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High-Dose Deferoxamine in Intracerebral Hemorrhage (HI-DEF)

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: NCT01662895
Recruitment Status : Terminated (By DSMB on October 18, 2013 due to increased incidence of ARDS. See modified protocol [NCT02175225)
First Posted : August 13, 2012
Results First Posted : May 30, 2019
Last Update Posted : June 12, 2019
Sponsor:
Collaborators:
Medical University of South Carolina
National Institute of Neurological Disorders and Stroke (NINDS)
Massachusetts General Hospital
Tufts Medical Center
University of Massachusetts, Worcester
University of Pennsylvania
Johns Hopkins University
University of Maryland, College Park
University of Virginia
Duke University
University of North Carolina
University of Florida
The Cleveland Clinic
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 Hospital
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
Dalhousie University
Information provided by (Responsible Party):
Magdy Selim, Beth Israel Deaconess Medical Center

Brief Summary:
The main 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 brain hemorrhage.

Condition or disease Intervention/treatment Phase
Intracerebral Hemorrhage Drug: Deferoxamine Drug: Normal saline Phase 2

Detailed Description:

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. The investigators recently concluded a phase-I, safety and dose-finding study of DFO in patients with ICH; repeated daily intravenous (IV) infusions of DFO in doses up to 62 mg/kg/day (up to a maximum daily dose of 6000 mg/day) were well-tolerated and did not increase serious adverse events or mortality. The current study builds on these results to assess the potential utility of DFO as a therapeutic intervention in ICH.

This is 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. The investigators 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 (≤12h vs. >12-24h), so that the resulting randomization ratio is 1:1 within each ICH score and OTT window strata.

The 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). 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.
  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.

Secondary and exploratory objectives include:

1- Determining the overall distribution of scores on mRS at 3 months in DFO-treated subjects, and to perform a dichotomized analysis considering the proportion of DFO- and placebo-treated subjects with mRS 0-3.

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 from 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 study demonstrating the efficacy of DFO would be of considerable public health significance.

Update: Enrollment into the trial was terminated by the Data and Safety Monitoring Board because of an imbalance in subjects with reported ARDS. At the time of termination, 42 subjects had been enrolled. As a result, any formal evaluation of these objectives would be under-powered, but descriptive statistics are provided. The protocol was subsequently modified to protect subject safety, and the trial was re-initiated as iDEF (NCT02175225).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 42 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Futility Study of Deferoxamine in Intracerebral Hemorrhage
Actual Study Start Date : March 18, 2013
Actual Primary Completion Date : January 15, 2014
Actual Study Completion Date : May 10, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bleeding

Arm Intervention/treatment
Active Comparator: Deferoxamine
Deferoxamine mesylate supplied in vials containing 2 gm of sterile, lyophilized, powdered deferoxamine mesylate. The drug will be reconstituted for injection, by dissolving in 20 ml of sterile water. The reconstituted drug will be further diluted in normal saline to achieve a final concentration of 7.5 mg per ml.
Drug: Deferoxamine
Deferoxamine mesylate(62 mg/kg/day up to a maximum daily dose of 6000 mg/day) given by a continuous IV infusion for 5 consecutive days beginning within 24 hours of ICH symptom onset.
Other Name: Deferoxamine Mesylate

Placebo Comparator: Normal Saline
0.9% sodium chloride
Drug: Normal saline
This is a placebo. Normal saline will be given by a continuous IV infusion for 5 consecutive days beginning within 24 hours of ICH symptom onset.
Other Name: 0.90% Sodium Chloride Solution




Primary Outcome Measures :
  1. Number of Subjects With Modified Rankin Scale (mRS) Score 0-2 [ 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 minimum mRS score is 0 (i.e. no disability). The maximum score is 6 (i.e. dead).



Secondary Outcome Measures :
  1. Number of Subjects With mRS Score 0-3 [ Time Frame: 90 days ]
    The proportion of DFO- and placebo-treated subjects with mRS 0-3 vs. 4-6 at 90 days


Other Outcome Measures:
  1. Number of Subjects With Allergic/Anaphylactic Reaction [ Time Frame: within 7 days or discharge ]
  2. Number of Patients With Hypotension [ Time Frame: within 7 days or discharge ]
  3. Number of Patients With New Visual or Auditory Changes [ Time Frame: within 7 days or discharge ]
  4. Number of Patients With Serious Adverse Events [ Time Frame: 90 days ]
  5. Number of Patients Who Died During the 90-day Study Period [ Time Frame: 90 days ]
    Mortality at any time from randomization through day-90



Information from the National Library of Medicine

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

Inclusion Criteria:

  1. Age ≥ 18 and ≤ 80 years
  2. The diagnosis of ICH is confirmed by brain CT scan
  3. NIHSS score ≥ 6 and GCS > 6 upon presentation
  4. The first dose of the study drug can be administered within 24h of ICH symptom onset
  5. Functional independence prior to ICH, defined as pre-ICH mRS ≤ 1
  6. Signed and dated informed consent is obtained.

Exclusion Criteria:

  1. Previous chelation therapy or known hypersensitivity to DFO products
  2. Known severe iron deficiency anemia (defined as hemoglobin concentration < 7g/dL or requiring blood transfusions)
  3. Abnormal renal function, defined as serum creatinine > 2 mg/dL
  4. Planned surgical evacuation of ICH prior to administration of study drug (placement of a catheter for ventricular drainage is not a contraindication to enrollment)
  5. Suspected secondary ICH related to tumour, ruptured aneurysm or arteriovenous malformation, hemorrhagic transformation of an ischemic infarct, or venous sinus thrombosis
  6. Infratentorial hemorrhage
  7. Irreversibly impaired brainstem function (bilateral fixed and dilated pupils and extensor motor posturing)
  8. 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)
  9. Pre-existing disability, defined as pre-ICH mRS ≥ 2
  10. 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 low-molecular-weight heparin
  11. Taking iron supplements containing ≥ 325 mg of ferrous iron, or prochlorperazine
  12. Patients with heart failure taking > 500 mg of vitamin C daily
  13. Known severe hearing loss
  14. Known pregnancy, or positive pregnancy test, or breastfeeding
  15. 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
  16. Positive drug screen for cocaine upon presentation
  17. Any condition which, in the judgement of the investigator, might increase the risk to the patient
  18. Life expectancy of less than 90 days due to comorbid conditions
  19. Concurrent participation in another research protocol for investigation of another experimental therapy
  20. Indication that a new Do Not Resuscitate (DNR) or Comfort Measures Only (CMO) order will be implemented within the first 72 hours of hospitalization.

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): NCT01662895


Locations
Show Show 29 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
Tufts Medical Center
University of Massachusetts, Worcester
University of Pennsylvania
Johns Hopkins University
University of Maryland, College Park
University of Virginia
Duke University
University of North Carolina
University of Florida
The Cleveland Clinic
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 Hospital
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
Dalhousie University
Investigators
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Principal Investigator: Magdy Selim, MD, PhD Beth Israel Deaconess Medical Center/Harvard Medical School
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Magdy Selim, Professor of Neurology, Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier: NCT01662895    
Other Study ID Numbers: 2012P-000005
U01NS074425 ( U.S. NIH Grant/Contract )
First Posted: August 13, 2012    Key Record Dates
Results First Posted: May 30, 2019
Last Update Posted: June 12, 2019
Last Verified: May 2019
Keywords provided by Magdy Selim, Beth Israel Deaconess Medical Center:
Brain hemorrhage
Cerebral Hemorrhage
Deferoxamine
Hi-DEF Trial
Additional relevant MeSH terms:
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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