Evaluating Dietary Intervention Before surgicaL Treatment for Epilepsy

NCT02261753 | Terminated DMC

• 1 other identifier: 13/0688
• Study Type: interventional
• Target: 3
• Locations: 8 countries
• Sites: 15

Brief 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.

Conditions

Cortical Dysplasia

Keywords

epilepsy surgery, outcome, ketogenic diet, ortical dysplasia

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (9)

• Time to first seizure from date of randomisation;

  33 months

• Time to 12 month remission after randomisation

  45 months

• Time to 24 month remission after randomisation (if enough time for follow-up is available)

  45 months

• Quality of life at 12 (and at 24 months if enough time for follow-up is available)

  45 months

• Adaptive behaviour assessment at 12 months, after randomisation (and at 24 months if enough time for follow-up is available);

  45 months

Study Arms (2)

A: Classical ketogenic diet

ACTIVE COMPARATOR

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

B: No pretreatment

NO INTERVENTION

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.

Interventions

Classical ketogenic diet DIETARY_SUPPLEMENT

A high fat low carbohydrate, low protein diet.

A: Classical ketogenic diet

Eligibility Criteria

• Age: 3 Years - 15 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

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

You may not qualify if:

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

Sponsors & Collaborators

• University College, London: lead
• University of Liverpool: collaborator

Study Sites (15)

Johns Hopkins Hospital

Baltimore, Maryland, 21218, United States

Location

Medical University Vienna

Vienna, Austria

Location

Motol University Hospital

Prague, Czechia

Location

Hospices Civil De Lyon

Lyon, 69500, France

Location

Hopital de Hautepierre

Strasbourg, 67098, France

Location

Krakenhaus Mara Maraweg

Bielefeld, 33617, Germany

Location

Schpn Klinik Vogtareuth

Vogtareuth, 83569, Germany

Location

Childrens Hospital Meyer

Florence, 50139, Italy

Location

Ospedale Pediatric Bambino Gesu

Rome, 00165, Italy

Location

Hopitaux Universitaires de Geneve

Geneva, CH-1211, Switzerland

Location

Birmingham Childrens Hospital

Birmingham, B4 6NH, United Kingdom

Location

Bristol Childrens Hospital

Bristol, BS2 8AE, United Kingdom

Location

Royal Hospital for Sick Children

Edinburgh, EH9 1LF, United Kingdom

Location

Great Ormond Street Hospital for Children NHS Trust

London, WC1N 3JH, United Kingdom

Location

Manchester Childrens Hospital

Manchester, M27 4HA, United Kingdom

Location

Related Publications (15)

• 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.

  PMID: 11484687 BACKGROUND

• 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.

  PMID: 22396514 BACKGROUND

• 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.

  PMID: 18042232 BACKGROUND

• 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.

  PMID: 19175385 BACKGROUND

• 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.

  PMID: 21219302 BACKGROUND

• 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.

  PMID: 22419282 BACKGROUND

• 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.

  PMID: 18456557 BACKGROUND

• 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.

  PMID: 19054400 BACKGROUND

• 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.

  PMID: 23294191 BACKGROUND

• 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.

  PMID: 18676519 BACKGROUND

• 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.

  PMID: 18230051 BACKGROUND

• 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.

  PMID: 11742974 BACKGROUND

• 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.

  PMID: 22215131 BACKGROUND

• 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.

  PMID: 20228804 BACKGROUND

• 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.

  PMID: 24005891 BACKGROUND

MeSH Terms

Conditions

Malformations of Cortical Development

Condition Hierarchy (Ancestors)

Nervous System Malformations; Nervous System Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• J Helen Cross, MB ChB PhD

  UCL-London

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 26, 2014
• First Posted: October 10, 2014
• Study Start: October 1, 2014
• Primary Completion: July 26, 2017
• Study Completion: July 26, 2017
• Last Updated: September 25, 2017

Record last verified: 2014-10

Locations

CZ (1); FR (2); GB (5); US (1); AU (1); IT (2); CH (1); DE (2)