Deferoxamine mesylate in patients with intracerebral haemorrhage (i-DEF)

a multicentre, randomised, placebo-controlled, double-blind phase 2 trial

i-DEF Investigators

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: Iron 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. Methods: We 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. Findings: We 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. Interpretation: Deferoxamine 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. Funding: US National Institutes of Health and US National Institute of Neurological Disorders and Stroke.

Original languageEnglish (US)
Pages (from-to)428-438
Number of pages11
JournalThe Lancet Neurology
Volume18
Issue number5
DOIs
StatePublished - May 1 2019

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Deferoxamine
Cerebral Hemorrhage
Placebos
Medical Futility
Iron
National Institute of Neurological Disorders and Stroke
Safety
butyl phosphorotrithioate
National Institutes of Health (U.S.)
Chelating Agents
Random Allocation
Pharmaceutical Preparations
Population
Canada
Research Personnel
Hemorrhage
Wounds and Injuries

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Deferoxamine mesylate in patients with intracerebral haemorrhage (i-DEF) : a multicentre, randomised, placebo-controlled, double-blind phase 2 trial. / i-DEF Investigators.

In: The Lancet Neurology, Vol. 18, No. 5, 01.05.2019, p. 428-438.

Research output: Contribution to journalArticle

@article{189c74ac58614b3a9bc2234bc325b056,
title = "Deferoxamine mesylate in patients with intracerebral haemorrhage (i-DEF): a multicentre, randomised, placebo-controlled, double-blind phase 2 trial",
abstract = "Background: Iron 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. Methods: We 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. Findings: We 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. Interpretation: Deferoxamine 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. Funding: US National Institutes of Health and US National Institute of Neurological Disorders and Stroke.",
author = "{i-DEF Investigators} and Magdy Selim and Foster, {Lydia D.} and Moy, {Claudia S.} and Guohua Xi and Hill, {Michael D.} and Morgenstern, {Lewis B.} and Greenberg, {Steven M.} and James, {Michael L.} and Vineeta Singh and Wayne Clark and Casey Norton and Palesch, {Yuko Y.} and Yeatts, {Sharon D.} and Monica Dolan and Erlinda Yeh and Kevin Sheth and Kimberly Kunze and Susanne Muehlschlegel and Iryna Nieto and Jan Claassen and Cristina Falo and David Huang and Anne Beckwith and Steven Messe and Melissa Yates and Kristine O'Phelan and Andrea Escobar and Kyra Becker and Patricia Tanzi and Nicole Gonzales and Chad Tremont and Chitra Venkatasubramanian and Rosita Thiessen and Supriya Save and Steven Verrault and Karin Collard and Michael DeGeorgia and Valerie Cwiklinski and Bradford Thompson and Lesley Wasilewski and Charles Andrews and Robert Burfeind and Michel Torbey and Mohammad Hamed and Kenneth Butcher and Leka Sivakumar and Nicolaou Varelas and Kathleen Mays-Wilson and Enrique Leira and Heena Olalde",
year = "2019",
month = "5",
day = "1",
doi = "10.1016/S1474-4422(19)30069-9",
language = "English (US)",
volume = "18",
pages = "428--438",
journal = "The Lancet Neurology",
issn = "1474-4422",
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TY - JOUR

T1 - Deferoxamine mesylate in patients with intracerebral haemorrhage (i-DEF)

T2 - a multicentre, randomised, placebo-controlled, double-blind phase 2 trial

AU - i-DEF Investigators

AU - Selim, Magdy

AU - Foster, Lydia D.

AU - Moy, Claudia S.

AU - Xi, Guohua

AU - Hill, Michael D.

AU - Morgenstern, Lewis B.

AU - Greenberg, Steven M.

AU - James, Michael L.

AU - Singh, Vineeta

AU - Clark, Wayne

AU - Norton, Casey

AU - Palesch, Yuko Y.

AU - Yeatts, Sharon D.

AU - Dolan, Monica

AU - Yeh, Erlinda

AU - Sheth, Kevin

AU - Kunze, Kimberly

AU - Muehlschlegel, Susanne

AU - Nieto, Iryna

AU - Claassen, Jan

AU - Falo, Cristina

AU - Huang, David

AU - Beckwith, Anne

AU - Messe, Steven

AU - Yates, Melissa

AU - O'Phelan, Kristine

AU - Escobar, Andrea

AU - Becker, Kyra

AU - Tanzi, Patricia

AU - Gonzales, Nicole

AU - Tremont, Chad

AU - Venkatasubramanian, Chitra

AU - Thiessen, Rosita

AU - Save, Supriya

AU - Verrault, Steven

AU - Collard, Karin

AU - DeGeorgia, Michael

AU - Cwiklinski, Valerie

AU - Thompson, Bradford

AU - Wasilewski, Lesley

AU - Andrews, Charles

AU - Burfeind, Robert

AU - Torbey, Michel

AU - Hamed, Mohammad

AU - Butcher, Kenneth

AU - Sivakumar, Leka

AU - Varelas, Nicolaou

AU - Mays-Wilson, Kathleen

AU - Leira, Enrique

AU - Olalde, Heena

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Background: Iron 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. Methods: We 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. Findings: We 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. Interpretation: Deferoxamine 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. Funding: US National Institutes of Health and US National Institute of Neurological Disorders and Stroke.

AB - Background: Iron 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. Methods: We 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. Findings: We 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. Interpretation: Deferoxamine 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. Funding: US National Institutes of Health and US National Institute of Neurological Disorders and Stroke.

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JO - The Lancet Neurology

JF - The Lancet Neurology

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