Conditions: Osteoarthritis, Hip
Keywords: Osteoarthritis Hip Pain Intra-articular Injection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 70
Healthy volunteers: no

Brief summary:
This is a two-part, multi-center, randomized, double-blind, placebo-controlled, parallel-group study in patients with hip OA. Approximately 70 patients will be enrolled in Part I and approximately 440 patients will be enrolled in Part II of the study. In each part, patients will be randomized to one of two treatment groups (1:1) and treated with a single IA injection of either 32 mg FX006 or normal saline.

Detailed description:
This is a two-part, multi-center, randomized, double-blind, placebo-controlled, parallel-group study in patients with hip OA. Approximately 70 patients will be enrolled in Part I and approximately 440 patients will be enrolled in Part II of the study. In each part, patients will be randomized to one of two treatment groups (1:1) and treated with a single IA injection of either 32 mg FX006 or normal saline.

FX006 or saline placebo will be administered as a single IA injection with a 12-week follow-up period in the double-blind phase.

Patients participating in Part I of the study will be treated with a single IA injection of either 32 mg FX006 or normal saline and will return for follow up visits at Weeks 12, 16, 20, and 24. The patients will be discontinued at the time of notification by the Investigator.

Patients participating in Part II of the study will be treated with a single IA injection of either 32 mg FX006 or normal saline and will return for follow up visits at Weeks 12, 16, 20, and 24.

Patients participating in Part II of the study that are not clinically indicated for a second injection at Week 12 will return to the clinic at Weeks 16, 20, and 24 and will receive an open-label injection of FX006 at the first evaluation where the patient has been determined to meet all criteria. Patients will then return for follow-up visits every 4 weeks for 12 weeks post second injection and will complete the study 12 weeks post second injection (e.g., Week 24, 28, 32, or 36 depending on when the patient receives the open-label injection).

Patients participating in Part II of the study who are not eligible for a second injection after evaluation at Weeks 12, 16, 20, and 24 will complete the study at the Week 24 visit and complete the End of Study (EOS) assessments.

Arms:
arm 1: FX006 32mg arm 2: Normal Saline

Interventions: intervention 1: FX006 intervention 2: Normal saline
Intervention descriptions: intervention 1: Single Intra-articular injection intervention 2: Single Intra-articular injection

Protocol document:
Prot_000.pdf: 
 
CONFIDENTIAL INFORMATION 
CLINICAL STUDY PROTOCOL 
 
A Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy 
and Safety of FX006 in Patients with Hip Osteoarthritis 
 
PROTOCOL NUMBER: 
FX006-2018-015 
 
PHASE: 
3 
 
 
STUDY MEDICATION(S): FX006 
 
INDICATION: 
Osteoarthritis of the hip 
  
MEDICAL MONITOR: 
Robert D. Arbeit, M.D. 
                                           
 
 
 
SPONSOR: 
Flexion Therapeutics 
10 Mall Road, Suite 301 
Burlington, Massachusetts 01803 
Tel: 617-762-6783 
 
 
 
DATE: 
31 JUL 2019 
  
VERSION: 
Version 3.0 (Amendment 2.0) 
 
SUPERSEDES:  
Version 2.0 (Amendment 1.0; 13 MAR 2019) 
 




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TABLE OF CONTENTS 
1. 
ABBREVIATIONS AND DEFINITION OF TERMS ................................................9 
2. 
SYNOPSIS .................................................................................................................12 
3. 
ETHICS ......................................................................................................................21 
3.1. 
Institutional Review Board/Ethics Committee ...........................................................21 
3.2. 
Ethical Conduct of Study ............................................................................................21 
3.3. 
Patient Information and Consent ................................................................................21 
4. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .................22 
4.1. 
Investigators ................................................................................................................22 
4.2. 
Study Administrative Structure ..................................................................................22 
5. 
INTRODUCTION ......................................................................................................23 
5.1. 
Osteoarthritis ...............................................................................................................23 
5.2. 
Background .................................................................................................................23 
5.2.1. 
Investigational Medicinal Product:  FX006 ................................................................23 
5.2.2. 
Rationale for FX006 in Hip Osteoarthritis .................................................................24 
5.2.3. 
Non-Clinical Toxicology ............................................................................................24 
5.2.4. 
Systemic and Local Pharmacokinetics (PK) in Patients with Osteoarthritis of 
the Knee ......................................................................................................................25 
5.2.5. 
Pharmacodynamics (PD) in Patients with Osteoarthritis of the Knee ........................25 
5.2.6. 
Efficacy in Patients with Osteoarthritis of the Knee ..................................................25 
5.2.7. 
Systemic and Local Safety in Patients with Osteoarthritis of the Knee .....................26 
5.2.8. 
Rationale for Protocol Amendment ............................................................................27 
5.2.9. 
Experience with FX006 Administered IA in Patients with OA of the Hip ................28 
5.2.10. 
Conclusion ..................................................................................................................28 
6. 
STUDY OBJECTIVES ..............................................................................................29 
6.1. 
Primary Objective .......................................................................................................29 
6.1.1. 
Part I ............................................................................................................................29 
6.1.2. 
Part II ..........................................................................................................................29 
6.2. 
Secondary Objectives .................................................................................................29 
6.2.1. 
Part I ............................................................................................................................29 
6.2.2. 
Part II ..........................................................................................................................29 
6.3. 
Open Label Phase Objectives .....................................................................................29 
6.3.1. 
Secondary Objective: ..................................................................................................29 


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6.3.2. 
Primary Objective: ......................................................................................................29 
7. 
INVESTIGATIONAL PLAN .....................................................................................30 
7.1. 
Overall Study Design and Plan ...................................................................................30 
7.1.1. 
Flow of Study Participation ........................................................................................30 
7.2. 
Site Staffing Requirements .........................................................................................31 
7.3. 
Discussion of Study Design ........................................................................................33 
7.3.1. 
Rationale for Study Population ...................................................................................33 
7.3.2. 
Rationale for Dose Selection ......................................................................................33 
7.3.3. 
Rationale for Study Parameters ..................................................................................33 
7.3.4. 
Rationale for Control Type .........................................................................................33 
7.3.5. 
Rationale for Blinding Approach ................................................................................33 
7.4. 
Selection of Study Population ....................................................................................34 
7.4.1. 
Number of Patients .....................................................................................................34 
7.4.2. 
Inclusion Criteria ........................................................................................................34 
7.4.3. 
Exclusion Criteria .......................................................................................................35 
7.4.4. 
Second Injection Inclusion Criteria (Part II Patients Only) ........................................37 
7.4.5. 
Second Injection Exclusion Criteria (Part II Patients Only) .......................................38 
7.4.6. 
Removal of Patients from Therapy or Assessments ...................................................38 
7.4.7. 
Screen Failures ............................................................................................................39 
7.5. 
Treatment Administered .............................................................................................39 
7.5.1. 
Study Medication Treatment Arms ............................................................................39 
7.5.2. 
Identity of Investigational Product(s) .........................................................................39 
7.5.3. 
Identity of Reference Compound ................................................................................40 
7.5.4. 
Receipt, Preparation, Dispensing and Storage ............................................................40 
7.5.5. 
Packaging and Labeling of Study Medication ............................................................40 
7.5.6. 
Return of Study Medication ........................................................................................40 
7.5.7. 
Method of Assigning Patients to Treatment Groups ..................................................40 
7.5.8. 
Blinding ......................................................................................................................40 
7.5.9. 
Breaking The Blind .....................................................................................................43 
7.5.10. 
Investigational Medicinal Product Administration Procedure ...................................43 
7.5.11. 
Treatment Compliance ................................................................................................44 
7.6. 
Prior and Concomitant Therapy ..................................................................................44 
7.6.1. 
Allowable Medications/Non-Pharmacologic Therapies .............................................44 


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7.6.2. 
Prohibited Medications/Non-Pharmacologic Therapies .............................................45 
7.6.3. 
Rescue Medication ......................................................................................................46 
7.7. 
Study Variables ...........................................................................................................46 
7.7.1. 
Safety Variables ..........................................................................................................46 
7.7.2. 
Efficacy Variables ......................................................................................................46 
7.8. 
Schedule of Study Assessments..................................................................................47 
7.9. 
Study Procedures ........................................................................................................50 
7.9.1. 
Informed Consent .......................................................................................................50 
7.9.2. 
Randomization ............................................................................................................50 
7.9.3. 
Review of Eligibility, Medical History, Prior Treatment and Medications ...............50 
7.9.4. 
Physical Examination .................................................................................................50 
7.9.5. 
Index Hip Assessment ................................................................................................51 
7.9.6. 
Index Hip X-ray ..........................................................................................................51 
7.9.7. 
Vital Signs ..................................................................................................................51 
7.9.8. 
Height, Weight and BMI Determination ....................................................................51 
7.9.9. 
Central Clinical Laboratory Evaluations ....................................................................52 
7.9.10. 
Index Hip Aspiration ..................................................................................................53 
7.9.11. 
Second Injection Criteria ............................................................................................53 
7.9.12. 
Rescue Medication Dispensing and Accountability ...................................................53 
7.9.13. 
Accurate Pain Reporting and Placebo Response Reduction Training ........................53 
7.9.14. 
Patient Questionnaires ................................................................................................53 
7.9.15. 
Review of Adverse Events and Concomitant Medications ........................................54 
8. 
ADVERSE EVENTS..................................................................................................55 
8.1. 
Definitions ..................................................................................................................55 
8.2. 
Monitoring of Adverse Events ....................................................................................56 
8.2.1. 
Monitoring of Laboratory Assessments and Other Diagnostic Tests .........................56 
8.2.2. 
Adverse Events That Occur During the Injection Procedure .....................................56 
8.2.3. 
Reporting Arthralgia in the Index Hip ........................................................................57 
8.3. 
Assessment of Adverse Events ...................................................................................57 
8.3.1. 
Assessment of Seriousness .........................................................................................57 
8.3.2. 
Assessment of Severity ...............................................................................................57 
8.3.3. 
Assessment of Relationship to Study Medication ......................................................57 
8.4. 
Recording of Adverse Events .....................................................................................58 


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8.4.1. 
Reporting of Serious Adverse Events .........................................................................58 
8.4.2. 
Unblinding Treatment for a Patient during the Trial ..................................................59 
8.5. 
Safety Monitoring Roles .............................................................................................59 
8.6. 
Clinical Management of Index Hip-Related Events ...................................................59 
8.7. 
Pregnancy ...................................................................................................................60 
9. 
STATISTICAL CONSIDERATIONS .......................................................................61 
9.1. 
Statistical and Analytical Plans ..................................................................................61 
9.1.1. 
Planned Analyses ........................................................................................................61 
9.2. 
General Considerations and Methods .........................................................................61 
9.2.1. 
Analysis Populations ..................................................................................................62 
9.2.2. 
Study Data ..................................................................................................................62 
9.2.2.1. 
Clinical Data – CDISC Study Data Tabulation Model (SDTM) ................................62 
9.2.2.2. 
Analysis Data – CDISC Analysis Data Model (ADaM) ............................................62 
9.2.3. 
Study Endpoints for Assessment ................................................................................62 
9.2.3.1. 
Key Primary Efficacy Endpoint..................................................................................63 
9.2.3.2. 
Key Secondary Efficacy Endpoints ............................................................................63 
9.2.3.3. 
Additional Secondary Efficacy Endpoints: ................................................................63 
9.2.4. 
Sub-Groups and Covariates ........................................................................................64 
9.3. 
Determination of Sample Size ....................................................................................64 
9.3.1. 
Sample Size Considerations .......................................................................................64 
9.4. 
General Statistical Methods ........................................................................................64 
9.4.1. 
Demographics and Baseline Characteristics ...............................................................64 
9.4.2. 
Exposure .....................................................................................................................64 
9.4.3. 
Efficacy Analyses .......................................................................................................65 
9.4.4. 
Safety Analyses ..........................................................................................................65 
10. 
DATA QUALITY ASSURANCE ..............................................................................66 
11. 
DATA HANDLING AND RECORDKEEPING .......................................................67 
11.1. 
Case Report Forms .....................................................................................................67 
11.2. 
Study Medication Accountability ...............................................................................67 
11.3. 
Rescue Medication Accountability .............................................................................67 
11.4. 
Confidentiality of Data ...............................................................................................67 
11.5. 
Retention of Records ..................................................................................................67 
11.6. 
Protocol Adherence ....................................................................................................68 


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12. 
PUBLICATION POLICY ..........................................................................................69 
12.1. 
Sponsor’s Publication Policy ......................................................................................69 
12.2. 
Site Publication ...........................................................................................................69 
13. 
REFERENCES ...........................................................................................................70 
 


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LIST OF TABLES 
Table 7-1: Commonly Prescribed Anti-depressants by Drug Class .............................................45 
Table 7-2: Schedule of Study Assessments for Double Blind Phase ...........................................48 
Table 7-3: Schedule of Study Assessments for Open Label Extension (OLE) Phase .................49 
Table 7-4: Height, Weight and BMI Determination ....................................................................52 
Table 7-5: Clinical Laboratory Panel ...........................................................................................52 
Table 7-6: Patient Questionnaires ................................................................................................54 
Table 7-7: Patient Questionnaire Sequence if Screening 1 and Screening 2 Visits are 
Combined ....................................................................................................................54 
 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Chart (Part II Patients Only) ...................................................................31 
 
 
 
 


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1. 
ABBREVIATIONS AND DEFINITION OF TERMS 
ACR 
American College of Rheumatology 
ADaM 
Analysis Data Model 
ADP  
Average Daily Pain 
ADRG 
Analysis Data Reviewer’s Guide 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
APR 
Accurate Pain Reporting 
AUE  
Area Under the Effect Curve 
BMI  
Body Mass Index 
CBD 
Cannabidiol 
CDISC SDTM 
Clinical Data Interchange Standards Consortium Study Data 
Tabulation Model 
CFR  
Code of Federal Regulations 
CGIC  
Clinical Global Impression of Change 
CI  
Confidence Interval 
CMC  
Carboxymethylcellulose Sodium 
CSR  
Clinical Study Report 
ECG  
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EOS 
End of study 
EQ-5D-5L 
EuroQol 5 Dimensions 5 Levels questionnaire 
EULAR  
European League Against Rheumatism 
FAS 
Full Analysis Set 
FBR 
Foreign Body Response 
FDA 
Food and Drug Administration 
GAD-7 
General Anxiety Disorder questionnaire-7 
GCP 
Good Clinical Practice 
HBsAg  
Hepatitis B Surface Antigen 
HCV  
Hepatitis C Virus 
HEENT 
Head, ears, eyes, nose, throat 
HIPAA  
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HOOS 
Hip injury and Osteoarthritis Outcome Score 
HPA  
Hypothalamic-pituitary-adrenal 
IA 
Intra-articular 
IB 
Investigator’s Brochure 
IM 
Intramuscular 
IRB/EC 
Institutional Review Board/Ethics Committee 
ISI 
Insomnia Severity Index 


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IV  
Intravenous 
JSN 
Joint Space Narrowing 
kg  
Kilogram 
KL 
Kellgren-Lawrence 
KOOS 
Knee injury and Osteoarthritis Outcome Score 
LSM 
Least square mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
MMRM 
Mixed model for repeated measures 
n 
Number 
NaCl  
Sodium Chloride 
NaCMC 
Sodium carboxymethylcellulose 
NRS 
Numeric Rating Scale 
NSAID 
Non-steroidal anti-inflammatory drug 
NSRI 
Non-selective serotonin reuptake inhibitors 
OA 
Osteoarthritis 
OARSI 
Osteoarthritis Research Society International 
OLE 
Open Label Extension  
OMERACT 
Outcome Measures in Rheumatology 
PCS 
Pain Catastrophizing Scale 
PD 
Pharmacodynamic 
PD-Q 
PainDETECT Questionnaire 
PGIC 
Patients’ Global Impression of Change 
PHQ-9 
Patient Health Questionnaire-9 
PLGA 
Poly[lactic-co-glycolic acid] 
PK  
Pharmacokinetic 
PRP 
Platelet Rich Plasma 
PRR 
Placebo Response Reduction 
QOL 
Quality of Life 
RBC 
Red Blood Cells 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDRG 
Study Data Reviewer’s Guide 
SI 
Sleep Interference 
SNRI 
Serotonin and norepinephrine reuptake inhibitor 
SSRI 
Selective serotonin reuptake inhibitor 
TEAE 
Treatment-emergent Adverse Event 
TENS 
Transcutaneous electrical nerve stimulation 


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TA1 
Triamcinolone Acetonide  
TAcs2 
Triamcinolone Acetonide Injectable Suspension, Immediate-Release 
(commercially available) 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
USA 
United States of America 
USP 
United States Pharmacopeia 
VAS 
Visual analogue scale 
w/w 
weight by weight 
WBC 
White Blood Cells 
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 
                                                 
1 Abbreviated in past protocols and documents as TCA 
2 Abbreviated in past protocols and documents as TCA IR 


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2. 
SYNOPSIS 
Title of Study:  A Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy 
and Safety of FX006 in Patients with Hip Osteoarthritis 
Study Centers:  Multiple centers, approximately 40-50 
Study Phase:  Phase 3 
Objectives 
Part I 
Double-Blind Objectives 
Primary: 
• 
To assess the treatment effect of FX006 on pain following an intra-articular (IA) injection in patients 
with hip osteoarthritis (OA) 
Secondary: 
• 
To assess the effect of FX006 on function, global impression of change, stiffness, quality of life, 
treatment satisfaction, sleep quality and consumption of rescue medication in patients with hip OA 
• 
To assess the safety of FX006 in patients with hip OA 
 
Part II 
Double-Blind Phase Objectives 
Primary: 
• 
To assess the efficacy of FX006 on pain following an intra-articular (IA) injection in patients with hip 
osteoarthritis (OA) 
Secondary: 
• 
To assess the efficacy of FX006 on function, global impression of change, stiffness, quality of life, 
treatment satisfaction, sleep quality and consumption of rescue medication in patients with hip OA 
• 
To assess the safety of FX006 in patients with hip OA 
Open Label Extension (OLE) Phase Objectives 
Primary: 
• 
To assess the overall safety of a second injection of FX006 in patients with hip OA 
Secondary: 
• 
To examine efficacy following a second injection of FX006 in patients with hip OA 
Study Design and Methodology: 
This is a two-part, multi-center, randomized, double-blind, placebo-controlled, parallel-group study in patients 
with hip OA.  Approximately 70 patients will be enrolled in Part I and approximately 440 patients will be 
enrolled in Part II of the study.  In each part, patients will be randomized to one of two treatment groups (1:1) and 
treated with a single IA injection of either 32 mg FX006 or normal saline. 
Eligible patients will be randomized within strata defined by Baseline Western Ontario and McMaster 
Universities Osteoarthritis Index (WOMAC) A (pain) (0-10 numeric ratings scale (NRS) average of Screening 2 
and Day 1 with the following classifications: 5.0 to < 6.0, 6.0 to < 7.0, and ≥ 7.0 to 9.0 (see Section 9 for details). 
FX006 or saline placebo will be administered as a single IA injection with a 12-week follow-up period in the 
double-blind phase.   
Patients participating in Part I of the study will be treated with a single IA injection of either 32 mg FX006 or 
normal saline and will return for follow up visits at Weeks 12, 16, 20, and 24 or up until the time of this 
amendment. The patients will be discontinued at the time of notification by the Investigator.  Patients 
participating in Part II of the study will be treated with a single IA injection of either 32 mg FX006 or normal 


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saline and will return for follow up visits at Weeks 12, 16, 20, and 24. Patients who are eligible for the second 
injection in the open-label phase at Week 12 will receive an open-label injection of FX006 at Week 12 and return 
for follow-up visits at Weeks 16, 20, and 24.  These patients will complete the study at Week 24. 
Patients participating in Part II of the study that are not clinically indicated for a second injection at Week 12 will 
return to the clinic at Weeks 16, 20, and 24 and will receive an open-label injection of FX006 at the first 
evaluation where the patient has been determined to meet all criteria.  Patients will then return for follow-up 
visits every 4 weeks for 12 weeks post second injection and will complete the study 12 weeks post second 
injection (e.g., Week 24, 28, 32, or 36 depending on when the patient receives the open-label injection).   
Patients participating in Part II of the study who are not eligible for a second injection after evaluation at Weeks 
12, 16, 20, and 24 will complete the study at the Week 24 visit and complete the End of Study (EOS) 
assessments. 
Number of Patients: 
Approximately 70 patients in Part I and approximately 440 patients in Part II will be randomized and treated in 
the double-blind phase of the study.   
Test Product, Dose and Mode of Administration: 
FX006 – an extended release formulation of triamcinolone acetonide (TA) in 75:25 poly (lactic-co-glycolic) acid 
(PLGA) microspheres.  Nominal 32 mg TA, IA administered as a single 5 mL injection into the index hip OA 
joint under fluoroscopy guidance per injection procedure. 
Reference Compound(s), Dose and Mode of Administration: 
Normal saline, sodium chloride (0.9% NaCl) solution, IA, administered as a 5 mL injection into the index hip OA 
joint under fluoroscopy guidance per injection procedure. 
Duration of Dosing: 
Single IA injection for all enrolled patients at Day 1 (Parts I and II) and a second IA injection for those patients 
enrolled in Part II of the study who meet second injection eligibility criteria at either Week 12, 16, 20, or 24. 
Inclusion Criteria 
To be included in the trial, patients must fulfill the following criteria to participate in the study: 
1. Written informed consent has been obtained prior to initiating any study specific procedures 
2. Willingness and ability to comply with the study procedures and visit schedules and ability to follow 
verbal and written instructions 
3. Patients 40 to 80 years of age, inclusive, on the day of consent 
4. Body Mass Index (BMI) ≤ 40 kg/m2 
5. Symptoms (including pain) associated with OA of the index hip for ≥ 3 months prior to Screening visit 
(patient self-report is acceptable).  
6. Moderate to severe index hip pain due to OA for >15 days over the last month (as reported by the 
patient) 
7. Currently meet the American College of Rheumatology (ACR) Criteria (clinical and radiological) for 
OA of the index hip (Altman et al, 1991): 
• 
Hip pain and radiographic femoral and/or acetabular osteophytes; 
OR  
 
• 
Hip pain and erythrocyte sedimentation rate (ESR) < 20 mm/hour and radiographic axial joint 
space narrowing 
8. Kellgren-Lawrence (KL) Grade 2 or 3 in the index hip as confirmed by X-ray during Screening visit 
(centrally read) 
9. WOMAC A (pain) score in index hip ≥ 5.0 and ≤ 9.0 (0-10 NRS scale) at Screening 2 visit and at Day 1 
10. WOMAC C (function) score in index hip ≥ 4.0 (0-10 NRS scale) at Screening 2 visit and at Day 1 
11. Ambulatory and no change in use or addition of assistive devices within 3 months prior to screening 
12. Agree to maintain the similar activity level and stable non-pharmacological therapies throughout the 
study 
13. Willingness to abstain from use of protocol-specified restricted medications. (see Section 7.6.2) 


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Exclusion Criteria 
Patients fulfilling at least one of the following criteria may not be included in the study: 
Disease-related criteria 
1. Patients who cannot washout of prohibited medications (Refer to Section 7.6.2) (e.g., opioids or other 
analgesics) 
2. Diagnosed as secondary OA in the index hip including but not limited to articular fracture, major 
dysplasia or congenital abnormality, osteochondritis dissecans, acromegaly, ochronosis, 
hemochromatosis, Wilson's disease, or primary osteochondromatosis, etc. 
3. Current or any history of ipsilateral chronic knee pain (lasting ≥ 3 months) 
4. Contralateral hip and/or knee pain ≥ 4.0 (0-10 NRS scale) within 1 month prior to Screening visit 
5. Current or any history of chronic Sciatica (lasting ≥ 3 months) 
6. Current or any history of acetabular labrum tear in the study hip 
7. Atrophic osteoarthritis, femoral head necrosis and/or collapse, or subchondral bone insufficiency 
fracture in the index hip joint determined via central reading 
8. Current or history of infection in the index hip (e.g., osteomyelitis) or current skin infection at injection 
site 
9. Concurrent chronic pain conditions with pain score ≥ 4.0 (0-10 NRS scale) within 1 month prior to 
Screening 1 visit, including but not limited to: 
• 
hip impingement syndrome, trochanteric bursalgia 
• 
peripheral or central neuropathy that may affect sensation of the index hip 
• 
non-radicular low back pain 
• 
peripheral nerve entrapment 
• 
diabetic neuropathy 
• 
post-herpetic neuralgia 
• 
post-stroke pain 
• 
fibromyalgia 
10. Major surgery or clinically significant trauma (e.g., fracture) of lower limbs within 12 months prior to 
Screening visit or with ongoing sequelae. 
11. painDETECT Questionnaire (PD-Q) score > 18 during Screening visit  
12. History or current evidence of reactive arthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing 
spondylitis, or arthritis associated with inflammatory bowel disease, systemic lupus erythematosus or 
other autoimmune diseases 
13. Any planned surgeries in the lower limbs during the study period 
Previous or concomitant treatment-related criteria 
14. Presence of surgical hardware or other foreign body in the index hip 
15. Planned/anticipated surgery that would require use of a restricted medication during the study period 
16. IA corticosteroid of any joint within 3 months of Screening visit (investigational or marketed, including 
FX006) 
17. IA treatment of index hip with any of the following agents within 6 months of Screening: any biologic 
agent (e.g., platelet rich plasma (PRP) injection, stem cells, prolotherapy, amniotic fluid injection) or 
hyaluronic acid (investigational or marketed) 
18. Intravenous (IV) or Intramuscular (IM) corticosteroids (investigational or marketed) within 3 months of 
Screening 
19. Oral corticosteroids (investigational or marketed) within 1 month of Screening 
20. Inhaled, intranasal or topical corticosteroids (investigational or marketed) within 2 weeks of Screening 
visit 


