Epilepsy epileptic seizures
Conditions
Interventions
-Valproic acid oral solution 1000 mg single oral dose
-Levetiracetam oral solution 2000 mg single oral dose
-Lorazepam capsule 2 mg single oral dose
- Placebo
Sponsors
Centre for Human Drug Research
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Healthy male subjects, 18 to 45 years of age, inclusive. Healthy status is defined by absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, hematology, blood chemistry, and urinalysis. 2. Body mass index (BMI) between 18 and 32 kg/m2, inclusive, and with a minimum weight of 50 kg. 3. Able to participate and willing to give written informed consent and to comply with the study restrictions.
Exclusion criteria
Exclusion criteria: 1. Legal incapacity or inability to understand or comply with the requirements of the study. 2. Positive test for drugs of abuse at screening or pre-dose. 3. History (within 3 months of screening) of alcohol consumption exceeding 2 standard drinks per day on average (1 standard drink = 10 grams of alcohol). Alcohol consumption will be prohibited during study confinement and at least 24 hours before screening, before dosing, and before each scheduled visit. 4. History or symptoms of any significant disease including (but not limited to), neurological, psychiatric, endocrine, cardiovascular, respiratory, gastrointestinal, hepatic, or renal disorder. 5. A history of epilepsy or febrile seizures. 6. Having metal objects in brain or skull. 7. Having a cochlear implant or implanted deep brain stimulator. 8. Abnormal sleeping pattern (e.g. working night shifts) 9. Resting motor threshold (rMT) of more than 83% of the maximum stimulator output, measured using TMS-EMG during screening. 10. History of active malignancy within the last 5 years, with the exception of localized or in situ carcinoma (e.g., skin basal or squamous cell carcinoma). 11. Positive Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening. 12. Systolic blood pressure (SBP) greater than 140 or less than 90 mmHg, and diastolic blood pressure (DBP) greater than 90 or less than 50 mmHg. 13. Use of any medications (prescription or over-the-counter [OTC]), vitamin, mineral, herbal, and dietary supplements within 14 days of study drug administration, or less than 5 half-lives (whichever is longer). Exceptions will only be made if the rationale is discussed and clearly documented by the Investigator. 14. Clinically significant abnormalities, as judged by the Investigator, in laboratory test results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis). In the case of uncertain or questionable results, tests performed during screening may be repeated before randomization to confirm eligibility or judged to be clinically irrelevant for healthy subjects. 15. Participation in an investigational drug or device study within 3 months prior to screening. 16. Any blood donation or other loss of blood greater than 500 mL within 3 months of screening or plasma donation within 2 weeks of screening. 17. Concomitant disease or condition that could interfere with, or for which the treatment of might interfere with, the conduct of the study, or that would, in the opinion of the Investigator, pose an unacceptable risk to the subject in this study (following a detailed medical history, physical examination, vital signs (systolic and diastolic blood pressure, pulse rate, body temperature) and 12-lead electrocardiogram (ECG)). Minor deviations from the normal range may be accepted, if judged by the Investigator to have no clinical relevance. 18. Use of tobacco or nicotine products within the previous month before the first dose administration. 19. Clinically significant abnormalities in ECG, as judged by the Investigator, including evidence of atrial fibrillation, atrial flutter, complete branch block, Wolf-Parkinson-White Syndrome, or cardiac pacemaker. 20. Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any drug, or multiple drug allergies (non-active hay fever is acceptable). 2
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| TMS-EMG (MEP) and TMS-EEG (TEP) response measured by: - Motor evoked potential (MEP): o Resting motor threshold (rMT) * (% of maximal output) o Peak-to-peak amplitude (µV) o Long intracortical inhibition (LICI) * (percentage ratio of the mean peak-to-peak amplitude of the response to the second pulse (TR) and the first conditioning pulse (CR) at each ISI (TR/CR%)), measured at 50, 100, 150, 200, 250 and 300 ms intervals o Short intracortical inhibition (SICI) * (percentage ratio of the mean peak-to-peak amplitude of the response to the second pulse (TR) and an unconditioned pulse (MEP) at each ISI (TR/MEP%)), measured at 2 and 5 ms intervals. - TMS evoked potential (TEP), measured on the Cz electrode with single pulse and paired pulse TMS at 8 different ISIs: 2, 5, 50, 100, 150, 200, 250 and 300 ms. o Amplitude of components - (µV) - N15 - P30 - N45 - P55 - N100 - P180 | — |
Secondary
| Measure | Time frame |
|---|---|
| Safety and tolerability endpoints - Treatment-emergent (serious) adverse events ((S)AEs). - Concomitant medication Pharmacokinetic endpoints The following endpoints will be determined for levetiracetam, valproic acid and lorazepam following each treatment. They will be derived by non-compartmental analysis of the plasma concentration-time data: - The area under the plasma concentration-time curve from zero to infinity(AUC0-inf); - The maximum plasma concentration (Cmax); - The area under the plasma concentration-time curve from zero to t of the last measured concentration above the limit of quantification (AUC0-last); - The time to reach maximum plasma concentration (tmax); - The terminal disposition rate constant (*z) with the respective half-life (t*). - Other parameters, including Vz/F, CL/F, and other parameters as appropriate, as well as dose adjusted parameters, may be determined. | — |
Countries
Netherlands
Outcome results
None listed