A Duloxetine Dosing Strategy Study in Korean Patients With Major Depressive Disorder

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00960986
• Collaborator: Boehringer Ingelheim (Industry)
• Enrollment: 249
• Locations: 7
• Arms: 4
• Duration (Months): 20
• Patients Per Site: 35.6
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

The purpose of this study is to assess nausea severity in response to four different drug dosing strategies of Duloxetine (30 mg with food, 60 mg with food, 30 mg without food, and 60 mg without food) in Korean patients with major depressive disorder (MDD).

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder (MDD)	Drug: Duloxetine hydrochloride	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 249 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 4 Comparison of Duloxetine Dosing Strategies in the Treatment of Korean Patients With Major Depressive Disorder
• Study Start Date: Aug 1, 2009
• Actual Primary Completion Date: Feb 1, 2011
• Actual Study Completion Date: Apr 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Duloxetine 60 mg with food Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks	Drug: Duloxetine hydrochloride; po, QD; Other Names: Cymbalta LY248686
Experimental: Duloxetine 60 mg without food Duloxetine 60 mg capsule po QD without food for 8 weeks	Drug: Duloxetine hydrochloride; po, QD; Other Names: Cymbalta LY248686
Experimental: Duloxetine 30 mg with food Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks	Drug: Duloxetine hydrochloride; po, QD; Other Names: Cymbalta LY248686
Experimental: Duloxetine 30 mg without food Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks	Drug: Duloxetine hydrochloride; po, QD; Other Names: Cymbalta LY248686

Outcome Measures

Primary Outcome Measures

1. Mean Maximum Nausea Severity, Association for Methodology and Documentation in Psychiatry (AMDP-5) Adverse Event (AE) Scale Item 112 (Nausea) [1 week and 8 weeks]

   AMDP-5 AE scale Item 112 (nausea) measured nausea severity during treatment (Week 0-8). The scores ranged from 0-3: 0=Not present; 1=Mild; 2=Moderate; 3=Severe.

Secondary Outcome Measures

1. Mean Change From Baseline to 8-Week Endpoint in Association for Methodology and Documentation in Psychiatry (AMDP-5) Adverse Event (AE) Scale Item 112 (Nausea) [Baseline, 8 weeks]

   Scores for AE scale Item 112 (nausea) of AMDP-5 (Week 0-8) ranged from 0-3: 0=Not present; 1=Mild; 2=Moderate; 3=Severe. Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix.

2. Mean Change From Baseline to 1-Week and 8-Week Endpoints in Association for Methodology and Documentation in Psychiatry (AMDP-5) Measure: Gastric Events Score [Baseline, 1 week and 8 weeks]

   Gastric events scores (average of Item 112 [nausea] + Item 113 [vomiting]) of AMDP-5 (Week 0-8) ranged from 0-3: 0=Not present; 1=Mild; 2=Moderate; 3=Severe. Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix.

3. Mean Change From Baseline to 1-Week and 8-Week Endpoints in Association for Methodology and Documentation in Psychiatry (AMDP-5) Measure: Common Adverse Events (AEs) Score [Baseline, 1 week, 8 weeks]

   AMDP-5 common AEs score was used to create a composite measure of AEs from previous duloxetine studies (incidence >5% and 2X placebo rate). The common AEs total score was the sum of the following 8 AMDP-5 items: 1) Mean of Item 112 (nausea) + 113 (vomiting); 2) Item 111 (dry mouth); 3) Item 115 (constipation); 4) Mean of Items 101-104 (insomnia); Item 122 (increased perspiration); 8) Item 106 (decreased appetite). Score was based on a 5-point scale: 1=absent, 2=mild, 3=moderate, 4=severe, 5=extremely severe; Higher score=worse severity.

4. Mean Change From Baseline to 1-Week and 8-Week Endpoints in 17-Item Hamilton Depression Rating Scale (HAMD-17) Total Score [Baseline, 1 week, 8 weeks]

   The HAMD-17 total score ranged from 0 (not at all depressed)-52 (severely depressed). Least squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariance matrix.

