<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02205931</url>
  </required_header>
  <id_info>
    <org_study_id>13/0656</org_study_id>
    <nct_id>NCT02205931</nct_id>
  </id_info>
  <brief_title>Ketogenic Diet in Infants With Epilepsy (KIWE)</brief_title>
  <acronym>KIWE</acronym>
  <official_title>A Randomised Controlled Trial of the Ketogenic Diet in the Treatment of Epilepsy in Children Under the Age of Two Years</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University College, London</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Great Ormond Street Hospital for Children NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Cambridge University Hospitals NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Alder Hey Children's NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Bristol Royal Hospital for Children</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Birmingham Women's and Children's NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Leeds Teaching Hospitals NHS Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Manchester University NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Sheffield Children's NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute for Health Research, United Kingdom</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Lancashire Care NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Newcastle-upon-Tyne Hospitals NHS Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>St George's University Hospitals NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University College, London</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Epilepsy, a condition where individuals are prone to recurrent epileptic seizures, is the&#xD;
      most common chronic neurological disorder in children. Epilepsy onset is most common in the&#xD;
      first two years of life and is associated with poor prognosis for seizure control and&#xD;
      neurodevelopmental outcome.&#xD;
&#xD;
      The ketogenic diet (KD) is a medically supervised diet that is high in fat and restricted in&#xD;
      carbohydrates and protein. KD therapy has shown to be an effective treatment for seizures in&#xD;
      children with epilepsy older than two. Associated benefits include: a reduced requirement for&#xD;
      routine and emergency antiepileptic drugs (AED) and fewer seizure related hospital&#xD;
      admissions. Although reports suggest that KD therapy improves seizures in younger children&#xD;
      there is no high quality trial data that demonstrates effectiveness and safety in this age&#xD;
      group. The KD is resource intensive, requiring dietetic and physician time; data is required&#xD;
      to justify expansion of services to cater for the apparent need.&#xD;
&#xD;
      The investigators therefore propose a prospective multicentre randomised trial to investigate&#xD;
      the effectiveness and safety of the KD in children with epilepsy under the age of 2, who have&#xD;
      failed to respond to two or more AEDs. Children will be randomly assigned to either receive&#xD;
      the KD or further AEDs. The allocated treatment will be started after a 2week baseline&#xD;
      period, and it's effectiveness assessed after 8 weeks. Seizure diaries will be used to record&#xD;
      seizures and related events, a questionnaire will be used to assess diet tolerance; also&#xD;
      growth and blood biochemistry will be monitored.&#xD;
&#xD;
      The information obtained from this study is necessary to optimise choices in epilepsy&#xD;
      treatment, aiming to improve outcomes and thus determine whether and when the KD should&#xD;
      should be used.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The project proposed is a randomised controlled multicentre study of infants with epilepsy&#xD;
      who have failed to respond to two or more pharmacological treatments (antiepileptic drugs&#xD;
      (AEDs) or corticosteroids), comparing ketogenic diet to treatment with a further AED.&#xD;
&#xD;
      Children for this study will be recruited from 8 paediatric neurology centres in the South of&#xD;
      England who have an established KD service for children with epilepsy. The collaborating&#xD;
      paediatric neurologists based in these centres are named co-applicants on this proposal. All&#xD;
      children ages 3 to 24 months will be considered if they have a diagnosis of epilepsy, namely&#xD;
      continuing seizures despite a trial of 2 or more AEDs (including corticosteroids) and are&#xD;
      experiencing at least 8 seizures a week.&#xD;
&#xD;
      Children will be excluded if they are shown to have: a metabolic disease contradicting the&#xD;
      use of KD; a progressive neurological disease; severe gastrooesophageal reflux or have&#xD;
      undergone a previous failed trial of KD. In addition, families should be able to attend&#xD;
      clinic on the required timeline. KD meal plans will be accurately calculated for each child&#xD;
      individually by a dietitian with consideration of daily calorie requirements, fat to&#xD;
      carbohydrate ratio (3:1 or 4:1), adequate protein intake and vitamin and mineral&#xD;
