Effect of Poloxamer 188 vs Placebo on Painful Vaso-Occlusive Episodes in Children and Adults With Sickle Cell Disease

Abstract

IMPORTANCEAlthough effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea.OBJECTIVE To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes.DESIGN, SETTING, AND PARTICIPANTS Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-β 0 thalassemia, or S-β + thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included. INTERVENTIONS A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194).MAIN OUTCOMES AND MEASURES Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup. RESULTSOf 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, −7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%).CONCLUSIONS AND RELEVANCE Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes.

Design of an adaptive randomized clinical trial of intravenous citrulline for sickle cell pain crisis in the emergency department

“…Since the discovery of SCD in modern history in 1910, there are only four FDA approved drugs for the prevention of pain in SCD, three of which received approval only in the last 5 years [ [10] , [11] , [12] ]. Currently, there is no FDA approved drug for the treatment of acute VOC, although a few drugs have been tested in clinical trials and without successful results [ [13] , [14] , [15] ]. The conduct of clinical trials in SCD has been challenging in this minority population for an otherwise complicated clinical outcome of pain.…”

“…In the last several years, there has been an exponential growth in the number of clinical trials in SCD, made possible due to close partnerships between the pharmaceutical industry and academia [ 16 ]. However, the design of the clinical trial in SCD is critically important for the successful outcome; for example, the poloxamer 188 trial for VOC showed significant and positive findings initially, but unfortunately failed to achieve approval because of negative results in the final phase 3 trial [ 15 , 17 ]. This is partly because the clinical endpoints were different between the different phases of the trials [ 18 ].…”

Poloxamer-188 Adjuvant Efficiently Maintains Adaptive Immunity of SARS-CoV-2 RBD Subunit Vaccination through Repressing p38MAPK Signaling

“…In a clinical trial of children and adults with sickle cell disease, P188 of intravenous therapy (100 mg/kg) for one hour triggered adverse events including abdominal distension, hepatobiliary disorders, hyperbilirubinemia; the above adverse events were resolved in 30 days [ 29 ]. In addition, a recent pharmacological study reported that treatment of P188 alone induced the expression of IL-6 [ 30 ], suggesting P188 is potential immune stimulator. Above studies support the mechanism, application, and safety dose of P188 as potential adjuvant in formulation of subunit vaccine.…”

Ticagrelor vs placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: the HESTIA3 study

“…At present, we conclude that ticagrelor is not effective for the prevention of vaso-occlusive crises in pediatric patients with the SCD genetic traits HbSS and HbS/β 0 . Unfortunately, the negative result of the HESTIA3 trial of ticagrelor joins a list of negative results for other investigational agents in SCD, including senicapoc, 38 prasugrel, 23 regadenoson, 39 sevuparin, 40 poloxamer 188, 41 olinciguat, 42 and rivipansel. 43 There continues to be a significant unmet need for prevention and treatment of vaso-occlusive crises in SCD.…”