Arginine Therapy Does Not Benefit Children with Sickle Cell Anemia — Results of the CSCC Clinical Trial Consortium Multi-Institutional Study.
Authors: Styles Lori , Kuypers Frans , Kesler Karen , Reiss Ulrike , Lebeau Petra , Nagel Ronald , Fabry Mary 
Published: April 2020

Abstract
Nitric oxide (NO) is an important inflammatory mediator produced from arginine. NO has a multitude of functions which could impact favorably on vaso-occlusion in sickle cell disease (SCD) including improvement in endothelial dysfunction, increased blood flow and a decrease in antioxidant stress. SCD patients have low NO and arginine levels. In preliminary animal studies using the sickle mouse model, arginine supplementation decreased the mean corpuscular hemoglobin concentration and the percentage of dense cells via a reduction in Gardos channel activity1. In humans with SCD, oral arginine increased NO levels in patients with vaso-occlusive crisis but not when patients were at well. In an attempt to determine if daily oral arginine would result in an increase in NO and other beneficial effects, the CSCC launched a multi-institution, blinded, phase II study of arginine in SCD. Children and adults were treated for three months with one of two doses of arginine (.05g/kg/day or .1 g/kg/day) or placebo. The pediatric and adult cohorts were analyzed separately. For this phase II study, the following laboratory values were chosen as surrogates for clinical benefit: NOx, RBC Gardos channel activity, RBC density, sVCAM, nitrotyrosine, ektacytometry, endothelin-1, and fetal hemoglobin. To determine the impact of arginine on these laboratory measures, patients had 3 baseline assessments in the 4 weeks prior to starting therapy with arginine. An average of these 3 measurements was used to determine change from baseline during therapy with arginine. Laboratory outcomes after one month and three months of therapy with arginine were compared with the average baseline measurement. This report summarizes the results of the pediatric cohort of patients. Fifty-one children were enrolled in the study and 48 completed at least one month of study drug making them evaluable. Arginine levels did not change significantly during treatment in any of the arms. The average percent change from baseline to 3 months on study drug being +18% for placebo, +35% for low dose arginine, and +19% for high dose arginine). None of the three primary outcome variables (NO, Gardos channel activity, RBC density) changed significantly with arginine therapy after one month or after 3 months of arginine. After 3 months of study drug, the average percentage change from baseline in NO was −33% for low dose arginine, +4% for high dose arginine, and +8% for placebo. Gardos channel activity changes were −1% for low dose, +3% for high dose, and +9% for placebo. RBC density changes were +10% for low dose, +11% for high dose, and −6% for placebo. Similarly, none of the other outcome variables changed with treatment at either one or 3 months. There were no significant differences in adverse events between the three treatment groups. Our data indicate that oral arginine therapy does not seem to provide clinical benefit for pediatric patients with SCD based on assessment of these selected laboratory outcomes. It is possible that the doses of arginine used in this study were not sufficient to produce significant changes in the laboratory measures chosen. It is also possible that children, due to less severe arginine deficiency, did not respond as well as adults with SCD.
Supported by NHLBI U54HL070587.