source: Blood

year: 2022

authors: Claudia R. Morris, Nitya Bakshi, Deborah Leake, Scott Gillespie, Lou Ann Scism Brown, Frank Harris, Kirshma Khemani, Alexus Locke, Christopher A Rees, Mark A Griffiths, Loretta Reyes, Polly Kumari, Sruti Shiva, Carlton D. Dampier

Introduction:
Vaso-occlusive pain episodes (VOE) are the leading cause of emergency department (ED) visits & hospitalization in patients with sickle cell disease (SCD). During SCD-VOE, patients develop an acute arginine (Arg) deficiency. Supplementation with Arg has shown opioid-sparing effects, improves blood pressure & cardiopulmonary function & decreases length of hospital stay. Though we have previously demonstrated that intravenous (IV) Arg improves mitochondrial (mito) function, the precise mechanisms by which Arg mediates these positive effects remain unclear.

Methods:
Prospective single-center double-blind randomized controlled trial (RCT) of IV Arg (TID, up to 7 days) in children with SCD age 3-21 years hospitalized for VOE requiring IV opioids. Patients with significant liver/renal dysfunction or those previously enrolled were excluded. Subjects were randomized into 1 of 3 arms: 1) 100 mg/kg/dose Arg, standard dose (SD), 2) loading dose: 200 mg/kg followed by SD or 3) placebo. Demographics, total parenteral opioid (TPO) use (morphine equivalents, mg/kg) time to crisis resolution (time of study drug delivery to last IV opioid in hours), pain scores, patient reported outcomes (PROMIS) & mito function were obtained before treatment & at discharge. The primary outcome measure was TPO use between study arms. Hypothesis tests & unadjusted & covariate-adjusted fixed & mixed effects generalized linear regression models were used, as appropriate, to compare cross-sectional & longitudinal outcomes within & between randomization arms. This protocol utilized IND#66943 (Sponsor-Morris), registered with ClinicalTrials.gov (NCT02536170).

Results:
1,548 patients were screened, 266 were eligible, 114 consented, & 108 were randomized. Safety results of this RCT have been previously reported (Reyes et al, Am J Hematol 2022). Demographics & clinical outcomes of subjects randomized by treatment arm are provided in Table 1. While statistically insignificant, there was a clinically relevant decrease in TPO & time to crisis resolution in both Arg arms compared to placebo. The placebo group required 45% higher TPO & experienced >15 hours longer mean time to crisis resolution compared to combined Arg-treated groups when adjusted for HU use, continuous age and sex. Among children <17 years, the placebo group (n=33) required 80% more TPO compared to combined Arg groups (n=57; p=0.075). No differences in ED vs discharge pain scores or patient/parent PROMIS reports across arms were found. Mito Complex V activity was higher (p=0.02) & protein carbonyl levels were lower (p=0.003) at ED visit in patients on Hydroxyurea (HU). Notably mito Complex IV & V activity increased significantly in both Arg arms while there was no change in the placebo group (Fig 1, p<0.001); protein carbonyl levels in platelet rich plasma decreased in both Arg groups (Fig 1, p<0.001), suggesting a decrease in oxidative stress that increased in the placebo arm (p=0.02). Greatest mito improvement occurred with Arg loading dose.

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