Safety and Efficacy Study in Patients With Major Depressive Disorder

Study Overview
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Brief Summary
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The purpose of this study is to test if GSK163090 can reduce the symptoms of depression. The safety and how well the body can handle the drug will also be investigated. The study will be conducted in Russia in hospitalised patients with severe depression. GSK163090 will be compared with placebo, which looks like the study drug but does not contain any active substance. Subjects will be given either the study drug or the matching placebo.

Detailed Description
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This is a randomised, multi-centre, double-blind, placebo-controlled, repeat dose, parallel group study in male and female patients with severe depression requiring hospitalization. Efficacy, safety and tolerability will be assessed in three treatment arms. The study will consist of a screening period, a treatment phase (up to 6 weeks) and a post-treatment follow-up visit. The study duration from screening to follow up will be approximately 9 weeks. Subjects who pass screening will be randomized on Day 1 to one of three treatment arms (low dose arm, high dose arm or placebo). Each treatment arm will contain approximately 50 subjects. The subject's depressive symptoms will be assessed using the HAMD17- CR.

Official Title
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A Randomised, Double-Blind, Parallel-Group, Placebo-Controlled Study Evaluating the Efficacy and Safety of GSK163090 in Subjects With Major Depressive Disorder

Conditions
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Depressive Disorder

Intervention / Treatment
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* Drug: GSK163090 1 mg
* Drug: GSK163090 Placebo
* Drug: GSK163090 3 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Currently have severe depression (Major Depressive Disorder - without psychotic features) meet criteria (DSM IV-TR ) for current major depressive episode for at least 4 weeks but for no greater than 24 months depression questionnaire (HAMD17) total score greater than or equal to 24 subject must read and able to give written informed consent male or female 18 to 64 years use appropriate birth control method BMI 18.8 - 35.0 kg/m2 (inclusive) Exclusion Criteria: Primary diagnosis of other psychiatric disorders thoughts of killing ones self or someone else taking psychiatric medicine or therapy within the six months Has previously failed an adequate course of medication for MDD from two different classes of antidepressants. Unstable medical disorder or a disorder that would interfere with the action of the drug Abuse of alcohol or drugs Past history of serotonin syndrome or a history of clinical significant intolerance of SSRIs (class of drugs used for depression). History of migraine headaches that respond to treatment with triptan medication. History of a clinically significant abnormality of the neurological system (including dementia and other cognitive disorders or significant head injury) or any history of seizure (excluding febrile seizure). Currently taking part in another clinical study or has done so within six months Pregnant, planning to become pregnant shortly or breastfeeding History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy

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

Sexes Eligible for Study
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All

