Intracerebral Hemorrhage Deferoxamine Trial - iDEF Ttrial

Intracerebral Hemorrhage Clinical Trial

Official title:

Study of Deferoxamine Mesylate in Intracerebral Hemorrhage

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02175225
• Other study ID #: 2012P000005
• Secondary ID: U01NS074425
• Status: Completed
• Phase: Phase 2
• Start date: October 2014
• Est. completion date: May 30, 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 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 294
• Est. completion date: May 30, 2018
• Est. primary completion date: February 10, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Cerebral Hemorrhage
• Hemorrhage
• Intracerebral Hemorrhage

Intervention

Drug:
• Deferoxamine Mesylate

• Placebo (for Deferoxamine Mesylate)

Locations

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

Sponsors (32)

Lead Sponsor

Collaborator

Beth Israel Deaconess Medical Center

Columbia University, Duke University, Hartford Hospital, Henry Ford Hospital, Hopital de l'Enfant-Jesus, Johns Hopkins University, Loyola University, Massachusetts General Hospital, Medical University of South Carolina, Mount Sinai Hospital, New York, National Institute of Neurological Disorders and Stroke (NINDS), NYU Langone Health, Ohio State University, Oregon Health and Science University, Rhode Island Hospital, Rush University Medical Center, St. Joseph's Hospital and Medical Center, Phoenix, Stanford University, The University of Texas Health Science Center, Houston, University Hospitals Cleveland Medical Center, University of Alberta, University of Calgary, University of California, San Francisco, University of Florida, University of Iowa, University of Massachusetts, Worcester, University of North Carolina, University of Pennsylvania, University of Washington, Weill Medical College of Cornell University, Yale New Haven Health System Center for Healthcare Solutions

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (7)

Hatakeyama T, Okauchi M, Hua Y, Keep RF, Xi G. Deferoxamine reduces neuronal death and hematoma lysis after intracerebral hemorrhage in aged rats. Transl Stroke Res. 2013 Oct;4(5):546-53. doi: 10.1007/s12975-013-0270-5. — View Citation

Okauchi M, Hua Y, Keep RF, Morgenstern LB, Schallert T, Xi G. Deferoxamine treatment for intracerebral hemorrhage in aged rats: therapeutic time window and optimal duration. Stroke. 2010 Feb;41(2):375-82. doi: 10.1161/STROKEAHA.109.569830. Epub 2009 Dec 31. — 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

Sonni S, Lioutas VA, Selim MH. New avenues for treatment of intracranial hemorrhage. Curr Treat Options Cardiovasc Med. 2014 Jan;16(1):277. doi: 10.1007/s11936-013-0277-y. — View Citation

Xie Q, Gu Y, Hua Y, Liu W, Keep RF, Xi G. Deferoxamine attenuates white matter injury in a piglet intracerebral hemorrhage model. Stroke. 2014 Jan;45(1):290-2. doi: 10.1161/STROKEAHA.113.003033. Epub 2013 Oct 30. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Ordinal Distribution of Scores on mRS at Day 90	The overall ordinal distribution of scores on mRS at 90 days in DFO- and placebo-treated subjects will be determined.	90 days
Other	Ordinal Distribution of Scores on mRS at 180 Days	The overall ordinal distribution of scores on mRS at 180 days in DFO- and placebo-treated subjects will be determined.	180 days
Other	Adverse Event of Special Interest: Number of Patients With Allergic Reactions (During Infusion of Study Drug)	Adverse event of special interest: anaphylaxis at any time during the study infusion	during the study infusion
Other	Adverse Event of Special Interest: Number of Patients With Hypotension	Hypotension requiring medical intervention at any time during the study infusion that could not be explained by other causes	during the study infusion
Other	Adverse Event of Special Interest: Number of Patients With New Visual or Auditory Changes	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
Other	Adverse Event of Special Interest: Number of Patients With Respiratory Compromise	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
Other	Number of Patients With Symptomatic Cerebral Edema	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
Primary	Proportion of Patients With Modified Rankin Scale (mRS) Score 0-2 at 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
Primary	Number of Subjects Experiencing Serious Adverse Events	Number of subjects experiencing Serious adverse events at any time from randomization through day 90	90 days
Primary	Number of Subjects With Serious Adverse Events Within 7 Days	Number of Subjects Experiencing Serious Adverse Events within 7 days of randomization	7 days
Secondary	Proportion of Patients With mRS Score 0-3 at 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
Secondary	Proportion of Patients With Modified Rankin Scale (mRS) Score 0-2 at 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
Secondary	Proportion of Patients With Modified Rankin Scale (mRS) Score 0-3 at 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
Secondary	Proportion of Subjects With Good Outcome (mRS 0-2) in the Early vs. Delayed Treatment Time Windows	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