Progesterone in the Treatment of ischemic Stroke

黄体酮治疗缺血性中风

基本信息

批准号：
8018117
负责人：
DONALD G. STEIN
金额：
$ 64.2万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8018117
关键词：
Acute Adult Animal Model Animals Area Attention Behavior Therapy Behavioral Behavioral Assay Blinded Brain Brain Injuries Cerebral Infarction Cerebral Ischemia Cerebrum Characteristics Clinical Clinical Treatment Clinical Trials Clinical Trials Design Cognitive Cognitive deficits Contracts Data Development Dose Double-Blind Method Empirical Research Evaluation Exclusion Failure Female Future Gender Goals Guidelines Human Hypertension Infarction Injury Ischemia Ischemic Stroke Laboratories Laboratory Finding Lead Lesion Measures Middle Cerebral Artery Occlusion Modeling Motor Neurologic Outcome Outcome Study Patients Pharmaceutical Preparations Pharmacotherapy Phase Physiological Placebos Policies Population Populations at Risk Principal Investigator Progesterone Protocols documentation Public Health Publishing Randomized Rattus Recommendation Recovery Recovery of Function Research Resolution Risk Risk Factors Safety Sex Characteristics Stroke Suggestion Testing Therapeutic Time Translational Research Traumatic Brain Injury U-Series Cooperative Agreements United States National Institutes of Health Work base behavior test clinically relevant comparative efficacy drug development expectation experience functional outcomes improved male meetings middle age mortality motor deficit neurosteroids normotensive pre-clinical programs research clinical testing research study response restoration sex stroke therapy treatment effect

项目摘要

DESCRIPTION (provided by applicant): To date, clinical trials for the treatment of ischemic stroke after it has occurred have been disappointing. However, in a recently completed Phase lla, single-center, randomized, double-blind trial in patients with moderate to severe traumatic brain injury (TBI), progesterone (PROG), given intravenously for three days after injury, reduced mortality by almost 60% and significantly improved functional outcome at 30 days survival compared to patients given state-of-the-art treatment and placebo. Preliminary data with PROG in the treatment of stroke are promising, but before PROG can be tested in a clinical trial for stroke, more animal studies are needed to determine whether dose response relationships and window of treatment opportunity differ between stroke and TBI. We will establish the safety, dosing parameters, and effects on physiological and functional outcomes of PROG in the target class of animal subjects. We will then apply for, and gain, FDA approval to use PROG in a clinical trial for the treatment of ischemic stroke. In the present proposal we will use both transient and permanent cerebral ischemic stroke models in both female and male rats. Our Primary goal will be to determine whether PROG will work effectively in "middle-aged" male and female rats (about 15 months), which are better models of the middle-aged population more at risk for stroke than younger counterparts. Second, we will collaborate with three laboratories known for their animal stroke research to model a randomized, double-blind "multi-laboratory trial" in rats. Third, we will examine long- term functional outcomes after the injury and treatment to see whether PROG's effects are enduring. Fourth, we will extend our treatment parameters to stroke-prone rats, so our stroke models are more characteristic of the risk factors seen in humans. Fifth, we will use these data to apply to the FDA for an IND to test PROG in human stroke patients. We believe the U01 cooperative agreement for translational research is an ideal way for our laboratory and those of our collaborators to provide the translational data needed to move to clinical testing of PROG as a treatment for stroke. RELEVANCE: Stroke remains a major public health problem worldwide. Aside from tPA, of the more than 700 drugs studied, none have proven effective in clinical trial. PROG has been shown to be safe and effective in clinical TBI and we now need to determine whether it can be as effective in the clinical treatment of ischemic stroke. The studies proposed here move us closer to that possibility.

描述（由申请人提供）：迄今为止，缺血性中风发生后治疗的临床试验令人失望。然而，在最近完成的一项针对中度至重度创伤性脑损伤 (TBI) 患者的 IIa 期、单中心、随机、双盲试验中，在受伤后静脉注射黄体酮 (PROG) 三天，可将死亡率降低近 60与接受最先进治疗和安慰剂的患者相比，30 天生存期的功能结果显着改善。 PROG 治疗中风的初步数据很有希望，但在中风临床试验中测试 PROG 之前，需要更多的动物研究来确定中风和 TBI 之间的剂量反应关系和治疗机会窗口是否不同。我们将确定 PROG 在目标动物受试者中的安全性、剂量参数以及对生理和功能结果的影响。然后，我们将申请并获得 FDA 批准，在临床试验中使用 PROG 治疗缺血性中风。在本提案中，我们将在雌性和雄性大鼠中使用短暂性和永久性脑缺血性中风模型。我们的主要目标是确定 PROG 是否能在“中年”雄性和雌性大鼠（约 15 个月）中有效发挥作用，这些模型是比年轻小鼠更容易患中风的中年人群的更好模型。其次，我们将与三个以动物中风研究而闻名的实验室合作，在大鼠身上进行随机、双盲“多实验室试验”模型。第三，我们将检查受伤和治疗后的长期功能结果，看看 PROG 的效果是否持久。第四，我们将把治疗参数扩展到易发生中风的大鼠，因此我们的中风模型更能体现人类危险因素的特征。第五，我们将利用这些数据向 FDA 申请 IND，以在人类中风患者中测试 PROG。我们相信 U01 转化研究合作协议是我们实验室和合作者提供 PROG 治疗中风临床测试所需的转化数据的理想方式。相关性：中风仍然是全球主要的公共卫生问题。除了 tPA 之外，在研究的 700 多种药物中，没有一种药物在临床试验中被证明有效。 PROG 已被证明在临床 TBI 中安全有效，我们现在需要确定它是否可以在缺血性中风的临床治疗中同样有效。这里提出的研究使我们更接近这种可能性。