A Phase 2 interventional study of GW856553 and Placebo in Depressive Disorder, Major, sponsored by GlaxoSmithKline. Completed at 21 sites in 5 countries. Open to participants aged 18 Years to 60 Years. Per ClinicalTrials.gov, last updated 2017-11-14.
Sponsored by GlaxoSmithKline · Phase 2, Interventional, and Treatment
In this randomized, double-blind, multi-centre, placebo controlled, exploratory, adaptive design study, the antidepressant and plasma cytokine lowering effects of the GW856553 will be investigated in adult subjects diagnosed with MDD. Subjects will receive oral doses of GW856553 or placebo for six weeks. Safety, tolerability, pharmacokinetics and pharmacodynamics, defined as biomarkers in blood and clinical symptoms, will be assessed.
The primary endpoint is the change from baseline associated with GW856553 versus placebo at Week 6 in the Bech (6-item HAMD-17) score. Interim analyses of the primary endpoint will be performed throughout the study to potentially adapt the study design by changing the randomization ratio and/ or reducing the total number of subjects to be randomized into the study. Exploratory analyses will be performed by associating changes in cytokine levels and selected clinical symptoms; PK/PD modelling will also be used to identify the most sensitive clinical and biological markers.
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Key Inclusion Criteria:
Key Exclusion Criteria:
GW856553 7.5 mg BID
Drug: GW856553
Matching Placebo BID
Other: Placebo
Wet Granulated, film coated white, 9mm round, biconvex, plain faced tablets, containing 7.5 mg of GW856553
Film coated white, 9mm round, biconvex, plain faced tablets obtained by direct compression.
Change From Randomization (Week 0) Associated With GW856553 Versus Placebo at Week 6 in the Bech (6-item HAMD-17 [Hamilton Depression Rating Scale]) Score.
HAMD-17 has 17 questions. The HAMD-17 Total Score was calculated by summing the individual response scores over the 17 individual components of the interview. The highest possible score was 52, which represented the most severe measure of depression; the lowest possible score was 0, which represented an absence of depression. There were 9 five point questions and 8 three point questions. The responses to the individual questions had values of 0-2 (three points response) or 0-4 (five points response). The BECH scale was extracted from the HAMD-17 and comprises of 6 items out of which 5 are 5 point questions and 1 is 3 point question. The Bech Total Score was calculated by summing the individual response scores and ranged from 0 to 22, with higher scores indicating more severe depression. Week 0 values were considered as Baseline.The change from randomization was analysed using suitable Bayesian mixed-effects model repeated measures (BMMRM) assuming missing at random (MAR).
Time frame: At Week 6
Number of Participants With Adverse Events
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A Serious Adverse Event (SAE) is 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. The AEs row include participants with SAEs.
Time frame: 6 Weeks
Number of Participants With Suicidality as Assessed by the Columbia Suicidality Severity Rating Scale Score
Suicidility was defined as participants with major depressive disorder who experienced worsening of their depression and/or the emergence of suicidal ideation and behavior. Number of partcipants who experienced suicidality were reported. On the Suicidal Ideation scale of the Columbia Suicide-Severity Rating Scale (C-SSRS) participants were scored as "non-suicidal" (00), "wish to be dead" (01), "non-specific active suicidal thoughts" (02), "active suicidal ideation with associated thoughts of methods without intent" (03), "active suicidal ideation with some intent to act on suicidal thoughts without clear plan" (04) and "active suicidal ideation with plan and intent" (05), based on the most severe score (5 being the most severe).Suicidal ideation of type 4 or 5 in the C-SSRS was categorized as suicidility here.
Time frame: Upto Week 6
Number of Participants With Abnormal Haematology and Clinical Chemistry Values
Samples for haematology and clinical chemistry were collected on Weeks 1, 5 and 6. The analyzed haematological parameters were platelet count, red blood cells count, white blood cells count, reticulocyte count, hemoglobin and hematocrit. The analyzed clinical chemistry parameters were urea, creatinine, glucose (fasting), sodium, lactate dehydrogenase (LDH), potassium, chloride, calcium, triglycerides, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase, creatine kinase (CK), total and direct bilirubin, albumin, total protein and total cholesterol. Number of participants with any abnormal haematological or clinical chemistry parametrs are summarized here.
Time frame: Upto Week 6
Number of Participants With Abnormal Vital Signs (Blood Pressure, Heart Rate)
Vital signs including systolic and diastolic blood pressure and heart rate were taken from day 1 upto follow-up visit. Number of participants with abnormal systolic blood pressure, diastolic blood pressure and heart rate values were summarized.
Time frame: Up to follow-up Visit (Day 53)
Number of Participants With Abnormal Electrocardiogram (ECG) Findings
ECG was obtained at Week 2 and Week 6. ECG was recorded using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and Corrected QT (QTc) intervals (Bazett's correction was applied to QTc measurements). Number of participants with abnormal ECG readings are summarized.
