Effect of Poloxamer 188 vs Placebo on Painful Vaso-Occlusive Episodes in Patients With Sickle Cell Disease | Hematology | JN Learning | AMA Ed Hub [Skip to Content]
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Effect of Poloxamer 188 vs Placebo on Painful Vaso-Occlusive Episodes in Children and Adults With Sickle Cell DiseaseA Randomized Clinical Trial

Educational Objective
To understand the pathophysiology of vaso-occlusive episodes in patients with sickle cell disease.
1 Credit CME
Key Points

Question  Can poloxamer 188, an agent that is reported to reduce blood viscosity and cell-cell interactions, effectively reduce the duration of vaso-occlusive episodes (painful crises) in hospitalized patients with sickle cell disease?

Findings  In this randomized clinical trial that included 388 children and adults with sickle cell disease, treatment with poloxamer 188 vs placebo resulted in mean time to last dose of parenteral opioids during vaso-occlusive episodes of 81.8 vs 77.8 hours, a difference that was not statistically significant.

Meaning  Among patients with sickle cell disease, poloxamer 188 did not significantly shorten the duration of painful vaso-occlusive episodes.

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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Article Information

Corresponding Author: James F. Casella, MD, Pediatric Hematology, The Johns Hopkins University School of Medicine, 720 Rutland Ave, Baltimore, MD 21205 (jcasella@jhmi.edu).

Accepted for Publication: February 23, 2021.

Author Contributions: Drs Casella and Barton had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Casella, Barton, Kanter-Washko, Black, Kilinc, Thompson, Quinn, Lopes de Castro Lobo, Almomen, Emanuele, Padgett, Parsley, Kato, Gladwin.

Acquisition, analysis, or interpretation of data: Casella, Barton, Kanter-Washko, Black, Majumdar, Inati, Wali, Drachtman, Abboud, Kilinc, Fuh, Al-Khabori, Takemoto, Salman, Sarnaik, Shah, Morris, Keates-Baleeiro, Raj, Alvarez, Hsu, Thompson, Sisler, Pace, Noronha, Lasky, Cela de Julian, Godder, Thornburg, Kamberos, Nuss, Marsh, Owen, Schaefer, Tebbi, Chantrain, Cohen, Karakas, Piccone, George, Fixler, Singleton, Moulton, Quinn, Goyal-Khemka, Maes, Emanuele, Gorney, Padgett, Parsley, Kronsberg, Kato.

Drafting of the manuscript: Casella, Barton, Kanter-Washko, Black, Majumdar, Drachtman, Sarnaik, Karakas, Parsley, Kronsberg.

Critical revision of the manuscript for important intellectual content: Casella, Barton, Kanter-Washko, Black, Majumdar, Inati, Wali, Abboud, Kilinc, Fuh, Al-Khabori, Takemoto, Salman, Sarnaik, Shah, Morris, Keates-Baleeiro, Raj, Alvarez, Hsu, Thompson, Sisler, Pace, Noronha, Lasky, Cela de Julian, Godder, Thornburg, Kamberos, Nuss, Marsh, Owen, Schaefer, Tebbi, Chantrain, Cohen, Piccone, George, Fixler, Singleton, Moulton, Quinn, Lopes de Castro Lobo, Almomen, Goyal-Khemka, Maes, Emanuele, Gorney, Padgett, Parsley, Kato, Gladwin.

Statistical analysis: Barton, Black, Kronsberg.

Obtained funding: Emanuele, Gladwin.

Administrative, technical, or material support: Casella, Kanter-Washko, Black, Inati, Kilinc, Fuh, Al-Khabori, Sarnaik, Keates-Baleeiro, Hsu, Thompson, Lasky, Nuss, Chantrain, Karakas, George, Lopes de Castro Lobo, Goyal-Khemka, Emanuele, Gorney, Padgett, Parsley, Kato, Gladwin.

Supervision: Casella, Barton, Inati, Drachtman, Morris, Pace, Lasky, Godder, Owen, Chantrain, Fixler, Singleton, Almomen, Maes, Emanuele, Parsley, Kato.

Other - drafting protocol, membership in steering committee, involvement in manuscript drafting: Kato.

Other - Conduct of the clinical trial and data collection for analysis: Padgett.

Other - site PI for study; recruitment and management of study participants; participation in investigator meetings: Takemoto.

Other - Responsible for recruitment of patients at my institution, administration of study drug, collection of data on every enrolled patient: Keates-Baleeiro.

Other - patient enrollment and supervision of study interventions: Owen.

Other - center investigator for this trial: Alvarez.

