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.: WELL AK130931 Title: A multicenter, double-blind, placebo-controlled comparison of the efficacy and safety of flexible dose extendedrelease bupropion hydrochloride (HCl) 300-450mg/day and placebo administered for eight weeks for the treatment of adult outpatients with major depressive disorder including symptoms of decreased energy, pleasure, and interest. Rationale: The purpose of this study was to evaluate the efficacy and safety of extended-release bupropion () versus placebo () in the treatment of subjects with a diagnosis of major depressive disorder including symptoms of decreased energy, pleasure, and interest, and to determine the effect of versus on this symptom triad. Phase: IIIB/IV Study Period: 24 June 2003 to 30 June 2004 Study Design: This was a multicenter, double-blind, randomized, parallel-group, -controlled study. Centers: 24 centers in the United States Indication: Major Depressive Disorder Treatment: Following a screening phase, subjects were enrolled in an 8-week treatment phase and received or matching placebo tablets. Subjects randomized to received 150mg/day for approximately 1 week and then their dose was uptitrated to 300mg/day. Subjects remained on 300mg/day for 3 weeks. If clinically indicated (i.e., additional efficacy was desired and the subject tolerated the current dose) the dose of could be increased to 450mg/day at Week 4. Any subject unable to tolerate 450mg/day was allowed to decrease their dose to 300mg/day for the duration of the study. Subjects unable to tolerate 300mg/day were allowed to decrease their dose to 150mg/day once during the study; subjects were then required to increase their dose back to 300mg/day after 1-2 weeks. If these subjects were unable to tolerate 300mg/day, they were to be discontinued from the study. Objectives: The primary objective of this study was to compare the effectiveness of versus in the treatment of adult outpatients with major depressive disorder including symptoms of decreased energy, pleasure, and interest as measured by the Inventory of Depressive Symptomatology-Self Report (IDS-SR). Primary Outcome/Efficacy Variable: The primary efficacy endpoint was the mean change from baseline (randomization) to Week 8/Study Exit in the IDS-SR total score. Secondary Outcome/Efficacy Variable(s): Secondary efficacy endpoints were the: (1) mean change from baseline to Week 8/Study Exit in the Inventory of Depressive Symptomatology-Clinician Rated (IDS-C) total score; (2) mean change from baseline to Week 8/Study Exit in the 5-item (Items 19, 20, 21, 22, and 30) subscale score of the IDS-SR assessing energy, pleasure, and interest; (3) percentage of IDS-SR responders (subjects with a reduction in IDS-SR total score of 50% from baseline) at Week 8/Study Exit); (4) percentage of IDS-SR remitters (subjects whose IDS- SR total score was 15) at Week 8/Study Exit; (5) percentage of Clinical Global Impression Improvement (CGI-I) responders (subjects with a score of much or very much improved on the CGI-I) at each study visit; (6) mean change from baseline to Week 8/Study Exit in the Clinical Global Impression Severity of Illness (CGI-S) total score; (7) percentage of Patient Global Impression Improvement (PGI-I) responders (subjects with a score of much or very much improved on the PGI-I) at each study visit); (8) mean change from baseline to Week 8/Study Exit in the Patient Global Impression Severity of Illness (PGI-S) total score; (9) mean change from baseline to Week 8/Study Exit in the 3-item (Items 1, 2, and 3) subscale score of the IDS-SR assessing insomnia. Health Outcome Variable(s): Health outcomes were assessed by the: (1) mean change from baseline to Week 8/Study Exit in the Quality of Life Enjoyment and Satisfaction Questionnaire Short-Form (Q-LES-Q-SF) General Activities Scale