PECARN STArT Fails to Improve Time-to-Crisis Resolution in SCD Pain, With Claudia Morris, MD

The PECARN STArT trial has failed to meet its primary outcome of time-to-crisis resolution (TCR) in patients with sickle cell disease (SCD) who have developed vaso-occlusive pain episodes (VOE).1

Presented at the 67th American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida, by Claudia Morris, MD, professor of pediatrics and emergency medicine at Emory University School of Medicine, these results have consigned PECARN STArT to a long list of prior phase 3 randomized clinical trials which failed to meet their primary outcomes. These trials face significant challenges due to shorter hospital stays and interpatient variability in TCR.1

“Unfortunately, the study was closed early by the Data Safety Monitoring Board. Not for any safety reasons, but for failure to meet time-to-crisis resolution,” Morris told HCPLive in an exclusive interview. “And we joined every other phase 3 trial in acute pain for not meeting this outcome measure.”

VOEs are the leading cause of emergency department (ED) visits and hospitalizations for patients with SCD. During SCD-VOEs, patients develop an acute arginine (Arg) deficiency, which is associated with adverse clinical outcomes such as longer TCR and greater total parental opioid use (TPO) during hospitalization.2

PECARN STArT was a multicenter, double-blind, phase 3 trial of intravenous Arg therapy. Patients aged 3-21 years with SCD-VOE who were actively receiving intravenous opioids utilizing the Pediatric Emergency Care Applied Research Network (PECARN) were included in the study. The primary outcome of TCR was defined as the time from study drug delivery to the last dose of intravenous opioid delivery. Secondary outcomes included TPO, defined as total intravenous morphine equivalents in mg/kg from study drug delivery to last parental opioid, and patient-reported outcomes at admission, discharge, and 7-12 days post-discharge.1

Within 12 hours of receiving their first opioid dose, patients were randomly assigned in a 1:1 ratio to either a 1-time leading dose of intravenous Arg (200 mg/kg with a maximum of 20g) followed by a standard dose of 100 mg/kg (maximum 10g 3 times per day) or a normal saline placebo at equivalent volumes and duration as the study drug.1

A total of 2629 patients were screened, of whom 1034 were eligible. Ultimately, 271 were randomized, with 129 receiving Arg and 142 receiving placebo. Mean age was 14 years (standard deviation [SD] +/-4), 51% of patients were male, 71% had Hb-SS, 76% were on hydroxyurea, and 41% had chronic pain defined as SCD-pain ≥15 days per month for the last 6 months.1

TCR was similar in the Arg arm versus placebo (82 +/- 80 vs 89 +/- 152 hours; P = .98). TPO was also similar across both arms (2.6 +/- 4.5 vs 1.9 +/- 2.8 mg/kg; P = .33). There were no differences in safety outcomes, adverse events, pain scores, or patient-reported pain interference. A total of 54 participants developed acute chest syndrome.1

Ultimately, the trial was halted early for futility to achieve the primary outcome of TCR. Morris and colleagues attribute this decision to larger than expected site variation, outliers, and SD. Sample size recalculation based on STArT data would require randomization of >900 subjects.1

“I think the silver lining is identifying a subgroup of patients who may truly benefit from arginine therapy,” Morris said. “It’s hard to know if their biochemistry is different from patients who come in with chest pain and no acute chest syndrome or if it’s just the fact that patients with acute chest syndrome are in the hospital for over 7 days. But it raises additional questions that we need to answer, and I think that the jury is still out for treatment with arginine therapy.”

Editor’s Note: Morris reports disclosures with CSL Behring, Roche, and Trility.

References

1. Morris C, Ahmad F, Airewele G, et al. Sickle Cell Disease Treatment With Arginine Therapy (STArT) – Results of a Phase-3 Randomized Controlled Trial. Abstract presented at the 67th American Society of Hematology Annual Meeting. Orlando, FL. December 6-9, 2025.

2. Novelli EM, Gladwin MT. Crises in Sickle Cell Disease. Chest. 2016;149(4):1082-1093. doi:10.1016/j.chest.2015.12.016