1. Investigator Meeting January 2010 Protocol Review and Refresher

2. Overview Enrollment Deviations Reminders Cases and questions (time permitting) RS

3. Enrollment

9. Deviations

13. Good news Deviations suspected of causing an serious adverse event: Ø (Knock on wood)

14. Protocol Reminders

15. In a nutshell (from last January) 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 RS

16. Key Reminders - Eligibility ONLY treat patients who are convulsing NEVER give either study med if not convulsing Convulsions continuous for >5 minutes OR recurring over >5 minutes without waking up in between convulsions NO awake patients with only focal seizures RS

17. Key Reminders - Eligibility NEVER enroll KIDS in the RED zone Check glucose / treat hypoglycemia per local clinical protocols Do NOT enroll PRISONERS RS

18. Key Reminders - Enrollment NEVER touch the orange end of the autoinjector IM medications ALWAYS, ALWAYS come first ADULTS always get the WHITE dose tier KIDS may get NO dose, PURPLE, or WHITE ALWAYS use tape to determine KIDS dose RS

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

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

21. Synopsis - Dose Lorazepam 4 mg or Midazolam 10 mg

22. Synopsis - Dose Lorazepam 4 mg or Midazolam 10 mg

23. Key Reminders - Enrollment IV medications ONLY go in an IV or IO NEVER give IV medicine IM When CONVULSIONS stop, NO more study meds Waking up has NOTHING to do with this part If seizures recur later, use RESCUE meds per your regular local protocol NOT remaining study meds RS

24. Key Reminders - Enrollment TALK to the box IM given IV started IV given Convulsions stopped (if they did) Rescue given (if it was) Convulsing or not at ED arrival RS

25. Key Reminders – Team Response Collect INITIAL info at notification if possible RESPOND in person to the ED within 4 hours Primary outcome determination “Was patient convulsing then, based on what you know now?” Collect ED data form while in ED RS

26. Key Reminders – Team Response LOG all attempts at NOTIFICATION and consent Some now use notification forms and letters to supplement efforts when needed Process box promptly, properly label and ship SD card RS

27. Key Reminders – Follow up VISIT subject in person and REVIEW chart at 24- 36 hours Submit AE promptly, follow up until resolved REVIEW chart, COMPLETE forms promptly at end of study RS

28. Key Reminders – Regulatory STAY regulatory ready Expirations Study team changes Other reportable information to IRB RS

29. Ongoing responsibilities Screen failure logs Visit (and feed) your medics EMS and ED retraining Continue public disclosure IRB reporting and renewals Monitoring EZ

30. The damndest things happen…. Color blindedness –Grabbed the wrong color bundle… –Ouch…touched the orange end Ingenuity –Gave the IV medicine IM… Absent mindedness –“Didn’t occur to them” to give the IM med at all Short sheeted –Didn’t put the head where it says “Head” RS

31. Enrollment is great, but…. Deviation rate needs to improve Train, re-train, and train some more Be meticulous Don’t touch the orange end of the injector

32. rampart.umich.edu

33. A patient convulses for 5 minutes then is unresponsive, but not convulsing on EMS evaluation. This patient is… A.Eligible B.Not eligible

34. A patient is convulsing for 5 minutes, and is still convulsing on EMS evaluation. The patient is … A.Eligible B.Not eligible

35. A patient convulses for 5 minutes, is convulsing on EMS evaluation, and the study autoinjector is administered. Just after the IV is placed, the convulsions stop. The patient is still unresponsive. The medics should.... A.Go ahead and give the study IV syringe B.Not give the study IV syringe

36. A patient convulses for 5 minutes, then stops convulsing during the EMS evaluation, but remains unresponsive. She is correctly deemed ineligible. 3 minutes later she begins convulsing again without having woken up at all. Which is correct… A.She is now eligible, administer autoinjector B.Wait another 5 min, if still convulsing, then she is eligible C.She is still not eligible, give routine care

37. A patient convulses for 5 minutes, then stops convulsing during the EMS evaluation. He become conscious but with substantial postictal confusion. 3 minutes later he starts convulsing again. Which is correct… A.He is now eligible, administer autoinjector B.Wait another 5 min, if still convulsing, then she is eligible C.She is still not eligible, give routine care

38. A patient convulses for more than 5 minutes, and the family gives rectal diazepam. He is still convulsing on EMS evaluation. This patient is… A.Eligible B.Not eligible because of the diazepam C.Only if it has been 10 minutes since the diazepam is the patient eligible

