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Nutritional Formulation for Angelman Syndrome (FANS)

Primary Purpose

Angelman Syndrome

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Nutritional Formulation Containing Exogenous Ketones
Placebo Formulation
Sponsored by
University of Colorado, Denver
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Angelman Syndrome focused on measuring Angelman Syndrome, Ketosis, Children

Eligibility Criteria

4 Years - 11 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Children's Hopsital Colorado

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Investigational

Placebo

Arm Description

Subjects assigned to this arm will receive the Nutritional Formulation containing exogenous ketones.

Subjects assigned to this arm will receive the Placebo Formulation.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.
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.
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.
Nutrient Intake
Food diaries recorded daily to establish total caloric and macro-nutrient intake.
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.
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.
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.
Height
Height (cm)
Weight
Weight (kg)
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.

Full Information

First Posted
August 13, 2018
Last Updated
August 18, 2020
Sponsor
University of Colorado, Denver
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1. Study Identification

Unique Protocol Identification Number
NCT03644693
Brief Title
Nutritional Formulation for Angelman Syndrome
Acronym
FANS
Official Title
Evaluation of the Safety and Tolerability of a Nutritional Formulation in Angelman Syndrome
Study Type
Interventional

2. Study Status

Record Verification Date
August 2020
Overall Recruitment Status
Completed
Study Start Date
November 1, 2018 (Actual)
Primary Completion Date
January 15, 2020 (Actual)
Study Completion Date
January 15, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Colorado, Denver

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Angelman Syndrome
Keywords
Angelman Syndrome, Ketosis, Children

7. Study Design

Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
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
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Investigational
Arm Type
Experimental
Arm Description
Subjects assigned to this arm will receive the Nutritional Formulation containing exogenous ketones.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Subjects assigned to this arm will receive the Placebo Formulation.
Intervention Type
Dietary Supplement
Intervention Name(s)
Nutritional Formulation Containing Exogenous Ketones
Intervention Description
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.
Intervention Type
Dietary Supplement
Intervention Name(s)
Placebo Formulation
Intervention Description
A placebo formulation providing similar amounts of carbohydrates, proteins and minerals as the nutritional formulation. Given orally as food or beverage three times daily.
Primary Outcome Measure Information:
Title
Compliance with feeding protocol
Description
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.
Time Frame
16 weeks
Secondary Outcome Measure Information:
Title
Convenience, taste, and acceptability
Description
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.
Time Frame
16 weeks (measured 2 times)
Title
Urinary Ketosis
Description
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.
Time Frame
16 weeks
Title
Serum Ketosis
Description
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.
Time Frame
16 weeks (measured 3 times)
Title
Number of Patients with Adverse Events
Description
All adverse events will be monitored throughout the study. The number and type of adverse event will be recorded.
Time Frame
16 weeks (measured 3 times)
Title
Change in Mobility Measured Using Zeno Walkway
Description
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.
Time Frame
16 weeks (measured 3 times)
Title
Change in Cognition as Measured by Event Related Potentials (ERP)
Description
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.
Time Frame
16 weeks (measured 3 times)
Title
Change in Cortical Irritability Measured Using Electroencephalogram (EEG)
Description
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.
Time Frame
16 weeks (measured 3 times)
Title
Number of Patients with Treatment Related Adverse Events as Assessed by Blood Metabolic Panel
Description
Blood samples will be taken and assessed for complete blood count, comprehensive metabolic panel, ketones, and lipids.
Time Frame
16 weeks (measured 3 times)
Title
Nutrient Intake
Description
Food diaries recorded daily to establish total caloric and macro-nutrient intake.
Time Frame
16 weeks
Title
Changes in Gastrointestinal (GI) Health
Description
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.
Time Frame
16 weeks
Title
Changes in Sleep
Description
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.
Time Frame
16 weeks
Title
Changes in Seizures
Description
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.
Time Frame
16 weeks
Title
Height
Description
Height (cm)
Time Frame
16 weeks (measured 3 times)
Title
Weight
Description
Weight (kg)
Time Frame
16 weeks (measured 3 times)
Title
Change from Baseline in the Vineland Adaptive Behavior Score
Description
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.
Time Frame
16 weeks (measured 3 times)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Years
Maximum Age & Unit of Time
11 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jessica Duis, MD, MS
Organizational Affiliation
Children's Hospital Colorado
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hopsital Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
34510212
Citation
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.
Results Reference
derived
PubMed Identifier
31918761
Citation
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.
Results Reference
derived

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Nutritional Formulation for Angelman Syndrome

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