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）是一种严重的精神疾病， 全世界的死亡率。迫切需要为退伍军人开发有效的药物治疗 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-肾上腺的失调有关 (HPA)轴，并表示治疗的潜在靶点。糖皮质激素受体（GR）拮抗剂已经显示 治疗创伤后应激障碍和严重抑郁症的承诺。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枢GR重新校准HPA轴，并增强中枢GR。 糖皮质激素信号在PTSD中，增强的中枢糖皮质激素信号传导和HPA轴的正常化 调节可以限制应激反应系统，如交感神经系统， 创伤后应激障碍导致临床改善。最近完成的一项关于GR拮抗剂米非司酮的试验 可以调节HPA轴的失调，在4周时在一个亚组中表现出临床益处， 没有创伤性脑损伤史的创伤后应激障碍退伍军人米非司酮也能拮抗孕酮 受体（PR），并具有流产作用，限制了其广泛使用的潜力。CORT 108297是第二个- 第二代糖皮质激素受体拮抗剂，对PR没有亲和力，建议用于IIa期 在患有创伤后应激障碍的退伍军人中进行的临床试验CORT 108297已显示在临床前CNS模型中具有功效， 在I期健康志愿者研究中耐受性良好且安全，使其成为进一步研究的候选药物。 发展因此，目标将是完成CORT 108297的IIa期概念验证试验， 安全性和耐受性，并获得初步疗效数据，为未来临床试验的设计提供信息。 我们提出了一个两个中心的平行组，随机，双盲，安慰剂对照的IIa期临床试验，以测试 CORT 108297 - 180 mg每日一次，持续7天，治疗退伍军人PTSD症状的有效性和安全性。关键 将在基线、第7、28和56天获得结果测量。男性和女性退伍军人之间 年龄在18-69岁的符合当前完全综合征PTSD标准的人将被纳入2个地点的试验。每两 研究中心将招募44名医学上健康的患有慢性PTSD的男性和女性退伍军人，他们将被随机分配（1：1 a）CORT 108297或B）安慰剂（每个研究中心每种条件n=22），最终样本量为88 参与者在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.