.0452) reduction in blood glucose elevation relative to TAcs over a 72-hour period 
following IA injection. The time in glycemic target range (70-180 mg/dL) (American Diabetes 
Association, 2016) was greater for FX006 as compared to TAcs over the 48 hours post IA 
injection, providing another indication of the improvement in glycemic control. Over the entire 
time course of the 15-day post injection glucose monitoring period, blood glucose levels 
associated with FX006 remained at levels similar to or lower than those produced by TAcs. This 
observation is consistent with PK studies demonstrating low systemic exposure to TA associated 
with FX006. 
5.2.7. 
Clinical Efficacy 
5.2.7.1. 
Study FX006-2011-001 
In Study FX006-2011-001, a dose-ranging, active comparator trial of a single IA injection of 
FX006 in patients with OA of the knee: 
 The 40 mg dose of FX006 produced a statistically significant (p<0.05, 1-sided) and 
potentially clinically meaningful improvement in pain relief relative to TAcs between 
Weeks 5 and 10 and also demonstrated significant improvement over TAcs (p<0.05, 


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1-sided) at Week 8 in secondary outcomes that assessed pain, stiffness, function, 
PGIC, and CGIC. 
 The 60 mg dose did not provide additional benefit relative to the 40 mg dose of 
FX006. 
 The median time to onset of pain relief was similar across all treatments, occurring 1 
to 2 days following injection. (Bodick et al, 2015) 
5.2.7.2. 
Study FX006-2014-006 
In Study FX006-2014-006, a Phase 2b dose-ranging, placebo-controlled trial of a single IA 
injection of FX006 in patients with OA of the knee:  
 The 20 and 32 mg doses of FX006 achieved maximal analgesic effect of similar 
magnitude at Week 5 post-injection. A dose effect was evident in the maintenance of 
maximal effect, which persisted through Week 9 with FX006 20 mg and through 
Week 13 with FX006 32 mg. In secondary outcomes that assessed pain, stiffness, 
function, and Patient and Clinical Global Impressions of Change, 32 mg FX006 
demonstrated significantly better or trending better outcomes versus placebo at 
Weeks 4, 8, and 12. 
 The 32 mg FX006 dose was associated with rapid onset of action, larger magnitude of 
analgesic effect, and prolonged duration of action relative to placebo. 
5.2.7.3. 
Study FX006-2014-008 
In Study FX006-2014-008, a Phase 3 double-blind, randomized, single-dose study to assess the 
safety and efficacy of FX006 for the treatment of pain in patients with OA of the knee: 
 32 mg FX006 administered as a single IA injection provided more rapid onset of 
action, increased magnitude of analgesia, and prolonged duration of effect relative to 
placebo.  
 When compared to 40 mg TAcs, 32 mg FX006 was numerically superior at Weeks 2 
through 19 on the weekly mean of average daily pain (ADP) scores, although it did 
not achieve statistical significance, likely as a result of an unexpected loss of assay 
sensitivity in that measure. However, in pre-specified exploratory OA specific 
measures, compared to 40 mg TAcs, 32 mg FX006 achieved statistical significance 
through 12 weeks on WOMAC A (pain), WOMAC B (stiffness), and WOMAC C 
(function) and the validated KOOS QOL subscale.  
 A single IA injection of 32 mg FX006 was well tolerated, with systemic and local 
safety profiles generally similar to placebo and 40 mg TAcs 
5.2.8. 
Clinical Safety 
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 completed FX006 clinical studies are largely consistent.  


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 The number of treatment-emergent adverse events (TEAEs) reported was similar 
across groups (FX006 46.0%; placebo 49.2%; TAcs 51.0%). 
 The majority of TEAEs in FX006-treated patients were mild or moderate (Grade 1 or 
2).  Severe or life threatening events occurred in the FX006-treated patients at a rate 
of 3.0% as compared to 5.0% and 2.6% in the placebo and TAcs groups, respectively, 
 In the FX006-treated patients (n=687), the most common TEAEs were: 
 Arthralgia (in any joint) 9.8% (n=67) 
 Headache 5.4% (n=37) 
 Upper Respiratory Tract Infection 3.1% (n=21) 
 Joint swelling 2.8% (n=19) 
 Contusion and back pain 2.3% (n=16) 
 Nasopharyngitis 2.2% (n=15) 
 The rate of serious adverse events (SAEs) was low and consistent across groups 
(FX006 1.9%; placebo 1.1%; TAcs 2.3%); none were considered related to the study 
drug. 
 Across all studies there were no deaths.  
In Study FX006-2014-008, qualitative assessments based on X-rays of the index knee at 
24 weeks post injection included joint space narrowing (JSN), subchondral bone changes, 
osteonecrosis, and insufficiency fracture.  
 The overall rate of JSN worsening of at least 1-grade between baseline and Week 24 
was low and similar among treatment groups (5.0% [7/140], 4.1% [6/148], and 3.5% 
[5/145] of patients with both baseline and Week 24 X-rays in the FX006 32 mg, 
placebo, and TAcs groups respectively); for all but 1 of these 18 patients, JSN 
worsened by 1 grade only. The remaining patient (in the placebo group) had a 2-grade 
worsening in JSN (from 0 at baseline to Grade 2 at Week 24). 
 No FX006-treated patient had X-ray evidence of treatment-emergent insufficiency 
fracture, subchondral bone changes, or osteonecrosis at Week 24. 
 Eighteen patients discontinued the study prior to Week 24 and completed a final X-
ray as part of early termination visit. Of these, 2 patients, 1 in the FX006 32 mg group 
and 1 in the placebo group, had a 1-grade increase in JSN. There were no reports of 
insufficiency fracture, subchondral bone changes, or osteonecrosis. 
Please refer to the current Investigator’s Brochure for further safety details. 
5.2.9. 
Conclusion 
These data provide a strong rationale for further clinical study of FX006 and these data also 
provide the ethical basis for future clinical studies. 


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6. 
THESE DATA PROVIDE BASES FOR CONTINUED CLINICAL 
STUDY OF FX006.STUDY OBJECTIVES 
6.1. 
Primary Objective 
The primary objective of this study is to assess the overall safety and general tolerability of 
repeat administration of FX006 (two doses of 32 mg FX006) in patients with symptomatic OA of 
the knee. 
6.2. 
Exploratory Objective 
Exploratory objectives of this study include the following: 
 examine efficacy signals for sustained pain reduction following two doses of 32 mg 
FX006. 
 collect synovial fluid samples to enable potential future examination of synovial fluid 
biomarkers that may contribute to the pathogenesis of OA and/or be associated with 
responsiveness to FX006 treatment.   


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
This study is an open-label, repeat administration design of 32 mg FX006. The study will be 
conducted in male and female patients ≥ 40 years of age with symptomatic OA of the knee. 
Eligible patients will be offered participation to receive an initial IA injection of FX006 
administered to the index knee at Day 1 
Patients who receive an initial injection of FX006 will return at Weeks 4 and 8 before being 
evaluated at 12, 16, 20, and 24 weeks following the initial administration of FX006 for repeat 
administration.  At the first visit where the patient has been determined to meet repeat 
administration eligibility criteria described in Section 7.4.3, the patient will be eligible to receive 
a second IA injection of FX006 administered to the index knee.   
Patients who are eligible to receive a second injection will be evaluated for a total of 52 weeks 
post initial injection at: Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52, regardless of 
the visit at which they receive their second injection. 
Patients that do not benefit from the initial treatment as determined by evaluation at Week 12 
will complete the study at the Week 12 follow-up visit.  These patients will be evaluated for a 
total of 12 weeks post initial injection at: Weeks 4, 8, 12. 
Patients who are not eligible for a second injection of FX006 after evaluation at Weeks 12, 16, 
20, and 24 will complete the study at the Week 24 follow-up visit.  These patients will be 
evaluated for a total of 24 weeks post initial injection at: Weeks 4, 8, 12, 16, 20, and 24.   
Refer to Appendix 2 Study Visit Flow Chart. 
The study is expected to enroll over approximately 6 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 


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Injector/Aspirator  
 must be a medical doctor, a physician’s assistant, or nurse practitioner experienced in 
administering IA injections and performing synovial fluid aspirations of the index 
knee 
 is responsible for performing IA injections of study medication and synovial fluid 
aspirations of the index knee 
Assessor  
 must be a medical doctor, a physician’s assistant, or nurse practitioner 
 must have relevant OA experience 
 responsible for performing the physical examination and index knee assessments and 
assessing causality of an adverse event (AE) or SAE. 
The same individual may serve in multiple roles (e.g., a physician sub-investigator may serve as 
both the Injector/Aspirator and/or Assessor). 
7.3. 
Discussion of Study Design 
7.3.1. 
Rationale for Study Population 
Patients with pain associated with OA of the knee as defined by clinical and radiologic criteria 
that are otherwise in good health or that have chronic conditions (for example, hypertension) that 
are well controlled are included.  In general this population tolerates IA injections of 
commercially available corticosteroids (Habib 2009).  In prior clinical studies of FX006 in this 
population, single injections of up to 60 mg of FX006 were well tolerated. 
7.3.2. 
Rationale for Dose Selection 
The rationale supporting dosing at this level couples nonclinical data summarized in the 
Investigator Brochure (Section 4), and clinical experience with FX006.  In study FX006-2011-
001, the prior dose-ranging study that included 10, 40, and 60 mg doses of FX006 and TAcs 
(e.g., Kenalog®-40 Injection), a dose response was evident between 10 and 40 60 mg doses over 
the entire 12 weeks of therapy. At no point in the course of therapy did the 60 mg dose provide 
additional improvement relative to the 40 mg dose. Thus, it was assumed that the minimum dose 
to achieve maximal efficacy was >10 and ≤40 mg.  As well, 40 mg FX006 has been shown to be 
well tolerated in previous single dose clinical trials. 
7.3.3. 
Rationale for Study Design 
Evidence from non-clinical repeat dose studies, the overall safety profile of 32 mg FX006 being 
well tolerated and the common practice of repeating corticosteroid injections support the 
evaluation of repeat administration of 32 mg FX006.   
7.3.4. 
Rationale for Study Parameters 
The clinical safety parameters to be assessed (adverse events, physical examinations, index knee 
examinations, index knee X-rays, vital signs, and clinical laboratory evaluations) are standard 


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safety and tolerability assessments and support the clinical monitoring necessary based on the 
toxicology profile for FX006. 
The efficacy parameters to be assessed are recommended outcome measures for the assessment 
of chronic pain (Dworkin et al, 2005). 
7.4. 
Selection of Study Population 
7.4.1. 
Number of Patients 
Approximately 200 patients will be enrolled to ensure that at least 100 patients receive two doses 
of FX006 and complete the study through Week 52.  
7.4.2. 
Screening Criteria 
7.4.2.1. 
Screening Inclusion Criteria 
To be included in the trial, patients must fulfill the following criteria:  
1. Written consent to participate in the study 
2. Willingness and ability to comply with the study procedures and visit schedules and 
ability to follow verbal and written instructions 
3. Male or female 40 years of age 
4. Symptoms associated with OA of the index knee for ≥ 6 months prior to Screening 
(patient self-report is acceptable)   
5. Currently meets ACR Criteria (clinical and radiological) for OA (Altman et al, 1986) as 
follows:  
 Knee pain 
 at least 1 of the following: 
o Age > 50 years 
o Stiffness < 30 minutes 
o Crepitus 
 Osteophytes  
6. Kellgren-Lawrence (KL) Grade 2, 3 or 4 in the index knee based on X-ray performed 
during Screening (locally read) 
7. WOMAC A total sum score of ≥ 6 at Screening and Day 1/Baseline 
8. Index knee pain for >15 days over the last month (as reported by the patient) 
9. If bilateral OA exists, pain in the contralateral knee must be less than pain in the index 
knee as reported by the patient 
10. Body mass index (BMI) ≤ 40 kg/m2s 
11. Ambulatory and in good general health  


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12. Willingness to abstain from use of the following protocol-restricted medications during 
the study: 
 Intravenous (IV), intramuscular (IM), and oral corticosteroids (Note: inhaled, 
intranasal, and topical corticosteroids are allowed) 
 IA corticosteroids in any joint 
 IA viscosupplementation (hyaluronic acid) or any IA intervention (IA injection, IA 
aspiration, etc.) in the index knee 
 Opiates  
 Any investigational drug, device, or biologic 
 Immunomodulators, immunosuppressives, or chemotherapeutic agents  
 Live or live attenuated vaccines 
7.4.2.2. 
Screening 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 knee joint 
3. Clinical signs and symptoms of active knee infection or crystal disease of the index knee 
within 1 month of Screening 
4. Presence of surgical hardware or other foreign body in the index knee 
5. Unstable index knee joint (such as a torn anterior cruciate ligament) within 12 months of 
Screening 
Previous or concomitant treatment-related criteria 
6. IA corticosteroid (investigational or marketed) in index knee within 3 months of 
Screening  
7. IA hyaluronic acid (investigational or marketed) in the index knee within 6 months of 
Screening 
8. IV or IM corticosteroids (investigational or marketed) within 3 months of Screening 
9. Oral corticosteroids (investigational or marketed) within 1 month of Screening 
10. Any other IA drug/biologic use within 6 months of Screening or 5 half-lives (whichever 
is longer) (e.g., platelet rich plasma (PRP) injection, stem cells, prolotherapy, and 
amniotic fluid injection) 
11. Prior administration of FX006  


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12. Prior arthroscopic or open surgery of the index knee within 12 months of Screening 
13. Planned/anticipated surgery of the index knee during the study period 
Patient-related criteria 
14. Known hypersensitivity to any form of triamcinolone 
15. History of sarcoidosis or amyloidosis  
16. Active or history of malignancy within the last 5 years, with the exception of resected 
basal cell carcinoma, squamous cell carcinoma of the skin, or effectively managed 
cervical carcinoma 
17. Known active or quiescent systemic fungal, bacterial, mycobacterial (including 
tuberculosis), viral or parasitic infections, or, shingles, herpes zoster, and ocular herpes 
simplex  
18. Any infection requiring IV antibiotics within 4 weeks of Screening or oral antibiotics 
within 2 weeks of Screening 
19. History of osteomyelitis 
20. Known or clinically suspected infection with human immunodeficiency virus (HIV), 
hepatitis B or C viruses 
21. Any clinically significant electrocardiogram (ECG) abnormality as judged by the 
Investigator 
22. Patients requiring or likely to require chronic treatment with corticosteroids during the 
study period based on patient medical history 
23. History of or active Cushing’s syndrome 
24. Active substance abuse (drugs or alcohol), history of chronic substance abuse within the 
past year, or prior chronic substance abuse judged by the investigator as likely to recur 
during the study 
25. Skin breakdown at the knee where the injection would take place 
26. Women who are pregnant or nursing or plan to become pregnant during the study; men 
who plan to conceive during the study 
27. Women of child-bearing potential (not surgically sterile or post-menopausal for at least 1 
year as documented in medical history) not using a 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 
male sterilization (vasectomy)] 
28. Use of immunomodulators, immunosuppressives, or chemotherapeutic agents within 5 
years of Screening  
29. Has received a live or live attenuated vaccine within 3 months of Screening 