Time frame: Up to follow-up Visit (Day 53)
Changes From Randomization (Week 0)in IL-6 and TNF-alpha Associated With GW856553 Versus Placebo at Week 1 and Week 6 in the Morning Plasma Levels
Interlukin-6 (IL-6) and Tumor Necrosis Factor-Alpha (TNF-alpha) from the participants with Major Depressive Disorder (MDD) were evaluated and analyzed using suitable mixed-effects model repeated measures (MMRM). Exploratory analysis on plasma levels of IL-6 and TNF-alpha were performed. Week 0 values were considered as Baseline.The change from Baseline was calculated by subtracting the baseline values from the individual post-randomisation values.
Time frame: Upto Week 6
Change From Randomisation Bech Total Score: Bech Score
HAMD-17 has 17 questions. The BECH scale was extracted from the HAMD-17 and comprises of 6 items out of which 5 are 5 point questions and 1 is 3 point question. The Bech scale was extracted from the HAMD-17 and comprised of 6 items out of which 5 were 5 point questions and 1 was 3 point question. The Bech Total Score was calculated by summing the individual response scores and ranged from 0 to 22, with higher scores indicating more severe depression. Due to the small number of items, missing data was not imputed for the Bech Total Score. If any of the 6 items were missing, the total score was not calculated at that visit. The change from randomization was analysed using suitable Bayesian Mixed-Effects Models for Repeated Measures (BMMRM) assuming missing at random MAR.
Time frame: Up to Follow-up visit (Day 53)
Mean HAMD-17 Total Score
HAMD-17 is Hamilton Depression Rating Scale which has 17 questions. The HAMD-17 Total Score was calculated by summing the individual response scores over the 17 individual components of the interview. The highest possible score was 52, which represented the most severe measure of depression; the lowest possible score was 0, which represented an absence of depression. If not more than 1 response was missing, the total score was caculated as Observed Total Score \* \[1 + (Sum of the Maximum Score of the missing values/Sum of the Maximum Score of the non -missing values)\]. There were 9 five point questions and 8 three point questions. The responses to the individual questions can have values of 0-2 (three points response) or 0-4 (five points response).
Time frame: Up to Follow-up visit (Day 53)
Mean Inventory of Depressive Symptomatology Clinician (IDS-C) Total Score
The 30 item IDS is available in two versions IDS-C and Inventory of Depressive Symptomatology self-rated (IDS-SR). To calculate the total score of IDS, 28 out of the 30 items were scored. Either weight loss or weight gain, appetite loss or appetite gain is scored because only one member of each pair is applicable to any given respondent. The standard total score is obtained by summing the ratings of 28 of the 30 items. Each of the 28 items is scored on a 0 to 3 scale (0 - the absence of pathology; 3 - severe pathology). The total scores range from 0 to 84. If more than one response was missing then the score was calculated using the formula Observed Total Score\*\[1+(Sum of the Maximum Score of the missing values/Sum of the Maximum Score of the non -missing values)\].
Time frame: Up to Follow-up visit (Day 53)
Mean IDS-SR Total Score
The 30 item IDS is available in two versions IDS-SR and IDS-C. To calculate the total score of IDS, 28 out of the 30 items were scored. Either weight loss or weight gain, appetite loss or appetite gain is scored because only one member of each pair is applicable to any given respondent. The standard total score is obtained by summing the ratings of 28 of the 30 items. Each of the 28 items is scored on a 0 to 3 scale (0 - the absence of pathology; 3 - severe pathology). The total scores range from 0 to 84. If more than one response was missing then the score was calculated using the formula Observed Total Score\*\[1+(Sum of the Maximum Score of the missing values/Sum of the Maximum Score of the non -missing values)\].
Time frame: Up to Week 6
Mean Quick Inventory of Depressive Symptomatology Self Report-16 Item (QIDS-SR16) Total Score Derived From the IDS-SR (Only at Weeks 0, 2, 4 and 6)
QIDS-SR assesses symptoms severity of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criterion for major depressive disorder. It contains 16 separate items (corresponding to 16 items of the much longer IDS-SR), defining 9 DSM-IV symptom criterion domains. A total score was obtained by summing scores on each domain. The QIDS-SR total score was calculated by summing over the domain scores. The highest possible score was 27, which represented the most severe measure of depression; the lowest possible score was 0, which represented an absence of depression. Due to the small number of items, missing data was not imputed for the QIDS-SR total score.
Time frame: Weeks 0, 2, 4 and 6
Percentage of IDS-C Responders (Participants With a Reduction in Total Score of ≥50% From Randomization at Week 6/Study Exit).
The 30 item IDS is available in two versions IDS-C and IDS-SR. To calculate the total score of IDS, 28 out of the 30 items were scored. Either item 11 or 12 (and 13 or 14) were scored. If 11 and 12 (or 13 and 14) both are scored then the item with the highest score was considered. The total score of the 28 items ranged between 0-84. A responder is a participant who has a ≥50% reduction from randomisation in the total score for IDS-C. The total score was calculated for each participant at each timepoint and the percentage change from randomisation was then calculated as (\[Total score at post randomisation visit - Total score at randomisation visit\]/ Total score at randomisation visit) \* 100%. Responders were those with values of ≤ -50%. The change from randomization was analysed using suitable Bayesian mixed-effects model repeated measures (BMMRM) assuming missing at random (MAR).
