James F Casella, Bruce A Barton, Julie Kanter, L Vandy Black, Suvankar Majumdar, Adlette Inati, Yasser Wali, Richard A Drachtman, Miguel R Abboud, Yurdanur Kilinc, Beng R Fuh, Murtadha K Al-Khabori, Clifford M Takemoto, Emad Salman, Sharada A Sarnaik, Nirmish Shah, Claudia R Morris, Jennifer Keates-Baleeiro, Ashok Raj, Ofelia A Alvarez, Lewis L Hsu, Alexis A Thompson, India Y Sisler, Betty S Pace, Suzie A Noronha, Joseph L Lasky, Elena Cela de Julian, Kamar Godder, Courtney Dawn Thornburg, Natalie L Kamberos, Rachelle Nuss, Anne M Marsh, William C Owen, Anne Schaefer, Cameron K Tebbi, Christophe F Chantrain, Debra E Cohen, Zeynep Karakas, Connie M Piccone, Alex George, Jason M Fixler, Tammuella C Singleton, Thomas Moulton, Charles T Quinn, Clarisse Lopes de Castro Lobo, Abdulkareem M Almomen, Meenakshi Goyal-Khemka, Philip Maes, Marty Emanuele, Rebecca T Gorney, Claire S Padgett, Ed Parsley, Shari S Kronsberg, Gregory J Kato, Mark T Gladwin
Journal: JAMA 2021;325(15):1513-1523
PMID: 33877274
IMPORTANCE
Although 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-β0 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.
RESULTS
Of 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.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01737814.
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