Conditions: Osteoarthritis, Hip
Keywords: Osteoarthritis Hip Intra-articular Injection
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 16
Healthy volunteers: no

Brief summary:
This is a multi-center, single-arm, open-label study of FX006 in patients with hip OA. A maximum number of approximately 30 patients may be enrolled in this protocol. All enrolled patients will receive a single intra-articular (IA) injection of FX006.

Detailed description:
This is a multi-center, single-arm, open-label study in patients with hip OA to evaluate a procedure for intra-articular injection of FX006 in patients with hip OA. A maximum number of approximately 30 patients may be enrolled in this protocol.

All enrolled patients will receive a single intra-articular (IA) injection on Day 1 and be followed for 8 weeks.

Arms:
arm 1: Single intra-articular (IA) injection of FX006 32 mg

Interventions: intervention 1: FX006 32 mg
Intervention descriptions: intervention 1: Extended-release 32 mg FX006 IA injection

Protocol document:
Prot_000.pdf: 
 
Clinical Study Protocol 
 
 
Protocol Title 
A Single-arm, Open-label Study to Evaluate a Procedure for Intra-
articular (IA) Injection of FX006 in Patients with Osteoarthritis 
(OA) of the Hip 
Protocol Number 
FX006-2019-017 
Phase 
2 
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: 781-305-7777 
Date 
11 July 2019 
Version 
Version 2.0 (Amendment 1.0) 
Supersedes 
Version 1.0 Original (28 June 2019) 
 
 
 
 
 
 
 




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TABLE OF CONTENTS 
1. 
ABBREVIATIONS AND DEFINITION OF TERMS ................................................7 
2. 
SYNOPSIS ...................................................................................................................9 
3. 
ETHICS ......................................................................................................................15 
3.1. 
Institutional Review Board/Ethics Committee ...........................................................15 
3.2. 
Ethical Conduct of Study ............................................................................................15 
3.3. 
Patient Information and Consent ................................................................................15 
4. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .................16 
4.1. 
Investigators ................................................................................................................16 
4.2. 
Study Administrative Structure ..................................................................................16 
5. 
INTRODUCTION ......................................................................................................17 
5.1. 
Osteoarthritis ...............................................................................................................17 
5.2. 
Background .................................................................................................................17 
5.2.1. 
Investigational Medicinal Product:  FX006 ................................................................17 
5.2.2. 
Rationale for FX006 in Hip Osteoarthritis .................................................................18 
5.2.3. 
Non-Clinical Toxicology ............................................................................................18 
5.2.4. 
Systemic and Local Pharmacokinetics (PK) in Patients with OA of the Knee ..........19 
5.2.5. 
Pharmacodynamics (PD) in Patients with Osteoarthritis of the Knee ........................19 
5.2.6. 
Efficacy in Patients with Osteoarthritis of the Knee ..................................................19 
5.2.7. 
Systemic and Local Safety in Patients with Osteoarthritis of the Knee .....................20 
5.2.8. 
Experience with FX006 Administered IA in Patients with OA of the Hip ................21 
5.2.9. 
Conclusion ..................................................................................................................22 
6. 
STUDY OBJECTIVES ..............................................................................................23 
6.1. 
Primary Objective .......................................................................................................23 
6.2. 
Secondary Objectives .................................................................................................23 
7. 
INVESTIGATIONAL PLAN .....................................................................................24 
7.1. 
Overall Study Design and Plan ...................................................................................24 
7.2. 
Flow of Study Participation ........................................................................................24 
7.3. 
Site Staffing Requirements .........................................................................................24 
7.4. 
Discussion of Study Design ........................................................................................25 
7.4.1. 
Rationale for Study Population ...................................................................................25 
7.4.2. 
Rationale for Dose Selection ......................................................................................25 


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7.4.3. 
Rationale for Study Parameters ..................................................................................25 
7.5. 
Selection of Study Population ....................................................................................26 
7.5.1. 
Number of Patients .....................................................................................................26 
7.5.2. 
Inclusion Criteria ........................................................................................................26 
7.5.3. 
Exclusion Criteria .......................................................................................................27 
7.5.4. 
Removal of Patients from Therapy or Assessments ...................................................28 
7.5.5. 
Screen Failures ............................................................................................................29 
7.6. 
Treatment Administered .............................................................................................29 
7.6.1. 
Study Medication Treatment Arms ............................................................................29 
7.6.2. 
Identity of Investigational Product .............................................................................29 
7.6.3. 
Receipt, Preparation, Dispensing and Storage ............................................................29 
7.6.4. 
Packaging and Labeling of Study Medication ............................................................30 
7.6.5. 
Return of Study Medication ........................................................................................30 
7.6.6. 
Method of Assigning Patients to Treatment Groups ..................................................30 
7.6.7. 
Blinding ......................................................................................................................30 
7.6.8. 
Breaking the Blind ......................................................................................................30 
7.6.9. 
Standardized Procedure of IA Administration of FX006 in the Hip ..........................30 
7.6.10. 
Post-Injection Care .....................................................................................................30 
7.6.11. 
Treatment Compliance ................................................................................................30 
7.7. 
Prior and Concomitant Therapy ..................................................................................30 
7.7.1. 
Prior Therapy ..............................................................................................................30 
7.7.2. 
Concomitant Therapy Allowed During the Study ......................................................31 
7.7.3. 
Prohibited Medications/Non-Pharmacologic Therapies .............................................31 
7.8. 
Study Variables ...........................................................................................................31 
7.8.1. 
Procedure Variables ....................................................................................................31 
7.8.2. 
Safety Variables ..........................................................................................................32 
7.9. 
Study Procedures ........................................................................................................32 
7.9.1. 
Schedule of Study Assessments..................................................................................32 
7.9.2. 
Informed Consent .......................................................................................................32 
7.9.3. 
Review of Eligibility, Medical History, Prior Treatment and Medications ...............32 
7.9.4. 
Physical Examination .................................................................................................32 
7.9.5. 
Index Hip Assessment ................................................................................................33 
7.9.6. 
Index Hip X-ray ..........................................................................................................33 


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7.9.7. 
Vital Signs ..................................................................................................................33 
7.9.8. 
Local Clinical Laboratory Evaluations .......................................................................33 
7.9.9. 
Index Hip Aspiration ..................................................................................................34 
7.9.10. 
Study Drug Administration.........................................................................................34 
7.9.11. 
Review of Adverse Events and Concomitant Medications ........................................34 
8. 
ADVERSE EVENTS..................................................................................................35 
8.1. 
Definitions ..................................................................................................................35 
8.2. 
Monitoring of Adverse Events ....................................................................................36 
8.2.1. 
Monitoring of Laboratory Assessments and Other Diagnostic Tests .........................36 
8.2.2. 
Adverse Events That Occur During the Injection Procedure .....................................36 
8.3. 
Assessment of Adverse Events ...................................................................................37 
8.3.1. 
Assessment of Seriousness .........................................................................................37 
8.3.2. 
Assessment of Severity ...............................................................................................37 
8.3.3. 
Assessment of Relationship to Study Medication ......................................................37 
8.4. 
Recording of Adverse Events .....................................................................................38 
8.4.1. 
Reporting of Serious Adverse Events .........................................................................38 
8.5. 
Safety Monitoring Roles .............................................................................................38 
8.6. 
Clinical Management of Index Hip-Related Events ...................................................39 
8.7. 
Pregnancy ...................................................................................................................39 
9. 
STATISTICAL CONSIDERATIONS .......................................................................40 
9.1. 
Statistical and Analytical Plans ..................................................................................40 
9.1.1. 
Planned Analyses ........................................................................................................40 
9.2. 
General Considerations and Methods .........................................................................40 
9.2.1. 
Analysis Populations ..................................................................................................40 
9.2.2. 
Study Data ..................................................................................................................40 
9.2.2.1. 
Clinical Data – CDISC Study Data Tabulation Model (SDTM) ................................40 
9.2.2.2. 
Analysis Data – CDISC Analysis Data Model (ADaM) ............................................41 
9.2.3. 
Study Endpoints for Assessment ................................................................................41 
9.2.3.1. 
Primary Endpoint ........................................................................................................41 
9.2.4. 
Sub-Groups and Covariates ........................................................................................41 
9.3. 
Determination of Sample Size ....................................................................................41 
9.3.1. 
Sample Size Considerations .......................................................................................41 
9.4. 
General Statistical Methods ........................................................................................41 


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9.4.1. 
Demographics and Baseline Characteristics ...............................................................41 
9.4.2. 
Exposure .....................................................................................................................41 
9.4.3. 
Efficacy Analyses .......................................................................................................41 
9.4.4. 
Safety Analyses ..........................................................................................................42 
10. 
DATA QUALITY ASSURANCE ..............................................................................43 
11. 
DATA HANDLING AND RECORDKEEPING .......................................................44 
11.1. 
Case Report Forms .....................................................................................................44 
11.2. 
Study Medication Accountability ...............................................................................44 
11.3. 
Confidentiality of Data ...............................................................................................44 
11.4. 
Retention of Records ..................................................................................................44 
11.5. 
Protocol Adherence ....................................................................................................45 
12. 
PUBLICATION POLICY ..........................................................................................46 
12.1. 
Sponsor’s Publication Policy ......................................................................................46 
12.2. 
Site Publication ...........................................................................................................46 
13. 
REFERENCES ...........................................................................................................47 
14. 
APPENDICES ............................................................................................................49 
 
 
LIST OF TABLES 
Table 1: 
Schedule of Study Assessments..................................................................................14 
Table 2: 
Clinical Laboratory Panel ...........................................................................................34 
 
 
 
 
 


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1. 
ABBREVIATIONS AND DEFINITION OF TERMS 
ACR 
American College of Rheumatology 
ADRG 
Analysis Data Reviewer’s Guide 
AE 
Adverse Event 
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 
EULAR  
European League Against Rheumatism 
FAS 
Full Analysis Set 
FBR 
Foreign Body Response 
FDA 
Food and Drug Administration 
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 
HPA  
Hypothalamic-pituitary-adrenal 
IA 
Intra-articular 
IB 
Investigator’s Brochure 
IM 
Intramuscular 
IP 
Investigational Product 
IRB/EC 
Institutional Review Board/Ethics Committee 
IV  
Intravenous 
JSN 
Joint Space Narrowing 
kg  
Kilogram 
KL 
Kellgren-Lawrence 
LSM 
Least square mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
n 
Number 
NaCl  
Sodium Chloride 


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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 
PD 
Pharmacodynamic 
PLGA 
Poly [lactic-co-glycolic acid] 
PK  
Pharmacokinetic 
PRP 
Platelet Rich Plasma 
RBC 
Red Blood Cells 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDRG 
Study Data Reviewer’s Guide 
TEAE 
Treatment-emergent Adverse Event 
TENS 
Transcutaneous electrical nerve stimulation 
TA1 
Triamcinolone Acetonide  
TAcs2 
Triamcinolone Acetonide Injectable Suspension, Immediate-Release 
(commercially available) 
USA 
United States of America 
USP 
United States Pharmacopeia 
w/w 
weight by weight 
WBC 
White Blood Cells 
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 Single-arm, Open-label Study to Evaluate a Procedure for Intra-articular (IA) Injection of FX006 in 
Patients with Osteoarthritis (OA) of the Hip  
Study Centers  
Multiple centers, up to 6 
Study Phase   
Phase 2 
Objectives 
Primary 
• 
To evaluate the ability of injection procedures to achieve successful intra-articular (IA) 
injection of FX006 into the hip joints of patients with OA of the hip 
Secondary: 
• 
To assess the safety of FX006 administered by IA injection in patients with hip OA 
Number of Patients 
A maximum number of approximately 30 patients may be enrolled in this protocol.   
Initially, up to 22 patients will be enrolled.   
In the event there is one (1) unsuccessful IA administration of FX006, 7 additional patients may be 
enrolled.  
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, administered as a single 5 mL IA injection 
into the index hip under image guidance per injection procedure. 
Reference Compound(s), Dose and Mode of Administration 
None (single-arm, open-label study) 
Blinding 
Not applicable (single-arm, open-label study) 
Duration of Participation 
All enrolled patients will receive a single IA injection on Day 1 and be followed for 8 weeks. 
Study Rationale 
During clinical trials, FX006, now marketed as Zilretta®, was administered without difficulty by IA 
injection into the knee joint to >800 patients with knee OA and demonstrated an acceptable safety 
profile and clear therapeutic effect (see Section 5.2). In two recent studies of patients with hip OA, 
incomplete IA injections of FX006 into the hip joint occurred. A Sponsor-conducted investigation 
identified procedural factors as potentially contributing to these incomplete injections in the hip.  
Specifically, (a) vertical orientation of the syringe of resuspended FX006; and (b) restriction at the 
outflow from the needle.  Notably, during IA injection into the knee joint the FX006 syringe is 
generally in the horizontal orientation during injection; further, the patient positioning routinely used 
for injection of the knee joint readily relaxes the surrounding structures.   


