In this study, we investigate how two new measurement methods can demonstrate the effects of two existingdrugs, modafinil and alprazolam, on the excitability of the brain. We test these effects only in healthy subjects.The effects of modafinil and…
ID
Source
Brief title
Condition
- Neurological disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
- Other intervention
N.a.
Outcome measures
Primary outcome
<p>To demonstrate the pharmacodynamic (PD) effects of modafinil and alprazolam in healthy male and <br>female postmenopausal adults when compared to placebo on: </p><ul><li>Cortical excitability as measured by single-pulse TMS-EMG motor evoked potential (MEP) <br>amplitude </li><li>Brain E/I ratio using the Mean Field Model (MFM) and 1/f parameters from raw qEEG data.</li></ul>
Secondary outcome
<ul><li>To evaluate the PD effects of modafinil and alprazolam on cortical excitability as measured by <br>single- and paired-pulse TMS-EMG in healthy male and female postmenopausal adults when <br>compared to placebo.</li><li>To evaluate the PD effects of modafinil and alprazolam on cortical excitability as measured by <br>single- and paired-pulse TMS-EEG in healthy male and female postmenopausal adults when <br>compared to placebo.</li><li> To evaluate the PD effects of modafinil and alprazolam on qEEG spectral power in healthy <br>male and female postmenopausal adults when compared to placebo.<br>CHDR2431<br>Protocol Version 1 / 15-Apr-2025 Confidential Page 14 of 54</li><li>To evaluate the brain excitation/inhibition ratio using the Mean Field Model (MFM) and 1/f <br>parameters from raw qEEG data.</li></ul>
Background summary
Cortical excitability and related biomarkers are Central Nervous System (CNS) features of growing
interest. There is clear evidence that disbalance in the brain excitation and inhibition (E/I), and
subsequent abnormal cortical excitability, plays an important role in various neurological disorders
(e.g. epilepsy, depression, amyotrophic lateral sclerosis), and that different pharmacological
interventions can modulate cortical excitability (ion-channel modulators, neurotransmitter-modulators), which could potentially restore the imbalance. Therefore, it is important to develop and
validate biomarkers that measure cortical excitability and investigate the brain E/I ratio, both to better
understand the pathophysiology mechanisms that lead to cortical hyperexcitability and the
pharmacological activity of drugs that affect cortical excitability. Transcranial Magnetic Stimulation
combined with Electromyography (TMS-EMG) and quantitative electroencephalography (qEEG) have
already proven to be sensitive methods to capture effects of pharmacological interventions, and could
be used to further investigate how these modulate the brain E/I ratio. An expansion of data for
compounds with different mechanisms of action would not only improve our understanding of different
TMS parameters and their relationship to biological processes, but also strengthen the relevance of
these biomarkers for cortical excitability. Furthermore, methods have been developed to analyze
qEEG data in new ways that may inform on the E/I ratio of the cortex. This may provide a new
biomarker for the effects of drugs that can be expected to affect E/I ratio. This study aims to explore
the E/I ratio as a biomarker for cortical excitability in humans after administration of modafinil and
alprazolam.
Study objective
In this study, we investigate how two new measurement methods can demonstrate the effects of two existing
drugs, modafinil and alprazolam, on the excitability of the brain. We test these effects only in healthy subjects.
The effects of modafinil and alprazolam are compared with the effect of a placebo.
Furthermore, collected data from this study can also be used to learn more about the diseases for which the study drug is used and the treatments for those diseases. This is done to ultimately find the best treatment for patients.
Study design
This is a randomized, double-blind, placebo-controlled, three-way cross-over study to assess the
sensitivity of TMS-EMG-EEG and qEEG as measures of cortical excitability to the effects of
alprazolam and modafinil as challenge drugs in healthy male and female postmenopausal adults .
The total duration of the study for each subject will be up to 60 days divided as follows:
- Screening: Between 42 and 4 days before dosing;
- Treatment periods: 3 study periods, with a washout period of at least 7 days between each
visit. Each study period consists of 1 study day; - Follow-up visit: 9 ± 2 days after last dose.
We will include healthy male and postmenopausal female study participants, 18 to 55 years of age,
and aim for 24 study participants to complete all study treatments, based on our sample size calculations. Per study period the study participants will be dosed with a single dose of modafinil,
alprazolam and/or placebo.
