Slide #1.

ESETT Established Status Epilepticus Treatment Trial (ESETT) A multicenter, randomized, blinded, comparative effectiveness study of fosphenytoin, valproic acid, or levetiracetam in the emergency department treatment of patients with benzodiazepine-refractory status epilepticus. 1
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ESETT 2 Project Teams, NETT & PECARN
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ESETT Project Teams • Investigators (listed on protocol page): Jaideep Kapur (Uva), • • • • • • • • • James Chamberlain (Children’s National), Jordan Elm (MUSC), Robert Silbergleit (UMICH) Project manager: Amy Fansler (Uva) Site management: Erin Bengelink and Arthi Ramakrishnan (UMICH) PECARN contact: Kate Shreve Human Subjects Protect Coordinator: Deneil Harney (UMICH) Site Education: Joy Pinkerton (UMICH) Data management: Cassidy Conner, Catherine Dillon (MUSC) Financial: Emily Gray (Uva), Valerie Stevenson (UMICH) Project Monitors: TBD (UMICH) NETT and PECARN sites
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ESETT Geography NETT Hubs PECARN Sites ● ●■ ● ● ● ● ●● ● ● ● ● ● ●● ● ● ●●
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ESETT Rationale 5
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6 ESETT Status Epilepticus: Epidemiology Status epilepticus: a prolonged self-sustaining seizure or recurrent seizures without recovery of consciousness. Incidence 41-61/100,000. Episodes of status epilepticus in US in 2010: 120,000-188,459. Mortality in patients with status epilepticus to 17%. Mortality correlates with cause & duration of SE. Mortality DeLorenzo et al. Neurology 1996 Towne et al. J. Clin. Neurophysiology 1994
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ESETT 7 Effects of Fever Associated Status Epilepticus in Children: FEBSTAT 1) 11% incidence of Hippocampal injury (T2 signal increase) compared to 0% in control (febrile seizures). 2) Hippocampal T2 hyperintensity after FSE represents acute injury often evolving to a radiological appearance of HS after 1 year. Shinnar et al. Neurology 2012 Lewis et al. Annals of Neurology 2014
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8 ESETT Benzodiazepines: Initial Treatment IM midazolam vs IV lorazepam Lorazepam vs diazepam for pediatric status epilepticus PHTSE Number of patients 60 Lorazepam Diazepam Placebo 40 20 0 Convusions stopped Ongoing
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Slide #9.

ESETT 9 Need for Trial • There is no well-controlled prospective clinical trial to guide the treatment of SE in patients who fail benzodiazepines. • SE not responding to benzodiazepines is called Established Status Epilepticus (ESE). • Episodes of SE in US in 2010: 41- 61/100,000 X 309 million = 120,000-188459 • 35-45 % of patients with convulsive SE do not respond to benzodiazepines i.e.42-72,000 ESE patient.
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Slide #10.

10 ESETT Therapy of Established SE: Real world choices Property/AED Fosphenytoin Levetiracetam Valproic Acid Popularity of use in the US Most commonly used (60-65%) Used often (20-30) Least often Ease of administration Slow Fast Fast Speed of action Slow administration Enters brain Slowly, acts slowly Yes Action last long Yes Yes Yes Efficacious in animal Least effective models In combination with diazepam Very effective Terminates seizures Partial seizures Partial and generalized Partial and generalized Safe Hypotension, cardiac arrhythmia. safe Safe for acute use
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11 ESETT EFIC • Justification: • Convulsive status epilepticus is a life threatening disease • Best available treatment is unproven • Clinical trials are needed • Obtaining prospective informed consent is not feasible • Subject altered (actively seizing and unconscious) • An acute seizing patient cannot be identified prospectively • LAR is often not available in the short time frame required. Even when an LAR is available, meaningful informed consent is impossible to obtain because of the time constraints and the emotional distress caused by witnessing convulsive SE. • Subjects may benefit from the research • Research could not be carried out without EFIC • Therapeutic window too short
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Slide #12.

