TY - JOUR
T1 - Effect of Poloxamer 188 vs Placebo on Painful Vaso-Occlusive Episodes in Children and Adults with Sickle Cell Disease
T2 - A Randomized Clinical Trial
AU - Casella, James F.
AU - Barton, Bruce A.
AU - Kanter, Julie
AU - Black, L. Vandy
AU - Majumdar, Suvankar
AU - Inati, Adlette
AU - Wali, Yasser
AU - Drachtman, Richard A.
AU - Abboud, Miguel R.
AU - Kilinc, Yurdanur
AU - Fuh, Beng R.
AU - Al-Khabori, Murtadha K.
AU - Takemoto, Clifford M.
AU - Salman, Emad
AU - Sarnaik, Sharada A.
AU - Shah, Nirmish
AU - Morris, Claudia R.
AU - Keates-Baleeiro, Jennifer
AU - Raj, Ashok
AU - Alvarez, Ofelia A.
AU - Hsu, Lewis L.
AU - Thompson, Alexis A.
AU - Sisler, India Y.
AU - Pace, Betty S.
AU - Noronha, Suzie A.
AU - Lasky, Joseph L.
AU - De Julian, Elena Cela
AU - Godder, Kamar
AU - Thornburg, Courtney Dawn
AU - Kamberos, Natalie L.
AU - Nuss, Rachelle
AU - Marsh, Anne M.
AU - Owen, William C.
AU - Schaefer, Anne
AU - Tebbi, Cameron K.
AU - Chantrain, Christophe F.
AU - Cohen, Debra E.
AU - Karakas, Zeynep
AU - Piccone, Connie M.
AU - George, Alex
AU - Fixler, Jason M.
AU - Singleton, Tammuella C.
AU - Moulton, Thomas
AU - Quinn, Charles T.
AU - De Castro Lobo, Clarisse Lopes
AU - Almomen, Abdulkareem M.
AU - Goyal-Khemka, Meenakshi
AU - Maes, Philip
AU - Emanuele, Marty
AU - Gorney, Rebecca T.
AU - Padgett, Claire S.
AU - Parsley, Ed
AU - Kronsberg, Shari S.
AU - Kato, Gregory J.
AU - Gladwin, Mark T.
N1 - Publisher Copyright:
© 2021 American Medical Association. All rights reserved.
PY - 2021/4/20
Y1 - 2021/4/20
N2 - 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.
AB - 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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U2 - 10.1001/jama.2021.3414
DO - 10.1001/jama.2021.3414
M3 - Article
C2 - 33877274
AN - SCOPUS:85104562253
SN - 0098-7484
VL - 325
SP - 1513
EP - 1523
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
IS - 15
ER -