Study No.: Title: Rationale: Phase: Study Period: Study Design: Centers: Indication: Treatment: Objectives: Primary Outcome/Efficacy Variable:

Transcription

1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: CRS Title: A Six-Week, Multicenter, Randomized, Double-Blind, -Controlled, Parallel-Group Study Evaluating the Efficacy, Safety, and Tolerability of GSK Compared to in Female Subjects, Diagnosed with Major Depressive Disorder Rationale: The primary purpose of this study was to evaluate the efficacy, safety, and tolerability of GSK compared with placebo in the treatment of female subjects with Major Depressive Disorder. Major Depressive Disorder (MDD) is a potentially serious illness that is associated with notable chronicity and disability. All antidepressants currently marketed world-wide for depression and anxiety target monoaminergic neurotransmitters. While available therapies are effective for many patients, more than half of depressed subjects may not achieve full remission and will continue to experience residual symptoms, with even greater challenges presenting for the treatment of severely depressed patients. Current pharmacological agents for depression and anxiety are not well tolerated by a significant proportion of individuals, and for those individuals that are able to tolerate treatment often several weeks of dosing are required to attain full benefits which may result in patients becoming discouraged and discontinuing treatment permanently. GSK is a selective corticotropin-releasing factor 1 (CRF1) receptor antagonist. Some preclinical data suggest that suppression of CRF hypersecretion may be a critical component of antidepressant treatment efficacy. Consequently, CRF1 receptor antagonists may provide a therapeutic approach to depression and anxiety by reducing a dispositional hypersensitivity to stress which results in low mood, increased emotionality and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis. Phase: IIa Study Period: 02 October 2008 to 18 June 2010 Study Design: A randomized, multicenter, double-blind, placebo-controlled study comprising of a 1 to 3-week Screening Phase, a 6-week Double-blind Treatment Phase, and a 4-week Follow-up Phase. Centers: There were 18 centers initiated across the United States (US). A total of 16 centers screened and enrolled at least 1 subject. Indication: Major Depressive Disorder (MDD) Treatment: Subjects were randomized 1:1 to either the /day or the placebo treatment groups. Subjects randomized to the GSK treatment group took 3 x 100 mg tablets plus 1 x 50 mg tablet once daily in the evening (approximately 6 pm to 8 pm), for 6 weeks. Subjects randomized to receive placebo took 4 placebo tablets once daily in the evening (approximately 6 pm to 8 pm), for 6 weeks. GlaxoSmithKline (GSK) supplied GSK in 100 mg and 50 mg tablet strengths, and matching GSK placebo tablets. Objectives: The primary objective of this study was to evaluate the antidepressant efficacy of GSK compared with placebo in female subjects diagnosed with Major Depressive Disorder (MDD). Primary Outcome/Efficacy Variable: Change from randomization to the end of the 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 (HAMD-17). Secondary Outcome/Efficacy Variable(s): Change from randomization to Weeks 1, 2, and 4 in the Bech Melancholia scale score. Change from randomization to Weeks 1, 2, 4, and 6 in the Hamilton Anxiety Scale (HAM A). Change from randomization to Weeks 1, 2, 3, 4, and 6 in the Inventory of Depressive Symptomatology-Self- Report (IDS-SR) total score. Change from randomization to Weeks 1, 2, 4, and 6 in the Hamilton Rating Scale for Depression (HAMD-17) total score. 1

