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Evaluation of the safety and tolerability of a nutritional Formulation in patients with ANgelman Syndrome (FANS): study protocol for a randomized controlled trial.

ABSTRACT: BACKGROUND:Ketogenic and low-glycemic-index diets are effective in treating drug-resistant seizures in children with Angelman syndrome. Cognition, mobility, sleep, and gastrointestinal health are intrinsically linked to seizure activity and overall quality of life. Ketogenic and low-glycemic diets restrict carbohydrate consumption and stabilize blood glucose levels. The ketogenic diet induces ketosis, a metabolic state where ketone bodies are preferentially used for fuel. The use of exogenous ketones in promoting ketosis in Angelman syndrome has not been previously studied. The study formulation evaluated herein contains the exogenous ketone beta-hydroxybutyrate to rapidly shift the body towards ketosis, resulting in enhanced metabolic efficiency. METHODS/DESIGN:This is a 16-week, randomized, double-blind, placebo-controlled, crossover study to assess the safety and tolerability of a nutritional formula containing exogenous ketones. It also examines the potential for exogenous ketones to improve the patient's nutritional status which can impact the physiologic, symptomatic, and health outcome liabilities of living with Angelman syndrome. DISCUSSION:This manuscript outlines the rationale for a study designed to be the first to provide data on nutritional approaches for patients with Angelman syndrome using exogenous ketones. TRIAL REGISTRATION:ClinicalTrials.gov, ID: NCT03644693. Registered on 23 August 2018. Last updated on 23 August 2018.

SUBMITTER: Herber DL

PROVIDER: S-EPMC6953273 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Evaluation of the safety and tolerability of a nutritional Formulation in patients with ANgelman Syndrome (FANS): study protocol for a randomized controlled trial.

Herber Donna L DL Weeber Edwin J EJ D'Agostino Dominic P DP Duis Jessica J

Trials 20200109 1

<h4>Background</h4>Ketogenic and low-glycemic-index diets are effective in treating drug-resistant seizures in children with Angelman syndrome. Cognition, mobility, sleep, and gastrointestinal health are intrinsically linked to seizure activity and overall quality of life. Ketogenic and low-glycemic diets restrict carbohydrate consumption and stabilize blood glucose levels. The ketogenic diet induces ketosis, a metabolic state where ketone bodies are preferentially used for fuel. The use of exog ...[more]

PMID: 31918761

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Project description:BackgroundAngelman syndrome (AS) patients often respond to low glycemic index therapy to manage refractory seizures. These diets significantly affect quality of life and are challenging to implement. These formulations may have benefits in AS even in the absence of biomarkers suggesting ketosis.ObjectivesWe aimed to compare an exogenous medical food ketone formulation (KF) with placebo for the dietary management of AS.MethodsThis randomized, double-blind, placebo-controlled, crossover clinical trial was conducted in an academic center from 15 November, 2018 to 6 January, 2020. Thirteen participants with molecularly confirmed AS aged 4-11 y met the criteria and completed the 16-wk study. The study consisted of four 4-wk phases: a baseline phase, a blinded KF or placebo phase, a washout phase, and the crossover phase with alternate blinded KF or placebo. Primary outcomes were safety and tolerability rated by retention in the study and adherence to the formulation. Additional secondary outcomes of safety in this nonverbal population included blood chemistry, gastrointestinal health, seizure burden, cortical irritability, cognition, mobility, sleep, and developmental staging.ResultsData were compared between the baseline, KF, and placebo epochs. One participant exited the trial owing to difficulty consuming the formulation. Adverse events included an increase in cholesterol in 1 subject when consuming KF and a decrease in albumin in 1 subject when consuming placebo. Stool consistency improved with KF consumption, from 6.04 ± 1.61 at baseline and 6.35 ± 1.55 during placebo to 4.54 ± 1.19 during KF (P = 0.0027). Electroencephalograph trends showed a decrease in Δ frequency power during the KF arm and event-related potentials suggested a change in the frontal memory response. Vineland-3 showed improved fine motor skills in the KF arm.ConclusionsThe exogenous KF appears safe. More data are needed to determine the utility of exogenous ketones as a nutritional approach in children with AS.This trial was registered at clinicaltrials.gov as NCT03644693.

Project description:BACKGROUND:Minocycline is an old tetracycline antibiotic that has shown antiinflammatory and antiapoptotic properties in different neurological disease mouse models. Previous single arm study in humans demonstrated benefits in individuals with Angelman Syndrome (AS); however, its efficacy in patients with Angelman Syndrome has not been assessed in a controlled trial. This was a randomized, double-blind, placebo-controlled, crossover trial in individuals with AS, aged 6 years to 30 years (n = 32, mean age 12 [SD 6·29] years). Participants were randomized to minocycline or placebo for 8 weeks and then switched to the other treatment (a subset of 22 patients) or to receive minocycline for up to 16 weeks (10 patients). After week 16, all patients entered a wash-out 8-week follow-up period. RESULTS:Thirty-six subjects were screened and 34 were randomized. Thirty two subjects (94·1%) completed at least the first period and all of them completed the full trial. Intention-to-treat analysis demonstrated the lack of significantly greater improvements in the primary outcome, mean changes in age equivalent of the development index of the Merrill-Palmer Revised Scale after minocycline compared with placebo (1·90 ± 3·16 and 2·00 ± 3·28, respectively, p = 0·937). Longer treatment duration up to 16 weeks did not result in better treatment outcomes (1·86 ± 3·35 for 8 weeks treatment vs 1·20 ± 5·53 for 16 weeks treatment, p = 0·667). Side effects were not significantly different during minocycline and placebo treatments. No serious adverse events occurred on minocycline. CONCLUSIONS:Minocycline treatment for up to 16 weeks in children and young adults with AS resulted in lack of significant improvements in development indexes compared to placebo treatment. Treatment with minocycline appears safe and well tolerated; even if it cannot be completely ruled out that longer trials might be required for a potential minocycline effect to be expressed, available results and lack of knowledge on the actual mechanism of action do not support this hypothesis. TRIAL REGISTRATION:European Clinical Trial database ( EudraCT 2013-002154-67 ), registered 16th September 2013; US Clinical trials database ( NCT02056665 ), registered 6th February 2014.

Dataset Information

Evaluation of the safety and tolerability of a nutritional Formulation in patients with ANgelman Syndrome (FANS): study protocol for a randomized controlled trial.

Publications

Evaluation of the safety and tolerability of a nutritional Formulation in patients with ANgelman Syndrome (FANS): study protocol for a randomized controlled trial.

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