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

Study Overview
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Brief Summary
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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
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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).

Official Title
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A Six-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Evaluating the Efficacy, Safety, and Tolerability of GSK561679 Compared to Placebo in Female Subjects, Diagnosed With Major Depressive Disorder

Conditions
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Depressive Disorder, Major

Intervention / Treatment
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* Drug: GSK561679
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Female outpatients aged 25-64 years, inclusive. Subjects must have the ability to comprehend the consent form, and provide informed consent. Subject currently meets the diagnosis for MDD (without psychotic features), 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 in psychiatry (e.g., Board Certification in psychiatry in the US or equivalent local qualification in other countries) 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. Subject has an IVRS HamD17 total score ≥ 23 at the Screening and Randomization Visits and the HAMD17 score is confirmed to be at least 20 by the Independent Efficacy Rater at the Screening and Randomization Visits. The subject is eligible to enter and participate in this study if she is not lactating and: Is of non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal [defined as one year without menses]); is surgically sterile [via hysterectomy and/or removal of the ovaries] or, is of child-bearing potential, has a negative pregnancy test at both screening and baseline (prior to investigational product administration), and agrees to acceptable methods of contraception. Exclusion Criteria Symptoms of the presenting illness which are better accounted for by another diagnosis*; or A current DSM-IV-TR Axis I diagnosis of Dementia; or Antisocial or Borderline Personality Disorder or other current DSM-IV-TR Axis II diagnosis that would suggest unresponsiveness to pharmacotherapy or non-compliance with the protocol; or A current (or within 12 months prior to the Screening visit) diagnosis of anorexia nervosa or bulimia; or A lifetime history of Schizophrenia, Schizoaffective Disorder, or a Bipolar Disorder. Subject has an unstable medical disorder or a disorder that would interfere with the action, absorption, distribution, metabolism, or excretion of GSK561679 or may pose a safety concern, or interfere with the accurate assessment of safety or efficacy. 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 the Screening visit) and who agree to maintain the same therapy schedule during the trial may be included. Subject has received vagus nerve stimulation, electroconvulsive therapy, or transcranial magnetic stimulation within the six months prior to the Screening visit. Subject has previously failed adequate therapeutic courses of pharmacotherapy for MDD (e.g., maximum-labeled/tolerated doses for ≥ 4 weeks) from two different classes of antidepressants. Subject, who, in the investigator's judgement, poses a homicidal or serious suicidal risk, has had any previous suicide attempt (including aborted, interrupted or ineffective attempts) or who has ever been homicidal. Subject has no contact with an adult on a daily basis (i.e., subjects who are not living with at least one other adult or subjects who do not have an adult who contacts them on a daily basis). This criterion only applies to sites in Canadian sites and others where this is a local requirementa. Subject has a positive urine test at screening for illegal drug use and/or history of substance abuse or dependence (alcohol or drugs as defined by DSM-IV TR criteria) within the past 12 months. Subject has a blood alcohol level of ≥ 15mg/dL (0.015%) at the Screening Visit. If a subject has a positive blood alcohol or positive illegal drug results, the subject is provisionally excluded and the test cannot be repeated without prior approval of the GSK medical monitor. NOTE: Subjects must be told to avoid consumption of alcoholic beverages for at least eight hours prior to the Screening Visit. The use of alcohol by subjects participating in the study is not recommended. 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. 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. Subject is (a) 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 (b) has participated in a clinical study for an illness unrelated to depression/anxiety within the preceding month; or (c) has participated in a clinical study related to depression/anxiety within the preceding six months. Documented history of hepato-biliary disease including a history of, or positive laboratory results for hepatitis (hepatitis B surface antigen and/or hepatitis C antibody) at Screening, and/or clinically significant hepatic enzyme elevation 13.Subjects who are not euthyroid as evidenced by normal TSH (subjects maintained on thyroid medication must be euthyroid for a period of at least six months prior to the screen visit). Subject has a positive serum Human Chorionic Gonadotropin (HCG) pregnancy test at