Clinical trial NCT03406702: CX-8998 for Absence Seizures
Official title: A Phase 2a, Safety, Tolerability, Pharmacokinetics, and Quantitative EEG Study of CX-8998 in Adolescents and Adults With Idiopathic Generalized Epilepsy With Absence Seizures
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Epilepsy
Keywords: Epilepsy, Idiopathic Generalized Epilepsy, Absence Seizures
Lead sponsor: Jazz Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2018-01-23
Enrollment: 7
Sex: ALL
Minimum age (years): 16
Maximum age (years): 55
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

Subjects will participate for a total of up to 9 weeks, including screening, the 4-week treatment period and follow-up.

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.

Primary outcomes:
measure: Change From Baseline to End of Treatment in QT Interval Corrected for Heart Rate Using Fridericia's Formula (QTcF)
timeFrame: Baseline (Day 1) to end of treatment 1-2 hours post-dose, up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Clinical Alanine Aminotransferase Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Clinical Albumin Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Clinical Albumin/Globulin Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Clinical Alkaline Phosphatase Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Clinical Aspartate Aminotransferase Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline Clinical Blood Urea Nitrogen/Creatinine Serum Chemistry Concentration
timeFrame: Baseline (Day 1)
measure: Change From Baseline to End of Treatment in Clinical Bilirubin Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Clinical Blood Urea Nitrogen Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Clinical Carbon Dioxide Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Clinical Chloride Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Clinical Calcium Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Clinical Cholesterol Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline Clinical Cholesterol/HDL-Cholesterol Serum Chemistry Concentration
timeFrame: Baseline (Day 1)
measure: Change From Baseline to End of Treatment in Clinical Creatine Kinase Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Clinical Creatinine Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Clinical Globulin Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline Clinical Glomerular Filtration Rate (GFR) Adjusted for Body Surface Area (BSA) Serum Chemistry Concentration
timeFrame: Baseline (Day 1)
measure: Change From Baseline to End of Treatment in Clinical Estimated Glomerular Filtration Rate (GFR) Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Clinical Glucose Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline Clinical HDL Cholesterol Serum Chemistry Concentration
timeFrame: Baseline (Day 1)
measure: Baseline Clinical LDL Cholesterol Serum Chemistry Concentration
timeFrame: Baseline (Day 1)
measure: Change From Baseline to End of Treatment in Clinical Lactate Dehydrogenase Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Clinical Magnesium Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline Clinical Non-HDL Cholesterol Serum Chemistry Concentration
timeFrame: Baseline (Day 1)
measure: Change From Baseline to End of Treatment in Clinical Phosphate Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Clinical Potassium Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Clinical Protein Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Clinical Sodium Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Clinical Triglycerides Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Clinical Urate Serum Chemistry Concentration
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Basophils Hematology Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Basophils/Leukocytes Hematology Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Eosinophils Hematology Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Eosinophils/Leukocytes Hematology Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Mean Corpuscular Hemoglobin (HGB) Concentration Hematology Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Mean Corpuscular Hemoglobin (HGB) Hematology Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Mean Corpuscular Volume Hematology Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Erythrocytes Hematology Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Erythrocytes Distribution Width Hematology Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Hematocrit Hematology Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Hemaglobin Hematology Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Leukocytes Hematology Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Lymphocytes Hematology Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Lymphocytes/Leukocytes Hematology Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Mean Platelet Volume Hematology Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Monocytes Hematology Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Monocytes/Leukocytes Hematology Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Neutrophils Hematology Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Neutrophils/Leukocytes Hematology Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Platelets Hematology Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline to End of Treatment in Bacteria Urinalysis Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline to End of Treatment in Urine Bilirubin Urinalysis Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline to End of Treatment in Epithelial Cells Urinalysis Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline to End of Treatment in Urine Erythrocytes Urinalysis Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline to End of Treatment in Urine Glucose Urinalysis Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline to End of Treatment in Ketones Urinalysis Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline to End of Treatment in Leukocyte Esterase Urinalysis Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline to End of Treatment in Urine Leukocytes Urinalysis Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline to End of Treatment in Mucous Threads Urinalysis Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline to End of Treatment in Nitrite Urinalysis Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline to End of Treatment in Occult Blood Urinalysis Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline to End of Treatment in Protein Urinalysis Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline to End of Treatment in Specific Gravity Urinalysis Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline to End of Treatment in Specimen Appearance Urinalysis Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Urobilinogen Urinalysis Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline to End of Treatment in pH Urinalysis Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Baseline to End of Treatment in Urine Color Urinalysis Assessment
timeFrame: Baseline (Day 1) to end of treatment, or up to 4 weeks post-dose.
measure: Number (%) of Participants Who Did Not Complete The Study Due to Treatment-Emergent Adverse Events
timeFrame: Baseline (Day 1) up to Day 26 post-dose, or up to 1 year 3 weeks.
measure: Number (%) of Participants With Adverse Events of Special Interest
timeFrame: Baseline (Day 1) up to Day 26 post-dose, or up to 1 year 3 weeks.
measure: Change From Baseline to End of Treatment in Respiration Rate
timeFrame: Baseline (Day 1) to end of treatment 1-2 hours post-dose, up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Temperature
timeFrame: Baseline (Day 1) to end of treatment 1-2 hours post-dose, up to 4 weeks post-dose.
measure: Baseline Weight
timeFrame: Baseline (Day 1)
measure: Change From Baseline to End of Treatment in Pulse
timeFrame: Baseline (Day 1) to end of treatment 1-2 hours post-dose, up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Systolic Blood Pressure
timeFrame: Baseline (Day 1) to end of treatment 1-2 hours post-dose, up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Diastolic Blood Pressure
timeFrame: Baseline (Day 1) to end of treatment 1-2 hours post-dose, up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in QT Interval
timeFrame: Baseline (Day 1) to end of treatment 1-2 hours post-dose, up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in QRS Interval
timeFrame: Baseline (Day 1) to end of treatment 1-2 hours post-dose, up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in PR Interval
timeFrame: Baseline (Day 1) to end of treatment 1-2 hours post-dose, up to 4 weeks post-dose.
measure: Change From Baseline to End of Treatment in Heart Rate
timeFrame: Baseline (Day 1) to end of treatment 1-2 hours post-dose, up to 4 weeks post-dose.
Secondary outcomes:
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Epilepsy Program
state: Arkansas
city: Tampa
country: United States
facility: University of Florida
state: Florida
city: Lexington
country: United States
facility: Bluegrass Epilepsy Research, LLC
state: Kentucky
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: New York
country: United States
facility: NYU Comprehensive Epilepsy Center
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
Study officials:
References: