Evaluation of Clonidine and Doxazosin for Nightmare Reduction in Posttraumatic Stress Disorder: A Randomized, Placebo-Controlled Feasibility Study

The primary objective of this study is to evaluate whether oral **clonidine** (0.075-0.375 mg) or **doxazosin** (1-10 mg) can reduce nightmares more effectively than a placebo in patients diagnosed with **Posttraumatic Stress Disorder** (PTSD). This is clinically relevant as nightmares are a common and distressing symptom of PTSD, significantly impacting the quality of life and overall mental health of affected individuals.

Secondary objectives include assessing the efficacy of oral clonidine or doxazosin in reducing other PTSD-specific symptoms, improving general sleep parameters, and alleviating depressive symptoms in patients with PTSD. These secondary outcomes are important for understanding the broader therapeutic potential of these medications in managing PTSD-related symptoms beyond nightmares.

The clinical trial focuses on individuals diagnosed with **Posttraumatic Stress Disorder** (PTSD), aiming to assess the efficacy of oral clonidine and doxazosin in reducing nightmares compared to a placebo. The study population includes both male and female participants aged between 18 and 65 years. Participants are required to have a diagnosis of PTSD according to DSM 5, with a CAPS-5 total score of 26 or higher, and experience at least two nightmares per week with a specified intensity. The trial includes individuals who have been on stable pharmacological medication for a minimum of four weeks prior to the study baseline. Participants must provide written informed consent and have the capacity to understand the nature and effects of the medical intervention. Women of child-bearing potential are required to have a negative pregnancy test and all participants must use highly effective contraception. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the efficacy of **clonidine hydrochloride** and **doxazosin** in reducing nightmares in patients with **Posttraumatic Stress Disorder (PTSD)**. This study is a randomized, double-blind, controlled trial, with a primary objective to compare the effects of these medications against a placebo. The trial is expected to span a duration of approximately 44 months, with an estimated end date in February 2026. Participants will be involved in the study for a maximum treatment period of 12 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of PTSD according to DSM-5, a minimum CAPS-5 total score of 26, and the presence of at least two nightmares per week. Following the screening, participants will be randomized to receive either clonidine, doxazosin, or a placebo. The trial includes multiple follow-up visits to monitor the frequency and intensity of nightmares, as well as other PTSD-related symptoms, using validated scales such as the Clinician-Administered PTSD Scale-IV (CAPS-IV) and the Pittsburgh Sleep Quality Index (PSQI).

The primary endpoint is the change in the frequency and intensity of nightmares, measured by the CAPS-IV B2 score from baseline to the end of the treatment period. Secondary endpoints include changes in overall PTSD symptoms, sleep quality, and depression scores, assessed at various visits throughout the trial. Participants will be required to maintain stable pharmacological medication for at least four weeks prior to the study baseline and adhere to highly effective contraception methods if applicable.

Participant involvement may be terminated early if they experience significant adverse effects, fail to comply with study protocols, or withdraw consent. The study aims to provide insights into the therapeutic potential of clonidine and doxazosin for managing nightmares in PTSD, contributing to the development of effective treatment strategies for this condition.

The clinical trial involves the administration of several treatments to evaluate their efficacy in reducing nightmares in patients with **posttraumatic stress disorder**. The experimental medications include **Clonidine** and **Doxazosin**, both administered in tablet form. **Clonidine**, marketed as Clonidin-ratiopharm® 75, is provided in 75 microgram tablets. The active substance is **clonidine hydrochloride**, and the maximum daily dose is 0.37 mg, with a total maximum dose of 22.27 mg over a 12-week period. The route of administration is oral, and the medication is produced by Ratiopharm GmbH.

**Doxazosin** is administered in two formulations. The first is Doxacor® 2 mg tablets, containing the active substance **doxazosin**. The maximum daily dose is 10 mg, with a total maximum dose of 594 mg over a 12-week period. The second formulation is Doxazosin STADA® 1 mg tablets, containing **doxazosin mesilate**. The maximum daily dose for this formulation is 1 mg, with a total maximum dose of 3 mg over a 3-week period. Both formulations are administered orally, with Doxacor® produced by HEXAL AG and Doxazosin STADA® by STADAPHARM GmbH.

The study also includes the use of placebo treatments to serve as a comparator. Placebo 1 is administered during week 1 and consists of capsules colored swedish-orange, containing 320 mg of mannitol (type 60) and 0.5% siliciumdioxid, or 247 mg of standardized capsule filler according to NRF S.38. Placebo 2 is administered from weeks 1 to 11, with similar capsule composition, containing either 320 mg of mannitol and 0.5% siliciumdioxid or 273 mg of standardized capsule filler. Both placebos are designed to match the appearance of the active treatments and are administered orally.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The trial aims to determine the effectiveness of the experimental medications compared to placebo in reducing the frequency and severity of nightmares in the target patient population.

Efficacy in this clinical trial will be assessed primarily through the change in frequency and intensity of nightmares in patients with **posttraumatic stress disorder** (PTSD). The primary efficacy endpoint is the change in the Clinician-Administered PTSD Scale-IV (CAPS-IV) B2 score, which ranges from 0 to 8, from baseline until directly after the last intervention at 10 weeks (Visit 9). A lower score indicates less frequent and/or intense nightmares.

Secondary efficacy endpoints include several measures: changes from baseline in the CAPS-IV B2 score at Visits 2 through 8, changes in the CAPS-5 total score at Visits 7 and 9, and changes in the Pittsburgh Sleep Quality Index-Addendum for PTSD (PSQI A) at the same visits. Additional assessments involve the Montgomery Asberg Depression Inventory (MADRS), the PTSD Checklist for DSM-5 (PCL-5), the Borderline Symptom List 23 (BSL-23), and the Health-Related Quality of Life (EQ-5D) score, all evaluated at Visits 7 and 9. Patient-reported outcomes will be collected using sleep diaries to assess weekly changes in total sleep time, sleep onset latency, night sleep recuperation, time awake at night, number of nightmares, and nightmare intensity from Visit 2 to Visit 9.

Further assessments include the Patient Global Impression of Change (PGIC), the Social and Occupational Functioning Assessment Scale (SOFAS), and the Pittsburgh Sleep Quality Index (PSQI), all measured at Visits 7 and 9. The International Trauma Questionnaire (ITQ) will be used to assess symptoms of PTSD and complex PTSD according to ICD-11 at the same visits. Responder analysis will determine the proportion of patients showing a ≥50% decrease in CAPS-IV B2 score, and remitter analysis will identify patients achieving full remission of nightmares, defined as a CAPS-IV B2 score of 0, both assessed at the end of treatment (Visit 9).