Evaluating Dietary Intervention Before surgicaL Treatment for Epilepsy (EDIBLE)

September 21, 2017 updated by: University College, London

A Randomised Controlled Trial to Compare Seizure Remission Outcome Following Resective Surgery With or Without Prior Treatment With Ketogenic Diet in Children With Epilepsy the Result of Focal Cortical Dysplasia Type II

The investigators are undertaking the first European Randomised Controlled Trial (RCT) for epilepsy surgery in children with FCD type II, to prospectively evaluate the role of the KD prior to surgery in improving seizure outcome. The investigators will evaluate the role of KD as a disease-modifying treatment to achieve seizure control and improve neurodevelopment and quality of life. Children age 3 - 15 years with pharmacoresistant epilepsy believed to be the result of focal cortical dysplasia type II, considered to be surgically treatable, will be randomised to either receive 6m treatment presurgery with a ketogenic diet, or to proceed direct to surgery (no pretreatment). Primary outcome will be the time to achieve a period of 6 months of seizure freedom from the date of randomisation. Tissue resected at surgery will also be evaluated with regard to the degree of any methylation of DNA.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Epilepsy surgery is now an accepted and effective management for individuals with drug resistant focal onset epilepsy in carefully selected candidates. This aside, only two RCTs have been performed in adults in temporal lobe epilepsy [1,2], and none in children . Malformations of cortical development are the most common pathology responsible for drug resistant focal epilepsy in childhood [3}. In retrospective studies, successful surgical resection resulting in seizure freedom in malformations of cortical development has been reported in 42-87% of cases [4], dependent on the series reviewed and the completeness of resection. Outcome is related to extent and completeness of resection, but the extent of tissue to be removed remains a challenge, especially in very young patients, where the limits of a lesion may be unclear and eloquent cortex may be involved.

FCD is one specific type of malformation, of localised areas of abnormal cortex that may be subdivided into I, II and III dependent on the pattern determined and cell types involved. This is by definition a histological diagnosis as was recently classified by the International League Against Epilepsy [5]. Specifically FCD type II can usually be suggested by characteristic changes on an MRI scan. These changes include increased cortical thickness, blurring of the cortical-white matter junction, increased signal on T2-weighted images, a radially oriented linear or conical transmantle strip of T2 hyperintensity, cortical thinning and localized brain atrophy. FCD type II may be subdivided histopathologically into IIa and IIb but it can be difficult to distinguish between the two radiologically.

The KD is a high fat diet with a proven efficacy in the treatment of drug resistant epilepsy in children [6]. An RCT performed in children aged 2-16 years diagnosed with drug resistant epilepsy utilising either a classical or medium chain triglyceride KD, demonstrated >50% reduction in seizures in 38% of participants after 3 months compared to 6% where there was no change in standard treatment, with no difference seen between the two diets [7,8]. A further RCT utilising a more relaxed approach of the KD, the modified Atkins diet, demonstrated similar results [9]. One open label study suggested particular efficacy in children with epilepsy due to FCD [10].

Clinical trials of epigenetic pharmacological treatment are promising and already have been approved for cancer [11]. Intriguingly, the most commonly used AED is valproic acid (VPA), in which histone deacetylase (HDAC) inhibitor activity was discovered in 2001 [12]. The HDAC antagonizing effect of VPA is, however, considerably low compared to second generation HDAC inhibitors suberoylanilide hydroxamic acid (SAHA, Zolinza, Vorinostat), LBH598 or Romidepsin [11]. Unfortunately, all HDAC inhibitors bear the risk of severe side effects when systemically administered during pregnancy. Nevertheless, there is also evidence that the epigenetic machinery can be modified by nutrition and dietary concepts [13]; such a dietary concept is the KD. Stimulus-induced DNA methylation changes have been identified in postnatal brain [14], thus it can be anticipated that DNA methylation modifications contribute to the molecular memory of postmitotic neurons also in the epileptogenic network. We propose that therapies such as the KD that are directly or indirectly targeting the epigenetic machinery could be helpful to prevent, delay or retard drug-resistant epilepsy.

Recent experimental data in an animal model has shown that the classical KD attenuates epigenetic chromatin modifications (i.e. DNA methylation), a master regulator for gene expression and functional adaptation of the cell, thereby modifying disease progression [15]. This hypothesis suggests that epigenetic mechanisms play a pivotal role in epileptogenesis and that seizures can by themselves induce epigenetic chromatin modifications, aggravating the epileptogenic condition [15].

We will conduct the first RCT for epilepsy surgery in children with FCD type II, to prospectively evaluate the role of the KD prior to surgery.

120 children aged 3 - 15 years with a diagnosis of Focal Cortical Dysplasia (FCD) type II a or b (with consistent MRI changes), treatment failure of at least two anti-epileptic drugs (AEDs) in controlling continuing seizures, with seizure semiology consistent with focal onset agreed to be surgically treatable through FCD resection and continuing seizures for less than 5 years, will be included in the trial after parental/ legal representative consent. Children will be excluded if they have a history of less than two seizures in 6 months prior to randomisation or they have previously used the Ketogenic diet (KD) or administration of the KD is medically contraindicated. Patients will be recruited from 19 participating European sites in 8 countries undertaking ketogenic diet and epilepsy surgery in children.