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 |
| --- | --- |
| Active Comparator: Active<br>Parallel Group - High Dose Arm, Low Dose Arm | Drug: GSK163090 1 mg<br>* Developed for the treatment of Major Depressive Disorder<br>Drug: GSK163090 3 mg<br>* Developed for the treatment of Major Depressive Disorder<br>|
| Placebo Comparator: Placebo<br>Parallel Group | Drug: GSK163090 Placebo<br>* Developed for the treatment of Major Depressive Disorder<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Hamilton Depression Rating Scale (HAMD17), on Day 14 and 42 | HAMD-17 is a 17-item scale that evaluates depressed mood, vegetative and cognitive symptoms of depression, and co-morbid anxiety symptoms. The 17 items were rated on either a 5-point (0-4) or a 3-point (0-2) scale. In general, the 5 point scale items use a rating of 0=absent; 1=doubtful to mild; 2=mild to moderate; 3=moderate to severe; 4=very severe. The 3-point scale items use a rating of 0=absent; 1=probable or mild; 2=definite. The total HAMD-17score ranges from 0 (not ill) to 52 (severely ill). The highest possible score was 52, which represented the most severe measure of depression; the lowest possible score was 0, which represents an absence of depression. Baseline was defined as the assessment done on Day 1 (pre-dose). Change from baseline in total Score was the difference between HAMD total score at the time point being analyzed to Day 1. | Baseline (Day 1, pre-dose), Day 14 and Day 42 | 
| Change From Baseline in Bech Melancholia Subscale (BECH 6) Scale, on Day 14 and 42 | The bech melancholia is sum of scores on 6 items- depressed mood, feelings of guilt, work and activities, retardation, anxiety psychic, somatic symptoms general (items 1, 2, 7, 8, 10 and 13 respectively). Each item having 5 responses. The items are rated on a scale of 0-4, where 0=absent; 1=doubtful to mild; 2=mild to moderate; 3=moderate to severe; 4=very severe. Total possible score is 0-24. where the lowest possible score was 0, which represented an absence of depression and higher scores reflecting greater severity of diseases. Baseline was defined as the assessment done on Day 1. Change from baseline was the difference between BECH 6 scale at the time point being analyzed to randomization. | Baseline (Day 1, pre-dose), Day 14 and Day 42 | 
| Change From Baseline in Quick Inventory of Depressive Symtomatology - Self Rated (QIDS-SR) Scale, on Day 14 and 42 | The QIDS-SR is a 16-item, participant-rated short form of the Inventory of Depressive Symptomatology that assesses 9 domains: sad mood, concentration, self-criticism, suicidal ideation, interest, energy/fatigue, sleep disturbance (initial, middle, and late insomnia or hypersomnia), appetite/weight increase/decrease and psychomotor agitation/retardation. A total score was obtained by summing scores on each domain. the scores ranges from 0 (none) to 27 (very severe), where the highest possible score was 27, which represented the most severe measure of depression; the lowest possible score was 0, which represents an absence of depression. Baseline was defined as the assessment done on Day 1. Change from Randomization in total score was the difference between QIDS total score at the time point being analyzed to randomization. | Baseline (Day 1, pre-dose), Day 14 and Day 42 | 
| Number of Participants With Suicidal Behavior and Suicidal Ideation Subscales of the Columbia Suicide Severity Rating Scale (C-SSRS) | The C-SSRS was a clinician-rated scale that evaluated severity and change of suicidality by integrating both behaviour and ideation. The 2 of 3 sections of the scale were suicidal behavior and suicidal ideation. For suicidal behaviour participants were scored as non-suicidal-0, preparatory acts or behavior communicating ideation-01, aborted attempt-2, interrupted attempt-3 or actual attempt-4. The score ranges from 0-4, where 0 was absence of suicidal behavior and 4 being the most severe form of suicidal behavior. On the Suicidal Ideation scale, participants were scored as non-suicidal-0, wish to be dead-1, non-specific active suicidal thoughts-2, active suicidal ideation with associated thoughts of methods without intent-3, active suicidal ideation with some intent to act on suicidal thoughts without clear plan-4, active suicidal ideation with plan and intent-5. The score ranges from 0-5, where 0 was absence of suicidal ideation and 5 being the most severe form of suicidal ideation. | Up to Day 52 | 
| Number of Participants With Abnormal Hematology Values of Clinical Concern Range (CCR). | Only those parameters for which at least one value of CC was reported were summarized. Pre-defined limits of CC (CC Low [relative to the lower limit of normal], CC High [relative to the upper limit of normal]) were: hemoglobin (Hb): > 25, 180; hematocrit (Hct): > 0.075, 0.54; absolute neutrophil count (ANC): < 1.5, NA; platelet: < 100, > 550; white blood cells (WBC): < 3,> 20 | Up to Day 42 | 
| Number of Participants With Abnormal Chemistry Values of CCR | Only those parameters for which at least one value of CC was reported were summarized. Pre-defined limits of CC (CC Low [relative to the lower limit of normal], CC High [relative to the upper limit of normal]) were: albumin (unit: gram per liter): < 30, NA; alanine aminotransferase (ALT): NA, >= 3 times upper limit of normal; aspartate aminotransferase (AST): NA, >= 3 times upper limit of normal; total bilirubin: NA, >=1.5 times upper limit of normal; calcium: < 2.0, > 2.75; gamma glutamyl transferase (GGT): < 3.0, > 9; potassium: < 3.0, > 5.5; magnesium: < 0.5, > 1.23. | Up to Day 42 | 
| Change From Baseline in Liver Chemistry -Alkaline Phosphatase (ALP), ALT, AST and GGT | Clinical liver chemistry parameters of Alkaline Phosphatase , ALT, AST, GGT were assessed on screening, Day 7, Day 14, Day 28 and Day 42. Screening was defined as Baseline. Change from Baseline in liver chemistry was the difference between the value at time point analyzed and screening. | Baseline (screening) up to Day 42 | 
