Evaluating Dietary Intervention Before surgicaL Treatment for Epilepsy

Cortical Dysplasia Clinical Trial

— EDIBLE  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02261753
• Other study ID #: 13/0688
• Status: Terminated
• Phase: N/A
• First received: September 26, 2014
• Last updated: September 21, 2017
• Start date: October 2014
• Est. completion date: July 26, 2017

Study information

• Verified date: October 2014
• Source: University College, London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 3
• Est. completion date: July 26, 2017
• Est. primary completion date: July 26, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 15 Years

Eligibility

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.

Related Conditions & MeSH terms

• Cortical Dysplasia
• Epilepsy

Intervention

Dietary Supplement:
• Classical ketogenic diet
A high fat low carbohydrate, low protein diet.

Locations

Country	Name	City	State
Austria	Medical University Vienna	Vienna
Czechia	Motol University Hospital	Prague
France	Hospices Civil De Lyon	Lyon
France	Hopital de Hautepierre	Strasbourg
Germany	Krakenhaus Mara Maraweg	Bielefeld
Germany	Schpn Klinik Vogtareuth	Vogtareuth
Italy	Childrens Hospital Meyer	Florence
Italy	Ospedale Pediatric Bambino Gesu	Rome
Switzerland	Hopitaux Universitaires de Geneve	Geneva
United Kingdom	Birmingham Childrens Hospital	Birmingham
United Kingdom	Bristol Childrens Hospital	Bristol
United Kingdom	Royal Hospital for Sick Children	Edinburgh
United Kingdom	Great Ormond Street Hospital for Children NHS Trust	London
United Kingdom	Manchester Childrens Hospital	Manchester
United States	Johns Hopkins Hospital	Baltimore	Maryland

Sponsors (2)

Lead Sponsor	Collaborator
University College, London	University of Liverpool

Countries where clinical trial is conducted

United States,  Austria,  Czechia,  France,  Germany,  Italy,  Switzerland,  United Kingdom, 

References & Publications (15)

Blümcke I, Thom M, Aronica E, Armstrong DD, Vinters HV, Palmini A, Jacques TS, Avanzini G, Barkovich AJ, Battaglia G, Becker A, Cepeda C, Cendes F, Colombo N, Crino P, Cross JH, Delalande O, Dubeau F, Duncan J, Guerrini R, Kahane P, Mathern G, Najm I, Ozkara C, Raybaud C, Represa A, Roper SN, Salamon N, Schulze-Bonhage A, Tassi L, Vezzani A, Spreafico R. The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia. 2011 Jan;52(1):158-74. doi: 10.1111/j.1528-1167.2010.02777.x. Epub 2010 Nov 10. — View Citation

Engel J Jr, McDermott MP, Wiebe S, Langfitt JT, Stern JM, Dewar S, Sperling MR, Gardiner I, Erba G, Fried I, Jacobs M, Vinters HV, Mintzer S, Kieburtz K; Early Randomized Surgical Epilepsy Trial (ERSET) Study Group. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA. 2012 Mar 7;307(9):922-30. doi: 10.1001/jama.2012.220. — View Citation

Feil R, Fraga MF. Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet. 2012 Jan 4;13(2):97-109. doi: 10.1038/nrg3142. Review. — View Citation

Feng J, Zhou Y, Campbell SL, Le T, Li E, Sweatt JD, Silva AJ, Fan G. Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci. 2010 Apr;13(4):423-30. doi: 10.1038/nn.2514. Epub 2010 Mar 14. — View Citation

Göttlicher M, Minucci S, Zhu P, Krämer OH, Schimpf A, Giavara S, Sleeman JP, Lo Coco F, Nervi C, Pelicci PG, Heinzel T. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001 Dec 17;20(24):6969-78. — View Citation

Hahnen E, Hauke J, Tränkle C, Eyüpoglu IY, Wirth B, Blümcke I. Histone deacetylase inhibitors: possible implications for neurodegenerative disorders. Expert Opin Investig Drugs. 2008 Feb;17(2):169-84. doi: 10.1517/13543784.17.2.169. Review. — View Citation