Time frame: Week 6
Percentage of IDS-C Remitters (Participants Whose Total Score Was ≤ 15 at Week 6/Study Exit).
The 30 item IDS is available in two versions IDS-C and IDS-SR. To calculate the total score of IDS, 28 out of the 30 items were scored. Either item 11 or 12 (and 13 or 14) were scored. If 11 and 12 (or 13 and 14) both are scored then the item with the highest score was considered. The total score of the 28 items ranged between 0-84. IDS-C total score was calculated for each participant at each timepoint and those participants with non-missing values for IDS-C total scores were categorised as having an IDS-C for the respective endpoint of ≤ 15 or \> 15. Participants whose total score was ≤ 15 were included here.
Time frame: Week 6
Percentage of IDS-SR Responders (Participants With a Reduction in Total Score of ≥ 50% From Randomization at Week 6/Study Exit).
The 30 item IDS is available in two versions IDS-C and IDS-SR. To calculate the total score of IDS, 28 out of the 30 items were scored. Either item 11 or 12 (and 13 or 14) were scored. If 11 and 12 (or 13 and 14) both are scored then the item with the highest score was considered. The total score of the 28 items ranged between 0-84. A responder is a participant who has a ≥50% reduction from randomisation in the total score for IDS-SR. The total score was calculated for each participant at each timepoint and the percentage change from randomisation was then calculated as (\[Total score at post randomisation visit - Total score at randomisation visit\]/ Total score at randomisation visit) \* 100%. Responders were those with values of ≤ -50%. The change from randomization was analysed using suitable BMMRM assuming missing at random.
Time frame: Week 6
Percentage of IDS-SR Remitters (Participants Whose Total Score Was ≤ 15 at Week 6/Study Exit).
The 30 item IDS is available in two versions IDS-C and IDS-SR. To calculate the total score of IDS, 28 out of the 30 items were scored. Either item 11 or 12 (and 13 or 14) were scored. If 11 and 12 (or 13 and 14) both are scored then the item with the highest score was considered. The total score of the 28 items ranged between 0-84. IDS-SR total score was calculated for each participant at each timepoint and those participants with non-missing values for IDS-SR total scores were categorised as having an IDS-C for the respective endpoint of ≤ 15 or \> 15. Participants whose total score was ≤ 15 were included here.
Time frame: Week 6
Percentage of QIDS-SR16 Responders (Participants With a Reduction in Total Score of ≥ 50% From Randomization at Week 6/Study Exit).
QIDS-SR assesses symptoms severity of DSM-IV diagnostic criterion for major depressive disorder. It contains 16 separate items (corresponding to 16 items of the much longer IDS-SR), defining 9 DSM-IV symptom criterion domains. A total score was obtained by summing scores on each domain.The highest possible score was 27, which represented the most severe measure of depression; the lowest possible score was 0, which represented an absence of depression. Due to the small number of items, missing data was not imputed for the QIDS-SR total score. A responder is a participant who has a ≥50% reduction from randomisation in the total score for that given endpoint. The total score was calculated for each participant at each timepoint and the percentage change from randomisation was then calculated as (\[Total score at post randomisation visit - Total score at randomisation visit\]/ Total score at randomisation visit) \* 100%. Responders were those with values of ≤ -50%.
Time frame: Week 6
Percentage of QIDS-SR16 Remitters (Subjects Whose Total Score Was ≤ 5 at Week 6/Study Exit).
QIDS-SR assesses symptoms severity of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criterion for major depressive disorder. It contains 16 separate items (corresponding to 16 items of the much longer IDS-SR), defining 9 DSM-IV symptom criterion domains. A total score was obtained by summing scores on each domain. The QIDS-SR total score was calculated by summing over the domain scores. The highest possible score was 27, which represented the most severe measure of depression; the lowest possible score was 0, which represented an absence of depression. Due to the small number of items, missing data was not imputed for the QIDS-SR total score. The QIDS total score was calculated for each subject at each timepoint and those subjects with no missing value for QIDS total score was categorised as having a QIDS total score of ≤ 5 or \> 5. Participants whose total score was ≤ 5 were included here.
Time frame: Week 6
Percentage of Bech Responders (Participants With a Reduction in Total Score of ≥ 50% From Randomization at Week 6/Study Exit).
The Bech scale was extracted from the HAMD-17 and comprised of 6 items out of which 5 were 5 point questions and 1 was 3 point question. The Bech Total Score was calculated by summing the individual response scores. Due to the small number of items, missing data was not imputed for the Bech Total Score. If any of the 6 items were missing, the total score was not calculated at that visit. A responder is a participant who has a ≥50% reduction from randomisation in the total score for that given endpoint. The total score was calculated for each participant at each timepoint and the percentage change from randomisation was then calculated as (\[Total score at post randomisation visit - Total score at randomisation visit\]/ Total score at randomisation visit) \* 100%. Responders were those with values of ≤ -50%. The change from randomization was analysed using suitable BMMRM assuming missing at random.
