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Epilepsies, PartialNCT02635633

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

A study testing continuous thetaburst stimulation in people with Epilepsies, Partial, run by University Hospital, Ghent at 1 site in Belgium.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 18 to 65 years
Conditions the study is for
Epilepsies, Partial
What is being tested?
continuous thetaburst stimulation
Type of treatment
Medical device
Could I receive a placebo?
No, everyone receives an active treatment
How many people
7 participants
Where
1 siteBelgium
Study dates
Aug 2015to Sep 2018
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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.

Trial locations and contacts

1 site in 1 country.

Belgium1 site

  • University Hospital Ghent

    Ghent, 9000

Other trials in Belgium

About this study

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.

Read the 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.

Being tested
continuous thetaburst stimulation
Keywords
partial epilepsy, unifocal neocortical, treatment resistant, transcranial magnetic stimulation, thetaburst stimulation
Medical subject headings
Epilepsies, Partial

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • continuous thetaburst stimulationDevice

    Also called rTMS, cTBS

    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).

Study groups in NCT02635633
Study groupRoleWhat they receive
continuous thetaburst stimulationExperimentalTranscranial magnetic stimulation over the epileptogenic focus using a cTBS stimulation protocol.
Receives: Device: continuous thetaburst stimulation

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Seizure induction

    Induction of epileptic seizures during or in-between rTMS stimulation trains as a measure of safety

    Measured: Throughout stimulation, 4 days

Secondary outcomes (16)

  1. Seizure diary

    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)

    Measured: Throughout the study, lasting 13 weeks

  2. Adverse events diary

    Description of all experienced adverse event during the study as a measure of safety and tolerability.

    Measured: Throughout the study, lasting 13 weeks

  3. Number of interictal epileptiform discharges (IEDs) on hd-EEG

    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.

    Measured: 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)

  4. Number of interictal epileptiform discharges (IEDs) on normal EEG

    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.

    Measured: Throughout the study, lasting 13 weeks: assessment immediately before and after each treatment session

  5. Cortical resting motor threshold (rMT)

    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.

    Measured: 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)

  6. TMS-EEG evoked potentials (TEPs)

    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.

    Measured: 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)

  7. Magnetic resonance imaging (MRI)

    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.

    Measured: 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)

  8. High-density EEG (hd-EEG)

    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.

    Measured: 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)

  9. Change in Montreal Cognitive Assessment score (MoCA)

    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.

    Measured: 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)

  10. Change in Computerized Visual Searching Task (CVST)

    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.

    Measured: 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)

  11. Change in Quality of life in epilepsy-31 (QOLIE-31)

    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.

    Measured: Throughout the study, lasting 13 weeks: baseline (before treatment) and 8 weeks after stimulation (long-term follow-up)

  12. Change in Beck depression inventory (BDI-II)

    Questionnaire scoring depression ranged from 0 to 63 as a measure of well-being.

    Measured: Throughout the study, lasting 13 weeks: baseline (before treatment) and 8 weeks after stimulation (long-term follow-up)

  13. Change in Positive affect negative affect schedule (PANAS)

    Questionnaire scoring affect as a measure of well-being.

    Measured: Throughout the study, lasting 13 weeks: baseline (before treatment) and 8 weeks after stimulation (long-term follow-up)

  14. Change in State-trait anxiety inventory (STAI)

    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.

    Measured: Throughout the study, lasting 13 weeks: baseline (before treatment) and 8 weeks after stimulation (long-term follow-up)

  15. Change in Visual analogue scale (VAS) of general well-being

    Score ranged from 0 [lowest well-being] to 100 [highest well-being] as a measure of well-being.

    Measured: Throughout the study, lasting 13 weeks: baseline (before treatment) and 8 weeks after stimulation (long-term follow-up)

  16. Change in Visual analogue scale (VAS) of tolerability of the treatment

    Score ranged from 0 [absolutely tolerable] -100 [absolutely intolerable] as a measure of tolerability and feasibility.

