Authors :
Michael Sperling, MD – Thomas Jefferson University; Sunita Misra, MD, PhD – Neurelis, Inc.; Vikram Rao, MD, PhD – University of California; Jurriaan Peters, MD, PhD – Boston Children's Hospital; Charles Davis, PhD – SD Biostatistics, Inc; Enrique Carrazana, MD – Neurelis, Inc.; University of Hawaii John A. Burns School of Medicine; Adrian Rabinowicz, MD – Neurelis, Inc.
Rationale: Some patients with epilepsy experience seizure clusters while receiving daily antiseizure drugs (ASD). The impact of a change in these concomitant medications on the recurrence of seizure clusters treated with intermittent rescue therapy is unclear. Here, we examined the duration between seizure clusters (SEIzure cluster interVAL [SEIVAL]) treated with diazepam nasal spray across time in subgroups of patients who had a change in concomitant medications and in those who did not. Diazepam nasal spray (Valtoco
®) is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years.
Methods: Patients (6-65 years) in a long-term, open-label safety study of diazepam nasal spray
received 5-, 10-, 15-, or 20-mg doses (based on age and weight) to treat seizure clusters. SEIVAL was determined using 90-day periods for patients treated with ≥2 doses per period across 4 periods (360 days). This consistent cohort was selected for analysis to reduce the influence of confounding differences in populations across time. Second doses administered within 24 hours of the first dose were excluded from the analysis to eliminate retreatments (ie, second doses) for the same seizure cluster. A change in concomitant ASD medications was defined as any change in dose or drug (yes/no). A paired t test was used to detect statistically significant differences between groups.
Results: Of 175 patients enrolled in the study, 163 were treated with ≥1 dose of diazepam nasal spray. Of these patients, 151 had SEIVAL data, and 76 had ≥1 SEIVAL for 4 consecutive periods (consistent cohort). In the consistent cohort, mean SEIVAL increased by 12.9 days, from 13.9 days in Period 1 to 26.8 days in Period 4 (P≤0.001). Of these 76 patients, 56 (73.7%) had a change in concomitant medications during periods 1–4. In patients who had no change in concomitant medications (n=20), SEIVAL increased by a mean of 8.3 days from periods 1 to 2 and by 15.5 days from periods 1 to 4 (Figure). In patients who had a change in concomitant medications, similar mean increases in SEIVAL were noted between periods 1 to 2 (7.2 days) and periods 1 to 4 (11.9 days) (Figure).
Conclusions: In this subanalysis from a long-term safety study of diazepam nasal spray for patients with seizure clusters, a change in concomitant medications did not appear to alter the increase in SEIVAL over the study period when compared with the group without an ASD change. These data suggest that changes in ASD regimens do not explain the increase in SEIVAL with long-term use of diazepam nasal spray. Hypothesis generation on this SEIVAL observation is needed to identify potential biological or behavioral explanations.
Funding: Neurelis, Inc.