| 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 | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012378 |
| E.1.2 | Term | Depression |
|
| 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 assess the percentage of responders in both treatment groups, Milnacipran or Venlafaxine administered up to 200 mg/day in flexible doses, during a treatment period of 8 weeks including up-titration, in out patients with Major Depressive Disorder. |
|
| E.2.2 | Secondary objectives of the trial |
- To assess safety in each treatment group.
- To assess pain and anxiety symptoms associated with Major Depressive Disorder. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Out patient, aged 18 years to 70 years
- Male, or female of childbearing potential using a medically accepted and well documented method of contraception (e.g. oral contraceptives, intrauterine devices, patch, contraceptive implant...) during 2 months before the inclusion in the study, documented sterility or postmenopause (one year amenorrhoea)
- Meeting DSM IV-TR criteria for Major Depressive Disorder diagnosed using a structured interview (MINI) moderate or severe, recurrent, unipolar, without psychotic features
- Total score MADRS > or = to 23 at selection and inclusion visits
- Without any clinically relevant abnormalities in clinical examination, laboratory tests and ECG parameters
- Patient having signed the written informed consent |
|
| E.4 | Principal exclusion criteria |
Psychiatric criteria
- Patient at significant suicidal risk as assessed with the MINI 5.0.0 - section C
- Resistance to two well-conducted antidepressant treatments (defined by the lack of response to at least two treatments prescribed at their optimal dose and during at least 4 weeks) for the current episode
- Any history of psychotic episode or disorder
- Any history of bipolar disorder
- Any current panic disorder, agoraphobia, or obsessive compulsive disorder, generalised anxiety disorder or post traumatic stress disorder whose onset preceded the onset of the depressive disorder (diagnosis confirmed with MINI) .
- Current major personality disorder of clinical significance or any other condition that might affect compliance (Cluster A, B and C ex: borderline, paranoid, histrionic, avoidant…)
- History of alcohol and/or drug abuse and/or dependence, except tobacco according to DSM IV-TR criteria in the 12 months preceding inclusion
Somatic criteria
- Severe underlying or ongoing systemic disease that could interfere with the study
- Fibromyalgia or chronic fatigue
- Previous history of generalised or partial seizure
- Organic cerebral disease
- Known closed angle glaucoma
- Cardiovascular disease including recent myocardial infarction, cardiac failure, post stroke, uncontrolled arterial hypertension
- Known cardiac rhythm or conduction disorder
- Hepatic insufficiency
- Known prostatic disorder and/or dysuria
- Renal failure
- Pregnancy or breast-feeding
- Gastrointestinal disorders (due to glucose and galactose malabsorption or lactase deficit) or congenital galactosemia
- History of hemostasis disorders.
Laboratory criteria
- AST/SGOT and ALT/SGPT greater than 1.5 times the upper normal values
- Creatinine > 150 µmol/L or documented creatinine clearence< 60 ml/min
- Positive pregnancy test
- Clinically relevant abnormal values according to the investigator's opinion for the other laboratory parameters
ECG criteria
- QT or QTc greater than the upper limit of the normal range
- Clinically relevant abnormal values according to the investigator's opinion for the other ECG parameters
Treatment related criteria
- Known hypersensitivity or allergy to one of the study treatments
- Non-response to milnacipran or venlafaxine for a previous episode
- Previous treatment with Milnacipran or Venlafaxine for this episode
- Patient involved in any other biomedical research currently or within the past 3 months
- Electroconvulsive therapy in the 3 months preceding inclusion
- Structured psychotherapy initiated within the past 6 weeks
- Treatment with a depot-neuroleptic during the past 12 months
- Chronic use (at least 5 days per week) of benzodiazepines in the past 3 months or initiation within the 3 months prior to D1, at doses strictly superior to 10 mg diazepam/day equivalent.
- Chronic use (at least 5 days per week) of anxiolytics and hypnotics other than
benzodiazepines in the past 3 months
- Chronic use (at least 5 days per week) in the past month of neuroleptic at doses strictly superior to 25 mg per day of levomepromazine or chlorpromazine, or strictly superior to 50 mg per day of alimemazine, or equivalent
- Light therapy
- Treatment within the 7-day period preceding D1 (V2 randomisation visit):
- mood stabilisers (including SAMe, melatonine, DHEA, tryptophan …)
- adrenaline or noradrenaline, dopamine
- digoxin
- clonidine
- linezolide
- 5-HT1D and 5-HT3 agonists
- oral anticoagulants
- ß blockers
- levomepromazine
- treatment within the 14 days before D1: selegiline (B selective MAO inhibitor)
If the patient is already treated by an antidepressant for this episode, this previous treatmentcould be stopped only for lack of efficacy or side effects. In this case, the following wash-out periods preceding inclusion (D1) must be respected :
- a 21-day wash-out period for MAOIs (except RIMAs), fluoxetine,
- a 14-day wash-out period for hypericum,
- a 7-day wash-out period for other non MAOI antidepressants and RIMAs, lithium
Other non-inclusion criteria:
- Is a family member or a work associate (secretary, nurse, technician) of the Investigator,
- Having forfeited his/her freedom of an administrative or legal obligation or being under guardianship. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy criterion:
Decrease of 50.0% or more of the total score of MADRS between inclusion and last visit performed at the end of the treatment period at fixed dose (D56 or visit of premature withdrawal) |
|
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | 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.8.4.1 | Number of sites anticipated in Member State concerned | 40 |
| 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 | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 study is the date of the last visit of the last patient 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 | 16 |
| E.8.9.1 | In the Member State concerned days | |
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