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

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-beta0 thalassemia, or S-beta+ 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

Adherence to hip protectors and implications for U.S. long-term care settings

OBJECTIVES: Determine nursing home characteristics related to adherence to use of a hip protector (HP) to prevent fracture; also describe adherence and related resident characteristics. DESIGN: A multicenter, randomized controlled trial of a HP in which adherence to wearing the HP was monitored by research staff 3 times a week for up to 21 months; data were collected by interviews and chart review. SETTING: Thirty-five nursing homes in Boston, St. Louis, and Baltimore. PARTICIPANTS: A total of 797 eligible residents, 633 (79%) of whom passed the run-in period, 397 (63%) of whom remained in the study until the end of follow-up. INTERVENTION: Residents wore a single HP on their right or left side. MEASUREMENTS: In addition to regular monitoring of adherence, data were collected regarding facility characteristics, staffing, policies and procedures, perception of HPs and related experience, and research staff ratings of environmental and overall quality; and also resident demographic characteristics, and function, health, and psychosocial status. RESULTS: Facility characteristics related to more adherence were not being chain-affiliated; less Medicaid case-mix; fewer residents wearing HPs; more paraprofessional staff training; more rotating workers; and having administrators who were less involved in meetings. CONCLUSION: Efforts to increase adherence to the use of HPs should focus on facilities with more Medicaid case-mix to reduce disparities in care, and those that have less of a culture of training. Staff may need support to increase adherence, and when adherence cannot be maintained, HP use should be targeted to those who remain adherent. Elsevier Inc. All rights reserved

Ex Vivo Antibody-Dependent Cellular Cytotoxicity Inducibility Predicts Efficacy of Cetuximab

We conducted in vitro studies and a clinical trial for patients with squamous cell carcinoma of the head and neck (SCCHN) to study the relationship between FcγRIIIa polymorphisms and antibody-dependent cellular cytotoxicity (ADCC). In vitro, FcγRIIIa genotype was correlated with ADCC and innate cytotoxicity using natural killer (NK) cells harvested from healthy donors. In the phase II study, patients with recurrent or metastatic SCCHN were treated with cetuximab (500 mg/m(2) i.v. every 2 weeks) and lenalidomide (25 mg daily). FcγRIIIa genotype and ex vivo ADCC were correlated with clinical response, progression-free survival (PFS), and overall survival (OS). In vitro, healthy donors with a FcγRIIIa 158-V allele demonstrated more effective ADCC against two colon cancer cell lines HT29 and SW480, mean cytotoxicity: FF 16.1%, VF/VV 24.3% (P = 0.015) and FF 11.7%, VF/VV 21.0% (P = 0.008), respectively. We observed a linear relationship between ADCC response and innate cytotoxicity. In the phase II trial, 40 patients received cetuximab and lenalidomide with median PFS of 7.2 weeks and OS of 16.4 weeks. Thirty-six patients had FcγRIIIa genotype: VV (2), VF (20), and FF (14), and 25 patients had sufficient NK-cell yield to perform ex vivo ADCC. FcγRIIIa genotype was not associated with any clinical outcomes. Patients mounting ex vivo ADCC response had a higher likelihood of stable disease (P = 0.01) and showed a trend toward increased PFS: 14 weeks versus 6.8 weeks, respectively (P = 0.13). Enhanced ex vivo ADCC and innate immunity responses were more predictive of clinical response than FcγRIIIa and may offer a functional assay to select patients suitable for cetuximab therapy

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

Key PointsQuestionCan 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? FindingsIn 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. MeaningAmong patients with sickle cell disease, poloxamer 188 did not significantly shorten the duration of painful vaso-occlusive episodes

Effect of poloxamer 188 vs placebo on painful vaso-occlusive episodes in children and adults with sickle cell disease : a randomized clinical trial

Key PointsQuestionCan 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? FindingsIn 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. MeaningAmong patients with sickle cell disease, poloxamer 188 did not significantly shorten the duration of painful vaso-occlusive episodes