High-Dose Deferoxamine in Intracerebral Hemorrhage
Status: | Suspended |
---|---|
Conditions: | Neurology |
Therapuetic Areas: | Neurology |
Healthy: | No |
Age Range: | 18 - 80 |
Updated: | 1/27/2019 |
Start Date: | March 2013 |
End Date: | June 30, 2019 |
Futility Study of Deferoxamine in Intracerebral Hemorrhage
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.
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.
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.
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.
We found this trial at
26
sites
San Francisco General Hospital San Francisco General Hospital and Trauma Center (SFGH) is an essential...
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Tufts Medical Center Tufts Medical Center is an internationally-respected academic medical center – a teaching...
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Beth Israel Deaconess Medical Center Beth Israel Deaconess Medical Center (BIDMC) is one of the...
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3181 Southwest Sam Jackson Park Road
Portland, Oregon 97239
Portland, Oregon 97239
503 494-8311
Oregon Health and Science University In 1887, the inaugural class of the University of Oregon...
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Rhode Island Hospital Founded in 1863, Rhode Island Hospital in Providence, RI, is a private,...
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Johns Hopkins Hospital Patients are the focus of everything we do at The Johns Hopkins...
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University of Maryland Medical Center Founded in 1823 as the Baltimore Infirmary, the University of...
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171 Ashley Avenue
Charleston, South Carolina 29425
Charleston, South Carolina 29425
843-792-1414
Medical University of South Carolina The Medical University of South Carolina (MUSC) has grown from...
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University of Virginia Health System UVA Health System includes a 604-bed hospital, level I trauma...
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Cleveland Clinic Foundation The Cleveland Clinic (formally known as The Cleveland Clinic Foundation) is a...
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Henry Ford Hospital Founded in 1915 by auto pioneer Henry Ford and now one of...
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The Hartford Hospital Hartford Hospital is the major teaching hospital affiliated with the University of...
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Yale-New Haven Hospital Relying on the skill and expertise of more than 4,500 university and...
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Harborview Medical Center Harborview Medical Center is the only designated Level 1 adult and pediatric...
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