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Continuous Thetaburst Stimulation for the Treatment of Refractory Epilepsy - Safety, Feasibility and Proof-of-concept

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ClinicalTrials.gov Identifier: NCT02635633
Recruitment Status : Suspended (Researcher performing the study is temporarily working outside the study center.)
First Posted : December 21, 2015
Last Update Posted : September 20, 2018
Sponsor:
Information provided by (Responsible Party):
Neurologie, University Hospital, Ghent

Brief Summary:
The purpose of this study is to investigate a novel stimulation protocol of repetitive transcranial magnetic stimulation (rTMS) for the treatment of unifocal neocortical epilepsy, namely continuous thetaburst stimulation (cTBS). As this is a pilot study, the primary endpoint is on safety and tolerability of the treatment. However, information on clinical efficacy and mechanism of action will also be collected.

Condition or disease Intervention/treatment Phase
Epilepsies, Partial Device: continuous thetaburst stimulation Not Applicable

Detailed Description:
  1. Study design:

    This is an open label prospective pilot trial of continuous thetaburst stimulation (cTBS) in patients with unifocal neocortical epilepsy.

    The study comprises a 13-week period, consisting of 4 weeks baseline seizure frequency assessment, a one-week treatment period with baseline assessments on Monday (T0) and stimulation sessions from Tuesday to Friday (T1-T4), and an 8-week follow-up period with short-term assessments immediately after the final stimulation session on Friday afternoon (T4) and long-term assessments after 2 weeks (FU2) and 8 weeks (FU8).

  2. Objectives:

    The primary objective is to assess the feasibility, safety and tolerability of cTBS in refractory epilepsy patients. The secondary objectives are to assess the clinical efficacy and associated mechanism of action of cTBS in unifocal neocortical epilepsy.

  3. Rationale:

An open label prospective design allows to make a first estimate on the safety, feasibility and tolerability of cTBS in refractory epilepsy patients. There are currently no reports available of cTBS performed in epilepsy patients. The ultimate aim is to assess clinical efficacy of cTBS with regard to seizure frequency, but a feasibility and safety study is a prerequisite in order to achieve this goal.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Continuous Thetaburst Stimulation for the Treatment of Refractory Epilepsy - Safety, Feasibility and Proof-of-concept
Actual Study Start Date : August 2015
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : August 2020


Arm Intervention/treatment
Experimental: continuous thetaburst stimulation
Transcranial magnetic stimulation over the epileptogenic focus using a cTBS stimulation protocol.
Device: continuous thetaburst stimulation
On 4 consecutive days patients receive 5 cTBS trains with a 10min intertrain-interval. One cTBS train consists of 600 pulses delivered in bursts at theta frequency (200ms) during 40s. Each burst comprises 3 pulses at 50Hz. Focal stimulation occurs over the epileptogenic focus (EF), perpendicular to the local gyral geometry, using online neuronavigation. Stimulation intensity is set relative to the resting motor threshold (rMT) determined at baseline (80% rMT). Stimulation intensity is further adjusted to the coil-cortex distance at the EF with the following formula: adjusted MT% (AdjMT) = rMT + 2,7*(DEF-DM1) [DEF = distance over EF; DM1 = distance over M1]. If rMT exceeds the capacity of the stimulator output, stimulation intensity is 100% of maximal stimulator output (MSO).
Other Names:
  • rTMS
  • cTBS




Primary Outcome Measures :
  1. Seizure induction [ Time Frame: Throughout stimulation, 4 days ]
    Induction of epileptic seizures during or in-between rTMS stimulation trains as a measure of safety


Secondary Outcome Measures :
  1. Seizure diary [ Time Frame: Throughout the study, lasting 13 weeks ]

    Self-reported seizure frequency throughout the study as a measure of clinical efficacy.

    Four separate seizure diaries are provided:

    • Baseline period: 4 weeks prior to treatment
    • Treatment week: from monday to friday evening
    • Follow-up part 1: two weeks following the treatment week
    • Follow-up part 2: week 3 to week 8 following treatment Patients note down if the seizure was habitual, atypical or if it was an episode of uncertain etiology (eg. non-epileptic)

  2. Adverse events diary [ Time Frame: Throughout the study, lasting 13 weeks ]
    Description of all experienced adverse event during the study as a measure of safety and tolerability.

