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| ID | Type | Description | Link |
|---|---|---|---|
| K23NS087151 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Neurological Disorders and Stroke (NINDS) | NIH |
| Hugo W. Moser Research Institute at Kennedy Krieger, Inc. | OTHER |
| ALD Connect, Inc. | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Vitamin D3 | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| vitamin D3 | Dietary Supplement | Daily oral supplement provided by study investigators |
|
| 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 |
| 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. |
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Criteria for enrollment to screening:
Criteria for assignment to drug:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Keith Van Haren, MD | Stanford University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Stanford University | Palo Alto | California | 94304 | United States |
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| Label | URL |
|---|---|
| Stanford University Neurosciences Patient Registry for Clinical Trials | View source |
| Multiple Sclerosis and Neuroimmunology Clinical Trials | View source |
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Deidentified data will be made available to clinical investigators upon reasonable request.
For up to 10 years following study completion
Reasonable request via email to study PI (kpv@stanford.edu)
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| ICF | No | No | Yes | Informed Consent Form | Apr 10, 2019 | May 30, 2019 | ICF_000.pdf |
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| ID | Term |
|---|---|
| D000326 | Adrenoleukodystrophy |
| D003711 | Demyelinating Diseases |
| D007249 | Inflammation |
| ID | Term |
|---|---|
| D020739 | Brain Diseases, Metabolic, Inborn |
| D001928 | Brain Diseases, Metabolic |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| D002762 | Cholecalciferol |
| D014807 | Vitamin D |
| ID | Term |
|---|---|
| D002782 | Cholestenes |
| D002776 | Cholestanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
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single-arm dose escalation
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| 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 |
| D009422 | Nervous System Diseases |
| D020279 | Hereditary Central Nervous System Demyelinating Diseases |
| D056784 | Leukoencephalopathies |
| D038901 | X-Linked Intellectual Disability |
| D008607 | Intellectual Disability |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D040181 | Genetic Diseases, X-Linked |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D008661 | Metabolism, Inborn Errors |
| D018901 | Peroxisomal Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D000309 | Adrenal Insufficiency |
| D000307 | Adrenal Gland Diseases |
| D004700 | Endocrine System Diseases |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D011083 |
| Polycyclic Compounds |
| D013261 | Sterols |
| D012632 | Secosteroids |
| D008563 | Membrane Lipids |
| D008055 | Lipids |