Vitamin E Supplementation in Hyperinsulinism/Hyperammonemia Syndrome

Overview

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

Study Type

  • Study Type: Interventional
  • Study Design
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Other
    • Masking: None (Open Label)
  • Study Primary Completion Date: January 31, 2020

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.

Interventions

  • 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.

Arms, Groups and Cohorts

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

Clinical Trial Outcome Measures

Primary Measures

  • tolerability of Vitamin E based on responses to a subject/parent-reported symptom questionnaire after Vitamin E supplementation compared to baseline
    • Time Frame: 2 weeks
    • The following symptoms will be scored as either “none” (did not occur), “mild” (minimal symptoms, no treatment needed), “moderate” (symptoms requiring treatment at home or as an outpatient, or “severe” (symptoms requiring hospitalization or emergency room visit, or life-threatening or potentially life-threatening symptoms): Seizure, Headache, Vision change/blurred vision, Weakness, Fatigue, Nausea, Vomiting, Diarrhea, Stomach pain, Constipation, Bruising, Bleeding, Rash, Itching, Other

Secondary Measures

  • plasma alpha-tocopherol concentration
    • Time Frame: 2 weeks
    • change in fasting plasma alpha-tocopherol concentration before versus after Vitamin E supplementation
  • delta-plasma glucose concentration
    • Time Frame: 2 weeks
    • change in delta-glucose concentration (fasting plasma glucose – nadir plasma glucose during oral protein tolerance test) before versus after Vitamin E supplementation
  • fasting plasma glucose concentration
    • Time Frame: 2 weeks
    • change in fasting plasma glucose concentration before versus after Vitamin E supplementation
  • nadir plasma glucose concentration
    • Time Frame: 2 weeks
    • change in nadir plasma glucose concentration during oral protein tolerance test before versus after Vitamin E supplementation
  • fasting plasma insulin concentration
    • Time Frame: 2 weeks
    • change in fasting plasma insulin concentration before versus after Vitamin E supplementation
  • peak plasma insulin concentration
    • Time Frame: 2 weeks
    • change in peak plasma insulin concentration during oral protein tolerance test before versus after Vitamin E supplementation
  • delta-plasma insulin concentration
    • Time Frame: 2 weeks
    • change in delta-plasma insulin concentration (peak plasma insulin – fasting plasma insulin during oral protein tolerance test) before versus after Vitamin E supplementation
  • fasting plasma ammonia concentration
    • Time Frame: 2 weeks
    • change in fasting plasma ammonia concentration before versus after Vitamin E supplementation
  • delta-plasma ammonia concentration
    • Time Frame: 2 weeks
    • change in delta-plasma ammonia concentration (plasma ammonia at 60 minutes – fasting plasma ammonia during oral protein tolerance test) before versus after Vitamin E supplementation
  • hypoglycemia frequency
    • Time Frame: 2 weeks
    • frequency of hypoglycemia (plasma glucose <70 mg/dL) detected on home glucose meter

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 1 Year

Maximum Age: 40 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Amanda M Ackermann
  • Provider of Information About this Clinical Study
    • Sponsor-Investigator: Amanda M Ackermann, Attending Physician, Assistant Professor – Children’s Hospital of Philadelphia
  • Overall Official(s)
    • Amanda M Ackermann, MD, PhD, Principal Investigator, Children’s Hospital of Philadelphia
  • Overall Contact(s)
    • Amanda M Ackermann, MD, PhD, 215-906-2161, ackermanna@email.chop.edu

References

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. Review.

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.

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 α-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. Review.

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.

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.

Clinical trials entries are delivered from the US National Institutes of Health and are not reviewed separately by this site. Please see the identifier information above for retrieving further details from the government database.

At TrialBulletin.com, we keep tabs on over 200,000 clinical trials in the US and abroad, using medical data supplied directly by the US National Institutes of Health. Please see the About and Contact page for details.