- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02838472
Ascorbic Acid Treatment in Congenital Glucocorticoids and Mineralocorticoids Deficiency Due to NNT Mutation
Ascorbic Acid Treatment for Patients With Combined Mineralocorticoid and Glucocorticoid Deficiency Secondary to Nicotinamide Nucleotide Transhydrogenase Mutation
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.
Study Overview
Detailed 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.
Study Type
Enrollment (Anticipated)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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Jerusalem, Israel, 99305
- Hadassah Medical Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- NNT mutation homozygous patients with glucocorticoids deficiency
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: NON_RANDOMIZED
- Interventional Model: SINGLE_GROUP
- Masking: NONE
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
glucocorticoids secretion in response to ACTH test
Time Frame: 1 year
|
1 year
|
basal ACTH levels
Time Frame: 1 year
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1 year
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Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
insulin and glucose levels in OGTT
Time Frame: 1 year
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1 year
|
Collaborators and Investigators
Sponsor
Collaborators
Publications and helpful links
General Publications
- Meimaridou E, Kowalczyk J, Guasti L, Hughes CR, Wagner F, Frommolt P, Nurnberg 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.
- 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. Available from http://www.ncbi.nlm.nih.gov/books/NBK225483/
- 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 transhydrogenase mutation that alters mitochondrial morphology and increases oxidative stress. J Med Genet. 2015 Sep;52(9):636-41. doi: 10.1136/jmedgenet-2015-103078. Epub 2015 Jun 12.
Study record dates
Study Major Dates
Study Start
Primary Completion (ANTICIPATED)
Study Completion (ANTICIPATED)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ESTIMATE)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 0631-15-HMO
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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