Treatment with diazepam nasal spray resulted in a statistically significant change in time between seizure clusters, potentially reflecting a beneficial effect of intermittent rescue therapy.
New post-hoc data from a recently completed phase 3 trial (NCT02721069) assessing diazepam nasal spray (valtoco; Neurelis), an FDA-approved antiseizure medication (ASM), indicated that faster time to administration was associated with shorter time to seizure cluster cessation and overall shorter seizure duration. Over a 12-month span, investigators also noticed a statistically significant change in SEIzure interVAL (SEIVAL), or the time between seizure clusters, that was independent of age of changes in concomitant ASMs.1-3
These data were part of 2 poster presentations given at the 35th International Epilepsy Congress (IEC), held September 2-6, in Dublin, Ireland. In the first analysis, investigators assessed the temporal patterns of seizure clusters treated with diazepam nasal spray while the second characterized SEIVAL in treated individuals. If the 175 enrolled patients aged 6-65 years, 163 received at least 1 dose of the therapy, and 120 had SEIVAL data in period 1 and another period.
To characterize temporal patterns, seizure cluster data were analyzed based on the timing of treatment administration after seizure start: 0-5, 5-15, and more than 15 minutes. After excluding observations of seizure duration more than 24 hours, negative duration, and invalid dose date/time values, 3325 observations were included. In the 0–5-minute group, the median time from seizure start to administration of diazepam nasal spray, time from dosing to cessation, and total seizure duration, were 1, 2, and 4 minutes, respectively. In the 5–15-minute group, median times were 6, 7, and 15 minutes, respectively. Patients who received treatment after 15 minutes showed the least benefit, with median times of 35, 15, and 70 minutes, respectively.2
"Despite availability of chronic, daily oral medications to help control seizures, many patients continue to experience acute repetitive seizures," Adrian L. Rabinowicz, MD, chief medical officer, Neurelis, said in a statement.1 "The clinical evidence presented at IEC further supports the utility of VALTOCO in acute seizure management to minimize the potential negative consequences of seizure clusters and have meaningful impact for people with epilepsy."
The second analysis evaluated SEIVAL across 4 consecutive 90-day periods, totaling 360 days, with paired t tests to assess statistical significance. In total, 76 patients had data in all 4 periods, representing a consistent cohort. In the general population, findings showed that from period 1 to 4, treated patients had mean SEIVAL increase from 14.8 to 35.8 days. In the consistent cohort, mean SEIVAL increased from 13.9 to 26.8 days (P ≤.001).
Among a subgroup of pediatric participants aged 6-17 years old (n = 32), mean SEIVAL increased from 13.0 to 25.9 days (P = .02). In adults (n = 44), mean SEIVAL increased from 14.6 to 27.5 days (P = .01). Notably, treatment with diazepam nasal spray resulted in increased mean SEIVAL among patients with (n = 56) changes in concomitant ASM therapy, going from 13.9 to 25.8 days, and those without (n = 20), increasing from 14.1 to 29.6 days. Investigators concluded that these findings may "reflect patient behavior or other factors, including a change in the underlying pathophysiology of seizure clusters."
The original phase 3 study, an open-label trial, included a 12-month treatment period, with study visits at day 30 and every 60 days thereafter, after which patients could elect to continue treatment. In total, 81.6% of patients were exposed to diazepam nasal spray for at least 12 months. Throughout the observed time, there was death because of sudden unexpected death in epilepsy and 1 withdrawal owing to a treatment-related AE, both considered unlikely to be related to treatment. Only 13 patients (7.9%) showed nasal irritation, and there were no relevant olfactory changes. The safety profile of diazepam nasal spray was generally similar across subgroups based on age, monthly usage, concomitant benzodiazepine therapy, or seasonal allergy/rhinitis.