A Study of the Effects of a New Antidepressant Treatment (GSK561679) in Females With Major Depressive Disorder

Phase 2

Completed

Conditions: Depressive Disorder, Major

Interventions: Drug: GSK561679
Other: Placebo

Registration Number: NCT00733980

Lead Sponsor: GlaxoSmithKline

Brief Summary: This six-week study will evaluate the efficacy, safety and tolerability of GSK561679 compared to placebo in female subjects with major depressive disorder

Detailed Description: This is a double-blind placebo controlled study to assess the CRF1 receptor antagonist, GSK561679, for treatment of depression in adult females diagnosed with Major Depressive Disorder (MDD). A treatment regimen of 350mg/day will be utilized to assess both efficacy and tolerability. Subjects will be randomized in equal numbers (n=75/arm) to the treatment arm and the placebo arm for a 6-week treatment period.

Efficacy will be assessed by determining the change from baseline in symptoms of MDD and anxiety utilizing the Bech Melancholia scale (Bech), Hamilton Rating Scale for Depression (HamD17), Inventory of Depressive Symptomatology-Self-Report (IDS-SR), Clinical Global Impression - Severity of Illness (CGI-S), Clinical Global Impression - Global Improvement (CGI-I), Medical Outcomes Study 12-item Sleep Module (MOS 12), Cohen Perceived Stress Test (PSS), Hamilton Anxiety Scale (HamA), and Dexamethasone Suppression Test (DST). Safety and tolerability will be assessed by determining the incidence of adverse events (AEs), vital signs, BMI, weight, clinical laboratory parameters, including ECGs, during the treatment and pre \& post-treatment phases, and Discontinuation Emergent Signs and Symptoms (DESS). In addition, the incidence of suicidality will be assessed by the Columbia Suicide Severity Rating Scale (C-SSRS).

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 150

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
GSK561679 arm	GSK561679	Double blind GSK561679
placebo arm	Placebo	Double blind placebo

Primary Outcome Measures

Name	Time	Method
Change From Randomization to the End of Treatment Phase (Week 6) in the Bech Melancholia Subscale (Bech) (Items 1, 2, 7, 8, 10 and 13) From the Hamilton Rating Scale for Depression (HamD17).	Randomization (Week 0) and Week 6	The Bech Melancholia Sub-scale is extracted from the HAMD-17 and is comprised of the following 6 items: Depressed Mood, Feelings of Guilt, Work and Activities, Retardation, Anxiety Psychic, and Somatic Symptoms General. The items Depressed Mood, Feelings of Guilt, Work and Activities, Retardation, Anxiety Psychic are scored on a 5-point scale from 0 to 4 except for Somatic Symptoms General which is scored on a 3-point scale from 0 to 2 where the higher scores reflecting greater severity. The Bech Melancholia Scale total score is calculated by summing the individual response scores. The highest possible score is 22 (indicative of greater severity) and the lowest possible score is 0 (indicating absence of symptoms). Change from randomization was defined as the post-baseline value minus the value at randomization. Randomization was defined as Week 0.

