Vitamin E Supplementation in Hyperinsulinism/Hyperammonemia Syndrome

Investigators will assess the tolerability of oral Vitamin E supplementation in subjects with congenital hyperinsulinism (HI) and hyperammonemia (HA) syndrome.

Study Overview

• Status: Completed
• Conditions: Hyperinsulinism-Hyperammonemia Syndrome
• Intervention / Treatment: Dietary supplement: Vitamin E

Detailed Description

Congenital hyperinsulinism (HI) is a rare disorder of pancreatic beta cell insulin secretion that causes persistent and severe hypoglycemia starting at birth. Hyperinsulinism/hyperammonemia (HI/HA) syndrome is the second most common type of congenital HI and is caused by activating mutations in glutamate dehydrogenase (GDH). Patients with HI/HA exhibit fasting hyperinsulinemic hypoglycemia, protein-induced hypoglycemia, hyperammonemia, seizures, and intellectual disability independent of hypoglycemia. These effects result from abnormal GDH activity in the beta cells, liver and kidney cells, neurons, and astrocytes. The only available treatment for HI/HA syndrome is diazoxide, which acts on the beta cells to decrease insulin secretion but has no effect on GDH activity itself or on other cell types. Thus, there remains a significant unmet need for improved therapies for this disorder. Preliminary data show that Vitamin E (alpha-tocopherol) inhibits GDH activity in cell lines and improves hypoglycemia in a GDH HI mouse model. Based on these preclinical studies, Investigators hypothesize that Vitamin E will inhibit GDH activity and may impact hyperinsulinemic hypoglycemia and hyperammonemia in subjects with HI/HA syndrome. This hypothesis will be tested in a future study. In this initial pilot study, investigators will assess the tolerability of oral Vitamin E supplementation in subjects with HI/HA syndrome.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 40 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Individuals age ≥12 months and ≤40 years
• Diagnosis of HI/HA syndrome
• On diazoxide therapy for treatment of hypoglycemia
• Females ≥11 years of age or menstruating must have a negative urine/serum pregnancy test and must use an acceptable method of contraception, including abstinence, a barrier method (diaphragm or condom), Depo-Provera, or an oral contraceptive, for the duration of the study.
• Informed consent for participants ≥18 years. Parental/guardian permission (informed consent) and, if appropriate, child assent for participants <18 years.

Exclusion Criteria:

• Individuals age <12 months or >40 years
• Individuals who have experienced an allergic reaction to Vitamin E
• Individuals with a known allergy to dairy, whey, or soy
• On concurrent therapy with a medication known to be metabolized by the CYP3A pathway
• Individuals with a known increased risk of bleeding (bleeding disorder or on antiplatelet or anticoagulation therapy)
• Vitamin E supplementation within 30 days prior to enrollment, including multivitamins containing Vitamin E
• Severe hypoglycemia (plasma glucose <50 mg/dL on repeat checks using home glucose meter) more than once weekly within 30 days prior to enrollment.
• Evidence of a medical condition that might alter results or compromise the interpretation of results, including active infection, kidney failure, severe liver dysfunction, severe respiratory or cardiac failure.
• Evidence of severe hematologic abnormality including severe anemia and/or thrombocytopenia.
• Any investigational drug use within 30 days prior to enrollment.
• Pregnant or lactating females.
• Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.
• Unable to provide informed consent (e.g. impaired cognition or judgment).
• Parents/guardians or subjects with limited English proficiency.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Vitamin E Supplementation; Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks.

Dietary supplement: Vitamin E; Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if >17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive <600 IU daily, or for any subjects who prefer liquid medication to capsules.; Other Names: alpha-tocopherol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerability of Vitamin E Based on Responses to a Subject/Parent-reported Symptom Questionnaire After Vitamin E Supplementation Compared to Baseline	The following symptoms will be scored as either "none" (did not occur)=0, "mild" (minimal symptoms, no treatment needed)=1, "moderate" (symptoms requiring treatment at home or as an outpatient=2, or "severe" (symptoms requiring hospitalization or emergency room visit, or life-threatening or potentially life-threatening symptoms)=4: Seizure, Headache, Vision change/blurred vision, Weakness, Fatigue, Nausea, Vomiting, Diarrhea, Stomach pain, Constipation, Bruising, Bleeding, Rash, Itching, Other Symptom scores will be summed to yield a Tolerability Questionnaire Score for each participant. The Tolerability Questionnaire Score has a minimum score of 0 (symptoms did not occur) and a maximum score of 60 (all of the measured symptoms occurred, each with severe designation). The number (count) of participants with an increase in Tolerability Questionnaire Score from baseline to 2 weeks (following Vitamin E supplementation) will be reported.	2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Alpha-tocopherol Concentration	change in fasting plasma alpha-tocopherol concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])	2 weeks
Delta-plasma Glucose Concentration	change in delta-glucose concentration (fasting plasma glucose - nadir plasma glucose during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])	2 weeks
Fasting Plasma Glucose Concentration	change in fasting plasma glucose concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])	2 weeks
Nadir Plasma Glucose Concentration	change in nadir plasma glucose concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])	2 weeks
Fasting Plasma Insulin Concentration	change in fasting plasma insulin concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])	2 weeks
Peak Plasma Insulin Concentration	change in peak plasma insulin concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])	2 weeks
Delta-plasma Insulin Concentration	change in delta-plasma insulin concentration (peak plasma insulin - fasting plasma insulin during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])	2 weeks
Fasting Plasma Ammonia Concentration	change in fasting plasma ammonia concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])	2 weeks
Delta-plasma Ammonia Concentration	change in delta-plasma ammonia concentration (plasma ammonia at 60 minutes - fasting plasma ammonia during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])	2 weeks
Hypoglycemia Frequency	change in frequency of hypoglycemia (plasma glucose <70 mg/dL) detected on home glucose meter following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])	2 weeks

