Safety and Tolerability Study of SPN-817 in Adult Patients With Treatment Resistant Epilepsy

Inclusion criteria

• A diagnosis of treatment resistant epilepsy as adjudicated by the Epilepsy Study Consortium.
• Is male or female, aged 18 to ≤ 70 years at screening.
• Is able to read, understand, and sign the Informed Consent Form (ICF). If the participant is unable to sign informed consent, a Legally Authorized Representative (LAR) will complete the ICF.
• Ability to keep accurate seizure diaries (with the aid of a caregiver as needed).
• Weight within the normal or overweight ranges according to accepted values of the Body Mass Index Chart (18.0 to 40 kg/m2).
• Is able to swallow capsules whole without crushing, chewing, or cutting.
• Is willing to adhere to all study procedures and able to attend study visits within the specified time windows.
• Failure of at least 2 tolerated, appropriately chosen and adequately dosed ASM drug schedules to achieve sustained seizure freedom.
• Taking at least 1 ASM at Screening and Baseline. If following a diet plan along with the ASM, the participant should have been on a stable diet plan for at least 1 month prior to screening (Visit 1). The diet plan should be maintained throughout the duration of the study. Participants on a ketogenic diet will not be permitted to participate in the intense PK group.
• At least 4 seizures accepted by the Epilepsy Study Consortium for the secondary outcome (adjudicated as "probable seizures" that are countable) during the 42-day baseline seizure diary period, and no more than a 21-day period that was seizure-free.
• A clinical diagnosis of Focal Cortical Dysplasia (FCD) Type I or Type II (approximately n=10) confirmed by:
• Likely FCD supported by neuroimaging that has been performed in the last 5 years, or
• History of surgical resection of the cortical dysplasia that is histopathologically confirmed in patients who continue to have uncontrolled seizures without a compelling alternate explanation for ongoing seizures.
• Note: The Epilepsy Study Consortium will review to confirm FCD/probable FCD diagnosis.
• Be in good general health as per PI's judgment based upon medical history, physical exams, standard 12-lead ECG, and clinical laboratory evaluations obtained during the Screening Period
• Be able to comply with and complete all study-specified procedures; enrollment for participants with limited ability to complete self-reported questionnaires or cognitive assessments may be permitted on a case-by-case basis after approval by the MM and Sponsor
• Non-pregnant females of childbearing potential (FOCP) who are either in an exclusive same-sex relationship or sexually inactive (abstinent), or if sexually active with a male partner who is biologically capable of having children, must agree to use one of the following acceptable birth control methods beginning 30 days prior to the first dose of SPN-817, throughout the study, and for 30 days following the last dose:
• Simultaneous use of male condom and intra-uterine contraceptive device (IUD) placed at least 4 weeks prior to first SPN-817 administration
• Surgically sterile male partner (6 months minimum)
• Simultaneous use of any male barrier (condom) combined with any female barrier
• Established hormonal contraceptive
• Female participants are considered not to be of childbearing potential if they are either postmenopausal (amenorrhea for at least 2 years and serum follicle-stimulating hormone \[FSH\] level of \>40 IU/L) or permanently sterilized (eg, bilateral tubal ligation, hysterectomy, bilateral oophorectomy) for 6 months minimum.
• Males must:
• Use 2 methods of contraception in combination if his female partner is of childbearing potential; this combination of contraceptive methods must be used from the screening visit to 90 days after the last dose of SPN-817, or
• Have been surgically sterilized (6 months minimum) prior to the screening visit
• Refrain from donating any sperm from the first administration of SPN-817 until 90 days after the last dose of SPN-817
• Males who are in same-sex partner relationships or with those who are not biologically capable of having children are required to use a condom from the first dose through 7 days after the last dose of the SM.

