| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Posttraumatic Stress Disorder |
| Posttraumatische Belastungsstörung |
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| E.1.1.1 | Medical condition in easily understood language |
| Posttraumatic Stress Disorder |
| Posttraumatische Belastungsstörung |
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| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To examine whether oral clonidine (0.075-0.375 mg) or doxazosin (1-10 mg) reduces nightmares to a greater extent than placebo in patients with posttraumatic stress disorder. |
| Es sollte untersucht werden, ob orales Clonidin (0,075-0,375 mg) oder Doxazosin (1-10 mg) bei Patienten mit posttraumatischer Belastungsstörung Albträume in einem größeren Ausmaß reduziert als Placebo. |
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| E.2.2 | Secondary objectives of the trial |
| Secondary objectives of the study are to examine the efficacy of oral clonidine or doxazosin in reducing other PTSD-specific symptoms, general sleep parameters and depressive symptoms in patients with posttraumatic stress disorder. |
| Sekundäre Ziele der Studie sind die Untersuchung der Wirksamkeit von oralem Clonidin oder Doxazosin bei der Reduktion anderer PTBS-spezifischer Symptome, allgemeiner Schlafparameter und depressiver Symptome bei Patienten mit posttraumatischer Belastungsstörung. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. neurocognitive testing
For this purpose, the patients are asked to solve test tasks on a computer before taking the test substance for the first time. The test lasts approx. 45 min and is repeated in the last week of stable drug intake (week 10).
2. cell function
Markers for chronic stress and inflammatory reaction are to be measured on the patients' blood cells. For this purpose, 60 ml of blood will be taken by venous blood collection before the first intake of the study medication and in the last week of intake of the study medication (week 10), which corresponds to about 4 tablespoons per blood collection.
3. follow-up survey
A short interview and three questionnaires will be used to assess nightmares, sleep and symptoms of post-traumatic stress disorder 2 weeks after discontinuation of the study drug. The examination will take place during the regular visit 10 in week 12.
4. sexual symptoms
Participants are asked to answer the questionnaire before taking the test substance for the first time and in the last week of intake of the study medication (week 10).
5. virtual reality
Participants are invited to participate in two behavioral testing paradigms in virtual reality. This is done before taking the test substance for the first time.
6. accelerometry
For this, the patients are asked to wear an accelerometer for 5-7 days to measure sleep before taking the test substance and during the intake of test substance in stable dosis. In addition, during these 2 weeks of accelerometry further symptoms of posttraumatic stress disorder and sleep are measured with short computer tasks and three questionnaires.
7. heart rate variability
Heart rate variability is determined with a heart rate monitor (pulse watch) before taking the test drug and while taking it.
8. polysomnography
For this, the patients are asked to spend one night in the sleep laboratory. The polysomnography is performed twice, once before taking the test substance for the first time and the second time during the last 2 weeks of intake of the test substance.
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1. Neurokognitive Testung
Hierzu werden die Patienten gebeten vor erster Einnahme der Prüfsubstanz an einem Computer Testaufgaben zu lösen. Die Testung dauert ca. 45 min und wird in der Letzten Woche der stabilen Medikamenteneinnahme (Woche 10) wiederholt.
2. Zellfunktion
An den Blutzellen der Patienten sollen Marker für chronischen Stress und Entzündungsreaktion gemessen werden. Hierzu werden, vor erster Einnahme der Studienmedikation und in der letzten Woche der Einnahme der Studienmedikation (Woche 10) 60 ml Blut per venöser Blutentnahme entnommen, die entspricht etwa 4 Esslöffel pro Blutentnahme.
3. Nacherhebung
Mittels eines kurzen Interviews und von drei Fragebögen sollen Albträume, Schlaf und Symptome der Posttraumatischen Belastungsstörung 2 Wochen nach Absetzen des Prüfpräparates untersucht werden. Die Untersuchung erfolgt im Rahmen der regulären Visite 10 in Woche 12.
4. Sexuelle Symptome
Die Teilnehmer werden gebeten, einen Fragebogen vor der ersten Einnahme der Testsubstanz und in der letzten Woche der Einnahme der Studienmedikation (Woche 10) zu beantworten.
5. Virtuelle Realität
Die Teilnehmer werden gebeten, an zwei Verhaltensuntersuchungen in der virtuellen Realität (mit Hilfe einer VR-Brille) teilzunehmen. Dies geschieht vor der erstmaligen Einnahme der Testsubstanz.
6. Akzelerometrie
Hierfür werden die Patienten gebeten 5-7 Tage lang einen Akzelerometer (Beschleunigungsmesser an einem Bauchgurt) zu tragen, um den Schlaf vor der Einnahme der Prüfsubstanz und während der Einnahme der Prüfsubstanz (in stabiler Dosis) zu messen. Zusätzlich werden in diesen 2 Wochen der Akzelerometrie weitere Symptome der posttraumatischen Belastungsstörung und des Schlafes mit kurzen Computeraufgaben und drei Fragebögen gemessen.
7. Herzfrequenzvariabilität
Die Herzfrequenzvariabilität wird mit einem Herzfrequenzmessgerät (Pulsuhr) vor und während der Einnahme des Prüfpräparates bestimmt.
8. Polysomnographie
Hierfür werden die Patienten gebeten, zweimalig eine Nacht im Schlaflabor zu verbringen. Die Messzeitpunkte sind einmal vor der erstmaligen Einnahme der Prüfsubstanz und während der letzten 2 Wochen der Einnahme der Prüfsubstanz.
