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

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01138007
• Collaborator: (none)
• Enrollment: 572
• Locations: 59
• Arms: 3
• Duration (Months): 25.7
• Patients Per Site: 9.7
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Depressive Disorder, Major	Drug: 323U66 SR 150 mg tablet; Drug: 323U66 SR 150 mg placebo tablet	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 572 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Jun 17, 2010
• Actual Primary Completion Date: Aug 1, 2012
• Actual Study Completion Date: Aug 7, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 323U66 SR 150 mg cohort 323U66 SR 150 mg tablet is orally administered once in the morning and 323U66 SR 150 mg placebo tablet is orally administered once in the evening throughout the treatment phase.	Drug: 323U66 SR 150 mg tablet; 323U66 SR 150 mg tablet is orally administered once in the morning and/or once in the evening during the teatment phase.; Drug: 323U66 SR 150 mg placebo tablet; 323U66 SR 150 mg placebo tablet is orally administered once in the evening and/or once in the morning during the teatment phase.
Experimental: 323U66 SR 300 mg cohort 323U66 SR 150 mg tablet is orally administered once in the morning and 323U66 SR 150 mg placebo tablet is orally administered once in the evening during the first week of the treatment phase. At the second week, 323U66 SR 300mg cohort is up-titrated to a daily dose of 323U66 SR 300 mg, administered as 323U66 SR 150 mg tablet twice daily in the morning and in the evening, and the same daily dose is maintained to administer until the end of the treatment phase.	Drug: 323U66 SR 150 mg tablet; 323U66 SR 150 mg tablet is orally administered once in the morning and/or once in the evening during the teatment phase.; Drug: 323U66 SR 150 mg placebo tablet; 323U66 SR 150 mg placebo tablet is orally administered once in the evening and/or once in the morning during the teatment phase.
Placebo Comparator: Placebo cohort 323U66 SR placebo tablet is orally administered twice daily throughout the treatment phase.	Drug: 323U66 SR 150 mg placebo tablet; 323U66 SR 150 mg placebo tablet is orally administered once in the evening and/or once in the morning during the teatment phase.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at Week 8/Withdrawal [Baseline and Week 8/Withdrawal]

   The MADRS scale measures the depression level of a participant. The total score was derived by adding the scores of the following 10 items: 1, Apparent sadness; 2, Reported sadness; 3, Inner tension; 4, Reduced sleep; 5, Reduced appetite; 6, Concentration difficulties; 7, Lassitude; 8, Inability to feel; 9, Pessimistic thoughts; 10, Suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score is 60; 0, no depression; 60, severely depressed. Change from Baseline in the total score was calculated as the value at Week 8/Withdrawal minus the value at Baseline. The least squared means were estimated based on the Analysis of Covariance (ANCOVA) model including Baseline MADRS score and region as covariates.

Secondary Outcome Measures

1. Change From Baseline in the MADRS Total Score at Weeks 1, 2, 4, and 6 [Baseline; Weeks 1, 2, 4, and 6]

   The MADRS scale measures the depression level of a participant. The total score was derived by adding the scores of the following 10 items: 1, Apparent sadness; 2, Reported sadness; 3, Inner tension; 4, Reduced sleep; 5, Reduced appetite; 6, Concentration difficulties; 7, Lassitude; 8, Inability to feel; 9, Pessimistic thoughts; 10, Suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score is 60; 0, no depression; 60, severely depressed. Change from Baseline in the total score was calculated as the value at Week 1, 2, 4 and 6 minus the value at Baseline. The least squared means were estimated based on the ANCOVA model including Baseline MADRS score and region as covariates.

2. Change From Baseline in the MADRS Individual Item Scores at Weeks 1, 2, 4, 6, and 8 [Baseline; Week 1, 2, 4, 6, and 8]

   The MADRS scale measures the depression level of a participant using the following 10 items: 1, Apparent sadness; 2, Reported sadness; 3, Inner tension; 4, Reduced sleep; 5, Reduced appetite; 6, Concentration difficulties; 7, Lassitude; 8, Inability to feel; 9, Pessimistic thoughts; 10, Suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). Scores for MADRS items 1, 2, 6, 7, and 8 were evaluated for this endpoint. Change from Baseline was calculated as the value at Week 1, 2, 4, 6, and 8 minus the value at Baseline. The least squared means were estimated based on the ANCOVA model including Baseline MADRS score of each item and region as covariates.

3. Number of MADRS Responders at Week 8 [Baseline and Week 8]

   The MADRS scale measures the depression level of a participant. The total score was derived by adding the scores of the following 10 items: 1, Apparent sadness; 2, Reported sadness; 3, Inner tension; 4, Reduced sleep; 5, Reduced appetite; 6, Concentration difficulties; 7, Lassitude; 8, Inability to feel; 9, Pessimistic thoughts; 10, Suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score is 60; 0, no depression; 60, severely depressed. A MADRS responder is defined as a participant with a >=50% reduction from Baseline in the MADRS total score at Week 8.

