| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Major Depressive Disorder |
| Akute Episode einer depressiven Erkrankung |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10083288 |
| E.1.2 | Term | Clinical depression |
| E.1.2 | System Organ Class | 100000004873 |
|
| 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 |
| The primary objective is to demonstrate superiority of 80 mg/day Silexan once daily vs placebo with respect to the change of the MADRS total score between baseline and week 8 when treating Major Depressive Disorders (MDD) of mild to moderate intensity, regardless of adherence to the treatment regime and under the hypothetical condition that treatments which ease depressive symptoms are not available for patients who discontinue from the randomised treatment. |
| Das primäre Ziel der Studie ist der Überlegenheitsnachweis von Silexan 80 mg/Tag gegenüber Placebo bezüglich der Änderung des MADRS-Gesamtscores zwischen Baseline und Woche 8. |
|
| E.2.2 | Secondary objectives of the trial |
- To investigate the efficacy of Silexan, the response and remission criteria based on the MADRS total score will be analyzed at Week 8
- to investigate the safety of Silexan, the following will be analyzed:
-rate of patients who discontinue the randomized treatment prematurely due to inefficacy or intolerability
- rate of subjects suffering from an adverse event or an adverse drug reaction during the treatment phase or the post treatment exposure phase
- rate of subjects suffering from a serious adverse event or a serious adverse drug reaction during the treatment phase or the post treatment exposure phase
- Changes of laboratory values between screening visit / baseline and end of trial
- Changes of other safety parameters between screening / baseline and end of trial
- rate of subjects with item 10 of MADRS > 0 at any individual visit
- rate of subjects with Beck Scale for Suicide Ideation (BSS)-5-Item Screen total score > 0 at any individual visit |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age of at least 18 years
2. Diagnosis of a major depressive episode according to ICD 10 (single episode: F32.0, 32.1, recurrent episode: F33.0, 33.1) of mild to moderate intensity (a maximum of 2 main- and ≤4 additional symptoms) with a duration of at least two weeks but not longer than one year.
3. MADRS total score for the inclusion in the run-in and into the acute treatment phase: 19 - 34
4. Out-patient treatment by a general or specialized physician.
5. Body weight: BMI between 18 and 35 kg/m2
6. Written informed consent in accordance with the legal requirement.
7. Readiness and ability on the part of the patient to comply with the physician’s instructions and to fill in the self-assessment scales. |
|
| E.4 | Principal exclusion criteria |
1. Participation in a further clinical trial at the same time or in the last 12 weeks before screening
2. Diagnosis of MDD of severe intensity as defined by ICD-10 or rating of the MADRS total score > 34 at baseline visit.
3. Any clinically important psychiatric or neurological diagnoses according to ICD-10, other than study indication, within 6 months before the study such as:
• schizophrenia,
• acute anxiety disorder as primary diagnosis,
• episodes of depression with any characteristics of a psychotic nature, depressive disorders not defined as inclusion criteria, bipolar disorder, cyclothymia, mania
• organic, including symptomatic, mental disorders
• post-traumatic stress disorder
• eating disorders
4. History or evidence of alcohol and/or substance abuse or dependence, particularly of sedatives, hypnotics and anxiolytics.
5. Risk of suicide, or previous suicide attempt or clear display of auto-aggressive behaviour as defined (but not limited to) MADRS item 10
6. Lack of response to any adequate antidepressant therapy in the present episode of depression (adequate means ≥ 150 mg amitriptyline-equivalents per day or SSRI treatment during at least 6 weeks) or lack of response to Sertraline (≥ 50 mg and during at least 6 weeks) in any previous episode. Patients who are already well adjusted to an antidepressant therapy in the present episode may not be enrolled into this study.
7. Any of the following treatments within 30 days before baseline visit:
• Antidepressants
• depot neuroleptics
• MAO inhibitors
• pimozide
• benzodiazepines
• other psychotropic drugs
• intravenous methylene blue
• linezolid.