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The approach being investigated in this study addresses these factors by (a) providing tubing as an 
accessory connector that enables the syringe of FX006 to be kept in a horizontal orientation during 
injection and (b) specifies positioning the patient and supporting the leg to minimize tension on the hip 
joint. The goal is to confirm if such procedural changes can result in reliable successful clinical IA 
administration of FX006 in the hip joint.    
Study Design and Methodology 
This is a prospective, multicenter, single-arm, open-label study to evaluate the feasibility of an IA 
injection procedure of 32 mg FX006 under image guidance in patients with hip osteoarthritis (OA). The 
study will be conducted at up to 6 sites with approximately 22 patients. If one (1) unsuccessful IA 
administration is observed, 7 additional patients will be enrolled.  Eligible subjects will be administered 
a single IA injection of FX006 on Day 1 and then followed for safety for 8 weeks.  
Inclusion Criteria 
To be eligible for this trial, a patient must meet all of the following criteria: 
1. Provides written informed consent prior to initiating any study specific procedures 
2. Is willing and able to comply with the study procedures and visit schedule and to follow verbal 
and written instructions 
3. Is 40 to 80 years of age, inclusive, on the day of consent 
4. Has Body Mass Index (BMI) ≤ 40 kg/m2 
5. Has a documented clinical diagnosis of unilateral or bilateral hip OA for at least six (6) months. 
6. Has Kellgren-Lawrence (KL) Grade 2 or 3 in the index hip (i.e., the hip identified by the 
Investigator as appropriate for injection) confirmed by local read of X-ray obtained during 
Screening or ≤ 6 months of Screening visit.  
7. Has clinically significant pain in the index hip (≥ 4.0 (0-10 NRS scale)) at Screening as 
reported by patient  
8. Sexually active males and females of child-bearing potential (defined as neither surgically 
sterile nor post-menopausal, i.e., age >45 years and no menstrual periods for at least 1 year) 
must agree to use, from Screening through 14 weeks post-injection for females and through 
23 weeks post-injection for males, a highly effective method of contraception, defined as one of 
the following: abstinence; oral, injected or implanted hormonal methods of contraception; 
intrauterine device or intrauterine contraceptive system; condom or occlusive cap (diaphragm 
or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; sexual intercourse 
only with man ≥6 months post-vasectomy.  
Exclusion Criteria 
Patients meeting one or more of the following criteria are excluded from the study:  
1. Has a history of hypersensitivity to triamcinolone acetonide, PLGA or lidocaine.   
2. Is receiving anticoagulants, including warfarin, dabigatran, rivaroxaban, apixaban or low 
molecular weight heparin), ritonavir or cobicistat. (Aspirin for cardio-protection is permitted at 
a maximum dose of 325 mg per day provided the dose has been stable at least 3 months prior to 
Screening.) 
3. Has had any previous surgery on the index hip. 
4. Presence of surgical hardware or other foreign body in the index hip. 
5. Has a history of infection of the index hip. 
6. Has a diagnosis of other disorders in the index hip that can cause pain (e.g. trochanteric bursitis, 
avascular necrosis, pain referred from back). 


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7. Has received any intra-articular injection in the index hip of corticosteroids, investigational 
(including FX006) or marketed (including Zilretta) within the 3 months prior to Screening. 
8. Has received intra-articular treatment in the index hip with any of the following agents: any 
biologic agent (e.g., platelet rich plasma (PRP), stem cells, prolotherapy, amniotic fluid) or 
hyaluronic acid within the 6 months prior to Screening.   
9. Has had trauma to the index hip in the past 3 months requiring immobilization. 
10. Has a history or evidence of active or latent systemic fungal or mycobacterial infection 
(including tuberculosis), or of ocular herpes simplex  
11. Has within the past 3 months received corticosteroids by mouth, or by parenteral injection.  
Multiple courses or chronic intermittent use of inhaled, intranasal, or topical steroids is also 
exclusionary. Single courses of 14 days or less by those routes are permitted 
12. Has received a live (e.g., MMR vaccine, chicken pox vaccine, rotavirus vaccine) or live- 
attenuated vaccine (e.g., FluMist, Zostavax) within 12 weeks of Day 1.  
13. Has, at screening, a positive test for hepatitis B surface antigen, HIV or hepatitis C.  
14. Has, at screening, any abnormal laboratory value(s) that in in the opinion of the Principal 
Investigator (PI) (or other authorized clinical delegate) precludes trial participation.  
15. Has, at screening, or any time prior to day of scheduled injection (Day 1), clinical suspicion of 
local or systemic infection, including any infection in the index leg. 
16. Has a history of or active significant concomitant illness (known or suspected) including, but 
not limited to: 
- 
Inflammatory joint disease, e.g. rheumatoid arthritis, seronegative spondyloarthropathy, 
ankylosing spondylitis, psoriatic arthritis, reactive arthritis, inflammatory-bowel disease 
associated inflammatory arthritis. 
- 
Systemic inflammatory disease, e.g., polymyalgia rheumatica, systemic lupus 
erythematosus   
- 
Sarcoidosis or amyloidosis 
- 
Cushing’s syndrome 
- 
Malignancy requiring systemic therapy within the past five (5) years (excludes basal cell 
carcinoma or cervical cancer treated only with surgical removal more than one (1) year 
ago.) 
- 
Other autoimmune disease.  
17. Any infection requiring parental antibiotics within 4 weeks of Day 1 or oral antibiotics within 2 
weeks of Day 1 
18. Has a history or current diagnosis of any other medical illness which in the opinion of the local 
Principal Investigator (PI) (or other authorized clinical delegate) precludes trial participation 
19. Is a woman who is pregnant, nursing, lactating, or plans to become pregnant during the study 
20. Is a man who plans to conceive during the study 
21. 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.   


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Prior Therapy 
Exclusionary medications are noted in the Exclusion Criteria. 
Other medications reported at Screening will be recorded as Concomitant Medications and may be 
continued during the study if, in the judgement of the Investigator, usage and the underlying condition 
have been stable and are expected to remain stable for the duration of the study.  
During the study, any changes in prior concomitant medications and the associated reasons for the 
changes will be recorded in source documentation and reported in the eCRF. 
Concomitant Therapy Allowed During the Study  
Concomitant medication required for the treatment of a treatment-emergent AEs is permitted and both 
the AE and the treatment will be recorded and reported.  
Prohibited Medications/Non-Pharmacologic Therapies 
The following medications should not be taken from consent through the EOS visit: 
• 
Aspirin (>325 mg per day) 
• 
Any treatment administered by IA injection in the index hip, including hyaluronic acid, plasma, cell 
therapies, local anesthetics through 8 weeks post injection. 
• 
IV, IM, or oral corticosteroids. Inhaled, intranasal and topical steroids are prohibited from 
Screening through Week 1 visit. 
• 
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) for 8 weeks post injection.   
Criteria for Evaluation: 
Safety  
• 
Adverse Events 
• 
Vital signs 
• 
Index hip examinations 
Sample Size Considerations: 
Approximately 22 patients will be treated in this study. If there are no incomplete IA administrations, 
the study may be considered complete. Observing 0 incomplete injections (0%) in 22 patients gives 
90% confidence that the true incomplete IA injection rate is between 0 and 10%. If one (1) unsuccessful 
IA administration of study drug is observed, 7 additional patients may be enrolled. Observing 1 
incomplete IA injection in 29 patients (3%) gives 80% confidence that the true incomplete IA injection 
rate is between 0 and 10%. 


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Statistical Methods: 
Complete details of the statistical analysis will be specified in the statistical analysis plan (SAP).   
Data collected in this study will be presented using summary tables and subject data listings.  
Continuous variables will be summarized using descriptive statistics; specifically, the mean, median, 
standard deviation, minimum and maximum.  Categorical variables will be summarized using 
frequencies and percentages.  Confidence intervals may also be provided.  Figures may be used to 
support the presentation of certain data.   
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.  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 index hip 
TEAEs. Laboratory data, vital signs and X-ray KL grade will be presented as descriptive summary 
statistics.  Vital sign data will also be presented as change from Baseline at each individual time point.   
 
 


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Table 1: 
Schedule of Study Assessments 
List of Assessments 
Screening1 
Day 1 
Week 1 
Week 4 
Week 8 
Window 
-14 to -1 
– 
±2 days 
±5 Days 
±5 days 
Informed consent 
X 
 
 
 
 
Inclusion/Exclusion Review 
X 
X2 
 
 
 
Medical History/Update 
X 
X2 
 
 
 
Patient Demographics 
X 
 
 
 
 
OA Medical History 
X 
 
 
 
 
Prior Treatments and 
Medications 
X 
X2 
 
 
 
Physical examination 
X 
 
 
 
 
Vital signs 
X 
X2 
X 
 
X 
Height 
X 
 
 
 
 
Weight and BMI 
X 
 
 
 
 
Index Hip Assessment 
X 
X2 
X 
 
X 
Index Hip X-ray 3 
X 
 
 
 
 
Hematology, Chemistry4 
X 
 
 
 
 
HIV, Hep B/C4 
X 
 
 
 
 
Pregnancy Test5 
X5 
X2,5 
 
 
 
Index Hip Aspiration6 
 
X 
 
 
 
IP administration7 
 
X 
 
 
 
AE/SAE & ConMeds8 
X 
X 
X 
X9 
X 
 
                                                 
1 Screening period is up to 14 days. 
2 To be completed on Day 1 prior to injection procedure 
3 A weight-bearing anterior-posterior view for index hip is recommended. Screening X-ray will be read locally for 
radiologic findings of OA meeting criteria for Kellgren-Lawrence Grade 2-3. 
4 To be performed via local laboratory. 
5 Pregnancy test will be done in women of childbearing potential.  Serum Pregnancy Test to be performed at 
Screening visit by local lab; Urine Pregnancy Test to be performed on Day 1 by study site or local lab with result 
available prior to injection of study medication. 
6 Aspiration must be attempted prior to IP administration. Synovial fluid volume aspirated will be recorded prior to 
discard.  
7 To be performed under image guidance in compliance with protocol specified procedure. 
8 AE/SAE’s and concomitant medications will be captured from signing of informed consent through EOS visit. 
9 To be conducted via telephone 


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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 Clinical Site Responsibilities and Signature Log. 
The contact information for all Principal Investigators participating in the trial will be kept in the 
Trial Master File. 
4.2. 
Study Administrative Structure 
The study will be managed by the Sponsor with specific responsibilities delegated to contract 
research organizations. 
 


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5. 
INTRODUCTION 
5.1. 
Osteoarthritis 
Osteoarthritis (OA) is a painful and debilitating musculoskeletal disease that is characterized by 
intra-articular (IA) inflammation, deterioration of articular cartilage, and degenerative changes to 
peri-articular and subchondral bone (Creamer and Hochberg, 1997; Goldring and Goldring, 
2006).  Arthritis is the most common cause of disability in the United States 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 (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 benefit/risk profile for hip OA patients. 
5.2.3. 
Non-Clinical Toxicology  
Overall, single or repeat IA administration of FX006 at the 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 OA 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 knee 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 
effect curve (AUE) analyses for Weeks 1 through 12 and Weeks 1 through 24.  Results 


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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. 
Key safety observations from the FX006 clinical studies of OA of the knee 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 two Phase 3 studies (FX006-2014-008 and FX006-2016-011), 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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Study FX006-2014-008 
• 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 single dose FX006, placebo, 
and TCA IR 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. 
 
Study FX006-2016-011 
• The overall rate of JSN worsening of at least 1 grade between baseline and end of study 
(Week 52 or early termination) among patients who received two FX006 doses and had X-
ray data at both timepoints (N=165) was low 3.6% [6/165].  
• There were no indications of chondrolysis, osteonecrosis, subchondral insufficiency 
fractures, or clinically significant subchondral bone changes. 
5.2.8. 
Experience with FX006 Administered IA in Patients with OA of the Hip 
Studies of FX006 were recently expanded to include studies in patients with symptomatic OA of 
the hip joint. Among approximately 45 patients administered 32mg FX006 by IA into the hip, 
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.  
However, in contrast with the prior experience in the knee, there were occurrences of incomplete 
administration of FX006 variously reported as "increased resistance" or "blockage" encountered 
during injection procedure. Careful review of the cases failed to identify a common factor and 
initial laboratory studies were inconclusive.  
However, subsequent laboratory models suggested two procedural factors potentially 
contributing to these incomplete injections of the hip. Specifically, if a syringe of resuspended 
FX006 was attached directly to a vertical spinal needle (as typically encountered during IA 
injection in the hip) and outflow from the needle was mildly restricted by tubing, then blockage 
was observed at an appreciable rate. If the syringe was held horizontally or if the restricting 
tubing was omitted (giving conditions similar to IA injection in the knee), such events did not 
occur.  
The approach being investigated in this study addresses these factors by (a) providing tubing as 
an accessory connector that enables the syringe of FX006 to be kept in a horizontal orientation 
during injection and (b) specifies positioning the patient and supporting the leg to minimize 


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tension on the hip joint (Kumar et al, 2017). The goal is to confirm if such procedural changes 
can result in reliable successful clinical IA administration of FX006 in the hip joint. 
5.2.9. 
Conclusion 
Intra-articular administration of FX006, an extended-release microsphere formulation of 
triamcinolone acetonide, demonstrated safety and efficacy in the relief of pain in patients with 
pain associated with osteoarthritis of the knee. Given the insufficient symptomatic management 
of hip OA patients and similar pathogenesis between knee and hip OA, it is anticipated that 
FX006 will provide similar benefit to these patients.  However, to fully assess the safety, efficacy 
and determine a benefit/risk profile for administration of FX006 to patients with hip OA, the 
procedure for intra-articular administration of FX006 into the hip joint needs to be addressed. 
Thus, the sponsor is proposing a specific study to evaluate the ability of injection procedures to 
achieve successful intra-articular (IA) injection of FX006 into the hip joints of patients with OA 
of the hip.  