4. Number of MADRS Remitters at Week 8 [Week 8]

   The MADRS scale measures the depression level of a participant. The total score was derived by adding the scores of the following 10 items: 1, Apparent sadness; 2, Reported sadness; 3, Inner tension; 4, Reduced sleep; 5, Reduced appetite; 6, Concentration difficulties; 7, Lassitude; 8, Inability to feel; 9, Pessimistic thoughts; 10, Suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score is 60; 0, no depression; 60, severely depressed. A MADRS remitter is defined as a participant with a MADRS total score <=11 at Week 8.

5. Number of Clinical Global Impression-Global Improvement (CGI-GI) Responders at Week 8 [Week 8]

   A CGI-GI assessment was performed at Week 8 (or withdrawal) in comparison with severity in depression observed at Baseline (Week 0; no actual assessment was performed at Baseline [the comparison was subjective]), by using scores from 0 to 7: 0, Not assessed; 1, Very much improved; 2, Much improved; 3, Minimally improved; 4, No change; 5, Minimally worse; 6, Much worse; 7, Very much worse. A CGI-GI responder is defined as a participant with a CGI-GI score of very much improved or much improved at Week 8.

6. Change From Baseline in the Clinical Global Impression-Severity of Illness (CGI-SI) Scores at Weeks 1, 2, 4, 6, and 8 [Baseline; Weeks 1, 2, 4, 6, and 8]

   A CGI-SI assessment was performed in terms of severity in depression, by using scores from 0 to 7: 0, Not assessed; 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 participants. Change from Baseline in the CGI-SI score was calculated as the value at Week 1, 2, 4, 6, and 8 minus the value at Baseline. The least squared means were estimated based on the ANCOVA model including Baseline CGI-SI score and region as covariates.

7. Change From Baseline in the Inventory of Depressive Symptomatology-Self Report (IDS-SR) Total Score at Weeks 1, 2, 4, 6, and 8 [Baseline; Weeks 1, 2, 4, 6, and 8]

   The IDS-SR is a 30-item scale used to evaluate the severity and changes in depressive symptoms. Each item was scored from 0 (no symptoms) to 3 (greatest symptom severity). The maximum total score is 84 (0: no symptoms; 84: greatest symptom severity), as participants were asked to answer either item 11 (decreased appetite) or item 12 (increased appetite) (not both) and either item 13 (decreased weight) or item 14 (increased weight) (not both). Change from Baseline was calculated as the value at Week 1, 2, 4, 6, and 8 minus the value at Baseline. The least squared means were estimated based on the ANCOVA model including Baseline IDS-SR score and region as covariates.

8. Change From Baseline in the IDS-SR Subscores for Energy, Pleasure, and Interest at Weeks 1, 2, 4, 6, and 8 [Baseline; Weeks 1, 2, 4, 6, and 8]

