STArT Trial Raises Questions About How Acute Sickle Cell Pain Trials Measure Treatment Success

The phase 3 Sickle Cell Disease Treatment with Arginine Therapy (STArT) trial (NCT04839354) did not demonstrate that intravenous arginine shortened acute pain episodes in children and young adults with sickle cell disease (SCD), but its findings may carry implications extending beyond the investigational therapy itself.¹

STArT randomly assigned 274 participants with SCD-related acute pain requiring parenteral opioids and hospitalization to intravenous arginine or placebo. The study was stopped early for futility after arginine failed to significantly improve the primary end point, time to crisis resolution, or key secondary outcomes.¹

Despite this, Claudia R. Morris, MD, professor of pediatrics and emergency medicine at Emory University School of Medicine and principal investigator of STArT, said the trial may be most informative for what it revealed about how acute SCD pain studies are designed.

“We were hoping that this was going to be the definitive study for arginine therapy, but unfortunately it didn’t answer the question,” Morris said in an interview with Pharmacy Times. “We’re not going to understand the benefits of these drugs if we’re asking the wrong question.”

Is Time to Crisis Resolution the Right End Point?

STArT defined time to crisis resolution as the interval between study drug administration and the final parenteral opioid dose, an outcome used in other acute SCD trials. Morris said the terminology itself can be misleading. “We call it crisis resolution, but that’s really a misnomer,” she explained. “Many patients go home still in significant pain, but it represents the transition of moving from [intravenous] (IV) opioids to oral opioids.”

That transition can be shaped by much more than treatment biology. An analysis of the STArT placebo cohort demonstrated substantial variation among hospitals, with median time to crisis resolution differing by as much as 114 hours between sites.²

“If you were admitted at one hospital, you were likely to be there for 2 to 3 days no matter what, versus another hospital that would keep patients longer for 5 to 6 days,” Morris said.

The issue becomes particularly important when a trial is designed to detect a comparatively modest treatment effect. Using the variability observed in STArT, investigators estimated that more than 900 participants could have been required to detect the originally hypothesized 17-hour difference.²

Morris explained this raises fundamental questions about whether the last IV opioid dose is sufficiently sensitive to distinguish a biological treatment effect from institutional practice. “I think what we need is more objective end points, surrogate biomarkers maybe that look at the underlying mechanism of disease that takes the subjectivity out of it,” she said.

Acute Pain Does Not Represent a Single SCD Phenotype

Another major challenge was patient heterogeneity. Approximately 41% of STArT participants met criteria for chronic SCD pain, suggesting that patients presenting with severe pain may have markedly different underlying mechanisms. “Not all pain is created equal,” Morris said. “We’re calling it vaso-occlusive pain, and some of it may truly be vaso-occlusive…but you’ve also got chronic pain [and] neuropathic pain.”

Current American Society of Hematology guidance also recognizes the distinction between acute, chronic, and acute-on-chronic SCD pain.³ For therapies directed at vaso-occlusive biology, enrolling patients primarily according to pain severity could therefore dilute a treatment signal if a meaningful proportion of participants have another dominant pain phenotype.

The placebo analysis further identified factors associated with longer time to crisis resolution that were less obvious than age, sex, genotype, or hydroxyurea use.² These included prior surgery and having no recent emergency department visits that ended in discharge.

According to Morris, patients in the latter group were often still using the emergency department but were admitted every time, potentially indicating a more severe clinical phenotype. Surgeries such as splenectomy and cholecystectomy may similarly serve as indirect markers of more severe hemolytic disease. She also raised another possibility: painful experiences earlier in life could contribute to altered pain sensitivity.

“Early pain experiences inform your future experiences,” Morris said. “It’s possible that patients who had surgery…could have contributed to some hyperalgesia, where they’re more sensitive to pain.”

Earlier Intervention Could Be Critical

Timing may represent another piece of the puzzle. Participants received study treatment a median of approximately 8 hours after their first IV opioid, and 23 participants had already received their final IV opioid before study drug administration.¹

Although Morris said these participants alone did not explain the negative trial result, she believes earlier treatment deserves further study. “In an ideal world, we would potentially get a new drug delivered to patients in the prehospital setting, while they’re still home, before they’re in the emergency department.”

STArT also found that patients who had been experiencing pain for more than 24 hours before presentation had longer time to crisis resolution.² Morris noted that clinicians often encourage patients to manage pain at home until symptoms become severe, but these findings suggest earlier intervention could potentially alter the trajectory of an episode.