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30. Use of any other investigational drug or device within 30 days of Screening or within 5 
half-lives (whichever is longer) or an investigational biologic within 60 days of Screening 
or within 5 half-lives (whichever is longer) 
31. 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 
7.4.3. 
Repeat Administration Criteria 
Patients who receive an initial injection of FX006 must meet the following criteria in order to 
receive a repeat administration. 
7.4.3.1. 
Repeat Administration Inclusion Criteria 
To be eligible to receive a repeat administration, patients must fulfill the following criteria:  
1. Benefit from the initial dose of FX006 in the opinion of both the patient and the 
Investigator 
2. No major safety concerns during the initial dose period as assessed by the Investigator 
3. Clinically indicated to receive a second dose of FX006 in the opinion of both the patient 
and the Investigator 
4. WOMAC A total sum score of ≥ 6 or a clinical rationale as to why a second dose is 
indicated 
5. Compliant with study procedures and visit schedules through at least Week 12 and the 
willingness and ability to continue to comply through Week 52  
6. Willingness to abstain from use of protocol-restricted medications during the study  
7.4.3.2. 
Repeat Administration Exclusion Criteria 
Patients fulfilling at least one of the following criteria may not receive repeat administration: 
1. Clinical signs and symptoms of active knee infection or crystal disease of the index knee  
2. Received a non-protocol specified IA intervention (IA injection, IA aspiration, etc.) in 
index knee during study participation 
3. Use of immunomodulators, immunosuppressives, or chemotherapeutic agents during 
study participation 
4. Received a live or attenuated vaccine during study participation 
5. Use of any other investigational drug, device, or biologic during study participation 
6. Allergic reaction to initial dose of FX006 
7. Any infection requiring IV antibiotics within 4 weeks or oral antibiotics within 2 weeks 
of second dose of FX006 
8. Skin breakdown at the knee where the injection would take place 


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9. Women who are pregnant or nursing or plan to become pregnant during the study; men 
who plan to conceive during the study 
10. Women of child-bearing potential (not surgically sterile or post-menopausal for at least 1 
year as documented in medical history) not using a 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 
male sterilization (vasectomy)] 
11. 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. 
Removal of Patients from Therapy or Assessments 
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 complete the study assessments defined for the Early Termination Visit* 
2. determine whether the patient is willing to be contacted to follow ongoing or new AEs 
through Week 12 for patients who only receive a single injection, or through Week 52 for 
patients who receive a second injection (if reason for discontinuation is not “withdrew 
consent”) and contact patient as necessary (via phone or in-person). Concomitant 
medications associated with any AE will also be captured. 
3. document patient consent in the source document for continued follow-up 
*Note: Early Termination visits should follow the Week 52 visit schedule  
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. 
7.4.5. 
Screen Failures 
Minimal data for patients who fail screening, such as demographic information and the reason 
for screen failure will be collected. 
Patients who 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.   


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7.5. 
Treatment Administered 
7.5.1. 
Study Medication Treatment Arms 
Investigational Medicinal Product Arm:  
FX006 – extended-release formulation of TA formulated in in 75:25 PLGA microspheres. 
Nominal 32mg TA, administered as a single 5 mL IA injection 
Reference Compound: 
Not applicable 
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. 
Receipt, Dispensing, and Storage 
Study medication will be shipped to the site from the drug supply distribution center as a 
packaged kit.  Receipt and dispensation of study medication will be properly documented within 
the Drug Tracking Module. Any temperature excursions should be documented in the Drug 
Tracking Module for Sponsor assessment and authorization for continued use. 
The packaged kits will be stored in a secure area and will be stored refrigerated at 2 to 8°C. 
7.5.4. 
Packaging and Labeling of Study Medication 
The packaged kit 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.    
7.5.5. 
Return of Study Medication 
All study medications (packaged kits /used and unused vials) will be returned to the Sponsor.  
Return of study medications will be properly documented. 
7.5.6. 
Method of Assigning Patients to Treatment Groups 
This is a single-arm, open-label study.  All eligible patients will receive one or two doses of 
FX006.  


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7.5.7. 
Blinding 
This is an open-label study. 
7.5.8. 
Intra-articular Injection Procedure 
IA injections will be performed by the assigned injector.  The injector may choose the position of 
the knee (e.g., extended or flexed), the approach for the injection (e.g., medial or lateral) and the 
numbing agent to be used (e.g., ethyl chloride, subcutaneous lidocaine; IA anesthetics are not 
allowed) based on standard of care. Sterile technique should be used.   
Prior to injection, the index knee should be thoroughly cleansed using a bactericidal solution.  
The index knee will be aspirated in all cases prior to administration of study medication.  
Following attempted aspiration, 5 mL of the reconstituted FX006 will be injected into the 
synovial space.  Refer to the Pharmacy Binder for detailed instructions on how to prepare 
FX006.  
The same needle used for IA injection of the study medication may also be used for synovial 
fluid aspiration, thereby allowing for a single injection with syringe replacement.  The injector 
will use a 21 gauge or larger needle for injection and aspiration of fluid. 
Patients should be advised to avoid strenuous activities or prolonged weight-bearing activities for 
approximately 24 to 48 hours following the injection and to also maintain a stable lifestyle with 
regard to physical activity throughout the duration of the study. 
In the event that the patient has an immediate reaction (e.g., tenderness, increased pain, swelling, 
effusion, decreased mobility of the index knee), the patient should be treated according to local 
clinical guidelines and physician experience (see also Protocol Section Section 8.1.5). 
7.5.9. 
Treatment Compliance 
Study medication will be administered by the injector in the clinic.  Details regarding study 
medication administration will be documented in the electronic Case Report Form (eCRF).  The 
receipt, dispensation, and return of any study medication will be properly documented. 
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. 
7.6. 
Prior and Concomitant Therapy 
During the study, all existing (prior to study entry), new, or changes in concomitant medications 
and the associated reasons for use or change will be documented and reported. 
7.6.1. 
Allowable Medications/Therapies 
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 as restricted below 
 Physical therapy for index knee 
 Bracing of index knee 


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7.6.2. 
Restricted Medications 
The exclusion criteria indicate that a patient may not be enrolled if he/she has used any of the 
following within the specified windows detailed in the Exclusion criteria (Section 7.4.2.2).  In 
addition these medications should not be taken or used throughout the study:   
 IV, IM, or oral corticosteroids (Note: inhaled, intranasal, and topical corticosteroids 
are allowed) 
 IA corticosteroids in any joint 
 IA viscosupplementation (hyaluronic acid) or any IA intervention (IA injection, IA 
aspiration, etc.) in the index knee 
 Opiates  
 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 knee assessments, vital signs, and clinical laboratory evaluations.  In 
addition the index knee will be evaluated by X-ray and assessed by a central imaging vendor for 
joint space narrowing, chondrolysis, subchondral bone changes, bone infarcts, avascular 
necrosis, joint swelling, and insufficiency fracture.  
7.7.2. 
Exploratory Efficacy Variables 
 Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index (Likert 
(LK) 3.1, 5-point scale): pain, stiffness and function domains independently and 
collectively (Bellamy et al, 1988).  
 Knee injury and Osteoarthritis Outcome Score (KOOS) Quality of Life (QOL) 
Subscale (http://www.koos.nu/). 
 Daily activity measured as steps per day. 
 Global Physical Activity Questionnaire (GPAQ) domains for occupational physical 
activity, transport-related physical activity, and physical activity during discretionary 
or leisure time (http://www.who.int/chp/steps/GPAQ/en/ ) 
7.7.3. 
Pharmacodynamic Variables 
Synovial fluid samples will be preserved for potential future analyses of biomarkers that may 
contribute to the pathogenesis of OA and/or be associated with responsiveness to FX006 
treatment.   


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7.8. 
Schedule of Study Assessments 
A summary of the schedule of 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 
Screen1 
 
Baseline 
Day 1 
Week 
42 
Week 
82 
Week 
12, 16, 20, 242 
Week 
28, 32, 36, 40, 44, 482 
Week 
522/End of Study 
Informed consent 
X3 
 
 
 
 
 
 
Inclusion/Exclusion Review 
X 
X4 
 
 
 
 
 
Medical History/Update 
X 
X4 
 
 
 
 
 
OA Medical History 
X 
 
 
 
 
 
 
Prior Treatment & Medications  
X5 
X4 
 
 
 
 
 
Physical Examination 
X 
 
 
 
X6 
 
X 
Index Knee X-ray7 
X 
 
 
 
 
 
X8 
Index Knee Assessment9 
X 
X4 
 
 
X6 
 
X 
12-Lead ECG 
X 
 
 
 
 
 
 
Vital Signs 
X 
X4 
 
 
X6 
 
X 
Height 
X 
 
 
 
 
 
 
Weight and BMI  
X 
 
 
 
 
 
X 
Hematology & Chemistry10 
X 
 
 
 
X6 
 
X 
HIV, Hepatitis B/C10 
X 
 
 
 
 
 
 
Serum Pregnancy Test10,11 
X 
 
 
 
 
 
 
Urine Pregnancy Test9,10, 11 
 
X4 
 
 
X6 
 
X 
WOMAC12 
X 
X4 
X 
X 
X 
X 
X 
KOOS QOL12 
 
X4 
X 
X 
X 
X 
X 
GPAQ13 
 
X4 
 
 
X13 
 
 
Measured Function Device14 
--------------------------------------X-------------------------------------- 
 
 
Index knee aspiration and collection 
of synovial fluid 
 
X4 
 
 
X15 
 
 
1st treatment administration 
 
X 
 
 
 
 
 
Evaluation for repeat administration 
 
 
 
 
X 
 
 
2nd (repeat) treatment administration 
 
 
 
 
X16 
 
 
AEs & ConMeds17 
 
---------------------------------------------------X--------------------------------------------------- 
                                                 
1 Screening period is a minimum of 7 days, up to 21 days. 
2 Visit should be conducted within +/- 7 days from scheduled date. 
3 Consent must be obtained prior to any study-specific procedures. 
4 Complete assessment prior to dosing. 
5 Record any prior medications received within 30 days prior to the Screening visit. 
6 To be completed prior to dosing only if patient is to receive the 2nd dose of FX006. For patients not eligible to receive 2nd dose, complete at the 
final study visit. 
7 Standing, fixed flexion PA view, weight bearing X-ray of the index knee will be taken using a standardized knee positioning device.  The 
Screening X-ray will be read locally for K-L grade.  The Screening and Week 52 X-rays will be sent to central imaging vendor for safety 
assessment. 
8 End of Study x-ray will only be performed if patient has received a repeat administration of FX006. 
9 Index knee will be assessed for tenderness, heat/redness, swelling, effusion, and Baker’s cyst. New clinically significant findings or findings that 
worsen for the patient’s baseline condition should be recorded as AEs. 
10 Via Central Laboratory. 
11 Conduct for women of childbearing potential only. 
12 Patient questionnaires to be completed prior to all other assessments. 
13 Complete GPAQ at Week 12 only regardless of when and if second dose is given. 
14 Steps per day will be captured using a measured function device.  Patients will be provided with a device at the Screening visit to be worn for at 
least 7 days prior to Baseline/Day 1 through Week 12. The site will confirm patient compliance with wearing the device to capture steps per 
day data at each patient visit from Day 1 through Week 12. 
15 To be completed prior to dosing only if patient is to receive the 2nd dose of FX006. 
16 Repeat administration may occur at either Week 12, 16, 20, or 24. 
17 AEs and Concomitant Medications will be captured from Day 1 (post injection) to Week 12 or 24 for patients who only receive a single 
injection or to Week 52 for patients who receive a second injection or to Early Discontinuation Visit for patients who discontinue the study 
early. 


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7.9. 
Study Procedures 
7.9.1.1. 
Informed Consent 
Prior to initiation of any study related procedures, patients will review and sign the study’s 
informed consent form 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. 
7.9.2. 
Review of Eligibility, Medical History, Prior Treatment, and Medications 
Eligibility criteria (inclusion and exclusion criteria), medical history (including OA history), 
prior treatment and medications are reviewed during screening and again at Baseline/Day 1. 
OA medical history includes ACR diagnosis details, OA diagnosis date (if available), K-L grade 
(See Appendix 1), number of days with index knee pain in the last month, and previous IA 
steroid or hyaluronic injections.  
7.9.3. 
Physical Examination 
The physical exam will assess the following body systems:  
1. General Appearance 
2. Skin 
3. Lymphatics 
4. HEENT (head, ears, eyes, nose, throat) 
5. Cardiovascular 
6. Respiratory 
7. Abdominal 
8. Musculoskeletal 
9. Neurological  
Any clinically significant findings 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 baseline at one of 
the post-baseline visits. 
7.9.4. 
Index Knee X-ray 
A diagnostic quality X-ray of the index knee is required (standing, fixed flexion PA view; 
weight-bearing; use of standardized knee positioning device is required) at Screening and Week 
52 (for patients that receive a second injection). The Screening X-ray will be read locally for K-L 
grading by a radiologist or clinician with rheumatology or orthopedic specialty.  In addition, the 
Screening and Week 52 X-rays will be sent to the central imaging vendor for safety assessments. 
An image acquisition protocol will be distributed to sites with simple instructions for radio-
anatomic positioning for reliable grading. 


