CX-8998 for Absence Seizures
Condition: Epilepsy
MeSH terms: Epilepsy; Seizures; Epilepsy, Absence
Intervention: CX-8998
Intervention description: T-type calcium channel blocker
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 7.0
Sex: All
Minimum age: 16 Years
Maximum age: 55 Years
Healthy volunteers: No
Keywords: Epilepsy, Idiopathic Generalized Epilepsy, Absence Seizures

Summary:

      This is a Phase 2a, open-label study consisting of a screening period of up to 4 weeks and a
      4-dose-titration treatment period to a dose of up to 10 mg twice daily (BID) of CX-8998,
      followed by a 1-week safety follow-up period after the last dose of study medication.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Signed informed consent form (ICF) indicating that the subject has been informed of
             the procedures to be followed, the experimental nature of the therapy, alternatives,
             potential benefits, side effects, risks, and discomforts.

          2. Men or non-pregnant, non-breastfeeding women 16 to 55 years-of-age who are able to
             read and understand written and spoken local language.

          3. Clinical diagnosis of IGE (including, but not limited to, CAE, JAE, juvenile myoclonic
             epilepsy, or Jeavons syndrome) with absence seizures consistent with the International
             League against Epilepsy Revised Classification of Seizures (2017).

          4. Absence seizures persisting despite standard of care (SOC) treatment, defined as
             treatment with at least 2 AEDs appropriate for the patient's epilepsy syndrome. SOC
             failure, per investigator discretion, will be defined as insufficient clinical
             response or intolerable side effects, which precludes use of the appropriate AED.

          5. Observation of at least 3 instances of generalized discharges of approximately 2.5 - 4
             Hz lasting ≥2 seconds via 24-hour ambulatory EEG (centrally reviewed), with
             approximately 75% normal background based on age and medication use per the central
             EEG reader's discretion. Intermittent focal spikes are allowed.

          6. On stable doses of one or more antiepileptic medication(s) for at least 30 days. If a
             subject is not on medication, adequate documentation justifying lack of therapy may be
             acceptable for the subject after sponsor review. Ketogenic, modified Atkins diet
             (MAD), or low glycemic diet with stable carbohydrate ratio for at least 30 days before
             screening is an acceptable antiepileptic therapy. Vagal nerve stimulation at stable
             settings (for at least 30 days before screening), without use of the magnet, is also
             acceptable.

          7. Body weight ≥ 45 kg at screening.

          8. Subjects with reproductive capability including all males and women of child-bearing
             potential (WOCBP) must agree to practice continuous abstinence or adequate
             contraception methods (appropriate double barrier method or oral, patch, implant, or
             injectable contraception) from as soon as feasible during screening period until at
             least 30 days after the last dose (i.e., intermittent abstinence based on "rhythm",
             temperature monitoring, or other means of timing is not acceptable). WOCBP include any
             woman who has experienced menarche and who has not undergone successful surgical
             sterilization (hysterectomy, bilateral tubal ligation, and/or bilateral oophorectomy)
             or is not post-menopausal. Post-menopausal is defined as amenorrhea ≥ 12 consecutive
             months without another cause, and a documented serum follicle stimulating hormone
             (FSH) level ≥ 35 mIU/mL.

          9. Male subjects with a partner of child-bearing potential must be surgically sterilized
             or be willing to use condoms with spermicide from as soon as feasible during screening
             period until at least 30 days after the last dose.

         10. Able and willing to comply with scheduled visits, treatment plan, laboratory tests,
             and other study procedures.

         11. Approval by the sponsor medical personnel or delegate as to final eligibility for the
             study.

        Exclusion Criteria:

          1. History of surgical intervention for treatment of epilepsy.

          2. Additional seizure (clinical and electrographic) types, including, but not limited to,
             epileptic spasms, generalized tonic seizures, atonic seizures, or focal seizures.
             Subjects with GTCS or myoclonic seizures are eligible for the study.

          3. Inadequately treated psychotic or mood disorder (e.g., schizophrenia, major
             depression, bipolar disorder).

          4. Presence of severe intellectual disability, severe autism spectrum disorder, or severe
             developmental disorder such that the subject cannot sign the ICF or cannot cooperate
             with the study procedures.

          5. Presence of positive urine drug screen for drugs of abuse, except if this is explained
             by use of an allowed prescription medicine.

          6. Regular use of more than 2 standard drinks of alcohol per day (28 grams of pure
             alcohol).

          7. Hypersensitivity/allergic reaction to other T-type calcium agents, such as (but not
             limited to) ethosuximide and zonisamide.

          8. Use of strong CYP3A4 inhibitors, including prescription or non-prescription drugs or
             other products (i.e. grapefruit juice), which cannot be discontinued at least 2 weeks
             prior to Day 1 of dosing and throughout the study (Appendix C).

          9. Concurrent illnesses that would be a contraindication to trial participation,
             including, but not limited to:

               1. Severe arterial thromboembolic events (myocardial infarction, unstable angina
                  pectoris, stroke) less than 6 months before screening

               2. NYHA Class III or IV congestive heart failure, ventricular arrhythmias or
                  uncontrolled hypertension

               3. Clinically significant ECG abnormality per the Investigator assessment or any of
                  the following: i) QTcF ≥450 msec (males) or ≥470 msec (females) ii) PR interval
                  ≥250 msec iii) Atrioventricular block of second degree or higher, including
                  Mobitz I iv) Persistent sinus bradycardia ≤ 50 beats per minute; persistent means
                  the bradycardia is present on the first ECG and on one repeat ECG performed on
                  another day v) For other ECG findings (e.g., including, but not necessarily
                  limited to, tachycardia, bundle branch block, frequent ectopic beats, etc.) the
                  Investigator should send a scanned, identity-blinded copy of the ECG tracing to
                  the Study Safety Representative for review.

         10. Positive result for HIV, Hepatitis B [indicating ongoing infection], or Hepatitis C at
             screening or otherwise known ongoing infection with HIV, hepatitis B, or hepatitis C,
             unless curative therapy completed; for hepatitis C curative therapy is defined as
             negative PCR for HCV RNA.

         11. Significant hepatic (AST/ALT or bilirubin ≥ 2X upper limit of normal) or renal disease
             (creatinine clearance ≤39 mL/min) at screening.

         12. History of alcohol or substance abuse within the last year.

         13. A current C-SSRS score of 4 or 5 at screening or history of suicide attempt.

         14. Psychological, social, familial, or geographical reasons that would hinder or prevent
             compliance with the requirements of the protocol or compromise the informed consent
             process.

         15. Any other condition and/or situation that causes the Investigator or Study Safety
             Representative to deem a subject unsuitable for the study (including, but not limited
             to, expected study medication non-compliance, inability to medically tolerate the
             study procedures, or a subject's unwillingness to comply with study-related
             procedures).

         16. Treatment with an investigational agent within 30 days prior to the first dose of
             CX-8998 or planning to receive an investigational agent during the study.