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Participants were randomized into 1 of 3 arms:\n Standard\u2010dose<\/jats:italic>\n (SD; 100\u2009mg\/kg\/dose) every 8\u2009h,\n Loading\u2010dose<\/jats:italic>\n (200\u2009mg\/kg followed by SD), or\n Placebo<\/jats:italic>\n . The primary outcome was total parenteral opioid use (TPO). Secondary outcomes included time\u2010to\u2010crisis\u2010resolution, pain scores, patient\u2010reported outcomes (PROs), arginine bioavailability, and biomarkers of oxidative stress\/mitochondrial function. Of 1548 patients screened, 108 were randomized (36 per study\u2010arm; mean 12.6\u2009\u00b1\u20093.8\u2009years, 52% female, and 65% hemoglobin\u2010SS). This study did not meet its primary endpoint. TPO, time\u2010to\u2010crisis\u2010resolution, pain scores, and PROs at discharge were similar across arms.\n Post hoc<\/jats:italic>\n sensitivity analyses of children 5\u201316\u2009years old demonstrated nearly double TPO utilization in those receiving placebo versus arginine (\n n<\/jats:italic>\n \u2009=\u200987,\n p<\/jats:italic>\n \u2009=\u20090.056), achieving significance in patients with plasma arginine <\u200960\u2009\u03bcM. Arginine was low at presentation in 79% of patients (mean 50\u2009\u00b1\u200928\u2009\u03bcM), and increased with arginine therapy (\n p<\/jats:italic>\n \u2009<\u20090.001). Arginine bioavailability at VOE presentation inversely correlated with time\u2010to\u2010crisis\u2010resolution (\n r<\/jats:italic>\n \u2009=\u2009\u22120.39,\n p<\/jats:italic>\n \u2009=\u20090.01) after placebo, an association eliminated by arginine supplementation (\n r<\/jats:italic>\n \u2009=\u2009\u22120.04,\n p<\/jats:italic>\n \u2009=\u20090.70). A dose\u2010dependent increase in platelet\u2010mitochondrial activity occurred after arginine versus no change after placebo (\n p<\/jats:italic>\n \u2009<\u20090.001); plasma protein\u2010carbonyl levels, a measure of oxidative stress, decreased after arginine therapy (\n p<\/jats:italic>\n \u2009<\u20090.001) but increased in the placebo group (\n p<\/jats:italic>\n \u2009=\u20090.02). SCD\u2010VOE is associated with an acquired arginine deficiency that correlates with worse clinical outcomes. Arginine improved mitochondrial function and decreased oxidative stress compared to placebo, with clinically relevant opioid\u2010sparing becoming significant in children with the lowest arginine concentration.\n <\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n Registered with\n ClinicalTrials.gov<\/jats:ext-link>\n (NCT02536170) in August 2015\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/ajh.27692","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T03:40:59Z","timestamp":1745466059000},"page":"1119-1131","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Arginine Therapy for Pain in Sickle Cell Disease: A Phase\u20102 Randomized, Placebo\u2010Controlled Trial"],"prefix":"10.1002","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6019-2858","authenticated-orcid":false,"given":"Claudia 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