12 ESETT Inclusion Criteria Inclusion criteria Patient witnessed to have a seizure in the past 5-30 minutes. Measure Time of first seizure is when EMS personnel were called if eyewitness account available or first seizure witnessed by EMS personnel. Patient received adequate dose of benzodiazepines in the past 5-30 minutes. EMS or ED record of treatment: The doses may be divided. Time is counted from the last dose. For those 10-40 Kg adequate doses are: diazepam 0.3 mg/kg IV or rectal, lorazepam 0.1 mg/kg IV or midazolam 0.3 mg/kg IM or 0.2 mg/Kg IV   For those > 40 kg--diazepam 10 mg IV or rectal, lorazepam 4 mg, IV, or midazolam 10 mg IM or IV.   Continueded seizure in the Emergency Department Clinical observation Age more than 2 years Caretakers report the age or clinical observation
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13 ESETT Patient Enrollment Open study box remove study drug Estimate weight: Use Broselow like tape if necessary Wt. (kg) Vol. 7.5 9 10 12 12.5 15 15 18 20 24 25 30 30 36 35 42 40 48 50 60 60 72 70 84 75 90 >75 90 Connect to patient IV catheter Dial appropriate volume in the infusion pump. Press start
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Slide #14.

ESETT Intervention Drug Dose FOS 20 mg /kg (PE) Viewed as standard with dose. maximum 1500 mg LEV 60 mg/kg with max 4500 mg Highest approved dose for children, Published reports suggest safety of 4500 mg. VPA 40 mg/kg with max 3,000 mg Doses ranging between 15-45 mg/kg have been reported. ESETT Comments Supporting References PDR: Package insert Limdi, et al (2007) 14
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Slide #15.

ESETT 15
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ESETT 16 Primary Outcome Clinical cessation of status epilepticus, determined by the absence of clinically apparent seizures and improving responsiveness, at 60 minutes after the start of study drug infusion, without the use of additional anti-seizure medication. (*Note if patient is intubated within 60 minutes of enrollment, it is failure to meet primary outcome, because sedatives are used)
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17 ESETT Primary Outcome (T0 + 60 min)   Yes NO There has been no clinical seizure since 20 minutes after the start of study drug infusion Responsiveness has improved No anti-seizure medications used since start of study drug infusion, (includes sedatives for intubation)             To +10 min 9:51:00
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18 ESETT Recording Prospective Data: Primary & Back up Primary record Paper record produced by the clinical coordinator Based on review of the chart, interviews with clinical care team. However…coordinator could be late, team busy, shifts may change and there is potential for lost data Back up data recording device
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Slide #19.

ESETT TO+20 MIN Responds to verbal command To +20 min 10:00:14 Clinical seizure absent? Yes No Yes NO Consider Phenobarbital Anesthesia Second line agent VPA
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Slide #20.

ESETT Why wait for 20 minutes for seizures to end: drug entry is slow Fosphenytoin Levetiracetam Blood Brain
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Slide #21.

ESETT 21 Safety Outcomes at T0 +60 • Life-threatening hypotension: Within 1 hour of start of infusion of the study drug, systolic blood pressure remains below specified levels on two consecutive readings at least 10 minutes apart and remains below specified levels for more than 10 minutes despite reduced drug infusion rate or its termination and a fluid challenge. • “Specified levels” for systolic blood pressure are 90 mmHg in adults and children older than 13 years old, 80 mmHg in children 7 to 12 years old, and 70 mmHg in children 2 to 6 years of age. • Life-threatening cardiac arrhythmia: Any arrhythmia that occurs within 1 hour of start of infusion of the drug that persists despite reducing rate of drug infusion, or that requires termination with chest compressions, pacing, defibrillation, or use of an anti-arrhythmic agent or procedure.
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Slide #22.

ESETT Primary outcome
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Slide #23.

ESETT Safety outcome at To +60
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ESETT 24 Secondary Outcomes o Occurrence of life threatening Hypotension or cardiac arrhythmia, o Richmond agitation and sedation score at primary outcome determination o Time to termination of seizures o Intubation, o Admission to ICU o Seizure recurrence o Length of stay in the ICU and hospital, o Mortality
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Slide #25.

ESETT Study Design 25
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ESETT 26 Primary Objective • To determine the most effective and/or the least effective treatment of benzodiazepine-refractory status epilepticus (SE) among patients older than 2 years. • Three active treatment arms: • fosphenytoin (FOS) • levetiracetam (LEV) • valproic acid (VPA)
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Slide #27.

ESETT 27 Primary Outcome Clinical cessation of status epilepticus, determined by the absence of clinically apparent seizures and improving responsiveness, at 60 minutes after the start of study drug infusion, without the use of additional anti-seizure medication.
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Slide #28.

