Study to Evaluate the Efficacy, Safety and Tolerability of Bupropion Hydrochloride Extended-release Tablet, and Escitalopram Oxalate Capsule in Subjects With Major Depressive Disorder

Sponsor

GlaxoSmithKline (Industry)

Overall Status

Completed

CT.gov ID

NCT02191397

Collaborator

(none)

534

Enrollment

Locations

Arms

20.5

Actual Duration (Months)

26.7

Patients Per Site

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This multi-centre study will follow a randomised, double-blind, parallel-group, active-controlled design and will evaluate the efficacy, safety and tolerability of bupropion extended-release (XL) (300 mg/day) compared with escitalopram (10-20 mg/day) in outpatients and inpatients with major depressive disorder (MDD). The total duration of the study will be 11 weeks consisting of three phases. The screening phase (phase I) will be lasting for 0-14 days, subjects will be randomised to bupropion XL or escitalopram in a 1:1 ratio for acute phase treatment phase (phase II) for 8 weeks. There are 3 dose levels during this acute treatment phase. The 3-dose level plan is designed to ensure each drug is titrated according to the prescribing information and to reach an optimal clinical dose. Finally patients will enter the taper phase (phase III) for up to 1 week to assess and reduce the possible withdrawal symptoms.

In China almost all existing antidepressants are available on the market, but bupropion XL has not yet been approved. This Phase III clinical trial will be used for the purpose of registering bupropion XL in China.

Condition or Disease	Intervention/Treatment	Phase
Depressive Disorder, Major	Drug: Bupropion Drug: Bupropion Matching Placebo Drug: Escitalopram Drug: Escitalopram Matching Placebo	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

534 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

A Multi-centre, Randomised, Double-blind, Parallel Active-controlled Study Evaluating the Efficacy, Safety and Tolerability of Bupropion Hydrochloride Extended-release (Bupropion XL 300mg Once Daily), Escitalopram Oxalate (Escitalopram, 10mg-20mg Once Daily) in Subjects With Major Depressive Disorder

Actual Study Start Date :

Feb 10, 2015

Actual Primary Completion Date :

Oct 10, 2016

Actual Study Completion Date :

Oct 25, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bupropion Treatment Arm Subject will receive bupropion in 3 dose levels along with escitalopram matching placebo to maintain the blind in acute treatment phase. At dose level 1 (Week 0 to Week 1), Subjects will receive bupropion XL 150 milligram (mg) per day for a week. At dose level 2 (Week 1 to Week 4), bupropion XL dose will be increased to 300mg/day for further 3 weeks. At dose level 3 (Week 4 to Week 8), bupropion XL dose will be maintained at 300mg/day. Subjects intolerable to dose level 3 will be allowed to down titrate to dose level 2 at anytime, and maintain the dose until the end of acute treatment phase (Week 8, Visit 7). At the end of acute treatment phase, the dose of bupropion XL will be reduced to 150mg/day for 1 week before discontinuation.	Drug: Bupropion Bupropion is an extended-release plain creamy white colored tablet which contains bupropion hydrochloride equivalent to 150 mg of bupropion. Drug: Escitalopram Matching Placebo Escitalopram oxalate matching placebo tablets will be supplied to maintain blinding
Active Comparator: Escitalopram Treatment Arm Subject will receive escitalopram in 3 dose levels along with bupropion matching placebo to maintain the blind in acute treatment phase. At dose level 1 (Week 0 to Week 1), Subjects will receive escitalopram 10mg/day for a week. At dose level 2 (Week 1 to Week 4), escitalopram dose will be maintained at 10mg/day for further 3 weeks. At dose level 3 (Week 4 to Week 8), escitalopram dose will be increased to 20mg/day. Subjects intolerable to dose level 3 will be allowed to down titrate to dose level 2 at anytime, and maintain the dose until the end of acute treatment phase (Week 8, Visit 7). At the end of acute treatment phase, the dose of escitalopram 20mg/day, the dose will be reduced to 10 mg/day for 1 week before discontinuation, while those receiving 10mg/day will discontinuation directly.	Drug: Bupropion Matching Placebo Bupropion hydrochloride matching placebo tablets will be supplied to maintain blinding Drug: Escitalopram Escitalopram is available as a Swedish orange capsule containing escitalopram oxalate equivalent to 10 mg of escitalopram.

Arm

Intervention/Treatment

Experimental: Bupropion Treatment Arm

Subject will receive bupropion in 3 dose levels along with escitalopram matching placebo to maintain the blind in acute treatment phase. At dose level 1 (Week 0 to Week 1), Subjects will receive bupropion XL 150 milligram (mg) per day for a week. At dose level 2 (Week 1 to Week 4), bupropion XL dose will be increased to 300mg/day for further 3 weeks. At dose level 3 (Week 4 to Week 8), bupropion XL dose will be maintained at 300mg/day. Subjects intolerable to dose level 3 will be allowed to down titrate to dose level 2 at anytime, and maintain the dose until the end of acute treatment phase (Week 8, Visit 7). At the end of acute treatment phase, the dose of bupropion XL will be reduced to 150mg/day for 1 week before discontinuation.

Drug: Bupropion

Bupropion is an extended-release plain creamy white colored tablet which contains bupropion hydrochloride equivalent to 150 mg of bupropion.

Drug: Escitalopram Matching Placebo

Escitalopram oxalate matching placebo tablets will be supplied to maintain blinding

Active Comparator: Escitalopram Treatment Arm

Subject will receive escitalopram in 3 dose levels along with bupropion matching placebo to maintain the blind in acute treatment phase. At dose level 1 (Week 0 to Week 1), Subjects will receive escitalopram 10mg/day for a week. At dose level 2 (Week 1 to Week 4), escitalopram dose will be maintained at 10mg/day for further 3 weeks. At dose level 3 (Week 4 to Week 8), escitalopram dose will be increased to 20mg/day. Subjects intolerable to dose level 3 will be allowed to down titrate to dose level 2 at anytime, and maintain the dose until the end of acute treatment phase (Week 8, Visit 7). At the end of acute treatment phase, the dose of escitalopram 20mg/day, the dose will be reduced to 10 mg/day for 1 week before discontinuation, while those receiving 10mg/day will discontinuation directly.

Drug: Bupropion Matching Placebo

Bupropion hydrochloride matching placebo tablets will be supplied to maintain blinding

Drug: Escitalopram

Escitalopram is available as a Swedish orange capsule containing escitalopram oxalate equivalent to 10 mg of escitalopram.

Outcome Measures

Primary Outcome Measures

Mean Change in Hamilton Depression Rating Scale - 17 (HAMD-17) Total Score From Baseline to End of Acute Treatment Phase (Week 8) [Baseline (Week 0) and Week 8]
HAMD-17 is used to assess the severity of depression and symptom improvement. It consisted of 17 questions. The HAMD-17 total score is calculated by summing the individual response scores if there is no missing response. HAMD-17 has a total score in a range of 0 (not present) to 52 (severe). Change from Baseline was calculated by subtracting the Baseline total score (at Day 0, Week 0) from Week 8 observed total score. The Per Protocol (PP) Population is defined as all randomized participants in the Intent-To-Treat (ITT) Population who do not meet criteria of a major protocol deviation, with overall compliance of active drug for acute treatment phase in the range of 75%-125% and complete the first 6 weeks treatment and has HAMD-17 assessment at/after week 6 (that is >=35 days). All participants in the PP population were included in the mixed model repeated measures analysis. Only those participants with data available at the specified time point were analyzed.

