Progesterone in the Treatment of ischemic Stroke

描述（由申请人提供）：迄今为止，缺血性脑卒中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重度创伤性脑损伤（TBI）患者的单中心、随机、双盲试验中，与接受最先进治疗和安慰剂的患者相比，在损伤后静脉注射孕酮（PROG） 3天，可将死亡率降低近60%，并显著改善30天生存率的功能结果。PROG治疗脑卒中的初步数据是有希望的，但在PROG用于脑卒中的临床试验之前，需要更多的动物研究来确定脑卒中和脑外伤之间的剂量反应关系和治疗机会窗口是否存在差异。我们将建立安全性，给药参数，以及对目标类动物的生理和功能结果的影响。然后，我们将申请并获得FDA批准，将PROG用于治疗缺血性中风的临床试验。在目前的建议中，我们将在雌性和雄性大鼠中使用短暂性和永久性脑缺血模型。我们的主要目标是确定PROG在“中年”雄性和雌性大鼠（大约15个月大）中是否有效，它们是中年人群比年轻人群更容易中风的更好的模型。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、双盲的“多实验室试验”。第三，我们将检查损伤和治疗后的长期功能结果，看看PROG的影响是否持久。第四，我们将把我们的治疗参数扩展到中风易感的大鼠，因此我们的中风模型更具有人类危险因素的特征。第五，我们将利用这些数据向FDA申请在人类中风患者中测试PROG的IND。我们相信，U01合作协议的转化研究是我们实验室和我们的合作者提供所需的转化数据的理想方式，以进入PROG作为中风治疗的临床测试。

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.