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21. Changes to lifestyle with regard to physical activity, physical therapy, acupuncture, transcutaneous 
electrical nerve stimulation (TENS), or bracing within 1 month prior to Screening; or planned or 
expected changes during the study. 
Patient-related criteria 
22. Patients with a total score of ≥ 15 or >0 on Question #9 on the Patient Health Questionnaire-9 (PHQ-9) 
at Screening visit 
23. Patients with a score of ≥ 15 on the Generalized Anxiety Disorder (GAD-7) at Screening visit 
24. Patients with Pain Catastrophizing Scale (PCS) score of ≥ 30 at Screening visit 
25. Patients with Insomnia Severity Index (ISI) Questionnaire score ≥ 15 (moderate severity) at Screening 
visit 
26. Known or suspected hypersensitivity to any form of triamcinolone or PLGA 
27. Laboratory evidence of infection with human immunodeficiency virus (HIV), positive test for hepatitis 
B surface antigen (HBsAg) or positive serology for hepatitis C virus (HCV) antibody with positive test 
for HCV Ribonucleic acid (RNA) 
28. A medical history suggesting the patient will or is likely to require a course of systemic corticosteroids 
during the study period 
29. History or evidence of active or latent systemic fungal or mycobacterial infection (including 
tuberculosis), or of ocular herpes simplex 
30. History of sarcoidosis or amyloidosis 
31. History of or active Cushing’s syndrome 
32. Medical therapy for depression, including selective or non-selective serotonin reuptake inhibitors 
(SSRIs, NSRIs, SNRIs) and tricyclics, if dose/regimen has not been stable for ≥ 6 months prior to 
Screening 
33. Use of immunomodulators, immunosuppressives, or chemotherapeutic agents within 5 years of 
Screening 
34. Active or history of malignancy within 5 years of Screening, with the exception of resected basal cell 
carcinoma, squamous cell carcinoma of the skin, or effectively managed cervical carcinoma 
35. Active substance abuse (drugs or alcohol) or history of substance abuse within the past 12 months of 
Screening 
36. Has received a live (e.g., MMR vaccine, chicken pox vaccine, rotavirus vaccine) or live-attenuated 
vaccine (e.g., FluMist, Zostavax) within 3 months of Day 1 
37. Use of any other investigational drug, biologic or device within 3 months of Screening visit 
38. Any bacterial or viral infection requiring parenteral antibiotics within 4 weeks of Day 1 or oral 
antibiotics within 2 weeks of Day 1 
39. Any other clinically significant acute or chronic medical conditions (e.g., uncontrolled diabetes) 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 
40. Patients contraindicated to the use of acetaminophen/paracetamol (allowed rescue pain medicine) per 
National Product Labeling and/or Investigator's judgment 
41. Patient is the Investigator or any Sub investigator, research assistant, pharmacist, study coordinator, 
other staff or relative thereof directly involved in the conduct of the study 
42. Women who are pregnant or nursing or plan to become pregnant during the study; men who plan to 
conceive during the study 
43. 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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Second Injection Inclusion Criteria (Part II Only): 
To be eligible to receive the second injection during the open-label phase, patients must fulfill the following 
criteria: 
1. Completed the double-blind phase of the study through Week 12 
2. No major safety concerns during the initial dose period (including allergic reaction to initial dose of 
study medication) as assessed by the Investigator and patient 
3. Clinically indicated to receive FX006, in the opinion of the Investigator and patient 
4. WOMAC A (pain) score of ≥ 3 (0-10 NRS) 
5. Compliant with study procedures and visit schedules up to the open-label injection with FX006 and the 
willingness and ability to continue to comply for additional 12 weeks after the second injection 
6. Willingness to continue abstaining from use of protocol-restricted medications during the study (Refer 
to Section 7.6.2) 
Second Injection Exclusion Criteria (Part II Only): 
Patients fulfilling at least one of the following criteria may not be included in OLE phase of the study: 
1. Clinical signs and symptoms of active hip infection or crystal disease of the index hip 
2. Received a non-protocol specified IA intervention (IA injection, IA aspiration, etc.) in index hip during 
study participation 
3. Use of immunomodulators, immunosuppressives, or chemotherapeutic agents during study participation. 
4. Received a live (e.g., MMR vaccine, chicken pox vaccine, rotavirus vaccine) or live-attenuated (e.g., 
FluMist, Zostavax) vaccine during study participation 
5. Use of any other investigational drug, device or biologic during study participation 
6. Any bacterial or viral infection requiring parenteral antibiotics within 4 weeks or oral antibiotics within 
2 weeks of second injection 
7. Skin breakdown at the hip where the injection would take place 
8. Women who are pregnant or nursing or plan to become pregnant during the study; men who plan to 
conceive during the study 
9. 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)] 
10. 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 
Procedures and Assessments: 
The study will involve a Screening period (a minimum of 10 days, up to a maximum of 30 days), dosing at 
Day 1, and four additional outpatient visits at Weeks 1, 4, 8, and 12 during the double-blind phase.  
Patients participating in Part I of the study will return to the clinic at Weeks 12, 16, 20, and 24 or up until the 
time of this amendment. The patients will be discontinued at the time of notification by the Investigator. 
Patients participating in Part II of the study who are eligible for the second injection in the open-label phase at 
Week 12 will receive an open-label injection of FX006 at Week 12 and return for follow-up visits at Weeks 16, 
20, and 24.  These patients will complete the study at Week 24.  Patients participating in Part II of the study that 
are not clinically indicated for a second injection at Week 12 will return to the clinic at Weeks 16, 20, and 24 and 
will receive an open-label injection of FX006 at the first evaluation where the patient has been determined to 
meet all criteria.  Patients participating in Part II of the study will then return for follow-up visits every 4 weeks 
for 12 weeks post second injection and will complete the study 12 weeks post second injection (e.g., Week 24, 
28, 32, or 36 depending on when the patient receives the open-label injection).   
At specified times throughout the study, patients will undergo physical examinations, index hip assessments and 
index hip X-rays; blood will be collected for laboratory safety tests, and vital signs will be collected.  Information 
regarding adverse events (AEs) and concomitant medications will be collected.   


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During out-patient visits, patients will complete accurate pain reporting (APR) and placebo response reduction 
(PRR) training prior to completing the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis 
Index, Patient Global Impression of Change (PGIC), Hip injury and Osteoarthritis Outcome Score (HOOS) 
Quality of Life (QOL) Subscale, Sleep Interference (SI) question, EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) 
and the Abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9).   
See Schedule of Assessments for full details.   
Blinding: 
The blinded-assessor technique will be used in this study in order to maintain double-blind conditions.  Key site 
staff roles are defined in Section 7.2 and a site specific blinding plan will be developed to ensure the blind is 
maintained throughout the duration of the study.  Treatments will be prepared by an unblinded 
pharmacist/coordinator who has experience with the preparation of study medication and who has been properly 
trained by the Sponsor or designee.  
IA injections will be performed by an unblinded injector.   
Full details are located in Section 7.5.8. 
IP Administration Procedure: 
IA administration into the hip joint 
• 
IA injections will be performed by the assigned unblinded injector.  The injector may choose the numbing 
agent to be used based on standard of care, if needed 
• 
A 20 gauge or larger, 3.5 inch needle or longer is to be used for injection 
• 
Sterile technique will be used 
• 
Prior to injection, the injection site should be thoroughly cleansed using a bactericidal solution.  The 
injection contents will not be visible to the patient 
• 
Aspiration must be attempted prior to all injections.  If effusion is detected by fluoroscopy, withdraw to 
near dryness prior to injection 
• 
Either 5 mL of the reconstituted FX006 or 5 mL of normal saline will be injected into the index hip joint.  
Refer to the Pharmacy Binder for detailed instructions on how to prepare FX006.  Reconstitution process 
should not be visualized by any blinded study staff or by the patients.  
• 
Injection into the hip joint will be done with fluoroscopy guidance by the assigned injector (using contrast 
or air).  The injector may choose the position of the hip (e.g., supine position with lower extremity 
internally rotated) and the approach for injection (e.g., anterior.) 
Patients will be observed per standard of care after the procedure. 
Refer to the Pharmacy Binder for detailed references on study drug preparation and IA administration. 
Post-Injection Care 
Patients should be advised to avoid strenuous activities or prolonged weight-bearing activities for approximately 
48 hours following the injection and to also maintain a stable lifestyle with regard to physical activity throughout 
the duration of the study. 
Prior and Concomitant Therapy 
During the study, all existing (prior to study entry), new or changes in concomitant medications during the course 
of the study and the associated reasons for use or change will be documented and reported. 
Allowable Medications/Non-Pharmacologic Therapies 
The following medications/non-pharmacological therapies may be taken or used throughout the study: 
• 
Any treatment for a pre-existing condition or for an AE, outside of the study indication, that is not listed as 
restricted  
• 
Study-allocated rescue medication 
• 
Aspirin for cardio protection at a maximum stable dose of 325 mg per day provided the dose has been 


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stable over the 3 months prior to Screening 
• 
Medical therapy for depression, including selective or non-selective serotonin reuptake inhibitors (SSRIs, 
SNRIs, NSRIs) and tricyclics provided the dose has been stable over the 6 months prior to Screening 1 
(see Table 7-1) 
• 
Stable lifestyle with regard to physical activity, physical therapy, acupuncture, TENS, or bracing during 
the 1 month prior to Screening and expected to remain stable throughout the duration of the study 
Prohibited Medications/Non-Pharmacologic Therapies 
The following medications should not be taken or used for the duration of the study, after the patient signs 
informed consent.  The washout (at least 5 half-lives after the last dose) must be completed at least 2 days prior to 
Screening 2 visit. 
• 
Oral non-steroidal anti-inflammatory drugs (NSAIDs) 
• 
Aspirin (>325 mg per day) 
• 
Centrally-acting pain medications (e.g., pregabalin, gabapentin) 
• 
Opioids, Marijuana, Cannabidiol (CBD) 
• 
Topical therapies (e.g., NSAIDs, capsaicin, lidocaine patches, other local treatments) applied to the index 
hip 
• 
Anesthetic medications injected locally in the index hip (other than lidocaine if used for IA injection 
procedure) 
• 
Muscle relaxants (e.g., cyclobenzaprine, tetrazepam, diazepam) 
• 
IV, IM, oral, inhaled, intranasal or topical corticosteroids 
• 
IA corticosteroids in any joint 
• 
Any IA intervention in the index hip (e.g., IA viscosupplementation (hyaluronic acid))  
• 
Initiation of or change in medical therapy for depression, including selective or non-selective serotonin 
reuptake inhibitors (SSRIs, SNRIs, NSRIs) and tricyclics; see Section 7.6.1 for examples of specific 
agents in each class  
• 
Any investigational drug, device or biologic 
• 
Immunomodulators, immunosuppressives, or chemotherapeutic agents 
• 
Live (e.g., MMR vaccine, chicken pox vaccine, rotavirus vaccine) or live-attenuated vaccines (e.g., 
FluMist, Zostavax)   
• 
Changes to lifestyle with regard to physical activity, physical therapy, acupuncture, TENS, or bracing 
throughout the duration of the study 
Rescue Medication 
To standardize pain-relief rescue medication across all patients, starting at screening, patients will discontinue all 
prohibited medications and follow procedures: 
• 
The designated rescue medication is acetaminophen (paracetamol) 500 mg, one tablet every 4 to 6 hr to a 
maximum of 6 (six) tablets (3000 mg) per 24 hr period 
• 
Patients may not take any rescue medication during the 48 hr prior to a study visit 
• 
Starting at screening and at each study visit, patients will be provided with a sufficient quantity of rescue 
medication for the interval to the next scheduled visit 
• 
At each visit, patients will return the bottles provided at the previous visit for rescue medication 
accountability and be issued a new supply 


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Criteria for Evaluation: 
Efficacy 
• 
WOMAC Osteoarthritis Index (0-10 NRS): pain, stiffness and function domains independently and 
collectively (Bellamy et al, 1988) 
• 
PGIC: 7-point scale (Farrar et al, 2001; Guy, 1976; Dworkin et al, 2005) 
• 
HOOS QOL Subscale (http://www.koos.nu/) 
• 
Sleep Interference (SI): Question 9F from the Brief Pain Inventory (Short Form) 
• 
EQ-5D-5L: consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS) 
(https://euroqol.org) 
• 
Abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) 
• 
Responder status as defined by: 
o 
Proportion of patients experiencing either ≥50%, ≥30% or ≥20% decrease (improvement) in pain) 
(substantial, at least moderate and minimum clinically important difference, respectively, as defined by 
(Dworkin et al, 2008) 
o 
Outcome Measures in Rheumatology (OMERACT) - Osteoarthritis Research Society International 
(OARSI) criteria (Pham, 2004) 
• 
Consumption of rescue medication 
Safety  
• 
Adverse Events 
• 
Physical examinations 
• 
Index hip examinations 
• 
Index hip X-rays 
• 
Vital signs 
• 
Clinical laboratory evaluations (hematology, chemistry) 
Sample Size Considerations: 
Approximately 70 patients will be randomized in Part I and approximately 440 patients will be randomized in 
Part II in this study (an estimated 35 and 220 per treatment group, respectively). 
For Part I, a sample size of approximately 35 per arm will provide information regarding the treatment effect. For 
Part II of the study, the expected sample size was determined based on the primary endpoint as follows. A 
minimum sample size of N=212 per arm for the placebo and the FX006 group has 90% power to yield a 
statistically significant difference (alpha=0.05, 2-sided) if the true underlying difference at Week 12 is 0.65 and 
with an assumption of 2.0 for the standard deviation (SD).  For the first key secondary endpoint, the sample size 
of N=220 per treatment group has 90% power to yield a statistically significant difference between FX006 and 
placebo if the true underlying difference is 0.68 at Week 12, assuming a SD of 2.125.  An early discontinuation 
rate of 6% was assumed. The data from Part I may be used to inform if the above assumptions were appropriate 
and the planned sample size for Part II should remain at 440, or whether a smaller sample size would be feasible.   
Statistical Methods: 
Complete details of the statistical analysis will be specified in the statistical analysis plan (SAP).  A separate SAP 
will be prepared for Part I and Part II of the study prior to database lock for each part of the study.   
Parts I and II of the study will enroll separate patients, and as such all analyses will be performed independently 
of one another. Analyses for Parts I and II of the study will be performed in the same manner, as detailed below.  
The analyses of the Part I data will be performed in an unblinded manner and results may be used to inform the 
conduct of Part II; as the analyses of Part I will be completed prior to the enrollment of any patients in Part II, 
this will have no impact on maintaining the blind for Part II.  All analyses of Part I data are exploratory in nature. 


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Data collected in this study will be presented using summary tables, figures, and subject 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 mean, median, standard deviation, minimum and 
maximum.  Categorical variables will be summarized by frequencies and percentages.  Confidence intervals may 
also be provided.  Figures will be used to support the presentation of certain data.  Sensitivity analyses may be 
performed to examine the effect of missing data, as well as the effect of Baseline imbalance, should one occur. 
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. 
All patients who receive study medication and have Baseline and at least one post-dose pain evaluation will be 
included in the Full Analysis Set (FAS). The FAS will be the primary analysis population for efficacy. 
The primary endpoint will be analyzed with a longitudinal mixed model for repeated measures (MMRM) with 
fixed effects for treatment group, study week, treatment-by-week interaction and Baseline score.  Subject will be 
the random effect.  Treatment differences from control will be estimated via least square means from the analysis 
model along with 95% confidence intervals, and associated 2-sided p-values.  This model assumes missing at 
random and includes only observed data.  
Key secondary endpoints will be assessed similarly to the primary endpoint.  Multiplicity will be addressed by 
analyzing the key secondary endpoints sequentially in the order presented in the protocol, testing each endpoint at 
the nominal alpha=0.05, 2-sided level to ensure overall type I error control at the 2-sided 0.05 level. 
Additional continuous secondary efficacy endpoints will also be assessed similarly to the primary endpoint, but 
are not part of the sequential testing approach.  Categorical end points will be compared via chi-square or exact 
tests depending on incidence rates. 
AUE will be calculated and comparisons of the AUE endpoints will be estimated from an Analysis of Covariance 
(ANCOVA) with model parameters for treatment and covariates of Baseline WOMAC A score and study site.  
Full details of the AUE analyses will be detailed in the SAP. 
Safety analyses will be performed on the Safety Population.  AEs will be coded using MedDRA.  Incidences 
(number and percent) of TEAEs, those events that start 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 hip TEAEs 
following the first dose and second dose (Part II only), as well as the cumulative incidence of TEAEs after all 
doses of FX006 (Part II only). 
Laboratory data, vital sign information and X-ray data will be presented as descriptive summary statistics for 
value and change from Baseline at each individual time point.  Categorical variables will be summarized by 
frequencies and percentages. 
 


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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 subjects.  Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study 
subjects are protected, consistent with the principles that have originated in the Declaration of 
Helsinki and that the clinical study data are credible. 
3.3. 
Patient Information and Consent 
Prior to initiation of any study related procedures, patients will give their written consent to 
participate in the study after having been informed about the nature and purpose of the study, 
participation and termination conditions, and risks and benefits. 
An IRB/EC-approved informed consent document must be signed by the patient 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 Delegation of Responsibilities form. 
The contact information for all Principal Investigators participating in the trial will be kept in the 
Trial Master File. 
4.2. 
Study Administrative Structure 
The study will be managed by the Sponsor with specific responsibilities delegated to contract 
research organizations. 
 


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5. 
INTRODUCTION 
5.1. 
Osteoarthritis 
Osteoarthritis (OA) is a painful and debilitating musculoskeletal disease that is characterized by 
intra-articular (IA) inflammation, deterioration of articular cartilage, and degenerative changes to 
peri-articular and subchondral bone (Creamer and Hochberg, 1997; Goldring and Goldring, 
2006).  Arthritis is the most common cause of disability in the United States of America (USA), 
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.  It is estimated that by 2030, 45 million people will have OA.  
OA commonly affect large weight-bearing joints like the knees and hips, but also occurs in the 
shoulders, hands, feet and spine.  Patients with OA suffer from joint pain, tenderness, stiffness 
and limited movement.  As the disease progresses, it becomes increasingly painful and 
debilitating, culminating, in many cases, in the need for total joint arthroplasty. 
Current Guidelines from the American College of Rheumatology (ACR), Osteoarthritis Research 
Society International (OARSI) and the European League against Rheumatism (EULAR) 
recommend the use of IA corticosteroids for short-term acute pain relief (Hochberg et al, 2012; 
Jordan et al, 2003; Menge et al, 2014). 
The prevalence of hip osteoarthritis is estimated to range from 6.7% to 9.2% among adults ≥45 
years of age and increases with age (Lawrence et al, 2008; Murphy et al, 2012).  It is recognized 
that chronic inflammation occurs in all stages of OA (Benito et al, 2005; Sellam and Berenbaum, 
2010; Wenham and Conaghan, 2010).  As inflammation is correlated with clinical symptoms and 
joint degeneration, it should be an important target for corticosteroid intervention. 
5.2. 
Background 
5.2.1. 
Investigational Medicinal Product:  FX006 
FX006 is an extended-release formulation of triamcinolone acetonide (TA) for IA 
administration.  It is approved in the US under the trade name ZILRETTA® (triamcinolone 
acetonide extended-release injectable suspension) for the management of pain of osteoarthritis 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% (weight by weight [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 Hip Osteoarthritis 
Similar as in knee OA, hip OA patients are confronted with insufficient management of their 
symptoms (Zhang et al, 2008).  Conventional corticosteroids have demonstrated clinical benefits 
in patients with hip OA (Lambert et al, 2007; Qvistgaard et al, 2006; Atchia et al, 2011), but with 
short duration of effect (approximately 4-8 weeks) and side effects from burst release of steroids 
into systemic circulation (Habib et al, 2011).  Due to its slow release formulation, FX006 has the 
potential to offer longer duration of efficacy and minimized systemic exposure, thus, an 
improved benefits/risk profile for hip OA patients. 
5.2.3. 
Non-Clinical Toxicology  
Overall, single or repeat IA administration of FX006 at the proposed clinical dose of 32 mg has 
no new safety liabilities compared to TAcs in healthy animals: 
• Systemic findings were similar among TAcs and FX006 groups following single and repeat 
dosing and were generally reversible.  Initial effects on clinical pathology parameters were 
more pronounced for the immediate-release form.  The incidence and/or intensity of steroid 
associated systemic histopathological findings at the later time points were slightly higher 
for high dose FX006 than for TAcs at the same dose level of TA (18.75 mg/mL/joint), as 
expected based on the sustained release of TA. Microspheres were not detected in tissues 
outside of the synovial space 
• Local findings were similar among the TAcs and the FX006 groups and were reversible.  
The single and repeat dose dog toxicity studies recapitulated known, previously published, 
effects of TA in normal animal joints following prolonged exposure.  These include 
decreased Safranin O staining (single or repeat dose) and changes in structure and 
cellularity of articular cartilage (repeated dosing only) 
• An expected, mild, reversible Foreign Body Response (FBR) was noted to the PLGA 
component of FX006 microspheres 
- 
The local tissue response to the presence of blank microspheres as well as FX006 
microspheres consisted of an expected FBR of macrophage and multinucleated giant 
cell infiltration involving the synovium.  Following a single dose, the FBR was evident 
at Day 4, peaked at approximately 6 weeks and was completely resolved by 6 months 
in all FX006-dosed animals.  Occasional lymphocyte and plasma cell infiltrates and 
sporadic focal-to-multifocal areas of minimal-to-slight fibrosis resolved by 9 months.  
Following repeat IA dosing, a similar local, reversible FBR was noted 
- 
Further, the dogs in these studies showed no local signs of inflammation on or around 
the joint and did not display pain, discomfort or difficulty in ambulation in any 
treatment group; hence, this local response was considered to be non-adverse.   
Information available for TA from the literature, corticosteroid product labels and clinical 
experience suggest that the potential of genetic toxicity, reproductive toxicity and carcinogenic 
potential of TA are well understood.  Similarly, the biocompatibility and local safety of PLGA 
microspheres, and genotoxic, reproductive toxicological and carcinogenic potential of PLGA 
have been described in a combination of literature and product information packages.  Therefore, 
no new risks relative to TAcs are presented by FX006 as intended for use. 


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5.2.4. 
Systemic and Local Pharmacokinetics (PK) in Patients with Osteoarthritis of the 
Knee 
Overall, FX006 displayed a favorable plasma PK profile relative to that of TAcs.  
Pharmacokinetic observations resulted in a controlled and stable release of TA from PLGA 
microspheres into synovial tissues, where concentrations remained high relative to plasma 
concentrations for at least 12 weeks. Triamcinolone acetonide 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 (Kraus et al, 2018; 
Bodick et al, 2013). 
Relative to TAcs, 32 mg FX006 produced substantially lower peak plasma levels and decreased 
pharmacodynamic effects on glucose metabolism and adrenal-cortical axis.  FX006 performed as 
expected, prolonging the residence of TA in the joint while minimizing acutely elevated levels of 
TA. 
5.2.5. 
Pharmacodynamics (PD) in Patients with Osteoarthritis of the Knee 
In a Phase 2 PK/ PD study evaluating three dose levels of FX006 (10 mg, 40 mg, 60 mg) 
administered as a 3 mL injection, suppression of cortisol in the days following injection 
produced by the 10 and 40 mg dose of FX006 was less than that produced by injection of TAcs; 
the 60 mg dose of FX006 produced effects similar to 40 mg TAcs.  Cortisol suppression 
subsequent to Day 1-2 associated with all doses of FX006 would not be expected to be of clinical 
consequence in adult patients without otherwise compromised hypothalamic-pituitary-adrenal 
(HPA) axis function.  In a Phase 2 study in diabetic patients with knee OA, treatment with 32 mg 
FX006 resulted in a statistically significant (p=0.0452) reduction in blood glucose elevation 
relative to TAcs over a 72-hour period following IA injection.  The time in glycemic target range 
(70-180 mg/dL) (American Diabetes Association, 2016) was greater for FX006 as compared to 
TAcs over the 48 hours post IA injection, providing another indication of the improvement in 
glycemic control. 
Over the entire time course of the 15-day post injection glucose monitoring period, blood 
glucose levels associated with FX006 remained at levels similar to or lower than those produced 
by TAcs.  This observation is consistent with PK studies demonstrating low systemic exposure to 
TA associated with FX006. 
5.2.6. 
Efficacy in Patients with Osteoarthritis of the Knee 
Efficacy data from three studies provide substantial evidence supporting the effectiveness of 
32 mg FX006 in the management of OA pain (Bodick et al, 2015; Conaghan et al, 2018a; 
Conaghan et al, 2018b).  Results of the primary endpoint from the Phase 3, multi-center, 
adequate, and well-controlled trial showed that patients treated with 32 mg FX006 had a rapid, 
durable, and meaningful analgesic response that was statistically significantly better than placebo 
treated patients (P<0.0001).  This finding was supported by a second smaller Phase 2b study, 
where a highly similar pattern of response to 32 mg FX006 was demonstrated. 
Robustness of the primary outcome in the Phase 3 study was further supported by the internal 
consistency demonstrated in favor of 32 mg FX006 through secondary analyses utilizing the 
primary outcome data (average daily pain [ADP]) to evaluate durability and magnitude of 
response.  These included least square mean (LSM) testing at each week and area under the 


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effect curve (AUE) analyses for Weeks 1 through 12 and Weeks 1 through 24.  Results 
demonstrated that the analgesic effect of 32 mg FX006 is significant at Week 1, increases 
through Week 7, and is sustained through at least Week 16.  Responder analyses further 
suggested that FX006 provides clinically relevant improvement from Weeks 1 through 16 
relative to placebo. 
Analyses utilizing data collected from other instruments or measures, i.e., Western Ontario and 
McMaster Universities Osteoarthritis Index (WOMAC), Patients’ Global Impression of Change 
(PGIC), Clinical Global Impression of Change (CGIC), and Knee injury and Osteoarthritis 
Outcome Score (KOOS) Quality of Life (QOL), provided additional insight into effects on pain 
relief as well as physical function and global well-being.  At 32 mg, FX006 provides clinically 
relevant improvement relative to placebo through Week 12 for WOMAC and KOOS QOL and 
through at least Week 16 for PGIC and CGIC.  Additionally, significant reduction of rescue 
medication utilization in patients treated with 32 mg FX006 is of potential important clinical 
consequence and adds a meaningful element to the overall effectiveness profile of 32 mg FX006.  
Collectively, these results provide substantial evidence to support 32 mg FX006 as an effective 
therapy for the management of OA knee pain. 
5.2.7. 
Systemic and Local Safety in Patients with Osteoarthritis of the Knee 
The evaluation of 687 patients treated with a single IA injection of FX006 at any dose in the 
FX006 clinical studies suggest that it was well tolerated with systemic and local safety profiles 
similar to those of TAcs and placebo. 
The safety data from the FX006 clinical studies are largely consistent. 
• The number of treatment-emergent adverse events (TEAEs) reported was similar across 
groups (FX006 46.0%; placebo 49.2%; TAcs 51.0%) 
• The majority of TEAEs in FX006-treated patients were mild or moderate (Grade 1 or 2).  
Severe or life-threatening events occurred in the FX006-treated patients at a rate of 3.0% as 
compared to 5.0% and 2.6% in the placebo and TAcs groups, respectively 
• In the FX006-treated patients (n=687), the most common TEAEs were: 
- 
Arthralgia (in any joint) 9.8% (n=67) 
- 
Headache 5.4% (n=37) 
- 
Upper Respiratory Tract Infection 3.1% (n=21) 
- 
Joint swelling 2.8% (n=19) 
- 
Contusion and back pain 2.3% (n=16) 
- 
Nasopharyngitis 2.2% (n=15) 
• The rate of serious adverse events (SAEs) was low and consistent across groups (FX006 
1.9%; placebo 1.1%; TAcs 2.3%); none were considered related to the study drug 
• Across all studies there were no deaths 
In the Phase 3 study, qualitative assessments based on X-rays of the index knee at 24 weeks post 
injection included joint space narrowing (JSN), subchondral bone changes, osteonecrosis, and 
insufficiency fracture (Conaghan et al, 2018b). 


