Relievant Medsystems INTRACEPT CIP 0006, Rev E Title: INTRACEPT: A Prospective, Randomized, Multi-Center Study of Intraosseous Basivertebral Nerve Ablation for the Treatment of Chronic Low Back Pain Protocol Number: CIP 0006, REV E Device: INTRACEPT® INTRAOSSEOUS NERVE ABLATION SYSTEM The device has FDA 510(k) clearance in the US and is CE Regulatory Status: marked in the EU for its intended purpose as defined in the Instructions for Use Sponsor: Relievant Medsystems 385 Moffett Park Drive, Suite 105 Sunnyvale, CA 94089 Date: OCTOBER 17, 2018 CONFIDENTIAL This document contains confidential information. It is intended solely for the recipient and must not be disclosed to any other party. The material may be used only for evaluating or conducting clinical investigations; any other proposed use requires Sponsor written consent. Page 1 of 65 CONFIDENTIAL AND PROPRIETARY October 17, 2018 Relievant Medsystems INTRACEPT CIP 0006, Rev E TABLE OF CONTENTS TABLE OF CONTENTS ............................................................................................................. 2 1.0 SYNOPSIS ................................................................................................................... 6 2.0 LIST OF ABBREVIATIONS ........................................................................................... 11 3.0 BACKGROUND .......................................................................................................... 12 3.1 Causes of Low Back Pain................................................................................................... 12 3.2 Epidemiology of Chronic Low Back Pain ............................................................................ 13 3.3 The Differential Diagnosis of Chronic Lower Back Pain ...................................................... 13 3.4 Pathophysiology of Vertebrogenic Back Pain .................................................................... 15 3.4.1 Discogenic versus Vertebrogenic Back Pain .......................................................................... 16 3.5 Treatments for Chronic Lower Back Pain ........................................................................... 17 3.6 Non-surgical Treatments for Lower Back Pain ................................................................... 18 3.6.1 Education............................................................................................................................... 18 3.6.2 Analgesics .............................................................................................................................. 18 3.6.3 Exercise.................................................................................................................................. 18 3.6.4 Physical Treatments .............................................................................................................. 18 3.6.5 Spinal Manipulative Therapy ................................................................................................. 19 3.6.6 Needle Acupuncture ............................................................................................................. 19 3.6.7 Multidisciplinary Rehabilitation ............................................................................................ 20 3.6.8 Injections and Nerve Treatments .......................................................................................... 20 3.7 Surgical Treatments for Chronic Lower Back Pain .............................................................. 20 3.7.1 Intradiscal Procedures ........................................................................................................... 20 3.7.2 Fusion Surgery ....................................................................................................................... 21 3.7.3 Total Disc Arthroplasty .......................................................................................................... 22 3.8 RF Ablation of the BVN for Treatment of Vertebrogenic Back Pain .................................... 22 3.9 Clinical Experience to Date ............................................................................................... 23 3.9.1 Feasibility Study .................................................................................................................... 23 3.9.2 Pivotal Clinical Trial – the SMART Study................................................................................ 23 4.0 DEVICE DESCRIPTION ................................................................................................ 24 4.1 The Intracept® Intraosseous Nerve Ablation System (Intracept System) ............................. 24 5.0 STUDY PROTOCOL .................................................................................................... 26 5.1 Study Objectives .............................................................................................................. 26 5.1.1 Primary Objectives ................................................................................................................ 26 5.1.2 Secondary Objectives ............................................................................................................ 26 5.2 Study Design .................................................................................................................... 26 5.3 Number of Sites ............................................................................................................... 27 5.4 Number of Subjects.......................................................................................................... 27 5.5 Study Duration................................................................................................................. 27 5.6 Study Population ............................................................................................................. 27 5.7 Subject Selection Criteria ................................................................................................. 27 5.7.1 Inclusion Criteria ................................................................................................................... 27 5.7.2 Exclusion Criteria ................................................................................................................... 28 5.8 Treatment Plan ................................................................................................................ 30 5.8.1 Screening ............................................................................................................................... 30 Page 2 of 65 CONFIDENTIAL AND PROPRIETARY October 17, 2018 Relievant Medsystems INTRACEPT CIP 0006, Rev E 5.8.2 Enrollment Monitor .............................................................................................................. 30 5.8.3 Baseline Assessments ............................................................................................................ 30 5.8.4 Randomization ...................................................................................................................... 31 5.8.5 Choosing the Target Vertebral Bodies .................................................................................. 31 5.8.6 Procedure for RF Ablation of the BVN using the Intracept System ...................................... 31 5.9 Schedule of Assessments.................................................................................................. 33 5.10 Crossover......................................................................................................................... 36 5.11 Study Exit ........................................................................................................................ 36 5.12 Study Withdrawal/Termination ........................................................................................ 36 6.0 STUDY ASSESSMENTS AND OUTCOME MEASURES .................................................... 37 6.1 Medical History ................................................................................................................ 37 6.2 Laboratory Tests .............................................................................................................. 37 6.3 Beck Depression Inventory (BDI-II) ................................................................................... 37 6.4 Imaging ........................................................................................................................... 38 6.5 Neurologic and Physical (Orthopedic) Exam ...................................................................... 39 6.6 Oswestry Disability Index (ODI) ........................................................................................ 39 6.7 Visual Analogue Scale (VAS) ............................................................................................. 39 6.8 Short Form-36 Instrument (SF-36) .................................................................................... 39 6.9 EuroQOL Quality of Life Instrument (EQ-5D-5L) ................................................................. 39 6.10 Patient Satisfaction .......................................................................................................... 40 6.11 Concomitant Back Pain Medications ................................................................................. 40 6.12 Concomitant Therapy ....................................................................................................... 40 6.13 Adverse