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7.9.5. 
Index Knee Assessment 
The index knee assessment will be performed by the designated assessor at the days indicated in 
Table 1.  The index knee will be assessed for tenderness, heat/redness, swelling, effusion, and 
Baker’s cyst.  If there is a clinically significant finding outside of the patient’s typical disease 
state at the Screening or Baseline Visit, add to the Medical History.  At time points post-baseline, 
if there are new clinically significant findings outside of the patient’s typical disease state or 
findings that worsen from the patient’s baseline condition, record as AEs. 
7.9.6. 
12-lead ECG 
At Screening, a 12-lead ECG will be obtained in the supine position.   Measures of heart rate, PR 
interval, RR interval, QT interval, QTc (corrected for Bazett’s or Fridericia’s) interval and QRS 
duration will be obtained.  If QTc > 450 msec for male patients or > 470 msec for female 
patients on the first 10-second 12-lead ECG recording, two additional 10-second 12-lead ECG 
recordings must be collected approximately 1 minute 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 Table 1. 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 Table 1.   Height will be measured 
in centimeters or inches. Weight will be measured in kilograms or pounds. BMI will be 
calculated using the formulas in Table 2 (reference: www.cdc.gov): 
Table 2: 
BMI Calculations 
Measurement Units 
Formula and Calculation 
Kilograms and meters (or 
centimeters)  
Formula: weight (kg) / [height (m)]2 
With the metric system, the formula for BMI is weight in kilograms divided by 
height in meters squared. Since height is commonly measured in centimeters, divide 
height in centimeters by 100 to obtain height in meters. 
Example: Weight = 68 kg, Height = 165 cm (1.65 m) 
Calculation: 68 ÷ (1.65)2 = 24.98 
Pounds and inches 
Formula: weight (lb) / [height (in)]2 x 703  
Calculate BMI by dividing weight in pounds (lbs) by height in inches (in) squared 
and multiplying by a conversion factor of 703. 
Example: Weight = 150 lbs, Height = 5'5" (65") 
Calculation: [150 ÷ (65)2] x 703 = 24.96 


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7.9.9. 
Central Clinical Laboratory Evaluations 
Blood samples will be taken at the days indicated in the Table 1.  The specific laboratory panels 
to be run can be found in Table 3.  Follow the Central Laboratory Manual for detailed sample 
collection, handling, storage, and shipping instructions. 
Table 3: 
Clinical Laboratory Panel 
HEMATOLOGY 
CLINICAL CHEMISTRY  
Hemoglobin 
Sodium  
Hematocrit  
Potassium  
Erythrocyte count (RBC) 
Bicarbonate  
Mean cell volume 
Chloride  
Leukocytes (WBC)  
Calcium   
Absolute counts of:  
Total bilirubin  
 Neutrophils  
Alkaline phosphatase  
 Lymphocytes  
Alanine aminotransferase  
 Monocytes  
Aspartate aminotransferase  
 Eosinophils  
Blood urea nitrogen 
 Basophils  
Creatinine  
 Platelets 
Uric acid  
INFECTIOUS DISEASES 
Total protein  
Hepatitis B Surface Antigen 
Albumin  
Hepatitis C Antibody 
Glucose 
HIV  
 
SERUM PREGNANCY TEST (women of 
child-bearing age only) 
 
URINE PREGNANCY TEST (women of 
child-bearing age only) test provided by 
central laboratory but read locally 
 
 
7.9.10. 
Patient Questionnaires 
The following questionnaires will be completed by patient prior to all other assessments 
scheduled for the visit day at the days indicated in Table 1.  
 WOMAC LK 3.1 
 KOOS - Quality of Life Subscale (Q1-Q4)     
 GPAQ 
7.9.11. 
Daily Activity  
Steps per day will be captured using a measured function device.  Patients will be provided with 
a device at the Screening visit to be worn for at least 7 days prior to Baseline/Day 1 through 
Week 12. The site will confirm patient compliance with wearing the device to capture steps per 
day data at each patient visit from Day 1 through Week 12.  


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7.9.12. 
Synovial Fluid Aspiration 
Synovial fluid samples for potential future biomarker evaluation will be obtained from all 
patients via aspiration on Baseline/Day 1 prior to study medication administration and the week 
at which the second dose is administered prior to study medication administration (if the patient 
is eligible to receive a second dose).  Patients that are not eligible to receive a second dose will 
not have synovial fluid drawn at their final study visit.  The injector/aspirator will attempt to 
aspirate synovial fluid from the index knee using sterile technique.  The volume of the synovial 
fluid obtained will be recorded in the eCRF. If no synovial fluid is obtained then 0 mLs should 
be recorded.  Procedures for sample collection, handling, storage and shipment will be described 
in the Study Laboratory Manual.  The synovial fluid samples will be preserved for potential 
future analyses of biomarkers that may contribute to the pathogenesis of OA and/or be associated 
with responsiveness to FX006 treatment.       
7.9.13. 
Treatment Administration 
At Baseline/Day 1 and the week at which the second dose is to be administered (if the patient is 
eligible to receive a second dose), the following will occur: 
 Study medication will be prepared by the pharmacist/coordinator (Refer to the 
Pharmacy Binder for instructions on how to prepare FX006).   
 Synovial fluid will be aspirated from the index knee just prior to administration of 
study medication (refer to Section 7.9.12 for more details of the synovial fluid 
aspiration).   
 The injector/aspirator will perform the IA injection of the study medication (refer to 
Section 7.5.8 for instructions).   
7.9.14. 
Review of Adverse Events and Concomitant Medications 
After receiving study medication, the patient will be monitored for any AEs.  Review of any 
Concomitant Medications will also be performed and documented in source documentation.  
Refer to Section 8.1 for further information in regard to reporting of AEs.  Refer to Section 7.6 
for further information in regard to allowed and restricted concomitant medication. 


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8. 
CLINICAL SAFETY ASSESSMENTS   
Safety evaluations will be based on the assessment of AEs occurring after the initiation of study 
medication on Day 1 through the last study visit.  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 patient 
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, 
o This serious criterion applies if the patient’s death is a direct outcome of a 
reported AE. 
 Is life-threatening, 
o This serious criterion refers to an event in which the patient was at substantial risk 
of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe.   
 Requires inpatient hospitalization or prolongation of existing hospitalization, 
o This serious criterion applies if the reported AE requires at least a 24-hour 
inpatient hospitalization or, if in the opinion of the Principal Investigator, 
prolongs an existing hospitalization.  A hospitalization for an elective procedure 
or a routinely scheduled treatment is not an SAE by this criterion because a 
“procedure” or a “treatment” is not an untoward medical occurrence. 


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 Results in permanent or significant disability/incapacity, or 
o This serious criterion applies if the “disability” caused by the reported AE results 
in a substantial disruption of the patient’s ability to carry out normal life 
functions. 
 Is a congenital anomaly/birth defect. 
o This serious criterion applies if a patient exposed to a medicinal (investigational) 
product gives birth to a child with congenital anomaly or birth defect. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above.  These should 
also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or 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 
an assessor. 
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).   


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For AEs not listed in the CTCAE, the following definitions should be used: 
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 patient’s clinical state or by other modes of therapy administered to 
the patient. 
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 patient’s clinical state. 
5.  Definitely Related: The reaction follows a reasonable temporal sequence from 
administration of study medication; that follows a known or expected 


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response pattern to the study medication; and that is confirmed by 
improvement on stopping or reducing the dosage of the study 
medication, and reappearance of the reaction on repeated exposure. 
If discernible at the time of completing an AE eCRF, a specific disease or syndrome rather than 
individual associated signs and symptoms should be identified by the Investigator and recorded 
on the appropriate AE eCRF.  However, if an observed or reported sign, symptom, or clinically 
significant laboratory anomaly is not considered by the Investigator to be a component of a 
specific disease or syndrome, then it should be recorded as a separate AE on the appropriate AE 
eCRF. 
8.1.3. 
Reporting of Serious Adverse Events 
When an SAE occurs, the Investigator or designee must log into the electronic data capture 
(EDC) system and complete the SAE Report form within 24 hours of first becoming aware of the 
SAE. The SAE will automatically be reported to the Medical Monitor or designee electronically.   
Follow-up information relating to a SAE must be reported to the Medical Monitor within 24 
hours of receipt by the Investigator by entering new information into the electronic SAE form. 
The updated SAE will automatically be reported to the Medical Monitor or designee 
electronically. 
If one is unable to log into the EDC system, the SAE hotline may be contacted (information 
located in the Investigator Site File in the Study Contact list). 
All SAEs that occur at a given site should, in addition, be reported by the Investigators to the 
responsible IRB/EC without undue delay, if applicable according to IRB/EC requirements. 
During the conduct of the study, the Sponsor will provide expedited safety reports (AEs 
classified as serious, unexpected and at least possibly related to investigational product) to the 
investigative sites as notification of new safety findings.  If this occurs, the investigative site 
must report the information to their IRB/EC per local guidelines (may be submitted by the 
Sponsor or designee for sites that use a central IRB). 
8.1.4. 
Safety Monitoring Roles 
The site personnel will carefully monitor each patient throughout the study for possible AEs.  All 
AEs will be documented on the eCRF designed specifically for this purpose, and will be 
followed until either completely resolved or until a stable chronic outcome is determined by the 
Principal Investigator.  SAEs will be reported in accordance with Section 8.1.3. 
The Medical Monitor must promptly review all information relevant to the safety of an 
investigational new product received from any source.  The Medical Monitor will also review 
alert laboratory results in real time and will contact Investigators as needed to ensure that issues 
are managed in an appropriate manner. 
The medical monitor and the Sponsor will review safety data approximately on a quarterly basis, 
accessed through the EDC system and associated reporting tools, in order to identify potential 
safety issues/trends that may not be apparent through individual AE reporting.  If systematic 
review identifies a pattern of concern, Sponsor will take steps to address the issues including, but 


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not limited to, modifying the protocol and/or notifying investigator, authorities and 
IRB/ECs.  Each review will be documented and filed in the Trial Master File.  
8.1.5. 
Clinical Management of Index Knee-related Events 
In the event that the patient has an immediate reaction following administration of study 
medication or returns to the clinic with an acute exacerbation (e.g., tenderness, increased pain, 
swelling, effusion, decreased mobility of the index knee), the patient should be treated according 
to local clinical guidelines and physician experience.   
If the index knee is aspirated at any time after administration of study medication for any reason, 
the volume of synovial fluid aspirated must be documented, synovial fluid should be (1) 
cultured, (2) evaluated for presence of crystals, and (3) assessed for white cell count at a local 
laboratory, and the results should be documented.   
Any event that is a change from the patient’s baseline status (new or worsening case) should be 
reported as an AE and those meeting the definition of serious must be reported in accordance 
with Section 8.1.3. 
8.1.6. 
Pregnancy 
All pregnancies occurring during the study will be reported in the same timeframe as SAEs. All 
reports of pregnancy, including male patients who conceive, must be followed for information 
regarding the course of the pregnancy and delivery, as well as the condition of the newborn.  
Follow-up information concerning the outcome of the pregnancy should be provided to the 
Sponsor in a timely manner.  Additional follow-up is not needed when a newborn baby is 
healthy.            


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical and Analytical Plans 
A comprehensive statistical analysis plan (SAP) will be written and approved prior to database 
lock for this study that describes the final analyses to be completed for safety and exploratory 
efficacy endpoints. 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, along with an 
explanation as to why they occurred, in the Clinical Study Report (CSR). The key aspects of 
those analyses are summarized below. 
9.1.1. 
Interim Analysis 
No formal interim analysis is planned for the primary safety endpoints in this open-label study to 
assess the safety and tolerability of FX006 after repeat administration.  However, interim 
analysis may be conducted with exploratory endpoints to examine efficacy signals following 
administration of one or two doses of 32mg FX006. These interim analyses on exploratory 
endpoints may be completed for data review, regulatory updates, and/or publication (or 
presentation at congresses) for this open-label study. Any interim analysis completed will have 
an interim analysis plan written and approved to describe the purpose and analytical objectives of 
the interim analysis.  Final analyses, described in the protocol and statistical analysis plan, will 
be conducted after completion of the study, when all subjects have either discontinued the study 
early (prior to Week 52) or completed the study through Week 52. 
9.1.2. 
Final Analyses 
All final analyses will be completed following database lock. Final analyses specified in the 
protocol and SAP will be completed and reported in the CSR. Interim analyses conducted with 
exploratory endpoints to examine efficacy signals prior to database lock will also be reported in 
the final CSR. Post-hoc, or additional exploratory analyses, not defined in the SAP may be 
completed to further understanding and elucidation of the study results. Any post-hoc, 
exploratory, analyses completed will be clearly identified as such in the final CSR.  
9.2. 
General Considerations and Methods 
Data collected in this study will be presented using summary tables, figures, and patient data 
listings.  Summary tables will present data by treatment group and, if applicable, by time of 
collection.  Continuous variables will be summarized using descriptive statistics, specifically the 
number of patients (n), the mean, median, standard deviation, minimum and maximum, and 
coefficient of variations (%CV).  Categorical variables will be summarized by frequencies and 
percentages.  Confidence intervals will be provided where appropriate for derived endpoints.  
Figures will be used to support the presentation of certain data.  Sensitivity analyses may be 
performed to examine the effect of missing data, as well as the effect of Baseline imbalance for 
secondary endpoints. 
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 
multiple comparisons in the exploratory efficacy endpoint analyses. 