5. Mean Change From Baseline to 1-Week and 8-Week Endpoints in 17-Item Hamilton Depression Rating Scale (HAMD-17) Maier Subscale [Baseline, 1 week, 8 weeks]

   The HAMD-17 Maier subscale (Items 1, 2, 7, 8, 9, 10 of HAMD-17 questionnaire) represented the "core" symptoms of depression. Total subscale scores ranged from 0 (normal)-24 (severe). Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix.

6. Mean Change From Baseline to 1-Week and 8-Week Endpoints in 17-Item Hamilton Depression Rating Scale (HAMD-17) Core Mood Subscale [Baseline, 1 week, 8 weeks]

   The HAMD-17 Core Mood subscale (Items 1, 2, 3, 7, 8 of HAMD-17 questionnaire) represented the core symptoms of depression. Total subscale scores ranged from 0 (normal)-20 (severe). Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix.

7. Mean Change From Baseline to 1-Week and 8-Week Endpoints in 17-Item Hamilton Depression Rating Scale (HAMD-17) Anxiety/Somatization Subscale [Baseline, 1 week, 8 weeks]

   The HAMD-17 Anxiety/Somatization subscale (Items 10, 11, 12, 13, 15, 17 of HAMD-17 questionnaire) evaluated the severity of psychic and somatic manifestations of anxiety and agitation. Total subscale scores ranged from 0 (normal)-18 (severe). Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix.

8. Mean Change From Baseline to 1-Week and 8-Week Endpoints in 17-Item Hamilton Depression Rating Scale (HAMD-17) Retardation/Somatization Subscale [Baseline, 1 week, 8 weeks]

   The HAMD-17 Retardation/Somatization subscale (Items 1, 7, 8, 14 of HAMD-17 questionnaire) evaluated dysfunction in mood, work, sexual activity, and overall motor retardation. Total subscale scores ranged from 0 (normal)-14 (severe). Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix.

9. Mean Change From Baseline to 1-Week and 8-Week Endpoints in 17-Item Hamilton Depression Rating Scale (HAMD-17) Sleep Subscale [Baseline, 1 week, 8 weeks]

   The HAMD-17 Sleep subscale (Items 4, 5, 6 of HAMD-17 questionnaire) evaluated initial, middle, and late insomnia. Total subscale scores ranged from 0 (no difficulty)-6 (difficulty). Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix.

10. Mean Change From Baseline to 1-Week and 8-Week Endpoints in Clinical Global Impressions of Severity (CGI-S) [Baseline, 1 week, 8 weeks]

    The CGI-S Rating Scale was a 7-point scale: 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; or 7=extremely ill. Least squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariance matrix.

11. Patient Global Impression of Improvement (PGI-I) at 1 Week and 8 Weeks [1 week, 8 weeks]

    The PGI-I Rating Scale was a 7-point scale: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; or 7=very much worse. Least squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction and an unstructured covariance matrix.

12. Time to Onset of Nausea [Baseline to onset of nausea (Baseline up to 8 weeks)]

    Events of nausea were taken from the adverse event (AE) data. Participants were censored based on the following rules: 1=study discontinuation date if the participant discontinues the study; 2=study lost to follow-up date if the participant drops out of the study.

13. Time to Resolve Nausea [Nausea onset up to nausea resolve (Baseline up to 8 weeks)]

    Events of nausea were taken from the adverse event (AE) data. Participants were censored based on the following rules: 1=study discontinuation date if the participant discontinues the study; 2=study lost to follow-up date if the participant drops out of the study.

14. Percentage of Participants Achieving Response [Baseline up to 8 weeks]

    Response was defined as ≥50% decrease from baseline on the 17-item Hamilton Depression Rating Scale (HAMD-17) total score. HAMD-17 total scores ranged from 0 (not at all depressed)-52 (severely depressed).

15. Percentage of Patients Achieving Remission [Baseline up to 8 weeks]

    Remission was defined as 17-item Hamilton Depression Rating Scale (HAMD-17) total score ≤7. HAMD-17 total scores ranged from 0 (not at all depressed)-52 (severely depressed).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• For females of child-bearing potential test negative for pregnancy at the time of enrollment based on a urine pregnancy test and agree to use a reliable method of birth control during the study and for 1 month following the last dose of study drug.

