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Safety and tolerability of deferoxamine mesylate in patients with acute intracerebral hemorrhage.

ABSTRACT: Treatment with the iron chelator, deferoxamine mesylate (DFO), improves neurological recovery in animal models of intracerebral hemorrhage (ICH). We aimed to evaluate the feasibility, safety, and tolerability of varying dose-tiers of DFO in patients with spontaneous ICH, and to determine the maximum tolerated dose to be adopted in future efficacy studies.This was a multicenter, phase-I, dose-finding study using the Continual Reassessment Method. DFO was administered by intravenous infusion for 3 consecutive days, starting within 18 hours of ICH onset. Subjects underwent repeated clinical assessments through 90 days, and computed tomography neuroimaging pre- and post-drug-administration.Twenty subjects were enrolled onto 5 dose tiers, starting with 7 mg/kg per day and ending with 62 mg/kg per day as the maximum tolerated dose. Median age was 68 years (range, 50-90); 60% were men; and median Glasgow Coma Scale and National Institutes of Health Stroke Scale scores on admission were 15 (5-15) and 9 (0-39), respectively. ICH location was lobar in 40%, deep in 50%, and brain stem in 10%; intraventricular hemorrhage was present in 15%. DFO was discontinued because of adverse events in 2 subjects (10%). Six subjects (30%) experienced 12 serious adverse events, none of which were drug-related. DFO infusions were associated with mild blood-pressure-lowering effects. Fifty percent of patients had modified Rankin scale scores ?2, and 39% had modified Rankin scale scores of 4 to 6 on day 90; 15% died.Consecutive daily infusions of DFO after ICH are feasible, well-tolerated, and not associated with excessive serious adverse events or mortality. Our findings lay the groundwork for future studies to evaluate the efficacy of DFO in ICH.

SUBMITTER: Selim M

PROVIDER: S-EPMC3202043 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Safety and tolerability of deferoxamine mesylate in patients with acute intracerebral hemorrhage.

Selim Magdy M Yeatts Sharon S Goldstein Joshua N JN Gomes Joao J Greenberg Steven S Morgenstern Lewis B LB Schlaug Gottfried G Torbey Michel M Waldman Bonnie B Xi Guohua G Palesch Yuko Y

Stroke 20110825 11

<h4>Background and purpose</h4>Treatment with the iron chelator, deferoxamine mesylate (DFO), improves neurological recovery in animal models of intracerebral hemorrhage (ICH). We aimed to evaluate the feasibility, safety, and tolerability of varying dose-tiers of DFO in patients with spontaneous ICH, and to determine the maximum tolerated dose to be adopted in future efficacy studies.<h4>Methods</h4>This was a multicenter, phase-I, dose-finding study using the Continual Reassessment Method. DFO ...[more]

PMID: 21868742

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Project description:BackgroundIron from haemolysed blood is implicated in secondary injury after intracerebral haemorrhage. We aimed to assess the safety of the iron chelator deferoxamine mesylate in patients with intracerebral haemorrhage and to establish whether the drug merits investigation in a phase 3 trial.MethodsWe did a multicentre, futility-design, randomised, placebo-controlled, double-blind, phase 2 trial at 40 hospitals in Canada and the USA. Adults aged 18-80 years with primary, spontaneous, supratentorial intracerebral haemorrhage were randomly assigned (1:1) to receive deferoxamine mesylate (32 mg/kg per day) or placebo (saline) infusions for 3 consecutive days within 24 h of haemorrhage onset. Randomisation was done via a web-based trial-management system centrally in real time, and treatment allocation was concealed from both participants and investigators. The primary outcome was good clinical outcome, which was defined as a modified Rankin Scale score of 0-2 at day 90. We did a futility analysis: if the 90% upper confidence bound of the absolute risk difference between the two groups in the proportion of participants with a good clinical outcome was less than 12% in favour of deferoxamine mesylate, then to move to a phase 3 efficacy trial would be futile. Primary outcome and safety data were analysed in the modified intention-to-treat population, comprising only participants in whom the study infusions were initiated. This trial is registered with ClinicalTrials.gov, number NCT02175225, and is completed.FindingsWe recruited 294 participants between Nov 23, 2014, and Nov 10, 2017. The modified intention-to-treat population consisted of 144 patients assigned to the deferoxamine mesylate group and 147 assigned to the placebo group. At day 90, among patients with available data for the primary outcome, 48 (34%) of 140 participants in the deferoxamine mesylate group, and 47 (33%) of 143 patients in the placebo group, had modified Rankin Scale scores of 0-2 (adjusted absolute risk difference 0·6% [90% upper confidence bound 6·8%]). By day 90, 70 serious adverse events were reported in 39 (27%) of 144 patients in the deferoxamine mesylate group, and 78 serious adverse events were reported in 49 (33%) of 147 patients in the placebo group. Ten (7%) participants in the deferoxamine mesylate and 11 (7%) in the placebo group died. None of the deaths were judged to be treatment related.InterpretationDeferoxamine mesylate was safe. However, the primary result showed that further study of the efficacy of deferoxamine mesylate with anticipation that the drug would significantly improve the chance of good clinical outcome (ie, mRS score of 0-2) at day 90 would be futile.FundingUS National Institutes of Health and US National Institute of Neurological Disorders and Stroke.

Dataset Information

Safety and tolerability of deferoxamine mesylate in patients with acute intracerebral hemorrhage.

Publications

Safety and tolerability of deferoxamine mesylate in patients with acute intracerebral hemorrhage.

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