Keith P Van Haren, Kristen Cunanan, Avni Awani, Meng Gu, Dalia Peña, Lindsay C Chromik, Michal Považan, Nicole C Rossi, Jordan Goodman, Vandana Sundaram, Jennifer Winterbottom, Gerald V Raymond, Tina Cowan, Gregory M Enns, Emmanuelle Waubant, Lawrence Steinman, Peter B Barker, Daniel Spielman, Ali Fatemi
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After a midstudy 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.</p><p><strong>Results: </strong>Between October 2016 and June 2019, we enrolled 21 participants (n = 12, fixed-dose regimen; n = 9, weight-stratified regimen) with a median age of 6.7 years (range: 1.9-22 years) and median weight of 20 kg (range: 11.7-85.5 kg). The number of participants achieving target vitamin D levels was similar in both groups at 6 months (fixed dose: 92%; weight stratified: 78%) and 12 months (fixed dose: 67%; weight stratified: 67%). Among the 12 participants in the fixed-dose regimen, half had asymptomatic elevations in either urine calcium:creatinine or plasma 25-hydroxyvitamin D; no laboratory deviations occurred with the weight-stratified regimen. 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引用次数: 0
摘要
背景和目的：目前还没有预防X连锁肾上腺白质营养不良症（ALD）脑脱髓鞘的疗法。较高的血浆维生素 D 水平与较低的脑部炎症病变风险有关。我们评估了口服维生素 D 给药方案在患有 ALD 的男孩和年轻男性中的安全性和药代动力学：在这项开放标签、多中心、1 期研究中，我们招募了没有脑部病变的 ALD 男孩和年轻男性，进行为期 12 个月的每日口服维生素 D3 补充剂研究。我们的主要结果是在6个月和12个月时血浆25-羟维生素D水平达到目标范围（40-80纳克/毫升）。次要结果包括安全性和大脑中的谷胱甘肽水平（通过磁共振光谱法测量）以及血液中的谷胱甘肽水平（通过质谱法测量）。参与者最初被分配到一个固定的剂量方案，从每天 2,000 IU 开始，与体重无关。在进行中期研究安全性评估后，我们修改了给药方案，因此所有后续参与者都被分配到按体重分级的给药方案中，最低剂量为每天1000 IU：2016 年 10 月至 2019 年 6 月期间，我们招募了 21 名参与者（固定剂量方案，n = 12；体重分层方案，n = 9），他们的中位年龄为 6.7 岁（范围：1.9-22 岁），中位体重为 20 千克（范围：11.7-85.5 千克）。两组在 6 个月（固定剂量：92%；体重分层：78%）和 12 个月（固定剂量：67%；体重分层：67%）达到目标维生素 D 水平的人数相似。在采用固定剂量疗法的 12 名参与者中，有一半人的尿钙：肌酐或血浆 25- 羟维生素 D 出现无症状升高；而采用体重分层疗法的参与者没有出现实验室偏差。大脑中的谷胱甘肽水平在基线和12个月之间显著增加，但血液中的谷胱甘肽水平没有增加：讨论：我们的维生素 D 给药方案耐受性良好，大多数参与者的 25- 羟维生素 D 水平都达到了目标值。脑谷胱甘肽水平作为维生素 D 和 ALD 的生物标志物值得进一步研究：本研究提供了IV级证据，证明固定或体重分层维生素D补充剂可使无脑部病变的X-ALD男孩和年轻男性的25-羟维生素D达到目标水平。
A Phase 1 Study of Oral Vitamin D3 in Boys and Young Men With X-Linked Adrenoleukodystrophy.
Background and objectives: There are no therapies for preventing cerebral demyelination in X-linked adrenoleukodystrophy (ALD). Higher plasma vitamin D levels have been linked to lower risk of inflammatory brain lesions. We assessed the safety and pharmacokinetics of oral vitamin D dosing regimens in boys and young men with ALD.
Methods: In this open-label, multicenter, phase 1 study, we recruited boys and young men with ALD without brain lesions to a 12-month study of daily oral vitamin D3 supplementation. Our primary outcome was attainment of plasma 25-hydroxyvitamin D levels in target range (40-80 ng/mL) at 6 and 12 months. Secondary outcomes included safety and glutathione levels in the brain, measured with magnetic resonance spectroscopy, and blood, measured via mass spectrometry. Participants were initially assigned to a fixed dosing regimen starting at 2,000 IU daily, regardless of weight. After a midstudy 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 enrolled 21 participants (n = 12, fixed-dose regimen; n = 9, weight-stratified regimen) with a median age of 6.7 years (range: 1.9-22 years) and median weight of 20 kg (range: 11.7-85.5 kg). The number of participants achieving target vitamin D levels was similar in both groups at 6 months (fixed dose: 92%; weight stratified: 78%) and 12 months (fixed dose: 67%; weight stratified: 67%). Among the 12 participants in the fixed-dose regimen, half had asymptomatic elevations in either urine calcium:creatinine or plasma 25-hydroxyvitamin D; no laboratory deviations occurred with the weight-stratified regimen. Glutathione levels in the brain, but not the blood, increased significantly between baseline and 12 months.
Discussion: Our vitamin D dosing regimens were well tolerated and achieved target 25-hydroxyvitamin D levels in most participants. Brain glutathione levels warrant further study as a biomarker for vitamin D and ALD.
Classification of evidence: This study provides Class IV evidence that fixed or weight-stratified vitamin D supplementation achieved target levels of 25-hydroxyvitamin D in boys and young men with X-ALD without brain lesions.
期刊介绍：
Neurology: Genetics is an online open access journal publishing peer-reviewed reports in the field of neurogenetics. Original articles in all areas of neurogenetics will be published including rare and common genetic variation, genotype-phenotype correlations, outlier phenotypes as a result of mutations in known disease-genes, and genetic variations with a putative link to diseases. This will include studies reporting on genetic disease risk and pharmacogenomics. In addition, Neurology: Genetics will publish results of gene-based clinical trials (viral, ASO, etc.). Genetically engineered model systems are not a primary focus of Neurology: Genetics, but studies using model systems for treatment trials are welcome, including well-powered studies reporting negative results.
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