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9.2.1. 
Analysis Populations 
Three main analysis populations are planned for this study as follows: 
 Safety Population: All patients who received study medication. The Safety Population 
will be used to assess safety and tolerability for the primary endpoint. 
 FAS Population: All patients who received study drug and provide at least one post-
baseline efficacy endpoint assessment. The FAS population will be used to examine 
exploratory efficacy endpoints. 
 Biomarker Population: All patients who received study medication and provide at 
least one synovial fluid sample for biomarker analysis.  
During the course of this study interim analyses may be completed to examine efficacy signals. 
Populations utilized for those interim analyses will be clearly defined in an interim analysis plan, 
and in the final CSR. 
9.2.2. 
Study Data 
Study data identified in this protocol are to be collected, and source verified, on 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. Observed study data 
will be mapped to the Clinical Data Interchange Standards Consortium (CDISC) Study Data 
Tabulation Model (SDTM) and serve as the source data from the trial. All study analyses will be 
completed using analysis data sets that are derived from the SDTM and follow the CDISC 
Analysis Data Model (ADaM) architecture. 
9.2.2.1. 
Clinical Data – CDISC Study Data Tabulation Model (SDTM) 
Domains will be mapped to CDISC SDTM version 3.2. No derived data required for analysis are 
included in the SDTM domains. All SDTM domains will be fully documented with define 
documents (DEFINE.XML) and a Study Data Reviewer’s Guide (SDRG) after database lock and 
final analyses are completed. 
9.2.2.2. 
Analysis Data – CDISC Analysis Data Model (ADaM) 
All planned and exploratory analyses will be completed using CDISC compliant ADaM data sets 
derived from the SDTM domains for this study. Analysis data sets will contain all derived study 
endpoints required for analysis. All ADaM analysis data sets will be fully documented with 
define documents (DEFINE.XML) and an Analysis Data Reviewer’s Guide (ADRG) after 
database lock and final analyses are completed. 
9.2.3. 
Study Variables for Assessment 
Please refer to Section 7.7.1 for study variables for the primary safety endpoint.  
9.2.4. 
Sub-Groups and Covariates 
No pre-planned sub-groups are identified for this study. Sub-groups may be defined for interim 
analyses of exploratory efficacy endpoints. In the final analysis, Sub-groups may also be defined 


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and explored after all pre-planned analyses have been completed to further elucidate study 
results.  
Covariates for exploratory efficacy analyses will be fully defined in the SAP and interim analysis 
plans.  
9.3. 
Determination of Sample Size 
A sample size of approximately 100 patients who receive two doses of FX006 is considered a 
reasonable sample size in order to assess the safety profile of repeat administration of FX006.  
No formal power and sample size calculations have been made as the analysis of the efficacy 
data collected from this study will be considered exploratory and hypothesis-generating for 
future multiple dose studies of FX006. In order to ensure at least 100 patients who receive two 
doses of FX006 are enrolled and followed for 52 weeks, approximately 200 patients will be 
enrolled based on an estimate that approximately 66% of patients enrolled will be eligible to 
receive a second dose of FX006 and approximately 75% of subjects who receive a second dose 
will complete the study through Week 52. 
9.4. 
General statistical Methods 
9.4.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be listed by study site and patient, and will be 
summarized by treatment.  Frequencies and proportions will be presented for the categorical 
variables and descriptive statistics will be presented for continuous variables.  
9.4.2. 
Exposure 
Treatment exposure will be listed by study site and patient, and will be summarized by doses 
administered, as well as total exposure to FX006. Time between FX006 exposure (1st and 2nd 
doses) will be summarized.  
9.4.3. 
Exploratory Efficacy Analyses 
The examination of efficacy is exploratory in this study. Data from the WOMAC® questionnaire 
will be presented in by-patient listings with summary presentation of the data and exploratory 
analyses.  
Analysis of the magnitude of pain relief observed with WOMAC A (pain), stiffness (WOMAC 
B), and function (WOMAC C) will be explored between patients who receive one or two doses 
of FX006 will be explored with longitudinal mixed model for repeated measures (MMRM) with 
fixed effects of number of doses (1 or 2) received, and a dose by time interaction. Model 
covariates will include study site, and potentially other variables.  Subject will be a random 
effect in the model. The exact configuration for the MMRM will be fully described in the SAP or 
interim analysis plans.   
A within subject analysis will be completed to examine the differences in WOMAC scores 
following the first dose, and then following a second dose of FX006. Change from baseline for 
the first dose and change from last assessment prior to second dose will be completed with linear 
models. The details of the linear model will be specified in the SAPEvaluation of dose-response 


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will be assessed descriptively with an examination of WOMAC A responses at the time (in 
weeks) of second dose administration to assess the magnitude of scores at each week that a 
second dose may be administered. The time to maximal pain relief response with WOMAC A 
(pain) following the first and second doses of FX006 will be examined using a Kaplan-Meier 
(KM) procedure. 
Questionnaire data from the GPAQ domains (occupational physical activity, transport-related 
physical activity, and physical activity during discretionary or leisure time) will be described 
descriptively at the two time points collected (Screening and Week 12). The change in GPAQ 
domain scores and total score will be examined with an analysis of variance (ANOVA) model 
with summaries comparing patients who receive one dose to those receiving two doses of 
FX006.  GPAQ information collected at Screening will be utilized to normalize steps per day 
based on lifestyles activity.  GPAQ information will be a model covariate in subsequent 
analyses. 
9.4.4. 
Safety Analyses 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary.  
Incidences (number and percent) TEAEs, those events that started after dosing or worsened in 
severity after dosing, will be presented by treatment group.  Incidences of TEAEs will also be 
presented by maximum severity and relationship to study medication. Similar presentations will 
be provided for serious AEs, AEs leading to withdrawal from the study, or AEs leading to death.  
Analysis of AE data will include examination of the incidence rates and changes in severity of 
TEAEs and index knee related TEAEs following the first dose and second dose, as well as the 
cumulative incidence of TEAEs after all doses of FX006. Both the number of events and the 
number of patients experiencing an event will be examined to assess the by patient cumulative 
incidence of TEAEs associated with repeat administration. The cumulative TEAE incidence rate 
will also be compared with total exposure to FX006. 
Clinical laboratory data and vital sign information will be presented as descriptive summary 
statistics for value and change from Baseline at each individual time point. 


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10. 
DATA QUALITY ASSURANCE 
At the time the study is initiated, the clinical study monitor will thoroughly review the final 
protocol and the eCRF with the Principal Investigator and staff.  During the course of the study, 
the clinical study monitor will visit the clinical site regularly to check the completeness of the 
patient records, the accuracy of entries into the eCRF, the adherence to the final protocol and to 
International Conference on Harmonisation GCP, the progress of enrollment, and the storage, 
dispensing and accountability of study medication. The Principal Investigator and key study 
personnel should be available to assist the clinical study monitor during these visits.   
The Principal Investigator will give the monitor, auditor(s), Sponsor, Sponsor designee and 
regulatory authorities direct access to relevant clinical records to confirm their consistency with 
the eCRF entries.  No information in these records about the identity of the patients will leave the 
clinical site.  The Sponsor will maintain the confidentiality of all patient records. 
Source data is all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained in source documents 
(original records or certified copies). 
Independent clinical quality assurance audits may be performed at any time during or following 
completion of the Study by the Sponsor, or its authorized agents, and Competent Authorities 
and/or the IRB/EC. 
 


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11. 
DATA HANDLING AND RECORDKEEPING 
11.1. 
Case Report Forms 
The eCRF will be supplied by the Sponsor or designee and should be handled in accordance with 
the instructions provided. All study data should initially be documented in source documents 
(e.g., patient charts, notes, laboratory reports, ECG recordings, etc.) and then subsequently 
entered from the source into the eCRF.  All eCRFs should be filled out completely by examining 
personnel or the study coordinator.  The eCRF is reviewed, signed, and dated electronically by 
the Principal Investigator. 
11.2. 
Study Medication Accountability 
All study medication required for completion of this study will be provided by the Sponsor or 
designee.  Study medication will be acknowledged upon receipt indicating shipment content and 
condition.  Damaged supplies will be replaced. 
Accurate records of all study medications received by, dispensed from, or returned by the study 
site should be maintained within the Drug Tracking Module. 
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 productcomplaints@flexiontherapeutics.com. The assigned monitor or 
clinical manager 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.  
If local records retention regulations are more stringent than that specified above, the local 
regulations will prevail. 
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 trial this may not require prior approval by the IRB/EC. The Principal 
Investigator will be responsible for enrolling only those patients who have met protocol 
eligibility criteria. 


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


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13. 
REFERENCES 
Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, et al. The American College of 
Rheumatology criteria for the classification and reporting of osteoarthritis of the knee. Arthritis 
Rheum 1986;29:1039-1049 
Ayral X, Pickering EH, Woodworth TG, Mackillop N, Dougados M. Synovitis: a potential 
predictive factor of structural progression of medial tibiofemoral knee osteoarthritis -- results of 
a 1 year longitudinal arthroscopic study in 422 patients. Osteoarthritis Cartilage 2005;13:361-7. 
Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Cochrane Database Syst Rev. 
2006 Apr 19;(2):CD005328 
Benito MJ, Veale DJ, FitzGerald O, van den Berg WB, Bresnihan B.  Synovial tissue 
inflammation in early and late osteoarthritis.  Ann Rheum Dis 2005;64:1263-1267. 
Bodick N, Lufkin J, Willwerth C, Blanks R, Inderjeeth C, Kumar A, Clayman M.  FX006 
prolongs the residency of triamcinolone acetonide in the synovial tissues of patients with knee 
osteoarthritis. Osteoarthritis Cartilage. 2013;21:(Suppl); S144-5. 
Bodick N, Lufkin J, Willwerth C, Kumar A, Bolognese J, Schoonmaker C, Ballal R, Hunter D, 
Clayman, M.  An Intra-Articular, Extended-Release Formulation of Triamcinolone Acetonide 
Prolongs and Amplifies Analgesic Effect in Patients with Osteoarthritis of the Knee, A 
Randomized Clinical Trial. J Bone Joint Surg Am. 2015;97:877-88 
Creamer P, Hochberg MC.  Osteoarthritis.   Lancet 1997;350(906):503–508. 
Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, Kerns RD, Stucki 
G, Allen RR, Bellamy N, Carr DB, Chandler J, Cowan P, Dionne R, Galer BS, Hertz S, Jadad 
AR, Kramer LD, Manning DC, Martin S, McCormich CG, McDermott MP, McGrath P, Quessy 
S, Rappaport BA, Robbins W, Robinson JP, Rothman M, Royal MA, Simon L, Stauffer JW, 
Stein W, Tollet J, Wernicke J, Witter J.  Core outcome measures for chronic pain clinical trials: 
IMMPACT recommendations.  Pain 2005; 113:9-19. 
Goldring SR, Goldring MB.  Clinical aspects, pathology and pathophysiology of osteoarthritis.   
J Musculoskelet Neuronal Interact 2006;6(4):376–378. 
Habib GS.  Systemic effects of intra-articular corticosteroids. Clin Rheumatol 2009;28:749–756. 
Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, Towheed T, Welch 
V, Wells G, Tugwell P.  American College of Rheumatology 2012 Recommendations for the 
Use of Nonpharmacologic and Pharmacologic Therapies in Osteoarthritis of the Hand, Hip, and 
Knee.  Arthritis Care & Research 2012; 64:465-474. 
Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, Gunther K, 
Hauselmann H, Herrero-Beaumont, Kaklamanis P, Lohmander S, Leeb B, Lequesne M, 
Mazieres B, Martin-Mola E, Pavelka K, Pendleton A, Punzi L, Serni U, Swoboda B, Verbruggen 
G, Zimmerman-Gorska I, Dougados M.  EULAR Recommendations 2003: an evidence based 
approach to the management of knee osteoarthritis: Report of a Task Force of the Standing 
Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT).  Ann 
Rheum Dis 2003;62(12):1145–1155. 


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


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14. 
APPENDICES 
APPENDIX 1. KNEE OA DIAGNOSIS ASSESSMENTS 
American College of Rheumatology Criteria for Classification of Idiopathic OA of the 
Knee (Altman et al, 1986) 
Clinical and radiological 
 Knee Pain 
 + at least 1 of 3: 
o Age > 50 years 
o Stiffness < 30 minutes 
o Crepitus 
 + Osteophytes 
Kellgren-Lawrence Grade of Knee X-ray  
 
 Grade 0: no findings 
 Grade 1: doubtful narrowing of joint pace and possible osteophytic lipping 
 Grade 2: definite osteophytes and possible narrowing of joint space 
 Grade 3: moderate multiple osteophytes, definite narrowing of joint space and some 
sclerosis and possible deformity of bone ends 
 Grade 4: large osteophytes, marked narrowing of joint space, severe sclerosis and definite 
deformity of bone ends 
 
 
 
 
 


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APPENDIX 2. STUDY VISIT FLOW CHART 
 
 
 

SAP_001.pdf: 
Confidentiality 
This document is confidential and proprietary property of Flexion Therapeutics and to be used only as authorized 
by Flexion Therapeutics.  No part is to be reproduced, disclosed to others, or quoted without prior written 
authorization from Flexion Therapeutics 
STATISTICAL ANALYSIS PLAN 
Protocol FX006-2016-011 
An Open-label Study to Assess the Safety of Repeat Administration of FX006 to 
Patients with Osteoarthritis of the Knee 
Protocol Number: 
(Version Date) 
FX006-2016-011 
Version 2.0, 16 October 2017 
Name of Test Drug: 
FX006 
Phase: 
3b 
Methodology: 
Open-label, Repeat Dose Design 
Sponsor: 
Flexion Therapeutics 
10 Mall Road, Suite 301 
Burlington, Massachusetts 01803 
Tel: 781-305-7777 
Sponsor Representative: 
Scott Kelley, MD 
Chief Medical Officer 
Document Date: 
01 Aug 2018 
Document Version: 
Final Version 2.0 
 






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TABLE OF CONTENTS 
Section 
Page 
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS............................................9
1.1. 
Introduction .......................................................................................................... 9
1.2. 
Objectives of Statistical Analysis ........................................................................ 9
1.2.1. 
Primary Objective ................................................................................... 9
1.2.2. 
Exploratory Objectives ........................................................................... 9
2. 
STUDY DESIGN ............................................................................................................ 10
2.1. 
Synopsis of Study Design ................................................................................... 10
2.2. 
Randomization Methodology ............................................................................ 10
2.3. 
Unblinding .......................................................................................................... 11
2.4. 
Study Procedures ............................................................................................... 11
2.5. 
Study Variables .................................................................................................. 12
2.5.1. 
Safety Variables .................................................................................... 12
2.5.2. 
Exploratory Efficacy Variables ............................................................ 12
3. 
PATIENT POPULATIONS .......................................................................................... 14
3.1. 
Population Definitions ....................................................................................... 14
4. 
STATISTICAL METHODS ......................................................................................... 15
4.1. 
Sample Size Justification ................................................................................... 15
4.2. 
General Statistical Methods and Data Handling ............................................ 15
4.2.1. 
General Methods ................................................................................... 15
4.2.2. 
Computing Environment ...................................................................... 16
4.2.3. 
Methods of Pooling Data ...................................................................... 16
4.2.4. 
Adjustments for Covariates .................................................................. 16
4.2.5. 
Multiple Comparisons/Multiplicity ...................................................... 16
4.2.6. 
Subpopulations ..................................................................................... 16
4.2.7. 
Discontinuations and Loss to Follow-up .............................................. 16
4.2.8. 
Missing, Unused, and Spurious Data .................................................... 16
4.2.9. 
Visit Windows ...................................................................................... 17
4.2.10. 
Baseline Definitions .............................................................................. 18
4.3. 
Interim Analyses ................................................................................................ 19