screen visit, a positive urine dipstick test at randomization, or who is lactating or planning to become pregnant within the next 13 weeks following the Screen Visit. Subject has clinical evidence of, or ECG results indicating any of the following at either screen or Randomization Visit unless repeat ECG shows that the parameter had returned to within normal range by the Randomisation Visit. (The ECG may be repeated to see if the parameter returns to within range): QTc > 450 msec; any cardiac condition or ECG evidence that the investigator feels may predispose the subject to ischemia or arrhythmia; or any ECG abnormality that, in the investigator's judgment, may pose a potential safety concern. Subject has taken other psychoactive drugs within one week prior to the ScreeningScreening Randomization Visit Subject has taken systemic corticosteroids acutely within two weeks or chronically within the last 6 months of the Randomization Visit (NOTE: Topical hydrocortisone and inhaled corticosteroids are allowed). Subject has taken other (non-psychoactive) prescription, non-prescription, dietary, or herbal products metabolized via the cytochrome P450 3A4 pathway, or P-gp substrates with a narrow therapeutic index within 2 weeks (or 5 half-lives, whichever is longer) prior to the Randomization Visit. Subject has taken other (non-psychoactive) prescription, non-prescription, dietary, or herbal products that are potent inducers or inhibitors of the cytochrome P450 3A4 pathway for 2 weeks (or 5 half lives, whichever is longer) prior to the Randomization Visit. Subject has previously participated in an investigational trial involving GSK561679 or closely related compounds. Subject has a history of allergic reaction to, or significant adverse effects from excipients in the GSK561679 tablet.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK561679 arm<br>Double blind GSK561679 | Drug: GSK561679<br>* GSK561679<br>|
| Placebo Comparator: placebo arm<br>Double blind placebo | Other: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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. | Randomization (Week 0) and Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Randomization to Weeks 1, 2, and 4 in the Bech Melancholia Scale Score. | 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. | Randomization (Week 0) and Week 1, 2 and 4 | 
| Change From Randomization to Weeks 1, 2, 4, and 6 in the Hamilton Anxiety Scale (HAM A) | 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. | Randomization (Week 0) and Week 1, 2, 4 and Week 6 | 
| Change From Randomization to Weeks 1, 2, 3, 4, and 6 in the Inventory of Depressive Symptomatology-Self- Report (IDS-SR) Total Score. | 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. | Randomization (Week 0) and Week 1, 2, 3,4 and Week 6 | 
| Change From Randomization to Weeks 1, 2, 4, and 6 in the Hamilton Rating Scale for Depression (HAMD-17) | 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. | Randomization (Week 0) and Week 1, 2, 4 and Week 6 | 
| Percentage HAMD-17 Responders at 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. | Weeks 1, 2, 4, and 6. | 
| Time to Maintained Antidepressant Response at the End of Treatment Phase (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 | Week 6 | 
| Change From Randomization in the Clinical Global Impression - Severity of Illness (CGI-S) Score at 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. | Randomization (Week 0) and Weeks 1, 2, 4, and 6. | 
| Percentage of Clinical Global Impression - Global Improvement (CGI-I) Responders at 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). | Weeks 1, 2, 4, and 6. | 
| Change From Randomization in the Medical Outcomes Study 12-item Sleep Module (MOS 12) at 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. | Randomization (Week 0) and Week 6 | 
| Change From Randomization in the Cohen Perceived Stress Scale (PSS) at 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. | Randomization (Week 0) and Week 6. | 
| Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | 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. | Up to 28-day FU (18 months) | 
| Number of Participants With Vital Sign of Potential Clinical Importance (PCI) | 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. | Up to Week 10 | 
| Number of Participants With Abnormal Urinalysis Data | 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. | Randomization (Week 0), Week 3, Week 6/ Early withdrawal (EW) and 28 Day follow-up (FU) | 
| Number of Participants With Abnormal Electrocardiograph (ECG) Values | 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. | Randomization (Week 0), Week 4, Week 6 and 28 Day follow-up | 
| Number of Participants With Abnormal Hematology Values of PCI-Platelet | 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. | Upto 28-day FU | 
| Number of Participants With Clinical Chemistry Laboratory Data Outside Reference Range | 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. | Upto Week 10 | 
| Number of Participants With Hormonal Data of PCI | 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) . | up to Week 10 | 
| Discontinuation-Emergent Signs and Symptoms | 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. | At Week 6, 7-day (D) FU and 28-D FU | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Depressive Disorder, Major