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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1513-1523 |
| Number of pages | 11 |
| Journal | JAMA - Journal of the American Medical Association |
| Volume | 325 |
| Issue number | 15 |
| DOIs | |
| State | Published - Apr 20 2021 |
ASJC Scopus subject areas
- General Medicine
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In: JAMA - Journal of the American Medical Association, Vol. 325, No. 15, 20.04.2021, p. 1513-1523.
Research output: Contribution to journal › Article › peer-review
}
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 - Funding Information: 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 Barton reported receiving grants from Mast Therapeutics Inc during the conduct of the study. Dr Kanter-Washko reported receiving institutional research support to conduct the study from Mast Therapeutics Inc during the conduct of the study; receiving personal fees for serving on a steering committee from Novartis and AstraZeneca; receiving personal fees from Guidepoint Global and GLG; and serving on a data and safety monitoring board for NovoNordisc outside the submitted work. Dr Black reported receiving grants from Mast Therapeutics Inc during the conduct of the study and grants from the National Hearth, Lung, and Blood Institute, the Health Resources Service Administration, Pfizer, Novartis, and Sancilio and Company and personal fees from Prolong Pharmaceuticals and Sanofi outside the submitted work. Dr Wali reported receiving a research grant from Mast Therapeutics Inc during the conduct of the study. Dr Drachtman reported receiving personal fees from Global Therapeutics and Novartis outside the submitted work. Dr Abboud reported receiving grants from Novartis; serving on a data and safety monitoring board for CRISPR Therapeutics; receiving grants from AstraZeneca; serving on an advisory board for Emmaus and Novartis; and receiving personal fees from Amgen outside the submitted work. Dr Fuh reported receiving personal fees for consultancy from Bayer, Novartis, and Pfizer and grants from Global Blood Therapeutics outside the submitted work. Dr Al-Khabori reported receiving investigator fees from Mast Therapeutics Inc during the conduct of the study and honoraria from Novartis outside the submitted work. Dr Takemoto reported receiving grants from Johns Hopkins University during the conduct of the study and personal fees from Novartis for serving on a data and safety monitoring board for an aplastic anemia trial, personal fees from Genentech for serving on an advisory board for hemophilia, and grants from Daiichi Sankyo for serving as a site primary investigator for an anticoagulant medication trial outside the submitted work. Dr Shah reported receiving grants from Novartis and Global Blood Therapeutics; being a speaker for Alexion; and consulting for CSL Behring and bluebird bio outside the submitted work. Dr Morris reported receiving grants from Mast Therapeutics Inc to support the EPIC study at Emory-Grady during the conduct of the study and personal fees from Pfizer outside the submitted work and having a patent for diagnostics and therapies for conditions of decreased arginine bioavailability issued; multiple patents issues to Children's Hospital Oakland Research Institute and a patent for methods of treating autism/apraxia with royalties paid from Lifetrients; and multiple patents issues to Children's Hospital Oakland Research Institute. Dr Keates-Baleeiro reported receiving grants from Mast Therapeutics Inc for EPIC to enroll patients (data entry by clinical research associates), but personally did not receive any payments for institutional participation in the trial, during the conduct of the study and grants from TN Sickle Cell for data collection outside the submitted work. Dr Raj reported receiving grants from the University of Louisville during the conduct of the study and personal fees from Forma Therapeutics and Global Blood Therapeutics outside the submitted work. Dr Alvarez reported being an advisory board member for Novartis and Forma Therapeutics outside the submitted work. Dr Hsu reported receiving grants from Mast Therapeutics Inc to participate in this multicenter clinical trial during the conduct of the study and serving on an advisory board for AstraZeneca, Cyclerion, Hoffman LaRoche, Novartis, Emmaus, Pfizer, and Forma Therapeutics; receiving grants from Forma Therapeutics, Imara, Global Blood Therapeutics, Pfizer, AstraZeneca, and Novartis for clinical