2 Percentage of responders defined as: HAMD-17 Responders: Subjects with a 50% reduction from randomization in their HAMD-17 total score at Weeks 1, 2, 4, and 6. Time to maintained antidepressant response defined as: Maintained response in HAMD-17 total score: Subjects with a 50% reduction from randomization in HAMD-17 total score sustained until the end of the Treatment Phase (Week 6). Note: Not available (n/a) is noted in the results section for this endpoint. This analysis was not conducted as a result of the proportions of subjects meeting the criteria for maintained antidepressant response being low in both groups and greater for the placebo group as compared with the GSK treated group (20.2% for the placebo group; 11.3% for the GSK group). Change from randomization in the Clinical Global Impression - Severity of Illness (CGI-S) score at Weeks 1, 2, 4, and 6. Percentage of Clinical Global Impression - Global Improvement (CGI-I) responders (defined as subjects with a score of 1 [ very much improved ] or 2 [ much improved ] in the CGI-I) at Weeks 1, 2, 4, and 6. Change from randomization in the Medical Outcomes Study 12-item Sleep Module (MOS 12) at Week 6. Change from randomization in the Cohen Perceived Stress Scale (PSS) at Week 6. Statistical Methods: Planned enrollment was 150 subjects to obtain approximately 120 evaluable subjects completing at least Week 4 of the 6-week Double-blind Treatment Phase. The primary population of interest for efficacy analyses was the Intent-to-Treat (ITT) population, defined as all subjects who gave informed consent, were randomized, received at least one dose of double-blind medication, and had at least one post-randomization efficacy assessment available. The All Subjects Population, defined as all randomized subjects that had data present on the electronic case report form (ecrf), was the primary population of interest for safety analyses. All baseline values were collected at the Randomization Visit.The primary efficacy analysis was carried out on change from randomization to the end of the Treatment Phase (Week 6) in the total score for the Bech Melancholia subscale (Bech) from the Hamilton Rating Scale for Depression (HAMD-17). The planned Week 6 assessment also included the early withdrawal assessments performed for those subjects who discontinued from the study prematurely. The primary endpoint was analyzed using a Mixed-Model Repeated-Measures (MMRM) analysis. The MMRM model included terms for depression type (typicals versus atypicals), treatment, week, treatment*week, and baseline*week. Week was fitted as a repeated effect, and an unstructured correlation structure was employed. The results of the analysis were presented as point estimates, 80% confidence intervals (CIs) and associated p-values for the adjusted mean differences between GSK and placebo at each week. Secondary analyses were produced on all remaining efficacy endpoints. These analyses consisted of: MMRM analyses of change from randomization at each week in the o Bech scale total score (Weeks 1, 2 and 4) o HAMD-17 total score o IDS-SR total score o HAM-A total score o CGI-S score Analysis of Covariance (ANCOVA) of the following change from randomization endpoints measured at the end of treatment: o MOS-12, subscale SLP9 (sleep problem index 2 based on items # 1, 3, 4, 5, 6, 7, 8, 9, 12) score o Cohen PSS total score Logistic regression at each week to investigate the proportion of responders for the HAMD scale and for the CGI-I score A Cox proportional hazards model to investigate time to maintained antidepressant response 2

3 Study Population: Key inclusion criteria were: Non-pregnant, non-lactating female subjects between 18 to 64 years of age inclusive, with a psychiatric diagnosis of a Major Depressive Episode (MDE) associated with MDD according to the Diagnostic and Statistical Manual of Mental Disorders 4th Edition, Text Revision [DSM-IV-TR (296.2/296.3)]. Subject must, in the investigator s opinion based on clinical history, have met DSM IV-TR criteria for their current MDE for at least 4 weeks and had an Interactive Voice Response System (IVRS) HamD-17 total score 23, along with a confirmed score of at least 20 by the Independent Efficacy Rater, at the Screening and Randomization Visits. Subjects of child-bearing potential agreed to one of the protocol specified methods of contraception Subject was capable of understanding and providing informed consent Key exclusion criteria were: Subjects with a diagnosis or history of dementia, schizophrenia, bipolar disorder, borderline personality disorder, anorexia, bulimia, suicide attempts or suicidal behavior Subjects with significant lab abnormalities or unstable medical conditions Subjects that had initiated psychotherapy within one month prior to the Screening Visit Subjects that had received electroconvulsive therapy or transcranial magnetic stimulation within 6 months prior to screening Subjects that had failed to respond to an adequate course of pharmacotherapy of at least 2 different classes of antidepressants Subjects with positive urine drug screen or positive blood alcohol Subjects who were pregnant or nursing Subjects that had received psychoactive drugs (except sleep aids) within 1 week of Screening Visit Subjects with a history of peptic ulcer disease (PUD) not meeting protocol specified conditions Number of Subjects: Planned, N Randomized, N Completed, n (%) 55 (72) 52 (70) Total Number Subjects Withdrawn, N (%) 21 (28) 22 (30) Withdrawn due to Adverse Events n (%) 2 (3) 5 (7) Withdrawn due to Lack of Efficacy n (%) 1 (1) 0 Withdrawn for other reasons n (%) 18 (24) 17 (23) Demographics (All Subjects Population) N Females Mean Age, years (SD) 40.8 (12.17) 38.8 (11.31) African American/ African Heritage, n (%) 38 (50) 43 (58) White, n (%) 35 (46) 30 (41) Primary Efficacy Results (ITT Population): 6-item Bech scale from HAMD-17 (MMRM analysis) N=72 Baseline, mean (SD) 12.3 (1.84) 12.3 (1.66) Change from Randomization to Week 6 (Adjusted Mean [SE]) (0.5101) (0.5314) Difference between treatments % Confidence Interval [ , ] p-value