39. An eligible patient is treated with the autoinjector but paramedics have difficulty placing the IV. The paramedics can… A.Place intraosseous access and give the IV dose through the IO line B.Give routine rescue care after trying to get IV access for 10 minutes after IM C.Doesn’t matter, the patient will be excluded D.Either A or B

40. An otherwise eligible patient is enrolled but is taken to a non-participating hospital. Which is correct… A.This is a protocol violation B.Notification and consent may need to be delayed until after hospital discharge C.No data can be collected on this subject D.Both A and B

41. An enrolled subject is conscious, confused, but conversant on ED arrival. She is triaged and placed in a room. 30 minutes later her nurse finds her convulsing and calls the attending into the room. Regarding the primary outcome determination… A.Attending cannot provide determination, since she didn’t evaluate the patient on arrival B.Attending determines patient was seizing because she was seizing on her first contact with patient C.Attending determines no seizure because patient was not seizing when the study team arrived D.Attending determines no seizure on arrival because patient was talking on arrival

42. An enrolled subject is unconscious on ED arrival. The attending observes deviated gaze and nonreactive pupils, but no convulsions. 5 minutes later the subject begins convulsing again. Regarding the primary outcome determination… A.If the attending thinks the patient was still seizing on arrival that is the correct determination B.If the attending thinks the patient was not seizing on arrival that is the correct determination C.Based on this description, the patient was probably seizing D.All of the above

43. An subject is convulsing on ED arrival, and is seen by a resident physician, who orders more anticonvulsants that terminate the seizure. The patient is post ictal but awake when first seen by the attending. Regarding the primary outcome determination… A.The determination of seizing on arrival should be made by the resident B.The determination of seizing on arrival should be made by the attending C.The determination of not seizing on arrival should be made by the attending D.None of the above

44. When receiving a drug shipment… A.The shipment must be immediately checked in within WebDCU B.The shipment can wait for up to 72 hours before being check in and refrigerated C.The shipment must be immediately put in study boxes and distributed D.The 60 day expiration clock starts as soon as you receive and refrigerate the shipment

45. Which of the following constitutes a subject’s end of study… A.Admission at a nonparticipating hospital B.Discharge to home from the ED C.Hospital discharge after a 115 day long hospital stay

46. Screen failure logs… A.Must be completed monthly B.Must include all EMS patients with a seizure complaint C.Must include all ED patients with a seizure complaint

47. At the scene of a seizing patient, paramedics should… A.Perform the initial evaluation they would provide in routine clinical care B.Provide routine care if they are not confident that the patient is eligible C.NOT delay study or routine treatment to describe the study or routine care to family D.All of the above

48. SAE Reporting Key Points Narrative Templates Better narratives RS

49. Adverse Events – key points AEs are any UNTOWARD medical occurrence in a subject Do not report events EXISTING PRIOR to randomization (unless there is a change in severity) Report the DIAGNOSIS, not the symptoms: Fever, cough, chest pain, crackles = pneumonia Death, surgery, intubation, etc. are NOT adverse events. They are outcomes of adverse events CD

50. Adverse Events – key points Exception to the diagnosis not symptom rule! We want all endotracheal intubations reported…. But intubation is still the outcome not the event So if intubation is for airway protection only, consider using “coma” or “sedation” even though these are symptoms. RS

51. Adverse Events – key points From Randomization through 24 hrs: Report all AEs From 24 hours through EOS: Report only serious AEs Follow previously reported AEs to resolution or end of study (whichever comes first) CD

52. Serious if: Fatal, Life-Threatening, Result in hospitalization (prolonged hospitalization), Result in disability/congenital anomaly, or Require intervention to prevent permanent impairment or damage Submit SAEs within 24 hours of discovery Serious AEs – key points CD

53. SAE Reporting - Relatedness algorithm Not Related The timing is wrong and there was clearly another cause Unlikely (both of the following, but timing doesn’t matter) Another cause is possible Not something the intervention is known to cause Possibly (2 of 3) or Probably (must have all 3) Timing is suggestive. No other likely causes. This is something the intervention is known to cause. Definitely (must have all 3) Timing suggests intervention caused the problem. No other possible cause. This is something the intervention is known to cause. RS

