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

7.0项目摘要/摘要 这项第二阶段临床试验(VIDAS-2)将确定对患有镰刀病的儿童是否每天服用维生素D。 细胞疾病可以降低呼吸道并发症的风险，呼吸道并发症是发病率和 死亡率。我们之前的VIDAS-1临床试验提供了每月口服维生素片剂的证据 镰状细胞病儿童服用D3补充剂可降低呼吸道年发病率 并发症增加超过50%(P=0.0005)，但仅在治疗一年后且没有 维生素D3标准剂量(12,000个单位/月)和高剂量(100,000个单位/月)之间的显著差异 Iu/mo)剂量治疗。拟议的临床试验的科学前提是增加了 循环浓度的维生素D3，母体化合物，是抗感染所需的 补充剂的免疫调节作用。每月口服维生素D3一次， 循环中的维生素D3在几天内就会被清除。在早期的VIDAS-1临床中 每月口服维生素D3的试验，无论是标准剂量还是高剂量治疗都不会 使循环中的维生素D3持续增加，可能解释了两者的一致性 对这两种治疗的反应以及在降低呼吸事件发生率方面的延迟。使用 每月口服剂量，维生素D3在脂肪组织中缓慢积累，只会 逐渐增加循环中的维生素D3浓度。我们的假设是每天口服维生素 D3会迅速增加循环中的维生素D3，并通过以下方式降低呼吸道并发症的发生率 在治疗的第一年内50%或更多。我们建议一项为期两年的受控、双掩蔽、 随机二期临床试验，比较其降低呼吸频率的疗效 每日口服维生素D3(3,333IU/d)与每月口服维生素团剂的镰状细胞病事件 D3，(10万IU/mo)作为对照。人体内25-羟基维生素D的基线浓度 人群(平均~14 ng/毫升)指导选择大剂量的日常治疗，而且太低 以允许纳入安慰剂对照。这项第二阶段临床试验有三个具体目标： (1)确定每日口服维生素D3(3333IU/d)是否适合患有 镰状细胞病，与每月口服维生素D3相比，(10万国际单位/月)会更多 迅速降低呼吸道事件的发生率，定义为呼吸道感染、恶化 哮喘和急性胸腔综合征的发作； (2)评价每日口服维生素D3对肺功能的影响； (3)观察每日口服维生素D3对免疫功能的影响。 全身性炎症和T细胞效应及调节功能。

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..