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• The overall rate of JSN worsening of at least 1-grade between Baseline and Week 24 was 
low and similar among treatment groups (5.0% [7/140], 4.1% [6/148], and 3.5% [5/145] of 
patients with both Baseline and Week 24 X-rays in the 32 mg FX006, placebo, and TAcs 
groups respectively); for all but 1 of these 18 patients, JSN worsened by 1-grade only.  The 
remaining patient (in the placebo group) had a 2-grade worsening in JSN (from 0 at 
Baseline to Grade 2 at Week 24) 
• No FX006-treated patient had X-ray evidence of treatment-emergent insufficiency fracture, 
subchondral bone changes, or osteonecrosis at Week 24 
• Eighteen patients discontinued the study prior to Week 24 and completed a final X-ray as 
part of early termination visit.  Of these, 2 patients, 1 in the 32 mg FX006 group and 1 in 
the placebo group, had a 1-grade increase in JSN.  There were no reports of insufficiency 
fracture, subchondral bone changes, or osteonecrosis 
5.2.8. 
Rationale for Protocol Amendment 
In contrast with the prior experience injecting FX006 into the knee joint, there have been 
occurrences of incomplete administration of FX006 variously reported as "increased resistance" 
or "blockage" encountered during the injection of FX006 into the hip joint. Careful review of the 
cases failed to identify a common factor and initial laboratory studies were inconclusive.  
Therefore, screening and enrollment for the FX006-2018-015 study was suspended by the 
Sponsor to allow for additional review of these cases of incomplete administration of FX006 and 
further investigation. Repeat administration of FX006 for qualifying patients in the OLE Phase 
was also suspended. 
As part of the investigation to determine the root cause for these incomplete administrations, a 
laboratory model was developed to explore factors that could contribute to these events.  The 
laboratory model identified two procedural factors potentially contributing to these incomplete 
administrations of FX006 into the hip joint. Specifically, if a syringe of resuspended FX006 was 
attached directly to a vertically placed spinal needle (as typically encountered during IA injection 
in the hip) and outflow from the needle was mildly restricted by the laboratory model simulating 
constrained joint space conditions, then blockage was observed at an appreciable rate. If the 
syringe was held horizontally or if the constrained joint space model was omitted (giving 
conditions similar to IA injection in the knee), such events did not occur.  
Based on these findings, the FX006-2019-017 study was implemented to determine the 
feasibility of administering FX006 into the hip joint using a technique(s) based upon the 
laboratory findings.  
Due to the duration of the enrollment and dosing hold, and the restriction that patients enrolled 
were not able to receive an open-label administration of FX006 per protocol, this amended 
protocol was created to separate this patient population impacted by the study hold (Part I). Per 
this amendment, patients enrolled up to that time were followed for at least 12 weeks or up to the 
time of this amendment.  At the time that this amendment is implemented, patients are to be 
discontinued from the study without further assessments required.  
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5.2.9. 
Experience with FX006 Administered IA in Patients with OA of the Hip 
Studies of FX006 were expanded to include studies in patients with symptomatic OA of the hip 
joint. Among approximately 12 patients administered 32 mg FX006 by IA into the hip (from 
Study FX006-2017-013), the incidence, nature, and intensity of treatment-emergent AEs was 
indistinguishable from that observed with IA injection into the knee. There were no treatment 
related SAEs.  
5.2.10. 
Conclusion 
FX006, an extended-release microsphere formulation of triamcinolone acetonide, demonstrated 
comparable safety profile to TAcs in animals after single or repeat IA administrations.  Much 
lower peak plasma level and much longer duration than TAcs after IA injection in knee OA 
patients contributed to a better systemic safety profile, as evidenced by decreased duration and 
magnitude in hyperglycemia of diabetic patients.  Furthermore, FX006 demonstrated comparable 
local joint safety as TAcs in patients with knee OA. Larger magnitude and longer duration of 
efficacy was observed with FX006 than TAcs as shown by WOMAC pain and function scores.  
Given the insufficient symptomatic management of hip OA patients and similar pathogenesis 
between knee and hip OA, it is anticipated that FX006 will provide improved benefit/risk 
profiles to hip OA patients. Thus, the sponsor is proposing continued clinical study of FX006 for 
hip OA.  
 


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6. 
STUDY OBJECTIVES 
6.1. 
Primary Objective 
6.1.1. 
Part I 
Double-Blind Objectives 
• To assess the treatment effect of FX006 on pain following an intra-articular (IA) injection 
in patients with hip osteoarthritis (OA) 
6.1.2. 
Part II 
Double-Blind Phase Objectives 
• To assess the efficacy of FX006 on pain following an intra-articular (IA) injection in 
patients with hip osteoarthritis (OA) 
6.2. 
Secondary Objectives 
6.2.1. 
Part I 
Double-Blind Objectives 
• To assess the efficacy of FX006 on function, global impression of change, stiffness, quality 
of life, treatment satisfaction, sleep quality and consumption of rescue medication in 
patients with hip OA 
• To assess the safety of FX006 in patients with hip OA 
6.2.2. 
Part II 
Double-Blind Phase Objectives 
• To assess the effect of FX006 on function, global impression of change, stiffness, quality of 
life, treatment satisfaction, sleep quality and consumption of rescue medication in patients 
with hip OA 
• To assess the safety of FX006 in patients with hip OA 
6.3. 
Open Label Phase Objectives 
6.3.1. 
Secondary Objective: 
• To examine efficacy following a second injection of FX006 in patients with hip OA 
6.3.2. 
Primary Objective: 
• To assess the overall safety of a second injection of FX006 in patients with hip OA 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
This is a two-part, multi-center, randomized, double-blind, placebo-controlled, parallel-group 
study in patients with hip OA.  Approximately 70 patients will be enrolled in Part I and 
approximately 440 patients will be enrolled in Part II of the study.  In each part, patients will be 
randomized to one of two treatment groups (1:1) and treated with a single IA injection of either 
32 mg FX006 or normal saline. 
Eligible patients will be randomized within strata defined by Baseline Western Ontario and 
McMaster Universities Osteoarthritis Index (WOMAC) A (pain) (0-10 numeric ratings scale 
(NRS) average of Screening 2 and Day 1 with the following classifications: 5.0 to < 6.0, 
6.0 to < 7.0, and ≥ 7.0 to 9.0 (see Section 9 for details). 
FX006 or saline placebo will be administered as a single IA injection with a 12-week follow-up 
period in the double-blind phase.   
Patients participating in Part I of the study will be treated with a single IA injection of either 
32 mg FX006 or normal saline and will return for follow up visits at Weeks 12, 16, 20, and 24 or 
up until the time of this amendment. The patients will be discontinued at the time of notification 
by the Investigator. 
Patients participating in Part II of the study will be treated with a single IA injection of either 
32 mg FX006 or normal saline and will return for follow up visits at Weeks 12, 16, 20, and 24. 
Patients who are eligible for the second injection in the open-label phase at Week 12 will receive 
an open-label injection of FX006 at Week 12 and return for follow-up visits at Weeks 16, 20, 
and 24.  These patients will complete the study at Week 24. 
Patients participating in Part II of the study that are not clinically indicated for a second injection 
at Week 12 will return to the clinic at Weeks 16, 20, and 24 and will receive an open-label 
injection of FX006 at the first evaluation where the patient has been determined to meet all 
criteria.  Patients will then return for follow-up visits every 4 weeks for 12 weeks post second 
injection and will complete the study 12 weeks post second injection (e.g., Week 24, 28, 32, or 
36 depending on when the patient receives the open-label injection).   
Patients participating in Part II of the study who are not eligible for a second injection after 
evaluation at Weeks 12, 16, 20, and 24 will complete the study at the Week 24 visit and 
complete the End of Study (EOS) assessments. 
7.1.1. 
Flow of Study Participation 
Patients participating in this study will complete visit schedules and procedures as detailed in the 
Study Flow Chart (Figure 1) and the Schedule of Study Assessments (Table 7-2 and Table 7-3). 
The study will involve a Screening period (a minimum of 10 days, up to a maximum of 30 days), 
dosing at Day 1, and four additional outpatient visits at Weeks 1, 4, 8, and 12 during the double-
blind phase. 


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Figure 1: 
Study Flow Chart (Part II Patients Only) 
 
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 on the 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. 


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At a minimum, the study staff should consist of: 
Unblinded 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 
• Will not share treatment assignments with the blinded assessor, the patient and other 
blinded study personnel or Sponsor personnel/representatives and will make every effort to 
maintain the blind 
• Will have no other contact with the patient throughout patient’s participation in the study 
Unblinded Injector 
• Must be a Medical Doctor, Doctor of Osteopathy, or certified Physician Assistant with 
experience in administering IA injections of the hip using fluoroscopy guidance 
• Is responsible for performing all IA injections of study medication using fluoroscopy 
guidance 
• Will not share treatment assignments with the blinded assessor, the patient and other 
blinded study personnel or Sponsor personnel/representatives and will make every effort to 
maintain the blind 
• Will have no other contact with the patient outside of treatment administration through 
patient’s participation in the study other than obtaining informed consent at the Screening 
visit, if applicable 
Blinded Assessor 
• Must be a medical doctor, a physician’s assistant, or nurse practitioner 
• Must have relevant OA experience 
• Is responsible for performing the physical examination and index hip assessments 
• Is responsible for the overall safety of the patient, including assessing all adverse events for 
seriousness, severity, and relationship to study medication 
• Must not be present during the administration of study medication, but should be available 
afterward to assess the patient for any adverse events that occurred during the procedure. 
(see Section 7.5.8 and Section 8.2 for details regarding handling of those events).  
Delegation of responsibilities will be documented at each site and specified in each site’s 
Blinding Plan.  An individual that serves as an unblinded pharmacist/coordinator or an unblinded 
injector can only serve in the unblinded role for the duration of the study and must adhere to the 
roles as outlined above.  It is permitted to have three (3) individuals delegated to each unblinded 
role defined above to ensure adequate back-up coverage if necessary; however, the Principal 
Investigator must not serve as an unblinded injector but will serve as one of the blinded 
assessors. 


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7.3. 
Discussion of Study Design 
7.3.1. 
Rationale for Study Population 
Most recently a few placebo-controlled randomized trials using conventional triamcinolone 
formulation at doses of 40 mg for hip OA have demonstrated acceptable safety profiles (Lambert 
et al, 2007; Qvistgaard et al, 2006; Atchia et al, 2011).  This study will evaluate a similar patient 
population.  In addition, the safety profile of FX006 has been demonstrated to be well-tolerated 
in over 600 patients with knee OA in clinical trials.  Given the similar pathogenesis between 
knee and hip OA and demonstrated efficacy in knee OA, it is hypothesized that FX006 should be 
beneficial to hip OA patients, and thus supports FX006 evaluation in this patient population. 
7.3.2. 
Rationale for Dose Selection 
FX006 at IA doses up to 60 mg has been tested in knee OA patients with acceptable safety 
profile.  FX006 has been approved to treat knee OA pain at dose of 32 mg.  The hip joint is a 
large weight-bearing synovial joint, like the knee.  There is no apparent pathological difference 
between hip OA and knee OA.  Therefore, 32 mg IA dose for hip OA is selected. 
7.3.3. 
Rationale for Study Parameters 
Pain, function and patient global impression of change are the three core efficacy measures that 
are accepted by regulatory agencies and various scientific committees for hip OA trials.  Rescue 
medication use is commonly monitored in OA trials to further confirm symptomatic 
improvements.  Sleep disturbance commonly occurs in hip OA patients, and as such, it is 
meaningful to reflect potential quality of life benefit.  Patient satisfaction to therapeutics can 
assess overall satisfaction from various perspectives to the test article.  Patient quality of life 
(e.g., EuroQol 5 Dimensions 5 Levels questionnaire (EQ-5D-5L) and Hip injury and 
Osteoarthritis Outcome Score quality of life (HOOS QOL)) are required measures per research 
committees (McAlindon et al, 2015).  The clinical safety parameters to be assessed (physical 
examinations, index knee examinations, X-rays, vital signs, clinical laboratory evaluations and 
adverse events [AEs]) are standard safety and tolerability assessments. 
7.3.4. 
Rationale for Control Type 
Normal saline (NaCl; 0.9% w/w) has been selected as the placebo control for this study because 
it is the base component of the FX006 diluent.  The other excipients of the FX006 diluent, 
sodium carboxymethylcellulose (NaCMC 0.5% w/w) and polysorbate-80 (0.1% w/w), have been 
accepted as standard inactive excipients by the FDA.  These excipients are present in 
commercially available TCA IR (e.g., Kenalog-40®) which also utilizes sodium chloride for 
tonicity adjustment.  Normal saline has been employed as a control in published studies of TCA 
and other corticosteroids (Gaffney et al, 1995). 
7.3.5. 
Rationale for Blinding Approach 
FX006 and normal saline will not be identical in appearance and administration differences may 
be apparent.  As such, the blinded-assessor technique has been selected for this study. 


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7.4. 
Selection of Study Population 
7.4.1. 
Number of Patients 
 Approximately 70 patients in Part I and approximately 440 patients in Part II will be randomized 
and treated in the double-blind phase of the study.   
7.4.2. 
Inclusion Criteria 
To be included in the trial, patients must fulfill the following criteria to participate in the study: 
1. Written informed consent has been obtained prior to initiating any study specific 
procedures 
2. Willingness and ability to comply with the study procedures and visit schedules and 
ability to follow verbal and written instructions 
3. Patients 40 to 80 years of age, inclusive, on the day of consent 
4. Body Mass Index (BMI) ≤ 40 kg/m2 
5. Symptoms (including pain) associated with OA of the index hip for ≥ 3 months prior to 
Screening visit (patient self-report is acceptable). 
6. Moderate to severe index hip pain due to OA for >15 days over the last month (as 
reported by the patient) 
7. Currently meet the American College of Rheumatology (ACR) Criteria (clinical and 
radiological) for OA of the index hip (Altman et al, 1991): 
• Hip pain and radiographic femoral and/or acetabular osteophytes; 
 
 
OR  
• Hip pain and erythrocyte sedimentation rate (ESR) < 20 mm/hour and 
radiographic axial joint space narrowing 
8. Kellgren-Lawrence (KL) Grade 2 or 3 in the index hip as confirmed by X-ray during 
Screening visit (centrally read) 
9. WOMAC A (pain) score in index hip ≥ 5.0 and ≤ 9.0 (0-10 NRS scale) at Screening 2 
visit and Day 1 
10. WOMAC C (function) score in index hip ≥ 4.0 (0-10 NRS scale) at Screening 2 visit and 
Day 1 
11. Ambulatory and no change in use or addition of assistive devices within 3 months prior 
to screening 
12. Agree to maintain the similar activity level and stable non-pharmacological therapies throughout 
the study 
13. Willingness to abstain from use of protocol-specified restricted medications (See 
Section 7.6.2) 


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7.4.3. 
Exclusion Criteria 
Patients fulfilling at least one of the following criteria may not be included in the study: 
Disease-related criteria 
1. Patients who cannot washout of prohibited medications (e.g., opioids or other analgesics) 
(Refer to Section 7.6.2) 
2. Diagnosed as secondary OA in the index hip including but not limited to articular 
fracture, major dysplasia or congenital abnormality, osteochondritis dissecans, 
acromegaly, ochronosis, hemochromatosis, Wilson's disease, or primary 
osteochondromatosis, etc. 
3. Current or any history of ipsilateral chronic knee pain (lasting ≥ 3 months) 
4. Contralateral hip and/or knee pain ≥ 4.0 (0-10 NRS scale) within 1 month prior to 
Screening visit 
5. Current or any history of chronic Sciatica (lasting ≥ 3 months) 
6. Current or any historyof acetabular labrum tear in the study hip 
7. Atrophic osteoarthritis, femoral head necrosis and/or collapse, or subchondral bone 
insufficiency fracture in the index hip joint determined via central reading 
8. Current or history of infection in the index hip (e.g., osteomyelitis) or current skin 
infection at injection site 
9. Concurrent chronic pain conditions with pain score ≥ 4.0 (0-10 NRS scale) within 1 
month prior to Screening 1 visit, including but not limited to: 
• hip impingement syndrome, trochanteric bursalgia 
• peripheral or central neuropathy that may affect sensation of the index hip 
• non-radicular low back pain 
• peripheral nerve entrapment 
• diabetic neuropathy 
• post-herpetic neuralgia 
• post-stroke pain 
• fibromyalgia 
10. Major surgery or clinically significant trauma (e.g., fracture) of lower limbs within 12 
months prior to Screening visit or with ongoing sequelae. 
11. painDETECT Questionnaire (PD-Q) score > 18 during Screening visit  
12. History or current evidence of reactive arthritis, rheumatoid arthritis, psoriatic arthritis, 
ankylosing spondylitis, or arthritis associated with inflammatory bowel disease, systemic 
lupus erythematosus or other autoimmune diseases 
13. Any planned surgeries in the lower limbs during the study period 


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Previous or concomitant treatment-related criteria 
14. Presence of surgical hardware or other foreign body in the index hip 
15. Planned/anticipated surgery that would require use of a restricted medication during the 
study period 
16. IA corticosteroid of any joint within 3 months of Screening visit (investigational or 
marketed, including FX006) 
17. IA treatment of index hip with any of the following agents within 6 months of Screening: 
any biologic agent (e.g., platelet rich plasma (PRP) injection, stem cells, prolotherapy, 
amniotic fluid injection) or hyaluronic acid (investigational or marketed) 
18. Intravenous (IV) or Intramuscular (IM) corticosteroids (investigational or marketed) 
within 3 months of Screening 
19. Oral corticosteroids (investigational or marketed) within 1 month of Screening 
20. Inhaled, intranasal or topical corticosteroids (investigational or marketed) within 2 weeks 
of Screening visit 
21. Changes to lifestyle with regard to physical activity, physical therapy, acupuncture, 
transcutaneous electrical nerve stimulation (TENS), or bracing within 1 month prior to 
Screening; or planned or expected changes during the study 
Patient-related criteria 
22. Patients with a total score of ≥ 15 or >0 on Question #9 on the Patient Health 
Questionnaire-9 (PHQ-9) at Screening visit 
23. Patients with a score of ≥ 15 on the Generalized Anxiety Disorder (GAD-7) at Screening 
visit 
24. Patients with Pain Catastrophizing Scale (PCS) score of ≥ 30 at Screening visit 
25. Patients with Insomnia Severity Index (ISI) Questionnaire score ≥ 15 (moderate severity) 
at Screening visit 
26. Known or suspected hypersensitivity to any form of triamcinolone or PLGA 
27. Laboratory evidence of infection with human immunodeficiency virus (HIV), positive 
test for hepatitis B surface antigen (HBsAg) or positive serology for hepatitis C virus 
(HCV) antibody with positive test for HCV Ribonucleic acid (RNA) 
28. A medical history suggesting the patient will or is likely to require a course of systemic 
corticosteroids during the study period 
29. History or evidence of active or latent systemic fungal or mycobacterial infection 
(including tuberculosis), or of ocular herpes simplex 
30. History of sarcoidosis or amyloidosis 
31. History of or active Cushing’s syndrome 
32. Medical therapy for depression, including selective or non-selective serotonin reuptake 
inhibitors (SSRIs, NSRIs, SNRIs) and tricyclics, if dose/regimen has not been stable for 
≥ 6 months prior to Screening 
33. Use of immunomodulators, immunosuppressives, or chemotherapeutic agents within 
5 years of Screening 


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34. Active or history of malignancy within 5 years of Screening, with the exception of 
resected basal cell carcinoma, squamous cell carcinoma of the skin, or effectively 
managed cervical carcinoma 
35. Active substance abuse (drugs or alcohol) or history of substance abuse within the past 
12 months of Screening 
36. Has received a live (e.g., MMR vaccine, chicken pox vaccine, rotavirus vaccine) or live-
attenuated vaccine (e.g., FluMist, Zostavax) within 3 months of Day 1 
37. Use of any other investigational drug, biologic or device within 3 months of Screening 
visit 
38. Any bacterial or viral infection requiring parenteral antibiotics within 4 weeks of Day 1 
or oral antibiotics within 2 weeks of Day 1 
39. Any other clinically significant acute or chronic medical conditions (e.g., uncontrolled 
diabetes) 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 
40. Patients contraindicated to the use of acetaminophen/paracetamol (allowed rescue pain 
medicine) per National Product Labeling and/or Investigator's judgment 
41. Patient is the Investigator or any Sub investigator, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the study 
42. Women who are pregnant or nursing or plan to become pregnant during the study; men 
who plan to conceive during the study 
43. 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)] 
7.4.4. 
Second Injection Inclusion Criteria (Part II Patients Only) 
To be eligible to receive the second injection during the open-label phase, patients must fulfill 
the following criteria: 
1. Completed the double-blind phase of the study through Week 12 
2. No major safety concerns during the initial dose period (including allergic reaction to 
initial dose of study medication) as assessed by the Investigator and patient 
3. Clinically indicated to receive FX006, in the opinion of the Investigator and patient 
4. WOMAC A (pain) score of ≥ 3 (0-10 NRS) 
5. Compliant with study procedures and visit schedules up to the open-label injection with 
FX006 and the willingness and ability to continue to comply for additional 12 weeks after 
the second injection 
6. Willingness to continue abstaining from use of protocol-restricted medications during the 
study (Refer to Section 7.6.2) 


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7.4.5. 
Second Injection Exclusion Criteria (Part II Patients Only) 
Patients fulfilling at least one of the following criteria may not be included in OLE phase of the 
study: 
1. Clinical signs and symptoms of active hip infection or crystal disease of the index hip 
2. Received a non-protocol specified IA intervention (IA injection, IA aspiration, etc.) in 
index hip during study participation 
3. Use of immunomodulators, immunosuppressives, or chemotherapeutic agents during 
study participation 
4. Received a live (e.g., MMR vaccine, chicken pox vaccine, rotavirus vaccine) or live-
attenuated (e.g., FluMist, Zostavax) vaccine during study participation 
5. Use of any other investigational drug, device or biologic during study participation 
6. Any bacterial or viral infection requiring parenteral antibiotics within 4 weeks or oral 
antibiotics within 2 weeks of second injection 
7. Skin breakdown at the hip where the injection would take place 
8. Women who are pregnant or nursing or plan to become pregnant during the study; men 
who plan to conceive during the study 
9. 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)] 
10. 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 
7.4.6. 
Removal of Patients from Therapy or Assessments 
Each randomized and treated patient in Part I and the Part II double blind phase of the study 
receives study medication as a single administration.  Therefore, discontinuation from treatment 
is not applicable.  Patients may be discontinued from study follow-up as detailed below. Data 
collected from discontinued patients will be included in the clinical study report.  Patients who 
discontinue the study may be replaced at the discretion of the Sponsor. 
Withdrawal of Consent  
Each patient will be informed of his/her right to withdraw from the study at any time for any 
reason and without prejudice to alternative treatment.  If a patient decides to withdraw from the 
study, effectively withdrawing his/her informed consent, the Principal Investigator will: 
1. document in patient’s source their withdrawal of consent and reason for withdrawing 
from the study, 
2. assess the patient’s clinical condition and take appropriate therapeutic measures if 
necessary, 


