Clinical trial NCT03529942
Conditions: Osteoarthritis, Knee
Keywords: Osteoarthritis Knee Pain Intra-articular Injection Corticosteroid
Sponsor: Pacira Pharmaceuticals, Inc
Start date: 2018-04-24; Completion date: 2020-03-09
Enrollment: 129 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label study assessing the effect of the administration of a single intra-articular (IA) injection of FX006 32 mg on synovial volume in patients with osteoarthritis (OA) of the knee.

Detailed description:
This is an open-label study assessing the effect of the administration of a single intra-articular (IA) injection of FX006 32 mg on synovial volume in patients with osteoarthritis (OA) of the knee. The study will be conducted in male and female patients who are ≥ 40 years of age.

Eligible patients who provide written consent and meet all entry criteria will undergo initial ultrasound examination and MRI with contrast of the index knee, and then receive a single IA injection of FX006 administered to the index knee at Baseline/Day 1. Patients will return to the clinic at Weeks 6 and 24 for an MRI with contrast of the index knee and other assessments. Patients must also have a blood sample drawn for Estimated Glomerular Filtration Rate (eGFR) testing within 30 days prior to the scheduled MRIs. In addition, a patient questionnaire will be administered and adverse events (AEs) and concomitant medication updates will be collected via telephone at Weeks 12 and 18.

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 documents:
SAP_002.pdf: 
 
Document No.: STAT C002-TP01 v2.0 
 
Confidentiality 
This document is confidential and proprietary property of Flexion Therapeutics, Inc. and to be used only as 
authorized by Flexion Therapeutics, Inc..  No part is to be reproduced, disclosed to others, or quoted without prior 
written authorization from Flexion Therapeutics, Inc. 
STATISTICAL ANALYSIS PLAN 
Protocol FX006-2017-014 
 
An Open-Label Study to Evaluate the Effect of the Administration of FX006 on 
Synovial Inflammation in Patients with Osteoarthritis of the Knee 
Protocol Number: 
(Version Date) 
FX006-2017-014 
Version 6.0 (12 July 2019)
Name of Test Drug: 
FX006 
Phase: 
3b 
Methodology: 
Open-label, single group, one intra-articular injection study 
Sponsor: 
Flexion Therapeutics 
10 Mall Road, Suite 301 
Burlington, Massachusetts, USA  
Tel: 781-305-7777
Sponsor Representative: 
Amy Cinar, PhD 
Director, Biostatistics 
Document Date: 
05 Nov 2019 
Document Version: 
Version 2.0 
 






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TABLE OF CONTENTS 
Section 
Page
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS..................... 11 
1.1. 
Introduction ................................................................................... 11 
1.2. 
Objectives of Statistical Analysis ................................................. 11 
2. 
STUDY DESIGN ....................................................................................... 13 
2.1. 
Synopsis of Study Design .............................................................. 13 
2.2. 
Randomization Methodology ....................................................... 13 
2.3. 
Stopping Rules and Unblinding ................................................... 13 
2.4. 
Study Procedures .......................................................................... 13 
2.5. 
Safety, Imaging, Efficacy, and Biomarker Variables ................ 15 
2.5.1. 
Safety Variables ............................................................... 15 
2.5.2. 
Imaging Variables ............................................................ 15 
2.5.3. 
Efficacy Variables ............................................................ 15 
2.5.4. 
Biomarker Variables ........................................................ 15 
3. 
PATIENT POPULATIONS ..................................................................... 16 
3.1. 
Population Definitions .................................................................. 16 
3.2. 
Protocol Deviations ....................................................................... 16 
4. 
STATISTICAL METHODS .................................................................... 17 
4.1. 
Sample Size Justification .............................................................. 17 
4.2. 
General Statistical Methods and Data Handling ....................... 17 
4.2.1. 
General Methods .............................................................. 17 
4.2.2. 
Computing Environment .................................................. 18 
4.2.3. 
Methods of Pooling Data ................................................. 18 
4.2.4. 
Adjustments for Covariates .............................................. 18 
4.2.5. 
Multiple Comparisons/Multiplicity ................................. 18 
4.2.6. 
Subpopulations ................................................................. 18 
4.2.7. 
Discontinuations and Loss to Follow-up ......................... 18 
4.2.8. 
Missing, Unused, and Spurious Data ............................... 19 
4.2.9. 
Visit Windows ................................................................. 19 
4.2.10. 
Baseline Definitions ......................................................... 19 
4.2.11. 
Baseline Synovitis Definition .......................................... 19 


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Section 
Page
4.3. 
Interim Analyses ........................................................................... 19 
4.4. 
Patient Disposition ........................................................................ 20 
4.5. 
Protocol Deviations ....................................................................... 20 
4.6. 
Demographic and Baseline Characteristics ................................ 20 
4.6.1. 
Demographic characteristics ............................................ 20 
4.6.2. 
OA Medical History ......................................................... 21 
4.6.3. 
Prior medication ............................................................... 21 
4.7. 
Study Drug Exposure .................................................................... 21 
4.8. 
Safety Analyses .............................................................................. 21 
4.8.1. 
Adverse Events ................................................................ 21 
4.8.2. 
Laboratory Data ............................................................... 23 
4.8.3. 
Vital Signs, Physical Examinations and Index Knee 
Assessment ....................................................................... 23 
4.8.4. 
Ultrasound ........................................................................ 23 
4.8.5. 
Electrocardiogram ............................................................ 24 
4.8.6. 
Index Knee X-Ray ........................................................... 24 
4.8.7. 
Concomitant Medications ................................................ 24 
4.8.8. 
Surgical Procedures ......................................................... 24 
4.9. 
Imaging Analyses .......................................................................... 24 
4.9.1. 
Synovial Volume Change from Baseline ......................... 25 
4.9.2. 
Change in Bone Area and Cartilage Thickness ............... 26 
4.9.3. 
Structural Changes in Femur Bone Shape Score (B-score)
 .......................................................................................... 26 
4.9.4. 
Other Imaging Variables .................................................. 26 
4.9.5. 
Contrast Enhancement and Responders/Non-Responders
 .......................................................................................... 26 
4.10.  Efficacy Analyses ........................................................................... 27 
4.10.1. 
WOMAC .......................................................................... 27 
4.10.2. 
KOOS QOL ..................................................................... 28 
4.10.3. 
Pain/Stiffness Questionnaire ............................................ 28 
4.11.  Biomarker Analyses ...................................................................... 28 
4.11.1. 
IL-1β mRNA .................................................................... 28 
5. 
CHANGES TO PLANNED ANALYSES ............................................... 30 


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Section 
Page
6. 
References .................................................................................................. 31 
7. 
CLINICAL STUDY REPORT APPENDICES ...................................... 32 
7.1. 
Statistical Tables and Figures to be Generated .......................... 32 
7.1. 
Data Listings to be Generated ...................................................... 35 
 
 
 
 


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LIST OF IN-TEXT TABLES 
Table 
Page 
Table 1: 
Schedule of Study Assessments .......................................................................................14 
 


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ABBREVIATIONS 
ACR 
American College of Rheumatology 
AE 
Adverse Event 
BMI 
Body Mass Index 
BP 
Biomarker Population 
CI 
Confidence Interval 
cm 
Centimeter 
CM 
Concomitant Medications 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EOS 
End of Study 
EP 
Efficacy Population 
EULAR 
European League Against Rheumatism 
HIV 
Human Immunodeficiency Virus 
IA 
Intra-articular 
IL-1β 
Interleukin 1 beta 
IP 
Imaging Population 
IQ 
Interquartile Range 
IV 
Intravenous 
JSW 
Joint Space Width 
K-L 
Kellgren-Lawrence 
kg 
Kilogram 
KOOS  
Knee injury and Osteoarthritis Outcome Score  
LK 
Likert 
LSM 
Least Square Mean  
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MI 
Multiple Imputation 
mL 
Milliliter 
m2 
Square meter 
mm 
Millimeter 
mm2 
Square millimeter 
MRI 
Magnetic Resonance Imaging 
mRNA 
Messenger Ribonucleic Acid (RNA) 
n 
Number of non-missing values 
OA 
Osteoarthritis 


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OARSI 
Osteoarthritis Research Society International 
PT 
Preferred Term 
QOL 
Quality of Life 
RNA 
Ribonucleic Acid  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SIP 
Synovitis Imaging Population 
SP 
Safety Population 
TEAE 
Treatment-emergent Adverse Event 
TA1 
Triamcinolone Acetonide  
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 
                                                     
1 Abbreviated in past protocols and documents as TCA 


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REVISION HISTORY 
Version 
Description of Change 
1.0 
Original Issue 
2.0 
 Section 4.9.1: Changed “baseline femur bone size” to baseline 
“femur bone volume (mm3)”. 
 Section 4.9.2, 4.9.3: Changed “femur bone size” to “femur bone 
volume”. 
 Section 4.9.4: Added “Femur bone volume”. 
 Section 7.1:  
o Changed IL-1β mRNA Level units from “copy number” to 
“ΔΔct”. 
o Changed “Imaging Population and Biomarker Population” 
to “Patients in the Imaging and Biomarker Populations”. 
o Changed Listing 16.2.6.1.5 title from “Additional Imaging 
Variables” to “Femur Bone Volume”. 
o Removed Listing 16.2.9.6 Index Knee X-ray Results since 
Listing 16.2.4.7 Screening Index Knee X-ray Results 
would present the same data. Renumbered subsequent 
outputs. 
 
 


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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 US, and OA is the most common joint 
disease, affecting 27 million Americans, with numbers expected to grow as a result of aging, 
obesity and sports injuries.  Recent data suggest that OA accounts for over $185 billion of annual 
healthcare expenditures in the US, which does not include loss of productivity costs.  It is estimated 
that by 2030, 45 million people will have OA.  OA commonly affects large weight-bearing joints 
like the knees and hips, but also occurs in the shoulders, hands, feet and spine.  Patients with OA 
suffer from joint pain, tenderness, stiffness and limited movement.  As the disease progresses, it 
becomes increasingly painful and debilitating, culminating, in many cases, in the need for total 
joint arthroplasty. 
Current Guidelines from the American College of Rheumatology (ACR), Osteoarthritis Research 
Society International (OARSI) and the European League against Rheumatism (EULAR) 
recommend the use of IA corticosteroids for short-term acute pain relief (Hochberg et al, 2012; 
Jordan et al, 2003; Menge et al, 2014). 
While historically OA has been considered a non-inflammatory disease, it is increasingly being 
recognized that chronic synovitis occurs in all stages of knee OA (Benito et al, 2005; Sellam and 
Berenbaum, 2010; Wenham and Conaghan, 2010). As synovial inflammation is correlated with 
clinical symptoms and joint degeneration, it should be an important target for therapeutic 
intervention. The inflamed synovium may well be the target for IA corticosteroids which are 
widely used in knee OA (Ayral et al, 2005). 
FX006 is an extended-release formulation of triamcinolone acetonide (TA) for IA administration. 
It is approved in the US under the trade name ZILRETTA® (triamcinolone acetonide extended-
release injectable suspension) for the management of OA pain 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).  
1.2. Objectives of Statistical Analysis 
The primary objective of this study is to assess the effect of a single IA injection of FX006 32 
milligrams (mg) to control inflammation as measured by a reduction in Magnetic Resonance 
Imaging (MRI) assessed synovial volume in patients with symptomatic OA of the knee and 
defined synovial volume at baseline. 
Secondary objectives of the study include the following: 
 
To assess the effect of FX006 on pain, stiffness, function, and quality of life (QOL) 
 
To assess changes in bone area and cartilage thickness of the knee  
Exploratory objectives of the study include the following: 
 
To assess structural changes in bone, cartilage and meniscus 
 
To assess changes in contrast enhancement of tissue other than synovial tissue 


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 
To identify Responders and Non-Responders by assessing structural and contrast changes in 
bone, cartilage and other tissues 
 
Through assessment of blood Interleukin 1 beta (IL-1β) Messenger Ribonucleic Acid 
(mRNA) levels, to segment patients into inflammatory and non-inflammatory phenotypes, 
and to examine the response to therapy of these phenotypes 
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis 
of study data in order to answer the study objective(s). Populations for analysis, data handling 
rules, statistical methods, and formats for data presentation are provided.  The statistical analyses 
and summary tabulations described in this SAP will provide the basis for the results sections of 
the clinical study report (CSR) for this trial, as well as used for regulatory filings and 
manuscripts and presentations. 
This SAP also will outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol. 


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2. 
STUDY DESIGN 
2.1. Synopsis of Study Design 
This is an open-label study assessing the effect of the administration of a single IA injection of 
FX006 32 mg on synovial volume in patients with OA of the knee. The study will be conducted in 
male and female patients who are ≥ 40 years of age. 
Eligible patients who provide written consent and meet all entry criteria will undergo initial 
ultrasound examination and MRI with contrast of the index knee. For each MRI, a pretreatment 
synovial volume measurement will be derived by quantitative image analysis. Patients will then 
receive a single IA injection of FX006 administered to the index knee at Baseline/Day 1. Patients 
will return to the clinic at Weeks 6 and 24 for an MRI with contrast of the index knee and other 
assessments. Patients must also have a blood sample drawn for Estimated Glomerular Filtration 
Rate (eGFR) testing within 30 days prior to the scheduled MRIs. In addition, a patient 
questionnaire will be administered and adverse events (AEs) and concomitant medication (CM) 
updates will be collected via telephone at Weeks 12 and 18. 
2.2. Randomization Methodology 
This is a single arm, open-label study design.  Participants are not randomized.  Neither patients 
nor study personnel are blinded to treatment assignment. 
2.3. Stopping Rules and Unblinding 
Unblinding of treatment group is not applicable to this study since this is an open label-study. 
There will be no data review committee for this study. 
2.4. Study Procedures 
The study will involve a Screening period (up to 28 days), a pretreatment day when an 
Ultrasound and MRI of the index knee will be performed, dosing at Baseline/Day 1 and 
two additional clinic visits at Weeks 6 and 24. In addition, patients must also have a blood 
sample drawn for eGFR testing within 30 days prior to the scheduled MRIs. Follow-up via 
telephone will occur at Weeks 12 and 18. 
At specified times throughout the study, patients will undergo physical examinations, index knee 
assessments, imaging of the index knee (MRI with contrast), 12-lead Electrocardiogram (ECG); 
blood samples will be collected for laboratory safety tests and vital signs will be collected or 
measured. Information regarding AEs and CMs will be collected, and patient questionnaires 
(Western Ontario and McMaster Universities (WOMAC®) Osteoarthritis Index 
Likert (LK) 3.1, the Knee injury and Osteoarthritis Outcome Score (KOOS) QOL Subscale, and 
a set of questions exploring pain and stiffness of the knee will be completed. 
The schedule of assessments, as outlined in the study protocol, is provided in Table 1. 


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Table 1: 
Schedule of Study Assessments 
Procedures 
Screening1 
 
Pre-
Treatment2 Baseline /
Day 1 
Week 
63 
Week 
123,4 
Week 
183,4 
Week 24 /  
End of Study3 
Informed consent 
X5 
 
 
 
 
 
 
Inclusion/Exclusion Review 
X 
 
X6 
 
 
 
 
Medical History/Update 
X 
 
X6 
 
 
 
 
OA Medical History/Update 
X 
 
X6 
 
 
 
 
Prior Treatment & Medications7 
X 
 
X6 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
X 
Index Knee X-ray8 
X 
 
 
 
 
 
 
Index Knee Assessment9  
X 
 
X6 
X 
 
 
X 
Ultrasound examination of index knee10 
 
X 
 
 
 
 
 
MRI with contrast of index knee11 
 
X 
 
X 
 
 
X 
12-Lead ECG 
X 
 
 
 
 
 
 
Vital Signs 
X 
 
X6 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
Weight and BMI 
X 
 
 
 
 
 
X 
Hematology & Chemistry12 
X 
 
 
 
 
 
X 
HIV, Hepatitis B/C12 
X 
 
 
 
 
 
 
IL-1β mRNA levels12 
 
 
X6 
 
 
 
 
eGFR12,13 
X 
 
 
X 
 
 
X 
Serum Pregnancy Test14 
X 
 
 
 
 
 
 
Urine Pregnancy Test 14 
 
 
X6 
 
 
 
X 
WOMAC15  
X 
 
X6 
X 
X 
X 
X 
Supplemental pain and stiffness questionnaire15 
 
 
X6 
X 
 
 
X 
KOOS QOL15 
 
 
X6 
X 
 
 
X 
Index knee aspiration and collection of synovial fluid6 
 
 
X6 
 
 
 
 
Treatment administration 
 
 
X 
 
 
 
 
AEs & ConMeds 16  
 
 
-------------------------------------X------------------------------------- 
SAEs17 
-------------------------------------------------X----------------------------------------------- 
 
                                                     
1 Screening may occur up to 28 days prior to Day 1. 
2 The Pre-Treatment visit must be within 10 days of Baseline/Day 1 and once eligibility is confirmed. 
3 Visit should be conducted within +/- 7 days from scheduled date. 
4 Via telephone. 
5 Consent must be obtained prior to performing any study-specific procedures. 
6 Complete assessment prior to dosing. 
7 Record any medications received within 30 days prior to the Screening visit 
8 Standing, fixed flexion PA view, weight bearing X-ray of the index knee will be taken using a standardized knee positioning device. The 
Screening X-ray will be read centrally for KL grade, the presence of osteophytes, and the measurement of joint space width. 
9 Index knee will be assessed for tenderness, heat/redness, swelling, effusion, and Baker’s cyst. New clinically significant findings or findings that 
worsen from the patient’s baseline condition should be recorded as AEs. 
10 Ultrasound must be performed within -10 days prior to Baseline/Day 1 and using a linear transducer and with the knee in a semi-flexed 
position. Synovial proliferation will be confirmed in a transverse view but measured in a longitudinal view only. 
11 MRI must be performed within -10 days prior to Baseline/Day 1 and +/- 7 days of Weeks 6 and 24 and only if eGFR results are ≥ 40 mL/min 
per the central laboratory. MRI images should follow the vendor specific knee sequences as detailed in MRI Acquisition Manual.  
12 Via Central Laboratory. 
13 Must be performed within 30 days prior to Week 6 and Week 24 MRI with contrast. 
14 Conduct for females of childbearing potential only. Serum pregnancy test to be performed via central laboratory at Screening; urine pregnancy 
test to be performed locally at Baseline/Day 1, and results available prior to dosing. 
15 Patient questionnaires to be completed prior to all other assessments. 
16 AEs and Concomitant Medications will be captured from Day 1 (from start of study drug administration) to Week 24/Final Visit. 
17 SAEs will be recorded from Informed Consent to the end of participation in the study or Week 24/Final Visit. 


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2.5. Safety, Imaging, Efficacy, and Biomarker Variables 
2.5.1. Safety Variables 
Safety and tolerability will be evaluated based on AEs spontaneously reported by the patient or 
discovered by the Investigator and findings from the following assessments: physical 
examinations, index knee assessments, vital signs, and clinical laboratory evaluations. 
2.5.2. Imaging Variables 
Synovial volume and structural changes in various tissues (bone, cartilage, meniscus) and change 
in contrast enhancement of tissues other than synovium will be evaluated on the basis of MRI by 
a central imaging vendor. 
2.5.3. Efficacy Variables 
Efficacy will be evaluated on the basis of the results of the WOMAC pain, stiffness and function 
domains independently and collectively (Bellamy et al, 1988), the KOOS QOL Subscale 
(http://www.koos.nu/) and a set of questions exploring pain and stiffness of the knee. 
2.5.4. Biomarker Variables 
Whole blood samples will be taken from patients at Baseline/Day 1. Total RNA will be isolated 
from these samples for analysis of mRNA levels of the pro-inflammatory cytokine IL-1β.  The 
expression of baseline IL-1β among patients will be compared to several other parameters, such 
as MRI images, with the goal of determining if baseline mRNA IL-1β expression contributes to 
the pathogenesis of OA and/or is associated with responsiveness to FX006 treatment. 


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3. 
PATIENT POPULATIONS 
3.1. Population Definitions 
The following patient populations will be evaluated and used for presentation and analysis of the 
data: 
Safety Population (SP): 
The SP will include all patients who receive any amount of study drug. The Safety Population 
will be used to assess safety and tolerability. 
Synovitis Imaging Population (SIP): 
The SIP will include all patients from the SP who have a pre-treatment synovial volume 
measurement of greater than 3000 mm3 of gadolinium enhancement as determined by 
quantitative image analysis, as well as quality pre-treatment and Week 6 MRIs. In addition, the 
patients included in this population will have no major protocol deviations and/or imaging 
variations (i.e. change in coil, machine, or software) deemed to potentially impact the imaging 
analysis.  
Imaging Population (IP): 
The IP will include all patients from the SP who have quality MRI data available for pre-
treatment and at least one post-baseline timepoint and with no major protocol deviations and/or 
imaging variations (i.e. change in coil, machine or software) deemed to potentially impact the 
imaging analysis.  
Efficacy Population (EP): 
The EP will include all patients from the SP, who have at least one post-Baseline/Day 1 
WOMAC or KOOS assessment.  
Biomarker Population (BP): 
The BP will include all patients from the SP, who have a Baseline/Day 1 IL-1β result.  
Patients must be included in both relevant study populations to be included in analyses 
comparing two parameters. 
3.2. Protocol Deviations 
All protocol deviations will be tabulated and presented in the data listings. 


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4. 
STATISTICAL METHODS 
4.1. Sample Size Justification 
Approximately 100 patients will be enrolled and treated with a single IA injection of 32 mg FX006 
to ensure a minimum of 70 evaluable Synovitis Imaging patients, as defined by pre-treatment MRI 
synovial volume measurement of greater than 3000 mm3 of gadolinium enhancement as 
determined by quantitative image analysis, with quality pre-treatment and Week 6 MRIs.  Previous 
trials had similar sample sizes (Gait et al., 2016; O’Neill et al., 2016). 
4.2. General Statistical Methods and Data Handling 
4.2.1. General Methods 
Once all enrolled patients have completed the Week 24 visit, all final analyses specified in the 
SAP will be completed following database lock and reported in the CSR. Post-hoc, exploratory 
analyses, may also be performed to further understand and elucidate study results; these analyses 
will be clearly identified as such in the CSR. 
All output will be incorporated into Portable Document Format (PDF) or Word files, sorted and 
labeled according to the International Conference on Harmonization (ICH) recommendations, 
and formatted to the appropriate page size(s). 
All analyses will be done overall and stratified by baseline synovitis (yes/no). Stratified analyses 
will be descriptive in nature. There will be no statistical comparisons between baseline synovitis 
groups. Tables will be presented with one column for those with BL synovitis, one column for 
those without baseline synovitis and one columns for all patients. Figures will be presented 
stratified by baseline synovitis (yes/no) and for all patients.  
Tabulations will be produced for appropriate demographic, baseline, safety, imaging, and 
efficacy parameters.   
For categorical variables, summary tabulations of the number and percentage within each 
category (with a category for missing data) of the parameter will be presented. 
For continuous variables, the number of non-missing values (n), the mean, median, SD minimum 
and maximum values will be presented. 95% Confidence Intervals (CI) may be provided.  
Additional statistics may be presented for certain endpoints as described below. 
All CIs, statistical tests, and resulting p-values will be reported as 2-sided.  Significance will be 
assessed at α = 0.05 level and the significance level will not be adjusted for the secondary 
endpoint analyses. P-values of less than or equal to 0.05 will be described as statistically 
significant and potentially informative. 
All collected data will be presented in by-patient listings sorted by patient number. 
All data listings that contain an evaluation date will contain relative analysis day (Rel Day). Pre-
treatment and post treatment analysis days are numbered relative to the day of the first dose of 
study treatment (i.e., injection in the first knee), which is designated as Day 1. The preceding day 
is Day-1; the day before that is Day-2, etc. 
The sections below describe the intended analysis of the endpoints. Sensitivity analysis may be 
employed in the event of any unforeseen data anomalies or data issues not known at the time of 
writing this analysis plan. 


