A randomized double-blind, placebo-controlled phase 2 clinical trial of intravenous citrulline for vaso-occlusive crisis in sickle cell disease

Project Abstract Sickle cell disease is a genetic red blood cell disorder affecting approximately 100,000 individuals, primarily of African descent, in the United States alone. The presence of abnormal hemoglobin (hemoglobin S) leads to sickling of red blood cells and vaso-occlusion, resulting in acute episodes of pain. Acute pain, or “vaso- occlusive crisis” (VOC), is the most frequent cause of emergency room visits and hospital admissions in sickle cell disease, contributing to the high burden of health care costs for these patients. Opioids are the mainstay of treatment for a VOC. However, treatment with opioids runs the risk of both short and long term side effects such as itching, constipation, respiratory depression, opioid tolerance and addiction. Because of these often severe consequences, alternative treatment modalities to opioid therapy are urgently needed in this high-risk population. Nitric oxide, which is generated from the amino acid citrulline through the urea cycle, is a powerful vasodilator, and low nitric oxide levels play an important role in the pathogenesis of vaso-occlusion. Citrulline plays an important role in nitric oxide production in endothelial cells, and consequently may be able to ameliorate vaso- occlusion. We hypothesize that the introduction of L-citrulline to standard (opioid) therapy will shorten hospital length of stay and decrease opioid use. In this phase 2 clinical trial, patients with sickle cell disease will be randomized to receive either the study drug (intravenous citrulline) or placebo to determine if citrulline administration leads to improvements in pain and decreases in hospital length of stay. In addition, we will evaluate how the body reacts to the study medication by measuring tissue oxygenation, nitric oxide levels etc., while closely monitoring for side effects. To better assess how this new treatment might be tailored to meet individual needs, DNA will be collected to evaluate the link between genetic variation in the nitric oxide pathway and response to treatment with citrulline. The novel therapeutic option of intravenous citrulline has the potential to significantly decrease opioid use and improve clinical outcomes for hospitalized sickle cell patients suffering from vaso-occlusive sickle cell pain crisis.