score; (2) mean change from baseline to Week 8/Study Exit in the Q-LES-Q-SF Life Satisfaction and Contentment Scale Score; (3) mean change from baseline to Week 8/Study Exit in the Motivation and Energy Inventory (MEI) total score; and (4) baseline and Week 8/Study Exits Q-LES-Q-SF Satisfaction with Medication questionnaire. Statistical Methods: Two populations were defined for the study: (1) the safety population, which consisted of any randomized subject who took at least one dose of study drug; and (2) the intent-to-treat (ITT) population, which consisted of all randomized subjects who took at least one dose of study drug and provided a baseline (Day 1) IDS- SR assessment and at least one IDS-SR assessment post-baseline. All efficacy analyses and all health outcome analyses were conducted using the ITT population. Treatment comparisons were primarily made using lastobservation-carried-forward (LOCF) values. Continuous endpoints were analyzed using analysis of covariance (ANCOVA) with center and treatment as fixed factors and value at baseline (randomization) visit as the continuous
covariate. Categorical endpoints were analyzed using Cochran-Mantel-Haenszel test controlling for center. Consistent with the fact that is a known antidepressant, the alternative hypothesis that was better than was tested, and one-sided p-values were calculated. [Note: The mean change from baseline in PGI-S score was not analyzed because PGI-S data were inadvertently not collected at Week 8/Study Exit.] Mean change from baseline in the IDS-SR total score, IDS-C total score, and 5-item energy, pleasure, and interest subscale score of the IDS-SR at Week 8/Study Exit were analyzed using one-sided p-values unadjusted for multiplicity. For secondary endpoints (3) through (9) in the Secondary Outcome/Efficacy Variable(s) section above, endpoints unadjusted and adjusted one-sided p-values (Hochberg) were compiled. Study Population: Male or female subjects of at least 18 years of age were eligible for this study if he/she had: (1) a primary diagnosis of major depressive disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders (4 th Edition)(DMS-IV) criteria and determined by a psychiatric interview that included the Mini International Neuropsychiatric Interview (MINI); (2) a minimum score of 25 on the IDS-SR when measured at screen (Day 7) and at baseline/randomization (Day 1); (3) scores of at least 1 on 4 out of 5 items on the 5-item subscale of the IDS-SR and a total score of at least 7 on the 5-item subscale of the IDS-SR at screening and baseline; and (4) a duration of current depressive episode of at least 12 weeks but no greater than 2 years and met all other inclusion/exclusion criteria. Number of Subjects: Planned, N 134 134 Enrolled/Randomized, N 135 139 Safety Population 135 139 ITT Population Completed, n (% Randomized) 103 (76.3) 110 (79.1) Total Number of Subjects Withdrawn, n (% Randomized) 32 (23.7) 29 (20.9) Withdrawn due to AEs, n (% Randomized) 12 (8.9) 3 (2.2) Withdrawn due to Lack of Efficacy, n (% Randomized) 1 (0.7) 6 (4.3) Withdrawn for Other Reasons, n (% Randomized) 19 (14.1) 20 (14.4) Demographics: (Safety Population) Females: Males 89:46 96:43 Mean Age, years (sd) 40.0 (12.2) 39.8 (11.9) White, 104 (77.0) 108 (77.7) Primary Efficacy Results: ITT Population N= N= Exit in IDS-SR Total Score (LOCF) Baseline Score Mean, 45.9 (0.8) 46.0 (0.8) -21.3 (1.4) -17.6 (1.4) p-value 0.018 Secondary Efficacy Results: (ITT Population) N= N= Exit in IDS-C Total Score (LOCF) Baseline Score Mean, 44.5 (0.7) 43.9 (0.7) -20.6 (1.3) -14.9 (1.3) Exit in 5-Item IDS-SR Energy, Pleasure, and Interest Subscale Score (LOCF) Baseline Score Mean, 11.6 (0.2) 11.9 (0.2) -6.7 (0.4) -5.3 (0.4) Percentage of IDS-SR Responders ( 50% reduction in IDS-SR Total Score from Baseline at Week 8/Study Exit) (LOCF) 71 (53.4) 61 (44.5) Percentage of IDS-SR Remitters (IDS-SR Total Score of 15 at
