NEWS FROM THE AMERICAN EPILEPSY SOCIETY ANNUAL MEETING
An EpiPen-Like Device with Diazepam Found Effective for Stopping Seizures
ARTICLE IN BRIEF
Investigators reported that in a phase 3 placebo-controlled, multicenter study, intramuscular injection of diazepam was significantly effective in stopping cluster seizures.
A double-blind placebo-controlled study of a diazepam auto-injector, an EpiPen-like device that injects medication intramuscularly, has proven effective at stopping acute repetitive or cluster seizures. The only medication federally approved is a rectal form of diazepam, which can be difficult and compromising to administer.
The results of the phase 3 multicenter study were reported during the American Epilepsy Society annual meeting last month.
Bassel Abou-Khalil, MD, professor of neurology and director of the epilepsy center at Vanderbilt University Medical Center, said that the diazepam auto-injector was safe and effective “and would certainly be good for patients and their caregivers.”
The study involved 163 patients who received care at 68 centers around the country. Patients were stratified into groups based on age, assigned one of four doses, and blindly assigned to active medicine or a placebo dose. Patients and their caretakers were provided with the EpiPen-like device and shown how to inject it into their thigh or other soft tissue.
The primary endpoint was the time to the next seizure or rescue (with the rectal diazepam gel) from 15 minutes to 12 hours after the dose was given. There were a number of secondary endpoints, including the frequency of rescue events, numbers of seizures experienced post-dose, caregiver and physician treatment assessments, and safety.
According to Dr. Abou-Khalil, 45 patients on placebo had another seizure observed between 15 minutes to 12 hours compared with 29 patients on the active medicine (p=0.012). The median time to the event could not be estimated for the diazepam group because of the low number of events, he said, but the 25th percentile time to the seizure was 1.18 hours in the placebo group versus 2.70 hours in the diazepam group.
“Obviously, it is working, but we needed to show that there is a statistically significant difference between the two groups,” said Dr. Abou-Khalil. “There was. This study tells us that this is a good option and we know it is far more convenient to administer.”
Meridian Medical Technologies, Inc., a Pfizer company, is developing the diazepam auto-injector and will present the results of this multicenter study to the Food and Drug Administration for approval in epilepsy patients with acute repetitive or cluster seizures, Dr. Abou-Khalil added.
Treatment-emergent adverse events were reported in 43 percent (34/79) of those on placebo and 42 percent (34/81) of patients using the auto-injector. The most common adverse events were injection site pain in 14 percent of the placebo group and 17 percent in those who were administered the diazepam auto-injection; and in injection site hemorrhage, 6 percent in the placebo group versus 5 percent in the diazepam auto-injector group. One patient in the diazepam group experienced a gait disturbance shortly after the drug was administered.
Intramuscular injection of midazolam via an auto-injector has also been studied. The Rapid AntiConvulsant Medication Prior to Arrival Trial (RAMPART), which was funded by the NINDS and the NIH Countermeasures Against Chemical Threats Program and the Biomedical Advanced Research and Development Authority, compared the benefits of two delivery methods — IV injection of lorazepam versus midazolam via the auto-injector — en route to the hospital in an ambulance. Paramedics throughout the country were trained in the study protocols. The investigators reported in the Feb. 16, 2012, issue of the New England Journal of Medicine that 73.4 percent of patients randomized to receive midazolam through an auto-injector were seizure-free by the time they reached the hospital compared with 63.4 percent of those who received IV lorazepam (p<0.001). [See the Neurology Today story about the RAMPART study: http://bit.ly/Sk5GjF.]
EXPERTS WEIGH IN
Jacqueline A. French, MD, director of the clinical trials consortium at the New York University Comprehensive Epilepsy Center, and a member of the editorial advisory board of Neurology Today, noted there has been growing interest in looking at the safety and effectiveness of acute in-home treatment of seizure clusters with benzodiazepines, and patients and/or their caregivers could possibly self-administer these therapies. But at this point, she said in an e-mail, “we don't know which is more efficacious.”
Sheryl Haut, MD, associate professor of clinical neurology and director of adult epilepsy at Montefiore Medical School and Albert Einstein College of Medicine in New York, said: “The results [of the current study] are impressive. The auto-injection formula interrupted the seizure cluster, which can become a seizure emergency if not treated promptly. Right now, the only acute treatment available is a rectal formula. The rectal diazepam gel can be difficult to use and socially challenging, especially for adults. Our community is in dire need of additional modalities.
“Acute repetitive seizures are a challenging aspect of epilepsy,” she continued. “The condition increases visits to the emergency room and can lead to health risks and significant impairments in the quality of life for our patients.”