Randomized, double-blind, double-dummy, placebo-controlled, four-way crossover single dosestudy to determine the test-retest reliability of, and the effect of oral valproic acid, levetiracetam and lorazepam on, cortical excitability measurements in healthy volunteers as measured by TMS-EEG and TMS-EMG

Recruiting

Conditions: Epilepsy, epileptic seizures

Registration Number: NL-OMON28239

Lead Sponsor: Centre for human drug research

Brief Summary: A

Detailed Description: Not available

Recruitment & Eligibility

Status: Recruiting

Sex: Not specified

Target Recruitment: 16

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.

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.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
TMS-EMG (MEP) and TMS-EEG (TEP) response measured by:<br /><br>- Motor evoked potential (MEP):<br /><br>o Resting motor threshold (rMT) – (% of maximal output)<br /><br>o Peak-to-peak amplitude (μV)<br /><br>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<br /><br>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.<br /><br>- 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.<br /><br>o Amplitude of components - (μV)<br /><br>- N15<br /><br>- P30<br /><br>- N45<br /><br>- P55<br /><br>- N100<br /><br>- P180<br>

Secondary Outcome Measures

Name	Time	Method
Safety and tolerability endpoints<br /><br>- Treatment-emergent (serious) adverse events ((S)AEs).<br /><br>- Concomitant medication<br /><br>Pharmacokinetic endpoints<br /><br>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:<br /><br>- The area under the plasma concentration-time curve from zero to infinity(AUC0-inf);<br /><br>- The maximum plasma concentration (Cmax);<br /><br>- The area under the plasma concentration-time curve from zero to t of the last measured concentration above the limit of quantification (AUC0-last);<br /><br>- The time to reach maximum plasma concentration (tmax);<br /><br>- The terminal disposition rate constant (λz) with the respective half-life (t½).<br /><br>- Other parameters, including Vz/F, CL/F, and other parameters as appropriate, as well as dose adjusted parameters, may be determined.<br>