Vitamin E Efficacy in HI/HA

• Status: Not yet recruiting
• Trial end date: 2022-06-30
• Target enrollment: 0
• Participant gender: All

Summary

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. Pre-clinical data show that vitamin E inhibits GDH activity in human cell lines and improves fasting hypoglycemia in a GDH HI mouse model. Pilot study data show that vitamin E supplementation with a moderate dose is well-tolerated in children and adults with HI/HA syndrome, while continuing diazoxide treatment. However, most subjects continued to exhibit protein-induced hyperinsulinemic hypoglycemia. We hypothesize that a higher vitamin E dose will inhibit GDH over-activity in subjects with HI/HA syndrome, resulting in improved hyperinsulinemic hypoglycemia, reduced blood ammonia concentration, and decreased seizure activity.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Children's Hospital of Philadelphia
• Collaborators: Lawson Wilkins Pediatric Endocrine Society; University of Pennsylvania
• Treatments: alpha-Tocopherol; Tocopherols; Vitamin E

Criteria

Inclusion Criteria:

• Males or females age ≥18 years.

• Diagnosis of HI/HA syndrome (based on glutamate dehydrogenase 1 [GLUD1] genetic test result and/or history of diazoxide-responsive hyperinsulinism with persistently elevated blood ammonia concentrations).

• Able to swallow softgels.

• Informed consent.

Exclusion Criteria:

• Vitamin E supplementation within 30 days prior to enrollment, including multivitamins containing vitamin E.

• Individuals who have experienced an allergic reaction to vitamin E.

• On concurrent therapy with a medication known to adversely interact with vitamin E.

• On concurrent therapy with a medication, supplement, or herbal remedy known to increase bleeding risk, including antiplatelet or anticoagulation therapy.

• Known increased risk of bleeding (coagulopathy, hemophilia, platelet defect, or platelet disorder) based on history, known or suspected vitamin K deficiency, baseline international normalized ratio (INR) >1.5, baseline prothrombin time (PT) >1.5 times the upper limit of normal, baseline partial thromboplastin time (PTT) >1.5 times the upper limit of normal, or baseline abnormal platelet function test result (VerifyNow-Aspirin <550 aspirin reactivity units [ARU], VerifyNow-adenosine diphosphate [ADP]/PRU <180 P2Y12 reaction units [PRU]).

• Known clotting disorder, including prior episodes of deep vein thrombosis or pulmonary embolism within the past 6 months.

• Evidence of severe hematologic abnormality including severe anemia (Hgb <10 g/dL) and/or thrombocytopenia (platelet count <150,000/mm3).

• Abnormal score on International Society on Thrombosis and Haemostasis (ISTH)-Bleeding Assessment Tool (>4 if male; >5 if female).

• Planned elective surgical procedure during study period.

• 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.

• Any investigational drug use within 30 days prior to enrollment.

• Current use of somatostatin analog.

• Current adherence to a ketogenic diet.

• Pregnant or lactating females. Females must have a negative urine 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 and a minimum of 2 weeks after the last dose of study drug.

• 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).

• Limited English proficiency.