  3. Number of interictal epileptiform discharges (IEDs) on hd-EEG [ Time Frame: Throughout the study, lasting 13 weeks: baseline (before treatment), following final stimulation session (short-term follow-up), 2 weeks after stimulation and 8 weeks after stimulation (long-term follow-up) ]
    A 15min hd-EEG is recorded and IEDs are counted during acquisition. Comparison of number of IEDs between the different time points as a measure of clinical efficacy.

  4. Number of interictal epileptiform discharges (IEDs) on normal EEG [ Time Frame: Throughout the study, lasting 13 weeks: assessment immediately before and after each treatment session ]
    Fifteen min EEG with 21 scalp electrodes is recorded immediately before and following each stimulation session. Number of IEDs are counted and compared between pre- and post acquisition as a measure of clinical efficacy.

  5. Cortical resting motor threshold (rMT) [ Time Frame: Throughout the study, lasting 13 weeks: baseline (before treatment), following final stimulation session (short-term follow-up), 2 weeks after stimulation and 8 weeks after stimulation (long-term follow-up) ]

    Cortical resting motor threshold is determined using single-pulse TMS over the primary motor cortex (M1) (ipsilateral to epileptogenic focus). Motor-evoked potential (MEP) is measured over the first dorsal interosseus (FDI) of the contralateral hand. Using a threshold tracking tool (Adaptive PEST) the minimally required stimulation intensity that elicits an MEP of 50 microvolt is determined.

    RMT at different time points throughout the study is compared to assess the effect of the treatment on cortical excitability as a measure of mechanism of action.


  6. TMS-EEG evoked potentials (TEPs) [ Time Frame: Throughout the study, lasting 13 weeks: baseline (before treatment), following final stimulation session (short-term follow-up), 2 weeks after stimulation and 8 weeks after stimulation (long-term follow-up) ]

    TMS-EEG evoked potentials are measured over the epileptogenic focus and the primary motor cortex by performing single-pulse TMS (100 consecutive pulses jittered around an interval of 5s) with continuous EEG acquisition. The EEG is processed in order to obtain quantitative and comparable TEPs measures that reflect cortical excitability.

    These TEP measures obtained at different time points throughout the study are compared to assess the effect of the treatment on cortical excitability as a measure of mechanism of action.


  7. Magnetic resonance imaging (MRI) [ Time Frame: Throughout the study, lasting 13 weeks: baseline (before treatment), following final stimulation session (short-term follow-up), 2 weeks after stimulation and 8 weeks after stimulation (long-term follow-up) ]
    Resting-state functional MRI (rs-fMRI) is acquired at the four main time points of the study to assess the effects of treatment on functional connectivity as a measure of mechanism of action.

  8. High-density EEG (hd-EEG) [ Time Frame: Throughout the study, lasting 13 weeks: baseline (before treatment), following final stimulation session (short-term follow-up), 2 weeks after stimulation and 8 weeks after stimulation (long-term follow-up) ]
    A 128-channel EEG for resting-state EEG acquisition is obtained at the four main time points of the study to assess the effects of treatment on functional connectivity as a measure of mechanism of action.

  9. Change in Montreal Cognitive Assessment score (MoCA) [ Time Frame: Throughout the study, lasting 13 weeks: baseline (before treatment), following final stimulation session (short-term follow-up) and 8 weeks after stimulation (long-term follow-up) ]
    Score ranging from 0 [worst cognitive state] to 30 [best cognitive state], with a score of 26 or higher reflecting normal cognitive function. Cognitive assessment as a measure of safety: comparison at different time points throughout the study using MoCA version 7, 7.2 and 7.3 respectively.

  10. Change in Computerized Visual Searching Task (CVST) [ Time Frame: Throughout the study, lasting 13 weeks: baseline (before treatment), following final stimulation session (short-term follow-up), 2 weeks after stimulation and 8 weeks after stimulation (long-term follow-up) ]
    A 24-figure task assessing mean trial time [the faster the better] and number of errors [the lower the better] Assessment of mental flexibility and information processing as a measure of safety: comparison at different time points throughout the study.