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3. attempt to complete the study assessments defined for the Final/Early Termination Visit, 
and 
4. determine whether the patient is willing to be contacted on a monthly basis (via phone or 
in person) to follow ongoing or new AEs (including concomitant medication(s) 
associated with an AE) through the patient’s scheduled final visit 
Discontinuation of Follow-up by Investigator 
The Principal Investigator may discontinue the patient for safety and poor compliance to study 
procedures. The Principal Investigator should contact the Medical Monitor prior to discontinuing 
the patient. 
Discontinuation of Follow-up by Sponsor 
Patients participating in Part I of the study will return for follow up visits at Weeks 12, 16, 20, 
and 24 or up until the time of this amendment at which time they will be discontinued. The 
patients will be discontinued at the time of notification by the Investigator. 
7.4.7. 
Screen Failures 
Minimal data for patients who fail screening such as demographic information and the reason for 
screen failure will be collected. 
Patients that fail to meet eligibility criteria may be re-screened with the approval of the Medical 
Monitor, the preferred method being a request through the General Log in EDC.  The Medical 
Monitor will document the rationale for any re-screening decision.   
Patients that are re-screened will be assigned a new screening number, re-consented, and will 
have screening assessments repeated if necessary. 
7.5. 
Treatment Administered 
7.5.1. 
Study Medication Treatment Arms 
Investigational Medicinal Product Arm: 
• FX006 – an extended release formulation of triamcinolone acetonide (TA) in 75:25 poly 
(lactic-co-glycolic) acid (PLGA) microspheres.  Nominal 32 mg TA, IA administered as a 
single 5 mL injection into the index hip OA joint under fluoroscopy guidance per injection 
procedure. 
Reference Compound: 
• Normal saline, sodium chloride (0.9% NaCl) solution, IA, administered as a 5 mL injection 
into the index hip OA joint under fluoroscopy guidance per injection procedure. 
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 


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suspension prior to IA injection.  Diluent will be supplied as a sterile liquid in a 5 mL vial with a 
butyl rubber stopper, aluminum seal and plastic cap.  FX006 will be reconstituted in 5.0 mL of 
diluent to form a suspension immediately prior to IA injection.  FX006 will be administered as a 
single 5 mL IA injection. 
7.5.3. 
Identity of Reference Compound 
Normal saline (0.9% sodium chloride injection, USP, supplied as a 10 mL vial) is a sterile, 
nonpyrogenic, isotonic solution of sodium chloride and water for injection.  Each mL contains 
sodium chloride 9 mg.  
7.5.4. 
Receipt, Preparation, Dispensing and Storage 
Study medication will be shipped to the site from the drug supply distribution center.  Receipt 
and dispensation of study medication will be properly documented within the Drug Tracking 
Module.  Any temperature excursions should be documented in the Drug Tracking Module and 
on specified documents for Sponsor assessment and authorization for continued use. 
Dispensing, preparation and administration of investigational products occurs under the 
supervision of the Principal Investigator.  The Principal Investigator may only delegate these 
activities in accordance with state licensing board requirements, and local institutional policies, 
and applicable law.  Before delegating this activity, the Principal Investigator should also ensure 
that the delegate is trained on and understands the requirements of the protocol. 
The packaged kits of FX006 will be stored in a secure area and will be stored refrigerated at 2 to 
8 °C.  Normal saline will be stored in a secure area at room temperature. 
7.5.5. 
Packaging and Labeling of Study Medication 
The study medication will be labeled in accordance with local guidelines, as applicable. 
7.5.6. 
Return of Study Medication 
All study medications (packaged kits/used and unused vials) will be returned to the drug supply 
distribution center and will be documented within the Drug Tracking module.  Return of study 
medications will be properly documented. 
7.5.7. 
Method of Assigning Patients to Treatment Groups 
Eligible patients will be randomized within strata defined by Baseline Western Ontario and 
McMaster Universities Osteoarthritis Index (WOMAC) A (pain) (0-10 numeric ratings scale 
(NRS) average of Screening 2 and Day 1 as follows: 5.0 to < 6.0, 6.0 to < 7.0, and ≥ 7.0 to 9.0 
(see Section 9 for details). 
7.5.8. 
Blinding 
The blinded-assessor technique will be used in this study in order to maintain double blind 
conditions.  Key site staff roles are defined in Section 7.2 and a site specific blinding plan will be 
developed to ensure the blind is maintained throughout the duration of the study.  Treatments 
will be prepared by an unblinded pharmacist/coordinator who has experience with the 


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preparation of study medication and who has been properly trained by the Sponsor or designee.  
IA injections will be performed by an unblinded injector.   
Overall unblinded team responsibilities are as follows: 
• Will have no other contact with the patient and will not have any blinded roles on the 
study (the only exception is that the unblinded injector may be delegated the role of 
obtaining informed consent at the Screening visit) 
• Will not share treatment assignments with the blinded assessor, the patient and other 
blinded study personnel and Sponsor personnel/representatives 
• Will make every effort to maintain the blind (e.g., preparation of both study agents will 
include similar tapping actions, so both “sound” the same).   
Detailed responsibilities for the unblinded site staff are as follows: 
• Unblinded Pharmacist/Coordinator: 
o Receives the randomization notification of the subject’s study treatment  
o Dispenses the appropriate prepared study treatment and necessary materials for the 
injection  
o Completes the drug accountability logs  
o Transports assigned treatment to the location where injection will take place  
o Will remain with the patient and unblinded injector until the injection is completed  
o Ensures the blind is maintained by following the site specific blinding plan to ensure 
the patient is unaware of the treatment assignment prepared for injection 
o Performs the study drug reconstitution 
o Will ensure that the FX006 drug is re-suspended prior to injection  
o Will record details of study drug preparation, transport (if applicable) and 
administration. 
o Will, in collaboration with the Unblinded Injector as appropriate, record any product-
related issues relating to reconstitution or administration of FX006 (e.g., inability to 
achieve an appropriate suspension, inability to administer the full dose due to clogging 
of the needle) and report the occurrence to the Unblinded Site Monitor, as detailed in 
the Pharmacy Binder. 
o Will, in collaboration with the Unblinded Injector, prepare a blinded written record of 
any clinical AE and report the event to the (blinded) Principal Investigator and the 
Blinded Study Coordinator who will enter the event in the EDC and assess, treat, and 
follow-up the patient as appropriate. 
o Will transport the used vials back to the drug storage location to be held until drug 
accountability is performed by the unblinded monitor.  
Depending on site specific requirements, the unblinded pharmacist/coordinator may be split into 
two roles.  Details will be specified in the site specific blinding plan 


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• 
Unblinded Injector 
o Performs the study drug reconstitution (if not completed by the unblinded 
pharmacist/coordinator) 
o Will ensure that the FX006 drug is re-suspended prior to injection  
o Performs the aspiration and injection of the index hip using fluoroscopy in accordance 
with both their experience and the protocol-specified procedure. 
o Will, in collaboration with the Unblinded Pharmacist/Coordinator, record any product-
related issues relating to reconstitution or administration of FX006. 
o Will, if the patient experiences any clinical AE while in the procedure suite, provide 
prompt medical care, as appropriate, including requesting additional assistance. Patient 
safety is always paramount, but, if feasible, minor events should be handled without 
unblinding the blinded study team.   
o Will prepare a blinded written record of the AE and report it to the blinded assessor, 
who will assess, treat, and follow-up with the patient as clinically appropriate  
All other site and Sponsor personnel/representatives involved in the study at the site will be 
blinded with regard to the study medication being administered with the following 
Sponsor/representative exceptions: 
• Unblinded monitor(s):  
o Responsible for unblinded site monitoring.  
o Will perform study drug accountability (used and unused vials) 
o Is the primary point-of-contact for the Unblinded site personnel in the event of any 
“product complaint” (e.g., difficulty reconstituting study drug, inability to inject 
complete dose of study drug) 
o Will report all product-related issues within 24 hours to the designated unblinded 
personnel at the Sponsor. 
• Unblinded clinical manager: 
o Responsible for oversight of unblinded site monitoring. 
o Will review unblinded monitoring visit reports and escalate unblinded site issues to 
unblinded Sponsor representative 
• Unblinded Sponsor representative  
o Point of escalation for unblinded team 
o Will address any product related issues 
o Will escalate in a blinded manner to the blinded study team, if necessary 
• Sponsor Regulatory and Pharmacovigilance personnel for safety assessment and reporting, 
if necessary 


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Information regarding the treatment assignments will be kept securely by Sponsor or designee, 
per its standard operating procedures. 
7.5.9. 
Breaking The Blind 
If there is a clinical adverse event that the Investigator judges requiring unblinding of study 
medication, they will promptly contact the Medical Monitor and review the situation. If the 
consensus is to unblind the subject’s treatment, a trained and authorized site user will log into the 
Emergency Study Code Break Module and will be provided the patient’s treatment assignment. 
If there is a clinical adverse event that Pharmacovigilance or Regulatory judge requires 
unblinding of study medication, the Sponsor’s internal procedure will be followed. 
If any site team member is unblinded for any reason, the Investigator will notify the Sponsor that 
unblinding has occurred, without revealing the treatment, and document who was unblinded, the 
reason for doing so, and the date of unblinding in a note to file. 
7.5.10. 
Investigational Medicinal Product Administration Procedure 
IA Administration Into The Hip Joint 
• IA injections will be performed by the assigned unblinded injector.  The injector may 
choose the numbing agent to be used based on standard of care, if needed 
• A 20 gauge or larger, 3.5 inch needle or longer is to be used for injection 
• Sterile technique will be used 
• Prior to injection, the injection site should be thoroughly cleansed using a bactericidal 
solution.  The injection contents will not be visible to the patient. 
• Aspiration must be attempted prior to all injections.  If effusion is detected by fluoroscopy, 
withdraw to near dryness prior to injection 
• Either 5 mL of the reconstituted FX006 or 5 mL of normal saline will be injected into the 
index hip joint.  Refer to the Pharmacy Binder for detailed instructions on how to prepare 
FX006. Reconstitution process should not be visualized by any blinded study staff or by the 
patients 
• Injection into the hip joint will be done with fluoroscopy guidance by the assigned injector 
(using contrast or air).  The injector may choose the position of the hip (e.g., supine 
position with lower extremity internally rotated) and the approach for injection (e.g., 
anterior.) 
• Patients will be observed per standard of care after the procedure 
Refer to the Pharmacy Binder for detailed references on study drug preparation and IA 
administration. 
Post-Injection Care 
Patients should be advised to avoid strenuous activities or prolonged weight-bearing activities for 
approximately 24 to 48 hours following the injection and to also maintain a stable lifestyle with 
regard to physical activity throughout the duration of the study. 


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7.5.11. 
Treatment Compliance 
Study medication will be administered by the unblinded injector in the clinic.  Details regarding 
study medication administration will be documented in the electronic Case Report Form (eCRF).  
The receipt, dispensation and return/destruction of any study medication will be properly 
documented. 
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 
during the course of the study and the associated reasons for use or change will be documented 
and reported 
7.6.1. 
Allowable Medications/Non-Pharmacologic Therapies 
The following medications/non-pharmacological therapies may be taken or used throughout the 
study: 
• Any treatment for a pre-existing condition or for an AE, outside of the study indication, 
that is not listed as restricted  
• Study-allocated rescue medication 
• Aspirin for cardio protection at a maximum stable dose of 325 mg per day provided the 
dose has been stable over the 3 months prior to Screening 
• Medical therapy for depression, including selective or non-selective serotonin reuptake 
inhibitors (SSRIs, NSRIs, SNRIs) and tricyclics provided the dose has been stable over the 
6 months prior to Screening 1 (See Table 7-1) 
• Stable lifestyle with regard to physical activity, physical therapy, acupuncture, TENS, or 
bracing during the 1 month prior to Screening and expected to remain stable throughout the 
duration of the study 
Table 7-1 below lists the major classes of anti-depressants and examples of commonly 
prescribed agents by generic and brand name; it is not a complete listing. If a concomitant 
medication named by a patient being screened is not familiar, please check at 
https://www.pdr.net or post a query in the General Log. 


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Table 7-1: 
Commonly Prescribed Anti-depressants by Drug Class 
Class  
Class name 
Generic name 
Brand names 
SSRIs 
selective serotonin reuptake 
inhibitors 
Citalopram 
Celexa 
 
Escitalopram 
Lexapro, Cipralex 
 
 
Fluoxetine 
Prozac, Sarafem 
 
 
Fluvoxamine 
Luvox 
 
 
Paroxetine 
Paxil, Seroxat 
 
 
Sertraline 
Zoloft 
SNRIs 
serotonin norepinephrine 
reuptake inhibitors 
Tramadol 
Ultram 
 
Venlafaxine 
Effexor 
TCAs 
tricyclic antidepressants 
Amitriptyline 
Elavil 
 
 
Doxepin 
Sinequan 
 
 
Imipramine 
Tofranil 
 
 
Nortriptyline 
Aventyl, Noritren, Pamelor 
NDRI 
norepinephrine-dopamine 
reuptake inhibitor 
Bupropion 
Wellbutrin, Zyban 
7.6.2. 
Prohibited Medications/Non-Pharmacologic Therapies 
The following medications should not be taken or used for the duration of the study, after the 
patient signs informed consent.  The washout (at least 5 half-lives after the last dose) must be 
completed at least 2 days prior to Screening 2 visit. 
• Oral non-steroidal anti-inflammatory drugs (NSAIDs) 
• Aspirin (>325 mg per day) 
• Centrally-acting pain medications (e.g., pregabalin, gabapentin) 
• Opioids, Marijuana, Cannabidiol (CBD) 
• Topical therapies (e.g., NSAIDs, capsaicin, lidocaine patches, other local treatments) 
applied to the index hip 
• Anesthetic medications injected locally in the index hip (other than lidocaine if used for IA 
injection procedure) 
• Muscle relaxants (e.g., cyclobenzaprine, tetrazepam, diazepam) 
• IV, IM, oral, inhaled, intranasal or topical corticosteroids 
• IA corticosteroids in any joint 
• Any IA intervention in the index hip (e.g., IA viscosupplementation (hyaluronic acid))  
• Initiation of or change in medical therapy for depression, including selective or non-
selective serotonin reuptake inhibitors (SSRIs, SNRIs, NSRIs) and tricyclics; see 
Section 7.6.1 for examples of specific agents in each class  
• Any investigational drug, device or biologic 
• Immunomodulators, immunosuppressives, or chemotherapeutic agents 


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• Live (e.g., MMR vaccine, chicken pox vaccine, rotavirus vaccine) or live-attenuated (e.g., 
FluMist, Zostavax) vaccines  
• Changes to lifestyle with regard to physical activity, physical therapy, acupuncture, TENS, 
or bracing throughout the duration of the study 
7.6.3. 
Rescue Medication 
To standardize pain-relief rescue medication across all patients, starting at screening, patients 
will discontinue all prohibited medications and follow procedures: 
• The designated rescue medication is acetaminophen (paracetamol) 500 mg, one tablet 
every 4 to 6 hr to a maximum of 6 (six) tablets (3000 mg) per 24 hr period. 
• Patients may not take any rescue medication during the 48 hr prior to a study visit. 
• Starting at screening and at each study visit, patients will be provided with a sufficient 
quantity of rescue medication for the interval to the next scheduled visit. 
• At each visit, patients will return the bottles provided at the previous visit for rescue 
medication accountability and be issued a new supply. 
7.7. 
Study Variables 
7.7.1. 
Safety Variables 
• Adverse Events 
• Physical examinations 
• Index hip examinations 
• Index hip X-rays 
• Vital signs 
• Clinical laboratory evaluations (hematology, chemistry) 
7.7.2. 
Efficacy Variables 
• WOMAC Osteoarthritis Index (0-10 NRS): pain, stiffness and function domains 
independently and collectively (Bellamy et al, 1988) 
• PGIC:  7-point scale (Farrar et al, 2001; Guy, 1976; Dworkin et al, 2005) 
• HOOS-QOL Subscale (http://www.koos.nu/) 
• Sleep Interference (SI): Question 9F from the Brief Pain Inventory (Short Form) 
• EQ-5D-5L: consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue 
scale (EQ VAS) (https://euroqol.org) 
• Abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) 
• Responder status as defined by: 


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o Proportion of patients experiencing either ≥50%, ≥30% or ≥20% decrease 
(improvement) in pain) (substantial, at least moderate and minimum clinically 
important difference, respectively, as defined by (Dworkin et al, 2008) 
o Outcome Measures in Rheumatology (OMERACT) - Osteoarthritis Research Society 
International (OARSI) criteria (Pham, 2004) 
• Consumption of rescue medication 
7.8. 
Schedule of Study Assessments 
A summary of the schedule of assessments is provided in Table 7-2 and Table 7-3.  Refer to 
Section 7.9 for details of each assessment. 


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Table 7-2: 
Schedule of Study Assessments for Double Blind Phase 
List of Assessments 
Screening 1n  
Day -30 to -1 
Screening 2n 
Day -10 to -4 
Day 1 
Weeks 1, 4, 8m 
Week 12 
EOS for Double blind phasea, m 
Informed consent 
X 
 
 
 
 
Inclusion/Exclusion Review 
X 
 
Xb 
 
 
Medical History/Update 
X 
 
Xb 
 
 
Patient Demographics 
X 
 
 
 
 
OA Medical History 
X 
 
 
 
 
Prior Treatments and Medications 
X 
 
Xb 
 
 
Physical examination 
X 
 
 
 
X 
Index Hip Assessment 
X 
 
Xb 
X 
X 
Index Hip X-ray c 
X 
 
 
 
X 
Vital signs 
X 
 
Xb 
X 
X 
Height 
X 
 
 
 
 
Weight and BMI 
X 
 
 
 
X 
Hematology, Chemistryh 
X 
 
 
 
X 
ESR 
X 
 
 
 
 
HIV, Hep B/Ch 
X 
 
 
 
 
Pregnancy Test f 
Xh 
 
Xb 
 
X  
Washout of restricted pain medication 
Xd 
 
 
 
 
PD-Q, PHQ-9, GAD-7, PCS, ISI  
X 
 
 
 
 
Randomization 
 
 
Xb 
 
 
Second Injection Criteria 
 
 
 
 
X 
Index Hip Aspiration 
 
 
Xb, g 
 
 
IMP administrationi 
 
 
X 
 
 
Rescue Medication dispensing and 
accountabilitye 
X 
 
X 
X  
X 
Accurate pain reporting and placebo 
response reduction training j 
 
X 
Xb 
X 
X 
WOMACk 
 
X 
Xb 
X 
X 
PGICk 
 
 
 
X 
X 
TSQM-9k 
 
 
 
 
X 
SI, HOOS-QOL, EQ-5D-5Lk 
 
 
Xb 
X 
X 
AE/SAE & ConMedsl 
 
 
------------------------------X------------------------------ 
a. The Double-Blind Phase of the study ends at Week 12. Patients participating in Part I of the study will not receive a second injection but will 
return to the clinic at Weeks 12, 16, 20, and 24 or up until the time of this amendment.  Patients participating in Part II of the study who are 
eligible for the second injection in the open-label phase at Week 12 will receive an open-label injection of FX006 at Week 12 and return for 
follow-up visits at Weeks 16, 20, and 24.  These patients will complete the study at Week 24. Patients participating in Part II of the study who  
are not clinically indicated for a second injection at Week 12 will return to the clinic at Weeks 16, 20, and 24 and will receive an open-label 
injection of FX006 at the first evaluation where the patient has been determined to meet all criteria. 
b. To be collected or assessed prior to injection of study medication 
c. X-ray of weight-bearing anterior-posterior view for index hip will be taken for central reading. 
d. After signing the ICF, patients must stop all restricted medications (other than rescue medication).  The washout (at least 5 half-lives) must be 
completed at least 2 days prior to Screening 2 visit. 
e. Rescue medication will be dispensed to the patient at the Screening visit, and a new bottle will be dispensed at each subsequent visit as needed.  
Drug accountability will be done at each visit 
f. Pregnancy tests will be done in women of child bearing potential. Serum Pregnancy Test to be collected only at Screening visit.  Urine 
Pregnancy Test to be collected prior to injection of study medication and at EOS (when it occurs) 
g. Aspiration must be attempted prior to all injections.  If effusion is detected by fluoroscopy guidance, withdraw to near dryness prior to 
injection 
h. Via Central Laboratory 
i. To be performed under fluoroscopy guidance 
j. To be completed prior to questionnaires 
k. To be completed after APR and PRR training but prior to any other assessments following the sequence in Table 7-5. 
l. AEs and concomitant medications will be captured from Day 1 (post injection) to EOS visit. 
m. Visit should be conducted within +/- 3 days from scheduled date. 
n. Screening 1 and Screening 2 visits can be combined into one visit provided the patient does not have a washout from prohibited medications. If 
there is no washout, please perform APR/PRR first, then the questionnaires in order they are shown on Table 7-6 , with the WOMAC being 
completed after APR/PRR, then all subsequent questionnaires as they are listed for Screening 1.  


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Table 7-3: 
Schedule of Study Assessments for Open Label Extension (OLE) Phase 
List of Assessments 
Second Injection OLE 
 (Week 12i, 16, 20, 24) c,n 
Follow-up  
(every 4 weeks post 2nd 
injection) g,n,o 
EOS for OLE e, g, n, p 
Second Injection Criteria 
X 
 
 
Physical examination 
 
 
X 
Index Hip Assessment 
X 
X 
X 
Index Hip X-rayb 
  
 
X 
Vital signs 
Xa 
X 
X 
Weight and BMI 
 
 
X 
Hematology, Chemistryj 
 
 
X 
Pregnancy Testh 
Xa, o 
 
X 
Index Hip Aspiration 
Xa, f, o 
 
 
IMP administrationc, k 
Xa, o 
 
 
Rescue Medication dispensing and accountabilityd 
X 
X 
X 
Accurate pain reporting and placebo response reduction 
trainingl 
X 
X 
X 
WOMACm 
X 
X 
X 
PGICm 
X 
X 
X 
SI, HOOS-QOL, EQ-5D-5Lm 
X 
X 
X 
AE/SAE & ConMeds 
To be collected at every visit and whenever applicable 
a. 
To be collected or assessed prior to 2nd injection of study medication only if patient is receiving an open label injection of FX006.  
b. 
X-ray of weight-bearing anterior-posterior view for index hip will be taken for central reading 
c. 
Open-label injection of FX006 may occur at either Week 12, 16, 20, or 24 depending on when the patient is clinically indicted to receive a 
second injection 
d. 
Rescue medication will be dispensed to the patient at each visit as needed.  Drug accountability will be done at each visit 
e. 
To be performed at Week 24, 28, 32, or 36, depending on timing of second injection 
f. 
Aspiration must be attempted prior to all injections.  If effusion is detected by fluoroscopy guidance, withdraw to near dryness prior to 
injection 
g. 
If second injection occurs at Week 12, FU visits occur at Weeks 16, 20, and EOS occurs at Week 24.  If second injection occurs at Week 
16, FU visits occur at Week 20, 24, and EOS occurs at Week 28, and so on in sequence 
h. 
Pregnancy test will be done in women of child bearing potential.  Urine Pregnancy Test to be collected prior to injection of study 
medication and at EOS (when it occurs) 
i. 
If patient receives the open-label injection at Week 12, assessments for this visit do not need to be duplicated as per the Week 12 double -
blind period. 
j. 
Via Central Laboratory 
k. 
To be performed under fluoroscopy guidance 
l. 
To be completed prior to questionnaires 
m. 
To be completed after APR and PRR training but prior to any other assessments following the sequence in Table 7-6. 
n. 
Visit should be conducted within +/- 3 days from scheduled date. 
o. 
Not performed on Part I patients 
p. 
Not required for Part I patients discontinued upon implementation of this amendment (Protocol V 3.0; Amendment 2.0) 
 
 
 
 
 


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7.9. 
Study Procedures 
7.9.1. 
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. 
Randomization 
At Day 1, after confirmation of eligibility and completion of all required assessments per Table 
7-2, blinded site personnel will randomize eligible patients within the randomization module in a 
1:1 ratio. 
7.9.3. 
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 at Day 1 per the schedule 
noted in Table 7-2. 
OA medical history includes ACR diagnosis details, OA diagnosis date (if available), number of 
days with index hip pain in the last month, previous IA steroid, PRP or hyaluronic injections, 
presence of OA in other joints, prior procedures or surgeries for index hip OA. 
At Day 1, eligibility should be confirmed (inclusion/exclusion criteria review against any new 
information/findings through Day 1 assessment). 
7.9.4. 
Physical Examination 
The physical exam will assess the following body systems: 
• 
General Appearance 
• 
Skin 
• 
Lymphatics 
• 
HEENT (head, ears, eyes, nose, throat) 
• 
Cardiovascular 
• 
Respiratory 
• 
Abdominal 
• 
Musculoskeletal 
• 
Neurological 
Physical exams are to be conducted at the days indicated in Table 7-2 and Table 7-3. 
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. 


