Treatment of Difficult to Control Focal Epilepsy With Rep... | NCT01745952

Treatment of Difficult to Control Focal Epilepsy With Rep... | NCT01745952 | Trialant

Description Module

Detailed Description

Background and study aims

Epilepsy is a disease that causes repetitive seizures. In 60% of people with epilepsy, these seizures start in a small zone of the brain (focal or partial epilepsy). This zone can be in the depth of the temporal lobe (mesial temporal lobe epilepsy) or in another brain region (neocortical epilepsy). Even with optimal medical care, up to 30% of people with epilepsy continue to have seizures.

The investigators will treat people with neocortical partial epilepsy with a technique that delivers magnetic waves (transcranial magnetic stimulation, TMS) to the region that causes the epilepsy. The investigators have good reasons to believe that there will be fewer seizures during several weeks after treatment.
Who can participate?

You have neocortical focal epilepsy. A doctor who specializes in epilepsy made this diagnosis. You had at least one seizure recorded while in an epilepsy monitoring unit. You had an MRI scan of the brain. You can deliver us all the results of the tests you had.

You continue to have more than 4 seizures a month. You tried a least two different schemes of anti-epileptic drugs as prescribed by your doctor and those schemes were well tolerated. Nevertheless this never cured the seizures.

You are older than 16 years. You don't plan to become pregnant during the study. You need to faithfully continue your treatment as prescribed by your doctor and don't change the drugs you take from at least 4 weeks before the study until 8 weeks after the last TMS session. You need to be able to keep a diary of your seizures.
What does the study involve?

You will need to come to the hospital every weekday during two consecutive weeks, every three months during nine months for the TMS-treatment. So you will have three treatment sessions. You will have a brain scan (FDG-PET) before the first treatment and after each session.

The magnetic pulses will be delivered differently during each of the three treatment sessions: once on a rather small area of the brain, once on a larger brain area and once using a dummy coil, i.e. you will have two active treatment sessions and one dummy or placebo session. The investigators will not tell in which order they deliver the treatments.
What are the possible benefits and risks of participating?

The investigators have good reasons to believe you will have fewer seizures in the weeks following the active treatment.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
figure-of-eight active rTMS coil	Experimental	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.	Device: figure-of-eight active rTMS coil
round active rTMS coil	Experimental	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.	Device: round active rTMS coil
sham rTMS coil (figure-of-eight)	Sham Comparator	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.	Device: sham rTMS coil (figure-of-eight)

Interventions

Name	Type	Description	Arm Group Labels	Other Names
figure-of-eight active rTMS coil	Device	navigated rTMS over epileptogenic focus using figure-of-eight active rTMS coil	figure-of-eight active rTMS coil

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
50% Responder Rate After Active rTMS Treatment Compared With Placebo Treatment	Number of participants achieving a 50% or greater reduction in seizure frequency from baseline	week 12 after each intervention

Secondary Outcomes

Measure	Description	Time Frame
Seizure Frequency After Active rTMS Treatment Compared With Placebo Treatment	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.	week 12 after each treatment

Other Outcomes

Measure	Description	Time Frame
Alteration of Brain Activation as Measured by 18-2-fluoro-2-deoxy-D-glucose Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) on Individual Patient Level	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.

Contacts/Locations Module

Name	Affiliation	Role
Van Paesschen Wim, MD, PhD	Universitaire Ziekenhuizen KU Leuven	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
University Hospitals Leuven, department of Neurology		Leuven		3000	Belgium

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
22950513	Background	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.
17068786

Arm/Group Information

ID	Title	Description
FG000	Figure-of-eight Active Coil; Then Round Active Coil; Then Sham	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
FG001	Round Active Coil; Then Sham; Then Figure-of-eight Active Coil	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
FG002	Sham Coil; Then Figure-of-eight Active Coil; Then Round Active	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

Periods

Title

Milestones

Reasons Not Completed

Overall Study

Type	Comment	Milestone Data
STARTED		FG0004 subjects FG0014 subjects FG0023 subjects
COMPLETED		FG0003 subjects FG0013 subjectsdata of one patient not used due to no seizure diary entries on multiple occasions FG0023 subjects
NOT COMPLETED		FG0001 subjects FG0011 subjects FG0020 subjects

Baseline Characteristics Module

ID	Title	Description
BG000	All Participants	description of the patients at the onset of the study

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

50% Responder Rate After Active rTMS Treatment Compared With Placebo Treatment

Number of participants achieving a 50% or greater reduction in seizure frequency from baseline

Besides the reported participants that went through whole protocol, one supplementary participant underwent the first rTMS session of the first protocol and one supplementary participant underwent the first rTMS session of the second protocol