   The IDS-SR is a 30-item scale used to evaluate the severity and changes in depressive symptoms. Each item was scored from 0 (no symptoms) to 3 (greatest symptom severity). Only five items (item 19: general interest; item 20: energy level; item 21: capacity for pleasure or enjoyment, excluding sex; item 22: interest in sex; item 30: leaden paralysis/physical energy) were evaluated for this endpoint, as a subset of the total score. The lowest possible total score and subset total score of IDS-SR are 0 and 0, and the highest possible total score and subset total score of IDS-SR are 84 and 15, respectively. Change from Baseline was calculated as the value at Week 1, 2, 4, 6, and 8 minus the value at Baseline. The least squared means were estimated based on the ANCOVA model including Baseline IDS-SR subscore and region as covariates.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Aichi		Japan	470-1141
2	GSK Investigational Site	Aichi		Japan	479-0837
3	GSK Investigational Site	Fukuoka		Japan	802-0006
4	GSK Investigational Site	Fukuoka		Japan	810-0001
5	GSK Investigational Site	Fukuoka		Japan	810-0004
6	GSK Investigational Site	Fukuoka		Japan	810-0022
7	GSK Investigational Site	Fukuoka		Japan	812-0011
8	GSK Investigational Site	Fukuoka		Japan	815-0041
9	GSK Investigational Site	Fukushima		Japan	960-0102
10	GSK Investigational Site	Fukushima		Japan	961-0021
11	GSK Investigational Site	Fukushima		Japan	963-0207
12	GSK Investigational Site	Hiroshima		Japan	731-0121
13	GSK Investigational Site	Hyogo		Japan	673-0891
14	GSK Investigational Site	Ibaraki		Japan	311-3193
15	GSK Investigational Site	Kanagawa		Japan	214-0014
16	GSK Investigational Site	Kanagawa		Japan	221-0835
17	GSK Investigational Site	Kanagawa		Japan	231-0023
18	GSK Investigational Site	Kanagawa		Japan	244-0816
19	GSK Investigational Site	Kanagawa		Japan	251-0055
20	GSK Investigational Site	Kumamoto		Japan	861-8002
21	GSK Investigational Site	Kyoto		Japan	616-8421
22	GSK Investigational Site	Nara		Japan	639-0225
23	GSK Investigational Site	Osaka		Japan	545-0001
24	GSK Investigational Site	Osaka		Japan	573-0032
25	GSK Investigational Site	Osaka		Japan	576-0054
26	GSK Investigational Site	Osaka		Japan	589-0011
27	GSK Investigational Site	Osaka		Japan	596-0076
28	GSK Investigational Site	Saga		Japan	842-0192
29	GSK Investigational Site	Saga		Japan	843-0023
30	GSK Investigational Site	Saga		Japan	847-0053
31	GSK Investigational Site	Saitama		Japan	341-0018
32	GSK Investigational Site	Shizuoka		Japan	420-0839
33	GSK Investigational Site	Tochigi		Japan	321-0953
34	GSK Investigational Site	Tokyo		Japan	102-0071
35	GSK Investigational Site	Tokyo		Japan	110-0003
36	GSK Investigational Site	Tokyo		Japan	125-0041
37	GSK Investigational Site	Tokyo		Japan	141-0021
38	GSK Investigational Site	Tokyo		Japan	142-0051
39	GSK Investigational Site	Tokyo		Japan	150-0001
40	GSK Investigational Site	Tokyo		Japan	151-0053
41	GSK Investigational Site	Tokyo		Japan	154-0004
42	GSK Investigational Site	Tokyo		Japan	154-0012
43	GSK Investigational Site	Tokyo		Japan	160-0022
44	GSK Investigational Site	Tokyo		Japan	160-0023
45	GSK Investigational Site	Tokyo		Japan	164-0012
46	GSK Investigational Site	Tokyo		Japan	166-0011
47	GSK Investigational Site	Tokyo		Japan	170-0002
48	GSK Investigational Site	Tokyo		Japan	173-0004
49	GSK Investigational Site	Tokyo		Japan	180-0005
50	GSK Investigational Site	Gyeonggi-do		Korea, Republic of	431-070
51	GSK Investigational Site	Incheon		Korea, Republic of	405-760
52	GSK Investigational Site	Seoul		Korea, Republic of	110-746
53	GSK Investigational Site	Seoul		Korea, Republic of	135-710
54	GSK Investigational Site	Seoul		Korea, Republic of	136-705
55	GSK Investigational Site	Seoul		Korea, Republic of	137-701
56	GSK Investigational Site	Seoul		Korea, Republic of	138-736
57	GSK Investigational Site	Seoul		Korea, Republic of	143-729
58	GSK Investigational Site	Seoul		Korea, Republic of	150-713
59	GSK Investigational Site	Seoul		Korea, Republic of	156-707

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT01138007
• Other Study ID Numbers: 113351
• First Posted: Jun 7, 2010
• Last Update Posted: Aug 10, 2018
• Last Verified: Jun 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by GlaxoSmithKline: Bupropion; 323U66 Sustained Release (SR); MDD (Major Depressive Disorder); IVRS HAM-D; IDS-SR; MADRS
• Additional relevant MeSH terms: Disease; Depressive Disorder; Depression; Depressive Disorder, Major

Study Results

Participant Flow

Recruitment Details	A total of 572 participants were enrolled in the study; however, 3 of these participants were mistakenly registered and were not randomized to study treatment.
Pre-assignment Detail	Participants who met the inclusion criteria enrolled in the 1- to 2-week Run-in Phase before entering the 8-week Treatment Phase, followed by the 2-week Follow-up Phase. In the Run-in Phase, the previous/existing prohibited medications administered were washed out, and participants' clinical symptoms were carefully monitored.

Arm/Group Title	Placebo	323U66 SR 150 mg	323U66 SR 300 mg
Arm/Group Description	A 323U66 sustained release (SR) placebo tablet was administered orally twice daily, in the morning and the evening (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 milligram (mg) tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 mg tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses, during the first week of the Treatment Phase (Dose level 1). At Week 2, participants were up-titrated to a daily dose of 323U66 SR 300 mg, administered as a 323U66 SR 150 mg tablet twice daily, in the morning and in the evening, with an interval of at least 8 hours between successive doses (Dose level 2). Dose level 2 was maintained from Week 2 to Week 8.
Period Title: Overall Study
STARTED	187	190	192
COMPLETED	165	160	144
NOT COMPLETED	22	30	48