• 17-item Hamilton Depression Rating Scale (HAMD-17) total score >15 at Screening and Randomization

• Have signed the informed consent document (ICD)

• Have a level of understanding sufficient to provide informed consent and to communicate with the investigators and site personnel

• Are judged to be reliable and agree to keep all appointments for clinic visits, tests, and procedures required by the protocol

• Patients must meet Diagnostic and Statistical Manual of Mental Disorders-fourth edition-text revision (DSM-IV-TR) criteria for Major Depressive Disorder (MDD). The Mini International Neuropsychiatric Interview (MINI) will be used to establish the diagnosis and exclude other psychiatric illnesses.

Exclusion Criteria:

• Treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry

• Have any current primary Axis I disorder other than MDD

• Have any previous diagnosis of bipolar disorder, schizophrenia, or other psychotic disorders

• Lack of response of the current episode of major depression to two or more adequate courses of antidepressant therapy at clinically appropriate dose for a minimum of 4 weeks or, in the judgment of the investigator, the patient meets criteria for treatment-resistant depression

• Have a history of a lack of response, at any time, to an adequate trial of duloxetine (defined as treatment with at least 60 mg/day of duloxetine for a minimum of 4 weeks)

• Presence of an Axis II disorder that, in the judgment of the investigator, would interfere with study compliance

• DSM-IV-TR-defined history of substance abuse or dependence within the past 6 months, excluding nicotine and caffeine

• Patients judged to be at serious suicidal risk in the opinion of the investigator and/or score ≥3 on Item 3 (suicide) of the HAMD-17

• Serious medical illness or clinically significant laboratory abnormalities that, in the judgment of the investigator, are likely to require intervention/hospitalization/excluded medication during the course of the study Note: Patients with acute liver injury (such as hepatitis) or severe (Child-Pugh Class C) cirrhosis will be excluded

• Have an acute or chronic medical illness with the main symptoms of nausea or gastrointestinal discomfort or taking any medication known to have major gastric effects that would interfere with nausea ratings.

• Electroconvulsive therapy (ECT) or Transcranial Magnetic Stimulation (TMS) within the past year

• Taking any excluded medications within 7 days prior to Randomization.

• Treatment with a monoamine oxidase inhibitor (MAOI) within 14 days prior to Randomization or potential need to use a MAOI within 5 days after discontinuation of study drug.

• Treatment with fluoxetine within 30 days prior to Randomization.

• Frequent and/or severe allergic reactions with multiple medications or known hypersensitivity to duloxetine.

• Abnormal thyroid stimulating hormone (TSH) concentration. Note: Participants diagnosed with hyperthyroidism or hypothyroidism who were treated with a stable dose of thyroid supplement for at least the past 3 months, have medically appropriate TSH concentration, and are clinically euthyroid, are allowed to enroll in this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Cheong Ju-City		Korea, Republic of	361-711
2	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Goyang-Si		Korea, Republic of	410-719
3	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Seongnam-Si		Korea, Republic of	463-707
4	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Seoul		Korea, Republic of	134-791
5	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Sungnam-Si		Korea, Republic of	463-712
6	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Suwon-City		Korea, Republic of	442-721
7	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Yangsan		Korea, Republic of	626-770

Sponsors and Collaborators

• Eli Lilly and Company
• Boehringer Ingelheim

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon-Fri 9AM - 5PM Eastern time (UTC/GMT - 5hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT00960986
• Other Study ID Numbers: 9884; F1J-MC-HMFL
• First Posted: Aug 18, 2009
• Last Update Posted: Dec 31, 2014
• Last Verified: Dec 1, 2014

• Additional relevant MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major; Duloxetine Hydrochloride

Study Results

Participant Flow

Pre-assignment Detail	Period 1 was a 3- to 30-day screening and washout period; Period 2 (Week 0-1) was a 1-week initial dosing period (randomization to duloxetine 30 mg with food, 30 mg without food, 60 mg with food, or 60 mg without food); Period 3 (Week 1-8) was a 7-week therapy period (treatment switched to duloxetine 60 mg once daily (QD) until study end.

