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

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

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).

Study Overview

• Status: Completed
• Conditions: Depressive Disorder
• Intervention / Treatment: Drug: Placebo; Drug: 323U66 (Bupropion Hydrochloride Sustained Release)

• Study Type: Interventional
• Enrollment (Actual): 325
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Aichi, Japan, 462-0831
    • GSK Investigational Site
  • Aichi, Japan, 470-1141
    • GSK Investigational Site
  • Aichi, Japan, 475-0074
    • GSK Investigational Site
  • Chiba, Japan, 270-1613
    • GSK Investigational Site
  • Fukuoka, Japan, 810-0001
    • GSK Investigational Site
  • Fukuoka, Japan, 816-0864
    • GSK Investigational Site
  • Fukuoka, Japan, 802-0006
    • GSK Investigational Site
  • Fukuoka, Japan, 814-0180
    • GSK Investigational Site
  • Fukuoka, Japan, 816-0801
    • GSK Investigational Site
  • Fukushima, Japan, 960-0102
    • GSK Investigational Site
  • Fukushima, Japan, 961-0021
    • GSK Investigational Site
  • Fukushima, Japan, 963-0207
    • GSK Investigational Site
  • Hokkaido, Japan, 002-8029
    • GSK Investigational Site
  • Hokkaido, Japan, 004-0052
    • GSK Investigational Site
  • Hokkaido, Japan, 004-0841
    • GSK Investigational Site
  • Hokkaido, Japan, 047-0155
    • GSK Investigational Site
  • Hokkaido, Japan, 060-0042
    • GSK Investigational Site
  • Hokkaido, Japan, 060-0061
    • GSK Investigational Site
  • Hokkaido, Japan, 062-0922
    • GSK Investigational Site
  • Hokkaido, Japan, 063-0061
    • GSK Investigational Site
  • Hokkaido, Japan, 063-0804
    • GSK Investigational Site
  • Hokkaido, Japan, 080-0014
    • GSK Investigational Site
  • Hyogo, Japan, 651-0092
    • GSK Investigational Site
  • Hyogo, Japan, 651-0097
    • GSK Investigational Site
  • Hyogo, Japan, 653-0841
    • GSK Investigational Site
  • Hyogo, Japan, 657-0846
    • GSK Investigational Site
  • Ibaraki, Japan, 311-3193
    • GSK Investigational Site
  • Ibaraki, Japan, 300-0812
    • GSK Investigational Site
  • Ishikawa, Japan, 920-0939
    • GSK Investigational Site
  • Kagawa, Japan, 761-0793
    • GSK Investigational Site
  • Kanagawa, Japan, 231-0023
    • GSK Investigational Site
  • Kanagawa, Japan, 238-0042
    • GSK Investigational Site
  • Kanagawa, Japan, 213-0001
    • GSK Investigational Site
  • Kanagawa, Japan, 223-0052
    • GSK Investigational Site
  • Kanagawa, Japan, 225-0011
    • GSK Investigational Site
  • Kumamoto, Japan, 861-8002
    • GSK Investigational Site
  • Nagano, Japan, 390-8510
    • GSK Investigational Site
  • Nara, Japan, 639-0225
    • GSK Investigational Site
  • Okayama, Japan, 700-0941
    • GSK Investigational Site
  • Osaka, Japan, 530-0026
    • GSK Investigational Site
  • Osaka, Japan, 571-0048
    • GSK Investigational Site
  • Osaka, Japan, 576-0054
    • GSK Investigational Site
  • Osaka, Japan, 582-0025
    • GSK Investigational Site
  • Osaka, Japan, 589-0011
    • GSK Investigational Site
  • Osaka, Japan, 590-0018
    • GSK Investigational Site
  • Tokyo, Japan, 170-0005
    • GSK Investigational Site
  • Tokyo, Japan, 107-0052
    • GSK Investigational Site
  • Tokyo, Japan, 108-0072
    • GSK Investigational Site
  • Tokyo, Japan, 110-0005
    • GSK Investigational Site
  • Tokyo, Japan, 114-0014
    • GSK Investigational Site
  • Tokyo, Japan, 120-0033
    • GSK Investigational Site
  • Tokyo, Japan, 141-0032
    • GSK Investigational Site
  • Tokyo, Japan, 152-0012
    • GSK Investigational Site
  • Tokyo, Japan, 154-0003
    • GSK Investigational Site
  • Tokyo, Japan, 154-0004
    • GSK Investigational Site
  • Tokyo, Japan, 160-0023
    • GSK Investigational Site
  • Tokyo, Japan, 170-0002
    • GSK Investigational Site
  • Tokyo, Japan, 178-0063
    • GSK Investigational Site
  • Tokyo, Japan, 194-0022
    • GSK Investigational Site
  • Tokyo, Japan, 204-0022
    • GSK Investigational Site
  • Tottori, Japan, 682-0023
    • GSK Investigational Site
  • Tottori, Japan, 683-8504
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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]

1. HAM-D (17 items) total score is ≥14.
2. 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]

1. HAM-D (17 items) total score is ≥14.
2. 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]

1. Patients whose compliance of paroxetine during the pretreatment phase is less than 70%.
2. 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
3. Patients with systolic blood pressure of >=160 mmHg or diastolic blood pressure of >=100 mmHg

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Subjects with Major Depressive Disorder who were randomised to placebo to match Bupropion SR during the treatment period.	Drug: Placebo; Subjects with Major Depressive Disorder who were randomised to placebo to match Bupropion SR during the treatment period.
Experimental: Bupropion SR; 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); 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start (Actual): January 19, 2006
• Primary Completion (Actual): March 28, 2008
• Study Completion (Actual): March 28, 2008

Study Registration Dates

• First Submitted: February 23, 2006
• First Submitted That Met QC Criteria: February 23, 2006
• First Posted (Estimate): February 27, 2006

Study Record Updates

• Last Update Posted (Actual): December 4, 2019
• Last Update Submitted That Met QC Criteria: November 19, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: depression; placebo-controlled; double-blind; SSRI; comparative study; bupropion hydrochloride; non-responder
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Dopamine Uptake Inhibitors; Bupropion
• Other Study ID Numbers: AK1102365

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• IPD Sharing Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• IPD Sharing Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
• IPD Sharing Supporting Information Type: Informed Consent Form (ICF); Clinical Study Report (CSR)