Long‑Term Safety and Tolerability of Probenecid (PTI5803) as Adjunctive Therapy in Patients ≥ 14 Years with Drug‑Resistant Focal Epilepsy due to Focal Cortical Dysplasia

Primary objective: To assess the long‑term safety and tolerability of PTI5803 as adjunctive therapy in patients ≥14 years with drug‑resistant focal epilepsy associated with focal cortical dysplasia, thereby defining the risk profile of sustained exposure in this population.

Secondary objectives include:

• Evaluation of seizure severity and its impact during prolonged PTI5803 exposure.
• Assessment of health‑related quality of life over the long term.
• Monitoring of depressive symptoms throughout extended treatment.
• Analysis of trends in seizure frequency with continued therapy.
• Determination of patient retention rate during the study period.

The trial enrolled both female and male patients with drug‑resistant focal epilepsy related to focal cortical dysplasia, spanning the age categories coded as 2 and 3 (approximately children and adolescents). The sponsor did not provide the total number of participants. Eligible individuals were required to have successfully completed the treatment period of the preceding primary study (A_CL_002) with at least 80 % adherence to the dosing regimen and seizure‑diary completion, and to be free of significant protocol deviations or ongoing adverse events that could compromise safety or data integrity. Additional requirements included the ability of the participant or caregiver to comply with all study procedures, written informed consent, and, for females of child‑bearing potential, adherence to contraception protocols. Participants were generally in a stable health condition aside from their refractory seizures, and no specific lifestyle restrictions such as diet or physical activity were stipulated.

The study is an open‑label, Phase 4, multicenter extension trial evaluating the long‑term safety and tolerability of PTI5803 as adjunctive therapy in participants aged ≥14 years with drug‑resistant focal epilepsy related to focal cortical dysplasia. Eligible subjects must have completed the primary study treatment period, demonstrated ≥80 % compliance with dosing and diary requirements, and have no ongoing adverse events or significant protocol deviations; females of child‑bearing potential must adhere to contraception. The trial employs a single‑arm design without randomization or blinding and enrolment began 1 April 2027 with an anticipated end date 30 April 2030. After a screening visit to confirm eligibility, participants enter the extension at baseline and attend scheduled follow‑up visits at approximately months 6, 12, 18 and 24, with the final visit constituting the end‑of‑study assessment. Each visit includes physical examination, vital signs, body weight, laboratory tests, 12‑lead ECG, and collection of seizure diary data; safety monitoring focuses on adverse events, clinically significant findings, and suicide risk using the C‑SSRS. Participants remain in the study for up to 24 months unless early discontinuation occurs due to non‑compliance, emergence of serious adverse events, or investigator‑determined safety concerns.

The investigational product identified as PTI5803 consists of PROBENECID formulated as PROLONGED-RELEASE GRANULES. It is administered orally at a dose volume of 16 ml per administration; the specific dosing schedule and frequency are defined in the study protocol and are applied consistently throughout the extension phase.

Efficacy will be evaluated using secondary endpoints that compare each subject’s status with the baseline defined in the preceding study. The following parameters will be assessed: change from baseline in the Clinical Global Impression of Change (CGI-C), Patient Global Impression of Change (PGI-C), Clinical Global Impression of Severity (CGI‑S), Patient Global Impression of Severity (PGI‑S); change from baseline in health‑related quality‑of‑life measured by the Quality of Life in Epilepsy inventory for adults (QOLIE‑31) and for adolescents (QOLIE‑AD‑48); change from baseline in depressive symptoms using the Beck Depression Inventory‑II (BDI‑II); seizure diary‑derived outcomes including mean percent change in monthly (28‑day) seizure frequency and proportion of seizure‑free subjects per 28 days; and the proportion of participants remaining on study medication at months 6, 12, 18 and 24.

Assessments will be performed at the baseline visit and at scheduled follow‑up visits throughout the 24‑month extension period. Validated scales (CGI‑C, PGI‑C, CGI‑S, PGI‑S, QOLIE‑31, QOLIE‑AD‑48, BDI‑II) will be administered by trained study personnel. Seizure counts will be recorded daily by subjects or caregivers in a standardized diary and aggregated into 28‑day periods for analysis. Changes from baseline will be calculated using descriptive statistics and appropriate inferential methods as defined in the statistical analysis plan.