Daily vitamin D for sickle-cell respiratory complications: Phase 2: IND107584 - 11/14/17

7.0项目总结/摘要 这项2期临床试验（ViDAS-2）将确定是否每日口服维生素D的儿童镰刀， 细胞疾病可以降低呼吸系统并发症的风险，这是发病的主要原因， mortality.我们之前的ViDAS-1临床试验提供了证据，证明每月大剂量口服维生素 镰状细胞病儿童补充D3可降低呼吸道感染的年发病率 并发症减少50%以上（P=0.0005），但仅在治疗一年后， 维生素D3作为标准-（12，000 IU/mo）或高-（100，000 IU/mo）之间的显着差异 IU/mo）剂量治疗。拟议临床试验的科学前提是， 抗感染药物需要母体化合物维生素D3的循环浓度， 以及补充剂的免疫调节作用。每月口服维生素D3， 循环维生素D3在几天内从循环中清除。在早期的ViDAS-1临床试验中， 每月口服维生素D3的试验，无论是标准还是高剂量治疗， 产生循环维生素D3的持续增加，这可能解释了 对两种治疗的反应以及降低呼吸事件发生率的延迟。与 每月一次的大剂量口服给药，维生素D3在脂肪组织中缓慢积累， 逐渐增加循环维生素D3浓度。我们的假设是每天口服维生素 D3将迅速增加循环维生素D3，并通过以下方式降低呼吸系统并发症的发生率： 在治疗的第一年内达到50%或更多。我们提出了一个为期2年的对照，双盲， 一项比较降低呼吸道感染率的疗效的随机II期临床试验 每日口服维生素D3（3，333 IU/d）联合每月大剂量口服维生素D3治疗的镰状细胞病事件 D3，（100，000 IU/mo）作为对照。在我们的25-羟基维生素D的基线浓度 人群（平均值约14 ng/mL）指导选择高剂量每日治疗，且剂量过低 以允许纳入安慰剂对照。这项2期临床试验有三个具体目标： (1)确定是否每天口服维生素D3（3，333 IU/d）给儿童和青少年， 镰状细胞病，与每月大剂量口服维生素D3（100，000 IU/mo）相比， 迅速降低呼吸道事件（定义为呼吸道感染、急性加重）的发生率 哮喘和急性胸部综合征发作; (2)评估每日口服维生素D3对肺功能的影响;以及 (3)研究每日口服维生素D3对免疫功能的影响，使用生物标志物， 系统性炎症和T细胞效应和调节功能。

7.0 Project Summary/Abstract This Phase 2 clinical trial (ViDAS-2) will determine if daily oral vitamin D for children with sickle- cell disease can reduce the risk of respiratory complications, the leading cause of morbidity and mortality. Our previous ViDAS-1 clinical trial provided evidence that monthly bolus oral vitamin D3 supplementation in children with sickle cell disease reduced the annual rate of respiratory complications by more than 50% (P=0.0005) but only after a year of treatment and with no significant difference between vitamin D3 given as standard- (12,000 IU/mo) or high- (100,000 IU/mo) dose therapy. The scientific premise of the proposed clinical trial is that increased circulating concentrations of vitamin D3, the parent compound, are needed for the anti-infective and immunomodulatory effects of supplementation. With monthly bolus oral vitamin D3, circulating vitamin D3 is cleared from the circulation within days. In the earlier ViDAS-1 clinical trial of monthly bolus oral vitamin D3, neither the standard- nor high-dose treatments would produce sustained increases in circulating vitamin D3, potentially explaining both the uniformity of response to the two treatments and the delay in reducing the rates of respiratory events. With monthly bolus oral dosing, vitamin D3 slowly accumulates in adipose tissue and would only gradually increase circulating vitamin D3 concentrations. Our hypothesis is that daily oral vitamin D3 will rapidly increase circulating vitamin D3 and reduce the rate of respiratory complications by 50% or more within the first year of treatment. We propose a 2-year controlled, double-masked, randomized Phase 2 clinical trial comparing the efficacy in reducing the rate of respiratory events in sickle-cell disease of daily oral vitamin D3 (3,333 IU/d) with monthly bolus oral vitamin D3, (100,000 IU/mo) as a control. Baseline concentrations of 25-hydroxyvitamin D in our population (mean ~14 ng/mL) guide the choice of the high-dose daily treatment and are too low to permit inclusion of a placebo control. This Phase 2 clinical trial has three specific aims: (1) to determine whether daily oral vitamin D3 (3,333 IU/d) given to children and adolescents with sickle-cell disease, compared to monthly bolus oral vitamin D3, (100,000 IU/mo) will more rapidly reduce the rate of respiratory events, defined as respiratory infections, exacerbations of asthma, and episodes of the acute chest syndrome; (2) to evaluate the effects of daily oral vitamin D3 on pulmonary function; and (3) to examine the effects of daily oral vitamin D3 on immune function, using biomarkers of systemic inflammation and of T-cell effector and regulatory function..