STArT Trial: Arginine as Factor in Pediatric Sickle Cell Disease Vaso-Occlusive Pain

Описание: At Emory University School of Medicine in Atlanta, Georgia, Claudia Morris, MD, is a professor in the Department of Pediatrics and the nodal principal investigator for the Pediatric Emergency Care Applied Research Network (PECARN). She was the lead author on the PECARN Sickle Cell Disease Treatment with Arginine Therapy (STArT) trial, a phase 3 US multicenter randomly assigned controlled trial which evaluated intravenous (IV) arginine therapy for sickle cell disease (SCD) vaso-occlusive pain episodes (VOE) in pediatric to young adult patients receiving intravenous opioids.

The STArT trial was terminated early for not meeting its primary outcome of time-to-crisis-resolution of pain episodes. Dr. Morris presented the trial at the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida, and on-site she spoke about the trial with Heme Today.

Dr. Morris began by explaining that the most common reason pediatric patients with SCD present to the emergency department is to seek relief for severe acute pain caused by VOEs. Although there are agents approved by the FDA to prevent these acute episodes, there are currently no drugs approved for managing these episodes when they are already in progress.

“As an emergency medicine physician, I’m left with no tools to treat them except for symptomatic relief with analgesics such as morphine. Nothing that targets the underlying mechanism,” Dr. Morris elaborated.

To clarify the reasons why clinical investigators have viewed IV arginine as a potential way to treat SCD-related pain, Dr. Morris described how arginine deficiency is a factor within VOE pathophysiology. As hemolysis leads to oxidative stress, which is a driver of VOE, the spilling of arginase out of ruptured blood cells into the blood stream decreases arginine concentrations and exacerbates oxidative stress.

“What we have is a global disruption of the arginine-nitric oxide pathway that is induced from hemolysis. This has implications not just for sickle cell disease, but also for thalassemia, malaria, wherever you see hemolysis,” according to Dr. Morris.

Clinicians’ interest in bolstering arginine bioavailability as a possible approach to treat SCD pain, Dr. Morris continued, was also piqued by the findings of several phase 2 trials. Improvement in patient’s pain scores, which also translated into reduced opioid use, was among the benefits observed with arginine therapy in these trials.

“We can’t eliminate the additional analgesia that they need. Arginine is not a cure, but it’s really working like a pain medication. So, if we can decrease the amount of opioids that our patients are requiring then that’s also a win,” Dr. Morris remarked.

Dr. Morris also addressed the STArT trial’s failure to meet its primary outcome in time-to-crisis-resolution of pain episodes. She proposed that a major reason was that with the significant decrease over recent decades in the US in hospitalization time for pediatric patients who present with SCD pain, patients are not hospitalized long enough for a clinical trial to meet the time-to-crisis-resolution outcome.

“It becomes very, very difficult to achieve that outcome when kids are going home within three days, and I think that this has been part of the reason that a lot of our clinical trials have not met their outcome measure,” Dr. Morris commented.

References
American Society of Hematology (ASH) 2025 Annual Meeting and Exposition. Publication No. 616.