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Clinical Trial
. 2021 Apr 20;325(15):1513-1523.
doi: 10.1001/jama.2021.3414.

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

James F Casella  1 , Bruce A Barton  2 , Julie Kanter  3   4 , L Vandy Black  5   6 , Suvankar Majumdar  7   8 , Adlette Inati  9   10 , Yasser Wali  11 , Richard A Drachtman  12 , Miguel R Abboud  13 , Yurdanur Kilinc  14 , Beng R Fuh  15 , Murtadha K Al-Khabori  11 , Clifford M Takemoto  1   16 , Emad Salman  17 , Sharada A Sarnaik  18   19 , Nirmish Shah  20 , Claudia R Morris  21   22 , Jennifer Keates-Baleeiro  23 , Ashok Raj  24 , Ofelia A Alvarez  25 , Lewis L Hsu  26 , Alexis A Thompson  27 , India Y Sisler  28 , Betty S Pace  29 , Suzie A Noronha  30 , Joseph L Lasky 3rd  31   32 , Elena Cela de Julian  33 , Kamar Godder  34 , Courtney Dawn Thornburg  35   36 , Natalie L Kamberos  37   38 , Rachelle Nuss  39 , Anne M Marsh  40   41 , William C Owen  42 , Anne Schaefer  43 , Cameron K Tebbi  44 , Christophe F Chantrain  45 , Debra E Cohen  46   47 , Zeynep Karakas  48 , Connie M Piccone  49   50 , Alex George  51   52 , Jason M Fixler  53 , Tammuella C Singleton  54   55 , Thomas Moulton  56   57 , Charles T Quinn  58 , Clarisse Lopes de Castro Lobo  59 , Abdulkareem M Almomen  60 , Meenakshi Goyal-Khemka  61   62 , Philip Maes  63 , Marty Emanuele  64   65 , Rebecca T Gorney  1 , Claire S Padgett  65   66 , Ed Parsley  65   67 , Shari S Kronsberg  2 , Gregory J Kato  68   69 , Mark T Gladwin  69
Affiliations
Clinical Trial

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

James F Casella et al. JAMA. .

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Casella 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 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.

Figures

Figure 1.
Figure 1.. Participant Flow in a Study of the Effect of Poloxamer 188 vs Placebo on Painful Vaso-Occlusive Episodes in Children and Adults With Sickle Cell Disease
aIncluding 1 participant with known or suspected bleeding disorder, 1 with pain crisis requiring hospitalization in the preceding 14 days, 1 for whom it was the investigator’s belief that the participant was suffering from chronic pain and not acute pain associated with an ongoing vaso-occlusive episode, and 1 who was not an appropriate study candidate (investigator decision). bIncluding 3 participants who did not receive the investigational drug, 3 whose total duration of infusion exceeded 53 hours, 1 for whom infusion could not be started within 24 hours of presentation to site, and 1 who withdrew immediately after the start of the loading dose.
Figure 2.
Figure 2.. Time From Randomization to Last Administration of Parenteral Opioids in a Study of the Effect of Poloxamer 188 vs Placebo on Painful Vaso-Occlusive Episodes in Children and Adults With Sickle Cell Disease
A, The mean values are represented as diamonds. Outliers are represented as circles beyond the whiskers. Error bars indicate the highest and lowest values within 1.5 × the interquartile range. The median (interquartile range) time from randomization to last administration of parenteral opioids was 69.2 (44.7-108.7) hours in the poloxamer 188 group and 66.4 (37.8-107.3) hours in the placebo group. B, No significant difference in time from randomization to last administration of parenteral opioids was observed between treatment groups in the primary analysis population.
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