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Treatment of Difficult to Control Focal Epilepsy With Repetitive Transcranial Magnetic Stimulation (rTMS)

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ClinicalTrials.gov Identifier: NCT01745952
Recruitment Status : Completed
First Posted : December 10, 2012
Results First Posted : April 26, 2016
Last Update Posted : April 26, 2016
Sponsor:
Information provided by (Responsible Party):
Universitaire Ziekenhuizen Leuven

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Triple (Participant, Care Provider, Outcomes Assessor);   Primary Purpose: Treatment
Condition Epilepsies, Partial
Interventions Device: figure-of-eight active rTMS coil
Device: round active rTMS coil
Device: sham rTMS coil (figure-of-eight)
Enrollment 11
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Figure-of-eight Active Coil; Then Round Active Coil; Then Sham Round Active Coil; Then Sham; Then Figure-of-eight Active Coil Sham Coil; Then Figure-of-eight Active Coil; Then Round Active
Hide Arm/Group Description
  • rTMS using the figure-of-eight active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the round active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the sham coil, over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the round active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the sham coil, over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the figure-of-eight active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the sham coil over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the figure-of-eight active coil, at 90% of the resting motor threshold, over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the round active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
Period Title: Overall Study
Started 4 4 3
Completed 3 3 [1] 3
Not Completed 1 1 0
[1]
data of one patient not used due to no seizure diary entries on multiple occasions
Arm/Group Title All Participants
Hide Arm/Group Description description of the patients at the onset of the study
Overall Number of Baseline Participants 11
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 11 participants
<=18 years
0
   0.0%
Between 18 and 65 years
11
 100.0%
>=65 years
0
   0.0%
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 11 participants
35
(24 to 61)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 11 participants
Female
7
  63.6%
Male
4
  36.4%
baseline seizure frequency per week  
Mean (Full Range)
Unit of measure:  Seizures/week
Number Analyzed 11 participants
24.9
(0.5 to 124.6)
1.Primary Outcome
Title 50% Responder Rate After Active rTMS Treatment Compared With Placebo Treatment
Hide Description Number of participants achieving a 50% or greater reduction in seizure frequency from baseline
Time Frame week 12 after each intervention
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Figure-of-eight Active Coil; Then Round Active Coil; Then Sham Round Active Coil; Then Sham; Then Figure-of-eight Active Coil Sham Coil; Then Figure-of-eight Active Coil; Then Round Active
Hide Arm/Group Description:
  • rTMS using the figure-of-eight active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the round active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the sham coil, over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the round active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the sham coil, over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the figure-of-eight active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the sham coil over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the figure-of-eight active coil, at 90% of the resting motor threshold, over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the round active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
Overall Number of Participants Analyzed 3 2 3
Overall Number of Units Analyzed
Type of Units Analyzed: Participants with data from first period
4 3 3
Measure Type: Number
Unit of Measure: participants
50% seizure reduction over any of three periods 0 0 0
50% seizure reduction over whole study 0 0 0
2.Secondary Outcome
Title Percentage of Seizure Reduction After Active rTMS Treatment Compared With Placebo Treatment
Hide Description Seizure frequency was recorded in patient diaries and reviewed with the neurologist/epileptologist (outcomes assessor) at visits 12 weeks (+/- 1 week) after each intervention. The average weekly seizure rate was calculated and compared to baseline frequency over all participants.
Time Frame week 12 after each treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
baseline weekly seizure frequency over all participants was 24.8 (95% confidence interval 8.2-76.1)
Arm/Group Title Figure-of-eight Active rTMS Coil Round Active rTMS Coil Sham rTMS Coil (Figure-of-eight)
Hide Arm/Group Description:

rTMS is administered using the figure-of-eight active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.

All patients who have undergone this treatment are taken together, irrespective of order the other treatments were administered.

rTMS is administered using the round active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.

All patients who have undergone this treatment are taken together, irrespective of order the other treatments were administered

rTMS is administered using the figure-of-eight sham coil, over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.

