Nutritional Formulation for Angelman Syndrome

Study Overview
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Brief Summary
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Low carbohydrate diets such as the ketogenic (KD) and low glycemic index (LGIT) diets have been shown to be effective in treating drug resistant seizures in children with Angelman syndrome (AS). The investigators hypothesize that consuming a fat based nutritional formulation with an exogenous ketone throughout the day will produce urinary ketosis in children consuming both low and high carbohydrate diets, depending upon dietary background. The nutritional formulation will provide fuel substrates that push metabolism away from carbohydrates and towards fat utilization. This research is being done to assess the safety and tolerability of a nutritional formulation for use in dietary interventions in AS.

Detailed Description
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An evaluation of the safety and tolerability of a nutritional formulation in Angelman syndrome in children ages 4-11 years. Study is conducted over 16 weeks: 2 week baseline period - Patient continues on current dietary regimen they were on before joining the study (standard, ketogenic, or LGIT). 4 week intervention period - Patient consumes either placebo or nutritional formulation for 4 weeks, maintaining their current diet. 4 week washout period - Patient continues on current dietary regimen without consuming any study formulations. 4 week intervention period - Patient consumes either placebo or nutritional formulation for 4 weeks (crossover), maintaining their current diet. 2 week washout period - Patient continues on current dietary regimen without consuming any study formulations. Follow-up phone call to be conducted by study personnel during this time. Data is captured by the investigator during baseline, intervention, and washout periods, and by the parent/caregiver daily throughout the protocol using apps loaded on a provided tablet.

Official Title
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Evaluation of the Safety and Tolerability of a Nutritional Formulation in Angelman Syndrome

Conditions
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Angelman Syndrome

Intervention / Treatment
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* Dietary Supplement: Nutritional Formulation Containing Exogenous Ketones
* Dietary Supplement: Placebo Formulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female 4-11 years of age Diagnosed with Angelman syndrome with prior lab report indicating genetic diagnosis Currently on a LGIT, KD, or standard diet consistently for at least three months Motivated to maintain the LGIT or KD for at least the duration of the trial period, as applicable Written informed consent from patient and/or parent/caregiver Willing to drink provided formulations, or to eat them mixed with food Daytime toilet trained, or parents willing to use cotton balls in diapers to sample urine Willing to test urine daily Willing to comply with protocol examinations, including EEG, ERP, and venipuncture Ambulatory, willing to perform gait tracking Exclusion Criteria: Being pregnant or planning pregnancy Requiring parenteral nutrition Major hepatic or renal dysfunction History of a diagnosis of diabetes Participation in other clinical intervention studies within 1 month prior to entry of this study Allergy to any of the study product ingredients Investigator concern around willingness/ability of patient or parent/caregiver to comply with protocol requirements Any contraindications for the use of the ketogenic or low carbohydrate diets Significantly underweight (Body Mass Index <18.5) Unwilling to drink provided formulations, or to consume formulation mixed with food Not ambulatory, or unwilling to perform gait tracking Not daytime toilet trained, or parents unwilling to use cotton balls in diapers to sample urine Unwilling to test urine daily

