TOPLINE

Intravenous arginine therapy does not reduce time to crisis resolution compared with placebo in children and young adults hospitalized for sickle cell disease (SCD) acute pain episodes, according to a phase 3 randomized controlled trial (RCT) involving 271 participants. The study was halted early for futility after median time to crisis resolution showed no difference between groups.

METHODOLOGY

• FDA-approved drugs for acute pain are lacking, and multiple RCTs have established that arginine supplementation is safe, has opioid-sparing effects, improves pain scores and cardiopulmonary function, and decreases time to crisis resolution and length of stay compared with placebo. Growing evidence supporting arginine as an adjuvant treatment of SCD acute pain episodes led to its designation as an orphan drug by the FDA on May 8, 2024, prompting this phase 3 trial to assess efficacy and safety.
• The study participants, who were aged 3-21 years, presented to emergency departments in 10 US children’s hospitals with acute pain episodes requiring parenteral opioids. Participants were randomly assigned 1:1 to receive either intravenous arginine (200 mg/kg initial dose followed by 100 mg/kg every 8 hours until discharge, maximum 21 doses) or saline placebo, with 129 receiving arginine and 142 receiving placebo, between June 21, 2021, and June 13, 2024.
• The primary outcome was time to crisis resolution, defined as hours from initial study drug delivery to last intravenous opioid dose, while secondary outcomes included total parenteral opioid use, pain scores, and patient-reported outcomes.
• The trial was halted early after the second interim analysis in June 2024 indicated conditional power for the primary outcome was less than 6%, even under the original hypothesized effect size of a 17-hour difference.

TAKEAWAY

• Time to crisis resolution showed no difference between arginine and placebo groups, with median times of 60.8 hours vs 65.8 hours. Total parenteral opioid use did not differ between groups, with median doses of 1.4 mg/kg in the arginine group vs 1.0 mg/kg in the placebo group.
• No differences were observed in pain scores, patient-reported outcomes including Patient-Reported Outcomes Measurement Information System scores for pain interference, pain behavior and fatigue, or safety events between study groups.
• Large variations in time to crisis resolution were observed across sites, with median and mean differences of up to 61 hours and 80 hours, respectively, requiring more than 900 patients to detect a 17-hour difference with the observed variation.

IN PRACTICE

“To date, all US-based phase 3 RCTs targeting SCD acute pain have failed to demonstrate an effect on shortening hospital length of stay or time to crisis resolution after promising results from phase 2 trials. The current trial is the latest addition to this list, stopped early for futility to achieve its primary endpoint,” the authors of the study wrote.

SOURCE

The study was led by Claudia R. Morris, MD, Emory University School of Medicine in Atlanta. It was published online on August 19 in JAMA.

LIMITATIONS

According to the authors, larger-than-expected outliers and standard deviations, additional confounders, frequently short length of stay, and site-based practice variations decreased precision, likely rendering the trial underpowered to detect differences in outcomes that might have been identified with a larger cohort. Pain scores were obtained at different times of day and may have been influenced by recent analgesic treatments that were not adjusted for, suggesting future trials should standardize timing of daily pain score assessments. Pain scale assessment and postdischarge follow-up patient-reported outcomes were available only for a subset of patients, limiting power to identify potential differences, and other subgroup comparisons were also likely underpowered. The authors noted that pain mechanisms are multifactorial and not all pain is vaso-occlusive, making it unlikely that a single therapy can ameliorate all SCD acute pain, with 41% of participants reporting chronic pain, including a third of patients younger than 12 years, which could adversely impact the ability to detect differences in pain-related endpoints.

DISCLOSURES

This study received support from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) under award SUH3HL148560, and in part by the NIH/National Center for Complementary and Integrative Health K24 award ATO09893, the Doris Duke Charitable Foundation COVID-19 Fund to Retain Clinical Scientists-PeRSEVERE Program at the Emory University School of Medicine, the Georgia Clinical and Translational Science Alliance under award UL1-TROO2378, NIH/NHLBI award 5U24HL148563 for the Data Coordinating Center at the University of Utah, and the Pediatric Emergency Care Applied Research Network. Morris disclosed receiving personal fees from CSL Behring, Pfizer, Octapharma, and UpToDate; grants/research support from Google, Clarivate Analytics LLC, CSL Behring, the US FDA, the Health Resources and Services Administration, and the NIH, and being a scientific advisory board member for Trility, an inventor of licensed patents generating royalties for UCSF Benioff Children’s Hospital Oakland, an inventor of a patent pending for arginine-based nutrition for pain for the Emory University, and founder and executive director of Food as Medicine Therapeutics LLC and Sigma Spero LLC. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.