Secondary Outcome Measures

Name	Time	Method
Change From Randomization to Weeks 1, 2, and 4 in the Bech Melancholia Scale Score.	Randomization (Week 0) and Week 1, 2 and 4	The Bech Melancholia Sub-scale is extracted from the HAMD-17 and is comprised of the following 6 items: Depressed Mood, Feelings of Guilt, Work and Activities, Retardation, Anxiety Psychic, and Somatic Symptoms General. The items Depressed Mood, Feelings of Guilt, Work and Activities, Retardation, Anxiety Psychic are scored on a 5-point scale from 0 to 4 except for Somatic Symptoms General which is scored on a 3-point scale from 0 to 2 where the higher scores reflecting greater severity. The Bech Melancholia Scale total score is calculated by summing the individual response scores. The highest possible score is 22 (indicative of greater severity) and the lowest possible score is 0 (indicating absence of symptoms). Change from randomization was defined as the post-baseline value minus the value post randomization (Weeks 1, 2 and 4). Randomization was defined as Week 0.
Change From Randomization to Weeks 1, 2, 4, and 6 in the Hamilton Anxiety Scale (HAM A)	Randomization (Week 0) and Week 1, 2, 4 and Week 6	HAM A, is internationally accepted and validated measurement tool for assessment of severity of anxiety symptoms. Used to assess severity of overall anxiety in participants who met criteria for anxiety of depressive disorders and to monitor outcome of treatment. Instrument does not distinguish symptoms of specific anxiety disorder or distinguish an anxiety disorder from an anxious depression. It is clinician-administered and consists of 14 individual questions, each rated on five point scale from 0 (not present) to 4 (very severe). Total HAM A range from 0 to 56 with higher scores reflecting more severe anxiety. Change from randomization was defined as post-baseline value minus value at randomization. Randomization was defined as Week 0. Provided no more than 1 response was missing for any one visit assessment for a participant, total score was calculated adjusting for missing data as follows: Total score = (14/13)\* observed total score the score was rounded to nearest integer number.
Change From Randomization to Weeks 1, 2, 4, and 6 in the Hamilton Rating Scale for Depression (HAMD-17)	Randomization (Week 0) and Week 1, 2, 4 and Week 6	The HAMD-17 scale is a subset of HAMD-28. It is a standard used to measure depression severity. The HAMD-17 score ranges from 0 to 52; a score of 0-7 is generally accepted to be within the normal range (or in clinical remission), while a score of 20 or higher indicates at least moderate severity; a reduction of 50% or more in total score from Baseline indicates clinical response. Thus a higher score was indicative of more severity. Change from randomization was defined as the post-baseline value minus the value at randomization. Randomization was defined as Week 0.
Percentage HAMD-17 Responders at Weeks 1, 2, 4, and 6.	Weeks 1, 2, 4, and 6.	HAMD-17 Responders were defined as the participants with a \> or = 50% reduction from randomization in their HAMD-17 total score at Weeks 1, 2, 4, and 6. The HAMD-17 scale is a subset of HAMD-28. It is a standard used to measure depression severity. The HAMD-17 score ranged from 0 to 52; a score of 0-7 is generally accepted to be within the normal range (or in clinical remission), while a score of 20 or higher indicated at least moderate severity; a reduction of 50% or more in total score from Baseline indicates clinical response. Thus a higher score was indicative of more severity.
Time to Maintained Antidepressant Response at the End of Treatment Phase (Week 6)	Week 6	The time to maintained antidepressant response at the end of treatment phase (week 6), as the participants with a \> or = to 50 % reduction from randomization in their HAMD-17 total score, sustained until the end of the Treatment Phase \[Week 6\]). This OM "time to maintained antidepressant response" was not evaluated due to lower number of participants in the GSK561679 group as compared to placebo
Change From Randomization to Weeks 1, 2, 3, 4, and 6 in the Inventory of Depressive Symptomatology-Self- Report (IDS-SR) Total Score.	Randomization (Week 0) and Week 1, 2, 3,4 and Week 6	The IDS-SR is self-report rating scale that assesses symptom severity of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), diagnostic criterion for major depressive disorder. The IDS-SR is a 30 item self report used to assess the severity of depressive symptoms. Each item has a 4-likert scale and each symptom item is given equivalent weightings and scored on 0 to 3 scale, with 3 representing the worst symptom. The total score of IDS-SR is calculated as a sum of each item score. The range of possible score is between 0 and 90, 0 as no symptom and 90 the worst symptom. The higher the score, the more severe the depression. Change from randomization was defined as the post-baseline value minus the value post randomization (Weeks 1, 2,3, 4 and 6). Randomization was defined as Week 0.
Change From Randomization in the Clinical Global Impression - Severity of Illness (CGI-S) Score at Weeks 1, 2, 4, and 6.	Randomization (Week 0) and Weeks 1, 2, 4, and 6.	The CGI is a widely accepted measure of illness severity and clinical improvement in a variety of psychiatric disorders. The CGI is psychiatrist rated, and is based on all information available at the time of the rating. Both the CGI-I and CGI-S items are rated on a 1 to 7 point scale. Scores on the CGI-I range from 1 (very much improved) to 7 (very much worse). Scores, on the CGI-S, range from 1 (normal, not ill at all) to 7 (amongst the most extremely ill). Change from randomization was defined as the post-baseline value minus the value at randomization. Randomization was defined as Week 0.
