- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02175225
Intracerebral Hemorrhage Deferoxamine Trial - iDEF Ttrial
Study of Deferoxamine Mesylate in Intracerebral Hemorrhage
The investigators hypothesize that treatment with the iron chelator, Deferoxamine Mesylate, improves the outcome of patients with brain hemorrhage.
The purpose of this study is to determine whether treatment with Deferoxamine Mesylate is of sufficient promise to improve outcome before pursuing a larger clinical trial to examine its effectiveness as a treatment for intracerebral hemorrhage.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
This is a prospective, multi-center, double-blind, randomized, placebo-controlled, phase-II clinical trial.
Subjects will be randomized to either deferoxamine mesylate (DFO) at 32 mg/kg/day (up to a maximum daily dose of 6000 mg/day), or saline placebo, given by IV infusion for 3 consecutive days.
Treatment will be initiated within 24 hours after ICH symptom onset. Randomization will control baseline imbalances associated with baseline ICH score, ICH onset-to-treatment time (OTT), ICH volume, baseline NIHSS score, and warfarin use.
All subjects will be followed for 6 months and will receive standard of care therapy while participating in the study.
Throughout the study, we will continue to assess the safety of DFO. At the conclusion of the study, the proportion of DFO-treated subjects with a good clinical outcome at 3 months (defined as modified Rankin Scale (mRS) score of 0-2) will be compared to the placebo proportion in a futility analysis to determine if it is futile to move DFO forward to Phase III efficacy evaluation.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Québec, Canada
- CHU de Quebec - Hopital de l'Enfant-Jésus
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Alberta
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Calgary, Alberta, Canada
- Foothills Hospital - University of Calgary
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Edmonton, Alberta, Canada
- University of Alberta - Mackenzie Health Sciences Centre
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Arizona
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Phoenix, Arizona, United States
- St. Joseph's Hospital / Barrow Neurological Institute
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California
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Palo Alto, California, United States
- Stanford University Medical Center
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San Francisco, California, United States
- San Francisco General Hospital
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Connecticut
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New Haven, Connecticut, United States
- Yale New Haven Hospital
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Florida
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Jacksonville, Florida, United States
- University of Florida
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Illinois
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Chicago, Illinois, United States
- Rush University Medical Center
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Chicago, Illinois, United States
- Loyola University Medical Center
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Iowa
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Iowa City, Iowa, United States
- University of Iowa Medical Center
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Maryland
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Baltimore, Maryland, United States
- Johns Hopkins Hospital
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Massachusetts
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Boston, Massachusetts, United States
- Beth Israel Deaconess Medical Center
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Worcester, Massachusetts, United States
- UMass Memorial Medical Center
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Michigan
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Detroit, Michigan, United States
- Henry Ford Hospital
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New York
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New York, New York, United States
- Columbia University
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New York, New York, United States
- Weill Medical College of Cornell University
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New York, New York, United States
- NYU Langone Medical Center
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New York, New York, United States
- Mount Sinai Hospital
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North Carolina
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Chapel Hill, North Carolina, United States
- University of North Carolina Medical Center
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Durham, North Carolina, United States
- Duke University Medical Center
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Ohio
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Cleveland, Ohio, United States
- University Hospital Case Medical Center
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Columbus, Ohio, United States
- The Ohio State University Medical Center
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Oregon
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Portland, Oregon, United States
- Oregon Health & Science University Medical Center
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Pennsylvania
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Philadelphia, Pennsylvania, United States
- University of Pennsylvania Medical Center
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Rhode Island
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Providence, Rhode Island, United States
- Rhode Island Hospital
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South Carolina
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Charleston, South Carolina, United States
- Medical University of South Carolina
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Texas
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Houston, Texas, United States
- University of Texas Health Sciences Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Age ≥ 18 and ≤ 80 years
- The diagnosis of ICH is confirmed by brain CT scan
- NIHSS score ≥6 and GCS >6 upon presentation
- The first dose of the study drug is expected to be administered within 24h of ICH symptom onset
- Functional independence prior to ICH, defined as pre-ICH mRS ≤1
- Signed and dated informed consent is obtained.