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6. 
STUDY OBJECTIVES 
6.1. 
Primary Objective 
To evaluate the ability of injection procedures to achieve successful intra-articular (IA) injection 
of FX006 into the hip joints of patients with OA of the hip 
6.2. 
Secondary Objectives 
The secondary objective of this study is to assess the safety of FX006 administered by IA 
injection in patients with hip OA. 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
This is a prospective, multicenter, single-arm, open-label study to evaluate and confirm 
feasibility of an IA injection procedure of 32 mg FX006 under image guidance in patients with 
hip osteoarthritis (OA). The study will be conducted at up to 6 sites with approximately 22 
patients. If one (1) unsuccessful IA administration is observed, 7 additional patients will be 
enrolled. Eligible subjects will be administered a single IA injection of FX006 on Day 1 and then 
followed for safety for 8 weeks.   
7.2. 
Flow of Study Participation 
The study will involve the following segments: 
• A Screening period of up to 14 days 
• IA administration of FX006 in the index hip on Day 1 
• Follow-up visit on Week 1 (±2 days) 
• Follow-up contact conducted by telephone to monitor AE/SAEs and Con Meds on Week 4 
(±5 days) 
• End-of-Study (EOS) visit on Week 8 (±5 days) 
7.3. 
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. 
At a minimum, additional study staff should consist of: 
Pharmacist/Coordinator  
• Must be a registered pharmacist or an individual with the qualifications and training required 
to handle and prepare study medications.  Can also be the PI or Injector. The responsibilities 
itemized below may be fulfilled by one person or by two different persons. 
• Responsibilities:  
– Receiving and storing investigational product and maintaining accountability records 
– Preparing FX006 for injection  
– Documenting injection procedure activities 
 


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Injector 
• Must be a medical doctor, doctor of osteopathy, or certified physician assistant with 
experience in administering IA injections of the hip using image guidance 
• Is responsible for performing all IA injections of study medication in compliance with the 
standardized protocol injection procedure, using image guidance  
Assessor 
• Must be a medical doctor, doctor of osteopathy, certified physician 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 
Note: The Injector, Assessor, and PI may be the same or different individuals.  
Delegation of responsibilities will be documented at each site and specified in each site’s 
Clinical Site Responsibilities and Signature Log. 
7.4. 
Discussion of Study Design 
7.4.1. 
Rationale for Study Population 
The safety profile of FX006 has been demonstrated to be well-tolerated in over 800 patients with 
knee OA and 45 patients with hip 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. 
7.4.2. 
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 manage 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. 
7.4.3. 
Rationale for Study Parameters 
During clinical trials, FX006, now marketed as Zilretta, was administered without difficulty by 
IA injection into the knee joint to >800 patients with knee OA and demonstrated an acceptable 
safety profile and clear therapeutic effect (see Section 5.2). In two recent studies of patients with 
hip OA, incomplete IA injections of FX006 into the hip joint occurred. A Sponsor-conducted 
investigation identified procedural factors as potentially contributing to these incomplete 
injections in the hip.  Specifically, (a) vertical orientation of the syringe of resuspended FX006; 
and (b) restriction at the outflow from the needle.  Notably, during IA injection into the knee 
joint the FX006 syringe is generally in the horizontal orientation during injection; further, the 
patient positioning routinely used for injection of the knee joint readily relaxes the surrounding 
structures.   


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The approach being investigated in this study addresses these factors by (a) providing tubing as 
an accessory connector that enables the syringe of FX006 to be kept in a horizontal orientation 
during injection and (b) specifies positioning the patient and supporting the leg to minimize 
tension on the hip joint. The goal is to confirm if such procedural changes can result in reliable 
successful clinical IA administration of FX006 in the hip joint. 
7.5. 
Selection of Study Population 
7.5.1. 
Number of Patients 
A maximum number of approximately 30 patients may be enrolled in this protocol.   
Initially, up to 22 patients will be enrolled.   
In the event there is one (1) unsuccessful IA administration of FX006, 7 additional patients may 
be enrolled. 
7.5.2. 
Inclusion Criteria 
To be eligible for this trial, a patient must meet all of the following criteria: 
1. Provides written informed consent prior to initiating any study specific procedures 
2. Is willing and able to comply with the study procedures and visit schedule and to follow 
verbal and written instructions 
3. Is 40 to 80 years of age, inclusive, on the day of consent 
4. Has Body Mass Index (BMI) ≤ 40 kg/m2 
5. Has a documented clinical diagnosis of unilateral or bilateral hip OA for at least six (6) 
months. 
6. Has Kellgren-Lawrence (KL) Grade 2 or 3 in the index hip (i.e., the hip identified by the 
Investigator as appropriate for injection) confirmed by local read of X-ray obtained 
during Screening or ≤ 6 months of Screening visit.  
7. Has clinically significant pain in the index hip (≥ 4 (0-10 NRS scale) at Screening as 
reported by patient  
8. Sexually active males and females of child-bearing potential (defined as neither 
surgically sterile nor post-menopausal, i.e., age >45 years and no menstrual periods for at 
least 1 year) must agree to use, from Screening through 14 weeks post-injection for 
females and through 23 weeks post-injection for males, a highly effective method of 
contraception, defined as one of the following: abstinence; oral, injected or implanted 
hormonal methods of contraception; intrauterine device or intrauterine contraceptive 
system; condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository; sexual intercourse only with man ≥6 months post-
vasectomy.  


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7.5.3. 
Exclusion Criteria 
Patients meeting one or more of the following criteria are excluded from the study:  
1. Has a history of hypersensitivity to triamcinolone acetonide, PLGA or lidocaine.   
2. Is receiving anticoagulants, including warfarin, dabigatran, rivaroxaban, apixaban or low 
molecular weight heparin), ritonavir or cobicistat. (Aspirin for cardio-protection is 
permitted at a maximum dose of 325 mg per day provided the dose has been stable at 
least 3 months prior to Screening.) 
3. Has had any previous surgery on the index hip. 
4. Presence of surgical hardware or other foreign body in the index hip. 
5. Has a history of infection of the index hip. 
6. Has a diagnosis of other disorders in the index hip that can cause pain (e.g. trochanteric 
bursitis, avascular necrosis, pain referred from back). 
7. Has received any intra-articular injection in the index hip of corticosteroids, 
investigational (including FX006) or marketed (including Zilretta®) within the 3 months 
prior to Screening. 
8. Has received intra-articular treatment in the index hip with any of the following agents: 
any biologic agent (e.g., platelet rich plasma (PRP), stem cells, prolotherapy, amniotic 
fluid) or hyaluronic acid within the 6 months prior to Screening.   
9. Has had trauma to the index hip in the past 3 months requiring immobilization. 
10. Has a history or evidence of active or latent systemic fungal or mycobacterial infection 
(including tuberculosis), or of ocular herpes simplex  
11. Has within the past 3 months received corticosteroids by mouth or by parenteral 
injection. Multiple courses or chronic intermittent use of inhaled, intranasal, or topical 
steroids is also exclusionary. Single courses of 14 days or less by those routes are 
permitted 
12. Has received a live vaccine (e.g., MMR, chicken pox, rotavirus) or live- attenuated 
vaccine (e.g., FluMist, Zostavax) within 12 weeks of Day 1.  
13. Has, at screening, a positive test for hepatitis B surface antigen, hepatitis C antibody, HIV 
antibody.  
14. Has, at screening, any abnormal laboratory value(s) that in in the opinion of the Principal 
Investigator (PI) (or other authorized clinical delegate) precludes trial participation.  
15. Has, at screening, or any time prior to day of scheduled injection (Day 1), clinical 
suspicion of local or systemic infection, including any infection in the index leg. 
16. Has a history of or active significant concomitant illness (known or suspected) including, 
but not limited to: 
- 
Inflammatory joint disease, e.g. rheumatoid arthritis, seronegative 
spondyloarthropathy, ankylosing spondylitis, psoriatic arthritis, reactive arthritis, 
inflammatory-bowel disease associated inflammatory arthritis. 


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- 
Systemic inflammatory disease, e.g., polymyalgia rheumatica, systemic lupus 
erythematosus   
- 
Sarcoidosis or amyloidosis 
- 
Cushing’s syndrome 
- 
Malignancy requiring systemic therapy within the past five (5) years (excludes basal 
cell carcinoma or cervical cancer treated only with surgical removal more than one 
(1) year ago.) 
- 
Other autoimmune disease.  
17. Any infection requiring parental antibiotics within 4 weeks of Day 1 or oral antibiotics 
within 2 weeks of Day 1 
18. Has a history or current diagnosis of any other medical illness which in the opinion of the 
local Principal Investigator (PI) (or other authorized clinical delegate) precludes trial 
participation 
19. Is a woman who is pregnant, nursing, lactating, or plans to become pregnant during the 
study 
20. Is a man who plans to conceive during the study 
21. 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.   
7.5.4. 
Removal of Patients from Therapy or Assessments 
Each treated patient receives study medication as a single administration on Day 1.  Therefore, 
subsequent 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: 
• Document in patient’s source their withdrawal of consent and reason for withdrawing from 
the study 
• Assess the patient’s clinical condition and take appropriate therapeutic measures if necessary 
• Attempt to complete the study assessments defined for the Week 8 (EOS) Visit 
• Determine whether the patient is willing to be contacted on a periodic 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 


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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. 
7.5.5. 
Screen Failures 
Minimal data will be collected for patients who fail screening (e.g., demographic information, 
the reason for screen failure).  
Patients that fail to meet eligibility criteria may be re-screened with the approval of the Medical 
Monitor by request through the General Log in the EDC system.  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. 
7.6. 
Treatment Administered 
7.6.1. 
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 administered IA as a single 5 mL 
injection into the index hip OA joint under image guidance per injection procedure. 
7.6.2. 
Identity of Investigational Product 
FX006 is supplied as a sterile, white to off white powder in a single unit dose 5 mL vial with a 
butyl rubber stopper, aluminum seal and plastic cap.  FX006 is reconstituted in diluent 
containing an isotonic, sterile aqueous solution of sodium chloride (NaCl; 0.9% w/w), 
carboxymethylcellulose sodium (CMC; 0.5% w/w) and polysorbate-80 (0.1% w/w) to form a 
suspension prior to IA injection.  Diluent will be supplied as a sterile liquid in a 5 mL vial with a 
butyl rubber stopper, aluminum seal and plastic cap.  FX006 will be reconstituted in 5.0 mL of 
diluent to form a suspension immediately prior to IA injection.  FX006 will be administered as a 
single 5 mL IA injection. 
7.6.3. 
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 in compliance with the 
Pharmacy Binder instructions.  Any temperature excursions should be documented as specified 
in the Pharmacy Binder.  
Dispensing, preparation and administration of investigational products occurs under the 
supervision of the Principal Investigator and in compliance with the Pharmacy Binder. 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. 