research and on a data and safety monitoring board for Aruvant outside the submitted work. Dr Thompson reported receiving personal fees from Agios, Beam, and Celgene and grants from Baxalta, Biomarin, bluebird bio, and Novartis outside the submitted work. Dr Pace reported receiving funding from Mast Therapeutics Inc during the conduct of the study. Dr Cela de Julian reported receiving funding from Mast Therapeutics Inc during the conduct of the study and contribution to Novartis advisory boards. Dr Thornburg reported receiving grants from Mast Therapeutics Inc during the conduct of the study and personal fees from Ironwood Pharmaceuticals, now Cyclerion, outside the submitted work. Dr Nuss reported receiving grants from the University of Colorado during the conduct of the study. Dr Cohen reported receiving the drug and research-associated tests from Mast Therapeutics Inc during the conduct of the study. Dr Karakas reported receiving grants from Mast Therapeutics Inc during the conduct of the study. Dr Piccone reported being a speaker for Novartis and Global Blood Therapeutics outside the submitted work. Dr Singleton reported being in a speakers bureau for and receiving advisory board fees from Novo Nordisk, Takeda, Bayer, Biomarin, CSL Behring, Grifols, Hema Biologics, Spark, Sanofi-Genzyme, and Genetech outside the submitted work. Dr Moulton reported receiving funding from Mast Therapeutics Inc to cover costs of participating in the current study and being an employee of Bayer US LLC Pharmaceuticals (not when participating in the study, but when reviewing the manuscript). Dr Quinn reported receiving clinical trial funding from Mast Therapeutics Inc during the conduct of the study and clinical trial funding from Emmaus Medical Inc and Aruvant and grants from the National Heart, Lung, and Blood Institute outside the submitted work. Dr Goyal-Khemka reported receiving grants and nonfinancial support from Phoenix Children’s Hospital for the administrative support for opening and running the study and study drug and travel expenses to the annual study meeting during the conduct of the study. Dr Emanuele reported being employed by Mast Therapeutics Inc during the conduct of the study. Ms Gorney reported receiving grants from Mast Therapeutics Inc for conduct of the trial. Dr Parsley reported receiving personal fees from and being employed by Mast Therapeutics Inc during the conduct of the study. Ms Kronsberg reported receiving grants from Mast Therapeutics Inc during the conduct of the study. Dr Kato reported receiving support to the University of Pittsburgh for salary support as a steering committee member from Mast Therapeutics Inc during the conduct of the study and grants from Bayer; receiving personal fees from Global Blood Therapeutics and Novartis; receiving personal fees from and full-time employment with CSL Behring; and having a patent for topical sodium nitrite issued, held by the National Institutes of Health, outside the submitted work. Dr Gladwin reported receiving grants from Bayer and personal fees from Actelion, Pfizer, Fulcrum, and Novartis outside the submitted work; being a co-inventor of patents and patent applications directed to the use of recombinant neuroglobin and heme-based molecules as antidotes for carbon monoxide poisoning, which have been licensed by Globin Solutions Inc; being a shareholder, advisor, and director in Globin Solutions Inc; being a co-inventor on patents directed to the use of nitrite salts in cardiovascular diseases, which were previously licensed to United Therapeutics, and are now licensed to Globin Solutions and Hope Pharmaceuticals; being a principal investigator in a research collaboration with Bayer Pharmaceuticals to evaluate riociguate as a treatment for patients with sickle cell disease; actively serving as a scientific consultant for Actelion, Pfizer, Bayer Healthcare, Fulcrum, and Novartis; previously serving as a consultant for Acceleron Pharma Inc, Sujana Biotech, Epizyme Inc, Catalyst Biosciences, Complexa, United Therapeutics, and Modus Therapeutics; and serving on a research advisory board for Bayer HealthCare LLC's Heart and Vascular Disease. No other disclosures were reported. Funding Information: reported receiving grants from Mast Therapeutics Inc (previously Adventrx Pharmaceuticals Inc) and receiving an honorarium, travel expenses, and salary support through Johns Hopkins for providing consultative advice to Mast Pharmaceuticals Inc 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 -