Percentage of Clinical Global Impression - Global Improvement (CGI-I) Responders at Weeks 1, 2, 4, and 6.	Weeks 1, 2, 4, and 6.	The CGI is a widely accepted measure of illness severity and clinical improvement in a variety of psychiatric disorders. The CGI is psychiatrist rated, and is based on all information available at the time of the rating. The CGI -responders, are defined as participants with a score of 1 (very much improved) or 2 (much improved) in the CGI-I).
Change From Randomization in the Medical Outcomes Study 12-item Sleep Module (MOS 12) at Week 6	Randomization (Week 0) and Week 6	The MOS-12 Sleep Scale is a 12-item questionnaire which measures specific aspects of sleep in participants that may have varying co-morbidities, as a result, is appropriate for a medically diverse participant population. It consist of following items: initiation (2 items), maintenance (2 items), respiratory problems (2 items), quantity (1 item), perceived adequacy (2 items), and somnolence (3 items). All items were given equivalent weightage from 1 to 6. Each index summarizes information across most or all sleep dimensions. The total score is transformed linearly to a common metric with a possible range of 0-100 and is averaged across items in the same scale. The higher score indicates a greater degree of the attribute implied by the scale name. Change from randomization was calculated by randomization value minus the value at Week 6. Randomization was defined as Week 0.
Change From Randomization in the Cohen Perceived Stress Scale (PSS) at Week 6.	Randomization (Week 0) and Week 6.	The PSS is most widely used psychological instrument for measuring the perception of stress. It is a 10-item questionnaire that measures an individual's subjective evaluation the stressfulness of situations in their life in past month (how unpredictable, uncontrollable, and overloaded respondents find their lives). Individual items were rated on a scale of 0-4, where 0(never) to 4 (very often) that best describes how often they have had the feelings or thoughts described in the last month for each question. The total scores can range from 0-40, where 0 score indicated no stress and a higher score indicated more stress. Change from randomization was defined as the post-baseline value minus the value at randomization. Randomization was defined as Week 0. Thus a negative change from randomization indicated improvement.
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)	Up to 28-day FU (18 months)	An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse. SAE was any experience that: resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was medically significant.
Number of Participants With Vital Sign of Potential Clinical Importance (PCI)	Up to Week 10	Vital sign measurements included height (screening only), systolic blood pressure(SBP) and diastolic blood pressure (DBP) and heart rate (HR). Sitting vital signs were measured at all clinic visits. Standing vital signs were measured at screening, Week 3 and at any other times as clinically indicated. Only the PCI values for SBP, DBP and HR were reported.
Number of Participants With Clinical Chemistry Laboratory Data Outside Reference Range	Upto Week 10	The number of participants with clinical chemistry values outside the clinical importance range (CIR) were reported. The values for chemistry parameters outside CRI were reported for Alanine amino transferase (ALT), Aspartate amino transferase, total bilirubin, calcium, Creatine Kinase, carbon dioxide (CO\^2) content/bicarbonate (BC), glucose and potassium were reported.
Number of Participants With Hormonal Data of PCI	up to Week 10	The number of participants with hormone values outside the CRI were reported. The hormone data was analyzed for parameters like Cortisol total, Dehydroepiandrosterone, Thyroxine, free, and thyroid stimulating hormone (TSH) .
Discontinuation-Emergent Signs and Symptoms	At Week 6, 7-day (D) FU and 28-D FU	The discontinuation signs and symptoms scale consisted of 43 signs and symptoms, scored as 'new symptom (NS)', 'old symptom (OS) but worse', 'OS but improved' or ' symptom not present/old symptom but unchanged'. The total number of new signs and symptoms, old symptoms but worse, and old symptoms but improved was calculated for each participant. The number of participants with Discontinuation-Emergent Signs and Symptoms were reported. The visits were at Week 6 Visit, 7-D FU and 28-D FU visit.
Number of Participants With Abnormal Urinalysis Data	Randomization (Week 0), Week 3, Week 6/ Early withdrawal (EW) and 28 Day follow-up (FU)	Urinalysis included analysis for urine bilirubin, urine occult blood, urine glucose, urine ketones, urine nitrite, urine proteins and urine Leukocyte Esterase test (LET) via dipstick analysis. The number of participants with abnormal urinalysis data were reported. In the dipstick test the levels for urine bilirubin, urine occult blood, urine glucose, urine ketones, urine nitrite, urine proteins and urine LET with results of trace, negative, positive,1+=slightly positive, 2+=positive, 3+=high positive were reported.
Number of Participants With Abnormal Electrocardiograph (ECG) Values	Randomization (Week 0), Week 4, Week 6 and 28 Day follow-up	The 12-lead ECG, were obtained at each time-point during the study using an ECG machine. The number of participants with ECG abnormal values were reported.
Number of Participants With Abnormal Hematology Values of PCI-Platelet	Upto 28-day FU	Number of participants with abnormal Hematology values of PCI were reported. The abnormal values were reported only for platelet, diagnosed at Week 6 or Early withdrawal visit.