Time frame: Week 6
Percentage of Bech Remitters (Participants Whose Total Score Was ≤ 4 at Week 6/Study Exit).
The Bech scale was extracted from the HAMD-17 and comprised of 6 items out of which 5 were 5 point questions and 1 was 3 point question. The Bech Total Score was calculated by summing the individual response scores. Due to the small number of items, missing data was not imputed for the Bech Total Score. If any of the 6 items were missing, the total score was not calculated at that visit. The change from randomization was analysed using suitable BMMRM assuming missing at random MAR. The BECH total score was calculated for each subject at each timepoint and those perticipants with no missing value for BECH total score were categorised as having a BECH total score of ≤ 4 or \> 4.
Time frame: Week 6
Percentage of Participants With a Clinicians Global Impression of Improvement (CGI-I) Score of 1 ("Very Much Improved") or 2 ("Much Improved") at Weeks 1, 2, 3, 4, 5 and 6.
The number of participantts with a CGI-I score of either 1 ("very much improved") or 2 (much improved") were grouped together for each timepoint. Participants with no missing CGI-I scores were categorised as having a CGI-I score of ≤ 2 or \> 2.
Time frame: Weeks 1, 2, 3, 4, 5 and 6
Assessment of Clinical Global Impression-Severity of Illness (CGI-S) up to 6 Weeks
CGI-S assesses the severity of the participant's condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill). The number of participants with a CGI-I score of either 1 ("very much improved") or 2 (much improved") were grouped together for each timepoint. Participants with no missing CGI-S scores were categorised as having a CGI-S score of ≤ 2 or \> 2. The total score was calculated for each participant at each timepoint and percentage was calculated.
Time frame: Upto Week 6
The study was conducted between 25 Sep 2009 to 7 July 2010. The study was conducted at 21 centers in 5 countries (Bulgaria \[4\], Estonia \[1\], Germany \[7\], Russia \[5\], United States \[4\]).
| Milestone | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Started | 64 | 64 |
| Completed | 50 | 51 |
| Not completed | 14 | 13 |
| Withdrew: Adverse event | 5 | 5 |
| Withdrew: Lack of efficacy | 3 | 5 |
| Withdrew: Protocol violation | 1 | 0 |
| Withdrew: Lost to follow-up | 1 | 0 |
| Withdrew: Physician decision | 2 | 0 |
| Withdrew: Withdrawal by subject | 2 | 3 |
HAMD-17 has 17 questions. The HAMD-17 Total Score was calculated by summing the individual response scores over the 17 individual components of the interview. The highest possible score was 52, which represented the most severe measure of depression; the lowest possible score was 0, which represented an absence of depression. There were 9 five point questions and 8 three point questions. The responses to the individual questions had values of 0-2 (three points response) or 0-4 (five points response). The BECH scale was extracted from the HAMD-17 and comprises of 6 items out of which 5 are 5 point questions and 1 is 3 point question. The Bech Total Score was calculated by summing the individual response scores and ranged from 0 to 22, with higher scores indicating more severe depression. Week 0 values were considered as Baseline.The change from randomization was analysed using suitable Bayesian mixed-effects model repeated measures (BMMRM) assuming missing at random (MAR).
| Scores on scale | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Change From Randomization (Week 0) Associated With GW856553 Versus Placebo at Week 6 in the Bech (6-item HAMD-17 [Hamilton Depression Rating Scale]) Score. | -6.5 ± 3.62 | -5.6 ± 3.74 |
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A Serious Adverse Event (SAE) is 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. The AEs row include participants with SAEs.
| Participants | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| AEs | 28 | 26 |
| SAEs | 1 | 1 |
Suicidility was defined as participants with major depressive disorder who experienced worsening of their depression and/or the emergence of suicidal ideation and behavior. Number of partcipants who experienced suicidality were reported. On the Suicidal Ideation scale of the Columbia Suicide-Severity Rating Scale (C-SSRS) participants were scored as "non-suicidal" (00), "wish to be dead" (01), "non-specific active suicidal thoughts" (02), "active suicidal ideation with associated thoughts of methods without intent" (03), "active suicidal ideation with some intent to act on suicidal thoughts without clear plan" (04) and "active suicidal ideation with plan and intent" (05), based on the most severe score (5 being the most severe).Suicidal ideation of type 4 or 5 in the C-SSRS was categorized as suicidility here.
| Participants | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Week 1, Non-suicidal | 55 | 57 |
| Week 2, Non-suicidal | 54 | 55 |
| Week 3, Non-suicidal | 49 | 54 |
| Week 4, Non-suicidal | 50 | 54 |
| Week 5, Non-suicidal | 49 | 50 |
| Week 6, Non-suicidal | 50 | 49 |
Samples for haematology and clinical chemistry were collected on Weeks 1, 5 and 6. The analyzed haematological parameters were platelet count, red blood cells count, white blood cells count, reticulocyte count, hemoglobin and hematocrit. The analyzed clinical chemistry parameters were urea, creatinine, glucose (fasting), sodium, lactate dehydrogenase (LDH), potassium, chloride, calcium, triglycerides, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase, creatine kinase (CK), total and direct bilirubin, albumin, total protein and total cholesterol. Number of participants with any abnormal haematological or clinical chemistry parametrs are summarized here.
