The Winner by a Nose: Intranasal Midazolam

OBJECTIVE: To evaluate the safety and efficacy of a novel formulation of midazolam administered as a single-dose nasal spray (MDZ-NS) in the outpatient treatment of patients experiencing seizure clusters (SCs).

METHODS: This was a phase III, randomized, double-blind, placebo-controlled trial ( ClinicalTrials.gov NCT01390220) with patients aged at least 12 years on a stable regimen of antiepileptic drugs. Following an in-clinic test dose phase (TDP), patients entered an outpatient comparative phase (CP) and were randomized (2:1) to receive double-blind MDZ-NS 5 mg or placebo nasal spray, administered by caregivers when they experienced an SC. The primary efficacy end point was treatment success (seizure termination within 10 minutes and no recurrence 10 minutes to 6 hours after trial drug administration). Secondary efficacy end points were proportion of patients with seizure recurrence 10 minutes to 4 hours and time to next seizure >10 minutes after double-blind drug administration. Safety was monitored throughout.

RESULTS: Of 292 patients administered a test dose, 262 patients were randomized and 201 received double-blind treatment for an SC (n = 134 MDZ-NS, n = 67 placebo, modified intent-to-treat population). A significantly greater proportion of MDZ-NS than placebo-treated patients achieved treatment success (53.7% vs 34.4%; P = .0109). Significantly, fewer MDZ-NS- than placebo-treated patients experienced seizure recurrence (38.1% vs 59.7%; P = .0043). Time-to-next seizure analysis showed early separation (within 30 minutes) between MDZ-NS and placebo that was maintained throughout the 24-hour observation period (21% difference at 24 hours; P = .0124). Sixteen (5.5%) patients discontinued because of a treatment-emergent adverse event (TEAE) during the TDP and none during the CP. During the CP, 27.6% and 22.4% of patients in the MDZ-NS and placebo groups, respectively, experienced at least 1 TEAE.

SIGNIFICANCE: The midazolam administered as a single-dose nasal spray was superior to placebo in providing rapid, sustained seizure control when administered to patients experiencing an seizure clusters in the outpatient setting and was associated with a favorable safety profile.

Antiepileptic Drugs: Evolution of Our Knowledge and Changes in Drug Trials

This article summarizes methodological changes in antiepileptic drug trials and associated advances in knowledge starting from 1938, the year phenytoin was introduced and also the year when evidence of safety was made a requirement for the marketing of medicines in the United States.

The first period (1938-1969) saw the introduction of over 20 new drugs for epilepsy, many of which did not withstand the test of time. Only few well controlled trials were completed in that period and trial designs were generally suboptimal due to methodological constraints.

The intermediate period (1970-1988) did not see the introduction of any major new medication, but important therapeutic advances took place due to improved understanding of the properties of available drugs. The value of therapeutic drug monitoring and monotherapy were recognized during the intermediate period, which also saw major improvements in trial methodology.

The last period (1989-2019) was dominated by the introduction of second-generation drugs, and further evolution in the design of monotherapy and adjunctive-therapy trials.

A blond woman cradles her infant in her arms, trying to soothe them.

Better Seizure Control with Ketogenic Diet in Infants with Genetic Epilepsy

Infants and young children with epilepsy due to a confirmed genetic abnormality had a better response to treatment with ketogenic diet compared to patients with other types of epilepsy, according to a review of 10-year experience at Ann & Robert H. Lurie Children’s Hospital of Chicago. Results were published in Scientific Reports.

“Overall, we observed that ketogenic diet continues to be a safe, effective and well-tolerated treatment for patients under 3 years of age with drug-resistant epilepsy,” says study author John Millichap, MD, an epilepsy specialist at Lurie Children’s and Associate Professor of Pediatrics at Northwestern University Feinberg School of Medicine. “Based on our experience, clinicians could consider offering ketogenic diet earlier to infants diagnosed with genetic epilepsy, perhaps even before it becomes clear that the patient is not responding to anticonvulsant medication.”

Ketogenic diet is a high fat, low carbohydrate and protein restricted diet that is rigorously medically supervised. It is widely recognized as an effective treatment for epilepsy that does not respond to medications.

