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Statistical Analysis Plan for Protocol No.: P261-402 67$7,67,&$/$1$/<6,63/$1 $Q2SHQ/DEHO6DIHW\6WXG\RI86/LQWKH2XWSDWLHQW7UHDWPHQWRI 6XEMHFWVZLWK6HL]XUH&OXVWHUV 3URWRFRO1XPEHU3 8SVKHU6PLWK/DERUDWRULHV,QF (YHQVWDG'ULYH REDACTED COPY 0DSOH*URYH01 'DWHRI3ODQ 0$< Y &21),'(17,$/ This document cannot be used to support any marketing authorization application and any extensions or variations thereof. REDACTED COPY This document cannot be used to support any marketing authorization application and any extensions or variations thereof. Upsher-Smith Laboratories, Inc. Statistical Analysis Plan for Protocol No.: P261-402 7$%/(2)&217(176 LIST OF ABBREVIATIONS ..........................................................................................................5 1. INTRODUCTION ........................................................................................................6 2. STUDY DESIGN .........................................................................................................6 2.1. General Study Design and Plan ....................................................................................6 2.2. Randomization and Method of Treatment Assignment ..............................................10 2.3. Study Procedures ........................................................................................................10 3. STUDY OBJECTIVES AND CLINICAL ENDPOINTS ..........................................13 3.1. Study Objectives .........................................................................................................13 3.2. Clinical Endpoints ......................................................................................................13 3.2.1. Safety Endpoints .........................................................................................................13 3.2.2. Efficacy Endpoints ......................................................................................................13 3.2.3. Exploratory Efficacy Endpoints .................................................................................13 3.2.4. Outcome Endpoints ....................................................................................................14 4. ANALYSIS POPULATIONS ....................................................................................14 4.1. Enrolled Population ....................................................................................................14 4.2. Safety Population ........................................................................................................14 4.3. Efficacy Evaluable Population ...................................................................................14 REDACTED COPY 5. GENERAL STATISTICAL CONSIDERATIONS ....................................................14 5.1. General Consideration ................................................................................................14 5.2. Baseline .......................................................................................................................14 5.3. Handling of Missing Data ...........................................................................................15 5.4. Interim Analysis ..........................................................................................................15 5.5. Data and Safety Monitoring Board (DSMB) ..............................................................16 5.6. Multiple Comparisons and Multiplicity......................................................................16 6. STATISTICAL ANALYSIS ......................................................................................16 6.1. Subject Disposition .....................................................................................................16 6.2. Treatment Exposure and Treated Seizure Clusters .....................................................16 6.3. Protocol Deviations ....................................................................................................17 6.4. Demographics and Baseline Characteristics ...............................................................17 6.5. Medical and Surgical History .....................................................................................18 This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 6.6. Prior and Concomitant Medications ...........................................................................18 15May2017 3 Upsher-Smith Laboratories, Inc. Statistical Analysis Plan for Protocol No.: P261-402 6.7. Analyses of Efficacy and Outcome Endpoints ...........................................................19 6.7.1. Efficacy Endpoint .......................................................................................................19 6.7.2. Exploratory Efficacy Endpoints .................................................................................21 6.7.3. Subject and Caregiver Outcome Assessments ............................................................23 6.8. Safety Analyses ..........................................................................................................24 6.8.1. Adverse Events (AEs) .................................................................................................25 6.8.2. Requirement for Unscheduled ER or EMS Visit ........................................................27 6.8.3. Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................27 6.8.4. Physical, Nasal, and Neurological Examinations .......................................................28 6.8.5. Olfactory testing with Brief Smell Identification Test (B-SIT)..................................28 6.8.6. Laboratory Parameters ................................................................................................28 6.8.7. Vital Signs / Weight ....................................................................................................29 6.8.8. Caregiver-Recorded Respiration Rate ........................................................................29 7. DEVIATIONS FROM THE PROTOCOL SPECIFIED ANALYSIS .......................29 8. MOCK TABLES, FIGURES, AND DATA LISTINGS ............................................29 9. REFERENCES ...........................................................................................................30 Appendix 1 Potentially Clinically Significant Laboratory Values .................................................31 Appendix 2 List of AEs of special REDACTEDinterest ............................... COPY ......................................................32 This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 15May2017 4 Upsher-Smith Laboratories, Inc. Statistical Analysis Plan for Protocol No.: P261-402 /,672)$%%5(9,$7,216 $EEUHYLDWLRQ 'HILQLWLRQ ȝ/ Microliter AE Adverse event AED Antiepileptic Drugs ATC Anatomic Therapeutic Chemical B-SIT Brief Smell Identification Test C-SSRS Columbia-Suicide Severity Rating Scale CI Confidence interval CRO Contract Research Organization DSMB Data and Safety Monitoring Board EMS Emergency Medical Services ER Emergency Room ET Early Termination IN Intranasal IRT Interactive Response Technology ITI Intranasal Therapeutics, Inc. ITIQ Intranasal Therapy Impact Questionnaire IV Intravenous LAR Legally acceptable representative MCS Mental Health Component Score (SF-12v2) Mg Milligram MedDRA Medical Dictionary for Regulatory Activities PCI Potentially clinically important PCS PotentiallyREDACTED clinically COPY significant PHCS Physical Health Component Score (SF-12v2) PK Pharmacokinetic PMP Patient Management Plan PT Preferred Term in MedDRA SF-12v2 SF-12v2 Health Survey SAS Statistical Analysis Software SD Standard deviation USL Upsher-Smith Laboratories, Inc. USL261 Intranasal midazolam, study drug (formerly ITI-111) SOC System Organ Class in MedDRA TEAE Treatment-emergent adverse event TSQM Treatment Satisfaction Questionnaire for Medication VNS Vagus Nerve Stimulator WHO World Health Organization This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 15May2017 5 Upsher-Smith Laboratories, Inc. Statistical Analysis Plan for Protocol No.: P261-402 ,1752'8&7,21 Acute repetitive seizures and seizure clusters occur in a subset of epilepsy patients. Seizure clusters have distinguishable characteristics that are easily recognized by patients, caregivers, and physicians and include a consistent onset (auras, prodrome) that may be indicative of convulsive or non-convulsive symptoms. Although patients typically recover between seizures, these seizure can last anywhere from minutes to hours.1 When a cluster of seizures occurs outside a hospital, the patient must often be transported to an acute care facility so medical personnel can administer intravenous (IV) therapy to stop the seizure(s).2 The primary goals of seizure cluster treatment are seizure cessation and prevention of seizure recurrence.1 Acute benzodiazepine treatment is effective for seizure control and often results in rapid seizure cluster termination; however, most treatment options rely on intervention by emergency medical personnel and therefore delay treatment while the patient is transported to a medical facility.3 The development of an easily administered outpatient treatment of seizure clusters may reduce the need for emergency medical intervention and decrease seizure cluster duration. This statistical analysis plan
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