Poloxamer 188 failed to shorten the duration of painful vaso-occlusive episodes in children and adults with sickle cell disease (SCD), a multicenter phase III trial showed.
In over 300 patients, the mean time from randomization to the last administration of parenteral opioids was similar with poloxamer 188 compared with placebo (81.8 vs 77.8 hours, respectively) — a difference that was not statistically significant, reported James Casella, MD, of Johns Hopkins University School of Medicine in Baltimore, and colleagues.
These results, published in JAMA, conflicted with an earlier phase III study that found a benefit with poloxamer 188 in SCD patients — particularly those treated with hydroxyurea — who were hospitalized with a vaso-occlusive episode.
Treatments such as hydroxyurea can be used to prevent painful vaso-occlusive episodes in patients with SCD. However, efforts to reduce the severity or duration of these episodes with treatments such as inhaled nitric oxide, intravenous magnesium, and intravenous sevuparin have been less successful.
In an accompanying editor’s note, JAMA Deputy Editor Jody Zylke, MD, suggested that the likely explanation for the very different results between the current trial and the earlier trial was the choice of primary outcome.
The primary outcome in the earlier trial was time from randomization to crisis resolution — a difficult outcome to verify, Zylke pointed out, considering that the resolution of pain is subjective and the criteria used to determine crisis resolution was stringent and difficult to implement, and thus resulted in a high proportion of patients having incomplete documentation.
“In the trial by Casella et al., a different, more easily verified primary outcome was selected, with data available for 99% of participants,” Zylke noted.
Poloxamer 188 is a highly purified form of the nonionic block copolymer that reduces blood viscosity, improves microvascular blood flow, and decreases red blood cell aggregation and cell injury, Casella and team said.
This double-blind, international trial included 388 patients (mean age 15.2 years, 45.4% women) who had been hospitalized with severe pain typical of vaso-occlusive episodes and required treatment with parenteral opioid analgesia.
From May 2013 to February 2016, patients were randomly assigned on a 1:1 basis to receive either poloxamer 188 or placebo, with randomization stratified by age (under 16 vs 16 or older), use of hydroxyurea, and pain scores (<8 or ≥8) using the Wong-Baker FACES Pain Rating Scale.
“Based on a significant interaction of age and treatment,” there was a difference in the mean time from randomization to last administration of opioids for patients younger than 16: 88.7 hours in the poloxamer 188 group versus 71.9 hours in the placebo group (difference 16.8 hours, 95% CI 1.7-32.0), they noted.
“In contrast to the apparent benefit to participants younger than 16 years in the previous phase 3 study, apparent harm with poloxamer 188 was found in this age group in the current study,” Casella’s group wrote.
On the other hand, for patients 16 and older, the mean time from randomization to last administration of parenteral opioids was 71.7 hours in the poloxamer 188 group versus 86.0 hours in the placebo group (difference -14.3 hours, 95% CI -32.8 to 4.3).
The authors also found that there was no significant reduction in the duration of vaso-occlusive crises for patients who received hydroxyurea in either of the two treatment groups.
Common adverse events in the poloxamer 188 group included abdominal distension, hepatobiliary disorders, hyperbilirubinemia, and upper respiratory infections, while hypoxia and infusion site swelling/pain were more common in the placebo group.
“These findings do not support the use of poloxamer 188 for vaso-occlusive episodes,” Casella and colleagues concluded.
Study limitations included the fact that the primary outcome measure, while relatively easy to determine, still has subjective aspects. Additionally, “although appropriate blinding procedures were in place, assessment of their success was not performed in this study or previous studies of poloxamer 188,” the authors noted.
Casella reported receiving grants from Mast Therapeutics (previously Adventrx Pharmaceuticals) and receiving an honorarium, travel expenses, and salary support through Johns Hopkins for providing consultative advice to Mast during development of the clinical trial and for serving as the principal investigator for the clinical trial. He also is an inventor and a named party on a patent and licensing agreement to ImmunArray through Johns Hopkins for a panel of brain biomarkers for the detection of brain injury, and holds a patent for aptamers as a potential treatment for sickle cell disease.
Co-authors reported other financial relationships with industry.
Zylke had no disclosures to report.