Journal Article Randomized Controlled Trial Clinical Trial, Phase II Multicenter Study Ppublish 4 citations
PubMed: 40270092 DOI: 10.1002/ajh.27692
Arginine Therapy for Pain in Sickle Cell Disease: A Phase-2 Randomized, Placebo-Controlled Trial.
Am J Hematol 100(7):1119-1131
Authors: Claudia R Morris, Dunia Hatabah, Rawan Korman, Scott Gillespie, Nitya Bakshi, Lou Ann Brown, Frank Harris, Deborah Leake, Chris A Rees, Kirshma Khemani, Elliott P Vichinsky, Alexus Locke, Bridget Wynn, Mark A Griffiths, Hagar Wilkinson, Polly Kumari, Lisa Sudmeier, Sruti Shiva, Carlton D Dampier
Affiliations
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
- Department of Emergency Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
- Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
- Yale School of Medicine, New Haven, Connecticut, USA.
- Department of Hematology/Oncology, UCSF Benioff Children's Hospital Oakland, Oakland, California, USA.
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.
- Department of Pharmacology and Chemical Biology, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Abstract
We present a prospective randomized, placebo-controlled trial of intravenous arginine in patients 3-21 years hospitalized with sickle cell disease vaso-occlusive pain episodes (SCD-VOE) at two tertiary-care children's hospitals. Participants were randomized into 1 of 3 arms: Standard-dose (SD; 100 mg/kg/dose) every 8 h, Loading-dose (200 mg/kg followed by SD), or Placebo. The primary outcome was total parenteral opioid use (TPO). Secondary outcomes included time-to-crisis-resolution, pain scores, patient-reported outcomes (PROs), arginine bioavailability, and biomarkers of oxidative stress/mitochondrial function. Of 1548 patients screened, 108 were randomized (36 per study-arm; mean 12.6 ± 3.8 years, 52% female, and 65% hemoglobin-SS). This study did not meet its primary endpoint. TPO, time-to-crisis-resolution, pain scores, and PROs at discharge were similar across arms. Post hoc sensitivity analyses of children 5-16 years old demonstrated nearly double TPO utilization in those receiving placebo versus arginine (n = 87, p = 0.056), achieving significance in patients with plasma arginine < 60 μM. Arginine was low at presentation in 79% of patients (mean 50 ± 28 μM), and increased with arginine therapy (p < 0.001). Arginine bioavailability at VOE presentation inversely correlated with time-to-crisis-resolution (r = -0.39, p = 0.01) after placebo, an association eliminated by arginine supplementation (r = -0.04, p = 0.70). A dose-dependent increase in platelet-mitochondrial activity occurred after arginine versus no change after placebo (p < 0.001); plasma protein-carbonyl levels, a measure of oxidative stress, decreased after arginine therapy (p < 0.001) but increased in the placebo group (p = 0.02). SCD-VOE 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-sparing becoming significant in children with the lowest arginine concentration. TRIAL REGISTRATION: Registered with ClinicalTrials.gov (NCT02536170) in August 2015.
MeSH
Cells, Biological Availability, Hematology, Anemia, Sickle Cell, Arginine, Pain, Stress, Physiological, Oxidative Stress, Therapeutics, Child, Plasma