Other - Care of patients on trial, local PI: Drachtman.

Other - interpretation of children VOC episodes: Cela de Julian.

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.

Funding/Support: This clinical trial was funded by Mast Therapeutics Inc (previously Adventrx Therapeutics Inc).

Role of the Funder/Sponsor: Mast Therapeutics Inc provided funding and selected the clinical coordinating center (Theradex), statistical center (Department of Quantitative Health Sciences, University of Massachusetts Medical School, Dr Barton), primary investigator (Dr Casella), and steering committee for the study. All data collection and management was performed by the clinical coordinating center. Statistical analysis and interpretation of data were performed by the statistical center. Neither Mast Therapeutics Inc nor its successor by merger, Savara Inc, had control over or participated in the decision to submit this manuscript for publication, preparation, review of the manuscript or analysis of data, nor had any control of the journal selected. Drs Emanuele, Parsley and Padgett were previously employed by Mast Therapeutics Inc and participated in manuscript preparation after severance from the company.

Data Sharing Statement: See Supplement 4.

Members of the Steering Committee: James Casella, MD (chair); Gregory Kato, MD; Mark Gladwin, MD; Marty Emanuele, PhD; Ed Parsley, DO; and Claire Padgett, PhD (Santosh Vetticaden, MD, PhD, and Jeffrey Keefer, MD, PhD, did not complete their terms). Drs Parsley, Vetticaden (chief medical officers), Padgett (vice president of development operations), and Emanuele (scientific officer) were employees of Mast Therapeutics Inc.

