- To evaluate effects of levetiracetam 2000 mg on single and paired pulse TMS-EMG and TMS-EEG in patients with epilepsy treated with mono-therapy levetiracetam, when compared to placebo (levetiracetam trough concentrations). - To evaluatethe effects…
ID
Source
Brief title
Condition
- Seizures (incl subtypes)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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 ISI (TR/CR%)), measured at a 50 and 100 ms
interval.
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 a 2 ms interval.
- TMS evoked potential (TEP) using single pulse, and paired pulse TMS at 3
different ISIs: 2, 50 and 100 ms:
o Amplitude of components - (µV)
N15
P30
N45
P55
N100
P180
Secondary outcome
NA
Background summary
Transcranial magnetic stimulation (TMS) combined with electromyography (EMG) or
electroencephalography (EEG) offers a non-invasive 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.
Study objective
- To evaluate effects of levetiracetam 2000 mg on single and paired pulse
TMS-EMG and TMS-EEG in patients with epilepsy treated with mono-therapy
levetiracetam, when compared to placebo (levetiracetam trough concentrations).
- To evaluatethe effects of levetiracetam 2000 mg on single and paired pulse
TMS-EMG and TMS-EEG endpoints in levetiracetam-naïve epilepsy patients (using
valproic acid), when compared to placebo (valproic acid trough concentrations)
Study design
This is a randomized, double-blind, two-way cross over study to determine the
effects of levetiracetam on cortical excitability in patients with epilepsy, as
measured by single and paired pulse TMS-EMG and TMS-EEG. Epilepsy patients will
be recruited in two groups: patients using levetiracetam mono-therapy, and
levetiracetam-naïve patients, who are using valproic acid mono-therapy.
Intervention
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
Study burden and risks
TMS is a non-invasive, safe, easy, and painless technique to stimulate the
brain. A MagPro R30 with MagOption stimulator (MagVenture GmbH, Hückelhoven,
Germany) and a MCF-B65 butterfly coil (2x75mm) (MagVenture GmbH, Hückelhoven,
Germany) are used to apply the TMS. Both the TMS stimulator and coil are
developed and manufactured in accordance with the standard ISO 13485:2012 and
are approved as medical devices in Europe.
In 2009 Rossi and colleagues published the *Safety, ethical considerations, and
application guidelines for the use of transcranial magnetic stimulation in
clinical practice and research*. This article is based on a consensus
conference (Siena, Italy; 2008), intended to update the previous safety
guidelines for the application of TMS in research and clinical settings. When
applied according to these guidelines TMS is generally well tolerated; however
there are some possible side effects and risks.
• Temporary hearing problems
• Syncope: When a subject reports nausea, dizziness or feelings of (almost)
fainting, the experiment is stopped and will not be continued. During the
experiment, the subject will be asked frequently if he/she experiences any of
these feelings. Syncope is not related to direct brain effects of paired pulse
TMS.
• Headache, local pain or discomfort on the day of the TMS session: Most
participants experience paired pulse TMS as painless, however we will warn
subjects that TMS may not be pleasant and may cause some discomfort. This is
probably caused by stimulation of the trigeminus nerve. If subjects do not
tolerate paired pulse TMS, the experiment is stopped and will not be continued.
• Seizures: Rarely, there have been reports of seizures during or after TMS. In
a study on the risk of seizures in epilepsy patients, the crude risk of a
TMS-associated seizure in TMS in epilepsy patients was 0 to 3.6%. A recent
study has published the number of reported TMS induced seizures between 2012
and 2016. A total of 24 seizures was reported, in the 318.560 reported
sessions. This is 0.08 seizures per 1000 sessions. The risk of seizures during
TMS was largely influenced by risk factors: only 4 out of 24 seizures occurred
in subjects without risk factors. Out of the 24 reported seizures, 7 occurred
in epilepsy patients.
Overall, the risk of an epileptic seizure in TMS is extremely low in healthy
subjects and low in epilepsy patients, especially when these guidelines are
followed. Personnel skilled in the management of syncope and seizure will be
present in the clinical research unit. The patients in this study will have
been seizure free for at least 1 year. They will be on a stable dose of
antiepileptic treatment for at least 3 months. Subjects are asked to refrain
from their regular dose of AEDs until 4 hours after t=0h, which might increase
the risk of seizures in the placebo arm. However, the risk is small and
considered to be outweighed by the scientific benefit.
Levetiracetam is a registered drug. The safety profile of this compound is
known, however, side effects might occur. Therefore, study drug administrations
will be done in the clinical research unit under medical supervision. Subjects
will be closely monitored and will only be discharged from the unit if their
medical condition allows this. As subjects will receive a single dose of
levetiracetam, the risk is small and considered to be outweighed by the
scientific benefit.
Risk of SARS-CoV2 infection during pandemic.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
1. Signed informed consent prior to any study-mandated procedure
2. Male or female subjects, 18 to 54 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 30 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.
Exclusion criteria
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 this 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.
21. Study participant has a history of seizures during a year before dosing.
22. Study participant has epilepsy with a clear focal onset.
23. Any comorbidity known as a risk factor for COVID-19, including
cardiovascular, pulmonary or immune system diseases.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-004320-38-NL |
| CCMO | NL71944.056.19 |
| OMON | NL-OMON25822 |