| Participants | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Glucose High, Week 6 | 1 | 0 |
| Total Bilirubin High, Week 4 | 1 | 0 |
Vital signs including systolic and diastolic blood pressure and heart rate were taken from day 1 upto follow-up visit. Number of participants with abnormal systolic blood pressure, diastolic blood pressure and heart rate values were summarized.
| Participants | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Low Diastolic blood pressure, Week 4 | 1 | 0 |
| High Systolic blood pressure, Week 2 | 1 | 0 |
ECG was obtained at Week 2 and Week 6. ECG was recorded using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and Corrected QT (QTc) intervals (Bazett's correction was applied to QTc measurements). Number of participants with abnormal ECG readings are summarized.
| Participants | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings | 0 | 0 |
Interlukin-6 (IL-6) and Tumor Necrosis Factor-Alpha (TNF-alpha) from the participants with Major Depressive Disorder (MDD) were evaluated and analyzed using suitable mixed-effects model repeated measures (MMRM). Exploratory analysis on plasma levels of IL-6 and TNF-alpha were performed. Week 0 values were considered as Baseline.The change from Baseline was calculated by subtracting the baseline values from the individual post-randomisation values.
| picogram/mililitre (pg/mL) | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| IL-6, Week 1, Predose | -1.06 ± 8.04 | -0.27 ± 4.36 |
| IL-6, Week 1, 3 hours (hrs) | -1.86 ± 9.72 | -1.57 ± 4.30 |
| IL-6, Week 6, Predose | -0.67 ± 11.29 | -0.96 ± 5.68 |
| IL-6, Week 6, 3 hrs | -0.11 ± 8.93 | -0.98 ± 9.36 |
| IL-6, Early Withdrawal | -7.44 ± 15.54 | 0.35 ± 4.52 |
| TNF-alpha, Week 1, Predose | 1.04 ± 9.65 | -0.26 ± 1.43 |
| TNF-alpha, Week 1, 3 hrs | 1.41 ± 12.61 | -0.65 ± 1.61 |
| TNF-alpha, Week 6, Predose | 3.80 ± 28.78 | -0.10 ± 1.57 |
| TNF-alpha, Week 6, 3 hrs | 4.11 ± 29.20 | -0.63 ± 1.49 |
| TNF-alpha, Eary Withdrawal | 0.31 ± 0.96 | -1.07 ± 2.24 |
HAMD-17 has 17 questions. The BECH scale was extracted from the HAMD-17 and comprises of 6 items out of which 5 are 5 point questions and 1 is 3 point question. The Bech scale was extracted from the HAMD-17 and comprised of 6 items out of which 5 were 5 point questions and 1 was 3 point question. The Bech Total Score was calculated by summing the individual response scores and ranged from 0 to 22, with higher scores indicating more severe depression. Due to the small number of items, missing data was not imputed for the Bech Total Score. If any of the 6 items were missing, the total score was not calculated at that visit. The change from randomization was analysed using suitable Bayesian Mixed-Effects Models for Repeated Measures (BMMRM) assuming missing at random MAR.
| Scores on scale | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Week 1 | -1.2 ± 2.14 | -1.6 ± 2.47 |
| Week 2 | -2.5 ± 2.73 | -2.2 ± 2.91 |
| Week 3 | -3.9 ± 3.20 | -3.4 ± 3.07 |
| Week 4 | -5.1 ± 2.97 | -4.1 ± 3.43 |
| Week 5 | -6.2 ± 3.49 | -5.0 ± 3.60 |
| Week 6 | -6.5 ± 3.62 | -5.6 ± 3.74 |
| Follow Up | -5.6 ± 3.58 | -5.2 ± 4.12 |
| Early Withdrawal | 0.3 ± 1.26 | -2.0 ± 4.00 |
HAMD-17 is Hamilton Depression Rating Scale which has 17 questions. The HAMD-17 Total Score was calculated by summing the individual response scores over the 17 individual components of the interview. The highest possible score was 52, which represented the most severe measure of depression; the lowest possible score was 0, which represented an absence of depression. If not more than 1 response was missing, the total score was caculated as Observed Total Score \* \[1 + (Sum of the Maximum Score of the missing values/Sum of the Maximum Score of the non -missing values)\]. There were 9 five point questions and 8 three point questions. The responses to the individual questions can have values of 0-2 (three points response) or 0-4 (five points response).