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Section 
Page 
4.4. 
Final Analysis .....................................................................................................19
4.5. 
Patient Disposition ............................................................................................. 19
4.6. 
Protocol Deviations ............................................................................................ 20
4.7. 
Demographic and Baseline Characteristics ..................................................... 20
4.8. 
Study Drug Exposure ........................................................................................ 21
4.9. 
Exploratory Efficacy Analyses.......................................................................... 22
4.9.1. 
WOMAC ............................................................................................... 22
4.9.1.1.  Descriptive statistics, all patients ........................................... 22
4.9.1.2.  Change from baseline, patients receiving two 
doses ....................................................................................... 23
4.9.1.3.  Responders ............................................................................. 25
4.9.1.4.  Area Under the Effect Curve (AUE) for Change 
from Baseline in WOMAC over Time ................................... 26
4.9.2. 
KOOS ................................................................................................... 28
4.9.3. 
Daily activity measured as steps per day .............................................. 28
4.9.4. 
GPAQ ................................................................................................... 29
4.9.5. 
Sensitivity Analyses .............................................................................. 29
4.10.  Safety Analyses ................................................................................................... 29
4.10.1. 
Adverse Events ..................................................................................... 30
4.10.2. 
Laboratory Data .................................................................................... 32
4.10.3. 
Vital Signs, Physical Examination, and Index Knee 
Assessment............................................................................................ 32
4.10.4. 
Electrocardiogram ................................................................................. 33
4.10.5. 
Index Knee X-ray .................................................................................. 33
4.10.6. 
Concomitant Medications ..................................................................... 35
4.10.7. 
Surgical Procedures .............................................................................. 35
5. 
CHANGES TO PLANNED ANALYSES .................................................................... 36
6. 
REFERENCES ............................................................................................................... 37
Appendix A. Laboratory Grade Definitions  - CTCAE 4.03 ................................................. 38
Appendix B. Study Visit Flow Chart........................................................................................ 41
 


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LIST OF IN-TEXT TABLES 
Table 
Page 
Table 1 
Schedule of Assessments ................................................................................................. 12 
Table 2 
Evaluation Intervals for the Data Points to be Included in the Table .............................. 18 
Table 3 
AUE Change from Baseline Comparisons ...................................................................... 27 
 


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ABBREVIATIONS 
Abbreviation 
Definition 
ACR 
American College of Rheumatology 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
AUE 
Area Under the Effect Curve 
BMI 
Body Mass Index 
BP 
Biomarker Population 
CI 
Confidence Interval 
CM  
Concomitant Medication 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
EULAR 
European League against Rheumatism  
FAS 
Full Analysis Set 
GPAQ 
Global Physical Activity Questionnaire 
HIV 
Human Immunodeficiency Virus 
IA 
Intra-articular 
ICH 
International Conference on Harmonisation 
iSAP 
Interim Statistical Analysis Plan 
JSN 
Joint Space Narrowing 
K-L 
Kellgren-Lawrence 
KOOS 
Knee injury and Osteoarthritis Outcome Score 
LSM 
Least Square Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MET 
Metabolic Equivalent 
mg 
milligram 
mmol 
millimole 
MMRM 
Mixed Effects Model for Repeat Measures 
OA 
Osteoarthritis 
OARSI 
Osteoarthritis Research Society International 
PDF 
Portable Document Format 
PPIP 
Per Protocol Imaging Population 
PT 
Preferred Term 
QOL 
Quality of Life 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System 


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Abbreviation 
Definition 
SBC 
Subchondral Bone Changes 
SD 
Standard Deviation 
SE 
Standard Error 
SI 
International System of Units 
SOC 
System Organ Class 
SP 
Safety Population 
TA 
Triamcinolone Acetonide 
TAcs 
Triamcinolone Acetonide Injectable Suspension, Immediate-Release 
(Commercially Available)  
TEAE 
Treatment Emergent AE 
US 
United States 
WHO 
World Health Organization 
WOMAC 
Western Ontario and McMaster Universities 
 
 


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1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1.1. 
Introduction 
Osteoarthritis (OA) is a painful and debilitating musculoskeletal disease that is characterized by 
intra-articular (IA) inflammation, deterioration of articular cartilage, and degenerative changes 
to peri-articular and subchondral bone (Creamer and Hochberg, 1997; Goldring and Goldring, 
2006). Arthritis is the most common cause of disability in the United States (US) and OA is the 
most common joint disease, affecting 27 million Americans, with numbers expected to grow as 
a result of aging, obesity and sports injuries. Recent data suggest that OA accounts for over 
$185 billion of annual healthcare expenditures in the US, which does not include loss of 
productivity costs. We estimate that by 2030, 45 million people will have OA. OA commonly 
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 (ACR 
Subcommittee 2000; Hochberg et al, 2012; Jordan et al, 2003). 
While historically OA has been considered a non-inflammatory disease, it is increasingly being 
recognized that chronic synovitis occurs in all stages of knee OA (Benito et al, 2005; Sellam and 
Berenbaum, 2010; Wenham and Conaghan, 2010). As synovial inflammation is correlated with 
clinical symptoms and joint degeneration, it should be an important target for therapeutic 
intervention. The inflamed synovium may well be the target for IA corticosteroids which are 
widely used in knee OA (Ayral et al, 2005). 
FX006 is an extended-release formulation of triamcinolone acetonide (TA) for IA 
administration that is being developed for the treatment of patients with pain attributed to OA of 
the knee. 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). 
Available clinical and nonclinical data indicate that FX006 is likely to be safe and well tolerated 
and has the potential to provide pain relief that is meaningfully better and more persistent than 
that provided by immediate release triamcinolone acetonide (TAcs).   
1.2. 
Objectives of Statistical Analysis 
1.2.1. 
Primary Objective 
The primary objective of this study is to assess the overall safety and general tolerability of 
repeat administration of FX006 (two doses of 32 mg FX006) in patients with symptomatic OA 
of the knee. 
1.2.2. 
Exploratory Objectives 
Exploratory objectives of this study include the following: 


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 examine efficacy signals for sustained pain reduction following two doses of 32 mg 
FX006. 
 collect synovial fluid samples to enable potential future examination of synovial fluid 
biomarkers that may contribute to the pathogenesis of OA and/or be associated with 
responsiveness to FX006 treatment.   
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. 
This SAP also will outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol.  
This SAP may be amended as study data are reviewed and interim analyses of these data are 
conducted. 
2. 
STUDY DESIGN 
2.1. 
Synopsis of Study Design 
This study is an open-label, repeat administration design of 32 mg FX006. The study will be 
conducted in male and female patients ≥ 40 years of age with symptomatic OA of the knee. 
Eligible patients will be offered participation to receive an initial IA injection of FX006 
administered to the index knee at Day 1. 
Patients who receive an initial injection of FX006 will return at Weeks 4 and 8 before being 
evaluated at 12, 16, 20 and 24 weeks following the initial administration of FX006 for repeat 
administration. At the first visit where the patient has been determined to meet repeat 
administration eligibility criteria, the patient will be eligible to receive a second IA injection of 
FX006 administered to the index knee.   
Patients who are eligible to receive a second injection will be evaluated for a total of 52 weeks 
post initial injection at: Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52, regardless of 
the visit at which they receive their second injection. 
Patients that do not benefit from the initial treatment as determined by evaluation at Week 12 
will complete the study at the Week 12 follow-up visit. These patients will be evaluated for a 
total of 12 weeks post initial injection at: Weeks 4, 8, 12. 
Patients who are not eligible for a second injection of FX006 after evaluation at Weeks 12, 16, 
20, and 24 will complete the study at the Week 24 follow-up visit. These patients will be 
evaluated for a total of 24 weeks post initial injection at: Weeks 4, 8, 12, 16, 20 and 24.   
Refer to Appendix B for the study flow chart. 
2.2. 
Randomization Methodology 
No randomization technique is required to assign patients to treatment in this study.  


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2.3. 
Unblinding 
Not applicable to the current study since this is an open-label study.  
2.4. 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Table 1. 
 


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Table 1 
Schedule of Assessments 
 
Procedures 
Screen 
 
Baseline 
Day 1 
Week
4 
Week
8 
Week 
12, 16, 20, 24 
Week 
28, 32, 36, 40, 44, 48 
Week 
52/End of Study 
Informed consent, OA Medical History,  
HIV, Hepatitis B/C , Serum Pregnancy Test, 
12-Lead ECG, Height 
X 
 
 
 
 
 
 
Inclusion/Exclusion Review, Medical 
History/Update, Prior Treatment & 
Medications 
X 
X 
 
 
 
 
 
Physical Examination, Hematology & 
Chemistry 
X 
 
 
 
X 
 
X 
Index Knee X-ray, Weight and BMI  
X 
 
 
 
 
 
X 
Index Knee Assessment, Vital Signs 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
 
X 
 
 
X 
 
X 
WOMAC 
X 
X 
X 
X 
X 
X 
X 
KOOS QOL 
 
X 
X 
X 
X 
X 
X 
GPAQ, Index knee aspiration and collection 
of synovial fluid 
 
X 
 
 
X 
 
 
Measured Function Device 
----------------------------X--------------------------------------
 
 
1st treatment administration 
 
X 
 
 
 
 
 
Evaluation for repeat administration, 2nd 
(repeat) treatment administration 
 
 
 
 
X 
 
 
AEs & ConMeds 
 
---------------------------------------------------X--------------------------------------------------- 
 
2.5. 
Study Variables 
2.5.1. 
Safety Variables 
Safety and tolerability will be evaluated on the basis of findings from the following 
assessments:   
 Adverse events 
 Physical examinations  
 Index knee assessments  
 Vital signs 
 Clinical laboratory evaluations 
 Index knee X-ray 
2.5.2. 
Exploratory Efficacy Variables 
The following exploratory efficacy endpoints will be analyzed as described in the SAP: 
 
 Western Ontario and McMaster Universities (WOMAC) A (pain subscale), B (stiffness 
subscale), C (function subscale), and total score at all time points. 
 


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 Knee injury and Osteoarthritis Outcome Score (KOOS) Quality of Life (QOL) Subscale 
at all time points. 
 
 Daily activity measured as steps per day from Day 1 to Week 12. 
 
 Global Physical Activity Questionnaire (GPAQ) domains (activity at work, travel to and 
from places and recreational activities) and total score at baseline/Day 1 and Week 12. 


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3. 
PATIENT POPULATIONS 
3.1. 
Population Definitions 
The following patient populations will be evaluated and used for presentation and analysis of 
data at the conclusion of the study: 
Safety Population (SP):  
The Safety Population (SP) will include all patients who receive study treatment. The Safety 
Population will be used to assess safety and tolerability endpoints.  
Full Analysis Set (FAS):  
The Full Analysis Set (FAS) population will include all patients who receive study treatment 
and provide at least one post-baseline efficacy endpoint assessment. The FAS population 
will be used to examine exploratory efficacy endpoints. 
Biomarker Population (BP) 
The Biomarker Population (BP) will include all patients who receive study treatment and 
provide at least one synovial fluid sample for biomarker analysis. The BP will be used for 
future biomarker analyses. 
Per Protocol Imaging Population (PPIP) 
The Per Protocol Imaging Population (PPIP) will include all patients in the SP who have 
quantifiable x-ray imaging values at baseline and Week 52/End of Study except those 
patients who are terminated early or have major protocol deviations that could affect image 
results. These major protocol deviations will be identified by Flexion medical without regard 
to individual patient imaging data. 
Additional study populations may be defined to meet interim analysis requirements. These 
population definitions will be fully specified and documented an interim SAP (iSAP) and in the 
final CSR. 


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4. 
STATISTICAL METHODS 
4.1. 
Sample Size Justification 
A sample size of approximately 100 patients who receive two doses of FX006 is considered a 
reasonable sample size in order to assess the safety profile of repeat administration of FX006. 
No formal power and sample size calculations have been made as the analysis of the efficacy 
data collected from this study will be considered exploratory and hypothesis-generating for 
future multiple dose studies of FX006. In order to ensure at least 100 patients who receive two 
doses of FX006 are enrolled and followed for 52 weeks, approximately 200 patients will be 
enrolled based on an estimate that approximately 66% of patients enrolled will be eligible to 
receive a second dose of FX006 and approximately 75% of patients who receive a second dose 
will complete the study through Week 52. 
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 Harmonisation (ICH) recommendations, 
and formatted to the appropriate page size(s). 
A list of tables, figures and listings to be generated, as well as mock shells, are provided in a 
separate document.  
Tabulations will be produced for appropriate demographic, baseline, efficacy and safety 
parameters. Each table will present all patients combined, regardless of number of doses, unless 
otherwise specified. 
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), confidence intervals (CI), minimum and maximum will be presented. Additional 
statistics may be presented for certain endpoints as described in the sections below. 
Time to event data will be summarized using Kaplan-Meier Methodology using 25th, 50th 
(median), and 75th percentiles with associated 2-sided 95% confidence intervals, as well as 
percent of censored observations.   
If performed, all statistical tests will be two-sided and a difference resulting in a p-value of less 
than or equal to 0.05 will be described as statistically significant and potentially informative. 
All collected data will be presented in patient listings. 
The sections below describe the intended analysis of the endpoints. Additional sensitivity 
analysis may be employed in the event of any unforeseen data anomalies or data issues not 
known at the time of writing this analysis plan. 


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4.2.2. 
Computing Environment 
All statistical analyses will be performed using SAS® Software1  (Version 9.4) or higher, unless 
otherwise noted. Adverse events will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) version 19.1 Concomitant medications will be coded using World Health 
Organization (WHO) Drug (March 2014 edition). 
4.2.3. 
Methods of Pooling Data 
Not applicable to the present study. 
4.2.4. 
Adjustments for Covariates 
The exploratory continuous endpoints will include baseline score and study site as covariates. 
Other covariates may be explored.   
4.2.5. 
Multiple Comparisons/Multiplicity 
Since these are exploratory analyses, there will be no adjustment for multiple endpoints. 
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.  
4.2.7. 
Discontinuations and Loss to Follow-up 
Each treated patient in this study will receive an initial injection of FX006 and then be 
reevaluated starting at Week 12 for eligibility to receive a second injection. Therefore, 
discontinuation from treatment is not applicable. Whether or not patients receive the entire 
contents of study drug injection will be considered in the study drug exposure analyses.  
Each patient may discontinue from the study for further assessments and study visits. Data 
collected from discontinued patients will be included in the CSR. Patients who discontinue from 
the study may be replaced at the discretion of the sponsor.   
4.2.8. 
Missing, Unused, and Spurious Data 
For WOMAC, the rules as described in the WOMAC user guide (Bellamy 2011) will be used. 
Specifically, if at least 2 pain, both stiffness, or at least 4 function items are missing, the 
patient's response will be regarded as invalid and the score for that given subscale as well as the 
total score will be left missing. If no more than 1 pain, 1 stiffness, and less than 4 function items 
are missing, the missing value in a given subscale will be imputed using the average of all items 
in the given subscale. Imputed WOMAC scores will be flagged in the data listings. 
                                                     
1 Copyright 2015, SAS Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered 
trademarks or trademarks of SAS Institute Inc., Cary, NC, USA. 