| Change From Baseline in Liver Chemistry- Direct Bilirubin and Total Bilirubin | Liver chemistry parameters: Direct Bilirubin and Total Bilirubin were assessed on screening, Day 7, Day 14, Day 28 and Day 42. Screening was defined as Baseline. Change from Baseline in liver chemistry was the difference between the value at time point analyzed and screening. | Baseline (screening) up to Day 42 | 
| Number of Participant of Urinanalysis Assessment Over Period | Urinalysis parameters included: Urine Occult Blood, Urine Ketones, Urine Ketones. data for number of participants with abnormal urinanalysis parameters was reported by dipstick method. dipstick was a strip used to detect the presence or absence of these parameters in the urine sample. dipstick test gives results in a semi-quantitative manner, and results can be read as negative, Trace, 1+, 2+, and 3+, indicating proportional concentrations in the urine sample. Urine occult blood dipstick and urine general dipstick were semi quantitative results. Urine glucose and urine ketones dipstick results were in milimole per liter, urine protein dipstick results were in gram per liter. | Screening (Day -10 to -2), Day 14 and Day 42 | 
| Change From Baseline in Electrocardiogram (ECG) Values -PR Interval, QRS Duration, QT Interval, QTcB, QTcF, RR Interval | Data for change from Baseline was reported for PR Interval, QRS Duration, QT Interval, QTcB, QTcF, and RR Interval. 12-lead ECGs was obtained at each time point during the study using an ECG machine that automatically calculated the heart rate and measures PR, QRS, QT, and QTcB ,QTcF, and RR intervals. Day -1 evening (PM) was the Baseline for participants with only Day -1 records. Day 1 PM Dose was the Baseline for participants with Day 1 records. Baseline was the mean of replicate assessments. Change from Baseline was the difference between the value at the time point analyzed and baseline value. | Baseline (Day 1) and up to Day 42 | 
| Mean of Change From Baseline in Systolic and Diastolic Blood Pressure (BP) | Semi-supine systolic and diastolic blood pressure was assessed at the specified time points. Measurements were taken after the participant has been semi-supine for at least 5 minutes. BP was measured at least every hour until the values were within the normal range. Day 1 was Baseline and change from Baseline was difference between the value at the time point analyzed and baseline value. | Baseline (Day 1) , Day 2, 3, 4, 5, 6, 7, 8, 14, 21, 28 and 42 | 
| Mean of Change From Baseline in Heart Rate | Heart rate is the speed of the heartbeat measured by the number of contractions of the heart per minute, (beats per minute). Heart rate was assessed at the specified time points. Measurements were taken after the participant has been semi-supine for at least 5 minutes. Day 1 was Baseline and change from Baseline was difference between the value at the time point analyzed and baseline value. | Baseline (Day 1), Day 2, 3, 4, 5, 6, 7, 8, 14, 21, 28 and 42 | 
| Number of Participants With All Adverse Events (AEs), and Serious Adverse Events (SAEs) | Data for number of participants who presented one or more adverse events (serious or non serious) was reported. An AE was defined as any untoward medical occurrence (MO) in a participant temporally associated with the use of a medicinal product (MP), whether or not considered related to the MP and can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. The SAE was any untoward MO that, at any dose, results in death, life threatening, persistent or significant disability/incapacity, results in or prolongs inpatient hospitalization, congenital abnormality or birth defect, that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition. | Up to Day 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Last Observed Quantifiable Concentration (Ct) of GSK163090 Over the Period | Ctrough is defined as trough plasma concentration (measured concentration at the end of a dosing interval at steady state [taken directly before next administration]). Concentration was reported at specified time points. | Day 4 (AM pre-dose), Day 7 (AM and PM pre-dose), Day 10 (AM and PM pre-dose), Day 14 (AM and PM pre-dose), Day 21 (AM pre dose), Day 28 (AM pre dose), Day 42 (AM pre-dose and 4-6 h post AM dose) | 
| Area Under Concentration-time Curve (AUC) at Steady State | PK samples were supposed to be collected to estimate individual specific parameters like AUC however data for this outcome was not collected. | Day 4 (AM pre-dose), Day 7 (AM and PM pre-dose), Day 10 (AM and PM pre-dose), Day 14 (AM and PM pre-dose), Day 21 (AM pre dose), Day 28 (AM pre dose), Day 42 (AM pre-dose and 4-6 h post AM dose) | 
| Average Concentration (Cave) at Steady State | PK samples were supposed to be collected to estimate individual specific parameters like Cave however data for this outcome was not collected. | Day 4 (AM pre-dose), Day 7 (AM and PM pre-dose), Day 10 (AM and PM pre-dose), Day 14 (AM and PM pre-dose), Day 21 (AM pre dose), Day 28 (AM pre dose), Day 42 (AM pre-dose and 4-6 h post AM dose) | 
| Preliminary Pharmacokinetic/ Pharmacodynamic (PK/PD)Relationships for GSK163090 in Participants With MDD. | PK/PD relationships for GSK163090 in participants with MDD data was not collected. | Day 4 (AM pre-dose), Day 7 (AM and PM pre-dose), Day 10 (AM and PM pre-dose), Day 14 (AM and PM pre-dose), Day 21 (AM pre dose), Day 28 (AM pre dose), Day 42 (AM pre-dose and 4-6 h post AM dose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anti-depressant, Severe Depression, Efficacy, Major Depressive Disorder, Major Depressive Episode