Exclusion criteria

• Has taken huperzine A within the past year
• Is planning to become pregnant or impregnate spouse, not using an acceptable method of birth control (defined as use of double-barrier birth control methods, use of oral contraceptives, or surgical sterilization), pregnant, or nursing.
• Participants with Lennox-Gastaut syndrome. Participants should also be excluded in case of nondiagnostic information.
• Has non-epileptic events that could be confused by the patient and/or study staff as epileptic seizures.
• Has only seizures that are difficult to count; for example, has seizures that are not clinically observable.
• Has a history of only seizure clusters, for example, seizure clusters defined as multiple seizures with at least one seizure within 30 minutes of the previous seizure.
• Has a history of status epilepticus in the 6 months prior to Screening.
• Change in ASM regimen in the last 28 days prior to screening. No changes in ASMs are allowed during the Screening, Titration/Optimization, or Maintenance Period. Changes in ASM regimen (including any diet plan used as an ASM) are allowed during the OLE Period only.
• Vagus nerve stimulation (VNS), deep brain stimulation (DBS), responsive neurostimulator system (RNS), or other neurostimulation for epilepsy device implanted or activated \<1 year prior to screening; stimulation parameters that have been stable for \<3 months; or epilepsy surgery \<1 year prior to screening.
• Any suicidal behavior or suicidal ideation of type 4 (active suicidal ideation with some intent to act without specific plan) or type 5 (active suicidal ideation with specific plan and intent) based on the C-SSRS in the 2 years before screening; a history of suicide attempt in the last 2 years; or more than 1 lifetime suicide attempt.
• Any condition that may impact a patient's ability to follow study procedures or a patient's safety, based on what is known about the pharmacology/toxicology profile of the trial agent(s).
• Has a pre-existing medical condition (including an existing progressive or degenerative neurological disorder including brain tumor, active encephalitis, active meningitis or abscess) or takes medications that, in the PI's opinion, could interfere with the patient's suitability for participation in the study.
• Has a history or evidence of current significant psychiatric disturbance (e.g., schizophrenia, schizoaffective, or bipolar disorder) that would preclude meaningful participation in the study procedures.
• Has a history in the past 2 years or evidence of current alcohol and/or substance use disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders 5th edition.
• Has had any clinical laboratory abnormalities within the 2 months prior to screening considered of clinical significance by the PI.
• Is human immunodeficiency virus (HIV)/Hepatitis B/Hepatitis C positive or has a positive urine drug screen (UDS) with the following considerations:
• Participants who have a diagnosis of cannabis use disorder (per DSM-5) within 6 months before Screening and have a positive UDS for cannabis at Screening will be excluded. At the discretion of the Sponsor, recreational use of cannabis is allowed and should be kept consistent during the study. Participants must agree to refrain from using cannabis 48 h prior to the study visits.
• Cannabis (including cannabidiol \[CBD\] products) prescribed for a medical condition or used as an ASM is allowed if taken at a stable regimen for at least 28 days prior to Screening. Newly prescribed cannabis treatment and/or a change to the existing regimen is prohibited. When applicable, participants should show proof of their prescription for medical cannabis.
• Participants who also test positive for specific medications (benzodiazepines, amphetamines, etc.) must show proof of the prescription and should not be excluded due to a positive UDS if the positive UDS is related to a prescribed medication.
• Is on concomitant therapy with non-ASMs that are cholinergic prior to Visit 5
• Is currently taking or within the 3 days prior to first administration of SPN-817 has taken over-the-counter supplements containing epigallocatechin gallate (EGCG) such as concentrated green tea extracts or products containing synthetic EGCG, or foods containing \> 100 grams of carob powder. Also current or within the 3 days prior the first administration of SPN-817, excessive consumption (\> 3 cups per day) of foods or drinks containing EGCG (eg, all green, white, or oolong teas and all black teas) is prohibited.
• Has participated in any clinical investigational drug or device study within 4 weeks prior to study entry or within 5 half-lives of the clinical investigational drug, whichever is longer.
• Clinically significant cardiologic abnormalities at screening. One repeat assessment is allowed per Investigator discretion.
• Abnormal ECG that is, in the Investigator's opinion, clinically significant including:
• Heart rate (HR) \<50 bpm
• PR interval \>220 ms
• QRS interval ≥120 ms
• QTcF (QT interval corrected for heart rate using Fridericia's method) \>450 ms for males and \>470 ms for female participants
• Second or third-degree atrioventricular block
• Any rhythm, other than sinus rhythm, that is interpreted by the Investigator to be clinically significant
• Has abnormal renal function as demonstrated by estimated glomerular filtration rate (eGFR) of \<60 mL/min according to the eGFR Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation at screening.
• Clinically significant vital signs abnormalities (systolic blood pressure \<90 or \>140 mmHg, diastolic blood pressure \<50 or \>90 mmHg, or HR \<50 or \>100 bpm) at screening.
• Participant has had \>2 allergic reactions to an ASM or 1 serious hypersensitivity reaction to an ASM.
• Participants who donated 50-499 mL of blood within 30 days or \>499 mL within 56 days prior to Day 1 administration or have hemoglobin \<128 g/L (male) or \<115 g/L (female) and hematocrit \<0.37 L/L (males) or \<0.32 L/L (female) at screening. Following screening and throughout the study, participants should not donate blood.
• Any reason which, in the opinion of the PI, would prevent the participant from participating in the study.