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Intracerebral Hemorrhage Deferoxamine Trial - iDEF Ttrial

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02175225
Recruitment Status : Completed
First Posted : June 26, 2014
Results First Posted : May 30, 2019
Last Update Posted : May 30, 2019
Sponsor:
Collaborators:
Medical University of South Carolina
National Institute of Neurological Disorders and Stroke (NINDS)
Massachusetts General Hospital
University of Massachusetts, Worcester
University of Pennsylvania
Johns Hopkins University
Duke University
University of North Carolina
University of Florida
Henry Ford Hospital
Ohio State University
St. Joseph's Hospital and Medical Center, Phoenix
University of California, San Francisco
Oregon Health and Science University
Yale New Haven Health System Center for Healthcare Solutions
University of Iowa
Hartford Hospital
The University of Texas Health Science Center, Houston
Rhode Island Hospital
Stanford University
University of Washington
University of Calgary
Hopital de l'Enfant-Jesus
University of Alberta
Rush University Medical Center
University Hospitals Cleveland Medical Center
Columbia University
Weill Medical College of Cornell University
NYU Langone Health
Mount Sinai Hospital, New York
Loyola University
Information provided by (Responsible Party):
Magdy Selim, Beth Israel Deaconess Medical Center

Study Description
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Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Intracerebral Hemorrhage Drug: Deferoxamine Mesylate Drug: Placebo (for Deferoxamine Mesylate) Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 294 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Study of Deferoxamine Mesylate in Intracerebral Hemorrhage
Actual Study Start Date : October 2014
Actual Primary Completion Date : February 10, 2018
Actual Study Completion Date : May 30, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bleeding

Arms and Interventions
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Arm Intervention/treatment
Experimental: Deferoxamine Mesylate
Deferoxamine Mesylate (32 mg/kg/day) given by an intravenous infusion for 3 consecutive days
 Drug: Deferoxamine Mesylate
Placebo Comparator: Normal Saline
Normal saline (0.9% sodium chloride) given by intravenous infusion for 3 consecutive days
 Drug: Placebo (for Deferoxamine Mesylate)


Outcome Measures
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Primary Outcome Measures :
  1. Proportion of Patients With Modified Rankin Scale (mRS) Score 0-2 at 90 Days [ Time Frame: 90 days ]
    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.

  2. Number of Subjects Experiencing Serious Adverse Events [ Time Frame: 90 days ]
    Number of subjects experiencing Serious adverse events at any time from randomization through day 90

  3. Number of Subjects With Serious Adverse Events Within 7 Days [ Time Frame: 7 days ]
    Number of Subjects Experiencing Serious Adverse Events within 7 days of randomization


Secondary Outcome Measures :
  1. Proportion of Patients With mRS Score 0-3 at 90 Days [ Time Frame: 90 days ]

    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.


  2. Proportion of Patients With Modified Rankin Scale (mRS) Score 0-2 at 180 Days [ Time Frame: 180 days ]
    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.

  3. Proportion of Patients With Modified Rankin Scale (mRS) Score 0-3 at 180 Days [ Time Frame: 180 days ]
    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.

  4. Proportion of Subjects With Good Outcome (mRS 0-2) in the Early vs. Delayed Treatment Time Windows [ Time Frame: 90 days ]
    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.


Other Outcome Measures:
  1. Ordinal Distribution of Scores on mRS at Day 90 [ Time Frame: 90 days ]
    The overall ordinal distribution of scores on mRS at 90 days in DFO- and placebo-treated subjects will be determined.

  2. Ordinal Distribution of Scores on mRS at 180 Days [ Time Frame: 180 days ]
    The overall ordinal distribution of scores on mRS at 180 days in DFO- and placebo-treated subjects will be determined.

  3. Adverse Event of Special Interest: Number of Patients With Allergic Reactions (During Infusion of Study Drug) [ Time Frame: during the study infusion ]
    Adverse event of special interest: anaphylaxis at any time during the study infusion

  4. Adverse Event of Special Interest: Number of Patients With Hypotension [ Time Frame: during the study infusion ]
    Hypotension requiring medical intervention at any time during the study infusion that could not be explained by other causes

  5. Adverse Event of Special Interest: Number of Patients With New Visual or Auditory Changes [ Time Frame: after initiation of study infusion ]
    Adverse event of special interest: development of new and unexplained visual or auditory changes after initiation of the study infusion

  6. Adverse Event of Special Interest: Number of Patients With Respiratory Compromise [ Time Frame: 7 days ]
    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]

  7. Number of Patients With Symptomatic Cerebral Edema [ Time Frame: 7 days ]
    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.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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:

    1. Tachypnea (respiratory rate >30)
    2. SpO2 <95%
    3. Obesity (BMI >30)
    4. Acidosis (pH <7.35)
    5. Hypoalbuminemia (albumin <3.5 g/dL)
    6. 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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02175225


Locations
Show Show 28 study locations
Sponsors and Collaborators
Beth Israel Deaconess Medical Center
Medical University of South Carolina
National Institute of Neurological Disorders and Stroke (NINDS)
Massachusetts General Hospital
University of Massachusetts, Worcester
University of Pennsylvania
Johns Hopkins University
Duke University
University of North Carolina
University of Florida
Henry Ford Hospital
Ohio State University
St. Joseph's Hospital and Medical Center, Phoenix
University of California, San Francisco
Oregon Health and Science University
Yale New Haven Health System Center for Healthcare Solutions
University of Iowa
Hartford Hospital
The University of Texas Health Science Center, Houston
Rhode Island Hospital
Stanford University
University of Washington
University of Calgary
Hopital de l'Enfant-Jesus
University of Alberta
Rush University Medical Center
University Hospitals Cleveland Medical Center
Columbia University
Weill Medical College of Cornell University
NYU Langone Health
Mount Sinai Hospital, New York
Loyola University
Investigators
Layout table for investigator information
Study Chair: Magdy Selim, MD, PhD Beth Israel Deaconess Medical Center
  Study Documents (Full-Text)

Documents provided by Magdy Selim, Beth Israel Deaconess Medical Center:
Study Protocol  [PDF] May 15, 2014
Statistical Analysis Plan  [PDF] July 11, 2018

More Information
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Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Magdy Selim, MD, PhD, Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier: NCT02175225    
Other Study ID Numbers: 2012P000005
U01NS074425 ( U.S. NIH Grant/Contract )
First Posted: June 26, 2014    Key Record Dates
Results First Posted: May 30, 2019
Last Update Posted: May 30, 2019
Last Verified: May 2019
Keywords provided by Magdy Selim, Beth Israel Deaconess Medical Center:
Brain hemorrhage
Cerebral hemorrhage
Bleeding in the brain
Deferoxamine
iDEF trial
Additional relevant MeSH terms:
Layout table for MeSH terms
Cerebral Hemorrhage
Hemorrhage
Pathologic Processes
Intracranial Hemorrhages
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
 Vascular Diseases
Cardiovascular Diseases
Deferoxamine
Siderophores
Iron Chelating Agents
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action