Exclusion Criteria:
- Previous chelation therapy or known hypersensitivity to DFO products
- Known severe iron deficiency anemia (defined as hemoglobin concentration < 7g/dL or requiring blood transfusions)
- Abnormal renal function, defined as serum creatinine >2 mg/dL
- Planned surgical evacuation of ICH prior to administration of study drug (placement of a catheter for ventricular drainage is not a contraindication to enrollment)
- SUSPECTED secondary ICH related to tumour, ruptured aneurysm or arteriovenous malformation, hemorrhagic transformation of an ischemic infarct, or venous sinus thrombosis
- Infratentorial hemorrhage
- Irreversibly impaired brainstem function (bilateral fixed and dilated pupils and extensor motor posturing)
- Complete unconsciousness, defined as a score of 3 on item 1a of the NIHSS (Responds only with reflex motor or autonomic effects or totally unresponsive, and flaccid)
- Pre-existing disability, defined as pre-ICH mRS ≥2
- Coagulopathy - defined as elevated aPTT or INR >1.3 upon presentation; concurrent use of direct thrombin inhibitors (such as dabigatran), direct factor Xa inhibitors (such as rivaroxaban or apixaban), or low-molecular-weight heparin
- Patients with confirmed aspiration, pneumonia, or evident bilateral pulmonary infiltrates on chest x-ray or CT scan prior to enrollment
- Patients with significant respiratory disease such as chronic obstructive pulmonary disease, pulmonary fibrosis, or any use (chronic or intermittent) of inhaled O2 at home
- FiO2 >0.35 (>4 L/min) prior to enrollment
- Sepsis (present source of infection ± lactic acidosis); Systemic Inflammatory Response Syndrome (Temp >100.4F or <96.8F; Heart rate >90; Respiratory rate >20 or PaCo2 <32 mmHg; WBC >12, <4, or bands >10%); or shock (SBP <90 mmHg) at presentation
The presence of 4 or more of the following risk modifiers for ARDS prior to enrollment:
- Tachypnea (respiratory rate >30)
- SpO2 <95%
- Obesity (BMI >30)
- Acidosis (pH <7.35)
- Hypoalbuminemia (albumin <3.5 g/dL)
- Concurrent use of chemotherapy
- Taking iron supplements containing ≥ 325 mg of ferrous iron, or prochlorperazine
- Patients with heart failure taking > 500 mg of vitamin C daily
- Known severe hearing loss
- Known pregnancy, or positive pregnancy test, or breastfeeding
- Positive drug screen for cocaine upon presentation
- Patients known or suspected of not being able to comply with the study protocol due to alcoholism, drug dependency, noncompliance, living in another state or any other cause
- Any condition which, in the judgement of the investigator, might increase the risk to the patient
- Life expectancy of less than 90 days due to co-morbid conditions
- Concurrent participation in another research protocol for investigation of another experimental therapy
- Indication that a new DNR or Comfort Measures Only (CMO) order will be implemented within the first 72 hours of hospitalization
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Deferoxamine Mesylate
Deferoxamine Mesylate (32 mg/kg/day) given by an intravenous infusion for 3 consecutive days
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Placebo Comparator: Normal Saline
Normal saline (0.9% sodium chloride) given by intravenous infusion for 3 consecutive days
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Proportion of Patients With Modified Rankin Scale (mRS) Score 0-2 at 90 Days
Time Frame: 90 days
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The primary outcome measure of efficacy is the modified Rankin Scale (mRS) score, dichotomized to define good functional outcome as mRS 0-2 at 90 days.
The mRS ranges from 0 to 6, with higher scores indicating worse outcome.
