Clinical trial NCT00809146: Paramedic Treatment of Prolonged Seizures by Intramuscular Versus Intravenous Anticonvulsant Medications
Official title: A Double-blind Randomized Clinical Trial of the Efficacy of IM Midazolam Versus IV Lorazepam in the Pre-hospital Treatment of Status Epilepticus by Paramedics
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Status Epilepticus
Keywords: Status Epilepticus
Emergency Medical Services
Anticonvulsants
Drug Administration Routes
Seizures
Lead sponsor: University of Michigan
Sponsor class: OTHER
Collaborators: name: Medical University of South Carolina
name: University of California, San Francisco
name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2008-12-17
Enrollment: 1023
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The goal of this non-inferiority trial is to determine which type of routine care is the best for paramedics to stop someone from seizing.

Detailed description: Seizures are a common medical problem. Although they can be frightening to watch, most seizures are brief and stop by themselves. Seizures that don't stop in seconds or minutes are a dangerous life-threatening medical emergency. Paramedics often have medications that can stop seizures, but the best way to give the medicines is not known. Paramedics often give medicine directly into a vein, which is called intravenous (IV) administration. This works well, but can be hard to do in a person who is seizing. It can also take some time and delay treatment. Another way to give the medicine is as a shot given into a muscle, which is called intramuscular (IM) administration. Giving the medicine this way is faster, but it may not stop the seizure as quickly.

This clinical trial, the Rapid Anti-convulsant Medication Prior to ARrival Trial (RAMPART), is designed to figure out whether giving anti-seizure medicine works similarly well and more quickly when given through an IV or when given as a shot in the muscle. Two similar medicines will be used. Both are already used by paramedics in the field and by doctors in the hospital to stop seizures. One is commonly given by IV, and the other is commonly given as a shot in the muscle. In this study, the shot will be given using a device similar to an EpiPen-which is an autoinjector used by people with severe allergies.

Approximately 1,024 persons whose seizures are continuing after emergency medical service (EMS) arrival and who meet all eligibility criteria will be enrolled in the trial. Every participant will be treated with anti-seizure medicine by the paramedics. At random, half the participants will be in one group and half in another. Half the participants will receive the study medicine through an IV and will be given a shot in the muscle without medicine (placebo). The other half will receive the medicine as a shot in the muscle plus an IV without medicine (placebo).

In September 2010, more rapid than expected enrollment made it feasible to increase the sample size of the study from 800 to 1,024 with the already available funding. The goals of the expansion were to enroll more pediatric subjects (since the trial was enrolling slightly fewer than anticipated) and to improve the power of the study to 90%, which was initially desired. It is important to understand that the extended enrollment was not a sample size re-estimation in any way. The opportunity to extend the trial is pragmatic, based solely on the early enrollment success of the trial. It is not informed by the planned interim analyses that have been performed, the results of which remain sequestered, and there have been no unscheduled interim analyses. The firewall that prevents the blinded leadership from any knowledge of the outcome data has been diligently maintained throughout the process of proposing and implementing this extension.

Eligibility criteria: Inclusion Criteria:

* Paramedics or reliable witnesses verify 5 minutes of either continuous seizure activity or of repeated convulsive seizure activity where the patient does not regain consciousness (operationally defined as meaningful speech or obeying commands) between seizures.
* Patient is still seizing at the time of paramedic treatment with study medications.
* Estimated weight equal to or greater than 13 kg.
* Subject to be transported to a RAMPART participating hospital.

Exclusion Criteria:

* Major trauma as the precipitant of the seizure
* Hypoglycemia (as defined by local EMS protocol or a glucose \< 60 mg/dL)
* Known allergy to midazolam or lorazepam
* Cardiac arrest or heart rate (HR) \<40 beats per minute
* Sensitivity to benzodiazepines
* Medical alert tag marked with "RAMPART declined"
* Prior treatment of this seizure with diazepam autoinjector as part of another study
* Known pregnancy
* Prisoners

Primary outcomes:
measure: Number of Subjects With Termination of Seizures at ED Arrival With no Rescue Therapy Given
timeFrame: Duration of prehospital care, outcome is determined upon arrival at the ED on the day of enrollment (average 20 minutes).
Secondary outcomes:
measure: Number of Subjects With Endotracheal Intubation Within 30 Min After ED Arrival
timeFrame: anytime before 30 minutes after ED arrival
measure: Number of Subjects Hospitalized
timeFrame: at ED disposition on day of enrollment
measure: Number of Subjects Admitted to an Intensive Care Unit (ICU)
timeFrame: at time of disposition on day of enrollment
measure: Number of Subjects With Recurrent Seizure Within 12 Hours After ED Arrival
timeFrame: within 12 hours after ED arrival
measure: Number of Subjects With Hypotension
timeFrame: participants were followed for the duration of hospital stay, an average of 6 days
measure: Number of Subjects With IM Injection-site Complications
timeFrame: participants were followed for the duration of hospital stay, an average of 6 days
measure: Number of Subjects With IV Injection-site Complications
timeFrame: participants were followed for the duration of hospital stay, an average of 6 days
measure: Length of Intensive Care Unit (ICU) Stay in Days
timeFrame: participants were followed for the duration of hospital stay, an average of 6 days
measure: Length of Hospital Stay in Days
timeFrame: participants were followed for the duration of hospital stay, an average of 6 days
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: San Francisco
country: United States
facility: University of California-San Francisco
state: California
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: New York
country: United States
facility: New York Presbyterian Hospital
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania/York
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University-Main Line
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas-Houston
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: University of Michigan
name: Robert Silbergleit, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Daniel H Lowenstein, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical University of South Carolina
name: Valerie L Durkalski, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sherman NA, Silbergleit R, Bengelink EM, Durkalski V, Wolter KD. The Midazolam RAMPART Study Medical Records Project: A Unique Use of Real-World Data in a Complex Collaborative Partnership to Support a New Drug Application. Ther Innov Regul Sci. 2023 Jan;57(1):132-141. doi: 10.1007/s43441-022-00447-4. Epub 2022 Aug 20.
citation: Silbergleit R, Lowenstein D, Durkalski V, Conwit R; NETT Investigators. Lessons from the RAMPART study--and which is the best route of administration of benzodiazepines in status epilepticus. Epilepsia. 2013 Sep;54 Suppl 6(0 6):74-7. doi: 10.1111/epi.12284.
citation: Silbergleit R, Biros MH, Harney D, Dickert N, Baren J; NETT Investigators. Implementation of the exception from informed consent regulations in a large multicenter emergency clinical trials network: the RAMPART experience. Acad Emerg Med. 2012 Apr;19(4):448-54. doi: 10.1111/j.1553-2712.2012.01328.x.
citation: Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, Palesch Y, Barsan W; NETT Investigators. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012 Feb 16;366(7):591-600. doi: 10.1056/NEJMoa1107494.
citation: Silbergleit R, Lowenstein D, Durkalski V, Conwit R; Neurological Emergency Treatment Trials (NETT) Investigators. RAMPART (Rapid Anticonvulsant Medication Prior to Arrival Trial): a double-blind randomized clinical trial of the efficacy of intramuscular midazolam versus intravenous lorazepam in the prehospital treatment of status epilepticus by paramedics. Epilepsia. 2011 Oct;52 Suppl 8(Suppl 8):45-7. doi: 10.1111/j.1528-1167.2011.03235.x.