Baseline Characteristics

Arm/Group Title	Placebo	323U66 SR 150 mg	323U66 SR 300 mg	Total
Arm/Group Description	A 323U66 sustained release (SR) placebo tablet was administered orally twice daily, in the morning and the evening (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 milligram (mg) tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 mg tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses, during the first week of the Treatment Phase (Dose level 1). At Week 2, participants were up-titrated to a daily dose of 323U66 SR 300 mg, administered as a 323U66 SR 150 mg tablet twice daily, in the morning and in the evening, with an interval of at least 8 hours between successive doses (Dose level 2). Dose level 2 was maintained from Week 2 to Week 8.	Total of all reporting groups
Overall Participants	186	190	188	564
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	37.9 (11.09)	36.0 (10.42)	37.5 (10.96)	37.1 (10.83)
Sex: Female, Male (Count of Participants)
Female	101 54.3%	98 51.6%	105 55.9%	304 53.9%
Male	85 45.7%	92 48.4%	83 44.1%	260 46.1%
Race/Ethnicity, Customized (participants) [Number]
Asian - Japanese Heritage	149 80.1%	154 81.1%	147 78.2%	450 79.8%
Asian - East Asian Heritage	37 19.9%	36 18.9%	40 21.3%	113 20%
Asian - Mixed Race	0 0%	0 0%	1 0.5%	1 0.2%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at Week 8/Withdrawal
Description	The MADRS scale measures the depression level of a participant. The total score was derived by adding the scores of the following 10 items: 1, Apparent sadness; 2, Reported sadness; 3, Inner tension; 4, Reduced sleep; 5, Reduced appetite; 6, Concentration difficulties; 7, Lassitude; 8, Inability to feel; 9, Pessimistic thoughts; 10, Suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score is 60; 0, no depression; 60, severely depressed. Change from Baseline in the total score was calculated as the value at Week 8/Withdrawal minus the value at Baseline. The least squared means were estimated based on the Analysis of Covariance (ANCOVA) model including Baseline MADRS score and region as covariates.
Time Frame	Baseline and Week 8/Withdrawal

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all participants who took at least one dose of investigational product and provided at least one efficacy observation at a Treatment Phase visit (i.e. Week 1 or later). Missing values were imputed using Last Observation Carried Forward (LOCF): last observed non-missing value was used to fill missing values at a later point.

Arm/Group Title	Placebo	323U66 SR 150 mg	323U66 SR 300 mg
Arm/Group Description	A 323U66 sustained release (SR) placebo tablet was administered orally twice daily, in the morning and the evening (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 milligram (mg) tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 mg tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses, during the first week of the Treatment Phase (Dose level 1). At Week 2, participants were up-titrated to a daily dose of 323U66 SR 300 mg, administered as a 323U66 SR 150 mg tablet twice daily, in the morning and in the evening, with an interval of at least 8 hours between successive doses (Dose level 2). Dose level 2 was maintained from Week 2 to Week 8.
Measure Participants	186	190	188
Least Squares Mean (Standard Error) [Scores on a scale]	-13.9 (0.77)	-14.4 (0.77)	-12.9 (0.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 323U66 SR 150 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.853
	Comments	The p-value was estimated based on the ANCOVA model including Baseline MADRS score and region as covariates. The multiplicity was adjusted by Dunnett's step-down procedure.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squared Mean Difference
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -2.7 to 1.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	The confidence interval was estimated based on the ANCOVA model including Baseline MADRS score and region as covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, 323U66 SR 300 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.0
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.00
	Estimation Comments	In the analysis plan, the second comparison of interest was not to be performed if the first comparison failed to show statistical significance.

2. Secondary Outcome

Title	Change From Baseline in the MADRS Total Score at Weeks 1, 2, 4, and 6
Description	The MADRS scale measures the depression level of a participant. The total score was derived by adding the scores of the following 10 items: 1, Apparent sadness; 2, Reported sadness; 3, Inner tension; 4, Reduced sleep; 5, Reduced appetite; 6, Concentration difficulties; 7, Lassitude; 8, Inability to feel; 9, Pessimistic thoughts; 10, Suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score is 60; 0, no depression; 60, severely depressed. Change from Baseline in the total score was calculated as the value at Week 1, 2, 4 and 6 minus the value at Baseline. The least squared means were estimated based on the ANCOVA model including Baseline MADRS score and region as covariates.
Time Frame	Baseline; Weeks 1, 2, 4, and 6

Outcome Measure Data

Analysis Population Description

FAS. Missing values were imputed using LOCF. Only participants who were available at the specified time points were analyzed.

