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

选择性糖皮质激素受体拮抗剂治疗患有创伤后应激障碍 (PTSD) 退伍军人的 IIa 期试验

• 批准号: 10596461
• 负责人: Thomas C Neylan
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10596461
• 关键词: Abortifacient Agents; Adverse event; Affinity; Age; Antidepressive Agents; Antipsychotic Agents; Calibration; Chemistry; Chronic Post Traumatic Stress Disorder; Clinical; Clinical Trials; DSM-V; Data; Development; Dose; Double-Blind Method; Dropout; Drops; Electrocardiogram; Enrollment; FDA approved; Female; Frequencies; Functional disorder; Future; Generations; Glucocorticoid Receptor; Glucocorticoids; Goals; Hematology; Hormones; Hydrocortisone; Hypothalamic structure; Laboratories; Major Depressive Disorder; Measures; Mediating; Medical; Mental Depression; Mental disorders; Mifepristone; Military Personnel; Modeling; Mood stabilizers; Morbidity - disease rate; Outcome Measure; Participant; Patients; Peripheral; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Physical Examination; Pituitary-Adrenal System; Placebo Control; Placebos; Population; Post-Traumatic Stress Disorders; Progesterone; Progesterone Receptors; Quality of life; Randomized; Recording of previous events; Regimen; Regulation; Reporting; Safety; Sample Size; Secondary to; Severities; Signal Transduction; Site; Stress; Subgroup; Suicide; Sympathetic Nervous System; Symptoms; Syndrome; System; Test Result; Testing; Traumatic Brain Injury; Veterans; Woman; World Health Organization; antagonist; combat veteran; design; dexamethasone suppression test; drug testing; efficacy evaluation; efficacy testing; healthy volunteer; hypnotic; improved; indexing; male; military veteran; mortality; pre-clinical; safety testing; screening; sedative; side effect; targeted treatment; trauma exposure; week trial; Abortifacient Agents; Adverse event; Affinity; Age; Antidepressive Agents; Antipsychotic Agents; Calibration; Chemistry; Chronic Post Traumatic Stress Disorder; Clinical; Clinical Trials; DSM-V; Data; Development; Dose; Double-Blind Method; Dropout; Drops; Electrocardiogram; Enrollment; FDA approved; Female; Frequencies; Functional disorder; Future; Generations; Glucocorticoid Receptor; Glucocorticoids; Goals; Hematology; Hormones; Hydrocortisone; Hypothalamic structure; Laboratories; Major Depressive Disorder; Measures; Mediating; Medical; Mental Depression; Mental disorders; Mifepristone; Military Personnel; Modeling; Mood stabilizers; Morbidity - disease rate; Outcome Measure; Participant; Patients; Peripheral; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Physical Examination; Pituitary-Adrenal System; Placebo Control; Placebos; Population; Post-Traumatic Stress Disorders; Progesterone; Progesterone Receptors; Quality of life; Randomized; Recording of previous events; Regimen; Regulation; Reporting; Safety; Sample Size; Secondary to; Severities; Signal Transduction; Site; Stress; Subgroup; Suicide; Sympathetic Nervous System; Symptoms; Syndrome; System; Test Result; Testing; Traumatic Brain Injury; Veterans; Woman; World Health Organization; antagonist; combat veteran; design; dexamethasone suppression test; drug testing; efficacy evaluation; efficacy testing; healthy volunteer; hypnotic; improved; indexing; male; military veteran; mortality; pre-clinical; safety testing; screening; sedative; side effect; targeted treatment; trauma exposure; week trial

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.

创伤后应激障碍（PTSD）是一种严重的精神疾病，与明显的发病率和 全球死亡率。为退伍军人开发有效的药理治疗有迫切需要 与PTSD。 PTSD的病理生理与下丘脑 - 垂体 - 肾上腺的失调有关 （HPA）轴，代表了治疗的潜在靶标。糖皮质激素受体（GR）拮抗剂已显示 有望治疗PTSD和重度抑郁症。糖皮质激素受体拮抗剂，例如米非酮 假设通过外围和中央GR的阻塞重新校准HPA轴，并增强中央 糖皮质激素信号传导。在PTSD中，增强的中央糖皮质激素信号传导和HPA轴的归一化 调节可能会限制压力响应系统，例如交感神经系统， 在PTSD中破坏了临床改善。 GR拮抗剂的最近完成的Mifepristone试验 可以调节HPA轴的失调，在4周的子组中显示出临床益处 具有创伤性脑损伤病史的PTSD的退伍军人。米非酮也拮抗孕酮 受体（PR）具有流拟反的作用，限制了其广泛使用的潜力。 Cort108297是第二 生成糖皮质激素受体拮抗剂，对PR没有亲和力，并提出针对IIA期 具有PTSD的退伍军人的临床试验。 Cort108297已显示在临床前中枢神经系统模型中具有功效， 在I期健康的志愿者研究中，耐受性良好且安全，使其成为进一步的候选者 发展。因此，目标是完成Cort108297的IIA阶段概念验证证明，以关注 安全性和耐受性，并获取试验性数据，以告知未来临床试验的设计。 我们提出了一个两点平行组，随机，双盲，安慰剂对照期IIA临床试验进行测试 Cort108297-每天7天的Cort108297-180mg的功效和安全性在退伍军人中出现PTSD症状。钥匙 结果指标将在基线，第7、28和第56天获得。 符合当前全综合症PTSD标准的18-69岁年龄将参加2个现场试验。两者中的每一个 站点将招募44名具有慢性PTSD的医学健康男性和女性退伍军人（1：1） 到a）cort108297或b）安慰剂（每个位置n = 22），最终样本量为88 参加26个月的入学窗口的参与者。