| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment resistant depression |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10057840 |
| E.1.2 | Term | Major 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 |
The primary objective of the study is to evaluate the efficacy of Quetiapine extended release in combination with an SSRI or Venlafaxine versus Lithium in combination with an selective serotonin reuptake inhibitor or Venlafaxine versus Quetiapine extended release monotherapy in subjects with treatment resistant depression as assessed by the changes from randomisation to week 6 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score.
As an independent objective, the primary objective will also be evaluated in two subgroups of patients: (1) patients who were resistant to two previous antidepressant therapies and (2) in the subgroup of patients with one previous failure. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of the study are to compare the effects of the three different treatment regimen as assessed by the following variables and, if applicable, by their changes from randomisation to week 6 (end of study). Additionally the time of onset of therapeutic effect will be assessed by evaluating efficacy data after the first four days (Day 4) of treatment as well as after the first week of treatment (Day 8). These analyses will also be performed in the subgroups of patients with 2 failed previous antidepressants and patients with 1 failure. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of signed written informed consent before initiation of any study related
procedures
2. Male and female patients aged ≥ 18 and ≤ 65 years
3. Documented clinical diagnosis as confirmed by the M.I.N.I. meeting criteria from
the Diagnostic and Statistical Manual of Mental disorders, 4th Edition (DSM-IV) for
any of the following:
− 296.2x Major Depressive Disorder, Single Episode
− 296.3x Major Depressive Disorder, Recurrent
4. Current episode of depression present, at least 42 days prior to enrolment but not
more than 18 months
5. MADRS-Score ≥ 25 at enrolment and randomisation
6. During the current depressive episode history of inadequate response to one or two
of the following antidepressants: citalopram, escitalopram, paroxetine, sertraline, or
venlafaxine with a maximum dose of 225 mg/day before enrolment to the study.
Therefore, patients can be included having failed on one SSRI, Venlafaxine alone,
one SSRI then Venlafaxine, Venlafaxine then one SSRI.
An inadequate response to treatment is defined as being treated with at least
minimum effective dose of an antidepressant according to label for 30 days prior to
study inclusions, and with at least one dose increase when permitted according to
label without achieving remission from depressive symptoms.
7. Treatment resistance Stage I or II according to Thase ME et al., 1997:
Stage I: failure of at least one adequate trial of one major class of antidepressant
Stage II: Stage I resistance plus treatment failure of an adequate trial of an
antidepressant in a distinctly different class from that used in stage I
8. Outpatient or inpatient status at enrolment (except patients admitted for compulsory
treatment). Patients from day hospitals can also be enrolled
9. Female patients of childbearing potential must have a negative serum human
chorionic gonadotropin (hCG) pregnancy test at enrolment and be willing to use a
reliable method of birth control (i.e., barrier method, oral contraceptive, implant,
dermal contraception, long-term injectable contraceptive, intrauterine device, or
tubal ligation) during the study
10. Ability of the patient to understand and comply with the requirements of the study,
as judged by the investigator |
|
| E.4 | Principal exclusion criteria |
1. Patients with a DSM-IV Axis I disorder other than MDD within 6 months of
randomisation
2. Patients with a diagnosis of DSM-IV Axis II disorder which has a major impact on
the patient’s current psychiatric status
3. Patients who, in the investigator’s judgment pose a current serious suicidal or
homicidal risk, or have made a suicide attempt within the past 6 months
4. Substance or alcohol abuse or dependence within 6 months prior to randomisation
(with the exception of caffeine and/or nicotine dependence and/or substance or
alcohol dependence in full remission), as defined in DSM-IV criteria. Patients with
a positive urine toxicology screen (UTS) will be excluded, with the exception of
patients testing positive for cannabinoids or prescribed medications (see Section
7.3.5). Patients can be re-tested if the initial UTS is positive, but should be excluded
if the results are still positive at the second test. Patients with a positive UTS for (a)
drug(s) legally prescribed, must provide evidence of the prescription
5. Patients receiving treatment with a SNRI other than venlafaxine or any other
substance not allowed according to the protocol
6. Patients prescribed venlafaxine at a dose higher than 225 mg/day
7. Concomitant use of any medication or herbal supplement that may induce or inhibit
the hepatic metabolising cytochrome P450 and P3A4 enzymes within 14 days prior
to randomisation, e.g.,
− inducers: barbiturates, carbamazepine, glucocorticoids, phenytoin, rifampin,
rafabutin, thioridazine, and St John’s Wort − inhibitors: ketoconazole (except for topical use), itraconazole, fluconazole,
erythromycin, clarithromycin, fluvoxamine, nefazodone, troleandomycin,
indinavir, nelfinavir, ritonavir, and saquinavir
8. Use of mood stabilisers other than those allowed according to the protocol, other
antipsychotic or psychoactive drugs within 7 days prior to randomisation. The use
of MAO inhibitors, anxiolytic drugs or hypnotics (except medications specified in
Table 4) within 14 days before randomisation, or the use of an antipsychotic depot
injection within two dosing intervals prior to randomisation
9. Patients who in the investigators opinion will require psychotherapy (other than
supportive psychotherapy) during the study period. Psychotherapy initiated more
than 90 days prior to randomisation is allowed
10. Pregnant or breast-feeding women
11. Low sodium diet
12. Psoriasis
13. Use of diuretic medication (thiazides, potassium-sparing diuretics, osmotic
diuretics, and carbonic anhydrase inhibitors), ACE inhibitors, cyclooxygenase II
inhibitors, angiotensin receptor II antagonists, calcium-blocking agents,
methyldopa, theophylline, pentoxifylline, xanthinol nicotinate, non-steroidal antiflammatory
drugs, non-steroidal antirheumatic agents, triptans, metronidazole,
tetracyclines and alkalescent substances
14. Evidence of clinically relevant diseases, e.g., renal or hepatic impairment,
significant coronary artery disease, cerebrovascular disease, viral hepatitis B or C,
acquired immunodeficiency syndrome (AIDS)
15. Any unstable clinical finding (e.g., hypertension, poorly controlled diabetes,
unstable angina) or finding that in the investigator’s opinion, would negatively be
affected by the study medication or affect the efficacy or tolerability of the study
medication
16. Conditions that could affect absorption and metabolism of study medication (e.g.,
malabsorption syndrome, liver disease)
17. A current diagnosis of cancer (except basal or squamous cell skin carcinoma),
unless in remission for the past 5 years
18. Bronchial asthma or other diseases which cause significant airway hypersensitivity
19. Current or past diagnosis of stroke or transient ischemic attacks (TIA)
20. History of seizure disorders, except febrile convulsions
21. Electroconvulsive therapy (ECT) 90 days prior to randomisation
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable is the change in depressive symptoms between randomisation and week 6 as measured by the MADRS. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 50 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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