Neurological EmergenciesTreatment Trials Network

RAMPARTOverview

Robert Silbergleit

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

• 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 MedicationPrior to Arrival Trial (RAMPART)

Status Epilepticus

120,000 to 200,000 cases / yrMortality 22% at 30 days55,000 deaths in the US

1st Yr cost $40,000 /patient

Bassin S, et al. Crit Care 2002;6(2):137-42Claassen J, et al. Neurology 2002;58(1):139-42

DeLorenzo RJ, et al. Neurology 1996;46(4):1029-35Penberthy LT, et al. Seizure 2005;14(1):46-51Wu YW, et al. Neurology 2002;58(7):1070-6

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

Intramuscular midazolam

• Favorable pharmacology for treatment of SE– Effectiveness– Rapidity

• Better stability – lower cost• Increasing acceptance by EMS• Optimal agent for organophosphate toxicity

Midazolam levels near 80% of peak as early as 5 minutes after IM administration

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Alfonzo-Echeverri, Anesth Prog 1990;37:277-281

IM midazolam stops seizures 4 times faster than IM diazepam (in mice)

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lower dose0.2 mg DZP0.1 mg MDZ

higher dose0.4 mg DZP0.2 mg MDZ

90 ± 7 minRaines, Epilepsia. 1990;31:313-7

Brain midazolam concentration remains high even as serum concentration is dropping

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Megarbane, Toxicology Letters 2005;159:22–31

Duration of seizure suppression with midazolam is hours, and similar to that of diazepam

Towne, J Emerg Med 1999;17:323–328

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midazolam 10mg IM

diazepam 10mg IV

diazepam 20mg IV

Review: IV diazepam versus IM/IN midazolam for treatment of seizuresComparison: 01 Effectiveness of IM/IN MDZ as compared to IV DZP

Outcome: 01 Termination of seizure

Study

IVDiazepam

IM/INMidazola

m RR (fixed) Weight RR (fixed)

n/N n/N 95% CI % 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) 201 169 100.00 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

Review: IV diazepam versus IM/IN midazolam for treatment of seizuresComparison: 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)N Mean (SD) N Mean (SD) 95% CI % 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 89 100.00 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)

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Favors IV DZP Favors IM/IN MDZ

Meta-analysis of IM/IN midazolam shows more rapid termination of seizures compared to IV diazepam

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

Inclusion criteria

• Continuous or repeated convulsive seizure activity for > 5 minutes

• Patient is still seizing

• Estimated weight > 13 kg

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

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

RAMPART Datalogger

Providing data loggers, stepper controllers, data acquisition and custom engineering services to customers worldwide

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

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

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

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

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

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.

Secondary outcomes

• Rapidity of seizure termination• Frequency of subsequent tracheal intubation• Frequency and duration of ICU and hospital stay

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)

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

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

Exception to Informed Consent

• Community Consultation• Public Notification

• Local Context• Centralized Support

• Local Outreach – attend community meetings• Patient Focus Groups – survivors and clinics

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

Timeline

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

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

nett.umich.edu