Statistical Analysis Plan Study: ENGAGE-E-001
Statistical Analysis Plantionsthereof.Study: ENGAGE-E-001variaSTATISTICAL ANALYSIS PLANtensionsorFinal v1.0anyexProtocol ENGAGE-E-001(Amendment 6, v7.0, 01FEB2019)ar Rke Etin DAg Cau TEth Dor Ciz Oat Pio YnapplicationandA Double-Blind, Placebo-Controlled, Inpatient, Dose-Ranging Efficacy Study ofStaccato Alprazolam (STAP-001) in Subjects with Epilepsy with a PredictableSeizure PatternThisdocumentcannotbeusedtosupportanymDate: July 8, 2019Page 1 of 20Page 2140 of 8417Confidential & Proprietary Informationof Peachtree BioResearch Solutions, Inc.
TABLE OF CONTENTSThisdocumentcannotbeusedtosupportanymar Rke Etin DAg Cau TEth Dor Ciz Oat Pio ist of Abbreviations . 31. INTRODUCTION . 41.1Objectives . 41.2Design . 41.2.1Part 1: Open-Label Feasibility . 41.2.2Part 2: Double-Blind. 42. ELABORATION OF STUDY PROTOCOL . 52.1Study Populations . 52.2Study Endpoints . 52.2.1Efficacy . 52.2.2Pharmacokinetic . 62.2.3Safety . 62.3Sample Size . 63. STATISTICAL METHODS . 63.1General. 63.2Subject Disposition, Demographics, Baseline Characters and Study Drug Compliance . 73.3Analysis of Study Endpoints . 73.3.1Efficacy . 73.3.2Pharmacokinetics . 83.3.3Safety Analysis . 83.3.4Multiplicity Adjustment . 9Handling of Missing Data . 93.43.5Protocol Deviations . 103.6Key Data Items . 103.7Change to Planned Protocol Analysis . 124. OUTPUT PLANNED FOR THE STUDY REPORT (BLINDED PHASE) . 124.1Tables to be Included in Study Report . 124.1.1Summary of Subject Information . 124.1.2Summary of Efficacy Endpoints . 124.1.3Summary of PK/PD Endpoints . 134.1.4Summary of Safety Endpoints . 134.2Listings to be Included in the Clinical Study Report. 144.2.1Listings of Subject Information . 144.2.2Listings of Efficacy Data . 144.2.3Listings of PK Data . 144.2.4Listings of Safety Data . 144.3Figures to be Included in the Clinical Study Report . 155. REFERENCES . 166. ATTACHMENT: The Shells of Tables, Figures and Listings planned for Clinical Study Report . 167. APPENDIX: Common Terminology Criteria for Adverse Events (CTCAE, v4.03) . 17Page 2 of 20Page 2141 of 8417Confidential & Proprietary Informationof Peachtree BioResearch Solutions, Inc.
LIST OF ABBREVIATIONSadverse eventsAEDantiepileptic drugsATCanatomical-therapeutic-chemicalAUCinfarea under the concentration curve from 0 to infinityAUClastarea under the concentration curve from 0 to the last measurable valueCIconfidence intervalCmaxmaximum concentrationCRUclinical research unitCTCAECommon Terminology Criteria for Adverse EventsEMUepilepsy monitoring unitFDAFood and Drug AdministrationITTintend-to-treatICHInternational Committee for HarmonizationMedDRAMedical Dictionary for Drug Regulatory AffairsPBRSPeachtree BioResearch SolutionPCSpotentially clinically ncipal investigatorPPper-protocolSAEserious adverse eventsSAPstatistical analysis planSASstatistical analysis systemSDstandard deviationSOCsystem organ classTmaxtime to maximumnstioriavaorsionnsteexyanandnioaticar Rke Etin DAg Cau TEth Dor Ciz Oat Pio YnapplmtanyporsuptodusebenotUnited Statesvisual analog scaleumentVAScanUSthereof.AEThisdocWHODRUG World Health Organization Drug DictionaryPage 3 of 20Page 2142 of 8417Confidential & Proprietary Informationof Peachtree BioResearch Solutions, Inc.
