NL58621.041.16 / BASCET RESEARCH PROTOCOL Bumetanide for the Autism Spectrum Clinical Effectiveness Trial Short title: BASCET Multicenter double-blind randomized placebo-controlled trial EudraCT-study number: 2016-002875-81 Version August 2017 NL58621.041.16 / BASCET Bumetanide for the Autism Spectrum Clinical Effectiveness Trial Protocol ID BASCET Short title BASCET Study EudraCT number 2016-002875-81 Version 4.0 Date August 2017 Sponsor UMC Utrecht Dr. F.E. Scheepers @umcutrecht.nl Department of Psychiatry Phone : Principal investigators Dr. H. Bruining Phone : UMC Utrecht Department of Psychiatry Phone : Dr. I.D.C. van Balkom Phone : Jonx Groningen, Lentis Psychiatric Institute Department of (Youth) Mental Health and Autism Phone : Collaborators: Dr. M.G. Keijzer-Veen Phone : UMC Utrecht Department of Pediatrics Phone : Dr. F.E. Jansen Phone : UMC Utrecht Department of Pediatric Neurology Phone : Dr. W.B. Gunning Phone : Stichting Epilepsie Instellingen Nederland Zwolle UMC Utrecht Department of Genetics Center for Molecular Medicine Phone : NL58621.041.16 / BASCET Dr. H.F. van Stel Phone : UMC Utrecht Julius Centrum Phone : Dr. H.T. Swelheim Phone : Ommelander Ziekenhuis / Jonx Department of Pediatrics / FASD-poli Dr. A. Van Eeghen Phone : Expertise Centrum De Hartekamp Groep Phone : Dr. S. Piening Phone : Jonx Groningen Autisme Team Noord-Nederland Dr. A.M. Euser Phone : Jonx Groningen Autisme Team Noord-Nederland MSc. D.M. van Andel Phone : UMC Utrecht Department of Psychiatry Phone : Subsidising party Hersenstichting Nederland (Dutch Brain Foundation) Independent experts Dr. M. Ermers Dr. E. Sevenhuijsen Laboratory sites Laboratory UMC Utrecht, Laboratory Certe Pharmacy Pharmacy UMC Utrecht NL58621.041.16 / BASCET PROTOCOL SIGNATURE SHEET NL58621.041.16 / BASCET TABLE OF CONTENTS 1. INTRODUCTION AND RATIONALE .............................................................................10 2. OBJECTIVES ................................................................................................................14 3. STUDY DESIGN ...........................................................................................................14 4. STUDY POPULATION ..................................................................................................15 4.1 Population (base) .....................................................................................................15 4.2 Inclusion criteria .......................................................................................................15 4.3 Exclusion criteria ......................................................................................................15 4.4 Sample size calculation ............................................................................................15 5. TREATMENT OF SUBJECTS .......................................................................................17 5.1 Investigational product/treatment .............................................................................17 5.2 Use of co-intervention ..............................................................................................17 5.3 Escape medication ...................................................................................................17 6. INVESTIGATIONAL PRODUCT ....................................................................................18 6.1 Name and description of investigational product(s) ..................................................18 6.2 Summary of findings from non-clinical studies ..........................................................18 6.3 Summary of findings from clinical studies .................................................................21 6.4 Summary of known and potential risks and benefits .................................................23 6.5 Description and justification of route of administration and dosage ..........................24 6.6 Dosages, dosage modifications and method of administration .................................24 6.7 Preparation and labelling of Investigational Medicinal Product .................................25 6.8 Drug accountability ...................................................................................................25 7. NON-INVESTIGATIONAL PRODUCT ...........................................................................27 8. METHODS ....................................................................................................................28 8.1 Study parameters/endpoints ....................................................................................28 8.1.1 Main study parameter/endpoint .........................................................................28 8.1.2 Secondary study parameters/endpoints ............................................................28 8.1.3 Other study parameters .....................................................................................29 8.2 Randomization, blinding and treatment allocation ....................................................30 8.3 Study procedures .....................................................................................................31 8.3.1 Study phase and procedures.............................................................................31 8.3.2 Study investigations ..........................................................................................34 8.3.3 Safety investigations .........................................................................................35 8.4 Withdrawal of individual subjects ..............................................................................40 8.4.1 Specific criteria for withdrawal ...........................................................................41 8.5 Replacement of individual subjects after withdrawal .................................................41 8.6 Follow-up of subjects withdrawn from treatment .......................................................41 8.7 Premature termination of the study ..........................................................................41 9. SAFETY REPORTING ..................................................................................................42 9.1 Temporary halt for reasons of subject safety ............................................................42 9.2 AEs, SAEs and SUSARs ..........................................................................................42 9.2.1 Adverse events (AEs) .......................................................................................42 NL58621.041.16 / BASCET 9.2.2 Serious adverse events (SAEs) .........................................................................42 9.2.3 Suspected unexpected serious adverse reactions (SUSARs) ...........................43 9.3 Annual safety report .................................................................................................43 9.4 Follow-up of adverse events ....................................................................................44 9.5 Data Safety Monitoring Board (DSMB) / Safety Committee ......................................44 10. STATISTICAL ANALYSIS .........................................................................................45 10.1 Primary study parameter(s) ......................................................................................45 10.2 Secondary study parameter(s) .................................................................................45 10.3 Other study parameters............................................................................................45 10.4 Interim analysis ........................................................................................................45 10.5 Economic evaluation ................................................................................................45 11. ETHICAL CONSIDERATIONS ..................................................................................46 11.1 Regulation statement ...............................................................................................46 11.2 Recruitment and consent .........................................................................................46 11.3 Objection by minors or incapacitated subjects ..........................................................46 11.4 Benefits and risks assessment, group relatedness ...................................................46 11.5 Compensation for injury ...........................................................................................47 11.6 Incentives .................................................................................................................47 12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ........................48 12.1 Handling and storage of data and documents ..........................................................48 12.2 Monitoring and Quality Assurance ............................................................................48 12.3 Amendments ............................................................................................................50 12.4 Annual progress report .............................................................................................50 12.5 Temporary halt and (prematurely) end of study report ..............................................50 12.6 Public disclosure and publication policy ...................................................................50 13. STRUCTURED RISK ANALYSIS ..............................................................................51