Study In Patients With Depression Not Responding to Selective Serotonin Re-uptake Inhibitors

Study Overview
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Brief Summary
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This study is designed to evaluate the efficacy and safety in depressive patients who did not respond sufficiently to selective serotonin re-uptake inhibitors (SSRI).

Official Title
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Clinical Evaluation of 323U66 SR in Patients With Depression - Placebo-controlled, Double-blind, Comparative Study in Patients With Depression Who Did Not Respond Sufficiently to Selective Serotonin Re-uptake Inhibitors

Conditions
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Depressive Disorder

Intervention / Treatment
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* Drug: 323U66 (Bupropion Hydrochloride Sustained Release)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: [At the start of the pretreatment phase] Target disease: Patients diagnosed as having the following primary disease on the basis of DSM-IV-TR criteria. Major Depressive Disorder, Single Episode (296.2x) (excluding with psychotic features) Major Depressive Disorder, Recurrent (296.3x) (excluding with psychotic features) HAM-D (17 items) total score is >=16. Patients who have been treated with marketed paroxetine (Paxil®) at 20mg/day to 40mg/day for 4 weeks and more at the start of the pretreatment phase. Age: >=18 years old (at the time of informed consent) , <65 years old (at the start of treatment phase ) Gender: Male or female. Inpatients or outpatients: Either Informed consent: The subject himself/herself must give written informed consent. However, if the subject is under 20 at the time of giving consent, both the subject himself/herself and his/her legally acceptable representative must give written informed consent. [At the end of the pretreatment phase] HAM-D (17 items) total score is ≥14. Percentage of change from the start of the pretreatment phase in the HAM-D (17 items) total score is <50% [At the start of the treatment phase] HAM-D (17 items) total score is ≥14. Percentage of change from the start of the pretreatment phase in the HAM-D (17 items) total score is <50% Exclusion Criteria: [At the start of the pre-treatment phase] Patients with a complication of glaucoma Patients concomitantly using a drug increasing the risk of bleeding and patients with bleeding tendency or predisposition to bleeding Patients with predisposition to seizure (who currently have or have a past history of seizure, febrile convulsive seizure in infancy, cerebral tumour, cerebrovascular disorder or head injury, who have a family history of idiopathic seizure, patients with diabetes who have been treated with oral hypoglycaemics or insulin, or who use drugs lowering the threshold of seizure). Patients who currently have or have a past history of the following disorders: Anorexia nervosa (DSM-IV-TR 307.1) Bulimia nervosa (DSM-IV-TR 307.51) Patients with a history of manic episode Patients with a past or current DSM- IV-TR diagnosis of schizophrenia or other psychotic disorder Patients with a current DSM-IV-TR Axis II diagnosis (e.g., antisocial or borderline personality disorder) Patients starting psychotherapy (except for supportive psychotherapy not aimed at therapeutic efficacy and unlikely to affect efficacy evaluation) and formal cognitive behaviour therapy within 5 weeks prior to the start of the pre-treatment phase Patients with a diagnosis of substance abuse (alcohol or drug) by the DSM-IV-TR criteria or with a diagnosis of substance dependence within 1 year prior to the start of the pre-treatment phase Patients who have received electroconvulsive therapy within 17 weeks prior to the start of the pre-treatment phase Patients who have taken MAO inhibitors (selegiline hydrochloride) within 2 weeks prior to the start of the pre-treatment phase Patients who have taken another investigational drug within 12 weeks prior to the start of the pre-treatment phase Female patients who are pregnant, possibly pregnant or are nursing, and those who want to become pregnant before 30 days after the last dose of the investigational product Patients who have attempted suicide within 17 weeks prior to the start of the pre-treatment phase, or patients for whom the score of suicide-related item No. 3 of HAM-D is >=3, or patients in whom the risk of suicide is judged to be high by the investigator (sub-investigator) Patients in whom the risk of homicide is judged to be high by the investigator (sub-investigator) Patients with a history of hypersensitivity to 323U66 and/or paroxetine Patients with serious cerebral disease Patients who have ECG or clinical evidence of any cardiac condition that the investigator (sub-investigator) feels may predispose the subject to ischemia or arrhythmia Patients with serious physical symptoms (i.e. cardiac/hepatic/renal disorder, hematopoietic disorder) The index of seriousness is Grade 3 of Criteria for classification of seriousness of adverse drug reactions to pharmaceutical products, etc. (PAB/PSD No.80 in 1992). Patients with a history or complication of cancer or malignant tumour. Patients whose major depressive disorder is due to direct physiological effects of a general medical condition (for example, hypothyroidism, Parkinson's disease, chronic pain) Patients with systolic blood pressure of >=160 mmHg or diastolic blood pressure of >=100 mmHg Patients who are inappropriate for participating in the study in the judgement of the investigator (sub-investigator) [At the start of the treatment phase] Patients whose compliance of paroxetine during the pretreatment phase is less than 70%. Patients who have ECG or clinical evidence of any cardiac condition that the investigator (sub-investigator) feels may predispose the subject to ischemia or arrhythmia Patients with systolic blood pressure of >=160 mmHg or diastolic blood pressure of >=100 mmHg