A similar timing signal was observed in the RESET trial (NCT02187003) of rivipansel, in which the overall study was negative but post hoc analysis suggested greater benefit when treatment was administered earlier in the vaso-occlusive episode.⁴

Biomarkers May Help Identify the Right Patients

Earlier arginine studies also provide a reason to continue investigating biological subgroups. A phase 2 study found improvements in measures of mitochondrial function and oxidative stress with arginine supplementation, while low baseline arginine concentrations were common.⁵

Morris said this raises a different way of thinking about the therapy. “I’ve been struggling with this concept of… ‘is arginine really a drug?’” she said. “Are we treating an underlying nutritional deficiency?”

Arginine is the obligate substrate for nitric oxide production, and hemolysis can disrupt the arginine–nitric oxide pathway through release of cell-free hemoglobin and arginase. Morris suggested that future research could potentially enrich enrollment using arginine deficiency, hemolysis, oxidative stress, or other mechanistic biomarkers instead of grouping all severe pain episodes together.

She also pointed to acute chest syndrome as a potential target for future research. Because these patients typically remain hospitalized longer and have a clear vaso-occlusive component, outcomes such as length of stay may be more informative.

Patient-Reported Outcomes May Need Better Timing

The trial also raised concerns about when patient-reported outcomes are measured. Morris explained that many instruments ask patients to reflect on the previous 7 days. At emergency department presentation, that period may include several relatively normal days before the pain episode. At hospital discharge, however, the same recall period can be dominated by severe pain, sleep disruption, and hospitalization. “It’s no surprise that they’re worse,” Morris said.

STArT therefore added follow-up assessments 7 to 10 days after discharge for a subset of participants. Morris said these later assessments showed significant improvements in pain-related outcomes and fatigue compared with emergency department presentation, with a numerical difference favoring arginine that was not powered for statistical significance.

“I’m hoping that we will incorporate use of PROs in our acute pain studies, but making sure that we’re comparing their presentation to 7 to 10 days [later],” she said.

Pharmacists Could Improve How Opioid Exposure Is Measured

For pharmacists, STArT also exposed a practical data challenge. Investigators wanted to quantify parenteral opioid exposure, but pharmacy systems at participating hospitals could not consistently provide a simple total amount administered. Research teams instead reconstructed exposure from patient-controlled analgesia settings, infusion duration, and bolus doses, creating opportunities for calculation errors.

“It would have been so much more helpful if the pharmacy was able to tell us, ‘This is how much opioid this patient used on this day,’” Morris said.

Improved pharmacy-supported reporting of opioid exposure could strengthen future trials by providing a validated measure of analgesic use without requiring investigators to manually reconstruct doses.

For Morris, the lesson from STArT is therefore broader than the negative primary outcome. Multicenter networks have demonstrated that large acute SCD trials can now successfully enroll participants. The next challenge is ensuring that the outcomes being measured can distinguish treatment biology from differences in pain phenotype, timing, and clinical practice.

“If we continue to do trials the way that we’ve been doing [them], we are going to continue to have these studies that don’t answer the questions,” she said.

REFERENCES

1. Morris CR, Hatabah D, Korman R, et al. Arginine Therapy for Sickle Cell Disease Acute Pain Episodes: The STArT Randomized Clinical Trial. JAMA. Published online August 19, 2026. doi:10.1001/jama.2026.13310

2. Rees CA, Hatabah D, Korman R, et al. Hospital Variations in Time-To-Crisis-Resolution Among Children and Adolescents With Sickle Cell Disease. Am J Hematol. 2026;101(1):206-212. doi:10.1002/ajh.70129

3. Brandow AM, Carroll CP, Creary S, et al. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv. 2020;4(12):2656-2701. doi:10.1182/bloodadvances.2020001851

4. Dampier CD, Telen MJ, Wun T, et al. A randomized clinical trial of the efficacy and safety of rivipansel for sickle cell vaso-occlusive crisis. Blood. 2023;141(2):168-179. doi:10.1182/blood.2022015797

5. Morris CR, Hatabah D, Korman R, et al. Arginine Therapy for Pain in Sickle Cell Disease: A Phase-2 Randomized, Placebo-Controlled Trial. Am J Hematol. 2025;100(7):1119-1131. doi:10.1002/ajh.27692