Study participants will be admitted to the study unit on the morning of Day 1 and will be discharged
approximately 8 hours after study drug administration. There will be a single baseline measurement
for TMS on all occasions, and two baseline measurements for qEEG. After dosing, there will be 2
post-dose TMS and 3 qEEG measurements: at 2-, and 7-hours post-dose, and at 2-, 4.5- and 7-hours
post-dose respectively.
Intervention
One single oral dose of each of the following treatments is administered per treatment period:
- Alprazolam, 2 x 0.5 mg over-encapsulated tablets, with one placebo capsule
- Modafinil, 3 x 200 mg over-encapsulated tablets, without placebo capsules
- Three placebo capsules
Study burden and risks
Alprazolam and modafinil are both market approved drugs and there is extensive experience with their use. Alprazolam will be administered as a single dose, at a dose level that is recommended for its therapeutic indications (see SmPC). Modafinil will be administered as a single high dose, that has been deemed safe based on data available from the multiple ascending dose study in which this dose was administered for 7 days in 6 HVs and was well tolerated. Moreover, exposures following a single dose will be lower than those following multiple doses, so we expect the current dose to also be well tolerated.
Most common side effects are CNS-mediated and include: sedation, drowsiness, depression, ataxia,
memory impairment, dysarthria, dizziness, headache, fatigue, irritability, nausea and vomiting. Although rare, severe side-effects can occur and include severe skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis) and allergic reactions. Because of these effects, subjects should not drive a car and should not engage in activities that require operating vehicles or dangerous machinery following administration until the next day. The subjects will remain in the clinic under supervision and will be discharged only if their medical condition allows.
The pharmacodynamic measurements are minimally invasive. All tests included have been validated in previous studies for their safety and applicability in early-phase drug studies such as this study.
TMS is a non-invasive, safe, easy and painless technique to stimulate the brain. Both the TMS stimulator and coil are developed and manufactured in accordance with the standard International Standardization Organization number 13485:2012 and are approved as medical devices in Europe. 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, including temporary hearing problems, headache, local pain, discomfort on the day of the TMS session, syncope and seizures. The most serious side effects are syncope and epileptic seizures, which are sometimes clinically difficult to distinguish. 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 study participants 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 study participants 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.
G.J. Groeneveld
Zernikedreef 8
Leiden 2333CL
Netherlands
0715246400
clintrials@chdr.nl
G.J. Groeneveld
Zernikedreef 8
Leiden 2333CL
Netherlands
0715246400
clintrials@chdr.nl
Trial sites in the Netherlands
Listed location countries
Age
Inclusion criteria
1. Signed informed consent prior to any study-mandated procedure.
2. Healthy males or healthy postmenopausal females, 18 to 55 years of age, inclusive at
screening.
3. Body mass index (BMI) between 18 and 32 kg/m2, inclusive at screening, and with a
minimum weight of 50 kg.
4. Males who are sexually active and whose partners are women of childbearing potential
(WOCBP) must agree to use condoms from screening through at least 7 days after
administration of the last dose of IMP, or their partners must be willing to use a highly
effective method of contraception (e.g. intrauterine device [IUD], diaphragm with spermicide,
oral contraceptive, injectable progesterone, subdermal implant, or tubal ligation). Other
effective male contraception also includes a vasectomy with negative semen analysis at
follow up. Abstinence can be considered an acceptable method of contraception at the
discretion of the investigator. Males must also agree not to donate sperm through 7 days
after administration of the last dose of IMP. For females, follicle-stimulating hormone (FSH)
levels will be determined during screening to confirm postmenopausal status.
5. 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 that could interfere with, or for which the treatment 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 and neurological examination, vital signs (systolic and diastolic blood pressure, pulse rate, body temperature) and 12-lead 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 study participants.
3. History or presence of conditions which, in the judgment of the investigator, might increase the risk of performing TMS, including but not limited to epilepsy or febrile seizures, intracranial mass lesion, hydrocephalus, clinically significant head injury or trauma, metal objects in the brain or skull, cochlear implant or a deep brain stimulation device.
4. Personal or relevant family history of psychiatric diseases, including but not limited to bipolar
disorder and anxiety disorder.
5. Any condition that could interfere with the quality of, or ability to perform, TMS, such as an abnormal sleeping pattern (e.g., working night shifts), dreadlocks or hairpieces that cannot be removed, or a resting motor threshold (rMT) of more than 62% of the maximum stimulator output as measured using TMS-EMG during screening.
Design
Recruitment
Medical products/devices used
IPD sharing statement
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In other registers
| Register | ID |
|---|---|
| Research portal | NL-009436 |