54. Better narratives - sample Respiratory Depression A 38 year old male with a history of seizures, was found seizing and was enrolled in RAMPART at approximately 20:45 on 9/1/2009. The patient was unresponsive but not convulsing at hospital arrival at 20:59. He subsequently underwent endotracheal intubation for respiratory depression in the ED at 21:20. The patient was not thought to be seizing at the time of intubation, but was felt to have respiratory depression from the combination of alcohol intoxication and benzodiazepines. The patient was treated with propofol and admitted to the ICU. The patient was subsequently extubated on 9/2/2009. RS

55. Better narratives – key points Concise, not comprehensive All necessary detail, no unnecessary detail Provide age, only pertinent history Include time and date of enrollment CD

56. Better narratives – key points Describe the adverse event If treatment was given, report the response Provide the outcome if known CD

57. Better narratives – key points Seizing on arrival? Seizing at time of SAE? Generic drug names, not brand names Do not capitalize generic drug names CD

58. Better narratives – key points When reporting times closely following the previous times, do not add dates When reporting events on subsequent days, only report times if relevant In addition to the times, report the time interval from enrollment to SAE when appropriate CD

59. Narrative template respiratory depression A [age] year old [male/female] was found seizing on [date] at [time] and was enrolled in RAMPART. The patient [stopped/did not stop] seizing prior to ED arrival. The patient subsequently underwent endotracheal intubation for respiratory depression [by EMS/in the ED] at [time]. The patient [was/was not] still thought to be seizing at the time of intubation. [The patient was subsequently extubated on [date].] [The patient remained intubated as of [date] because of [suspected etiology].] RS

60. Let’s edit one together

61. Intubation 67 year old Black female found seizing and was enrolled in Rampart on 4-Sep-2009 at unknown time (EMS sheets were not turned in). EMS brought her into hospital at 00:25 on 4-Sep-2009 in active seizing state. Had come around briefly in squad following Rampart kit usage and then began seizing again on entering the hospital. Seizing continued and at 01:03 patient was intubated following administration of 20 mg etomidate and 200 mg succinylcholine. At 01:04 was given vecuronium 5 mg. At 1:06 was given 2 mg of lorazepam. AT 10:39, a propofol drip was started. Patient was admitted to the ICU at 03:57 with continuing seizures by EEG. Patient remained intubated until noon on 4-Sep-2009 when she was extubated. An MRI on 06-Sep-2009 at 11:24 confirmed ischemic infarct along left occipitopariental lobe as well as portions of the left centrum ovale.Recurrent Seizure

62. Intubation Recurrent Seizure 67 year old Black female found seizing and was enrolled in Rampart on 4-Sep-2009 at unknown time (EMS sheets were not turned in). EMS brought her into hospital at 00:25 on 4-Sep-2009 in active seizing state. Had come around briefly in squad following Rampart kit usage and then began seizing again on entering the hospital. Seizing continued and at 01:03 patient was intubated following administration of 20 mg etomidate and 200 mg succinylcholine. At 01:04 was given vecuronium 5 mg. At 1:06 was given 2 mg of lorazepam. AT 10:39, a diprivan drip was started. Patient was admitted to the ICU at 03:57 with continuing seizures by EEG. Patient remained intubated until noon on 4-Sep-2009 when she was extubated. An MRI on 06-Sep-2009 at 11:24 confirmed ischemic infarct along left occipitopariental lobe as well as portions of the left centrum ovale.

63. Recurrent Seizure 67 year old Black female found seizing and was enrolled in Rampart on 4-Sep-2009 at unknown time (EMS sheets were not turned in). 67 year old female was found seizing on 9/4/2009 prior to 00:25 and was enrolled in RAMPART. EMS brought her into hospital at 00:25 on 4-Sep-2009 in active seizing state. Had come around briefly in squad following Rampart kit usage and then began seizing again on entering the hospital. Seizing continued and at 01:03 patient was intubated following administration of 20 mg etomidate and 200 mg succinylcholine. At 01:04 was given vecuronium 5 mg. At 1:06 was given 2 mg of lorazepam. AT 10:39, a diprivan drip was started. Patient was admitted to the ICU at 03:57 with continuing seizures by EEG. Patient remained intubated until noon on 4-Sep-2009 when she was extubated. An MRI on 06-Sep-2009 at 11:24 confirmed ischemic infarct along left occipitopariental lobe as well as portions of the left centrum ovale.