Arm/Group Title	Duloxetine 60 mg With Food	Duloxetine 60 mg Without Food	Duloxetine 30 mg With Food	Duloxetine 30 mg Without Food
Arm/Group Description	Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks	Duloxetine 60 mg capsule po QD without food for 8 weeks	Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks	Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks
Period Title: Period 1 (Screening and Washout)
STARTED	59	63	63	64
COMPLETED	56	59	59	61
NOT COMPLETED	3	4	4	3
Period Title: Period 1 (Screening and Washout)
STARTED	56	59	59	61
COMPLETED	56	59	59	61
NOT COMPLETED	0	0	0	0
Period Title: Period 1 (Screening and Washout)
STARTED	56	59	59	61
COMPLETED	26	36	39	36
NOT COMPLETED	30	23	20	25

Baseline Characteristics

Arm/Group Title	Duloxetine 60 mg With Food	Duloxetine 60 mg Without Food	Duloxetine 30 mg With Food	Duloxetine 30 mg Without Food	Total
Arm/Group Description	Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks	Duloxetine 60 mg capsule po QD without food for 8 weeks	Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks	Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks	Total of all reporting groups
Overall Participants	59	63	63	64	249
Age (years) [Mean (Inter-Quartile Range) ]
Mean (Inter-Quartile Range) [years]	44.65	47.90	49.94	44.65	46.81
Sex: Female, Male (Count of Participants)
Female	43 72.9%	47 74.6%	47 74.6%	40 62.5%	177 71.1%
Male	16 27.1%	16 25.4%	16 25.4%	24 37.5%	72 28.9%
Race/Ethnicity, Customized (participants) [Number]
Korean	59 100%	63 100%	63 100%	64 100%	249 100%
Region of Enrollment (participants) [Number]
Korea, Republic of	59 100%	63 100%	63 100%	64 100%	249 100%
Body Mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	24.56 (4.034)	23.28 (3.133)	23.06 (3.430)	23.84 (3.612)	23.67 (3.584)
Previously diagnosed with major depressive disorder (MDD) (participants) [Number]
Number [participants]	59 100%	63 100%	63 100%	64 100%	249 100%
Duration since first major depressive disorder (MDD) episode (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	1.47	2.65	2.52	1.29	1.92
Age at first major depressive disorder (MDD) episode (years) [Mean (Inter-Quartile Range) ]
Mean (Inter-Quartile Range) [years]	41.21	43.33	43.86	41.58	42.52
Number of previous MDD episodes/exacerbations in the last 24 months (number of episodes in last 24 months) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [number of episodes in last 24 months]	1.0	1.0	1.0	1.0	1.0
Received previous therapy for current episode (participants) [Number]
yes	18 30.5%	25 39.7%	18 28.6%	26 40.6%	87 34.9%
no	41 69.5%	38 60.3%	45 71.4%	38 59.4%	162 65.1%
17-item Hamilton Depression Rating Scale (HAMD-17) Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	21.0 (5.18)	22.3 (5.69)	22.9 (5.45)	20.3 (5.23)	21.6 (5.46)
Clinical Global Impression of Severity (CGI-S) Score (units on a scale) [Mean (Inter-Quartile Range) ]
Mean (Inter-Quartile Range) [units on a scale]	4.4	4.5	4.7	4.2	4.4
Association for Methodology and Documentation in Psychiatry (AMDP-5) Item 112 (Nausea) Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	0.3 (0.72)	0.2 (0.59)	0.2 (0.61)	0.1 (0.38)	0.2 (0.58)

Outcome Measures

1. Primary Outcome

Title	Mean Maximum Nausea Severity, Association for Methodology and Documentation in Psychiatry (AMDP-5) Adverse Event (AE) Scale Item 112 (Nausea)
Description	AMDP-5 AE scale Item 112 (nausea) measured nausea severity during treatment (Week 0-8). The scores ranged from 0-3: 0=Not present; 1=Mild; 2=Moderate; 3=Severe.
Time Frame	1 week and 8 weeks

Outcome Measure Data

Analysis Population Description

The safety population included all participants who took at least 1 study drug dose analysed according to the drug dose actually taken.