Arm/Group Title	Placebo	323U66 SR 150 mg	323U66 SR 300 mg
Arm/Group Description	A 323U66 SR placebo tablet was administered orally twice daily, in the morning and the evening (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 mg tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 mg tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses, during the first week of the Treatment Phase (Dose level 1). At Week 2, participants were up-titrated to a daily dose of 323U66 SR 300 mg, administered as a 323U66 SR 150 mg tablet twice daily, in the morning and in the evening, with an interval of at least 8 hours between successive doses (Dose level 2). Dose level 2 was maintained from Week 2 to Week 8.
Measure Participants	186	190	188
Week 1, n=182, 187, 184	-3.4 (0.38)	-2.9 (0.38)	-2.7 (0.38)
Week 2, n=186, 190, 188	-6.2 (0.47)	-5.0 (0.47)	-5.0 (0.47)
Week 4, n=186, 190, 188	-9.2 (0.61)	-8.3 (0.60)	-8.2 (0.60)
Week 6, n=186, 190, 188	-11.8 (0.70)	-11.7 (0.70)	-11.1 (0.69)

3. Secondary Outcome

Title	Change From Baseline in the MADRS Individual Item Scores at Weeks 1, 2, 4, 6, and 8
Description	The MADRS scale measures the depression level of a participant using the following 10 items: 1, Apparent sadness; 2, Reported sadness; 3, Inner tension; 4, Reduced sleep; 5, Reduced appetite; 6, Concentration difficulties; 7, Lassitude; 8, Inability to feel; 9, Pessimistic thoughts; 10, Suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). Scores for MADRS items 1, 2, 6, 7, and 8 were evaluated for this endpoint. Change from Baseline was calculated as the value at Week 1, 2, 4, 6, and 8 minus the value at Baseline. The least squared means were estimated based on the ANCOVA model including Baseline MADRS score of each item and region as covariates.
Time Frame	Baseline; Week 1, 2, 4, 6, and 8

Outcome Measure Data

Analysis Population Description

FAS. Missing values were imputed using LOCF. Only participants who were available at the specified time points were analyzed.

Arm/Group Title	Placebo	323U66 SR 150 mg	323U66 SR 300 mg
Arm/Group Description	A 323U66 SR placebo tablet was administered orally twice daily, in the morning and the evening (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 mg tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 mg tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses, during the first week of the Treatment Phase (Dose level 1). At Week 2, participants were up-titrated to a daily dose of 323U66 SR 300 mg, administered as a 323U66 SR 150 mg tablet twice daily, in the morning and in the evening, with an interval of at least 8 hours between successive doses (Dose level 2). Dose level 2 was maintained from Week 2 to Week 8.
Measure Participants	186	190	188
Item 1: Week 1, n=182, 187, 184	-0.5 (0.07)	-0.3 (0.07)	-0.3 (0.07)
Item 1: Week 2, n=186, 190, 188	-0.7 (0.08)	-0.5 (0.08)	-0.6 (0.08)
Item 1: Week 4, n=186, 190, 188	-1.0 (0.09)	-0.9 (0.09)	-1.0 (0.09)
Item 1: Week 6, n=186, 190, 188	-1.4 (0.10)	-1.3 (0.10)	-1.3 (0.10)
Item 1: Week 8, n=186, 190, 188	-1.6 (0.10)	-1.6 (0.10)	-1.5 (0.10)
Item 2: Week 1, n=182, 187, 184	-0.5 (0.08)	-0.4 (0.08)	-0.5 (0.08)
Item 2: Week 2, n=186, 190, 188	-0.8 (0.09)	-0.8 (0.09)	-0.7 (0.09)
Item 2: Week 4, n=186, 190, 188	-1.2 (0.10)	-1.2 (0.10)	-1.1 (0.10)
Item 2: Week 6, n=186, 190, 188	-1.6 (0.11)	-1.6 (0.11)	-1.4 (0.11)
Item 2: Week 8, n=186, 190, 188	-1.8 (0.12)	-2.0 (0.12)	-1.7 (0.12)
Item 6: Week 1, n=182, 187, 184	-0.3 (0.07)	-0.4 (0.07)	-0.4 (0.07)
Item 6: Week 2, n=186, 190, 188	-0.6 (0.08)	-0.6 (0.08)	-0.7 (0.08)
Item 6: Week 4, n=186, 190, 188	-1.0 (0.10)	-1.1 (0.10)	-1.0 (0.09)
Item 6: Week 6, n=186, 190, 188	-1.3 (0.10)	-1.4 (0.10)	-1.4 (0.10)
Item 6: Week 8, n=186, 190, 188	-1.5 (0.11)	-1.7 (0.11)	-1.6 (0.11)
Item 7: Week 1, n=182, 187, 184	-0.3 (0.08)	-0.3 (0.08)	-0.4 (0.08)
Item 7: Week 2, n=186, 190, 188	-0.7 (0.09)	-0.6 (0.09)	-0.7 (0.08)
Item 7: Week 4, n=186, 190, 188	-1.0 (0.10)	-0.9 (0.10)	-1.1 (0.10)
Item 7: Week 6, n=186, 190, 188	-1.4 (0.11)	-1.3 (0.11)	-1.4 (0.11)
Item 7: Week 8, n=186, 190, 188	-1.6 (0.11)	-1.6 (0.11)	-1.6 (0.11)
Item 8: Week 1, n=182, 187, 184	-0.4 (0.08)	-0.3 (0.08)	-0.3 (0.08)
Item 8: Week 2, n=186, 190, 188	-0.8 (0.09)	-0.6 (0.09)	-0.6 (0.08)
Item 8: Week 4, n=186, 190, 188	-1.1 (0.10)	-0.9 (0.10)	-1.0 (0.10)
Item 8: Week 6, n=186, 190, 188	-1.3 (0.11)	-1.2 (0.11)	-1.3 (0.11)
Item 8: Week 8, n=186, 190, 188	-1.7 (0.12)	-1.7 (0.12)	-1.5 (0.11)