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4.2.2. Computing Environment 
All descriptive statistical analyses will be performed using SAS/STAT® software (Version 9.4 
or higher), unless otherwise noted. 
AEs will be coding using Medical Dictionary for Regulation Activity (MedDRA) Version 20.1 
(or higher).  
CMs will be coded using World Health Organization (WHO) Drug Dictionary (DD) (Mar 2014 
or higher).  
4.2.3. Methods of Pooling Data 
Not applicable to the present study. 
4.2.4. Adjustments for Covariates 
Continuous endpoints will include baseline score and study site as covariates. Covariates specific 
to particular endpoints are described in the sections below.  Other covariates may be explored.   
4.2.5. Multiple Comparisons/Multiplicity 
Although confidence intervals and p-values will be calculated for change from baseline for 
primary, secondary and exploratory endpoints, only the primary endpoint is hypothesis driven.  
These measures are used for guidance regarding the strength of the association, informally.  
4.2.6. Subpopulations 
The following variables will be used for subgroup analyses: 
1. Gender (Male/Female) 
2. WOMAC A 30% and 50% responders at Week 6 as defined in Section 4.10.1.2. 
(Yes/No) 
3. Prior IA steroid injection in index knee at Baseline (Yes/No) 
4. Joint space width (JSW) at Screening (2-4 mm vs. >4 mm) 
Details about whether particular subgroup analyses will be performed or not are described in the 
sections for each endpoint. Additional subgroup tables and figures may be completed that are not 
identified in the list of planned tables and figures if needed to further explain results.  
4.2.7. Discontinuations and Loss to Follow-up 
Each treated patient from this study receives study drug 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.  
Data collected at unscheduled visits will be mapped to the closest scheduled visit, but only if that 
data is not already available in that visit. For assessments that are not collected at every visit, 
data will be mapped to the next scheduled visit where that assessment is to be performed (e.g., 
Hematology and Chemistry collected at Week 6 would be mapped to Week 24 / End of Study 
(EOS) since Hematology and Chemistry is not a planned assessment at Week 6). 


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4.2.8. Missing, Unused, and Spurious Data 
Unless noted below, missing values will not be imputed and data will be analyzed “as observed”. 
Sensitivity analyses, such as multiple imputation (MI), may be performed to examine the effect 
of missing data where a particular variable is missing for >10% of a data point. 
4.2.8.1. Safety data 
Missing AE data will be imputed or otherwise handled as indicated in Section 4.8.1. Missing CM 
data will be handled as indicated in Section 4.8.7.  
4.2.8.2. Efficacy data 
For WOMAC, the rules as described in the WOMAC user guide (Bellamy 2011) will be used. 
Specifically, if at least 2 pain, both stiffness, or at least 4 function items are missing, the patient's 
response will be regarded as invalid and the score for that given subscale as well as the total 
score will be left missing. If no more than 1 pain, 1 stiffness, and less than 4 function items are 
missing, the missing value in a given subscale will be imputed using the average of all items in 
the given subscale. Imputed WOMAC scores will be flagged in the data listings. 
For the KOOS QOL subscale, the rules as described in KOOS Scoring 2012 
(http://www.koos.nu/) will be used. Specifically, the score is only calculated if at least 2 items 
are non-missing. Otherwise the score will be set to missing. 
4.2.9. Visit Windows 
No analysis visit windows are defined in this study. All parameters will be summarized and 
presented according to the nominal visit as recorded on the Electronic Case Report Form 
(eCRF), with the exception of unscheduled visits, which are mapped as detailed in Section 4.2.7. 
4.2.10. 
Baseline Definitions 
For all endpoints, for exposed patients, baseline is the Baseline/Day 1 assessment prior to study 
drug administration date and time. If baseline result is missing, the last non-missing result prior 
to study drug administration may be used from the Screening period. For enrolled patients who 
are not exposed to study drug, the latest assessment during the screening period will be used. 
4.2.11. 
Baseline Synovitis Definition 
The definition for baseline synovitis is the same definition that is used to determine the SIP 
population: pre-treatment synovial volume measurement of greater than 3000 mm3 of 
gadolinium enhancement as determined by quantitative image analysis.  
 
4.3. Interim Analyses 
Once all enrolled patients in the SIP have completed the Week 6 visit, the mean standardized 
change from baseline at 6 weeks in synovial volume (the primary endpoint) and the mean absolute 
(non-standardized) change from baseline at 6 weeks in synovial volume will be analyzed. The 
descriptive statistics described in Section 4.9.1 will be presented for baseline and Week 6 only. 
The synovial volume analysis will also be performed by WOMAC A 30% and 50% responders at 
Week 6 subgroups, as defined in Section 4.2.6. No other subgroup analyses will be presented. 
The following efficacy endpoints will also be presented for baseline and Week 6 only, as described 
in the sections below: 


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 WOMAC A, B, C and Total  
 WOMAC A 30% and 50% responders 
 KOOS QOL 
In addition, patient disposition, demographic and baseline characteristics, OA medical history, 
study drug exposure and adverse events will be presented as described in the sections below.  
Full results of this interim analysis will be presented to the Sponsor. 
4.4. Patient Disposition 
All patients who are enrolled will be accounted for in this study.  
Patient disposition will be tabulated and include the number enrolled, treated and completed; the 
number in each patient population for analysis; and the number who discontinued prior to 
completing the study and reason(s) for discontinuation.   
Data listings will be provided for the following: 
 Study completion information, including the reason for early study discontinuation, if 
applicable. 
 Analysis populations, including reason for exclusion from an analysis population. 
 
Inclusion and exclusion criteria not met. 
4.5. Protocol Deviations 
The number and percentage of patients with at least one protocol deviation will be presented for 
the SP. Additionally, incidence by type of deviation will be presented; in these tabulations 
patients could be counted in more than one category if they have a deviation attributed to 
multiple categories. All protocol deviations will be presented in a data listing.  
 
4.6. Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized for the SP. 
No formal statistical comparisons will be performed. 
All collected demographic, baseline characteristic and medical history data will be tabulated and 
provided in data listings.  
4.6.1. Demographic characteristics 
The following baseline parameters will be described: 
 Age (year) at consent - Age will be calculated as the years between date of birth and date 
of informed consent, and will be rounded down to the nearest year. 
 Weight (kilogram (kg)); 
 Height (centimeter (cm)); 
 Gender (Male/Female); 
 Body mass index (BMI) (kg/m²); 
 BMI category: 
o Underweight: <18.0 kg/square meter (m²) 


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o Normal: 18.0 to <25.0 kg/m² 
o Overweight: 25.0 to <30.0 kg/m2 
o Obesity Class I:  30.0 to <35.0 kg/m2 
o Obesity Class II: 35.0 to <40.0 kg/m2 
o Obesity Class III: >=40.0 kg/m2 
 Ethnicity (Hispanic or Latino / Not Hispanic or Latino); 
 Race (White, Asian / Black or African American / American Indian or Alaska Native / 
Native Hawaiian or Other Pacific Islander); 
 
4.6.2. OA Medical History 
General OA and knee OA medical history data as collected on the CRF will be tabulated for the 
SP. 
Years since primary diagnosis of OA in the index knee to Day 1 of the study in days (dose date – 
date of diagnosis + 1)/365.25, will be computed and presented descriptively.  If only month and 
year of initial diagnosis is available, day will be imputed as 1 for calculations.  If month and day 
are missing, the time from primary diagnosis will be computed as year of first dose minus year of 
diagnosis. If year is missing, time from diagnosis will not be computed. 
4.6.3. Prior medication  
All prior medications will be presented in the CM data listing with a flag identifying which 
medications are prior medications (refer to Section 4.8.7 for details on defining prior and 
concomitant medications). 
4.7. Study Drug Exposure 
Details of study drug administration will be tabulated and presented for the SP. Specifically, the 
position of the knee during injection, the approach during injection, the numbing agent used, 
whether or not the entire contents of the syringe were injected, needle size used and synovial 
fluid volume aspirated will be presented. 
All dosing data will be presented in a data listing. 
 
4.8. Safety Analyses 
Safety analyses will be conducted using the SP.   
4.8.1. Adverse Events 
AEs will be coded using the 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 EOS. 


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If the start date/time of an AE is partially or completely missing, the date/time will be compared 
as far as possible with the date/time of the start of administration of study drug.  The AE will be 
assumed to be treatment emergent if it cannot be definitively shown that the AE did not occur or 
worsen during the treatment-emergent period (worst case approach).  The following general rules 
will be used: 
 If the start time of an AE is missing but the start date is complete, an AE will only be 
excluded as being treatment emergent if the start date is before the date of study drug 
administration or if the stop date/time is before study drug administration. 
 If the start time and day are missing but the start month and year are complete, an AE 
will only be excluded as being treatment emergent if the start month/year is before the 
month/year of study drug administration or if the stop date/time is before study drug 
administration. 
 If the start day and month are missing but the start year is complete, an AE will only be 
excluded as being treatment emergent if start year is before the year of study drug 
administration or if the stop date/time is before study drug administration. 
 If the start date is completely missing, an AE will be considered treatment-emergent 
unless the stop date/time is before study drug administration. 
AEs will be summarized by patient incidence rates; therefore, in any tabulation, a patient 
contributes only once to the count for a given SOC or PT. 
Summary tables will display the number and percentage of patients who experienced at least one 
treatment emergent AE (TEAE) in each of the following categories: 
 Any TEAE 
 Any Serious AE (SAE) 
 Any TEAE leading to study discontinuation 
 Any TEAE by severity (mild/moderate/severe) 
 Any TEAE by relationship 
 Any index-knee related TEAE  
 Any index-knee related SAE 
 Any index-knee related TEAE leading to study discontinuation  
 Any index-knee related TEAE by severity (mild/moderate/severe) 
 Any index-knee related TEAE by relationship  
 Any TEAE related to injection procedure 
Separate tabulations will be produced for each of following categories: 
 All TEAEs by SOC and PT  
 All TEAEs by PT (decreasing frequency) 
 All SAEs by SOC and PT  


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 All TEAEs related to study drug by SOC and PT 
 All TEAEs by maximum severity by SOC and PT 
 All TEAEs leading to study discontinuation 
 All TEAEs leading to death 
 All index-knee related TEAEs by SOC and PT 
 All index-knee related TEAEs related to study drug by SOC and PT 
 All index-knee related TEAEs by maximum severity by SOC and PT 
In the summary table for "Any TEAE by SOC and PT", an additional row with the number of 
events observed will be presented. A patient will be counted once for the number of patients if 
they have multiple events. The total number of events will be the absolute number of events 
observed, and a patient will be counted more than once for the event totals if they have multiple 
events.  
In these tabulations, related is defined as any TEAE deemed related to study drug by the 
investigator. If relationship is missing, it will be imputed as related and flagged in the listings.  
No formal hypothesis-testing analysis of AE incidence rates will be performed. 
By-patient listings of all AEs occurring on-study will be provided as well as for the following, 
for all patients:  patient deaths, SAEs, and AEs leading to discontinuation, as applicable. 
4.8.2. Laboratory Data 
Clinical laboratory values will be expressed in SI units. 
The actual value and change from baseline (Day 1 or Screening if Day 1 is missing) will be 
summarized for each hematology and clinical chemistry laboratory parameter. For hematology 
and chemistry, in the event of repeat values, the last non-missing value prior to the visit will be 
used.  
All laboratory data will be provided in data listings. 
4.8.3. Vital Signs, Physical Examinations and Index Knee Assessment 
The actual value and change from baseline (Day 1) at each time point will be summarized for 
vital signs. Vital sign measurements will be presented in a data listing. 
All physical examination abnormalities will be presented in a data listing. 
The incidence of inflammation, as determined from the index knee assessment, will be tabulated 
for each visit. For those patients experiencing inflammation, the details of the inflammation will 
also be tabulated. In these tabulations, percentages will be based on those patients who have a 
non-missing index knee assessment at a given visit. Index knee assessment as well as knee 
aspiration data will be presented in a data listing. 
4.8.4. Ultrasound 
Ultrasound data will be provided in patient data listing.  


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4.8.5. Electrocardiogram  
ECG data will be provided in patient data listing.  
4.8.6. Index Knee X-Ray 
Kellgren-Lawrence (K-L) grade, presence of osteophytes (Yes/No) and JSW data at Screening 
will be summarized and presented with the OA history and index knee characteristics data. X-ray 
data for each patient will also be provided in a data listing.   
4.8.7. Concomitant Medications 
CMs will be defined as those medications that were initiated after first dose of treatment or those 
that were ongoing at the time of first study drug administration.  If the start date or stop date of a 
medication is partially missing, the date will be compared as far as possible with the date of the 
start of administration of study drug.  The medication will be assumed to be prior medication if it 
cannot be definitively shown that the medication did not start or continue during the treatment 
period.  The following approach will be taken: 
 If the start date of medication is complete and occurs on or after the day of the first dose, 
the medication will be assumed concomitant.  If the start date occurs prior to the first 
dose date but the end date is on or after the first dose date or the medication is recorded 
as ongoing, the medication will be considered concomitant. 
 If the start day is missing but the start month and year are complete, a medication will 
only be excluded as being concomitant if the start month/year is before the month/year of 
study drug administration and if the stop date (full date, month and year if missing day, or 
year if missing month and day) is before study drug administration. 
 If the start day and month are missing but the start year is complete, a medication will 
only be excluded as concomitant if the start year is before the year of study drug 
administration and if the stop date (full date, month and year if missing day, or year if 
missing month and day) is before study drug administration.  
 If the start date is completely missing and the stop date is prior to first dose or completely 
missing, the medication will be assumed to be a prior medication. 
All prior and concomitant medications 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, restrictive or per-protocol) and whether the CM was used for treatment of 
an AE. 
4.8.8. Surgical Procedures 
Surgical procedures that occurred during the study will be provided in a data listing. 
 
4.9. Imaging Analyses 
All imaging analyses will be conducted using the IP. The following MRI collection data will be 
presented in a listing: 
 Was the eGFR performed within 30 days prior to the MRI assessment with result ≥ 40 
mL/min per central laboratory?  
 Was the MRI with contrast of index knee performed? 


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 Use of MRI contrast? 
 Date performed 
Analyses of imaging data are presented below. 
4.9.1. Synovial Volume Change from Baseline 
The primary efficacy endpoint is the mean standardized change from baseline at 6 weeks in 
synovial volume. Secondary efficacy endpoints are mean absolute change from baseline at 6 
weeks in synovial volume as well as mean standardized and absolute change from baseline in 
synovial volume at Week 24.  
Descriptive statistics (number of observations, unadjusted mean, SD, median, 25th and 75th 
percentiles, minimum and maximum) will be presented for synovial volume by visit (baseline, 
Week 6 and Week 24/EOS). Change from baseline will also be presented. For the change from 
baseline calculation, baseline is the synovial volume result obtained at baseline (pretreatment).  
The adjusted change from baseline will also be presented. This will be done using a mixed 
effects model for repeat measures (MMRM) with fixed effects for study time point, study site, 
baseline score and baseline femur bone volume (mm3).  Baseline femur bone volume will be 
included because synovial volume is related to patient size. Change from baseline is the 
outcome. Patient will be the random effect. The analysis will include all study visits of data. This 
model assumes that missing values are missing at random.  
This model will be run using the SAS/STAT PROC MIXED procedure with an unstructured 
correlation matrix to model the within-subject errors. If the unstructured covariance matrix does 
not converge when fitting the mixed model, further investigation into the most appropriate 
correlation matrix will be conducted. The final selection of the correlation matrix to be used in 
fitting the mixed model will be presented in the table output and fully documented in the results 
section of the CSR.  
This model will provide the change from baseline estimated at each visit with the corresponding 
standard error (SE), 95% CI and 2-sided p-value. The standardized change from baseline and 
corresponding 95% CIs will also be presented. These values will be calculated by dividing the 
model-derived LSM and 95% CIs by the adjusted SD.  
Sample SAS code that can be used to implement the mixed effects analysis is provided below: 
proc mixed data=dsin1 method=reml; 
class subjid avisitn siteid; 
model chg= base avisitn siteid femursize; 
repeated avisitn/type=un subject = subjid; 
lsmeans avisitn /pdiff cl; 
run; 
 
Line plots presenting observed mean and LSM change from baseline in synovial volume over 
time will be produced for absolute values. Line plots presenting standardized LSM change from 
baseline in synovial volume over time will be produced as well. In these plots, all visits will be 
presented. There will be standard deviation bars for observed values and standard error bars for 
adjusted values. LSM change from baseline will come from a mixed model as described above. 
In addition, by-patient spaghetti plots will be presented using unadjusted absolute patient values. 
The population mean will also be presented on these plots. 


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The synovial volume analysis will also be performed by the following subgroups, as defined in 
Section 4.2.6: gender, WOMAC A 30% and 50% responders at Week 6, prior IA steroid 
injection in index knee at baseline, and JSW at Screening. 
 
4.9.2. Change in Bone Area and Cartilage Thickness 
The following parameters will be analyzed: 
 Bone area of the medial femur (square millimeters [mm2]) 
 Cartilage thickness of the central medial femur (millimeters [mm]) 
Descriptive statistics (number of observations, unadjusted mean, SD, median, minimum and 
maximum) will be presented for bone area and cartilage thickness by visit (baseline, Week 6 and 
Week 24/EOS). Change from baseline will be presented as well.  
The adjusted change from baseline will also be presented. This will be performed similarly to 
synovial volume as described in Section 4.9.1. Models for change in bone area will include 
baseline femur bone volume as a covariate, but models for change in cartilage thickness will not. 
Line plots will also be presented as described in Section 4.9.1. Analyses will not be performed 
for subgroups and standardized change from baseline will not be presented. 
4.9.3. Structural Changes in Femur Bone Shape Score (B-score) 
Femur bone shape score (B-score) measures bone age, with lower scores indicating a healthier 
knee.  
Descriptive statistics (number of observations, unadjusted mean, SD, median, minimum and 
maximum) will be presented for femur bone shape by visit (baseline, Week 6 and Week 
24/EOS). Change from baseline will be presented as well.  
Femur bone shape will be analyzed similarly to synovial volume as described in Section 4.9.1.  
Models for change in B-score will not include femur bone volume as a covariate, since this 
endpoint is already normalized for the size of the individual knee. Analyses will not be 
performed for subgroups and standardized change from baseline will not be presented. 
 
4.9.4. Other Imaging Variables 
Additional imaging variables, including the following, will also be available and will be 
presented in data listings:  
 Femur bone volume 
 Bone area for lateral/medial femur, tibia and patella 
 Cartilage thickness for central lateral femur, medial/lateral tibia/patella 
 Tibia/patella bone shape. 
4.9.5. Contrast Enhancement and Responders/Non-Responders 
Changes in contrast enhancement of tissue other than synovial tissue and the dichotomization of 
patients into responders/non-responders based on changes in synovial volume and/or pain are 
exploratory in nature, and will be detailed in a separate SAP.  


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4.10. Efficacy Analyses 
All efficacy analyses will be conducted using the EP.  
4.10.1. 
WOMAC 
The following WOMAC scales/questionnaires will be analyzed: 
 WOMAC A (pain subscale) 
 WOMAC B (stiffness subscale)  
 WOMAC C (function subscale) 
 WOMAC (total) 
For the WOMAC subscales, scores at each assessment time point (baseline, Week 6, Week 12, 
Week 18 and Week 24/EOS) will be calculated as the average of the responses to all questions in 
the subscale. Total score will be computed as the average of the average responses on each of the 
subscales (e.g. Average A + Average B + Average C divided by 3). This will provide a uniform 
scoring of 0 to 4 for each subscale and easier interpretation. Imputation rules are as presented in 
Section 4.2.8.  
Eligibility in this trial is based upon the WOMAC A total sum score at Screening and Day 
1/baseline (maximum score of 20). This will be provided for all visits in a data listing.  
4.10.1.1. Change from Baseline 
Descriptive statistics (number of observations, unadjusted mean, SD, median, minimum and 
maximum) will be presented for WOMAC A, WOMAC B, WOMAC C and WOMAC total by 
visit (baseline through Week 24/EOS) for the EP. Change from baseline will also be presented. 
For the change from baseline calculation, baseline is the WOMAC result obtained on Day 1, 
prior to first dose.  
WOMAC change from baseline will be analyzed similarly to synovial volume change from 
baseline, as described in Section 4.9.1. Fixed effects will be study time point, study site and 
baseline score. This model will be run separately for WOMAC A, WOMAC B, WOMAC C and 
WOMAC total.  
 
Line plots presenting observed mean and LSM change from baseline in WOMAC A, WOMAC 
B, WOMAC C and WOMAC total score over time will be produced. In these plots, all visits will 
be presented. There will standard deviation bars for observed values and standard error bars for 
adjusted values. LSM change from baseline will come from separate mixed models as described 
above. 
4.10.1.2. Responders 
Responders are defined as patients who have ≥50% decrease in the WOMAC A score from 
baseline at a given visit. Descriptive statistics (number of evaluable patients and number and 
percent with ≥50% response) will be presented for Weeks 6 through Week 24/EOS.  
Response rate will be plotted with a bar chart.  
Additionally, for Week 12, a continuous responder curve will display the cumulative proportion 
of responders on the y-axis versus percentage of improvement from baseline on the x-axis.  


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The same descriptive analyses will be done where responders are defined as patients who have 
≥30% decrease in the WOMAC A score from baseline at a given visit. 
 