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90 days
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Number of Subjects Experiencing Serious Adverse Events
Time Frame: 90 days
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Number of subjects experiencing Serious adverse events at any time from randomization through day 90
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90 days
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Number of Subjects With Serious Adverse Events Within 7 Days
Time Frame: 7 days
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Number of Subjects Experiencing Serious Adverse Events within 7 days of randomization
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7 days
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Proportion of Patients With mRS Score 0-3 at 90 Days
Time Frame: 90 days
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Another measure of efficacy is the modified Rankin Scale (mRS) score, dichotomized to define good functional outcome as mRS 0-3 at 90 days. The mRS ranges from 0 to 6, with higher scores indicating worse outcome. Although mRS 0-3 is less favorable than the primary outcome of mRS 0-2, it would still be a desirable effect in patients with ICH given that no treatments exist to reduce disability. |
90 days
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Proportion of Patients With Modified Rankin Scale (mRS) Score 0-2 at 180 Days
Time Frame: 180 days
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Another measure of efficacy is the modified Rankin Scale (mRS) score, dichotomized to define good functional outcome as mRS 0-2 at 180 days.
The mRS ranges from 0 to 6, with higher scores indicating worse outcome.
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180 days
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Proportion of Patients With Modified Rankin Scale (mRS) Score 0-3 at 180 Days
Time Frame: 180 days
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Another measure of efficacy is the modified Rankin Scale (mRS) score, dichotomized to define good functional outcome as mRS 0-3 at 180 days.
The mRS ranges from 0 to 6, with higher scores indicating worse outcome.
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180 days
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Proportion of Subjects With Good Outcome (mRS 0-2) in the Early vs. Delayed Treatment Time Windows
Time Frame: 90 days
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Analyses will be expanded to include an interaction between treatment and OTT window and the magnitude of the treatment effect, and corresponding confidence interval, will be estimated for each time window (<12 hours vs. >/= 12 hours) in order to explore the presence of a differential treatment effect in the OTT windows.
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90 days
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Ordinal Distribution of Scores on mRS at Day 90
Time Frame: 90 days
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The overall ordinal distribution of scores on mRS at 90 days in DFO- and placebo-treated subjects will be determined.
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90 days
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Ordinal Distribution of Scores on mRS at 180 Days
Time Frame: 180 days
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The overall ordinal distribution of scores on mRS at 180 days in DFO- and placebo-treated subjects will be determined.
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180 days
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Adverse Event of Special Interest: Number of Patients With Allergic Reactions (During Infusion of Study Drug)
Time Frame: during the study infusion
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Adverse event of special interest: anaphylaxis at any time during the study infusion
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during the study infusion
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Adverse Event of Special Interest: Number of Patients With Hypotension
Time Frame: during the study infusion
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Hypotension requiring medical intervention at any time during the study infusion that could not be explained by other causes
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during the study infusion
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Adverse Event of Special Interest: Number of Patients With New Visual or Auditory Changes
Time Frame: after initiation of study infusion
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Adverse event of special interest: development of new and unexplained visual or auditory changes after initiation of the study infusion
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after initiation of study infusion
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Adverse Event of Special Interest: Number of Patients With Respiratory Compromise
Time Frame: 7 days
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Adverse event of special interest: Respiratory compromise of any cause, including acute respiratory distress syndrome, in hospital until day 7 or discharge [whichever was earlier]
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7 days
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Number of Patients With Symptomatic Cerebral Edema
Time Frame: 7 days
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Edema accompanied by an unexplained increase of more than four points on the US National Institutes of Health Stroke Scale or a decrease of more than two points in Glasgow Coma Scale score during the first week after the intracerebral haemorrhage.
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7 days
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Collaborators and Investigators
Collaborators
Investigators
- Study Chair: Magdy Selim, MD, PhD, Beth Israel Deaconess Medical Center
Publications and helpful links
General Publications
- Okauchi M, Hua Y, Keep RF, Morgenstern LB, Schallert T, Xi G. Deferoxamine treatment for intracerebral hemorrhage in aged rats: therapeutic time window and optimal duration. Stroke. 2010 Feb;41(2):375-82. doi: 10.1161/STROKEAHA.109.569830. Epub 2009 Dec 31.
- Selim M. Deferoxamine mesylate: a new hope for intracerebral hemorrhage: from bench to clinical trials. Stroke. 2009 Mar;40(3 Suppl):S90-1. doi: 10.1161/STROKEAHA.108.533125. Epub 2008 Dec 8.
