Ascorbic Acid Treatment in Congenital Glucocorticoids and Mineralocorticoids Deficiency Due to NNT Mutation

Glucocorticoids Deficiency Clinical Trial

Official title:

Ascorbic Acid Treatment for Patients With Combined Mineralocorticoid and Glucocorticoid Deficiency Secondary to Nicotinamide Nucleotide Transhydrogenase Mutation

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT02838472
• Other study ID #: 0631-15-HMO
• Status: Enrolling by invitation
• Phase: N/A
• First received: July 17, 2016
• Last updated: July 19, 2016
• Start date: June 2016
• Est. completion date: December 2017

Study information

• Verified date: June 2016
• Source: Hadassah Medical Organization
• Contact: n/a
• Is FDA regulated: No
• Health authority: Israel: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

Nicotinamide nucleotide transhydrogenase (NNT) mutations cause glucocorticoid and mineralocorticoid deficiencies through decreased detoxification of reactive oxygen species (ROS) in adrenocortical cells.

Ascorbic acid is well known by its high antioxidant activity due to the neutralization of free radicals and other reactive oxygen species.

Preliminary results of NNT_p.G200S homozygous fibroblasts' treatment with 10 micro molar L-ascorbic acid shows significant improvement in mitochondrial morphology and in ROS content.

The aim of this study is to figure out if ascorbic acid treatment improves the phenotype of NNT patients by reducing ROS in their adrenocortical cells and preventing their apoptosis.

Description:

Most cases of familial glucocorticoid and mineralocorticoid deficiency are caused by mutations interrupting steroidogenesis such as 21- hydroxylase deficiency. Recently, nicotinamide nucleotide transhydrogenase (NNT) mutations were found to cause isolated glucocorticoid deficiency or combined mineralocorticoid and glucocorticoid deficiency through decreased detoxification of reactive oxygen species (ROS) in adrenocortical cells.

NNT mutation in mice causes also glucose intolerance. Ascorbic acid is an essential water-soluble vitamin with excellent reducing properties, well known by its high antioxidant activity due to the neutralization of free radicals and other reactive oxygen species. This vitamin acts as the first line of defense during oxidative stress in the human body.

Ascorbic acid treatment for variant disease (e.g. - cancer, type 2 diabetes, anxiety, depression, asthma and cardiovascular diseases) have been meticulously studies with no major adverse effects.

In a previous study, the investigators demonstrated a higher ROS levels, a lower ATP content and a change in mitochondrial morphology in NNT_p.G200S homozygous fibroblasts compared with control fibroblasts.

Preliminary results of NNT_p.G200S homozygous fibroblasts' treatment with 10 micro molar L-ascorbic acid shows significant improvement in mitochondrial morphology and in ROS content.

The aim of this study is to figure out if ascorbic acid treatment improves the phenotype of NNT patients by reducing ROS in their adrenocortical cells and preventing their apoptosis.

During the study NNT_p.G200S homozygous patients (no.-3) will be hospitalised for ACTH and OGTT tests and start ascorbic acid treatment at a doses of 75-80% of the upper limit of allowance according to IOM. ACTH and OGTT will be repeated 6 months later to assess improvement in glucocorticoids production and insulin resistance.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 3
• Est. completion date: December 2017
• Est. primary completion date: August 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year and older

Eligibility

Inclusion Criteria:

• NNT mutation homozygous patients with glucocorticoids deficiency

Study Design

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Glucocorticoids Deficiency

Intervention

Drug:
• Ascorbic Acid
Ascorbic acid administration at a doses of 75-80% of the upper limit of allowance according to IOM

Locations

Country	Name	City	State
Israel	Hadassah medical center	Jerusalem

Sponsors (2)

Lead Sponsor	Collaborator
Hadassah Medical Organization	Soroka Medical Center

Country where clinical trial is conducted

Israel, 

References & Publications (3)

Institute of Medicine (US) Panel on Dietary Antioxidants and Related Compounds. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington (DC): National Academies Press (US); 2000. — View Citation

Meimaridou E, Kowalczyk J, Guasti L, Hughes CR, Wagner F, Frommolt P, Nürnberg P, Mann NP, Banerjee R, Saka HN, Chapple JP, King PJ, Clark AJ, Metherell LA. Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. Nat Genet. 2012 May 27;44(7):740-2. doi: 10.1038/ng.2299. — View Citation

Weinberg-Shukron A, Abu-Libdeh A, Zhadeh F, Carmel L, Kogot-Levin A, Kamal L, Kanaan M, Zeligson S, Renbaum P, Levy-Lahad E, Zangen D. Combined mineralocorticoid and glucocorticoid deficiency is caused by a novel founder nicotinamide nucleotide transhydro — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	glucocorticoids secretion in response to ACTH test		1 year	No
Primary	basal ACTH levels		1 year	No
Secondary	insulin and glucose levels in OGTT		1 year