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

> **NIH VA I01** · VETERANS AFFAIRS MED CTR SAN FRANCISCO · 2024 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 10812404
- **Project number:** 5I01CX001917-03
- **Recipient organization:** VETERANS AFFAIRS MED CTR SAN FRANCISCO
- **Principal Investigator:** Thomas C Neylan
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812404

## Citation

> US National Institutes of Health, RePORTER application 10812404, Phase IIa Trial of a Selective Glucocorticoid Receptor Antagonist in the Treatment ofVeterans with Posttraumatic Stress Disorder (PTSD) (5I01CX001917-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10812404. Licensed CC0.

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