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

Abstract

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. 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.

Effect of vitamin D supplementation on cerebral blood flow in male patients with adrenoleukodystrophy

“…Drug compliance was examined using quarterly compliance questionnaires and by analyzing plasma 25‐hydroxyvitamin D levels. The dosing regimens and primary study outcomes were described previously by the senior author of this work (Haren et al, 2022). In short, all participants were assigned to daily oral vitamin D supplementation with a sublingually dissolvable tablet with an assigned daily dose ranging from 1000 IU daily to 4000 IU daily depending on the body weight and phase of enrollment.…”

“…All participants had normal developmental histories and normal neurologic exams at enrollment and throughout the study period. The full description of the procedure can be found in our previous work (Haren et al, 2022). The procedures were conducted according to the Declaration of Helsinki, and the data were collected between November 2016 and February 2020.…”