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For the KOOS QOL subscale, the rules as described in KOOS Scoring 2012 
(http://www.koos.nu/) will be used. Specifically, the score is only calculated if at least 2 items 
are non-missing. Otherwise the score will be set to missing. 
For calculating weekly mean steps per day using Fitbit data, patients need to have at least 3 of 7 
daily values in a given week to provide a robust assessment of activity. The denominator used 
for calculating means will be the total number of days in which steps per day is non-missing.  
To be included in the GPAQ analyses, there must be a valid response for at least one domain 
and no invalid responses for any domains. 
Other than for the WOMAC and KOOS QOL, missing data will not be imputed and will be 
analyzed "as observed".   
4.2.9. 
Visit Windows 
All data listings that contain an evaluation date will contain a relative study day (Rel Day Dose 
1). Pre-treatment and post-treatment study 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. Listings will also contain a study day (Rel Day Dose 2) relative to the second 
dose of study treatment, which is designated as Day 1. For patients that do not receive a second 
dose, Rel Day Dose 2 will be "NA". For Rel Day Dose 2, preceding days (e.g., Day -1, -2) will 
not be derived or presented. In other words, if the date is prior to Dose 2, only Rel Day Dose 1 
will be presented. If the date is after Dose 2, then both Rel Day Dose 1 and Rel Day Dose 2 will 
be presented.  
Steps per Day (Fitbit) data windowing: 
The visit windows to be used for computing steps per day are provided in Table 2. Observations 
collected in these windows will be averaged and presented according to the nominal visit label 
for that window.  


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Table 2 
Evaluation Intervals for the Data Points to be Included in the Table 
Visit 
Relative Day Interval for 
Analysis 
Baseline 
Day –7 to Day -1 
Week 1 
Day 1 to Day 7 
Week 2 
Day 8 to Day 14 
Week 3 
Day 15 to Day 21 
Week 4 
Day 22 to Day 28 
Week 5 
Day 29 to Day 35 
Week 6 
Day 36 to Day 42 
Week 7 
Day 43 to Day 49 
Week 8 
Day 50 to Day 56 
Week 9 
Day 57 to Day 63 
Week 10 
Day 64 to Day 70 
Week 11 
Day 71 to Day 77 
Week 12 
Day 78 to Day 84 
Unscheduled visit windowing: 
If a patient receives their second dose of study medication at an unscheduled visit that is not >3 
weeks after Week 24, the dosing information and all other data collected at that visit will be 
mapped to the closest nominal visit, based on Rel Day Dose 1, even if data is already available 
in that visit. All data collected at the time of the second dose will be used for analysis. If data is 
available in the nominal visit, but was not collected at the unscheduled visit associated with the 
second dose, the data from the nominal visit will be used. If a patient receives their second dose 
at an unscheduled visit that is > 3 weeks past Week 24, data from that unscheduled visit will not 
be used for time to second dose analyses or exploratory efficacy analyses involving two-dose 
patients.  
Data collected at unscheduled visits that are not associated with the second dose will be mapped 
to the closest scheduled visit, but only if that data is not already available in that visit. Otherwise 
data will be summarized and presented according to the nominal visit as recorded on the Case 
Report Form (CRF). 
4.2.10. 
 Baseline Definitions 
Baseline for the first dose is the baseline/Day 1 assessment prior to administration of the first 
dose of study treatment. If the baseline result is missing, the last non-missing result prior to 
administration of study treatment may be used from the Screening period.  
Baseline for the second dose of study treatment is defined as the last data collected prior to the 
second dose of study treatment administration. This is the same study visit, as long as the data 
are collected prior to the second dose. 
 
Where noted in this SAP, change from baseline for efficacy analyses are also performed where 
baseline for the second dose is defined as the baseline/Day 1 assessment prior to administration 
of the first dose of study treatment.  


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Additional baselines may be defined to explore efficacy endpoints comparing the first dose and 
the second dose of study treatment administration. All new baseline definitions will be fully 
specified and documented an interim SAP (iSAP) and in the final CSR. 
4.3. 
Interim Analyses 
Interim analyses may be conducted evaluating safety and efficacy signals following 
administration of one or two doses of 32mg FX006. These interim analyses on exploratory 
endpoints may be completed for data review, regulatory updates, and/or publication (or 
presentation at congresses) for this open-label study. For any analyses completed not presently 
identified in this SAP an iSAP will be written and approved prior to interim analysis.. The iSAP 
will describe the purpose and analytical objectives of the interim analysis. Any changes made to 
the final analysis will be documented in an amendment to the SAP prior to final analysis. Final 
analyses will be conducted after completion of the study, when all patients have either 
discontinued the study early (prior to Week 52) or completed the study through Week 52. 
4.4. 
Final Analysis 
All final analyses will be completed following database lock. Final analyses specified in the 
protocol and SAP will be completed and reported in the CSR. Interim analyses conducted with 
exploratory endpoints to examine efficacy signals prior to database lock will also be reported in 
the final CSR. Post-hoc, or additional exploratory analyses, not defined in the SAP may be 
completed to further understanding and elucidation of the study results. Any post-hoc, 
exploratory, analyses completed will be clearly identified as such in the final CSR. 
4.5. 
Patient Disposition 
All patients who are enrolled will be accounted for in this study.  
Patient disposition will be tabulated and include the total number of patients enrolled, treated, 
completed and early terminated, reason for early termination and the number in each patient 
population for analysis.  
Subject completion will be presented overall and by the following categories: 
1. At Week 12 (no clinical benefit) 
2. At Week 24 (not clinically indicated to received second injection) 
3. At Week 52 
 
Early termination will be presented overall and by the following time periods: 
1. Prior to Week 12, which is the first visit for second dose eligibility 
2. On or after Week 12, but prior to receiving second dose 
3. On or after second dose and prior to 12 Weeks after second dose 
4. On or after receiving the second dose but prior to Week 52 


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The following by-patient data listings will be presented: 
 Study completion information including the reason for premature study discontinuation, 
if applicable. 
 Inclusion/exclusion criteria not met.  
 Repeat dose inclusion/exclusion criteria not met for all patients. If a patient receives a 
repeat dose on a visit where repeat dose inclusion/exclusion criteria were not met, that 
visit will be flagged. 
 Repeat dose eligibility at Weeks 12, 16, 20 and 24. 
 Patient inclusion in each of the analysis populations (SP, FAS, BP and PPIP). Reasons 
for exclusion from the PPIP will be presented. 
4.6. 
Protocol Deviations 
The number and percentage of patients with at least one protocol deviation will be presented for 
the SP. Additionally, incidence by type of deviation will be presented; in these tabulations 
patients could be counted in more than one category if they have a deviation attributed to 
multiple categories. All protocol deviations will be presented in a data listing. 
4.7. 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized and presented for the SP for 
patients receiving only one dose, patients receiving two doses, and all patients combined. Age, 
height, weight, and body mass index (BMI) will be summarized using descriptive statistics 
(number of patients, mean, standard deviation, median, minimum, and maximum). 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. The number and percentage of patients in each gender, ethnicity and 
race category will also be presented.  Additionally, for two-dose patients only, demographic and 
baseline characteristic data will be presented separately based on the time at which the second 
dose was administered. These statistics will be presented for the following groups. Each group 
will be displayed as a different column in the same table, in this order: 
1. Patients receiving the second dose at Week 12  
2. Patients receiving the second dose at Week 16 
3. Patients receiving the second dose at Week 20 
4. Patients receiving the second dose at Week 24 
5. Patients Receiving the Second Dose after Week 24 
OA background characteristic data and index knee characteristic data as collected on the CRF 
will also be tabulated for the SP for all patients combined. Time from primary diagnosis of OA 
in the index knee to Day 1 of the study in years (dose date – date of diagnosis + 1)/365.25, will 
be computed and presented descriptively. Additionally, for two-dose patients only, OA 
background characteristic data and index knee characteristic data will be presented separately 
based on the time at which the second dose was administered. These statistics will be presented 


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for the following groups. Each group will be displayed as a different column in the same table, 
in this order: 
1. Patients receiving the second dose at Week 12  
2. Patients receiving the second dose at Week 16 
3. Patients receiving the second dose at Week 20 
4. Patients receiving the second dose at Week 24 
5. Patients Receiving the Second Dose after Week 24 
For all time to diagnosis calculations, 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 administration of study treatment minus year of diagnosis. 
If year is missing, time from diagnosis will not be computed. 
All collected demographic, baseline characteristics, and medical history data will be provided in 
data listings, sorted by patient. 
4.8. 
Study Drug Exposure 
Details of study drug administration will be tabulated and presented for the SP by the following 
groups: 
 First (and only) dose for patients receiving one dose 
 First dose for patients receiving two doses 
 Second dose for patients receiving two doses 
The position of knee during injection, approach during injection, whether or not the entire 
contents of the syringe was injected, reason (if entire contents not injected), the numbing agent 
used, whether or not ultrasound guidance was used, volume of synovial fluid aspirated, and 
whether a 20 or 21-gauge needle was used will be presented. 
Benefit from the initial dose of FX006 and patients with no major safety concerns during the 
initial dose period will be summarized for the Week 12 visit.  In addition, patients clinically 
indicated to receive a second dose of FX006 and patients eligible for the second dose at Weeks 
12, 16, 20 and 24 will be summarized, as well as the number of patients receiving the second 
dose at each of these visits. These data come from the “Repeat Dose Eligibility” CRF. 
Patients receiving one dose and two doses and the visit at which the second dose was received 
will be summarized. 
 
A summary of time to second dose will be displayed for patients receiving two doses. The 
median time to second dose will be estimated based on the 50th percentile of the Kaplan-Meier 
distribution. Additional summary statistics will be presented, including the 25th and 75th 
percentiles, and the corresponding 95% confidence intervals.  
Additionally, repeat dose data will be presented separately by the following subgroups: 
 K-L Grade 2, 3 and 4 


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 Prior IA steroid injection 
 Unilateral/bilateral knee OA 
 Prior index knee OA surgery or procedure 
All study drug exposure data will be presented in a data listing. 
4.9. 
Exploratory Efficacy Analyses 
The examination of efficacy is exploratory in this study. All efficacy analyses will be conducted 
using the FAS.  
4.9.1. 
WOMAC 
The following WOMAC scales/questions will be analyzed: 
 WOMAC A (pain subscale) 
 WOMAC B (stiffness subscale)  
 WOMAC C (function subscale) 
 WOMAC (total) 
For the WOMAC subscales, scores at each assessment time point (baseline, Week 4, Week 8, 
Week 12, etc.) will be calculated as the average of the responses to all questions in the subscale. 
Total score will be computed as the average of the average responses on each of the subscales 
(e.g. Average A + Average B + Average C divided by 3). This will provide a uniform scoring of 
0 to 4 for each subscale and easier interpretation. Imputation rules are as presented in section 
4.2.8.  
Eligibility in this trial is based upon the WOMAC A total sum score at Screening and Day 
1/baseline (maximum score of 20). This will be provided for all visits in a data listing.  
4.9.1.1. 
Descriptive statistics, all patients 
Descriptive statistics will be presented for the following groups. Each group will be displayed as 
a different column in the same table, in this order: 
1. Patients receiving the second dose at Week 12  
2. Patients receiving the second dose at Week 16 
3. Patients receiving the second dose at Week 20 
4. Patients receiving the second dose at Week 24 
5. Patients receiving only one dose 
6. All patients, first dose – all patients through patient discontinuation, study completion 
(through Week 12 or Week 24), or until the second dose is received (whichever happens 
sooner) 
Descriptive statistics (number of observations, unadjusted mean, SD, median, minimum and 
maximum) will be presented for WOMAC A, WOMAC B, WOMAC C and WOMAC total by 
visit (baseline through Week 52). Change from baseline will also be presented. For the change 
from baseline calculation, baseline is the WOMAC result obtained on Day 1 prior to first dose.  


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The adjusted change from baseline will also be presented. This will be done using a longitudinal 
mixed effects model for repeat measures (MMRM) with fixed effects for study time point, study 
site and baseline score. Patient will be the random effect.  The analysis will include all study 
visits of data. This model assumes that missing values are missing at random. This model will 
be run separately for each group and for WOMAC A, WOMAC B, WOMAC C and WOMAC 
total.  
This model will be run using the SAS/STAT® PROC MIXED procedure with an unstructured 
correlation matrix to model the within-subject errors.  If the unstructured covariance matrix does 
not converge when fitting the mixed model, further investigation into the most appropriate 
correlation matrix will be conducted.  The final selection of the correlation matrix to be used in 
fitting the mixed model will be fully documented in the results section of the CSR. 
This model will provide the baseline adjusted Least Square Means (LSM) at each visit with the 
corresponding standard error (SE) and associated 95% CI. 
Sample SAS code that can be used to implement the mixed effects analysis is provided below: 
proc mixed data=dsin1 method=reml; 
by group; 
class subjid group avisitn siteid; 
model chg= base group avisitn siteid; 
repeated avisitn /type=un subject=subjid; 
lsmeans group/diff=control (‘1’) cl; 
run; 
 
In the above code, "group" refers to the groups listed below. The model will be run for each 
group separately. 
A line plot presenting LSM change from baseline in WOMAC score over time will be produced. 
Each group will be plotted on a separate line with SE bars. Jitter will be used as needed to 
distinguish overlapping data. 
4.9.1.2. 
Change from baseline, patients receiving two doses 
Change from Baseline to Week 12 
A within patient analysis will be completed for patients who receive two doses of FX006. 
Change in WOMAC A, WOMAC B, WOMAC C and WOMAC total from first dose (Day 1) to 
Week 12 will be compared to change in WOMAC from second dose to 12 weeks after the 
second dose using a paired t-test. 
The paired t-test will be completed by using the SAS/STAT® PROC MIXED procedure. Using 
the PROC MIXED procedure allows for multivariate modelling. Model covariates are study 
site, baseline WOMAC score, and potentially other covariates. Baseline WOMAC score for the 
first dose comes from the baseline visit. Baseline WOMAC score for the second dose comes 
from the second dose visit. 