Secondary Outcome Measures

Response Rate Based on HAMD-17 Total Score [Up to Week 8]
HAMD-17 is an extensively used tool to assess the severity of depression and symptom improvement during the treatment. The HAMD-17 adopted for this study consisted of 17 questions with multiple choice responses, each of which is numerically scored. The HAMD-17 total score is calculated by summing the individual response scores if there is no missing response. HAMD-17 has a total score in a range of 0 (not present) to 52 (severe). Values at Day 0, Week 0 was considered as Baseline value. Response was defined as decrease in HAMD-17 total scores at end of acute treatment phase (Week 8) relative to Baseline by at least 50%. Non-responder Imputation was used in calculation of rates.
Remission Rate Based on HAMD-17 Total Score [Up to Week 8]
HAMD-17 is an extensively used tool to assess the severity of depression and symptom improvement during the treatment. The HAMD-17 adopted for this study consisted of 17 questions with multiple choice responses, each of which is numerically scored. The HAMD-17 total score is calculated by summing the individual response scores if there is no missing response. HAMD-17 has a total score in a range of 0 (not present) to 52 (severe). Values at Day 0, Week 0 was considered as Baseline value. Remission was defined as HAMD-17 total scores at end of acute treatment phase (Week 8) <=7.
Sustained Response Rate Based on HAMD-17 Total Score [Up to Week 8]
HAMD-17 is an extensively used tool to assess the severity of depression and symptom improvement during the treatment. The HAMD-17 adopted for this study consisted of 17 questions with multiple choice responses, each of which is numerically scored. The HAMD-17 total score is calculated by summing the individual response scores if there is no missing response. HAMD-17 has a total score in a range of 0 (not present) to 52 (severe). Values at Day 0, Week 0 was considered as Baseline value. Sustained response was defined as response at end of acute treatment phase and an earlier visit and the decrease from Baseline in non-missing HAMD-17 total scores at all visits between these two visits by at least 40%.
Sustained Remission Rate Based on HAMD-17 Total Score [Up to Week 8]
HAMD-17 is an extensively used tool to assess the severity of depression and symptom improvement during the treatment. The HAMD-17 adopted for this study consisted of 17 questions with multiple choice responses, each of which is numerically scored. The HAMD-17 total score is calculated by summing the individual response scores if there is no missing response. HAMD-17 has a total score in a range of 0 (not present) to 52 (severe). Values at Day 0, Week 0 was considered as Baseline value. Sustained remission was defined as remission at end of acute treatment phase and an earlier visit and non-missing HAMD-17 total scores at all visits between these two visits <=8.
Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at Weeks 1, 2, 4, 6 and 8 [Baseline (Week 0) and Weeks 1, 2, 4, 6 and 8]
MADRS is a 10-point rating scale. Each item is scored on a scale of 0-6, with a total score range of 0-60. Higher score indicates worst symptoms. This scale is mainly used to assess the efficacy of antidepressant treatment. The ratings were based on the signs and symptoms during the preceding week prior to the visit. Values at Day0, Week 0 was considered as Baseline value. The observed MADRS total score was considered as missing if any item is missing. Change from Baseline in MADRS was obtained by subtracting the Baseline value from the specific post-Baseline value. All participants in the PP population were analyzed and n=X in the category titles represented the number of participants with data available at the specified time points.
Change From Baseline in HAMD-17 Depressed Mood Subscale Score (Score of Item 1) at Weeks 1, 2, 4, 6 and 8 [Baseline (Week 0) and Weeks 1, 2, 4, 6 and 8]
HAMD-17 is an extensively used tool to assess the severity of depression and symptom improvement during the treatment. The HAMD-17 adopted for this study consisted of 17 questions with multiple choice responses, each of which is numerically scored. The HAMD-17 Depressed Mood Subscale is a factor score of item-1 (Depressed Mood) of HAMD-17 scale. This subscale has a score in a range of 0 (absence of depressed mood feelings) to 4 (when participants report virtually only these feeling states in his/her spontaneous verbal and non-verbal communicationtotal score). Values at Day 0, Week 0 was considered as Baseline value. Change from Baseline was calculated by subtracting the Baseline response from the specific post-Baseline response. All participants in the PP population were analyzed and n=X in the category titles represented the number of participants with data available at the specified time points.
Change From Baseline in HAMD-17 Anxiety/Somatization Subscale Score (Sum of Scores of Items 10, 11, 12, 13, 15 and 17) at Weeks 1, 2, 4, 6 and 8 [Baseline (Week 0) and Weeks 1, 2, 4, 6 and 8]
HAMD-17 is an extensively used tool to assess the severity of depression and symptom improvement during the treatment. The HAMD-17 adopted for this study consisted of 17 questions with multiple choice responses, each of which is numerically scored. The HAMD-17 Anxiety/Somatization subscale score was derived as sum of scores of items 10, 11, 12, 13, 15 and 17 from HAMD-17. This subscale has a score in a range of 0 (absence of condition) to 18 (most severe condition). Values at Day 0, Week 0 was considered as Baseline value. Change from Baseline was calculated by subtracting the Baseline response from the specific post-Baseline response. All participants in the PP population were analyzed and n=X in the category titles represented the number of participants with data available at the specified time points.
Change From Baseline in HAMD-17 Retardation Subscale Score (Sum of Scores of Items 1, 7, 8 and 14) at Weeks 1, 2, 4, 6 and 8 [Baseline (Week 0) and Weeks 1, 2, 4, 6 and 8]
HAMD-17 is an extensively used tool to assess the severity of depression and symptom improvement during the treatment. The HAMD-17 adopted for this study consisted of 17 questions with multiple choice responses, each of which is numerically scored. The HAMD-17 Retardation subscale score was derived as sum of scores of items 1, 7, 8 and 14 from HAMD-17. This subscale has a score in a range of 0 (absence of condition) to 14 (most severe condition). Values at Day 0, Week 0 was considered as Baseline value. Change from Baseline was calculated by subtracting the Baseline response from the specific post-Baseline response. All participants in the PP population were analyzed and n=X in the category titles represented the number of participants with data available at the specified time points.
Change From Baseline in HAMD-17 Sleep Disorder Subscale Score (Sum of Scores of Items 4, 5 and 6) at Weeks 1, 2, 4, 6 and 8 [Baseline (Week 0) and Weeks 1, 2, 4, 6 and 8]
HAMD-17 is an extensively used tool to assess the severity of depression and symptom improvement during the treatment. The HAMD-17 adopted for this study consisted of 17 questions with multiple choice responses, each of which is numerically scored. The HAMD-17 Sleep Disorder subscale score was derived as sum of scores of items 4, 5 and 6 from HAMD-17. This subscale has a score in a range of 0 (absence of condition) to 6 (most severe condition). Values at Day 0, Week 0 was considered as Baseline value. Change from Baseline was calculated by subtracting the Baseline response from the specific post-Baseline response. All participants in the PP population were analyzed and n=X in the category titles represented the number of participants with data available at the specified time points.
Change From Baseline in Clinical Global Impression-Severity of Illness Scale (CGI-S) Score at Weeks 1, 2, 4, 6 and 8 [Baseline (Week 0) and Weeks 1, 2, 4, 6 and 8]
CGI-S records the severity of illness at specific time points, with a range of responses from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). Participants with zero values (0) representing "Not assessed" were excluded from analysis. Values at Day 0, Week 0 was considered as Baseline value. Change from Baseline was obtained by subtracting the Baseline value from the specific post-Baseline value. All participants in the PP population were analyzed and n=X in the category titles represented the number of participants with data available at the specified time points.
Percentage of Participants With a Clinical Global Impression Global Improvement (CGI-I) Score of 1 ("Very Much Improved") or 2 ("Much Improved") at Weeks 1, 2, 4, 6 and 8 [Baseline (Week 0) and Weeks 1, 2, 4, 6 and 8]
For CGI-I rating, the raters indicated their assessment of the participant's total improvement or worsening compared to the participant's condition at the Baseline visit, whether or not the improvement or worsening was thought to be treatment related. Scores ranges from 0 to 7 where 0 represents "Not assessed", and the remaining values 1-7 represent "Very much improved" (1) to "Very much worse" (7). Participants with score 0 were excluded from analysis. All participants in the PP population were analyzed and n=X in the category titles represented the number of participants with data available at the specified time points.
Number of Participants With Any Non-serious Adverse Event (AE) and Any Serious AE (SAE) [Up to Week 10]
An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment 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 or all events of possible drug-induced liver injury with hyperbilirubinemia were categorized as SAE. Participants who received any of the study treatment and had any non-serious AE or SAE were considered for analysis. Safety Population comprised of all participants who took at least one dose of the study medication.
Change From Baseline in Hemoglobin, Total Protein, Albumin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points [Up to Week 10]
Blood samples were collected at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). Baseline was considered as the value obtained at Screening. Change from Baseline was calculated by subtracting the Baseline value from the specific post-Baseline values. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Change From Baseline in Hematocrit at the Indicated Time Points [Up to Week 10]
Blood samples were collected at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). Baseline was considered as the value obtained at Screening. Change from Baseline was calculated by subtracting the Baseline value from the specific post-Baseline values. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Change From Baseline in White Blood Cell (WBC) Count, Total Neutrophil, Lymphocyte, Basophil, Eosinophil, Monocyte and Platelet Count at the Indicated Time Points [Up to Week 10]
Blood samples were collected at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). Baseline was considered as the value obtained at Screening. Change from Baseline was calculated by subtracting the Baseline value from the specific post-Baseline values. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Change From Baseline in Total Bilirubin, Direct Bilirubin and Creatinine at the Indicated Time Points [Up to Week 10]
Blood samples were collected at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). Baseline was considered as the value obtained at Screening. Change from Baseline was calculated by subtracting the Baseline value from the specific post-Baseline values. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Change From Baseline in Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), Gamma-glutamyl Transpeptidase (GGT) and Lactose Dehydrogenase (LD) at the Indicated Time Points [Up to Week 10]
Blood samples were collected at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). Baseline was considered as the value obtained at Screening. Change from Baseline was calculated by subtracting the Baseline value from the specific post-Baseline values. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Change From Baseline in Calcium, Chloride, Cholesterol, Glucose, Potassium, Sodium, Triglyceride and Urea at the Indicated Time Points [Up to Week 10]
Blood samples were collected at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). Baseline was considered as the value obtained at Screening. Change from Baseline was calculated by subtracting the Baseline value from the specific post-Baseline values. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Change From Baseline in Mean Corpuscle Hemoglobin (MCH) at the Indicated Time Points [Up to Week 10]
Blood samples were collected at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). Baseline was considered as the value obtained at Screening. Change from Baseline was calculated by subtracting the Baseline value from the specific post-Baseline values. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Change From Baseline in Mean Corpuscle Volume (MCV) at the Indicated Time Points [Up to Week 10]
Blood samples were collected at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). Baseline was considered as the value obtained at Screening. Change from Baseline was calculated by subtracting the Baseline value from the specific post-Baseline values. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Change From Baseline in Red Blood Cell (RBC) Count at the Indicated Time Points [Up to Week 10]
Blood samples were collected at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). Baseline was considered as the value obtained at Screening. Change from Baseline was calculated by subtracting the Baseline value from the specific post-Baseline values. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Number of Participants With Urinalysis Data Outside the Normal Range [Up to Week 10]
Urine samples were collected at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). Number of participants with urine specific gravity and potential of hydrogen (pH) outside (higher or lower) the normal range are presented. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Number of Participants With Vital Sign Parameters Outside the Clinical Concern Range [Up to Week 10]
Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were taken at Screening (within 14 days prior to dosing), randomization visit (Week 0) and at Weeks 1, 2, 4, 6, 8, Taper visit (Week 9) and Follow-up visit (Week 10). SBP <30 or >170 millimeter of mercury (mmHg); DBP <20 or >110 mmHg and heart rate <40 or >120 beats per minute (bpm) were considered as values outside of clinical concern range and were presented as 'High' or 'Low' values. Number of participants with vital signs outside of clinical concern range at any post-Baseline visit are presented. Only those participants with data available at the specified time points were analyzed.
Number of Participants With Electrocardiogram (ECG) Data Outside the Clinical Concern Range [Up to Week 10]
ECG was recorded at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). PR interval <110 or >220 millisecond (msec); QRS interval <60 or >120 msec and corrected QT (QTc) interval >450 msec were considered as values outside of clinical concern range and were presented as 'High' or 'Low' values. Number of participants with ECG data outside of clinical concern range at any post-Baseline visit are presented. Only those participants with data available at the specified time points were analyzed.
Change From Baseline in Changes in Sexual Function Questionnaire (CSFQ) [Baseline (Day 0) and Week 8]
CSFQ is a questionnaire about sexual activity and sexual function (sexual intercourse, masturbation, sexual fantasies and other activity). CSFQ is a gender-specific questionnaire. Both male and female versions consist of 14 items, each with 5 possible answers. CSFQ has a score in a range of 14 to 70. Higher score indicates higher sexual activity and sexual function. Value at Day 0 (Week 0) was considered as Baseline value. Change from Baseline at Week 8 was calculated by subtracting the Baseline score from the specific post-Baseline score. Only those participants with data available at the specified time points were analyzed.
Number of Participants With Suicidal Ideation or Behavior During Treatment Assessed by Columbia Suicide Severity Rating Scale (C-SSRS) [Baseline and up to Taper visit (Week 9)]
C-SSRS is an assessment tool that evaluates suicidal ideation and behavior. It consists of 10 items, each with two possible answers (yes/no). Suicidal ideation was interpreted if "yes" answer at any time during treatment to any one of the five suicidal ideation questions (item 1-5) on the C-SSRS. Suicidal behavior was interpreted if a "yes" answer at any time during treatment to any one of the five suicidal behavior questions (item 6-10) on the C-SSRS. Suicidal ideation or behavior is interpreted if a "yes" answer at any time during treatment to any one of the ten suicidal ideation and behavior questions (item 1-10) on the C-SSRS. Number of participants with at least one on-treatment C-SSRS assessment were analyzed. Only those participants with data available at the specified time points were analyzed.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Subjects must have the ability to effectively communicate with investigator, complete study related documents, comprehend the key components of the consent form and must provide written informed consent to participate in the study prior to any study-specific assessments or procedures.
An in- patient or out-patient (male or female) and aged >=18 years.
A diagnosis of MDD, nonpsychotic, single episode or recurrent, Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) (296.2/296.3), utilizing the Mini International Neuropsychiatric Interview (MINI).
Established MDD diagnosis with a duration of at least 4 weeks.
HAMD-17 total score of >=20 and a CGI-S score of >=4 at both the Screening Visit and the Baseline Visit.
Subject must be in general good health and be considered clinically appropriate for therapy with bupropion or escitalopram, based upon the investigator's overall clinical evaluation.
Female patients of child-bearing potential only: patients must not be lactating and must test negative for pregnancy at screening and agree to use a medically accepted method of birth control during the study.
Liver function tests: alanine aminotransferase (ALT) <2x upper limit of normal (ULN); alkaline phosphatase and bilirubin <=1.5xULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
Corrected QT (QTc) criteria： QTc <450 milliseconds (msec) or QTc <480msec for patients with bundle branch block. The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB), Fridericia's formula (QTcF), or machine or manual overread. For subject eligibility and withdrawal, QTcF will be used. For purpose of data analysis, QTcF will be used. The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period.