4.10.2. 
KOOS QOL 
The KOOS QOL subscale (http://www.koos.nu/) has 4 questions, each of which is assigned a 
score from 0 to 4 (0=none, 1=mild, 2=moderate, 3=severe, 4=extreme). A normalized score (100 
indicating no symptoms and 0 indicating extreme symptoms) is calculated using this formula: 
100-AVERAGE(Q1-Q4)/4*100. Scores are calculated at each assessment time point (baseline, 
Week 6 and Week 24/EOS). Missing data rules are as presented in Section 4.2.8.  
The KOOS QOL subscale will be analyzed similarly to the WOMAC Change from Baseline, as 
described in Section 4.10.1.1.  
4.10.3. 
Pain/Stiffness Questionnaire 
The supplemental pain and stiffness questionnaire has 10 questions that ask about the patient’s 
pain in the last 7 days. Descriptive statistics (number of evaluable patients and number and 
percent with each possible response) will be presented for each question by visit (Baseline, Week 
6 and Week 24/EOS) for the EP. 
4.11. Biomarker Analyses 
4.11.1. 
IL-1β mRNA 
Pro-inflammatory cytokine interleukin 1 beta (IL-1β) mRNA analyses will be done using 
patients that are in both the IP and BP. Whole blood samples will be taken from patients at 
Baseline/Day 1.  Total Ribonucleic Acid (RNA) will be isolated from these samples for analysis 
of messenger RNA (mRNA) levels of the pro-inflammatory cytokine interleukin 1 beta (IL-1β).  
The expression of baseline IL-1β mRNA among patients will be compared to several other 
parameters, with the goal of determining if baseline IL-1β mRNA expression contributes to the 
pathogenesis of OA and/or is associated with responsiveness to FX006 treatment.  These 
parameters will include: 
 Change from Baseline in imaging endpoints as defined in Section 4.9 
o Synovial Volume Change 
o Bone Area and Cartilage Thickness 
o Femur Bone Shape Score (B-score) 
The correlation between baseline IL-1β mRNA expression and change from baseline for each of 
the imaging variables and time points will be explored.  Pearson correlation will be used if both 
parameters are normally distributed. Spearman correlation will be used if either parameter is not 
normally distributed. The mean and median values for each parameter and the correlation 
coefficient will be presented in a table. Each of the imaging variables versus baseline IL-1β 
mRNA will be presented in scatter plots, which will also include regression lines.  
 
Per the protocol, patients were to be segmented into inflammatory and non-inflammatory 
phenotypes through assessment of blood IL-1β mRNA levels, and to examine the response to 
therapy of these phenotypes.  However, given that there is no prior evidence for such a cut-point, 


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the baseline IL-1β mRNA levels will instead be summarized using descriptive statistics.  If the 
graphical summaries demonstrate that a reasonable cut-point to define an inflammatory 
phenotype group exists then the response to therapy within the phenotypes may be further 
explored. 


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5. 
CHANGES TO PLANNED ANALYSES 
There are no major changes to the planned analyses. 
The following minor changes were made: 
1. The biomarker population definition was added to support the planned biomarker 
analysis (Section 3.1). 
2. Changes in contrast enhancement of tissue other than synovial tissue and the 
responder/non-responder analysis will be performed separately and detailed in a separate 
document (Section 4.9.5). 
3. The analyses of inflammatory and non-inflammatory phenotypes defined by the IL-1β 
levels will only be performed in the case that a clear cut-point exists (Section 4.11.1). 
4. The correlative analyses of IL-1β levels is intended to determine if IL-1β levels 
contribute to the pathogenesis of OA.  The protocol stated that correlations between the 
IL-1β levels and the x-ray and MRI imaging endpoints would be examined.  However, as 
x-ray is only performed at baseline, such an analysis would not provide any information 
as to the pathogenesis of OA and has been removed (Section 4.11.1). 
 
 


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6. 
REFERENCES 
 
Ayral X, Pickering EH, Woodworth TG, Mackillop N, Dougados M. Synovitis: a potential 
predictive factor of structural progression of medial tibiofemoral knee osteoarthritis -- results of 
a 1 year longitudinal arthroscopic study in 422 patients. Osteoarthritis Cartilage. 2005 
May;13(5):361-7.  
Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW.  Validation study of 
WOMAC: A health status instrument for measuring clinically important patient relevant 
outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J 
Rheumatol 1988;15(12):1833-1840. 
Benito MJ, Veale DJ, FitzGerald O, van den Berg WB, Bresnihan B. Synovial tissue 
inflammation in early and late osteoarthritis. Ann Rheum Dis. 2005 Sep;64(9):1263-7. 
Bodick N, Lufkin J, Willwerth C, Blanks R, Inderjeeth C, Kumar A, Clayman M. FX006 
prolongs the residency of triamcinolone acetonide in the synovial tissues of patients with knee 
osteoarthritis. Osteoarthritis Cartilage. 2013;21:(Suppl); S144-5. 
Creamer P, Hochberg MC.  Osteoarthritis. Lancet 1997;350(906):503–508. 
Gait AD, Hodgson R, Parkes MJ, Hutchinson CE, O’Neill TW, Maricar N, et al. Synovial 
volume vs synovial measurements from dynamic contract enhanced MRI as measures of 
response in osteoarthritis. Osteoarthritis and Cartilage 2016;24: 1392-1398. 
Goldring SR and Goldring MB.  Clinical aspects, pathology and pathophysiology of 
osteoarthritis. J Musculoskelet Neuronal Interact 2006;6(4):376–378. 
Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, 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. 
Menge TJ, Boykin RE, Byram IR, Bushnell BD. A Comprehensive Approach to Glenohumeral 
Arthritis. South Med J. 2014;107(9):567-573. 
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. 


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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
Table 14.1.2 
Demographic and Baseline Characteristics (Safety Population) 
Table 14.1.3 
Osteoarthritis History and Index Knee Characteristics (Safety 
Population)
Table 14.1.4 
Summary of Protocol Deviations (Safety Population) 
Table 14.1.5 
Study Drug Exposure Summary (Safety Population) 
Table 14.2.1.1 
Summary of Synovial Volume (mm3) (Imaging Population) 
Figure 14.2.1.1.1 
Mean (+/- SD) Synovial Volume (mm3) over Time (Imaging 
Population)
Figure 14.2.1.1.2 
LS Mean Change from Baseline (+/- SE) in Synovial Volume (mm3) 
over Time (Imaging Population)
Figure 14.2.1.1.3 
Individual Patient Plots of Synovial Volume (mm3) over Time 
(Imaging Population)
Table 14.2.1.2.1 
Summary of Synovial Volume (mm3), Males (Imaging Population)
Table 14.2.1.2.2 
Summary of Synovial Volume (mm3), Females (Imaging Population) 
Figure 14.2.1.2.1.1 
Mean (+/- SD) Synovial Volume (mm3) over Time, by Gender 
(Imaging Population)
Figure 14.2.1.2.1.2 
LS Mean Change from Baseline (+/- SE) in Synovial Volume (mm3) 
over Time, by Gender (Imaging Population)
Table 14.2.1.3.1 
Summary of Synovial Volume (mm3), WOMAC A 30% Responders 
(Imaging Population)
Table 14.2.1.3.2 
Summary of Synovial Volume (mm3), WOMAC A 30% Non-
Responders (Imaging Population) 
Figure 14.2.1.3.1.1 
Mean (+/- SD) Synovial Volume (mm3) over Time, by WOMAC A 
30% Responder (Yes/No) (Imaging Population)
Figure 14.2.1.3.1.2 
LS Mean Change from Baseline (+/- SE) in Synovial Volume (mm3) 
over Time, by WOMAC A 30% Responder (Yes/No) (Imaging 
Population)
Table 14.2.1.4.1 
Summary of Synovial Volume (mm3), WOMAC A 50% Responders 
(Imaging Population)
Table 14.2.1.4.2 
Summary of Synovial Volume (mm3), WOMAC A 50% Non-
Responders (Imaging Population) 
Figure 14.2.1.4.1.1 
Mean (+/- SD) Synovial Volume (mm3) over Time, by WOMAC A 
50% Responder (Yes/No) (Imaging Population)
Figure 14.2.1.4.1.2 
LS Mean Change from Baseline (+/- SE) in Synovial Volume (mm3) 
over Time, by WOMAC A 50% Responder (Yes/No) (Imaging 
Population)
Table 14.2.1.5.1 
Summary of Synovial Volume (mm3), Patients with Previous Intra-
Articular Steroid Injection in Index Knee (Imaging Population)


Flexion Therapeutics 
Protocol FX006-2017-014 
05 Nov 2019 
 
Page 33 
CONFIDENTIAL 
Table 14.2.1.5.2 
Summary of Synovial Volume (mm3), Patients without Previous 
Intra-Articular Steroid Injection in Index Knee (Imaging Population) 
Figure 14.2.1.5.1.1 
Mean (+/- SD) Synovial Volume (mm3) over Time, by Previous 
Intra-Articular Steroid Injection in Index Knee (Yes/No) (Imaging 
Population)
Figure 14.2.1.5.1.2 
LS Mean Change from Baseline (+/- SE) in Synovial Volume (mm3) 
over Time, by Previous Intra-Articular Steroid Injection in Index 
Knee (Yes/No) (Imaging Population)
Table 14.2.1.6.1 
Summary of Synovial Volume (mm3), Patients with Screening Joint 
Space Width 2-4 mm (Imaging Population) 
Table 14.2.1.6.2 
Summary of Synovial Volume (mm3), Patients with Screening Joint 
Space Width >4 mm (Imaging Population) 
Figure 14.2.1.6.1.1 
Mean (+/- SD) Synovial Volume (mm3) over Time, by Screening 
Joint Space Width (2-4 mm vs. >4 mm) (Imaging Population) 
Figure 14.2.1.6.1.2 
LS Mean Change from Baseline (+/- SE) in Synovial Volume (mm3) 
over Time, by Screening Joint Space Width (2-4 mm vs. >4 mm) 
(Imaging Population)
Table 14.2.2 
Summary of Bone Area (mm2) (Imaging Population) 
Figure 14.2.2.1 
Mean (+/- SD) Bone Area (mm2) over Time (Imaging Population)
Figure 14.2.2.2 
LS Mean Change from Baseline (+/- SE) in Bone Area (mm2) over 
Time (Imaging Population)
Table 14.2.3.1 
Summary of Cartilage Thickness (mm) (Imaging Population) 
Figure 14.2.3.1.1 
Mean (+/- SD) Cartilage Thickness (mm) over Time (Imaging 
Population)
Figure 14.2.3.1.2 
LS Mean Change from Baseline (+/- SE) in Cartilage Thickness 
(mm) over Time (Imaging Population)
Table 14.2.4 
Summary of Femur Bone Shape Score (Vector Units) (Imaging 
Population) 
Figure 14.2.4.1 
Mean (+/- SD) Femur Bone Shape Score (Vector Units) over Time 
(Imaging Population) 
Figure 14.2.4.2 
LS Mean Change from Baseline (+/- SE) in Femur Bone Shape Score 
(Vector Units) over Time (Imaging Population) 
Table 14.2.5.1 
Summary of WOMAC A Pain Subscale (Efficacy Population) 
Figure 14.2.5.1.1 
Mean (+/- SD) WOMAC A Pain Subscale over Time (Efficacy 
Population)
Figure 14.2.5.1.2 
LS Mean Change from Baseline (+/- SE) in WOMAC A Pain 
Subscale over Time (Efficacy Population)
Table 14.2.5.2 
Summary of WOMAC B Stiffness Subscale (Efficacy Population)
Figure 14.2.5.2.1 
Mean (+/- SD) WOMAC B Stiffness Subscale over Time (Efficacy 
Population)
Figure 14.2.5.2.2 
LS Mean Change from Baseline (+/- SE) in WOMAC B Stiffness 
Subscale over Time (Efficacy Population)


Flexion Therapeutics 
Protocol FX006-2017-014 
05 Nov 2019 
 
Page 34 
CONFIDENTIAL 
Table 14.2.5.3 
Summary of WOMAC C Function Subscale (Efficacy Population)
Figure 14.2.5.3.1 
Mean (+/- SD) WOMAC C Function Subscale over Time (Efficacy 
Population)
Figure 14.2.5.3.2 
LS Mean Change from Baseline (+/- SE) in WOMAC C Function 
Subscale over Time (Efficacy Population)
Table 14.2.5.4 
Summary of WOMAC Total (Efficacy Population) 
Figure 14.2.5.4.1 
Mean (+/- SD) WOMAC Total over Time (Efficacy Population) 
Figure 14.2.5.4.2 
LS Mean Change from Baseline (+/- SE) in WOMAC Total over 
Time (Efficacy Population)
Table 14.2.5.6 
Analysis of WOMAC A 30% Responders (Full Analysis Set) 
Figure 14.2.5.6.1 
Proportion of WOMAC A 30% Responders (Full Analysis Set)
Figure 14.2.5.6.2 
Continuous WOMAC A 30% Responder Curve at Week 12 (Full 
Analysis Set)
Table 14.2.5.7 
Analysis of WOMAC A 50% Responders (Full Analysis Set) 
Figure 14.2.5.7.1 
Proportion of WOMAC A 50% Responders (Full Analysis Set)
Figure 14.2.5.7.2 
Continuous WOMAC A 50% Responder Curve at Week 12 (Full 
Analysis Set)
Table 14.2.6.1 
Summary of KOOS QOL Subscale (Efficacy Population) 
Figure 14.2.6.1.1 
Mean (+/- SD) KOOS QOL Subscale over Time (Efficacy 
Population)
Figure 14.2.6.1.2 
LS Mean Change from Baseline (+/- SE) in KOOS QOL Subscale 
over Time (Efficacy Population)
Table 14.2.7 
Summary of Pain/Stiffness (Efficacy Population) 
Table 14.2.8 
Correlation between Baseline IL-1β mRNA Level (ΔΔct) and 
Imaging Endpoints Change from Baseline (Patients in the Imaging 
and Biomarker Populations)
Figure 14.2.8.1 
Scatter Plots of Baseline IL-1β mRNA Level (ΔΔct) and Synovial 
Volume (mm3) Change from Baseline at Week 6 and Week 24 
(Patients in the Imaging and Biomarker Populations) 
Figure 14.2.8.2 
Scatter Plots of Baseline IL-1β mRNA Level (ΔΔct) and Bone Area 
(mm2) Change from Baseline at Week 6 and Week 24 (Patients in the 
Imaging and Biomarker Populations)
Figure 14.2.8.3 
Scatter Plots of Baseline IL-1β mRNA Level (ΔΔct) and Cartilage 
Thickness Change (mm) from Baseline at Week 6 and Week 24 
(Patients in the Imaging and Biomarker Populations) 
Figure 14.2.8.4 
Scatter Plots of Baseline IL-1β mRNA Level (ΔΔct) and Femur Bone 
Shape Score (Vector Units) Change from Baseline at Week 6 and 
Week 24 (Patients in the Imaging and Biomarker Populations) 
Table 14.3.1.1 
Summary of Treatment-Emergent Adverse Events (Safety 
Population)


Flexion Therapeutics 
Protocol FX006-2017-014 
05 Nov 2019 
 
Page 35 
CONFIDENTIAL 
Table 14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term (Safety Population)
Table 14.3.1.3 
Treatment-Emergent Adverse Events by Preferred Term (Safety 
Population)
Table 14.3.1.4 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term - Related to Study Drug (Safety Population) 
Table 14.3.1.5 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term - Related to Injection Procedure (Safety Population)
Table 14.3.1.6 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term by Maximum Severity (Safety Population) 
Table 14.3.1.7 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term – Leading to Study Discontinuation (Safety 
Population)
Table 14.3.1.8 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term – Leading to Death (Safety Population) 
Table 14.3.1.9 
Index Knee-Related Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term (Safety Population) 
Table 14.3.1.10 
Index Knee Related Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term- Related to Study Drug (Safety 
Population)
Table 14.3.1.11 
Index Knee Related Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term by Maximum Severity (Safety 
Population)
Table 14.3.1.12 
Serious Adverse Events by System Organ Class and Preferred Term 
(Safety Population)
Table 14.3.2.1 
Patient Listing of Deaths
Table 14.3.2.2 
Patient Listing of Serious Adverse Events
Table 14.3.2.3 
Patient Listing of Discontinuations Due to Adverse Events 
Table 14.4.1.1 
Summary and Change from Baseline for Hematology Parameters by 
Visit (Safety Population)
Table 14.4.1.2 
Summary and Change from Baseline for Chemistry Parameters by 
Visit (Safety Population)
Table 14.4.2 
Summary and Change from Baseline for Vital Signs by Visit (Safety 
Population)
Table 14.4.3 
Summary of Index Knee Assessments (Safety Population) 
 
 
 
7.1. Data Listings to be Generated 
 
Listing 16.2.1.1 
Patient Disposition
Listing 16.2.1.2 
Inclusion/Exclusion Criteria Not Met


Flexion Therapeutics 
Protocol FX006-2017-014 
05 Nov 2019 
 
Page 36 
CONFIDENTIAL 
Listing 16.2.2 
Protocol Deviations
Listing 16.2.3 
Analysis Populations
Listing 16.2.4.1 
Demographics and Baseline Characteristics
Listing 16.2.4.2 
Medical History
Listing 16.2.4.3 
Medical History – Index Knee Osteoarthritis
Listing 16.2.4.4 
Medical History - Prior Treatment of Knee Osteoarthritis 
Listing 16.2.4.5 
Medical History - Other Osteoarthritis
Listing 16.2.4.6 
Medical History - Other Osteoarthritis Procedures or Surgeries
Listing 16.2.4.7 
Screening Index Knee X-ray Results
Listing 16.2.5 
Study Drug Exposure
Listing 16.2.6.1.1 
MRI Collection Data
Listing 16.2.6.1.2 
Synovial Volume
Listing 16.2.6.1.3 
Bone Area and Cartilage Thickness
Listing 16.2.6.1.4 
Bone Shape
Listing 16.2.6.1.5 
Femur Bone Volume
Listing 16.2.6.2.1 
WOMAC Questionnaire – List of Questions by Section 
Listing 16.2.6.2.2 
WOMAC A Pain Subscale
Listing 16.2.6.2.3 
WOMAC B Stiffness Subscale
Listing 16.2.6.2.4 
WOMAC C Function Subscale
Listing 16.2.6.2.5 
WOMAC Total (Subscale Means and Total Score) 
Listing 16.2.6.3.1 
KOOS QOL Subscale - List of Questions
Listing 16.2.6.3.2 
KOOS QOL Subscale
Listing 16.2.6.4.1 
Pain and stiffness – List of Questions
Listing 16.2.6.4.2 
Pain and stiffness
Listing 16.2.6.5.1 
Biomarker Assessments - IL-1β 
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 Assessments – Hematology
Listing 16.2.8.2 
Laboratory Assessments – Chemistry
Listing 16.2.8.3 
Laboratory Assessments – eGFR
Listing 16.2.8.4 
Screening Laboratory Assessments 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 Knee Assessments
Listing 16.2.9.4 
Ultrasound Results


Flexion Therapeutics 
Protocol FX006-2017-014 
05 Nov 2019 
 
Page 37 
CONFIDENTIAL 
Listing 16.2.9.5 
Electrocardiogram Results
Listing 16.2.9.6 
Prior and Concomitant Medications
Listing 16.2.9.7 
Index Knee Aspiration
Listing 16.2.9.8 
Surgical Procedures
 

ICF_001.pdf: 
Flexion Therapeutics, Inc. / Protocol Number FX006-2017-014 
Page 1 of 14   
  
 
Subject Information and Consent Form  
  
 
 
Initials __________    Date __________  
 
«PiFullName» 
Advarra IRB Approved Version 9 May 2019 
Revised «PIApprovalDate» 
 
 
Sponsor / Study Title: 
  
Flexion Therapeutics, Inc. / “An Open-Label Study to 
Evaluate the Effect of the Administration of  
FX006 on Synovial Inflammation in Patients with 
Osteoarthritis of the Knee” 
 
Protocol Number: 
 
FX006-2017-014  
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Additional Contact(s): 
(Study Staff) 
 
«AdditionalStaffMemberContacts» 
 
Address: 
«PiLocations» 
 
 
READ THE FOLLOWING CAREFULLY  
You are being invited to participate in a drug research study.  Before you give your 
consent to be part of this study, please read the following and ask as many questions as 
necessary to be sure that you understand what your participation will involve.    
PURPOSE OF STUDY  
The study doctor is participating in a research study being conducted by Flexion 
Therapeutics, Inc. (the Sponsor) evaluating a drug called FX006. FX006 is approved in 
the United States to manage Osteoarthritis (OA) pain of the knee. OA produces pain in 
the knee (and other joints) that typically is worsened by activities such as long distance 
walking and is alleviated by rest. You are being asked to take part in this research study 
because you have OA of the knee.  
The purpose of this research study is to evaluate the effect of a single intra-articular (IA) 
(into the joint) injection of FX006 to control inflammation in the knee. This will be 
measured by checking the fluid volume in the study knee by an imaging technique called 
Magnetic Resonance Imaging (MRI).  
Be aware that this consent form refers to FX006 as “study drug.”  
FX006 is approved in the United States under the trade name Zilretta for single injection 
in the knee for osteoarthritis.   


Flexion Therapeutics, Inc. / Protocol Number FX006-2017-014 
Page 2 of 14   
  
 
Subject Information and Consent Form  
  
 
 
Initials __________    Date __________  
 
«PiFullName» 
Advarra IRB Approved Version 9 May 2019 
Revised «PIApprovalDate» 
 
About 100 participants will participate in this study at approximately 10 different research 
sites.  The expected length of time of your participation in the study will be up to 28 weeks 
(including the screening period).    
If you agree to participate in this study, you will be asked not to take the following 
medications during the study:  
   
• 
Topical (applied to the skin) or oral NSAIDs [aspirin] (from 5 days prior to Pre-
treatment MRI through Week 6, and again from 5 days prior to Week 24 MRI)  
• 
Intravenous (IV), Intramuscular (IM) or oral corticosteroids   
• 
Intraarticular (IA) corticosteroids in any joint   
• 
Any IA intervention in the study knee including aspiration (removing fluid) or the 
injection of any approved or investigational agent, including 
viscosupplementation (hyaluronic acid, which acts as a lubricating fluid)  
• 
Any investigational drug, device or biologic  
• 
Immunomodulators, immunosuppressives, or chemotherapeutic agents (all of 
which can alter your body’s ability to fight off foreign substances)  
• 
Live or attenuated (weakened) vaccines  
 
PROCEDURES TO BE FOLLOWED DURING THE STUDY  
The study involves a Screening period (which may occur up to 28 days prior to Study Day 
1) and 5 study visits following the Study Day 1 visit, for a total of 4 visits at the study site 
and 2 follow-up telephone calls. If you agree to participate in this study, you will need to 
sign this form. The study doctor will then need to determine whether this study is suitable 
for you.  If you do not meet the requirements of this study, your participation will end with 
the screening visit.  Below is a description of what will be expected to occur.  
If you decide to be in this study, you might have to stop taking or change the dose 
of your regular medication(s) during the entire study as noted above.    
 
