Back to results

Vitamin E Supplementation in Hyperinsulinism/Hyperammonemia Syndrome

Primary Purpose

Hyperinsulinism-Hyperammonemia Syndrome

Status

Completed

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Vitamin E

About this trial

This is an interventional other trial for Hyperinsulinism-Hyperammonemia Syndrome focused on measuring hyperinsulinism, hyperammonemia, hypoglycemia, vitamin e

Eligibility Criteria

1 Year - 40 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Children's Hospital of Philadelphia

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Vitamin E Supplementation

Arm Description

Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks.

Outcomes

Primary Outcome Measures

Tolerability of Vitamin E Based on Responses to a Subject/Parent-reported Symptom Questionnaire After Vitamin E Supplementation Compared to Baseline

The following symptoms will be scored as either "none" (did not occur)=0, "mild" (minimal symptoms, no treatment needed)=1, "moderate" (symptoms requiring treatment at home or as an outpatient=2, or "severe" (symptoms requiring hospitalization or emergency room visit, or life-threatening or potentially life-threatening symptoms)=4: Seizure, Headache, Vision change/blurred vision, Weakness, Fatigue, Nausea, Vomiting, Diarrhea, Stomach pain, Constipation, Bruising, Bleeding, Rash, Itching, Other Symptom scores will be summed to yield a Tolerability Questionnaire Score for each participant. The Tolerability Questionnaire Score has a minimum score of 0 (symptoms did not occur) and a maximum score of 60 (all of the measured symptoms occurred, each with severe designation). The number (count) of participants with an increase in Tolerability Questionnaire Score from baseline to 2 weeks (following Vitamin E supplementation) will be reported.

Secondary Outcome Measures

Plasma Alpha-tocopherol Concentration

change in fasting plasma alpha-tocopherol concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])

Delta-plasma Glucose Concentration

change in delta-glucose concentration (fasting plasma glucose - nadir plasma glucose during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])

Fasting Plasma Glucose Concentration

change in fasting plasma glucose concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])

Nadir Plasma Glucose Concentration

change in nadir plasma glucose concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])

Fasting Plasma Insulin Concentration

change in fasting plasma insulin concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])

Peak Plasma Insulin Concentration

change in peak plasma insulin concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])

Delta-plasma Insulin Concentration

change in delta-plasma insulin concentration (peak plasma insulin - fasting plasma insulin during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])

Fasting Plasma Ammonia Concentration

change in fasting plasma ammonia concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])

Delta-plasma Ammonia Concentration

change in delta-plasma ammonia concentration (plasma ammonia at 60 minutes - fasting plasma ammonia during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])

Hypoglycemia Frequency

change in frequency of hypoglycemia (plasma glucose <70 mg/dL) detected on home glucose meter following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])

Full Information

NCT ID

NCT03797222

First Posted

January 6, 2019

Last Updated

November 2, 2022

Sponsor

Elizabeth A Rosenfeld

Collaborators

University of Pennsylvania, Lawson Wilkins Pediatric Endocrine Society, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

1. Study Identification

Unique Protocol Identification Number

NCT03797222

Brief Title

Vitamin E Supplementation in Hyperinsulinism/Hyperammonemia Syndrome

Official Title

Vitamin E Supplementation in Hyperinsulinism/Hyperammonemia Syndrome

Study Type

Interventional

2. Study Status

Record Verification Date

November 2022

Overall Recruitment Status

Completed

Study Start Date

April 15, 2019 (Actual)

Primary Completion Date

March 23, 2020 (Actual)

Study Completion Date

March 23, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Elizabeth A Rosenfeld

Collaborators

University of Pennsylvania, Lawson Wilkins Pediatric Endocrine Society, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hyperinsulinism-Hyperammonemia Syndrome

Keywords

hyperinsulinism, hyperammonemia, hypoglycemia, vitamin e

7. Study Design

Primary Purpose

Other

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

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.

Masking

None (Open Label)

Allocation

N/A

Enrollment

14 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Vitamin E Supplementation

Arm Type

Experimental

Arm Description

Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks.

Intervention Type

Dietary Supplement

Intervention Name(s)

Vitamin E

Other Intervention Name(s)

alpha-tocopherol

Intervention Description

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.

Primary Outcome Measure Information:

Title

Tolerability of Vitamin E Based on Responses to a Subject/Parent-reported Symptom Questionnaire After Vitamin E Supplementation Compared to Baseline

Description

Time Frame

2 weeks

Secondary Outcome Measure Information:

Title

Plasma Alpha-tocopherol Concentration

Description

change in fasting plasma alpha-tocopherol concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])

Time Frame

2 weeks

Title

Delta-plasma Glucose Concentration

Description

change in delta-glucose concentration (fasting plasma glucose - nadir plasma glucose during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])

Time Frame

2 weeks

Title

Fasting Plasma Glucose Concentration

Description

change in fasting plasma glucose concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])

Time Frame

2 weeks

Title

Nadir Plasma Glucose Concentration

Description

change in nadir plasma glucose concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])

Time Frame

2 weeks

Title

Fasting Plasma Insulin Concentration

Description

change in fasting plasma insulin concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])

Time Frame

2 weeks

Title

Peak Plasma Insulin Concentration

Description

change in peak plasma insulin concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])

Time Frame

2 weeks

Title

Delta-plasma Insulin Concentration

Description

Time Frame

2 weeks

Title

Fasting Plasma Ammonia Concentration

Description

change in fasting plasma ammonia concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])

Time Frame

2 weeks

Title

Delta-plasma Ammonia Concentration

Description

Time Frame

2 weeks

Title

Hypoglycemia Frequency

Description

change in frequency of hypoglycemia (plasma glucose <70 mg/dL) detected on home glucose meter following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])

Time Frame

2 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Year

Maximum Age & Unit of Time

40 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Elizabeth Rosenfeld, MD

Organizational Affiliation

Children's Hospital of Philadelphia

Official's Role

Principal Investigator

Facility Information:

Facility Name

Children's Hospital of Philadelphia

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

20936362

Citation

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.

Results Reference

background

PubMed Identifier

23275527

Citation

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.

Results Reference

background

PubMed Identifier

11241047

Citation

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.

Results Reference

background

PubMed Identifier

940710

Citation

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

Results Reference

background

PubMed Identifier

19531491

Citation

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.

Results Reference

background

PubMed Identifier

26287975

Citation

McBurney MI, Yu EA, Ciappio ED, Bird JK, Eggersdorfer M, Mehta S. Suboptimal Serum alpha-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.

Results Reference

background

PubMed Identifier

23642196

Citation

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.

Results Reference

background

PubMed Identifier

23596164

Citation

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.

Results Reference

background

PubMed Identifier

8429120

Citation

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.

Results Reference

background

PubMed Identifier

20332361

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.

Results Reference

background

Learn more about this trial

Vitamin E Supplementation in Hyperinsulinism/Hyperammonemia Syndrome

We'll reach out to this number within 24 hrs