Intracerebral Hemorrhage Deferoxamine Trial - iDEF Ttrial

May 29, 2019 updated by: Magdy Selim, Beth Israel Deaconess Medical Center

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

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

Interventional

Enrollment (Actual)

294

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Québec, Canada
        • CHU de Quebec - Hopital de l'Enfant-Jésus
    • Alberta
      • Calgary, Alberta, Canada
        • Foothills Hospital - University of Calgary
      • Edmonton, Alberta, Canada
        • University of Alberta - Mackenzie Health Sciences Centre
    • Arizona
      • Phoenix, Arizona, United States
        • St. Joseph's Hospital / Barrow Neurological Institute
    • California
      • Palo Alto, California, United States
        • Stanford University Medical Center
      • San Francisco, California, United States
        • San Francisco General Hospital
    • Connecticut
      • New Haven, Connecticut, United States
        • Yale New Haven Hospital
    • Florida
      • Jacksonville, Florida, United States
        • University of Florida
    • Illinois
      • Chicago, Illinois, United States
        • Rush University Medical Center
      • Chicago, Illinois, United States
        • Loyola University Medical Center
    • Iowa
      • Iowa City, Iowa, United States
        • University of Iowa Medical Center
    • Maryland
      • Baltimore, Maryland, United States
        • Johns Hopkins Hospital
    • Massachusetts
      • Boston, Massachusetts, United States
        • Beth Israel Deaconess Medical Center
      • Worcester, Massachusetts, United States
        • UMass Memorial Medical Center
    • Michigan
      • Detroit, Michigan, United States
        • Henry Ford Hospital
    • New York
      • New York, New York, United States
        • Columbia University
      • New York, New York, United States
        • Weill Medical College of Cornell University
      • New York, New York, United States
        • NYU Langone Medical Center
      • New York, New York, United States
        • Mount Sinai Hospital
    • North Carolina
      • Chapel Hill, North Carolina, United States
        • University of North Carolina Medical Center
      • Durham, North Carolina, United States
        • Duke University Medical Center
    • Ohio
      • Cleveland, Ohio, United States
        • University Hospital Case Medical Center
      • Columbus, Ohio, United States
        • The Ohio State University Medical Center
    • Oregon
      • Portland, Oregon, United States
        • Oregon Health & Science University Medical Center
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States
        • University of Pennsylvania Medical Center
    • Rhode Island
      • Providence, Rhode Island, United States
        • Rhode Island Hospital
    • South Carolina
      • Charleston, South Carolina, United States
        • Medical University of South Carolina
    • Texas
      • Houston, Texas, United States
        • University of Texas Health Sciences Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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:

    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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

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

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
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.
90 days
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
90 days
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
7 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.

90 days
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.
180 days
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.
180 days
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.
90 days

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
90 days
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.
180 days
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
during the study infusion
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
during the study infusion
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
after initiation of study infusion
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 days
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.
7 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2014

Primary Completion (Actual)

February 10, 2018

Study Completion (Actual)

May 30, 2018

Study Registration Dates

First Submitted

June 25, 2014

First Submitted That Met QC Criteria

June 25, 2014

First Posted (Estimate)

June 26, 2014

Study Record Updates

Last Update Posted (Actual)

May 30, 2019

Last Update Submitted That Met QC Criteria

May 29, 2019

Last Verified

May 1, 2019

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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