ESETT 28 Study Design • Bayesian Adaptive Design (extensive simulation study) • Maximum sample size is N=795 total. • Primary endpoint at 60 minutes • Followed until discharge/30 days • Randomization will be stratified by three age groups • 2-18 years • 19-65 years • 66 years and older
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29 ESETT Bayesian Adaptive Design Features • Adaptively allocate to favor better treatments • Drop poor performing arms • Relative to one another • Relative to 25% goal • Stop early if we know the answer or know we won’t know • Efficacy stop if treatment clearly better • Futility stop if unlikely to ID a ‘best’ or ‘worst’ • Do not stop if 1 worse and other 2 equally good • Futility stopping if all arms bad
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Slide #30.

ESETT 30
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ESETT 31 Adaptive Allocation • Randomize N=300 patients equally • At N=300 begin adaptive allocation • Update allocation probability after every 100 subjects (N = 300, 400, … , 700 ) • Adaptive allocations after every 100 subjects equates to approx. every 6 months given expected accrual
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32 ESETT Early Stopping • Begins after 400 patients • Evaluated after every additional 100 patients accrued to coincide with adaptive allocation assessments (i.e. N= 400, 500, 600, 700) for early success stopping and early futility stopping.
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Slide #33.

ESETT Study Logistics 33
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34 ESETT Recruitment Goals • Milestones • 2 patients by Sept 2015 • 10 by December 2015 900 800 700 • Target is 795 subjects enrolled over 4 years 600 500 400 300 200 • Target recruitment (16.6 subjects/month) is linear although staggered startup. 100 0 9/1/2015 9/1/2016 9/1/2017 9/1/2018 9/1/2019
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Slide #35.

35 ESETT ESETT 2 Year Timeline Drug testing IND review EFIC activities IRB review App Development Site prep incl investigator mtg Subcontracts executed 11/15/2014 - 2/15/2015 3/1/2015 - 4/1/2015 4/1/2015 - 8/1/2016 4/1/2015 - 8/12/2016 4/1/2015 - 8/1/2015 9/1/2015 - 2/15/2016 10/1/2014 - 12/31/2015 Operationalize phenomenology core 4/1/2015 - 9/1/2015 IRB review complete 2 sites & Enrollment commences 9/1/2015 Drug testing complete EFIC activities complete at 2 sites 9/1/2015 2/15/2015 IND review complete and study cleared 4/30/2015 2014 Oct 100 patients enrolled 2 patients enrolled 2015 Dec Feb 9/30/2016 9/30/2015 2016 Apr Jun Aug Oct Dec Feb Apr Jun Aug 2016
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Slide #36.

ESETT Analysis Plan 36
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ESETT 37 Statistical Analysis • Intent-to-Treat sample • All subjects who are randomized**, except re-enrollers • Minimal missing data (imputed as treatment failure) • Primary Analysis is Bayesian/non-informative prior • Trial success defined as • Posterior probability that a treatment is the most effective > 0.975 or the • Posterior probability that a treatment is the least effective is > 0.975 **Defined as when the infusion pump is connected to study drug vial and the patient’s IV catheter is switched on
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Slide #38.

ESETT 38 Planned Interim Analyses • Interim analyses are planned after 400, 500, 600 and 700 patients are enrolled. • At each interim analysis, the trial may stop early for success or futility. • Estimate that the first planned analysis will occur after the first 24 months of enrollment.
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Slide #39.

ESETT Secondary Analysis at End of Trial • Secondary analysis of primary outcome: • Per protocol • Re-enroller analysis • An analysis by age group • Secondary outcomes: • time to termination of seizures • admission to ICU • length of ICU and hospital stays 39
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Slide #40.

ESETT Safety Outcomes • Life-threatening hypotension • Life-threatening cardiac arrhythmia • Mortality • Need for endotracheal intubation • Acute recurrent seizure • Acute anaphylaxis • Respiratory depression • Hepatic transaminase or ammonia elevations • Purple glove syndrome 40
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Slide #41.

ESETT 41 SAE Reporting • Site enters SAE in WebDCU (within 24 hours of knowledge of the event) which triggers automated notification for internal review • Administrative review by CCC Project Site Manager (SM) • Clinical content review by Internal Quality and Safety Reviewer (IQSR) • Upon approval, automated notification triggers for review by external safety monitor • External Safety Monitor (ESM) • Designates whether event is serious, unexpected, unanticipated and related to study drug • If criteria for expedited reporting are met, clinical site will complete MedWatch form and sponsor will submit
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Slide #42.

ESETT Information & Resources • ESETT Home Page: www.esett.org • ESETT Toolbox is available within www.esett.org • NETT home page www.nett.umich.edu • PECARN home page http://www.pecarn.org/ • WebDCU https://webdcu.musc.edu/ • New team member information and training http://nett/nett/new_team_member_information
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