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Subjects with Major Depressive Disorder who were randomised to placebo to match Bupropion SR during the treatment period. | Drug: Placebo<br>* Subjects with Major Depressive Disorder who were randomised to placebo to match Bupropion SR during the treatment period.<br>|
| Experimental: Bupropion SR<br>Subjects with Major Depressive Disorder who were randomized to take 100mg of Bupropion SR in the morning and placebo in the evening for one week. Week 2 subjects were given 100mg dose of Bupropion morning and evening. Weeks 3 thru 12 received 150mg dose morning and evening. Week 1=dose level 1, 100 mg. Week 2=dose level 2, 200 mg. Weeks 3 - 12=dose level 3, 300 mg. | Drug: 323U66 (Bupropion Hydrochloride Sustained Release)<br>* Subjects with Major Depressive Disorder who were randomized to take 100mg of Bupropion SR in the morning and placebo in the evening for one week. Week 2 subjects were given 100mg dose of Bupropion morning and evening. Weeks 3 thru 12 received 150mg dose morning and evening. Week 1=dose level 1, 100 mg. Week 2=dose level 2, 200 mg. Weeks 3 - 12=dose level 3, 300 mg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Hamilton Depression Scale (HAM-D 17 Items) Total Score | The Hamilton Rating Scale for Depression contains 17 questions which detect change and measure illness severity. Individual items are rated on a scale of 0-4, 0-3, and 0-2 with total HAM-D score range from 0 (not ill) to 52 (severely ill). | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hamilton Depression Scale (HAM-D 17 Items) Total Score | The Hamilton Rating Scale for Depression contains 17 questions which detect change and measure illness severity. Individual items are rated on a scale of 0-4, 0-3, and 0-2 with total HAM-D score range from 0 (not ill) to 52 (severely ill). | Week 8 and Week 12 | 
| Change From Baseline in the Hamilton Depression Scale (HAM-D 17 Items) Total Score at Week 8 and Total Score at Week 12 | The Hamilton Rating Scale for Depression contains 17 questions which detect change and measure illness severity. Individual items are rated on a scale of 0-4, 0-3, and 0-2 with total HAM-D score range from 0 (not ill) to 52 (severely ill). | Baseline to Week 8 and Week 12 | 
| Percentage of Change From Baseline of the Hamilton Depression (HAM-D 17 Items) Total Score at Weeks 8 and 12. | The Hamilton Rating Scale for Depression contains 17 questions which detect change and measure illness severity. Individual items are rated on a scale of 0-4, 0-3, and 0-2 with total HAM-D score range from 0 (not ill) to 52 (severely ill). | Baseline to Week 8 and Week 12 | 
| Percentage of Responders Based on Hamilton Depression (HAM-D 17 Items) Scale Total Score at Weeks 8 and 12 | The Hamilton Rating Scale for Depression contains 17 questions which detect change and measure illness severity. Individual items are rated on a scale of 0-4, 0-3, and 0-2 with total HAM-D score range from 0 (not ill) to 52 (severely ill). Responders are defined as subjects with 50% or greater reduction from baseline in HAM-D total score. | Baseline to Week 8 and Week 12 | 
| Percentage of Remitters Based on Hamilton Depression (HAM-D 17 Items) Scale Total Score at Weeks 8 and 12 | The Hamilton Rating Scale for Depression contains 17 questions which detect change and measure illness severity. Individual items are rated on a scale of 0-4, 0-3, and 0-2 with total HAM-D score range from 0 (not ill) to 52 (severely ill). Remitters are defined as subjects with HAM-D total score ≤ 7. | Baseline to Week 8 and Week 12 | 
| Change From Baseline in Each Item of the Hamilton Depression Scale (HAM-D 17 Items) Score at Weeks 8 and 12 | The Hamilton Rating Scale for Depression contains 17 questions which detect change and measure illness severity. Individual items are rated on a scale of 0-4, 0-3, and 0-2, with total HAM-D scores ranging from 0 (not ill) to 54 (severely ill). | Baseline to Week 8 and Week 12 | 
| Percentage of Change From Baseline in Each Item of the Hamilton Depression Scale (HAM-D 17 Items) Score at Weeks 8 and 12 | The Hamilton Rating Scale for Depression contains 17 questions which detect change and measure illness severity. Individual items are rated on a scale of 0-4, 0-3, and 0-2, with total HAM-D scores ranging from 0 (not ill) to 54 (severely ill). | Baseline to Week 8 and Week 12 | 
| Change From Baseline in Clinical Global Impressions - Severity of Illness (CGI-S) Scale at Weeks 1, 2, 3, 4, and 8 and 12 | The 7-point Clinical Global Impressions-Severity of Illness Scale (CGI-S) measures the severity of psychiatric symptoms. The following scores can be given: 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill patients. | Baseline to Weeks 1, 2, 3, 4, 8, and 12 | 
| Percentage of Responders Based on the Clinical Global Impression - Global Improvement (CGI-I) Scale at Weeks 8 and 12 | The CGI-I assesses the investigator's impression of the patient's current illness. The time span is the week before the rating and the score ranges from 1 (very much improved) to 7 (very much worse). Responders are subjects that have a score of 1 (very much improved) or 2 (much improved) on the CGI-I. | Baseline to Week 8 and Week 12 | 
| Study Continuation Rate as Assessed by the Number of Participants at Risk at Week 12 | Kaplan-Meier estimates were calculated using event or censoring and time to event or censoring. Participants at risk refers to participants with either a censoring or event time beyond the time point of interest (Week 12). | Week 12 | 
| Safety: Adverse Events by Organ System Class, Intensity, and Frequency | Assessment of intensity was based on investigators/subinvestigator's clinical judgement per protocol instructions: Mild event, easily tolerated, with minimal discomfort and not interfering with Activities of Daily Living (ADLs); moderate event, with discomfort that interferes with ADLs; severe event, prevents ADLs. | Baseline to Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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depression, double-blind, placebo-controlled, bupropion hydrochloride, SSRI, comparative study, non-responder