Safety of Intravenous Arginine Therapy in Children with Sickle Cell Disease Hospitalized for Vaso-Occlusive Pain: A Randomized Placebo-Controlled Trial in Progress

Introduction: Vaso-occlusive pain episodes (VOE) are the leading cause of emergency department (ED) visits & hospitalizations in sickle cell disease (SCD). Low arginine (Arg) bioavailability has been associated with pain severity & need for pediatric hospitalization (Morris et al, 2000). Mitochondrial (mito) function is also impaired in SCD (Cardenes et al, 2014). We reported a dose-dependent impact of IV Arg on mito activity & oxidative stress in children with SCD (Morris, ASH 2018). Arg therapy was found to significantly decrease pain scores & reduced opioid use in children hospitalized with SCA-VOE compared to placebo in a phase 2 randomized placebo-controlled trial (RCT; Morris et al, 2013). IV Arg has an excellent safety profile, having received FDA approval for growth hormone stimulation testing in 1973, utilizing 500 mg/kg/dose or up to 30 grams/dose. Safety experience with its use in SCD is growing. Safety results of an ongoing phase 2 RCT at Emory/Children's Healthcare of Atlanta are reported here.

Objectives: To review safety of IV arginine and enrollment in an ongoing RCT in children with SCD-VOE.

Methods: A double-blind RCT of IV Arg (100 mg/kg/dose every 8 hours until discharge; up to 7 days/21 doses maximum) is underway in children age 3-21 years with SCD (any genotype) hospitalized for VOE requiring parenteral opioids. Patients with significant liver/renal dysfunction or those previously enrolled are excluded. Subjects are randomized into 1 of 3 arms: 1) 100 mg/kg/dose, standard dose (SD), 2) loading dose: 200 mg/kg followed by SD or 3) placebo. Demographics, clinical characteristics, total parenteral opioid use (morphine equivalents, mg/kg) time-to-crisis-resolution (time of initial study drug delivery to last parenteral opioid), length of hospital stay (hours), pain scores & biomarkers, including exhaled nitric oxide, global arginine bioavailability (plasma arginine & arginine/[ornithine+citrulline] ratio), mito function & patient reported outcomes (PROMIS) are obtained before & after treatment. The 1° outcome measure is total parenteral opioid use between study arms (power calculation based on Morris et al, 2013 & assuming 10% drop out); total sample size is 114 patients (38 per arm). Chi-squared/fisher exact tests were utilized as appropriate to compare development of adverse events (AEs) and serious AEs (SAEs) across randomization arms. This protocol utilizes IND#66943 (Sponsor-Morris), is registered with ClinicalTrials.gov (NCT02536170) & is funded by FDA-R01FD004814-01A2 & in part by NCCIH K24AT009893-01 (both to CRM).

Results: A total of 1,129 patients have been screened, 220 were eligible with a guardian present, 87 were consented, and 83 were randomized; there were 4 screen failures. Most were enrolled in the ED (76%); guardians were often not present once transferred to the inpatient unit. Study drug was withdrawn by the PI on 4 patients (< 5%) for a variety of reasons that were reported as AEs; all patients completed the study with respect to monitoring per protocol. Demographics of subjects randomized by treatment group are provided in Table 1. There has been cumulative total of 16 SAEs in 13 unique patients, all involving re-hospitalization within 30 days or prolonged hospitalization. Six SAEs were "possibly related" (re-hospitalization within 7 days) and the rest were unlikely/probably not or not related to the study. 72-hour re-hospitalization rate is currently 6%. Table 2 includes a summary of the cumulative 309 AEs in 75 unique patients by system per treatment arm. Headache (33%), nausea (45%) & vomiting (25%) were common, but there were no significant differences across treatment arms. No difference in the seriousness, severity or relatedness for all events (SAEs & AEs) was identified across treatment arms. The 1^st patient was enrolled in March 2016; enrollment is 76.3% completed through July 2019.

Conclusion: All SAEs were expected events related to SCD. Additionally, SAE/AE rates were similar across study arms, providing further support for the safety of arginine therapy in children with SCD. Re-hospitalization rates within 72-hours are less than the ~20% previously reported in the literature. The availability of study team members to obtain consent in the ED prior to admission is essential for successful enrollment into acute VOE studies, since guardians are often not available once the child is transferred to the inpatient unit. Recruitment is ongoing.

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