Abstract
BACKGROUND: Vaso-occlusive pain crisis (VOC) is the most frequent cause for Emergency Department (ED) visits and hospital admissions for patients with sickle cell disease (SCD). Nitric oxide plays a critical role in the pathogenesis of vaso-occlusion. The amino acid, citrulline, is the main endothelial nitric oxide booster that offers the potential to ameliorate vaso-occlusion and decrease the risk of hospitalization. OBJECTIVE: In this two-part study, the goal of the first part is to determine the pharmacokinetic profile of intravenous (IV) l-citrulline and optimal dose for the second part of the study, which is to determine the efficacy and tolerability of the intervention in patients with SCD. DESIGN: A phase I/IIA open-label dose-finding study with subsequent double-blind, placebo-controlled, randomized Study of l-citrulline in children and adolescents with SCD presenting to the ED in VOC. METHODS: Part 1: Subjects experiencing VOC are enrolled in an open-label, ascending dose of IV l-citrulline to identify the optimum dose with endpoints of pharmacokinetic parameters, pain scores, reduction of opioid use, quality of life, proportion admitted to the hospital for treatment of pain, readmission rates, and assessment of adverse events. Part 2 of the trial is a double-blind, placebo-controlled adaptive "pick-the-winner" design to evaluate the efficacy and tolerability of IV l-citrulline in patients with SCD while receiving standard of care therapy for VOC. SUMMARY: This ED based sickle cell adaptive trial will determine the optimal dose for IV citrulline and whether the intervention improves outcome as a potential novel therapy for VOC in SCD.