A Double-blind, Randomized Clinical Trial Evaluating the Efficacy and Safety of Vormatrigine in Adults with Focal Seizures

Prior treatment

• E 12. Has received any other experimental or investigational drug, device or other therapy within 30 days or 5 half-lives (whichever is longer) prior to Screening, or any prior use of gene or cell therapy.
• E 14. Felbamate: If used as a concomitant ASM, patients must be on felbamate for at least 2 years, with a stable dose for 2 months prior to Screening. If a patient received felbamate in the past, it must have been discontinued 2 months prior to screening.
• E 15. Patient is receiving prohibited medication(s) as per the prohibited concomitant medications section of the protocol (including Appendix 4).
• E 18. Previous exposure to vormatrigine or known hypersensitivity to any component used in the vormatrigine formulation.
• E 3. Previously documented EEG which shows any pattern not consistent with focal etiology of seizures (a new EEG is not required, if not available).
• E 5. History of any of the following: a) neurosurgery for seizures <1 year prior to enrollment b) radiosurgery <2 years prior to enrollment c) neurostimulator placed <1 year prior to Screening d) neurostimulator placed >1 year prior to Screening but settings have not been stable for at least 2 months prior to Screening

Other illness

• E 1. Participant has had any of the following within the 12-month period preceding trial entry: a) evidence of experiencing pseudo or psychogenic seizures b) cluster seizures where the individual seizures cannot be counted c) an episode of convulsive status epilepticus requiring hospitalization and intubation d) seizures secondary to illicit drug or alcohol use
• E 11. History of or active HIV infection or positive screening result for: HIV 1 or 2 antibodies. Evidence of active hepatitis B or hepatitis C infection, as determined by relevant screening assessments.
• E 16. Significant allergic reaction to an ASM(s), including dermatological (e.g. Stevens-Johnson syndrome), hematological, or organ toxicity reactions. Severe reactions do not include simple maculopapular eruption and allergic rhinitis.
• E 2. Seizures secondary to ongoing infection, neoplasia, demyelinating disease, progressive degenerative disease, metabolic illness deemed progressive, progressive structural lesion or encephalopathy. Evidence by CT or MRI for a progressive cause of epilepsy.
• E 4. Planned epilepsy surgery during the course of the clinical trial.
• E 6. Active suicidal plan/intent in the past 6 months, or a history of suicide attempt in the last 2 years, or more than 1 lifetime suicide attempt, as confirmed by C-SSRS.
• E 8. Participants with a history of malignancy, myeloproliferative or lymphoproliferative disorders within the past 3 years are excluded. Exceptions:1) Participants with completely excised non-melanoma skin cancer (such as basal cell carcinoma or squamous cell carcinoma), cervical carcinoma in situ, ductal breast carcinoma in situ, are permitted at any time, or 2) Participants with a history of other malignancies deemed cured by adequate treatment are also permitted at any time. Participants with a history of indolent or early-stage malignancies that are unlikely to progress or other malignancies deemed cured by adequate treatment are also permitted at any time.

Lab values

• E 10. Total bilirubin value >1.5×ULN; an ALT or AST value >3×ULN. As an exception, participants that present with elevated bilirubin in the absence of elevations in ALT or AST that fits the pattern of Gilbert’s syndrome may be enrolled after discussion with the medical monitor and/or sponsor designee if their conjugated bilirubin is below the ULN.
• E 17. Is pregnant or breastfeeding at the time of Screening or has a positive serum pregnancy test at Screening or is planning to become pregnant during the clinical trial or prior to end of study visit.
• E 7. Has any significant ongoing disease, disorder, laboratory abnormalities, alcohol or drug abuse or dependence, environmental factor, or ongoing or recent history of any psychiatric, medical, or surgical condition that in the judgement of the investigator in consultation with the medical monitor and/or sponsor designee, might jeopardize the participant’s safety or influence or confound the clinical trial objectives.
• E 9. History or presence of uncontrolled cardiac diseases including conduction and structural abnormalities (e.g. family history of sudden death, long QT syndrome, familial short QT syndrome, Brugada syndrome, myocardial infarction, or sustained ventricular arrythmia, etc.) which may place patients at increased risk as determined by the investigator.

Other

• E 13. Vigabatrin: Use in the last 5 years without stable visual fields tested twice over the 12 months after the last dose of vigabatrin.

• I 1. Participant and caregiver, if applicable, is willing to sign an informed consent document in accordance with ICH/GCP guidelines, indicating that they understand the purpose of the clinical trial; understands, and can perform, complete, and comply with all the procedures and assessments that are required during the clinical trial, including the seizure diary and is willing and able to adhere to the contraception methods (defined in Section 5.4.3 and Section 5.4.4), as applicable, and is willing to participate in the clinical trial.
• I 2. Aged ≥18 to ≤85 at the time of consent for this trial.
• I 3. Has a diagnosis of focal onset epilepsy according to the International League Against Epilepsy Classification of Epilepsy (2017).
• I 4. Prior to randomization, past evidence by CT or MRI that has ruled out a progressive cause of epilepsy in the judgement of the investigator and/or in consultation with the medical monitor.
• I 5. Participant must attest to be taking stable doses of 1 or up to 3 acceptable ASMs (none listed as a prohibited concomitant medication) for at least 4 weeks prior to screening and during screening prior to Day 1. ASM doses should not be greater than the maximum indicated daily dosage in the local product information.
• I 6. Has at least XXX countable focal onset seizures during the XXX weeks of Observation Period immediately prior to randomization with no more than XXX days seizure free during this period.
• I 7. Seizure diary must be completed for ≥80% days in the Observation Period.