High-Dose Deferoxamine in Intracerebral Hemorrhage (HI-DEF)

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

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.

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: 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. 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).

Deferoxamine 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.

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.

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.

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).

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 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. 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 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.

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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.