Exclusion Criteria:

Has been diagnosed or received treatment for a primary Axis I disorder with the exception of MDD (including current or past diagnosis of anorexia nervosa or bulimia). Additionally, subjects diagnosed with dysthymic disorder within the past 2 years will be excluded.
Current DSM-IV Axis II diagnosis that suggests non-compliance with the protocol.
A subject who, in the assessment with the Columbia Suicide Severity Rating Scale (C-SSRS) and investigator's judgment, poses suicidal risk, or had suicide attempt or behavior within 6 months prior to the Screening Visit.
Current or past history of seizure disorder or brain injury (traumatic or disease related); or any condition which, in the opinion of the investigator, predisposed to seizure; subjects treated with other medications or treatment regimes that lower seizure threshold. Note: single childhood febrile seizure is not exclusionary.
In the Investigator's judgment, presence of clinically significant laboratory test results (including ECG, hematology, chemistry and urine), or the conditions which render patients unsuitable for the study (such as serious cardiovascular disease, uncontrolled hypertension, liver or renal insufficiency) and pose a safety concern or interfere with the accurate safety and efficacy assessments. Subjects with co-morbidities (such as diabetes, hypertension, hypothyroid, chronic respiratory diseases or other physical illness) were eligible if their condition had been stable for at least three months and they had been receiving standard therapy for the condition for at least three months.
Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
Frequent and/or severe allergic reactions with multiple medications, or history of a medically significant adverse effect (including allergic reaction) from any medications or compounds in the study.
Use of prohibited psychotropic drugs not allowed within seven days (14 days for monoamine oxidase inhibitors (MAOIs), 30 days for fluoxetine) prior to the Baseline Visit.
Subjects who have attended any studies investigating bupropion or escitalopram 6 months prior to this study, or use of bupropion or escitalopram in the last 4 weeks.
Participation in other clinical studies unrelated to the current illness within 30 days or participation in other clinical studies related to the current illness within 3 months.
Initiation of systematic psychotherapy within three months prior to the Screening Visit, or plans to initiate systematic psychotherapy during the study.
Received electroconvulsive therapy (ECT), modify electroconvulsive therapy (MECT), transcranial magnetic stimulation (TMS), or other physical therapy within the 6 months prior to the Screening Visit.
Previous failure of bupropion or escitalopram treatment with adequate courses and doses.
Previous or present failure of two different classes of antidepressants treatment with adequate courses (e.g. maximum labelled doses for >=4 weeks).
History of substance abuse (alcohol or drugs) or substance dependence within 12 months (as defined in the DSM-IV).
Other conditions which, in the Investigator's judgment, render patients unsuitable for the clinical study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Guangzhou	Guangdong	China	510180
2	GSK Investigational Site	Nanning	Guangxi	China	530021
3	GSK Investigational Site	Guiyang	Guizhou	China	550004
4	GSK Investigational Site	Baoding	Hebei	China	071000
5	GSK Investigational Site	Harbin	Heilongjiang	China	150070
6	GSK Investigational Site	Changsha	Henan	China	410011
7	GSK Investigational Site	Changsha	Hunan	China
8	GSK Investigational Site	Nanjing	Jiangsu	China	210029
9	GSK Investigational Site	Xian	Shaanxi	China	710032
10	GSK Investigational Site	Taiyuan	Shanxi	China
11	GSK Investigational Site	Xi'an	Shanxi	China
12	GSK Investigational Site	Kunming	Yunnan	China	650032
13	GSK Investigational Site	Hangzhou	Zhejiang	China	310003
14	GSK Investigational Site	Beijing		China	100083
15	GSK Investigational Site	Beijing		China	100088
16	GSK Investigational Site	Beijing		China	100096
17	GSK Investigational Site	Guangzhou		China	510370
18	GSK Investigational Site	Shanghai		China	200030
19	GSK Investigational Site	Shanghai		China	200065
20	GSK Investigational Site	Wuhan		China

Sponsors and Collaborators

GlaxoSmithKline

Investigators

Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Publications

Shen Y, Zhao Q, Yu Y, Tan Y, Zhang H, Xu X, Wang Z, Li Y, Hu J, Zhong J, Li H. Efficacy and safety of bupropion hydrochloride extended-release versus escitalopram oxalate in Chinese patients with major depressive disorder: Results from a randomized, double-blind, non-inferiority trial. J Affect Disord. 2019 Oct 1;257:143-149. doi: 10.1016/j.jad.2019.07.023. Epub 2019 Jul 5.

Responsible Party:

GlaxoSmithKline

ClinicalTrials.gov Identifier:

NCT02191397

Other Study ID Numbers:

114589

First Posted:

Jul 16, 2014

Last Update Posted:

Feb 25, 2020

Last Verified:

Feb 1, 2020

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Keywords provided by GlaxoSmithKline

Escitalopram

Major depressive disorder

Non-inferiority

Bupropion

Additional relevant MeSH terms:

Disease

Depressive Disorder

Depression

Depressive Disorder, Major

Dexetimide

Citalopram

Bupropion

Study Results

Participant Flow

Recruitment Details	This was a multi-center, randomized, double-blind, parallel active-controlled study to evaluate the efficacy, safety and tolerability of bupropion hydrochloride extended-release (XL) and escitalopram oxalate in participants with major depressive disorder. This study was conducted in China from 10-February-2015 to 25-October-2016.
Pre-assignment Detail	The study had screening phase (up to 14 days), 8-week double blind treatment phase and taper phase (up to 1 week). A total of 655 participants were screened and 538 were randomized into the study. 4 participants were randomized but discontinued prior to receiving any study treatment. Hence, the Safety Population was comprised of 534 participants.

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Period Title: Overall Study
STARTED	266	268
COMPLETED	183	198
NOT COMPLETED	83	70

Baseline Characteristics

Arm/Group Title	Bupropion XL	Escitalopram	Total
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	Total of all reporting groups
Overall Participants	266	268	534
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	36.9 (11.92)	37.6 (12.09)	37.3 (12.00)
Sex: Female, Male (Count of Participants)
Female	168 63.2%	172 64.2%	340 63.7%
Male	98 36.8%	96 35.8%	194 36.3%
Race/Ethnicity, Customized (Count of Participants)
Asian - East Asian Heritage	266 100%	268 100%	534 100%

Outcome Measures

1. Primary Outcome

Title	Mean Change in Hamilton Depression Rating Scale - 17 (HAMD-17) Total Score From Baseline to End of Acute Treatment Phase (Week 8)
Description	HAMD-17 is used to assess the severity of depression and symptom improvement. It consisted of 17 questions. The HAMD-17 total score is calculated by summing the individual response scores if there is no missing response. HAMD-17 has a total score in a range of 0 (not present) to 52 (severe). Change from Baseline was calculated by subtracting the Baseline total score (at Day 0, Week 0) from Week 8 observed total score. The Per Protocol (PP) Population is defined as all randomized participants in the Intent-To-Treat (ITT) Population who do not meet criteria of a major protocol deviation, with overall compliance of active drug for acute treatment phase in the range of 75%-125% and complete the first 6 weeks treatment and has HAMD-17 assessment at/after week 6 (that is >=35 days). All participants in the PP population were included in the mixed model repeated measures analysis. Only those participants with data available at the specified time point were analyzed.
Time Frame	Baseline (Week 0) and Week 8

Outcome Measure Data

Analysis Population Description
PP Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	176	188
Least Squares Mean (Standard Error) [Scores on a scale]	-14.5 (0.41)	-15.4 (0.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	A one-sided 97.5% confidence interval for the between-treatment difference (bupropion XL-escitalopram) was compared with the pre-defined non-inferiority margin of 2.2. If the upper limit of the one-sided 97.5% confidence interval was below 2.2, then it indicated that bupropion was not inferior in efficacy to escitalopram.