Screening Period   
Screening for this study will occur up to 28 days before you receive study drug.  This visit 
to your study doctor should not take more than 3 hours.   
During Screening the following information will be reviewed with you to determine whether 
you are eligible to participate in this study:  
• 
Medical history, including a detailed review of your OA medical history in your 
study knee  


Flexion Therapeutics, Inc. / Protocol Number FX006-2017-014 
Page 3 of 14   
  
 
Subject Information and Consent Form  
  
 
 
Initials __________    Date __________  
 
«PiFullName» 
Advarra IRB Approved Version 9 May 2019 
Revised «PIApprovalDate» 
 
• 
Medications and treatments you have taken including any surgeries or therapy you 
have had. For your safety, it is very important to tell the study doctor about all 
medications you are taking, including herbal or “natural” remedies, and to check 
with the study doctor before you begin taking a new medication while on this study.  
  
You will also have the following evaluations performed to determine whether you are 
eligible to participate in this study:  
• 
Physical Exam (including weight and height)  
• 
X-ray of your study knee  
• 
Assessment of your study knee  
• 
Electrocardiogram (ECG) – measures the electrical activity of your heart  
• 
Vital signs – blood pressure, heart rate, breathing rate and temperature  
• 
Blood sample collection (about 1 teaspoon) to perform routine laboratory tests, 
including kidney function, and a pregnancy test (only if you are a woman able to 
become pregnant, that means, you are not surgically sterile or have not been 
postmenopausal for at least 1 year),  
o An additional 2 teaspoons of blood will be sampled for infectious diseases 
including Human Immunodeficiency Virus (HIV), Hepatitis B and C.In order 
to take part in this study, you must agree for the HIV and Hepatitis tests to 
be performed on samples of your blood. Depending on local laws, you may 
have to sign a separate consent form before this testing can start.  If you do 
not want to have the tests, or if you do not wish to be told in the event that 
some of these tests are abnormal, you should not take part in this study. 
Accordingly, local laws may require the reporting of positive results.  You 
may prefer to discuss the HIV and Hepatitis tests further with an 
independent counselor. Your study doctor can arrange this for you.  If a 
positive result for hepatitis or HIV is found, your study doctor will inform your 
family physician and the local public health authority as required by law.  
The results of these tests must be negative in order for you to be in the 
study.   
o The study doctor or study staff will tell you if the pregnancy test results are 
positive.  The results of the pregnancy test must be negative in order for you 
to be in the study.  
• 
Questionnaire about how much pain, function and stiffness you have in your study 
knee  


Flexion Therapeutics, Inc. / Protocol Number FX006-2017-014 
Page 4 of 14   
  
 
Subject Information and Consent Form  
  
 
 
Initials __________    Date __________  
 
«PiFullName» 
Advarra IRB Approved Version 9 May 2019 
Revised «PIApprovalDate» 
 
If your study doctor determines that you are eligible after the screening evaluations are 
completed and all results are received, you will be invited to take part in the study.  You 
will be expected to make every effort to keep your scheduled visits in the study.  If you 
think you will be unable to meet this responsibility, please inform the study doctor as soon 
as possible.   
Pre-Treatment 
You will attend the study clinic within 10 days prior to the planned injection in order to 
have the following procedures completed: 
• 
Ultrasound examination of your study knee – an ultrasound examination uses high 
frequency sound waves to look at structures inside the body.  
• 
MRI of your study knee – This test uses powerful magnets, radio waves, and a 
computer to take pictures inside your body. You will lie on a table inside the MRI 
machine which is a large tube with a hole at both ends.  The MRI test will include 
administration of contrast agent (dye) to provide special pictures of your knee.  
Contrast agent is administered through an intravenous catheter (a small tube 
placed in your vein) inserted in your arm.    
Once it is confirmed that the MRI is acceptable, you will be scheduled to come in for the 
Study Day 1 visit. 
Treatment Period  
Study Day 1  
You will attend the study clinic on the day that your study knee will be injected with the 
study drug (Study Day 1).  On Study Day 1, your study doctor will perform several 
evaluations to make sure you are still eligible for the study.  These procedures and tests 
include:    
• 
Review of eligibility criteria  
• 
Updated medical history  
• 
Review of prior treatment and medications  
• 
Examination and assessment of your study knee  
• 
Vital signs - blood pressure, heart rate, breathing rate and temperature  
• 
Blood sample collection (about 1 teaspoon) for testing of markers (Interleukin-1 
Beta) for the presence of inflammation phenotypes (observable traits) that may be 
associated with your OA.  


Flexion Therapeutics, Inc. / Protocol Number FX006-2017-014 
Page 5 of 14   
  
 
Subject Information and Consent Form  
  
 
 
Initials __________    Date __________  
 
«PiFullName» 
Advarra IRB Approved Version 9 May 2019 
Revised «PIApprovalDate» 
 
• 
Urine sample collection to perform a pregnancy test (only if you are a woman able 
to become pregnant)  
• 
Questionnaires about how much pain, function and stiffness you have in your 
study knee and quality of life  
After those assessments are complete, a study doctor will clean your study knee with a 
bactericidal solution and a numbing agent will be used based on standard of care at your 
study site. The study doctor will place a needle inside your knee joint and withdraw 
(aspirate) any joint fluid from your study knee.  You will then receive your study drug 
given as a single direct injection into the study knee joint through the same needle used 
to aspirate your knee.  
The Joint fluid removed from your knee will be kept for a maximum of 5 years for potential 
future testing of biomarkers that may be associated with your OA. There is no plan to 
complete genetic testing as part of this potential testing. You will be able to withdraw your 
consent at any time that these samples are held in storage by sending a letter to your 
study doctor.   
The study staff will assess how you are feeling during and after you receive study drug. 
You will be advised to avoid strenuous activities or prolonged weight-bearing activities for 
approximately 24 to 48 hours following the injection. You may need to stay at the study 
clinic after the injection if the study doctor feels you need to be monitored longer.   
Follow-up Period (Through Week 24)  
You should contact the study doctor if you think you may be having a side effect of the 
study drug at any time during the course of this study.  
You will return to the clinic for 2 additional visits after Study Day 1, and you will have 2 
follow-up phone calls with the site staff. Each visit will last up to 2 hours, depending on 
the procedures performed. During each visit, the study staff will discuss with you how you 
have been feeling, any health problems that you are having, and what medications you 
have taken since the last visit.  You will have the following tests performed: 
  Week 6 (± 7 days) 
• 
Blood sample collection (about 1 teaspoon) to check your kidney function. This is 
done within 30 days of the Week 6 to make sure it is safe for you to receive the 
contrast agent for the MRI at your Week 6 (± 7 days) visit 
• 
Examination and assessment of your study knee  
• 
MRI test of your study knee  
• 
Questionnaires about how much pain, function and stiffness you have in your 
study knee and about your quality of life  


Flexion Therapeutics, Inc. / Protocol Number FX006-2017-014 
Page 6 of 14   
  
 
Subject Information and Consent Form  
  
 
 
Initials __________    Date __________  
 
«PiFullName» 
Advarra IRB Approved Version 9 May 2019 
Revised «PIApprovalDate» 
 
Week 12 (± 7 days) Phone Call and Week 18 (± 7 days) Phone Call  
• 
The study staff will ask you questions over the phone about how much pain, 
function and stiffness you have in your study knee  
Week 24/End of Study (± 7 days)  
• 
Blood sample collection (about 1 teaspoon) to check your kidney function. This is 
done within 30 days of the Week 24 visit to make sure it is safe for you to receive 
the contrast agent for the MRI at your Week 24/End of Study (± 7 days) visit 
• 
Physical Examination (including height and weight)  
• 
Assessment of your study knee  
• 
MRI of your study knee  
• 
Vital Signs (blood pressure, heart rate, breathing rate and temperature)  
• 
Blood sample collection to perform routine laboratory tests (about 1 teaspoon)  
• 
Urine sample collection to perform a pregnancy test (only if you are a woman able 
to become pregnant)  
• 
Questionnaires about how much pain, function and stiffness you have in your 
study knee and about your quality of life  
FORESEEABLE RISKS AND DISCOMFORTS   
All drugs may cause side effects.  There is a risk that your condition may not improve with 
any treatment received on this study.  
The active ingredient in FX006 is triamcinolone acetonide. Triamcinolone acetonide is a 
corticosteroid that has been injected into the knees of people with osteoarthritis for many 
years. FX006 keeps triamcinolone acetonide in the joint longer than injections of other 
forms of triamcinolone acetonide.  
Injection of corticosteroids into joints is a common medical procedure, with approximately 
six million injections in the United States each year. The risks associated with the 
injection of corticosteroids into joints have been well studied. In completed studies, a total 
of 687 patients have been injected with a single injection of FX006. To date there have 
been no new safety concerns compared to the known effects of triamcinolone acetonide.  
The most common side effects (two percent or more of the time) seen to date in 
participants treated with FX006 are the following:  
• 
Joint pain (9.8%)  
• 
Joint swelling (2.8%)  
• 
Headaches (5.4%)  
• 
Upper respiratory infection (3.1%)  


Flexion Therapeutics, Inc. / Protocol Number FX006-2017-014 
Page 7 of 14   
  
 
Subject Information and Consent Form  
  
 
 
Initials __________    Date __________  
 
«PiFullName» 
Advarra IRB Approved Version 9 May 2019 
Revised «PIApprovalDate» 
 
• 
Back pain (2.3%)  
• 
Bruising (2.3%)  
• 
Cold symptoms (2.2%)  
 
There is a rare chance that the procedure may not be able to be completed, or that you 
will not receive the entire amount of the study drug. If this happens, you will be informed 
by site personnel and will complete all assessments through the end of the study.  
 
Possible side effects of corticosteroids outside of the knee joint: For people with 
diabetes, there may be a temporary hyperglycemia (increase in blood sugar) associated 
with injection. There may be temporary elevated blood pressure associated with injection. 
Injection of corticosteroids is sometimes associated with a flushing (reddening) reaction of 
the face and upper body. Rarely, corticosteroid injections have been associated with a 
temporary feeling of numbness and weakness in the limbs. Also rarely, repeated 
corticosteroid injections have been associated with conditions limiting the body’s ability to 
fight infections or causing low blood pressure, changes in weight and fat deposits, or an 
allergic reaction. These rare events could possibly be life threatening.   
Possible side effects of corticosteroids specific to the knee joint: The most common 
side effects in the joint from injected corticosteroids are thinning and lightening of the skin 
at the site of injection.  Injection of corticosteroids has been associated with joint infection 
and joint deterioration has also been reported.  
Ask the study doctor if you have questions about the signs or symptoms of any side 
effects that you read about in this consent form.  
Allergic Reaction: Sometimes people have allergic reactions to drugs. If you have a very 
bad allergic reaction, you could die. Some things that happen during an allergic reaction 
that could be a sign or symptom of a life-threatening allergic (anaphylaxis) are:  
• 
a rash  
• 
having a hard time breathing  
• 
wheezing  
• 
a sudden drop in blood pressure (making you feel dizzy or lightheaded)  
• 
swelling around the mouth, throat, or eyes  
• 
a fast pulse  
• 
sweating  
You should get medical help and contact the study doctor or staff if you have any of these 
or other side effects during the study.  Please tell the study doctor if you have ever had 
allergic reactions that included any of these signs or symptoms in the past. 


Flexion Therapeutics, Inc. / Protocol Number FX006-2017-014 
Page 8 of 14   
  
 
Subject Information and Consent Form  
  
 
 
Initials __________    Date __________  
 
«PiFullName» 
Advarra IRB Approved Version 9 May 2019 
Revised «PIApprovalDate» 
 
Stopping Regular Medication: If you stop or change the dose of your regular medication 
to be in the study, your osteoarthritis symptoms might come back or get worse. Please tell 
the study doctor or staff right away if you have any problems when you stop using or 
change the dose of your regular medication.   
Joint Fluid Removal: Joint fluid will be removed from the study knee prior to 
intraarticular injection of study drug. There is a risk of infection as well as fainting with 
joint fluid removal.  
Injection into the joint: The study drug will be injected into the study knee joint. 
Injections of corticosteroids into the knee may result in pain, swelling, restriction of joint 
movement, and infection of the joint. Rarely, there may be a flare reaction that 
simultaneously produces pain, warmth, joint swelling, and fluid in the joint that will last for 
days or weeks. In addition, injections carry a risk of damage to blood vessels, muscles, 
nerves, and other tissues. Rarely, multiple injections of joints have been associated with 
deterioration of joint structures.  
Blood Samples: Blood sampling may cause pain, bleeding and/or bruising at the site 
where the needle enters the skin. Lightheadedness, dizziness, fainting, and in rare cases, 
infection, may occur.   
Electrocardiogram (ECG):  The only known complication from a diagnostic ECG is 
possible skin irritation from the ECG electrode pads or discomfort when removing the 
pads.  
X-Ray: There is exposure to small amounts of radiation with X-ray. The risk of developing 
a radiation-induced cancer or cataracts at some time later in life or defects due to 
damaged ovarian cells or sperm cells is very low.   
MRI:  During the MRI, you may feel mild vibrations in your body. The machine will 
produce a loud knocking noise. This is normal. You may receive earplugs or earphones to 
protect your ears. The scanner used in the MRI is a small space. Some people may feel 
uncomfortable or become anxious while in the scanner. The scanner has an intercom, 
which lets you to speak to the staff during the procedure. If you feel ill or anxious during 
scanning, tell the MRI staff and the scanning will be stopped if you wish. The MRI will 
require a catheter to be inserted into one of your veins to inject the MRI contrast agent.  
The contrast agent gadolinium will be injected into your vein to enhance visibility.  You 
may experience coolness, minor swelling, pain, bleeding and/or bruising at the injection 
site.  The most common risks associated with gadolinium are rash and hives. Rarely, mild 
nausea, headache, temporary low blood pressure, chest pain, back pain, fever, 
weakness, seizures and shortness of breath from narrowing of the air tubes in your lungs 
may occur.  A rare and severe disease called nephrogenic systemic fibrosis (involves 
fibrosis/hardening of skin, joints, eyes, and internal organs) has occurred in certain 


Flexion Therapeutics, Inc. / Protocol Number FX006-2017-014 
Page 9 of 14   
  
 
Subject Information and Consent Form  
  
 
 
Initials __________    Date __________  
 
«PiFullName» 
Advarra IRB Approved Version 9 May 2019 
Revised «PIApprovalDate» 
 
individuals with severe kidney disease who received gadolinium-based contrast agents.  
There is no risk for this disease in individuals with normal or mild problems in kidney 
function.  Before you undergo the MRI with contrast, your study doctor will determine if 
the contrast dye is safe for you. The MRI scan does not expose you to x-ray radiation. 
You may have an allergic reaction to the contrast agent. If you have implants containing 
metal, you face certain risks. The magnets used in an MRI can cause problems with 
pacemakers or make implanted screws or pins shift in the body. If you have metal or a 
device in your body, you must inform your study doctor. 
Ultrasound: Diagnostic ultrasound is a safe procedure that uses low-power sound 
waves. There are no known risks. If your knee is tender, the ultrasound exam could hurt a 
bit.  
Questionnaires:  Filling out the questionnaires could lead you to feel uncomfortable or 
upset. Please tell the study doctor or staff if you feel uncomfortable or upset while filling 
out a questionnaire at the site or over the phone. You have the right to refuse to answer 
any questions.  
Loss of Confidentiality: There is a risk of loss of confidentiality of your information that 
is used in this study.  You will read more about the protection of your information later in 
this form.  Please ask the study doctor or study staff if you would like to know more about 
how your information will be protected while you are in this study. 
For Men:  Specific risks of FX006 to the male reproductive system are unknown at this 
time. However, the following risks are defined for corticosteroids in general including 
Kenalog-40®: Corticosteroids may increase or decrease motility and number of 
spermatozoa in some people. If your partner becomes pregnant during the study or 
through Week 24 if you discontinue early, you must tell the study doctor immediately. The 
study doctor will advise you regarding your partner’s further medical care and your study 
participation.  The study doctor or study staff will ask for information about the pregnancy 
and the birth of the baby. The study doctor or study staff will share this information with 
the sponsor and institutional review board (IRB) (a group of people who review research 
studies to protect the rights and welfare of research participants).  
For Women: Specific risks of FX006 to the female reproductive system and to the human 
embryo, fetus, or nursing infant are unknown at this time. Some drugs can cause 
premature (early) birth or birth defects. However, the risks are defined for corticosteroids 
in general including Kenalog-40®.  Corticosteroids taken by the mother have been shown 
to cause birth defects and affect infant growth.     
You cannot take part in this study if you are pregnant or nursing an infant. If you are 
a woman who is able to become pregnant, you must agree not to become pregnant 
during your participation in this study or through Week 24 if you discontinue early.  


Flexion Therapeutics, Inc. / Protocol Number FX006-2017-014 
Page 10 of 14   
  
 
Subject Information and Consent Form  
  
 
 
Initials __________    Date __________  
 
«PiFullName» 
Advarra IRB Approved Version 9 May 2019 
Revised «PIApprovalDate» 
 
Female and male participants must use birth control throughout the study. The form of 
birth control you use must be discussed with, and approved by, the study doctor before 
you begin the study. You must agree to use one of the following effective birth control 
methods:  abstinence (if this is consistent with your lifestyle), oral, injected, or implanted 
hormonal methods of contraception, condoms, a diaphragm or cervical cap with 
spermicidal foam/gel/film/cream/suppository, intrauterine device (IUD), intrauterine 
system, or intercourse with a surgically sterile partner (post-vasectomy/hysterectomy, or 
tubal ligation) are acceptable for use during the study. The birth control methods listed are 
not totally effective in preventing pregnancy. If you or your partner becomes pregnant 
during the study, you must tell the study doctor immediately. The study doctor will advise 
you regarding your further medical care and study participation.  The study doctor or 
study staff will ask for information about the pregnancy and the birth of the baby. The 
study doctor or study staff will share this information with the sponsor and IRB.  
Unknown Risks:  There may be risks associated with the injection of FX006 that are not 
currently known. You could have problems which include your osteoarthritis of the knee 
getting worse or even death. Significant new findings that develop during the course of 
the study which may relate to your willingness to continue participation will be provided to 
you in a timely manner.     
Although unlikely, if you suffer a serious or lasting injury as a result of participation in this 
study, it may affect your ability to obtain private health insurance, your employability, 
and/or quality of life.  
If you experience any side effects, you should contact the study doctor immediately.  
Please tell them if you have any other problems with your health or the way you feel 
during the study, whether or not you think these problems are related to the study drug.  
COMPENSATION FOR STUDY-RELATED INJURY   
If you have any questions during the study or if you experience a side effect or research 
related injury, contact the study doctor.  
In the event of a research-related injury, necessary medical treatment will be provided 
primarily through the study doctor.  The Sponsor will reimburse you the reasonable costs, 
in excess of what is covered by your private medical health insurance; of any immediate 
care and/or treatment you receive for injury that is determined by the study doctor to be a 
direct result of the use of the FX006.  The study doctor shall determine the medical care 
which is necessary and appropriate.  If there is an emergency, please seek immediate 
treatment outside of the study doctor if you are not able to reach the study doctor. Injury 
or illness resulting from the use of the FX006 does not include the normal progression of 
your disease or any underlying pre-existing medical conditions.    


Flexion Therapeutics, Inc. / Protocol Number FX006-2017-014 
Page 11 of 14   
  
 
Subject Information and Consent Form  
  
 
 
Initials __________    Date __________  
 
«PiFullName» 
Advarra IRB Approved Version 9 May 2019 
Revised «PIApprovalDate» 
 
You agree to cooperate in obtaining any proceeds from insurance or other third-party 
coverage that may be available. There are no plans to provide other financial 
compensation (including without limitation) for such things as lost wages, disability, or 
discomfort due to research-related injury.    
Be aware that your health care payer/insurer might not cover the costs of study-related 
injuries or illness.  Provision of medical care and/or payment of medical expenses does 
not imply fault or wrongdoing on the part of the Sponsor, your study doctor, or the study 
site. If you experience an injury or side effects, you should contact your study doctor listed 
on page 1.    
Please note that you do not give up any of your legal rights by signing this consent form, 
including your right at law to claim compensation for injury where you can prove 
negligence.  
POTENTIAL BENEFITS OF THE STUDY  
No direct benefit is guaranteed to you from taking part in this study. Your condition may 
improve, remain the same, or worsen during the study.  It is expected that new 
information, which may benefit participants or society in general, will be obtained by this 
study.    
SPONSORING COMPANY  
Flexion Therapeutics, Inc. will pay the study doctor (and/or the study clinic) for conducting 
this study and for your participation. 
 
COSTS  
The study drug, clinical evaluations, and study procedures will be provided at no charge 
to you, your private medical insurance (if any), or the public health insurance plan.   
PAYMENT  
<<Site Specific Compensation language>> 
 
Your participation in this study may contribute to the development of FX006, from which 
the Sponsor or others may receive economic benefit.  You will have no rights to any 
patents or discoveries arising from this study and you will receive no economic benefit.    
ALTERNATIVE TREATMENT  
Instead of taking part in this study, you may choose to receive no treatment or to receive 
standard treatment, which may include medications such as Tylenol®, non-steroidal anti-


Flexion Therapeutics, Inc. / Protocol Number FX006-2017-014 
Page 12 of 14   
  
 
Subject Information and Consent Form  
  
 
 
Initials __________    Date __________  
 
«PiFullName» 
Advarra IRB Approved Version 9 May 2019 
Revised «PIApprovalDate» 
 
inflammatory drugs such as Advil®, other IA steroids like TCA IR (commonly referred to 
as cortisone shots), hyaluronic acid such as Synvisc-One®, other pain therapies, physical 
therapy or surgery. The risks and benefits of alternative (other) standard treatments and 
courses of therapy will be explained to you by the study doctor. The study doctor will 
answer any questions you have about these other treatments. In addition, you may 
discuss your options with your regular health care provider.  
FX006 is approved in the United States for a single injection in the knee. The study doctor 
will discuss treatment options with you at the end of the study.  
VOLUNTARY PARTICIPATION / WITHDRAWAL FROM STUDY  
Your participation in this study is voluntary. You may refuse to participate, or withdraw 
from the study at any time, without penalty or loss of benefits to which you are otherwise 
entitled.  This will not affect the medical care you receive from the study doctor. You must 
tell the study doctor if you wish to stop taking part in the study. Your participation in this 
study may be discontinued, without your consent, at any time by the study doctor if 
he/she believes that participation in the study is no longer in your best interest or if the 
study is stopped by the Sponsor.  The regulatory authorities (for example, US Food and 
Drug Administration), or the Sponsor may also discontinue your participation in the study.   
If you decide to withdraw from the study or the study doctor requests your withdrawal, you 
will be asked to have a final visit for safety reasons.  If you leave the study, the study 
doctor and study staff will still be able to use your information that they have already 
collected.    
WHOM TO CONTACT ABOUT THIS STUDY 
During the study, if you experience any medical problems, suffer a research-related 
injury, or have questions, concerns or complaints about the study, please contact the 
Investigator at the telephone number listed on the first page of this consent document.  If 
you seek emergency care, or hospitalization is required, alert the treating physician that 
you are participating in this research study.   
 