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The packaged kits of FX006 will be stored in a secure area and will be stored refrigerated at 2 to 
8 °C.   
7.6.4. 
Packaging and Labeling of Study Medication 
The study medication will be labeled in accordance with local guidelines, as applicable. 
7.6.5. 
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 in compliance with the Pharmacy Binder instructions.  
Return of study medications will be properly documented. 
7.6.6. 
Method of Assigning Patients to Treatment Groups 
Not Applicable (single arm, open-label study). 
7.6.7. 
Blinding 
Not Applicable (single arm, open-label study). 
7.6.8. 
Breaking the Blind 
Not Applicable (single arm, open-label study). 
7.6.9. 
Standardized Procedure of IA Administration of FX006 in the Hip 
Refer to Appendix A. 
7.6.10. 
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. 
7.6.11. 
Treatment Compliance 
Study medication will be administered by the Injector.  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 and refer to 
Pharmacy Binder for instructions. 
7.7. 
Prior and Concomitant Therapy 
7.7.1. 
Prior Therapy 
Exclusionary medications are noted in the Exclusion Criteria. 
Other medications reported at Screening will be recorded as Concomitant Medications and may 
be continued during the study if, in the judgement of the Principal Investigator, usage and the 


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underlying condition have been stable and are expected to remain stable for the duration of the 
study.  
During the study, any changes in prior concomitant medications and the associated reasons for 
the changes will be recorded in source documentation and reported in the eCRF. 
7.7.2. 
Concomitant Therapy Allowed During the Study 
The following medications/non-pharmacological therapies may be taken or used throughout the 
study: 
• Concomitant medication required for the treatment of a treatment-emergent AEs that is 
not listed as restricted. 
7.7.3. 
Prohibited Medications/Non-Pharmacologic Therapies 
Per the exclusion criteria, a patient is not eligible for this study if he/she has received any of the 
indicated treatments within the specified windows detailed in the Exclusion criteria 
(Section 7.5.3 Exclusion Criteria).   
Changes to lifestyle with regard to physical activity, physical therapy, acupuncture, TENS, or 
bracing are prohibited for the first 4 weeks after injection.  
In addition, the following medications should not be taken or used from the time of obtaining 
consent to the End of Study visit: 
• Aspirin (>325 mg per day) 
• Any treatment administered by IA injection in the index hip, including hyaluronic acid, 
plasma, cell therapies, anesthetics through 8 weeks post injection. 
• IV, IM, or oral corticosteroids. Inhaled, intranasal and topical steroids are prohibited from 
Screening through Week 1 visit. 
• 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) through 8 weeks post injection  
7.8. 
Study Variables 
7.8.1. 
Procedure Variables 
• Compliance with standardized procedure for Study Drug Administration 
– Patient position 
– Attempted aspiration of hip joint fluid with documentation of volume, if any, 
collected  
– Total volume administered; inclusive of FX006, contrast dye, if used, and saline  
• Outcome of Standardized Procedure for Study Drug Administration 


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7.8.2. 
Safety Variables 
• Adverse events 
• Vital signs 
• Index hip examinations 
7.9. 
Study Procedures 
7.9.1. 
Schedule of Study Assessments 
A summary of the schedule of assessments is provided in Table 1.  
7.9.2. 
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. 
7.9.3. 
Review of Eligibility, Medical History, Prior Treatment and Medications 
Eligibility criteria (inclusion and exclusion criteria), medical history (including OA history, prior 
trauma, infection), prior treatment and medications are reviewed during Screening and at Day 1. 
OA medical history includes Kellgren-Lawrence (K-L) Grade,  OA diagnosis date (if available), 
presence of OA in other joints, previous IA injections in the index hip or other joints (e.g., 
steroids, PRP, hyaluronic injections, investigational), prior procedures, or surgeries involving the 
index hip. 
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 
Complete physical exam will be conducted at Screening. 


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Any clinically significant findings observed at Screening must be documented in the source and 
added to the medical history; new or worsening findings observed subsequently will be recorded 
as an AE with physical exams conducted by the Investigator as relevant to the adverse event. 
7.9.5. 
Index Hip Assessment 
The index hip assessment will be performed by the Principal Investigator, or designee, at the 
days indicated in Table 1. 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). Clinically 
significant findings will be recorded as detailed for other physical exam observations.   
7.9.6. 
Index Hip X-ray 
A diagnostic quality X-ray of the index hip is required at Screening. A weight-bearing, anterior-
posterior pelvic view with the lower limbs in 10-degree internal rotation is recommended if an 
existing X-ray obtained ≤ 6 months of Screening is not available. 
The Screening X-ray will be read locally for Kellgren-Lawrence (KL) grading.   
Kellgren-Lawrence (KL) 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):iv42:   
• 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 
Patients will be considered radiographically eligible for enrollment in the study if the index hip 
meets criteria for Kellgren-Lawrence Grade 2 or 3. 
7.9.7. 
Vital Signs 
Vital signs are to be taken at the days indicated in Table 1. 
• Blood pressure (taken after sitting at rest for five minutes with feet flat on the floor)  
• Heart rate 
• Oral temperature 
• Weight (with BMI calculated by the EDC system). 
• Height (required for calculation of BMI) will be measured and recorded only at Screening.  
7.9.8. 
Local Clinical Laboratory Evaluations 
Blood samples for clinical laboratory testing as detailed below will be obtained on the visit days 
indicated in Table 1 and analyzed by the local laboratory.  


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If the PI feels that any subsequent clinical laboratory tests are required to evaluate AEs, those 
laboratory tests will be performed locally.  
Table 2: 
Clinical Laboratory Panel 
Clinical Laboratory Panels 
Hematology 
Clinical Chemistry  
Hemoglobin 
Sodium  
Hematocrit  
Potassium  
Erythrocyte count (RBC) 
Bicarbonate  
Mean cell volume (MCV) 
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 Serology1 
Total protein  
Hepatitis B Surface Antigen 
Albumin  
Hepatitis C Antibody 
 
HIV Antibody 
 
Pregnancy Tests (women of childbearing potential only) 
Serum: Screening – submitted to and performed by local laboratory 
Urine: On Day 1 prior to injection using test provided by local laboratory and read at the site 
1. Patients positive for any serology will be excluded and referred to their PCP for further management. 
7.9.9. 
Index Hip Aspiration 
Aspiration of the index hip joint must be attempted prior to injection of contrast and study 
medication at Day 1.  If an effusion is detected, synovial fluid will be withdrawn to near dryness 
prior to injection.  The synovial fluid volume, if any, will be documented prior to discarding. 
7.9.10. 
Study Drug Administration 
FX006 will be prepared in compliance with the Dose Preparation Procedure for FX006 Hip 
Studies located in the Pharmacy Binder.  IA administration to the index hip will be performed 
according to Appendix A. 
7.9.11. 
Review of Adverse Events and Concomitant Medications 
After signing informed consent and at all visits, the patient should be monitored for any AEs by 
the Principal Investigator.  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 7.7 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 the time of informed consent 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 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 
informed consent. 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 Principal 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. 
The Principal 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 Principal 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 Injector will record the details of 
the AE in the patient’s chart and provide a full report of the event to the Principal Investigator, or 
designee. Reporting procedures in the event of any difficulties with preparing or administering 
the study drug are detailed in the Pharmacy Binder.  


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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: 
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 


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• 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. 
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). 
8.4.1. 
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 within 24 hours of becoming aware of the SAE.  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). 
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 Principal Investigator.  All AEs will be documented on 


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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 and the Sponsor will review AE data on an ongoing 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. 
Principal 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. 
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 prior to database 
lock for this 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. 
9.1.1. 
Planned Analyses 
A final analysis will be conducted when all patients have completed 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 and subject data listings.  
Summary tables will present data by injection procedure connector used and by time of 
collection, if applicable.  Continuous variables will be summarized using descriptive statistics, 
specifically the mean, median, standard deviation, minimum and maximum.  Categorical 
variables will be summarized using frequencies and percentages.  Confidence intervals may also 
be provided.  Figures may be used to support the presentation of certain data.   
9.2.1. 
Analysis Populations 
The analysis population planned for this study as follows: 
• Safety Population:  All subjects who received an attempted administration of study drug.   
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. 


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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 
9.2.3.1. 
Primary Endpoint 
Successful study drug administration – defined as Injector reporting complete study drug 
administration. 
9.2.4. 
Sub-Groups and Covariates 
Sub-group analyses per aspiration status, KL grade, gender, etc. may be detailed in the SAP.   
9.3. 
Determination of Sample Size 
9.3.1. 
Sample Size Considerations 
Approximately 22 patients will be treated in this study. If there are no incomplete IA 
administrations, the study may be considered complete. Observing 0 incomplete injections (0%) 
in 22 patients gives 90% confidence that the true incomplete IA injection rate is between 0 and 
10%. If one (1) unsuccessful IA administration of study drug is observed, 7 additional patients 
may be enrolled. Observing 1 incomplete IA injection in 29 patients (3%) gives 80% confidence 
that the true incomplete IA injection rate is between 0 and 10%. 
9.4. 
General Statistical Methods 
9.4.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be listed by study site and subject and will be 
summarized.  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.  
9.4.3. 
Efficacy Analyses 
The rate and 90% CI of successful FX006 administration will calculated all subjects dosed. 
Exploratory analyses may be conducted to aid in determination of root causes of unsuccessful 
injections should any occur.  


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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 informed consent, will be presented.  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 index hip TEAEs. 
Other Safety Analyses 
Laboratory data, vital signs and X-ray KL grade will be presented as descriptive summary 
statistics.  Vital signs and lab data will also be presented as change from Baseline at each 
individual time point. 


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


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11. 
DATA HANDLING AND RECORDKEEPING 
11.1. 
Case Report Forms 
The eCRF will be supplied by the Sponsor or designee and should be handled in accordance with 
the instructions provided.  All study data should initially be documented in source documents 
(e.g., patient charts, notes, laboratory reports, etc.) and then subsequently entered from the source 
into the eCRF.  All eCRFs should be filled out completely by examining personnel or the study 
coordinator.  The eCRF is reviewed, signed, and dated electronically by the Principal 
Investigator. 
11.2. 
Study Medication Accountability 
All study medication required for completion of this study will be provided by the Sponsor or 
designee.  Study medication will be acknowledged upon receipt indicating shipment content and 
condition.  Damaged supplies will be replaced. 
Accurate records of all study medications received by, dispensed from, or returned by the study 
site should be maintained per instructions in the Pharmacy Binder. 
In the event of a temperature excursion, refer to the Pharmacy Binder for instructions. 
In the event of a product complaint, complete the Complaint Notification Form located in the 
Pharmacy binder.  
11.3. 
Confidentiality of Data 
Patient medical information obtained by this study is confidential, and disclosure to third parties 
other than those noted below is prohibited. 
Upon the patient’s permission, medical information may be given to his or her personal 
physician or other appropriate medical personnel responsible for his or her welfare. 
Data generated by this study must be available for inspection by representatives of Competent 
Authorities, the Sponsor or their representative, and the IRB/EC. 
To maintain patient privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the patient by initials where permitted and/or by the assigned 
patient number.  The patient’s confidentiality will be maintained and will not be made publicly 
available to the extent permitted by the applicable laws and regulations. 
11.4. 
Retention of Records 
In accordance with US federal regulations (21 CFR 312.62[c]), the Sponsor requires that records 
and documents pertaining to the conduct of this study and the distribution of study medications, 
including eCRFs, consent forms, laboratory test results, source data, and medical inventory 
records, must be retained by the Principal Investigator for 2 years after marketing application 
approval.  If no application is filed, these records must be kept 2 years after the investigation is 
discontinued and the regulatory authorities are notified.  The Sponsor or their 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 


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retention regulations are more stringent than that specified above, the local regulations will 
prevail. 
11.5. 
Protocol Adherence 
The Principal Investigator must adhere to the protocol as detailed in this document and agrees 
that any changes to the protocol must be approved by the Sponsor or their representative prior to 
seeking approval from the IRB/EC.  When the changes involved are only logistical and 
administrative in nature to trial this may not require prior approval by the IRB/EC.  The Principal 
Investigator will be responsible for enrolling only those patients who have met protocol 
eligibility criteria. 


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


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13. 
REFERENCES 
American Diabetes Association. Diabetes Care 2016 Jan; 39(Supplement 1): S39-S46 
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. 
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. 
Bodick N, Lufkin J, Willwerth C, Kumar A, Bolognese J, Schoonmaker C, Ballal R, Hunter D, 
Clayman, M.  An Intra-Articular, Extended-Release Formulation of Triamcinolone Acetonide 
Prolongs and Amplifies Analgesic Effect in Patients with Osteoarthritis of the Knee, A 
Randomized Clinical Trial. J Bone Joint Surg Am. 2015; 97:877-88. 
Conaghan PG, Cohen SB, Berenbaum F, Lufkin J, Johnson JR, Bodick N. Brief report: a phase 
IIb trial of a novel extended-release microsphere formulation of triamcinolone acetonide for 
intra-articular injection in knee osteoarthritis. Arthritis Rheumatol. 2018a;70(2):204-211.  
Conaghan PG, Hunter DJ, Cohen SB, Kraus VB, Berenbaum F, Lieberman JR, et al. Effects of a 
single intra-articular injection of a microsphere formulation of triamcinolone acetonide on knee 
osteoarthritis pain: a double-blinded, randomized, placebo-controlled, multinational study. J 
Bone Joint Surg Am. 2018b;100(8):666-677.  
Creamer P, Hochberg MC.  Osteoarthritis. Lancet 1997;350(906):503–508. 
Croft P. An Introduction to the Atlas of Standard Radiographs of Arthritis. Rheumatology 2005; 
44(suppl. 4):iv42.  
Goldring SR and Goldring MB.  Clinical aspects, pathology and pathophysiology of 
osteoarthritis. J Musculoskelet Neuronal Interact 2006;6(4):376–378. 
Guy W. ECDEU assessment manual for psychopharmacology (DHEW Publication No. ADM 
76-338). Washington, DC: US Government Printing Office; 1976. 
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.  
Kraus VB, Conaghan PG, Aazami HA, Mehra P, Kivitz AJ, Lufkin J, et al. Synovial and 
systemic pharmacokinetics (PK) of triamcinolone acetonide (TA) following intra-articular (IA) 


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injection of an extended-release microsphere-based formulation (FX006) or standard crystalline 
suspension in patients with knee osteoarthritis (OA). Osteoarthritis Cartilage. 2018;26(1):34-42. 
Kumar VS, Chacko VJ, Jain MV, et al. Intra-articular hip injection: Tips & Pearls. Techniques in 
Orthopedics 2017:32: e5-e7 
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. 
Menge TJ, Boykin RE, Byram IR, Bushnell BD. A Comprehensive Approach to Glenohumeral 
Arthritis. South Med J. 2014;107(9):567-573. 
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. 
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. 
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. 


