A Study of GW856553X For the Treatment of Depression

An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.

The suicidality assessment throughout the study was made using the STS. The STS is an 8-item checklist, developed from the MINI Tracking, Module C, designed to assess change in suicidality. Individual items are rated on a 5-point scale from 0 (not at all) to 4 (extremely). The total score ranged from 0-32, where 0 indicated absence of symptoms and higher score indicated greater severity of diseases. Each item in the scale started with question of "yes" or "no", where the participants were asked to score themselves if the response was "yes". This assessment was administered by a physician with adequate training in psychiatry. The STS was administered at every Visit.

The assessments were done at Week 0, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6 and Follow-up Visit. The following laboratory parameters of clinical chemistry were analyzed: alkaline phosphatase, alanine transaminase (ALT), aspartate transaminase (AST), bilirubin (total, direct and indirect), total protein, blood urea nitrogen (BUN), albumin, glucose, creatinine, gamma-glutamyl transpeptidase (ϒ-GGT), sodium, potassium, chloride, calcium, phosphate, lactate dehydrogenase (LDH), creatine kinase (CK), C-reactive protein (high sensitivity assay), triglycerides, high-density lipoproteins (HDL), low-density lipoproteins (LDL) and total cholesterol. Randomization value was the value at Week 0 (Day 1). Only those parameters for which at least one abnormal value was reported are summarized.

The assessments were done at Week 0, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6 and Follow-up Visit. The following laboratory parameters of clinical chemistry were analyzed: hemoglobin, hematocrit, red blood cells (RBC), reticulocytes, platelets, total white blood cells (WBC), total neutrophils, lymphocytes, monocytes, eosinophils, basophils, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean cell hemoglobin concentration (MCHC). Randomization value was the value at Week 0 (Day 1). Only those parameters for which at least one abnormal value was reported are summarized.

The assessments were done at Week 0, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6 and Follow-up Visit. The urinalysis parameters of glucose, protein, blood and ketones by dipstick test, RBC, WBC and microscopy (if urine dipstick test was abnormal) for WBC, RBC, hyaline casts, granular casts and cellular casts were assessed. The categories with results of few, moderate, many, 3+, 1-3, few (1-5) and trace is presented. Randomization value was the value at Week 0 (Day 1).

Vital signs assessment included heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP), done whilst the participant was in a sitting position for 5 minutes before each reading. Criteria for vital sign values meeting PCI included: SBP < 85 and > 160 millimeters of mercury (mmHg) and increase or decrease from Baseline >= 20 and >= 40 mmHg; DBP < 45 and > 100 mmHg; HR < 40 and > 110 beats per minute (bpm). Assessments were done at Week 0 (at pre-dose and at 3-4 h post-dose ), Week 1, Week 2 (at pre-dose and at 3-4 h post-dose), Week 3, Week 4 (at post-dose only ), Week 5, Week 6 (at pre-dose and at 3-4 h post-dose) and Follow-up Visit. Randomization value was the value at Week 0 (Day 1). Only those parameters for which at least one value of PCI was reported are summarized.

Full 12-lead ECGs was recorded whilst the participant was in supine position, using an ECG machine that automatically calculated the HR and measured PR, QRS, QT, QTc (b) intervals (Bazett's correction was applied to QTc measurements). The measurement of ECGs were taken at Week 0, Week 2 and Week 6 at pre-dose around 8.00 h and at 12.00-13.00 h, at about 3-4 h post-dose. At Week 4, measurement was taken post-dose only. Randomization value was defined as the assessment done on Day 1 (Week 0). Abnormal ECG findings both not clinically significant (NCS) and clinically significant (CS) is categorized. If the QTc(b) rised above 430 millisecond (msecs) for males and 450 msecs for females during the study, it was considered as abnormal. Other abnormal ranges of PCI included : PR interval <110 and >220 msec; QRS interval <75 and >110 msec; absolute QTc interval >450 and <=499 msec.

The HAMD is an instrument for evaluating severity of symptoms of depression, was completed by the participant. The instrument used in this study was the 17-item version (HAM-D17). The Bech subscale of the HAMD-17 is composed of 6 identified items out of the 17 items rated in HAMD-17 scale. Each item is rated on either a 3-point scale (0 to 2) or a 5-point scale (0 to 4). The following symptoms were rated on a 5-point scale (0-4): depressed mood, low self-esteem (guilt), work and interests, psychomotor retardation, and anxiety (psychic). The following symptom was rated on a 3-point scale (0-2): somatic symptoms (general). Total score ranged from 0 to 22, with 0 indicating absence of symptoms and a higher score indicating greater severity of symptoms. Randomization value was defined as the assessment done on Day 1 (Week 0). Change from randomization was calculated by subtracting the randomization value from the individual post-randomization (Week 1, 2, 3, 4 and 5) values.