An institutional review board (IRB) is an independent committee established to help 
protect the rights of research subjects.  If you have any questions about your rights as a 
research subject, and/or concerns or complaints regarding this research study, contact: 
 


Flexion Therapeutics, Inc. / Protocol Number FX006-2017-014 
Page 13 of 14   
  
 
Subject Information and Consent Form  
  
 
 
Initials __________    Date __________  
 
«PiFullName» 
Advarra IRB Approved Version 9 May 2019 
Revised «PIApprovalDate» 
 
By mail: 
Study Subject Adviser 
Advarra IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
• or call toll free:        877-992-4724 
• or by email:              adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00026180. 
 
CONFIDENTIALITY  
To the extent permitted by laws and/or regulations, your medical records will be kept 
confidential and will not be made publicly available. As part of this research, the study 
doctor will collect the results of your study-related tests, including results of tests for HIV 
and other communicable diseases and illegal drug use, and procedures and may also 
access your personal medical records for health information such as past medical history 
and test results.  
Information from this study will be submitted to the Sponsor, Sponsor’s representatives or 
other entities the Sponsor does business with, and to the US Food and Drug 
Administration and possibly to governmental agencies in other countries where the study 
drug may be considered for approval. The information obtained from this study, including 
the results of all tests you undergo, will be held in both computerized and manual filing 
systems.  Except as required by law, you will not be identified on any study form by name, 
address, telephone number or any other direct personal identifier. Instead, you will be 
assigned a participant identification number. The study doctor will keep a list that matches 
participant identification numbers to participant names, but the study doctor will not send 
that list to the Sponsor.  However, the study forms will contain other information about 
you, such as your age, sex and medical history. It is possible that this other information 
could be used to identify you even though your name does not appear.    
 
The results of this research may be presented at scientific or medical meetings or 
published in scientific journals, but your identity will not be made known.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  At 
most, the Web site will include a summary of the results.  You can search this Web site at 
any time.   


Flexion Therapeutics, Inc. / Protocol Number FX006-2017-014 
Page 14 of 14   
  
 
Subject Information and Consent Form  
  
 
 
Initials __________    Date __________  
 
«PiFullName» 
Advarra IRB Approved Version 9 May 2019 
Revised «PIApprovalDate» 
 
AGREEMENT OF DECISION TO PARTICIPATE  
I have been given enough time to read this consent. This study has been explained to my 
satisfaction and all of my questions relating to taking the study drug, the study 
procedures, possible risks and discomforts, and side effects have been answered.  I have 
been given the opportunity to consider whether or not to participate. If I have any further 
questions regarding this study, or in the event of a study-related injury, I should contact 
the appropriate person named above.  I voluntarily agree to take part in this study.  By 
signing this document, I have not waived any of my legal rights.  
I authorize the collection, access, use and disclosure of my information as described 
above.  
I will receive a copy of this signed informed consent form.  
  
  
  
__________________  
Printed Name of Subject    
  
  
  
  
Time of Signature  
  
  
  
  
  
  
 
  
Signature of Subject  
  
Date  
   
I have given a verbal explanation of the research study, its procedures and risks and I 
believe that the participant has understood that explanation.  I attest that the participant 
had enough time to consider this information, had an opportunity to ask questions, and 
voluntarily agreed to be in this study.   
  
  
  
____________________  
Printed Name of Person Obtaining Consent  
  
  
Time of Signature  
  
  
  
 
  
Signature of Person Obtaining Consent   
  
  
Date  

Prot_000.pdf: 
 
CONFIDENTIAL INFORMATION 
CLINICAL STUDY PROTOCOL 
 
An Open-Label Study to Evaluate the Effect of the Administration of FX006 on Synovial 
Inflammation in Patients with Osteoarthritis of the Knee 
 
PROTOCOL NUMBER:   
FX006-2017-014 
 
EudraCT Number: 
2018-000529-30 
 
UTN NUMBER:  
U1111-1214-3078 
 
PHASE:   
3b 
 
STUDY MEDICATION(S): FX006 
 
INDICATION:   
Osteoarthritis of the knee 
  
MEDICAL MONITOR:  
Scott Kelley, MD 
 
Chief Medical Officer 
 
Flexion Therapeutics 
Tel: 781-305-7142 
 
 
 
SPONSOR:   
Flexion Therapeutics 
 
10 Mall Road 
 
Burlington, MA 01803 
 
Tel: 781-305-7777 
 
DATE:   
12 July2019 
VERSION:  
6.0 
 
 
SUPERCEDES:  
Version 5.0 
 




Flexion Therapeutics, Inc. 
Protocol FX006-2017-014 
FX006 
Version 6.0 (12 July 2019) 
CONFIDENTIAL 
Page 3 of 54 
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 OA of the Knee .....................................................................18 
5.2.3. 
Toxicology ..................................................................................................................18 
5.2.4. 
Systemic and Local Pharmacokinetics (PK) in Patients with Osteoarthritis 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. 
Conclusion ..................................................................................................................21 
6. 
STUDY OBJECTIVES ..............................................................................................22 
6.1. 
Primary Objective .......................................................................................................22 
6.2. 
Secondary Objectives .................................................................................................22 
6.3. 
Exploratory Objectives ...............................................................................................22 
7. 
INVESTIGATIONAL PLAN .....................................................................................23 
7.1. 
Overall Study Design and Plan ...................................................................................23 
7.2. 
Site Staffing Requirements .........................................................................................23 
7.3. 
Discussion of Study Design ........................................................................................24 
7.3.1. 
Rationale for Study Population ...................................................................................24 
7.3.2. 
Rationale for Dose Selection ......................................................................................24 
7.3.3. 
Rationale for Study Design .........................................................................................24 


Flexion Therapeutics, Inc. 
Protocol FX006-2017-014 
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Version 6.0 (12 July 2019) 
CONFIDENTIAL 
Page 4 of 54 
7.3.4. 
Rationale for Study Parameters ..................................................................................24 
7.3.5. 
Rationale for Control Type .........................................................................................25 
7.4. 
Selection of Study Population ....................................................................................25 
7.4.1. 
Number of Patients .....................................................................................................25 
7.4.2. 
Inclusion Criteria ........................................................................................................25 
7.4.3. 
Exclusion Criteria .......................................................................................................26 
7.4.4. 
Screen Failures ............................................................................................................28 
7.5. 
Treatment Administered .............................................................................................28 
7.5.1. 
Study Medication Treatment Arm(s) ..........................................................................28 
7.5.2. 
Identity of Investigational Product(s) .........................................................................28 
7.5.3. 
Receipt, Preparation, Dispensing, and Storage ...........................................................29 
7.5.4. 
Packaging and Labeling of Study Medication ............................................................29 
7.5.5. 
Return of Study Medication ........................................................................................29 
7.5.6. 
Method of Assigning Patients to Treatment Groups ..................................................29 
7.5.7. 
Blinding ......................................................................................................................29 
7.5.8. 
Study Drug Administration Procedure .......................................................................29 
7.5.9. 
Treatment Compliance ................................................................................................31 
7.5.10. 
Removal of Patients from Therapy or Assessments ...................................................31 
7.6. 
Prior and Concomitant Medications and Therapies ....................................................31 
7.6.1. 
Allowable Medications and Therapies .......................................................................32 
7.6.2. 
Restricted Medications ...............................................................................................32 
7.7. 
Study Variables ...........................................................................................................32 
7.7.1. 
Safety Variables ..........................................................................................................32 
7.7.2. 
Imaging Variables .......................................................................................................32 
7.7.3. 
Efficacy Variables ......................................................................................................32 
7.7.4. 
Biomarker Variables ...................................................................................................33 
7.8. 
Schedule of Study Assessments..................................................................................33 
7.9. 
Study Procedures ........................................................................................................35 
7.9.1. 
Informed Consent .......................................................................................................35 
7.9.2. 
Review of Eligibility, Medical History, Prior Treatment, and Medications ..............35 
7.9.3. 
Physical Examination .................................................................................................35 
7.9.4. 
Index Knee X-ray .......................................................................................................35 
7.9.5. 
Index Knee Ultrasound ...............................................................................................36 


Flexion Therapeutics, Inc. 
Protocol FX006-2017-014 
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Version 6.0 (12 July 2019) 
CONFIDENTIAL 
Page 5 of 54 
7.9.5.1. 
Machine Capabilities ..................................................................................................36 
7.9.5.2. 
Scanning Method ........................................................................................................36 
7.9.5.3. 
Image Capture .............................................................................................................36 
7.9.6. 
Index Knee MRI with Contrast ...................................................................................36 
7.9.7. 
Index Knee Assessment ..............................................................................................37 
7.9.8. 
12-lead ECG ...............................................................................................................37 
7.9.9. 
Vital Signs ..................................................................................................................37 
7.9.10. 
Height, Weight, and BMI Determination ...................................................................37 
7.9.11. 
Synovial Fluid Aspiration ...........................................................................................38 
7.9.12. 
Central Clinical Laboratory Evaluations ....................................................................38 
7.9.13. 
Patient Questionnaires ................................................................................................39 
7.9.14. 
Treatment Administration ...........................................................................................39 
7.9.15. 
Review of Adverse Events and Concomitant Medications ........................................40 
8. 
ADVERSE EVENTS..................................................................................................41 
8.1. 
Definitions ..................................................................................................................41 
8.2. 
Monitoring of Adverse Events ....................................................................................42 
8.2.1. 
Monitoring of Laboratory Assessments and other Diagnostic Tests ..........................42 
8.3. 
Assessment of Adverse Events ...................................................................................42 
8.3.1. 
Assessment of Severity ...............................................................................................42 
8.3.2. 
Assessment of Relationship to Study Medication ......................................................43 
8.4. 
Recording of Adverse Events .....................................................................................43 
8.4.1. 
Reporting of Serious Adverse Events .........................................................................43 
8.4.2. 
Safety Monitoring Roles .............................................................................................44 
8.4.3. 
Clinical Management of Index Knee Related Events .................................................44 
8.4.4. 
Pregnancy ...................................................................................................................45 
9. 
STATISTICAL CONSIDERATIONS .......................................................................46 
9.1. 
Statistical and Analytical Plans ..................................................................................46 
9.1.1. 
Interim Analysis ..........................................................................................................46 
9.1.2. 
Final Analyses ............................................................................................................46 
9.2. 
General Considerations and Methods .........................................................................46 
9.2.1. 
Analysis Populations ..................................................................................................46 
9.2.2. 
Study Data ..................................................................................................................47 
9.2.3. 
Study Variables for Assessment .................................................................................47 


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Protocol FX006-2017-014 
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Page 6 of 54 
9.2.4. 
Sub-Groups and Covariates ........................................................................................47 
9.3. 
Determination of Sample Size ....................................................................................47 
9.4. 
General Statistical Methods ........................................................................................47 
9.4.1. 
Demographics and Baseline Characteristics ...............................................................47 
9.4.2. 
Exposure .....................................................................................................................47 
9.4.3. 
Efficacy Analyses .......................................................................................................47 
9.4.4. 
Safety Analyses ..........................................................................................................48 
9.4.4.1. 
Analysis of Adverse Events ........................................................................................48 
9.4.4.2. 
Other Safety Analyses ................................................................................................48 
10. 
DATA QUALITY ASSURANCE ..............................................................................49 
11. 
DATA HANDLING AND RECORDKEEPING .......................................................50 
11.1. 
Case Report Forms .....................................................................................................50 
11.2. 
Study Medication Accountability ...............................................................................50 
11.3. 
Confidentiality of Data ...............................................................................................50 
11.4. 
Retention of Records ..................................................................................................50 
11.5. 
Protocol Adherence ....................................................................................................51 
12. 
PUBLICATION POLICY ..........................................................................................52 
12.1. 
Sponsor’s Publication Policy ......................................................................................52 
12.2. 
Site Publication ...........................................................................................................52 
13. 
REFERENCES ...........................................................................................................53 
 
 
LIST OF TABLES 
Table 1: 
Schedule of Study Assessments..................................................................................34 
Table 2: 
BMI Calculations ........................................................................................................38 
Table 3: 
Clinical Laboratory Panel ...........................................................................................39 
 
 
 
 
 


Flexion Therapeutics, Inc. 
Protocol FX006-2017-014 
FX006 
Version 6.0 (12 July 2019) 
CONFIDENTIAL 
Page 7 of 54 
1. 
ABBREVIATIONS AND DEFINITION OF TERMS 
ACR 
American College of Rheumatology 
ADP 
Average Daily Pain 
AE 
Adverse Event 
AUE 
Area Under the Effect Curve  
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CGIC 
Clinical Global Impression of Change 
CI 
Confidence Interval 
cm 
Centimeter 
CMC 
Carboxymethylcellulose Sodium 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EULAR 
European League Against Rheumatism 
FBR 
Foreign Body Response 
FDA 
Food and Drug Administration  
FOV 
Field of View 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HPA 
Hypothalamic-pituitary-adrenal 
IA 
Intra-articular 
IB 
Investigator’s Brochure 
IL-1β 
Interleukin 1 beta 
IRB/EC 
Institutional Review Board/Ethics Committee 
IM 
Intramuscular 
IV 
Intravenous 
JSN 
Joint Space Narrowing 
kg 
Kilogram 
KOOS  
Knee injury and Osteoarthritis Outcome Score  
LK 
Likert 
LSM 
Least Square Mean  
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 


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mm 
Millimeter 
MRI 
Magnetic Resonance Imaging 
mRNA 
Messenger Ribonucleic Acid (RNA) 
msec 
Millisecond 
NaCl 
Sodium Chloride 
OA 
Osteoarthritis 
OARSI 
Osteoarthritis Research Society International 
PD 
Pharmacodynamic(s) 
PGIC 
Patients’ Global Impression of Change 
PI 
Principal Investigator 
PLGA 
Poly[lactic-co-glycolic acid] 
PK 
Pharmacokinetic(s) 
PRP 
Platelet Rich Plasma 
QOL 
Quality of Life 
QTc 
QT interval corrected for heart rate 
RBC 
Red Blood Cells 
RNA 
Ribonucleic Acid  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
TEAE 
Treatment-emergent Adverse Event 
TA1 
Triamcinolone Acetonide  
TAcs2 
Triamcinolone Acetonide Injectable Suspension, Immediate-Release 
(commercially available) 
US 
United States of America 
USP 
United States Pharmacopeia 
w/w 
weight by weight 
WBC 
White Blood Cells 
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 
                                                 
1 Abbreviated in past protocols and documents as TCA 
2 Abbreviated in past protocols and documents as TCA-IR 


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2. 
SYNOPSIS 
Title of Study: An Open-Label Study to Evaluate the Effect of the Administration of FX006 on Synovial 
Inflammation in Patients with Osteoarthritis of the Knee 
Study Centers:  Approximately 10 centers 
Study Phase:  3b 
Objectives: 
The primary objective of this study is to assess the effect of a single intra-articular (IA) injection of FX006 32 
milligrams (mg) to control inflammation as measured by a reduction in Magnetic Resonance Imaging (MRI) 
assessed synovial volume in patients with symptomatic osteoarthritis (OA) of the knee and defined synovial volume 
at baseline. 
Secondary objectives of the study include the following: 
• 
To assess the effect of FX006 on pain, stiffness, function and quality of life  
• 
To assess changes in bone area and cartilage thickness of the knee 
Exploratory objectives of the study include the following:  
• 
To assess structural changes in bone, cartilage and meniscus   
• 
To assess changes in contrast enhancement of tissue other than synovial tissue  
• 
To identify Responders and Non-Responders by assessing structural and contrast changes in bone, 
cartilage and other tissues  
• 
Through assessment of blood IL-1b Messenger Ribonucleic Acid (mRNA) levels, to segment patients into 
inflammatory and non-inflammatory phenotypes, and to examine the response to therapy of these 
phenotypes 
Study Design and Methodology: 
This is an open-label study assessing the effect of the administration of a single IA injection of FX006 32 mg on 
synovial volume in patients with OA of the knee. The study will be conducted in male and female patients who are 
≥ 40 years of age.   
Eligible patients who provide written consent and meet all entry criteria will undergo initial ultrasound examination 
and MRI with contrast of the index knee. For each MRI, a pretreatment synovial volume measurement will be 
derived by quantitative image analysis. Patients will then receive a single IA injection of FX006 administered to the 
index knee at Baseline/Day 1. Patients will return to the clinic at Weeks 6 and 24 for an MRI with contrast of the 
index knee and other assessments. Patients must also have a blood sample drawn for Estimated Glomerular 
Filtration Rate (eGFR) testing within 30 days prior to the scheduled MRIs. In addition, a patient questionnaire will 
be administered and adverse events (AEs) and concomitant medication updates will be collected via telephone at 
Weeks 12 and 18. 
The study is expected to enroll over approximately 15 months. 
Number of Patients: 
Approximately 100 patients will be enrolled and treated with a single IA injection of 32 mg FX006 to ensure a 
minimum of 70 evaluable Synovitis Imaging patients, as defined by pre-treatment MRI synovial volume 
measurement. 
Test Product, Dose and Mode of Administration: 
FX006 – extended release formulation of triamcinolone acetonide (TA) in 75:25 poly(lactic-co-glycolic) acid 
(PLGA) microspheres: Nominal 32 mg TA, IA injection, administered as a 5 milliliter (mL) injection 
Reference Compound(s), Dose and Mode of Administration: 
Not applicable 
 


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Duration of Dosing: 
Single IA injection of FX006 
Inclusion Criteria:  
To be included in the trial, patients must fulfill the following criteria:  
1. Written consent to participate in the study 
2. Male or female ≥ 40 years of age 
3. Body mass index (BMI) ≤ 40 kg/m2 
4. Ambulatory and in good general health  
5. Willing and able to comply with the study procedures and visit schedules and able to follow verbal and 
written instructions 
6. Willing to abstain from use of the following protocol-restricted medications during the study: 
a. 
Topical or oral NSAIDs (from 5 days prior to Pre-treatment MRI through Week 6 MRI, and again 
from 5 days prior to Week 24 MRI) 
b. Intravenous (IV), intramuscular (IM) and oral corticosteroids (Note: inhaled, intranasal, and 
topical corticosteroids are allowed) 
c. 
IA corticosteroids in any joint other than the study medication 
d. Any IA intervention in the index knee including aspiration or the injection of any approved or 
investigational agent, including viscosupplementation (hyaluronic acid) 
e. 
Any investigational drug, device, or biologic 
f. 
Immunomodulators, immunosuppressives, or chemotherapeutic agents  
g. Live or attenuated vaccines 
7. Symptoms associated with OA of the index knee for ≥ 6 months prior to Screening (patient self-report is 
acceptable) 
8. Currently meets American College of Rheumatology (ACR) Criteria (clinical and radiological) for OA 
(Altman et al, 1986) as follows:  
a. 
Knee pain 
b. at least 1 of the following: 
i. Age > 50 years 
ii. Stiffness < 30 minutes 
iii. Crepitus 
c. 
Osteophytes (as determined by central reading facility of index knee X-ray obtained at Screening)  
9. Kellgren-Lawrence (K-L) Grade 2 or 3 in the index knee based on X-ray performed during Screening 
(centrally read)  
a. 
Grade 2: definite osteophytes and possible narrowing of joint space 
b. Grade 3: moderate multiple osteophytes, definite narrowing of joint space and some sclerosis and 
possible deformity of bone ends 
10. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC A) total sum score of ≥ 6 at 
Screening and Baseline/Day 1 
11. Index knee pain on most days over the last month (as reported by the patient).  
12. If bilateral OA exists, pain in the contralateral knee must be less than pain in the index knee as reported by 
the patient; if pain is equal, index knee will be identified based on knee with highest level of inflammation 
as determined by ultrasound 
13. Sexually active males and females of child-bearing potential (defined as not surgically sterile or post-
menopausal [defined as 12 consecutive months with no menses without an alternative medical cause] for at 
least 1 year as documented in medical history) agree to use one of the following highly effective methods 
of contraception: abstinence; oral, injected or implanted hormonal methods of contraception; intrauterine 
device or intrauterine system; condom or occlusive cap (diaphragm or cervical/vault caps) with 
spermicidal foam/gel/film/cream/suppository; or monogamous intercourse with a partner who is surgically 
sterile (post-vasectomy, post-hysterectomy, or tubal ligation). Such contraceptive measures should be used 
throughout the duration of the study. 