| Scores on Scale | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Week 1 | 21.7 ± 4.88 | 21.2 ± 4.78 |
| Week 2 | 18.9 ± 5.59 | 19.7 ± 5.36 |
| Week 3 | 16.5 ± 6.76 | 17.8 ± 5.57 |
| Week 4 | 14.1 ± 6.10 | 16.6 ± 5.39 |
| Week 5 | 12.6 ± 7.43 | 14.8 ± 6.14 |
| Week 6 | 11.7 ± 7.05 | 13.8 ± 6.50 |
| Follow up | 13.4 ± 7.34 | 14.4 ± 7.41 |
| Early Withdrawal | 27.8 ± 5.74 | 23.5 ± 4.18 |
The 30 item IDS is available in two versions IDS-C and Inventory of Depressive Symptomatology self-rated (IDS-SR). To calculate the total score of IDS, 28 out of the 30 items were scored. Either weight loss or weight gain, appetite loss or appetite gain is scored because only one member of each pair is applicable to any given respondent. The standard total score is obtained by summing the ratings of 28 of the 30 items. Each of the 28 items is scored on a 0 to 3 scale (0 - the absence of pathology; 3 - severe pathology). The total scores range from 0 to 84. If more than one response was missing then the score was calculated using the formula Observed Total Score\*\[1+(Sum of the Maximum Score of the missing values/Sum of the Maximum Score of the non -missing values)\].
| Scores on Scale | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Week1 | 39.7 ± 8.7 | 39.2 ± 8.5 |
| Week 2 | 35.2 ± 9.8 | 35.9 ± 9.1 |
| Week 3 | 30.9 ± 11.8 | 32.4 ± 9.3 |
| Week 4 | 26.9 ± 10.7 | 30.9 ± 9.8 |
| Week 5 | 23.4 ± 13.5 | 27.1 ± 11.3 |
| Week 6 | 22.0 ± 12.8 | 25.8 ± 12.1 |
| Follow-up | 25.3 ± 13.6 | 26.6 ± 12.8 |
| Early Withdrawal | 47.0 ± 13.5 | 41.8 ± 7.0 |
The 30 item IDS is available in two versions IDS-SR and IDS-C. To calculate the total score of IDS, 28 out of the 30 items were scored. Either weight loss or weight gain, appetite loss or appetite gain is scored because only one member of each pair is applicable to any given respondent. The standard total score is obtained by summing the ratings of 28 of the 30 items. Each of the 28 items is scored on a 0 to 3 scale (0 - the absence of pathology; 3 - severe pathology). The total scores range from 0 to 84. If more than one response was missing then the score was calculated using the formula Observed Total Score\*\[1+(Sum of the Maximum Score of the missing values/Sum of the Maximum Score of the non -missing values)\].
| Scores on Scale | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Week 2 | 34.7 ± 11.02 | 38.1 ± 10.79 |
| Week 4 | 29.2 ± 11.84 | 32.8 ± 12.15 |
| Week 6 | 24.7 ± 14.98 | 27.5 ± 13.28 |
| Early Termination | 48.8 ± 14.13 | 47.0 ± 10.64 |
QIDS-SR assesses symptoms severity of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criterion for major depressive disorder. It contains 16 separate items (corresponding to 16 items of the much longer IDS-SR), defining 9 DSM-IV symptom criterion domains. A total score was obtained by summing scores on each domain. The QIDS-SR total score was calculated by summing over the domain scores. The highest possible score was 27, which represented the most severe measure of depression; the lowest possible score was 0, which represented an absence of depression. Due to the small number of items, missing data was not imputed for the QIDS-SR total score.
| Scores on Scale | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Week 0 | 18.0 ± 2.79 | 17.8 ± 2.66 |
| Week 2 | 13.0 ± 4.22 | 14.1 ± 3.99 |
| Week 4 | 10.6 ± 4.69 | 11.8 ± 4.46 |
| Week 6 | 9.3 ± 5.81 | 10.0 ± 4.75 |
The 30 item IDS is available in two versions IDS-C and IDS-SR. To calculate the total score of IDS, 28 out of the 30 items were scored. Either item 11 or 12 (and 13 or 14) were scored. If 11 and 12 (or 13 and 14) both are scored then the item with the highest score was considered. The total score of the 28 items ranged between 0-84. A responder is a participant who has a ≥50% reduction from randomisation in the total score for IDS-C. The total score was calculated for each participant at each timepoint and the percentage change from randomisation was then calculated as (\[Total score at post randomisation visit - Total score at randomisation visit\]/ Total score at randomisation visit) \* 100%. Responders were those with values of ≤ -50%. The change from randomization was analysed using suitable Bayesian mixed-effects model repeated measures (BMMRM) assuming missing at random (MAR).
| Percentage of Participants | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Percentage of IDS-C Responders (Participants With a Reduction in Total Score of ≥50% From Randomization at Week 6/Study Exit). | 50 | 41 |
The 30 item IDS is available in two versions IDS-C and IDS-SR. To calculate the total score of IDS, 28 out of the 30 items were scored. Either item 11 or 12 (and 13 or 14) were scored. If 11 and 12 (or 13 and 14) both are scored then the item with the highest score was considered. The total score of the 28 items ranged between 0-84. IDS-C total score was calculated for each participant at each timepoint and those participants with non-missing values for IDS-C total scores were categorised as having an IDS-C for the respective endpoint of ≤ 15 or \> 15. Participants whose total score was ≤ 15 were included here.