      supplementation. Ongoing adjustments to the diet by the dietitian are determined by weight&#xD;
      gain and the degree of ketosis.&#xD;
&#xD;
        1. Baseline assessment: Written consent will be obtained from eligible children. Full&#xD;
           history including seizure type, neurological examination, weight, length and head&#xD;
           circumference will be documented. Randomisation to KD or standard AED group will be&#xD;
           carried out with the support of the UCL PRIMENT Clinical Trials Unit (CTU).&#xD;
&#xD;
           Investigations to be performed in the KD group (or if clinically indicated in the AED&#xD;
           group) will include FBC, U&amp;Es, Glucose, LFTs, Calcium, Magnesium, Phosphate, Zinc,&#xD;
           Selenium, Acylcarnitine profile, Cholesterol, Triglycerides, Urate, 25 hydroxy Vitamin&#xD;
           D, urine calcium/creatinine, urine organic acids. An EEG will be performed if clinically&#xD;
           indicated.&#xD;
&#xD;
        2. Observation period of 2 weeks: No changes of regular AEDs. Emergency seizure treatments&#xD;
           will continue as required( acute treatment with benzodiazepines). The following data&#xD;
           will be recorded in a standardized diary (these data will continue to be recorded&#xD;
           throughout the intervention period of 8 weeks): seizure types, seizure frequency, number&#xD;
           of emergency seizure treatments required, contacts with the NHS due to seizure&#xD;
           exacerbation (hospital admissions number of days, A&amp;E and or GP attendances)&#xD;
&#xD;
        3. Start of the classical KD or further AED. The classical KD will be administered as per&#xD;
           protocol of the treating service. The recording of seizure types and frequency is to be&#xD;
           continued.&#xD;
&#xD;
        4. Second Assessment (4 weeks after the start of the treatment period, all patients):&#xD;
           clinical review including weight; documentation of seizure frequency, and tolerability&#xD;
           of the diet in randomised KD group by questionnaire.&#xD;
&#xD;
        5. Third/final assessment (8 weeks after starting treatment/all patients). Clinical review&#xD;
           including neurological examination, weight, length and head circumference. Documentation&#xD;
           of seizure outcome (from seizure diaries). KD group only: completion of tolerability&#xD;
           questionnaire, blood investigations (FBC, U&amp;Es, Glucose, LFTs, plasma bicarbonate,&#xD;
           calcium, magnesium, phosphate, zinc, selenium, acylcarnitine profile, cholesterol,&#xD;
           triglycerides, urate, nonesterified fatty acids, blood ketones) and urine&#xD;
           calcium/creatinine ratio. EEG will be performed if clinically indicated.&#xD;
&#xD;
      Dependent on seizure response, KD (diet group) or AED (standard AED group) will then be&#xD;
      continued or changed. Those in the AED group of failed will be offered KD outside the context&#xD;
      of the trial. It would be anticipated that clinical data would be collected on all patients&#xD;
      to 12 months to determine retention rates.&#xD;
&#xD;
      Exit criteria: Children will withdraw from the treatment prior to 8 weeks should there be q&#xD;
      &gt;50% increase in seizure frequency from the baseline, or if intolerable side effects are not&#xD;
      resolved by manipulation of KD or medication. A safety monitoring committee will be convened.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>January 2015</start_date>
  <completion_date type="Anticipated">June 2019</completion_date>
  <primary_completion_date type="Anticipated">June 2018</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of seizures</measure>
    <time_frame>6 - 8 weeks</time_frame>
    <description>Number of seizures experienced during weeks 6 - 8</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Responder rate</measure>
    <time_frame>8 weeks</time_frame>
    <description>number of children seizure free and relationship between medium chain fatty acids and seizure control</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Retention on treatment</measure>
    <time_frame>12 months</time_frame>
    <description>retention on treatment, quality of life and neurodevelopmental outcome</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">160</enrollment>
  <condition>Epilepsy</condition>
  <arm_group>
    <arm_group_label>Ketogenic diet</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Antiepileptic drug therapy</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Ketogenic diet</intervention_name>
    <description>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.</description>
    <arm_group_label>Ketogenic diet</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Antiepileptic drug therapy</intervention_name>
    <description>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.</description>
    <arm_group_label>Antiepileptic drug therapy</arm_group_label>
    <other_name>Carbamazepine</other_name>
    <other_name>Clobazam</other_name>
    <other_name>Clonazepam</other_name>
    <other_name>Ethosuximide</other_name>