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Exclusion Criteria: 
Patients fulfilling at least one of the following criteria may not be included in the study: 
Disease-related criteria 
1. Any inflammatory arthritis including reactive arthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing 
spondylitis, arthritis associated with inflammatory bowel disease, gout or secondary OA from gout 
2. History of infection or crystal disease in the index knee joint  
3. Unstable index knee joint (such as a torn anterior cruciate ligament) within 12 months of Screening 
 
Previous or concomitant treatment-related criteria 
4. Presence of surgical hardware or other foreign body in the index knee 
5. Surgery or arthroscopy of the index knee within 12 months of Screening 
6. IA corticosteroid (investigational or marketed) in any joint within 3 months of Screening  
7. IA treatment of the index knee with hyaluronic acid (investigational or marketed) within 6 months of 
Screening  
8. IV or IM corticosteroids (investigational or marketed) within 3 months of Screening 
9. Oral corticosteroids (investigational or marketed) within 1 month of Screening 
10. Any other IA drug/biologic in the index knee within 6 months of Screening or 5 half-lives (whichever is 
longer) (e.g., platelet rich plasma (PRP) injection, stem cells, prolotherapy, and amniotic fluid injection) 
11. Prior administration of FX006 (Zilretta®) 
12. Planned/anticipated surgery of the index knee during the study period 
 
Patient-related criteria 
13. Suspected hypersensitivity to any form of triamcinolone 
14. History of sarcoidosis or amyloidosis  
15. Active or history of malignancy within the last 5 years, with the exception of resected basal cell 
carcinoma, squamous cell carcinoma of the skin, or effectively managed cervical carcinoma 
16. History or evidence of active or latent systemic fungal or mycobacterial (including tuberculosis), or of 
ocular herpes simplex  
17. Any bacterial or viral infection requiring IV antibiotics within 4 weeks of Screening or oral antibiotics 
within 2 weeks of Screening 
18. History of osteomyelitis in the index leg at any time, or of other areas within 5 years 
19. Laboratory evidence of infection with human immunodeficiency virus (HIV), positive test for hepatitis B 
surface antigen (HbsAg) or positive serology for hepatitis C virus (HCV) with positive test for HCV 
Ribonucleic Acid (RNA) 
20. Any electrocardiogram (ECG) abnormality judged clinically significant by the Investigator. 
21. A medical history suggesting the patient will or is likely to require a course of parenteral or oral 
corticosteroids during the study period  
22. eGFR results < 40 mL/minute (reported as Creatinine Clearance) 
23. Any contraindication to MRI Scanning (e.g., presence of certain ferromagnetic foreign bodies or electronic 
devices including most cardiac pacemakers, claustrophobia) 
24. Known hypersensitivity to any form of MRI contrast 
25. History of or active Cushing’s syndrome 
26. Active substance abuse (drugs or alcohol), or history of substance abuse within 12 months of screening 
27. Skin breakdown at the knee where the injection would take place 
28. Females who are pregnant or nursing or plan to become pregnant during the study; men who plan to 
conceive during the study 


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29. Use of immunomodulators, immunosuppressives, or chemotherapeutic agents within 5 years of Screening 
30. Has received a live or live attenuated vaccine within 3 months of Screening 
31. Use of any other investigational drug, biologic or device within 3 months of Screening 
32. Any other clinically significant acute or chronic medical conditions (e.g., bleeding disorder) that, in the 
judgment of the Investigator, would preclude the use of an IA corticosteroid or that could compromise 
patient safety, limit the patient’s ability to complete the study, and/or compromise the objectives of the 
study 
Procedures and Assessments: 
The study will involve a Screening period (up to 28 days), a pretreatment day when an Ultrasound and MRI of the 
index knee will be performed, dosing at Baseline/Day 1 and two additional clinic visits at Weeks  6 and 24. In 
addition, patients must also have a blood sample drawn for eGFR testing within 30 days prior to the scheduled 
MRIs.  Follow-up via telephone will occur at Weeks 12 and 18.  
At specified times throughout the study, patients will undergo physical examinations, index knee assessments, 
imaging of the index knee (MRI with contrast), 12-lead ECG; blood samples will be collected for laboratory safety 
tests and vital signs will be collected or measured.  Information regarding AEs and concomitant medications will be 
collected, and patient questionnaires (Western Ontario and McMaster Universities (WOMAC®) Osteoarthritis Index 
Likert (LK) 3.1, the Knee injury and Osteoarthritis Outcome Score (KOOS) Quality of Life (QOL) Subscale), and a 
set of questions exploring pain and stiffness of the knee will be completed. 
Patients will have index knee synovial fluid collected at Baseline/Day 1. These samples will be preserved for 
potential future OA biomarker analyses. 
Refer to Schedule of Study Assessments for full details. 
Blinding:  
Not applicable; this is an open-label study. 
Study Drug Administration Procedure:  
IA injections will be performed by the assigned injector.  The injector may choose the position of the knee (e.g., 
extended or flexed), the approach for the injection (e.g., medial or lateral) and the numbing agent to be used (e.g., 
ethyl chloride, subcutaneous lidocaine; IA anesthetics are not allowed) based on standard of care. Sterile technique 
should be used.   
Prior to injection, the index knee should be thoroughly cleansed using a bactericidal solution.  The index knee will 
be aspirated in all cases prior to administration of study medication.  Following attempted aspiration, 5 mL of the 
reconstituted FX006 will be injected into the synovial space.  Refer to the Pharmacy binder for detailed instructions 
on how to prepare FX006.  
The same needle used for IA injection of the study medication may also be used for synovial fluid aspiration, 
thereby allowing for a single injection with syringe replacement.  The injector will use a 21 gauge or larger needle 
for injection and aspiration of fluid. 
Injector will record injection procedure and any product related issues relating to reconstitution or administration of 
FX006 (e.g. inability to achieve an appropriate suspension, inability to administer the full dose due to clogging of 
the needle) and report the occurrence to the Site Monitor, as detailed in the Pharmacy Binder. 
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. 
If the patient has an immediate reaction (e.g., tenderness, increased pain, swelling, effusion, decreased mobility of 
the index joint), the patient should be treated according to local clinical guidelines and physician experience. 


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Concomitant Medications: 
The exclusion criteria indicate that a patient may not be enrolled if he/she has used any of the following within the 
specified windows. In addition, these medications should not be taken or used throughout the study:  
• 
IV, IM, or oral corticosteroids  
• 
IA corticosteroids in any joint  
• 
Any IA intervention in index knee including aspiration or the injection of any approved or investigational 
agent, including viscosupplementation (hyaluronic acid).  
• 
Any investigational drug, device, or biologic 
• 
Immunomodulators, immunosuppressives, or chemotherapeutic agents  
• 
Live or attenuated vaccines 
• 
If patient is currently using other analgesics for pain relief, continued use is permitted; however, patient 
must abstain from use of topical or oral NSAIDs from 5 days prior to Pre-treatment MRI through Week 6, 
and again from 5 days prior to Week 24 MRI. 
Criteria for Evaluation: 
Imaging Variables 
Synovial volume and structural changes in various tissues (bone, cartilage, meniscus) and change in contrast 
enhancement of tissues other than synovium will be evaluated based on MRI by a central imaging vendor. 
 
Efficacy Variables 
Efficacy will be evaluated based on the results of the WOMACLK 3.1, 5-point scale): pain, stiffness and function 
domains independently and collectively (Bellamy et al, 1988), the KOOS QOL and a set of questions exploring 
pain and stiffness of the knee.  
 
Safety Variables 
Safety and tolerability will be evaluated on the basis of AEs spontaneously reported by the patient or discovered by 
the Investigator and findings from the following assessments: physical examinations, index knee assessments, vital 
signs, and clinical laboratory evaluations.  
 
Biomarker Variables 
Synovial fluid samples will be preserved for a maximum of 5 years for potential future analyses of biomarkers that 
may contribute to the pathogenesis of OA and/or be associated with responsiveness to FX006 treatment. No 
genomic analyses (gene sequencing studies) will be performed using these samples. Patients will be able to 
withdraw consent throughout the duration of storage. Once analysis has begun, consent will no longer be able to be 
withdrawn. 
Whole blood samples will be taken from patients at Baseline/Day 1.  Total Ribonucleic Acid (RNA) will be isolated 
from these samples for analysis of messenger RNA (mRNA) levels of the pro-inflammatory cytokine interleukin 1 
beta (IL-1β).  The expression of baseline IL-1β among patients will be compared to several other parameters, such 
as Index Knee X-rays and MRI images, with the goal of determining if baseline mRNA IL-1β expression 
contributes to the pathogenesis of OA and/or is associated with responsiveness to FX006 treatment.  
Sample Size Considerations: 
Approximately 100 patients will be enrolled to ensure a minimum of 70 evaluable Synovitis Imaging patients, as 
defined by pre-treatment MRI synovial volume measurement of greater than 3000 mm3 of gadolinium enhancement 
as determined by quantitative image analysis, with quality Pretreatment and Week 6 MRIs. Previous trials had 
similar sample sizes (Gait et al, 2016) (O’Neill et al., 2016).  


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Statistical Methods: 
Complete details of the statistical analyses will be specified in the statistical analysis plan (SAP). Four analysis 
populations are planned for the study as follows: 
• 
 The Safety Population will include all patients who receive study drug. The Safety Population will be used 
to assess safety and tolerability. 
• 
The Synovitis Imaging Population will include all patients from the Safety Population who have a pre-
treatment synovial volume measurement of greater than 3000 mm3 of gadolinium enhancement as 
determined by quantitative image analysis, as well as quality pre-treatment and Week 6 MRIs. In addition, 
the patients included in this population will have no major protocol deviations and/or imaging variations 
(i.e. change in coil, machine, or software) deemed to potentially impact the imaging analysis.  
• 
The Imaging Population will include all patients from the Safety Population, who have quality MRI data 
available for pre-treatment and at least one post- baseline timepoint and with no major protocol deviations 
and/or imaging variations (i.e. change in coil, machine or software) deemed to potentially impact the 
imaging analysis.   
• 
The Efficacy Population will include all patients from the Safety Population, who have at least one post- 
Baseline/Day 1 WOMAC or KOOS assessment.   
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. 
Primary efficacy analysis will be the mean standardized change from baseline at 6 weeks in synovial volume will be 
determined and the 95% confidence interval (CI) will be calculated. Secondary efficacy analyses include an 
absolute change (mm3) from baseline at 6 weeks in synovial volume will also be calculated and the 95% CI will be 
presented. Standardized and absolute change from baseline will also be analyzed for synovial volume at 24 weeks.   
Descriptive statistics and the 95% CIs will be calculated on pain, stiffness, function and quality of life. Other 
efficacy variables such as structural and contrast changes in bone, cartilage and other tissues based on the MRI 
results will be provided in the SAP and described in the Imaging Manual.  A responder/non-responder analysis will 
be conducted to describe associations between physiological and functional/QOL measures and MRI results 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary.  Incidences 
(number and percent) of treatment-emergent adverse events (TEAEs), those events that started after dosing or 
worsened after dosing, will be presented.  Additional analyses of incidences of TEAEs will also be presented by 
maximum severity and by relationship to study medication. 
Similar presentations will be provided for serious AEs, AEs leading to death, AEs leading to withdrawal from the 
study, and for AEs related to the index knee.  
Clinical laboratory data and vital sign information will be summarized as summary statistics for value and change 
from Day 1 at each individual time point. Summary statistics will include n, mean, median, standard deviation, 
minimum, and maximum. 
 


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3. 
ETHICS 
The study will be conducted according to the Declaration of Helsinki, and in accordance with 
local laws and regulations. 
3.1. 
Institutional Review Board/Ethics Committee  
This study will be conducted in compliance with current Good Clinical Practices (GCP), and in 
accordance with local laws and regulations.  
This study protocol and other related study documents will be submitted to the Institutional 
Review Board/Ethics Committee (IRB/EC) by the site or the Sponsor for review and approval as 
dictated by local regulations. IRB/EC approval must be obtained before commencement of any 
study procedures. The study will be conducted only at sites where IRB/EC approval has been 
obtained. 
3.2. 
Ethical Conduct of Study 
This study will be conducted in accordance with the protocol, GCP guidelines and applicable 
national regulatory requirements. 
GCP is an international ethical and scientific quality standard for designing, conducting, 
recording, and reporting studies that involve the participation of human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study 
subjects are protected, consistent with the principles that have originated in the Declaration of 
Helsinki and that the clinical study data are credible. 
3.3. 
Patient Information and Consent 
Prior to initiation of any study related procedures, patients will give their written consent to 
participate in the study after having been informed about the nature and purpose of the study, 
participation and termination conditions, and risks and benefits. 
An IRB/EC-approved informed consent document must be signed by the patient before his or her 
participation in the study.  A copy of the informed consent document must be provided to the 
patient.  If applicable, it will be provided in a certified translation of the local language. 
Signed informed consent forms must remain in each patient’s study file and must be available for 
verification by study monitors at any time. 


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4. 
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE  
4.1. 
Investigators 
A Principal Investigator (PI) will be responsible for study conduct at each center and may 
delegate study-related activities to appropriately qualified and trained staff. This delegation will 
be documented in a study-specific Delegation of Responsibilities form. 
The contact information for all PIs 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 (US), 
and OA is the most common joint disease, affecting 27 million Americans, with numbers 
expected to grow as a result of aging, obesity and sports injuries.  Recent data suggest that OA 
accounts for over $185 billion of annual healthcare expenditures in the US, which does not 
include loss of productivity costs.  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). 
While historically OA has been considered a non-inflammatory disease, it is increasingly being 
recognized that chronic synovitis occurs in all stages of knee OA (Benito et al, 2005; Sellam and 
Berenbaum, 2010; Wenham and Conaghan, 2010). As synovial inflammation is correlated with 
clinical symptoms and joint degeneration, it should be an important target for therapeutic 
intervention. The inflamed synovium may well be the target for IA corticosteroids which are 
widely used in knee OA (Ayral et al, 2005). 
5.2. 
Background 
5.2.1. 
Investigational Medicinal Product:  FX006 
FX006 is an extended-release formulation of triamcinolone acetonide (TA) for IA 
administration. It is approved in the US under the trade name ZILRETTA® (triamcinolone 
acetonide extended-release injectable suspension) for the management of pain of osteoarthritis of 
the knee.  FX006 is intended to deliver TA to the synovial and peri-synovial tissues for a period 
of approximately 3 months depending on the dose administered (Bodick et al, 2013). 
FX006 contains TA, United States Pharmacopeia (Ph. Eur/USP), formulated in 75:25 
poly(lactic-co-glycolic acid) (PLGA) microspheres with a nominal drug load of 25% (weight by 
weight [w/w]) and is provided as a sterile white to off-white powder for reconstitution. The drug 
product is reconstituted with diluent containing an isotonic, sterile aqueous solution of sodium 
chloride (NaCl; 0.9% w/w), carboxymethylcellulose sodium (CMC; 0.5% w/w) and polysorbate-
80 (0.1% w/w) to form a suspension prior to IA injection.   
Further details of the physiochemical properties of FX006 can be found in the Investigator’s 
Brochure (IB). 


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5.2.2. 
Rationale for FX006 in OA of the Knee 
Available clinical and nonclinical data indicate that FX006 is safe and well tolerated when 
administered as a single injection into one knee and provides pain relief that is meaningfully 
better and more persistent than that provided by triamcinolone acetonide injectable suspension, 
immediate-release (commercially available) (TAcs).  Nonclinical data and the literature suggest 
that this potential could extend to limiting structural progression in patients with inflammatory 
joint disorders. The near term clinical development program for FX006 focuses on analgesics 
effects in patient with OA (bilateral knee, hip, and shoulder) as well as other shoulder maladies. 
5.2.3. 
Toxicology 
Overall, single or repeat administration of FX006 at the proposed clinical dose of 32 mg has no 
new safety liabilities compared to TAcs: 
• Systemic findings were similar among TAcs and FX006 groups following single and repeat 
dosing and were generally reversible.  Initial effects on clinical pathology parameters were 
more pronounced for the immediate-release form.  The incidence and/or intensity of steroid-
associated systemic histopathological findings at the later time points were slightly higher for 
high dose FX006 than for TAcs at the same dose level of TA (18.75 mg/mL/joint), as 
expected based on the sustained release of TA.  Microspheres were not detected in tissues 
outside of the synovial space. 
• Local findings were similar among 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 nonadverse.  
Information available for TA from the literature, corticosteroid product labels and clinical 
experience suggest that the potential of genetic toxicity, reproductive toxicity and carcinogenic 
potential of TA are well understood.  Similarly, the biocompatibility and local safety of PLGA 
microspheres, and genotoxic, reproductive toxicological and carcinogenic potential of PLGA 
have been described in a combination of literature and product information packages.  Therefore, 
no new risks relative to TAcs are presented by FX006 as intended for use. 


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5.2.4. 
Systemic and Local Pharmacokinetics (PK) in Patients with Osteoarthritis of the 
Knee 
Overall, FX006 displayed a favorable plasma PK profile relative to that of TAcs. 
PK observations resulted in a controlled and stable release of TA from PLGA microspheres into 
synovial tissues, where concentrations remained high relative to plasma concentrations for at 
least 12 weeks.  TA was absorbed systemically, with a plateau in plasma TA concentrations 
occurring in the first 24 hours post-dose, and slow elimination from the systemic circulation 
observed in the weeks thereafter.  
Relative to TAcs, 32 mg FX006 produced substantially lower peak plasma and systemic 
exposure to TA. FX006 performed as expected, prolonging the residence of TA in the joint while 
minimizing systemic exposure to TA. 
5.2.5. 
Pharmacodynamics (PD) in Patients with Osteoarthritis of the Knee 
In a Phase 2 PK/ PD study evaluating three dose levels of FX006 (10 mg, 40 mg, 60 mg) 
administered as a 3 mL injection, suppression of cortisol in the days following injection 
produced by the 10 and 40 mg dose of FX006 was less than that produced by injection of TAcs; 
the 60 mg dose of FX006 produced effects similar to 40 mg TAcs. Cortisol suppression 
subsequent to Day 1-2 associated with all doses of FX006 would not be expected to be of clinical 
consequence in adult patients without otherwise compromised hypothalamic-pituitary-adrenal 
(HPA) axis function. 
In a Phase 2 study in diabetic patients with knee OA, treatment with 32 mg FX006 resulted in a 
statistically significant (p=0.0452) reduction in blood glucose elevation relative to TAcs over a 
72-hour period following IA injection. The time in glycemic target range (70-180 mg/dL) 
(American Diabetes Association, 2016) was greater for FX006 as compared to TAcs over the 
48 hours post IA injection, providing another indication of the improvement in glycemic control. 
Over the entire time course of the 15-day post injection glucose monitoring period, blood 
glucose levels associated with FX006 remained at levels similar to or lower than those produced 
by TAcs. This observation is consistent with PK studies demonstrating low systemic exposure to 
TA associated with FX006. 
5.2.6. 
Efficacy in Patients with Osteoarthritis of the Knee 
Efficacy data from three studies provide substantial evidence supporting the effectiveness of 
32 mg FX006 in the management of OA pain. (Bodick et al, 2015; Conaghan et al, 2017) 
Results of the primary endpoint from the Phase 3, multi-center, adequate, and well-controlled 
trial, showed that patients treated with 32 mg FX006 had a rapid, durable, and meaningful 
analgesic response that was statistically significantly better than placebo treated patients 
(P<0.0001). This finding was supported by a second smaller Phase 2b study, where a highly 
similar pattern of response to 32 mg FX006 was demonstrated. 
Robustness of the primary outcome in the Phase 3 study was further supported by the internal 
consistency demonstrated in favor of 32 mg FX006 through secondary analyses utilizing the 
primary outcome data (average daily pain [ADP]) to evaluate durability and magnitude of 
response. These included least square mean (LSM) testing at each week and area under the effect 
curve (AUE) analyses for Weeks 1 through 12 and Weeks 1 through 24. Results demonstrated 


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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.  FX006 32 mg provides clinically 
relevant improvement relative to placebo through Week 12 for WOMAC and KOOS QOL and 
through at least Week 16 for PGIC and CGIC. Additionally, significant reduction of rescue 
medication utilization in patients treated with FX006 32 mg is of potential important clinical 
consequence and adds a meaningful element to the overall effectiveness profile of FX006 32 mg. 
Collectively, these results provide substantial evidence to support FX006 32 mg as an effective 
therapy for the management of OA knee pain.  
5.2.7. 
Systemic and Local Safety in Patients with Osteoarthritis of the Knee 
The evaluation of 687 patients treated with a single IA injection of FX006 at any dose in the 
FX006 clinical studies suggests that it was well tolerated with systemic and local safety profiles 
similar to those of TAcs and placebo.   
The safety data from the FX006 clinical studies are largely consistent.  
• The number of TEAEs reported was similar across groups (FX006 46.0%; placebo 49.2%; 
TAcs 51.0%).   
• The majority of TEAEs in FX006-treated patients were mild or moderate (Grade 1 or 2). 
Severe or life-threatening events occurred in the FX006-treated patients at a rate of 3.0% as 
compared to 5.0% and 2.6% in the placebo and TAcs groups, respectively.  
• In the FX006-treated patients (n=687), the most common TEAEs were: 
− Arthralgia (in any joint) 9.8% (n=67) 
− Headache 5.4% (n=37) 
− Upper Respiratory Tract Infection 3.1% (n=21) 
− Joint swelling 2.8% (n=19) 
− Contusion and back pain 2.3% (n=16) 
− Nasopharyngitis 2.2% (n=15) 
• The rate of serious adverse events (SAEs) was low and consistent across groups (FX006 
1.9%; placebo 1.1%; TAcs 2.3%); none were considered related to the study drug.  
• Across all studies there were no deaths.   
In the Phase 3 study, qualitative assessments based on X-rays of the index knee at 24 weeks post 
injection included joint space narrowing (JSN), subchondral bone changes, osteonecrosis, and 
insufficiency fracture. 


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• The overall rate of JSN worsening of at least 1-grade between baseline and Week 24 was low 
and similar among treatment groups (5.0% [7/140], 4.1% [6/148], and 3.5% [5/145] of 
patients with both baseline and Week 24 X-rays in the 32 mg FX006, placebo, and TAcs 
groups respectively); for all but 1 of these 18 patients, JSN worsened by 1-grade only. The 
remaining patient (in the placebo group) had a 2-grade worsening in JSN (from 0 at baseline 
to Grade 2 at Week 24).  
• No FX006-treated patient had X-ray evidence of treatment-emergent insufficiency fracture, 
subchondral bone changes, or osteonecrosis at Week 24. 
• Eighteen patients discontinued the study prior to Week 24 and completed a final X-ray as 
part of early termination visit. Of these, 2 patients, 1 in the 32 mg FX006 group and 1 in the 
placebo group, had a 1-grade increase in JSN. There were no reports of insufficiency 
fracture, subchondral bone changes, or osteonecrosis. 
5.2.8. 
Conclusion 
These data provide bases for continued clinical study of FX006.   


