Effects of Lacosamide on Human Motor Cortex Excitability: a Transcranial Magnetic Stimulation Study

Study Overview
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Brief Summary
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This study has been designed to explore dose-depended effects of lacosamide (LCM) on motor cortex excitability with TMS in a randomized, double-blind, placebo-controlled crossover trial in young healthy human subjects, and to compare the pattern of excitability changes induced by LCM with those of carbamazepine (CBZ). LCM selectively enhances slow inactivation of voltage-gated sodium channel, and, in contrast to CBZ, does not affect steady-state fast inactivation (Errington et al., 2006). The enhancement of slow inactivation of sodium channels by LCM is a novel manner to modulate sodium channels and leads to normalization of activation thresholds and a reduced pathophysiological hyper-responsiveness, thereby effectively controlling neuronal hyperexcitability without affecting physiological activity (Beyreuther et al., 2007). Therefore, it is thought that LCM, compared to CBZ, will be better tolerated in clinical settings while being as or even more effective in controlling seizure activity. On the basis of the results from nonhuman studies, it is hypothesized that the TMS profile of LCM will be distinguishable from that of CBZ. CBZ, like other 'classical' sodium channel blockers such as phenytoin, predominantly demonstrated elevated TMS motor thresholds indicating reduced neuronal membrane excitability, without developing significant changes of synaptic intracortical inhibition and facilitation (Ziemann et al., 1996; Chen et al., 1997; Lee et al., 2005). Because of its novel mode of action it can only be speculated which TMS parameters LCM might affect. For example, more than exclusively affecting neuronal membrane excitability, LCM could possibly also affect inhibitory mechanisms such as short- and long-latency intracortical inhibition (Valls-Sole et al., 1992; Kujirai et al., 1993). This would in line with other well-tolerated modern antiepileptic drugs (Ziemann et al., 1996; Reis et al., 2002; Lang et al., 2006).

Conditions
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Healthy Male Volunteers

Intervention / Treatment
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* Drug: Lacosamide
* Drug: Placebo
* Drug: Carbamazepine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: healthy male right-handed aged 18-45 years Exclusion Criteria: cardiac pacemaker metal implants in the head intake of any medication previous neurologic, psychiatric, or chronic internal diseases pregnancy or breastfeeding; drug, nicotine, or alcohol abuse known or expected intolerance to soy beans, peanuts, LCM or CBZ; abnormal ECG with prolonged PQ-interval participation in another clinical trial within the previous 8 weeks

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo arm | Drug: Placebo<br>* Placebo<br>|
| Experimental: Lasosamide 200<br>Lacosamide 200 mg | Drug: Lacosamide<br>* Lacosamide 200 or 400 mg<br>|
| Experimental: Lacosamide 400<br>Lacosamide 400 mg | Drug: Lacosamide<br>* Lacosamide 200 or 400 mg<br>|
| Active Comparator: Carbamazepine 600<br>Carbamazepine 600 mg | Drug: Carbamazepine<br>* Carbamazepine 600 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TMS measures of cortical excitability | Transcranial magnetic stimulation (TMS) measurements included resting motor thresholds (RMT) and active motor thresholds (AMT), the intensity to evoke MEP of ∼1mV peak-to-peak amplitude (SI1mV), short-interval intracortical inhibition/intracortical facilitation (SICI/ICF), long-interval intracortical inhibition (LICI), short-interval intracortical facilitation (SICF), recruitment curves, MEP under tonic activation (aMEP), and cortical silent period (CSP), and MEP changes in response to short trains of repetitive TMS. | within 24h after intake of study medication | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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threshold, lacosamide, carbamazepine, placebo, transcranial magnetic stimulation, TMS, motor cortex, sodium channel, inhibition