Harvey AS, Cross JH, Shinnar S, Mathern GW; ILAE Pediatric Epilepsy Surgery Survey Taskforce. Defining the spectrum of international practice in pediatric epilepsy surgery patients. Epilepsia. 2008 Jan;49(1):146-55. Epub 2007 Nov 27. Erratum in: Epilepsia. 2013 Jun;54(6):1140. Mathern, Bary W [corrected to Mathern, Gary W]. — View Citation

Jung DE, Kang HC, Kim HD. Long-term outcome of the ketogenic diet for intractable childhood epilepsy with focal malformation of cortical development. Pediatrics. 2008 Aug;122(2):e330-3. doi: 10.1542/peds.2008-0012. — View Citation

Kobow K, Kaspi A, Harikrishnan KN, Kiese K, Ziemann M, Khurana I, Fritzsche I, Hauke J, Hahnen E, Coras R, Mühlebner A, El-Osta A, Blümcke I. Deep sequencing reveals increased DNA methylation in chronic rat epilepsy. Acta Neuropathol. 2013 Nov;126(5):741-56. doi: 10.1007/s00401-013-1168-8. Epub 2013 Sep 5. — View Citation

Lerner JT, Salamon N, Hauptman JS, Velasco TR, Hemb M, Wu JY, Sankar R, Donald Shields W, Engel J Jr, Fried I, Cepeda C, Andre VM, Levine MS, Miyata H, Yong WH, Vinters HV, Mathern GW. Assessment and surgical outcomes for mild type I and severe type II cortical dysplasia: a critical review and the UCLA experience. Epilepsia. 2009 Jun;50(6):1310-35. doi: 10.1111/j.1528-1167.2008.01998.x. Epub 2009 Jan 21. Review. — View Citation

Levy RG, Cooper PN, Giri P. Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database Syst Rev. 2012 Mar 14;(3):CD001903. doi: 10.1002/14651858.CD001903.pub2. Review. Update in: Cochrane Database Syst Rev. 2016;2:CD001903. — View Citation

Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH. A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Epilepsia. 2009 May;50(5):1109-17. doi: 10.1111/j.1528-1167.2008.01870.x. Epub 2008 Nov 19. — View Citation

Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol. 2008 Jun;7(6):500-6. doi: 10.1016/S1474-4422(08)70092-9. Epub 2008 May 2. — View Citation

Sharma S, Sankhyan N, Gulati S, Agarwala A. Use of the modified Atkins diet for treatment of refractory childhood epilepsy: a randomized controlled trial. Epilepsia. 2013 Mar;54(3):481-6. doi: 10.1111/epi.12069. Epub 2013 Jan 7. — View Citation

Wiebe S, Blume WT, Girvin JP, Eliasziw M; Effectiveness and Efficiency of Surgery for Temporal Lobe Epilepsy Study Group. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001 Aug 2;345(5):311-8. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to 6 month remission	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	Time to first seizure from date of randomisation;	The time to first seizure from date of randomisation, KD pretreated vs non pretreated group	33 months
Secondary	Time to 12 month remission after randomisation	Time to 12 month remission from seizures from date of randomisation, KD pretreated vs non pretreated group	45 months
Secondary	Time to 24 month remission after randomisation (if enough time for follow-up is available)	Time to 24 months remission from seizures from date of randomisation, KD pretreated vs non pretreated group	45 months
Secondary	Quality of life at 12 (and at 24 months if enough time for follow-up is available)	As determined by KINDL questionnaire, comparison of pretreated vs non pretreated group	45 months
Secondary	Adaptive behaviour assessment at 12 months, after randomisation (and at 24 months if enough time for follow-up is available);	Comparison of neurodevelopmental change between pretreated and non pretreated KD group, as measured by Vineland adaptive behaviour scales	45 months
Secondary	Methylation changes in tissue (DNA) from children pre-treated with the ketogenic diet compared to those not pretreated	As measured from tissue resected at surgery	60 months
Secondary	Changes in peripheral DNA (blood platelets) following treatment with the KD	As measured from samples taken following the KD	60 months
Secondary	Proportion of immediate AEs following resective surgery (i.e. surgical complications within 30 days)	As compared between groups, group pre-treated with KD compared to those without	45 months
Secondary	Compare the general AE occurrence	As compared between groups, group pre-treated with KD compared to those without	60 months