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7.9.5. 
Index Hip Assessment 
The index hip assessment will be performed by the blinded assessor at the days indicated in the 
Table 7-2 and Table 7-3.  The index hip will be assessed for tenderness, warmth, redness, 
swelling, and effusion, limitation on range of motion (directions: flexion, extension, abduction, 
adduction, internal rotation or external rotation; severity: mild, moderate or severe). If there is a 
clinically significant finding at the Screening or Day 1 Visit (pre-injection), add to the Medical 
History.  At time points post-injection, if there are new clinically significant findings or findings 
that worsen for the patient’s baseline condition, record as AEs. 
7.9.6. 
Index Hip X-ray 
A diagnostic quality X-ray of the index hip is required (weight-bearing anterior-posterior pelvic 
view with the lower limbs in 10 degree internal rotation with a size ratio of 1:1) at Screening, Week 
12 and End of Study Visit (for patients who receive an open-label injection of FX006) (see Table 
7-2 and Table 7-3). 
The Screening X-ray will be read centrally for K-L grading and potential risk signs of rapidly 
progressive OA (e.g., atrophic osteoarthritis, femoral head necrosis and/or collapse, subchondral 
bone insufficiency fracture, etc.).  In addition to the Screening X-ray, the Week 12 and End of 
Study X-rays will be read centrally. An image acquisition protocol will be distributed to sites 
with instructions for radio-anatomic positioning for reliable grading. 
Kellgren-Lawrence grading is a global scoring method that considers osteophytes, JSN, 
subchondral bone sclerosis and/or bone attrition. Grading criteria for the hip are (Rheumatology 
2005;44 Suppl 4:54):   
Grade 0: Normal appearance. 
Grade 1: Possible osteophytes, possible JSN medially. 
Grade 2: Definite osteophytes, definite JSN, slight sclerosis. 
Grade 3: Mild osteophytes, marked JSN, moderate sclerosis, cysts and deformity 
Grade 4: Large osteophytes, severe JSN, cysts sclerosis and deformity 
Subjects will be considered radiographically eligible for enrollment in the study if the (index) hip 
is Kellgren-Lawrence Grade 2 or 3. 
7.9.7. 
Vital Signs 
Vital signs are to be taken at the days indicated in Table 7-2 and Table 7-3. 
The following measurements will be taken: sitting blood pressure, heart rate, respiration rate, and 
oral temperature. 
7.9.8. 
Height, Weight and BMI Determination 
Height and weight are to be taken at the days indicated in Table 7-2 and Table 7-3.  Height will 
be measured in centimeters or inches.  Weight will be measured in kilograms or pounds.  BMI 
will be calculated using the following formulas (reference: www.cdc.gov): 


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Table 7-4: 
Height, Weight and BMI Determination 
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 
7.9.9. 
Central Clinical Laboratory Evaluations 
Blood samples will be taken as follows at the days indicated Table 7-2 and Table 7-3.  The 
specific laboratory panels to be run can be found in the table below.  Follow the Central 
Laboratory Manual for detailed sample collection, handling, storage, and shipping instructions.  
Please see Table 7-5 below. 
Table 7-5: 
Clinical Laboratory Panel 
CLINICAL LABORATORY PANELS 
HEMATOLOGY 
CLINICAL CHEMISTRY  
Hemoglobin 
Sodium  
Hematocrit  
Potassium  
Erythrocyte count (RBC) 
Bicarbonate  
Mean cell volume 
Chloride  
Leukocytes (WBC)  
Calcium   
Absolute counts of:  
Total bilirubin  
• 
Neutrophils  
Alkaline phosphatase  
• 
Lymphocytes  
Alanine aminotransferase  
• 
Monocytes  
Aspartate aminotransferase  
• 
Eosinophils  
Blood urea nitrogen 
• 
Basophils  
Creatinine  
• 
Platelets 
Uric acid  
 
Glucose 
INFECTIOUS DISEASES 
Total protein  
Hepatitis B Surface Antigen 
Albumin  
Hepatitis C Antibody1 
 
HIV2  
ESR: test provided by Central Laboratory but performed and 
read at the site  
PREGNANCY TESTS (WOMEN OF CHILD BEARING POTENTIAL ONLY) 
• 
Serum: submitted to and performed by Central Laboratory 
• 
Urine: test provided by Central Laboratory but performed and read at the site 
1. Patients positive for HCV Antibody will have reflex testing for circulating HCV RNA. 
2. HIV screening will use a current 4th generation test for both antibody and viral antigen. 


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7.9.10. 
Index Hip Aspiration 
Aspiration must be attempted prior to injection of study medication at Day 1 and prior to second 
injection of study medication.  If effusion is detected by fluoroscopy guidance, withdraw to near 
dryness prior to injection.   
7.9.11. 
Second Injection Criteria 
Second Injection Inclusion and Exclusion Criteria must be assessed prior to administration of 
second injection of study medication.  Please reference Section 7.4.4 and Section 7.4.5 for 
Second Injection Inclusion/Exclusion criteria listing.  Please also reference Table 7-3.    
7.9.12. 
Rescue Medication Dispensing and Accountability 
Rescue medication (500 mg tablets of acetaminophen or paracetamol) will be dispensed to 
patients at the Screening visit.  At each subsequent visit, at any time during the visit, rescue 
medication accountability will be performed.  Additional rescue medication will be 
returned/dispensed as needed.  Refer to Section 7.6.3 for further information regarding rescue 
medication. 
7.9.13. 
Accurate Pain Reporting and Placebo Response Reduction Training 
Placebo Response Reduction (PRR) Training  
This training (“Participating in a Research Study, What you need to know,” Analgesic Solutions, 
Wayland, MA) consists of a set of patient and staff educational materials for training on 
appropriate expectations of personal benefit while participating in a clinical trial. The purpose is 
to provide patients truthful information that will neutralize the potentially excessive expectations 
that drive high placebo responses in clinical trials. Patients will receive training at each study 
visit indicated in Table 7-2 and Table 7-3. The training video takes approximately 5 minutes to 
complete, and should be completed prior to any patient questionnaires.  
All staff that have contact with patients must also complete the staff assigned PRR portion of the 
training prior to injection/dosing of patient. 
Accurate Pain Reporting (APR) Training 
The Accurate Pain Reporting Program (“Reporting Your Pain,” Analgesic Solutions, Wayland, 
MA) consists of a set of patient and staff educational materials and instructions on how to 
accurately and reliably report pain scores, and on the proper use of pain intensity scales, with the 
aim of increasing patients’ pain reporting accuracy. Staff training is conducted prior to the first 
subject visit. Patients will receive training at each study visit indicated in Table 7-2 and Table 
7-3.  The training video takes approximately 5 minutes to complete, and should be completed 
prior to any patient questionnaires.  
All staff that have contact with patients must also complete the staff assigned APR portion of the 
training prior to injection/dosing of patient.  
7.9.14. 
Patient Questionnaires 
Questionnaires will be completed by the patient at each visit as scheduled (see Table 7-2 and 
Table 7-3).  APR and PRR training will be completed first and then the patient will complete the 


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questionnaires based on the sequence listed below in Table 7-6 and Table 7-7.  All other 
assessments or procedures will occur after completion of the questionnaires.  
Note: If Screening 1 and Screening 2 are combined into one visit (provided the patient does not 
have a washout from prohibited medications), please perform APR/PRR first, then the 
questionnaires in order they are shown below on Table 7-7, with the WOMAC being completed 
after APR/PRR, then all subsequent questionnaires completed as they are listed for Screening 1.  
Table 7-6: 
Patient Questionnaires 
Sequence 
at Visit 
Screening 1 Screening 2 
Day 1  
Weeks  
1, 4, 8 
Week 12 
Every 4 weeks 
during the 
OLE 
1 
PD-Q 
WOMAC 
WOMAC 
WOMAC 
WOMAC 
WOMAC 
2 
PHQ-9 
 
 
PGIC 
PGIC 
PGIC 
3 
GAD-7 
 
SI 
SI 
SI 
SI 
4 
PCS 
 
HOOS-QOL HOOS-QOL 
HOOS-QOL 
HOOS-QOL 
5 
ISI 
 
EQ-5D-5L 
EQ-5D-5L 
EQ-5D-5L 
EQ-5D-5L 
6 
 
 
 
 
TSQM-9 
 
 
 
Table 7-7: 
Patient Questionnaire Sequence if Screening 1 and Screening 2 Visits are 
Combined 
Sequence at Visit 
Screening 1 
& Screening 2 (combined) 
1 
APR/PRR Training 
2 
WOMAC 
3 
PD-Q 
4 
PHQ-9 
5 
GAD-7 
6 
PCS 
7 
ISI 
 
7.9.15. 
Review of Adverse Events and Concomitant Medications 
After receiving assigned study medication and at all visits, the patient should be monitored for 
any AEs by the blinded assessor.  Review of any Concomitant Medications should also be 
performed and documented in source documentation.  Refer to Section 8.4.1 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. 
ADVERSE EVENTS 
Subjects will be monitored for adverse events from first dose of study medication through the 
end of their participation in the study. 
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. 
Definitions 
Adverse Event (AE):  An AE is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and that does not necessarily have a 
causal relationship with this treatment.   
An AE can therefore be: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product 
• Any clinically significant abnormality found on an ECG, laboratory test, or physical 
examination 
• Any worsening (i.e., any clinically significant adverse change in frequency and/or 
intensity) of a preexisting condition, which is temporally associated with the use of the 
medicinal (investigational) product 
Pregnancy is not an AE; however, if a female patient or the female partner of a male patient who 
has received at least one dose of study medication becomes pregnant during the conduct of the 
study, the Investigator must notify the Sponsor according to the procedures in Section 8.4.1. 
Serious Adverse Event (SAE):  An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening 
o “Life-threatening” 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 Note:  Adverse events requiring hospitalizations that are less than 24 hours in duration 
do not meet this criterion.  A planned hospitalization for an elective procedure or a pre-
existing condition that has not worsened during participation in the study does not meet 
this criterion 
• Results in permanent or significant disability/incapacity; a substantial disruption of the 
patient’s ability to carry out normal life functions 
• Is a congenital anomaly/birth defect 


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• Is an important medical event: event 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 outcomes listed in the definition above 
Planned Hospitalization: 
A hospitalization planned prior to first dose of study medication is considered a therapeutic 
intervention.  If the planned hospitalization or procedure is executed as planned, it should be 
recorded in the patient’s medical history.  However, if complications arise during the planned 
hospitalization or procedure or the patient experiences an AE during the planned hospitalization 
or procedure, it must be reported as an AE. 
8.2. 
Monitoring of Adverse Events 
Each patient will be monitored for the occurrence of AEs, including SAEs, beginning with 
administration of the first dose of study medication. Each patient will be followed for safety 
monitoring until the last follow up visit in the trial as described in the Schedule of Assessments. 
Patients will be questioned and/or examined by the Investigator or a qualified designee for 
evidence of AEs. The questioning of patients with regard to the possible occurrence of adverse 
events should be generalized such as, “How have you been feeling since your last visit?” The 
presence or absence of specific AEs should not be elicited from patients. 
Results of study efficacy assessments and patient reported outcome surveys should not be 
reported as adverse events unless they indicate a significant worsening from baseline. 
The Investigator is required to follow SAEs until resolution or withdrawal of consent. Resolution 
is defined as: 
• A return to baseline for a pre-existing condition 
• Resolved with or without residual effects 
• The Investigator does not expect any further improvement or worsening of the event 
• Fatal outcome:  If an autopsy is performed on a deceased patient, the autopsy report should 
be provided to the Sponsor as soon as it is available 
8.2.1. 
Monitoring of Laboratory Assessments and Other Diagnostic Tests 
The Investigator will review results of laboratory and other diagnostic tests for clinical 
significance and consideration as an AE.  
8.2.2. 
Adverse Events That Occur During the Injection Procedure 
If an adverse event occurs during the injection procedure, the Unblinded Injector will record the 
details of the AE in the patient’s chart and provide a full report of the event to the Blinded 
Assessor in a blinded manner. Any difficulties with the study drug administration should not be 
reported to the Blinded Assessor unless it is a direct cause of an AE. For any difficulties with the 
study drug, the Unblinded Injector should refer to the Pharmacy Binder. 


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8.2.3. 
Reporting Arthralgia in the Index Hip 
Since all enrolled patients are required to have a certain level of arthralgia in the index hip before 
they receive study drug, the Investigator must take care to fully assess any patient reports of 
index hip arthralgia that occurs during the study. Incremental return of preexisting index hip 
arthralgia following post-injection pain relief does not meet the criteria for an adverse event, 
unless the arthralgia is clinically significantly worse from baseline (before study drug 
administration).  
8.3. 
Assessment of Adverse Events 
8.3.1. 
Assessment of Seriousness 
Each adverse event should be assessed for seriousness against the definition of Serious Adverse 
event in Section 8.1 above. 
8.3.2. 
Assessment of Severity 
Each adverse event should be evaluated for severity or intensity.  This is not the same as 
“serious,” which is based on patient/event outcome or action criteria usually associated with 
events that pose a threat to a patient’s life or functioning.  The severity of AEs will be assessed 
according to the following definitions: 
• Mild:  the AE is noticeable to the patient and/or the Investigator, but does not interfere with 
routine activity 
• Moderate:  the AE interferes with routine activity, but responds to symptomatic therapy or 
rest 
• Severe:  the AE significantly limits the patient’s ability to perform routine activities despite 
symptomatic therapy 
8.3.3. 
Assessment of Relationship to Study Medication 
A medically qualified Investigator must assess the relationship of any AE (including SAEs) to 
the use of the investigational product, as related or not related, based on clinical judgment and 
using all available information, and may include consideration of the following factors: 
• Possible alternative causes of the AE, including the disease under treatment, pre-existing 
conditions, concomitant use of other drugs, and presence of environmental or genetic 
factors 
• The temporal association between drug exposure and onset of the AE 
• Whether the manifestations of the AE are consistent with known actions or toxicity of the 
investigational product 
The causal relationship between the study medication and the AE will be assessed using one of 
the following categories: 


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Not Related:  An AE is not associated with study medication if: 
• Temporal relationship is lacking (e.g., the event did not occur within a reasonable time 
frame following administration of the study medication); or 
• Other causative factors more likely explain the event (e.g., a pre-existing condition, other 
concomitant treatments) 
Related:  An AE is attributed to the study medication if: 
• There is a positive temporal relationship (e.g., the event occurred within a reasonable time 
frame following administration of study medication); and 
• The AE is more likely explained by the investigational product than by another cause (e.g., 
the AE shows a pattern consistent with previous knowledge of the investigational product 
or the class of the investigational product) 
8.4. 
Recording of Adverse Events 
All AEs, regardless of seriousness, severity, or causal relationship to study medication, will be 
recorded on the AE page of the eCRF. 
When possible, adverse events should be reported as a specific disease or syndrome rather than 
individual signs and symptoms.  Additionally, procedures and diagnostic tests results should not 
be reported as AEs unless their underlying diagnosis is unknown.  For example, the diagnosis of 
‘influenza’ should be reported as an AE instead of the symptoms of fever, fatigue, malaise, and 
positive flu test when the Investigator believes that those are all associated with influenza.  
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. 
8.4.1. 
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 becoming aware of the 
SAE.  The EDC system will notify the Medical Monitor and other appropriate study personnel of 
the SAE. 
If the EDC SAE form is not available, the Investigator should complete and sign the paper SAE 
form and email it to the Sponsor.  When the EDC system is available again, the SAE should be 
input into the EDC SAE form. 
Follow up information relating to an SAE must be reported to the Sponsor within 24 hours of 
receipt by the Investigator by entering new or updated information into the EDC SAE form. 
All SAEs that occur at your site should, in addition, be reported by the Investigators to the 
responsible IRB/EC without undue delay, if applicable according to IRB/EC requirements. 
During the conduct of the study, the Sponsor will provide expedited safety reports (AEs 
classified as serious, unexpected and related to study medication) to the investigative sites.  If 
this occurs, the investigative site must report the information to their IRB per local guidelines 
(may be submitted by the Sponsor or designee for sites that use a central IRB). 


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8.4.2. 
Unblinding Treatment for a Patient during the Trial 
Requirements for emergency unblinding by the Investigator are detailed in Section 7.5.9.  To 
assess an occurrence of a serious adverse event for regulatory reporting purposes, Flexion 
Pharmacovigilance or Regulatory Operations may unblind the treatment of any subject. 
8.5. 
Safety Monitoring Roles 
The site personnel will carefully monitor each patient throughout the study for possible AEs.  All 
AEs will be reviewed and assessed by the Blinded Assessor.  All AEs will be documented on the 
eCRF 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 
8.4.1.  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 blinded AE 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 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. 
Investigators will receive prompt notification of any adverse experience associated with the use 
of the study medication that is both serious and unexpected, or any finding that suggests a 
significant risk for patients.  The Investigator will promptly inform the IRB/EC of the 
notification and insert the notification in the Investigator’s Regulatory Binder in accordance with 
local regulations. 
8.6. 
Clinical Management of Index Hip-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 hip), the patient should be treated according 
to local clinical guidelines and physician experience.  
If the index hip is aspirated at any time other than 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 8.4. 


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8.7. 
Pregnancy 
All pregnancies, female patients or female partners of male patients during the study, must be 
reported within 24 hours on the Pregnancy Report Form.  The Investigator must continue to 
follow the pregnancy until the completion of the pregnancy, including the outcome and the 
condition of the newborn (if applicable).  If not all information on the Pregnancy Report Form is 
available at the time of the initial report, follow-up reports should be provided to the Sponsor in a 
timely manner.  Additional subsequent 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 for Part I and Part 
II prior to database lock for each part of the study.  If, after the study has been completed, 
changes are made to the SAP 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 the proposed analyses are summarized below. Parts I and II of the study will enroll 
separate patients, and as such all analyses will be performed independently of one another. 
Analyses for Parts I and II of the study will be performed in the same manner, as detailed below.  
The analyses of the Part I data will be performed in an unblinded manner and results may be 
used to inform the conduct of Part II; as the analyses of Part I will be completed prior to the 
enrollment of any patients in Part II, this will have no impact on maintaining the blind for Part II.   
9.1.1. 
Planned Analyses 
Part I Analysis 
An unblinded analysis will be conducted when all Part I patients have completed the study.  All 
data collected on Part I patients will be analyzed.  All analyses of the Part I data are exploratory 
in nature. 
Part II Interim Analysis 
An unblinded interim analysis will be conducted when all Part II patients have completed the 
double-blind phase of the study.   
Final Analysis  
A final analysis will be conducted when all Part II patients have completed the OLE phase of the 
study.  Final analyses specified in the protocol and SAP will be completed and reported in the 
CSR. Post-hoc, exploratory analyses, may be completed to further understand and elucidate 
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 subject 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 
mean, median, standard deviation, minimum and maximum.  Categorical variables will be 
summarized by frequencies and percentages.  Confidence intervals may also be provided.  
Figures will be used to support the presentation of certain data.  Sensitivity analyses may be 
performed to examine the effect of missing data, as well as the effect of Baseline imbalance, 
should one occur. 
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. 


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9.2.1. 
Analysis Populations 
The following analysis populations are planned for each part of this study as follows: 
• Full Analysis Set (FAS) Population:  All patients who received study drug.  The FAS 
population will be used to examine efficacy endpoints for the double-blind phase of the 
study 
• Safety Population:  All subjects who received at least one dose of study drug.  The Safety 
Population will be used to assess safety and tolerability 
• Second Injection Population (Part II only):  All patients who received a second injection.  
The Second Injection Population will be used to examine efficacy endpoints in the open-
label extension phase of the study 
• Per Protocol Population (Part II Only):  All patients in the FAS population who completed 
the Week 12 visit with no major protocol deviations that may impact the evaluation of the 
primary efficacy endpoint based on blinded data prior to unblinding of the double-blind 
phase data. 
9.2.2. 
Study Data 
Study data identified in this protocol are collected, and source verified, on electronic Case Report 
Forms (eCRF) at sites completing the study.  All study data will be formulated into data sets to 
provide transparency, traceability, and integrity of trial analysis results from collection source.  
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 using implementation guide 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 Endpoints for Assessment 
The same endpoints for Part I and the double-blind phase of Part II of the study will be used.  
However, all endpoints will be exploratory in Part I of the study. 


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9.2.3.1. 
Key Primary Efficacy Endpoint 
• Change from Baseline on the WOMAC A (pain) score at Week 12 
9.2.3.2. 
Key Secondary Efficacy Endpoints  
• Change from Baseline on the WOMAC C (function) score at Week 12 
• PGIC score at Week 12 
9.2.3.3. 
Additional Secondary Efficacy Endpoints: 
• Area Under the Effect curve (AUE) of change from Baseline on the WOMAC A (pain) 
subscale over the time intervals (e.g., Weeks 1 to 4, Weeks 1 to 8, and Weeks 1 to 12) 
• AUE of change from Baseline on the WOMAC C (function) score over the time intervals 
(e.g., Weeks 1 to 4, Weeks 1 to 8, and Weeks 1 to 12) 
• PGIC at Weeks 1, 4, and 8 
• Change from Baseline on the WOMAC A (pain) score at Weeks 1, 4, and 8 
• Change from Baseline on the WOMAC C (function) score at Weeks 1, 4, and 8 
• Change from Baseline on the WOMAC B (stiffness) score at Weeks 1, 4, 8, and 12 
• Change from Baseline on the WOMAC total score at Weeks 1, 4, 8, and 12 
• Percent of responders (defined as patients with high improvement in pain or function) 
according to OMERACT-OARSI criteria at Weeks 1, 4, 8, and 12 
• Proportion of patients experiencing a ≥20%, ≥30%, or ≥50% decrease in WOMAC A 
(pain) at Weeks 1, 4, 8, and 12 
• Rescue medication use at Weeks 1, 4, 8, 12 and total consumption 
• Change from Baseline on the SI at Weeks 1, 4, 8, and 12 
• Change from Baseline on the EQ-5D-5L at Weeks 1, 4, 8, and 12 
• Change from Baseline on the HOOS-QOL at Weeks 1, 4, 8, and 12 
• TSQM-9 at Week 12 
• Change from Baseline on WOMAC A (pain), B (stiffness), C (function) and PGIC at 
Weeks 1, 4, 8, and 12 in patients with unilateral hip OA 
The same endpoints as above will be examined post Week 12 during the OLE phase of Part II 
with the addition of the following: 
• Time to second injection for patients who receive a second injection of FX006 


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9.2.4. 
Sub-Groups and Covariates 
Other pre-planned sub-groups analyses per aspiration status, KL grade, gender and the baseline 
pain score, etc. will be detailed in the SAP.  Sub-groups (e.g., second dose cohorts (Week 12, 16, 
20, or 24)) may be defined and explored after all pre-planned analyses have been completed to 
further elucidate study results. 
Covariates for efficacy analyses will include baseline WOMAC A score, baseline score for the 
endpoint and study site.  Other covariates may be explored and will be fully defined in the SAP. 
9.3. 
Determination of Sample Size 
9.3.1. 
Sample Size Considerations 
Approximately 70 patients will be randomized in Part I and approximately 440 patients will be 
randomized in Part II in this study (an estimated 35 and 220 per treatment group respectively.) 
For Part I, a sample size of approximately 35 per arm will provide information regarding the 
treatment effect. For Part II of the study, the expected sample size was determined based on the 
primary endpoint as follows. A minimum sample size of N=212 per arm for the placebo and the 
FX006 group has 90% power to yield a statistically significant difference (alpha=0.05, 2-sided) 
if the true underlying difference at Week 12 is 0.65 and with an assumption of 2.0 for the SD.  
For the first key secondary endpoint, the sample size of N=220 per treatment group has 90% 
power to yield a statistically significant difference between FX006 and placebo if the true 
underlying difference is 0.68 at Week 12, assuming a SD of 2.125.  An early discontinuation rate 
of 6% was assumed.  The data from Part I may be used to inform if the above assumptions were 
appropriate and the planned sample size for Part II should remain at 440, or whether a smaller 
sample size would be feasible.   
9.4. 
General Statistical Methods 
Complete details of the statistical analysis will be specified in the SAP.  A separate SAP will be 
prepared for Part I and Part II of the study prior to database lock for each part of the study.  Parts 
I and II of the study will enroll separate patients, and as such all analyses will be performed 
independently of one another. Analyses for Parts I and II of the study will be performed in the 
same manner, as detailed below.  The analyses of the Part I data will be performed in an 
unblinded manner and results may be used to inform the conduct of Part II; as the analyses of 
Part I will be completed prior to the enrollment of any patients in Part II, this will have no impact 
on maintaining the blind for Part II.  All analyses of Part I data are exploratory in nature. 
9.4.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be listed by study site and subject, 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 subject, and will be summarized by treatment 
and dose.  The number of doses administered as well as total exposure will be summarized.  
Time between first and second injections will also be summarized. 


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9.4.3. 
Efficacy Analyses 
Primary Efficacy Analysis 
The primary endpoint will be analyzed with a longitudinal mixed model for repeated measures 
(MMRM) with fixed effects for treatment group, study week, treatment-by-week interaction and 
Baseline score.  Subject will be the random effect.  Treatment differences from control will be 
estimated via least square means from the analysis model along with 95% confidence intervals, 
and associated 2-sided p-values.  This model assumes missing at random and includes only 
observed data. 
Secondary Efficacy Analyses 
Key secondary endpoints will be assessed similarly to the primary endpoint.  Multiplicity will be 
addressed by analyzing the key secondary endpoints sequentially in the order presented in the 
protocol, testing each endpoint at the nominal alpha=0.05, 2-sided level to ensure overall type I 
error control at the 2-sided 0.05 level. 
Additional continuous secondary efficacy endpoints will also be assessed similarly to the 
primary endpoint, but are not part of the sequential testing approach.  Categorical end points will 
be compared via chi-square or exact tests depending on incidence rates. 
AUE will be calculated and comparisons of the AUE endpoints will be estimated from an 
Analysis of Covariance (ANCOVA) with model parameters for treatment and covariates of 
Baseline WOMAC A score and study site.  Full details of the AUE analyses will be detailed in 
the SAP. 
Efficacy Analyses For The Open-Label Extension Phase (Part II) 
Exploratory efficacy endpoints for the open-label extension phase will be analyzed similarly to 
the primary and secondary endpoints, but separately for the time period prior to the second 
injection and the time period post the second injection.  Time-to-event endpoints will be assessed 
via log-rank tests and results will be presented in Kaplan-Meier plots. 
9.4.4. 
Safety Analyses 
Analysis of Adverse Events 
Safety analyses will be performed on the Safety Population.  AEs will be coded using MedDRA.  
Incidences (number and percent) of TEAEs, those events that start 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 hip TEAEs following the first dose and second dose, as well as the 
cumulative incidence of TEAEs after all doses of FX006. 
Other Safety Analyses 
Laboratory data, vital sign information and X-ray data will be presented as descriptive summary 
statistics for value and change from Baseline at each individual time point.  Categorical variables 
will be summarized by frequencies and percentages. 


