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Clinical Trial
. 2019 May;18(5):428-438.
doi: 10.1016/S1474-4422(19)30069-9. Epub 2019 Mar 18.

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

Magdy Selim  1 , Lydia D Foster  2 , Claudia S Moy  3 , Guohua Xi  4 , Michael D Hill  5 , Lewis B Morgenstern  6 , Steven M Greenberg  7 , Michael L James  8 , Vineeta Singh  9 , Wayne M Clark  10 , Casey Norton  11 , Yuko Y Palesch  2 , Sharon D Yeatts  2 ; i-DEF Investigators
Collaborators, Affiliations
Clinical Trial

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

Magdy Selim et al. Lancet Neurol. 2019 May.

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.

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Conflict of interest statement

DECLARATION OF INTERESTS

This was an investigator-initiated study, funded by the NINDS (U01 NS074425). Deferoxamine Mesylate is a generic drug, and there was no commercial or industrial support for the trial. None of the authors has any competing interests related to the submitted work. MS reports grants from the NIH/NINDS (i-DEF) and the American Heart Association (outside the submitted work), and personal fees for serving on the advisory board of CSL Behring (outside the submitted work) during the conduct of the trial. SDY reports grant support from the NINDS, personal fees from Genentech and other fees from CR Bard Inc. (outside the submitted work) during the conduct of the study. SG, LDF, YP, and GX report grants from the NIH/NINDS. MDH reports personal fees from Merck, non-financial support from Hoffmann-La Roche Canada Ltd, grants from Covidien (Medtronic), grants from Boehringer-Ingleheim, grants from Stryker Inc., grants from Medtronic LLC, grants from NoNO Inc., (outside the submitted work); In addition, MDH has a patent Systems and Methods for Assisting in Decision-Making and Triaging for Acute Stroke Patients pending to US Patent office Number: 62/086,077 and owns stock in Calgary Scientific Incorporated, a company that focuses on medical imaging software, is a director of the Canadian Federation of Neurological Sciences, a not-for-profit group and has received grant support from Alberta Innovates Health Solutions, CIHR, Heart & Stroke Foundation of Canada, and NINDS. LM, VS, WC, MJ, CM, and CN have nothing to disclose.

Figures

Figure 1:
Figure 1:
Trial profile.
Figure 2:
Figure 2:
Results of Futility Analyses at day-90 and day-180.
Figure 3:
Figure 3:
Ordinal Distribution of raw mRS Scores at Day-90 and Day-180 According to Treatment Group.
Figure 4:
Figure 4:
Good Outcome (mRS 0–2) at Day-90 and Day-180 According to Prespecified Subgroups
Figure 5:
Figure 5:
Kaplan-Mejer Survival Curves for 180-day Mortality by Treatment Group.
See this image and copyright information in PMC

Comment in

References

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