Investigator Kickoff Meeting January 2009

Protocol Review, Part 1 Robert Silbergleit, MD

Overview More background Trial Synopsis Chronological scaffolding Who does what where when? Fill in more details Cases and questions in the afternoon

In a nutshell Treat (only) patients who are convulsing Primary outcome determination “Was patient convulsing then, based on what you know now?” Enter all your data right away Visit (feed) your medics often Never touch the orange end of the autoinjector

Background – the problem SE is common 120, ,000 cases/yr SE is dangerous 22% mortality at 30 days PHTSE trial proved EMS treatment effective Ideal agent and route remain unknown Convulsions can make IV placement challenging Lorazepam has stocking / cost concerns Midazolam is promising and is being adopted Safety and efficacy in SE is untested

Background - Importance Controversy Serendipity Trail blazing

Background - Importance Controversy Serendipity Trail blazing

Background - Importance Controversy Serendipity Trail blazing

Synopsis - Hypotheses Primary IM midazolam is no less effective as IV lorazepam at stopping convulsions prior to ED arrival Secondary Convulsions stop more rapidly with treatment with IM midazolam versus IV lorazepam There is no difference in safety between the two treatments

Autoinjector midazolam Autoinjector placebo IV syringe lorazepam IV syringe placebo IM Route IV Route IM Active Treatment IV Active Treatment Randomized to: or Synopsis - double-dummy design All subjects get active treatment by either IM or IV route

Synopsis - Dose Infants and Children Estimated < 13 kg Are NOT enrolled

Synopsis - Dose Children (13-39 kg) purple dose tier Lorazepam 2 mg or Midazolam 5 mg

Synopsis - Dose Lorazepam 4 mg or Midazolam 10 mg

Synopsis - Dose Lorazepam 4 mg or Midazolam 10 mg

Synopsis - primary outcome Proportion of subjects with termination of clinically evident seizure determined at arrival in the Emergency Department (ED) after a single dose of study medication. Non-inferiority analysis designed to detect greater than 10% absolute difference in proportion with termination at ED arrival.

Synopsis - secondary outcomes Rapidity of seizure termination Frequency of subsequent tracheal intubation Frequency and duration of ICU and hospital stay

Synopsis - enrollment 800 subjects over 36 months 16 subjects per hub per year If each hub recruits using 14 ambulances the rate is 0.10 subjects/ambulance*month By comparison the PHTSE trial enrolled just over 0.20 subjects/ambulance*month and did not enroll children

Scaffolding who does what when? Getting regulatory ready Getting real world ready At the scene In the ED In the hospital Subject end of study Out and back again Ongoing responsibilities

Getting regulatory ready EFIC and IRB approvals EMS approvals Investigator/coordinator HSP training FDA 1572’s You also have to STAY regulatory ready

Getting real-world ready EMS training Study team activation Study team response Site initiation Getting boxes Getting drug

At the scene

At the scene - inclusion criteria Continuous or repeated convulsive seizure activity for > 5 minutes Patient is still convulsing at time of treatment Estimated weight > 13 kg Subject to be taken to participating hospital

At the scene - exclusion criteria Major trauma precipitating seizure Hypoglycemia Known allergy to midazolam or lorazepam Cardiac arrest or heart rate <40 beats/minute Medical alert tag with “RAMPART declined” Prior treatment of this seizure in another study Known pregnancy Prisoner

At the scene - sequence Medic arrives on scene and evaluates patient Ask bystanders duration of seizure and trauma Look for medical alert information Check glucose and vital signs For small children, check estimated weight Confirm that box display reads “ready” Continued….

At the scene - sequence (cont.) If criteria are met, study box is opened Medic states that entry criteria are met Open the bag, select dose bundle Give IM medication and verbalize Start IV, give IV med, and verbalize Dispose of sharps Monitor vital sings and transport Continued….

At the scene - sequence (cont.) Verbalize immediately if convulsions stop At 10 minute after treatment, provide “rescue” meds per local protocol if still seizing en route, verbalize that a rescue med was given At ED arrival, verbalize whether patient is still convulsing or not at that time All without ever touching the orange end of the autoinjector

In the ED

In the ED – primary outcome Study team determines by asking the attending physician caring for the subject Question is “based on everything you know now, was patient still seizing on ED arrival?” Attending evaluation did not necessarily need to occur right at ED arrival to make determination Study team needs to ask the attending this question with 5 hours of subjects arrival in ED

In the ED - sequence Study team activated on ED arrival of subject Arrive within 4 hours Ensure study box is collected Obtain box number Obtain primary outcome determination Obtain other treatment information Fill out ED CRF (Form 00, 01, and 02) Continued….

In the ED – sequence (cont.) Attempt notification and consent Fill out notification log (Form 04) Any SAE or AE up to this point? Fill out SAE/AE CRF (Form 05) Account for the remaining bundle Log destruction / disposition in WebDCU

In the hospital

In the hospital - sequence Re-assess subject after 24 hours Complete 24 hour CRF (Form 06) Serious adverse events (whenever you find out) Adverse events (only first 24 hours) If needed, fill out SAE/AE CRF (Form 05) Notification / consent? (every 24 hours till done) If needed, fill out notification log (Form 04)

Subject end of study 

ED discharge without admission Hospital discharge within 30 days Hospital stay reaches 30 days Death Withholds or withdraws consent Lost to follow up

Subject end of study - sequence Review chart Complete EOS CRF (Form 07) Any new SAE? Any prior AE/SAE unresolved? If needed, fill out SAE/AE CRF (Form 05)

Out and back again

Study boxes cycle every 60 days Getting more drug (routinely and urgently) Logging drugs in Resetting the box Matching boxes and drug bundles

Ongoing responsibilities

Screen failure logs Visit (and feed) your medics EMS and ED retraining Continue public disclosure IRB reporting and renewals Milestones and money Monitoring

Public disclosure Advertising Press releases Public service announcements Health system media Advocacy group dissemination Web internet presence

Emergency 24-Hour Investigator contact RAMP

So remember… Treat (only) patients who are convulsing Primary outcome determination “Was patient convulsing then, based on what you know now?” Enter all your data right away Visit (feed) your medics often Never touch the orange end of the autoinjector

rampart.umich.edu