| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Major Depressive Disorder |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 3.3 |
| E.1.2 | Level | P.T. |
| E.1.2 | Classification code | 10025453 |
|
| 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 demonstrate that agomelatine (25/50 mg) improves rest/activity circadian rhythms faster than sertraline in outpatients suffering from Major Depressive Disorder.
|
|
| E.2.2 | Secondary objectives of the trial |
| To study circadian rhythms’ evolution and to provide additional antidepressant efficacy and safety data on agomelatine in this population. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Selection criteria :
Demographic criteria : male or female out-patients, aged of 18 to 60 years (both inclusive),
Diagnostic criteria :
- Fulfilling DSM-IV-TR criteria for Major Depressive Disorder, single or recurrent episode of moderate or severe intensity:
. With or without melancholic features according to DSM-IV-TR criteria,
. Without seasonal pattern according to DSM-IV-TR criteria,
. Without psychotic features,
. Without post partum onset for the current episode,
. Without catatonic features,
. Current episode > or = 4 weeks,
- Hamilton Depression Rating Scale :
. HAM-D 17 items total score greater than or equal to 22,
. Sum of HAM-D item 5 “Insomnia: middle of the night” + item 6 “Insomnia: early hours of the morning” greater than or equal to 3,
- Requiring an antidepressant treatment,
- Hospital Anxiety Depression Scale : HAD completed by the patient to characterize the anxiety condition and to make sure that depression predominates on anxiety, if any.
- Barratt Impulsiveness Scale : BIS-11 completed by the patient to measure impulsivenes.
- Patient agrees to wear an actimeter and to fill in a sleep-wake diary during the seven continuous weeks, starting at the selection visit.
The safety examination of the patients includes the following tests and will check for the absence of any abnormalities likely to interfere with the study conduct or evaluations:
- prescription of laboratory tests (biochemistry including T3, T4, TSH and pregnancy test, haematology and benzodiazepines tests). Results must be available for the inclusion visit.
- Prescription of a 12-lead ECG. Results and ECG tracing must be available for the inclusion visit.
Inclusion criteria :
- The investigator will check that the selection criteria are still fulfilled, especially “Diagnostic criteria”,
- HAM-D 17-items total score still greater than or equal to 22,
- HAM-D item 3 (suicide) minor than or equal to 2,
- HAM-D decrease (if any) between ASSE and W0 minor than or equal to 20%,
- Sum of HAM-D items 5+6 greater than or equal to 3,
- Sum of items H1+H2+H5+H6+H7+H8+H10+H13 (core of depression + 2 items on sleep 5 and 6) of HAM-D 17-items greater than or equal to 55% of HAM-D 17-items total score, checked by IVRS,
- CGI item 1 “Severity of illness” greater than or equal to 4 (moderately to severely ill). |
|
| E.4 | Principal exclusion criteria |
Demographic and general non-selection criteria :
Women of childbearing potential without effective contraception.
Medical and therapeutic non-selection criteria :
Psychiatric criteria - Other Depressive Disorders :
- All types of depression other than Major Depressive Disorder :
. Bipolar Disorder I and II,
. Double Depression (Major Depressive Disorder superimposed on Dysthymic Disorder according to DSM-IV-TR),
. Chronic Depression (duration of the episode longer than 2 years),
. Schizoaffective Disorder Depressive or Bipolar type,
. Dysthymic Disorder according to DSM-IV criteria (checked by the M.I.N.I.)
- Depression onset within 3 months after a stroke.
- Current depressive episode having not responded to 2 different previous antidepressant treatments of at least 4 weeks at an appropriate dose.
- Previous non responders to sertraline or hypersensitivity to sertraline.
- Previous non responders to agomelatine (for patients having participated in a previous clinical trial).
- Marked suicidal intent and/or known suicidal tendencies for the current episode defined as HAM-D item 3 score > 2 and the investigator's opinion based on the patient’s medical history, previous suicide attempts, quality of social and familial support within the last 6 months.
- Patient treated with ECT (Electro Convulsive Therapy) within the last 3 months before selection or requiring ECT at present (according to investigator’s clinical judgement).
- Insight-oriented (psychoanalysis) and other structured psychotherapy (interpersonal therapy, cognitive behavioural therapy) started within 3 months before inclusion.
- Light-therapy started within 2 weeks before inclusion.
Psychiatric criteria - Other psychiatric conditions according to DSM-IV:
- Anxiety disorders according to DSM-IV criteria (checked by the M.I.N.I.).
. Current Panic Disorder,
. Obsessive Compulsive Disorder,
. Post Traumatic Stress Disorder,
. Acute Stress Disorder.
- Patients with acute or chronic psychosis.
- Patients with antisocial, borderline or histrionic personality disorders according to DSM IV-TR criteria.
- Patients with a severe personality disorder other than antisocial, borderline or histrionic personality disorders and prone to interfere with the evaluation of the study according to the investigator’s judgement.
- Delirium or dementia according to DSM-IV-TR.
Sleep Disorders :
- Known Obstructive Sleep Apnea Syndrome previously diagnosed and not treated.
- Restless legs syndrome.
- Shift workers.
- Transmeridian flight (greater than or equal to 3 time zones) in the past 10 days before inclusion or planned in the first 6 weeks of the study.
Non-inclusion criteria :
- Any clinically relevant abnormality detected during the physical examination or the laboratory tests, and likely to interfere with the conduct of the study or with the evaluations, especially:
. Hepatic failure : gGT or transaminases > than 3 times the upper limit,
. Renal failure : creatinin > 150 mmol/l,
. Positive beta hCG for women,
. Positive drug screening for benzodiazepines.
- Clinically relevant ECG abnormality, according to the investigator’s opinion.
- Treatment with a forbidden drug present at inclusion.
- IVRS refusal, if inclusion criteria not respected. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy criterion:
Faster improvement of rest/activity circadian rhythms of agomelatine compared to sertraline will be demonstrated using relative amplitude (actimetry).
Relative amplitude will be expressed in terms of value at each period.
Secondary efficacy criteria:
- Hamilton Depression Rating scale (HAM-D) 17-item total score,
Analysis on relative amplitude will be interpreted cautiously if a difference between treatment according to HAM-D results is shown.
Criteria issued from :
- Actimetry : other variables.
- Clinical Global Impression scale (CGI).
- Hamilton Anxiety Rating scale (HAM-A).
- Leeds Sleep Evaluation Questionnaire (LSEQ).
- Epworth Sleepiness Scale (ESS).
- Screening of sleep and circadian rhythms disorders (Cirscreen).
- Composite Scale of Morningness (CSM).
- Sleep-wake diary. |
|
| 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 | No |
| 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 | Information not present in EudraCT |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 18 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 18 |
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