Clinical trial NCT03797222: Vitamin E Supplementation in Hyperinsulinism/Hyperammonemia Syndrome
Official title: Vitamin E Supplementation in Hyperinsulinism/Hyperammonemia Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Hyperinsulinism-Hyperammonemia Syndrome
Keywords: hyperinsulinism
hyperammonemia
hypoglycemia
vitamin e
Lead sponsor: Children's Hospital of Philadelphia
Sponsor class: OTHER
Collaborators: name: University of Pennsylvania
name: Lawson Wilkins Pediatric Endocrine Society
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2019-01-09
Enrollment: 14
Sex: ALL
Minimum age (years): 1
Maximum age (years): 40
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This open-label tolerability and feasibility pilot clinical study will use a before-and-after design, with blood tests and fasting oral protein tolerance test performed prior to and after 2 weeks of daily oral Vitamin E supplementation in individuals with HI/HA syndrome.
Primary purpose: OTHER

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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Tolerability of Vitamin E Based on Responses to a Subject/Parent-reported Symptom Questionnaire After Vitamin E Supplementation Compared to Baseline
timeFrame: 2 weeks
Secondary outcomes:
measure: Plasma Alpha-tocopherol Concentration
timeFrame: 2 weeks
measure: Delta-plasma Glucose Concentration
timeFrame: 2 weeks
measure: Fasting Plasma Glucose Concentration
timeFrame: 2 weeks
measure: Nadir Plasma Glucose Concentration
timeFrame: 2 weeks
measure: Fasting Plasma Insulin Concentration
timeFrame: 2 weeks
measure: Peak Plasma Insulin Concentration
timeFrame: 2 weeks
measure: Delta-plasma Insulin Concentration
timeFrame: 2 weeks
measure: Fasting Plasma Ammonia Concentration
timeFrame: 2 weeks
measure: Delta-plasma Ammonia Concentration
timeFrame: 2 weeks
measure: Hypoglycemia Frequency
timeFrame: 2 weeks
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
Study officials:
affiliation: Children's Hospital of Philadelphia
name: Elizabeth Rosenfeld, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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.