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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 product complaint, complete the Complaint Notification Form located in the 
Pharmacy binder.  
11.3. 
Rescue Medication Accountability 
Each patient will be provided with a sufficient quantity of acetaminophen/paracetamol 500 mg 
tablets at each scheduled clinic visit starting at Screening. 
Patients will bring back the used and unused bottles at the next visit to allow for medication 
accountability. 
11.4. 
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. 
11.5. 
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, source data, and medical inventory 


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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 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. 
11.6. 
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 
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Atchia I, Kane D, Reed MR, Isaacs JD, Birrell F. Efficacy of a single ultrasound-guided injection 
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Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of 
WOMAC: A health status instrument for measuring clinically important patient relevant 
outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J 
Rheumatol 1988;15(12):1833-1840. 
Benito MJ, Veale DJ, FitzGerald O, van den Berg WB, Bresnihan B. Synovial tissue 
inflammation in early and late osteoarthritis. Ann Rheum Dis. 2005 Sep;64(9):1263-7. 
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 
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Clayman, M.  An Intra-Articular, Extended-Release Formulation of Triamcinolone Acetonide 
Prolongs and Amplifies Analgesic Effect in Patients with Osteoarthritis of the Knee, A 
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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: 
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Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, Haythornthwaite JA, 
Jensen MP, Kerns RD, Ader DN, Brandenburg N, Burke LB, Cella D, Chandler J, Cowan P, 


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Dimitrova R, Dionne R, Hertz S, Jadad AR, Katz NP, Kehlet H, Kramer LD, Manning DC, 
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SAP_001.pdf: 
Flexion Therapeutics 
Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
Confidentiality 
This document is confidential and proprietary property of Flexion Therapeutics, Inc. and to be used only as 
authorized by Flexion Therapeutics, Inc..  No part is to be reproduced, disclosed to others, or quoted without prior 
written authorization from Flexion Therapeutics, Inc. 
STATISTICAL ANALYSIS PLAN 
Protocol FX006-2018-015 
Part I 
 
A Randomized, Double-blind, Placebo-controlled, Parallel-group Study to 
Evaluate the Efficacy and Safety of FX006 in Patients with Hip Osteoarthritis 
 
Protocol Number: 
(Version Date) 
FX006-2018-015 
Version 3.0 (01 August 2019) 
Name of Test Drug: 
FX006 
Phase: 
3 
Methodology: 
Randomized, double-blind, placebo-controlled, parallel-
group study 
Sponsor: 
Flexion Therapeutics 
10 Mall Road, Suite 301 
Burlington, Massachusetts, USA  
Tel: 781-305-7777 
Sponsor Representative: 
Amy Cinar, PhD 
Director, Biostatistics 
Document Date: 
05 September 2019 
Document Version: 
Final Version 1.0 
 






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TABLE OF CONTENTS 
Section 
Page
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS.................... 10
1.1. 
Introduction .................................................................................. 10 
1.2. 
Objectives of Statistical Analysis ................................................ 12 
2. 
STUDY DESIGN ...................................................................................... 13 
2.1. 
Synopsis of Study Design and Randomization Methodology ... 13 
2.2. 
Stopping Rules and Unblinding .................................................. 13 
2.3. 
Study Procedures ......................................................................... 13 
2.4. 
Efficacy and Safety Endpoints .................................................... 15 
2.4.1. 
Primary Efficacy Endpoint .......................................... 15 
2.4.2. 
Key Secondary Efficacy Endpoints ............................. 15 
2.4.2.1.  Additional Secondary Efficacy Endpoints ...................... 15 
3. 
PATIENT POPULATIONS .................................................................... 17 
3.1. 
Population Definitions ................................................................. 17 
4. 
STATISTICAL METHODS ................................................................... 18 
4.1. 
Sample Size Justification ............................................................. 18 
4.2. 
General Statistical Methods and Data Handling ...................... 18 
4.2.1.  General Methods .......................................................................... 18 
4.2.2.  Computing Environment ............................................................. 19 
4.2.3.  Methods of Pooling Data ............................................................. 19 
4.2.4.  Adjustments for Covariates ........................................................ 19 
4.2.5.  Multiple Comparisons/Multiplicity ............................................ 19 
4.2.6.  Subpopulations ............................................................................. 19 
4.2.7.  Discontinuations and Loss to Follow-up .................................... 20 
4.2.8.  Missing, Unused, and Spurious Data ......................................... 20 
4.2.9.  Visit Windows ............................................................................... 20 
4.2.10. Baseline definitions ...................................................................... 20 
4.3. 
Interim Analyses .......................................................................... 20 
4.4. 
Final Analyses ............................................................................... 20 
4.5. 
Patient Disposition ....................................................................... 21 
4.6. 
Protocol Deviations ...................................................................... 21 


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CONFIDENTIAL - 5 - 
Section 
Page
4.7. 
Demographic and Baseline Characteristics............................... 21
4.7.1.  Demographic Characteristics ...................................................... 21 
4.7.2.  OA Medical History ..................................................................... 22 
4.7.3.  Prior medication ........................................................................... 22 
4.8. 
Patient Randomization ................................................................ 22 
4.9. 
Study Drug Exposure ................................................................... 23 
4.10.  Efficacy Evaluation ...................................................................... 23 
4.10.1. 
WOMAC ........................................................................ 23 
4.10.1.1. Change from Baseline ..................................................... 23 
4.10.1.2. AUE for Change from Baseline in WOMAC over Time 24 
4.10.1.3. WOMAC A (pain) Responder ........................................ 25 
4.10.2. 
PGIC Score .................................................................... 26 
4.10.2.1. Continuous ...................................................................... 26 
4.10.2.2. Categorical ...................................................................... 26 
4.10.3. 
OMERACT-OARSI and Responder Status ............... 26 
4.10.4. 
Consumption of Rescue Medications .......................... 27 
4.10.5. 
Sleep Interference (SI) .................................................. 28 
4.10.6. 
EQ-5D-5L ....................................................................... 28 
4.10.7. 
HOOS-QOL subscale .................................................... 28 
4.10.8. 
TSQM-9 ......................................................................... 29 
4.10.9. 
Sensitivity Analyses ....................................................... 29 
4.11.  Safety Analyses ............................................................................. 29 
4.11.1. 
Adverse Events .............................................................. 29 
4.11.2. 
Laboratory Data ............................................................ 31 
4.11.3. 
Vital Signs and Physical Examinations and Index Hip 
Assessment ..................................................................... 31 
4.11.4. 
Index Hip X-Ray ........................................................... 32 
4.11.5. 
Concomitant Medications ............................................ 34 
4.11.6. 
Surgical Procedures ...................................................... 34 
5. 
CHANGES TO PLANNED ANALYSES .............................................. 35 
6. 
References ................................................................................................. 36 


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Section 
Page
7. 
CLINICAL STUDY REPORT APPENDICES..................................... 38
7.1. 
Statistical Tables and Figures to be Generated ......................... 38 
7.2. 
Data Listings to be Generated ..................................................... 44 
7.3.  
Laboratory Grade Definitions  - CTCAE 4.03 .......................... 47 
 
 


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LIST OF IN-TEXT TABLES 
Table 
Page 
Table 1 
Schedule of Study Assessments for Double Blind Phase ................................................ 14 
 


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Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
CONFIDENTIAL - 8 - 
 
ABBREVIATIONS 
 
 
Abbreviation 
Definition 
AE 
Adverse Event 
ACR 
American College of Rheumatology 
ANCOVA 
Analysis of Covariance  
APR 
Accurate Pain Reporting  
AUE 
Area Under the Effect Curve  
BMI 
Body Mass Index 
CI 
Confidence Interval 
cm 
Centimeter 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
EOS 
End of Study 
EQ 
EuroQol 
EQ-5D-5L  
EQ 5 Dimensions 5 Levels questionnaire  
EQ VAS 
EQ Visual Analogue Scale 
EULAR 
European League Against Rheumatism  
FAS 
Full Analysis Set  
HIV 
Human Immunodeficiency Virus 
HOOS-QOL 
Hip Injury and Osteoarthritis Outcome Score – Quality of Life 
Subscale 
IA 
Intra-articular 
ICH 
International Conference on Harmonization 
JSN 
Joint Space Narrowing 
K-L 
Kellgren-Lawrence  
kg 
Kilogram 
LS 
Least Squares 
m 
Meter 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MMRM 
Mixed Model for Repeated Measures  
NRS 
Numeric Rating Scale 
OA 
Osteoarthritis 
OARSI 
Osteoarthritis Research Society International 
OLE 
Open Label Extension  
OMERACT 
Outcome Measures in Rheumatology  


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Abbreviation 
Definition 
OR 
Odds Ratio 
PDF 
Portable Document Format 
PGIC 
Patients’ Global Impression of Change  
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SI 
Sleep Interference  
SOC 
System Organ Class 
SP 
Safety Population 
TA
1 
Triamcinolone Acetonide 
TEAE 
Treatment Emergent AE 
TSQM 
Treatment Satisfaction Questionnaire for Medication  
US 
United States 
WHO 
World Health Organization 
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index  
1 Abbreviated in past protocols and documents as TCA 


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Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
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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 joints disease, affecting over 30 million Americans, with numbers expected to 
grow as a result of aging, obesity and sports injuries (Woolf, 2003; Cisternas, 2016; Martel-
Pelletier, 2008; Michael, 2010).  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.  It 
is estimated that by 2030, 45 million people will have OA.  OA commonly affects large weight-
bearing joints like the knees and hips, but also occurs in the shoulders, hands, feet and spine.  
Patients with OA suffer from joint pain, tenderness, stiffness and limited movement.  As the 
disease progresses, it becomes increasingly painful and debilitating, culminating, in many cases, 
in the need for total joint arthroplasty. 
Current Guidelines from the American College of Rheumatology (ACR), Osteoarthritis 
Research Society International (OARSI) and the European League against Rheumatism 
(EULAR) recommend the use of IA corticosteroids for short-term acute pain relief (Hochberg et 
al, 2012; Jordan et al, 2003; Menge et al, 2014).  
 
The prevalence of hip OA is estimated to range from 6.7% to 9.2% among adults ≥45 years of 
age and increases with age (Lawrence et al, 2008; Murphy et al, 2012). It is recognized that 
chronic inflammation occurs in all stages of OA (Benito et al, 2005; Sellam and Berenbaum, 
2010; Wenham and Conaghan, 2010). As inflammation is correlated with clinical symptoms and 
joint degeneration, it should be an important target for corticosteroid intervention. 
 
FX006 is an extended-release formulation of triamcinolone acetonide (TA) for IA 
administration. It is approved in the US under the trade name ZILRETTA® (triamcinolone 
acetonide extended-release injectable suspension) for the management of pain of OA of the 
knee. FX006 is intended to deliver TA to the synovial and peri-synovial tissues for a period of 
approximately 3 months (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% (weight by weight [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. 
 
Similar as in knee OA, hip OA patients are confronted with insufficient management of their 
symptoms (Zhang et al, 2008). Conventional corticosteroids have demonstrated clinical benefits 
in patients with hip OA (Lambert et al, 2007; Qvistgaard et al, 2006; Atchia et al, 2011), but 
with short duration of effect (approximately 4-8 weeks) and side effects from burst release of 
steroids into systemic circulation (Habib et al, 2011). Due to its slow release formulation, 


Flexion Therapeutics 
Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
CONFIDENTIAL - 11 - 
FX006 has the potential to offer longer duration of efficacy and minimized systemic exposure, 
thus, an improved benefits/risk profile for hip OA patients.  
 


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Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
CONFIDENTIAL - 12 - 
 
1.2. 
Objectives of Statistical Analysis 
Primary: 
• To assess the treatment effect of FX006 on pain following an intra-articular (IA) injection in 
patients with hip osteoarthritis (OA) 
 
Secondary:  
• To assess the efficacy of FX006 on function, global impression of change, stiffness, quality of 
life, treatment satisfaction, sleep quality and consumption of rescue medication in patients with 
hip OA  
 
• To assess the safety of FX006 in patients with hip OA  
 
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis 
of study data in order to answer the study objective(s). Populations for analysis, data handling 
rules, statistical methods, and formats for data presentation are provided.  The statistical 
analyses and summary tabulations described in this SAP will provide the basis for the Part I 
results sections of the clinical study report (CSR) for this trial, as well as used for regulatory 
filings and manuscripts and presentations. 
This SAP will also outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol. 


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Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
CONFIDENTIAL - 13 - 
2. 
STUDY DESIGN 
2.1. 
Synopsis of Study Design and Randomization Methodology 
This is a two-part, multi-center, randomized, double-blind, placebo-controlled, parallel-group 
study in patients with hip OA.  Approximately 70 patients will be enrolled in Part I and 
approximately 440 patients will be enrolled in Part II of the study.  In each part, patients will be 
randomized to one of two treatment groups (1:1) and treated with a single IA injection of either 
32 mg FX006 or normal saline. 
Eligible patients will be randomized within strata defined by Baseline Western Ontario and 
McMaster Universities Osteoarthritis Index (WOMAC) A (pain) (0-10 numeric ratings scale 
(NRS)) average of Screening 2 and Day 1 with the following classifications: 5.0 to < 6.0, 
6.0 to < 7.0, and ≥ 7.0 to 9.0. 
FX006 or saline placebo will be administered as a single IA injection with a 12-week follow-up 
period in the double-blind phase.   
Patients participating in Part I of the study will be treated with a single IA injection of either 
32 mg FX006 or normal saline and will return for follow up visits at Weeks 12, 16, 20, and 24 
or up until implementation of Protocol Version 3.0. The patients will be discontinued at the time 
of notification by the Investigator. 
 
2.2. 
Stopping Rules and Unblinding 
If there is a clinical adverse event (AE) that the Investigator judges requiring unblinding of 
study medication, they will promptly contact the Medical Monitor and review the situation. If 
the consensus is to unblind the subject’s treatment, a trained and authorized site user will log 
into the Emergency Study Code Break Module and will be provided the patient’s treatment 
assignment. 
  
If there is a clinical AE that Pharmacovigilance or Regulatory judge requires unblinding of 
study medication, the Sponsor’s internal procedure will be followed.  
If any site team member is unblinded for any reason, the Investigator will notify the Sponsor 
that unblinding has occurred, without revealing the treatment, and document who was 
unblinded, the reason for doing so, and the date of unblinding in a note to file.  
There will be no data review committee for this study. 
Furthermore, discontinuation from treatment is not applicable to this study as each randomized 
patient in the Part I and the Part II double blind phase of the study receives study medication at a 
single administration. 
 
2.3. 
Study Procedures 
Patients participating in this study will complete visit schedules and procedures as detailed in 
the Schedule of Study Assessments (Table 1). 
 
 


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Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
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Table 1 
Schedule of Study Assessments for Double Blind Phase 
a. The Double-Blind Phase of the study ends at Week 12. Patients participating in Part I of the study will not receive a second injection but 
will return to the clinic at Weeks 12, 16, 20, and 24 or up until the time of this amendment.  Patients participating in Part II of the study who 
are eligible for the second injection in the open-label phase at Week 12 will receive an open-label injection of FX006 at Week 12 and return 
for follow-up visits at Weeks 16, 20, and 24.  These patients will complete the study at Week 24. Patients participating in Part II of the study 
who are not clinically indicated for a second injection at Week 12 will return to the clinic at Weeks 16, 20, and 24 and will receive an open-
label injection of FX006 at the first evaluation where the patient has been determined to meet all criteria. 
b. To be collected or assessed prior to injection of study medication 
c. X-ray of weight-bearing anterior-posterior view for index hip will be taken for central reading. 
d. After signing the ICF, patients must stop all restricted medications (other than rescue medication).  The washout (at least 5 half-lives) must 
be completed at least 2 days prior to Screening 2 visit. 
e. Rescue medication will be dispensed to the patient at the Screening visit, and a new bottle will be dispensed at each subsequent visit as 
needed.  Drug accountability will be done at each visit 
f. 
Pregnancy tests will be done in women of child bearing potential. Serum Pregnancy Test to be collected only at Screening visit.  Urine 
Pregnancy Test to be collected prior to injection of study medication and at EOS (when it occurs) 
g. Aspiration must be attempted prior to all injections.  If effusion is detected by fluoroscopy guidance, withdraw to near dryness prior to 
injection 
h. Via Central Laboratory 
i. 
To be performed under fluoroscopy guidance 
j. 
To be completed prior to questionnaires 
k. To be completed after APR and PRR training but prior to any other assessments. 
 
List of Assessments 
Screeningn  
Day -30 to -1 
Screening 2n 
Day -10 to -4 
Day 1 
Weeks 1, 4, 8m 
 
Week 12 
EOS for Double blind phasea, m
Informed consent 
X 
 
 
 
 
Inclusion/Exclusion Review 
X 
 
Xb 
 
 
Medical History/Update 
X 
 
Xb 
 
 
Patient Demographics 
X 
 
 
 
 
OA Medical History 
X 
 
 
 
 
Prior Treatments and Medications 
X 
 
Xb 
 
 
Physical examination 
X 
 
 
 
X 
Index Hip Assessment 
X 
 
Xb 
X 
X 
Index Hip X-ray c 
X 
 
 
 
X 
Vital signs 
X 
 
Xb 
X 
X 
Height 
X 
 
 
 
 
Weight and BMI 
X 
 
 
 
X 
Hematology, Chemistryh 
X 
 
 
 
X 
ESR 
X 
 
 
 
 
HIV, Hep B/Ch 
X 
 
 
 
 
Pregnancy Test f 
Xh 
 
Xb 
 
X  
Washout of restricted pain medication 
Xd 
 
 
 
 
PD-Q, PHQ-9, GAD-7, PCS, ISI  
X 
 
 
 
 
Randomization 
 
 
Xb 
 
 
Second Injection Criteria 
 
 
 
 
X 
Index Hip Aspiration 
 
 
Xb, g 
 
 
IMP administrationi 
 
 
X 
 
 
Rescue Medication dispensing and 
accountabilitye 
X 
 
X 
X  
X 
Accurate pain reporting and placebo 
response reduction training j 
 
X 
Xb 
X 
X 
WOMACk 
 
X 
Xb 
X 
X 
PGICk 
 
 
 
X 
X 
TSQM-9k 
 
 
 
 
X 
SI, HOOS-QOL, EQ-5D-5Lk 
 
 
Xb 
X 
X 
AE/SAE & ConMedsl 
 
 
------------------------------X------------------------------ 


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Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
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CONFIDENTIAL - 15 - 
l. 
AEs and concomitant medications will be captured from Day 1 (post injection) to EOS visit. 
m. Visit should be conducted within +/- 3 days from scheduled date. 
n. Screening 1 and Screening 2 visits can be combined into one visit provided the patient does not have a washout from prohibited 
medications. If there is no washout, please perform APR/PRR first, then the questionnaires, with the WOMAC being completed after 
APR/PRR, then all subsequent questionnaires as they are listed for Screening 1. 
 
2.4. 
Efficacy and Safety Endpoints 
All endpoints will be exploratory in Part I of the study. The primary comparison for the primary 
endpoint will be FX006 32 mg versus placebo. 
 
2.4.1. 
Primary Efficacy Endpoint 
 Change from Baseline on the WOMAC A (pain) score at Week 12  
 
2.4.2. 
Key Secondary Efficacy Endpoints 
 Change from Baseline on the WOMAC C (function) score at Week 12 
 Patients’ Global Impression of Change (PGIC) score at Week 12 
 
2.4.2.1. 
Additional Secondary Efficacy Endpoints 
 Area Under the Effect curve (AUE) of change from Baseline on the WOMAC A (pain) 
subscale over the time intervals (e.g., Weeks 1 to 4, Weeks 1 to 8 and Weeks 1 to 12) 
 AUE of change from Baseline on the WOMAC C (function) score over the time 
intervals (e.g., Weeks 1 to 4, Weeks 1 to 8 and Weeks 1 to 12) 
 PGIC at Weeks 1, 4 and 8 
 Change from Baseline on the WOMAC A (pain) score at Weeks 1, 4, and 8 
 Change from Baseline on the WOMAC C (function) score at Weeks 1, 4, and 8 
 Change from Baseline on the WOMAC B (stiffness) score at Weeks 1, 4, 8, and 12 
 Change from Baseline on the WOMAC total score at Weeks 1, 4, 8, and 12 
 Percent of responders (defined as patients with high improvement in pain or function) 
according to Outcome Measures in Rheumatology OARSI (OMERACT-OARSI) criteria 
at Weeks 1, 4, 8, and 12 
 Proportion of patients experiencing a ≥20%, ≥30%, or ≥50% decrease in WOMAC A 
(pain) at Weeks 1, 4, 8, and 12 
 Rescue medication use at Weeks 1, 4, 8, 12 and total consumption 
 Change from Baseline on the SI at Weeks 1, 4, 8, and 12 


Flexion Therapeutics 
Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
CONFIDENTIAL - 16 - 
 Change from Baseline on the EuroQol (EQ) 5 Dimensions 5 Levels questionnaire (EQ-
5D-5L) at Weeks 1, 4, 8, and 12 
 Change from Baseline on the Hip Injury and Osteoarthritis Outcome Score – Quality of 
Life Subscale (HOOS-QOL) at Weeks 1, 4, 8, and 12 
 TSQM-9 at Week 12 
 Change from Baseline on WOMAC A (pain), B (stiffness), C (function) and PGIC at 
Weeks 1, 4, 8, and 12 in patients with unilateral hip OA  
 


Flexion Therapeutics 
Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
CONFIDENTIAL - 17 - 
3. 
PATIENT POPULATIONS 
3.1. 
Population Definitions 
The following patient populations will be used for presentation and analysis of the data: 
 Full Analysis Set (FAS) Population: All patients who received a full dose of study drug. 
The FAS Population will be used to examine efficacy endpoints for the double-blind phase 
of the study. This population will be analyzed as randomized. 
 Safety Population (SP):  All subjects who received at least one dose (full or partial) of 
study drug.  The Safety Population will be used to assess safety and tolerability. This 
population will be analyzed as treated. 
 
One Part I patient received a second dose under a previous version of the protocol. This 
patient’s data will be included in the SP in its entirety, but only data prior to the second dose 
will be used in the FAS. 
 


Flexion Therapeutics 
Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
CONFIDENTIAL - 18 - 
4. 
STATISTICAL METHODS 
4.1. 
Sample Size Justification 
Approximately 70 patients will be randomized in Part I and approximately 440 patients will be 
randomized in Part II in this study (an estimated 35 and 220 per treatment group, respectively.) 
For Part I, a sample size of approximately 35 per arm will provide information regarding the 
treatment effect. For Part II of the study, the expected sample size was determined based on the 
primary endpoint as follows. A minimum sample size of N=212 per arm for the placebo and the 
FX006 group has 90% power to yield a statistically significant difference (alpha=0.05, 2-sided) 
if the true underlying difference at Week 12 is 0.65 and with an assumption of 2.0 for the 
standard deviation (SD).  For the first key secondary endpoint, the sample size of N=220 per 
treatment group has 90% power to yield a statistically significant difference between FX006 and 
placebo if the true underlying difference is 0.68 at Week 12, assuming a SD of 2.125.  An early 
discontinuation rate of 6% was assumed.  The data from Part I may be used to inform if the 
above assumptions were appropriate and the planned sample size for Part II should remain at 
440, or whether a smaller sample size would be feasible.   
 
4.2. 
General Statistical Methods and Data Handling 
4.2.1. 
General Methods 
All outputs will be incorporated into Portable Document Format (PDF) or Word files, sorted and 
labeled according to the International Conference on Harmonization (ICH) recommendations, 
and formatted to the appropriate page size(s). 
Tables will be presented as described in the sections below. Summary data will be presented by 
treatment group. For patient disposition, protocol deviations, demographic and baseline 
characteristics, OA medical history and study drug exposure, a total group that includes both 
treatment groups will also be presented. Any exceptions to this are described in the appropriate 
sections below. 
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, SD, 
minimum and maximum values will be presented. 95% confidence intervals (CI) may be 
provided. Additional statistics may be presented for certain endpoints as described below. 
All collected data will be presented in by-patient listings sorted by treatment arm and patient 
number. 
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.  
The sections below describe the intended analysis of the endpoints. Additional sensitivity 
analyses may be employed in the event of any unforeseen data anomalies or data issues not 
known at the time of writing this analysis plan. 


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SAP, Final Version 1.0 
05 SEP 2019 
 
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4.2.2. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS® statistical software 
(Version 9.4 or higher), unless otherwise noted. 
AEs will be coding using Medical Dictionary for Regulatory Activities (MedDRA) Version 21.1 
(or higher).  
Concomitant medications will be coded using World Health Organization (WHO) Drug 
Dictionary (DD) (Version Mar 2014 or Higher).  
4.2.3. 
Methods of Pooling Data 
Not applicable to the present study. 
4.2.4. 
Adjustments for Covariates 
The primary endpoint and secondary endpoints will be analyzed with a longitudinal mixed 
model for repeated measures (MMRM) with fixed effects for treatment group, study week, 
treatment-by-week interaction, Baseline score of the endpoint, Baseline WOMAC A score and 
study site. All models will include Baseline WOMAC A score as a covariate, regardless of the 
endpoint, since randomization was stratified by WOMAC A scores. 
 
AUE will be calculated and comparisons of the AUE endpoints will be estimated from an 
Analysis of Covariance (ANCOVA) with model parameters for treatment group and covariates 
of Baseline score of the AUE endpoint, WOMAC A score and study site. All models will 
include Baseline WOMAC A score as a covariate, regardless of the AUE endpoint, since 
randomization was stratified by WOMAC A scores. 
 
