Vitamin E Efficacy in HI/HA

NCT04984798 | Withdrawn Phase 2 FDA Drug

• 1 other identifier: 20-018039
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Hyperinsulinism-Hyperammonemia Syndrome

Keywords

hypoglycemia; hyperinsulinism; vitamin E

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• mean glucose concentration

  4-11 weeks

• proportion of time spent with glucose <70 mg/dL

  4-11 weeks

• proportion of time spent with glucose <50 mg/dL

  4-11 weeks

• hypoglycemic episodes

  4-11 weeks

• protein-induced C-peptide release

  4-11 weeks

Other Outcomes (2)

• number of participants with EEG abnormalities

  8-11 weeks

• brain glutamate

  8-11 weeks

Study Arms (1)

Vitamin E Dose-Escalation

EXPERIMENTAL

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

Interventions

Vitamin E DRUG

Twice daily oral supplementation with Vitamin E for 6-9 weeks.

Also known as: dl-alpha-tocopherol

Vitamin E Dose-Escalation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Children's Hospital of Philadelphia: lead
• University of Pennsylvania: collaborator
• Lawson Wilkins Pediatric Endocrine Society: collaborator

Study Sites (1)

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (8)

• 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.

  PMID: 20936362 BACKGROUND

• 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.

  PMID: 23275527 BACKGROUND

• 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.

  PMID: 11241047 BACKGROUND

• 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.

  PMID: 11502802 BACKGROUND

• Stanley CA, Baker L. Hyperinsulinism in infancy: diagnosis by demonstration of abnormal response to fasting hypoglycemia. Pediatrics. 1976 May;57(5):702-11.

  PMID: 940710 BACKGROUND

• 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.

  PMID: 19531491 BACKGROUND

• 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.

  PMID: 20332361 BACKGROUND

• 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.

  PMID: 8429120 BACKGROUND

MeSH Terms

Conditions

Hyperinsulinemic hypoglycemia, familial, 6; Hypoglycemia; Hyperinsulinism

Interventions

Vitamin E; alpha-Tocopherol

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tocopherols

Study Officials

• Elizabeth A Rosenfeld, MD

  Children's Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PI

Model Details: This single-group open-label dose-finding clinical study will use a before-and-after design, with repeated outpatient evaluations.

Study Record Dates

• First Submitted: December 3, 2020
• First Posted: August 2, 2021
• Study Start: November 1, 2022
• Primary Completion: March 1, 2023
• Study Completion: March 1, 2023
• Last Updated: December 13, 2022

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)