The key objective of this study is to investigate whether modulation of cortical excitability by AEDs (such as levetiracetam), can be reliably measured using TMS-EMG and TMS-EMG in patients with epilepsy. Thereby, this study will assess whether TMS-…
ID
Bron
Verkorte titel
Aandoening
Epilepsy
Ondersteuning
Onderzoeksproduct en/of interventie
Uitkomstmaten
Primaire uitkomstmaten
TMS-EMG (MEP) and TMS-EEG (TEP) response measured by:
- Motor evoked potential (MEP)
o Resting motor threshold (rMT) – (percentage 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 lSl (TR/CR%)), measured at a 50, 100 and 300 ms interval.
o Short intracortical inhibition (SlCl) - (percentage ratio of the mean peak-to-peak amplitude of the response to the second pulse (TR)
and an unconditioned pulse (MEP) at each lSl (TR/MEP%)), measured a1 a 2 ms interval.
-TMS evoked potential (TEP) using single pulse, and paired pulse TMS at 4 different lSls: 2,50, 100 and 300 ms:
o Amplitude of components - (pV)
N15
P30
N45
P55
N100
P180
Achtergrond van het onderzoek
Transcranial magnetic stimulation (TMS) combined with electromyography (EMG) or electroencephalography (EEG) offers a noninvasive opportunity to study corticospinal excitability. Excitability of the cortex is especially interesting in the pathophysiology of epilepsy, which is considered to be related to cortical hyperexcitability. Different anti-epileptic drugs (AEDs) are known to affect different TMS measures of motor cortical excitability, which makes TMS an interesting biomarker to assess the efficacy of current and new AEDs.
This study is the second part of the TRACE project (Tms-eeg as a biomaRker for phArmacological effects on Cortical Excitability). The aim of the TRACE project is the development of a biomarker for effects of AEDs on cortical excitability, which ideally could be used to measure and also predict treatment efficacy in epilepsy. The first study was performed to investigate the reproducibility of single and paired pulse TMS-EMG and TMS-EEG measures and to investigate the sensitivity of the measurement to detect effects of levetiracetam, valproic acid and lorazepam on cortical excitability in healthy volunteers. This study has been successfully completed, showing effects of all three study drugs on cortical excitability as measured by single and paired TMS-EMG and/or TMS-EEG. This follow-up study will evaluate the effects of levetiracetam on cortical excitability in epilepsy patients as this treatment showed the most
pronounced effects on TMS-EMG and TMS-EEG in the previous study. The ultimate goal is to develop TMS-EMG and TMS-EEG as a biomarker that can assist in personalised treatment of patients with epilepsy. Unfortunately, it is practically and logistically not feasible to include treatment-naïve patients in this study. For this reason, two groups of patients that are stable on mono-therapy will be included, one group on levetiracetam and one on valproic acid. These are common treatments for epilepsy in the Netherlands and based on the previous study we know the effect profile of these drugs, at least in healthy volunteers.
Doel van het onderzoek
The key objective of this study is to investigate whether modulation of cortical excitability by AEDs (such as levetiracetam), can be reliably measured using TMS-EMG and TMS-EMG in patients with epilepsy. Thereby, this study will assess whether TMS-EMG and TMS-EEG could function as a biomarker to track the therapeutic efficacy of treatments aimed at modifying cortical excitability, for example in treatments of epilepsy and amyotrophic lateral sclerosis (ALS), in which cortical hyperexcitability plays an important role.
Onderzoeksopzet
Up to -42 day – EOS
Onderzoeksproduct en/of interventie
Group 1:
First dosing: levetiracetam 2000 mg or placebo
Second dosing after the last TMS measurement: placebo or levetiracetam 500 mg (subject’s regular dose of levetiracetam)
Group 2:
Levetiracetam 2000 mg or placebo
Publiek
Wetenschappelijk
Belangrijkste voorwaarden om deel te mogen nemen (Inclusiecriteria)
1. Signed informed consent prior to any study-mandated procedure
2. Male or female subjects, 18 to 70 years of age, inclusive at screening, with generalized epileptic seizures.
3. Study participant is currently treated for epilepsy with stable doses of the following for at least 3 months:
a. Group 1: levetiracetam mono-therapy (1000 mg daily)
b. Group 2: valproic acid mono-therapy (up to and including 1000 mg daily)
4. Body mass index (BMI) between 18 and 32 kg/m2, inclusive at screening, and with a minimum weight of 50 kg.
5. All women of child bearing potential must practice effective contraception during the study and be willing and able to continue contraception for at least 90 days after their last dose of study treatment.
6. Has the ability to communicate well with the Investigator in the Dutch language and willing to comply with the study restrictions.
Belangrijkste redenen om niet deel te kunnen nemen (Exclusiecriteria)
1. Evidence of any active or chronic disease or condition, apart from epilepsy, that could interfere with, or for which the treatment of might interfere with, the conduct of the study, or that would pose an unacceptable risk to the subject in the opinion of the investigator (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.
2. 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.
3. Positive Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening.
4. Abnormal findings in the resting ECG at screening defined as:
a. QTcF> 450 msec for males, or >470 for females; or < 300 msec
b. Evidence of atrial fibrillation, atrial flutter, complete branch block, Wolf-Parkinson-White Syndrome, or cardiac pacemaker.
5. Use of concomitant medications (prescription or over-the-counter [OTC]) that could interfere with the study drug or the TMS measurements, within 14 days of study drug administration, or less than 5 half-lives (whichever is longer), as judged by the investigator. This does not include the permitted medication as listed in chapter 4.4 of the protocol.
6. Participation in an investigational drug or device study within 3 months prior to first dosing.
7. History of abuse of addictive substances (alcohol, illegal substances) or current (within the last 6 months) use of more than 21 units alcohol per week, drug abuse, or regular user of sedatives, hypnotics, tranquillizers, or any other addictive agent.
8. Positive test for drugs of abuse at screening or pre-dose.
9. Alcohol will not be allowed from at least 24 hours before screening or pre-dose.
10. Use of tobacco or nicotine products within 24 before the dose administration.
11. A previous significant allergic reaction (urticaria or anaphylaxis) to levetiracetam.
12. Loss or donation of blood over 500 mL within three months (males) or four months (females) prior to screening or intention to donate blood or blood products during the study, or plasma donation within 2 weeks of screening.
13. If a woman, pregnant, or breast-feeding, or planning to become pregnant during the study.
14. Any known factor, condition, or disease that might interfere with treatment compliance, study conduct or interpretation of the results such as drug or alcohol dependence or psychiatric disease.
15. The subject has a history of intracranial mass lesion, hydrocephalus and/or clinically significant head injury or trauma that could increase the risk of applying TMS.
16. The subject has metal objects in brain or skull.
17. The subject has a cochlear implant or deep brain stimulation device.
18. The subject has abnormal sleeping patterns (eg, working night shifts).
19. The subject has an rMT of more than 83% of the maximum stimulator output, measured using TMS-EMG during screening.
20. History of side effects related to levetiracetam administration that would pose an unacceptable risk to the subject in the opinion of the investigator, such as suicidality.
Opzet
Deelname
Voornemen beschikbaar stellen Individuele Patiënten Data (IPD)
Toelichting
Opgevolgd door onderstaande (mogelijk meer actuele) registratie
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In overige registers
Register | ID |
---|---|
NTR-new | NL8335 |
CCMO | NL71944.056.19 |
OMON | NL-OMON49353 |