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

Futility Study of Deferoxamine in Intracerebral Hemorrhage

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.

Study Overview

• Status: Terminated
• Conditions: Intracerebral Hemorrhage
• Intervention / Treatment: Drug: Deferoxamine; Drug: Normal saline

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).

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Québec, Canada, G1J 1Z4
    • Hôpital de l'Enfant-Jésus - CHU de Québec
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Foothills Medical Center
    • Edmonton, Alberta, Canada, T6G 2B7
      • Mackenzie Health Sciences Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • Halifax Infirmary
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • St. Joseph's Hospital
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University Hospital
    • San Francisco, California, United States, 94110
      • San Francisco General Hospital
  • Connecticut
    • Hartford, Connecticut, United States, 06107
      • Hartford Hospital
    • New Haven, Connecticut, United States, 06510
      • Yale New Haven Hospital
  • Florida
    • Jacksonville, Florida, United States, 32209
      • The University of Florida College of Medicine
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Memorial Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina Medical Center
    • Durham, North Carolina, United States, 27705
      • Duke University Hospital
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Medical Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas Health Science Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System
  • Washington
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center

Participation Criteria

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:

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: 0.90% Sodium Chloride Solution
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 Names: Deferoxamine Mesylate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With Modified Rankin Scale (mRS) Score 0-2	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).	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With mRS Score 0-3	The proportion of DFO- and placebo-treated subjects with mRS 0-3 vs. 4-6 at 90 days	90 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With Allergic/Anaphylactic Reaction		within 7 days or discharge
Number of Patients With Hypotension		within 7 days or discharge
Number of Patients With New Visual or Auditory Changes		within 7 days or discharge
Number of Patients With Serious Adverse Events		90 days
Number of Patients Who Died During the 90-day Study Period	Mortality at any time from randomization through day-90	90 days

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Collaborators: Medical University of South Carolina; Johns Hopkins University; Massachusetts General Hospital; The University of Texas Health Science Center, Houston; University of Pennsylvania; University of Maryland; National Institute of Neurological Disorders and Stroke (NINDS); University of Iowa; The Cleveland Clinic; Duke University; University of Florida; University of Alberta; Oregon Health and Science University; University of Washington; University of California, San Francisco; Stanford University; Ohio State University; University of Calgary; Tufts Medical Center; Rhode Island Hospital; University of Virginia; Dalhousie University; University of Massachusetts, Worcester; Hopital de l'Enfant-Jesus; Hartford Hospital; St. Joseph's Hospital and Medical Center, Phoenix; University of North Carolina; Henry Ford Hospital; Yale New Haven Hospital
• Investigators: Principal Investigator: Magdy Selim, MD, PhD, Beth Israel Deaconess Medical Center/Harvard Medical School

Publications and helpful links

General Publications

• 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.
• Gu Y, Hua Y, Keep RF, Morgenstern LB, Xi G. Deferoxamine reduces intracerebral hematoma-induced iron accumulation and neuronal death in piglets. Stroke. 2009 Jun;40(6):2241-3. doi: 10.1161/STROKEAHA.108.539536. Epub 2009 Apr 16.
• Okauchi M, Hua Y, Keep RF, Morgenstern LB, Xi G. Effects of deferoxamine on intracerebral hemorrhage-induced brain injury in aged rats. Stroke. 2009 May;40(5):1858-63. doi: 10.1161/STROKEAHA.108.535765. Epub 2009 Mar 12.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 18, 2013
• Primary Completion (Actual): January 15, 2014
• Study Completion (Actual): May 10, 2018

Study Registration Dates

• First Submitted: July 30, 2012
• First Submitted That Met QC Criteria: August 8, 2012
• First Posted (Estimate): August 13, 2012

Study Record Updates

• Last Update Posted (Actual): June 12, 2019
• Last Update Submitted That Met QC Criteria: May 29, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: Cerebral Hemorrhage; Deferoxamine; Brain hemorrhage; Hi-DEF Trial
• 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: 2012P-000005; U01NS074425 (U.S. NIH Grant/Contract)