8. Unacceptability to discontinue or likelihood to need medication during the study that is prohibited as concomitant treatment. The following medication is not allowed during the study:
• any psychotropic drugs including
benzodiazepines, non-benzodiazepines, neuroleptics, tranquilizer, antidepressives, anxiolytics, antiepileptics, antihistaminics, MAO inhibitors, fluoxetine, pimozide, lamotrigine, linezolid, intravenous methylene blue
• long-term prophylactic treatment
• central-acting antihypertensive medication
• digoxin
• xanthine derivatives such as Theophylline
• antiparkinson medication
• phytopharmaceuticals with anxiolytic properties
• muscle relaxants
• analgesics of opiate type
• anaesthetics
• barbiturates
• nootropics
• coumarin derivates
9. Non-medicinal psychiatric treatment during the last two weeks prior to baseline visit and during the course of the study
10. History of hypersensitivity to Lavender preparations or Sertraline and/or known allergies to the IMP, placebo or excipients
11. Any unstable acute medical disorder or clinically relevant hepatic, renal, cardiovascular, respiratory, cerebrovascular, metabolic disorder or progressive diseases as cancer, haematologic diseases or thyroid insufficiency including, epilepsy or a history of seizure disorder or treatment with anticonvulsants for epilepsy or seizures, Parkinson’s disease
12. Any somatic disease that necessitate regular treatment with systemic steroids.
13. Medical history of angle-closure glaucoma or untreated anatomical "narrow angles" in any eye.
14. Medical history of syndrome of inappropriate antidiuretic hormone secretion or hyponatremia in the laboratory analysis at visit 1.
15. Clinically significant abnormality of ECG and/or laboratory value(s).
16. Any abnormal baseline finding considered by the investigator to be indicative of conditions that might affect study results.
17. Positive pregnancy test during visit 1
18. Pregnancy, planning of pregnancy or lactation
19. Patients capable of childbearing if not using adequate contraception these include:
- oral, intravaginal, transdermal combined hormonal contraception
- oral, injectable and implantable progestogen-only hormonal contraception
- intrauterine device
- intrauterine hormone-releasing system
- bilateral tubal occlusion
- vasectomised partner
- sexual abstinence
depending on the gender of the patient the respective contraception applies to their partners during the trial period.
20. Gastrointestinal disorders with uncertain absorption of orally administered drugs.
21. Unable to read, understand and/or complete questionnaires
22. History or suspicion of unreliability, poor cooperation or non-compliance with medical treatment.
Under no circumstances may a patient be enrolled into this study more than once
For more details, please refer to the protocol, chapter 4.4 Exclusion criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the individual difference of the total score of the Montgomery-Asberg-Depression Rating Scale (MADRS total score) between baseline and week 8. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy
Response and remission criteria based on the MADRS total score (comparison of the treatment groups with respect to the rate of patients with (i) at least 50% reduction of the MADRS total score between baseline and Week 8 and (ii) a total score of the MADRS total score of less than 10 points at Week 8).
Changes from baseline in the following outcome variables at week 8:
Single items of the MADRS, Beck depression inventory (BDI-II) total score, Clinical Global Impressions of severity of disorder (CGI Item 1) as an organized global assessment of severity conducted by the investigator, patient health questionnaire (PHQ-9) total score and Sheehan disability (SDS) total score for the documentation of social functioning.
Clinical global impression of change from baseline (CGI Item 2) as an organized global assessment of change from baseline conducted by the investigator at week 8
Safety:
Rate of patients who discontinue the randomized treatment prematurely due to inefficacy or intolerability
Rate of subjects suffering from an adverse event during the treatment phase or the post treatment exposure phase.
Rate of subjects suffering from an adverse drug reaction during the treatment phase or the post treatment exposure phase.
Rate of subjects suffering from a serious adverse event during the treatment phase or the post treatment exposure phase.
Rate of subjects suffering from a serious adverse drug reaction during the treatment phase or the post treatment exposure phase.
Changes of laboratory values between screening visit / baseline and end of trial.
Changes of other safety parameters (vital signs, ECG, physical examinations) between screening / baseline and end of trial
Rate of subjects with item 10 of MADRS > 0 at any individual visit
Rate of subjects with Beck Scale for Suicide Ideation (BSS)-5-Item Screen total score > 0 at any individual visit |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoint to analyze efficacy are week 1, 2, 4, 6 and 8
Safety will be evaluated on week 1, 2, 4, 6, 8 and 9
|
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| 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) | Yes |
| 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 | 40 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| 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
|
| The end of the trial is defined as the date of unblinding before start of statistical analysis due to follow up of patients with queries and adverse events |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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