DAILY VITAMIN D FOR SICKLE-CELL RESPIRATORY COMPLICATIONS: PHASE 2: IND107584 - 11/14/17

7.0 Project Summary/AbstractThis 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 andmortality. Our previous ViDAS-1 clinical trial provided evidence that monthly bolus oral vitaminD3 supplementation in children with sickle cell disease reduced the annual rate of respiratorycomplications by more than 50% (P=0.0005) but only after a year of treatment and with nosignificant difference between vitamin D3 given as standard- (12,000 IU/mo) or high- (100,000IU/mo) dose therapy. The scientific premise of the proposed clinical trial is that increasedcirculating concentrations of vitamin D3, the parent compound, are needed for the anti-infectiveand 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 clinicaltrial of monthly bolus oral vitamin D3, neither the standard- nor high-dose treatments wouldproduce sustained increases in circulating vitamin D3, potentially explaining both the uniformityof response to the two treatments and the delay in reducing the rates of respiratory events. Withmonthly bolus oral dosing, vitamin D3 slowly accumulates in adipose tissue and would onlygradually increase circulating vitamin D3 concentrations. Our hypothesis is that daily oral vitaminD3 will rapidly increase circulating vitamin D3 and reduce the rate of respiratory complications by50% 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 respiratoryevents in sickle-cell disease of daily oral vitamin D3 (3,333 IU/d) with monthly bolus oral vitaminD3, (100,000 IU/mo) as a control. Baseline concentrations of 25-hydroxyvitamin D in ourpopulation (mean ~14 ng/mL) guide the choice of the high-dose daily treatment and are too lowto 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..