4 Secondary Outcome Variables (ITT Population): N=72 Treatment Comparison Adjusted Mean SE Adjusted Mean SE Difference 80% CI 6-item Bech scale from HAMD-17 (MMRM analysis) Baseline, mean (SD) 12.3 (1.84) 12.3 (1.66) Week [ , ] Week [ , ] Week [0.2203, ] HAMD-17 Score (MMRM analysis) Baseline, mean (SD) 24.6 (3.41) 24.5 (3.02) Week [ , ] Week [ , ] Week [0.3078, ] Week [ , ] HAM A Score (MMRM analysis) Baseline, mean (SD) 23.6 (5.59) 21.8 (5.67) Week [ , ] Week [ , ] Week [0.1485, ] Week [ , ] IDS-SR Total Score (MMRM analysis) Baseline, mean (SD) 47.1 (12.33) 47.4 (9.93) Week [ , ] Week [ , ] Week [ , ] Week [ , ] Week [ , ] CGI-S Score (MMRM analysis) Baseline, mean (SD) 4.5 (0.50) 4.6 (0.58) Week [ , ] Week [ , ] Week [0.1745, ] Week [0.0461, ] MOS-SLP9 Score (ANCOVA analysis) Baseline, mean (SD) 68.1 (15.66) 68.4 (12.91) Week [ , ] PSS Total Score (ANCOVA analysis) Baseline, mean (SD) 27.3 (5.78) 28.3 (5.64) Week [ , ] 4

5 N=72 Treatment Comparison Observed Proportion Observed Proportion Responders (%) Responders (%) Odds Ratio 80% CI HAMD-17 Responder Analysis (logistic model) Week 1 3/74 (4) 2/71 (3) Week 2 11/74 (15) 5/71 (7) [0.2105, ] Week 4 18/74 (24) 12/71 (17) [0.3776, ] Week 6 21/74 (28) 19/71 (27%) [0.5580, ] CGI-I Responder Analysis (logistic model) Week 1 4/74 (5) 2/72 (3) Week 2 12/74 (16) 8/72 (11) [0.3378, ] Week 4 24/74 (32) 18/72 (25) [0.4554, ] Week 6 27/74 (36) 24/72 (33) [0.5863, ] HAMD-17 Time to Maintained Response (Cox model) Week 6 n/a n/a n/a n/a Safety Results: AEs and SAEs were collected from the start of Investigational Product and until the final follow-up contact. SAEs assessed as related to study participation (e.g. investigational product, protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication were recorded from the time a subject consented to participate in the study up to and including any follow-up contact. An on therapy adverse event (AE) was defined as an AE where onset date is on or after the first day of treatment or before or on the last day of treatment, OR onset date is missing and stop date is after the first day of randomized treatment and on or before the stop date of medication. Most Frequent Adverse Events On-Therapy (the most frequent 10 AEs in each treatment group) N=76 n (%) n (%) Subjects with any AE(s), n(%) 58 (76) 55 (74) Nausea 10 (13) 15 (20) Headache 17 (22) 9 (12) Nasopharyngitis 5 (7) 6 (8) Constipation 2 (3) 5 (7) Dry mouth 5 (7) 5 (7) Insomnia 1 (1) 4 (5) Decreased appetite 1 (1) 3 (4) Diarrhea 5 (7) 3 (4) Dizziness 4 (5) 3 (4) Dyspepsia 3 (4) 3 (4) Fatigue 5 (7) 2 (3) Vomiting 4 (5) 2 (3) Flatulence 4 (5) 1 (1) Irritability 4 (5) 0 Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] N=76 n (%) [related] n (%) [related] Subjects with non-fatal SAEs, n (%) 1 (1) 0 Breast cancer stage II 1 (1)[0] 0 n (%) [related] n (%) [related] Subjects with fatal SAEs, n (%) 0 0 5

6 Conclusion: There were no statistically significant differences between GSK and placebo at Week 6 for the primary endpoint, change from randomization to the end of the Treatment Phase (Week 6) in the 6-item Bech scale extracted from HAMD-17. In the GSK group 55 (74%) subjects reported non-serious adverse events with the 2 most frequently reported being nausea (15 [20%] subjects) and headache (9 [12%] subjects). In the placebo treated group 58 (76%) subjects reported non-serious adverse events with the 2 most frequently reported being headache (17 [22%] subjects) and nausea (10 [13%] subjects). One serious adverse event, Breast cancer stage II, was reported in the placebo group. There were no fatalities reported in study. 6