Clinical trial NCT01662895: High-Dose Deferoxamine in Intracerebral Hemorrhage
Official title: Futility Study of Deferoxamine in Intracerebral Hemorrhage
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Intracerebral Hemorrhage
Keywords: Brain hemorrhage
Cerebral Hemorrhage
Deferoxamine
Hi-DEF Trial
Lead sponsor: Beth Israel Deaconess Medical Center
Sponsor class: OTHER
Collaborators: name: Medical University of South Carolina
name: National Institute of Neurological Disorders and Stroke (NINDS)
name: Massachusetts General Hospital
name: Tufts Medical Center
name: University of Massachusetts, Worcester
name: University of Pennsylvania
name: Johns Hopkins University
name: University of Maryland
name: University of Virginia
name: Duke University
name: University of North Carolina
name: University of Florida
name: The Cleveland Clinic
name: Henry Ford Hospital
name: Ohio State University
name: St. Joseph's Hospital and Medical Center, Phoenix
name: University of California, San Francisco
name: Oregon Health and Science University
name: Yale New Haven Hospital
name: University of Iowa
name: Hartford Hospital
name: The University of Texas Health Science Center, Houston
name: Rhode Island Hospital
name: Stanford University
name: University of Washington
name: University of Calgary
name: Hopital de l'Enfant-Jesus
name: University of Alberta
name: Dalhousie University
First posted: 2012-08-13
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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).

Eligibility 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.

Primary outcomes:
measure: Number of Subjects With Modified Rankin Scale (mRS) Score 0-2
timeFrame: 90 days
Secondary outcomes:
measure: Number of Subjects With mRS Score 0-3
timeFrame: 90 days
Other outcomes:
measure: Number of Subjects With Allergic/Anaphylactic Reaction
timeFrame: within 7 days or discharge
measure: Number of Patients With Hypotension
timeFrame: within 7 days or discharge
measure: Number of Patients With New Visual or Auditory Changes
timeFrame: within 7 days or discharge
measure: Number of Patients With Serious Adverse Events
timeFrame: 90 days
measure: Number of Patients Who Died During the 90-day Study Period
timeFrame: 90 days
Locations:
city: Phoenix
country: United States
facility: St. Joseph's Hospital
state: Arizona
city: Palo Alto
country: United States
facility: Stanford University Hospital
state: California
city: San Francisco
country: United States
facility: San Francisco General Hospital
state: California
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: New Haven
country: United States
facility: Yale New Haven Hospital
state: Connecticut
city: Jacksonville
country: United States
facility: The University of Florida College of Medicine
state: Florida
city: Iowa City
country: United States
facility: University of Iowa Hospital
state: Iowa
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Memorial Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Chapel Hill
country: United States
facility: University of North Carolina Medical Center
state: North Carolina
city: Durham
country: United States
facility: Duke University Hospital
state: North Carolina
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Medical Center
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Houston
country: United States
facility: The University of Texas Health Science Center
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
city: Calgary
country: Canada
facility: Foothills Medical Center
state: Alberta
city: Edmonton
country: Canada
facility: Mackenzie Health Sciences Centre
state: Alberta
city: Halifax
country: Canada
facility: Halifax Infirmary
state: Nova Scotia
city: Québec
country: Canada
facility: Hôpital de l'Enfant-Jésus - CHU de Québec
Study officials:
affiliation: Beth Israel Deaconess Medical Center/Harvard Medical School
name: Magdy Selim, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.