Double-Blind, Placebo-Controlled, Crossover Study With Roll-over Extension of Two RE03 Doses for PTSD Sleep Disturbances

Post-traumatic stress disorder (PTSD) affects many people who have experienced traumatic events. A common issue with PTSD is severe sleep disturbances, such as nightmares. Current treatments often do not provide sufficient relief, especially for sleep problems. This study aims to determine whether dexmedetomidine - a medication already used in intensive care - can improve sleep quality in PTSD patients and be safely administered both in the sleep lab and in the patient's natural environment.

In the first phase, participants spend three nights in the sleep lab, where they receive either a low dose, a high dose of dexmedetomidine, or a placebo. All participants receive all three options, with only the sequence differing. After two additional nights in the sleep lab, which serve to evaluate the individual safety of at-home administration, the investigational product can then be self-administered for 19 days. For the at-home phase, participants are randomly assigned either the low or high dose of the investigational product (no placebo). In both study phases, participants and the study team are blinded and thus do not know which dose (or placebo) has been assigned.

Eligibility Criteria:
Inclusion Criteria:

* Male or female, aged ≥18 and ≤64 years (inclusive)
* Diagnosis of post-traumatic stress disorder (PTSD) according to the Diagnostic and Statistical Manual of
* Mental Disorders (DSM-5) for more than 6 months
* PTSD diagnosis assessed with Clinician-Administered PTSD Scale for DSM-5 (CAPS-5; life-time version) severity ≥ 2
* Sleep disturbance, e.g., difficulty falling or staying asleep, or restless sleep (Criterion E6 of the DSM-5 criteria for PTSD) is present for at least a month prior to screening and causes clinically significant distress or impairment in social, occupational, or other important areas of functioning
* Sleep disturbance assessed with the Pittsburgh Sleep Quality Index (PSQI); severity ≥ 5
* Ability (verified by investigator) and willingness to provide informed consent as documented by dated signature

Exclusion Criteria:

* Inability to comply with sleep-wake schedule related study requirements, e.g. due to crossing of time zones (≥ 2), extreme chronotypes, shift working within 2 weeks prior to the screening visit, or planned shift work during the study, self-reported usual daytime napping ≥1 hour per day, and ≥3 days per week
* Inability to follow the procedures of the study, e.g. due to insufficient understanding of the German language used in the study as evaluated by the investigator or anticipated problems with overnight stays at the sleep laboratory
* Participation in a clinical research study involving the administration of an investigational or marketed drug or device within 30 days prior to the first dose; administration of a biological product (e.g. vaccines, blood components, gene therapies, tissues, etc.) in the context of a clinical research study within 90 days prior to the first dose; or concomitant participation in an investigational study involving drug or device administration
* Females of childbearing potential who are sexually active with a non-sterile male partner (sterile male partners are defined as men vasectomised at least 6 months prior to the first study drug administration) not willing to use one of the following acceptable contraceptive methods throughout the study and for at least 3 months after the last study drug administration:
* Simultaneous use of condom and hormonal contraceptive (e.g., oral, patch, depot injection, implant, vaginal ring, intrauterine device) or non-hormonal intrauterine device used for at least 4 weeks prior to sexual intercourse for the female partner;
* Females of non-childbearing potential who are neither:
* Post-menopausal (status defined as an absence of menses for at least 12 months prior to the first study drug administration); or
* Surgically sterilized (complete hysterectomy or bilateral oophorectomy at least 3 months prior to the first study drug administration)
* Male participants who are not vasectomised for at least 6 months prior to dosing and who are sexually active with a female partner of childbearing potential not willing to use one of the following acceptable contraceptive methods from the first dose and for 3 months after the last dose:
* Use of condom and/or hormonal contraceptive (e.g., oral, patch, depot injection, implant, vaginal ring, intrauterine device) or non-hormonal intrauterine device used for at least 4 weeks prior to sexual intercourse for the female partner;
* Male participants (including men who have had a vasectomy) with a pregnant partner not willing to use a condom from the first dose and for 3 months after the last dose.
* Male participants not willing to abstain from sperm donation for 3 months after the last dose
* Body Mass Index lower than 17.5 kg/m2 or higher than 35 kg/m2
* History of any clinically significant cardiovascular disorder, including:
* Clinically significant atrioventricular conduction disturbance (e.g. higher-grade atrioventricular block \>grade 1), cardiac arrhythmias, sick sinus syndrome, or accessory bypass tract (e.g. Wolff-Parkinson-White)
* Patients with symptomatic, or pronounced and persistent bradycardia (heart rate \< 50 bpm) assessed during medical screening (during daytime)
* Patients with persistent tachycardia (heart rate \> 100 bpm) assessed during medical screening (during daytime)
* Patients with hypotension systolic blood pressure (sBP) \< 90 mmHg, diastolic blood pressure (dBP) \< 50 mmHg), orthostatic dysregulation or a history of syncopes (e.g. micturition syncope)
* Patients with hypertension ≥ Grade 2 (sBP ≥ 160 mmHg, dBP ≥ 100 mmHg)
* Patients with a trend towards a baseline prolongation of the QT/ heart-rate corrected QT (QTc) interval (men: \>440 ms; women: \>450 ms) at the screening visit, a history of additional risk factors for Torsade de pointes (e.g., heart failure, hypokalemia, hypomagnesemia, family history of Long QT syndrome)
* Patients with history of myocardial infarction or coronary ischemia
* Patients with cerebrovascular disease (e.g. Stroke, Hemorrhage, Transient
* Ischemic Attack, Aneurysm, Arteriovenous Malformation, Venous Thrombosis, Hematoma, etc.)
* Patients with peripheral arterial occlusive disease
* Patients with epilepsy, a history of seizures, or a history of severe head trauma or stroke
* Patients with chronic Obstructive Pulmonary Disease and related conditions which may cause respiratory depression under RE03 treatment
* Patients with any unstable medical condition, significant medical disorder or acute illness/injury (e.g. high fever) which, in the opinion of the Investigator, would jeopardize the safety of the participant, raise doubts about the feasibility of adhering to the trial protocol, or impact the validity of the study results
* Any laboratory test results deemed clinically significant by the Investigator, especially parameters relating to hepatic (Aspartate / Alanine aminotransferase) or renal metabolism / insufficiency (creatinine clearance) or diagnosed thyroid dysfunction (hypothyroidism or hyperthyroidism)
* Suicidality (Colombia-Suicidality Severity Rating Scale (C-SSRS) severity ≥ 4).
* Suicide attempt in the last 12 months
* Sleep-related conditions that may contribute to insomnia symptoms assessed via the Structured Clinical Interview for Sleep Disorders-Revised (SCISD-R) and polysomnography (PSG) screening including:
* Restless Leg Syndrome
* Obstructive Sleep Apnea
* Narcolepsy
* Delayed-Sleep Phase Syndrome
* rapid eye movement (REM) Sleep Behaviour disorder
* Non-rapid eye movement (NREM) Sleep Arousal disorder
* Prior or ongoing bipolar disorder, any psychotic disorder, including schizophrenia, schizophreniform disorder, schizoaffective disorder, brief psychotic disorder (unless substance induced or due to a medical condition), as assessed by a structured clinical interview (Mini International Neuropsychiatrisches Interview (MINI) 7.0.2.)
* Ongoing obsessive-compulsive disorder, or anorexia nervosa as assessed by medical history and a structured clinical interview (MINI 7.0.2.)
* Have a current moderate (not in early remission in the 3 months prior to enrollment; meets 5 of 11 diagnostic criteria per DSM-5) or severe alcohol use disorder within the 12 months prior to enrollment (meets at least 6 of 11 diagnostic criteria per DSM-5, MINI 7.0.2.)
* Current diagnosis of severe Substance-Use disorder (SUD) for nicotine (i.e. inability to refrain from smoking during the night) and cannabis (i.e. inability to refrain from smoking on study days) , and mild SUD for all other substances according to DSM-5 (MINI 7.0.2.)
* Concurrent daily and/or frequent use of any of the following restricted concomitant medications:
* Inability or unwillingness to withdraw sedative medications for the duration of the study, including hypnotics, sedative antidepressants, sedative neuroleptics, antihistamines, dual orexin receptor antagonists (DORAs), agomelatine, melatonin, etc. for a minimum of 5 half-lives plus 1 week for stabilization (or at the discretion of the investigator) until the end of the study
* Unstable Antidepressant treatment initiated less than 3 months prior to screening
* Concomitant use of RE03 with drugs with a risk for QT interval prolongation requires careful monitoring, in case clinically relevant QTc thresholds are exceeded during the trial (male \> 470 ms; female \> 480 ms), patients must be discontinued.
* Participants must not be currently enrolled in a psychological therapy program that involves varying frequency of sessions or different therapists throughout the study duration. Additionally, they should not have started any psychological therapy within 30 days prior to the screening or during the study