| Percentage of participants | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Percentage of IDS-C Remitters (Participants Whose Total Score Was ≤ 15 at Week 6/Study Exit). | 38 | 18 |
The 30 item IDS is available in two versions IDS-C and IDS-SR. To calculate the total score of IDS, 28 out of the 30 items were scored. Either item 11 or 12 (and 13 or 14) were scored. If 11 and 12 (or 13 and 14) both are scored then the item with the highest score was considered. The total score of the 28 items ranged between 0-84. A responder is a participant who has a ≥50% reduction from randomisation in the total score for IDS-SR. The total score was calculated for each participant at each timepoint and the percentage change from randomisation was then calculated as (\[Total score at post randomisation visit - Total score at randomisation visit\]/ Total score at randomisation visit) \* 100%. Responders were those with values of ≤ -50%. The change from randomization was analysed using suitable BMMRM assuming missing at random.
| Participants | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Percentage of IDS-SR Responders (Participants With a Reduction in Total Score of ≥ 50% From Randomization at Week 6/Study Exit). | 49 | 47 |
The 30 item IDS is available in two versions IDS-C and IDS-SR. To calculate the total score of IDS, 28 out of the 30 items were scored. Either item 11 or 12 (and 13 or 14) were scored. If 11 and 12 (or 13 and 14) both are scored then the item with the highest score was considered. The total score of the 28 items ranged between 0-84. IDS-SR total score was calculated for each participant at each timepoint and those participants with non-missing values for IDS-SR total scores were categorised as having an IDS-C for the respective endpoint of ≤ 15 or \> 15. Participants whose total score was ≤ 15 were included here.
| Percentage of participants | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Percentage of IDS-SR Remitters (Participants Whose Total Score Was ≤ 15 at Week 6/Study Exit). | 37 | 19 |
QIDS-SR assesses symptoms severity of DSM-IV diagnostic criterion for major depressive disorder. It contains 16 separate items (corresponding to 16 items of the much longer IDS-SR), defining 9 DSM-IV symptom criterion domains. A total score was obtained by summing scores on each domain.The highest possible score was 27, which represented the most severe measure of depression; the lowest possible score was 0, which represented an absence of depression. Due to the small number of items, missing data was not imputed for the QIDS-SR total score. A responder is a participant who has a ≥50% reduction from randomisation in the total score for that given endpoint. The total score was calculated for each participant at each timepoint and the percentage change from randomisation was then calculated as (\[Total score at post randomisation visit - Total score at randomisation visit\]/ Total score at randomisation visit) \* 100%. Responders were those with values of ≤ -50%.
| Percentage of Participants | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Percentage of QIDS-SR16 Responders (Participants With a Reduction in Total Score of ≥ 50% From Randomization at Week 6/Study Exit). | 55 | 45 |
QIDS-SR assesses symptoms severity of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criterion for major depressive disorder. It contains 16 separate items (corresponding to 16 items of the much longer IDS-SR), defining 9 DSM-IV symptom criterion domains. A total score was obtained by summing scores on each domain. The QIDS-SR total score was calculated by summing over the domain scores. The highest possible score was 27, which represented the most severe measure of depression; the lowest possible score was 0, which represented an absence of depression. Due to the small number of items, missing data was not imputed for the QIDS-SR total score. The QIDS total score was calculated for each subject at each timepoint and those subjects with no missing value for QIDS total score was categorised as having a QIDS total score of ≤ 5 or \> 5. Participants whose total score was ≤ 5 were included here.
| Percentage of participants | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Percentage of QIDS-SR16 Remitters (Subjects Whose Total Score Was ≤ 5 at Week 6/Study Exit). | 31 | 13 |
The Bech scale was extracted from the HAMD-17 and comprised of 6 items out of which 5 were 5 point questions and 1 was 3 point question. The Bech Total Score was calculated by summing the individual response scores. Due to the small number of items, missing data was not imputed for the Bech Total Score. If any of the 6 items were missing, the total score was not calculated at that visit. A responder is a participant who has a ≥50% reduction from randomisation in the total score for that given endpoint. The total score was calculated for each participant at each timepoint and the percentage change from randomisation was then calculated as (\[Total score at post randomisation visit - Total score at randomisation visit\]/ Total score at randomisation visit) \* 100%. Responders were those with values of ≤ -50%. The change from randomization was analysed using suitable BMMRM assuming missing at random.
| Percentage of participants | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Percentage of Bech Responders (Participants With a Reduction in Total Score of ≥ 50% From Randomization at Week 6/Study Exit). | 62 | 49 |
The Bech scale was extracted from the HAMD-17 and comprised of 6 items out of which 5 were 5 point questions and 1 was 3 point question. The Bech Total Score was calculated by summing the individual response scores. Due to the small number of items, missing data was not imputed for the Bech Total Score. If any of the 6 items were missing, the total score was not calculated at that visit. The change from randomization was analysed using suitable BMMRM assuming missing at random MAR. The BECH total score was calculated for each subject at each timepoint and those perticipants with no missing value for BECH total score were categorised as having a BECH total score of ≤ 4 or \> 4.
