Nutritional Formulation for Angelman Syndrome (FANS)

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

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.

Study Overview

• Status: Completed
• Conditions: Angelman Syndrome
• Intervention / Treatment: Dietary supplement: Nutritional Formulation Containing Exogenous Ketones; Dietary supplement: Placebo Formulation

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hopsital Colorado

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 11 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Investigational; Subjects assigned to this arm will receive the Nutritional Formulation containing exogenous ketones.	Dietary supplement: Nutritional Formulation Containing Exogenous Ketones; 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.
Placebo Comparator: Placebo; Subjects assigned to this arm will receive the Placebo Formulation.	Dietary supplement: Placebo Formulation; A placebo formulation providing similar amounts of carbohydrates, proteins and minerals as the nutritional formulation. Given orally as food or beverage three times daily.

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Investigators: Principal Investigator: Jessica Duis, MD, MS, Children's Hospital Colorado

Publications and helpful links

General Publications

• Carson RP, Herber DL, Pan Z, Phibbs F, Key AP, Gouelle A, Ergish P, Armour EA, Patel S, Duis J. Nutritional Formulation for Patients with Angelman Syndrome: A Randomized, Double-Blind, Placebo-Controlled Study of Exogenous Ketones. J Nutr. 2021 Dec 3;151(12):3628-3636. doi: 10.1093/jn/nxab284.
• Herber DL, Weeber EJ, D'Agostino DP, Duis J. Evaluation of the safety and tolerability of a nutritional Formulation in patients with ANgelman Syndrome (FANS): study protocol for a randomized controlled trial. Trials. 2020 Jan 9;21(1):60. doi: 10.1186/s13063-019-3996-x.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2018
• Primary Completion (Actual): January 15, 2020
• Study Completion (Actual): January 15, 2020

Study Registration Dates

• First Submitted: August 13, 2018
• First Submitted That Met QC Criteria: August 21, 2018
• First Posted (Actual): August 23, 2018

Study Record Updates

• Last Update Posted (Actual): August 20, 2020
• Last Update Submitted That Met QC Criteria: August 18, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Children; Ketosis; Angelman Syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Central Nervous System Diseases; Nervous System Diseases; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Movement Disorders; Abnormalities, Multiple; Chromosome Disorders; Syndrome; Angelman Syndrome
• Other Study ID Numbers: 20-0366

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No