The IDS-C is a standardized 30-item, clinician rated scale to assess the severity of a participant's depressive symptoms. The items were rated on a 4-point scale of 0-3, where 0 indicated absence of symptom and higher score indicated greater severity of symptom. In order to calculate the total score of IDS-C, the following procedures were used: either item 11 or 12 were scored; either item 13 or 14 were scored; if both items 11 and 12 (or 13 and 14) were scored, the highest of the items was scored. The total score was obtained by adding the scores of 28 items of the 30 items. Total scores range from 0-84, with a score of 0 indicating no depression and a score of 84 indicating the most severe depression. Randomization value was defined as the assessment done on Day 1 (Week 0). Change from Randomization was calculated by subtracting the Randomization value from the individual post-Randomization (Week 1, 2, 3, 4 and 5) values.

The QIDS-SR16 is a 16-item rating scale of depressive symptoms completed by the participant. The items were rated on a 4-point scale of 0-3, where 0 indicated absence of symptom and higher score indicated greater severity of symptom. The total score was obtained by adding the scores of the items of depressed mood, decreased interest, fatigue, guilt, concentration, suicidal ideation, the highest score on any 1 of the 4 sleep items, the highest score on any 1 appetite/weight item and the highest score on either of the 2 psychomotor items. Total scores range from 0-27, with a score of 0 indicating no depression and a score of 27 indicating the most severe depression. Randomization value was defined as the assessment done on Day 1 (Week 0). Change from Randomization was calculated by subtracting the Randomization value from the individual post-Randomization (Week 2 and 4) values.

HAMD-17 is a standardized, clinician-administered rating scale that assesses 17 items characteristically associated with major depression (symptoms such as depressed mood, work and activities, sleep, suicide, psychomotor agitation/retardation, appetite, sexual interest, anxiety, and somatic symptoms). The items of the HAMD-17 are rated on a scale of 0 to 2 or 0 to 4, and the total score ranges from 0 to 52, where 0 indicates absence of symptom and higher scores indicates more severe symptoms. Randomization value was defined as the assessment done on Day 1 (Week 0). Change from Randomization was calculated by subtracting the Randomization value from the individual post-Randomization (Week 1, 2, 3, 4, 5 and 6) values.

The HAMD is an instrument for evaluating severity of symptoms of depression, was completed by the participant. The Bech subscale of the HAMD-17 is composed of 6 identified items out of the 17 items rated in HAMD-17 scale. Each item is rated on either a 3-point scale (0 to 2) or a 5-point scale (0 to 4). The following symptoms were rated on a 5-point scale (0-4): depressed mood, low self-esteem (guilt), work and interests, psychomotor retardation, and anxiety (psychic). The following symptom was rated on a 3-point scale (0-2): somatic symptoms (general). Total score ranged from 0 to 22, with 0 indicating absence of symptoms and a higher score indicating greater severity of symptoms. Responders were defined as participants with a reduction in total score of >=50% from randomization at Week 6 or study exit. Remitters were defined as participants whose total score was <=4 at Week 6 or study exit. Randomization value was defined as assessment done at Day 1 (Week 0).

The IDS-C is a standardized 30-item, clinician rated scale to assess the severity of a participant's depressive symptoms. The items were rated on a 4-point scale of 0-3, where 0 indicated absence of symptom and higher score indicated greater severity of symptom. In order to calculate the total score of IDS-C, the following procedures were used: either item 11 or 12 were scored; either item 13 or 14 were scored; if both items 11 and 12 (or 13 and 14) were scored, the highest of the items was scored. The total score was obtained by adding the scores of 28 items of the 30 items. Total scores range from 0-84, with a score of 0 indicating no depression and a score of 84 indicating the most severe depression. Responders were defined as participants with a reduction in total score of >=50% from randomization at Week 6 or study exit. Remitters were defined as participants whose total score was <=15 at Week 6 or study exit. Randomization value was defined as assessment done at Day 1 (Week 0).

The QIDS-SR16 is a 16-item rating scale of depressive symptoms completed by the participant. The items were rated on a 4-point scale of 0-3, where 0 indicated absence of symptom and higher score indicated greater severity of symptom. The total score was obtained by adding the scores of the items of depressed mood, decreased interest, fatigue, guilt, concentration, suicidal ideation, the highest score on any 1 of the 4 sleep items, the highest score on any 1 appetite/weight item and the highest score on either of the 2 psychomotor items. Total scores range from 0-27, with a score of 0 indicating no depression and a score of 27 indicating the most severe depression. Responders were defined as participants with a reduction in total score of >=50% from randomization at Week 6 or study exit. Remitters were defined as participants whose total score was <=5 at Week 6 or study exit. Randomization value was defined as assessment done at Day 1 (Week 0).

