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Trial record 7 of 36 for:    Brain | "Adrenomyeloneuropathy"

A Pilot Study of Vitamin D in Boys With X-linked Adrenoleukodystrophy

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ClinicalTrials.gov Identifier: NCT02595489
Recruitment Status : Recruiting
First Posted : November 3, 2015
Last Update Posted : July 12, 2018
Sponsor:
Collaborators:
National Institute of Neurological Disorders and Stroke (NINDS)
Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
ALD Connect, Inc.
Information provided by (Responsible Party):
Keith Van Haren, Stanford University

Brief Summary:

In this pilot study, the investigators will assess the safety of two high-dose regimens of oral vitamin D supplementation and measure the effects of vitamin D supplementation on markers of oxidative stress and inflammation in the blood and brain of study participants before, during, and after taking vitamin D supplements.

The goal of the study is to establish research measures (i.e. biomarkers) and an optimal dose for vitamin D supplementation in boys with the X-linked adrenoleukodystrophy (ALD) genotype.


Condition or disease Intervention/treatment Phase
X-linked Adrenoleukodystrophy Dietary Supplement: vitamin D3 Phase 1

Detailed Description:

Prior research suggests that higher vitamin D levels in the blood are associated with reduced brain inflammation among individuals with multiple sclerosis, a disease that is similar to the cerebral demyelinating form of ALD. However, serious side effects (e.g. hypercalcemia, kidney stones) can occur if vitamin D levels get too high.

The current study is designed to establish a safe dose of vitamin D for boys with ALD. Although the doses chosen for this study are expected to be safe, the investigators will monitor participants for early signs of vitamin D-related toxicity. The investigators will also examine whether or not vitamin D supplementation affects markers of oxidative stress and inflammation in the blood and brains of ALD boys.

The study requires participants to agree to at least one year of participation. Participants will be asked to take a vitamin D supplement every day, submit blood for analysis every 3 months in the first year, and visit their study center (Stanford University or the Kennedy Krieger Institute) every 6 months throughout the period of study.

Participants will take 2,000 international units (IU) of vitamin D3 daily for a 6 month period, followed by an increase to 4,000 IU daily for at least 6 months thereafter. The vitamin D supplements will be provided by the study. In keeping with the current standard of care for ALD boys aged 3-12 years, participants will need to visit the study site every six months in order to complete a clinic visit and MRI of the brain with gadolinium. As part of this study, however, participants' will need to submit blood work every 3 months during the first year in order for the study investigators to ensure that the participants' calcium and vitamin D levels are in a safe range and to study the effects of vitamin D on markers in the blood. The MRI protocol during the first year will also include one additional sequence (magnetic resonance spectroscopy) in order to measure brain metabolites.

The data generated from this study are intended, in part, to help design a future, large-scale clinical trial to determine whether vitamin D supplementation is capable of reducing the risk of developing the cerebral demyelinating form of ALD.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Intervention Model Description: single-arm dose escalation
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A Pilot Study of Vitamin D in Boys With X-linked Adrenoleukodystrophy
Study Start Date : March 2016
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : December 2020


Arm Intervention/treatment
Experimental: Vitamin D3
Single-arm, dose-escalation starting at 2,000 IU of vitamin D3 daily for a 6 month period, followed by a 4,000 IU daily for at least 6 months thereafter. No placebo.
Dietary Supplement: vitamin D3
Daily oral supplement provided by study investigators
Other Name: vitamin D




Primary Outcome Measures :
  1. Percent of patients with a plasma 25-OH vitamin D level in the target range (40-80ng/ml) at 12 months [ Time Frame: Plasma 25-OH vitamin D will be measured at 12 months ]
    The investigators expect 100% of patients will be in the target range at 12 months (i.e. oral dose of 4000 IU daily)

  2. Percent of patients with a plasma 25-OH vitamin D level in the target range (40-80ng/ml) at 6 months [ Time Frame: Plasma 25-OH vitamin D will be measured at 6 months ]
    The investigators expect that 80% of patients will be in the target range 6 months (i.e. oral dose of 2000 IU daily)


Secondary Outcome Measures :
  1. Correlation between appearance of gadolinium enhancing brain lesion on MRI and most recent plasma 25-OH vitamin D level [ Time Frame: Brain MRI at baseline, 6, 12, 18, 24, 30, and 36 months study enrollment. Plasma 25-OH vitamin D levels at baseline, 3, 6, 9, 12, 18, 24, 30, 36 months of enrollment. ]
    For participants developing gadolinium enhancing lesions on MRI, the investigators will compare the most recent preceding 25-OH vitamin D level with the average 25-OH vitamin D level of participants in the study who did not develop gadolinium enhancing lesions. The investigators expect the development of gadolinium enhancing lesion on MRI will correlate with lower vitamin D levels. However, our current study is not sufficiently powered to measure this effect.

