This is a double-blind randomized non-inferiority clinical trial of the efficacy of IM midazolam versus IV lorazepam in the prehospital treatment of status epilepticus by paramedics. The trial is being carried out 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 NETT is composed of 17 enrollment Hub sites, a Clinical Coordinating Center, and a Statistical Data Management Center. The Hubs are academic medical centers that coordinate enrollment within a number of Spokes consisting of EMS agencies and other regional academic and community hospitals. RAMPART has relied on more than 4,000 paramedics, 33 EMS agencies, and 79 receiving hospitals across the United States.
Approximately 1,000 adult and pediatric patients with continuing seizure activity after EMS arrival and meeting all inclusion and exclusion criteria are being enrolled and randomized in this trial. All subjects receive active treatment by either IM or IV routes of administration. Adults and children greater than or equal to 40 kg who are randomized to active IM therapy are treated with 10 mg midazolam IM followed by IV placebo. Adults and children greater than or equal to 40 kg who are randomized to IV active therapy are treated with IM placebo followed by 4 mg lorazepam IV. The weight of children is estimated from their length using a length based weight estimation tape that is included in each study box. Active therapy in children estimated to be less than 40 kg is either 5 mg midazolam IM or 2 mg lorazepam IV. Children estimated to be less than 13 kg are not enrolled.
The specially-designed study box incorporates a voice recorder activated by opening the box. Study personnel are instructed to provide verbal statements at the following times: IM treatment, IV access obtained, IV administered, administration of any rescue treatments, when and if convulsions are observed to stop, and whether the subject is seizing on arrival at the ED. The study box has an internal clock that time-stamps all statements.
In situations where it is difficult to start an IV, medics are expected to continue attempts for at least 10 minutes. An intraosseous (IO) route can be used at any time in lieu of IV access. Rescue therapy, as dictated by local EMS protocol, is expected to be used in subjects who are still seizing 10 minutes after the last study medication is administered. In cases where there is a delay in starting the IV and a subject no longer has seizures before IV study drug is given, the study intervention will be considered over and IV study medication does not need to be used. When seizures are observed to resume later during EMS transport, medics are instructed to use rescue therapy defined by local EMS protocol.
The study is being conducted under 21 CFR 50.24, FDA regulations governing emergency clinical research performed with exception from informed consent (EFIC) (FDA, 2005
). An EFIC plan for the trial was included in the IND application submitted to the FDA and was approved by the Institutional Review Board (IRB) at the Clinical Coordinating Center. Institutional Review Boards (IRBs) at each NETT site have reviewed community consultation and public disclosure activities and provided local approval. Every EMS system participating in the study is covered under a new or existing Federal Wide Assurance delineating an IRB of record for that system. Subjects or their legally authorized representatives are notified about enrollment in the trial by the study team as soon as possible, and they are asked for approval for the study team to continue collecting data until the subject’s end of study.