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

• Proportion of patients with mRS score 0-3 [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  The proportion of DFO- and placebo-treated subjects with mRS 0-3 vs. 4-6 at 3 months.
• Proportion of patients with mRS score 0-2 in early vs. late ICH onset-to-treatment time windows [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  The proportion of DFO- and placebo-treated subjects with mRS 0-2 (and 0-3) in the early (≤12h) vs. late (>12-24h) ICH onset to treatment time windows.
• Frequency of Treatment-related Adverse Events [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  The safety endpoints will include all DFO-related adverse events until day-7 or discharge (whichever is earlier), and DFO-related SAEs and mortality through day-90.

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:

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.
2. Exploring the differences between early (≤12h) and late (>12-24h) OTT windows in DFO treatment effect on functional outcome.
3. Obtaining data on the National Institute of Health Stroke Scale (NIHSS), Montreal Cognitive Assessment (MoCA), and Stroke Impact Scale-16 (SIS-16)to explore the effects of treatment on neurological and cognitive functions.
4. Examining the effects of DFO on relative peri-hematoma edema (PHE) volume progression between baseline and post-treatment CT scans and the residual cavity volume/brain atrophy at 90 days, compared to placebo, as potential markers of DFO biological activity on brain tissue.
5. Exploring whether the effect of DFO on outcome is dependent on initial ICH volume, after adjusting for other prognostic variables, to determine if specific limits for ICH volume should be specified as exclusion/inclusion criteria for future studies.
6. Assessing the incidence of symptomatic cerebral edema (unexplained increase in NIHSS >4 points or decrease in GCS >2 points) during hospitalization, up to day 7 or discharge whichever is earlier.
7. Exploring whether progression of PHE can be a radiological/biological marker of activity which can be correlated with clinical outcomes and treatment effect of DFO.

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.

The HI-DEF study also provides an opportunity to "bank" blood samples from the participants for future innovative research in ICH. We, therefore, plan to collect additional blood samples from the participants in HI-DEF at baseline, before the start of the study drug infusion, and after completion of the last infusion to be stored and analyzed in the future. The exact questions to be asked and tests to be done in the future are not fully identified at this stage. If the efforts to develop deferoxamine as a therapy for ICH are successful, future pharmacogenetic studies may help to define other therapeutic targets and responders vs. non-responders to deferoxamine therapy. We tentatively plan to investigate the relationship between polymorphisms from a panel of genes encoding iron-handling proteins (which includes genes involved in both intra- and extra-cellular iron metabolism, such as ceruloplasmin, haptoglobin, hemopexin, transferrin receptor, ferritin heavy- and light-chain, and heme-oxygenase 1 and 2 genes) and peri-hematoma edema; outcome; and response to deferoxamine therapy.

• 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.
  Other Name: Deferoxamine Mesylate
• Drug: 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.
  Other Name: 0.90% Sodium Chloride Solution

• Active Comparator: Deferoxamine
  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.
  Intervention: Drug: Deferoxamine
• Placebo Comparator: Normal Saline
  0.9% sodium chloride
  Intervention: Drug: Normal saline

• Selim M. Deferoxamine mesylate: a new hope for intracerebral hemorrhage: from bench to clinical trials. Stroke. 2009 Mar;40(3 Suppl):S90-1. Epub 2008 Dec 8. Review.
• 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. Epub 2011 Aug 25.
• 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. Epub 2009 Apr 16.
• 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. Epub 2009 Mar 12.

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 DNR or Comfort Measures Only (CMO) order will be implemented within the first 72 hours of hospitalization.

• Medical University of South Carolina
• National Institute of Neurological Disorders and Stroke (NINDS)
• Massachusetts General Hospital
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