Ketogenic Diet in Infants With Epilepsy (KIWE)

NCT ID: NCT02205931

Last Updated: 2017-05-04

Study Results

Results pending

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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Recruitment Status

UNKNOWN

Clinical Phase

PHASE4

Total Enrollment

160 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-01-31

Study Completion Date

2019-06-30

Brief Summary

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Epilepsy, a condition where individuals are prone to recurrent epileptic seizures, is the most common chronic neurological disorder in children. Epilepsy onset is most common in the first two years of life and is associated with poor prognosis for seizure control and neurodevelopmental outcome.

The ketogenic diet (KD) is a medically supervised diet that is high in fat and restricted in carbohydrates and protein. KD therapy has shown to be an effective treatment for seizures in children with epilepsy older than two. Associated benefits include: a reduced requirement for routine and emergency antiepileptic drugs (AED) and fewer seizure related hospital admissions. Although reports suggest that KD therapy improves seizures in younger children there is no high quality trial data that demonstrates effectiveness and safety in this age group. The KD is resource intensive, requiring dietetic and physician time; data is required to justify expansion of services to cater for the apparent need.

The investigators therefore propose a prospective multicentre randomised trial to investigate the effectiveness and safety of the KD in children with epilepsy under the age of 2, who have failed to respond to two or more AEDs. Children will be randomly assigned to either receive the KD or further AEDs. The allocated treatment will be started after a 2week baseline period, and it's effectiveness assessed after 8 weeks. Seizure diaries will be used to record seizures and related events, a questionnaire will be used to assess diet tolerance; also growth and blood biochemistry will be monitored.

The information obtained from this study is necessary to optimise choices in epilepsy treatment, aiming to improve outcomes and thus determine whether and when the KD should should be used.

Detailed Description

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The project proposed is a randomised controlled multicentre study of infants with epilepsy who have failed to respond to two or more pharmacological treatments (antiepileptic drugs (AEDs) or corticosteroids), comparing ketogenic diet to treatment with a further AED.

Children for this study will be recruited from 8 paediatric neurology centres in the South of England who have an established KD service for children with epilepsy. The collaborating paediatric neurologists based in these centres are named co-applicants on this proposal. All children ages 3 to 24 months will be considered if they have a diagnosis of epilepsy, namely continuing seizures despite a trial of 2 or more AEDs (including corticosteroids) and are experiencing at least 8 seizures a week.

Children will be excluded if they are shown to have: a metabolic disease contradicting the use of KD; a progressive neurological disease; severe gastrooesophageal reflux or have undergone a previous failed trial of KD. In addition, families should be able to attend clinic on the required timeline. KD meal plans will be accurately calculated for each child individually by a dietitian with consideration of daily calorie requirements, fat to carbohydrate ratio (3:1 or 4:1), adequate protein intake and vitamin and mineral supplementation. Ongoing adjustments to the diet by the dietitian are determined by weight gain and the degree of ketosis.

1. Baseline assessment: Written consent will be obtained from eligible children. Full history including seizure type, neurological examination, weight, length and head circumference will be documented. Randomisation to KD or standard AED group will be carried out with the support of the UCL PRIMENT Clinical Trials Unit (CTU).

Investigations to be performed in the KD group (or if clinically indicated in the AED group) will include FBC, U\&Es, Glucose, LFTs, Calcium, Magnesium, Phosphate, Zinc, Selenium, Acylcarnitine profile, Cholesterol, Triglycerides, Urate, 25 hydroxy Vitamin D, urine calcium/creatinine, urine organic acids. An EEG will be performed if clinically indicated.
2. Observation period of 2 weeks: No changes of regular AEDs. Emergency seizure treatments will continue as required( acute treatment with benzodiazepines). The following data will be recorded in a standardized diary (these data will continue to be recorded throughout the intervention period of 8 weeks): seizure types, seizure frequency, number of emergency seizure treatments required, contacts with the NHS due to seizure exacerbation (hospital admissions number of days, A\&E and or GP attendances)
3. Start of the classical KD or further AED. The classical KD will be administered as per protocol of the treating service. The recording of seizure types and frequency is to be continued.
4. Second Assessment (4 weeks after the start of the treatment period, all patients): clinical review including weight; documentation of seizure frequency, and tolerability of the diet in randomised KD group by questionnaire.
5. Third/final assessment (8 weeks after starting treatment/all patients). Clinical review including neurological examination, weight, length and head circumference. Documentation of seizure outcome (from seizure diaries). KD group only: completion of tolerability questionnaire, blood investigations (FBC, U\&Es, Glucose, LFTs, plasma bicarbonate, calcium, magnesium, phosphate, zinc, selenium, acylcarnitine profile, cholesterol, triglycerides, urate, nonesterified fatty acids, blood ketones) and urine calcium/creatinine ratio. EEG will be performed if clinically indicated.

