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

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.