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6. 
STUDY OBJECTIVES 
6.1. 
Primary Objective 
The primary objective of this study is to assess the effect of a single IA injection of FX006 
32 mg to control inflammation as measured by a reduction in MRI-assessed synovial volume in 
patients with symptomatic OA of the knee and defined synovial volume at baseline. 
6.2. 
Secondary Objectives 
The secondary objectives of this study are: 
• to assess the effect of FX006 on pain, stiffness, function, and quality of life. 
• to assess changes in bone area and cartilage thickness of the knee. 
6.3. 
Exploratory Objectives 
The exploratory objectives of this study are: 
• to assess structural changes in bone, cartilage, and meniscus. 
• to assess changes in contrast enhancement of tissue other than synovial tissue. 
• to identify Responders and Non-Responders by assessing structural and contrast changes in 
bone, cartilage, and other tissues.  
• through assessment of blood IL-1b mRNA levels, to segment patients into inflammatory and 
non-inflammatory phenotypes, and to examine the response to therapy of these phenotypes. 
 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
This is an open-label study assessing the effect of the administration of a single IA injection of 
FX006 32 mg on synovial volume in patients with OA of the knee.  The study will be conducted 
in male and female patients who are ≥ 40 years of age.   
Eligible patients who provide written consent and meet all entry criteria will undergo initial 
ultrasound examination and MRI with contrast of the index knee. For each MRI, a pre-treatment 
synovial volume measurement will be derived by quantitative image analysis. Patients will then 
receive a single IA injection of FX006 administered to the index knee at Baseline/Day 1. Patients 
will return to the clinic at Weeks 6 and 24 for an MRI with contrast of the index knee and other 
assessments. Patients must also have a blood sample drawn for eGFR testing within 30 days 
prior to the scheduled MRIs.  In addition, a patient questionnaire will be administered, and AEs 
and concomitant medication updates will be collected via telephone at Weeks 12 and 18. 
Refer to Table 1, Schedule of Study Assessments for full details. 
The study is expected to enroll over approximately 15 months. 
7.2. 
Site Staffing Requirements 
The PI is responsible for overseeing the conduct of the study at his/her site, ensuring that 
sufficient and appropriately experienced staff are available to conduct the trial, and ensuring that 
activities are appropriately delegated and documented.  Any delegation of responsibilities will be 
documented in a study-specific Clinical Site Responsibilities and Signature log. The term 
‘Principal Investigator’ is used throughout this protocol to refer to the actual PI and/or his/her 
delegated team member(s) for the specific responsibility being described.  
Pharmacist/Coordinator  
• Must be a registered pharmacist or an individual with the qualifications and training required 
to handle and prepare study medications 
• Is responsible for handling and preparing all study medications and maintaining 
investigational product accountability records 
Injector/Aspirator  
• Must be a medical doctor, a physician’s assistant, or nurse practitioner experienced in 
administering IA injections and performing synovial fluid aspirations of the knee  
• Is responsible for performing IA injections of study medication and synovial fluid aspirations 
of the knee  
Assessor  
• Must be either the PI or sub-investigator listed on the FDA Form 1572 
• Must be a medical doctor, doctor of osteopathic medicine, a physician’s assistant, or nurse 
practitioner 


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• Must have relevant OA experience 
• Is responsible for performing the physical examination and index knee assessments  
• Can be responsible for assessing ultrasound images for the presence of synovitis only if a 
rheumatologist or orthopedic specialty   
• Is responsible for assessing all adverse event (AE)s including seriousness, severity, and 
causality 
Radiologist 
• Can be responsible for assessing ultrasound images for the presence of synovitis only if a 
medical doctor specializing in radiology 
− Must be either the PI or physician sub-investigator  
Imaging Technician 
• Must be an experienced technician in performing required imaging 
• Is responsible for performing the required imaging  
The same individual may serve in multiple roles (e.g., a physician sub-investigator may serve as 
both the Injector and/or Assessor).  
7.3. 
Discussion of Study Design 
7.3.1. 
Rationale for Study Population 
Patients with pain associated with OA of either the knee as defined by clinical and radiologic 
criteria that are otherwise in good health or that have chronic conditions (for example, 
hypertension) that are well controlled are eligible.  In general, this population tolerates IA 
injections of commercially available corticosteroids (Habib 2009).  In prior clinical studies of 
FX006 in this population, single injections of up to 60 mg of FX006 were well tolerated. 
7.3.2. 
Rationale for Dose Selection 
The US Food and Drug Administration (FDA) approved dose of FX006 as an approved 
treatment for pain associated with OA of the knee is 32 mg; therefore, this dose was selected for 
further study in investigational uses. 
7.3.3. 
Rationale for Study Design 
The current trial design is substantially similar to synovitis studies previously conducted in OA 
of the knee (Gait et al, 2016; O’Neill et al, 2016). The design applied in this protocol has proved 
reliable for evaluating changes in synovitis and synovial tissue volume.  
7.3.4. 
Rationale for Study Parameters 
Synovial volume and structural changes in various tissues (bone, cartilage, meniscus) and change 
in contrast enhancement of tissues other than synovium evaluated on the basis of MRI results 
directly support the assessment of the effect on synovial inflammation following IA 


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administration of FX006, and the analyses are substantially similar to those conducted for 
assessment of synovitis and changes in synovial tissue volume. 
The clinical safety parameters to be assessed (adverse events, physical examinations, index knee 
examinations, vital signs, and clinical laboratory evaluations) are standard safety and tolerability 
assessments and support the clinical monitoring necessary based on the safety profile for FX006. 
7.3.5. 
Rationale for Control Type 
Not applicable.  This is a single arm open-label study.  
7.4. 
Selection of Study Population 
7.4.1. 
Number of Patients 
Approximately 100 patients will be enrolled and treated with a single IA injection of 32 mg 
FX006 to ensure a minimum of 70 evaluable Synovitis Imaging patients, as defined by pre-
treatment MRI synovial volume measurement.   
7.4.2. 
Inclusion Criteria 
To be included in the trial, patients must fulfill the following criteria:  
1. Written consent to participate in the study 
2. Male or female ≥ 40 years of age 
3. Body mass index (BMI) ≤ 40 kg/m2 
4. Ambulatory and in good general health  
5. Willing and able to comply with the study procedures and visit schedules and able to follow 
verbal and written instructions 
6. Willing to abstain from use of the following protocol-restricted medications during the study: 
• Topical or oral NSAIDs (from 5 days prior to Pre-treatment MRI through Week 6, and 
again from 5 days prior to Week 24 MRI) 
• Intravenous (IV), intramuscular (IM) and oral corticosteroids (Note: inhaled, intranasal, 
and topical corticosteroids are allowed) 
• IA corticosteroids in any joint (other than the study medication) 
• Any IA intervention in the index knee including aspiration or the injection of any 
approved or investigational agent, including viscosupplementation (hyaluronic acid) 
• Any investigational drug, device or biologic 
• Immunomodulators, immunosuppressives, or chemotherapeutic agents  
• Live or attenuated vaccines 
7. Symptoms consistent with OA of the index knee for ≥ 6 months prior to Screening (patient 
self-report is acceptable) 


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8. Currently meets ACR Criteria (clinical and radiological) for OA (Altman et al, 1989) as 
follows:  
• Knee pain 
• at least 1 of the following: 
o Age > 50 years 
o Stiffness < 30 minutes 
o Crepitus 
• Osteophytes (as determined by central reading facility of index knee X-ray obtained at 
Screening) 
9. Kellgren-Lawrence (K-L) Grade 2 or 3 in the index knee based on X-ray performed during 
Screening (centrally read)  
a) Grade 2: definite osteophytes and possible narrowing of joint space 
b) Grade 3: moderate multiple osteophytes, definite narrowing of joint space and some 
sclerosis and possible deformity of bone ends 
10. WOMAC A total sum score of ≥ 6 at Screening and Baseline/Day 1 
11. Index knee pain on most days over the last month (as reported by the patient)  
12. If bilateral OA exists, pain in the contralateral knee must be less than pain in the index knee 
as reported by the patient; if pain is equal, index knee will be identified based on knee with 
highest level of inflammation as determined by ultrasound  
13. Sexually active males and females of child-bearing potential (defined as not surgically sterile 
or post-menopausal [defined as 12 consecutive months with no menses without an alternative 
medical cause] for at least 1 year as documented in medical history) agree to use one of the 
following highly effective methods of contraception: abstinence; oral, injected, or implanted 
hormonal methods of contraception; intrauterine device or intrauterine system; condom or 
occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository; or monogamous intercourse with a partner who is 
surgically sterile (post-vasectomy, post-hysterectomy, or tubal ligation). Such contraceptive 
measures should be used throughout the duration of the study. 
7.4.3. 
Exclusion Criteria 
Patients fulfilling at least one of the following criteria may not be included in the study: 
Disease-related criteria 
1. Any inflammatory arthritis including reactive arthritis, rheumatoid arthritis, psoriatic 
arthritis, ankylosing spondylitis, arthritis associated with inflammatory bowel disease, gout, 
or secondary OA from gout 
2. History of infection or crystal disease in the index knee joint  


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3. Unstable index knee joint (such as a torn anterior cruciate ligament) within 12 months of 
Screening.  
Previous or concomitant treatment-related criteria 
4. Presence of surgical hardware or other foreign body in the index knee 
5. Surgery or arthroscopy of the index knee within 12 months of Screening 
6. IA corticosteroid (investigational or marketed) in any joint within 3 months of Screening  
7. IA treatment of the index knee with hyaluronic acid (investigational or marketed) within 6 
months of Screening  
8. IV or IM corticosteroids (investigational or marketed) within 3 months of Screening 
9. Oral corticosteroids (investigational or marketed) within 1 month of Screening 
10. Any other IA drug/biologic in the index knee within 6 months of Screening or 5 half-lives 
(whichever is longer) (e.g., platelet rich plasma (PRP) injection, stem cells, prolotherapy, and 
amniotic fluid injection) 
11. Prior administration of FX006 (Zilretta®) 
12. Planned/anticipated surgery of the index knee during the study period 
Patient-related criteria 
13. Suspected hypersensitivity to any form of triamcinolone 
14. History of sarcoidosis or amyloidosis  
15. Active or history of malignancy within the last 5 years, with the exception of resected basal 
cell carcinoma, squamous cell carcinoma of the skin, or effectively managed cervical 
carcinoma 
16. History or evidence of active or latent systemic fungal or mycobacterial infection (including 
tuberculosis), or of ocular herpes simplex  
17. Any bacterial or viral infection requiring IV antibiotics within 4 weeks of Screening or oral 
antibiotics within 2 weeks of Screening 
18. History of osteomyelitis in the index leg at any time, or of other areas within 5 years 
19. Laboratory evidence of infection with human immunodeficiency virus (HIV), positive test 
for hepatitis B surface antigen (HbsAg), or positive serology for hepatitis C virus (HCV) 
with positive test for HCV Ribonucleic Acid (RNA)  
20. Any electrocardiogram (ECG) abnormality judged clinically significant by the Investigator 
21. A medical history suggesting the patient will or is likely to require a course of parenteral or 
oral corticosteroids during the study period  
22. eGFR results < 40 mL/minute (reported as Creatinine Clearance) 
23. Any contraindication to MRI Scanning (e.g., presence of certain ferromagnetic foreign 
bodies or electronic devices including most cardiac pacemakers, claustrophobia)  


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24. Known hypersensitivity to any form of MRI contrast 
25. History of or active Cushing’s syndrome 
26. Active substance abuse (drugs or alcohol) or history of substance abuse within 12 months of 
Screening 
27. Skin breakdown at the knee where the injection would take place 
28. Females who are pregnant or nursing or plan to become pregnant during the study; men who 
plan to conceive during the study 
29. Use of immunomodulators, immunosuppressives, or chemotherapeutic agents within 5 years 
of Screening 
30. Has received a live or live attenuated vaccine within 3 months of Screening 
31. Use of any other investigational drug, biologic, or device within 3 months of Screening  
32. Any other clinically significant acute or chronic medical conditions (e.g., bleeding disorder) 
that, in the judgment of the Investigator, would preclude the use of an IA corticosteroid or 
that could compromise patient safety, limit the patient’s ability to complete the study, and/or 
compromise the objectives of the study. 
7.4.4. 
Screen Failures 
Minimal data for patients who fail screening such as demographic information and the reason for 
screen failure will be collected. 
Patients that fail to meet eligibility criteria may be re-screened at the discretion of the Medical 
Monitor.  The Medical Monitor will clearly document the rationale for any re-screening decision.  
Patients that are allowed to re-screen will be assigned a new screening number, re-consented and 
may have screening assessments repeated if necessary.   
7.5. 
Treatment Administered 
7.5.1. 
Study Medication Treatment Arm(s) 
Investigational Medicinal Product Arm: 
• FX006: an extended-release formulation of TA in 75:25 PLGA microspheres. Nominal 
32 mg TA, administered as a single 5 mL IA injection. 
7.5.2. 
Identity of Investigational Product(s) 
FX006 is supplied as a sterile, white to off white powder in a single unit dose 5 mL vial with a 
butyl rubber stopper, aluminum seal and plastic cap.  FX006 is reconstituted in diluent 
containing an isotonic, sterile aqueous solution of sodium chloride (NaCl; 0.9% w/w), 
carboxymethylcellulose sodium (CMC; 0.5% w/w) and polysorbate-80 (0.1% w/w) to form a 
suspension prior to IA injection.  Diluent will be supplied as a sterile liquid in a 5 mL vial with a 
butyl rubber stopper, aluminum seal and plastic cap.  FX006 will be reconstituted in 5.0 mL of 
diluent to form a suspension immediately prior to IA injection.  FX006 will be administered as a 
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7.5.3. 
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 within the Drug Tracking 
Module. Any temperature excursions should be documented in the Drug Tracking Module and 
on specified documents for Sponsor assessment and authorization for continued use.  
Dispensing, preparation and administration of investigational products occurs under the 
supervision of the Principal Investigator or a qualified sub-investigator. The Principal 
Investigator may only delegate these activities in accordance with state licensing board 
requirements, local institutional policies, and applicable law. Before delegating this activity, the 
Principal Investigator should also ensure that the delegate is trained on and understands the 
requirements of the protocol.  
The packaged kits of FX006 will be stored in a secure area and will be stored refrigerated at 2 to 
8 °C. 
7.5.4. 
Packaging and Labeling of Study Medication 
The packaged kit of FX006 will contain one (1) vial of FX006, one (1) vial of Diluent, and a vial 
adapter.  The FX006 and diluent vials will be labelled with their respective unique lot numbers 
within the packaged kit, which will be affixed with its own label and kit number.   
7.5.5. 
Return of Study Medication 
All study medications (packaged kits/used and unused vials) will be returned to the drug supply 
distribution center.  Return of study medications will be properly documented. 
7.5.6. 
Method of Assigning Patients to Treatment Groups 
This is a single arm open-label study. All patients will receive a single IA injection of FX006 
32 mg. 
7.5.7. 
Blinding 
This is an open-label study.  
7.5.8. 
Study Drug Administration Procedure 
IA injections of study drug will be performed by the assigned injector.  The injector may choose 
the position of the knee (e.g., extended or flexed), the approach for the injection (e.g., medial or 
lateral) and the numbing agent to be used based on standard of care. Sterile technique should be 
used.   
Prior to injection, the index knee should be thoroughly cleansed using a bactericidal solution.  
The index knee will be aspirated in all cases prior to administration of study medication.  
Following attempted aspiration, 5 mL of the reconstituted FX006 will be injected into the 
synovial space.  Refer to the Pharmacy Binder for detailed instructions on how to prepare 
FX006.  


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The same needle used for synovial fluid aspiration may also be used for IA injection of study 
drug, thereby allowing for a single injection with syringe replacement. The injector will use a 21 
gauge or larger needle for injection and aspiration of fluid. 
Injector will record injection procedure and any product related issues relating to reconstitution 
or administration of FX006 (e.g. inability to achieve an appropriate suspension, inability to 
administer the full dose due to clogging of the needle) and report the occurrence to the Site 
Monitor, as detailed in the Pharmacy Binder. 
 
 


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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. 
If the patient has an immediate reaction (e.g., tenderness, increased pain, swelling, effusion, 
decreased mobility of the index joint) the patient should be treated according to local clinical 
guidelines and physician experience. Refer to protocol Section 8.4.3. 
7.5.9. 
Treatment Compliance 
Study medication will be administered by the injector in the clinic.  Details regarding study 
medication administration will be documented in the electronic Case Report Form (eCRF).  The 
receipt, dispensation, and return/destruction of any study medication will be properly 
documented per the instructions within the Drug Tracking Module. 
If for any reason the administration of study medication is stopped before the entire volume is 
injected, the injector should document the reason for stopping administration and record the 
volume delivered. 
7.5.10. 
Removal of Patients from Therapy or Assessments 
Each patient in this study receives study medication as a single IA injection. Therefore, 
discontinuation from treatment is not applicable. However, each patient may discontinue from 
the study for further assessments and study visits.  
Each patient will be informed of his/her right to discontinue from the study at any time for any 
reason and without prejudice to alternative treatment.  The PI may also discontinue a patient 
from the study at any time if, for example, he/she considers the patient’s health to be 
compromised by remaining in the study, or the study is prematurely terminated.  In these cases, 
the PI will: 
1. Attempt to arrange for a formal Early Termination Visit and complete the study assessments 
specified for the End-of-Study scheduled for Week 24.   
2. Determine whether the patient is willing to be contacted to follow ongoing or new AEs 
through Week 24 (if reason for discontinuation is not “subject withdrew consent”). 
3. Document patient consent in the source document for continued follow-up.  
4. Contact the patient as necessary (via phone or in-person) to follow ongoing or new AEs 
through Week 24 (concomitant medications associated with any AE will also be captured). 
Data collected from discontinued patients will be included in the clinical study report. Patients 
who discontinue from the study may be replaced at the discretion of the Sponsor. 
7.6. 
Prior and Concomitant Medications and Therapies  
During the study, all existing (prior to study entry), new, or changes in concomitant medications 
and the associated reasons for use or change will be documented and reported. 


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7.6.1. 
Allowable Medications and Therapies 
The following medications and therapies may be taken or used throughout the study: 
• Any treatment for a pre-existing condition or for an AE, including the study indication (e.g., 
analgesic medications), that is not listed below as restricted  
• Physical therapy for index knee 
• Bracing of index knee 
7.6.2. 
Restricted Medications 
Per the exclusion criteria, a patient is not eligible for this study if he/she has received any of the 
indicated treatments within the specified windows detailed in the Exclusion criteria 
(Section 7.4.3).  In addition, the following medications should not be taken or used from the time 
of obtaining consent to the End of Study visit:   
• Topical or oral NSAIDs (from 5 days prior to Pre-treatment MRI through Week 6, and again 
from 5 days prior to Week 24 MRI) 
• IV, IM, or oral corticosteroids  
• IA corticosteroids in any joint  
• Any IA intervention in index knee including aspiration or the injection of any approved or 
investigational agent, including viscosupplementation (hyaluronic acid)  
• Any investigational drug, device or biologic 
• Immunomodulators, immunosuppressives, or chemotherapeutic agents  
• Live or attenuated vaccines 
7.7. 
Study Variables 
7.7.1. 
Safety Variables  
Safety and tolerability will be evaluated based on AEs spontaneously reported by the patient or 
discovered by the Investigator and findings from the following assessments: physical 
examinations, index knee assessments, vital signs, and clinical laboratory evaluations.  
7.7.2. 
Imaging Variables 
Synovial volume and structural changes in various tissues (bone, cartilage, meniscus) and change 
in contrast enhancement of tissues other than synovium will be evaluated on the basis of MRI by 
a central imaging vendor.  
7.7.3. 
Efficacy Variables 
Efficacy will be evaluated on the basis of the results of the WOMAC Osteoarthritis Index LK 
3.1, 5-point scale): pain, stiffness and function domains independently and collectively (Bellamy 
et al, 1988), the KOOS QOL Subscale (http://www.koos.nu/) and a set of questions exploring 
pain and stiffness of the knee.  


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7.7.4. 
Biomarker Variables 
Synovial fluid samples will be preserved for a maximum of 5 years for potential future analyses 
of biomarkers that may contribute to the pathogenesis of OA and/or be associated with 
responsiveness to FX006 treatment. No genomic analyses (gene sequencing studies) will be 
performed using these samples. Patients will be able to withdraw consent throughout the duration 
of storage. Once analysis has begun, consent will no longer be able to be withdrawn. 
Whole blood samples will be taken from patients at Baseline/Day 1. Total RNA will be isolated 
from these samples for analysis of messenger RNA (mRNA) levels of the pro-inflammatory 
cytokine IL-1β.  The expression of baseline IL-1β among patients will be compared to several 
other parameters, such as index knee X-rays and MRI images, with the goal of determining if 
baseline mRNA IL-1β expression contributes to the pathogenesis of OA and/or is associated with 
responsiveness to FX006 treatment.  
7.8. 
Schedule of Study Assessments 
A summary of the schedule of study assessments is provided in Table 1.  Refer to Section 7.9 for 
details of each assessment.   
 


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Table 1: 
Schedule of Study Assessments 
Procedures 
Screening1 
 
Pre-
Treatment2 Baseline / 
Day 1 
Week 
63 
Week 
123,4 
Week 
183,4 
Week 24 /  
End of Study3 
Informed consent 
X5 
 
 
 
 
 
 
Inclusion/Exclusion Review 
X 
 
X6 
 
 
 
 
Medical History/Update 
X 
 
X6 
 
 
 
 
OA Medical History/Update 
X 
 
X6 
 
 
 
 
Prior Treatment & Medications7 
X 
 
X6 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
X 
Index Knee X-ray8 
X 
 
 
 
 
 
 
Index Knee Assessment9  
X 
 
X6 
X 
 
 
X 
Ultrasound examination of index knee10 
 
X 
 
 
 
 
 
MRI with contrast of index knee11 
 
X 
 
X 
 
 
X 
12-Lead ECG 
X 
 
 
 
 
 
Vital Signs 
X 
 
X6 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
Weight and BMI 
X 
 
 
 
 
 
X 
Hematology & Chemistry12 
X 
 
 
 
 
 
X 
HIV, Hepatitis B/C12 
X 
 
 
 
 
 
 
IL-1β mRNA levels12 
 
 
X6 
 
 
 
 
eGFR12,13 
X 
 
 
X 
 
 
X 
Serum Pregnancy Test14 
X 
 
 
 
 
 
 
Urine Pregnancy Test 14 
 
 
X6 
 
 
 
X 
WOMAC15  
X 
 
X6 
X 
X 
X 
X 
Supplemental pain and stiffness questionnaire15 
 
 
X6 
X 
 
 
X 
KOOS QOL15 
 
 
X6 
X 
 
 
X 
Index knee aspiration and collection of synovial fluid8 
 
 
X6 
 
 
 
 
Treatment administration 
 
 
X 
 
 
 
 
AEs & ConMeds 16  
 
 
-------------------------------------X------------------------------------- 
SAEs17 
-------------------------------------------------X----------------------------------------------- 
                                                 
1 Screening may occur up to 28 days prior to Day 1 
2 The Pre-Treatment visit must be within 10 days of Baseline/Day 1 and once eligibility is confirmed. 
3 Visit should be conducted within +/- 7 days from scheduled date 
4 Via telephone 
5 Consent must be obtained prior to performing any study-specific procedures 
6 Complete assessment prior to dosing 
7 Record any medications received within 30 days prior to the Screening visit 
8 Standing, fixed flexion PA view, weight bearing X-ray of the index knee will be taken using a standardized knee positioning device. The 
Screening X-ray will be read centrally for KL grade, the presence of osteophytes and the measurement of joint space width.  
9 Index knee will be assessed for tenderness, heat/redness, swelling, effusion, and Baker’s cyst. New clinically significant findings or findings that 
worsen from the patient’s baseline condition should be recorded as AEs. 
10 Ultrasound must be performed within -10 days prior to Baseline/Day 1 and using a linear transducer and with the knee in a semi-flexed 
position. Synovial proliferation will be confirmed in a transverse view but measured in a longitudinal view only. 
11 MRI must be performed within -10 days prior to Baseline/Day 1 and +/- 7 days of Weeks 6 and 24 and only if eGFR results are ≥ 40 mL/min 
per the central laboratory. MRI images should follow the vendor specific knee sequences as detailed in MRI Acquisition Manual.  
12 Via Central Laboratory 
13 Must be performed within 30 days prior to Week 6 and Week 24 MRI with contrast. 
14 Conduct for females of childbearing potential only. Serum pregnancy test to be performed via central laboratory at Screening; urine pregnancy 
test to be performed locally at Baseline/Day 1 and results available prior to dosing. 
15 Patient questionnaires to be completed prior to all other assessments 
16 AEs and Concomitant Medications will be captured from Day 1 (from start of study drug administration) to Week 24/Final Visit 
17 SAEs will be recorded from Informed Consent to the end of participation in the study or Week 24/Final Visit 


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7.9. 
Study Procedures 
7.9.1. 
Informed Consent 
Prior to initiation of any study related procedures, patients will be informed about the nature and 
purpose of the study, participation and termination conditions, and risks and benefits.  Patients 
will be given the opportunity to ask questions of site personnel and to discuss with family or 
friends if they wish.  After a patient has had ample opportunity to consider the information 
provided, they will be asked to sign the study’s informed consent form to participate in the study. 
7.9.2. 
Review of Eligibility, Medical History, Prior Treatment, and Medications 
Eligibility criteria (inclusion and exclusion criteria), medical history (including OA history), and 
prior treatment and medications are reviewed during screening and again at Day 1. 
OA medical history includes ACR diagnosis details, OA diagnosis date (if available), number of 
days with pain in both knees in the last month, and previous IA steroid or hyaluronic injections. 
7.9.3. 
Physical Examination 
The physical exam will assess the following body systems:  
1. General Appearance 
2. Skin 
3. Lymphatics 
4. HEENT (head, ears, eyes, nose, throat) 
5. Cardiovascular 
6. Respiratory 
7. Abdominal 
8. Musculoskeletal 
9. Neurological  
Any clinically significant findings, outside of the typical disease state, must be documented in 
the source and added to the medical history if found at Screening or recorded as an AE if new or 
worsened from pre-dosing on Day 1.    
7.9.4. 
Index Knee X-ray 
A diagnostic quality X-ray of the index knee is required (standing, fixed flexion PA view; 
weight-bearing; use of standardized knee positioning device is required) at Screening. The X-ray 
will be sent to the central imaging vendor for K-L grading, the presence of osteophytes (both 
required for eligibility), and joint space width. An image acquisition manual will be distributed 
to sites with simple instructions for radioanatomic positioning for reliable grading.  


