Study to Evaluate the Efficacy, Safety and Tolerability of Bupropion Hydrochloride Extended-release Tablet, and Escitalopram Oxalate Capsule in Subjects With Major Depressive Disorder
Condition: Depressive Disorder, Major
MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major
Intervention: Bupropion; Bupropion Matching Placebo; Escitalopram; Escitalopram Matching Placebo
Intervention description: Bupropion is an extended-release plain creamy white colored tablet which contains bupropion hydrochloride equivalent to 150 mg of bupropion.; Bupropion hydrochloride matching placebo tablets will be supplied to maintain blinding; Escitalopram is available as a Swedish orange capsule containing escitalopram oxalate equivalent to 10 mg of escitalopram.; Escitalopram oxalate matching placebo tablets will be supplied to maintain blinding
Intervention MeSH terms: Dexetimide; Citalopram; Bupropion; Escitalopram
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 534.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Escitalopram; Major depressive disorder; Non-inferiority; Bupropion

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.
    

Eligibility criteria:

        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.