Arm/Group Title	Duloxetine 60 mg With Food	Duloxetine 60 mg Without Food	Duloxetine 30 mg With Food	Duloxetine 30 mg Without Food
Arm/Group Description	Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks	Duloxetine 60 mg capsule po QD without food for 8 weeks	Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks	Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks
Measure Participants	56	59	59	61
Week 0-1	1.4	1.2	0.9	0.8
Week 1-8 (n=35; n=43; n=48; n=46)	0.5	0.5	0.7	0.4

2. Secondary Outcome

Title	Mean Change From Baseline to 8-Week Endpoint in Association for Methodology and Documentation in Psychiatry (AMDP-5) Adverse Event (AE) Scale Item 112 (Nausea)
Description	Scores for AE scale Item 112 (nausea) of AMDP-5 (Week 0-8) ranged from 0-3: 0=Not present; 1=Mild; 2=Moderate; 3=Severe. Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

The safety population included all participants who took at least 1 study drug dose analysed according to the drug dose actually taken. N = number of subjects with a baseline and post-baseline result at the Week 8 visit.

Arm/Group Title	Duloxetine 60 mg With Food	Duloxetine 60 mg Without Food	Duloxetine 30 mg With Food	Duloxetine 30 mg Without Food
Arm/Group Description	Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks	Duloxetine 60 mg capsule po QD without food for 8 weeks	Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks	Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks
Measure Participants	28	37	39	37
Least Squares Mean (Standard Error) [units on a scale]	-0.02 (0.08)	-0.02 (0.07)	-0.01 (0.07)	-1.12 (0.07)

3. Secondary Outcome

Title	Mean Change From Baseline to 1-Week and 8-Week Endpoints in Association for Methodology and Documentation in Psychiatry (AMDP-5) Measure: Gastric Events Score
Description	Gastric events scores (average of Item 112 [nausea] + Item 113 [vomiting]) of AMDP-5 (Week 0-8) ranged from 0-3: 0=Not present; 1=Mild; 2=Moderate; 3=Severe. Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix.
Time Frame	Baseline, 1 week and 8 weeks

Outcome Measure Data

Analysis Population Description

The safety population included all participants who took at least 1 study drug dose analysed according to the drug dose actually taken.

Arm/Group Title	Duloxetine 60 mg With Food	Duloxetine 60 mg Without Food	Duloxetine 30 mg With Food	Duloxetine 30 mg Without Food
Arm/Group Description	Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks	Duloxetine 60 mg capsule po QD without food for 8 weeks	Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks	Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks
Measure Participants	56	59	59	61
1-week change	0.73 (0.10)	0.72 (0.10)	0.35 (0.10)	0.37 (0.10)
8-week change (n=28; n=37; n=39; n=37)	-0.04 (0.04)	-0.04 (0.04)	-0.04 (0.04)	-0.09 (0.04)

4. Secondary Outcome

Title	Mean Change From Baseline to 1-Week and 8-Week Endpoints in Association for Methodology and Documentation in Psychiatry (AMDP-5) Measure: Common Adverse Events (AEs) Score
Description	AMDP-5 common AEs score was used to create a composite measure of AEs from previous duloxetine studies (incidence >5% and 2X placebo rate). The common AEs total score was the sum of the following 8 AMDP-5 items: 1) Mean of Item 112 (nausea) + 113 (vomiting); 2) Item 111 (dry mouth); 3) Item 115 (constipation); 4) Mean of Items 101-104 (insomnia); Item 122 (increased perspiration); 8) Item 106 (decreased appetite). Score was based on a 5-point scale: 1=absent, 2=mild, 3=moderate, 4=severe, 5=extremely severe; Higher score=worse severity.
Time Frame	Baseline, 1 week, 8 weeks

Outcome Measure Data

Analysis Population Description

The safety population included all participants who took at least 1 study drug dose analysed according to the drug dose actually taken.

Arm/Group Title	Duloxetine 60 mg With Food	Duloxetine 60 mg Without Food	Duloxetine 30 mg With Food	Duloxetine 30 mg Without Food
Arm/Group Description	Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks	Duloxetine 60 mg capsule po QD without food for 8 weeks	Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks	Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks
Measure Participants	56	59	59	61
1-week change	1.25 (0.44)	1.28 (0.42)	-0.00 (0.43)	-0.37 (0.41)
8-week change (n=28; n=37; n=39; n=37)	-3.54 (0.47)	-2.99 (0.42)	-2.33 (0.41)	-3.23 (0.41)

5. Secondary Outcome

Title	Mean Change From Baseline to 1-Week and 8-Week Endpoints in 17-Item Hamilton Depression Rating Scale (HAMD-17) Total Score
Description	The HAMD-17 total score ranged from 0 (not at all depressed)-52 (severely depressed). Least squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariance matrix.
Time Frame	Baseline, 1 week, 8 weeks

Outcome Measure Data

Analysis Population Description

The efficacy population included the number of participants with baseline and at least 1 post-baseline value analysed under the intent-to-treat (ITT) principle according to the drug dose they were assigned.

Arm/Group Title	Duloxetine 60 mg With Food	Duloxetine 60 mg Without Food	Duloxetine 30 mg With Food	Duloxetine 30 mg Without Food
Arm/Group Description	Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks	Duloxetine 60 mg capsule po QD without food for 8 weeks	Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks	Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks
Measure Participants	56	59	59	61
1-week change	-2.83 (0.57)	-2.85 (0.55)	-3.84 (0.56)	-4.34 (0.54)
8-week change (n=28; n=37; n=39; n=37)	-15.39 (1.01)	-13.45 (0.90)	-13.60 (0.88)	-13.07 (0.89)

6. Secondary Outcome

Title	Mean Change From Baseline to 1-Week and 8-Week Endpoints in 17-Item Hamilton Depression Rating Scale (HAMD-17) Maier Subscale
Description	The HAMD-17 Maier subscale (Items 1, 2, 7, 8, 9, 10 of HAMD-17 questionnaire) represented the "core" symptoms of depression. Total subscale scores ranged from 0 (normal)-24 (severe). Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix.
Time Frame	Baseline, 1 week, 8 weeks

Outcome Measure Data

Analysis Population Description

The efficacy population included the number of participants with baseline and at least 1 post-baseline value analysed under the intent-to-treat (ITT) principle according to the drug dose they were assigned.

Arm/Group Title	Duloxetine 60 mg With Food	Duloxetine 60 mg Without Food	Duloxetine 30 mg With Food	Duloxetine 30 mg Without Food
Arm/Group Description	Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks	Duloxetine 60 mg capsule po QD without food for 8 weeks	Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks	Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks
Measure Participants	56	59	59	61
1-week change	-2.06 (0.33)	-1.90 (0.32)	-2.15 (0.32)	-2.64 (0.31)
8-week change (n=28; n=37; n=39; n=37)	-8.01 (0.50)	-7.12 (0.45)	-7.55 (0.44)	-7.30 (0.44)

7. Secondary Outcome

Title	Mean Change From Baseline to 1-Week and 8-Week Endpoints in 17-Item Hamilton Depression Rating Scale (HAMD-17) Core Mood Subscale
Description	The HAMD-17 Core Mood subscale (Items 1, 2, 3, 7, 8 of HAMD-17 questionnaire) represented the core symptoms of depression. Total subscale scores ranged from 0 (normal)-20 (severe). Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix.
Time Frame	Baseline, 1 week, 8 weeks

Outcome Measure Data

Analysis Population Description

The efficacy population included the number of participants with baseline and at least 1 post-baseline value analysed under the intent-to-treat (ITT) principle according to the drug dose they were assigned.

Arm/Group Title	Duloxetine 60 mg With Food	Duloxetine 60 mg Without Food	Duloxetine 30 mg With Food	Duloxetine 30 mg Without Food
Arm/Group Description	Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks	Duloxetine 60 mg capsule po QD without food for 8 weeks	Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks	Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks
Measure Participants	56	59	59	61
1-week change	-1.43 (0.27)	-1.18 (0.26)	-1.52 (0.26)	-1.76 (0.25)
8-week change (n=28; n=37; n=39; n=37)	-6.18 (0.40)	-5.39 (0.36)	-5.85 (0.35)	-5.67 (0.35)

8. Secondary Outcome

Title	Mean Change From Baseline to 1-Week and 8-Week Endpoints in 17-Item Hamilton Depression Rating Scale (HAMD-17) Anxiety/Somatization Subscale
Description	The HAMD-17 Anxiety/Somatization subscale (Items 10, 11, 12, 13, 15, 17 of HAMD-17 questionnaire) evaluated the severity of psychic and somatic manifestations of anxiety and agitation. Total subscale scores ranged from 0 (normal)-18 (severe). Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix.
Time Frame	Baseline, 1 week, 8 weeks

Outcome Measure Data

Analysis Population Description

The efficacy population included the number of participants with baseline and at least 1 post-baseline value analysed under the intent-to-treat (ITT) principle according to the drug dose they were assigned.