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7.9.5. 
Index Knee Ultrasound 
A diagnostic quality ultrasound of the index knee is required within -10 days prior to Day 
1/Baseline. The ultrasound will be read locally for inflammation.  Please refer to Schedule of 
Study Assessments for specific timing requirements. 
7.9.5.1. 
Machine Capabilities 
The machines used in the study should be able to distinguish the edge of proliferated synovium 
from the surrounding periarticular fat.  For the patient with a higher BMI, a lower frequency 
transducer capability e.g., 7.5-10 MHz should be available, with a normal scanning frequency 
expected between 10MHz and 15 MHz being optimal.  All scanning will be performed with a 
linear transducer.  
7.9.5.2. 
Scanning Method 
The knee will be scanned in a semi-flexed position, approximately 30 degrees from horizontal, 
with the knee supported if needed. The transducer will be held in a longitudinal, midline position 
superficial to the quadriceps tendon. The suprapatellar recess will be located below the tendon. 
The pouch will be examined to its most proximal extreme.  Synovial proliferation will be 
confirmed in a transverse view but measured in a longitudinal view only.  
The measurement will be an average of synovial thickening of the opposite anterior and posterior 
surfaces of the pouch.  
To measure, gentle pressure will be applied by the transducer in order to displace any fluid. Once 
the anterior and posterior surfaces are gently touching, a total measurement of synovial thickness 
is made using the machine’s built-in electronic callipers. This measurement is recorded in mm. 
This is then divided by two to give an average single membrane measurement.  The use of 
≥ 2mm thickening synovium will define abnormal synovial thickening.  
7.9.5.3. 
Image Capture 
The best representative image should be captured, correctly labelled (left or right knee), and 
saved in both a longitudinal and transverse view. The same longitudinal image used to show the 
electronic callipers will be saved. The thickness of the synovium will be displayed on the screen 
in mm. For further external verification, a 5 second video sweep of the pouch should also be 
captured. 
7.9.6. 
Index Knee MRI with Contrast 
A diagnostic quality MRI with a gadolinium-based contrast agent of the index knee is required 
within 10 days prior to Day 1/Baseline, and then again at Week 6 and Week 24 (+/- 7 days).  
Once eligibility is confirmed, a pre-treatment MRI will be obtained and submitted to the central 
imaging facility to confirm image quality. Documentation of a quality MRI is needed prior to 
Day 1/Baseline.  If the initial pre-treatment MRI fails quality control (QC), another MRI will 
need to be completed prior to Day 1/Baseline but at least 3-4 days after the initial MRI to ensure 
that that contrast agent has washed out.  
All subsequent images (Week 6 and 24) will need to be completed on the same machine with the 
same coil and software as the Pre-treatment image and will need to be submitted to the central 
imaging vendor to confirm image quality.  If the image does not pass QC, another MRI will need 


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to be completed within the +/- 7 day visit window but at least 3-4 days after the initial MRI to 
ensure that that contrast agent has washed out.  
An MRI image acquisition manual will be distributed to sites with detailed technical instructions 
and specifications for imaging sequences, imaging coil and Field of View (FOV) positions. 
The MRI will be analyzed centrally for the primary endpoint as well as the secondary and 
exploratory endpoints based on imaging. 
7.9.7. 
Index Knee Assessment  
The index knee assessment will be performed by the designated assessor at the days indicated in 
the Schedule of Study Assessments. The index knee will be assessed for tenderness, 
heat/redness, swelling, effusion, and Baker’s cyst.  If there is a clinically significant finding 
outside of the patient’s typical disease state at the Screening or Day 1 Visit (pre-injection), add to 
the Medical History.  At time points post-injection, if there are new clinically significant findings 
or findings that worsen for the patient’s baseline condition, record as AEs. 
7.9.8. 
12-lead ECG 
At Screening, a 12-lead ECG will be obtained in the supine position. Measures of heart rate, PR 
interval, RR interval, QT interval, QT interval corrected for heart rate (QTc) (corrected for 
Bazett’s or Fridericia’s) interval, and QRS duration will be obtained.  ECGs will be locally read 
and a copy of each recording will be kept with the patient’s source documentation. If any 
abnormality is determined to be clinically significant by the Investigator, the patient would be a 
screen failure.   
7.9.9. 
Vital Signs 
Vital signs are to be taken at the days indicated in the Schedule of Study Assessments. The 
following measurements will be taken: sitting blood pressure, heart rate, respiration rate, and 
temperature.  
7.9.10. 
Height, Weight, and BMI Determination 
Height and weight are to be taken at the days indicated in the Schedule of Study Assessments.  
Height will be measured in centimeters (cm) or inches. Weight will be measured in kilograms or 
pounds. BMI will be calculated using the formulas in Table 2 (reference: www.cdc.gov): 


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Table 2: 
BMI Calculations 
Measurement Units 
Formula and Calculation 
Kilograms and meters 
(or centimeters)  
Formula: weight (kg) / [height (m)]2 
With the metric system, the formula for BMI is weight in kilograms 
divided by height in meters squared.  
If, as common, height is measured in centimeters, divide height in 
centimeters by 100 to obtain height in meters. 
Example: Weight = 68 kg, Height = 165 cm (1.65 m) 
Calculation: 68 ÷ (1.65)2 = 24.98 
Pounds and inches 
Formula: weight (lb) / [height (in)]2 x 703  
Calculate BMI by dividing weight in pounds (lbs) by height in inches 
(in) squared and multiplying by a conversion factor of 703. 
Example: Weight = 150 lbs, Height = 5’5” (65”) 
Calculation: [150 ÷ (65)2] x 703 = 24.96 
7.9.11. 
Synovial Fluid Aspiration 
Synovial fluid samples for potential future biomarker evaluation will be obtained from all 
patients via aspiration on Day 1 prior to study medication administration. The injector/aspirator 
will attempt to aspirate synovial fluid from the knee using sterile technique.  The volume of the 
synovial fluid obtained will be recorded in the eCRF. If no synovial fluid is obtained then 0 mLs 
should be recorded.  Procedures for sample collection, handling, storage, and shipment will be 
described in the Central Laboratory Manual.  The synovial fluid samples will be preserved for 
potential future analyses of biomarkers that may contribute to the pathogenesis of OA and/or be 
associated with responsiveness to FX006 treatment. 
7.9.12. 
Central Clinical Laboratory Evaluations 
Blood samples will be taken at the days indicated in the Schedule of Study Assessments.  The 
specific laboratory panels to be run can be found in Table 3.  Follow the Central Laboratory 
Manual for detailed sample collection, handling, storage, and shipping instructions. 


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Table 3: 
Clinical Laboratory Panel 
Hematology 
Clinical Chemistry  
Hemoglobin 
Sodium  
Hematocrit  
Potassium  
Erythrocyte count (red blood cells [RBC]) 
Bicarbonate  
Mean cell volume 
Chloride  
Leukocytes (white blood cells [WBC])  
Calcium   
Absolute counts of:  
Total bilirubin  
• 
Neutrophils  
Alkaline phosphatase  
• 
Lymphocytes  
Alanine aminotransferase  
• 
Monocytes  
Aspartate aminotransferase  
• 
Eosinophils  
Blood urea nitrogen 
• 
Basophils  
Creatinine  
• 
Platelets 
Uric acid  
 
Glucose 
Infectious diseases  
Total protein  
Hepatitis B Surface Antigen 
Albumin  
Hepatitis C Virus Antibody1 
 
HIV2 
 
 
 
Other  
 
IL-1β mRNA levels 
 
eGFR 
 
Pregnancy tests (females of child-bearing potential only) 
Serum: submitted to and performed by Central Laboratory 
Urine: test provided by central laboratory but performed and read at the site 
1. Patients positive for HCV Antibody will have reflex testing for circulating HCV RNA. 
2. HIV screening will use a current 4th generation test for both antibody and viral antigen. 
7.9.13. 
Patient Questionnaires 
The following questionnaires will be completed by patient prior to all other assessments 
scheduled for the visit day at the days indicated in Table 1. 
• WOMAC® LK 3.1  
• KOOS - Quality of Life Subscale (Q1-Q4) 
• Supplemental Pain and Stiffness Questions  
7.9.14. 
Treatment Administration 
At Day 1, and after completion of all required assessments, the following will occur: 
• Study medication will be prepared by the pharmacist/coordinator.  Refer to the Pharmacy 
Binder for FX006 dose preparation instructions.  
• Synovial fluid will be aspirated from the index knee just prior to administration of study 
medication (refer to Section 7.9.11 for more details of the synovial fluid aspiration). 


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• The injector/aspirator will perform the IA injection of the study medication (refer to 
Section 7.5.8 for instructions).   
7.9.15. 
Review of Adverse Events and Concomitant Medications 
Subjects will be monitored for adverse events from signing of informed consent through the end 
of their participation in the study. Refer to Section 8.4.1 for further information about reporting 
of AEs.   
Review of any Concomitant Medications will also be performed and documented in source 
documentation.  Refer to Section 7.6 for further information regarding allowed and restricted 
concomitant medications and therapies. 


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8. 
ADVERSE EVENTS 
Subjects will be monitored for adverse events from signing of informed consent through the end 
of their participation in the study.  
Between the signing of the informed consent and initiation of study medication, only serious 
adverse events will be recorded on the eCRF. Following the start of study drug administration, 
all treatment-emergent adverse events, including serious adverse events, will be collected 
through the Final Visit. Results of clinical safety assessments are to be recorded in the patient’s 
medical records and transcribed to the appropriate eCRF, including the AE eCRF for clinically 
significant findings. 
 
8.1. 
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 clinical significant adverse change in frequency and/or 
intensity) of a preexisting condition, which is temporally associated with the use of the 
medicinal (investigational) product 
Serious Adverse Event (SAE): An SAE is any untoward medical occurrence that at any dose: 
• Results in death, 
• Is life-threatening, 
o “Life-threatening” refers to an event in which the patient was at substantial risk of 
death at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe.   
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
o Note:  Adverse events requiring hospitalizations that are less than 24 hours in 
duration do not meet this criterion. A planned hospitalization for an elective 
procedure or a pre-existing condition that has not worsened during participation in the 
study does not meet this criterion.  
• Results in permanent or significant disability/incapacity; a substantial disruption of the 
patient’s ability to carry out normal life functions. 
• Is a congenital anomaly/birth defect. 


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• Is an important medical event: event that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the outcomes listed in the definition above. 
Planned Hospitalization:  
A hospitalization planned prior to first dose of study medication is considered a therapeutic 
intervention.  If the planned hospitalization or procedure is executed as planned, it should be 
recorded in the patient’s medical history.  However, if complications arise during the planned 
hospitalization or procedure or the patient experiences an AE during the planned hospitalization 
or procedure, it must be reported as an AE. 
8.2. 
Monitoring of Adverse Events 
At each visit, all AEs and SAEs that occur from the time of treatment and throughout a patient’s 
study participation that are observed or reported by the patient, will be recorded in the source 
documentation and appropriate section of the AE or SAE eCRF.   
The Investigator is required to follow SAEs until resolution or withdrawal of consent. Resolution 
is defined as: 
• A return to baseline for a pre-existing condition; 
• Resolved with or without residual effects; 
• The Investigator does not expect any further improvement or worsening of the event; 
• Fatal outcome: If an autopsy is performed on a deceased patient, the autopsy report 
should be provided to the Sponsor as soon as it is available. 
8.2.1. 
Monitoring of Laboratory Assessments and other Diagnostic Tests 
The Investigator will review results of laboratory and other diagnostic tests for clinical 
significance and consideration as an AE. 
8.3. 
Assessment of Adverse Events 
8.3.1. 
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. 


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8.3.2. 
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 
• The AE is more likely explained by the investigational product than by another cause 
(i.e., 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.   
If discernible at the time of completing an AE eCRF, a specific disease or syndrome rather than 
individual associated signs and symptoms should be identified by the Investigator and recorded 
on the appropriate AE eCRF.  However, if an observed or reported sign, symptom, or clinically 
significant laboratory anomaly is not considered by the Investigator to be a component of a 
specific disease or syndrome, then it should be recorded as a separate AE on the appropriate AE 
eCRF. 
8.4.1. 
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.  


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If the EDC SAE form is not available, the Investigator should complete and sign the paper SAE 
form and email it to the Sponsor. When the EDC system is available again, the SAE should be 
input into the 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). 
8.4.2. 
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 Investigator.    
The Sponsor must promptly review all information relevant to the safety of an investigational 
new product received from any source including AE data individually and in aggregate 
throughout the course of the study.   
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.  
The medical monitor and the Sponsor will review the study’s safety data approximately on a 
quarterly basis, in order to identify potential safety issues/trends that may not be apparent 
through individual AE reporting.  If systematic review identifies a concern, the Sponsor will take 
steps to address the issues including, but not limited to, modifying the protocol or Informed 
Consent, and/or notifying investigators, authorities and IRB/ECs.   
8.4.3. 
Clinical Management of Index Knee Related Events  
If the patient has an immediate reaction following administration of study medication or returns 
to the clinic with an acute exacerbation (e.g., tenderness, increased pain, swelling, effusion, 
decreased mobility of the index knee), the patient should be treated according to local clinical 
guidelines and physician experience.   
If the index knee is aspirated at any time after administration of study medication for any reason, 
the volume of synovial fluid aspirated must be documented, synovial fluid should be (1) 
cultured, (2) evaluated for presence of crystals and (3) assessed for white cell count at a local 
laboratory, and the results should be documented.   
Any event that is a change from the patient’s baseline status (new or worsening case) should be 
reported as an AE and those meeting the definition of serious must be reported in accordance 
with Section 8.4. 


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8.4.4. 
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 
Key aspects of the proposed statistical analyses are summarized below. A comprehensive 
Statistical Analysis Plan will be written and approved prior to database lock for this study. If, 
after the study has been completed, changes are made to the statistical analysis plan referenced 
below, these deviations to the plan will be listed in the Clinical Study Report (CSR), along with 
an explanation as to why they occurred.  
9.1.1. 
Interim Analysis  
Once all enrolled patients in the Synovitis Imaging Population have completed the Week 6 visit 
the mean standardized change from baseline at 6 weeks in synovial volume (the primary 
endpoint) and other efficacy measures, will be analyzed. Safety analyses may be included and 
will be detailed in the SAP. Full results of this interim analysis will be presented to the Sponsor.   
9.1.2. 
Final Analyses 
Once all enrolled patients have completed the Week 24 visit, all final analyses specified in the 
SAP will be completed following database lock and reported in the CSR. Post-hoc, exploratory 
analyses, may also be performed to further understand and elucidate study results; these analyses 
will be clearly identified as such in the CSR.  
9.2. 
General Considerations and Methods 
Data collected in this study will be presented using summary tables, figures, and data listings.  
Continuous variables will be summarized using descriptive statistics, including the mean, 
median, standard deviation, minimum and maximum.  Categorical variables will be summarized 
by frequencies and percentages.  CIs may also be provided.  Figures will be used to support the 
presentation of certain data.  Sensitivity analyses may be performed to examine the effect of 
missing data, as well as the effect of any baseline imbalance. 
All CIs, statistical tests, and resulting p values will be reported as 2-sided.  Significance will be 
assessed at α = 0.05 level and the significance level will not be adjusted for the secondary 
endpoint analyses. 
9.2.1. 
Analysis Populations 
Complete details of the statistical analysis will be specified in the SAP.  Four analysis 
populations are planned for this study as follows: 
• The Safety Population will include all patients who receive study drug. The Safety 
Population will be used to assess safety and tolerability. 
• The Synovitis Imaging Population will include all patients from the Safety 
Population, who have a pre-treatment synovial volume measurement of greater than 
3000 mm3 of gadolinium enhancement as determined by quantitative image analysis, 
as well as quality pre-treatment and Week 6 MRIs. In addition, the patients included 
in this population will have no major protocol deviations and/or imaging variations 


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(i.e. change in coil, machine or software) deemed to potentially impact the imaging 
analysis.  
• The Imaging Population will include all patients from the Safety Population, who 
have quality MRI data available for pre-treatment and at least one post baseline 
timepoint and with no major protocol deviations and/or imaging variations (i.e., 
change in coil, machine or software) deemed to potentially impact the imaging 
analysis. 
• The Efficacy Population will include all patients from the Safety Population, who 
have at least one post-Baseline WOMAC or KOOS assessment. 
9.2.2. 
Study Data 
Study data identified in this protocol are collected, and source verified, on electronic Case 
Record Forms (eCRF) at sites completing the study.  All study data will be formulated into data 
sets to provide transparency, traceability, and integrity of trial analysis results from collection 
source.  
9.2.3. 
Study Variables for Assessment 
Please refer to Section 7.7 for study variables.  
9.2.4. 
Sub-Groups and Covariates 
Sub-groups may be defined and explored and will be documented in the Statistical Analysis 
Plan. 
9.3. 
Determination of Sample Size 
Approximately 100 patients will be enrolled to ensure a minimum of 70 evaluable Synovitis 
Imaging patients, as defined by pre-treatment MRI synovial volume measurement of greater than 
3000 mm3 of gadolinium enhancement as determined by quantitative image analysis, with 
quality Pretreatment and Week 6 MRIs. Previous trials had similar sample sizes (Gait et al., 
2016) (O’Neill et al., 2016).  
9.4. 
General Statistical Methods 
9.4.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be listed by study site and patient, and will be 
summarized.  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 patient and will be summarized. 
9.4.3. 
Efficacy Analyses 
Primary efficacy endpoint:  


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• Mean standardized change from baseline at 6 weeks in synovial volume    
Secondary efficacy endpoints:  
• Mean absolute change (mm3) from baseline at 6 weeks in synovial volume  
• Mean standardized change from baseline at 24 weeks in synovial volume    
• Mean absolute change (mm3) from baseline at 24 weeks in synovial volume    
Analysis of additional secondary and exploratory endpoints will be defined in the SAP. 
9.4.4. 
Safety Analyses 
9.4.4.1. 
Analysis of Adverse Events 
AEs will be coded using MedDRA.  Incidences (number and percent) of TEAEs; (those events 
that started after dosing or worsened after dosing), will be presented. Additional analyses of 
incidences of TEAEs will also be presented by maximum severity and by relationship to study 
medication. Similar presentations will be provided for serious AEs, AEs leading to death, AEs 
leading to withdrawal from the study, and for AEs related to the index knee. 
9.4.4.2. 
Other Safety Analyses 
Clinical laboratory data and vital sign information will be summarized as summary statistics for 
value and change from Day 1 at each individual time point.  Summary statistics will include n, 
mean, median, standard deviation, minimum, and maximum. 
Details for the additional safety endpoints will be provided in the SAP. 
  


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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 PI and staff.  During 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 PI and key study personnel should be available to assist the clinical 
study monitor during these visits.   
The PI will give the monitor, auditor(s), Sponsor, Sponsor designee and regulatory authorities 
direct access to relevant clinical records. No information in these records about the identity of the 
patients will leave the clinical site.  The Sponsor will maintain the confidentiality of all patient 
records. 
Source data is all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained in source documents 
(original records or certified copies). 
Independent clinical quality assurance audits may be performed at any time during or following 
completion of the Study by the Sponsor, or its authorized agents, regulatory authorities, 
Competent Authorities and/or the IRB/EC. 


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11. 
DATA HANDLING AND RECORDKEEPING 
11.1. 
Case Report Forms 
The eCRF will be supplied by the Sponsor or designee and should be handled in accordance with 
the instructions provided. All study data should initially be documented in source documents 
(e.g., patient charts, notes, laboratory reports, ECG recordings, etc.) and then subsequently 
entered from the source into the eCRF.  All eCRFs should be filled out completely by examining 
personnel or the study coordinator.  The eCRF is reviewed, signed, and dated electronically by 
the PI. 
11.2. 
Study Medication Accountability 
All study medication required for completion of this study will be provided by the Sponsor or 
designee.  Study medication will be acknowledged upon receipt indicating shipment content and 
condition.  Damaged supplies will be replaced. 
Accurate records of all study medications received by, dispensed from or returned to the study 
site should be maintained per instructions in the Pharmacy Binder. 
In the event of a temperature excursion, refer to the Pharmacy Binder for instructions. 
In the event of a product complaint, complete the Product Complaint Form located in the 
Pharmacy Binder and send to the assigned monitor or clinical manager who will coordinate with 
the Sponsor for further guidance.  
11.3. 
Confidentiality of Data 
Patient medical information obtained by this study is confidential, and disclosure to third parties 
other than those noted below is prohibited. 
Upon the patient’s permission, medical information may be given to his or her personal 
physician or other appropriate medical personnel responsible for his or her welfare. 
Data generated by this study must be available for inspection by representatives of Competent 
Authorities, the Sponsor or their representative, and the IRB/EC. 
To maintain patient privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the patient by initials where permitted and/or by the assigned 
patient number.  The patient’s confidentiality will be maintained and will not be made publicly 
available to the extent permitted by the applicable laws and regulations. 
11.4. 
Retention of Records 
In accordance with United States of America Code of 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 and 
medical inventory records, must be retained by the PI 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 PI of these events.  If local regulations are more stringent than that specified above, the 
local regulations will be adhered to.   


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11.5. 
Protocol Adherence 
The PI must adhere to the protocol as detailed in this document and agrees that any changes to 
the protocol must be approved by the Sponsor or their representative prior to seeking approval 
from the IRB/EC.  When the changes involved are only logistical and administrative in nature to 
the trial this may not require prior approval by the IRB/EC. The PI 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 PI or any other person.  Each of 
Site and PI 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 Health Insurance 
Portability and Accountability Act (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 PI 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. 
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