    Measured: Throughout the study: after each treatment session and at the end of the study (8 weeks after stimulation)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Dec 2015 (estimated)
  2. Study startAug 2015
  3. Primary completionApr 2018
  4. Study completionSep 2018

Why it stopped: Difficulty identifying and including eligible patients

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
7 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02635633
Sponsor's protocol ID
EC/2015/0596
Status last verified
Jan 2022
First submitted
24 Aug 2015
Last updated
15 Feb 2022
Results posted
No
Data monitoring committee
Yes

Publications

  • Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005 Jan 20;45(2):201-6. doi: 10.1016/j.neuron.2004.12.033.

    PubMed 15664172

  • Sun W, Mao W, Meng X, Wang D, Qiao L, Tao W, Li L, Jia X, Han C, Fu M, Tong X, Wu X, Wang Y. Low-frequency repetitive transcranial magnetic stimulation for the treatment of refractory partial epilepsy: a controlled clinical study. Epilepsia. 2012 Oct;53(10):1782-9. doi: 10.1111/j.1528-1167.2012.03626.x. Epub 2012 Sep 5.

    PubMed 22950513

  • Fregni F, Otachi PT, Do Valle A, Boggio PS, Thut G, Rigonatti SP, Pascual-Leone A, Valente KD. A randomized clinical trial of repetitive transcranial magnetic stimulation in patients with refractory epilepsy. Ann Neurol. 2006 Oct;60(4):447-55. doi: 10.1002/ana.20950.

    PubMed 17068786

  • Cantello R, Rossi S, Varrasi C, Ulivelli M, Civardi C, Bartalini S, Vatti G, Cincotta M, Borgheresi A, Zaccara G, Quartarone A, Crupi D, Lagana A, Inghilleri M, Giallonardo AT, Berardelli A, Pacifici L, Ferreri F, Tombini M, Gilio F, Quarato P, Conte A, Manganotti P, Bongiovanni LG, Monaco F, Ferrante D, Rossini PM. Slow repetitive TMS for drug-resistant epilepsy: clinical and EEG findings of a placebo-controlled trial. Epilepsia. 2007 Feb;48(2):366-74. doi: 10.1111/j.1528-1167.2006.00938.x.

    PubMed 17295632

  • Theodore WH, Hunter K, Chen R, Vega-Bermudez F, Boroojerdi B, Reeves-Tyer P, Werhahn K, Kelley KR, Cohen L. Transcranial magnetic stimulation for the treatment of seizures: a controlled study. Neurology. 2002 Aug 27;59(4):560-2. doi: 10.1212/wnl.59.4.560.

    PubMed 12196649

  • Nyffeler T, Wurtz P, Luscher HR, Hess CW, Senn W, Pflugshaupt T, von Wartburg R, Luthi M, Muri RM. Repetitive TMS over the human oculomotor cortex: comparison of 1-Hz and theta burst stimulation. Neurosci Lett. 2006 Nov 27;409(1):57-60. doi: 10.1016/j.neulet.2006.09.011. Epub 2006 Oct 17.

    PubMed 17049743

  • Nyffeler T, Cazzoli D, Hess CW, Muri RM. One session of repeated parietal theta burst stimulation trains induces long-lasting improvement of visual neglect. Stroke. 2009 Aug;40(8):2791-6. doi: 10.1161/STROKEAHA.109.552323. Epub 2009 Jun 11.

    PubMed 19520986

  • Goldsworthy MR, Pitcher JB, Ridding MC. The application of spaced theta burst protocols induces long-lasting neuroplastic changes in the human motor cortex. Eur J Neurosci. 2012 Jan;35(1):125-34. doi: 10.1111/j.1460-9568.2011.07924.x. Epub 2011 Nov 25.

    PubMed 22118241

  • Carrette S, Boon P, Klooster D, Van Dycke A, Carrette E, Miatton M, Raedt R, Delbeke J, Meurs A, Vonck K. Continuous theta burst stimulation for drug-resistant epilepsy. Front Neurosci. 2022 Aug 17;16:885905. doi: 10.3389/fnins.2022.885905. eCollection 2022.

    PubMed 36061598

Questions about this trial

What is this clinical trial studying?

A study testing continuous thetaburst stimulation in people with Epilepsies, Partial, run by University Hospital, Ghent at 1 site in Belgium.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 15 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study was stopped early (reason given: Difficulty identifying and including eligible patients). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Seizure induction (time frame: Throughout stimulation, 4 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02635633, which also lists 9 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Feb 2022.

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