Evaluation of Long-Term Safety and Tolerability of Staccato Alprazolam in Patients Aged 12 and Older with Stereotypical Prolonged Seizures

The primary objective of this study is the evaluation of the long-term **safety** and tolerability of Staccato alprazolam in individuals aged 12 years and older with stereotypical prolonged seizures. This is clinically relevant as it aims to ensure that the treatment is safe for long-term use, which is crucial for managing a chronic condition like prolonged seizures.

Secondary objectives include: - Evaluation of the probability of success of repeated treatment with Staccato alprazolam for seizures occurring within the first 12 months, up to a maximum of 10 treated seizures. - Evaluation of the probability of success of repeated treatment with Staccato alprazolam with no recurrence of seizure(s) up to 2 hours for seizures occurring within the first 12 months, up to a maximum of 10 treated seizures. - Evaluation of the long-term pulmonary safety of Staccato alprazolam.

The clinical trial involves a total of **181 participants** who are being evaluated for the long-term safety and tolerability of Staccato alprazolam in the **treatment of stereotypical prolonged seizure**. The study population includes both male and female subjects, with an age range starting from 12 years and encompassing adolescents, adults, and the elderly. Participants were selected based on an established diagnosis of focal or generalized epilepsy, or combined focal and generalized epilepsy, with a documented history of stereotypical episodes of prolonged seizures. The trial includes a vulnerable population, as it involves individuals with epilepsy. Participants must have a study caregiver aged 18 or older who can recognize and observe the participant. Prior completion of a study using Staccato alprazolam is required, and additional criteria apply to certain treatment arms. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the long-term safety and tolerability of **Staccato alprazolam** in participants aged 12 years and older with stereotypical prolonged seizures. This is an open-label, multicenter, outpatient extension study. The trial involves the administration of **alprazolam** via a drug-device combination product, specifically the Staccato® delivery system, which is a hand-held, single-dose, non-reusable device. The study is expected to run from September 26, 2022, to November 30, 2028, with participants involved for a maximum treatment period of 48 weeks.

The trial follows a structured sequence of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, diagnosis of epilepsy, and previous participation in a related study. Participants must have a caregiver aged 18 or older who can recognize and observe seizures. Following the screening, participants will attend regular follow-up visits to monitor safety and efficacy, with the primary endpoints focusing on the frequency of treatment-emergent adverse events (TEAEs), including those leading to withdrawal and serious TEAEs. Secondary endpoints include treatment success after investigational medicinal product (IMP) administration and the frequency of respiratory TEAEs.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include the occurrence of serious adverse events or the participant's inability to comply with the study protocol. The trial is not categorized as low intervention and is conducted under Phase 5, focusing on the safety and tolerability of the treatment in a real-world setting. The study does not involve a placebo group, as it is an extension study following a previous efficacy trial.

The clinical trial involves the administration of **alprazolam** as the experimental medication. Alprazolam is provided in the form of an **inhalation powder, pre-dispensed**, and is delivered using a drug-device combination product known as Staccato®. This device is a hand-held, single-dose, single integral non-reusable system that utilizes Alexza's proprietary Staccato® delivery technology. The route of administration is via **inhalation use**. The maximum daily dose of alprazolam is 2 mg, with a total maximum dose of 2 mg over a treatment period of up to 48 hours. The formulation is not specifically designed for pediatric use. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen.

The study also includes a **placebo** treatment, which is designed to match the Staccato® alprazolam device but does not contain any active substance. The placebo is used to provide a comparator for evaluating the safety and tolerability of the experimental treatment. The placebo is administered in the same manner as the active treatment, ensuring that the study maintains blinding and controls for any potential placebo effects. The placebo device is identical in appearance and usage to the active device, ensuring that participants and investigators remain unaware of the treatment allocation.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints focus on the frequency of treatment-emergent adverse events (TEAEs), including those leading to withdrawal from the study and serious TEAEs. Secondary endpoints include the evaluation of treatment success after the administration of the investigational medicinal product (IMP) for seizures occurring within the first 12 months, as well as treatment success with no recurrence after 2 hours for seizures within the same period. Additionally, the frequency of respiratory TEAEs will be monitored.

The investigational product, **Staccato alprazolam**, is administered as an inhalation powder using a drug-device combination product. The trial is designed to evaluate the long-term safety and tolerability of this product in participants aged 12 years and older with stereotypical prolonged seizures. The study is an open-label, multicenter, outpatient extension study, and participants must have completed a prior study using Staccato alprazolam to be eligible. The trial is expected to conclude by November 2028.