Study Design

The Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) was a randomized, double-blind, phase 3, noninferiority clinical trial. It was designed and conducted by the Neurological Emergencies Treatment Trials (NETT) network, a multidisciplinary clinical trials infrastructure funded by the National Institute of Neurological Disorders and Stroke (NINDS). The investigators were responsible for all elements of the trial, including design, data collection, and analysis. The authors wrote the manuscript and vouch for the data and analysis. The trial was performed under an Investigational New Drug application with the Food and Drug Administration (FDA). Autoinjectors with active medication and placebo were purchased by the Department of Defense and provided to the NINDS through a cooperative agreement. The Department of Defense had no role in the design of the study, accrual or analysis of data, or preparation of the manuscript. The study was conducted in accordance with the protocol, which is available with the full text of this article at NEJM.org.

RAMPART involved 4314 paramedics, 33 EMS agencies, and 79 receiving hospitals across the United States. Paramedics received continuing medical education in the management of seizures and other neurologic emergencies, as well as supplemental training in human subjects research and protections and in the study protocol, with refresher protocol training provided throughout the trial.

The trial met the exception from informed-consent requirements for emergency research under the FDA code of regulations 21 CFR 50.24.4 Institutional review boards for all entities engaged in this research reviewed local community consultation activity, according to the regulations regarding the exception from informed consent, and provided approval. Subjects or their legally authorized representatives were notified about enrollment in the trial by the study team as soon as possible, usually while the subject was still in the emergency department, and provided written informed consent to allow continued data collection until follow-up was completed.

Study Subjects

The intended study population included children with an estimated body weight of 13 kg or more and adults requiring treatment with benzodiazepines for status epilepticus in the prehospital setting. Subjects were enrolled if they were having convulsive seizures at the time of treatment by paramedics and were reported by reliable witnesses to have been continuously convulsing for longer than 5 minutes or if they were having convulsive seizures at the time of treatment after having intermittent seizures without regaining consciousness for longer than 5 minutes.

Subjects were excluded for the following reasons: the acute precipitant of the seizures was major trauma, hypoglycemia, cardiac arrest, or a heart rate of less than 40 beats per minute (since these conditions require alternative treatments); they had a known allergy to midazolam or lorazepam; they were known to be pregnant or a prisoner; they were being treated as part of another study; or, preemptively, they opted out of this study by wearing a medical-alert tag marked “RAMPART declined.”

Study Intervention

When they arrived at the scene, the study paramedics rapidly performed an initial assessment and stabilized subjects who were in status epilepticus, according to their local EMS protocols. For subjects who met the eligibility criteria, the paramedics began the study procedure by opening an instrumented box containing a study drug kit. Each kit contained two color-coded, shrink-wrapped study-drug bundles, one for each dose tier; each bundle consisted of one intramuscular autoinjector (Investigational Midazolam Autoinjector [Meridian Medical Technologies]) and one prefilled intravenous syringe (Carpuject System [Hospira]). All adults and those children with an estimated body weight of more than 40 kg received either 10 mg of intramuscular midazolam followed by intravenous placebo or intramuscular placebo followed by 4 mg of intravenous lorazepam. In children with an estimated weight of 13 to 40 kg, the active treatment was 5 mg of intramuscular midazolam or 2 mg of intravenous lorazepam. Blinding and simple randomization with equal numbers of subjects assigned to the two study groups were achieved with the use of a double-dummy strategy, in which each kit was randomly assigned at the central pharmacy to contain either the active intramuscular drug with intravenous placebo or intramuscular placebo with the active intravenous drug. All subjects were treated with the intramuscular autoinjector, after which venous access was immediately achieved and treatment was administered by means of intravenous syringe. Subjects were considered to be enrolled in the trial when the intramuscular autoinjector was applied, regardless of whether the intramuscular dose was successfully delivered.