The IDS-C is a standardized 30-item, clinician rated scale to assess the severity of a participant's depressive symptoms. The Psychomotor Retardation subscale IDS-C is determined by a 5 item subscale of the IDS-C: item 5: mood (sad); item 15: concentration/decision making; item 20: energy/fatigability; item 23: psychomotor slowing; Item30: leaden paralysis/physical energy. The items were rated on a 4-point scale of 0-3, where 0 indicated absence of symptom and higher score indicated greater severity of symptom. The total score was obtained by adding the scores of the 5 items. Total scores range from 0-15, with a score of 0 indicating no depression and higher score indicating more severe depression. Randomization value was defined as the assessment done on Day 1 (Week 0). Change from Randomization was calculated by subtracting the Randomization value from the individual post-Randomization (Week 1, 2, 3, 4, 5 and 6) values.

The QIDS-SR16 is a 16-item rating scale of depressive symptoms completed by the participant. The Psychomotor Retardation subscale QIDS-SR16 is determined by a 4 item subscale of the QIDS-SR16: depressed mood, decision making, energy, psychomotor slowing. The items were rated on a 4-point scale of 0-3, where 0 indicated absence of symptom and higher score indicated greater severity of symptom. Total scores range from 0-12, with a score of 0 indicating no depression and higher score indicating more severe depression. Randomization value was defined as the assessment done on Day 1 (Week 0). Change from Randomization was planned to be calculated by subtracting the Randomization value from the individual post-Randomization (Week 1, 2, 3, 4, 5 and 6) values. Data for this outcome measure was not collected and hence no result summary was produced during analysis.

The IDS-C is a standardized 30-item, clinician rated scale to assess the severity of a participant's depressive symptoms. The Psychomotor Retardation-Psychomotor Slowing item 23 of the IDS-C scale was rated on a 4-point scale of 0-3, where 0 indicated absence of symptom and higher score indicated greater severity of symptom. Randomization value was defined as the assessment done on Day 1 (Week 0). Change from Randomization was calculated by subtracting the Randomization value from the individual post-Randomization (Week 1, 2, 3, 4, 5 and 6) values.

The QIDS-SR16 is a 16-item rating scale of depressive symptoms completed by the participant. The Psychomotor Slowing item 15 of QIDS-SR16 scale was rated on a 4-point scale of 0-3, where 0 indicated absence of symptom and higher score indicated greater severity of symptom. Randomization value was defined as the assessment done on Day 1 (Week 0). Change from Randomization was calculated by subtracting the Randomization value from the individual post-Randomization (Week 2, 4 and 6) values.

The Fatigue question is derived from the Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-F) questionnaire. The Sleepiness question is derived from the epidemiologic questionnaire used to identify Excessive Daytime Sleepiness (EDS) in a general population and in individual suffering from depression. Questions were planned to be asked by the Investigator or designee for fatigue as "Did you feel fatigued or tired during the past 7 days?"; for sleepiness as "In the past 7 days, did you either feel sleepy during the day (but managed to stay awake) or have an irresistible sleep attack during the day, or both?" The questions are scored on a 5-point scale of 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much. The score ranged from 0-5, where 0 indicated absence of symptom and higher score indicated greater severity of symptom. Data for this outcome measure was not collected and hence no result summary was produced during analysis.

Four different VAS (0-100 millimeter, minimum-maximum) for Sleepiness and Fatigue/Tiredness was scored before cytokine sampling at pre-dose, 2 h and 4 h post-dose. VAS score for Sleepiness and Fatigue/Tiredness consist of following: item 1: alert (0=alert, 100=drowsy); item 2: sleepy (0=sleepy, 100=awake); item 3: strong (0=strong, 100=feeble); item 4: most tired ever felt (0=most tired ever felt, 100=less tired ever felt). Fatigue/Tiredness was based on score of item 3 and 4 and sleepiness on score of item 1 and 2. All item scores do not move in same direction. Score for item 1 and 3 ranged from 0-100, where 0=absence of symptom and higher score=greater severity of symptom. Score for item 2 and 4 ranged from 0-100, where 0=most severe symptom and higher score=less severe symptom. Randomization value defined as assessment done on Day 1 (Week 0, pre-dose). Change from Randomization was calculated by subtracting Randomization value from individual post-Randomization (Week 0-6) values.

