<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02207673</url>
  </required_header>
  <id_info>
    <org_study_id>NL44527.041.13</org_study_id>
    <secondary_id>13-389</secondary_id>
    <secondary_id>2012-4</secondary_id>
    <nct_id>NCT02207673</nct_id>
  </id_info>
  <brief_title>A New Method for Delineation of Epileptic Brian Tissue During Epilepsy Surgery (The HFO Study)</brief_title>
  <official_title>Intra-operative Detection and Localisation of High Frequency Oscillations in the ECoG to Guide Epilepsy Surgery</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>UMC Utrecht</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Rudolf Magnus Institute - University of Utrecht</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>UMC Utrecht</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Epilepsy occurs in 0.5-0.7% of the population, of which 25% are children. 30% Of patients&#xD;
      with focal epilepsy do not respond well to medication and half of them are eligible for&#xD;
      epilepsy surgery. In recent years, the importance of early epilepsy surgery has been&#xD;
      stressed, as successful surgery may lead seizure and medication freedom and improved social&#xD;
      and cognitive development, especially in children. The current success rate of epilepsy&#xD;
      surgery is around 65%; During surgery intracranial electrocorticography (acute ECoG, aECoG)&#xD;
      is recorded in some medical centers. The presence of epileptiform brian activity, spikes,&#xD;
      identified by clinical neurophysiologists, is used to guide the neurosurgeon in the extent of&#xD;
      the brain tissue that needs to be resected. Spikes are considered markers of the presence of&#xD;
      epilepsy. High Frequency Oscillations (HFOs, &gt;80-500Hz) in the ECoG have recently been&#xD;
      identified as a new biomarker for epileptogenic tissue. Retrospective research shows that&#xD;
      their local presence strongly relates to the seizure onset, and removal of tissue with HFOs&#xD;
      could predict a better surgical outcome. The area showing HFOs usually overlaps with, but is&#xD;
      smaller than the area with spikes, and HFOs do not tend to propagate to distant sites as&#xD;
      spikes do. The identification of HFOs is more objective than of spikes and automatic&#xD;
      detection software exists.&#xD;
&#xD;
      A pilot study is performed to test the hypothesis : The intra-operative use of HFOs to&#xD;
      delineate the epileptogenic cortex does not yield significantly worse outcome in seizure&#xD;
      freedom than the current method based on spikes.&#xD;
&#xD;
      Study design is a single blinded multi-center randomized controlled trial. In two Dutch&#xD;
      centers, the VU medical center ( Amsterdam) and University Medical Center Utrecht.&#xD;
&#xD;
      The study population (sample size 78) consists of patients of all ages with refractory&#xD;
      epilepsy undergoing epilepsy surgery with aECoG to guide the extent of the resection.&#xD;
&#xD;
      Eligible patients are randomised, after informed consent, into group 1 (HFOs) in whom a&#xD;
      resection guided by HFOs in the aECoG (new), or into group 2 (spikes) in whom a resection is&#xD;
      guided by epileptiform spikes in the aECoG (current standard). Ictiform spike patterns will&#xD;
      always be resected.&#xD;
&#xD;
      Main study endpoint is outcome after epilepsy surgery after 1 year of follow-up dichotomized&#xD;
      in total seizure freedom (Engel Ia&amp;b) vs. seizure recurrence (Engel Ic-IV).&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date>November 2014</start_date>
  <completion_date type="Anticipated">June 2021</completion_date>
  <primary_completion_date type="Anticipated">February 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Post-surgical outcome</measure>
    <time_frame>12 months after surgery</time_frame>
    <description>To simplify analysis outcome scores will be dichotomized in two categories, total seizure freedom (Engel Ia+Ib) versus seizure recurrence (Engel Ic-IV).To enable interim analysis of the outcome in terms of seizures, we will determine preliminary post-surgical outcomes at 6-8 weeks and 6 months. A final outcome will be determined after 12 months. This will require the patients to fill in an additional short questionnaire on their seizure frequency at pre-surgical baseline (after singing informed consent), at 6-8 weeks, 6 and 12 months post- operatively (by telephone/email).&#xD;
So called 'running down' seizures, seizures that occur in the first 2 weeks after surgery are not considered as seizure recurrence.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Volume of resected tissue</measure>
    <time_frame>3 months after surgery a post-resection MRI is made</time_frame>
    <description>With HFOs being a more specific and sensitive biomarker for epileptogenic tissue than spikes, potentially the resection size could become smaller or larger. Therefore, the volume of resected tissue (in cm3) is investigated as a secondary parameter. The amount of resected tissue is determined by voxel-based volumetrics of the pre- and post-surgical MRI using Curryscan7 Neuroimaging Suite (Compumedics Neuroscan, Hamburg, GER).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurological deficits</measure>
    <time_frame>baseline + post operative before discharge, 6-8 weeks, 6 and 12 months</time_frame>
