Intracerebral Hemorrhage Deferoxamine Trial - iDEF Ttrial

Phase 2

Completed

Conditions: Intracerebral Hemorrhage

Interventions: Drug: Placebo (for Deferoxamine Mesylate)
Drug: Deferoxamine Mesylate

Registration Number: NCT02175225

Lead Sponsor: Beth Israel Deaconess Medical Center

Brief 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.

Detailed 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 & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 294

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Normal Saline	Placebo (for Deferoxamine Mesylate)	Normal saline (0.9% sodium chloride) given by intravenous infusion for 3 consecutive days
Deferoxamine Mesylate	Deferoxamine Mesylate	Deferoxamine Mesylate (32 mg/kg/day) given by an intravenous infusion for 3 consecutive days

Primary Outcome Measures

Name	Time	Method
Number of Subjects Experiencing Serious Adverse Events	90 days	Number of subjects experiencing Serious adverse events at any time from randomization through day 90
Proportion of Patients With Modified Rankin Scale (mRS) Score 0-2 at 90 Days	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.
Number of Subjects With Serious Adverse Events Within 7 Days	7 days	Number of Subjects Experiencing Serious Adverse Events within 7 days of randomization

Secondary Outcome Measures

Name	Time	Method
Proportion of Patients With mRS Score 0-3 at 90 Days	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.
Proportion of Patients With Modified Rankin Scale (mRS) Score 0-3 at 180 Days	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.
Proportion of Patients With Modified Rankin Scale (mRS) Score 0-2 at 180 Days	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.
Proportion of Subjects With Good Outcome (mRS 0-2) in the Early vs. Delayed Treatment Time Windows	90 days	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.

Trial Locations

Locations (28): Johns Hopkins Hospital
🇺🇸
Baltimore, Maryland, United States
UMass Memorial Medical Center
🇺🇸
Worcester, Massachusetts, United States
RUSH University Medical Center
🇺🇸
Chicago, Illinois, United States
University Hospital Case Medical Center
🇺🇸
Cleveland, Ohio, United States
University of Iowa Medical Center
🇺🇸
Iowa City, Iowa, United States
St. Joseph's Hospital / Barrow Neurological Institute
🇺🇸
Phoenix, Arizona, United States
Stanford University Medical Center
🇺🇸
Palo Alto, California, United States
Henry Ford Hospital
🇺🇸
Detroit, Michigan, United States
Columbia University
🇺🇸
New York, New York, United States
Loyola University Medical Center
🇺🇸
Chicago, Illinois, United States
Beth Israel Deaconess Medical Center
🇺🇸
Boston, Massachusetts, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
San Francisco General Hospital
🇺🇸
San Francisco, California, United States
Weill Medical College of Cornell University
🇺🇸
New York, New York, United States
University of Pennsylvania Medical Center
🇺🇸
Philadelphia, Pennsylvania, United States
Yale New Haven Hospital
🇺🇸
New Haven, Connecticut, United States
Oregon Health & Science University Medical Center
🇺🇸
Portland, Oregon, United States
Mount Sinai Hospital
🇺🇸
New York, New York, United States
The Ohio State University Medical Center
🇺🇸
Columbus, Ohio, United States
Medical University of South Carolina
🇺🇸
Charleston, South Carolina, United States
University of Texas Health Sciences Center
🇺🇸
Houston, Texas, United States
Foothills Hospital - University of Calgary
🇨🇦
Calgary, Alberta, Canada
CHU de Québec - Hôpital de l'Enfant-Jésus
🇨🇦
Québec, Canada
University of Alberta - Mackenzie Health Sciences Centre
🇨🇦
Edmonton, Alberta, Canada
University of North Carolina Medical Center
🇺🇸
Chapel Hill, North Carolina, United States
NYU Langone Medical Center
🇺🇸
New York, New York, United States
University of Florida
🇺🇸
Jacksonville, Florida, United States
Rhode Island Hospital
🇺🇸
Providence, Rhode Island, United States