  2. Change in protein carbonyl levels in whole blood at baseline and 12 months. [ Time Frame: Measurements at baseline and 12months ]
    The investigators expect a decrease in whole blood protein carbonyl levels between baseline and 12 months.

  3. Correlation between plasma 25-OH vitamin D and intracellular glutathione levels in peripheral monocytes [ Time Frame: Measurements at baseline and 12 months ]
    The investigators will use flow cytometry to measure intracellular GSH in CD14+ monocytes from participants peripheral blood at baseline and 12 months. The investigators will measure plasma 25-OH vitamin at the same time points. The investigators expect a positive correlation between plasma vitamin D levels and monocyte GSH levels.

  4. Change in glutathione (GSH) levels in blood [ Time Frame: Measurements will be obtained at baseline, 6months, and 12months ]
    The investigators expect a positive correlation between plasma 25-OH vitamin levels and GSH levels in whole blood (measured by tandem mass spectroscopy).

  5. Change in glutathione (GSH) levels in brain [ Time Frame: Measurements will be obtained at baseline, 6months, and 12months ]
    The investigators will examine the correlation between 25-OH vitamin D levels in plasma and total GSH levels in occipital white matter (measured by single-voxel MR spectroscopy).

  6. Occurrence of serious adverse events [ Time Frame: Measurements will be obtained at baseline, 3months, 6months, 9months, 12months ]
    The investigators do not expect any participants to develop hypercalcemia (serum calcium >10.7mg/dl) or related serious adverse events (e.g. kidney stones) while taking 2000 IU or 4000 IU daily.

  7. Change in plasma interleukin-8 levels [ Time Frame: Measurements a baseline and 12 months ]
    The investigators expect a decrease in plasma IL-8 levels between baseline and 12 months

  8. Change in plasma macrophage inflammatory protein-1b levels [ Time Frame: Measurements at baseline and 12 months ]
    The investigators expect a decrease in plasma MIP-1b levels between baseline and 12 months

  9. Change in plasma monocyte chemoattractant protein-1 levels [ Time Frame: Measurements at baseline and 12 months ]
    The investigators expect a decrease in plasma MCP-1 levels between baseline and 12 months



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Ages Eligible for Study:   18 Months to 25 Years   (Child, Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Criteria for enrollment to screening:

  1. Molecular confirmation of X-linked ALD (VLCFA elevation & ABCD1 mutation) known in patient or immediate family member)
  2. Male
  3. Age 1.5yrs (i.e. 18mos) - 25yrs at screening

Criteria for assignment to drug:

  1. Plasma 25-hydroxy vitamin D level ≤ 60ng/ml in past 30 days
  2. MRI brain in past 6 months that is negative for evidence of active cerebral demyelination

Exclusion Criteria:

  • history of liver or kidney disease
  • history of nephrolithiasis
  • history of hyperthyroidism
  • history of ulcerative colitis, Crohn's disease, celiac disease
  • taking medication interfering with gastrointestinal absorption
  • contraindication or inability to complete MRI every 6 months

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02595489


Contacts
Contact: Keith Van Haren, MD kpv@stanford.edu
Contact: Dalia Pena-Solorzano, BS 650-498-9732 dpena25@stanford.edu

Locations
United States, California
Stanford University Recruiting
Palo Alto, California, United States, 94304
Contact: Keith Van Haren, MD       kpv@stanford.edu   
Principal Investigator: Keith Van Haren, MD         
Sponsors and Collaborators
Stanford University
National Institute of Neurological Disorders and Stroke (NINDS)
Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
ALD Connect, Inc.
Investigators
Principal Investigator: Keith Van Haren, MD Stanford University

Additional Information:
Responsible Party: Keith Van Haren, Assistant Professor, Stanford University
ClinicalTrials.gov Identifier: NCT02595489     History of Changes
Other Study ID Numbers: 23596
K23NS087151 ( U.S. NIH Grant/Contract )
First Posted: November 3, 2015    Key Record Dates
Last Update Posted: July 12, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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

Keywords provided by Keith Van Haren, Stanford University:
Leukodystrophy
ABCD1
Demyelination
Inflammation
ALD
Vitamin D
Oxidative Stress
X- linked
Adrenoleukodystrophy

Additional relevant MeSH terms:
Adrenoleukodystrophy
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Hereditary Central Nervous System Demyelinating Diseases
Leukoencephalopathies
Demyelinating Diseases
Mental Retardation, X-Linked
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Heredodegenerative Disorders, Nervous System
Metabolism, Inborn Errors
Peroxisomal Disorders
Metabolic Diseases
Adrenal Insufficiency
Adrenal Gland Diseases
Endocrine System Diseases
Vitamins
Vitamin D
Ergocalciferols
Cholecalciferol
Micronutrients
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents