Phase IIa Trial of a Selective Glucocorticoid Receptor Antagonist in the Treatment ofVeterans with Posttraumatic Stress Disorder (PTSD)

创伤后应激障碍(PTSD)是一种严重的精神障碍，与显著的发病率和 全球范围内的死亡率。为退伍军人开发有效的药物治疗是一项迫切而未得到满足的需求 患有创伤后应激障碍。创伤后应激障碍的病理生理学与下丘脑-垂体-肾上腺的调节失调有关 (HPA)轴，是潜在的治疗靶点。糖皮质激素受体(GR)拮抗剂已显示 承诺同时治疗创伤后应激障碍和严重抑郁症。糖皮质激素受体拮抗剂，如米非司酮 假设通过阻断外周和中央GR来重新校准HPA轴，并增强中枢 糖皮质激素信号。创伤后应激障碍患者中枢糖皮质激素信号增强和HPA轴正常化 监管可能会限制压力反应系统，如交感神经系统，这些系统 导致临床改善的创伤后应激障碍。最近完成的GR拮抗剂米非司酮的试验 可以调节HPA轴的失调，在4周后在一组患者中显示出临床益处 患有创伤后应激障碍的退伍军人，没有创伤性脑损伤史。米非司酮也能拮抗黄体酮 受体(PR)和具有抗流产作用，限制了其广泛使用的潜力。CORT108297是第二个- 产生糖皮质激素受体拮抗剂，对PR没有亲和力，建议用于IIa期 退伍军人创伤后应激障碍的临床试验。CORT108297已被证明在临床前中枢神经系统模型中具有疗效， 在I期健康志愿者研究中耐受性和安全性良好，使其成为进一步研究的候选药物 发展。因此，目标将是完成CORT108297的IIa阶段概念验证试验，重点是 安全性和耐受性，并获得试点疗效数据，为未来临床试验的设计提供信息。 我们提出了一项两点平行分组、随机、双盲、安慰剂对照的IIa期临床试验来测试 CORT108297-180 mg/d治疗退伍军人创伤后应激障碍症状的疗效和安全性钥匙 结果测量将在基线、第7天、第28天和第56天获得。男性和女性退伍军人之间 符合目前完全综合征PTSD标准的18-69岁的人将被纳入两个站点的试验。这两个人都是 网站将招募44名患有慢性创伤后应激障碍的健康男性和女性退伍军人，他们将被随机(1：1 至a)CORT108297或b)安慰剂(每个部位每种情况n=22)，最终样本量为88 参与者超过26个月的注册窗口。

Posttraumatic stress disorder (PTSD) is a serious psychiatric disorder associated with significant morbidity and mortality worldwide. There is an urgent unmet need to develop effective pharmacologic treatments for Veterans with PTSD. The pathophysiology of PTSD is associated with dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis and represents a potential target for therapy. Glucocorticoid receptor (GR) antagonists have shown promise for treating both PTSD and Major Depression. Glucocorticoid receptor antagonists such as mifepristone are hypothesized to recalibrate the HPA axis through blockade of peripheral and central GR and enhance central glucocorticoid signaling. In PTSD, enhanced central glucocorticoid signaling and normalization of HPA axis regulation could constrain stress responsive systems, such as the sympathetic nervous system, that are disrupted in PTSD leading to clinical improvement. A recently completed trial of mifepristone, a GR antagonist that can modulate dysregulation of the HPA axis, demonstrated clinical benefits at 4 weeks in a sub-group of veterans with PTSD without history of traumatic brain injury. Mifepristone also antagonizes the progesterone receptor (PR) and has abortifacient effects, limiting its potential for widespread use. CORT108297 is a second- generation glucocorticoid receptor antagonist which has no affinity for the PR and is proposed for a Phase IIa clinical trial in veterans with PTSD. CORT108297 has been shown to have efficacy in preclinical CNS models, and was well tolerated and safe in Phase I healthy volunteer studies making it a candidate for further development. Thus, the goal will be to complete a Phase IIa proof of concept trial of CORT108297 to focus on safety and tolerability, and obtain pilot efficacy data to inform the design of future clinical trials. We propose a two-site parallel group, randomized, double-blind, placebo-controlled Phase IIa clinical trial to test the efficacy and safety of CORT108297- 180mg daily for 7 days for PTSD symptoms in Veterans. The key outcome measures will be obtained at baseline, day 7, 28, and day 56. Male and female Veterans between the ages of 18-69 who meet criteria for current full syndrome PTSD will be enrolled in a 2 site trial. Each of the two sites will enroll 44 medically healthy male and female Veterans with chronic PTSD who will be randomized (1:1 to either a) CORT108297 or b) placebo (n=22 per condition per site) resulting in a final sample size of 88 participants over a 26-month enrollment window.