Site Investigators: Adlette Inati, MD (Nini Hospitol, Tripoli, Lebanon); Yasser Wali, MD (Sultan Qaboos University Hospital – Child Health, Muscat, Oman); Julie Kanter, MD (Medical University of South Carolina, Charleston, South Carolina); Richard A. Drachtman, MD (Rutgers University, New Brunswick, New Jersey); Miguel R. Abboud (American University of Beirut Medical Center, Beirut, Lebanon); Yurdanur Kilinc, MD (University of Çukurova and Çukurova University Medical Faculty Balcali Hospital, Adana, Turkey); Beng R. Fuh, MD (East Carolina University, Greenville, North Carolina); Lucien Vandy Black, MD, MSc (Our Lady of the Lake Regional Medical Center, Baton Rouge, Louisiana); Jeffrey E. Deyo, MD (Our Lady of the Lake Regional Medical Center, Baton Rouge, Louisiana); Murtadha K. Al-Khabori, MD (Sultan Qaboos University, Muscat, Oman); Krismely Annalissa Moya Mejia, MD (Robert Reid Cabral Children's Hospital, Santo Domingo, Dominican Republic); Emad Salman, MD (Golisano Children’s Hospital of Southwest Florida, Fort Myers, Florida); Clifford M. Takemoto, MD (Johns Hopkins University School of Medicine, Baltimore, Maryland); Suvankar Majumdar, MD (University of Mississippi Medical Center, Jackson, Mississippi); Sharada A. Sarnaik, MD (Children’s Hospital of Michigan, Detroit, Michigan); Gladys Maria Paulino, MD (General Hospital Plaza de la Salud, Santo Domingo, Dominican Republic); Jean Williams-Johnson, MBBS, MSc, DM (Caribbean Institute of Medical Research, Mona, Jamaica); Hilze Maria Rodriguez de Ramirez, MD, DCSs, MCS (Hospital Del Nino, San Juan, Puerto Rico); Nirmish Shah, MD (Duke University, School of Medicine, Durham, North Carolina); Claudia R. Morris, MD (Grady Memorial Hospital, Atlanta, Georgia); Jennifer Keates-Baleeiro, MD (T.C. Thompson Children’s Hospital at Erlanger affiliated with the University of Tennessee, Chattanooga, Tennessee); Ashok Raj, MD (University of Louisville/Norton Children’s Hospital, Louisville, Kentucky); Ofelia A. Alvarez, MD (University of Miami, Miami, Florida); Clarissa Johnson, MD (Cook Children’s Hospital, Fort Worth, Texas); Monica Khurana, MD (Riley Hospital for Children, Indianapolis, Indiana); Lewis L. Hsu, MD (University of Illinois at Chicago, Chicago, Illinois); Alexis A. Thompson, MD, MPH (Ann & Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Evanston, Illinois); India Y. Sisler, MD (Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, Virginia); Betty S. Pace, MD (Augusta University, Augusta, Georgia); Suzie A. Noronha, MD (University of Rochester School of Medicine and Dentistry, Golisano Children’s Hospital at University of Rochester Medical Center, Rochester, New York); Joseph L. Lasky III, MD (Harbor-UCLA Medical Center, Torrance, California); Elena Cela de Julian, MD, MSc, PhD (Hospital General Universitario Gregorio Marañón, Universidad Complutense de Madrid, Madrid, Spain); Hala Saleh Alremawi (King Abdullah University Hospital, Ar Ramtha, Jordan); Selma Unal (Mersin University Medical Faculty Hospital, Mersin, Turkey); Kamar Godder, MD (Miami Children’s Hospital, Miami, Flordia); Courtney Dawn Thornburg, MD, MS (Rady Children’s Hospital - San Diego, San Diego, California); Natalie L. Kamberos, DO (University of Iowa Children’s Hospital, Iowa City, Iowa); Rachelle Nuss, MD (Children’s Hospital Colorado, University of Colorado, Aurora, Colorado); Anne M. Marsh, MD (UCSF Benioff Children’s Hospital Oakland [UBCHO], Oakland, California); William C. Owen, MD (Children’s Hospital of the King’s Daughters, Norfolk, Virginia); Sandra Regina Calegare (Hospital Santa Marcelina, São Paulo, Brazil); Anne Schaefer, MD (Joe DiMaggio Children’s Hospital, Hollywood, Florida); Dimas Ariel Quiel Rodriguez, MD (Metropolitan Hospital Complex Dr Arnulfo Arias Madrid, Panama City, Panama); Cameron K. Tebbi, MD (Tampa General Hospital, Tampa, Florida); Abdul Hafeez Siddiqui, MD (University of South Alabama, Mobile, Alabama); Gregory Hale, MD (All Children’s Hospital, St Petersburg, Florida); Christophe F. Chantrain, MD, PhD (Clinique MontLegia, CHC, Liège, Belgium); Debra E. Cohen, MD (UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania); Edna Kakitani Carbone, MD (Hospital Pequeno Principe, Curitiba, Parana, Brazil); Zeynep Karakas, MD (Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey); Renee Gardner, MD (LSUHC – Children’s Hospital of New Orleans, New Orleans, Louisiana); Connie M. Piccone, MD (Rainbow Babies and Children’s Hospital, Cleveland, Ohio); Jason M. Glover, MD (Randall Children’s Hospital, Portland, Oregon); Alex George, MD (Texas Children’s Hospital, Houston, Texas); Jason M. Fixler, MD (The Herman and Walter Samuelson Children’s Hospital at Sinai, Baltimore, MD); Tammuella C. Singleton, MD (Tulane University, New Orleans, Louisiana); Timothy L. McCavit, MD (University of Texas Southwestern Medical Center, Dallas, Texas); Shilpa Jain, MD (Women and Children’s Hospital of Buffalo, Buffalo, New York); Thomas Moulton, MD (Bronx-Lebanon Hospital, Bronx, New York City, New York); Charles T. Quinn, MD, MS (Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio); Clarisse Lopes de Castro Lobo, MD, PhD (Instituto estadual de Hematologia Arthur de Siqueira Cavalcanti – HEMORIO, Rio de Janeiro, Brazil); Alaaeldin Mohamed Abbas Morsi, MD (King Fahad Medical City, Riyadh, Saudi Arabia); Abdulkareem M. Almomen, MD (King Khalid University Hospital, King Saud University Medical City and Blood and Cancer Center, Riyadh, Saudi Arabia); Meenakshi Goyal-Khemka, MD (Phoenix Children’s Hospital, Phoenix, Arizona); Ashraf Abdelmonem Mohamed, MD (The Children’s Hospital at St Francis, Tulsa, Oklahoma); Philip Maes, MD (University Hospital of Antwerp, Edegem, Belgium); Rupa C. Redding-Lallinger, MD (University of North Carolina – Chapel Hill, Chapel Hill, North Carolina).

Additional Contributions: Clarissa Johnson, MD (Cook Children’s Hospital, Fort Worth, Texas), and Rupa C. Redding-Lallinger, MD (University of North Carolina – Chapel Hill, Chapel Hill, North Carolina), are acknowledged for their work as site principal investigators for the trial. Dr Johnson reported no compensation for her role in the study. Dr Redding-Lallinger reported that her site received only the per-patient compensation and that she did not receive other compensation. The authors wish to thank Theradex, the clinical coordinating center for the study; all of the study coordinators, pharmacists, and collaborating site investigators who participated in the trial; and, especially, the individuals with sickle cell disease who enrolled in the trial.

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