- Selim M, Yeatts S, Goldstein JN, Gomes J, Greenberg S, Morgenstern LB, Schlaug G, Torbey M, Waldman B, Xi G, Palesch Y; Deferoxamine Mesylate in Intracerebral Hemorrhage Investigators. Safety and tolerability of deferoxamine mesylate in patients with acute intracerebral hemorrhage. Stroke. 2011 Nov;42(11):3067-74. doi: 10.1161/STROKEAHA.111.617589. Epub 2011 Aug 25.
- Yeatts SD, Palesch YY, Moy CS, Selim M. High dose deferoxamine in intracerebral hemorrhage (HI-DEF) trial: rationale, design, and methods. Neurocrit Care. 2013 Oct;19(2):257-66. doi: 10.1007/s12028-013-9861-y.
- Hatakeyama T, Okauchi M, Hua Y, Keep RF, Xi G. Deferoxamine reduces neuronal death and hematoma lysis after intracerebral hemorrhage in aged rats. Transl Stroke Res. 2013 Oct;4(5):546-53. doi: 10.1007/s12975-013-0270-5.
- Xie Q, Gu Y, Hua Y, Liu W, Keep RF, Xi G. Deferoxamine attenuates white matter injury in a piglet intracerebral hemorrhage model. Stroke. 2014 Jan;45(1):290-2. doi: 10.1161/STROKEAHA.113.003033. Epub 2013 Oct 30.
- Sonni S, Lioutas VA, Selim MH. New avenues for treatment of intracranial hemorrhage. Curr Treat Options Cardiovasc Med. 2014 Jan;16(1):277. doi: 10.1007/s11936-013-0277-y.
- Lee KH, Lioutas VA, Marchina S, Selim M; iDEF Investigators. The Prognostic Roles of Perihematomal Edema and Ventricular Size in Patients with Intracerebral Hemorrhage. Neurocrit Care. 2022 Oct;37(2):455-462. doi: 10.1007/s12028-022-01532-0. Epub 2022 Jun 8.
- Foster L, Robinson L, Yeatts SD, Conwit RA, Shehadah A, Lioutas V, Selim M; i-DEF Investigators. Effect of Deferoxamine on Trajectory of Recovery After Intracerebral Hemorrhage: A Post Hoc Analysis of the i-DEF Trial. Stroke. 2022 Jul;53(7):2204-2210. doi: 10.1161/STROKEAHA.121.037298. Epub 2022 Mar 21.
- Wei C, Wang J, Foster LD, Yeatts SD, Moy C, Mocco J, Selim M; i-DEF Investigators. Effect of Deferoxamine on Outcome According to Baseline Hematoma Volume: A Post Hoc Analysis of the i-DEF Trial. Stroke. 2022 Apr;53(4):1149-1156. doi: 10.1161/STROKEAHA.121.035421. Epub 2021 Nov 18.
- Lun R, Yogendrakumar V, Ramsay T, Shamy M, Fahed R, Selim MH, Dowlatshahi D. Predicting long-term outcomes in acute intracerebral haemorrhage using delayed prognostication scores. Stroke Vasc Neurol. 2021 Dec;6(4):536-541. doi: 10.1136/svn-2020-000656. Epub 2021 Mar 23.
- Selim M, Foster LD, Moy CS, Xi G, Hill MD, Morgenstern LB, Greenberg SM, James ML, Singh V, Clark WM, Norton C, Palesch YY, Yeatts SD; i-DEF Investigators. Deferoxamine mesylate in patients with intracerebral haemorrhage (i-DEF): a multicentre, randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol. 2019 May;18(5):428-438. doi: 10.1016/S1474-4422(19)30069-9. Epub 2019 Mar 18.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Cardiovascular Diseases
- Vascular Diseases
- Cerebrovascular Disorders
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Intracranial Hemorrhages
- Hemorrhage
- Cerebral Hemorrhage
- Molecular Mechanisms of Pharmacological Action
- Chelating Agents
- Sequestering Agents
- Iron Chelating Agents
- Siderophores
- Deferoxamine
Other Study ID Numbers
- 2012P000005
- U01NS074425 (U.S. NIH Grant/Contract)
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