Week 8/Study Exit (LOCF) 54 (40.6) 37 (27.0) Percentage of CGI-I Responders (Score of much or very much improved from Baseline) at each Study Visit (LOCF) N= N= Week 1, n 20 (15.2) 6 (4.4) Week 2, n 41 (31.1) 24 (17.6) Week 4, n 58 (43.6) 42 (30.9) Week 6, n 68 (51.1) 47 (34.6) 70 (52.6) 51 (37.5) Exit in CGI-S Total Score (LOCF) Baseline Score Mean, 4.6 (0.1) 4.6 (0.1) -1.5 (0.1) -1.1 (0.1) Percentage of PGI-I Responders (Score of much or very much improved from Baseline) at each Study Visit (LOCF) Week 1, n 131 8 (6.1) 2 (1.5) Week 2, n 24 (18.2) 15 (10.9) Week 4, n 42 (31.6) 30 (21.9) Week 6, n 58 (43.6) 40 (29.2) 59 (44.4) 50 (36.5) Exit in PGI_S Total Score (LOCF) Baseline Score Mean, Not Available (NA) NA NA NA Exit in 3-Item IDS-SR Insomnia Subscale Score (LOCF) Baseline Score Mean, 5.9 (0.2) 5.7 (0.2) -2.1 (0.2) -1.5 (0.2) 32.9 (0.9) 32.5 (1.0) Exit in Q-LES-Q-SF General Activities 0-100 Scale Score (LOCF) Baseline Score Mean, 21.5 (1.8) 15.2 (1.8) 2.0 (0.1) 1.9 (0.1) Exit in Q-LES-Q-SF Life Satisfaction and Contentment Score (LOCF) Baseline Score Mean, 1.2 (0.1) 0.8 (0.1) 22.6 (1.0) 22.3 (1.0) Exit in MEI Total Score (LOCF) Baseline Score Mean, 24.5 (2.0) 17.4 (2.0)
Percentage of Subjects Taking Medication and Satisfied with Medication at Baseline and at Week 8/Study Exit (Randomized Population) Baseline, n Taking Medications Baseline Satisfaction Level, n Very Good, Good Fair Poor Very Poor 31 (23.3) 29 (21.2) 31 29 3 (9.7) 2 (6.9) 10 (32.3) 11 (37.9) 10 (32.3) 10 (34.5) 5 (16.1) 4 (13.8) 3 (9.7) 2 (6.9) 125 Taking Medications 63 (50.4) 74 (54.4) Week 8/Study Exit Satisfaction Level, n 63 74 Very Good, 14 (22.2) 9 (12.2) Good 15 (23.8) 16 (21.6) Fair 19 (30.2) 24 (32.4) Poor 9 (14.3) 17 (23.0) Very Poor 6 (9.5) 8 (10.8) Safety Results: All safety analyses were conducted using the Safety Population. An AE was defined as any untoward medical occurrence in a patient or clinical investigation subject temporally associated with the use of medicinal product, whether or not considered related to the product. Most Frequent Adverse Events On-Therapy (Safety Population) Subjects with any AE(s), n(%) 106 (78.5) 85 (61.2) Headache 31 (23.0) 32 (23.0) Dry Mouth 17 (12.6) 8 (5.8) Constipation 15 (11.1) 11(7.9) Nausea 14 (10.4) 7 (5.0) Dizziness 14 (10.4) 3 (2.2) Insomnia 1 11 (8.1) 3 (2.2) Anxiety 8 (5.9) 1 (0.7) Dyspepsia 8 (5.9) 0 Sinusitis 7 (5.2) 3 (2.2) Tremor 7 (5.2) 0 Back Pain 6 (4.4) 5 (3.6) Decreased Appetite 6 (4.4) 4 (2.9) Palpitations 6 (4.4) 4 (2.9) Diarrhea 5 (3.7) 12 (8.6) Irritability 3 (2.2) 6 (4.3) Upper Respiratory Tract Infection 5 (3.7) 5 (3.6) Upper Abdominal Pain 5 (3.7) 4 (2.9) Fatigue 2 (1.5) 4 (2.9) Myalgia 2 (1.5) 4 (2.9) Flatulence 0 4 (2.9) 1 Includes insomnia, initial insomnia, middle insomnia and early morning awakening Serious Adverse Events On Therapy (Safety Population) [n considered by the investigator to be related to study medication] Subjects with non-fatal SAE(s), n(%) 0 0 Subjects with fatal SAE(s), n(%) 0 0
Conclusion: See publication below. Publications: Rush J, VanMeter SA, Wightman D, Hampton KD, Krishen A, Modell JG. Wellbutrin XL for the treatment of adults with major depressive disorder. American Psychiatric Association 158 th Annual Meeting, Atlanta, GA, 21-26 May, 2005, Abstract No. 787. Rush J, VanMeter SA, Wightman DS, Hampton KD, Krishen A, Modell JG. Bupropion XL for the treatment of adults with major depressive disorder. 45 th Annual New Clinical Drug Evaluation Unit (NCDEU) Meeting, Boca Raton, FL, 6-9 June, 2005. Jefferson JW, Rush AJ, Nelson JC, VanMeter SA, Krishen A, Hampton KD, Wightman DS, Modell JG. Extendedrelease bupropion for major depressive disorder with symptoms of reduced energy, pleasure, and interest: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry, 2006; 67:865-873 Date Updated: 14-Jun-2007