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14. 
APPENDICES 
APPENDIX A:  PROCEDURE FOR IA HIP INJECTION OF FX006 
 
Materials to be provided by Sponsor for use in the injection procedure 
• Sterile 3.5” 20 gauge spinal needles with stylet (for the IA injection) 
• Sterile mini bore extension tubing set 7 inches (part #: TCBEXT001) 
– Note: Dead space is ≤0.2 mL 
• Study Drug Administration Source Documentation form – to be completed and signed by 
the Injector.  
Materials to be provided by the site for use in the injection procedure 
• Pillow (non-sterile) to support subject's leg during procedure (see details below) 
• Materials for sterile prep and draping of the patient  
• Masks and sterile gloves for the Injector 
• Materials for administration of local skin/subcutaneous tissue anesthetic (if needed) 
• Sterile syringe, empty (for attempting to aspirate joint fluid) 
• Sterile syringe for contrast dye (or air)  
• Fluoroscopy contrast dye (if to be used; alternative air) 
• Sterile syringe for the saline  
• Sterile saline for injection (to flush needle before and after injecting study agent) 
• Sterile 6” 20 gauge spinal needles with stylet (if Injector’s choice for the IA injection) 
Preparation of FX006 
• See detailed instructions in the Pharmacy Binder for preparation of FX006. 
• The syringe with FX006 should be provided to the Injector and used as detailed below. 
Notes applicable to all injection procedures:  
• Local anesthetic should not be mixed with the study drug.  
• In the event of difficulties during the procedure (i.e. needle placement), do not attempt a 
second needle placement  
– Stop the procedure and report the event to the Principal Investigator and to the 
Clinical Team at Flexion 
• In the event of difficulties with study drug administration,  
– Stop the procedure and report the event to the Principal Investigator and to the 
Clinical Team at Flexion 
– Complete the Complaint Notification Form located in the Pharmacy Binder  


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FX006 Injection Procedure  
1. 
 
 
2. 
 
 
 Photo taken from (Kumar 
et al, 2017). 
3. 
  
4. 
 
 
5. 
 
   
6. 
 
 
 
7.  
  
 
 
 
  
 
 
   
 
 
8. 
 
9. 
 
 
 
  
 
 
   
10. 
 
 
11. 
 
 
 
    


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SAP_001.pdf: 
Flexion Therapeutics 
Protocol FX006-2019-017 
SAP, Version 1.0 
18 December 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 FX006-2019-017 
 
 
A Single-arm, Open-label Study to Evaluate a Procedure for Intra-articular (IA) 
Injection of FX006 in Patients with Osteoarthritis (OA) of the Hip 
 
Protocol Number: 
(Version Date) 
FX006-2019-017 
Version 1.0 (28 June 2019) 
Name of Test Drug: 
FX006 
Phase: 
2 
Methodology: 
Single-arm, open-label 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: 
December 18, 2019 
Document Version: 
Version 1.0 
 


Flexion Therapeutics 
Protocol FX006-2019-017 
SAP, Version 1.0 
18 December 2019 
 
CONFIDENTIAL 
SIGNATURE PAGE 
Protocol Title: 
A Single-arm, Open-label Study to Evaluate a 
Procedure for Intra-articular (IA) Injection of FX006 in 
Patients with Osteoarthritis (OA) of the Hip 
Sponsor: 
Flexion Therapeutics 
10 Mall Road, Suite 301 
Burlington, Massachusetts, USA  
Tel:781-305-7777 
Protocol Number: 
FX006-2019-017 
Version 1.0 (28 June 2019) 
Document Title: 
Statistical Analysis Plan, Protocol FX006-2019-017 
Document Date / Version 
18 December 2019 / Final Version 1.0 
Cytel, Inc. Author: 
Laurel Bastone 
Associate Director, Biostatistics 
 
Signature:____________________________________ 
 
Date:________________________________________ 
 
 


Flexion Therapeutics 
Protocol FX006-2019-017 
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18 December 2019 
 
CONFIDENTIAL 
Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein.  I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol, clinical development plan, and all 
applicable regulatory guidances and guidelines. 
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author. 
I also understand that any subsequent changes to the planned statistical analyses, as described 
herein, may have a regulatory impact and/or result in timeline adjustments.  All changes to the 
planned analyses will be described in the clinical study report (CSR). 
Sponsor Signatories: 
 
Amy Cinar, PhD 
Director, Biostatistics 
 
Signature:____________________________________ 
 
Date:________________________________________ 
 
Scott Kelley, MD 
Chief Medical Officer 
 
Signature:____________________________________ 
 
Date:________________________________________ 


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TABLE OF CONTENTS 
                                          Section                                                                       Page 
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS ...................... 9 
1.1. 
Introduction .................................................................................... 9 
1.2. 
Objectives of Statistical Analysis ................................................ 11 
2. 
STUDY DESIGN ...................................................................................... 12 
2.1. 
Synopsis of Study Design ............................................................. 12 
2.2. 
Study Procedures ......................................................................... 12 
2.3. 
Efficacy Endpoints ....................................................................... 13 
2.3.1. 
Primary Efficacy Endpoint .......................................... 13 
3. 
PATIENT POPULATIONS .................................................................... 14 
3.1. 
Population Definitions ................................................................. 14 
4. 
STATISTICAL METHODS ................................................................... 15 
4.1. 
Sample Size Justification ............................................................. 15 
4.2. 
General Statistical Methods and Data Handling ...................... 15 
4.2.1. General Methods .......................................................................... 15 
4.2.2. Computing Environment ............................................................. 15 
4.2.3. Methods of Pooling Data ............................................................. 16 
4.2.4. Adjustments for Covariates ........................................................ 16 
4.2.5. Multiple Comparisons/Multiplicity ............................................ 16 
4.2.6. Subpopulations ............................................................................. 16 
4.2.7. Discontinuations and Loss to Follow-up .................................... 16 
4.2.8. Missing, Unused, and Spurious Data ......................................... 16 
4.2.9. Visit Windows ............................................................................... 16 
4.2.10. Baseline definitions ...................................................................... 17 
4.3. 
Interim Analyses .......................................................................... 17 
4.4. 
Final Analyses ............................................................................... 17 
4.5. 
Patient Disposition ....................................................................... 17 
4.6. 
Protocol Deviations ...................................................................... 17 
4.7. 
Demographic and Baseline Characteristics ............................... 18 
4.7.1. Demographic Characteristics ...................................................... 18 
4.7.2. OA Medical History ..................................................................... 18 


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                                          Section                                                                       Page 
4.7.3. Prior medication ........................................................................... 18 
4.8. 
Study Drug Exposure ................................................................... 19 
4.9. 
Efficacy Evaluation ...................................................................... 19 
4.10. Safety Analyses ............................................................................. 19 
4.10.1. 
Adverse Events .............................................................. 19 
4.10.2. 
Laboratory Data ............................................................ 21 
4.10.3. 
Vital Signs and Physical Examinations ....................... 21 
4.10.4. 
Index Hip Assessment and Aspiration ........................ 21 
4.10.5. 
Index Hip X-Ray ........................................................... 21 
4.10.6. 
Concomitant Medications ............................................ 22 
4.10.7. 
Surgical Procedures ...................................................... 22 
5. 
CHANGES TO PLANNED ANALYSES .............................................. 23 
6. 
References ................................................................................................. 24 
7. 
CLINICAL STUDY REPORT APPENDICES ..................................... 26 
7.1. 
Statistical Tables and Figures to be Generated ......................... 26 
7.2. 
Data Listings to be Generated ..................................................... 27 
7.3. 
Laboratory Unit Conversion Factors ......................................... 29 
7.4.  
Laboratory Normal Ranges ........................................................ 33 
7.5.  
Laboratory Grade Definitions - CTCAE 4.03 ........................... 38 
 
 


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LIST OF IN-TEXT TABLES 
Table 
Page 
Table 1 
Schedule of Study Assessments ...................................................................................... 13 
 


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ABBREVIATIONS 
 
 
Abbreviation 
Definition 
AE 
Adverse Event 
ACR 
American College of Rheumatology 
BMI 
Body Mass Index 
CI 
Confidence Interval 
cm 
Centimeter 
CM 
Concomitant Medications 
CMC 
Carboxymethylcellulose Sodium 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
eCRF 
Electronic Case Report Form 
EOS 
End of Study 
EULAR 
European League Against Rheumatism  
HDL 
High Density Lipoprotein 
HIV 
Human Immunodeficiency Virus 
IA 
Intra-articular 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
JSN 
Joint Space Narrowing 
KL 
Kellgren-Lawrence  
kg 
Kilogram 
LDL 
Low Density Lipoprotein 
LLN 
Lower Limit of Normal 
m 
Meter 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
NaCl 
Sodium Chloride 
OA 
Osteoarthritis 
OARSI 
Osteoarthritis Research Society International 
PDF 
Portable Document Format 
Ph. Eur/USP 
Pharmacopoeia Europaea/ United States Pharmacopeia 
PLGA 
Poly (Lactic-co-Glycolic Acid) 
PT 
Preferred Term 
SAE 
Serious Adverse Event 


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Abbreviation 
Definition 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SP 
Safety Population 
TA
1 
Triamcinolone Acetonide 
TEAE 
Treatment Emergent AE 
ULN 
Upper Limit of Normal 
US 
United States 
WHO 
World Health Organization 
1 Abbreviated in past protocols and documents as TCA 


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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 of America (USA), and OA is the most common joint 
disease, affecting 31 million Americans, with numbers expected to grow as a result of aging, obesity and 
sports injuries (Cisternas et al., 2016). 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. 
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 (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, FX006 has the potential to offer longer duration 
of efficacy and minimized systemic exposure, thus, an improved benefit/risk profile for hip OA patients.  
Intra-articular administration of FX006, an extended-release microsphere formulation of triamcinolone 
acetonide, demonstrated safety and efficacy in the relief of pain in patients with pain associated with OA 
of the knee. Given the insufficient symptomatic management of hip OA patients and similar 
pathogenesis between knee and hip OA, it is anticipated that FX006 will provide similar benefit to these 


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CONFIDENTIAL - 10 - 
patients. However, to fully assess the safety, efficacy and determine a benefit/risk profile for 
administration of FX006 to patients with hip OA, the procedure for IA administration of FX006 into the 
hip joint needs to be addressed. Thus, the sponsor is proposing a specific study to evaluate the ability of 
injection procedures to achieve successful IA injection of FX006 into the hip joints of patients with OA 
of the hip.  
 


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1.2. 
Objectives of Statistical Analysis 
Primary: 
• To evaluate the ability of injection procedures to achieve successful IA injection of FX006 into the hip 
joints of patients with OA of the hip. 
 
Secondary:  
• The secondary objective of this study is to assess the safety of FX006 administered by IA 
injection 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 results sections of the clinical study report 
(CSR) for this trial, as well as be 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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2. 
STUDY DESIGN 
2.1. 
Synopsis of Study Design  
This is a prospective, multicenter, single-arm, open-label study to evaluate and confirm feasibility of an 
IA injection procedure of 32 mg FX006 under image guidance in patients with hip OA. The study will be 
conducted at up to 6 sites with approximately 22 patients. If one (1) unsuccessful IA administration is 
observed, 7 additional patients may be enrolled. Eligible patients will be administered a single IA 
injection of FX006 on Day 1 and then followed for safety for 8 weeks. 
 
 
2.2. 
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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Table 1 
Schedule of Study Assessments  
 
List of Assessments 
Screening1 
Day 1 
Week 1 
Week 4 
Week 8 
Window 
-14 to -1 
– 
±2 days 
±5 days 
±5 days 
Informed consent 
X 
Inclusion/Exclusion Review 
X 
X2 
Medical History/Update 
X 
X2 
Patient Demographics 
X 
OA Medical History 
X 
Prior Treatments and 
Medications 
X 
X2 
Physical examination 
X 
Vital signs 
X 
X2 
X 
X 
Height 
X 
Weight and BMI 
X 
Index Hip Assessment 
X 
X2 
X 
X 
Index Hip X-ray 3 
X 
Hematology, Chemistry4 
X 
HIV, Hep B/C4 
X 
Pregnancy Test5 
X5 
X2,5 
Index Hip Aspiration6 
X 
IP administration7 
X 
AE/SAE & ConMeds8 
X 
X 
X 
X9 
X 
 
1 Screening period is up to 14 days. 
2 To be completed on Day 1 prior to injection procedure 
3 A weight-bearing anterior-posterior view for index hip is recommended. Screening X-ray will be read locally for radiologic findings of 
OA meeting criteria for Kellgren-Lawrence Grade 2-3. 
4 To be performed via local laboratory. 
5 Pregnancy test will be done in women of childbearing potential. Serum Pregnancy Test to be performed at Screening visit by local lab; 
Urine Pregnancy Test to be performed on Day 1 by study site or local lab with result available prior to injection of study medication. 
6 Aspiration must be attempted prior to IP administration. Synovial fluid volume aspirated will be recorded prior to discard. 
7 To be performed under image guidance in compliance with protocol specified procedure. 
8 AE/SAE’s and concomitant medications will be captured from signing of informed consent through EOS visit. 
9 To be conducted via telephone 
2.3. 
Efficacy Endpoints 
 
2.3.1. 
Primary Efficacy Endpoint 
The primary endpoint for this study is successful study drug administration, defined as the Injector 
reporting the complete administration of study drug. 