Participants will be followed-up for minimum 24 months/maximum 48 months (depending on the timing of randomisation) after randomisation. Primary outcome will be time to 6 month remission (i.e. the time to achieve a period of 6 months of seizure freedom from the date of randomisation). Tissue removed at surgery will be assessed for DNA methylation.

Study Type

Interventional

Enrollment (Actual)

3

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Austria
      • Vienna, Austria
        • Medical University Vienna
  • Czechia
      • Prague, Czechia
        • Motol University Hospital
  • France
      • Lyon, France, 69500
        • Hospices Civil de Lyon
      • Strasbourg, France, 67098
        • Hôpital de Hautepierre
  • Germany
      • Bielefeld, Germany, 33617
        • Krakenhaus Mara Maraweg
      • Vogtareuth, Germany, 83569
        • Schpn Klinik Vogtareuth
  • Italy
      • Florence, Italy, 50139
        • Childrens Hospital Meyer
      • Rome, Italy, 00165
        • Ospedale Pediatric Bambino Gesu
  • Switzerland
      • Geneva, Switzerland, CH-1211
        • Hopitaux Universitaires de Geneve
  • United Kingdom
      • Birmingham, United Kingdom, B4 6NH
        • Birmingham Childrens Hospital
      • Bristol, United Kingdom, BS2 8AE
        • Bristol Childrens Hospital
      • Edinburgh, United Kingdom, EH9 1LF
        • Royal Hospital for Sick Children
      • London, United Kingdom, WC1N 3JH
        • Great Ormond street Hospital for Children NHS Trust
      • Manchester, United Kingdom, M27 4HA
        • Manchester Childrens Hospital
  • United States
    • Maryland
      • Baltimore, Maryland, United States, 21218
        • Johns Hopkins Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

3 years to 15 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Children aged 3 - 15 years;
  2. MRI changes consistent with a diagnosis of FCD type II a or b;
  3. History of at least two epileptic seizures in the past 6 months before randomisation;
  4. Seizure semiology consistent with focal onset, agreed after pre-surgical discussion to be surgically treatable;
  5. Parent/ legal representative willing to give consent.

Exclusion Criteria:

  1. Previous use of the KD;
  2. Not a surgical candidate for FCD resection;
  3. Administration of the KD is medically contraindicated.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: A: Classical ketogenic diet
The KD is a high fat, low carbohydrate, low protein diet designed to mimic the effects of fasting on the body. It will be administered by calculation as per local standardised classical KD protocol with utilisation of long chain fat in a ratio of 2:1 to 4:1 carbohydrate and protein.
Dietary supplement: Classical ketogenic diet
A high fat low carbohydrate, low protein diet.
No Intervention: B: No pretreatment
Following the decision to proceed to surgery, if randomised to this arm a date will be given for surgery as per routine clinical practice. No KD pre-treatment will be undertaken.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to 6 month remission
Time Frame: Month 33
the time to achieve a period of 6 months of seizure freedom from the date of randomisation pretreated KD group vs non pretreated group
Month 33

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to first seizure from date of randomisation;
Time Frame: 33 months
The time to first seizure from date of randomisation, KD pretreated vs non pretreated group
33 months
Time to 12 month remission after randomisation
Time Frame: 45 months
Time to 12 month remission from seizures from date of randomisation, KD pretreated vs non pretreated group
45 months
Time to 24 month remission after randomisation (if enough time for follow-up is available)
Time Frame: 45 months
Time to 24 months remission from seizures from date of randomisation, KD pretreated vs non pretreated group
45 months
Quality of life at 12 (and at 24 months if enough time for follow-up is available)
Time Frame: 45 months
As determined by KINDL questionnaire, comparison of pretreated vs non pretreated group
45 months
Adaptive behaviour assessment at 12 months, after randomisation (and at 24 months if enough time for follow-up is available);
Time Frame: 45 months
Comparison of neurodevelopmental change between pretreated and non pretreated KD group, as measured by Vineland adaptive behaviour scales
45 months
Methylation changes in tissue (DNA) from children pre-treated with the ketogenic diet compared to those not pretreated
Time Frame: 60 months
As measured from tissue resected at surgery
60 months
Changes in peripheral DNA (blood platelets) following treatment with the KD
Time Frame: 60 months
As measured from samples taken following the KD
60 months
Proportion of immediate AEs following resective surgery (i.e. surgical complications within 30 days)
Time Frame: 45 months
As compared between groups, group pre-treated with KD compared to those without
45 months
Compare the general AE occurrence
Time Frame: 60 months
As compared between groups, group pre-treated with KD compared to those without
60 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University College, London

Collaborators

University of Liverpool

Investigators

  • Principal Investigator: J Helen Cross, MB ChB PhD, UCL-London

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2014

Primary Completion (Actual)

July 26, 2017

Study Completion (Actual)

July 26, 2017

Study Registration Dates

First Submitted

September 26, 2014

First Submitted That Met QC Criteria

October 6, 2014

First Posted (Estimate)

October 10, 2014

Study Record Updates

Last Update Posted (Actual)

September 25, 2017

Last Update Submitted That Met QC Criteria

September 21, 2017

Last Verified

October 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 13/0688

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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