4. Secondary Outcome

Title	Number of MADRS Responders at Week 8
Description	The MADRS scale measures the depression level of a participant. The total score was derived by adding the scores of the following 10 items: 1, Apparent sadness; 2, Reported sadness; 3, Inner tension; 4, Reduced sleep; 5, Reduced appetite; 6, Concentration difficulties; 7, Lassitude; 8, Inability to feel; 9, Pessimistic thoughts; 10, Suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score is 60; 0, no depression; 60, severely depressed. A MADRS responder is defined as a participant with a >=50% reduction from Baseline in the MADRS total score at Week 8.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

FAS. Missing values were imputed using LOCF.

Arm/Group Title	Placebo	323U66 SR 150 mg	323U66 SR 300 mg
Arm/Group Description	A 323U66 SR placebo tablet was administered orally twice daily, in the morning and the evening (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 mg tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 mg tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses, during the first week of the Treatment Phase (Dose level 1). At Week 2, participants were up-titrated to a daily dose of 323U66 SR 300 mg, administered as a 323U66 SR 150 mg tablet twice daily, in the morning and in the evening, with an interval of at least 8 hours between successive doses (Dose level 2). Dose level 2 was maintained from Week 2 to Week 8.
Measure Participants	186	190	188
Number [participants]	86 46.2%	98 51.6%	82 43.6%

5. Secondary Outcome

Title	Number of MADRS Remitters at Week 8
Description	The MADRS scale measures the depression level of a participant. The total score was derived by adding the scores of the following 10 items: 1, Apparent sadness; 2, Reported sadness; 3, Inner tension; 4, Reduced sleep; 5, Reduced appetite; 6, Concentration difficulties; 7, Lassitude; 8, Inability to feel; 9, Pessimistic thoughts; 10, Suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score is 60; 0, no depression; 60, severely depressed. A MADRS remitter is defined as a participant with a MADRS total score <=11 at Week 8.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

FAS. Missing values were imputed using LOCF.

Arm/Group Title	Placebo	323U66 SR 150 mg	323U66 SR 300 mg
Arm/Group Description	A 323U66 SR placebo tablet was administered orally twice daily, in the morning and the evening (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 mg tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 mg tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses, during the first week of the Treatment Phase (Dose level 1). At Week 2, participants were up-titrated to a daily dose of 323U66 SR 300 mg, administered as a 323U66 SR 150 mg tablet twice daily, in the morning and in the evening, with an interval of at least 8 hours between successive doses (Dose level 2). Dose level 2 was maintained from Week 2 to Week 8.
Measure Participants	186	190	188
Number [participants]	53 28.5%	60 31.6%	56 29.8%

6. Secondary Outcome

Title	Number of Clinical Global Impression-Global Improvement (CGI-GI) Responders at Week 8
Description	A CGI-GI assessment was performed at Week 8 (or withdrawal) in comparison with severity in depression observed at Baseline (Week 0; no actual assessment was performed at Baseline [the comparison was subjective]), by using scores from 0 to 7: 0, Not assessed; 1, Very much improved; 2, Much improved; 3, Minimally improved; 4, No change; 5, Minimally worse; 6, Much worse; 7, Very much worse. A CGI-GI responder is defined as a participant with a CGI-GI score of very much improved or much improved at Week 8.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

FAS. Missing values were imputed using LOCF. Only those participants who were available at Week 8 were analyzed.