    <description>Neurological changes (e.g visual field defects, hemiparesis, word finding difficulties) can be divided into pre-existing, aggravated /improved, or new deficits, and can be anticipated or unexpected. The neurological changes and severity will be assessed by the doctor in charge/neurologist before surgery and prior to discharge out of hospital. In case of deficits they will be classified/quantified using the National Institutes of Health Stroke Scale (NIHSS) . This will be repeated by the doctor in charge/neurologist/neurosurgeon after 6 months and 12 months in case of initial neurological changes/deficits. The patient's total NIHSS scores is calculated by summation of all scores (NIHSS score range 0-42). A difference of 1 point on the NIHSS scale between 2 tests is considered clinical relevant in our population of epilepsy patients.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cognitive functioning</measure>
    <time_frame>pre- vs. post surgery (6 or 12 months)</time_frame>
    <description>Comparison of test results of pre- and post-operative (6 or 12 months) neurophysiological 695 investigation (NPO). This routine neurophysiological investigation includes testing of IQ (verbal and performal), working memory and processing speed. All tests conform to the age of the patient, but report on the same domains. Per domain individual patients' results will be dichotomized into negative/no/positive change compared to pre-surgical performance. This enables comparison of all patients, independent from age, at group level.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health related Quality of life (HRQOL)</measure>
    <time_frame>pre- vs. post-operative (6 or 12 months)</time_frame>
    <description>Health related quality of life (HRQOL; QUOLI89 for adults and an age adapted comparable list for children) will be determined pre-and post-operatively (6 or 12 months) during routine neurophysiological investigation (NPO). Interim assessment of HRQol will be enabled by a visual analogue scale (VAS) on overall self-perceived health (including their epilepsy) included in the baseline and follow-up questionnaire. This VAS scale is also part of the HRQoL tests.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Procedure duration</measure>
    <time_frame>intraoperative</time_frame>
    <description>Post-hoc analysis of duration of surgery (minutes) and aECoG recording time (minutes).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complications related to study procedures</measure>
    <time_frame>during 12 months of post-opertive follow-up</time_frame>
    <description>Complications related to study procedures Accounts are kept of the number of (post-)operative complications, such as bleeding, infection, unexpected or aggravated neurological deficits. These events will also be reported as (Serious) Adverse Events ((S)AEs). Monitoring and interim analysis by the DMC will be based on these numbers , as well as end-point determination.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">78</enrollment>
  <condition>Refractory Localization-related Epilepsy</condition>
  <arm_group>
    <arm_group_label>Spikes as biomarker</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>In arm &quot; spikes&quot; the resection of epileptogenic tissue is guided by epileptiform spikes in the aECoG (current standard). (Independent of the randomisation ictiform spike patterns will always be resected.)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>HFOs as biomarker</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>In arm &quot;HFOs&quot; resection of epileptogenic tissue is guided by HFOs in the aECoG (new). (Independent of the randomisation ictiform spike patterns will always be resected.)</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Tailoring of the resection based on biomarker in aEcoG during epilepsy surgery</intervention_name>
    <arm_group_label>HFOs as biomarker</arm_group_label>
    <arm_group_label>Spikes as biomarker</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Patients of all ages with:&#xD;
&#xD;
          -  Refractory Focal Epilepsy; at least ≥2 experienced seizures in the past 24 months, in&#xD;
             spite of 2 or more different anti-epileptic drugs tried.&#xD;
&#xD;
          -  Planned neurosurgery with aECoG, with the goal of tailoring the resection.&#xD;
&#xD;
          -  Command of Dutch language of the patient/parents/legal representatives and capability&#xD;
             of completing the questionnaires (by email or phone).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who underwent chronic ECoG monitoring preceding epilepsy surgery (grids).&#xD;
             This is a biased population, since the results of the extensive pre-surgical work-up&#xD;
             as well as the results of the cECoG monitoring period are included in the final&#xD;
             decision making regarding the resection, and a precise seizure onset zone as well as&#xD;
             spike and HFO area are known.&#xD;
&#xD;
          -  Patients with an occipital focus undergoing aECoG. Currently, it is not possible to&#xD;
             discriminate between pathological or physiological occipital HFOs, and thus unsafe to&#xD;
             perform HFO guided resections in patients with a presumed occipital focus.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Maeike Zijlmans, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Medical Center Utrecht, the Netherlands</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Maryse van 't Klooster, MSc.</last_name>
