Study Title: A phase II, randomized, double-blind, placebo- controlled study of myrosinase-enriched glucoraphanin, a sulforaphane precursor system, in autism spectrum disorder NCT number 02909959 Document Date 12/14/2017 Clinical Protocol: Sulforaphane for ASD - 1 - A phase II, randomized, double-blind, placebo-controlled study of myrosinase-enriched glucoraphanin, a sulforaphane precursor system, in autism spectrum disorder Regulatory Sponsor: Laura C. Politte, M.D. Department of Psychiatry Carolina Institute for Developmental Disabilities University of North Carolina School of Medicine 101 Renee Lynne Court Carrboro, NC 27510 CB#7255 919-966-5171 Funding Sponsor: Supported by a collaborative grant from the UNC Nutrition Research Institute 500 Laureate Way Kannapolis, NC 28081 704-250-5003 Study Personnel: Laura Politte, M.D., principal investigator Joseph Piven, M.D., co-investigator Carol Cheatham, Ph.D., co-investigator Mark Weaver, Ph.D., biostatistician Study Product: Sulforaphane (Avmacol®) Protocol Number: UNC IRB #16-2059 IND Number: 131861 Initial version: 08/05/2016 Amended: [09/23/2016] Amended: [02/28/2017] Amended: [03/01/2017] Amended: [06/08/2017] Amended: [08/02/2017] Amended: [08/22/2017] Amended: [09/13/2017] Amended: [09/28/2017] Amended: [12/14/2017] Clinical Protocol: Sulforaphane for ASD - 2 - Table of Contents List of Abbreviations .................................................................................................................................. 6 Study Summary ........................................................................................................................................... 8 1 Introduction ......................................................................................................................................... 9 1.1 Background ................................................................................................................................. 9 1.2 Investigational Agent ................................................................................................................ 11 1.3 Preclinical Data ......................................................................................................................... 12 Clinical Data to Date ............................................................................................................................. 14 1.4 Dose Rationale and Risk/Benefits ............................................................................................ 15 2 Study Objectives ............................................................................................................................... 17 3 Study Design ..................................................................................................................................... 18 3.1 General Design.......................................................................................................................... 18 3.2 Primary Safety Endpoints ......................................................................................................... 20 4 Subject Selection and Withdrawal .................................................................................................... 20 4.1 Inclusion Criteria ...................................................................................................................... 20 4.2 Exclusion Criteria ..................................................................................................................... 21 4.3 Subject Recruitment and Screening .......................................................................................... 21 4.4 Early Withdrawal of Subjects ................................................................................................... 22 4.4.1 When and How to Withdraw Subjects .................................................................................. 22 4.4.2 Data Collection and Follow-up for Withdrawn Subjects ...................................................... 22 5 Study Drug ........................................................................................................................................ 23 5.1 Description ................................................................................................................................ 23 5.2 Treatment Regimen ................................................................................................................... 23 5.3 Method for Assigning Subjects to Treatment Groups .............................................................. 23 5.4 Preparation and Administration of Study Drug ........................................................................ 24 5.5 Subject Compliance Monitoring ............................................................................................... 24 5.6 Prior and Concomitant Therapy ................................................................................................ 24 5.7 Packaging .................................................................................................................................. 25 5.8 Blinding of Study Drug (if applicable) ..................................................................................... 25 5.9 Receiving, Storage, Dispensing and Return ............................................................................. 25 Clinical Protocol: Sulforaphane for ASD - 3 - 5.9.1 Receipt of Drug Supplies ...................................................................................................... 25 5.9.2 Storage .................................................................................................................................. 26 5.9.3 Dispensing of Study Drug ..................................................................................................... 26 6 Study Procedures .............................................................................................................................. 26 7 Statistical Plan ................................................................................................................................... 30 7.1 Sample Size Determination....................................................................................................... 30 7.2 Statistical Methods .................................................................................................................... 30 7.3 Subject Population(s) for Analysis ........................................................................................... 32 8 Safety and Adverse Events ............................................................................................................... 32 8.1 Definitions................................................................................................................................. 32 8.2 Recording of Adverse Events ................................................................................................... 34 8.3 Reporting of Serious Adverse Events and Unanticipated Problems ......................................... 35 8.3.1 Investigator reporting: notifying the study sponsor .............................................................. 35 8.3.2 Investigator reporting: ........................................................................................................... 35 8.3.3 Investigator reporting: ........................................................................................................... 36 8.3.4 Sponsor reporting: Notifying the FDA ................................................................................. 36 8.4 Unblinding Procedures.............................................................................................................. 37 8.5 Stopping Rules .......................................................................................................................... 37 8.6 Medical Monitoring .................................................................................................................. 39 8.6.1 Internal Data and Safety Monitoring Board or DSMP ........................................................ 39 9 Data Handling and Record Keeping ................................................................................................. 39 9.1 Confidentiality .......................................................................................................................... 39 9.2 Source Documents .................................................................................................................... 40 9.3 Case Report Forms .................................................................................................................... 40 9.4 Records Retention ..................................................................................................................... 40 10 Study Monitoring, Auditing, and Inspecting .................................................................................... 41 10.1 Study Monitoring Plan .............................................................................................................. 41 11 Ethical Considerations ...................................................................................................................... 41 12 Study Finances .................................................................................................................................. 41 12.1 Funding Source ........................................................................................................................