A Study to Evaluate Effects on Sleep and Safety of RE03 in PTSD Patients With Sleep Disturbances

Participants fulfilling all of the following inclusion criteria are eligible for the study:

• Male or female, aged ≥18 and ≤64 years (inclusive)
• Diagnosis of PTSD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) for more than 6 months
• PTSD diagnosis assessed with CAPS-5 (life-time) 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 PSQI; severity ≥ 5
• Ability (verified by investigator) and willingness to provide informed consent as documented by dated signature

The presence of any one of the following exclusion criteria will lead to exclusion of the participant:

• 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 AV 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 (sBP < 90 mmHg, 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/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, pulmonary fibrotic disease or generally restrictive 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)
• Patients with abnormal liver function
• Suicidality (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 PSG screening including:
• Restless Leg Syndrome
• Obstructive Sleep Apnea
• Narcolepsy
• Delayed-Sleep Phase Syndrome
• REM Sleep Behaviour disorder
• 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 (QuickSCID-5)
• Ongoing obsessive-compulsive disorder, or anorexia nervosa as assessed by medical history and a structured clinical interview (QuickSCID-5)
• 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, QuickSCID-5)
• 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 (QuickSCID-5)
• 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
• Concomitant use of RE03 with beta-blockers, due to increased risk of bradycardia; currently unstable or recent changes in antihypertensive medication.
• 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