4.2.5. 
Multiple Comparisons/Multiplicity 
As all analyses of the Part I data are exploratory in nature, there will be no controls for 
multiplicity. 
 
4.2.6. 
Subpopulations 
The analyses of WOMAC A, B and C change from Baseline and PGIC will be carried out for 
the subgroup of patients with WOMAC A (pain) average of Screening 2 and Day 1 scores of 5 
to <6, 6 to <7, and ≥7 to 9, in order to assess any differences in treatment response in those 
groups, which were used as a stratification factor in randomization. These analyses will also be 
presented by unilateral/bilateral hip OA.  
Other preplanned subgroups analyses (per aspiration status, Kellgren-Lawrence (K-L) grade, 
gender and the baseline pain score, etc.) will not be performed for Part I data. Other subgroups 
may be defined and explored after all pre-planned analyses have been completed to further 
elucidate study results. 


Flexion Therapeutics 
Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
CONFIDENTIAL - 20 - 
4.2.7. 
Discontinuations and Loss to Follow-up 
Each treated patient from this study receives study medication as a single IA injection. 
Therefore, discontinuation from treatment is not applicable.  
Each patient may only discontinue from the study for further assessments and study visits. Data 
collected from discontinued patients will be included in the CSR. Patients who discontinue from 
the study may be replaced at the discretion of the sponsor. Version 3.0 of the protocol separated 
the study into two parts as the study was put on-hold to new recruitment for an extended period 
to investigate six patients that did not receive complete study drug administration.  All patients 
enrolled up to the time that the amendment was implemented at each site were followed for at 
least 12 weeks or up to the time of this amendment, when they were discontinued from the 
study.   
4.2.8. 
Missing, Unused, and Spurious Data 
Missing values will not be imputed and data will be analyzed “as observed”. 
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. 
For the HOOS-QOL subscale, the rules as described in HOOS Scoring 2013 
(http://www.koos.nu/) will be used.  Specifically, the score is only calculated if 50% items (2 
out of 4) are non-missing.  Otherwise the score will be set to missing.  
 
4.2.9. 
Visit Windows 
Data collected at unscheduled visits will be mapped to the closest scheduled visit, but only if 
that data is not already available in that visit. 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 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.  
4.3. 
Interim Analyses 
There will be no interim analyses for Part I of this study. 
4.4. 
Final Analyses 
The analyses of the Part I data will be performed in an unblinded manner when all Part I 
patients have completed, withdrawn or discontinued from the study. Only data from Part I of the 


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Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
CONFIDENTIAL - 21 - 
study will be presented. Final analyses specified in the protocol and SAP will be completed and 
reported in the CSR.  
 
Post-hoc, exploratory analyses, may be completed to further understand and elucidate 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 randomized will be accounted for in this study. 
Patient disposition will be tabulated and include the total number of patients randomized, 
treated, completed and early terminated, reason for early termination and the number in each 
patient population.   
   
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.  
 Patient inclusion in each of the analysis populations (FAS, SP).  
 
4.6. 
Protocol Deviations 
The number and percentage of patients with at least one protocol deviation will be summarized 
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 
Demographic and Baseline characteristics will be summarized for the SP. 
No formal statistical comparisons will be performed. 
All collected demographic, Baseline characteristic, and medical history data will be provided in 
data listings.   
4.7.1. 
Demographic Characteristics 
The following Baseline parameters will be summarized for the SP: 
 Age (year) at consent - Age will be calculated as the years between date of birth and date 
of informed consent, and will be rounded down to the nearest year. 
 Weight (kilogram (kg)); 
 Height (centimeter (cm)); 
 Gender (Male/Female); 


Flexion Therapeutics 
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SAP, Final Version 1.0 
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 Body mass index (BMI) (kg/meter (m)2); 
 BMI category: 
o Underweight: <18.5 kg/m2 
o Normal: 18.5 to <25.0 kg/m2 
o Overweight: 25.0 to <30.0 kg/m2 
o Obesity Class I:  30.0 to <35.0 kg/m2 
o Obesity Class II: 35.0 to <40.0 kg/m2 
o Obesity Class III: >=40.0 kg/m2 
 Ethnicity (Hispanic or Latino / Not Hispanic or Latino); 
 Race (White / Asian / Black or African American / American Indian or Alaska Native / 
Native Hawaiian or Other Pacific Islander); 
Age, height, weight, and BMI will be summarized using descriptive statistics (number of 
patients, mean, SD, median, minimum, and maximum). The number and percentage of patients 
in each gender, ethnicity, race and BMI category will also be presented.  
WOMAC A (pain) average of Screening 2 and Day 1, which was used as a stratification factor 
in randomization, will be presented in the following classifications: 5 to < 6, 6 to < 7, and ≥ 7 to 
9.  
 
Patient questionnaires for Baseline PD-Q, PHQ-9, GAD-7, PCS, and ISI will be presented in 
data listings. 
4.7.2. 
OA Medical History 
OA history and index hip characteristics as collected on the CRF will be summarized for the SP. 
Time from primary diagnosis of OA in the index hip to Day 1 of the study in days (first dose 
date – date of diagnosis + 1), will be computed and presented descriptively.  If only month and 
year of initial diagnosis is available, day will be imputed as 1 for calculations.  If month and day 
are missing, the time from primary diagnosis will be computed as year of first dose minus year 
of diagnosis. If year is missing, time from diagnosis will not be computed. 
   
4.7.3. 
Prior medication  
All prior medications will be presented in the concomitant medication data listing with a flag 
identifying which medications are prior medications (refer to Section 4.11.5 for details on 
defining prior and concomitant medications). 
4.8. 
Patient Randomization 
Patient Randomization information will be provided in a listing, with assigned treatment, patient 
ID, date of informed consent, randomization date, dose date, completed study, study completion 
date, reason for early termination. 
 


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4.9. 
Study Drug Exposure  
Details of study drug administration will be summarized for the SP.  
The position of hip during injection, approach during injection, the numbing agent used, 
whether or not fluoroscopy guidance was used, volume of synovial fluid aspirated, whether a 20 
gauge, 3 1/2” or 6” needle, was used, whether entire contents of the syringe were injected, 
reason (if entire contents not injected), and volume remaining in syringe will be presented.  
All study drug exposure data will be presented in a data listing. 
4.10. 
Efficacy Evaluation 
All efficacy analyses will be conducted using the FAS.  
In addition to the analyses described below, subgroup analyses will be performed as described 
in Section 4.2.6.  
 
4.10.1. 
WOMAC  
The following WOMAC scales/questions will be analyzed: 
 WOMAC A (pain subscale) 
 WOMAC B (stiffness subscale)  
 WOMAC C (function subscale) 
 WOMAC (total) 
 
Since randomization is stratified by WOMAC A (pain) average of Screening 2 and Day 1 scores 
of 5 to <6, 6 to <7, and ≥7 to 9, this value will be provided in the data listing. 
 
4.10.1.1. 
Change from Baseline 
For the WOMAC subscales, scores at each assessment time point (Baseline, Week 1, 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 10 for each subscale and easier interpretation.  Imputation rules are as presented 
in Section 4.2.8. 
 
Each of the WOMAC subscales will be analyzed separately using a longitudinal MMRM with 
fixed effects for Baseline score for the endpoint, treatment group, study week, treatment-by-
week interaction, study site, and Baseline WOMAC A score. The analysis will include all study 
weeks of data, and not be confined to only that at Baseline and Week 12. Subject will be the 
random effect.  Treatment differences from placebo will be estimated via least squares (LS) 
means from the analysis model along with 95% CIs, and associated 2-sided p-values.  This 
model assumes missing at random and includes only observed data.  


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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 presented in the table output and fully documented in the results 
section of the CSR.  
Sample SAS code that can be used to implement the mixed analysis is provided below: 
 
proc mixed data= dsin1 method=reml; 
    class subjid armcd avisitn site; 
    model chg = base armcd avisitn armcd*avisitn site base_womaca; 
    repeated avisitn /type=un subject=subjid; 
    lsmeans armcd/diff=control ('0') cl; 
    /*[where 0 represents treatment=placebo]*/ 
    lsmeans armcd*avisitn /pdiff cl; 
run; 
 
Descriptive statistics will also be presented and will include number of observations, unadjusted 
mean, SD, median, minimum and maximum. 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. The adjusted change from Baseline will also be presented using results from the 
MMRM. 
A line plot presenting LS means change from Baseline over time will be produced. Each 
treatment group will be plotted on a separate line with SE bars. Jitter will be used as needed to 
distinguish overlapping data. 
4.10.1.2. 
AUE for Change from Baseline in WOMAC over Time 
AUE for change from Baseline in WOMAC A and C over various time intervals will be 
examined.   
AUE will be calculated for the subjects who have assessments in all available visits, from a 
linear trapezoidal rule using the following formula for change from Baseline in WOMAC A and 
WOMAC C: 
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. Only non-missing time intervals will be part of the sum for each AUE 
calculation (Farrar et al. 2000).  If a patient does not have a value for the last visit in a time 
interval, that patient will be excluded from the AUE analysis for that time interval.  For 
example, if a patient has missing data for Week 12, AUEWeek 1 to Week 12 will not be calculated.  


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The following AUE endpoints will be computed for each subject in the study over the sampling 
intervals: 
 AUEWeek 1 to Week 4 
 AUEWeek 1 to Week 8 
 AUEWeek 1to Week 12  
 
The comparisons the AUE endpoints will be estimated from an ANCOVA with model 
parameters for treatment and covariates of Baseline score of the AUE endpoint, WOMAC A 
score and study site. All models will include Baseline WOMAC A score as a covariate, 
regardless of the AUE endpoint, since randomization was stratified by WOMAC A scores. 
Descriptive statistics will include the LS means and standard error, 95% CI, LS mean difference 
from placebo, and 2-sided p-value relative to placebo. 
Sample SAS code that can be used to implement the AUE analysis is provided below: 
proc mixed data= dsin1; 
    class armcd site; 
    model aueval = base armcd site base_womaca; 
    lsmeans armcd/diff=control ('0') cl; 
    /*[where 0 represents treatment=placebo]*/ 
    ods output lsmeans = lsm diffs = diffs; 
run; 
 
All AUE data will be presented in a data listing.  
 
4.10.1.3. 
WOMAC A (pain) Responder  
Responders are defined as patients who have ≥20%, ≥30%, or ≥50% decrease in the WOMAC 
A score from Baseline at a given visit (Weeks 1, 4, 8, 12, etc.). All study visits will be analyzed 
and presented. 
Percentages will only be based on those with non-missing data.  The number of patients who 
have missing data at each visit will be presented. 
At each weekly assessment, proportions of FX006 responders will be compared to those 
responding in the placebo group using logistic regression, displaying the p-value and odds ratio 
(OR) (with CI) for each comparison.  Study site and Baseline WOMAC A score will be 
included as covariates in the model. 
Bar charts displaying the percentage of responders in each treatment group at each weekly 
assessment will be presented.  Additionally, for Week 12, a continuous responder curve will 
display the cumulative proportion of responders on the y-axis versus percentage of improvement 
from Baseline on the x-axis, by treatment group. 
 


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4.10.2. 
PGIC Score 
4.10.2.1. 
Continuous 
The continuous PGIC score will be analyzed similar the WOMAC A (pain) analysis described 
in Section 4.10.1.1. All available study visits will be analyzed and presented. 
4.10.2.2. 
Categorical 
In addition, the PGIC scores will be collapsed and categorized as follows: 
PGIC Score 
 
Category 
1 = Very Much Improved 
 
A = Improved 
2 = Much Improved 
 
A = Improved 
3 = Minimally Improved 
 
B = Minimal – No Change 
4 = No Change 
 
B = Minimal – No Change 
5 = Minimally Worse 
 
B = Minimal – No Change 
6 = Much Worse 
 
C = Worse 
7 = Very Much Worse 
 
C = Worse 
 
The percent of "Improved" subjects (among those patients with available data) at each study 
visit will be compared between the FX006 treatment group and the placebo group using logistic 
regression, displaying the p-value and OR (with CI) for each comparison.  Baseline score of the 
endpoint, Baseline WOMAC score and study site will be covariates in each model. Bar charts 
by visit and treatment will be presented for the collapsed categories of “Improved”, “Minimal – 
No Change”, and “Worse”.  
 
4.10.3. 
OMERACT-OARSI and Responder Status 
The OMERACT-OARSI responder criteria will also be used to define response (Pham, 2004) 
using a combination of pain, function, and a patient assessment to form a composite endpoint.  
The WOMAC A pain subscale, WOMAC C function subscale, and PGIC will be used to derive 
the composite responder variable.  While the OMERACT-OARSI defines patient assessment in 
terms of numeric changes from Baseline, this study only collects the PGIC which is a static 
assessment collected at post-Baseline visits asking how the patient feels relative to Baseline; 
thus, the responder criteria is being modified slightly for this context to consider PGIC 
responders as those reporting "Very Much Improved" or "Much Improved" status.  Patients will 
be considered responders at a given weekly assessment if they show: 
 At least a 50% improvement from Baseline in the WOMAC A pain subscale and an 
absolute improvement of at least 20 points or at least a 50% improvement from Baseline 
in the WOMAC C function subscale and an absolute improvement of at least 20 points; 
OR 
 At least two of the following: 


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o At least a 20% improvement from Baseline in the WOMAC A pain subscale and 
an absolute improvement of at least 10 points 
o At least a 20% improvement from Baseline in the WOMAC C function subscale 
and an absolute improvement of at least 10 points 
o PGIC of "Very Much Improved" or "Much Improved" 
 
It should be noted for the WOMAC Index that higher scores indicate worse function.  Also, the 
absolute change in the responder criteria assumes the WOMAC is on a 100 point scale. To 
normalize the WOMAC A pain score, the sum of the 5 pain questions will be multiplied by 2.  
To normalize the WOMAC C function score, the sum of the 17 function questions will be 
multiplied by 0.59. Imputation of WOMAC A and C scores will follow the rules as displayed in 
Section 4.2.8. If WOMAC A or C scores cannot be imputed due to the amount of missing data 
or patients are missing PGIC at a given week, those patients will be counted as missing/not 
evaluable in the tabulations.  
 
The OMERACT analysis will be conducted in the same way as the WOMAC A (pain) 
Responder analysis as described in Section 4.10.1.3.  All available study visits will be analyzed 
and presented. 
 
 
4.10.4. 
Consumption of Rescue Medications 
A descriptive summary of the average rescue medications taken per patient each day will be 
presented by visit and overall.   
Use of rescue medication is recorded on the Rescue Medication Accountability CRF. Each 
tablet of rescue medication contains 500mg of acetaminophen (paracetamol). The mean number 
of rescue medication tablets used per day will be computed for each patient according to the 
following algorithm: 
1. At each visit, the number of pills taken will be determined by subtracting the number 
returned at the current visit by the number dispensed at the previous visit. 
 
2. The number of days between the current and previous visits will be calculated by using 
the dates of each visit. 
 
3. The average number of pills taken per day will be calculated by dividing the total 
number of pills used between visits by the total days between visits.  
The value for each visit indicates the daily average for the period from the previous visit to the 
current visit. For example, the value for the Week 8 visit represents the daily average over the 
time period from Week 4 to Week 8.  


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Patients who do not report use of rescue medications at a given visit will be counted as having 
used 0 tablets when calculating the mean number of tablets used, and patients will only be 
analyzed through the time of study discontinuation or study completion.   
Rescue medication consumption will be analyzed similar the WOMAC A (pain) analysis 
described in Section 4.10.1.1. All available study visits will be analyzed and presented. 
 
Rescue medication usage and accountability data will be provided in by-patient listings.  
 
4.10.5. 
Sleep Interference (SI) 
SI is a single-item measure that was developed specifically to quantify sleep interference due to 
pain. SI has an 11-point response scale (ranging from 0 ‘did not interfere with sleep’ to 10 
‘completely interfered with sleep – unable to sleep due to pain’) and asks patients to select the 
number that best describes how much their pain has interfered with their sleep over a period of 
24 hours.  
SI change from Baseline will be analyzed similar the WOMAC A (pain) analysis described in 
Section 4.10.1.1. All available study visits will be analyzed and presented. 
 
4.10.6. 
EQ-5D-5L 
For the EQ-5D-5L, the scoring information that is described in the EQ-5D-5L User Guide 
(https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-5L_UserGuide_2015.pdf) will be used.  
The EQ-5D-5L has 2 parts: the EQ-5D descriptive system and the EQ visual analogue scale (EQ 
VAS). The EQ-5D has five dimensions: mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression. Each dimension is scored from 1 to 5 (best to worst).  The EQ VAS is a 
single question with the subject’s self-rated health, which is recorded on a vertical, visual 
analogue scale.  The available responses range from “Worst imaginable health state” (0) to 
“Best imaginable health state” (100).  In addition, an index score will be derived using the US 
value set, as described in the EQ-5D-5L User Guide.   
 
Each dimension of the EQ-5D, the EQ VAS and the index score changes from Baseline will be 
analyzed similar to the WOMAC A (pain) analysis described in Section 4.10.1.1. All available 
study visits will be analyzed and presented. 
 
4.10.7. 
HOOS-QOL subscale 
The HOOS-QOL subscale (http://www.koos.nu/) has 4 questions, each of which is assigned a 
score from 0 to 4.  The first questions, “How often are you aware of your hip problem?” is 
coded as follows: 0=never, 1=monthly, 2=weekly, 3=daily, 4=constantly). The remaining 
questions are coded as follows: 0=not at all, 1=mildly, 2=moderately, 3=severely, 4=totally. A 
normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) is 


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calculated using this formula: 100-AVERAGE(Q1-Q4)/4*100. Scores are calculated at each 
assessment time point. Imputation rules are as presented in Section 4.2.8.   
HOOS-QOL change from Baseline will be analyzed similar the WOMAC A (pain) analysis 
described in Section 4.10.1.1. All available study visits will be analyzed and presented. 
4.10.8. 
TSQM-9 
The Treatment Satisfaction Questionnaire for Medication (TSQM-9) consists of 9 items with a 5 
to 7 point scale for each item. There are 3 domains: global satisfaction, effectiveness and 
convenience. Each domain will be scored as described in the TSQM-9 User Manual (Version 
1.1, October 2018). Instructions for Version 1.4 of the TSQM-9 will be used. The TSQM-9 
score at Week 12 for each domain will be analyzed using ANCOVA in the same way as the 
WOMAC AUE analysis as described in Section 4.10.1.2 except that Baseline TSQM-9 score at 
Baseline will not be a covariate in the model since TSQM-9 was not administered at Baseline.  
In addition, a figure will not be produced since there is only one visit.  
4.10.9. 
Sensitivity Analyses 
Additional sensitivity analyses may be performed to examine the effect of missing data, as well 
as the effect of Baseline imbalance, should one occur.  
 
4.11. 
Safety Analyses 
Safety analyses will be conducted using the SP.   
4.11.1. 
Adverse Events 
AEs will be coded using MedDRA and displayed in tables and listings using System Organ 
Class (SOC) and Preferred Term (PT). 
Analyses of AEs will be performed for those events that are considered treatment emergent, 
where treatment emergent is defined as any AE with onset after the administration of study 
treatment, or any event that was present at Baseline but worsened in intensity through the end of 
the study. 
If the start date/time of an AE is partially or completely missing, the date/time will be compared 
as far as possible with the date/time of the start of administration of study drug.  The AE will be 
assumed to be treatment emergent if it cannot be definitively shown that the AE did not occur or 
worsen during the treatment-emergent period (worst case approach).  The following general 
rules will be used: 
 If the start time of an AE is missing but the start date is complete, an AE will only be 
excluded as being treatment emergent if the start date is before the date of study drug 
administration or if the stop date/time is before study drug administration. 
 If the start time and day are missing but the start month and year are complete, an AE 
will only be excluded as being treatment emergent if the start month/year is before the 
month/year of study drug administration or if the stop date/time is before study drug 
administration. 


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 If the start day and month are missing but the start year is complete, an AE will only be 
excluded as being treatment emergent if start year is before the year of study drug 
administration or if the stop date/time is before study drug administration. 
 If the start date is completely missing, an AE will be considered treatment-emergent 
unless the stop date/time is before study drug administration. 
AEs will be summarized by patient incidence rates; therefore, in any tabulation, a patient 
contributes only once to the count for a given SOC or PT. 
Summary tables will display the number and percentage of patients who experienced at least 
one treatment emergent AE (TEAE) in each of the following categories: 
 Any TEAE 
 Any Serious AE (SAE) 
 Any TEAE leading to study discontinuation 
 Any TEAE by severity (Mild/Moderate/Severe) 
 Any TEAE by relationship 
 Any index-hip related TEAE 
 Any index-hip related SAE 
 Any index-hip related TEAE leading to study discontinuation  
 Any index-hip related TEAE by severity (Mild/Moderate/Severe) 
 Any index-hip 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 TEAEs by PT (decreasing frequency of FX006 group) 
 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-hip related TEAEs by SOC and PT 
 All index-hip related TEAEs related to study drug by SOC and PT 
 All index-hip related TEAEs by maximum severity by SOC and PT 


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Summaries will be presented by treatment group. Within each treatment group, AEs will be 
presented by the following time periods:  
1. Baseline to Week 12 
2. Week 12 to Last Visit 
 
Date and time of onset of TEAE will be used to assign the time periods. TEAEs that occurred on 
the same day as the Week 12 visit will be counted in the “Baseline to Week 12” time period. 
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 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 of all AEs occurring on-study will be provided as well as for the following, 
for all patients: patient deaths, SAEs and AEs leading to discontinuation. 
 
4.11.2. 
Laboratory Data 
The following values will be summarized for each hematology and clinical chemistry laboratory 
parameter by treatment group: 
1. Baseline (Screening) - Observed  
2. Week 12 - Observed and change from Baseline 
3. EOS - 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 Section 7.3 for CTCAE grade definitions. 
 
4.11.3. 
Vital Signs and Physical Examinations and Index Hip Assessment 
The actual value and change from Baseline (Day 1) at each time point will be summarized by 
treatment group. Vital sign measurements will be presented for each patient in a data listing. 
All physical examination results will be presented in a data listing. 


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The incidence of inflammation, as determined from the index hip assessment, will be tabulated 
for each visit by treatment group. For those patients experiencing inflammation, the details of 
the inflammation will also be tabulated. In these tabulations, percentages will be based on those 
patients who have a non-missing index hip assessment at a given visit. Index hip assessment as 
well as index hip aspiration data will be presented in data listings.  
 
4.11.4. 
Index Hip X-Ray 
Index hip X-rays are performed at Screening and Week 12 for all patients and EOS for all some 
patients depending on the timing of the EOS visit. All X-rays will be read centrally. At 
Screening, each patient will have at least one X-ray reading. If the patient is found ineligible by 
the first reader, they will receive a second eligibility reading. Follow-up visits will have two 
independent safety readings and findings for osteonecrosis and subchondral insufficiency 
fracture will be adjudicated by a third reader. 
 
The Screening X-ray will include the following variables: 
 K-L grade (0-4) 
 Osteonecrosis (absent/present) 
 Subchondral insufficiency fracture (absent/present) 
 Joint Space Narrowing (JSN) (0-3) 
 Sclerosis (absent/present) 
 Attrition (absent/present) 
 
The Week 12 and EOS X-rays will include the following variables: 
 Osteonecrosis (absent/present) 
 Subchondral insufficiency fracture (absent/present) 
 Joint Space Narrowing (JSN) (0-3) 
 Sclerosis (absent/present) 
 Attrition (absent/present) 
 
The variables will be analyzed and presented as follows: 
 
K-L Grade 
K-L grade at Screening will be summarized and presented with the OA history and index hip 
characteristics data. If there is more than one eligibility reading, the second will be used for 
analysis.   
Osteonecrosis and Subchondral Insufficiency Fracture 
Osteonecrosis and subchondral insufficiency fracture will each be measured on a binary scale as 
absent or present (0=absent, 1=present).  For the Screening X-ray, if there is more than one 
eligibility reading, the second will be used for analysis.  Follow-up X-rays will be adjudicated as 
follows:  


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 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. 
 
JSN 
JSN will be scored 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. 
JSN 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. 
 
Sclerosis and Attrition 
Sclerosis and attrition will each be measured on a binary scale as absent or present (0=absent, 
1=present) by each reader. 
Sclerosis and attrition will each be defined as follows: 
 If Reader 1 and Reader 2 agree (are concordant), then that score will be used in the 
analysis. 
 If Reader 1 and Reader 2 do not agree (are discordant) a score of 0 (absent) will be used 
in the analysis. 
 
Change from Baseline to Week 12 and change from baseline to EOS (where available) in JSN 
score will be presented by treatment group. Any patients whose serial X-rays demonstrate a ≥ 1-
point grade increase in JSN will be categorized as indicating Chondrolysis. The frequency and 
percentage of Chondrolysis will be presented in a summary table.  
Shift tables of osteonecrosis, subchondral insufficiency fracture, JSN, sclerosis and attrition will 
be presented by treatment group. 
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 K-L grade. 


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After review of X-ray results additional sensitivity analyses may be performed to better 
understand imaging results. 
 
 
4.11.5. 
Concomitant Medications 
Concomitant medications will be defined as those medications that were initiated after study 
drug administration or those that were ongoing at the time of study drug administration. If the 
start date or stop date of a medication is partially missing, the date will be compared as far as 
possible with the date of the start of administration of study drug. The medication will be 
assumed to be prior medication if it cannot be definitively shown that the medication did not 
start or continue after study drug administration and was not ongoing at the time of study drug 
administration. 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 or restrictive) and whether the CM was used for treatment of an AE. 
4.11.6. 
Surgical Procedures 
Surgical procedures that occurred during the study will be provided in a data listing. 
 


