| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Major Depressive Disorder |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10057840 |
| E.1.2 | Term | Major depression |
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| 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 |
| Define profile of neurobiological and psychological response to paroxetine compared to placebo. |
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| E.2.2 | Secondary objectives of the trial |
Evaluate the longitudinal effects of active treatment following placebo treatment.
Quantify differential sensitivity of fMRI (and other biomarkers) to detect antidepressant treatment effects in addition to standard clinical instruments.
Prediction of symptom severity and response to treatment using, for example, structural and functional MRI, EEG at baseline (week 0).
Prediction of symptom severity and response to treatment using, for example, structural and functional MRI, EEG at first dose (week 2).
Prediction of symptom severity and response to treatment using, for example, changes in structural and functional MRI, EEG during placebo phase (week 2 – week 0).
To provide data to explore the relationship between state and/or changes in blood biomarkers and improvement of depressive symptomatology, placebo response, response prediction and patient stratification.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participants must have the ability to comprehend the key components of the consent form.
2. Male or female outpatients aged 18-55, inclusive.
3. A primary diagnosis of MDE associated with MDD, single episode or recurrent, according to DSM-IV-TR (296.2 or296.3), diagnosed through a comprehensive psychiatric evaluation [in conjunction with the Mini International Neuropsychiatric Interview (MINI), Clinician Rated Version 5.0], as assessed by a physician with adequate training in psychiatry (e.g. Postgraduate qualification in psychiatry).
4. Participants must, in the investigator’s opinion based on the participant’s history, have met DSM-IV-TR criteria for their current MDE for at least 8 weeks prior to the Screening Visit.
5. Participants with a Carroll Depression Scale-Revised (CDS-R) self-assessment total score of >= 17 and <=30 and Item 3 of the HAM-D grouping (Suicidal Tendency) <=2 at the Screening Visit.
6. Participants must have a CGI- Severity of Illness score >= 4 at the Screening Visit.
7. Women of childbearing potential must commit to consistent and correct use of an acceptable method of birth control that must be recorded in the source documentation at each visit; GSK acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of a physician, are as follows:
a. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal. For purposes of this study, postmenopausal is defined as one year without menses)
b. Child-bearing potential, has a negative serum pregnancy test result at screen and a negative pregnancy test at baseline (prior to study drug administration), and agrees to one of the following:
• Male partner who is sterile prior to the female participant's entry into the study and is the sole sexual partner for that female participant
• Oral contraceptives (either combined or progestogen only) with double-barrier method of contraception consisting of spermicide with either condom or diaphragm. Women of child-bearing potential using an oral contraceptive in combination with a double-barrier method of contraception are required to continue to use this form of contraception for 6 weeks following discontinuation of study medication
• Double-barrier method of contraception consisting of spermicide with either condom or diaphragm
• IUD with a documented failure rate of less than 1% per year
• Complete abstinence from intercourse for two weeks before exposure to the investigational product, throughout the clinical trial, and for a period after the trial to account for elimination of the drug (minimum of three days, equivalent to five half lives).
• If participants indicate they will remain abstinent during the period described above, they must agree to follow GSK guidelines for the consistent and correct use of an acceptable method of birth control should they become sexually active.
8. Participants must read and write in English at a level sufficient to complete study-related assessments
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| E.4 | Principal exclusion criteria |
1. Participants whose symptoms of the MDE are better accounted for by another diagnosis.
2. Participants with a history of schizophrenia, schizoaffective disorders or bipolar disorder.
3. Participants have a positive urine test at screening for illegal drug use at the discretion of the Investigator, and/or a history of substance abuse or dependence (alcohol or drugs as defined by DSM-IV-TR criteria) within the past 12 months. Participants have positive alcohol breath test at the Screening Visit, although they may be invited to return if it is within the 8 days following first contact. Note – participants must be told to avoid consumption of alcoholic beverages for at least 8 hours prior to their Screening Visit.
4. Participants are currently receiving regularly scheduled psychotherapy (individual or group), plan to initiate psychotherapy during the trial or have received regularly scheduled psychotherapy during the 12 week period prior to the Screening Visit.
5. Participants have previously failed to respond to adequate courses (e.g. maximum labeled dosages for >= 4 weeks) of pharmacotherapy from two different classes of antidepressants or have failed to respond to an adequate course of paroxetine.
6. Participants who, in the investigator's judgment, pose a homicidal or serious suicidal risk, have made a suicide attempt within the 6 months preceding the Screening Visit or who have ever been homicidal.
7. Participants who have received electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS) within the 6 months prior to the Screening Visit.
8. Participants with any history of a seizure disorder (except for febrile seizures in childhood).
9. Participants with an unstable medical disorder; or a disorder that would likely interfere with the action, absorption, distribution, metabolism or excretion of paroxetine, may pose a safety concern; or interfere with the accurate assessment of safety or efficacy.
10. Participants have any screening laboratory value outside of the Sponsor-specified ranges at Screening Visit (see Appendix 3); testing may be repeated once to see if value returns to within range but any such laboratory abnormality must be resolved by the Baseline Visit.
11. Participants have any laboratory abnormality that in the investigator's judgment is considered to be clinically significant and not resolved by the Baseline Visit (even if not outside of Sponsor-specified ranges in Appendix 3).
12. Participants maintained on thyroid medication must be euthyroid for a period of at least six months prior to the Screening Visit.
13. Participants who will likely require the use of the following medications:
a Non-steroidal anti-inflammatory drug. Use of any dose of a non-steroidal anti-inflammatory drug (including aspirin or COX2 inhibitor) is permitted only when administered with an anti-secretory agent (a proton pump inhibitor or histamine-2 receptor antagonist)
b Use of aspirin together with an NSAID including COX2 inhibitor is not permitted.
14. Women who have a positive pregnancy test at the Screening Visit, at the Baseline (Randomization) Visit, or who are lactating or planning to become pregnant within the 4 months following the Screen Visit.
15. Participants who have taken other psychoactive drugs (in particular, pimozide and thioridizine) within two weeks prior to the Baseline Visit or at any time during the Screening period:
a. All antidepressants including SSRI's (with the exception of fluoxetine, which requires four weeks). No participants will be asked to stop any existing antidepressant medication in order to participate in the study.
b. Monoamine Oxidase Inhibitors (MAOIs), benzodiazepines, other psychoactive medications (including psychoactive herbal treatments, e.g., St. John's Wort, SAM-e)
c. Hypnotics, and all other sedatives (including sedating antihistamines if used for their sedating and/or hypnotic properties)
d. Inducers of paroxetine metabolism.
16. Participants who are currently participating in another clinical trial in which the participant is or will be exposed to an investigational or non-investigational drug or device, or has done so within the preceding month for studies unrelated to MDD, or 6 months for studies related to MDD.
17. Participants who have no contact with an adult on a regular basis.
18. Participants who take triptan medications (e.g. sumatriptan, naratriptan, zolmitriptan), the antibiotic linezolid or tryptophan.
19. In the Investigator’s opinion, would be non-compliant with dosing, the visit schedule, or study procedures.
20. Meets exclusion criteria for being scanned by MRI and or cannot tolerate an fMRI scan procedure.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Changes from baseline in brain functional activation measured by fMRI in amygdala and anterior cingulate cortex during implicit processing of negatively valent (sad and fearful) facial expressions produced by the treatments. |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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