All patients who have undergone this treatment are taken together, irrespective of order the other treatments were administered

Overall Number of Participants Analyzed 8 9 7
Mean (95% Confidence Interval)
Unit of Measure: seizures/week
25.7
(7.4 to 89.4)
23.5
(7.2 to 76.2)
28.6
(8.2 to 99.8)
3.Other Pre-specified Outcome
Title Alteration of Brain Activation as Measured by 18-2-fluoro-2-deoxy-D-glucose Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) on Individual Patient Level
Hide Description Alterations were assessed by visual inspection of PET scans generated by subtracting the baseline individual PET scan from each of the follow-up scans. The subtraction PET scans were overlayed on the anatomical MRI of the patient and the focus of stimulation determined and an sphere with a 1cm radius around this point was analysed.
Time Frame within one week after the last treatment day of each session
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
patients of whom seizure journals were incomplete also included (one participant who went through all 3 trials and one patient of whom journals were not available from the sham session, that was reported by the patient as "ineffective")
Arm/Group Title Figure-of-eight Active rTMS Coil Round Active rTMS Coil Sham rTMS Coil (Figure-of-eight)
Hide Arm/Group Description:

rTMS is administered using the figure-of-eight active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.

All patients who have undergone this treatment are taken together, irrespective of order the other treatments were administered.

rTMS is administered using the round active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.

All patients who have undergone this treatment are taken together, irrespective of order the other treatments were administered.

rTMS is administered using the figure-of-eight sham coil, over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.

All patients who have undergone this treatment are taken together, irrespective of order the other treatments were administered.

Overall Number of Participants Analyzed 9 10 9
Measure Type: Number
Unit of Measure: participants
hypermetabolism compared to baseline 1 3 2
hypometabolism compared to baseline 3 3 3
4.Other Pre-specified Outcome
Title Difference in Seizure Reduction Using Different Coil Types
Hide Description any difference between the four conditions (baseline/ figure-of-eight treatment/ round coil treatment/ sham treatment) based in negative binomial model for count data
Time Frame 9 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
averaged weekly seizure count per condition is given for all patients combined
Arm/Group Title Any Difference Between the Four Conditions
Hide Arm/Group Description:
effect of baseline/ figure-of-eight/ round/ sham treatment period on the seizure frequency of the patients
Overall Number of Participants Analyzed 10
Mean (95% Confidence Interval)
Unit of Measure: number of seizures per week
seizures in condition 1 (baseline)
25
(8 to 76)
seizures in condition 2 (figure-8)
26
(7 to 89)
seizures in condition 3 (round)
24
(7 to 76)
seizures in condition 4 (sham)
29
(8 to 100)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Any Difference Between the Four Conditions
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9819
Comments [Not Specified]
Method negative binomial model + overdispersion
Comments [Not Specified]
5.Other Pre-specified Outcome
Title Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale
Hide Description
  • Quality of life in epilepsy (QOLIE-31): self-report (if cognitive faculties allowed) questionnaire of emotional well-being, social functioning, energy/ fatigue, cognitive functioning, seizure worry, medication effects & overall quality of life. Range 0-100, with higher numbers indicating better quality of life.
  • Global impression of change-scales (score 1-7, with 4 no change and lower/higher numbers implying grade of improvement/worsening) and Visual analogue scale (0-10: no problem to horrible): self-report or parent report about effect of treatment
  • Columbia Suicide Severity Rating Scale (CSSR): structured interview about suicidal risk
  • change in QOLIE scores considered better/worse are based on cut-off reported in DOI 10.1016/j.yebeh.2011.12.023 For global impression of change, the scoring was <4, 4 or >4.
Time Frame before the first treatment of each session and at the last evaluation visit
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
* Self-reporting questionnaires could only be filled in by 7 participants For global impression of change scales, the score reached by consensus between the patient and caregiver(s) was used if patient was unable to fill in questionaires: for the three arms, we thus have 7/8/6 scores for each arm respectively
Arm/Group Title Figure-of-eight Active rTMS Coil Round Active rTMS Coil Sham rTMS Coil (Figure-of-eight)
Hide Arm/Group Description:

rTMS is administered using the figure-of-eight active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.

All patients who have undergone this treatment are taken together, irrespective of order the other treatments were administered.

rTMS is administered using the round active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.

All patients who have undergone this treatment are taken together, irrespective of order the other treatments were administered.

rTMS is administered using the figure-of-eight sham coil, over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.

All patients who have undergone this treatment are taken together, irrespective of order the other treatments were administered.