INTRODUCTION1.1 ObjectivesnsThe overall objectives of the study are to assess the efficacy and safety of a single administration ofSTAP-001 in subjects with epilepsy with a predictable seizure pattern.thereof.1.riatioThe primary objectives are:To assess the efficacy of STAP-001 (1.0 mg and 2.0 mg) compared to placebo in treating aseizure episode To assess the clinical feasibility and safety of the inhalation of STAP-001 (1.0 mg and 2.0mg) compared to placebo in subjects during a seizure episode To assess the sedation associated with administration of STAP-001 (1.0 mg and 2.0 mg)compared to placeboandanyextensionsorva ion1.2 Designar Rke Etin DAg Cau TEth Dor Ciz Oat Pio YnapplicatThis is a multicenter, dose-ranging study to investigate the efficacy, safety, and clinical usability ofSTAP-001 in adult (18 years of age and older) subjects with epilepsy with a predictable seizure pattern.This is an in-patient study. Eligible and qualified subjects will be admitted to a Clinical Research Unit(CRU) or Epilepsy Monitoring Unit (EMU) for study participation. The duration of the stay in the inpatient unit during the Treatment phase will be 2-8 days. The study consists of two parts: Part 1- OpenLabel Feasibility; Part 2 - Double-Blind.1.2.1 Part 1: Open-Label FeasibilitynotbeusedtosupportanymThe first subjects enrolled in the study will participate in an open-label feasibility evaluation. Enrollmentin this phase will end when there are data from at least 8 individual subjects with a treated singleseizure episode in a CRU/EMU. Eligible subjects will receive a single dose of 1 mg STAP-001 at theonset of their predictable seizure episode. The subjects will undergo all study procedures andevaluations as outlined in this protocol. The feasibility data (with special emphasis on the drugadministration and clinical assessment procedures) from these 8 subjects will be analyzed andreviewed by the Sponsor before starting the double-blind part of the study. If deemed necessary basedon the feasibility data, the study protocol will be amended (for example, to change the drugadministration procedure or to redefine the time frame for primary endpoint assessment), beforestarting the double-blind part of the study.can1.2.2 Part 2: Double-BlindThisdocumentAfter admission to the in-patient unit eligible and qualified subjects will be stratified by the use ofinducing vs non-inducing AED and the use of chronic daily benzodiazepines (yes or no) and randomlyassigned (1:1:1) to one of two doses of STAP-001 (1 mg or 2 mg) or Staccato placebo. A blood samplefor PK analysis (pre-dose) will be obtained. For each subject, a single seizure episode will be treatedand assessed. Study medication will be self-administered (when feasible) or administered by a StaffCaregiver when a predictable seizure episode starts. Assessment of the seizure activity is based onclinical observation by the Staff Caregiver using a stop watch. In addition, a video EEG will record theoccurrence, start time, and duration, of the seizure event. PK samples will be collected 10, 30 and 60Page 4 of 20Page 2143 of 8417Confidential & Proprietary Informationof Peachtree BioResearch Solutions, Inc.
variationsthereof.minutes, and 2 and 6 hours after the administration of the study drug. If possible, subjects will signalwhen they experience a seizure event. Subject will be under video EEG surveillance throughout theTreatment Phase. The Staff Caregiver will signal the event for the video EEG recording, starts the stopwatch at the time of drug administration, and mark the occurrence of the seizure event on a seizurediary. If the seizure episode does not stop within 5 minutes of the study drug administration, rescuemedication other than alprazolam may be administered at the discretion of the principal investigator perthe protocol of the research unit. The study exit procedures will be conducted 24 to 32 hours after theadministration of study medication or when the subject discontinues from the study.nsionsorAfter discharge from the in-patient unit there will be a safety-follow-up phone contact 14 2 days afterthe subject received the study medication.anyexte2. ELABORATION OF STUDY PROTOCOLand2.1 Study PopulationsionFive analysis populations will be defined and analyzed:The Efficacy Population (ITT population) will include all subjects who have a seizure eventand receive study drug during the Treatment Period.2.Modified Intent to Treat (mITT) population will consist of all subjects who have a seizureevent, receive study drug, and have had at least one evaluation after study drugadministration. mITT will be used for primary efficacy analysis.3.The Per Protocol Population will include all subjects in the Efficacy Population who weredosed according to protocol and have no major protocol deviations. Major protocol deviationswill be identified by Engage Therapeutics, Inc., before the database is locked and unblinded.4.The PK Population will include all subjects who receive study drug and have at least onepharmacokinetic data point during the Treatment Period. Subjects who receive placebo willbe excluded from the PK Population. PK concentrations will be analyzed using PKpopulation.5.The Safety Population will include all subjects who receive study drug during the TreatmentPeriod from both Part 1 Open-label Feasibility and Part 2 Double-blind. All safety parameterswill be analyzed using safety population.usedtosupportanymar Rke Etin DAg Cau TEth Dor Ciz Oat Pio Ynapplicat1.be2.2 Study Endpointscannot2.2.1 Efficacy ThisdocumentPrimary efficacy endpoint:The proportion of responders in each treatment group achieving seizure activity cessationwithin 2 minutes after the administration of the study drug and no recurrence of seizureactivity within 2 hoursSecondary endpoints: Seizure episode severity assessed by subject and/or Staff Caregiver Use of rescue medicationPage 5 of 20Page 2144 of 8417Confidential & Proprietary Informationof Peachtree BioResearch Solutions, Inc.