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3. 
PATIENT POPULATIONS 
3.1. 
Population Definitions 
The following patient populations will be used for presentation and analysis of the data: 
• 
Safety Population: All patients who received an attempted administration of study drug. 


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4. 
STATISTICAL METHODS 
4.1. 
Sample Size Justification 
Approximately 22 patients will be treated in this study. If there are no incomplete IA administrations, the 
study may be considered complete. Observing 0 incomplete injections (0%) in 22 patients gives 90% 
confidence that the true incomplete IA injection rate is between 0 and 10%. If one (1) unsuccessful IA 
administration of study drug is observed, 7 additional patients may be enrolled. Observing 1 incomplete 
IA injection in 29 patients (3%) gives 80% confidence that the true incomplete IA injection rate is 
between 0 and 10%. 
 
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 by a single treatment arm. For categorical variables, summary tabulations of the 
number and percentage within each category (with a category for missing data) of the parameter will be 
presented.  For continuous variables, the number of non-missing values (n), the mean, median, standard 
deviation (SD), minimum and maximum values will be presented. 95% confidence intervals (CI) may be 
provided. Additional statistics may be presented for certain endpoints as described below. 
All collected data for enrolled patients will be presented in by-patient listings sorted by 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. 
 
4.2.2. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS® statistical software (Version 9.4 or 
higher), unless otherwise noted. 
Adverse Events (AEs) will be coding using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 22.0 (or higher).  
Concomitant medications will be coded using World Health Organization (WHO) Drug Dictionary (DD) 
(Version March 1, 2019 or Higher).  
 


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4.2.3. 
Methods of Pooling Data 
Not applicable to the present study. 
 
4.2.4. 
Adjustments for Covariates 
Not applicable to the present study. 
 
4.2.5. 
Multiple Comparisons/Multiplicity 
As all analyses are exploratory in nature, there will be no controls for multiplicity. 
 
4.2.6. 
Subpopulations 
Analysis of the primary endpoint would be carried out for subgroups defined by aspiration status, KL 
grade at baseline, and gender. 
 
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. 
  
4.2.8. 
Missing, Unused, and Spurious Data 
Missing values will not be imputed and data will be analyzed “as observed”. 
 
4.2.9. 
Visit Windows 
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 Electronic Case Report Form (eCRF). 
 


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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 this study. 
 
4.4. 
Final Analyses 
The analyses of study data will be performed in an unblinded manner when all patients have completed, 
withdrawn or discontinued from 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.   
 
4.5. 
Patient Disposition 
Patient disposition will be tabulated and include the total number of patients enrolled, treated, 
completed and early terminated, reason for early termination and the number in each patient 
population.   
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 the Safety Population. 
 
4.6. 
Protocol Deviations 
The number and percentage of patients with at least one protocol deviation will be summarized for the 
Safety Population. Additionally, incidence by type of deviation will be presented in the following 
categories: inclusion criteria not met, exclusion criteria met, informed consent form (ICF) related, visit 
out of window, study drug administration, missed visit, missed assessment / procedure, assessment out of 
window, prohibited medication taken, incorrect assessment sequence / timing, incorrect delegation, 
documentation issue, and other.  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.  
 


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4.7. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be listed by study site and patient and will be summarized. 
Frequencies and proportions will be presented for the categorical variables and descriptive statistics will 
be presented for continuous variables. 
 
4.7.1. 
Demographic Characteristics 
The following Baseline parameters will be summarized for the Safety Population: 
• 
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); 
• 
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.  
 
4.7.2. 
OA Medical History 
OA history and index hip characteristics as collected on the eCRF 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 4.10.6 for details on defining prior and 
concomitant medications). 


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4.8. 
Study Drug Exposure  
Details of study drug administration will be summarized for the SP.  
Descriptive statistics summarizing the index hip injected, approach for injection, needle size used, 
numbing agent used, use of fluoroscopy guidance, use of contrast dye or air used to confirm IA 
placement, total prepared volume, volume injected in the hip joint, air volume injected into hip joint, 
positioning of patient and index leg/hip, index leg rotation, degrees of rotation, use of connector for 
FX006 injection, and horizontal positioning of syringe during injection with FX006 will be presented in 
a summary table. 
All study drug exposure data will be presented in a data listing. 
 
4.9. 
Efficacy Evaluation 
All efficacy analyses will be conducted using the SP.  The rate and 90% CI of successful FX006 
administration will calculated using all patients dosed, using methodology for estimation of a binomial 
proportion.  Confidence intervals will be calculated via the score method, including a continuity 
correction. 
Exploratory analyses may be conducted to aid in determination of root causes of unsuccessful injections, 
should any occur. 
In addition to the analyses described above, subgroup analyses will be performed for subgroups defined 
by aspiration status, KL grade at baseline, and gender. 
 
4.10. 
Safety Analyses 
Safety analyses will be conducted using the SP.   
 
4.10.1. 
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: 


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


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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. 
 
4.10.2. 
Laboratory Data 
The Baseline (Screening) values will be summarized for each hematology and clinical chemistry 
laboratory parameter.  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. 
 
4.10.3. 
Vital Signs and Physical Examinations 
The observed value and change from Baseline at Week 1 and Week 8 for vital sign data will be 
summarized in a summary table. Vital sign measurements include blood pressure, heart rate, oral 
temperature, and weight, and BMI. Vital sign measurements will be presented for each patient in a data 
listing. 
All physical examination results will be presented in a data listing. 
 
4.10.4. 
Index Hip Assessment and Aspiration 
The index hip will be assessed for evidence of inflammation, including 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). Clinically significant 
findings will be summarized. Index hip assessment data will be presented in a data listing.  
Aspiration of the index hip joint must be attempted prior to injection of contrast and study medication at 
Day 1. The synovial fluid volume, if any, will be measured.  Data regarding protocol-required aspiration 
that is performed at the time of injection in will be included in the summary table and listing for Study 
Drug Exposure.  Additional aspirations, not required per protocol, will be presented in a separate 
aspiration listing. 
 
4.10.5. 
Index Hip X-Ray 
Index hip X-rays are performed at Screening.  The Screening X-ray will be read locally for Kellgren-
Lawrence (KL) grading. KL grading at baseline will be summarized, based on the following grades: 


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• 
Grade 0: Normal appearance. 
• 
Grade 1: Possible osteophytes, possible Joint Space Narrowing (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 
A patient listing of index hip X-ray will also be presented. 
 
4.10.6. 
Concomitant Medications 
Concomitant medications (CM) 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 CMs 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. 
 
4.10.7. 
Surgical Procedures 
Surgical procedures that occurred during the study will be provided in a data listing. 
 


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5. 
CHANGES TO PLANNED ANALYSES 
 
There are no major changes to the planned analyses. 
 
 


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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.  
 
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. 
 
Goldring SR and Goldring MB. Clinical aspects, pathology and pathophysiology of osteoarthritis. J 
Musculoskelet Neuronal Interact 2006;6(4):376–378. 
 
Guy W. ECDEU assessment manual for psychopharmacology (DHEW Publication No. ADM 76-338). 
Washington, DC: US Government Printing Office; 1976. 
 
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.  
 
Menge TJ, Boykin RE, Byram IR, Bushnell BD. A Comprehensive Approach to Glenohumeral Arthritis. 
South Med J. 2014;107(9):567-573.  
 


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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.  
 
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.  
 
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. 


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7. 
CLINICAL STUDY REPORT APPENDICES 
7.1. 
Statistical Tables and Figures to be Generated 
Table 14.1.1 
Patient Enrollment and Disposition (All Patients) 
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 Protocol Deviations (Safety Population) 
Table 14.1.5 
Study Drug Exposure Summary (Safety Population) 
Table 14.2.1.1 
Summary of Successful FX006 Administration (Safety Population) 
Table 14.2.1.2 
Summary of Successful FX006 Administration by Aspiration Status 
(Safety Population) 
Table 14.2.1.3 
Summary of Successful FX006 Administration by KL Grade at Baseline 
(Safety Population) 
Table 14.2.1.4 
Summary of Successful FX006 Administration by Gender (Safety 
Population) 
Table 14.3.1.1 
Summary of Treatment-Emergent Adverse Events (Safety Population) 
Table 14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.1.3 
Treatment-Emergent Adverse Events by 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) 


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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 (All Patients) 
Table 14.3.2.2 
Patient Listing of Serious Adverse Events (All Patients) 
Table 14.3.2.3 
Patient Listing of Discontinuations Due to Adverse Events (All Patients) 
Table 14.4.1.1 
Summary of Hematology Parameters at Baseline (Safety Population) 
Table 14.4.1.2 
Summary of Chemistry Parameters at Baseline (Safety Population) 
Table 14.4.1.3 
Summary and Change from Baseline for Vital Signs (Safety Population) 
Table 14.4.2.1 
Summary of Index Hip Assessments (Safety Population) 
Table 14.4.2.2 
Summary of Index Hip Aspiration (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 16.2.4.2 
Medical History 
Listing 16.2.4.3 
Medical History - Hip Osteoarthritis 


Flexion Therapeutics 
Protocol FX006-2019-017 
SAP, Version 1.0 
18 December 2019 
 
CONFIDENTIAL - 28 - 
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 
Study Drug Exposure 
Listing 16.2.6.1.1 
Efficacy Listing 
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, 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 Assessment Results 
Listing 16.2.9.4 
Index Hip Aspiration Results 
Listing 16.2.9.5 
Index Hip X-Ray Results 
Listing 16.2.9.6 
Prior and Concomitant Medications 
Listing 16.2.9.7 
Surgical Procedures 
 


Flexion Therapeutics 
Protocol FX006-2019-017 
SAP, Version 1.0 
18 December 2019 
 
CONFIDENTIAL - 29 - 
7.3. 
Laboratory Unit Conversion Factors 
Laboratory Parameter 
Original Unit 
Conversion Factor 
SI Units 
Alanine Aminotransferase 
IU/L 
x 1 
U/l 
Albumin 
g/dl 
x  10 
g/l 
Albumin 
mg/dl 
x 1/100 
g/l 
Albumin 
umol/l 
x 0.069 
g/l 
Alkaline Phosphatase 
mcKat/l 
x 1/0.01667 
U/l 
Alkaline Phosphatase 
umol/l 
x 1/0.01668 
U/l 
Alkaline Phosphatase 
mU/ml 
x 1 
U/l 
Alkaline Phosphatase 
nKat/l 
x 1/16.67 
U/l 
Alkaline Phosphatase 
nmol/dl 
x 1/1.667 
U/l 
Alkaline Phosphatase 
IU/l 
x 1 
U/l 
Alkaline Phosphatase 
UI/l 
x 1 
U/l 
Alpha-foetoprotein 
ng/ml 
x 1 
mcg/l 
Arginine test 
mg/dl 
x 57.4 
umol/l 
Aspartate Aminotransferase 
IU/L 
x 1 
U/l 
Basophils 
/mm^3 
x 1/1000 
10^9/l 
Basophils 
10^3/micrl 
x 1 
10^9/l 
Basophils 
10^3/ml 
x 1/1000 
10^9/l 
Basophils 
10^3/mmc 
x 1 
10^9/l 
Basophils 
10^3/mm^3 
x 1 
10^9/l 
Basophils 
10^6/ml 
x 1 
10^9/l 
Bicarbonate 
mEq/l 
x 1 
mmol/l 
Bilirubin (total) 
mg/dl 
x 1/0.0584671 
umol/l 
Bilirubin (total) 
mg/l 
x 1/0.584671 
umol/l 
Bilirubin (total) 
umol/l 
x 1 
umol/l 
BUN 
mg/dl 
x 0.357 
mmol/l 
Calcium (II) 
meq/l 
x 0.5 
mmol/l 
Calcium (II) 
mg/dl 
x 1/4.008 
mmol/l 
Calcium (II) 
mg/l 
x 1/40.08 
mmol/l 
CEA 
ng/ml 
x 1 
mcg/l 
Ceruloplasmin 
mg/dl 
 x 10 
mg/l 
Chloride 
mEq/l 
x 1 
mmol/l 
Cholesterol (total) 
mg/dl 
x 1/38.67 
mmol/l 
Chorionic Gonadotrophin 
mIU/ml 
x 1 
IU/l 
Copper (serum) 
mcg/dl 
x 0.1574 
umol/l 
Creatine kinase 
mcKat/l 
x 1/0.017 
U/l 
Creatinine 
mg/dl 
x 1/0.0113119 
umol/l 
Creatinine 
mg/l 
x 1/0.113119 
umol/l 
Creatinine 
micrmol/l 
x 1 
umol/l 
DHEA 
mcg/l 
x 3.467 
nmol/l 
DHEA-S 
mcg/dl 
x 0.027 
umol/l 
DHEA-S 
umol/l 
x 1/0.027 
umol/l 
Eosinophils 
/mm^3 
x 1/1000 
10^9/l 
Eosinophils 
10^3/micrl 
x 1 
10^9/l 
Eosinophils 
10^3/ml 
x 1/1000 
10^9/l 
Eosinophils 
10^3/mmc 
x 1 
10^9/l 
Eosinophils 
10^3/mm^3 
x 1 
10^9/l 
Eosinophils 
10^6/ml 
x 1 
10^9/l 
Estradiol (female) 
pg/ml 
x 1/0.2724 
pmol/l 
Ferritin 
ng/ml 
x 1 
mcg/l 
Fibrinogen 
g/dl 
x 29.41 
umol/l 
FSH (female) 
mIU/ml 
x 1 
IU/l 
GGT 
U/l 
x 1 
IU/l 
GGT 
UI/l 
x 1 
IU/l 
GGT 
mckat/l 
x 1/0.017 
IU/l 
GH 
ng/ML 
x 1 
mcg/l 
Glucose 
mg/% 
x 1/18.0157 
mmol/l 
Glucose 
g/l 
x 1/0.180157 
mmol/l 


