Poloxamer 188, a nonionic block polymer surfactant reported to reduce blood viscosity and cell-cell interactions, failed to shorten painful vaso-occlusive episodes in adults and children with sickle cell disease (SCD) in a randomized, placebo-controlled, phase 3 trial.
The findings contrast with those from a prior phase 3 trial showing benefits with treatment, James F. Casella, MD, professor of pediatrics and chief of pediatric hematology at Johns Hopkins University, Baltimore, and colleagues reported.
The time from randomization to the last dose of parenteral opioids in the current study did not differ in 194 patients randomized to the active treatment and 194 randomized to a placebo group (81.8 hours with poloxamer 188 vs. 77.8 hours with placebo), the authors found.
The study results were reported online in JAMA.
Participants in the double-blind study were individuals aged 4-65 years (mean, 15.2 years) with acute moderate to severe painful vaso-occlusive episodes requiring hospitalization. They were recruited between May 2013 and February 2016 from 66 hospitals in 12 countries.
Adverse events that were more common in the poloxamer 188 group included hyperbilirubinemia, which occurred in 12.7% of patients versus 5.2% in the placebo group. Hypoxia occurred more often in the placebo group (12.0% vs. 5.3%).
“Poloxamer 188 has been evaluated in three clinical trials of SCD demonstrating safety and possible efficacy for painful vaso-occlusive episodes and acute chest syndrome, which involves intrapulmonary vascular occlusion and/or infection,” the authors noted. “These studies included a previous phase 3 trial that suggested efficacy for painful vaso-occlusive episodes, particularly in children and participants receiving hydroxyurea.”
The mean duration of vaso-occlusive crisis was reduced by 8.8 hours overall, by 21 hours in those aged under 16 years, and by 16 hours in those receiving hydroxyurea. A small, nonsignificant difference was also seen in the incidence of acute chest syndrome for children in that study.
The findings were encouraging given the lack of disease-modifying therapies for ongoing painful vaso-occlusive episodes, which are associated with higher mortality in patients with SCD; although three agents are available for the prevention vaso-occlusive episodes, including hydroxyurea, L-glutamine, and crizanlizumab-tmca, no available agent effectively manages vaso-occlusive episodes once they have begun, the authors noted.
Current treatment therefore remains supportive, with analgesia and hydration, they added.
This is concerning since “acute pain is estimated to account for 95% of hospital admissions for those with SCD, creating a burden for individuals with SCD, their families, and health care systems,” they explained, adding that the ability to reduce the severity and duration of vaso-occlusive episodes would be a significant advance.
“Because intravenous poloxamer 188 is neither approved by the Food and Drug Administration nor available for clinical use and because other drugs for managing ongoing vaso-occlusive episodes are absent, the present trial was designed to determine whether poloxamer 188 is efficacious for painful vaso-occlusive episodes in SCD,” they said.
However, no benefit was seen for episode duration with treatment in the current study, nor was any beneficial effect on acute chest syndrome observed.
“Rather, although not statistically significant, there were more participants younger than 16 years who developed acute chest syndrome in the poloxamer 188 group than in the placebo group, paralleling the direction of effects on the primary outcome for participants younger than 16 years [in the current study],” they wrote, adding that there were also “no apparent effects on readmission for painful vaso-occlusive episodes in participants receiving hydroxyurea, despite the known effect of hydroxyurea in reducing rates of painful vaso-occlusive episodes and acute chest syndrome.”
Though limited by subjective aspects of assessing the primary outcome in this study and by challenges with effectively blinding poloxamer 188 use, the current findings do not support the use of poloxamer 188 for vaso-occlusive episodes, they concluded.
In an accompanying editorial, JAMA deputy editor Jody Zylke, MD, suggested that the most likely explanation for the differing conclusions in the current and prior phase 3 trials relates to the choice of primary outcome.
In the prior study, the primary outcome was time from randomization to crisis resolution.
“The resolution of pain is subjective, and the criteria to determine crisis resolution established by the investigators were extremely stringent and difficult to implement, leading to a high proportion of participants with incomplete documentation,” Dr. Zylke noted. “Also, incomplete documentation occurred more often in the placebo group than the intervention group, resulting in more imputation of missing values for the placebo group, which favored the poloxamer 188 group.”
In the current trial, a “more easily verified primary outcome was selected, with data available for 99% of participants.”
The report by Dr. Casella and colleagues “adds to the evidence base and illustrates some of the challenges in finding effective treatments for patients with sickle cell disease,” he said.
This study was funded by Mast Therapeutics (previously Adventrx Therapeutics). Dr. Casella reported receiving grants from Mast Therapeutics and receiving an honorarium, travel expenses, and salary support through Johns Hopkins for providing consultative advice to Mast Pharmaceuticals during development of the clinical trial and for serving as the principal investigator for the clinical trial; being 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 holding a patent for aptamers as a potential treatment for sickle cell disease. Dr. Zylke reported having no disclosures.