“The ketogenic diet helps control seizures by reducing fluctuations of blood sugar, which reduces hyper-excitability in the brain,” explains Dr. Millichap. “At Lurie Children’s we have used it since 1963.”

Antiepileptics Not Found to Improve Neurologic Outcome, Reduce Seizures in Spontaneous ICH

Antiepileptic drugs such as phenytoin, levetiracetam, and valproic acid may not result in improvements in neurologic outcomes or reductions in seizure activity in patients with spontaneous intracerebral hemorrhage (ICH), study results published in the Annals of Emergency Medicine suggest.

The study was a meta-analysis of 8 trials that included 4211 adult patients with spontaneous ICH. Only studies that compared prophylactic antiepileptic therapy vs no preventive therapy were included in the analysis.

A limitation of the meta-analysis was the inclusion of predominantly observational and retrospective studies.

The findings from this study do not appear to “support routine use of an antiepileptic drug for primary seizure prevention in adults with spontaneous intracerebral hemorrhage.” The study investigators do, however, believe that “there remains a need for further randomized data with consideration of patient injury severity.”

Is it a Tie at This Point in the Game? Efficacy of Levetiracetam and Phenytoin for the Second-Line Treatment of Convulsive Status Epilepticus

BACKGROUND: Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of pediatric convulsive status epilepticus in the United Kingdom; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of pediatric convulsive status epilepticus.

METHODS: This open-label, randomized clinical trial was undertaken at 30 United Kingdom emergency departments at secondary and tertiary care centers. Participants aged 6 months to less than 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomization schedule to receive levetiracetam (40 mg/kg over 5 minutes) or phenytoin (20 mg/kg over at least 20 minutes), stratified by center. The primary outcome was time from randomization to cessation of convulsive status epilepticus, analyzed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomization and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894.

FINDINGS: Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomized participants were treated and had available data: 152 allocated to levetiracetam and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomization to cessation of convulsive status epilepticus was 35 minutes (interquartile range: 20 to not assessable) in the levetiracetam group and 45 minutes (24 to not assessable) in the phenytoin group (hazard ratio: 1.20, 95% confidence interval: 0·91-1.60; P = .20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral edema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]).

INTERPRETATION: Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of pediatric convulsive status epilepticus.

Shortage of Epilepsy Medicine to Continue Until End of October, Manufacturer Says

Teva has announced that its epilepsy medicine Gabitril will be out of stock in the UK until the end of October 2019 as part of a “Europe-wide issue”.

All strengths of the epilepsy medicine Gabitril (tiagabine; Teva) will be out of stock in the UK until the end of October 2019, the drug’s manufacturer has said.

In a statement by the Epilepsy Society, a UK charity for patients with epilepsy, published on 20 August 2019, Teva said it had extended its return to market date from 30 September 2019 to “the end of October [2019]” as a result of issues in the manufacturing process that it said are out of its control.

Teva’s statement added that the 10mg Gabitril tablets “may experience further disruption in supply in early 2020”.

FDA-Approved Donepezil Protects Against Seizures in a Mouse Model of Dravet Syndrome

De novo loss-of-function mutations in SCN1A are the main cause of Dravet syndrome, a catastrophic encephalopathy characterized by recurrent early-life febrile seizures, a number of other afebrile seizure types that are often refractory to treatment, and behavioral abnormalities including social deficits, motor dysfunction, and cognitive impairment. This research team previously demonstrated that the reversible acetylcholinesterase inhibitor, Huperzine A, increases seizure resistance in Scn1a mutants.

In the present study, the team evaluated the therapeutic potential of donepezil, a reversible acetylcholinesterase inhibitor approved by the FDA, in a mouse model of Dravet syndrome (Scn1a +/-). The team found that donepezil conferred robust protection against induced seizures in Scn1a +/- mutants.

Study Recommends Physicians and Healthcare Providers Better Educate Patients about Epilepsy and Cannabis

INTRODUCTION: Medical cannabis is increasingly discussed as an alternative treatment option in neurological diseases, e.g. epilepsy. Supporters and opponents base their propositions mostly on subjective estimates, they confuse cannabis in whole versus extracts and botanical versus synthesized.