Statistical Test of Hypothesis	p-Value	0.139
	Comments	Analysis included Baseline HAMD-17 total score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95% -0.27 to 1.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	Observed Cases (OC) dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

2. Secondary Outcome

Title	Response Rate Based on HAMD-17 Total Score
Description	HAMD-17 is an extensively used tool to assess the severity of depression and symptom improvement during the treatment. The HAMD-17 adopted for this study consisted of 17 questions with multiple choice responses, each of which is numerically scored. The HAMD-17 total score is calculated by summing the individual response scores if there is no missing response. HAMD-17 has a total score in a range of 0 (not present) to 52 (severe). Values at Day 0, Week 0 was considered as Baseline value. Response was defined as decrease in HAMD-17 total scores at end of acute treatment phase (Week 8) relative to Baseline by at least 50%. Non-responder Imputation was used in calculation of rates.
Time Frame	Up to Week 8

Outcome Measure Data

Analysis Population Description
PP Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	184	199
Number [Percentage of Participants]	69.6 26.2%	72.9 27.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.479
	Comments	P-value was estimated from a Generalized Estimating Equation (GEE) model with Response based on HADM-17 as response variable and treatment, gender as explanatory variables.
	Method	GEE model
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95% 0.55 to 1.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Remission Rate Based on HAMD-17 Total Score
Description	HAMD-17 is an extensively used tool to assess the severity of depression and symptom improvement during the treatment. The HAMD-17 adopted for this study consisted of 17 questions with multiple choice responses, each of which is numerically scored. The HAMD-17 total score is calculated by summing the individual response scores if there is no missing response. HAMD-17 has a total score in a range of 0 (not present) to 52 (severe). Values at Day 0, Week 0 was considered as Baseline value. Remission was defined as HAMD-17 total scores at end of acute treatment phase (Week 8) <=7.
Time Frame	Up to Week 8

Outcome Measure Data

Analysis Population Description
PP Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	184	199
Number [Percentage of Participants]	39.7 14.9%	47.2 17.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.129
	Comments	P-value was estimated from a Generalized Estimating Equation (GEE) model with Response based on HADM-17 as response variable and treatment, gender as explanatory variables
	Method	GEE model
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95% 0.48 to 1.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Sustained Response Rate Based on HAMD-17 Total Score
Description	HAMD-17 is an extensively used tool to assess the severity of depression and symptom improvement during the treatment. The HAMD-17 adopted for this study consisted of 17 questions with multiple choice responses, each of which is numerically scored. The HAMD-17 total score is calculated by summing the individual response scores if there is no missing response. HAMD-17 has a total score in a range of 0 (not present) to 52 (severe). Values at Day 0, Week 0 was considered as Baseline value. Sustained response was defined as response at end of acute treatment phase and an earlier visit and the decrease from Baseline in non-missing HAMD-17 total scores at all visits between these two visits by at least 40%.
Time Frame	Up to Week 8

Outcome Measure Data

Analysis Population Description
PP Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	184	199
Number [Percentage of Participants]	51.6 19.4%	56.3 21%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.354
	Comments	P-value was estimated from a GEE model with Response based on HADM-17 as response variable and treatment, gender as explanatory variables
	Method	GEE model
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95% 0.55 to 1.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Sustained Remission Rate Based on HAMD-17 Total Score
Description	HAMD-17 is an extensively used tool to assess the severity of depression and symptom improvement during the treatment. The HAMD-17 adopted for this study consisted of 17 questions with multiple choice responses, each of which is numerically scored. The HAMD-17 total score is calculated by summing the individual response scores if there is no missing response. HAMD-17 has a total score in a range of 0 (not present) to 52 (severe). Values at Day 0, Week 0 was considered as Baseline value. Sustained remission was defined as remission at end of acute treatment phase and an earlier visit and non-missing HAMD-17 total scores at all visits between these two visits <=8.
Time Frame	Up to Week 8

Outcome Measure Data

Analysis Population Description
PP Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	184	199
Number [Percentage of Participants]	25.5 9.6%	28.6 10.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.489
	Comments	P-value was estimated from a GEE model with Response based on HADM-17 as response variable and treatment, gender as explanatory variables
	Method	GEE model
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95% 0.54 to 1.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at Weeks 1, 2, 4, 6 and 8
Description	MADRS is a 10-point rating scale. Each item is scored on a scale of 0-6, with a total score range of 0-60. Higher score indicates worst symptoms. This scale is mainly used to assess the efficacy of antidepressant treatment. The ratings were based on the signs and symptoms during the preceding week prior to the visit. Values at Day0, Week 0 was considered as Baseline value. The observed MADRS total score was considered as missing if any item is missing. Change from Baseline in MADRS was obtained by subtracting the Baseline value from the specific post-Baseline value. All participants in the PP population were analyzed and n=X in the category titles represented the number of participants with data available at the specified time points.
Time Frame	Baseline (Week 0) and Weeks 1, 2, 4, 6 and 8

Outcome Measure Data

Analysis Population Description
PP Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	184	199
Week 1, n=184, 199	-3.6 (0.34)	-3.8 (0.33)
Week 2, n=182, 199	-7.0 (0.47)	-8.3 (0.45)
Week 4, n=184, 198	-11.2 (0.58)	-12.4 (0.56)
Week 6, n=183, 196	-15.5 (0.59)	-16.3 (0.57)
Week 8, n=176, 188	-18.6 (0.57)	-19.5 (0.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.627
	Comments	Analysis included Baseline MADRS total score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95% -0.70 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 1. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.037
	Comments	Analysis included Baseline MADRS total score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95% 0.08 to 2.66
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 2. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.143
	Comments	Analysis included Baseline MADRS total score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 95% -0.40 to 2.78
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 4. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.330
	Comments	Analysis included Baseline MADRS total score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95% -0.81 to 2.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 6. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.278
	Comments	Analysis included Baseline MADRS total score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 95% -0.69 to 2.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 8. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

7. Secondary Outcome

Title	Change From Baseline in HAMD-17 Depressed Mood Subscale Score (Score of Item 1) at Weeks 1, 2, 4, 6 and 8
Description	HAMD-17 is an extensively used tool to assess the severity of depression and symptom improvement during the treatment. The HAMD-17 adopted for this study consisted of 17 questions with multiple choice responses, each of which is numerically scored. The HAMD-17 Depressed Mood Subscale is a factor score of item-1 (Depressed Mood) of HAMD-17 scale. This subscale has a score in a range of 0 (absence of depressed mood feelings) to 4 (when participants report virtually only these feeling states in his/her spontaneous verbal and non-verbal communicationtotal score). Values at Day 0, Week 0 was considered as Baseline value. Change from Baseline was calculated by subtracting the Baseline response from the specific post-Baseline response. All participants in the PP population were analyzed and n=X in the category titles represented the number of participants with data available at the specified time points.
Time Frame	Baseline (Week 0) and Weeks 1, 2, 4, 6 and 8

Outcome Measure Data

Analysis Population Description
PP Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	184	199
Week 1, n=184, 199	-0.4 (0.04)	-0.4 (0.04)
Week 2, n=182, 199	-0.7 (0.06)	-0.8 (0.05)
Week 4, n=184, 198	-1.1 (0.06)	-1.3 (0.06)
Week 6, n=183, 197	-1.5 (0.06)	-1.6 (0.06)
Week 8, n=176, 188	-1.9 (0.06)	-1.9 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.579
	Comments	Analysis included Baseline HAMD-17 depressed mood subscale score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95% -0.09 to 0.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 1. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.163
	Comments	Analysis included Baseline HAMD-17 depressed mood subscale score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95% -0.04 to 0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 2. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.050
	Comments	Analysis included Baseline HAMD-17 depressed mood subscale score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95% 0.00 to 0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 4. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.337
	Comments	Analysis included Baseline HAMD-17 depressed mood subscale score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95% -0.09 to 0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 6. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.714
	Comments	Analysis included Baseline HAMD-17 depressed mood subscale score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95% -0.14 to 0.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 8. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

8. Secondary Outcome

Title	Change From Baseline in HAMD-17 Anxiety/Somatization Subscale Score (Sum of Scores of Items 10, 11, 12, 13, 15 and 17) at Weeks 1, 2, 4, 6 and 8
Description	HAMD-17 is an extensively used tool to assess the severity of depression and symptom improvement during the treatment. The HAMD-17 adopted for this study consisted of 17 questions with multiple choice responses, each of which is numerically scored. The HAMD-17 Anxiety/Somatization subscale score was derived as sum of scores of items 10, 11, 12, 13, 15 and 17 from HAMD-17. This subscale has a score in a range of 0 (absence of condition) to 18 (most severe condition). Values at Day 0, Week 0 was considered as Baseline value. Change from Baseline was calculated by subtracting the Baseline response from the specific post-Baseline response. All participants in the PP population were analyzed and n=X in the category titles represented the number of participants with data available at the specified time points.
Time Frame	Baseline (Week 0) and Weeks 1, 2, 4, 6 and 8

Outcome Measure Data

Analysis Population Description
PP Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	184	199
Week 1, n=184, 199	-1.3 (0.12)	-1.1 (0.12)
Week 2, n=182, 199	-2.0 (0.15)	-2.4 (0.14)
Week 4, n=184, 198	-3.0 (0.19)	-3.4 (0.18)
Week 6, n=183, 197	-4.0 (0.17)	-4.4 (0.17)
Week 8, n=176, 188	-4.8 (0.16)	-5.1 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.358
	Comments	Analysis included Baseline HAMD-17 anxiety/somatization subscale score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95% -0.50 to 0.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 1. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.081
	Comments	Analysis included Baseline HAMD-17 anxiety/somatization subscale score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95% -0.04 to 0.75
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 2. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.062
	Comments	Analysis included Baseline HAMD-17 anxiety/somatization subscale score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95% -0.02 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 4. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.118
	Comments	Analysis included Baseline HAMD-17 anxiety/somatization subscale score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95% -0.10 to 0.85
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 6. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.252
	Comments	Analysis included Baseline HAMD-17 anxiety/somatization subscale score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95% -0.19 to 0.71
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 8. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

9. Secondary Outcome

Title	Change From Baseline in HAMD-17 Retardation Subscale Score (Sum of Scores of Items 1, 7, 8 and 14) at Weeks 1, 2, 4, 6 and 8
Description	HAMD-17 is an extensively used tool to assess the severity of depression and symptom improvement during the treatment. The HAMD-17 adopted for this study consisted of 17 questions with multiple choice responses, each of which is numerically scored. The HAMD-17 Retardation subscale score was derived as sum of scores of items 1, 7, 8 and 14 from HAMD-17. This subscale has a score in a range of 0 (absence of condition) to 14 (most severe condition). Values at Day 0, Week 0 was considered as Baseline value. Change from Baseline was calculated by subtracting the Baseline response from the specific post-Baseline response. All participants in the PP population were analyzed and n=X in the category titles represented the number of participants with data available at the specified time points.
Time Frame	Baseline (Week 0) and Weeks 1, 2, 4, 6 and 8

Outcome Measure Data

Analysis Population Description
PP Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	184	199
Week 1, n=184, 199	-1.0 (0.10)	-1.0 (0.10)
Week 2, n=182, 199	-1.8 (0.13)	-2.0 (0.13)
Week 4, n=184, 198	-2.9 (0.15)	-3.1 (0.15)
Week 6, n=183, 197	-3.9 (0.16)	-3.9 (0.16)
Week 8, n=176, 188	-4.7 (0.17)	-4.9 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.573
	Comments	Analysis included Baseline HAMD-17 Retardation subscale score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95% -0.20 to 0.35
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 1. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.209
	Comments	Analysis included Baseline HAMD-17 Retardation subscale score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95% -0.13 to 0.58
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 2. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.427
	Comments	Analysis included Baseline HAMD-17 Retardation subscale score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95% -0.25 to 0.58
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 4. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.851
	Comments	Analysis included Baseline HAMD-17 Retardation subscale score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95% -0.40 to 0.48
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 6. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.370
	Comments	Analysis included Baseline HAMD-17 Retardation subscale score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95% -0.25 to 0.66
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 8. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

