Phase 2a Open‑Label Study of Adjunctive PTI5803 (Probenecid) in Adolescents and Adults (≥14 y) With Drug‑Resistant Seizures Due to Focal Cortical Dysplasia

The primary objective is to evaluate safety, including drug‑drug interactions and tolerability, of PTI5803 administered as adjunctive therapy in patients with drug-resistant seizures associated with focal cortical dysplasia, thereby informing the risk profile of this treatment approach. Secondary objectives include:

• Assessment of the pharmacokinetics of probenecid in plasma following multiple ascending oral doses to refine PTI5803 PK modeling.
• Evaluation of the impact of PTI5803 on Quality of Life and Clinical Global Impression of severity and improvement.
• Investigation of early signals of clinical efficacy by measuring changes in seizure frequency using a seizure diary.
• Examination of the usability of the dosing Spoonbox® device.

The trial enrolled males and females aged 14 to 55 years who met the definition of drug‑resistant seizures associated to focal cortical dysplasia. Participants were required to have a body weight of at least 50 kg and a BMI not exceeding 40 kg/m², and to be in generally stable health without major ongoing medical conditions. Eligibility required a documented history of seizures for a minimum of two years, at least four countable focal seizures per 28 days during the prior three months, and stable use of one to three antiseizure medications (excluding recent changes in VNS settings or benzodiazepine use). Female participants of child‑bearing potential had to commit to highly effective contraception, while non‑child‑bearing females were defined by surgical sterilisation or menopause. Normal dietary habits were required, with no ketogenic diet for at least three months before enrolment. The sponsor did not provide information on the total number of participants. Selection was based on the outlined inclusion criteria and investigator judgment regarding suitability for the study.

The study is a Phase 2a, multicenter, open‑label investigation evaluating the safety, tolerability, pharmacokinetic/pharmacodynamic profile and preliminary efficacy of the oral, prolonged‑release granule formulation PTI5803 (containing probenecid) as adjunctive therapy in participants aged 14–55 years with drug‑resistant seizures associated to focal cortical dysplasia. The design incorporates a three‑dose escalation regimen administered orally in 16 ml increments, with each dose level maintained for approximately 28 ± 7 days before escalation, followed by an optional open‑label extension. The overall trial timeline spans from the estimated recruitment start on 2 January 2027 to the projected end on 30 September 2028. Participants undergo a screening visit to confirm eligibility, including seizure‑diary verification, MRI or histologic confirmation of focal cortical dysplasia, and stable antiseizure‑medication dosing; baseline assessments of vital signs, laboratory values, ECG, and concomitant drug levels are performed prior to the first dose. Subsequent study visits occur at the end of each dose‑level period to collect safety data, plasma probenecid concentrations, seizure frequency, quality‑of‑life questionnaires, and device‑usability feedback, with a final end‑of‑study visit after completion of the escalation phase or earlier if discontinuation criteria are met. Expected participant involvement extends for roughly three months of active dosing plus additional follow‑up, totaling approximately 4–5 months. Early termination may be initiated for clinically significant adverse events, intolerable toxicity, marked laboratory or ECG abnormalities, increase in suicide risk, substantial drug‑drug interaction effects, or participant withdrawal of consent or failure to comply with protocol‑required procedures.

The investigational product, identified as PTI5803, comprises PROBENECID formulated as prolonged‑release granules for oral administration. Each dose contains 16 ml of the granule suspension, delivered by mouth. The regimen follows a three‑dose escalation schedule, with each dose level administered once daily throughout the treatment period.

Participants continue their established antiepileptic drug regimen as background therapy. No placebo or alternative comparator is incorporated; standard‑of‑care treatment is maintained to reflect real‑world clinical practice.

Dosing occurs under direct supervision at study visits to ensure adherence. Pill counts and patient diaries are used to monitor compliance. Pharmacokinetic and pharmacodynamic sampling is performed at predefined intervals to characterize drug exposure and interaction with concomitant medications.

Efficacy will be evaluated by comparing seizure frequency during 28 ± 7 day assessment periods with the 28‑day baseline period. The primary efficacy parameters include the mean percentage change in seizure frequency, the proportion of participants achieving ≥50 % or ≥75 % reduction, the proportion seizure‑free, and the mean frequency of bilateral tonic‑clonic seizures. Measurements will be performed at baseline and after each dose escalation of PTI5803.

Additional efficacy assessments comprise patient‑reported outcome instruments administered at baseline and following each dose. Scores from the Quality of Life in Epilepsy questionnaire (QOLIE-31 for adults or QOLIE-AD-41 for adolescents), the Clinical Global Impression – Severity (CGI‑S), Patient Global Impression – Severity (PGI‑S), Clinical Global Impression – Change (CGI‑C), Patient Global Impression – Change (PGI‑C), and the Beck Depression Inventory‑II (BDI‑II) will be compared to baseline values. These tools provide quantitative data on quality of life, global clinical impression, and depressive symptoms, supporting the overall efficacy evaluation.