High-Dose Deferoxamine in Intracerebral Hemorrhage

Intracerebral Hemorrhage Clinical Trial

— HI-DEF  

Official title:

Futility Study of Deferoxamine in Intracerebral Hemorrhage

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01662895
• Other study ID #: 2012P-000005
• Secondary ID: U01NS074425
• Status: Terminated
• Phase: Phase 2
• Start date: March 18, 2013
• Est. completion date: May 10, 2018

Study information

• Verified date: May 2019
• Source: Beth Israel Deaconess Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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.

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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 42
• Est. completion date: May 10, 2018
• Est. primary completion date: January 15, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Cerebral Hemorrhage
• Hemorrhage
• Intracerebral Hemorrhage

Intervention

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.
• 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.

Locations

Country	Name	City	State
Canada	Foothills Medical Center	Calgary	Alberta
Canada	Mackenzie Health Sciences Centre	Edmonton	Alberta
Canada	Halifax Infirmary	Halifax	Nova Scotia
Canada	Hôpital de l'Enfant-Jésus - CHU de Québec	Québec
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	University of North Carolina Medical Center	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia Health System	Charlottesville	Virginia
United States	The Cleveland Clinic Foundation	Cleveland	Ohio
United States	The Ohio State University Medical Center	Columbus	Ohio
United States	Henry Ford Hospital	Detroit	Michigan
United States	Duke University Hospital	Durham	North Carolina
United States	Hartford Hospital	Hartford	Connecticut
United States	The University of Texas Health Science Center	Houston	Texas
United States	University of Iowa Hospital	Iowa City	Iowa
United States	The University of Florida College of Medicine	Jacksonville	Florida
United States	Yale New Haven Hospital	New Haven	Connecticut
United States	Stanford University Hospital	Palo Alto	California
United States	University of Pennsylvania Medical Center	Philadelphia	Pennsylvania
United States	St. Joseph's Hospital	Phoenix	Arizona
United States	Oregon Health & Science University	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	San Francisco General Hospital	San Francisco	California
United States	Harborview Medical Center	Seattle	Washington
United States	University of Massachusetts Memorial Medical Center	Worcester	Massachusetts

Sponsors (30)

Lead Sponsor

Collaborator

Beth Israel Deaconess Medical Center

Dalhousie University, Duke University, Hartford Hospital, Henry Ford Hospital, Hopital de l'Enfant-Jesus, Johns Hopkins University, Massachusetts General Hospital, Medical University of South Carolina, National Institute of Neurological Disorders and Stroke (NINDS), Ohio State University, Oregon Health and Science University, Rhode Island Hospital, St. Joseph's Hospital and Medical Center, Phoenix, Stanford University, The Cleveland Clinic, The University of Texas Health Science Center, Houston, Tufts Medical Center, University of Alberta, University of Calgary, University of California, San Francisco, University of Florida, University of Iowa, University of Maryland, University of Massachusetts, Worcester, University of North Carolina, University of Pennsylvania, University of Virginia, University of Washington, Yale New Haven Hospital

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (4)

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. — View 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. — View 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. — View 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. Review. — View Citation

Outcome

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