Overall Number of Participants Analyzed 5 6 5
Measure Type: Number
Unit of Measure: participants
better QOLIE score 3 3 1
worse QOLIE score 0 1 1
Global impression of change: no change 4 5 5
Global impression of change: worse 1 1 1
Global impression of change: better 1 1 0
Global impression change: first better, then worse 1 1 0
CSSR-scale increased suicidality 0 0 0
6.Other Pre-specified Outcome
Title Drop Out-rate
Hide Description exclusion by investigator was due to necessity to change drug regimen due to toxicity
Time Frame during the 9 months of the study
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
for this analysis, all patients randomised were included; this includes one patient in the second arm that was not included in any of the other outcome measures, due to lack of reliable outcome parameters
Arm/Group Title Figure-of-eight Active Coil; Then Round Active Coil; Then Sham Round Active Coil; Then Sham; Then Figure-of-eight Active Coil Sham Coil; Then Figure-of-eight Active Coil; Then Round Active
Hide Arm/Group Description:
  • rTMS using the figure-of-eight active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the round active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the sham coil, over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the round active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the sham coil, over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the figure-of-eight active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the sham coil over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the figure-of-eight active coil, at 90% of the resting motor threshold, over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
  • rTMS using the round active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.
  • 12 week follow-up period
Overall Number of Participants Analyzed 4 4 3
Measure Type: Number
Unit of Measure: participants
excluded by investigator from concluding study 0 1 0
stopped due to intolerance/ inefficiency 0 1 0
stopped due to seizure worsening 1 0 0
7.Other Pre-specified Outcome
Title Adverse Event Rate
Hide Description [Not Specified]
Time Frame during the 9 months of the study
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Figure-of-eight Active rTMS Coil Round Active rTMS Coil Sham rTMS Coil (Figure-of-eight)
Hide Arm/Group Description:

rTMS is administered using the figure-of-eight active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.

All patients who have undergone this treatment are taken together, irrespective of order the other treatments were administered.

rTMS is administered using the round active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.

All patients who have undergone this treatment are taken together, irrespective of order the other treatments were administered.

rTMS is administered using the figure-of-eight sham coil, over the epileptogenic region, in trains of 500 pulses with a total of 1500 pulses per day, during weekdays on two consecutive weeks.

All patients who have undergone this treatment are taken together, irrespective of order the other treatments were administered.

Overall Number of Participants Analyzed 9 10 8
Measure Type: Number
Unit of Measure: participants
worsening seizures 2 1 0
hearing problems 1 1 0
fatigue 2 2 2
concentration difficulties 1 1 1
Time Frame 9-month study duration
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Figure-of-eight Active rTMS Coil Round Active rTMS Coil Sham rTMS Coil (Figure-of-eight)
Hide Arm/Group Description

rTMS is administered using the figure-of-eight active coil, at 90% of the resting motor threshold over the epileptogenic region, at 0.5 Hertz with a total of 1500 pulses per day, during weekdays on two consecutive weeks.

figure-of-eight active rTMS coil: navigated rTMS over epileptogenic focus using figure-of-eight active rTMS coil

rTMS is administered using the round active coil, at 90% of the resting motor threshold over the epileptogenic region, at 0.5 Hertz with a total of 1500 pulses per day, during weekdays on two consecutive weeks.

round active rTMS coil: navigated rTMS over epileptogenic focus using round active rTMS coil

rTMS is administered using the figure-of-eight sham coil, over the epileptogenic region, at 0.5 Hertz with a total of 1500 pulses per day, during weekdays on two consecutive weeks.

sham rTMS coil (figure-of-eight): placebo coil that provides slight sensory stimulation and discharge noise without stimulating cortical tissue

All-Cause Mortality
Figure-of-eight Active rTMS Coil Round Active rTMS Coil Sham rTMS Coil (Figure-of-eight)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Figure-of-eight Active rTMS Coil Round Active rTMS Coil Sham rTMS Coil (Figure-of-eight)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/9 (22.22%)   1/10 (10.00%)   0/9 (0.00%) 
Nervous system disorders       
seizure excacerbation   2/9 (22.22%)  1/10 (10.00%)  0/9 (0.00%) 
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Figure-of-eight Active rTMS Coil Round Active rTMS Coil Sham rTMS Coil (Figure-of-eight)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   3/9 (33.33%)   3/10 (30.00%)   3/9 (33.33%) 
Nervous system disorders       
fatigue, concentration difficulties   3/9 (33.33%)  3/10 (30.00%)  3/9 (33.33%) 
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Prof W Van Paesschen & Dr L Seynaeve
Organization: UZ Leuven
Phone: +3216349062
Publications:
Responsible Party: Universitaire Ziekenhuizen Leuven
ClinicalTrials.gov Identifier: NCT01745952     History of Changes
Other Study ID Numbers: s52486
First Submitted: December 4, 2012
First Posted: December 10, 2012
Results First Submitted: December 15, 2015
Results First Posted: April 26, 2016
Last Update Posted: April 26, 2016