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

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.

Study Overview

• Status: Completed
• Conditions: X-linked Adrenoleukodystrophy
• Intervention / Treatment: Dietary supplement: vitamin D3

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 be assigned a vitamin D dose based on bodyweight at entry. Starting doses will include 1,000 or 2,000 international units (IU) of vitamin D3 daily for a 6 month period, followed by a conditional increase to 2,000, 3,000, or 4,000 IU daily thereafter if vitamin D levels have not achieved a target threshold. The vitamin D supplements will be provided by the study. In keeping with the current standard of care for ALD boys aged 18mos - 25 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
• Enrollment (Actual): 21
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vitamin D3; Single-arm, dose-escalation starting at 1,000 IU or 2,000 IU of vitamin D3 daily for a 6 month period, followed by a conditional titration up to 4,000 IU daily for at least 6 months thereafter. No placebo.	Dietary supplement: vitamin D3; Daily oral supplement provided by study investigators; Other Names: vitamin D

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of patients with a plasma 25-OH vitamin D level in the target range (40-80ng/ml) 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)	Plasma 25-OH vitamin D will be measured at 12 months
Percent of patients with a plasma 25-OH vitamin D level in the target range (40-80ng/ml) 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)	Plasma 25-OH vitamin D will be measured at 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between appearance of gadolinium enhancing brain lesion on MRI and most recent plasma 25-OH vitamin D level	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.	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.
Change in protein carbonyl levels in whole blood at baseline and 12 months.	The investigators expect a decrease in whole blood protein carbonyl levels between baseline and 12 months.	Measurements at baseline and 12months
Correlation between plasma 25-OH vitamin D and intracellular glutathione levels in peripheral monocytes	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.	Measurements at baseline and 12 months
Change in glutathione (GSH) levels in blood	The investigators expect a positive correlation between plasma 25-OH vitamin levels and GSH levels in whole blood (measured by tandem mass spectroscopy).	Measurements will be obtained at baseline, 6months, and 12months
Change in glutathione (GSH) levels in brain	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).	Measurements will be obtained at baseline, 6months, and 12months
Occurrence of serious adverse events	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.	Measurements will be obtained at baseline, 3months, 6months, 9months, 12months
Change in plasma interleukin-8 levels	The investigators expect a decrease in plasma IL-8 levels between baseline and 12 months	Measurements a baseline and 12 months
Change in plasma macrophage inflammatory protein-1b levels	The investigators expect a decrease in plasma MIP-1b levels between baseline and 12 months	Measurements at baseline and 12 months
Change in plasma monocyte chemoattractant protein-1 levels	The investigators expect a decrease in plasma MCP-1 levels between baseline and 12 months	Measurements at baseline and 12 months

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: 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

Publications and helpful links

Helpful Links

• Stanford University Neurosciences Patient Registry for Clinical Trials
• Multiple Sclerosis and Neuroimmunology Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2016
• Primary Completion (Actual): June 30, 2020
• Study Completion (Actual): June 30, 2020

Study Registration Dates

• First Submitted: October 29, 2015
• First Submitted That Met QC Criteria: November 2, 2015
• First Posted (Estimate): November 3, 2015

Study Record Updates

• Last Update Posted (Actual): June 9, 2022
• Last Update Submitted That Met QC Criteria: June 6, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: Inflammation; Vitamin D; Oxidative Stress; Leukodystrophy; Adrenoleukodystrophy; ALD; Demyelination; ABCD1; X- linked
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Demyelinating Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Endocrine System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Leukoencephalopathies; Adrenal Gland Diseases; Hereditary Central Nervous System Demyelinating Diseases; Peroxisomal Disorders; Adrenal Insufficiency; Adrenoleukodystrophy; Physiological Effects of Drugs; Micronutrients; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol; Vitamins; Ergocalciferols
• Other Study ID Numbers: 23596; K23NS087151 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Deidentified data will be made available to clinical investigators upon reasonable request.
• IPD Sharing Time Frame: For up to 10 years following study completion
• IPD Sharing Access Criteria: Reasonable request via email to study PI (kpv@stanford.edu)
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• 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