    <role>Study Director</role>
    <affiliation>University Medical Center Utrecht, the Netherlands</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>VU University medical center</name>
      <address>
        <city>Amsterdam</city>
        <zip>1081 HV</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Medical Center Utrecht</name>
      <address>
        <city>Utrecht</city>
        <zip>3584 CG</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <link>
    <url>http://research.umcutrechthersencentrum.nl/whos-who/bio/maeike-zijlmans/</url>
    <description>Related info</description>
  </link>
  <results_reference>
    <citation>van 't Klooster MA, Leijten FS, Huiskamp G, Ronner HE, Baayen JC, van Rijen PC, Eijkemans MJ, Braun KP, Zijlmans M; HFO study group. High frequency oscillations in the intra-operative ECoG to guide epilepsy surgery (&quot;The HFO Trial&quot;): study protocol for a randomized controlled trial. Trials. 2015 Sep 23;16:422. doi: 10.1186/s13063-015-0932-6.</citation>
    <PMID>26399310</PMID>
  </results_reference>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>July 31, 2014</study_first_submitted>
  <study_first_submitted_qc>August 1, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 4, 2014</study_first_posted>
  <last_update_submitted>November 3, 2020</last_update_submitted>
  <last_update_submitted_qc>November 3, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 4, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>UMC Utrecht</investigator_affiliation>
    <investigator_full_name>G.J.M. Zijlmans</investigator_full_name>
    <investigator_title>MD, PhD</investigator_title>
  </responsible_party>
  <keyword>epilepsy surgery</keyword>
  <keyword>biomarker</keyword>
  <keyword>high frequency oscillations (HFOs)</keyword>
  <keyword>acute electrocorticography (aECoG)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Epilepsy</mesh_term>
    <mesh_term>Epilepsies, Partial</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02207673
org study id: NL44527.041.13
secondary id: 13-389
secondary id: 2012-4
nct id: NCT02207673
lead sponsor: 
collaborator: 
has dmc: Yes
Epilepsy occurs in 0.5-0.7% of the population, of which 25% are children. 30% Of patients
      with focal epilepsy do not respond well to medication and half of them are eligible for
      epilepsy surgery. In recent years, the importance of early epilepsy surgery has been
      stressed, as successful surgery may lead seizure and medication freedom and improved social
      and cognitive development, especially in children. The current success rate of epilepsy
      surgery is around 65%; During surgery intracranial electrocorticography (acute ECoG, aECoG)
      is recorded in some medical centers. The presence of epileptiform brian activity, spikes,
      identified by clinical neurophysiologists, is used to guide the neurosurgeon in the extent of
      the brain tissue that needs to be resected. Spikes are considered markers of the presence of
      epilepsy. High Frequency Oscillations (HFOs, >80-500Hz) in the ECoG have recently been
      identified as a new biomarker for epileptogenic tissue. Retrospective research shows that
      their local presence strongly relates to the seizure onset, and removal of tissue with HFOs
      could predict a better surgical outcome. The area showing HFOs usually overlaps with, but is
      smaller than the area with spikes, and HFOs do not tend to propagate to distant sites as
      spikes do. The identification of HFOs is more objective than of spikes and automatic
      detection software exists.

      A pilot study is performed to test the hypothesis : The intra-operative use of HFOs to
      delineate the epileptogenic cortex does not yield significantly worse outcome in seizure
      freedom than the current method based on spikes.

      Study design is a single blinded multi-center randomized controlled trial. In two Dutch
      centers, the VU medical center ( Amsterdam) and University Medical Center Utrecht.

      The study population (sample size 78) consists of patients of all ages with refractory
      epilepsy undergoing epilepsy surgery with aECoG to guide the extent of the resection.

      Eligible patients are randomised, after informed consent, into group 1 (HFOs) in whom a
      resection guided by HFOs in the aECoG (new), or into group 2 (spikes) in whom a resection is
      guided by epileptiform spikes in the aECoG (current standard). Ictiform spike patterns will
      always be resected.

      Main study endpoint is outcome after epilepsy surgery after 1 year of follow-up dichotomized
      in total seizure freedom (Engel Ia&b) vs. seizure recurrence (Engel Ic-IV).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Participant)
measure: Post-surgical outcome
time frame: 12 months after surgery
description: To simplify analysis outcome scores will be dichotomized in two categories, total seizure freedom (Engel Ia+Ib) versus seizure recurrence (Engel Ic-IV).To enable interim analysis of the outcome in terms of seizures, we will determine preliminary post-surgical outcomes at 6-8 weeks and 6 months. A final outcome will be determined after 12 months. This will require the patients to fill in an additional short questionnaire on their seizure frequency at pre-surgical baseline (after singing informed consent), at 6-8 weeks, 6 and 12 months post- operatively (by telephone/email).
