1. Neurological Emergencies Treatment Trials Network RAMPART Overview Robert Silbergleit

2. Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) Paramedic treatment of status epilepticus Standard treatment is IV benzodiazepine IV starts difficult / dangerous in the convulsing patient Best IV agent, lorazepam, impractical for EMS IM treatment is faster and easier Best IM agent, midazolam, is practical for EMS

3. IM midazolam autoinjector v. IV lorazepam Double dummy blinded design Exception to consent for emergency research Outcome: termination of seizure prior to ED arrival Sample 700 patients (350 per group) Intention to treat, non-inferiority analysis Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART)

4. Status Epilepticus 120,000 to 200,000 cases / yr Mortality 22% at 30 days 55,000 deaths in the US 1st Yr cost $40,000 /patient Bassin S, et al. Crit Care 2002;6(2):137-42 Claassen J, et al. Neurology 2002;58(1):139-42 DeLorenzo RJ, et al. Neurology 1996;46(4):1029-35 Penberthy LT, et al. Seizure 2005;14(1):46-51 Wu YW, et al. Neurology 2002;58(7):1070-6

5. Pre-hospital care issues PHTSE trial proved EMS treatment effective Ideal agent and route remain unknown Convulsions can make IV placement challenging Lorazepam has stocking / cost concerns Mass casualty / battlefield are special concerns

6. Intramuscular midazolam Favorable pharmacology for treatment of SE –Effectiveness –Rapidity Better stability – lower cost Increasing acceptance by EMS Optimal agent for organophosphate toxicity

7. Midazolam levels near 80% of peak as early as 5 minutes after IM administration Alfonzo-Echeverri, Anesth Prog 1990;37:277-281

8. IM midazolam stops seizures 4 times faster than IM diazepam (in mice) Raines, Epilepsia. 1990;31:313-7

9. Brain midazolam concentration remains high even as serum concentration is dropping Megarbane, Toxicology Letters 2005;159:22–31

10. Duration of seizure suppression with midazolam is hours, and similar to that of diazepam Towne, J Emerg Med 1999;17:323–328

11. Review:IV diazepam versus IM/IN midazolam for treatment of seizures Comparison:01 Effectiveness of IM/IN MDZ as compared to IV DZP Outcome:01 Termination of seizure Study IV Diazepam IM/IN Midazolam RR (fixed) Weight RR (fixed) n/N 95% CI % Chamberlain 11/13 12/13 8.99 0.92 [0.69, 1.21] Lahat 24/26 23/26 17.23 1.04 [0.87, 1.25] Rainbow 23/62 23/45 19.96 0.73 [0.47, 1.12] Mahmoudian 28/35 21/35 15.73 1.33 [0.97, 1.83] Shah 54/65 45/50 38.10 0.92 [0.80, 1.07] Total (95% CI) 201 169100.00 0.97 [0.86, 1.09] Total events: 140 (IV Diazepam), 124 (IM/IN Midazolam) Test for heterogeneity: Chi² = 6.87, df = 4 (P = 0.14), I² = 41.8% Test for overall effect: Z = 0.54 (P = 0.59) 0.5 0.7 1 1.5 2 Favors IM/IN MDZ Favors IV DZP Meta-analysis of IM/IN midazolam shows the same efficacy as IV diazepam

12. Review:IV diazepam versus IM/IN midazolam for treatment of seizures Comparison:01 Effectiveness of IM/IN MDZ as compared to IV DZP Outcome:02 Time to seizure control Study IV DZP IM/IN MDZ WMD (fixed) Weight WMD (fixed) NMean (SD)N 95% CI % Chamberlain 11 11.20(3.60) 13 7.80(4.10) 3.51 3.40 [0.32, 6.48] Lahat 26 8.00(4.10) 26 6.10(3.60) 7.58 1.90 [-0.20, 4.00] Shah 65 4.20(2.30) 50 1.60(0.90) 88.91 2.60 [1.99, 3.21] Total (95% CI) 102 89100.00 2.58 [2.00, 3.15] Test for heterogeneity: Chi² = 0.68, df = 2 (P = 0.71), I² = 0% Test for overall effect: Z = 8.74 (P < 0.00001) -10 -5 0 5 10 Favors IV DZP Favors IM/IN MDZ Meta-analysis of IM/IN midazolam shows more rapid termination of seizures compared to IV diazepam