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| E.3 | Principal inclusion criteria |
1. Diagnosis of posttraumatic stress disorder (PTSD) according to DSM 5 with a 20 item CAPS-5 total score ≥ 26
2. At least two nightmares a week, an intensity score ≥ 2, with a CAPS-IV B2 (frequency and intensity for the last week) score ≥ 5
3. Men and women between 18 and 65 years of age
4. Written informed consent
5. The patient has the capacity to give consent (He/she is able to understand the nature and anticipated effects/side effects of the proposed medical intervention)
6. The patient is not breastfeeding
7. Women of child-bearing potential must have a negative urine or serum pregnancy test
8. All participants must use highly effective contraception
9. The patient received stable pharmacological medication for at least 4 weeks or at least five times the value of a elimination half-life prior to study baseline (any changes in medication dose or frequency of therapy must be answered with no)
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| E.4 | Principal exclusion criteria |
1. Disturbances of cardiac impulse formation and conduction, for example sick sinus syndrome or atrioventricular block second and third degree
2. Bradycardia, with a heart rate less than 50 beats per minute
3. Current major depressive episode and a MADRS score > 34
4. The patient does have a known allergy, hypersensitivity or contraindication against clonidine, doxazosin, or other types of quinazolines
5. History of severe orthostatic hypotension
6. Benign prostatic hyperplasia and concomitant congestion of the upper urinary tract, chronic urinary tract infection or bladder stones, hypotension (for benign prostate hyperplasia only)
7. Either overflow bladder or anuria with or without progressive renal insufficiency
8. Planned cataract surgery (risk of 'Intraoperative Floppy Iris Syndrome')
9. Intake of phosphodiesterase-5-inhibitors
10. Intake of methylphenidate
11. Severe hepatic impairment (ASAT or ALAT greater than two times normal)
12. Acute or unstable medical illness
13. Known HIV- and/or active Hepatitis-B- or Hepatitis-C-infection
14. Current or past malignant illness
15. The patient does have clinically significant abnormalities in 12-lead ECG
16. The patient does have clinically significant laboratory abnormalities
17. Epilepsy
18. Dementia
19. Current substance/alcohol use disorder (≤ 3 months)
20. Psychotic disorder
21. Bipolar disorder
22. Current anorexia nervosa
23. Acute suicidality (any suicidal ideation of type of 5 in the C-SSRS in the past month)
24. Intake of alpha adrenergic agents (Clonidine, doxazosin, or others) within 4 weeks prior to baseline (randomization)
25. Trauma-focused psychotherapy four weeks before the trial
26. Initiation of sleep medication 4 weeks prior to baseline
27. The patient is unwilling to consent to saving, processing and propagation of pseudonymized medical data for study reasons
28. Patients, who may be dependent on the sponsor, the investigator or the trial sites
29. The patient is legally detained in an official institution
30. The patient did participated in other interventional trials during the 3 months before and at the time of this trial
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary efficacy endpoint: Change of Frequency and intensity of nightmares, measured with the Clinician-Administered PTSD Scale-IV (CAPS-IV) B2 score for the last week, range 0–8, from baseline until directly after last intervention (10 weeks, visit 9). A lower score indicates less frequent and/or intense nightmares. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Timepoint of evaluation will be done after last Intervention. |
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| E.5.2 | Secondary end point(s) |
1. Change from baseline of the frequency and intensity of nightmares, measured with the Clinician-Administered PTSD Scale-IV (CAPS-IV) B2 score for the last week, range 0–8, at Visit 2 – Visit 8
2. Change from baseline of the CAPS-5 total score (overall PTSD symptoms, last week) at Visit 7 and Visit 9
3. Change from baseline of the Pittsburgh Sleep Quality Index-Addendum for PTSD (PSQI A) (PTSD related sleep symptoms) at Visit 7 and Visit 9
4. Change from baseline of the Montgomery Asberg Depression Inventory (MADRS) at Visit 7 and Visit 9
5. Weekly mean of change from baseline of the patients daily total sleep time (in minutes), sleep onset latency at night (in minutes), recuperation of night sleep (5-point Likert scale, 1 = very much; 5 = not at all), and time awake at night (in minutes), number of nightmares last night (0, 1, 3, 4 or more) and intensity of nightmares (5-point Likert scale, 0 = not at all; 5 = extreme) assessed with sleep diaries during Visit 2 – Visit 9
6. Change from baseline of PTSD symptoms assessed with the PTSD Checklist for DSM-5 (PCL-5) at Visit 7 and Visit 9
7. Change from baseline of the Borderline Symptom List 23 (BSL-23) score at Visit 7 and Visit 9
8. Change from baseline of the Health-Related Quality of Life (EQ-5D) score at Visit 7 and Visit 9
9. Overall patient status measured by the Patient Global Impression of Change (PGIC) at Visit 7 and Visit 9
10. Change from baseline of the Social and Occupational Functioning Assessment Scale (SOFAS) at Visit 7 and Visit 9
11. Change from baseline of the Pittsburgh Sleep Quality Index (PSQI) at Visit 7 and Visit 9
12. Change from baseline of symptoms of PTSD and complex PTSD according to ICD-11 assessed with the International Trauma Questionnaire (ITQ) at Visit 7 and Visit 9
13. Responder analysis: proportion of patients showing improvement in nightmares (change from baseline) defined as decrease of CAPS-IV B2 ≥ 50% assessed at the end of treatment (Visit 9)
14. Remitter analysis: proportion of patients showing full remission of nightmares defined as CAPS-IV B2 = 0, assessed at the end of treatment (Visit 9)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoint of evaluation will be done for secondary endpoint 1 after visit 8 and the others will be evalueted after visit 9. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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