Arm/Group Title	Duloxetine 60 mg With Food	Duloxetine 60 mg Without Food	Duloxetine 30 mg With Food	Duloxetine 30 mg Without Food
Arm/Group Description	Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks	Duloxetine 60 mg capsule po QD without food for 8 weeks	Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks	Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks
Measure Participants	56	59	59	61
1-week change	-0.75 (0.25)	-1.15 (0.24)	-1.36 (0.24)	-1.41 (0.23)
8-week change (n=28; n=37; n=39; n=37)	-4.93 (0.41)	-4.50 (0.36)	-4.57 (0.35)	-4.26 (0.35)

9. Secondary Outcome

Title	Mean Change From Baseline to 1-Week and 8-Week Endpoints in 17-Item Hamilton Depression Rating Scale (HAMD-17) Retardation/Somatization Subscale
Description	The HAMD-17 Retardation/Somatization subscale (Items 1, 7, 8, 14 of HAMD-17 questionnaire) evaluated dysfunction in mood, work, sexual activity, and overall motor retardation. Total subscale scores ranged from 0 (normal)-14 (severe). Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix.
Time Frame	Baseline, 1 week, 8 weeks

Outcome Measure Data

Analysis Population Description

The efficacy population included the number of participants with baseline and at least 1 post-baseline value analysed under the intent-to-treat (ITT) principle according to the drug dose they were assigned.

Arm/Group Title	Duloxetine 60 mg With Food	Duloxetine 60 mg Without Food	Duloxetine 30 mg With Food	Duloxetine 30 mg Without Food
Arm/Group Description	Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks	Duloxetine 60 mg capsule po QD without food for 8 weeks	Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks	Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks
Measure Participants	56	59	59	61
1-week change	-0.83 (0.22)	-0.87 (0.21)	-1.02 (0.22)	-1.20 (0.21)
8-week change (n=28; n=37; n=39; n=37)	-4.92 (0.35)	-4.37 (0.31)	-4.63 (0.31)	-4.55 (0.31)

10. Secondary Outcome

Title	Mean Change From Baseline to 1-Week and 8-Week Endpoints in 17-Item Hamilton Depression Rating Scale (HAMD-17) Sleep Subscale
Description	The HAMD-17 Sleep subscale (Items 4, 5, 6 of HAMD-17 questionnaire) evaluated initial, middle, and late insomnia. Total subscale scores ranged from 0 (no difficulty)-6 (difficulty). Least Squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariate matrix.
Time Frame	Baseline, 1 week, 8 weeks

Outcome Measure Data

Analysis Population Description

The efficacy population included the number of participants with baseline and at least 1 post-baseline value analysed under the intent-to-treat (ITT) principle according to the drug dose they were assigned.

Arm/Group Title	Duloxetine 60 mg With Food	Duloxetine 60 mg Without Food	Duloxetine 30 mg With Food	Duloxetine 30 mg Without Food
Arm/Group Description	Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks	Duloxetine 60 mg capsule po QD without food for 8 weeks	Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks	Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks
Measure Participants	56	59	59	61
1-week change	-0.72 (0.21)	-0.64 (0.21)	-0.66 (0.21)	-1.01 (0.20)
8-week change (n=28; n=37; n=39; n=37)	-2.77 (0.27)	-2.32 (0.24)	-2.09 (0.23)	-2.10 (0.23)

11. Secondary Outcome

Title	Mean Change From Baseline to 1-Week and 8-Week Endpoints in Clinical Global Impressions of Severity (CGI-S)
Description	The CGI-S Rating Scale was a 7-point scale: 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; or 7=extremely ill. Least squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction, and an unstructured covariance matrix.
Time Frame	Baseline, 1 week, 8 weeks

Outcome Measure Data

Analysis Population Description

The efficacy population included the number of participants with baseline and at least 1 post-baseline value analysed under the intent-to-treat (ITT) principle according to the drug dose they were assigned.

