James F Casella1, Bruce A Barton2, Julie Kanter3,4, L Vandy Black5,6, Suvankar Majumdar7,8, Adlette Inati9,10, Yasser Wali11, Richard A Drachtman12, Miguel R Abboud13, Yurdanur Kilinc14, Beng R Fuh15, Murtadha K Al-Khabori11, Clifford M Takemoto1,16, Emad Salman17, Sharada A Sarnaik18,19, Nirmish Shah20, Claudia R Morris21,22, Jennifer Keates-Baleeiro23, Ashok Raj24, Ofelia A Alvarez25, Lewis L Hsu26, Alexis A Thompson27, India Y Sisler28, Betty S Pace29, Suzie A Noronha30, Joseph L Lasky31,32, Elena Cela de Julian33, Kamar Godder34, Courtney Dawn Thornburg35,36, Natalie L Kamberos37,38, Rachelle Nuss39, Anne M Marsh40,41, William C Owen42, Anne Schaefer43, Cameron K Tebbi44, Christophe F Chantrain45, Debra E Cohen46,47, Zeynep Karakas48, Connie M Piccone49,50, Alex George51,52, Jason M Fixler53, Tammuella C Singleton54,55, Thomas Moulton56,57, Charles T Quinn58, Clarisse Lopes de Castro Lobo59, Abdulkareem M Almomen60, Meenakshi Goyal-Khemka61,62, Philip Maes63, Marty Emanuele64,65, Rebecca T Gorney1, Claire S Padgett65,66, Ed Parsley65,67, Shari S Kronsberg2, Gregory J Kato68,69, Mark T Gladwin69. 1. Johns Hopkins University School of Medicine, Baltimore, Maryland. 2. University of Massachusetts Medical School, Worcester. 3. Medical University of South Carolina, Charleston. 4. University of Alabama at Birmingham, Birmingham. 5. Our Lady of the Lake Regional Medical Center, Baton Rouge, Louisiana. 6. University of Florida College of Medicine, Gainesville. 7. University of Mississippi Medical Center, Jackson. 8. Children's National Hospital, Washington, DC. 9. Lebanese American University, Byblos and Beirut, Lebanon. 10. Nini Hospital, Tripoli, Lebanon. 11. Sultan Qaboos University, Muscat, Oman. 12. Rutgers University, New Brunswick, New Jersey. 13. American University of Beirut Medical Center, Beirut, Lebanon. 14. Çukurova University Medical Faculty Balcali Hospital, University of Çukurova, Adana, Turkey. 15. East Carolina University, Greenville, North Carolina. 16. St Jude Children's Research Hospital, Memphis, Tennessee. 17. Golisano Children's Hospital of Southwest Florida, Ft Myers. 18. Wayne State University School of Medicine, Detroit, Michigan. 19. Children's Hospital of Michigan, Detroit. 20. Duke University School of Medicine, Durham, North Carolina. 21. Emory University School of Medicine, Atlanta, Georgia. 22. Children's Healthcare of Atlanta, Atlanta, Georgia. 23. T.C. Thompson Children's Hospital at Erlanger, University of Tennessee, Chattanooga. 24. University of Louisville/Norton Children's Hospital, Louisville, Kentucky. 25. University of Miami, Miami, Florida. 26. University of Illinois at Chicago, Chicago. 27. Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Evanston, Illinois. 28. Children's Hospital of Richmond at Virginia Commonwealth University, Richmond. 29. Augusta University, Augusta, Georgia. 30. University of Rochester School of Medicine and Dentistry, Golisano Children's Hospital at University of Rochester Medical Center, Rochester, New York. 31. Harbor-UCLA Medical Center, Torrance, California. 32. Cure 4 The Kids Foundation, Las Vegas, Nevada. 33. Hospital General Universitario Gregorio Marañón, Universidad Complutense de Madrid, Madrid, Spain. 34. Nicklaus Children's Hospital, Miami, Florida. 35. Rady Children's Hospital - San Diego, San Diego, California. 36. UC San Diego School of Medicine, La Jolla, California. 37. University of Iowa Children's Hospital, Iowa City. 38. Loyola University Medical Center, Maywood, Illinois. 39. Children's Hospital Colorado, University of Colorado, Aurora. 40. UCSF Benioff Children's Hospital Oakland (UBCHO), Oakland, California. 41. University of Wisconsin-Madison, Madison. 42. Children's Hospital of the King's Daughters, Norfolk, Virginia. 43. Joe DiMaggio Children's Hospital, Hollywood, Florida. 44. Tampa General Hospital, Tampa, Florida. 45. Clinique MontLegia, CHC, Liège, Belgium. 46. UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania. 47. Studer Family Children's Hospital Ascension Sacred Heart, University of Florida, Pensacola. 48. Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. 49. Rainbow Babies and Children's Hospital, Cleveland, Ohio. 50. Carle Foundation Hospital, Urbana, Illinois. 51. Baylor College of Medicine, Houston, Texas. 52. Wake Forest School of Medicine, Winston-Salem, North Carolina. 53. The Herman and Walter Samuelson Children's Hospital at Sinai, Baltimore, Maryland. 54. Tulane University, New Orleans, Louisiana. 55. Mississippi Center for Advanced Medicine, Slidell, Louisiana. 56. Bronx-Lebanon Hospital, Bronx, New York City, New York. 57. Bayer Pharmaceuticals, Whippany, New Jersey. 58. Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 59. Instituto estadual de Hematologia Arthur de Siqueira Cavalcanti - HEMORIO, Rio de Janeiro, Brasil. 60. Blood and Cancer Center, King Khalid University Hospital (KKUH), King Saud University Medical City, Riyadh, Saudi Arabia. 61. Phoenix Children's Hospital, Phoenix, Arizona. 62. Rutgers Cancer Institute of New Jersey, New Brunswick. 63. University Hospital of Antwerp (UZA), Edegem, Belgium. 64. Visgenx, San Diego, California. 65. Mast Therapeutics Inc, San Diego, California. 66. Sanifit Therapeutics, San Diego, California. 67. Biotechnology, San Diego, California. 68. CSL Behring, King of Prussia, Pennsylvania. 69. University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Abstract
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.
RCT Entities:
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.