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 11 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The study design for this nutritional intervention protocol is a randomized, double blind, placebo controlled crossover study. Each patient will receive both nutritional formulation and placebo formulation, with a washout period between each arm. The dietary backgrounds will differ among patients. Acceptable diets include three basic diets: ketogenic diet (i.e. conventional 4:1 or 3:1, modified Atkins), low glycemic index diet (LGIT), and standard American diet (regular diet).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational<br>Subjects assigned to this arm will receive the Nutritional Formulation containing exogenous ketones. | Dietary Supplement: Nutritional Formulation Containing Exogenous Ketones<br>* A nutritional formulation providing beta-hydroxybutyrate, 2g of carbohydrate, 1g of protein, and 9g of fat, plus minerals, per 100kcal. Given orally as food or beverage three times daily.<br>|
| Placebo Comparator: Placebo<br>Subjects assigned to this arm will receive the Placebo Formulation. | Dietary Supplement: Placebo Formulation<br>* A placebo formulation providing similar amounts of carbohydrates, proteins and minerals as the nutritional formulation. Given orally as food or beverage three times daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compliance with feeding protocol | Tolerability will be demonstrated through patient compliance with the protocol as determined by the amount as measured in grams per day of nutritional formulation consumed as compared to the amount prescribed. | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Convenience, taste, and acceptability | Parents/caregivers will rate convenience, taste, and acceptability of the nutritional formulation on a ten-point Likert scale. Each parameter will be rated individually with 1 = poor and 10 = excellent. | 16 weeks (measured 2 times) | 
| Urinary Ketosis | The degree of nutritional ketosis will be evaluated in patients with different dietary backgrounds when consuming the nutritional formulation. Urine ketones will be recorded daily as mmol of acetoacetate. | 16 weeks | 
| Serum Ketosis | The degree of nutritional ketosis will be evaluated in patients with different dietary backgrounds when consuming the nutritional formulation. Serum ketones will be recorded as mmol of R-beta-hydroxybutyrate. | 16 weeks (measured 3 times) | 
| Number of Patients with Adverse Events | All adverse events will be monitored throughout the study. The number and type of adverse event will be recorded. | 16 weeks (measured 3 times) | 
| Change in Mobility Measured Using Zeno Walkway | Patients with Angelman Syndrome typically have motor coordination and physical developmental delays resulting in an ataxic gate. As a measure of safety, the patient's gate characteristics for cadence will be compared to baseline. | 16 weeks (measured 3 times) | 
| Change in Cognition as Measured by Event Related Potentials (ERP) | Patients with Angelman Syndrome have global severe intellectual disability. As a measure of safety, ERP waveform amplitude and timing in response to a presented stimuli will be compared to baseline. | 16 weeks (measured 3 times) | 
| Change in Cortical Irritability Measured Using Electroencephalogram (EEG) | Patients with Angelman Syndrome have a characteristic EEG signature and are prone to seizure. As a measure of safety, the EEG signature will be compared to baseline in terms of the numbers of epileptiform discharges, notched delta and rhythmic theta activity. | 16 weeks (measured 3 times) | 
| Number of Patients with Treatment Related Adverse Events as Assessed by Blood Metabolic Panel | Blood samples will be taken and assessed for complete blood count, comprehensive metabolic panel, ketones, and lipids. | 16 weeks (measured 3 times) | 
| Nutrient Intake | Food diaries recorded daily to establish total caloric and macro-nutrient intake. | 16 weeks | 
| Changes in Gastrointestinal (GI) Health | Patients with Angelman Syndrome frequently suffer from poor GI health. As a measure of safety, bowel movements will be characterized daily according to the Bristol Stool Chart and compared to baseline. | 16 weeks | 
| Changes in Sleep | Patients with Angelman Syndrome frequently suffer from sleep issues. As a measure of safety, sleep duration and stage will be characterized by recording movement, heart rate and breathing during nighttime sleep and compared to baseline. | 16 weeks | 
| Changes in Seizures | A significant percentage of Patients with Angelman Syndrome suffer from epileptic seizures. As a measure of safety, the number and type of seizures that occur will be recorded daily in a diary and compare to baseline. | 16 weeks | 
| Height | Height (cm) | 16 weeks (measured 3 times) | 
| Weight | Weight (kg) | 16 weeks (measured 3 times) | 
| Change from Baseline in the Vineland Adaptive Behavior Score | Patients with Angelman Syndrome have severe global developmental delays. As a measure of safety, the Vineland Adaptive Behavior Scale, Third Edition will be used to measure changes from baseline in skills and independence. | 16 weeks (measured 3 times) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Angelman Syndrome, Ketosis, Children