Efficacy and Safety of Ketogenic Diet as Adjunctive Treatment in Adults With Refractory Epilepsy (KD)

Evaluation of the Efficacy and Safety of Ketogenic Diet as Adjunctive Treatment in Adults With Refractory Epilepsy: a Pilot Study.

The purpose of the study is to obtain pilot data on safety and efficacy of ketogenic diet (KD) as adjunctive treatment of adults with refractory epilepsy. This will be an open label study comparing seizure frequency during 4 months of prospective baseline observation period with seizure frequency during 4 months of add-on KD treatment. 18-65 year old men and women with refractory epilepsy, defined as seizures persisting in spite of past/present treatments with ≥ 3 AEDs, with seizure frequency of ≥ 0.5/month, will be evaluated. Subjects with both primary generalized and localization-related epilepsy (PGE, LRE) will be recruited. Subjects will have had epilepsy for at least 2 years prior to enrollment. Following initial screening, subjects will be observed for 4 months, with no change in AEDs except when deemed necessary by the patient's neurologist according to standard clinical care. Patients will then start ketogenic diet. Evaluations will include seizure frequency using a seizure diary, adverse events, treatment compliance using urine and plasma ketone levels. Quality of life will be evaluated with a standardized questionnaire of Quality Of Life In patients with Epilepsy, QOLIE-31-P. Level of alertness will be evaluated with Epworth Sleepiness Scale. These questionnaires will be administered at each visit.

Study Overview

• Status: Unknown
• Conditions: Epilepsy
• Intervention / Treatment: Other: ketogenic diet

Detailed Description

The goal of the present open label study is to obtain pilot data to evaluate the efficacy and safety of KD in adults with intractable epilepsy. Investigators will evaluate the effect of KD on seizure frequency and on adverse events. Investigators will also evaluate serum levels of the ketone body, βhydroxybutyrate (BOH) and of glucose in order to determine whether changes in serum levels of these substances correlate with KD-associated changes in seizure frequency. The data from the present study will be used to design a large randomized study.

Laboratory evaluations will include complete blood count (CBC), serum electrolytes, including calcium, phosphate and magnesium, renal and liver functions, including total protein and albumin, uric acid, fasting serum lipid profile, glucose and b- hydroxybutyrate (BOH) levels, serum carnitine level, serum a.m. trough antiepilepsy drugs levels, and urine calcium and creatinine level. They will be obtained twice at baseline a month apart and monthly during KD treatment.

Primary outcome measures will include average monthly seizure frequency and adverse events. Secondary outcome measures will include treatment compliance, quality of life questionnaire (QOLIE-31-P) scores, and Epworth Sleepiness Scale scores.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • Midatlantic Epilepsy and Sleep Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18-65
2. Stable epilepsy, either primary generalized or localization-related with partial complex seizures including partial complex seizures with or without secondary generalization, partial simple seizures with a clear motor component with or without secondary generalization, and partial simple seizures with secondary generalization; primary generalized tonic clonic seizures; and absence seizures of > 10 sec duration.
3. Stable AED doses for at least 30 days
4. Epilepsy duration for > 1 year
5. Past/current treatment with > 3 AEDs. Vagal nerve stimulation treatment will be allowed and will not count as an AED. Vagal nerve stimulation setting must be stable for 3 months prior to enrollment
6. Seizure frequency of > 0.5/month

Exclusion Criteria:

1. Exclusively myoclonic seizures or absence seizures of ≤ 10 sec duration; simple partial seizures without motor components or secondary generalization
2. Non-epileptic seizures
3. Progressive neurological disease including neoplasm, central nerve system degenerative disorders including Alzheimer's disease, other forms of dementia
4. Any systemic illness or unstable medical condition that might pose additional risk, including: renal or liver disease, past history of renal calculi, hyperuricemia, hypercalcemia, mitochondrial disease, known disorder of fatty acid metabolism, porphyria, other unstable metabolic or endocrine disturbances, and active systemic cancer
5. Familial hyperlipidemia or uncontrolled hyperlipidemia
6. Body Mass Index (BMI) < 18
7. Change in the dose of any Antiepileptic Drug within 30 days prior to enrollment
8. Psychosis within six months of enrollment.
9. Active drug or alcohol dependence or any other factors that, in the opinion of the site investigators would interfere with adherence to study requirements;
10. Pregnancy
11. Use of any CNS-active investigational drugs within 3 months of enrollment.
12. Inability or unwillingness of subject or legal guardian/representative to give written informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Experimental: ketogenic diet; Treatment will consist of KD will consist of 3:1 [fat]: [protein + carbohydrate] weight ratio, with 1600 kcal restriction for patients with body mass index (BMI) of ≥ 21. The diet will be initiated with a 24 hour fast to induce ketosis. The diet will be supplemented with vitamins, calcium and phosphorus supplements to meet the requirements of US Dietary Reference Intakes (DRI) standard. If seizure frequency does not improve after 3 months of KD treatment, [fat]: [protein + carbohydrate] weight ratio will be increased to 4:1

Other: ketogenic diet; KD will consist of 3:1 [fat]: [protein + carbohydrate] weight ratio, with 1600 kcal restriction

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in epileptic seizure frequency.	Seizure frequency, adverse events and treatment compliance will be reviewed. The diet will be reviewed with the subject by the nutritionist before treatment initiation. Seizure frequency will be counted using a daily seizure diary. Subject's neurological and other clinical progress since the last visit will be reviewed. Concurrent medications will be documented. Vital signs and weight will be obtained, and a complete physical and neurological examination will be performed. Body mass index will be calculated. Subjects seizure/urine ketone diary will be reviewed at each visit. Treatment compliance will be evaluated with urine ketone levels using the diaries and with serum b-hydroxy-butyrate (b-OH-butyrate, BOH) levels.	baseline, 8 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate the number of participants with adverse events.	Adverse events and treatment compliance will be reviewed.Subject's neurological and other clinical progress since the last visit will be reviewed.	baseline, 8 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes from baseline in Quality of life.	Quality of life will be evaluated with a standardized questionnaire of quality of life in patients with epilepsy, QOLIE-31-P.	baseline, 8 months
Changes from baseline in alertness.	Alertness will be evaluated with Epworth Sleepiness Scale.	baseline, 8 months

Collaborators and Investigators

• Sponsor: Mid-Atlantic Epilepsy and Sleep Center, LLC
• Investigators: Principal Investigator: Pavel Klein, MD, Mid-Atlantic Epilepsy and Sleep Center

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (Anticipated): December 1, 2018
• Study Completion (Anticipated): December 1, 2018

Study Registration Dates

• First Submitted: June 11, 2013
• First Submitted That Met QC Criteria: July 23, 2013
• First Posted (Estimate): July 24, 2013

Study Record Updates

• Last Update Posted (Actual): February 23, 2018
• Last Update Submitted That Met QC Criteria: February 22, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: efficacy; ketogenic diet; Refractory epilepsy
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy; Drug Resistant Epilepsy
• Other Study ID Numbers: maes 001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED