Back to resultsContinuous Thetaburst Stimulation for the Treatment of Refractory Epilepsy - Safety, Feasibility and Proof-of-concept
Primary Purpose
Epilepsies, Partial
Status
Terminated
Phase
Not Applicable
Locations
Belgium
Study Type
Interventional
Intervention
continuous thetaburst stimulation
Sponsored by
About this trial
This is an interventional treatment trial for Epilepsies, Partial focused on measuring partial epilepsy, unifocal neocortical, treatment resistant, transcranial magnetic stimulation, thetaburst stimulation
Eligibility 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.
Sites / Locations
- University Hospital Ghent
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
continuous thetaburst stimulation
Arm Description
Transcranial magnetic stimulation over the epileptogenic focus using a cTBS stimulation protocol.
Outcomes
Primary Outcome Measures
Seizure induction
Induction of epileptic seizures during or in-between rTMS stimulation trains as a measure of safety
Secondary Outcome Measures
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)
Adverse events diary
Description of all experienced adverse event during the study as a measure of safety and tolerability.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Change in Beck depression inventory (BDI-II)
Questionnaire scoring depression ranged from 0 to 63 as a measure of well-being.
Change in Positive affect negative affect schedule (PANAS)
Questionnaire scoring affect as a measure of well-being.
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.
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.
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.
Full Information
NCT ID
NCT02635633
First Posted
August 24, 2015
Last Updated
January 31, 2022
Sponsor
University Hospital, Ghent
1. Study Identification
Unique Protocol Identification Number
NCT02635633
Brief Title
Continuous Thetaburst Stimulation for the Treatment of Refractory Epilepsy - Safety, Feasibility and Proof-of-concept
Official Title
Continuous Thetaburst Stimulation for the Treatment of Refractory Epilepsy - Safety, Feasibility and Proof-of-concept
Study Type
Interventional
2. Study Status
Record Verification Date
January 2022
Overall Recruitment Status
Terminated
Why Stopped
Difficulty identifying and including eligible patients
Study Start Date
August 2015 (Actual)
Primary Completion Date
April 2018 (Actual)
Study Completion Date
September 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Hospital, Ghent
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
Detailed Description
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).
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Epilepsies, Partial
Keywords
partial epilepsy, unifocal neocortical, treatment resistant, transcranial magnetic stimulation, thetaburst stimulation
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
7 (Actual)
8. Arms, Groups, and Interventions
Arm Title
continuous thetaburst stimulation
Arm Type
Experimental
Arm Description
Transcranial magnetic stimulation over the epileptogenic focus using a cTBS stimulation protocol.
Intervention Type
Device
Intervention Name(s)
continuous thetaburst stimulation
Other Intervention Name(s)
rTMS, cTBS
Intervention Description
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).
Primary Outcome Measure Information:
Title
Seizure induction
Description
Induction of epileptic seizures during or in-between rTMS stimulation trains as a measure of safety
Time Frame
Throughout stimulation, 4 days
Secondary Outcome Measure Information:
Title
Seizure diary
Description
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)
Time Frame
Throughout the study, lasting 13 weeks
Title
Adverse events diary
Description
Description of all experienced adverse event during the study as a measure of safety and tolerability.
Time Frame
Throughout the study, lasting 13 weeks
Title
Number of interictal epileptiform discharges (IEDs) on hd-EEG
Description
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.
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)
Title
Number of interictal epileptiform discharges (IEDs) on normal EEG
Description
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.
Time Frame
Throughout the study, lasting 13 weeks: assessment immediately before and after each treatment session
Title
Cortical resting motor threshold (rMT)
Description
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.
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)
Title
TMS-EEG evoked potentials (TEPs)
Description
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.
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)
Title
Magnetic resonance imaging (MRI)
Description
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.
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)
Title
High-density EEG (hd-EEG)
Description
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.
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)
Title
Change in Montreal Cognitive Assessment score (MoCA)
Description
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.
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)
Title
Change in Computerized Visual Searching Task (CVST)
Description
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.
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)
Title
Change in Quality of life in epilepsy-31 (QOLIE-31)
Description
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.
Time Frame
Throughout the study, lasting 13 weeks: baseline (before treatment) and 8 weeks after stimulation (long-term follow-up)
Title
Change in Beck depression inventory (BDI-II)
Description
Questionnaire scoring depression ranged from 0 to 63 as a measure of well-being.
Time Frame
Throughout the study, lasting 13 weeks: baseline (before treatment) and 8 weeks after stimulation (long-term follow-up)
Title
Change in Positive affect negative affect schedule (PANAS)
Description
Questionnaire scoring affect as a measure of well-being.
Time Frame
Throughout the study, lasting 13 weeks: baseline (before treatment) and 8 weeks after stimulation (long-term follow-up)
Title
Change in State-trait anxiety inventory (STAI)
Description
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.
Time Frame
Throughout the study, lasting 13 weeks: baseline (before treatment) and 8 weeks after stimulation (long-term follow-up)
Title
Change in Visual analogue scale (VAS) of general well-being
Description
Score ranged from 0 [lowest well-being] to 100 [highest well-being] as a measure of well-being.
Time Frame
Throughout the study, lasting 13 weeks: baseline (before treatment) and 8 weeks after stimulation (long-term follow-up)
Title
Change in Visual analogue scale (VAS) of tolerability of the treatment
Description
Score ranged from 0 [absolutely tolerable] -100 [absolutely intolerable] as a measure of tolerability and feasibility.
Time Frame
Throughout the study: after each treatment session and at the end of the study (8 weeks after stimulation)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kristl Vonck, MD, PhD
Organizational Affiliation
University Hospital, Ghent
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Ghent
City
Ghent
ZIP/Postal Code
9000
Country
Belgium
12. IPD Sharing Statement
Citations:
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15664172
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Continuous Thetaburst Stimulation for the Treatment of Refractory Epilepsy - Safety, Feasibility and Proof-of-concept
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