CLINICAL STUDY PROTOCOL A Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of FX006 in Patients with Hip Osteoarthritis PROTOCOL NUMBER: FX006-2018-015 PHASE: 3 STUDY MEDICATION(S): FX006 INDICATION: Osteoarthritis of the hip MEDICAL MONITOR: Robert D. Arbeit, M.D. SPONSOR: Flexion Therapeutics 10 Mall Road, Suite 301 Burlington, Massachusetts 01803 Tel: 617-762-6783 DATE: 31 JUL 2019 VERSION: Version 3.0 (Amendment 2.0) SUPERSEDES: Version 2.0 (Amendment 1.0; 13 MAR 2019) CONFIDENTIAL INFORMATION Flexion Therapeutics, Inc. Protocol FX006-2018-015 FX006 Version 3.0 (Amendment 2.0) (31JUL2019) TABLE OF CONTENTS 1. ABBREVIATIONS AND DEFINITION OF TERMS ................................................9 2. SYNOPSIS .................................................................................................................12 3. ETHICS ......................................................................................................................21 3.1. Institutional Review Board/Ethics Committee ...........................................................21 3.2. Ethical Conduct of Study ............................................................................................21 3.3. Patient Information and Consent ................................................................................21 4. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .................22 4.1. Investigators ................................................................................................................22 4.2. Study Administrative Structure ..................................................................................22 5. INTRODUCTION ......................................................................................................23 5.1. Osteoarthritis ...............................................................................................................23 5.2. Background .................................................................................................................23 5.2.1. Investigational Medicinal Product: FX006 ................................................................23 5.2.2. Rationale for FX006 in Hip Osteoarthritis .................................................................24 5.2.3. Non-Clinical Toxicology ............................................................................................24 5.2.4. Systemic and Local Pharmacokinetics (PK) in Patients with Osteoarthritis of the Knee ......................................................................................................................25 5.2.5. Pharmacodynamics (PD) in Patients with Osteoarthritis of the Knee ........................25 5.2.6. Efficacy in Patients with Osteoarthritis of the Knee ..................................................25 5.2.7. Systemic and Local Safety in Patients with Osteoarthritis of the Knee .....................26 5.2.8. Rationale for Protocol Amendment ............................................................................27 5.2.9. Experience with FX006 Administered IA in Patients with OA of the Hip ................28 5.2.10. Conclusion ..................................................................................................................28 6. STUDY OBJECTIVES ..............................................................................................29 6.1. Primary Objective .......................................................................................................29 6.1.1. Part I ............................................................................................................................29 6.1.2. Part II ..........................................................................................................................29 6.2. Secondary Objectives .................................................................................................29 6.2.1. Part I ............................................................................................................................29 6.2.2. Part II ..........................................................................................................................29 6.3. Open Label Phase Objectives .....................................................................................29 6.3.1. Secondary Objective: ..................................................................................................29 CONFIDENTIAL Page 3 of 72 Flexion Therapeutics, Inc. Protocol FX006-2018-015 FX006 Version 3.0 (Amendment 2.0) (31JUL2019) 6.3.2. Primary Objective: ......................................................................................................29 7. INVESTIGATIONAL PLAN .....................................................................................30 7.1. Overall Study Design and Plan ...................................................................................30 7.1.1. Flow of Study Participation ........................................................................................30 7.2. Site Staffing Requirements .........................................................................................31 7.3. Discussion of Study Design ........................................................................................33 7.3.1. Rationale for Study Population ...................................................................................33 7.3.2. Rationale for Dose Selection ......................................................................................33 7.3.3. Rationale for Study Parameters ..................................................................................33 7.3.4. Rationale for Control Type .........................................................................................33 7.3.5. Rationale for Blinding Approach ................................................................................33 7.4. Selection of Study Population ....................................................................................34 7.4.1. Number of Patients .....................................................................................................34 7.4.2. Inclusion Criteria ........................................................................................................34 7.4.3. Exclusion Criteria .......................................................................................................35 7.4.4. Second Injection Inclusion Criteria (Part II Patients Only) ........................................37 7.4.5. Second Injection Exclusion Criteria (Part II Patients Only) .......................................38 7.4.6. Removal of Patients from Therapy or Assessments ...................................................38 7.4.7. Screen Failures ............................................................................................................39 7.5. Treatment Administered .............................................................................................39 7.5.1. Study Medication Treatment Arms ............................................................................39 7.5.2. Identity of Investigational Product(s) .........................................................................39 7.5.3. Identity of Reference Compound ................................................................................40 7.5.4. Receipt, Preparation, Dispensing and Storage ............................................................40 7.5.5. Packaging and Labeling of Study Medication ............................................................40 7.5.6. Return of Study Medication ........................................................................................40 7.5.7. Method of Assigning Patients to Treatment Groups ..................................................40 7.5.8. Blinding ......................................................................................................................40 7.5.9. Breaking The Blind .....................................................................................................43 7.5.10. Investigational Medicinal Product Administration Procedure ...................................43 7.5.11. Treatment Compliance ................................................................................................44 7.6. Prior and Concomitant Therapy ..................................................................................44 7.6.1. Allowable Medications/Non-Pharmacologic Therapies .............................................44 CONFIDENTIAL Page 4 of 72 Flexion Therapeutics, Inc. Protocol FX006-2018-015 FX006 Version 3.0 (Amendment 2.0) (31JUL2019) 7.6.2. Prohibited Medications/Non-Pharmacologic Therapies .............................................45 7.6.3. Rescue Medication ......................................................................................................46 7.7. Study Variables ...........................................................................................................46 7.7.1. Safety Variables ..........................................................................................................46 7.7.2. Efficacy Variables ......................................................................................................46 7.8. Schedule of Study Assessments..................................................................................47 7.9. Study Procedures ........................................................................................................50