FANS Trial Testing Ketone Supplementation to Help Control Seizures in Children With Angelman Syndrome

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Neuren Pharmaceuticals

A clinical trial is evaluating the safety and tolerability of a nutritional formulation containing the ketone beta-hydroxybutyrate (BHB) as a treatment to help control seizures in children with Angelman syndrome.

More information about the trial (NCT03644693), called Nutritional Formulation for Angelman Syndrome (FANS), is available here.

The protocol of this trial was described in a paper, titled “Evaluation of the safety and tolerability of a nutritional Formulation in patients with ANgelman Syndrome (FANS): study protocol for a randomized controlled trial,” published in the journal Trials.

Seizures that are resistant to medication are estimated to occur in more than three-quarters of people with Angelman syndrome (AS). Certain dietary interventions, the ketogenic diet in particular, have shown considerable efficacy at controlling these seizures. This diet involves eating very few carbohydrates (sugars and starches) and consuming more fats.

Generally, cells in the body will preferentially use carbohydrates — particularly glucose — as an energy source. When carbohydrates are unavailable, the body will instead use fat for energy in a process called ketosis. This process, in turn, generates molecules called ketones, such as BHB.

While it is not entirely known why ketones are beneficial, a number of hypotheses have suggested that ingesting ketones leads to a metabolic shift that results in increased inhibition of cell toxicity and ultimately to a dampening of overall neuron excitability and decreased seizure activity.

Although the “keto diet” can help control seizures, many people with AS experience digestive problems and difficulty in feeding, which make it difficult for them to adhere to the diet and get enough nutrition.

In the FANS trial, instead of going on a ketogenic diet, participants will be given a nutritional formulation that is directly supplemented with BHB. The idea is that directly consuming the ketones could produce similar benefits as a ketogenic diet, but be easier to manage.

The trial will be conducted in the Angelman Syndrome clinic at Monroe Carell Jr. Children’s Hospital at Vanderbilt University Medical Center (in Nashville, Tennessee) in collaboration with sponsor Disruptive Nutrition. The study is being funded by the Foundation for Angelman Syndrome Therapeutics (FAST).

The trial is expected to enroll 15 participants with AS, ages 4 to 11. Participants must have been on a consistent diet (ketogenic or unmodified) for at least three months. Those who are underweight or unable to get enough nutrition from their diet are not eligible for participation, nor are those with diabetes, kidney or liver problems, or any other health concerns deemed a potential issue by the study’s investigators.

The study will last for 16 weeks. For the first two weeks, patients continue on the dietary regimen they were on before joining the study. During the next four weeks, participants will be randomized to receive either the nutritional formulation with BHB or a placebo (while maintaining their current diet). This is followed by a four-week “washout” period with no nutritional formulation. Then, for the next four weeks, participants are “crossed over” — if they originally got the placebo, they get the BHB during these four weeks, and vice versa. The last two weeks are another washout period.

The primary goal of the study is to assess the tolerability of the formulation through participant compliance with the protocol (i.e. willingness to use the formulation) and by a questionnaire given to the participants’ caregivers after the study is completed.

Safety will also be evaluated by changes in motor function, cognitive function, gastrointestinal tolerance, sleep, seizures, height, weight, and blood metabolites; participants will undergo clinical evaluations at the end of each four-week treatment period, in addition to at-home monitoring with an app, to help keep track of adverse events.

The degree of ketosis will also be assessed via daily evaluation of urine samples as well as blood analysis at the end of each intervention period. The researchers noted that, “[t]he degree and timing of ketosis may be clinically relevant to demonstrating better patient nutrition” as nutritional ketosis has been associated with better outcomes in terms of seizures.

This will be the first study to assess consuming ketones as a way to induce ketosis for the treatment of seizures in patients with Angelman, the researchers said.

“We hope that this will yield measures that benefit future trials in the Angelman community in addition to a clearer understanding of the overall effectiveness and mechanism of action of BHB for inducing ketosis,” they wrote. “The ultimate goal will be to positively impact nutritional status, which should enhance the ability of the patient to overcome the symptoms of AS.”