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Intracerebral HemorrhagePhase 2HI-DEFNCT01662895

High-Dose Deferoxamine in Intracerebral Hemorrhage

A Phase 2 study testing Deferoxamine and Normal saline in people with Intracerebral Hemorrhage, run by Beth Israel Deaconess Medical Center at 29 sites in 2 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 80 years
Conditions the study is for
Intracerebral Hemorrhage
What is being tested?
Deferoxamine and Normal saline
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
42 participants
Where
29 sitesin 2 countries
Study dates
18 Mar 2013to 10 May 2018
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 80 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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 can 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.

Who cannot join

  • 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
Show all 20Show fewer
  • 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 low-molecular-weight heparin
  • 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
  • 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
  • Positive drug screen for cocaine upon presentation
  • 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 comorbid conditions
  • Concurrent participation in another research protocol for investigation of another experimental therapy
  • Indication that a new Do Not Resuscitate (DNR) or Comfort Measures Only (CMO) order will be implemented within the first 72 hours of hospitalization.

Trial locations and contacts

29 sites in 2 countries.

29 sites in 2 countries

United States25 sites
  • University of Maryland Medical Center

    Baltimore, Maryland, 21201

  • Johns Hopkins Hospital

    Baltimore, Maryland, 21287

  • Tufts Medical Center

    Boston, Massachusetts, 02111

  • Massachusetts General Hospital

    Boston, Massachusetts, 02114

  • Beth Israel Deaconess Medical Center

    Boston, Massachusetts, 02215

  • University of North Carolina Medical Center

    Chapel Hill, North Carolina, 27514

  • Medical University of South Carolina

    Charleston, South Carolina, 29425

  • University of Virginia Health System

    Charlottesville, Virginia, 22908

  • The Cleveland Clinic Foundation

    Cleveland, Ohio, 44195

  • The Ohio State University Medical Center

    Columbus, Ohio, 43210

  • Henry Ford Hospital

    Detroit, Michigan, 48202

  • Duke University Hospital

    Durham, North Carolina, 27705

  • Hartford Hospital

    Hartford, Connecticut, 06107

  • The University of Texas Health Science Center

    Houston, Texas, 77030

  • University of Iowa Hospital

    Iowa City, Iowa, 52242

  • The University of Florida College of Medicine

    Jacksonville, Florida, 32209

  • Yale New Haven Hospital

    New Haven, Connecticut, 06510

  • Stanford University Hospital

    Palo Alto, California, 94304

  • University of Pennsylvania Medical Center

    Philadelphia, Pennsylvania, 19104

  • St. Joseph's Hospital

    Phoenix, Arizona, 85013

  • Oregon Health & Science University

    Portland, Oregon, 97239

  • Rhode Island Hospital

    Providence, Rhode Island, 02903

  • San Francisco General Hospital

    San Francisco, California, 94110

  • Harborview Medical Center

    Seattle, Washington, 98104

  • University of Massachusetts Memorial Medical Center

    Worcester, Massachusetts, 01655

Other trials in United States

Canada4 sites
  • Foothills Medical Center

    Calgary, Alberta, T2N 2T9

  • Mackenzie Health Sciences Centre

    Edmonton, Alberta, T6G 2B7

  • Halifax Infirmary

    Halifax, Nova Scotia, B3H 3A7

  • Hôpital de l'Enfant-Jésus - CHU de Québec

    Québec, G1J 1Z4

Other trials in Canada

About this study

Official title: 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.

Read the 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).

Being tested
Deferoxamine, Normal saline
Keywords
Brain hemorrhage, Cerebral Hemorrhage, Deferoxamine, Hi-DEF Trial
Medical subject headings
Cerebral Hemorrhage, Intracranial Hemorrhages

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DeferoxamineDrug

    Also called Deferoxamine Mesylate

    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.

  • Normal salineDrug

    Also called 0.90% Sodium Chloride Solution

    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.

Study groups in NCT01662895
Study groupRoleWhat they receive
DeferoxamineActive comparatorDeferoxamine 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.
Receives: Drug: Deferoxamine
Normal SalinePlacebo comparator0.9% sodium chloride
Receives: Drug: Normal saline

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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).

    Measured: 90 days

Secondary outcomes (1)
  1. 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

    Measured: 90 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted13 Aug 2012 (estimated)
  2. Study start18 Mar 2013
  3. Primary completion15 Jan 2014
  4. Study completion10 May 2018

Why it stopped: By DSMB on October 18, 2013 due to increased incidence of ARDS. See modified protocol \[NCT02175225

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
42 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01662895
Sponsor's protocol ID
2012P-000005
Other IDs
U01NS074425
Acronym
HI-DEF
Status last verified
May 2019
First submitted
30 Jul 2012
Last updated
12 Jun 2019
Data monitoring committee
Yes

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.

    PubMed 19064798
  • 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.

    PubMed 21868742
  • 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.

    PubMed 19372448
  • 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.

    PubMed 19286595
  • Roh DJ, Poyraz FC, Mao E, Shen Q, Kansara V, Cottarelli A, Song S, Nemkov T, Kumar A, Hudson KE, Ghoshal S, Park S, Agarwal S, Connolly ES, Claassen J, Kreuziger LB, Hod E, Yeatts S, Foster LD, Selim M. Anemia From Inflammation After Intracerebral Hemorrhage and Relationships With Outcome. J Am Heart Assoc. 2024 Jul 16;13(14):e035524. doi: 10.1161/JAHA.124.035524. Epub 2024 Jul 9.

    PubMed 38979830
  • 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.

    PubMed 23943316

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Deferoxamine and Normal saline in people with Intracerebral Hemorrhage, run by Beth Israel Deaconess Medical Center at 29 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 12 Jun 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 29 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 30 May 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Subjects With Modified Rankin Scale (mRS) Score 0-2 (time frame: 90 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01662895, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Jun 2019.

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