Dependent on seizure response, KD (diet group) or AED (standard AED group) will then be continued or changed. Those in the AED group of failed will be offered KD outside the context of the trial. It would be anticipated that clinical data would be collected on all patients to 12 months to determine retention rates.

Exit criteria: Children will withdraw from the treatment prior to 8 weeks should there be q \>50% increase in seizure frequency from the baseline, or if intolerable side effects are not resolved by manipulation of KD or medication. A safety monitoring committee will be convened.

Conditions

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Epilepsy

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

SINGLE

Outcome Assessors

Study Groups

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Ketogenic diet

8 week trial of the ketogenic diet (KD) therapy. Children allocated to KD therapy will have their diets individually calculated by a paediatric dietitian with consideration of daily calorie requirements, adequate protein intake for growth and vitamin and mineral supplementation. All diets will be implemented according to a classical KD protocol, i.e. based on a ratio of fat to carbohydrate and protein that will usually be between 2:1 and 4:1.

Group Type EXPERIMENTAL

Ketogenic diet

Intervention Type OTHER

The ketogenic diet is a high fat diet designed to mimic the effects on the body of starvation. The premise is the main energy intake is fat, which is utilised in the body and produces ketones.

Antiepileptic drug therapy

The control intervention will be drug therapy with the most appropriate further antiepileptic drug (AED) for a particular child, depending on their presenting seizures and syndrome and previous drugs used, and chosen by the expert clinician responsible for management of the patient's epilepsy according to a standardised manual (consensus document) written following the initial workshop of the paediatric neurologists from all the trial centres.

Group Type ACTIVE_COMPARATOR

Antiepileptic drug therapy

Intervention Type DRUG

The control intervention will be drug therapy with the most appropriate further antiepileptic drug for a particular child, depending on their presenting seizures and syndrome and previous drugs used, and chosen by the expert clinician responsible for management of the patient's epilepsy.

Interventions

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Ketogenic diet

The ketogenic diet is a high fat diet designed to mimic the effects on the body of starvation. The premise is the main energy intake is fat, which is utilised in the body and produces ketones.

Intervention Type OTHER

Antiepileptic drug therapy

The control intervention will be drug therapy with the most appropriate further antiepileptic drug for a particular child, depending on their presenting seizures and syndrome and previous drugs used, and chosen by the expert clinician responsible for management of the patient's epilepsy.

Intervention Type DRUG

Other Intervention Names

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Carbamazepine Clobazam Clonazepam Ethosuximide Lacosmide Lamotrigine Levetiracetam Nitrazepam Phenytoin Rufinamide Sodium Valproate Stiripentol Topiramate Vigabatrin Zonisamide

Eligibility Criteria

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Inclusion Criteria

1. Age between 1 month and 24 months of age (not beyond second birthday at baseline).
2. Diagnosis of epilepsy confirmed.
3. At least an average of 4 seizures/week in baseline period.
4. Failed response to previous trial of two anti-epileptic drugs. In the case of infantile spasms this could include a trial of corticosteroids.
5. Children with written informed consent from parent/guardian.

