Efficacy and Safety of GSK163090 in Subjects with Major Depressive Disorder; NCT00896363

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Male or female between the ages of 18 and 64 years inclusive. (1)

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A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhoea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MIU/ml and estradiol < 40 pg/ml (< 140 pmol/L) is confirmatory]. (Females of hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 8.1.1 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method]. or Childbearing potential and agrees to use one of the contraceptive methods listed in Section 8.1.1 for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until one month post last dose (2)

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Male subjects, if female partner not using an acceptable method of contraception, must agree to use one of the methods listed in Section 8.1.2. This criterion must be followed from the time of the first dose of study medication until one month post-last dose (3)

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BMI within the range of 18.8 - 35.0 kg/m2 (inclusive). (4)

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Capable of giving written consent, which includes compliance with the requirements and restrictions listed in the consent form. (5)

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Subject currently meets the diagnosis for MDD (without psychotic feature), single episode or recurrent, as defined in the DSM-IV-TR, diagnosed with SCID-CT (Structural Clinical Interview for DSM-IV Axis I disorders - Clinical Trials Version) as assessed by a physician with adequate training/psychiatry. *Assessment by a physician with adequate training in psychiatry must include a face-to-face evaluation of the subject, but may be aided by subject evaluation conducted by a healthcare professional with a clinically relevant qualification (e.g., psychiatric nurse of psychologist) and a minimum of two years documented experience assessing patients with MDD (6)

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Subject must, in the investigator's opinion based on clinical history, have met DSM IV-TR criteria for their current major depressive episode for at least 4 weeks but for no greater than 24 months. (7)

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Subject has an independent rater HAMD17 total score >= 24, that is within 10% of the computerised HAMD17 total score, at the baseline assessment. If scores are not within 10% the independent rater or principal investigator, physician from CRS and GSK medical monitor must agree that subject is suitable for inclusion in the study. (8)

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Non-smoker or smokers (< 20 cigarettes per day). (9)

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Subject must read and write at a level sufficient to complete study-related assessments. (10)

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Subject has: Symptoms of the presenting illness which are better accounted for by another diagnosis*; or A current DMS-IV-TR Axis I diagnosis of Dementia; or Antisocial or Borderline Personality or other current DSM-IV-TR Axis II diagnosis that would suggest non-responsiveness to pharmacotherapy or noncompliance with the protocol; or A current (or within six months prior to the Screening visit) diagnosis of anorexia nervosa or bulimia; or A lifetime history of Schizophrenia, Schizoaffective Disorder, or a Bipolar Disorder. *Major depressive disorder should be the condition that precipitates the evaluation (principal diagnosis) and the condition that best accounts for the clinical presentation (primary diagnosis). Secondary diagnoses of other anxiety disorders such as generalized anxiety disorder, post traumatic stress disorder, social anxiety disorder, acute stress disorder, and obsessive-compulsive disorder are permissible. (1)

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Subjects who, in the investigator's judgement, pose a homicidal or serious suicidal risk, have made a suicide attempt within 6 months preceding screening or who have ever been homicidal. (2)

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Subject has initiated psychotherapy within one month prior to the Screening visit. or plans to initiate psychotherapy during the trial. Subjects who present with their current MDD diagnosis despite longer term psychotherapy (i.e., greater than three months prior to to the Screening visit) and who agree to maintain the same therapy schedule during the trial may be included. (3)

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Subject has received vagus nerve stimulation, electroconvulsive therapy, or transcranial magnetic stimulation within the six months prior to the Screening visit. (4)

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Subject has previously failed an adequate therapeutic course of pharmacotherapy for MDD (e.g., for >) 4 weeks) from two different classes of antidepressants. (5)

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Subject has an unstable medical disorder or a disorder that would interfere with the action, absorption, distribution, metabolism, or excretion of GSK1633090 or may pose a safety concern, or interfere with the accurate assessment of safety of efficacy. (6)

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The subject has a past history of drug abuse or dependence according to DSM-IV-RT criteria within the past 12 months or has tested positive for urine drugs of abuse at pre-study screening except as detailed in Section 9.1.1. (7)

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Abuse of alcohol. To determine if a subject is abusing alcohol investigator will consider: average weekly intake of alcohol, score achieved on Alcohol Use Disorders Identification Test (AUDIT -C, Appendix 8) and results from laboratory assessments (in particular any abnormalities to AST:ALT ratio, GGT and MCV). (8)

