Clinical Development Afinitor®/Votubia® (everolimus) Clinical Trial Protocol CRAD001M2304 / NCT02962414 A three-arm, randomized, double-blind, placebo-controlled study of the efficacy and safety of two trough-ranges of everolimus as adjunctive therapy in patients with tuberous sclerosis complex (TSC) who have refractory partial-onset seizures Authors Document type Amended Protocol Version EUDRACT number 2011-000860-90 Version number 03 (Clean) Development phase III Document status Final Release date 25-Mar-2016 Property of Novartis Confidential May not be used, divulged, published, or otherwise disclosed without the consent of Novartis Novartis Confidential Page 2 Amended Protocol Version 03 (Clean) Protocol No. CRAD001M2304 Table of contents Table of contents .................................................................................................................2 List of figures ......................................................................................................................6 List of tables ........................................................................................................................6 List of abbreviations ............................................................................................................8 Glossary of terms...............................................................................................................10 Amendment 3 (25-Mar-2016) ...........................................................................................11 Summary of previous amendments ...................................................................................13 Protocol summary..............................................................................................................23 1 Background........................................................................................................................25 1.1 Overview of Tuberous Sclerosis and current treatment options............................25 1.1.1 Epilepsy associated with TSC...............................................................25 1.1.2 Role of mTOR in TSC and epileptogenesis..........................................26 1.1.3 Rapamycin and everolimus (RAD001) in TSC-epilepsy......................29 1.2 Introduction to investigational treatment(s) and other study treatment(s).............32 1.2.1 Overview of everolimus (RAD001)......................................................32 2 Rationale............................................................................................................................35 2.1 Study rationale and purpose...................................................................................35 2.2 Rationale for the study design ...............................................................................36 2.3 Rationale for dose and regimen selection..............................................................37 3 Objectives and endpoints...................................................................................................37 4 Study design ......................................................................................................................40 4.1 Description of study design ...................................................................................40 4.1.1 Baseline phase.......................................................................................41 4.1.2 Core phase.............................................................................................42 4.1.3 Extension phase.....................................................................................43 4.1.4 Post Extension Phase.............................................................................46 4.1.5 Definition of end of the study ...............................................................47 4.2 Early study termination..........................................................................................47 5 Population..........................................................................................................................47 5.1 Patient population ..................................................................................................47 5.2 Inclusion criteria ....................................................................................................47 5.3 Exclusion criteria...................................................................................................51 6 Treatment...........................................................................................................................53 6.1 Study treatment......................................................................................................53 6.1.1 Dosing Regimen....................................................................................53 Novartis Confidential Page 3 Amended Protocol Version 03 (Clean) Protocol No. CRAD001M2304 6.1.2 Rescue medication ................................................................................57 6.1.3 Treatment duration................................................................................57 6.2 Dose modification guidelines ................................................................................58 6.2.1 Starting dose rationale...........................................................................58 6.2.2 Dose Titration........................................................................................59 6.2.3 Rounding of doses.................................................................................60 6.2.4 Dose reduction or delay ........................................................................61 6.2.5 Management of specific toxicity...........................................................63 6.3 Concomitant medications ......................................................................................68 6.3.1 Permitted concomitant therapy requiring caution and/or action ...........68 6.3.2 Prohibited concomitant therapy ............................................................70 6.4 Patient numbering, treatment assignment or randomization .................................71 6.4.1 Patient numbering .................................................................................71 6.4.2 Treatment assignment or randomization...............................................71 6.4.3 Treatment blinding................................................................................72 6.5 Study Drug Supply ................................................................................................72 6.5.1 Study drug preparation and dispensation ..............................................72 6.5.2 Study drug packaging and labeling .......................................................73 6.5.3 Drug supply and storage........................................................................75 6.5.4 Study drug compliance and accountability ...........................................75 6.5.5 Disposal and destruction .......................................................................76 7 Visit schedule and assessments .........................................................................................76 7.1 Study flow and visit schedule ................................................................................76 7.1.1 Screening...............................................................................................87 7.1.2 Baseline phase.......................................................................................89 7.1.3 Core phase.............................................................................................90 7.1.4 Extension phase.....................................................................................90 7.1.5 Post Extension phase.............................................................................91 7.1.6 End of treatment visit and premature withdrawal .................................91 7.1.7 Follow up/Study completion.................................................................93 7.2 Assessment types ...................................................................................................94 7.2.1 Eligibility assessments ..........................................................................94 7.2.2 Efficacy assessments.............................................................................95 7.2.3 Safety and tolerability assessments.......................................................95 7.2.4 Pharmacokinetics ................................................................................104 7.2.5 Patient reported outcomes...................................................................111 Novartis Confidential Page 4 Amended Protocol Version 03 (Clean) Protocol No. CRAD001M2304 8 Safety monitoring and reporting......................................................................................111 8.1 Adverse events.....................................................................................................111 8.1.1 Definitions and reporting ....................................................................111 8.1.2 Laboratory test abnormalities..............................................................113 8.1.3 Adverse events of special interest.......................................................113 8.2 Serious adverse events.........................................................................................113 8.2.1 Definitions...........................................................................................113