Flexion Therapeutics 
Protocol FX006-2019-017 
SAP, Version 1.0 
18 December 2019 
 
CONFIDENTIAL - 30 - 
Glucose 
mg/dl 
x 1/18.0157 
mmol/l 
HBA1C 
% total HB 
x 100 
% 
HBA1C 
% 
x 1/100 
fract of 1 
HDL 
mg/dl 
x 0.0259 
mmol/l 
Haematocrit 
% 
x 0.01 
Vol. Fract. 
Haemoglobin 
g/100 ml 
x 10 
g/l 
Haemoglobin 
g/dl 
x 10 
g/l 
Haemoglobin 
mmol/l 
x 16.1145 
g/l 
IGF-I 
ng/ml 
x 1 
mcg/l 
Insulin 
mcg/l 
x 1/0.00580765 
pmol/l 
Insulin 
mU/l 
x 7.175 
pmol/l 
Insulin 
mcU/ml 
x 7.175 
pmol/l 
Iron (III) 
mcg/dl 
x 1/5.5847 
umol/l 
LDH 
mckat/l 
x 1/0.01666 
IU/l 
LDH 
umol/l*s 
x 1/0.01667 
IU/l 
LDH 
mmol/l 
x 1/16.67 
IU/l 
LDH 
mmol/l*s 
x 1/16.67 
IU/l 
LDH 
mymol/l*s 
x 1/0.01667 
IU/l 
LDH 
nkat/l 
x 1/16.67 
IU/l 
LDL 
mg/dl 
x 0.0259 
mmol/l 
LH (female) 
mIU/ml 
x 1 
IU/l 
Lymphocytes 
/mm^3 
x 1/1000 
10^9/l 
Lymphocytes 
10^3/micrl 
x 1 
10^9/l 
Lymphocytes 
10^3/ml 
x 1/1000 
10^9/l 
Lymphocytes 
10^3/mmc 
x 1 
10^9/l 
Lymphocytes 
10^3/mm^3 
x 1 
10^9/l 
Lymphocytes 
10^6/ml 
x 1 
10^9/l 
Magnesium (II) 
mEq/l 
x 0.5 
mmol/l 
Magnesium (II) 
mg/dl 
x 1/2.4305 
mmol/l 
Mean cell volume 
mcm^3 
x 1 
fL 
Mean cell volume 
micrmc 
x 1 
fL 
Mean cell volume 
micrm^3 
x 1 
fL 
Mean cell volume 
10^-15/l 
x 1 
fL 
Mean cell Hb 
pg/cell 
x 1 
pg/cell 
Mean cell Hb conc. 
% 
x 10 
g/l 
Mean cell Hb conc. 
g/100 ml 
x 10 
g/l 
Mean cell Hb conc. 
g/dl 
x 10 
g/l 
Monocytes 
/mm^3 
x 1/1000 
10^9/l 
Monocytes 
10^3/micrl 
x 1 
10^9/l 
Monocytes 
10^3/ml 
x 1/1000 
10^9/l 
Monocytes 
10^3/mmc 
x 1 
10^9/l 
Monocytes 
10^3/mm^3 
x 1 
10^9/l 
Monocytes 
10^6/ml 
x 1 
10^9/l 
Neutrophils 
/mm^3 
x 1/1000 
10^9/l 
Neutrophils 
10^3/micrl 
x 1 
10^9/l 
Neutrophils 
10^3/ml 
x 1/1000 
10^9/l 
Neutrophils 
10^3/mmc 
x 1 
10^9/l 
Neutrophils 
10^3/mm^3 
x 1 
10^9/l 
Neutrophils 
10^6/ml 
x 1 
10^9/l 
Packed cell volume 
l/l 
x 100 
% 
Phosphate 
mg/dl 
x 1/3.09737 
mmol/l 
Phosphate 
mg/l 
x 1/30.9737 
mmol/l 
Phosphate 
mEq/dl 
x 5 
mmol/l 
Phosphate 
mEq/l 
x 0.5 
mmol/l 
Platelets 
/mcl 
x 1/1000 
10^9/l 
Platelets 
/mm^3 
x 1/1000 
10^9/l 
Platelets 
/nl 
x 1 
10^9/l 
Platelets 
/pl 
x 1000 
10^9/l 
Platelets 
10^12/l 
x 1/1000 
10^9/l 
Platelets 
10^3/mcl 
x 1 
10^9/l 


Flexion Therapeutics 
Protocol FX006-2019-017 
SAP, Version 1.0 
18 December 2019 
 
CONFIDENTIAL - 31 - 
Platelets 
10^3/ml 
x 1/1000 
10^9/l 
Platelets 
10^3/mm^3 
x 1 
10^9/l 
Platelets 
10^3/ul 
x 1 
10^9/l 
Platelets 
k/mcl 
x 1 
10^9/l 
Platelets 
10^3/micrl 
x 1 
10^9/l 
Platelets 
10^3/mmc 
x 1 
10^9/l 
Platelets 
10^6/ml 
x 1 
10^9/l 
Potassium ion (K) 
mEq/l 
x 1 
mmol/l 
Potassium ion (K) 
mg/l 
x 1/39.098 
mmol/l 
Prolactin 
ng/ml 
x 1 
mcg/l 
Protein (Total) 
g/dl 
x 10 
g/l 
Protein (Total) 
mg/dl 
x 0.01 
g/l 
Prothrombin 
% 
x 1/100 
Fract of 1 
PT 
seconds 
x 1 
seconds 
PTT 
seconds 
x 1 
seconds 
RBC 
/mcl 
x 1/1000 
10^12/l 
RBC 
/pl 
x 1 
10^12/l 
RBC 
10^6/mcl 
x 1 
10^12/l 
RBC 
/nl 
x 1000 
10^12/l 
RBC 
10^6/mm3 
x 1 
10^12/l 
RBC 
10^9/l 
x 1000 
10^12/l 
RBC 
T/L 
x 1 
10^12/l 
RBC 
10^6/micrl 
x 1 
10^12/l 
RBC 
10^3/ml 
x 1000000 
10^12/l 
RBC 
10^6/mmc 
x 1 
10^12/l 
RBC 
10^6/mm^3 
x 1 
10^12/l 
SGOT (AST) 
mckat/l 
x 1/0.01667 
IU/l 
SGOT (AST) 
umol/l*s 
x 1/0.01668 
IU/l 
SGOT (AST) 
mmol/l 
x 1/16.67 
IU/l 
SGOT (AST) 
mmol/l*s 
x 1/16.67 
IU/l 
SGOT (AST) 
nkat/l 
x 1/16.67 
IU/l 
SGOT (AST) 
U/l 
x 1 
IU/l 
SGOT (AST) 
UI/l 
x 1 
IU/l 
SGPT (ALT) 
U/l 
x 1 
IU/l 
SGPT (ALT) 
UI/l 
x 1 
IU/l 
Sodium ion (Na) 
mEq/l 
x 1 
mmol/l 
Sodium ion (Na) 
mg/dl 
x 1/2.29898 
mmol/l 
Sodium ion (Na) 
g/l 
x 1/0.0229898 
mmol/l 
TBG 
mcg/dl 
x 12.87 
nmol/l 
Thyroxin (T4) 
mcg/dl 
x 1/0.0776874 
nmol/l 
Thyroxin (T4) 
mcg/l 
x 1/0.776874 
nmol/l 
Thyroxin free (fT4) 
ng/dl 
x 1/0.0776874 
pmol/l 
Transferrin 
mg/dl 
x 1/100 
g/l 
Triglycerides 
mg/dl 
x 1/88.5445 
mmol/l 
Triglycerides 
g/l 
x 1/0.885445 
mmol/l 
Triiodothyronine (T3) 
ng/dl 
x 1/65.0976 
nmol/l 
Triiodothyronine free (fT3) 
pg/dl 
'x 1/65.0976 
pmol/l 
Triiodothyronine Uptake 
% 
x 1/100 
fract of 1 
TSH (thyrotropin) 
mcU/ml 
1 
mU/l 
TT 
seconds 
x 1 
seconds 
Urea 
mg/dl 
x 1/6.00554 
mmol/l 
Urea 
mg/l 
x 1/60.0554 
mmol/l 
Urea 
g/l 
x 1/0.0600554 
mmol/l 
Uric acid 
mg/dl 
x 59.4800 
umol/l 
Uric acid 
mg/l 
x 5.9480 
umol/l 
Uric acid 
umol/l 
x 1 
umol/l 
WBC 
10^3/micrl 
x 1/1000 
10^9/l 
WBC 
/mm^3 
x 1/1000 
10^9/l 
WBC 
/pl 
x 1000 
10^9/l 
WBC 
10^3/ml 
x 1/1000 
10^9/l 


Flexion Therapeutics 
Protocol FX006-2019-017 
SAP, Version 1.0 
18 December 2019 
 
CONFIDENTIAL - 32 - 
WBC 
10^3/mcl 
x 1 
10^9/l 
WBC 
x 10^3/mm^3 
x 1 
10^9/l 
WBC 
/mcl 
x 1/1000 
10^9/l 
WBC 
10^3/mmc 
x 1 
10^9/l 
WBC 
10^6/ml 
x 1 
10^9/l 
 
 
 


Flexion Therapeutics 
Protocol FX006-2019-017 
SAP, Version 1.0 
18 December 2019 
 
CONFIDENTIAL - 33 - 
 
7.4.  Laboratory Normal Ranges  
Site 033: 
Lab Panel 
Analyte 
Male - LO 
Male - HI 
Female - LO 
Female - HI 
Units 
Chemistry 
Sodium 
133 
145 
133 
145 
mmol/L 
Chemistry 
Potassium 
3.6 
5.5 
3.6 
5.5 
mmol/L 
Chemistry 
Bicarbonate 
21 
31 
21 
31 
meq/mL 
Chemistry 
Chloride 
96 
110 
96 
110 
mmol/L 
Chemistry 
Calcium 
8.5 
10.4 
8.5 
10.4 
mg/dL 
Chemistry 
Total Bilirubin 
0.1 
1.5 
0.1 
1.5 
mg/dL 
Chemistry 
Alkaline Phosphatase 
39 
117 
39 
117 
U/L 
Chemistry 
Alanine Aminotransferase 
0 
40 
0 
40 
U/L 
Chemistry 
Aspartate Aminotransferase 
0 
37 
0 
37 
U/L 
Chemistry 
Blood Urea Nitrogen 
6 
19 
6 
19 
mg/dL 
Chemistry 
Creatinine 
0.5 
1.2 
0.5 
1.2 
mg/dL 
Chemistry 
Uric Acid 
3.4 
7 
3.4 
7 
mg/dL 
Chemistry 
Glucose 
65 
99 
65 
99 
mg/dL 
Chemistry 
Total Protein 
5.9 
8.4 
5.9 
8.4 
g/dL 
Chemistry 
Albumin 
3.2 
5.1 
3.2 
5.1 
g/dL 
Hematology 
Hemoglobin 
14 
18 
12 
16 
g/dL 
Hematology 
Hematocrit 
42 
52 
37 
47 
% 
Hematology 
Erythrocytes count 
4.7 
6.1 
4.2 
5.4 
x 106 / μl 
Hematology 
Mean Cell Volume 
80 
94 
81 
99 
fL 
Hematology 
Leukocytes 
4.8 
10.8 
4.8 
10.8 
x 103 / μl 
Hematology 
Neutrophils 
40 
70 
40 
70 
% 
Hematology 
Lymphocytes 
17 
45 
17 
45 
% 
Hematology 
Monocytes 
0 
12 
0 
12 
% 
Hematology 
Eosinophils 
0 
9 
0 
9 
% 
Hematology 
Basophils 
0 
3 
0 
3 
 