13. Hypotheses Primary IM midazolam is as 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

14. Inclusion criteria Continuous or repeated convulsive seizure activity for > 5 minutes Patient is still seizing Estimated weight > 13 kg

15. Exclusion criteria Major trauma precipitating seizure Hypoglycemia Known allergy to midazolam or lorazepam Sensitivity to benzodiazepines Cardiac arrest or heart rate <40 beats/minute Known pregnancy Prisoner

16. Intervention - Dose Two packages in each box, Child dose and Adult dose Each package has one IM injector, one IV dose, one of which is active, the other is dummy Child (13- 39 kg) – Lorazepam 2 mg or Midazolam 5 mg Adult (40 kg and up)– Lorazepam 4 mg or Midazolam 10 mg Midazolam is in an autoinjector Lorazepam is given IV

17. RAMPART Datalogger Providing data loggers, stepper controllers, data acquisition and custom engineering services to customers worldwide

18. Intervention Medic arrives on scene and evaluates patient Ask bystanders duration of seizure and trauma Look for medic alert jewelry Check glucose and vital signs For children, check estimated weight If criteria are met, study box is opened to enroll Medic states that entry criteria are met Select child dose or adult dose based on weight Give IM medication and verbalize

19. Intervention (continued) Start IV, give IV med, and verbalize Monitor vital sings and transport Verbalize if convulsions stop At 10 minute after treatment, provide “rescue” meds per local protocol if still seizing en route, verbalize tha med was given At ED arrival, verbailze whether patient is still seizing or not

20. ED and inpatient treatment Attempt standardized post-intervention care For further seizures in the ED or secondary treatment of prior status… Lorazepam 0.5-0.1 mg/kg plus Phenytoin or Fosphenytoin 18-20 mg/kg

21. ED and inpatient treatment If seizures continue then… Intubate and ventilate, keep ≤ 37°C Consider vecuronium 0.1 mg/kg Then add: –Midazolam 0.2 mg/kg then 1.2 ug/kg/min or –Propofol 1 mg/kg then 1-5 mg/kg/hr or –Pentobarbital 5-15 mg/kg over 1 hr, then 0.5-5 mg/kg/hr Admit to ICU, early EEG monitoring

22. Study Activity and Data Collection Study team activated on ED arrival of subject Investigator or coordinator in ED –Collect the data logger –Complete as many CRF items as possible –Approach subject or family for consent to continue to collect and use data Restock ambulance with new study kit Follow patient in hospital for AE’s –Collect remaining data at discharge

23. 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.

24. Secondary outcomes Rapidity of seizure termination Frequency of subsequent tracheal intubation Frequency and duration of ICU and hospital stay

25. Sample Size Non-inferiority margin of 10% Power of 0.85 Significance at 0.05 Inflation for data loss and recidivists at 15% N = 700 (350 per group)

26. Enrollment 700 subjects over 36 months 21 subjects per hub per year If each hub recruits using 14 ambulances the rate is 0.13 subjects/ambulance*month By comparison the PHTSE trial enrolled just over 0.20 subjects/ambulance*month and did not enroll children

27. Human subjects protection Benefits Both arms are accepted therapy Potential for direct benefit to subjects Challenges Exception to Informed Consent IRB approval at all receiving hospitals

28. Exception to Informed Consent Community Consultation Public Notification Local Context Centralized Support Local Outreach – attend community meetings Patient Focus Groups – survivors and clinics

29. Emergency Exception These regulations can improve the quality of research done in this network NETT can help the FDA, NIH, and OHRP ensure the quality of the regulations Build on experience, consensus, and innovation

30. Timeline 2007 –IND submission –IRB applications –Community consultations –Public notification –Acquire and test data loggers –EMS approvals

31. Timeline 2008-2010 –Enrollment –Initial and on-going EMS training –On-going AE reporting –One interim analysis at 350 subjects enrolled 2011 –Last patient in – database lock –Analysis –Public notification again

32. nett.umich.edu