The IDS-C is a standardized 30-item, clinician rated scale to assess the severity of a participant's depressive symptoms. The Fatigue-Energy item 20 of the IDS-C scale was rated on a 4-point scale of 0-3, where 0 indicated absence of symptom and higher score indicated greater severity of symptom. Randomization value was defined as the assessment done on Day 1 (Week 0). Change from Randomization was calculated by subtracting the Randomization value from the individual post-Randomization (Week 1, 2, 3, 4, 5 and 6) values.

The QIDS-SR16 is a 16-item rating scale of depressive symptoms completed by the participant. The Energy/Fatigue item 14 of the QIDS-SR16 scale was rated on a 4-point scale of 0-3, where 0 indicated absence of symptom and higher score indicated greater severity of symptom. Randomization value was defined as the assessment done on Day 1 (Week 0). Change from Randomization was calculated by subtracting the Randomization value from the individual post-Randomization (Week 2, 4 and 6) values.

The assessments were done at Randomization (Day1, pre-dose, 2 h and 4 h post dose), Week 2 (pre-dose, 2 h and 4 h post-dose) and Week 6 (pre-dose, 2 h and 4 h post-dose). Randomization value was defined as the assessment done on Day 1 (Week 0, pre-dose). Change from Randomization was calculated by subtracting the Randomization value from the individual post-Randomization (Week 0 [2 h and 4 h post dose], Week 2 [pre-dose, 2 h and 4 h post-dose] and Week 6 [pre-dose, 2 h and 4 h post-dose]) values.

The assessments were done at Week 0, Week 2 and Week 6. Serum samples for the assessment were taken at 8:00-9:00 h (before dosing and safety blood/urine sampling), 10:00-11:00 h and 12:00-13:00 h (± 30 minutes). Randomization value was defined as the assessment done on Day 1 (Week 0, pre-dose). Change from Randomization was calculated by subtracting the Randomization value from the individual post-Randomization (Week 0 [2 h and 4 h post-dose], Week 2 [pre-dose, 2 h and 4 h post-dose] and Week 6 [pre-dose, 2 h and 4 h post-dose]) values.

The assessments were done at Week 0, Week 2 and Week 6. Randomization value was defined as the assessment done on Day 1 (Week 0). Change from Randomization was calculated by subtracting the Randomization value from the individual post-Randomization (Week 2 and Week 6) values.

The assessments were done at Week 0, Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6. Randomization value was defined as the assessment done on Day 1 (Week 0). Change from Randomization was calculated by subtracting the Randomization value from the individual post-Randomization (Week 1 to 6) values.

Plasma concentration of GW856553X and of the metabolite GSK198602 was assessed during the treatment period. Blood samples were collected at 8:00 h (before dosing) and 12:00-13:00 h (about 4 h after dosing) at Weeks 2 and 6 of the treatment period.

Plasma concentration of GW856553X and of the metabolite GSK198602 was assessed during the treatment period. Blood samples were collected at 8:00 h (before dosing) and 12:00-13:00 h (about 4 h after dosing) at Weeks 2 and 6 of the treatment period. The first occurrence of the maximum observed plasma concentration was planned to be determined directly from the raw concentration-time data. The data for this outcome measure was not derived due to early termination.

Plasma concentration of GW856553X and of the metabolite GSK198602 was assessed during the treatment period. Blood samples were collected at 8:00 h (before dosing) and 12:00-13:00 h (about 4 h after dosing) at Weeks 2 and 6 of the treatment period. The time at which Cmax observed was planned to be determined directly from the raw concentration-time data. The apparent t1/2 was planned to be obtained as the ratio of ln2/λz, where λz is the terminal phase rate constant estimated by linear regression analysis of the log transformed concentration-time data. The data for this outcome measure was not derived due to early termination.

Blood samples were collected at 8:00 h (before dosing) and 12:00-13:00 h (about 4 h after dosing) at Weeks 2 and 6 of the treatment period. The AUC was planned to be assessed from time zero (pre-dose) extrapolated to infinite time (AUC0-infinity) and from time zero (pre-dose) to last time of quantifiable concentration within a participant across all treatments (AUC0-t). AUC0-t was planned to be determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. The AUC0-infinity was planned to be calculated, where data permitted, as the sum of AUC0-t and Ct/z, where Ct is the observed plasma concentration obtained from the log-linear regression analysis of the last quantifiable time-point and z is the terminal phase rate constant. The data for this outcome measure was not derived due to early termination.