RAMPART and Exception to Informed Consent for Emergency Research

1. RAMPART and Exception to Informed Consent for Emergency Research

2. Purpose of this meeting • Better Human Subjects Protection • Cultivate Cooperation

3. Objectives • Study Synopsis • Tenets and Approach • Teleological Pitch

4. RAMPARTSynopsis

5. Rapid Anticonvulsant MedicationPrior 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

6. Rapid Anticonvulsant MedicationPrior to Arrival Trial (RAMPART) • 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 800 patients (400 per group) • Intention to treat, non-inferiority analysis

7. 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 Status Epilepticus

8. 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

9. Intramuscular midazolam • Favorable pharmacology for treatment of SE • Effectiveness • Rapidity • Better stability – lower cost • Increasing acceptance by EMS

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

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

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

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

14. Meta-analysis of IM/IN midazolam shows the same efficacy as IV diazepam 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 IVDiazepam IM/INMidazolam RR (fixed) Weight RR (fixed) Study n/N n/N 95% CI % 95% CI Chamberlain 8.99 0.92 [0.69, 1.21] 11/13 12/13 Lahat 17.23 1.04 [0.87, 1.25] 24/26 23/26 Rainbow 19.96 0.73 [0.47, 1.12] 23/62 23/45 Mahmoudian 15.73 1.33 [0.97, 1.83] 28/35 21/35 38.10 0.92 [0.80, 1.07] Shah 54/65 45/50 Total (95% CI) 201 169 100.00 0.97 [0.86, 1.09] 0.5 0.7 1 1.5 2 Favors IM/IN MDZ Favors IV DZP 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)

15. Meta-analysis of IM/IN midazolam shows more rapid termination of seizures compared to IV diazepam 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 IV DZP IM/IN MDZ WMD (fixed) Weight WMD (fixed) Study N Mean (SD) N Mean (SD) 95% CI % 95% CI 11 11.20(3.60) 13 7.80(4.10) 3.51 3.40 [0.32, 6.48] Chamberlain 26 8.00(4.10) 26 6.10(3.60) 7.58 1.90 [-0.20, 4.00] Lahat 65 4.20(2.30) 50 1.60(0.90) 88.91 2.60 [1.99, 3.21] Shah 102 89 100.00 2.58 [2.00, 3.15] Total (95% CI) -10 -5 0 5 10 Favors IM/IN MDZ Favors IV DZP Test for heterogeneity: Chi² = 0.68, df = 2 (P = 0.71), I² = 0% Test for overall effect: Z = 8.74 (P < 0.00001)

16. 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

17. Inclusion criteria • Continuous or repeated convulsive seizure activity for > 5 minutes • Patient is still seizing • Estimated weight > 13 kg • Subject to be taken to participating hospital

18. Exclusion criteria • Major trauma precipitating seizure • Hypoglycemia • Known allergy to midazolam or lorazepam • Cardiac arrest or heart rate <40 beats/minute • Medic alert tag with “RAMPART declined” • Prior treatment of this seizure in another study • Known pregnancy • Prisoner

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

20. Intervention - Dose • Smaller Child (13- 39 kg)Lorazepam 2 mg or Midazolam 5 mg • Adolescent or Adult (40 kg and up)Lorazepam 4 mg or Midazolam 10 mg

21. RAMPART Datalogger

22. 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 small children, check estimated weight • If criteria are met, study box is opened to enroll • Medic states that entry criteria are met • Select dose bundle • Give IM medication and verbalize Continued….

23. 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

24. 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

25. 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

26. 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 to notify and seek consent to continue to collect and use data • Restock ambulance with new study kit • Follow patient in hospital for AE’s for 24 hours • Collect remaining data at discharge

27. 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.

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

29. Sample Size • Non-inferiority margin of 10% • Power of 0.80 • Significance at 0.025 • Inflation for data loss and recidivists at 15% • N = 800 (400 per group)

30. 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

31. Exception from Informed Consent in RAMPART

33. Does it qualify? • Life threatening? • Available therapy inadequate or unproven? • Informed consent not feasible? • Prospect of direct benefit? • Trial couldn’t be carried out with EFIC?

34. Tenets and Approach • Flexibility in methodology • Local decision making • Centralized resources • Communication and cooperation

35. Definitions of Community • Geographic • Condition-specific

36. Teleological Pitch If we knew why we are doing something… • We can do it better • We can judge how well we’ve done it

37. Possible answer… • These are the ways that good doctors and researchers act. • In fact, that is why we do informed consent when it is possible.

38. Built on the ideas of others… Carl Schneider, Chauncy Stillman Professor for Ethics, Morality, and the Practice of Law and a professor of internal medicine at the University of Michigan Nir Eyal is Instructor in Social Medicine (Division of Medical Ethics) at the Harvard Medical School, with a primary appointment at the university-wide Program in Ethics and Health.

39. People like to be asked more than they like to decide. • Even more, they want their doctor/researcher to be the kind of person who would ask.

40. How do we remain “that sort of doctor” when the emergency situation prevents us from asking? • What core values and acts are embodied in the proper moral agent? I’ll suggest 3 (or 4?)

41. We need to be… Heedful Respectful Transparent Humble

42. We need to be… Heedful  Comm. Consult. Respectful  Comm. Consult. Transparent  Public Disclosure Humble  Comm. Consult.

43. We need to be… Heedful  Listen and consider Respectful  Go to the people Transparent  Keep nothing concealed Humble  Do it yourself

44. These underlying ethical purposes mean that…. Focus is on due diligence of the investigator The investigator’s behavior is the metric

45. The community’s impact on the investigator matters more than the investigator’s impact on the community • It is more important to be transparent then it is to be seen

46. nett.umich.edu

47. Open Discussion

48. Discussion Stimuli • Collection of data after further participation is declined • What to do when IRBs don’t agree? • Can investigators decide the time to notify is not right? • Will existing IRBs cover new EMS FWAs? • What happens when emergency research is sustained and no longer novel?

49. Looking Forward • Best format for more cooperative discussion? • Electronic forums? Video conference? List-serv? • Meetings like this? For each EFIC trial? Annual? • As expertise builds, can this lead to a co-op cIRB?

50. Thank You !