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

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

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.

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.