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Descriptive statistics will include number of observations, unadjusted mean, standard deviation, 
median, minimum and maximum. Change from baseline LSM,SE and 95% CI from the mixed 
model will also be presented. The difference between the first dose (the control) and the second 
dose will be presented, and estimated via LSM from the analysis model along with 95% 
confidence intervals and associated 2-sided p-values. This model assumes that missing values 
are missing at random. Only patients that have data for both time points (i.e., change from Day 1 
to Week 12 and change from the second dose to 12 weeks after the second dose) will be 
included in the model. 
All patients who receive two doses of FX006 will be combined in the analysis and results will 
be displayed in the same table. 
Sample SAS code that can be used to implement the analysis is provided below: 
proc mixed data=<ADaM> method=type3; 
class subjid site arm;              
model chg = base site arm/ alpha=0.05 ddfm=kr outp=pred residual solution; 
random subjid; 
lsmeans arm / diff cl alpha=0.05; 
ods output diffs=diff1 lsmeans=lsml; 
run;  
quit;  
 
In the above code, "arm" refers to the first or second dose administered (coded as a 1 or 2). 
 
The analysis above will also be performed to compare the changes in WOMAC A, WOMAC B, 
WOMAC C and WOMAC total from first dose (Day 1) to Week 12 to the changes from first 
dose (Day 1) to 12 weeks after the second dose. 
 
Change from Baseline to Week 4, 8 and 12 
A second analysis will be completed for patients who receive two doses of FX006. Change in 
WOMAC A, WOMAC B, WOMAC C and WOMAC total from first dose (Day 1) to Week 4, 
Week 8 and Week 12 will be presented alongside change in WOMAC from second dose to 4, 8 
and 12 weeks after the second dose. 
This will be done using a longitudinal MMRM as described in section 4.9.1.1 with fixed effects 
for study time point (Week 4, Week 8 and Week 12), study site and baseline score. Patient will 
be the random effect.  The analysis will include all study visits of data (Week 4, 8 and 12) 
through Week 12. This model assumes that missing values are missing at random.  Separate 
models will be run for the first and second doses. 
 
This model will be run using the SAS/STAT® PROC MIXED procedure with an unstructured 
correlation matrix to model the within-subject errors.  If the unstructured covariance matrix does 
not converge when fitting the mixed model, further investigation into the most appropriate 


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correlation matrix will be conducted.  The final selection of the correlation matrix to be used in 
fitting the mixed model will be fully documented in the results section of the clinical study 
report. 
This model will provide the adjusted LSM estimates at each visit with the corresponding 
standard error and associated 95% confidence interval. 
 
In addition to change from baseline, descriptive statistics for the unadjusted observed WOMAC 
values will also be tabulated.   
The same analysis that is described above for change from baseline will also be performed for 
percent change from baseline. Percent change from baseline will be calculated as follows: 
Percent change from BL = (Value – BL value)/BL value * 100  
Line plots presenting observed, LSM change and LSM percent change from baseline in 
WOMAC A, WOMAC B, WOMAC C and WOMAC total score over time will be produced. In 
these plots, Week 4, Week 8 and Week 12 as well as 4, 8 and 12 weeks after the second dose, 
will be presented. There will be a separate line for the first and second dose along with standard 
deviation bars for observed values and standard error bars for adjusted values. LSM change 
from baseline and percent change from baseline will come from separate mixed models as 
described above. 
The analysis above will also be done where change in WOMAC A, WOMAC B, WOMAC C 
and WOMAC total from first dose (Day 1) to Week 4, Week 8 and Week 12 will be presented 
alongside change in WOMAC from first dose (Day 1) to dose to 4, 8 and 12 weeks after the 
second dose. 
 
4.9.1.3. 
Responders 
Responders are defined as patients who have ≥50% decrease in the WOMAC A score from 
baseline at a given visit. Descriptive statistics (number of evaluable patients and number and 
percent with ≥50% response) will be presented for Weeks 4 through 52 by the following groups. 
Each group will be displayed as a different column in the same table, in this order:  
1. Patients receiving the second dose at Week 12  
2. Patients receiving the second dose at Week 16 
3. Patients receiving the second dose at Week 20 
4. Patients receiving the second dose at Week 24 
5. Patients receiving only one dose 
6. All patients, first dose – all patients through patient discontinuation, study completion 
(through Week 12 or Week 24), or until the second dose is received (whichever happens 
sooner) 
Response rate will be plotted by group with a bar chart.  
Additionally, for Week 12, a continuous responder curve will display the cumulative proportion 
of responders on the y-axis versus the criteria/cut point used to define a responder on the x-axis; 


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in this figure, lines will display the proportion of patients responding under various % 
improvement cut points by group. Each group will be plotted on a separate line. Jitter will be 
used as needed to distinguish overlapping data. 
4.9.1.4. 
Area Under the Effect Curve (AUE) for Change from Baseline in WOMAC 
over Time 
The Area Under the Effect curve (AUE) for change from baseline in WOMAC A, B, C and total 
score over various time intervals will be examined.   
AUE will be calculated from a linear trapezoidal rule using the following formula for change 
from baseline in WOMAC A, WOMAC B, WOMAC C and WOMAC total: 
ܣܷܧ௧೔ି௧೔శ೙ൌ෍ሺሺܹܦ௜൅ܹܦ௜ାଵሻ/2ሻ∗ሺݐ௜ାଵെݐ௜ሻ
௧೔శ೙
௧೔
 
Where WDi = WOMAC difference (change) from baseline in WOMAC score for time ti, and 
WDi+1 = WOMAC difference (change) from baseline in WOMAC score for time ti+1, over the 
time interval ti to ti+1. (Note that the difference for ti+1 – ti will be 4 week intervals). Only non-
missing time intervals will be part of the sum for each AUE calculation (Farrar et al. 2000). 
Baseline for the first dose will be used for all WOMAC difference from baseline calculations. 
Two within patient analyses will be completed for patients who receive two doses of FX006. In 
the first analysis, the AUE for the change from baseline for the first dose from Week 4 to Week 
12 will be compared to the AUE for the change from baseline for the second dose from 4 to 12 
weeks after the second dose for all patients. In the second analysis, the AUE for the change from 
baseline for the first dose from Week 4 to the second dose will be compared to the AUE for the 
change from baseline for the second dose from 4 weeks after the second dose to the comparable 
period after the second dose. 
Comparison of change from baseline to Week 12 for the first and second doses  
AUE for WOMAC A, WOMAC B, WOMAC C and WOMAC total change from baseline for 
the first dose from Week 4 Week 12 will be compared to AUE for WOMAC A, WOMAC B, 
WOMAC C and WOMAC total for the change from baseline for the second dose from 4 to 12 
weeks after the second dose using a paired t-test. The examination of WOMAC A (Pain) will be 
an indication of the durability of the pain relief response, where WOMAC B (Stiffness) and 
WOMAC C (Function) will provide an indication of the durability of the responses for these 
two sub-scales over the course of two doses. 
The paired t-test will be completed by using the SAS/STAT® PROC MIXED procedure. Model 
covariates are study site, baseline WOMAC score, and potentially other covariates. Baseline 
WOMAC score for the first dose comes from the first dose visit. Baseline WOMAC score for 
the second dose comes from the second dose visit. Sample SAS code provided in section 4.9.1.2 
will be used. 
Descriptive statistics will include the LSM and standard error, 95% confidence interval, LSM 
difference from control (first dose Week 4 to Week 12), and 2-sided p-value. This model 
assumes missing at random and only includes observed data; missing data are not imputed in 


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this model. Only patients that have data for both time points (i.e., first dose Week 4 to Week 12 
and second dose Week 4 to Week 12) will be included in the model. 
All patients who receive two doses of FX006 will be combined in the analysis and results will 
be displayed in the same column. 
The analysis above will also be performed where baseline for the second dose is defined as the 
baseline/Day 1 assessment prior to administration of the first dose of study treatment. 
 
Comparison of change from baseline to second dose and change from second dose to 
comparable period after second dose 
AUE for WOMAC A, WOMAC B, WOMAC C and WOMAC total change from baseline for 
the first dose from Week 4 to the second dose will be compared to the AUE for WOMAC A, 
WOMAC B, WOMAC C and WOMAC total change from baseline for the second dose from 4 
weeks after the second dose to the comparable period after the second dose using a paired t-test. 
The paired t-test will be completed by using the SAS/STAT® PROC MIXED procedure. Model 
covariates are study site, baseline WOMAC score, and potentially other covariates. Baseline 
WOMAC score for the first dose comes from the baseline visit. Baseline WOMAC score for the 
second dose comes from the second dose visit. Sample SAS code provided in section 4.9.1.2will 
be used. 
Descriptive statistics will include the LSM and standard error, 95% confidence interval, LSM 
difference from control (first dose to second dose), and 2-sided p-value. This model assumes 
missing at random and only includes observed data; missing data are not imputed in this model. 
Only patients that have data for both time points will be included in the model. 
Table 3 shows the AUE intervals that will be computed and compared: 
Table 3 
AUE Change from Baseline Comparisons 
AUE 
Patients receiving 
the second dose at 
Week 12  
Patients receiving 
the second dose at 
Week 16 
Patients receiving 
the second dose at 
Week 20 
Patients receiving 
the second dose at 
Week 24 
First Dose 
Week 4 to Week 12 
Week 4 to Week 16 
Week 4 to Week 20 
Week 4 to Week 24 
Second 
Dose 
Second Dose Week 4 
to Week 12 (Week 
16 to Week 24) 
Second Dose Week 4 
to Week 16 (Week 
20 to Week 32) 
Second Dose Week 4 
to Week 20 (Week 
24 to Week 40) 
Second Dose Week 4 
to Week 24 (Week 
28 to Week 48) 
 
Both within patient analyses will be presented in the same table. Each group will be displayed as 
a different column in the same table, in this order: 
1. All patients receiving two doses 
2. Patients receiving the second dose at Week 12  


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3. Patients receiving the second dose at Week 16 
4. Patients receiving the second dose at Week 20 
5. Patients receiving the second dose at Week 24 
 
The analysis above will also be performed where baseline for the second dose is defined as the 
baseline/Day 1 assessment prior to administration of the first dose of study treatment. 
All AUE data will be presented in a data listing. For patients receiving only one dose, the AUE 
for change from baseline for Week 4 to Week 12 will be presented. 
 
 
4.9.2. 
KOOS 
The KOOS QOL subscale (http://www.koos.nu/) has 4 questions, each of which is assigned a 
score from 0 to 4 (0=none, 1=mild, 2=moderate, 3=severe, 4=extreme). A normalized score 
(100 indicating no symptoms and 0 indicating extreme symptoms) is calculated using this 
formula: 100-AVERAGE(Q1-Q4)/4*100. Scores are calculated at each assessment time point 
(baseline, Week 4, Week 8, Week 12, etc.). Missing data rules are as presented in section 4.2.8.  
The KOOS QOL subscale will be analyzed similarly to the WOMAC endpoints described in 
sections 4.9.1.1and 4.9.1.2. Change from baseline calculations will be based on the same time 
points that are described for WOMAC.  
4.9.3. 
Daily activity measured as steps per day 
Steps per day data are collected from baseline to Week 12, so analysis only applies to a single 
injection of FX006. Weekly mean steps per day from Fitbit data will be calculated for baseline 
through Week 12 using the visit windows presented in section 4.2.9. Values of <1000 will be set 
to missing since they were considered invalid upon review of the data. Handling of missing data 
is presented in section 4.2.8.  
A cumulative activity score will be calculated for each patient, defined as the incremental sum 
of the weekly average between Weeks 1 and 12. Incremental sum of weekly mean steps per day 
will be calculated as follows: 
 Incremental sum (Week 1) = Weekly mean steps per day (Week 1) 
 Incremental sum (Week 2) = Incremental sum (Week 1) + Weekly mean steps per 
day (Week 2) 
 Incremental sum (Week x) = Incremental sum (x-1) + Weekly mean steps per day 
(Week x) 
Descriptive statistics will include number of observations, unadjusted mean, standard deviation, 
median, minimum and maximum values by week. Values presented will be actual weekly mean 
steps per day, change from baseline in weekly mean steps per day, and incremental sum of 
weekly mean steps per day. A line plot will present each of these values by week. 


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A responder analysis will be performed in the same way that is described in section 4.9.1.3. 
Steps per day (Fitbit) responders are defined as patients who have ≥10% increase in weekly 
mean steps per day from baseline at a given visit. 
The correlation between change from baseline in steps per day and change from baseline in 
WOMAC A, B, C and total score and the KOOS QOL subscale at Week 4, Week 8 and Week 
12 will be explored. Pearson correlation will be used if both parameters are normally 
distributed. Spearman correlation will be used if either parameter is not normally distributed. 
The mean and median values for each parameter and the correlation coefficient will be 
presented in a table. Change from baseline for WOMAC A, B, C and total score and the KOOS 
QOL subscale versus change from baseline for average steps per day at Week 4, Week 8 and 
Week 12 will be presented in scatter plots, which will also include a best fit line.  
A data listing will present steps per day for each patient as well as number of days that 
contributed to each weekly average and the number that were missing.   
4.9.4. 
GPAQ 
GPAQ domains (activity at work, travel to and from places and recreational activities) and total 
will be presented descriptively at the two time points collected (baseline and Week 12). Average 
MET-minutes of moderate or vigorous physical activity per day will be calculated by domain 
and overall according to the GPAQ Analysis Guide. The change in average MET-minutes of 
physical activity per day from baseline to Week 12 will also be presented.  
Missing data rules are presented in section 4.2.8. Descriptive statistics will include number of 
observations, unadjusted mean, standard deviation, median, minimum and maximum. These 
statistics will be presented for all patients combined.  
The correlation between change from baseline in average MET-minutes per day from the total 
GPAQ (all domains combined) and change from baseline in average steps per day will be 
explored at baseline and Week 12 separately for all patients combined. Pearson correlation will 
be used if both parameters are normally distributed. Spearman correlation will be used if either 
parameter is not normally distributed. The mean and median values by visit for each parameter, 
and the correlation coefficient by visit will be presented in a table. Average MET-minutes per 
day versus average steps per day for each visit will be presented in scatter plots, which will also 
include a best fit line.  
4.9.5. 
Sensitivity Analyses 
Sensitivity analyses may be performed if required to better understand study results. Any 
sensitivity analyses will be identified as post-hoc in the clinical study report. 
4.10. 
Safety Analyses 
Safety analyses will be conducted using the SP. All change from baseline values will be 
calculated based on the pre-dose (screening) value. 
 