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The subject has a past history of serotonin syndrome or the the investigator's judgement, a history of clinical significant intolerance of SSRIs. (9)

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Subjects with a history of migraine headaches that respond to treatment with triptan medication. (10)

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The subject has a history of a clinically significant abnormality of the neurological system (including dementia and other cognitive disorders or significant head injury) or any history of seizure (excluding febrile seizure). (11)

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A positive pre-study HIV, Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening. (12)

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The subject is currently participating in another clinical study in which the subject is or will be exposed to an investigational or non-investigational drug or device, or has done so within the preceding moth for studies unrelated to the current illness, or six months for studies related to MDD. (13)

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The subject has a screening ECG with a QTc value of >450msec and or a PR interval outside of range 110 to 220msec or an ECG that is not suitable to QT measurements (e.g. poorly defined termination of the T-wave). (14)

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Any cardiac condition or ECG evidence that the investigator feels max predispose the subject to ischemia or arrhythmia or any ECG abnormality that, in the investigator's judgement, may pose a potential safety concern. (15)

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The subject has a systolic blood pressure (SBP= >= 160mmHg or a diastolic blood pressure (DBP) >= 100 mmHg verified by repeated measurement at the Screening or Randomization visit. (16)

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The subject has any liver function enzyme (ALT, AST, ALP or GGT) elevated > 2 times, or total or direct bilirubin > 1.5 times (unless consistent with presumed or diagnosed Gilbert's disease), above the reference range at pre-study screening that remains elevated with a repeat LFT. (17)

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Subjects who are not euthyroid based on lab results at the screening visit. Subjects maintained to thyroid medication must be euthyroid for a period of at least six months prior to the screen visit. (18)

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Subject has any laboratory abnormality that in the investigator's judgement is considered to be clinically significant and could potentially affect subject safety or study outcome. (19)

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Subject is female and has a positive Human Chorionic Gonadotropin (HCG) pregnancy test a screen visit, a positive urine dipstick test at randomization, or who is lactating or planning to become pregnant within 4 weeks following the last dose of study medication. (20)

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Subject has received depot antipsychotics within the 12 weeks before screening- (21)

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Subject has taken a regular course or other psychoactive drugs within the two weeks prior to the Screening Visit (except as discussed and permitted in Section 9.1.1): All antidepressants including SSRIs (with the exception of fluoxetine, which requires 5 weeks); Long acting benzodiazepines, other psychoactive medications (including psychoactive herbal treatments, e.g. St. John's Wort, SAM-E); Lithium, other mood stabilizers (including anticonvulsants) and oral antipsychotics; Opiates (including tramadol), hypnotics, and all other sedatives (including sedating antihistamines if the are used for sedating and/or hypnotic properties); All of above psychotropic drugs are not allowed for the duration of the study and used as specifies during the follow up period. A subject shall not be withdrawn from his or her current treatmentt regimen for the primary purpose of enrolling into this trial. Note: Zolpidem, Zalepion, and Zopiclone (or other specifies comparable sedative, including short acting benzodiazepines, depending upon local availability) will be permitted as a night-time sleep aid at the recommended dosage during the screening phase but are not permitted within 2 days of the Randomization Visit. The medications will also be permitted during the fist 2 weeks of the Treatment Phase as discussed in Section 9.1.1 but are not permitted the night before any HAMD17 assessments. (22)

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23:Subject has taken other (non-psychoactive) prescription, non-prescription, dietary, or herbal products that are potent or moderate inducers and/or inhibitors of the cytochrome P450 3A4 pathway for 2 weeks (or 5 half-lives, whichever is longer) prior to the Randomization visit. (23:Subject has taken other (non-psychoactive) prescription, non-prescription, dietary, or herbal products that are potent or moderate inducers and/or inhibitors of the cytochrome P450 3A4 pathway for 2 weeks (or 5 half-lives, whichever is longer) prior to the Randomization visit.)

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Subject has taken other (non-psychoactive) prescription, non-prescription, dietary, or herbal products metabolized via the cytochrome P450 3A4 pathway with a narrow therapeutic index within 2 weeks (or 5 half-lives, whichever is longer) prior to the Randomization visit. (24)

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Subject has taken other (non-psychoactive) prescription, non-prescription that are inhibitors or the P-glycoprotein for 2 weeks (or 5 half-lives, whichever is longer) prior to the Randomization visit. (25)

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Use of monoamine oxidase inhibitors (MAOI) and linezolid (antibiotic) for 1 month prior to first dose of study medication. (26)

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History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation. (27)