Background: Vaso-occlusive pain episodes (VOE) are the leading cause of emergency department (ED) visits and hospitalizations for patients with sickle cell disease (SCD). Yet, FDA-approved drugs for SCD-VOE are lacking. During SCD-VOE, patients develop an acute arginine (Arg) deficiency that is associated with adverse clinical outcomes including longer time-to-crisis-resolution (TCR), and greater total parenteral opioid use (TPO) during hospitalization. Multiple RCTs in the US, Brazil, Nigeria, and Egypt have established that supplementation with Arg is safe, has opioid-sparing effects, improves pain scores, blood pressure, and cardiopulmonary function and decreases length of hospital stay. We and others have shown that Arg increases nitric oxide production, improves mitochondrial function, and decreases both oxidative stress and biomarkers of hemolysis and inflammation. A phase-3 RCT was needed.

Objective: To determine the efficacy and safety of intravenous (IV) Arg for SCD-VOE.

Methods: We conducted a multicenter, double-blind, phase-3 RCT of IV Arg therapy in subjects aged 3-21 years with SCD-VOE receiving IV opioids at 10 US sites utilizing the Pediatric Emergency Care Applied Research Network (PECARN). Enrollment began in 2021 with a sample size goal of 360 patients. Within 12 hours of receiving their first dose of IV opioids, enrolled participants were randomized 1:1 to receive either 1) a one-time loading dose of IV Arg (200 mg/kg with a max of 20g) followed by a standard dose of 100 mg/kg (max 10g three times/day) or 2) placebo (normal saline) at equivalent volumes/duration as the study drug. Participants, research staff, and investigators were blinded to the patient's randomization. The primary outcome was TCR defined as the time in hours from study drug delivery to the last dose of IV opioid delivery. Secondary outcomes included TPO, defined as total IV morphine equivalents in mg/kg from study drug delivery to last parenteral opioid) and patient reported outcomes (PROMIS) at admission, discharge, and 7-12 days post-discharge. This protocol utilized FDA-IND#66943, registered with ClinicalTrials.gov (NCT04839354).Results: The STArT trial was halted early for futility to achieve the primary outcome of TCR. A total of 2,629 patients were screened, 1034 were eligible, 741 were approached, 293 consented, and 271 randomized who received study drug (129-Arg, 142-placebo) with enrollment milestones nearly a year ahead of schedule. Mean age ±standard deviation (SD) was 14±4 years, 51% were male, 71% had Hb-SS, 76% on hydroxyurea, and 41% had chronic pain (SCD-pain ≥15 days/month for the last 6 months). Demographics were similar across study arms. TCR was similar in the Arg arm vs placebo (82±80 vs. 89±152 hours, p=0.98). TPO was also similar across both arms (2.6±4.5 vs 1.9±2.8mg/kg, p=0.33). No differences in safety outcomes, adverse events, pain scores, PROMIS Pain Interference, Behavior or Fatigue were noted. 54 subjects had or developed acute chest syndrome (ACS). Among participants with ACS, there was a mean 76-hour difference in TCR in those treated with Arg vs placebo (108±98, n=29 vs. 184±327, n=25; p=0.16; median difference of 34 hours) that was not statistically significant. Larger than expected site variation, outliers and SD occurred; sample size recalculation based on STArT data would require randomization of over 900 subjects.

Conclusion: All phase-3 RCTs for SCD-VOE to date have failed to meet their primary outcomes after promising phase-2 RCTs. The PECARN STArT trial is the latest addition to this list, stopped early for futility to achieve the primary outcome of TCR. There were no safety concerns. Ultimately, RCTs evaluating orphan drugs for SCD-VOE face significant challenges due to shorter hospital lengths of stay over the last 20 years, and extensive interpatient variability in TCR that could confound RCT outcome measures. Larger than expected SD and outliers occurred. Clinically relevant differences in TCR among patients with VOE-ACS treated with Arg similar to a prior RCT (Morris et al, Am J Hematol 2025) requires further study with a larger sample size. Dialogue between the FDA, ASH, SCD researchers and patients is needed to identify more ideal outcome measures beyond TCR, currently FDA-preferred for orphan drug approval.

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2025
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