Collaborators and Investigators

• Sponsor: Elizabeth A Rosenfeld
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University of Pennsylvania; Lawson Wilkins Pediatric Endocrine Society
• Investigators: Principal Investigator: Elizabeth Rosenfeld, MD, Children's Hospital of Philadelphia

Publications and helpful links

General Publications

• Palladino AA, Stanley CA. The hyperinsulinism/hyperammonemia syndrome. Rev Endocr Metab Disord. 2010 Sep;11(3):171-8. doi: 10.1007/s11154-010-9146-0.
• Snider KE, Becker S, Boyajian L, Shyng SL, MacMullen C, Hughes N, Ganapathy K, Bhatti T, Stanley CA, Ganguly A. Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. J Clin Endocrinol Metab. 2013 Feb;98(2):E355-63. doi: 10.1210/jc.2012-2169. Epub 2012 Dec 28.
• Hsu BY, Kelly A, Thornton PS, Greenberg CR, Dilling LA, Stanley CA. Protein-sensitive and fasting hypoglycemia in children with the hyperinsulinism/hyperammonemia syndrome. J Pediatr. 2001 Mar;138(3):383-9. doi: 10.1067/mpd.2001.111818.
• Stanley CA, Baker L. Hyperinsulinism in infancy: diagnosis by demonstration of abnormal response to fasting hypoglycemia. Pediatrics. 1976 May;57(5):702-11.
• Li M, Smith CJ, Walker MT, Smith TJ. Novel inhibitors complexed with glutamate dehydrogenase: allosteric regulation by control of protein dynamics. J Biol Chem. 2009 Aug 21;284(34):22988-3000. doi: 10.1074/jbc.M109.020222. Epub 2009 Jun 15.
• McBurney MI, Yu EA, Ciappio ED, Bird JK, Eggersdorfer M, Mehta S. Suboptimal Serum alpha-Tocopherol Concentrations Observed among Younger Adults and Those Depending Exclusively upon Food Sources, NHANES 2003-20061-3. PLoS One. 2015 Aug 19;10(8):e0135510. doi: 10.1371/journal.pone.0135510. eCollection 2015.
• Ulatowski L, Manor D. Vitamin E trafficking in neurologic health and disease. Annu Rev Nutr. 2013;33:87-103. doi: 10.1146/annurev-nutr-071812-161252. Epub 2013 Apr 29.
• Pfeiffer CM, Sternberg MR, Schleicher RL, Haynes BM, Rybak ME, Pirkle JL. The CDC's Second National Report on Biochemical Indicators of Diet and Nutrition in the U.S. Population is a valuable tool for researchers and policy makers. J Nutr. 2013 Jun;143(6):938S-47S. doi: 10.3945/jn.112.172858. Epub 2013 Apr 17.
• Ferslew KE, Acuff RV, Daigneault EA, Woolley TW, Stanton PE Jr. Pharmacokinetics and bioavailability of the RRR and all racemic stereoisomers of alpha-tocopherol in humans after single oral administration. J Clin Pharmacol. 1993 Jan;33(1):84-8. doi: 10.1002/j.1552-4604.1993.tb03909.x.
• Treberg JR, Clow KA, Greene KA, Brosnan ME, Brosnan JT. Systemic activation of glutamate dehydrogenase increases renal ammoniagenesis: implications for the hyperinsulinism/hyperammonemia syndrome. Am J Physiol Endocrinol Metab. 2010 Jun;298(6):E1219-25. doi: 10.1152/ajpendo.00028.2010. Epub 2010 Mar 23.

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2019
• Primary Completion (Actual): March 23, 2020
• Study Completion (Actual): March 23, 2020

Study Registration Dates

• First Submitted: January 6, 2019
• First Submitted That Met QC Criteria: January 7, 2019
• First Posted (Actual): January 9, 2019

Study Record Updates

• Last Update Posted (Actual): November 25, 2022
• Last Update Submitted That Met QC Criteria: November 2, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: hypoglycemia; hyperammonemia; hyperinsulinism; vitamin e
• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Disease; Syndrome; Hyperinsulinism; Hyperammonemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Vitamins; Antioxidants; Vitamin E; Tocopherols; alpha-Tocopherol
• Other Study ID Numbers: 17-014550; T32DK063688 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No