    <other_name>Lacosmide</other_name>
    <other_name>Lamotrigine</other_name>
    <other_name>Levetiracetam</other_name>
    <other_name>Nitrazepam</other_name>
    <other_name>Phenytoin</other_name>
    <other_name>Rufinamide</other_name>
    <other_name>Sodium Valproate</other_name>
    <other_name>Stiripentol</other_name>
    <other_name>Topiramate</other_name>
    <other_name>Vigabatrin</other_name>
    <other_name>Zonisamide</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age between 1 month and 24 months of age (not beyond second birthday at baseline).&#xD;
&#xD;
          2. Diagnosis of epilepsy confirmed.&#xD;
&#xD;
          3. At least an average of 4 seizures/week in baseline period.&#xD;
&#xD;
          4. Failed response to previous trial of two anti-epileptic drugs. In the case of&#xD;
             infantile spasms this could include a trial of corticosteroids.&#xD;
&#xD;
          5. Children with written informed consent from parent/guardian.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Age &lt;1m or &gt; 24 months of age&#xD;
&#xD;
          2. No secure diagnosis of epilepsy&#xD;
&#xD;
          3. &lt; 4 seizures/week on average in baseline period&#xD;
&#xD;
          4. Trial of &lt; 2 AEDs&#xD;
&#xD;
          5. Continues on corticosteroids in previous 3 months prior to randomisation&#xD;
&#xD;
          6. Metabolic disease contraindicating use of the ketogenic diet e.g. pyruvate carboxylase&#xD;
             deficiency, MCAD from previous medical investigation and screening at baseline.&#xD;
&#xD;
          7. Progressive neurological disease&#xD;
&#xD;
          8. Severe gastroesophageal reflux&#xD;
&#xD;
          9. Previous treatment with the ketogenic diet&#xD;
&#xD;
         10. Concurrent participation in another clinical trial of an investigational medicinal&#xD;
             product.&#xD;
&#xD;
         11. Patients who are prescribed AEDs not listed in the trial IMPs&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Month</minimum_age>
    <maximum_age>2 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Helen Cross, FRCP(UK)</last_name>
    <role>Principal Investigator</role>
    <affiliation>UCL Institute of Child Health</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Helen Cross, FRCP(UK)</last_name>
    <phone>0044 207 599 4105</phone>
    <email>h.cross@ucl.ac.uk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Siobhan Titre-Johnson, MSc</last_name>
    <email>s.titre-johnson@ucl.ac.uk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Birmingham Children's Hospital</name>
      <address>
        <city>Birmingham</city>
        <zip>B4 6NH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Shakti Agrawal, MBBS</last_name>
      <phone>0044 1213338149</phone>
      <email>shakti.agrawal@bch.nhs.uk</email>
    </contact>
    <investigator>
      <last_name>Shakti Agrawal, MBBS</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Bristol Royal Hospital for Children</name>
      <address>
        <city>Bristol</city>
        <zip>BS2 8AE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Andrew Mallick, FRCPCH</last_name>
    </contact>
    <investigator>
      <last_name>Andrew Mallick</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Addenbrooke's Hospital</name>
      <address>
        <city>Cambridge</city>
        <zip>CB2 0QQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Alasdair Parker, MA</last_name>
      <phone>0044 1223 245151</phone>
      <email>alasdair.parker@addenbrookes.nhs.uk</email>
    </contact>
    <investigator>
      <last_name>Alasdair Parker, MA</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Lancashire Teaching Hospitals NHS Foundation Trust</name>
      <address>
        <city>Lancashire</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Helen Basu</last_name>
      <email>Helen.Basu@lthtr.nhs.uk</email>
    </contact>
    <investigator>
      <last_name>Helen Basu</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Leeds Teaching Hospital</name>
      <address>
        <city>Leeds</city>
        <zip>LS1 3EX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Helen McCullagh, RCPCH</last_name>
      <phone>0044 113 243 2799</phone>
      <email>h.mccullagh@nhs.net</email>
    </contact>
    <investigator>
      <last_name>Helen McCullagh, RCPCH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Alder Hey Children's Hospital</name>
      <address>
        <city>Liverpool</city>
        <zip>L12 2AP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Rachel Kneen, BMBS</last_name>
      <phone>0044 151 2525163</phone>
      <email>rachel.kneen@liverpool.ac.uk</email>
    </contact>
    <investigator>
      <last_name>Rachel Kneen, BMBS</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Great Ormond Street Hospital</name>
      <address>
        <city>London</city>
        <zip>WC1N 3JH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Christin Eltze, MD Res</last_name>
      <phone>0044 207 405 9200</phone>
      <phone_ext>5438</phone_ext>
      <email>christin.eltze@gosh.nhs.uk</email>
    </contact>
    <investigator>