10. Secondary Outcome

Title	Change From Baseline in HAMD-17 Sleep Disorder Subscale Score (Sum of Scores of Items 4, 5 and 6) at Weeks 1, 2, 4, 6 and 8
Description	HAMD-17 is an extensively used tool to assess the severity of depression and symptom improvement during the treatment. The HAMD-17 adopted for this study consisted of 17 questions with multiple choice responses, each of which is numerically scored. The HAMD-17 Sleep Disorder subscale score was derived as sum of scores of items 4, 5 and 6 from HAMD-17. This subscale has a score in a range of 0 (absence of condition) to 6 (most severe condition). Values at Day 0, Week 0 was considered as Baseline value. Change from Baseline was calculated by subtracting the Baseline response from the specific post-Baseline response. All participants in the PP population were analyzed and n=X in the category titles represented the number of participants with data available at the specified time points.
Time Frame	Baseline (Week 0) and Weeks 1, 2, 4, 6 and 8

Outcome Measure Data

Analysis Population Description
PP Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	184	199
Week 1, n=184, 199	-0.6 (0.10)	-0.7 (0.09)
Week 2, n=182, 199	-0.8 (0.11)	-1.2 (0.10)
Week 4, n=184, 198	-1.4 (0.11)	-1.6 (0.11)
Week 6, n=183, 197	-1.8 (0.11)	-2.0 (0.11)
Week 8, n=176, 188	-2.3 (0.11)	-2.4 (0.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.438
	Comments	Analysis included Baseline HAMD-17 Sleep Disorder subscale score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95% -0.16 to 0.37
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 1. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.014
	Comments	Analysis included Baseline HAMD-17 Sleep Disorder subscale score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95% 0.07 to 0.66
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 2. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.207
	Comments	Analysis included Baseline HAMD-17 Sleep Disorder subscale score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95% -0.11 to 0.50
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 4. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.137
	Comments	Analysis included Baseline HAMD-17 Sleep Disorder subscale score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95% -0.07 to 0.54
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 6. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.299
	Comments	Analysis included Baseline HAMD-17 Sleep Disorder subscale score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95% -0.14 to 0.46
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 8. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

11. Secondary Outcome

Title	Change From Baseline in Clinical Global Impression-Severity of Illness Scale (CGI-S) Score at Weeks 1, 2, 4, 6 and 8
Description	CGI-S records the severity of illness at specific time points, with a range of responses from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). Participants with zero values (0) representing "Not assessed" were excluded from analysis. Values at Day 0, Week 0 was considered as Baseline value. Change from Baseline was obtained by subtracting the Baseline value from the specific post-Baseline value. All participants in the PP population were analyzed and n=X in the category titles represented the number of participants with data available at the specified time points.
Time Frame	Baseline (Week 0) and Weeks 1, 2, 4, 6 and 8

Outcome Measure Data

Analysis Population Description
PP Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	184	199
Week 1, n=184, 199	-0.3 (0.04)	-0.4 (0.04)
Week 2, n=182, 199	-0.7 (0.05)	-0.8 (0.05)
Week 4, n=184, 198	-1.1 (0.07)	-1.3 (0.06)
Week 6, n=183, 197	-1.6 (0.07)	-1.7 (0.07)
Week 8, n=176, 188	-2.1 (0.07)	-2.2 (0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.804
	Comments	Analysis included Baseline CGI-S score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95% -0.10 to 0.13
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 1. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.079
	Comments	Analysis included Baseline CGI-S score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95% -0.02 to 0.28
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 2. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.036
	Comments	Analysis included Baseline CGI-S score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95% 0.01 to 0.38
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 4. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.248
	Comments	Analysis included Baseline CGI-S score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95% -0.08 to 0.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 6. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.110
	Comments	Analysis included Baseline CGI-S score as covariate, treatment, gender, visit and treatment-visit interaction as fixed effects. Unstructured covariance matrix was used.
	Method	Mixed model repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95% -0.04 to 0.35
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 8. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

12. Secondary Outcome

Title	Percentage of Participants With a Clinical Global Impression Global Improvement (CGI-I) Score of 1 ("Very Much Improved") or 2 ("Much Improved") at Weeks 1, 2, 4, 6 and 8
Description	For CGI-I rating, the raters indicated their assessment of the participant's total improvement or worsening compared to the participant's condition at the Baseline visit, whether or not the improvement or worsening was thought to be treatment related. Scores ranges from 0 to 7 where 0 represents "Not assessed", and the remaining values 1-7 represent "Very much improved" (1) to "Very much worse" (7). Participants with score 0 were excluded from analysis. All participants in the PP population were analyzed and n=X in the category titles represented the number of participants with data available at the specified time points.
Time Frame	Baseline (Week 0) and Weeks 1, 2, 4, 6 and 8

Outcome Measure Data

Analysis Population Description
PP Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	184	199
Week 1, n=184, 199	6 2.3%	7.5 2.8%
Week 2, n=182, 199	21.4 8%	22.1 8.2%
Week 4, n=184, 198	38.6 14.5%	52.5 19.6%
Week 6, n=183, 197	67.8 25.5%	71.6 26.7%
Week 8, n=176, 188	80.7 30.3%	83.5 31.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.545
	Comments	P-value was estimated from a GEE model repeated measures with CGI-I score of 1 or 2 as response variable and treatment, gender as explanatory variables
	Method	GEE model repeated measures
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio, log
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95% 0.35 to 1.75
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 1. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.822
	Comments	P-value was estimated from a GEE model repeated measures with CGI-I score of 1 or 2 as response variable and treatment, gender as explanatory variables
	Method	GEE model repeated measures
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95% 0.58 to 1.54
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 2. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.007
	Comments	P-value was estimated from a GEE model repeated measures with CGI-I score of 1 or 2 as response variable and treatment, gender as explanatory variables
	Method	GEE model repeated measures
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 95% 0.38 to 0.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 4. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.417
	Comments	P-value was estimated from a GEE model repeated measures with CGI-I score of 1 or 2 as response variable and treatment, gender as explanatory variables
	Method	GEE model repeated measures
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95% 0.54 to 1.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 6. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Bupropion XL, Escitalopram
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.485
	Comments	P-value was estimated from a GEE model repeated measures with CGI-I score of 1 or 2 as response variable and treatment, gender as explanatory variables
	Method	GEE model repeated measures
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95% 0.49 to 1.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Week 8. OC dataset was used, where available data at a given time point was used with no missing values filled in with estimates.

13. Secondary Outcome

Title	Number of Participants With Any Non-serious Adverse Event (AE) and Any Serious AE (SAE)
Description	An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment 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 or all events of possible drug-induced liver injury with hyperbilirubinemia were categorized as SAE. Participants who received any of the study treatment and had any non-serious AE or SAE were considered for analysis. Safety Population comprised of all participants who took at least one dose of the study medication.
Time Frame	Up to Week 10

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	266	268
Any non-serious AE	151 56.8%	150 56%
Any SAE	10 3.8%	11 4.1%

14. Secondary Outcome

Title	Change From Baseline in Hemoglobin, Total Protein, Albumin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points
Description	Blood samples were collected at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). Baseline was considered as the value obtained at Screening. Change from Baseline was calculated by subtracting the Baseline value from the specific post-Baseline values. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Time Frame	Up to Week 10

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	266	268
Hemoglobin, Week 8, n=176, 183	-0.22 (7.621)	-1.16 (7.874)
Hemoglobin, Taper, n=13, 16	-1.54 (5.868)	1.38 (8.057)
Hemoglobin, Follow-up, n=10, 8	-3.10 (12.449)	0.38 (6.163)
Total protein, Week 8, n=174, 183	-0.640 (5.2784)	-0.891 (4.0339)
Total protein, Taper, n=12, 15	1.197 (6.9347)	2.000 (8.7513)
Total protein, Follow-up, n=8, 12	-4.650 (5.5131)	-1.227 (4.8619)
Albumin, Week 8, n=175, 183	-0.254 (3.0207)	-0.678 (2.8483)
Albumin, Taper, n=12, 15	-0.086 (3.9688)	-0.027 (4.2372)
Albumin, Follow-up, n=8, 12	-1.925 (2.0084)	-1.577 (3.6313)
MCHC, Week 8, n=176, 183	-0.09 (8.933)	0.76 (9.821)
MCHC, Taper, n=13, 16	0.54 (8.828)	2.25 (9.030)
MCHC, Follow-up, n=10, 8	-2.10 (9.398)	-2.88 (5.055)

15. Secondary Outcome

Title	Change From Baseline in Hematocrit at the Indicated Time Points
Description	Blood samples were collected at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). Baseline was considered as the value obtained at Screening. Change from Baseline was calculated by subtracting the Baseline value from the specific post-Baseline values. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Time Frame	Up to Week 10

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	266	268
Hematocrit, Week 8, n=176, 183	0.0016 (0.06088)	-0.0044 (0.02587)
Hematocrit, Taper, n=13, 16	-0.0051 (0.02105)	0.0017 (0.02601)
Hematocrit, Follow-up, n=10, 8	-0.0076 (0.04403)	0.0051 (0.01509)

16. Secondary Outcome

Title	Change From Baseline in White Blood Cell (WBC) Count, Total Neutrophil, Lymphocyte, Basophil, Eosinophil, Monocyte and Platelet Count at the Indicated Time Points
Description	Blood samples were collected at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). Baseline was considered as the value obtained at Screening. Change from Baseline was calculated by subtracting the Baseline value from the specific post-Baseline values. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Time Frame	Up to Week 10