Secondary generalization (evolution to a complex partial seizure and/or a generalized tonicclonic seizure)thereof.Exploratory endpoints:Number of seizures during the 4, 6, and 12 hour time periods after study drug administration Time to next seizure event with start time 2 minutes after study drug administrationtions varia2.2.2 PharmacokineticionsorBlood samples will be collected for plasma alprazolam concentration measurement pre-dose and thenat 10, 30, and 60 minutes, and 2 and 6 hours after the dosing of the study drug.tens2.2.3 SafetyandanyexSafety and tolerability will be assessed by evaluating adverse events (AEs), vital signs, concomitantmedications, clinical laboratory, and electrocardiogram (ECG) results, as well as neurological andphysical examinations. Sedation will also be assessed using a subject visual analog scale (VAS).ion2.3 Sample Sizear Rke Etin DAg Cau TEth Dor Ciz Oat Pio YnapplicatThere are no studies in the literature to provide reliable estimates of active treatment or placeboresponse rates for this study. Assuming a 10% drop-out/protocol violation rate, approximately 115subjects will be enrolled in the double-blind part of the study to provide approximately 35 evaluablesubjects per treatment arm. Enrollment may be stopped after 105 evaluable subjects have completedthe study.tanymApproximately 30% of the overall study population randomized in the study may be subjects beingtreated with chronic daily benzodiazepines as part of their epilepsy management. Since the effect ofconcomitant chronic daily benzodiazepines use on study treatment is unknown, a 50% response ratefor chronic benzodiazepines users on active treatment arms is assumed. For subjects who are notchronic benzodiazepines users, a response rate of 60% for active treatment arms is assumed. With upto 30% of study population being chronic benzodiazepines users and these response assumptions, a57% response for the active treatment arm is targeted.dtosupporPower calculations assume a 2-sided test and significance level of 0.05 with 90% power and are basedon the assumption that the proportion of responders with STAP-001 is 57% (best active treatment arm)whereas the assumed placebo responder rate is 20%.beuse3. STATISTICAL METHODSnot3.1 GeneralcanAll data will be analyzed using the Statistical Analysis System (SAS ; Version 9.4).ThisdocumentSafety and efficacy data will be summarized and presented by treatment group and time point insummary tables. Continuous variables will be presented by descriptive statistics: n, mean, standarddeviation (SD), median, minimum, and maximum. Categorical variables will be tabulated by frequencycount and percentage.When the actual treatment received by a subject is different from the randomized treatment assigned,the subject will be analyzed per the randomized treatment for the efficacy parameters (using the ITT,and mITT populations); while the subject will be analyzed per actual treatment that was taken for thesafety parameters (using the safety population).Page 6 of 20Page 2145 of 8417Confidential & Proprietary Informationof Peachtree BioResearch Solutions, Inc.
tio3.2 Subject Disposition, Demographics, Baseline Characters and Study Drug CompliancensFor the Treatment Period, data will be summarized by active treatment by dose level versus placebotreated subjects (i.e., by treatment group). All data for analysis will be listed by subject.thereof.Unless otherwise stated, all statistical tests will be 2-sided hypothesis tests performed at the 5% level ofsignificance for main effects and all confidence intervals (CIs) will be 2-sided 95% confidence intervals.Disposition will be summarized by randomized treatment group. The number and percentageof subjects, who are randomized, treated, prematurely discontinued, and complete the studywill be summarized. Baseline characteristics will be summarized by treatment group. The number of subjects in each cohort’s treatment group will be summarized for eachinvestigative site for the Treatment Period. Medical history will be listed with reported terms. Concomitant medications will be summarized by World Health Organization Drug DictionaryAnatomical-Therapeutic-Chemical (WHODRUG ATC) classification and preferred term.3.3.1 Efficacyicar Rke Etin DAg Cau TEth Dor Ciz Oat Pio Ynappl3.3 Analysis of Study Endpointsationandanyextensionsorvaria All statistical tests will be 2-sided with a significance level of 0.05. Testing will be performed only for theTreatment Period.tanymData will be summarized by active treatment by dose level versus placebo-treated subjects (i.e., bytreatment group). Continuous measures will be summarized descriptively (mean, standard deviation,median, minimum value, and maximum value) and categorical measures will be presented as numberand percentage.supporThe primary efficacy analysis will be conducted following completion of the Treatment Period for thelast subject and data base lock.toPrimary Efficacy EndpointumentcannotbeusedThe primary efficacy endpoint will be the proportion of responders in each treatment group achievingseizure activity cessation within 2 minutes after the administration of the study drug and no recurrenceof seizure activity within 2 hours. The primary endpoint will be analyzed with a chi-squared test. Theoverall treatment comparison, as well as pair-wise comparisons between each dose level and placebowill be performed. The estimates of the treatment difference versus placebo and their 95% confidenceinterval will be presented.ThisdocThere will be no adjustment for multiple treatment group comparisons in this dose-ranging Phase 2bstudy. The dose-response relationship will be explored with a regression analysis.Secondary and Exploratory Efficacy EndpointsSecondary and exploratory endpoints will be summarized by treatment group and if applicable, byassessment time point. Exploratory statistical testing may be performed if warranted. The CochranPage 7 of 20Page 2146 of 8417Confidential & Proprietary Informationof Peachtree BioResearch Solutions, Inc.
