Vitamin E Efficacy in HI/HA

Efficacy of Vitamin E in Hyperinsulinism/Hyperammonemia Syndrome

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.

Study Overview

• Status: Withdrawn
• Conditions: Hyperinsulinism-Hyperammonemia Syndrome
• Intervention / Treatment: Drug: Vitamin E

Detailed Description

The primary objective of this study is to determine an effective dose of vitamin E to reduce protein-induced hyperinsulinemia in subjects with HI/HA syndrome. Secondary objectives are to assess the effects of vitamin E on plasma C-peptide concentrations, serum alpha-tocopherol concentrations, blood ammonia concentrations, hypoglycemic events, and seizure frequency. The effect of vitamin E on brain glutamate levels and electroencephalogram findings will be explored.

This single-group open-label dose-finding clinical study will use a before-and-after design to compare clinical and laboratory data before and after 2-3 weeks of escalating doses of oral vitamin E treatment in subjects with HI/HA syndrome.

This single-site outpatient study will recruit up to 5 adult participants (18 years of age or older) with HI/HA syndrome.

Each study visit will consist of blood tests, an IV leucine acute insulin response (AIR) test, home glucose meter and continuous glucose monitor (CGM) review, and a symptom questionnaire. The baseline and final visits will also include electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) with glutamate chemical exchange saturation transfer (GluCEST) analysis. After baseline assessments, including a 2 week run-in period of CGM use, subjects will take twice daily oral vitamin E (alpha-tocopherol) at home. After steady-state of that dose of vitamin E has been achieved (i.e. at least 2 weeks on the dose of vitamin E), subjects will return for the next study visit. If there is no dose-limiting toxicity, then the twice daily vitamin E dose will be increased, and the subjects will return for a subsequent study visit after at least 2 weeks. If there is no dose-limiting toxicity at this visit, then the twice daily vitamin E dose will be increased again, and the subjects will return for a final study visit after at least 2 weeks. If toxicity is identified at any point, vitamin E will be discontinued and final study visit procedures will be performed.

• Study Type: Interventional
• Phase: Phase 2

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: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• 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 Dose-Escalation; Subjects will take an oral Vitamin E (dl-alpha-tocopherol) supplement twice daily with a fat-containing meal for 6-9 weeks. The dose will be increased every 2-3 weeks over the course of the study (initial dose 600 IU twice daily, next dose 1,200 IU twice daily, final dose 2,400 IU twice daily). Formulations include softgel capsules in 200, 400, and 1,000 IU doses.

Drug: Vitamin E; Twice daily oral supplementation with Vitamin E for 6-9 weeks.; Other Names: dl-alpha-tocopherol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
protein-induced hyperinsulinemia	Change in plasma insulin concentration area under the curve (AUC) during leucine AIR test after vitamin E treatment compared to before.	4-11 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mean glucose concentration	Change in mean glucose concentration detected on continuous glucose monitor (CGM) during the study interval after vitamin E treatment compared to before.	4-11 weeks
proportion of time spent with glucose <70 mg/dL	Change in proportion of time spent with glucose <70 mg/dL, detected on continuous glucose monitor (CGM) during the study interval after vitamin E treatment compared to before.	4-11 weeks
proportion of time spent with glucose <50 mg/dL	Change in proportion of time spent with glucose <50 mg/dL, detected on continuous glucose monitor (CGM) during the study interval after vitamin E treatment compared to before.	4-11 weeks
hypoglycemic episodes	Change in frequency of hypoglycemic episodes (plasma glucose <70 mg/dL and plasma glucose <50 mg/dL) detected on home glucose meter and/or continuous glucose monitor (CGM) after vitamin E treatment compared to before.	4-11 weeks
protein-induced C-peptide release	Change in plasma C-peptide concentration area under the curve (AUC) during leucine AIR test after vitamin E treatment compared to before.	4-11 weeks
vitamin E	Change in serum alpha-tocopherol concentration after vitamin E treatment compared to before.	4-11 weeks
ammonia	Change in blood ammonia concentration after vitamin E treatment compared to before.	4-11 weeks
seizures	Change in frequency of seizures, based on symptom questionnaire, after vitamin E treatment compared to before.	4-11 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
number of participants with EEG abnormalities	Change in brain electrical activity after vitamin E treatment compared to before.	8-11 weeks
brain glutamate	Change in glutamate concentration, as measured by brain GluCEST percent contrast, after vitamin E treatment compared to before.	8-11 weeks

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: University of Pennsylvania; Lawson Wilkins Pediatric Endocrine Society
• Investigators: Principal Investigator: Elizabeth A 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.
• 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.
• Kelly A, Ng D, Ferry RJ Jr, Grimberg A, Koo-McCoy S, Thornton PS, Stanley CA. Acute insulin responses to leucine in children with the hyperinsulinism/hyperammonemia syndrome. J Clin Endocrinol Metab. 2001 Aug;86(8):3724-8. doi: 10.1210/jcem.86.8.7755.

Study record dates

Study Major Dates

• Study Start (Anticipated): November 1, 2022
• Primary Completion (Anticipated): March 1, 2023
• Study Completion (Anticipated): March 1, 2023

Study Registration Dates

• First Submitted: December 3, 2020
• First Submitted That Met QC Criteria: July 28, 2021
• First Posted (Actual): August 2, 2021

Study Record Updates

• Last Update Posted (Actual): December 13, 2022
• Last Update Submitted That Met QC Criteria: December 9, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: hypoglycemia; vitamin E; hyperinsulinism
• 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: 20-018039

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