Flexion Therapeutics 
Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
CONFIDENTIAL - 35 - 
5. 
CHANGES TO PLANNED ANALYSES 
 
There are no major changes to the planned analyses. 
 
The following minor changes were made: 
1. As a result of the six patients who were unable to receive complete study drug 
administration, the analysis populations were updated as follows: 
a. The FAS was updated to clarify that this includes only patients who received a 
full dose of study drug (Section 3.1). 
b. The SP was updated to clarify that this includes all patients who received at least 
one dose (full or partial) of study drug (Section 3.1). 
2. Study site was added as a covariate, since it was determined in previous studies to be an 
important covariate (Section 4.2.4). 
3. The protocol indicates that categorical end points will be compared via chi-square or 
exact tests. Instead, logistic regression will be used to analyze the WOMAC A pain 
(Section 4.10.1.3), PGIC categorical (Section 4.10.2.2) and OMERACT responder 
(Section 4.10.3) outcomes. This allows us to control for covariates in the models. 
 


Flexion Therapeutics 
Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
CONFIDENTIAL - 36 - 
6. 
REFERENCES 
 
Atchia I, Kane D, Reed MR, Isaacs JD, Birrell F. Efficacy of a single ultrasound-guided 
injection for the treatment of hip osteoarthritis. Ann Rheum Dis. 2011 Jan;70(1):110-6.  
 
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 Sep;64(9):1263-7.  
 
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.  
 
Cisternas MG, Murphy L, Sacks JJ, Solomon DH, Pasta DJ, Helmick CG. Alternative Methods 
for Defining Osteoarthritis and the Impact on Estimating Prevalence in a US Population-Based 
Survey. Arthritis Care Res (Hoboken). 2016;68(5):574–80. 
 
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. 
Habib GS and Miari W. The effect of intra-articular triamcinolone preparations on blood 
glucose levels in diabetic patients: a controlled study. J Clin Rheumatol 2011;17:302-305.  
 
Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, et al. American 
College of Rheumatology 2012 Recommendations for the Use of Nonpharmacologic and 
Pharmacologic Therapies in Osteoarthritis of the Hand, Hip, and Knee. Arthritis Care Res 
(Hoboken) 2012; 64(4):465-474.  
 
Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, et al. 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.  
 
Lambert RG, Hutchings EJ, Grace MG, Jhangri GS, Conner-Spady B, Maksymowych WP. 
Steroid injection for osteoarthritis of the hip: a randomized, double-blind, placebo-controlled 
trial. Arthritis Rheum. 2007 Jul;56(7):2278-87.  
 
Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, et al. Estimates of the 
prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis 
Rheum 2008;58:26-35. 
 


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Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
CONFIDENTIAL - 37 - 
Martel-Pelletier J, Boileau C, Pelletier JP, Roughley PJ. Cartilage in normal and osteoarthritis 
conditions. Best Pract Res Clin Rheumatol. 2008;22(2):351–84. 
 
Menge TJ, Boykin RE, Byram IR, Bushnell BD. A Comprehensive Approach to Glenohumeral 
Arthritis. South Med J. 2014;107(9):567-573.  
 
Michael JW, Schlüter-Brust KU, Eysel P. The epidemiology, etiology, diagnosis, and treatment 
of osteoarthritis of the knee. Dtsch Arztebl Int. 2010;107(9):152–62. 
 
Murphy L, Helmick CG. The impact of osteoarthritis in the United States: a population-health 
perspective: A population-based review of the fourth most common cause of hospitalization in 
U.S. adults. Orthop Nurs 2012;31:85-91.  
 
Pham T, van der Heijde D, Altman RD, Anderson JJ, Bellamy N, Hochberg M, Simon L, Strand 
V, Woodworth T, Dougados M. OMERACT–OARSI initiative: Osteoarthritis Research Society 
International set of responder criteria for osteoarthritis clinical trials revisited. Osteoarthritis 
Cartilage 2004;12:389–99.  
 
Qvistgaard E, Christensen R, Torp-Pedersen S, Bliddal H. Intra-articular treatment of hip 
osteoarthritis: a randomized trial of hyaluronic acid, corticosteroid, and isotonic saline. 
Osteoarthritis Cartilage. 2006 Feb;14(2):163-70.  
 
Sellam J and Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of 
osteoarthritis. Nat Rev Rheumatol. 2010 Nov;6(11):625-35.  
 
Wenham CY and Conaghan PG. The role of synovitis in osteoarthritis. Ther Adv Musculoskelet 
Dis. 2010 Dec;2(6):349-59.  
 
Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bull World Health Organ. 
2003;81(9):646–56. 
 
Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, et al. OARSI 
recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-
based, expert consensus guidelines. Osteoarthritis Cartilage 2008;16:137-162. 


Flexion Therapeutics 
Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
CONFIDENTIAL - 38 - 
7. 
CLINICAL STUDY REPORT APPENDICES 
7.1. 
Statistical Tables and Figures to be Generated 
Table 14.1.1 
Patient Enrollment and Disposition 
Table 14.1.2 
Demographic and Baseline Characteristics (Safety Population) 
Table 14.1.3 
Osteoarthritis History and Index Hip Characteristics (Safety Population) 
Table 14.1.4 
Summary of Major Protocol Deviations (Safety Population) 
Table 14.1.5 
Study Drug Exposure Summary (Safety Population) 
Table 14.2.1.1 
Analysis of WOMAC A Pain Subscale (Full Analysis Set) 
Figure 14.2.1.1 
LS Mean Change from Baseline (+/- SE) in WOMAC A Pain Subscale 
Over Time (Full Analysis Set) 
Table 14.2.1.1.1.1 
Analysis of WOMAC A Pain Subscale, Patients with Baseline 
WOMAC A Pain Score 5 to <6 (Full Analysis Set) 
Table 14.2.1.1.1.2 
Analysis of WOMAC A Pain Subscale, Patients with Baseline 
WOMAC A Pain Score 6 to <7 (Full Analysis Set) 
Table 14.2.1.1.1.3 
Analysis of WOMAC A Pain Subscale, Patients with Baseline 
WOMAC A Pain Score ≥7 to 9 (Full Analysis Set) 
Figure 14.2.1.1.1 
LS Mean Change from Baseline (+/- SE) in WOMAC A Pain Subscale 
Over Time by Baseline WOMAC A Pain Score (Full Analysis Set) 
Table 14.2.1.1.2.1 
Analysis of WOMAC A Pain Subscale, Patients with Unilateral Hip OA 
(Full Analysis Set) 
Table 14.2.1.1.2.2 
Analysis of WOMAC A Pain Subscale, Patients with Bilateral Hip OA 
(Full Analysis Set) 
Figure 14.2.1.1.2 
LS Mean Change from Baseline (+/- SE) in WOMAC A Pain Subscale 
Over Time by Unilateral/Bilateral Hip OA (Full Analysis Set) 
Table 14.2.1.2 
Analysis of WOMAC B Stiffness Subscale (Full Analysis Set) 
Figure 14.2.1.2 
LS Mean Change from Baseline (+/- SE) in WOMAC B Stiffness 
Subscale Over Time (Full Analysis Set) 
Table 14.2.1.2.1.1 
Analysis of WOMAC B Stiffness Subscale, Patients with Baseline 
WOMAC A Pain Score 5 to <6 (Full Analysis Set) 


Flexion Therapeutics 
Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
CONFIDENTIAL - 39 - 
Table 14.2.1.2.1.2 
Analysis of WOMAC B Stiffness Subscale, Patients with Baseline 
WOMAC A Pain Score 6 to <7 (Full Analysis Set) 
Table 14.2.1.2.1.3 
Analysis of WOMAC B Stiffness Subscale, Patients with Baseline 
WOMAC A Pain Score ≥7 to 9 (Full Analysis Set) 
Figure 14.2.1.2.1 
LS Mean Change from Baseline (+/- SE) in WOMAC B Stiffness 
Subscale Over Time by Baseline WOMAC A Pain Score (Full Analysis 
Set) 
Table 14.2.1.2.2.1 
Analysis of WOMAC B Stiffness Subscale, Patients with Unilateral Hip 
OA (Full Analysis Set) 
Table 14.2.1.2.2.2 
Analysis of WOMAC B Stiffness Subscale, Patients with Bilateral Hip 
OA (Full Analysis Set) 
Figure 14.2.1.2.2 
LS Mean Change from Baseline (+/- SE) in WOMAC B Stiffness 
Subscale Over Time by Unilateral/Bilateral Hip OA (Full Analysis Set) 
Table 14.2.1.3 
Analysis of WOMAC C Function Subscale (Full Analysis Set) 
Figure 14.2.1.3 
LS Mean Change from Baseline (+/- SE) in WOMAC C Function 
Subscale Over Time (Full Analysis Set) 
Table 14.2.1.3.1.1 
Analysis of WOMAC C Function Subscale, Patients with Baseline 
WOMAC A Pain Score 5 to <6 (Full Analysis Set) 
Table 14.2.1.3.1.2 
Analysis of WOMAC C Function Subscale, Patients with Baseline 
WOMAC A Pain Score 6 to <7 (Full Analysis Set) 
Table 14.2.1.3.1.3 
Analysis of WOMAC C Function Subscale, Patients with Baseline 
WOMAC A Pain Score ≥7 to 9 (Full Analysis Set) 
Figure 14.2.1.3.1 
LS Mean Change from Baseline (+/- SE) in WOMAC C Function 
Subscale Over Time by Baseline WOMAC A Pain Score (Full Analysis 
Set) 
Table 14.2.1.3.2.1 
Analysis of WOMAC C Function Subscale, Patients with Unilateral Hip 
OA (Full Analysis Set) 
Table 14.2. 1.3.2.2 
Analysis of WOMAC C Function Subscale, Patients with Bilateral Hip 
OA (Full Analysis Set) 
Figure 14.2.1.3.2 
LS Mean Change from Baseline (+/- SE) in WOMAC C Function 
Subscale Over Time by Unilateral/Bilateral Hip OA (Full Analysis Set) 
Table 14.2.4.1 
Analysis of WOMAC Total (Full Analysis Set) 


Flexion Therapeutics 
Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
CONFIDENTIAL - 40 - 
Figure 14.2.4.1 
LS Mean Change from Baseline (+/- SE) in WOMAC Total Over Time 
(Full Analysis Set) 
Table 14.2.1.5.1 
Analysis of Area Under the Effect Curve (AUE), WOMAC A Pain 
Subscale Change from Baseline (Full Analysis Set) 
Table 14.2.1.5.2 
Analysis of Area Under the Effect Curve (AUE), WOMAC C Function 
Subscale Change from Baseline (Full Analysis Set) 
Table 14.2.1.6 
Analysis of WOMAC A Responders (Full Analysis Set) 
Figure 14.2.1.6.1 
Proportion of Responders, ≥20% Improvement (Full Analysis Set) 
Figure 14.2.1.6.2 
Proportion of Responders, ≥30% Improvement (Full Analysis Set) 
Figure 14.2.1.6.3 
Proportion of Responders, ≥50% Improvement (Full Analysis Set) 
Figure 14.2.1.6.4 
Continuous Responder Curve at Week 12 (Full Analysis Set) 
Table 14.2.2.1 
Analysis of Patient Global Impression of Change (PGIC) (Full Analysis 
Set) 
Figure 14.2.2.1 
LS Mean Change from Baseline (+/- SE) Patient Global Impression of 
Change (PGIC) Over Time (Full Analysis Set) 
Table 14.2.2.1.1.1 
Analysis of Patient Global Impression of Change (PGIC), Patients with 
Baseline WOMAC A Pain Score 5 to <6 (Full Analysis Set) 
Table 14.2.2.1.1.2 
Analysis of Patient Global Impression of Change (PGIC), Patients with 
Baseline WOMAC A Pain Score 6 to <7 (Full Analysis Set) 
Table 14.2.2.1.1.3 
Analysis of Patient Global Impression of Change (PGIC), Patients with 
Baseline WOMAC A Pain Score ≥7 to 9 (Full Analysis Set) 
Figure 14.2.2.1.1 
LS Mean Change from Baseline (+/- SE) in Patient Global Impression 
of Change (PGIC) Over Time by Baseline WOMAC A Pain Score (Full 
Analysis Set) 
Table 14.2.2.1.2.1 
Analysis of Patient Global Impression of Change (PGIC), Patients with 
Unilateral Hip OA (Full Analysis Set) 
Table 14.2.2.1.2.2 
Analysis of Patient Global Impression of Change (PGIC), Patients with 
Bilateral Hip OA (Full Analysis Set) 
Figure 14.2.2.1.2 
LS Mean Change from Baseline (+/- SE) Patient Global Impression of 
Change (PGIC) by Unilateral/Bilateral Hip OA Over Time (Full 
Analysis Set) 


Flexion Therapeutics 
Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
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CONFIDENTIAL - 41 - 
Table 14.2.2.2 
Analysis of Patient Global Impression of Change (PGIC) Results by 
Category (Full Analysis Set) 
Figure 14.2.2.2 
Patient Global Impression of Change (PGIC) Results by Category (Full 
Analysis Set) 
Table 14.2.2.2.1.1 
Analysis of Patient Global Impression of Change (PGIC) Results by 
Category, Patients with Baseline WOMAC A Pain Score 5 to <6 (Full 
Analysis Set) 
Table 14.2.2.2.1.2 
Analysis of Patient Global Impression of Change (PGIC) Results by 
Category, Patients with Baseline WOMAC A Pain Score 6 to <7 (Full 
Analysis Set) 
Table 14.2.2.2.1.3 
Analysis of Patient Global Impression of Change (PGIC) Results by 
Category, Patients with Baseline WOMAC A Pain Score ≥7 to 9 (Full 
Analysis Set) 
Figure 14.2.2.2.1 
Patient Global Impression of Change (PGIC) Results by Category 
Baseline WOMAC A Pain Score (Full Analysis Set) 
Table 14.2.2.2.2.1 
Analysis of Patient Global Impression of Change (PGIC) Results by 
Category, Patients with Unilateral Hip OA (Full Analysis Set) 
Table 14.2.2.2.2.2 
Analysis of Patient Global Impression of Change (PGIC) Results by 
Category, Patients with Bilateral Hip OA (Full Analysis Set) 
Figure 14.2.2.2.2 
Patient Global Impression of Change (PGIC) Results by Category by 
Unilateral/Bilateral Hip OA (Full Analysis Set) 
Table 14.2.3 
Analysis of OMERACT-OARSI Responders (Full Analysis Set) 
Figure 14.2.3.1.1 
Proportion of OMERACT-OARSI Responders (Full Analysis Set) 
Figure 14.2.3.1.2 
Continuous OMERACT-OARSI Responder Curve at Week 12 (Full 
Analysis Set) 
Table 14.2.4 
Summary of Rescue Medication Usage (Full Analysis Set) 
Figure 14.2.4 
LS Mean (+/- SE) Average Rescue Medication Usage Over Time (Full 
Analysis Set) 
Table 14.2.5. 
Analysis of Sleep Interference (Full Analysis Set) 
Figure 14.2.5 
LS Mean Change from Baseline (+/- SE) in Sleep Interference Over 
Time (Full Analysis Set) 
Table 14.2.6.1 
Analysis of EQ-5D Mobility Dimension (Full Analysis Set) 


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Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
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CONFIDENTIAL - 42 - 
Figure 14.2.6.1 
LS Mean Change from Baseline (+/- SE) in EQ-5D Mobility Dimension 
Over Time (Full Analysis Set) 
Table 14.2.6.2 
Analysis of EQ-5D Self-Care Dimension (Full Analysis Set) 
Figure 14.2.6.2 
LS Mean Change from Baseline (+/- SE) in EQ-5D Self-Care 
Dimension Over Time (Full Analysis Set) 
Table 14.2.6.3 
Analysis of EQ-5D Usual Activities Dimension (Full Analysis Set) 
Figure 14.2.6.3 
LS Mean Change from Baseline (+/- SE) in EQ-5D Usual Activities 
Dimension Over Time (Full Analysis Set) 
Table 14.2.6.4 
Analysis of EQ-5D Pain/Discomfort Dimension (Full Analysis Set) 
Figure 14.2.6.4 
LS Mean Change from Baseline (+/- SE) in EQ-5D Pain/Discomfort 
Dimension Over Time (Full Analysis Set) 
Table 14.2.6.5 
Analysis of EQ-5D Anxiety/Depression Dimension (Full Analysis Set) 
Figure 14.2.6.5 
LS Mean Change from Baseline (+/- SE) in EQ-5D Anxiety/Depression 
Dimension Over Time (Full Analysis Set) 
Table 14.2.6.6 
Analysis of EQ Visual Analogue Scale (EQ VAS) (Full Analysis Set) 
Figure 14.2.6.6 
LS Mean Change from Baseline (+/- SE) in EQ Visual Analogue Scale 
(EQ VAS) Over Time (Full Analysis Set) 
Table 14.2.6.7 
Analysis of EQ-5D-5L Index Score (Full Analysis Set) 
Figure 14.2.6.7 
LS Mean Change from Baseline (+/- SE) in EQ-5D-5L Index Score 
Over Time (Full Analysis Set) 
Table 14.2.7 
Analysis of HOOS-QOL Over Time (Full Analysis Set) 
Figure 14.2.7 
LS Mean Change from Baseline (+/- SE) in HOOS-QOL Over Time 
(Full Analysis Set) 
Table 14.2.8.1 
Analysis of TSQM-9 Global Satisfaction Domain at Week 12 (Full 
Analysis Set) 
Table 14.2.8.2 
Analysis of TSQM-9 Effectiveness Domain at Week 12 (Full Analysis 
Set) 
Table 14.2.8.3 
Analysis of TSQM-9 Convenience Domain at Week 12 (Full Analysis 
Set) 


Flexion Therapeutics 
Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
CONFIDENTIAL - 43 - 
Table 14.3.1.1 
Summary of Treatment-Emergent Adverse Events by Treatment Arm 
(Safety Population) 
Table 14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.1.3 
Treatment-Emergent Adverse Events by Preferred Term (Safety 
Population) 
Table 14.3.1.4 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term - Related to Study Drug (Safety Population) 
Table 14.3.1.5 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term - Related to Injection Procedure (Safety Population) 
Table 14.3.1.6 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term by Maximum Severity (Safety Population) 
Table 14.3.1.7 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term – Leading to Study Discontinuation (Safety Population) 
Table 14.3.1.8 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term – Leading to Death  (Safety Population) 
Table 14.3.1.9 
Serious Adverse Events by System Organ Class and Preferred Term 
(Safety Population) 
Table 14.3.1.10 
Index Hip-Related Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term (Safety Population) 
Table 14.3.1.11 
Index Hip-Related Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term - Related to Study Drug (Safety 
Population) 
Table 14.3.1.12 
Index Hip-Related Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term by Maximum Severity (Safety 
Population) 
Table 14.3.2.1 
Patient Listing of Deaths 
Table 14.3.2.2 
Patient Listing of Serious Adverse Events 
Table 14.3.2.3 
Patient Listing of Discontinuations Due to Adverse Events 
Table 14.4.1.1 
Summary and Change from Baseline for Hematology Parameters by 
Visit (Safety Population) 


Flexion Therapeutics 
Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
CONFIDENTIAL - 44 - 
Table 14.4.1.2 
Summary and Change from Baseline for Chemistry Parameters by Visit 
(Safety Population) 
Table 14.4.1.3 
Summary and Change from Baseline for Vital Signs (Safety Population) 
Table 14.4.2 
Summary of Index Hip Assessments (Safety Population) 
Table 14.4.3.1 
Index Hip X-ray Joint Space Narrowing Change from Baseline (Safety 
Population) 
Table 14.4.3.2 
Shifts in Index Hip X-Ray Assessments from Baseline (Safety 
Population) 
 
7.2. 
Data Listings to be Generated 
 
Listing 16.2.1 
Patient Disposition  
Listing 16.2.2.1 
Inclusion/Exclusion Criteria Not Met 
Listing 16.2.2.2 
Protocol Deviations  
Listing 16.2.3 
Analysis Populations 
Listing 16.2.4.1.1 
Demographics and Baseline Characteristics 
Listing 16.2.4.1.2.1 
PD-Q Questionnaire - List of Questions 
Listing 16.2.4.1.2.2 
PD-Q 
Listing 16.2.4.1.3.1 
PHQ-9 Questionnaire - List of Questions 
Listing 16.2.4.1.3.2 
PHQ-9 
Listing 16.2.4.1.4.1 
GAD-7 Questionnaire - List of Questions 
Listing 16.2.4.1.4.2 
GAD-7 
Listing 16.2.4.1.5.1 
PCS Questionnaire - List of Questions 
Listing 16.2.4.1.5.2 
PCS 
Listing 16.2.4.1.6.1 
ISI Questionnaire - List of Questions 
Listing 16.2.4.1.6.2 
ISI 


Flexion Therapeutics 
Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
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CONFIDENTIAL - 45 - 
Listing 16.2.4.2 
Medical History 
Listing 16.2.4.3 
Medical History - Hip Osteoarthritis 
Listing 16.2.4.4 
Medical History - Prior Treatment of Hip Osteoarthritis 
Listing 16.2.4.5 
Medical History - Other Osteoarthritis 
Listing 16.2.4.6 
Medical History - Other Osteoarthritis Procedures or Surgeries 
Listing 16.2.4.7 
Screening Index Hip X-Ray/Kellgren-Lawrence Grade 
Listing 16.2.5.1 
Patient Randomization 
Listing 16.2.5.2 
Study Drug Exposure 
Listing 16.2.6.1.1 
WOMAC Questionnaire - List of Questions by Section 
Listing 16.2.6.1.2 
WOMAC A Pain Subscale 
Listing 16.2.6.1.3 
WOMAC B Stiffness Subscale 
Listing 16.2.6.1.4 
WOMAC C Function Subscale  
Listing 16.2.6.1.5 
WOMAC Total (Subscale Means and Total Score) 
Listing 16.2.6.1.6 
Area Under The Effect Curve (AUE), WOMAC A Pain Subscale 
Change from Baseline 
Listing 16.2.6.1.7 
Area Under The Effect Curve (AUE), WOMAC C Function Change 
from Baseline 
Listing 16.2.6.2 
PGIC  
Listing 16.2.6.3 
OMERACT-OARSI Responder Criteria 
Listing 16.2.6.4.1 
Rescue Medication Usage 
Listing 16.2.6.4.2 
Rescue Medication Accountability 
Listing 16.2.6.5.1 
Sleep Interference (SI) -  List of Questions 
Listing 16.2.6.5.2 
Sleep Interference (SI) 
Listing 16.2.6.6.1 
EQ-5D-5L -  List of Questions 
Listing 16.2.6.6.2 
EQ-5D-5L  


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Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
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CONFIDENTIAL - 46 - 
Listing 16.2.6.7.1 
HOOS-QOL Subscale -  List of Questions 
Listing 16.2.6.7.2 
HOOS-QOL Subscale 
Listing 16.2.6.8.1 
Abbreviated Treatment Satisfaction Questionnaire for Medication 
(TSQM-9) - List of Questions 
Listing 16.2.6.8.2 
Abbreviated Treatment Satisfaction Questionnaire for Medication 
(TSQM-9)  
Listing 16.2.7.1 
Adverse Events – Sorted By Patient and Onset Date 
Listing 16.2.7.2 
Adverse Events – Sorted by System Organ Class, Preferred Term, 
Treatment, Patient, and Onset Date 
Listing 16.2.7.3 
Adverse Events – Glossary by MedDRA SOC, Preferred Term and 
Verbatim 
Listing 16.2.8.1 
Laboratory Assessment – Hematology 
Listing 16.2.8.2 
Laboratory Assessment – Chemistry 
Listing 16.2.8.3 
Screening Laboratory Assessments: HIV, Hep B, Hep C, ESR, and 
Urine/Serum Pregnancy Test Results 
Listing 16.2.9.1 
Vital Signs 
Listing 16.2.9.2 
Physical Examination Findings 
Listing 16.2.9.3 
Index Hip Assessments 
Listing 16.2.9.4 
Index Hip X-Ray Results 
Listing 16.2.9.5 
Index Hip Aspiration Results 
Listing 16.2.9.6 
Prior and Concomitant Medications 
Listing 16.2.9.7 
Surgical Procedures 


Flexion Therapeutics 
Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
CONFIDENTIAL - 47 - 
 
 
7.3.  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 
Cholesterol 
Hyper 
Hypercholestremia 
 
mmol/L 
>ULN-7.75 
>7.75-10.34 
>10.34-12.92 
>12.92 
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 


Flexion Therapeutics 
Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
CONFIDENTIAL - 48 - 
Lab Parameter 
Hypo/Hyper 
CTCAE Definition 
SI Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Glucose 
Hyper 
Hyperglycemia 
mmol/L 
>ULN-8.9 
>8.9-13.9 
>13.9-27.8 
>27.8 
Phosphate 
Hypo 
Hypophosphatemia 
mmol/L 
<LLN-0.8 
<0.8-0.6 
<0.6-0.3 
<0.3 
Potassium 
Hypo 
 
Hypokalemia 
mmol/L 
<LLN-3 
<LLN-3 
<3-2.5 
<2.5 
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 
Triglycerides 
Hyper 
Hypertriglyceridemia 
mg/dL 
150-300 
>300-500 
>500-1000 
>1000 
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 
- 


Flexion Therapeutics 
Protocol FX006-2018-015, Part I 
SAP, Final Version 1.0 
05 SEP 2019 
 
CONFIDENTIAL - 49 - 
Lab Parameter 
Hypo/Hyper 
CTCAE Definition 
SI Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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 
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: 
 Blood Urea Nitrogen 
 Bicarbonate (removed from version 4.x; it was available in version 3) 
 Chloride 
 Erythrocyte Mean Corpuscular Volume 
 HDL Cholesterol 
 LDL Cholesterol 
 Urate 
 Basophils 
 Eosinophils 
 Erythrocytes 
 Hematocrit 
 Monocytes