Arm/Group Title	Placebo	323U66 SR 150 mg	323U66 SR 300 mg
Arm/Group Description	A 323U66 SR placebo tablet was administered orally twice daily, in the morning and the evening (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 mg tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 mg tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses, during the first week of the Treatment Phase (Dose level 1). At Week 2, participants were up-titrated to a daily dose of 323U66 SR 300 mg, administered as a 323U66 SR 150 mg tablet twice daily, in the morning and in the evening, with an interval of at least 8 hours between successive doses (Dose level 2). Dose level 2 was maintained from Week 2 to Week 8.
Measure Participants	177	186	173
Number [participants]	100 53.8%	103 54.2%	98 52.1%

7. Secondary Outcome

Title	Change From Baseline in the Clinical Global Impression-Severity of Illness (CGI-SI) Scores at Weeks 1, 2, 4, 6, and 8
Description	A CGI-SI assessment was performed in terms of severity in depression, by using scores from 0 to 7: 0, Not assessed; 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 participants. Change from Baseline in the CGI-SI score was calculated as the value at Week 1, 2, 4, 6, and 8 minus the value at Baseline. The least squared means were estimated based on the ANCOVA model including Baseline CGI-SI score and region as covariates.
Time Frame	Baseline; Weeks 1, 2, 4, 6, and 8

Outcome Measure Data

Analysis Population Description

FAS. Missing values were imputed using LOCF. Only participants who were available at the specified time points were analyzed.

Arm/Group Title	Placebo	323U66 SR 150 mg	323U66 SR 300 mg
Arm/Group Description	A 323U66 SR placebo tablet was administered orally twice daily, in the morning and the evening (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 mg tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 mg tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses, during the first week of the Treatment Phase (Dose level 1). At Week 2, participants were up-titrated to a daily dose of 323U66 SR 300 mg, administered as a 323U66 SR 150 mg tablet twice daily, in the morning and in the evening, with an interval of at least 8 hours between successive doses (Dose level 2). Dose level 2 was maintained from Week 2 to Week 8.
Measure Participants	186	190	188
Week 1, n=182, 187, 184	-0.2 (0.03)	-0.1 (0.03)	-0.1 (0.03)
Week 2, n=186, 190, 188	-0.3 (0.04)	-0.3 (0.04)	-0.2 (0.04)
Week 4, n=186, 190, 188	-0.7 (0.06)	-0.5 (0.06)	-0.6 (0.06)
Week 6, n=186, 190, 188	-0.9 (0.07)	-0.9 (0.07)	-0.9 (0.07)
Week 8, n=186, 190, 188	-1.2 (0.08)	-1.2 (0.08)	-1.1 (0.08)

8. Secondary Outcome

Title	Change From Baseline in the Inventory of Depressive Symptomatology-Self Report (IDS-SR) Total Score at Weeks 1, 2, 4, 6, and 8
Description	The IDS-SR is a 30-item scale used to evaluate the severity and changes in depressive symptoms. Each item was scored from 0 (no symptoms) to 3 (greatest symptom severity). The maximum total score is 84 (0: no symptoms; 84: greatest symptom severity), as participants were asked to answer either item 11 (decreased appetite) or item 12 (increased appetite) (not both) and either item 13 (decreased weight) or item 14 (increased weight) (not both). Change from Baseline was calculated as the value at Week 1, 2, 4, 6, and 8 minus the value at Baseline. The least squared means were estimated based on the ANCOVA model including Baseline IDS-SR score and region as covariates.
Time Frame	Baseline; Weeks 1, 2, 4, 6, and 8

Outcome Measure Data

Analysis Population Description

FAS. Missing values were imputed using LOCF. Only participants who were available at the specified time points were analyzed.

Arm/Group Title	Placebo	323U66 SR 150 mg	323U66 SR 300 mg
Arm/Group Description	A 323U66 SR placebo tablet was administered orally twice daily, in the morning and the evening (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 mg tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 mg tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses, during the first week of the Treatment Phase (Dose level 1). At Week 2, participants were up-titrated to a daily dose of 323U66 SR 300 mg, administered as a 323U66 SR 150 mg tablet twice daily, in the morning and in the evening, with an interval of at least 8 hours between successive doses (Dose level 2). Dose level 2 was maintained from Week 2 to Week 8.
Measure Participants	186	190	188
Week 1, n=182, 187, 184	-4.8 (0.57)	-4.2 (0.57)	-3.9 (0.57)
Week 2, n=186, 190, 188	-6.9 (0.68)	-6.7 (0.68)	-5.8 (0.68)
Week 4, n=186, 190, 188	-9.7 (0.82)	-9.3 (0.82)	-8.2 (0.81)
Week 6, n=186, 190, 188	-11.5 (0.88)	-12.3 (0.88)	-10.9 (0.87)
Week 8, n=186, 190, 188	-13.6 (0.95)	-14.5 (0.95)	-12.6 (0.94)

