Evaluating Dietary Intervention Before surgicaL Treatment for Epilepsy
NCT ID: NCT02261753
Last Updated: 2017-09-25
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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TERMINATED
NA
3 participants
INTERVENTIONAL
2014-10-31
2017-07-26
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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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.
Classical ketogenic diet
A high fat low carbohydrate, low protein diet.
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.
No interventions assigned to this group
Interventions
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Classical ketogenic diet
A high fat low carbohydrate, low protein diet.
Eligibility Criteria
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Inclusion Criteria
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
2. Not a surgical candidate for FCD resection;
3. Administration of the KD is medically contraindicated.
3 Years
15 Years
ALL
No
Sponsors
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University of Liverpool
OTHER
University College, London
OTHER
Responsible Party
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Principal Investigators
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J Helen Cross, MB ChB PhD
Role: PRINCIPAL_INVESTIGATOR
UCL-London
Locations
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Johns Hopkins Hospital
Baltimore, Maryland, United States
Medical University Vienna
Vienna, , Austria
Motol University Hospital
Prague, , Czechia
Hospices Civil De Lyon
Lyon, , France
Hopital de Hautepierre
Strasbourg, , France
Krakenhaus Mara Maraweg
Bielefeld, , Germany
Schpn Klinik Vogtareuth
Vogtareuth, , Germany
Childrens Hospital Meyer
Florence, , Italy
Ospedale Pediatric Bambino Gesu
Rome, , Italy
Hopitaux Universitaires de Geneve
Geneva, , Switzerland
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 Kingdom
Countries
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References
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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. doi: 10.1056/NEJM200108023450501.
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.
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. doi: 10.1111/j.1528-1167.2007.01421.x. Epub 2007 Nov 27.
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.
Blumcke 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.
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.
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.
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.
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.
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.
Hahnen E, Hauke J, Trankle C, Eyupoglu IY, Wirth B, Blumcke 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.
Gottlicher M, Minucci S, Zhu P, Kramer 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. doi: 10.1093/emboj/20.24.6969.
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.
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.
Kobow K, Kaspi A, Harikrishnan KN, Kiese K, Ziemann M, Khurana I, Fritzsche I, Hauke J, Hahnen E, Coras R, Muhlebner A, El-Osta A, Blumcke 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.
Other Identifiers
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13/0688
Identifier Type: -
Identifier Source: org_study_id