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	266	268
WBC count, Week 8, n=176, 183	-0.032 (1.6278)	-0.073 (1.6282)
WBC count, Taper, n=13, 16	0.065 (1.5513)	-0.715 (1.8547)
WBC count, Follow-up, n=10, 8	-0.743 (1.4455)	0.427 (0.9032)
Total Neutrophils, Week 8, n=176, 183	0.101 (1.4835)	-0.165 (1.5540)
Total Neutrophils, Taper, n=13, 16	0.306 (1.6222)	-0.772 (1.5656)
Total Neutrophils, Follow-up, n=10, 8	-0.869 (1.4578)	0.424 (0.7470)
Lymphocytes, Week 8, n=176, 183	-0.154 (0.4833)	0.072 (0.4190)
Lymphocytes, Taper, n=13, 16	-0.242 (0.4843)	0.077 (0.5053)
Lymphocytes, Follow-up, n=10, 8	0.042 (0.3937)	0.022 (0.4388)
Basophil, Week 8, n=176, 182	0.001 (0.0173)	0.002 (0.0218)
Basophil, Taper, n=13, 16	0.001 (0.0091)	0.001 (0.0131)
Basophil, Follow-up, n=10, 8	-0.003 (0.0163)	-0.012 (0.0087)
Eosinophil, Week 8, n=176, 182	-0.004 (0.0788)	0.010 (0.0899)
Eosinophil, Taper, n=13, 16	-0.012 (0.0592)	0.006 (0.0488)
Eosinophil, Follow-up, n=10, 8	-0.005 (0.0627)	0.019 (0.0813)
Monocyte, Week 8, n=176, 182	0.021 (0.1180)	0.003 (0.1113)
Monocyte, Taper, n=13, 16	-0.001 (0.1023)	-0.031 (0.0917)
Monocyte, Follow-up, n=10, 8	0.058 (0.1292)	0.010 (0.0920)
Platelet count, Week 8, n=176, 183	7.73 (32.725)	0.56 (29.492)
Platelet count, Taper, n=13, 16	17.15 (35.126)	7.19 (22.448)
Platelet count, Follow-up, n=10, 8	28.50 (35.600)	5.38 (24.784)

17. Secondary Outcome

Title	Change From Baseline in Total Bilirubin, Direct Bilirubin and Creatinine at the Indicated Time Points
Description	Blood samples were collected at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). Baseline was considered as the value obtained at Screening. Change from Baseline was calculated by subtracting the Baseline value from the specific post-Baseline values. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Time Frame	Up to Week 10

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	266	268
Total bilirubin, Week 8, n=175, 181	-0.812 (4.7591)	-0.071 (4.8022)
Total bilirubin, Taper, n=12, 15	-3.457 (6.5521)	1.198 (3.9442)
Total bilirubin, Follow-up, n=8, 12	0.382 (4.0151)	0.338 (3.4710)
Direct bilirubin, Week 8, n=175, 180	-0.072 (1.3659)	-0.006 (1.2310)
Direct bilirubin, Taper, n=11, 15	-1.554 (3.7607)	0.654 (1.7145)
Direct bilirubin, Follow-up, n=8, 12	-0.102 (1.1192)	0.382 (0.9070)
Creatinine, Week 8, n=174, 183	7.507 (10.6852)	0.307 (9.0811)
Creatinine, Taper, n=12, 15	6.675 (6.9134)	0.880 (10.3281)
Creatinine, Follow-up, n=8, 11	4.237 (8.9291)	1.618 (9.6668)

18. Secondary Outcome

Title	Change From Baseline in Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), Gamma-glutamyl Transpeptidase (GGT) and Lactose Dehydrogenase (LD) at the Indicated Time Points
Description	Blood samples were collected at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). Baseline was considered as the value obtained at Screening. Change from Baseline was calculated by subtracting the Baseline value from the specific post-Baseline values. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Time Frame	Up to Week 10

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	266	268
ALT, Week 8, n=176, 183	2.254 (14.7208)	1.315 (10.3019)
ALT, Taper, n=12, 16	7.993 (17.5985)	-1.812 (15.1544)
ALT, Follow-up, n=8, 12	-7.337 (21.7809)	5.938 (19.8234)
ALP, Week 8, n=176, 181	1.866 (13.2776)	0.407 (11.7870)
ALP, Taper, n=12, 15	3.674 (11.5803)	3.480 (19.2823)
ALP, Follow-up, n=7, 12	5.643 (9.2858)	-3.953 (11.6377)
AST, Week 8, n=176, 183	0.330 (7.6259)	1.099 (6.1029)
AST, Taper, n=12, 16	3.193 (7.4990)	0.381 (6.0938)
AST, Follow-up, n=8, 12	0.925 (23.3485)	2.867 (11.0264)
GGT, Week 8, n=175, 181	0.688 (17.0699)	-0.694 (11.1878)
GGT, Taper, n=12, 15	1.403 (6.2977)	-3.133 (4.8019)
GGT, Follow-up, n=7, 12	-2.029 (5.9637)	3.916 (25.9888)
LD, Week 8, n=176, 182	1.292 (32.4627)	2.879 (27.3838)
LD, Taper, n=13, 13	14.463 (28.9571)	-8.092 (55.0095)
LD, Follow-up, n=8, 10	11.037 (45.3316)	-4.150 (33.8871)

19. Secondary Outcome

Title	Change From Baseline in Calcium, Chloride, Cholesterol, Glucose, Potassium, Sodium, Triglyceride and Urea at the Indicated Time Points
Description	Blood samples were collected at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). Baseline was considered as the value obtained at Screening. Change from Baseline was calculated by subtracting the Baseline value from the specific post-Baseline values. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Time Frame	Up to Week 10

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	266	268
Calcium, Week 8, n=173, 183	-0.017 (0.1139)	-0.020 (0.1225)
Calcium, Taper, n=12, 12	-0.019 (0.1906)	0.012 (0.1091)
Calcium, Follow-up, n=8, 11	-0.060 (0.1032)	-0.060 (0.1352)
Chloride, Week 8, n=173, 182	0.259 (2.7943)	-0.293 (2.5913)
Chloride, Taper, n=10, 13	-0.498 (3.2001)	-0.566 (2.4684)
Chloride, Follow-up, n=8, 8	-0.287 (3.6588)	-0.178 (4.6453)
Cholesterol, Week 8, n=175, 181	-0.122 (0.5855)	0.051 (0.5931)
Cholesterol, Taper, n=12, 14	0.022 (0.5891)	0.082 (0.5991)
Cholesterol, Follow-up, n=9, 11	-0.124 (0.5149)	-0.122 (0.5899)
Glucose, Week 8, n=173, 181	-0.051 (0.6327)	-0.050 (0.5871)
Glucose, Taper, n=12, 16	0.352 (0.3822)	0.106 (0.9661)
Glucose, Follow-up, n=9, 11	-0.194 (0.4089)	0.025 (1.2117)
Potassium, Week 8, n=173, 182	-0.021 (0.3504)	0.009 (0.3552)
Potassium, Taper, n=10, 13	-0.114 (0.4165)	0.046 (0.5095)
Potassium, Follow-up, n=8, 8	-0.110 (0.6221)	0.036 (0.6556)
Sodium, Week 8, n=173, 182	-0.205 (2.4757)	-0.178 (2.5481)
Sodium, Taper, n=10, 13	-0.611 (3.0799)	0.978 (1.5853)
Sodium, Follow-up, n=8, 8	-0.175 (3.9085)	0.770 (3.6011)
Triglycerides, Week 8, n=175, 181	0.003 (1.0499)	0.022 (0.5844)
Triglycerides, Taper, n=13, 15	-0.032 (0.4359)	0.574 (2.0355)
Triglycerides, Follow-up, n=9, 11	0.637 (1.4045)	0.181 (0.7767)
Urea, Week 8, n=174, 183	-0.068 (1.3282)	0.015 (1.1723)
Urea, Taper, n=12, 16	0.517 (0.9249)	-0.269 (1.0223)
Urea, Follow-up, n=8, 11	0.687 (0.6998)	-0.419 (1.0801)

20. Secondary Outcome

Title	Change From Baseline in Mean Corpuscle Hemoglobin (MCH) at the Indicated Time Points
Description	Blood samples were collected at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). Baseline was considered as the value obtained at Screening. Change from Baseline was calculated by subtracting the Baseline value from the specific post-Baseline values. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Time Frame	Up to Week 10

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	266	268
MCH, Week 8, n=176, 183	-0.032 (0.7431)	0.049 (0.7052)
MCH, Taper, n=13, 16	0.269 (0.7941)	0.262 (0.7571)
MCH, Follow-up, n=10, 8	-0.050 (1.1909)	-0.250 (0.4598)

21. Secondary Outcome

Title	Change From Baseline in Mean Corpuscle Volume (MCV) at the Indicated Time Points
Description	Blood samples were collected at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). Baseline was considered as the value obtained at Screening. Change from Baseline was calculated by subtracting the Baseline value from the specific post-Baseline values. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Time Frame	Up to Week 10

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	266	268
MCV, Week 8, n=176, 183	4.668 (62.5158)	-0.090 (2.4759)
MCV, Taper, n=13, 16	0.508 (2.2291)	0.181 (2.1201)
MCV, Follow-up, n=10, 8	0.320 (3.3565)	0.287 (1.1205)

22. Secondary Outcome

Title	Change From Baseline in Red Blood Cell (RBC) Count at the Indicated Time Points
Description	Blood samples were collected at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). Baseline was considered as the value obtained at Screening. Change from Baseline was calculated by subtracting the Baseline value from the specific post-Baseline values. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Time Frame	Up to Week 10

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	266	268
RBC Count, Week 8, n=176, 183	-0.009 (0.2711)	-0.049 (0.2563)
RBC Count, Taper, n=13, 16	-0.088 (0.1599)	-0.007 (0.2560)
RBC Count, Follow-up, n=10, 8	-0.132 (0.4018)	0.036 (0.1859)

23. Secondary Outcome

Title	Number of Participants With Urinalysis Data Outside the Normal Range
Description	Urine samples were collected at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). Number of participants with urine specific gravity and potential of hydrogen (pH) outside (higher or lower) the normal range are presented. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Time Frame	Up to Week 10

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	266	268
Urine specific gravity, high,Screening, n=265, 255	20 7.5%	12 4.5%
Urine specific gravity, low,Screening, n=265, 255	1 0.4%	1 0.4%
Urine specific gravity,high, Week 8, n=171, 173	9 3.4%	7 2.6%
Urine specific gravity,low, Week 8, n=171, 173	0 0%	1 0.4%
Urine specific gravity, high, Taper, n=18, 28	0 0%	0 0%
Urine specific gravity, low, Taper, n=18, 28	0 0%	1 0.4%
Urine specific gravity, high, Follow-up, n=7, 14	0 0%	3 1.1%
Urine specific gravity, low, Follow-up, n=7, 14	0 0%	0 0%
Urine pH, high, Screening, n=265, 266	7 2.6%	18 6.7%
Urine pH, low, Screening, n=265, 266	37 13.9%	28 10.4%
Urine pH, high, Week 8, n=172, 178	5 1.9%	9 3.4%
Urine pH, low, Week 8, n=172, 178	23 8.6%	20 7.5%
Urine pH, high, Taper, n=18, 28	0 0%	1 0.4%
Urine pH, low, Taper, n=18, 28	2 0.8%	2 0.7%
Urine pH, high, Follow-up, n=7, 14	0 0%	0 0%
Urine pH, low, Follow-up, n=7, 14	2 0.8%	2 0.7%