thereof.Mantel-Haenszel (CMH) test for row-mean score difference will be used to test the treatment differencein the seizure episode severity. The Kruskal-Wallis test will be used to compare seizure frequencies.The time-to-next-seizure data will be summarized and displayed with Kaplan-Meier plots. No multiplicityadjustment will be implemented for exploratory tests.tioorvariaThe collection status of PK samples will be listed for each visit with scheduled pharmacokineticsampling. Plasma concentrations of study drug and the active metabolites may be summarizedseparately, as appropriate.ns3.3.2 PharmacokineticsyextensionsPK parameters including maximum concentration (Cmax), time to maximum (Tmax), area under theconcentration curve from 0 to the last measurable value (
Jul 08, 2019 · WHODRUG World Health Organization Drug Dictionary . Page 2142 of 8417 thereof. REDACTED COPY . Page 4 of 20 Confidential & Proprietary Information of Peachtree BioResearch Solutions, Inc. 1. INTRODUCTION. 1.1 Objectives . The overall objectives of the study are to ass
PLT Savi 8200 PLT Savi W 700 Jabra Engage 75 Jabra Engage 65 PLT Savi 400 Jabra Pro 930 PLT Savi 8200 PLT Savi W 700 Jabra Engage 75 Jabra Engage 65 PLT Savi 400 Jabra Pro 930 PLT Savi 8200 PLT Savi W 700 Jabra Engage 75 Jabra Engage 65 PLT Savi 400 Jabra Pro 930 * Neckband available as a
PLT Savi 8200 PLT Savi W 700 Jabra Engage 75 Jabra Engage 65 PLT Savi 400 Jabra Pro 930 PLT Savi 8200 PLT Savi W 700 Jabra Engage 75 Jabra Engage 65 PLT Savi 400 Jabra Pro 930 PLT Savi 8200 PLT Savi W 700 Jabra Engage 75 Jabra Engage 65 PLT Savi 400 Jabra Pro 930 * Neckband available as a
Module 5: Statistical Analysis. Statistical Analysis To answer more complex questions using your data, or in statistical terms, to test your hypothesis, you need to use more advanced statistical tests. This module revi
Statistical Methods in Particle Physics WS 2017/18 K. Reygers 1. Basic Concepts Useful Reading Material G. Cowan, Statistical Data Analysis L. Lista, Statistical Methods for Data Analysis in Particle Physics Behnke, Kroeninger, Schott, Schoerner-Sadenius: Data Analysis in High Energy Physics: A Practical Guide to Statistical Methods
3 Study C Shows a Highly Significant Result Study C: F 63.62, p .0000001 Study D: F 5.40, p .049 η2 for Study C .01, N 6,300 η2 for Study D .40, N 10 Correct interpretation of statistical results requires consider-ation of statistical significance, effect size, and statistical power
The ENGAGE app is compatible with iPhone 4S and newer models running iOS 9 or newer. Android devices require Android Kitkat 4.4 or newer. Register a new ENGAGE account An account is required to use the ENGAGE cloud-based web and mobile tools. Register for an ENGAGE account in the mobile app by selecting the
about statistical power? Why should researchers perform power analysis to plan sample size? Statistical power depends on three parameters: significance level (α level), effect size, and sample size. Given an effect size value and a fixed α level, recruiting more participants in a study increases statistical power and the accuracy of the result.
PAREXEL International Statistical Analysis Plan Medivir Protocol: MIV-711-202 Final 1.0 16 January 2018 Page 9 of 183 1. Statistical Analysis Plan