So called 'running down' seizures, seizures that occur in the first 2 weeks after surgery are not considered as seizure recurrence.
measure: Volume of resected tissue
time frame: 3 months after surgery a post-resection MRI is made
description: With HFOs being a more specific and sensitive biomarker for epileptogenic tissue than spikes, potentially the resection size could become smaller or larger. Therefore, the volume of resected tissue (in cm3) is investigated as a secondary parameter. The amount of resected tissue is determined by voxel-based volumetrics of the pre- and post-surgical MRI using Curryscan7 Neuroimaging Suite (Compumedics Neuroscan, Hamburg, GER).
measure: Neurological deficits
time frame: baseline + post operative before discharge, 6-8 weeks, 6 and 12 months
description: Neurological changes (e.g visual field defects, hemiparesis, word finding difficulties) can be divided into pre-existing, aggravated /improved, or new deficits, and can be anticipated or unexpected. The neurological changes and severity will be assessed by the doctor in charge/neurologist before surgery and prior to discharge out of hospital. In case of deficits they will be classified/quantified using the National Institutes of Health Stroke Scale (NIHSS) . This will be repeated by the doctor in charge/neurologist/neurosurgeon after 6 months and 12 months in case of initial neurological changes/deficits. The patient's total NIHSS scores is calculated by summation of all scores (NIHSS score range 0-42). A difference of 1 point on the NIHSS scale between 2 tests is considered clinical relevant in our population of epilepsy patients.
measure: Cognitive functioning
time frame: pre- vs. post surgery (6 or 12 months)
description: Comparison of test results of pre- and post-operative (6 or 12 months) neurophysiological 695 investigation (NPO). This routine neurophysiological investigation includes testing of IQ (verbal and performal), working memory and processing speed. All tests conform to the age of the patient, but report on the same domains. Per domain individual patients' results will be dichotomized into negative/no/positive change compared to pre-surgical performance. This enables comparison of all patients, independent from age, at group level.
measure: Health related Quality of life (HRQOL)
time frame: pre- vs. post-operative (6 or 12 months)
description: Health related quality of life (HRQOL; QUOLI89 for adults and an age adapted comparable list for children) will be determined pre-and post-operatively (6 or 12 months) during routine neurophysiological investigation (NPO). Interim assessment of HRQol will be enabled by a visual analogue scale (VAS) on overall self-perceived health (including their epilepsy) included in the baseline and follow-up questionnaire. This VAS scale is also part of the HRQoL tests.
measure: Procedure duration
time frame: intraoperative
description: Post-hoc analysis of duration of surgery (minutes) and aECoG recording time (minutes).
measure: Complications related to study procedures
time frame: during 12 months of post-opertive follow-up
description: Complications related to study procedures Accounts are kept of the number of (post-)operative complications, such as bleeding, infection, unexpected or aggravated neurological deficits. These events will also be reported as (Serious) Adverse Events ((S)AEs). Monitoring and interim analysis by the DMC will be based on these numbers , as well as end-point determination.
arm group label: Spikes as biomarker
arm group type: Active Comparator
description: In arm " spikes" the resection of epileptogenic tissue is guided by epileptiform spikes in the aECoG (current standard). (Independent of the randomisation ictiform spike patterns will always be resected.)
arm group label: HFOs as biomarker
arm group type: Experimental
description: In arm "HFOs" resection of epileptogenic tissue is guided by HFOs in the aECoG (new). (Independent of the randomisation ictiform spike patterns will always be resected.)
intervention type: Procedure
intervention name: Tailoring of the resection based on biomarker in aEcoG during epilepsy surgery
arm group label: HFOs as biomarker
arm group label: Spikes as biomarker
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: Maeike Zijlmans, MD, PhD
role: Principal Investigator
affiliation: University Medical Center Utrecht, the Netherlands
last name: Maryse van 't Klooster, MSc.
role: Study Director
affiliation: University Medical Center Utrecht, the Netherlands
facility: 
facility: 
country: Netherlands
url: http://research.umcutrechthersencentrum.nl/whos-who/bio/maeike-zijlmans/
description: Related info
citation: van 't Klooster MA, Leijten FS, Huiskamp G, Ronner HE, Baayen JC, van Rijen PC, Eijkemans MJ, Braun KP, Zijlmans M; HFO study group. High frequency oscillations in the intra-operative ECoG to guide epilepsy surgery ("The HFO Trial"): study protocol for a randomized controlled trial. Trials. 2015 Sep 23;16:422. doi: 10.1186/s13063-015-0932-6.
PMID: 26399310
responsible party type: Principal Investigator
investigator affiliation: UMC Utrecht
investigator full name: G.J.M. Zijlmans
investigator title: MD, PhD
mesh term: Epilepsy
mesh term: Epilepsies, Partial