24. Secondary Outcome

Title	Number of Participants With Vital Sign Parameters Outside the Clinical Concern Range
Description	Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were taken at Screening (within 14 days prior to dosing), randomization visit (Week 0) and at Weeks 1, 2, 4, 6, 8, Taper visit (Week 9) and Follow-up visit (Week 10). SBP <30 or >170 millimeter of mercury (mmHg); DBP <20 or >110 mmHg and heart rate <40 or >120 beats per minute (bpm) were considered as values outside of clinical concern range and were presented as 'High' or 'Low' values. Number of participants with vital signs outside of clinical concern range at any post-Baseline visit are presented. Only those participants with data available at the specified time points were analyzed.
Time Frame	Up to Week 10

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	260	253
SBP, high, Any visit post-Baseline	1 0.4%	0 0%
SBP, low,Any visit post-Baseline	0 0%	0 0%
DBP, high, Any visit post-Baseline	0 0%	0 0%
DBP, low, Any visit post-Baseline	0 0%	0 0%
HR, high, Any visit post-Baseline	0 0%	1 0.4%
HR, low, Any visit post-Baseline	0 0%	0 0%

25. Secondary Outcome

Title	Number of Participants With Electrocardiogram (ECG) Data Outside the Clinical Concern Range
Description	ECG was recorded at Screening (within 14 days prior to dosing) and at Week 8, Taper visit (Week 9) and Follow-up visit (Week 10). PR interval <110 or >220 millisecond (msec); QRS interval <60 or >120 msec and corrected QT (QTc) interval >450 msec were considered as values outside of clinical concern range and were presented as 'High' or 'Low' values. Number of participants with ECG data outside of clinical concern range at any post-Baseline visit are presented. Only those participants with data available at the specified time points were analyzed.
Time Frame	Up to Week 10

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	224	222
PR interval, high, Any visit post-randomization	0 0%	0 0%
PR interval, low,Any visit post-randomization	5 1.9%	2 0.7%
QRS interval, high, Any visit post-randomization	2 0.8%	3 1.1%
QRS interval, low, Any visit post-randomization	0 0%	1 0.4%
QTc interval, high, Any visit post-randomization	1 0.4%	3 1.1%
QTc interval, low, Any visit post-randomization	0 0%	0 0%

26. Secondary Outcome

Title	Change From Baseline in Changes in Sexual Function Questionnaire (CSFQ)
Description	CSFQ is a questionnaire about sexual activity and sexual function (sexual intercourse, masturbation, sexual fantasies and other activity). CSFQ is a gender-specific questionnaire. Both male and female versions consist of 14 items, each with 5 possible answers. CSFQ has a score in a range of 14 to 70. Higher score indicates higher sexual activity and sexual function. Value at Day 0 (Week 0) was considered as Baseline value. Change from Baseline at Week 8 was calculated by subtracting the Baseline score from the specific post-Baseline score. Only those participants with data available at the specified time points were analyzed.
Time Frame	Baseline (Day 0) and Week 8

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	173	179
Mean (Standard Deviation) [Scores on a scale]	3.0 (6.47)	0.9 (7.21)

27. Secondary Outcome

Title	Number of Participants With Suicidal Ideation or Behavior During Treatment Assessed by Columbia Suicide Severity Rating Scale (C-SSRS)
Description	C-SSRS is an assessment tool that evaluates suicidal ideation and behavior. It consists of 10 items, each with two possible answers (yes/no). Suicidal ideation was interpreted if "yes" answer at any time during treatment to any one of the five suicidal ideation questions (item 1-5) on the C-SSRS. Suicidal behavior was interpreted if a "yes" answer at any time during treatment to any one of the five suicidal behavior questions (item 6-10) on the C-SSRS. Suicidal ideation or behavior is interpreted if a "yes" answer at any time during treatment to any one of the ten suicidal ideation and behavior questions (item 1-10) on the C-SSRS. Number of participants with at least one on-treatment C-SSRS assessment were analyzed. Only those participants with data available at the specified time points were analyzed.
Time Frame	Baseline and up to Taper visit (Week 9)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Bupropion XL	Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.	In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
Measure Participants	255	249
Suicidal Ideation or Behavior	50 18.8%	43 16%
Suicidal Ideation	50 18.8%	43 16%
Suicidal Behavior	2 0.8%	1 0.4%
Self-Injurious Behavior, no suicidal attempt	1 0.4%	1 0.4%

Adverse Events

	Bupropion XL		Escitalopram
Time Frame	Adverse events (AEs) were collected from the start of study treatment and until the end safety follow-up visit (up to Week 10). SAEs were recorded from the time the consent form is signed until the follow-up visit (up to Week 10).
Adverse Event Reporting Description	SAEs and non-serious AEs were reported for the Safety Population which comprised of all participants who took at least one dose of the study medication.