64. Recurrent Seizure 67 year old female was found seizing on 9/4/2009 prior to 00:25 and was enrolled in RAMPART. EMS brought her into hospital at 00:25 on 4-Sep-2009 in active seizing state. Had come around briefly in squad following Rampart kit usage and then began seizing again on entering the hospital. The patient briefly stopped convulsing prior to ED arrival, but was still seizing upon ED arrival. Seizing continued and at 01:03 patient was intubated following administration of 20 mg etomidate and 200 mg succinylcholine. At 01:04 was given vecuronium 5 mg. At 1:06 was given 2 mg of lorazepam. AT 10:39, a diprivan drip was started. Patient was admitted to the ICU at 03:57 with continuing seizures by EEG. Patient remained intubated until noon on 4-Sep-2009 when she was extubated. An MRI on 06-Sep-2009 at 11:24 confirmed ischemic infarct along left occipitopariental lobe as well as portions of the left centrum ovale.

65. Recurrent Seizure 67 year old female was found seizing on 9/4/2009 prior to 00:25 and was enrolled in RAMPART. The patient briefly stopped convulsing prior to ED arrival, but was still seizing upon ED arrival. Seizing continued and at 01:03 patient was intubated following administration of 20 mg etomidate and 200 mg succinylcholine. At 01:04 was given vecuronium 5 mg. The patient subsequently underwent endotracheal intubation for status epilepticus in the ED at 01:03. The patient was still seizing at the time of intubation. At 1:06 was given 2 mg of lorazepam. AT 10:39, a diprivan drip was started. Patient was admitted to the ICU at 03:57 with continuing seizures by EEG. Patient remained intubated until noon on 4-Sep-2009 when she was extubated. An MRI on 06-Sep-2009 at 11:24 confirmed ischemic infarct along left occipitopariental lobe as well as portions of the left centrum ovale.

66. Recurrent Seizure 67 year old female was found seizing on 9/4/2009 prior to 00:25 and was enrolled in RAMPART. The patient briefly stopped convulsing prior to ED arrival, but was still seizing upon ED arrival. The patient subsequently underwent endotracheal intubation for status epilepticus in the ED at 01:03. The patient was still seizing at the time of intubation. At 1:06 was given 2 mg of lorazepam. AT 10:39, a diprivan drip was started. Patient was admitted to the ICU at 03:57 with continuing seizures by EEG. Continuing seizures were treated with lorazepam and then propofol and the patient was admitted to the ICU at 03:57. EEG confirmed continuing seizure activity at that time. Patient remained intubated until noon on 4-Sep-2009 when she was extubated. An MRI on 06-Sep-2009 at 11:24 confirmed ischemic infarct along left occipitopariental lobe as well as portions of the left centrum ovale.

67. Recurrent Seizure 67 year old female was found seizing on 9/4/2009 prior to 00:25 and was enrolled in RAMPART. The patient briefly stopped convulsing prior to ED arrival, but was still seizing upon ED arrival. The patient subsequently underwent endotracheal intubation for status epilepticus in the ED at 01:03. The patient was still seizing at the time of intubation. Continuing seizures were treated with lorazepam and then propofol and the patient was admitted to the ICU at 03:57. EEG confirmed continuing seizure activity at that time. Patient remained intubated until noon on 4-Sep-2009 when she was extubated. An MRI on 06- Sep-2009 at 11:24 confirmed ischemic infarct along left occipitopariental lobe as well as portions of the left centrum ovale. The patient was subsequently extubated around 12:00 on 9/4/2009.

68. Recurrent Seizure 67 year old female was found seizing on 9/4/2009 prior to 00:25 and was enrolled in RAMPART. The patient briefly stopped convulsing prior to ED arrival, but was still seizing upon ED arrival. The patient subsequently underwent endotracheal intubation for status epilepticus in the ED at 01:03. The patient was still seizing at the time of intubation. Continuing seizures were treated with lorazepam and then propofol and the patient was admitted to the ICU at 03:57. EEG confirmed continuing seizure activity at that time. The patient was subsequently extubated around 12:00 on 9/4/2009.

69. rampart.umich.edu

70. Study close out Supplies Data EFIC Regulatory

71. Study close out - supplies Destroy Remaining Study Drug –Remove all study boxes from field –Waste and retire study drug in WebDCU Remaining Supplies –Return study boxes to CCC –Return SD cards to CCC

72. Study close out - data DCR Completion –Review all open DCRs –Update per request, save, and re-submit

73. Study close out - EFIC Public Disclosure Activities –Contact local IRB to determine if study close out can occur prior to completion of PD –Complete all remaining PD activities

74. Study close out - regulatory Study Termination Report –Submit to IRB –Upload Termination Report in WebDCU along with documentation of IRB acknowledgment of study close-out Document Retention –Study documents should be retained for a minimum period of 6 years