METHODS: Two hundred seventy five patients with any kind of epilepsy (56% female, 44% seizure free, 91% on medication) answered a survey on the knowledge, expectations, fears, and willingness to be treated with medical cannabis. Data were analyzed with regard to patient characteristics and clinical data from patient files.

RESULTS: Overall, 70.5% of the patients were familiar with the possibility of medical cannabis treatment, 36.7% with its use in epilepsy. A minority of 10.9% gained the information from their physicians. The majority knew about organic compared to synthetic cannabis. The interest in further information is high (71.3%). Regression analysis (explaining 53.8% of the variance) indicated that positive expectations (in the order of relevance) were seizure control, relaxation, mood, and tolerability whereas fears mostly concerned addiction and delirant intoxication. Men showed a greater interest than women.

CONCLUSION: Many epilepsy patients knew about medical cannabis, were interested in this treatment, and wanted more information. Expectations, however, appear to be based on the connotations of the whole substance cannabis with tetrahydrocannabidiol and its commonly known effects. Unfortunately, patients did not get their information from physicians, but mostly by other sources. In order to avoid prejudices and potentially harmful self-medication, physicians and healthcare providers are called to become familiar with the substance and to inform patients adequately.

Therapy That Targets Underlying Cause of Dravet Syndrome Gets Orphan Drug Status

The FDA has granted Orphan Drug designation to STK-001 (Stoke Therapeutics) for the treatment of Dravet syndrome.

Dravet syndrome is a severe and progressive genetic epilepsy that starts within the first year of life and often leads to cognitive regression or developmental stagnation, ataxia, and speech impairment. The disease is characterized by frequent, prolonged and refractory seizures, in which approximately 85% of cases are due to a spontaneous, heterozygous loss of function mutations in the SCN1A gene.

STK-001 is an investigational antisense oligonucleotide that works by upregulating Nav1.1 protein expression from the non-mutant (wild type) copy of the SCN1A gene to restore physiological Nav1.1 levels. STK-001 is designed to address the underlying cause of Dravet syndrome, thereby reducing the occurrence of seizures and significant non-seizure comorbidities. The Company has generated preclinical data for STK-001 to demonstrate proof-of-mechanism.

Repeated, Intermittent, Acute Treatment of Seizure Clusters with Midazolam Nasal Spray Well-Tolerated

OBJECTIVE: To evaluate safety- and seizure-related outcomes with repeated intermittent use of a novel formulation of midazolam administered as a single-dose nasal spray (MDZ-NS) in the outpatient treatment of patients experiencing seizure clusters (SCs).

METHODS: In this open-label extension trial (ClinicalTrials.gov NCT01529034), patients aged 12 years or older and on a stable regimen of antiepileptic drugs who completed the original phase III, randomized controlled trial were enrolled. Caregivers administered MDZ-NS 5 mg when patients experienced SCs; a second dose could be given if seizures did not terminate within 10 minutes or recurred within 10 minutes-6 hours. Patients were monitored for treatment-emergent adverse events (TEAEs) throughout, and the main seizure-related outcome was treatment success, defined as seizure termination within 10 minutes and no recurrence 10 minutes-6 hours after drug administration.

RESULTS: Of 175 patients enrolled, 161 (92.0%) received one or more MDZ-NS dose, for a total of 1998 SC episodes. Median time spent by patients in the trial was 16.8 months (range = 1-55.7 months). TEAEs were experienced by 40.4% of patients within 2 days of drug administration and 57.1% overall. TEAEs reported by most patients (within 2 days and overall) were nasal discomfort (12.4%) and somnolence (9.3%). One patient each discontinued due to treatment-related nasal discomfort and somnolence. There were no patients with treatment-related respiratory depression, and none with TEAEs indicative of drug abuse or dependence. Treatment success criteria were met in 55% (1108/1998) of SC episodes after administration of a single 5-mg dose and in 80.2% (617/769) with the second dose. Treatment success was consistent over treated episode number.

SIGNIFICANCE: Repeated, intermittent, acute treatment of patients experiencing seizure clusters with midazolam nasal spray in the outpatient setting was well tolerated over an extended period, with maintenance of efficacy suggesting lack of development of tolerance.