Randomized Controlled Trial Evaluating Mifepristone for Amelioration of Treatment-Resistant Post-Traumatic Stress Disorder Symptoms

The primary objective of the study is to evaluate the efficacy of **mifepristone** (7-day, 1200 mg/day) compared to placebo in reducing symptom severity in patients with treatment-resistant **Post-Traumatic Stress Disorder (PTSD)**. This is assessed using the Clinician Administered PTSD Scale (CAPS-5) in a randomized controlled trial. The clinical relevance of this objective lies in addressing the unmet need for effective treatments in individuals with PTSD who do not respond to standard therapies, potentially offering a novel therapeutic approach through glucocorticoid receptor antagonism.

The clinical trial focuses on individuals diagnosed with **post-traumatic stress disorder (PTSD)**, specifically those with treatment-resistant PTSD. The study population includes both male and female participants aged 18 years and older, who are proficient in the Dutch language and capable of providing written consent. Participants must have a DSM-5 diagnosis of PTSD, confirmed through a clinical interview using the Clinician Administered PTSD Scale (CAPS-5), and must have a CAPS-5 score of 30 or higher, indicating treatment resistance. This resistance is characterized by nonresponse to at least two evidence-based PTSD treatments, one of which must be a full course of trauma-focused psychotherapy. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of **mifepristone** in reducing symptom severity in patients with treatment-resistant **post-traumatic stress disorder (PTSD)**. This is a **randomized, controlled trial** involving a double-blind methodology to ensure unbiased results. Participants will be randomly assigned to receive either mifepristone or a placebo, with the active treatment group receiving a daily dose of 1200 mg of mifepristone for a period of seven days. The placebo tablets are matched to the mifepristone tablets in shape, smell, and color to maintain blinding. The trial is expected to commence recruitment on June 3, 2024, and conclude by February 1, 2026.

The study will include several key visits: an initial screening visit, multiple follow-up visits, and an end-of-study visit. During the **screening visit**, eligibility will be confirmed based on criteria such as age, language proficiency, and a confirmed diagnosis of PTSD using the Clinician Administered PTSD Scale (CAPS-5). Participants must also demonstrate treatment resistance, defined by a CAPS-5 score of 30 or higher and nonresponse to two prior evidence-based treatments. Follow-up visits will occur at 1, 4, and 12 weeks post-intervention to assess primary and secondary endpoints, including PTSD symptom severity and other clinical outcomes such as disability, sleep quality, and anxiety levels. The **end-of-study visit** will finalize data collection and ensure participant safety.

Participant involvement is expected to last approximately 12 weeks from the start of the intervention. Conditions that may lead to early termination from the study include adverse reactions to the treatment, withdrawal of consent, or any significant protocol deviations. The primary endpoint is to assess the efficacy of mifepristone in reducing PTSD symptoms four weeks after the intervention, as measured by the CAPS-5. Secondary endpoints include long-term symptom severity and other clinical outcomes evaluated at various intervals throughout the study period.

The clinical trial involves the administration of **MIFEPRISTONE**, a glucocorticoid receptor antagonist, as the experimental medication. Mifepristone is provided in the form of a tablet and is administered orally. The dosage regimen for mifepristone is set at 1200 mg per day, with a maximum total dose of 8400 mg over the course of the treatment. The treatment period is limited to a maximum of 7 days. The administration of mifepristone is monitored to ensure participant compliance with the dosing schedule, which is critical for evaluating its efficacy in reducing symptom severity in patients with treatment-resistant Post Traumatic Stress Disorder (PTSD).

The study also includes a **PLACEBO** as a comparator treatment. The placebo is formulated as a film-coated tablet, designed to match the mifepristone tablets in shape, smell, and color to maintain blinding in the trial. The placebo is administered orally, with a maximum daily dose of 4 units and a total dose of 28 units over a 1-day treatment period. The use of placebo allows for the assessment of mifepristone's efficacy by providing a control group for comparison. Compliance with the placebo administration is similarly monitored to ensure the integrity of the trial results.

Efficacy in this clinical trial will be assessed by evaluating the reduction in **Post Traumatic Stress Disorder (PTSD)** symptom severity. The primary endpoint is the change in PTSD symptom severity, measured using the Clinician Administered PTSD Scale (CAPS-5), four weeks after the start of the intervention. This assessment will determine whether mifepristone, administered at a dosage of 1200 mg per day for seven days, is more effective than a placebo in patients with treatment-resistant PTSD.

Secondary endpoints include several measures: PTSD symptom severity will be evaluated using the weekly version of the PTSD Checklist for DSM-5 (PCL-5) from baseline to 12 weeks post-intervention. Long-term symptom severity will also be assessed with the CAPS-5 at 12 weeks. Additional secondary endpoints include the loss of PTSD diagnosis, defined as a CAPS-5 score of less than 26 and the absence of PTSD criteria, four weeks after the intervention. Treatment response is defined as a minimum decrease of 10 points on both the PCL-5 and CAPS-5 scores, assessed at 1, 4, and 12 weeks post-intervention.

Other clinical outcomes will be measured at 1, 4, and 12 weeks after the intervention, including disability (WHO Disability Schedule 2.0; WHO-DAS II), sleep quality (Insomnia Severity Index; ISI), subjective stress (Perceived Stress Scale; PSS), anxiety symptoms (Beck Anxiety Inventory; BAI), depressive symptoms (Inventory of Depressive Symptomatology-Self Report; IDS-SR), and suicidal ideation and behavior (Columbia-Suicide Severity Rating Scale). These assessments will provide a comprehensive evaluation of the efficacy of mifepristone in improving various aspects of PTSD and related symptoms.