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4.10.1. 
Adverse Events 
Adverse events will be coded using the MedDRA (version 19.1) coding system and displayed in 
tables and data 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. 
Adverse events will be summarized by patient incidence rates; therefore, in any tabulation, a 
patient contributes only once to the count for a given SOC or preferred term. 
Summary tables will display the number and percentage of patients who experienced at least 
one TEAE in each of the following categories: 
 Any TEAE 
 Any Serious Adverse Event (SAE) 
 Any TEAE leading to study discontinuation 
 Any TEAE by severity (grade 1-5) 
 Any TEAE by relationship 
 Any index-knee related TEAE 
 Any index-knee related SAE 
 Any index-knee related TEAE leading to study discontinuation  


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 Any index-knee related TEAE by severity (grade 1-5) 
 Any index-knee 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-knee related TEAEs by SOC and PT 
 All index-knee related TEAEs related to study drug by SOC and PT 
 All index-knee related TEAEs by maximum severity by SOC and PT 
Summary tables and the tabulation of All TEAEs by SOC and PT will be presented for the 
following patient groups and time periods, with a separate table for each patient group: 
1. Patients receiving only one dose 
a. First dose to Week 12 
b. First dose to Week 24 (end of study) 
2. Patients receiving the second dose at Week 12  
a. First dose to Week 12 
b. Week 12 to Week 24 
c. Week 12 to Week 52  
3. Patients receiving the second dose at Week 16 
a. First dose to Week 16 
b. Week 16 to Week 32 
c. Week 16 to Week 52 
4. Patients receiving the second dose at Week 20 
a. First dose to Week 20 
b. Week 20 to Week 40 
c. Week 20 to Week 52 
5. Patients receiving the second dose at Week 24 
a. First dose to Week 24 
b. Week 24 to Week 48 
c. Week 24 to Week 52 


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Summary tables and all tabulations will be presented for the following time periods for patients 
receiving two doses only (same table): 
1. Baseline to Week 52 
2. Baseline to Week 12 
3. Second dose to 12 weeks after second dose 
Date and time of onset of TEAE will be used to assign the time periods. 
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. 
If an event has a TEAE start date that, after imputation rules are applied, is not complete enough 
to determine the time period in which the TEAE occurred, that event will not be included in the 
tabulations by study day. 
Formal hypothesis-testing of AE incidence rates will not be performed. 
By-patient listings will be provided for the following, for all patients:  patient deaths, SAEs and 
AEs leading to discontinuation. 
4.10.2. 
Laboratory Data 
Clinical laboratory values will be expressed in the international system of units (SI). 
The following values will be summarized for each hematology and clinical chemistry laboratory 
parameter for all patients combined: 
1. Baseline (Screening) - Observed  
2. Second dose visit (two-dose group only) - Observed and change from baseline 
3. Final study visit - Observed and change from baseline 
In the event of repeat values, the last non-missing value per study visit will be used.   
All laboratory data, including Common Terminology Criteria for Adverse Events (CTCAE) 
4.03 grade, will be provided in data listings. See Appendix A for CTCAE grade definitions. 
4.10.3. 
Vital Signs, Physical Examination, and Index Knee Assessment 
The following values will be summarized for each vital sign parameter for all patients 
combined: 
1. Baseline - Observed  
2. Second dose visit (two-dose group only) - Observed and change from baseline 
3. Final study visit - Observed and change from baseline 


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In the event of repeat values, the last non-missing value per study visit will be used.  
Vital sign measurements will be presented for each patient in a data listing. 
All clinically significant abnormalities noted in the physical examination will be presented in a 
data listing. 
The following values will be summarized for incidence of inflammation, as determined from the 
index knee assessment, for all patient combined: 
1. Baseline - Observed  
2. Second dose visit (two-dose group only) - Observed  
3. Final study visit - Observed  
For those patients experiencing inflammation, the details of the inflammation (tenderness, 
swelling, effusion, heat/redness, Baker’s cyst) will also be presented. In these tabulations, 
percentages will be based on those patients who have a non-missing index knee assessment at a 
given visit.  
Index knee assessment as well as index knee aspiration data will be presented in a data listing. 
4.10.4. 
Electrocardiogram 
Electrocardiogram (ECG) data for each patient will be provided in a data listing. 
4.10.5. 
Index Knee X-ray 
Index knee X-rays are performed at Screening for all patients, and at Week 52/End of Study for 
patients that receive a second injection. The X-rays are read at a central imaging laboratory and 
are evaluated for joint space narrowing (JSN), subchondral bone changes (SBC), osteonecrosis, 
and insufficiency fracture at baseline and the end of study. Two independent radiologists will 
initially read and score each X-ray.  
JSN 
Joint space narrowing will be scored in two locations (medial and lateral tibiofemoral 
compartments) according to the following 4-point ordinal scale of 0 to 3 scale: 
0. None: Normal appearance. 
1. Mild: Presence of mild narrowing. 
2. Moderate: Presence of moderate narrowing. 
3. Severe: Presence of severe narrowing 
Joint space narrowing for each location will be defined as follows: 
 If Reader 1 and Reader 2 agree (are concordant) on the JSN score, then that score will be 
used in the analysis. 
 If Reader 1 and Reader 2 do not agree (are discordant) then the average score of Reader 
1 and Reader 2 will be obtained and used in the analysis. 
At each visit, the maximum score of the two locations as defined above will be used as the 
analysis value. 


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SBC 
SBC will be derived by determining the presence/absence (0=absent, 1=present) of sclerosis 
and/or bone attrition in each of four locations (medial femur, lateral femur, medial tibia and 
lateral tibia).  SBC will be presented overall, rather than by category or location and will be 
derived as follows: 
 For each of the 8 possible categories/locations, (sclerosis and bone attrition at each of 
four locations): 
o If Reader 1 and Reader 2 agree (are concordant) on the SBC score, then that 
score will be used in the analysis.  
o If Reader 1 and Reader 2 do not agree (are concordant) on the SBC score, then a 
score of 0 (absent) will be used in the analysis. 
If any of the 8 categories/locations are 1 (present), then the SBC will be considered 
present.  It will be considered 0 (absent) only if all of the parameters are 0 (absent).   
 
Osteonecrosis and Insufficiency Fracture 
Osteonecrosis and insufficiency fracture are each measured on a binary scale as absent or 
present (0=absent, 1=present) and will be adjudicated as follows: 
 If Reader 1 and Reader 2 agree (are concordant) on the score of absent or present, then 
that score is used in the analysis. 
 If Reader 1 and Reader 2 do not agree (are discordant) on the score of absent or present, 
then the X-ray will be read by a third independent radiologist and scored as absent or 
present. The adjudicated score will agree with either Reader 1 or Reader 2 and that score 
will be used in the analysis. 
Change from baseline to end of study in JSN score will be presented for two-dose patients by 
patient group (timing of second dose) and for all two-dose patients combined. Any patients 
whose serial x-rays demonstrate a ≥ 2-point grade increase in JSN will be categorized as 
indicating Chondrolysis. The frequency and percentage of Chondrolysis will be presented in a 
summary table for the PPIP and SP separately.  
Shift tables of joint space narrowing, subchondral bone changes, osteonecrosis and insufficiency 
fracture will be presented for two-dose patients, showing shifts from baseline to the end of study 
by patient group (timing of second dose) and for all two-dose patients combined. These tables 
will be presented for the PPIP and SP separately. 
These X-ray data for all patients, including results for each reader, will be presented in a by 
patient listing. A separate listing will present baseline Kellgren-Lawrence (K-L) Grade. 
After review of X-ray results additional sensitivity analyses may be performed to better 
understand imaging results. 


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4.10.6. 
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. 
 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 concomitant or pain/restrictive) and whether the CM was used for 
treatment of an AE. 
4.10.7. 
Surgical Procedures 
Surgical procedures that occurred during the study will be provided in a data listing. 


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5. 
CHANGES TO PLANNED ANALYSES 
In the original protocol the intended analysis was to compare the responses for those patients 
who received only a single dose to those patients who received two doses of FX006. During the 
study >90% of the patients enrolled have received a second dose, with approximately 10 
patients only receiving one dose. This limited enrollment in a single dose does not adequately 
support making the protocol specified one-dose to two-dose comparisons for safety and 
exploratory efficacy meaningful. These comparisons have been eliminated from planned 
analyses. 
 
According to the protocol, time to maximal pain relief response with WOMAC A (pain) 
following the first and second doses of FX006 would be examined using a Kaplan-Meier 
procedure. Instead, the time to second dose was examined using the Kaplan-Meier procedure as 
this provides a better indication of durability of first-dose response. 
 


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6. 
REFERENCES 
American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. 
Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 
update. Arthritis Rheum 2000;43(9):1905-1915. 
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. 
Bellamy N. WOMAC Osteoarthritis Index User Guide. Version X. Brisbane, Australia 2011. 
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. 
Farrar JT, Portenoy RK, Berlin, JA, Kinman JL, and Strom BL. Defining the clinically 
important difference in pain outcome measures. Pain 2000; 88:287-294 
Goldring SR, Goldring MB. Clinical aspects, pathology and pathophysiology of osteoarthritis. J 
Musculoskelet Neuronal Interact 2006;6(4):376–378. 
Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, Towheed T, Welch 
V, Wells G, Tugwell P. American College of Rheumatology 2012 Recommendations for the Use 
of Nonpharmacologic and Pharmacologic Therapies in Osteoarthritis of the Hand, Hip, and 
Knee. Arthritis Care & Research 2012; 64:465-474. 
Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, Gunther K, 
Hauselmann H, Herrero-Beaumont, Kaklamanis P, Lohmander S, Leeb B, Lequesne M, 
Mazieres B, Martin-Mola E, Pavelka K, Pendleton A, Punzi L, Serni U, Swoboda B, Verbruggen 
G, Zimmerman-Gorska I, Dougados M.  EULAR Recommendations 2003: an evidence based 
approach to the management of knee osteoarthritis: Report of a Task Force of the Standing 
Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT).  Ann 
Rheum Dis 2003;62(12):1145–1155. 
Sellam J and Berenbaum F.  The role of synovitis in pathophysiology and clinical symptoms of 
osteoarthritis.  Nature Reviews Rheumatology  2010;6:625-635. 
Wenham CYJ and Conaghan PG.  The role of synovitis in osteoarthritis.  Ther Adv Musculoskel 
Dis  2010;2:349-359. 


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APPENDIX A. LABORATORY GRADE DEFINITIONS  - CTCAE 4.03  
Lab Parameter 
Hypo/Hyper 
CTCAE Definition 
SI Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Alanine 
Aminotransferase  
Hyper 
Alanine Aminotransferase 
increased 
IU/L 
>ULN-3xULN 
>3-5xULN 
>5-20xULN 
>20xULN 
Albumin 
Hypo 
Hypoalbuminemia 
g/L 
<LLN-30 
<30-20 
<20 
- 
Alkaline Phosphatase 
Hyper 
Alkaline Phosphatase 
increased 
IU/L 
>ULN-
2.5xULN 
>2.5-5xULN 
>5-20xULN 
>20xULN 
Aspartate 
Aminotransferase 
Hyper 
Aspartate Aminotransferase 
increased 
IU/L 
>ULN-3xULN 
>3-5xULN 
>5-20xULN 
>20xULN 
Bilirubin 
Hyper 
Blood bilirubin increased 
umol/L 
>ULN-
1.5xULN 
>1.5-3xULN 
>3-10xULN 
>10xULN 
Calcium 
 
Hypo 
 
Hypocalcemia 
mmol/L 
<LLN-2 
<2-1.75 
<1.75-1.5 
<1.5 
Calcium 
 
Hyper 
 
Hypercalcemia 
mmol/L 
>ULN-2.9 
>2.9-3.1 
>3.1-3.4 
>3.4 
Creatinine 
Hyper 
Creatinine increased 
umol/L 
>1-1.5x 
baseline; 
>ULN-
1.5xULN 
>1.5-3x 
baseline; >1.5-
3x ULN 
>3x baseline; >3-
6xULN 
>6xULN 
Glucose 
Hyper 
Hyperglycemia 
mmol/L 
>ULN-8.9 
>8.9-13.9 
>13.9-27.8 
>27.8 
Potassium 
Hypo 
Hypokalemia 
mmol/L 
<LLN-3 
<LLN-3 
<3-2.5 
<2.5 


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Lab Parameter 
Hypo/Hyper 
CTCAE Definition 
SI Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Potassium 
Hyper 
Hyperkalemia 
mmol/L 
>ULN-5.5 
>5.5-6 
>6-7 
>7 
Sodium 
Hypo 
 
Hyponatremia 
mmol/L 
<LLN-130 
- 
<130-120 
<120 
Sodium 
Hyper 
Hypernatremia 
mmol/L 
ULN-150 
>150-155 
>155-160 
>160 
Hemoglobin 
Hypo 
Anemia 
g/L 
<LLN-100 
<100-80 
<80 
- 
Hemoglobin 
Hyper 
Hemoglobin increased 
g/L 
Increase in>0-
20 above ULN 
or above 
baseline 
if baseline is 
above ULN 
Increase in 
>20-40  
above ULN or 
above baseline 
if baseline is 
above ULN 
Increase in >40 
above 
ULN or above 
baseline if 
baseline is above 
ULN 
- 
Leukocytes 
Hypo 
White blood cells decreased 
10^9/L 
<LLN-3.0 
<3.0-2.0 
<2.0-1.0 
<1.0 
Leukocytes 
Hyper 
Leukocytosis 
10^9/L 
- 
- 
>100 
- 
Lymphocytes 
Hypo 
Lymphocyte count decreased 
10^9/L 
<LLN-0.8 
<0.8-0.5 
<0.5-0.2 
<0.2 
Lymphocytes 
Hyper 
Lymphocyte count increased 
10^9/L 
- 
>4-20 
>20 
- 
Neutrophils 
Hypo 
Neutrophils count decreased 
10^9/L 
<LLN-1.5 
<1.5-1 
<1-0.5 
<0.5 


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Lab Parameter 
Hypo/Hyper 
CTCAE Definition 
SI Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Platelets 
Hypo 
Platelet count decreased 
10^9/L 
<LLN-75 
<75-50 
<50-25 
<25 
The following hematology and chemistry parameters collected in the study are not gradable with CTCAE v4.03: 
 Bicarbonate (removed from version 4.x; it was available in version 3) 
 Blood urea nitrogen 
 Chloride 
 Basophils 
 Eosinophils 
 Erythrocyte count (RBC) 
 Hematocrit  
 Mean cell volume 
 Monocytes  
 Total protein 
 Uric acid 


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APPENDIX B. STUDY VISIT FLOW CHART