High-Dose Deferoxamine in Intracerebral Hemorrhage (HI-DEF)
Drug: Normal saline
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Futility Study of Deferoxamine in Intracerebral Hemorrhage|
- Proportion of patients with Modified Rankin Scale (mRS) Score 0-2 [ Time Frame: 3 months ] [ Designated as safety issue: No ]The primary outcome measure of efficacy is the modified Rankin Scale (mRS) score, dichotomized to define good functional out-come as mRS 0-2 at 90 days.
- 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.
|Study Start Date:||March 2013|
|Estimated Study Completion Date:||August 2017|
|Estimated Primary Completion Date:||August 2017 (Final data collection date for primary outcome measure)|
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.
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
Placebo Comparator: Normal Saline
0.9% sodium chloride
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
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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:
- 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.
- Exploring the differences between early (≤12h) and late (>12-24h) OTT windows in DFO treatment effect on functional outcome.
- 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.
- 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.
- 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.
- 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.
- 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01662895
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|Principal Investigator:||Magdy Selim, MD, PhD||Beth Israel Deaconess Medical Center/Harvard Medical School|