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. RAMPART Synopsis
Replace “Presenter's Name” with your name. Alternative title slides are available at the end of this presentation in the “alternatives” slide.

5. 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
For those whose attention span is getting short. The first two slides are the “everything you need to know slides”.
And yes, the study name is a tribute to Johnny and Roy, the inspirations for many young would-be emergency physicians.

6. Rapid Anticonvulsant Medication Prior 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. 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):
Penberthy LT, et al. Seizure 2005;14(1):46-51
Wu YW, et al. Neurology 2002;58(7):1070-6

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
Human study on healthy volunteers given 0.08 mg/kg to a max of 5 mg
Alfonzo-Echeverri, Anesth Prog 1990;37:

11. IM midazolam stops seizures 4 times faster than IM diazepam (in mice)
Raines, Epilepsia. 1990;31:313-7
A model system is described in which sustained clonic seizures are produced by a combination of phenytoin (PHT) and pentylenetetrazol (PTZ) in the mouse, the former agent preventing the terminal tonic spasms produced by the latter.

12. Brain midazolam concentration remains high even as serum concentration is dropping
Megarbane, Toxicology Letters 2005;159:22–31
This is an rat model of MDZ overdose (160 mg/kg IV over 20 minutes), but it makes the point that interstitial brain MDZ concentrations are maintained much longer than serum concentrations.

13. Duration of seizure suppression with midazolam is hours, and similar to that of diazepam
Towne, J Emerg Med 1999;17:323–328
This is based on a human study with 6 patients on continuous EEG monitoring after status epilepticus. It looked at the effect of midazolam versus diazepam versus saline at suppressing inter-ictal spikes after ictal control had been obtained.

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
IV Diazepam
IM/IN Midazolam
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
Lahat
17.23
1.04 [0.87, 1.25]
24/ /26
Rainbow
19.96
0.73 [0.47, 1.12]
23/ /45
Mahmoudian
15.73
1.33 [0.97, 1.83]
28/ /35
Shah
38.10
0.92 [0.80, 1.07]
54/ /50
Total (95% CI)
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
Chamberlain
(3.60) (4.10)
3.51
3.40 [0.32, 6.48]
Lahat
(4.10) (3.60)
7.58
1.90 [-0.20, 4.00]
Shah
(2.30) (0.90)
88.91
2.60 [1.99, 3.21]
Total (95% CI)
100.00
2.58 [2.00, 3.15]
-10 -5 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 < )

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

20. Intervention - Dose
Smaller Child ( 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 mg/kg plus
Phenytoin or Fosphenytoin 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 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…
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.
Carl Schneider, Chauncy Stillman Professor for Ethics, Morality, and the Practice of Law and a professor of internal medicine at the University of Michigan

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
Our website address

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 !