9. Secondary Outcome

Title	Change From Baseline in the IDS-SR Subscores for Energy, Pleasure, and Interest at Weeks 1, 2, 4, 6, and 8
Description	The IDS-SR is a 30-item scale used to evaluate the severity and changes in depressive symptoms. Each item was scored from 0 (no symptoms) to 3 (greatest symptom severity). Only five items (item 19: general interest; item 20: energy level; item 21: capacity for pleasure or enjoyment, excluding sex; item 22: interest in sex; item 30: leaden paralysis/physical energy) were evaluated for this endpoint, as a subset of the total score. The lowest possible total score and subset total score of IDS-SR are 0 and 0, and the highest possible total score and subset total score of IDS-SR are 84 and 15, respectively. Change from Baseline was calculated as the value at Week 1, 2, 4, 6, and 8 minus the value at Baseline. The least squared means were estimated based on the ANCOVA model including Baseline IDS-SR subscore and region as covariates.
Time Frame	Baseline; Weeks 1, 2, 4, 6, and 8

Outcome Measure Data

Analysis Population Description

FAS. Missing values were imputed using LOCF. Only participants who were available at the specified time points were analyzed.

Arm/Group Title	Placebo	323U66 SR 150 mg	323U66 SR 300 mg
Arm/Group Description	A 323U66 SR placebo tablet was administered orally twice daily, in the morning and the evening (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 mg tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses (Dose level 1 and 2), for 8 weeks.	A 323U66 SR 150 mg tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses, during the first week of the Treatment Phase (Dose level 1). At Week 2, participants were up-titrated to a daily dose of 323U66 SR 300 mg, administered as a 323U66 SR 150 mg tablet twice daily, in the morning and in the evening, with an interval of at least 8 hours between successive doses (Dose level 2). Dose level 2 was maintained from Week 2 to Week 8.
Measure Participants	186	190	188
Week 1, n=182, 187, 184	-1.1 (0.16)	-0.9 (0.16)	-0.9 (0.16)
Week 2, n=186, 190, 188	-1.3 (0.18)	-1.2 (0.18)	-1.3 (0.18)
Week 4, n=186, 190, 188	-2.1 (0.20)	-1.8 (0.20)	-2.0 (0.20)
Week 6, n=186, 190, 188	-2.5 (0.22)	-2.6 (0.22)	-2.5 (0.22)
Week 8, n=186, 190, 188	-2.9 (0.24)	-3.1 (0.24)	-3.0 (0.24)

Adverse Events

Time Frame	Serious adverse events (SAEs) and non-serious AEs were collected from the start of investigational product until the completion of the Follow-up Phase (up to 12 weeks from the start of the Run-in Phase).
Adverse Event Reporting Description	SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants who took at least one dose of investigational product.
Arm/Group Title	Placebo		323U66 SR 150 mg		323U66 SR 300 mg
Arm/Group Description	A 323U66 sustained release (SR) placebo tablet was administered orally twice daily, in the morning and the evening (Dose level 1 and 2), for 8 weeks.		A 323U66 SR 150 milligram (mg) tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses (Dose level 1 and 2), for 8 weeks.		A 323U66 SR 150 mg tablet was administered orally once in the morning, and a 323U66 SR 150 mg placebo tablet was administered orally once in the evening, with an interval of at least 8 hours between successive doses, during the first week of the Treatment Phase (Dose level 1). At Week 2, participants were up-titrated to a daily dose of 323U66 SR 300 mg, administered as a 323U66 SR 150 mg tablet twice daily, in the morning and in the evening, with an interval of at least 8 hours between successive doses (Dose level 2). Dose level 2 was maintained from Week 2 to Week 8.
All Cause Mortality
	Placebo		323U66 SR 150 mg		323U66 SR 300 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		323U66 SR 150 mg		323U66 SR 300 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/186 (1.1%)		2/190 (1.1%)		1/189 (0.5%)
General disorders
Pyrexia	0/186 (0%)		0/190 (0%)		1/189 (0.5%)
Injury, poisoning and procedural complications
Meniscus lesion	0/186 (0%)		1/190 (0.5%)		0/189 (0%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/186 (0.5%)		0/190 (0%)		0/189 (0%)
Nervous system disorders
Headache	0/186 (0%)		1/190 (0.5%)		0/189 (0%)
Psychiatric disorders
Depression	1/186 (0.5%)		0/190 (0%)		0/189 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		323U66 SR 150 mg		323U66 SR 300 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	63/186 (33.9%)		62/190 (32.6%)		80/189 (42.3%)
Gastrointestinal disorders
Dry mouth	8/186 (4.3%)		12/190 (6.3%)		28/189 (14.8%)
Nausea	15/186 (8.1%)		13/190 (6.8%)		16/189 (8.5%)
Constipation	3/186 (1.6%)		8/190 (4.2%)		11/189 (5.8%)
Infections and infestations
Nasopharyngitis	35/186 (18.8%)		26/190 (13.7%)		29/189 (15.3%)
Nervous system disorders
Headache	13/186 (7%)		15/190 (7.9%)		19/189 (10.1%)
Psychiatric disorders
Insomnia	6/186 (3.2%)		0/190 (0%)		10/189 (5.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.