Exclusion Criteria

1. Age \<1m or \> 24 months of age
2. No secure diagnosis of epilepsy
3. \< 4 seizures/week on average in baseline period
4. Trial of \< 2 AEDs
5. Continues on corticosteroids in previous 3 months prior to randomisation
6. Metabolic disease contraindicating use of the ketogenic diet e.g. pyruvate carboxylase deficiency, MCAD from previous medical investigation and screening at baseline.
7. Progressive neurological disease
8. Severe gastroesophageal reflux
9. Previous treatment with the ketogenic diet
10. Concurrent participation in another clinical trial of an investigational medicinal product.
11. Patients who are prescribed AEDs not listed in the trial IMPs
Minimum Eligible Age

1 Month

Maximum Eligible Age

2 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Great Ormond Street Hospital for Children NHS Foundation Trust

OTHER

Sponsor Role collaborator

Cambridge University Hospitals NHS Foundation Trust

OTHER

Sponsor Role collaborator

Alder Hey Children's NHS Foundation Trust

OTHER

Sponsor Role collaborator

Bristol Royal Hospital for Children

OTHER

Sponsor Role collaborator

Birmingham Women's and Children's NHS Foundation Trust

OTHER

Sponsor Role collaborator

The Leeds Teaching Hospitals NHS Trust

OTHER

Sponsor Role collaborator

Manchester University NHS Foundation Trust

OTHER_GOV

Sponsor Role collaborator

Sheffield Children's NHS Foundation Trust

OTHER

Sponsor Role collaborator

National Institute for Health Research, United Kingdom

OTHER_GOV

Sponsor Role collaborator

Lancashire Care NHS Foundation Trust

NETWORK

Sponsor Role collaborator

Newcastle-upon-Tyne Hospitals NHS Trust

OTHER

Sponsor Role collaborator

St George's University Hospitals NHS Foundation Trust

OTHER

Sponsor Role collaborator

University College, London

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Helen Cross, FRCP(UK)

Role: PRINCIPAL_INVESTIGATOR

UCL Institute of Child Health

Locations

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Birmingham Children's Hospital

Birmingham, , United Kingdom

Site Status RECRUITING

Bristol Royal Hospital for Children

Bristol, , United Kingdom

Site Status RECRUITING

Addenbrooke's Hospital

Cambridge, , United Kingdom

Site Status RECRUITING

Lancashire Teaching Hospitals NHS Foundation Trust

Lancashire, , United Kingdom

Site Status RECRUITING

Leeds Teaching Hospital

Leeds, , United Kingdom

Site Status RECRUITING

Alder Hey Children's Hospital

Liverpool, , United Kingdom

Site Status RECRUITING

Great Ormond Street Hospital

London, , United Kingdom

Site Status RECRUITING

St George's University Hospitals NHS Foundation Trust

London, , United Kingdom

Site Status RECRUITING

Royal Manchester Children's Hospital

Manchester, , United Kingdom

Site Status RECRUITING

The Newcastle Upon Tyne Hospitals NHS Foundation Trust

Newcastle upon Tyne, , United Kingdom

Site Status RECRUITING

Sheffield Children's NHS Foundation Trust

Sheffield, , United Kingdom

Site Status RECRUITING

Countries

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United Kingdom

Central Contacts

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Helen Cross, FRCP(UK)

Role: CONTACT

0044 207 599 4105

Siobhan Titre-Johnson, MSc

Role: CONTACT

Facility Contacts

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Shakti Agrawal, MBBS

Role: primary

0044 1213338149

Andrew Mallick, FRCPCH

Role: primary

Alasdair Parker, MA

Role: primary

0044 1223 245151

Helen Basu

Role: primary

Helen McCullagh, RCPCH

Role: primary

0044 113 243 2799

Rachel Kneen, BMBS

Role: primary

0044 151 2525163

Christin Eltze, MD Res

Role: primary

0044 207 405 9200 ext. 5438

Penny Fallon

Role: primary

Tim Martland, RCPCH

Role: primary

0044 161 276 1234

Anita Devlin

Role: primary

Archana Desurkar

Role: primary

References

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Titre-Johnson S, Schoeler N, Eltze C, Williams R, Vezyroglou K, McCullagh H, Freemantle N, Heales S, Kneen R, Marston L, Martland T, Nazareth I, Neal E, Lux A, Parker A, Agrawal S, Fallon P, Cross JH. Ketogenic diet in the treatment of epilepsy in children under the age of 2 years: study protocol for a randomised controlled trial. Trials. 2017 Apr 26;18(1):195. doi: 10.1186/s13063-017-1918-3.

Reference Type DERIVED
PMID: 28446244 (View on PubMed)

Other Identifiers

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13/0656

Identifier Type: -

Identifier Source: org_study_id

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