Hematology 
Platelets 
150 
400 
150 
400 
x 103 / μl 
 
 
 


Flexion Therapeutics 
Protocol FX006-2019-017 
SAP, Version 1.0 
18 December 2019 
 
CONFIDENTIAL - 34 - 
Site 053: 
Lab Panel 
Analyte 
Male - LO 
Male - HI 
Female - LO 
Female - HI 
Units 
Chemistry 
Sodium 
136 
145 
136 
145 
mmol/L 
Chemistry 
Potassium 
3.5 
5.2 
3.5 
5.2 
mmol/L 
Chemistry 
Bicarbonate 
21 
32 
21 
32 
mmol/L 
Chemistry 
Chloride 
98 
109 
98 
109 
mmol/L 
Chemistry 
Calcium 
8.8 
10.6 
8.8 
10.6 
mg/dL 
Chemistry 
Total Bilirubin 
0.3 
1 
0.3 
1 
mg/dL 
Chemistry 
Alkaline Phosphatase 
33 
125 
33 
125 
U/L 
Chemistry 
Alanine Aminotransferase 
7 
52 
7 
52 
U/L 
Chemistry 
Aspartate Aminotransferase 
13 
39 
13 
39 
U/L 
Chemistry 
Blood Urea Nitrogen 
7 
25 
7 
25 
mg/dL 
Chemistry 
Creatinine 
0.6 
1.3 
0.6 
1.3 
mg/dL 
Chemistry 
Uric Acid 
4.4 
7.6 
2.3 
6.6 
mg/dL 
Chemistry 
Glucose 
65 
99 
65 
99 
mg/dL 
Chemistry 
Total Protein 
6.4 
8.9 
6.4 
8.9 
g/dL 
Chemistry 
Albumin 
3.5 
5.7 
3.5 
5.7 
g/dL 
Hematology 
Hemoglobin 
13.7 
17.5 
11.2 
15.7 
g/dL 
Hematology 
Hematocrit 
40.1 
51 
34.1 
44.9 
% 
Hematology 
Erythrocytes count 
4.63 
6.08 
3.93 
5.22 
x 106 / μl 
Hematology 
Mean Cell Volume 
79 
92.2 
79.4 
94.8 
fL 
Hematology 
Leukocytes 
4.23 
9.07 
3.98 
10.04 
x 103 / μl 
Hematology 
Neutrophils 
1780 
5380 
1560 
6130 
Cell/Cmm 
Hematology 
Lymphocytes 
1.32 
3.57 
1.18 
3.74 
x 103 / μl 
Hematology 
Monocytes 
0.3 
0.82 
0.24 
0.86 
x 103 / μl 
Hematology 
Eosinophils 
0.04 
0.54 
0.04 
0.36 
x 103 / μl 
Hematology 
Basophils 
0.01 
0.08 
0.01 
0.08 
x 103 / μl 
Hematology 
Platelets 
163 
337 
182 
369 
x 103 / μl 
 
 
 


Flexion Therapeutics 
Protocol FX006-2019-017 
SAP, Version 1.0 
18 December 2019 
 
CONFIDENTIAL - 35 - 
Site 309: 
Lab Panel 
Analyte 
Male - LO 
Male - HI 
Female - LO 
Female - HI 
Units 
Chemistry 
Sodium 
136 
145 
136 
145 
mmol/L 
Chemistry 
Potassium 
3.4 
5 
3.4 
5 
mmol/L 
Chemistry 
Bicarbonate 
20 
31 
20 
31 
mmol/L 
Chemistry 
Chloride 
98 
108 
98 
108 
mmol/L 
Chemistry 
Calcium 
8.4 
10.2 
8.4 
10.2 
mg/dL 
Chemistry 
Total Bilirubin 
0 
1.2 
0 
1.2 
mg/dL 
Chemistry 
Alkaline Phosphatase 
35 
129 
35 
129 
U/L 
Chemistry 
Alanine Aminotransferase 
21 
72 
9 
52 
U/L 
Chemistry 
Aspartate Aminotransferase 
0 
40 
0 
34 
U/L 
Chemistry 
Blood Urea Nitrogen (17-60 years) 
5 
22 
5 
22 
mg/dL 
Chemistry 
Blood Urea Nitrogen (>60 years) 
5 
25 
5 
25 
mg/dL 
Chemistry 
Creatinine 
0.5 
1.3 
0.5 
1.3 
mg/dL 
Chemistry 
Uric Acid 
3.4 
8 
2.4 
7 
mg/dL 
Chemistry 
Glucose 
70 
109 
70 
109 
mg/dL 
Chemistry 
Total Protein 
6.6 
8.7 
6.6 
8.7 
g/dL 
Chemistry 
Albumin 
3.5 
5.7 
3.5 
5.7 
g/dL 
Hematology 
Hemoglobin 
14 
17.5 
13 
16 
g/dL 
Hematology 
Hematocrit 
38 
52 
35 
47 
% 
Hematology 
Erythrocytes count 
4.5 
6 
4 
5.2 
x 106 / μl 
Hematology 
Mean Cell Volume 
80 
100 
80 
100 
fL 
Hematology 
Leukocytes 
4.5 
11 
4.5 
11 
x 103 / μl 
Hematology 
Neutrophils 
44 
77 
44 
77 
% 
Hematology 
Lymphocytes 
16 
44 
16 
44 
% 
Hematology 
Monocytes 
5 
13 
5 
13 
% 
Hematology 
Eosinophils 
0 
8 
0 
8 
% 
Hematology 
Basophils 
0 
3 
0 
3 
% 
Hematology 
Platelets 
140 
400 
140 
400 
x 103 / mcl 
 
 
 


Flexion Therapeutics 
Protocol FX006-2019-017 
SAP, Version 1.0 
18 December 2019 
 
CONFIDENTIAL - 36 - 
Site 326: 
Lab Panel 
Analyte 
Male - LO 
Male - HI 
Female - LO 
Female - HI 
Units 
Chemistry 
Sodium 
135 
145 
135 
145 
mmol/L 
Chemistry 
Potassium 
3.5 
5.3 
3.5 
5.3 
mmol/L 
Chemistry 
Bicarbonate 
22 
31 
22 
31 
mmol/L 
Chemistry 
Chloride 
96 
108 
96 
108 
mmol/L 
Chemistry 
Calcium 
8.5 
10.5 
8.5 
10.5 
mg/dL 
Chemistry 
Total Bilirubin 
0.2 
1 
0.2 
1 
mg/dL 
Chemistry 
Alkaline Phosphatase 
45 
117 
45 
117 
U/L 
Chemistry 
Alanine Aminotransferase 
12 
42 
12 
42 
U/L 
Chemistry 
Aspartate Aminotransferase 
15 
37 
15 
37 
U/L 
Chemistry 
Blood Urea Nitrogen 
7 
23 
7 
23 
mg/dL 
Chemistry 
Creatinine 
0.5 
1.3 
0.5 
1.3 
mg/dL 
Chemistry 
Uric Acid 
3.5 
7.2 
2.6 
6 
mg/dL 
Chemistry 
Glucose 
70 
99 
70 
99 
mg/dL 
Chemistry 
Total Protein 
6.4 
8.2 
6.4 
8.2 
g/dL 
Chemistry 
Albumin 
3.4 
5 
3.4 
5 
g/dL 
Hematology 
Hemoglobin 
13 
17 
11.5 
15.5 
g/dL 
Hematology 
Hematocrit 
39 
50 
34.5 
45 
% 
Hematology 
Erythrocytes count 
4.2 
5.8 
3.8 
5.2 
M/uL 
Hematology 
Mean Cell Volume 
80 
100 
80 
100 
fL 
Hematology 
Leukocytes 
3.8 
10.5 
3.8 
10.5 
K/uL 
Hematology 
Neutrophils 
43 
77 
43 
77 
% 
Hematology 
Lymphocytes 
13 
44 
13 
44 
% 
Hematology 
Monocytes 
2 
14 
2 
14 
% 
Hematology 
Eosinophils 
0 
6 
0 
6 
% 
Hematology 
Basophils 
0 
2 
0 
2 
% 
Hematology 
Platelets 
150 
400 
150 
400 
K/uL 
 
 
 


Flexion Therapeutics 
Protocol FX006-2019-017 
SAP, Version 1.0 
18 December 2019 
 
CONFIDENTIAL - 37 - 
Site 330: 
Lab Panel 
Analyte 
Male - LO 
Male - HI 
Female - LO 
Female - HI 
Units 
Chemistry 
Sodium 
134 
147 
134 
147 
mmol/L 
Chemistry 
Potassium 
3.6 
5.3 
3.6 
5.3 
mmol/L 
Chemistry 
Bicarbonate 
19 
31 
19 
31 
mmol/L 
Chemistry 
Chloride 
95 
108 
95 
108 
mmol/L 
Chemistry 
Calcium 
8.8 
10.4 
8.8 
10.4 
mg/dL 
Chemistry 
Total Bilirubin 
0.2 
1.3 
0.2 
1.3 
mg/dL 
Chemistry 
Alkaline Phosphatase 
40 
140 
37 
127 
U/L 
Chemistry 
Alkaline Phosphatase (>50 years) 
40 
140 
42 
146 
U/L 
Chemistry 
Alanine Aminotransferase 
5 
46 
5 
46 
IU/L 
Chemistry 
Aspartate Aminotransferase 
10 
50 
10 
41 
IU/L 
Chemistry 
Blood Urea Nitrogen 
8 
25 
8 
25 
mg/dL 
Chemistry 
Creatinine 
0.6 
1.5 
0.6 
1.4 
mg/dL 
Chemistry 
Uric Acid (13-60) 
3.5 
8 
2.2 
6.5 
mg/dL 
Chemistry 
Uric Acid (>60 years) 
3.5 
8 
2.2 
7 
mg/dL 
Chemistry 
Glucose 
65 
99 
65 
99 
mg/dL 
Chemistry 
Total Protein 
6 
8 
6 
8 
g/dL 
Chemistry 
Albumin (1-50 years) 
3.6 
5.1 
3.6 
5.1 
g/dL 
Chemistry 
Albumin (>50 years) 
3.4 
4.9 
3.4 
3.9 
g/dL 
Hematology 
Hemoglobin 
13 
18 
11.5 
16 
g/dL 
Hematology 
Hematocrit 
35 
48 
35 
48 
% 
Hematology 
Erythrocytes count 
4.3 
6 
3.7 
5.4 
m/mm3 
Hematology 
Mean Cell Volume 
78 
100 
78 
100 
fL 
Hematology 
Leukocytes 
4 
11 
4 
11 
k/mm3 
Hematology 
Neutrophils 
1.6 
9.3 
1.6 
9.3 
k/uL 
Hematology 
Lymphocytes 
0.6 
5.5 
0.6 
5.5 
k/uL 
Hematology 
Monocytes 
0.1 
1.6 
0.1 
1.6 
k/uL 
Hematology 
Eosinophils 
0 
0.7 
0 
0.7 
k/uL 
Hematology 
Basophils 
0 
0.2 
0 
0.2 
k/uL 
Hematology 
Platelets 
130 
450 
130 
450 
k/mm3 
 
 
 
 


Flexion Therapeutics 
Protocol FX006-2019-017 
SAP, Version 1.0 
18 December 2019 
 
CONFIDENTIAL - 38 - 
 
 
7.5.  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 
Hypercholesterolemia 
 
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; 
>1.5-3x 
Baseline; 
>1.5-3x ULN 
>3x Baseline; 
>3-6xULN 
>6xULN 


Flexion Therapeutics 
Protocol FX006-2019-017 
SAP, Version 1.0 
18 December 2019 
 
CONFIDENTIAL - 39 - 
Lab Parameter 
Hypo/Hyper 
CTCAE Definition 
SI Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
>ULN-
1.5xULN 
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 


Flexion Therapeutics 
Protocol FX006-2019-017 
SAP, Version 1.0 
18 December 2019 
 
CONFIDENTIAL - 40 - 
Lab Parameter 
Hypo/Hyper 
CTCAE Definition 
SI Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Leukocytes 
Hyper 
Leukocytosis 
10^9/L 
- 
- 
>100 
- 
Lymphocytes 
Hypo 
Lymphocyte count decreased 
10^9/L 
<LLN-0.8 
<0.8-0.5 
<0.5-0.2 
<0.2 
Lymphocytes 
Hyper 
Lymphocyte count increased 
10^9/L 
- 
>4-20 
>20 
- 
Neutrophils 
Hypo 
Neutrophils count decreased 
10^9/L 
<LLN-1.5 
<1.5-1 
<1-0.5 
<0.5 
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