| Percentage of participants | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Percentage of Bech Remitters (Participants Whose Total Score Was ≤ 4 at Week 6/Study Exit). | 38 | 20 |
The number of participantts with a CGI-I score of either 1 ("very much improved") or 2 (much improved") were grouped together for each timepoint. Participants with no missing CGI-I scores were categorised as having a CGI-I score of ≤ 2 or \> 2.
| Percentage of participants | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Week 1 | 10 | 8 |
| Week 2 | 28 | 14 |
| Week 3 | 41 | 39 |
| Week 4 | 53 | 36 |
| Week 5 | 61 | 54 |
| Week 6 | 68 | 59 |
CGI-S assesses the severity of the participant's condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill). The number of participants with a CGI-I score of either 1 ("very much improved") or 2 (much improved") were grouped together for each timepoint. Participants with no missing CGI-S scores were categorised as having a CGI-S score of ≤ 2 or \> 2. The total score was calculated for each participant at each timepoint and percentage was calculated.
| Percentage of participants | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Week 1, Normal | 0 | 1.59 |
| Week 2, Normal | 0 | 1.69 |
| Week 3, Normal | 1.96 | 3.51 |
| Week 4, Normal | 0 | 1.79 |
| Week 5, Normal | 13.73 | 3.85 |
| Week 6, Normal | 12.00 | 3.92 |
| Week 1, Borderline Mentally ill | 0 | 1.59 |
| Week 2, Borderline Mentally ill | 3.45 | 3.39 |
| Week 3, Borderline Mentally ill | 9.80 | 1.75 |
| Week 4, Borderline Mentally ill | 16.98 | 7.14 |
| Week 5, Borderline Mentally ill | 17.65 | 17.31 |
| Week 6, Borderline Mentally ill | 20.00 | 23.53 |
| Week 1, Mildly ill | 9.84 | 3.17 |
| Week 2, Mildly ill | 18.97 | 6.78 |
| Week 3, Mildly ill | 29.41 | 24.56 |
| Week 4, Mildly ill | 41.51 | 26.79 |
| Week 5, Mildly ill | 33.33 | 28.85 |
| Week 6, Mildly ill | 34.00 | 29.41 |
| Week 1, Moderately ill | 40.98 | 46.03 |
| Week 2, Moderately ill | 46.55 | 50.85 |
| Week 3, Moderately ill | 29.41 | 40.35 |
| Week 4, Moderately ill | 22.64 | 39.29 |
| Week 5, Moderately ill | 17.65 | 25.00 |
| Week 6, Moderately ill | 20.00 | 19.61 |
| Week 1, Markedly ill | 36.07 | 38.10 |
| Week 2, Markedly ill | 20.69 | 30.51 |
| Week 3, Markedly ill | 21.57 | 22.81 |
| Week 4, Markedly ill | 16.98 | 19.64 |
| Week 5, Markedly ill | 15.69 | 23.08 |
| Week 6, Markedly ill | 10.00 | 21.57 |
| Week 1, Severely ill | 13.11 | 9.52 |
| Week 2, Severely ill | 10.34 | 6.78 |
| Week 3, Severely ill | 7.84 | 7.02 |
| Week 4, Severely ill | 1.89 | 5.36 |
| Week 5, Severely ill | 1.96 | 1.92 |
| Week 6, Severely ill | 4.00 | 1.96 |
Collected over Up to Follow-up visit (Day 53).. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo | 0/64 (0%) | 1/64 (1.6%) | 18/64 (28.1%) |
| GW856553 7.5 mg BID | 0/64 (0%) | 1/64 (1.6%) | 16/64 (25%) |
| Event | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| Suicidal ideationPsychiatric disorders | 1/64 | 1/64 |
| Event | Placebo | GW856553 7.5 mg BID |
|---|---|---|
| HeadacheNervous system disorders | 9/64 | 12/64 |
| DiarrhoeaGastrointestinal disorders | 7/64 | 1/64 |
| AnxietyPsychiatric disorders | 2/64 | 4/64 |
| FatigueGeneral disorders | 4/64 | 0/64 |
| Age, Customized(Participants) | Placebo | GW856553 7.5 mg BID | Total |
|---|---|---|---|
| 18 to 60 years | 64 | 64 | 128 |
| Sex: Female, Male(Participants) | Placebo | GW856553 7.5 mg BID | Total |
|---|---|---|---|
| Female | 37 | 39 | 76 |
| Male | 27 | 25 | 52 |
| Race (NIH/OMB)(Participants) | Placebo | GW856553 7.5 mg BID | Total |
|---|---|---|---|
| American Indian or Alaska Native | 1 | 0 | 1 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 3 | 1 | 4 |
| White | 60 | 63 | 123 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
Plan to share: Yes — Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
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