A voice recorder was activated by opening the study box. Paramedics were instructed to record oral statements when intramuscular treatment was administered, when intravenous access was obtained, when the intravenous study drug was administered, when any rescue treatments were given, and when convulsions were observed to stop. Each statement was time-stamped by the study box's internal clock. Paramedics also stated whether the subject was convulsing on arrival at the emergency department.

When it was difficult to obtain intravenous access, paramedics were instructed to continue attempts for at least 10 minutes, but they were permitted to use intraosseous access at any time in lieu of intravenous access. For the purposes of this trial, intraosseous access to the vascular space was considered equivalent to intravenous access. Rescue therapy, as dictated by local EMS protocol, was recommended for use in subjects who were still convulsing 10 minutes after the last study medication was administered. If there was a delay in obtaining intravenous access and the subject stopped having seizures before the intravenous study drug could be given, the intravenous study medication was not used. If convulsions resumed later during EMS transport, rescue therapy (according to the local protocol) was to be given.

Study Outcomes

The primary outcome was termination of seizures before arrival in the emergency department without the need for the paramedics to provide rescue therapy. Subjects did not reach the primary outcome if they were having seizures on arrival in the emergency department or if they received rescue medication before arrival. Termination of seizures on arrival was determined according to the clinical judgment of the attending emergency physician and was based on examination of the subjects, their clinical course, and results of any routine diagnostic testing (Section 6.1 of the protocol). This outcome measure was previously used in the PHTSE trial.1,5

Key secondary outcome measures included the time from study-box opening to termination of convulsions and the time from initiation of active-drug administration to termination of convulsions (among subjects in whom convulsions ceased before arrival in the emergency department), the frequency and duration of hospitalization and of admissions to the intensive care unit, and the frequencies of acute endotracheal intubation and acute seizure recurrence. Acute endotracheal intubation was defined as intubation performed or attempted by EMS personnel or performed within 30 minutes after arrival in the emergency department. Acute seizure recurrence was defined as any further convulsive or electrographic seizures that required additional antiepileptic medications during the first 12 hours of hospitalization in subjects who did not have seizures on arrival in the emergency department. Serious adverse events were recorded through the end of the study for every subject (see Table A2 in the Supplementary Appendix, available at NEJM.org).

Statistical Analysis

The primary objective of the study was to show that the proportion of subjects whose seizures were terminated before arrival in the emergency department (without the use of rescue medications) in the intramuscular midazolam group was not inferior to that in the intravenous lorazepam group by more than a prespecified amount (the noninferiority margin). The null hypothesis of inferiority was tested with the use of a one-sided z statistic.6 The primary analysis was followed by a one-sided test (conditional on the finding of noninferiority) for superiority at a significance level of 0.025, although this was not prespecified in the protocol. On the basis of published studies of similar patient populations, and accounting for differences in the dose of lorazepam and in the definition of efficacy, we estimated that after an initial dose of intravenous lorazepam had been administered, seizures would be terminated in 70% of subjects before arrival in the emergency department. Sample size was estimated on the basis of the comparison of independent proportions, with two planned interim analyses for futility with respect to the primary outcome; 90% power to show the noninferiority of intramuscular midazolam; a noninferiority margin of 10 percentage points; and a one-sided test with the probability of a type I error of 0.025. The maximum sample size required for randomization was 890 subjects (445 per treatment group). Because some patients have recurring episodes of status epilepticus, the total sample size was inflated by 15% (1024 subjects) to account for inadvertent repeated enrollment of the same subjects. (Repeated enrollments of the same subject were not analyzed.) Secondary outcomes were compared in a superiority framework with the use of a two-sided test with the probability of a type I error of less than 0.05. All analyses were conducted with the intention-to-treat population defined as all subjects randomly assigned to a study medication. A sensitivity analysis was conducted with the per-protocol population, which excluded subjects with any of the following three predefined protocol deviations: eligibility violation, incorrect dose of study medication, or incorrect administration.