A Fixed Dose Study of 323U66 SR in the Treatment of Major Depressive Disorder (MDD)

Study AK1113351, a Fixed Dose Study of 323U66 SR in the Treatment of Major Depressive Disorder (MDD) - a Multi-center, Placebo-controlled, Randomized, Double-blind, Parallel-comparison Study

This is a multi-center, placebo-controlled, randomized, double-blind, parallel-comparison study to confirm the efficacy of 323U66 Sustained Release (SR) orally administered to patients with MDD (Major Depressive Disorder) at doses level of 150 mg/day and 300 mg/day for 8 weeks based on the decrease in MADRS (Montgomery-Asberg Depression Rating Scale) total score, and to evaluate the safety based on adverse events, clinical laboratory tests and vital signs.

Inclusion Criteria:

[At the start time of the run-in phase]

• Subject must have a primary diagnosis of major depressive disorder as classified by the DSM-IV-TR criteria as below (however, to exclude those accompanied by comorbid psychiatric disorders), and be showing currently a symptom of depression or depressive status: Major depressive disorder, single episode (296.2x); Major depressive disorder, recurrent (296.3x).
• Subject must have a total score of >=20 on the IVRS HAM-D (17 items).
• Subject must have a total score of >=25 on the IDS-SR.
• Subject must have a score of >=1 on 4 out 5 items on the 5-item subscale of the IDS-SR (Item 19, 20, 21, 22 and 30), and a total score of >=7 on the 5-item subscale of the IDS-SR.
• Subject must have a CGI-SI score of >=4 (i.e., Moderately ill or much worse).
• Subject must have the current depressive episode's duration of >=8 weeks but <24 months.
• Subject is outpatient.
• Subject must show QTc <450 millisecond (msec) or <480msec with Bundle Branch Block - values based on either single ECG values or triplicate ECG averaged QTc values obtained over a brief recording period.
• Subject must show a value less than twice of the upper limit of normal value range of AST (GOT) and ALT (GPT), and a value <=1.5 times of the upper limit of normal value range of both Al-P and total bilirubin (however, subject who shows >35% of direct bilirubin with a value >=1.5 times of the upper limit of normal range of total bilirubin regards eligible).
• Subject must read and write at a level sufficient to provide written informed consent prior to study participation and complete study-related materials. If subject is <20 years of age at the time of giving consent, both the subject himself / herself and his / her proxy consenter must give written informed consent.

[At the start time of the treatment phase]

• Subject must have a total score of >=20 of the IVRS-based HAM-D (17 items).
• Subject whose IVRS HAM-D (17 items) total score has not been increased or decreased by >25% during the run-in phase.
• Subject must have a total score of >=25 on the IDS-SR.
• Subject must have a score of >=1 on 4 out 5 items on the 5-item subscale of the IDS-SR (Item 19, 20, 21, 22 and 30), and a total score of >=7 on the 5-item subscale of the IDS-SR.
• Subject must have a CGI-SI score of >=4 (i.e., Moderately ill or much worse).

Exclusion Criteria:

[At the start time of Run-in phase (Visit 1)]

• Subject has predispositions to seizure: who currently has or has a past history of seizure or seizure disorder, more than a single febrile seizure in infancy, cerebral tumour, or head / brain injury (traumatic); who has a family history of idiopathic seizure; who is diabetic patient with treating by oral hypoglycaemics or insulin; who uses drugs lowering the threshold of seizure.
• Subject has a history or current diagnosis of anorexia nervosa (DSM-IV-TR 307.1) or bulimia (DSM-IV-TR 307.51).
• Subject has a primary DSM-IV diagnosis of, or received treatment for, panic disorder, obsessive compulsive disorder (OCD), posttraumatic stress disorder (PTSD), or acute stress disorder within 12 months before the start time of Run-in phase.
• Subject has a DSM-IV diagnosis of schizophrenia, or other psychotic disorder(s) including bipolar disorder.
• Subject has a history of or currently has manic episode(s).
• Subject has any other DSM-IV axis II diagnosis that would suggest non-responsiveness to pharmacotherapy or non-compliance with the protocol (e.g., antisocial, borderline disorder or narcissistic personality disorder).
• Subject starting psychotherapy (except for supportive psychotherapy not aimed at therapeutic efficacy and unlikely to affect efficacy evaluation) or a cognitive behaviour therapy within 12 weeks before start time of the run-in phase.
• Subject received electroconvulsive therapy (ECT) within 24 weeks before start time of the run-in phase.
• Subject took MAO inhibitors (selegiline hydrochloride) within 2 weeks before start time of the run-in phase.
• Subject who has undergone treatment with a depot neuroleptic in the past.
• Subject has systolic blood pressure of >=160 mmHg or diastolic pressure of >=100 mmHg.
• Subject 1) is possibly pregnant, 2) is pregnant, lactating, or 3) does not agree to use contraceptive method(s) specified in the protocol to avoid pregnancy during the study (females only). Or subject wants to become pregnant during the study (females only).
• Subject has a history of alcohol / substance abuse or dependence within 12 months before start time of the run-in phase and/or has a positive result in a urine test for illicit drug use at start time of the run-in phase.
• Subject, who in the opinion of the investigator (or sub-investigator), poses a current serious suicidal risk or has made a suicide attempt within the past 6 months.
• Subject took another investigational product for the NDA filing or for the post manufacturing / marketing approval study within 12 weeks before start time of the run-in phase.
• Subject is currently participating in another clinical study in which the subject is or will be exposed to an investigational or non-investigational drug or medical device.
• Subject has a history of non-responsiveness to 323U66 SR treatment in the investigational clinical trial for major depressive disorder.
• Subject has a history of withdrawal from the investigational clinical trial of 323U66 SR for major depressive disorder due to any adverse event(s).
• Subject has a history of hypersensitivity to 323U66 (bupropion).
• Subject, who in the opinion of the investigator (or sub-investigator), has a risk of homicide.
• Subject has serious cerebral disease(s).
• Subject has serious physical symptom(s) (i.e., cardiac / hepatic / renal / hematopoietic disorder(s)).
• Subject whose major depressive disorder is due to direct physiological effects of a general medical condition(s) (e.g. hypothyroidism, Parkinson's disease, chronic pain).
• Subject is complicated by chronic hepatitis B or C being positive in test of hepatitis B surface antigen (HbsAg) or hepatitis C antibody.
• Subject who is in the process of quitting smoking with nicotine formulation.
• Subject has previously failed adequate (in terms of dose and duration of therapy) courses of pharmacotherapy with at least two different classes of antidepressants.
• Subjects undergoing abrupt discontinuation of alcohol or sedatives.
• Subject is inappropriate for participating in the study that is felt by the investigator (or sub-investigator).

[At the start time of the treatment phase]

• Subject, who in the opinion of the investigator (or sub-investigator), poses a current serious suicidal risk.
• Subject is inappropriate for participating in the study that is felt by the investigator (or sub-investigator).