Futility Study of Deferoxamine in Intracerebral Hemorrhage
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 42
- 试验地点
- 29
- 主要终点
- Number of Subjects With Modified Rankin Scale (mRS) Score 0-2
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Deferoxamine (Drug)
Normal Saline
0.9% sodium chloride
干预措施: Normal saline (Drug)
结局指标
主要结局
Number of Subjects With Modified Rankin Scale (mRS) Score 0-2
时间窗: 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 minimum mRS score is 0 (i.e. no disability). The maximum score is 6 (i.e. dead).
次要结局
- Number of Subjects With mRS Score 0-3(90 days)
研究者
Magdy Selim
Professor of Neurology
Beth Israel Deaconess Medical Center