Arm/Group Title	Bupropion XL		Escitalopram
Arm/Group Description	In a double-blind 8-week acute treatment phase, participants received 1 tablet of bupropion XL 150 milligram (mg) per day at dose level 1 (Week 0 to Week 1). At dose level 2 (Week 1 to Week 4), bupropion XL dose was increased to 300 mg per day (2 tablets of bupropion XL 150 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), bupropion XL dose was still maintained at 300 mg per day (2 tablets of bupropion XL 150 mg). To ensure study blind, the participants were dosed with placebo matching escitalopram at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.		In a double-blind 8-week acute treatment phase, participants received 1 capsule of escitalopram 10 mg per day at dose level 1 (Week 0 to Week 1). Escitalopram dose was maintained at 10 mg per day (1 capsule of Escitalopram 10 mg) for further 3 weeks to ensure that participants had achieved the clinical recommended dose. At dose level 3 (Week 4 to Week 8), the escitalopram dose could be increased to 20 mg per day (2 capsule of Escitalopram 10 mg). To ensure study blind, the participants were also dosed with placebo matching bupropion XL at each dose level. After treatment phase, participants entered in taper phase where dose in was down-titrated step by step to reduce the possible withdrawal symptoms. In taper phase, both dose level 2 and dose level 3 were down titrated to dose level 1 for 1 week before discontinuation.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/266 (0.4%)		0/268 (0%)
Serious Adverse Events
	Bupropion XL		Escitalopram
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/266 (3.8%)		11/268 (4.1%)
Ear and labyrinth disorders
Tinnitus	1/266 (0.4%)		0/268 (0%)
Infections and infestations
Upper respiratory tract infection	0/266 (0%)		1/268 (0.4%)
Conjunctivitis	1/266 (0.4%)		0/268 (0%)
Pneumonia	0/266 (0%)		1/268 (0.4%)
Injury, poisoning and procedural complications
Lacrimal structure injury	1/266 (0.4%)		0/268 (0%)
Muscle injury	0/266 (0%)		1/268 (0.4%)
Overdose	1/266 (0.4%)		0/268 (0%)
Radial nerve injury	0/266 (0%)		1/268 (0.4%)
Rib fracture	0/266 (0%)		1/268 (0.4%)
Investigations
Blood pressure increased	0/266 (0%)		1/268 (0.4%)
Metabolism and nutrition disorders
Electrolyte imbalance	0/266 (0%)		1/268 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Brain neoplasm	0/266 (0%)		1/268 (0.4%)
Psychiatric disorders
Depression	2/266 (0.8%)		4/268 (1.5%)
Depression suicidal	1/266 (0.4%)		0/268 (0%)
Intentional self-injury	0/266 (0%)		1/268 (0.4%)
Major depression	0/266 (0%)		1/268 (0.4%)
Somatic symptom disorder	1/266 (0.4%)		0/268 (0%)
Suicide attempt	1/266 (0.4%)		0/268 (0%)
Skin and subcutaneous tissue disorders
Urticaria	1/266 (0.4%)		0/268 (0%)
Other (Not Including Serious) Adverse Events
	Bupropion XL		Escitalopram
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	151/266 (56.8%)		150/268 (56%)
Blood and lymphatic system disorders
White blood cell disorder	1/266 (0.4%)		0/268 (0%)
Cardiac disorders
Palpitations	11/266 (4.1%)		5/268 (1.9%)
Tachycardia	3/266 (1.1%)		0/268 (0%)
Bundle branch block right	0/266 (0%)		1/268 (0.4%)
Defect conduction intraventricular	1/266 (0.4%)		0/268 (0%)
Sinus bradycardia	0/266 (0%)		1/268 (0.4%)
Ear and labyrinth disorders
Tinnitus	4/266 (1.5%)		2/268 (0.7%)
Ear discomfort	1/266 (0.4%)		0/268 (0%)
Motion sickness	1/266 (0.4%)		0/268 (0%)
Vertigo	1/266 (0.4%)		0/268 (0%)
Eye disorders
Vision blurred	2/266 (0.8%)		1/268 (0.4%)
Eye pain	1/266 (0.4%)		0/268 (0%)
Ocular discomfort	1/266 (0.4%)		0/268 (0%)
Photopsia	0/266 (0%)		1/268 (0.4%)
Gastrointestinal disorders
Nausea	28/266 (10.5%)		50/268 (18.7%)
Dry mouth	16/266 (6%)		15/268 (5.6%)
Constipation	14/266 (5.3%)		9/268 (3.4%)
Abdominal discomfort	9/266 (3.4%)		9/268 (3.4%)
Diarrhoea	4/266 (1.5%)		6/268 (2.2%)
Vomiting	7/266 (2.6%)		3/268 (1.1%)
Abdominal pain upper	5/266 (1.9%)		1/268 (0.4%)
Abdominal distension	3/266 (1.1%)		2/268 (0.7%)
Abdominal pain	4/266 (1.5%)		1/268 (0.4%)
Epigastric discomfort	1/266 (0.4%)		1/268 (0.4%)
Gastric dilatation	1/266 (0.4%)		1/268 (0.4%)
Gastritis	2/266 (0.8%)		0/268 (0%)
Gastrointestinal disorder	2/266 (0.8%)		0/268 (0%)
Mouth ulceration	1/266 (0.4%)		1/268 (0.4%)
Regurgitation	1/266 (0.4%)		1/268 (0.4%)
Toothache	1/266 (0.4%)		1/268 (0.4%)
Abnormal faeces	0/266 (0%)		1/268 (0.4%)
Dyspepsia	0/266 (0%)		1/268 (0.4%)
Eructation	1/266 (0.4%)		0/268 (0%)
Gastrooesophageal reflux disease	1/266 (0.4%)		0/268 (0%)
Haemorrhoids	1/266 (0.4%)		0/268 (0%)
Mallory-Weiss syndrome	1/266 (0.4%)		0/268 (0%)
General disorders
Asthenia	2/266 (0.8%)		5/268 (1.9%)
Fatigue	2/266 (0.8%)		5/268 (1.9%)
Thirst	3/266 (1.1%)		4/268 (1.5%)
Chest discomfort	3/266 (1.1%)		2/268 (0.7%)
Pyrexia	2/266 (0.8%)		1/268 (0.4%)
Chest pain	1/266 (0.4%)		1/268 (0.4%)
Malaise	0/266 (0%)		2/268 (0.7%)
Crying	0/266 (0%)		1/268 (0.4%)
Discomfort	0/266 (0%)		1/268 (0.4%)
Feeling hot	0/266 (0%)		1/268 (0.4%)
Hunger	0/266 (0%)		1/268 (0.4%)
Ill-defined disorder	1/266 (0.4%)		0/268 (0%)
Inflammation	0/266 (0%)		1/268 (0.4%)
Pain	0/266 (0%)		1/268 (0.4%)
Sensation of foreign body	0/266 (0%)		1/268 (0.4%)
Hepatobiliary disorders
Hepatic function abnormal	3/266 (1.1%)		2/268 (0.7%)
Cholecystitis	1/266 (0.4%)		0/268 (0%)
Infections and infestations
Viral upper respiratory tract infection	15/266 (5.6%)		13/268 (4.9%)
Urinary tract infection	3/266 (1.1%)		2/268 (0.7%)
Upper respiratory tract infection	3/266 (1.1%)		1/268 (0.4%)
Influenza	2/266 (0.8%)		1/268 (0.4%)
Pharyngitis	1/266 (0.4%)		1/268 (0.4%)
Peritonsillitis	1/266 (0.4%)		0/268 (0%)
Respiratory tract infection	0/266 (0%)		1/268 (0.4%)
Tinea versicolour	0/266 (0%)		1/268 (0.4%)
Tonsillitis	1/266 (0.4%)		0/268 (0%)
Injury, poisoning and procedural complications
Muscle strain	0/266 (0%)		1/268 (0.4%)
Radius fracture	0/266 (0%)		1/268 (0.4%)
Soft tissue injury	0/266 (0%)		1/268 (0.4%)
Investigations
Blood glucose increased	1/266 (0.4%)		5/268 (1.9%)
White blood cell count decreased	4/266 (1.5%)		1/268 (0.4%)
Heart rate increased	2/266 (0.8%)		1/268 (0.4%)
Alanine aminotransferase increased	1/266 (0.4%)		1/268 (0.4%)
Blood bilirubin increased	0/266 (0%)		2/268 (0.7%)
Blood pressure increased	2/266 (0.8%)		0/268 (0%)
Blood triglycerides increased	1/266 (0.4%)		1/268 (0.4%)
Electrocardiogram T wave abnormal	2/266 (0.8%)		0/268 (0%)
Weight increased	0/266 (0%)		2/268 (0.7%)
Bilirubin conjugated increased	0/266 (0%)		1/268 (0.4%)
Blood cholesterol increased	0/266 (0%)		1/268 (0.4%)
Blood creatinine increased	0/266 (0%)		1/268 (0.4%)
Blood urea increased	0/266 (0%)		1/268 (0.4%)
Blood uric acid increased	1/266 (0.4%)		0/268 (0%)
Electrocardiogram QT prolonged	0/266 (0%)		1/268 (0.4%)
Electrocardiogram ST-T change	1/266 (0.4%)		0/268 (0%)
Electrocardiogram abnormal	0/266 (0%)		1/268 (0.4%)
Electrocardiogram high voltage	0/266 (0%)		1/268 (0.4%)
Gamma-glutamyltransferase increased	0/266 (0%)		1/268 (0.4%)
Hepatic enzyme increased	0/266 (0%)		1/268 (0.4%)
Lipids abnormal	1/266 (0.4%)		0/268 (0%)
Lipoprotein (a) increased	1/266 (0.4%)		0/268 (0%)
Lymphocyte percentage increased	0/266 (0%)		1/268 (0.4%)
Neutrophil percentage increased	0/266 (0%)		1/268 (0.4%)
Platelet count increased	0/266 (0%)		1/268 (0.4%)
Red blood cells urine positive	0/266 (0%)		1/268 (0.4%)
Metabolism and nutrition disorders
Decreased appetite	11/266 (4.1%)		15/268 (5.6%)
Dyslipidaemia	1/266 (0.4%)		0/268 (0%)
Hyperlipidaemia	0/266 (0%)		1/268 (0.4%)
Hypoproteinaemia	1/266 (0.4%)		0/268 (0%)
Musculoskeletal and connective tissue disorders
Myalgia	1/266 (0.4%)		2/268 (0.7%)
Pain in extremity	0/266 (0%)		2/268 (0.7%)
Back pain	1/266 (0.4%)		0/268 (0%)
Exostosis	1/266 (0.4%)		0/268 (0%)
Fasciitis	1/266 (0.4%)		0/268 (0%)
Intervertebral disc protrusion	0/266 (0%)		1/268 (0.4%)
Muscle spasms	1/266 (0.4%)		0/268 (0%)
Muscle twitching	0/266 (0%)		1/268 (0.4%)
Musculoskeletal discomfort	1/266 (0.4%)		0/268 (0%)
Neck pain	1/266 (0.4%)		0/268 (0%)
Osteoporosis	1/266 (0.4%)		0/268 (0%)
Synovitis	1/266 (0.4%)		0/268 (0%)
Nervous system disorders
Dizziness	25/266 (9.4%)		23/268 (8.6%)
Headache	20/266 (7.5%)		15/268 (5.6%)
Somnolence	1/266 (0.4%)		13/268 (4.9%)
Tremor	8/266 (3%)		2/268 (0.7%)
Dysgeusia	4/266 (1.5%)		2/268 (0.7%)
Head discomfort	2/266 (0.8%)		2/268 (0.7%)
Paraesthesia	2/266 (0.8%)		1/268 (0.4%)
Poor quality sleep	2/266 (0.8%)		1/268 (0.4%)
Anticholinergic syndrome	2/266 (0.8%)		0/268 (0%)
Syncope	1/266 (0.4%)		1/268 (0.4%)
Extrapyramidal disorder	1/266 (0.4%)		0/268 (0%)
Head titubation	1/266 (0.4%)		0/268 (0%)
Hypersomnia	0/266 (0%)		1/268 (0.4%)
Hypertonia	0/266 (0%)		1/268 (0.4%)
Hypoaesthesia	1/266 (0.4%)		0/268 (0%)
Tension headache	1/266 (0.4%)		0/268 (0%)
Psychiatric disorders
Insomnia	6/266 (2.3%)		2/268 (0.7%)
Anxiety	5/266 (1.9%)		1/268 (0.4%)
Agitation	4/266 (1.5%)		1/268 (0.4%)
Dysphoria	2/266 (0.8%)		2/268 (0.7%)
Initial insomnia	2/266 (0.8%)		2/268 (0.7%)
Hallucination, auditory	1/266 (0.4%)		1/268 (0.4%)
Intentional self-injury	1/266 (0.4%)		1/268 (0.4%)
Sleep disorder	1/266 (0.4%)		1/268 (0.4%)
Abnormal dreams	0/266 (0%)		1/268 (0.4%)
Fear	0/266 (0%)		1/268 (0.4%)
Irritability	1/266 (0.4%)		0/268 (0%)
Libido decreased	0/266 (0%)		1/268 (0.4%)
Middle insomnia	1/266 (0.4%)		0/268 (0%)
Psychiatric symptom	1/266 (0.4%)		0/268 (0%)
Restlessness	0/266 (0%)		1/268 (0.4%)
Suicidal ideation	1/266 (0.4%)		0/268 (0%)
Suicide attempt	0/266 (0%)		1/268 (0.4%)
Renal and urinary disorders
Dysuria	2/266 (0.8%)		1/268 (0.4%)
Chromaturia	0/266 (0%)		1/268 (0.4%)
Nephrolithiasis	1/266 (0.4%)		0/268 (0%)
Reproductive system and breast disorders
Erectile dysfunction	3/266 (1.1%)		0/268 (0%)
Menopausal symptoms	1/266 (0.4%)		0/268 (0%)
Menstruation irregular	0/266 (0%)		1/268 (0.4%)
Prostatitis	1/266 (0.4%)		0/268 (0%)
Vaginal haemorrhage	0/266 (0%)		1/268 (0.4%)
Respiratory, thoracic and mediastinal disorders
Cough	4/266 (1.5%)		0/268 (0%)
Yawning	1/266 (0.4%)		3/268 (1.1%)
Oropharyngeal pain	1/266 (0.4%)		1/268 (0.4%)
Dry throat	1/266 (0.4%)		0/268 (0%)
Nasal congestion	0/266 (0%)		1/268 (0.4%)
Rhinorrhoea	0/266 (0%)		1/268 (0.4%)
Skin and subcutaneous tissue disorders
Rash	9/266 (3.4%)		2/268 (0.7%)
Hyperhidrosis	3/266 (1.1%)		5/268 (1.9%)
Urticaria	3/266 (1.1%)		1/268 (0.4%)
Alopecia	0/266 (0%)		2/268 (0.7%)
Cold sweat	0/266 (0%)		2/268 (0.7%)
Night sweats	1/266 (0.4%)		1/268 (0.4%)
Dermatitis	1/266 (0.4%)		0/268 (0%)
Eczema	0/266 (0%)		1/268 (0.4%)
Pruritus generalised	1/266 (0.4%)		0/268 (0%)
Rash maculo-papular	1/266 (0.4%)		0/268 (0%)
Vascular disorders
Hypertension	3/266 (1.1%)		2/268 (0.7%)
Orthostatic hypotension	0/266 (0%)		1/268 (0.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Results Point of Contact

Name/Title	GSK Response Center
Organization	GlaxoSmithKline
Phone	866-435-7343
Email

Responsible Party:

GlaxoSmithKline

ClinicalTrials.gov Identifier:

NCT02191397

Other Study ID Numbers:

114589

First Posted:

Jul 16, 2014

Last Update Posted:

Feb 25, 2020

Last Verified:

Feb 1, 2020