Efficacy and safety of ketogenic diet in infants with epilepsy: KIWE RCT
Authors: Schoeler Natasha E , Marston Louise , Lyons Laura , Halsall Sally , Jain Ruchika , Titre-Johnson Siobhan , Balogun Maryam , Heales Simon J R , Eaton Simon , Orford Michael , Neal Elizabeth , Eltze Christin , Stephen Elma , Mallick Andrew A , O’Callaghan Finbar , Agrawal Shakti , Parker Alasdair , Kirkpatrick Martin , Brunklaus Andreas , McLellan Ailsa , McCullagh Helen , Samanta Rajib , Kneen Rachel , Jeen Tan Hui , Devlin Anita , Prasad Manish , Rattihalli Rohini , Basu Helen , Desurkar Archana , Williams Ruth , Fallon Penny , Nazareth Irwin , Freemantle Nicholas , Cross J Helen 
Published: October 2024

Background
Many infancy-onset epilepsies have a poor prognosis for seizure control and neurodevelopmental outcome. Ketogenic diets can improve seizures in older children and adults unresponsive to antiseizure medicines. We aimed to determine the effectiveness of the ketogenic diet in reducing seizure frequency compared to further antiseizure medicine in infants with drug-resistant epilepsy.

Methods
In this randomised, open-label trial, 136 infants with epilepsy, aged 1–24 months, with > 4 seizures/week and a previous trial of ≥ 2 antiseizure medicines were recruited from 19 hospitals in the United Kingdom. Following a 1- or 2-week observation period, participants were randomised to receive the classical ketogenic diet or a further antiseizure medicine for 8 weeks, using a computer-generated schedule without stratification. Treatment allocation was concealed from research nurses involved in patient care, but not from participants. The primary outcome was the number of seizures/day recorded during weeks 6–8. All analyses were intention to treat. The trial is registered with the European Union Drug Regulating Authorities Clinical Trials Database (2013-002195-40).

Findings
Between 1 January 2015 and 30 September 2021, 136 eligible infants were randomised. Sixty-one (78%) of 78 assigned to a ketogenic diet and 47 (81%) of 58 assigned to antiseizure medicine had primary outcome data. At 8 weeks, the number of seizures per day, accounting for the baseline rate and randomised group, was not significantly different between groups [median (interquartile range) ketogenic diet 5 (1, 16); antiseizure medicine 3 (2, 11), incidence rate ratio 1.33, 95%, confidence internal 0.84 to 2.11; p = 0.22]. A similar number of infants reported at least one serious adverse event in both groups [antiseizure medicine: 24/56 (43%), ketogenic diet: 40/78 (51%)]. The most common serious adverse events were seizures in both groups. Three infants died during the course of the trial, all of whom were randomised to the ketogenic diet arm; deaths were considered to be unrelated to treatment.

Interpretation
There was no evidence that a ketogenic diet was better than further antiseizure medicine in achieving seizure control in infants with epilepsy. The two treatments were similarly tolerated and a ketogenic diet appears safe to use in infants with epilepsy. A ketogenic diet could be a treatment option in infants whose seizures continue despite trial of two standard antiseizure medicines.

Study registration
This study was registered as EudraCT 2013-002195-40.

Funding
This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/10/18) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 16. See the NIHR Funding and Awards website for further award information.