Posted

Number

participants

week 12 after each intervention

ID	Title	Description
OG000	Figure-of-eight Active Coil; Then Round Active Coil; Then Sham	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

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Figure-of-eight Active rTMS Coil	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

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
seizure excacerbation	Nervous system disorders		Systematic Assessment

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
fatigue, concentration difficulties	Nervous system disorders		Systematic Assessment

More Info Module

Certain Agreements

Title	Organization	Phone	Extension	Email
Prof W Van Paesschen & Dr L Seynaeve	UZ Leuven	+3216349062		laura.seynaeve@uzleuven.be

Condition Browse Module

ID	Term
D004828	Epilepsies, Partial

ID	Term
D004827	Epilepsy
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases

Secondary

Seizure Frequency After Active rTMS Treatment Compared With Placebo Treatment

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.

baseline weekly seizure frequency over all participants was 24.8 (95% confidence interval 8.2-76.1)

Posted

Mean

95% Confidence Interval

seizures/week

week 12 after each treatment

ID	Title	Description
OG000	Figure-of-eight Active rTMS Coil	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.
OG001	Round Active rTMS Coil	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
OG002	Sham rTMS Coil (Figure-of-eight)	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

Units	Counts
Participants	OG0008 OG0019 OG0027

Title

Denominators

Categories

Title	Measurements
	OG00025.7(7.4 to 89.4) OG00123.5(7.2 to 76.2) OG00228.6(8.2 to 99.8)

Other Pre-specified

Alteration of Brain Activation as Measured by 18-2-fluoro-2-deoxy-D-glucose Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) on Individual Patient Level

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.

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")

Posted

Number

participants

within one week after the last treatment day of each session

ID	Title	Description
OG000	Figure-of-eight Active rTMS Coil	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.
OG001	Round Active rTMS Coil	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.
OG002	Sham rTMS Coil (Figure-of-eight)	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.

Units	Counts
Participants	OG0009 OG00110 OG0029

Title

Denominators

Categories

hypermetabolism compared to baseline

Title	Measurements
	OG0001 OG0013 OG0022

hypometabolism compared to baseline

Other Pre-specified

Difference in Seizure Reduction Using Different Coil Types

any difference between the four conditions (baseline/ figure-of-eight treatment/ round coil treatment/ sham treatment) based in negative binomial model for count data

averaged weekly seizure count per condition is given for all patients combined

Posted

Mean

95% Confidence Interval

number of seizures per week

9 months

ID	Title	Description
OG000	Any Difference Between the Four Conditions	effect of baseline/ figure-of-eight/ round/ sham treatment period on the seizure frequency of the patients

Units	Counts
Participants	OG00010

Title

Denominators

Categories

seizures in condition 1 (baseline)

Title	Measurements
	OG00025(8 to 76)

seizures in condition 2 (figure-8)

Title	Measurements
	OG00026(7 to 89)

seizures in condition 3 (round)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000		negative binomial model + overdispersion		0.9819						2-Sided								Superiority or Other (legacy)

Other Pre-specified

Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale

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.

* 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

Posted

Number

participants

before the first treatment of each session and at the last evaluation visit

ID	Title	Description
OG000	Figure-of-eight Active rTMS Coil	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.
OG001	Round Active rTMS Coil	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.
OG002	Sham rTMS Coil (Figure-of-eight)	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.

Units	Counts
Participants	OG0005 OG0016 OG0025

Title

Denominators

Categories

better QOLIE score

Title	Measurements
	OG0003 OG0013 OG0021

worse QOLIE score

Other Pre-specified

Drop Out-rate

exclusion by investigator was due to necessity to change drug regimen due to toxicity

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

Posted

Number

participants

during the 9 months of the study

ID	Title	Description
OG000	Figure-of-eight Active Coil; Then Round Active Coil; Then Sham	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
OG001	Round Active Coil; Then Sham; Then Figure-of-eight Active Coil	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
OG002	Sham Coil; Then Figure-of-eight Active Coil; Then Round Active	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

Units	Counts
Participants	OG0004 OG0014 OG0023

Title

Denominators

Categories

excluded by investigator from concluding study

Title	Measurements
	OG0000 OG0011 OG0020

stopped due to intolerance/ inefficiency

Other Pre-specified

Adverse Event Rate

Posted

Number

participants

during the 9 months of the study

ID	Title	Description
OG000	Figure-of-eight Active rTMS Coil	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.
OG001	Round Active rTMS Coil	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.
OG002	Sham rTMS Coil (Figure-of-eight)	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.

Units	Counts
Participants	OG0009 OG00110 OG0028

Title

Denominators

Categories

worsening seizures

Title	Measurements
	OG0002 OG0011 OG0020

hearing problems