  11. Change in Quality of life in epilepsy-31 (QOLIE-31) [ Time Frame: Throughout the study, lasting 13 weeks: baseline (before treatment) and 8 weeks after stimulation (long-term follow-up) ]
    Questionnaire scoring quality of life (QoL) ranged from 0 [lowest QoL] to 100 [highest QoL] (with associated T-value per score) as a measure of well-being.

  12. Change in Beck depression inventory (BDI-II) [ Time Frame: Throughout the study, lasting 13 weeks: baseline (before treatment) and 8 weeks after stimulation (long-term follow-up) ]
    Questionnaire scoring depression ranged from 0 to 63 as a measure of well-being.

  13. Change in Positive affect negative affect schedule (PANAS) [ Time Frame: Throughout the study, lasting 13 weeks: baseline (before treatment) and 8 weeks after stimulation (long-term follow-up) ]
    Questionnaire scoring affect as a measure of well-being.

  14. Change in State-trait anxiety inventory (STAI) [ Time Frame: Throughout the study, lasting 13 weeks: baseline (before treatment) and 8 weeks after stimulation (long-term follow-up) ]
    Questionnaire scoring anxiety as a state (now) or a trait (more generally) separately, ranged from 20 [less anxious] - 80 [more anxious] as a measure of well-being.

  15. Change in Visual analogue scale (VAS) of general well-being [ Time Frame: Throughout the study, lasting 13 weeks: baseline (before treatment) and 8 weeks after stimulation (long-term follow-up) ]
    Score ranged from 0 [lowest well-being] to 100 [highest well-being] as a measure of well-being.

  16. Change in Visual analogue scale (VAS) of tolerability of the treatment [ Time Frame: Throughout the study: after each treatment session and at the end of the study (8 weeks after stimulation) ]
    Score ranged from 0 [absolutely tolerable] -100 [absolutely intolerable] as a measure of tolerability and feasibility.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Refractory unifocal neocortical epilepsy with a well-defined ictal onset zone based on a standardized presurgical evaluation
  • ≥ 4 seizures/month, for at least six months
  • On a stable drug regimen for at least 2 months
  • IQ >70
  • Reliable completion of a seizure diary by patient or caretakers
  • Therapeutic compliance in the past
  • Informed consent signed

Exclusion Criteria:

  • Pregnancy, short-term birth wish or childbearing age without adequate birth control
  • History of psychogenic non-epileptic seizures
  • Intracranial metal hardware (excluding dental filling): surgical clips, shrapnell, electrodes under the stimulation area
  • Presence of pacemaker, implantable cardioverter-defibrillator (ICD), permanent medication pumps, cochlear implants or deep brain stimulation (DBS)

Patients with a vagus nerve stimulator are not excluded, provided that adequate distance between the coil and the implanted material can be maintained.

As the short duration of the study will not interfere with an ongoing presurgical evaluation and/or its eventual conclusion, the patients in the course of the evaluation or awaiting surgery are also eligible for inclusion.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02635633


Locations
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Belgium
University Hospital Ghent
Ghent, Belgium, 9000
Sponsors and Collaborators
University Hospital, Ghent
Investigators
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Principal Investigator: Kristl Vonck, MD, PhD University Hospital, Ghent

Publications:

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Responsible Party: Neurologie, Prof. Dr. Boon, University Hospital, Ghent
ClinicalTrials.gov Identifier: NCT02635633     History of Changes
Other Study ID Numbers: EC/2015/0596
First Posted: December 21, 2015    Key Record Dates
Last Update Posted: September 20, 2018
Last Verified: September 2018

Keywords provided by Neurologie, University Hospital, Ghent:
partial epilepsy
unifocal neocortical
treatment resistant
transcranial magnetic stimulation
thetaburst stimulation

Additional relevant MeSH terms:
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Epilepsy
Drug Resistant Epilepsy
Epilepsies, Partial
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases