A phase I study of oral vitamin D3 in boys with X-linked adrenoleukodystrophy

Objective Vitamin D status has been linked to risk of inflammatory brain lesions. We sought to assess the safety and pharmacokinetics of oral vitamin D dosing regimens in boys with X-linked adrenoleukodystrophy (ALD). Methods In this open-label, multi-center, phase I study, we enrolled 21 ALD males without brain lesions, aged 1.5 to 25 years to oral vitamin D supplementation for 12 months. Our primary outcome was attainment of plasma 25-hydroxyvitamin D levels in target range (40-80ng/ml) at 6 and 12 months. Secondary outcomes included safety and glutathione levels in brain and blood. Participants were initially assigned to a fixed dosing regimen starting at 2,000 IU daily, regardless of weight. Following a mid-study safety assessment, we modified the dosing regimen so all subsequent participants were assigned to a weight-stratified dosing regimen starting as low as 1,000 IU daily. Results Between October 2016 and June 2019, we recruited 21 participants (n=12 fixed dose; n=9 weight-stratified) with a median age and weight of 6.7 years and 20 kilograms. Most participants achieved target plasma vitamin D levels at 6 and 12 months regardless of dosing regimen. In the fixed dose regimen, 6 of 12 participants had asymptomatic elevation in urine calcium:creatinine or plasma 25-hydroxyvitamin D; no laboratory deviations occurred with the weight-stratified regimen. Glutathione levels increased between baseline and 12 months in the brain but not in the blood. Conclusions Our weight-stratified vitamin D dosing regimen was well-tolerated and achieved target 25-hydroxyvitamin D levels in most participants. Brain glutathione levels increased over the 12-month trial period. [Clinicaltrials.gov][1] identifier NCT02595489 Classification of Evidence This study provides Class II evidence that a weight-stratified dosing regimen of vitamin D supplementation is safe, well-tolerated, and effective at achieving moderately high vitamin D levels in boys with ALD. Sources of funding NIH/NINDS K23NS087151 ### Competing Interest Statement All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare that the study described in the submitted work was supported by NIH/NINDS K23NS087151; KV has received research grants from Bluebird bio and Minoryx for clinical trials in ALD participants, separate from the submitted work; consulting fees from Bluebird bio, Minoryx, Viking Therapeutics, Poxel, and Orpheris for ALD therapy development separate from the submitted work. He participates in advisory boards for Poxel (paid), Viking (paid), ALD Connect (unpaid), and the United Leukodystrophy Foundations (unpaid). GVR has received consulting fees from Bluebird bio, Viking Therapeutics, and Minoryx for therapy development outside the submitted work. AF has received consulting fees from Minoryx, Viking, Autobahn, Vertex, Poxel, Aevi, and Calico for scientific advising outside the submitted work. He has participated in DSMB for Bluebird Bio. He is an unpaid board member at ALD Connect. No other relationships or activities that could appear to have influenced the submitted work. ### Clinical Trial NCT02595489 ### Clinical Protocols ### Funding Statement This study was funded by the NIH/NINDS #K23NS087151 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Boards of both Stanford University and Kennedy Krieger Institute gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: http://Clinicaltrials.gov