      <last_name>Christin Eltze, MD Res</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>St George's University Hospitals NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Penny Fallon</last_name>
      <email>Penny.Fallon@stgeorges.nhs.uk</email>
    </contact>
    <investigator>
      <last_name>Penny Fallon</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Royal Manchester Children's Hospital</name>
      <address>
        <city>Manchester</city>
        <zip>M13 0JE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Tim Martland, RCPCH</last_name>
      <phone>0044 161 276 1234</phone>
      <email>timothy.martland@cmft.nhs.uk</email>
    </contact>
    <investigator>
      <last_name>Tim Martland, RCPCH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>The Newcastle Upon Tyne Hospitals NHS Foundation Trust</name>
      <address>
        <city>Newcastle upon Tyne</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Anita Devlin</last_name>
      <email>Anita.Devlin@nuth.nhs.uk</email>
    </contact>
    <investigator>
      <last_name>Anita Devlin</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Sheffield Children's NHS Foundation Trust</name>
      <address>
        <city>Sheffield</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Archana Desurkar</last_name>
      <email>Archana.Desurkar@sch.nhs.uk</email>
    </contact>
    <investigator>
      <last_name>Archana Desurkar</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>May 2017</verification_date>
  <study_first_submitted>December 16, 2013</study_first_submitted>
  <study_first_submitted_qc>July 31, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 1, 2014</study_first_posted>
  <last_update_submitted>May 2, 2017</last_update_submitted>
  <last_update_submitted_qc>May 2, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">May 4, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Epilepsy</keyword>
  <keyword>Ketogenic diet</keyword>
  <keyword>Antiepileptic drugs</keyword>
  <keyword>Randomised controlled trial</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Epilepsy</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Topiramate</mesh_term>
    <mesh_term>Lamotrigine</mesh_term>
    <mesh_term>Zonisamide</mesh_term>
    <mesh_term>Carbamazepine</mesh_term>
    <mesh_term>Phenytoin</mesh_term>
    <mesh_term>Rufinamide</mesh_term>
    <mesh_term>Levetiracetam</mesh_term>
    <mesh_term>Valproic Acid</mesh_term>
    <mesh_term>Clonazepam</mesh_term>
    <mesh_term>Vigabatrin</mesh_term>
    <mesh_term>Anticonvulsants</mesh_term>
    <mesh_term>Clobazam</mesh_term>
    <mesh_term>Ethosuximide</mesh_term>
    <mesh_term>Stiripentol</mesh_term>
    <mesh_term>Nitrazepam</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02205931
org study id: 13/0656
nct id: NCT02205931
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has dmc: Yes
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
measure: Number of seizures
time frame: 6 - 8 weeks
description: Number of seizures experienced during weeks 6 - 8
measure: Responder rate
time frame: 8 weeks
description: number of children seizure free and relationship between medium chain fatty acids and seizure control
measure: Retention on treatment
time frame: 12 months
description: retention on treatment, quality of life and neurodevelopmental outcome
arm group label: Ketogenic diet
arm group type: Experimental
description: 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.
arm group label: Antiepileptic drug therapy
arm group type: Active Comparator
description: 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.
intervention type: Other
intervention name: Ketogenic diet
description: 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.
arm group label: Ketogenic diet
intervention type: Drug
intervention name: Antiepileptic drug therapy
description: 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.
arm group label: Antiepileptic drug therapy
other name: Carbamazepine
other name: Clobazam
other name: Clonazepam
other name: Ethosuximide
other name: Lacosmide
other name: Lamotrigine
other name: Levetiracetam
other name: Nitrazepam
other name: Phenytoin
other name: Rufinamide
other name: Sodium Valproate
other name: Stiripentol
other name: Topiramate
other name: Vigabatrin
other name: Zonisamide
criteria: 
gender: All
minimum age: 1 Month
maximum age: 2 Years
healthy volunteers: No
last name: Helen Cross, FRCP(UK)
role: Principal Investigator
affiliation: UCL Institute of Child Health
last name: Helen Cross, FRCP(UK)
phone: 0044 207 599 4105
email: h.cross@ucl.ac.uk
last name: Siobhan Titre-Johnson, MSc
email: s.titre-johnson@ucl.ac.uk
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status: Recruiting
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country: United Kingdom
responsible party type: Sponsor
mesh term: Epilepsy
mesh term: Topiramate
mesh term: Lamotrigine
mesh term: Zonisamide
mesh term: Carbamazepine
mesh term: Phenytoin
mesh term: Rufinamide
mesh term: Levetiracetam
mesh term: Valproic Acid
mesh term: Clonazepam
mesh term: Vigabatrin
mesh term: Anticonvulsants
mesh term: Clobazam
mesh term: Ethosuximide
mesh term: Stiripentol
mesh term: Nitrazepam