Several studies show that hemoglobin breakdown and subsequent iron accumulation in the brain play a role in mediating secondary neuronal injury after intracerebral hemorrhage (ICH);and that treatment with the iron chelator, deferoxamine (DFO), provides neuroprotection in animal models of ICH. We recently concluded a phase-I, safety and dose-finding study of DFO in patients with ICH;intravenous (IV) infusions of DFO in doses up to 62 mg/kg/day for 3 consecutive days were well-tolerated and did not increase serious adverse events or mortality. The current proposal builds on these results and brings together a team with world-class expertise in ICH and clinical trials to assess the potential utility of DFO as a therapeutic intervention in ICH. We propose a prospective, multi-center, double-blind, randomized, placebo-armed, phase-II, futility clinical study to determine if this maximum tolerated dose of DFO is of sufficient promise to improve outcome prior to embarking on a large-scale and costly phase III study to assess its efficacy in ICH. We will randomize 324 subjects with ICH equally (1:1) to either DFO at 62 mg/kg/day (up to a maximum daily dose of 6000 mg/day), or saline placebo, given by continuous IV infusion for 5 consecutive days. Treatment will be initiated within 24 hours after ICH symptom onset. Subjects will be stratified based on baseline ICH score (0-2 vs. 3-5) and ICH onset-to- treatment time (OTT) window (d12h vs. >12-24h), so that the resulting randomization ratio is 1:1 within each ICH score and OTT window strata. Our main objectives are: 1) To assess whether it would be futile to move DFO forward into a Phase III trial based on the end point of good outcome (defined as dichotomized modified Rankin Scale score of 0-2 at 3 months) and a pre-defined difference in effect size e12% in favor of DFO;and 2) To collect more data on treatment-related adverse events in order to ascertain that patients with ICH can tolerate this dose given over an extended 5-day duration of infusion without experiencing unreasonable neurological complications, increased mortality, or other serious adverse events related to DFO use. At the conclusion of the study, the proportion of DFO-treated subjects with a good outcome will be compared to the placebo proportion in a futility analysis. If the DFO-treated proportion is less than 12% greater than the placebo proportion, then it would be futile to move DFO forward to future Phase III testing. We generally hypothesize that treatment with DFO will minimize neuronal injury and, thus, improve the overall outcome after ICH. Successful completion of this study will provide a crucial """"""""go/no-go"""""""" signal for DFO in ICH. Futility will discourage a major phase III trial, whereas non-futility will offer strong support for a phase III study to detect clinical efficacy. Results fom this study can provide valuable information to guide the design and sample size estimation of a potential future Phase III trial. ICH is a frequent cause of disability and death. A successful stuy demonstrating the efficacy of DFO would be of considerable public health significance.

Public Health Relevance

Brain hemorrhage occurs in 60,000 Americans per year, and is a major cause of death and permanent disability. The financial and emotional burden of this devastating condition on the patients, their families, the society, and healthcare resources is enormous. This project aims to investigate a potential new treatment for ICH. It, therefore, can have important clinical implications;improve the welfare of these patients and their families;and minimize expenses related to long-term care of patients with ICH.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01NS074425-01A1
Application #
8295116
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Janis, Scott
Project Start
2012-09-01
Project End
2017-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$1,372,244
Indirect Cost
$419,701
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Hemorrhagic Stroke Academia Industry (HEADS) Roundtable Participants (2018) Basic and Translational Research in Intracerebral Hemorrhage: Limitations, Priorities, and Recommendations. Stroke 49:1308-1314
Hemorrhagic Stroke Academia Industry (HEADS) Roundtable Participants (2018) Unmet Needs and Challenges in Clinical Research of Intracerebral Hemorrhage. Stroke 49:1299-1307
Lioutas, Vasileios-Arsenios; Goyal, Nitin; Katsanos, Aristeidis H et al. (2018) Clinical Outcomes and Neuroimaging Profiles in Nondisabled Patients With Anticoagulant-Related Intracerebral Hemorrhage. Stroke 49:2309-2316
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Wang, Binli; Yan, Shenqiang; Xu, Mengjun et al. (2016) Timing of Occurrence Is the Most Important Characteristic of Spot Sign. Stroke 47:1233-1238
Butcher, Kenneth; Selim, Magdy (2016) Acute Blood Pressure Management in Intracerebral Hemorrhage: Equipoise Resists an Attack. Stroke 47:3065-3066
LeBlanc 3rd, Robert H; Chen, Ruiya; Selim, Magdy H et al. (2016) Heme oxygenase-1-mediated neuroprotection in subarachnoid hemorrhage via intracerebroventricular deferoxamine. J Neuroinflammation 13:244
Darger, Bryan; Gonzales, Nicole; Banuelos, Rosa C et al. (2015) Outcomes of Patients Requiring Blood Pressure Control Before Thrombolysis with tPA for Acute Ischemic Stroke. West J Emerg Med 16:1002-6
Selim, Magdy; Sheth, Kevin N (2015) Perihematoma edema: a potential translational target in intracerebral hemorrhage? Transl Stroke Res 6:104-6

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