Arm/Group Title	Duloxetine 60 mg With Food	Duloxetine 60 mg Without Food	Duloxetine 30 mg With Food	Duloxetine 30 mg Without Food
Arm/Group Description	Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks	Duloxetine 60 mg capsule po QD without food for 8 weeks	Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks	Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks
Measure Participants	56	59	59	61
1-week change	-0.36 (0.09)	-0.36 (0.09)	-0.44 (0.09)	-0.63 (0.09)
8-week change (n=28; n=37; n=39; n=37)	-2.43 (0.17)	-2.13 (0.15)	-2.23 (0.15)	-2.27 (0.15)

12. Secondary Outcome

Title	Patient Global Impression of Improvement (PGI-I) at 1 Week and 8 Weeks
Description	The PGI-I Rating Scale was a 7-point scale: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; or 7=very much worse. Least squares (LS) Means were adjusted for treatment group, site, visit and treatment-by-visit interaction, gender, age, baseline score and baseline score-by-visit interaction and an unstructured covariance matrix.
Time Frame	1 week, 8 weeks

Outcome Measure Data

Analysis Population Description

The efficacy population included the number of participants with baseline and at least 1 post-baseline value analysed under the intent-to-treat (ITT) principle according to the drug dose they were assigned.

Arm/Group Title	Duloxetine 60 mg With Food	Duloxetine 60 mg Without Food	Duloxetine 30 mg With Food	Duloxetine 30 mg Without Food
Arm/Group Description	Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks	Duloxetine 60 mg capsule po QD without food for 8 weeks	Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks	Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks
Measure Participants	56	59	59	61
1-week change	3.72 (0.13)	3.77 (0.13)	3.52 (0.13)	3.47 (0.12)
8-week change (n=28; n=37; n=39; n=37)	2.31 (0.19)	2.40 (0.17)	2.36 (0.16)	2.40 (0.16)

13. Secondary Outcome

Title	Time to Onset of Nausea
Description	Events of nausea were taken from the adverse event (AE) data. Participants were censored based on the following rules: 1=study discontinuation date if the participant discontinues the study; 2=study lost to follow-up date if the participant drops out of the study.
Time Frame	Baseline to onset of nausea (Baseline up to 8 weeks)

Outcome Measure Data

Analysis Population Description

The safety population included all participants who took at least 1 study drug dose analysed according to the drug dose actually taken.

Arm/Group Title	Duloxetine 60 mg With Food	Duloxetine 60 mg Without Food	Duloxetine 30 mg With Food	Duloxetine 30 mg Without Food
Arm/Group Description	Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks	Duloxetine 60 mg capsule po QD without food for 8 weeks	Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks	Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks
Measure Participants	40	38	38	37
Median (95% Confidence Interval) [days]	2.0	1.0	7.0	6.0

14. Secondary Outcome

Title	Time to Resolve Nausea
Description	Events of nausea were taken from the adverse event (AE) data. Participants were censored based on the following rules: 1=study discontinuation date if the participant discontinues the study; 2=study lost to follow-up date if the participant drops out of the study.
Time Frame	Nausea onset up to nausea resolve (Baseline up to 8 weeks)

Outcome Measure Data

Analysis Population Description

The safety population included all participants who took at least 1 study drug dose analysed according to the drug dose actually taken.

Arm/Group Title	Duloxetine 60 mg With Food	Duloxetine 60 mg Without Food	Duloxetine 30 mg With Food	Duloxetine 30 mg Without Food
Arm/Group Description	Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks	Duloxetine 60 mg capsule po QD without food for 8 weeks	Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks	Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks
Measure Participants	33	25	27	30
Median (95% Confidence Interval) [days]	6.0	8.0	15.0	6.0

15. Secondary Outcome

Title	Percentage of Participants Achieving Response
Description	Response was defined as ≥50% decrease from baseline on the 17-item Hamilton Depression Rating Scale (HAMD-17) total score. HAMD-17 total scores ranged from 0 (not at all depressed)-52 (severely depressed).
Time Frame	Baseline up to 8 weeks

Outcome Measure Data

Analysis Population Description

The efficacy population included the number of participants with baseline and at least 1 post-baseline value analysed under the intent-to-treat (ITT) principle according to the drug dose they were assigned.

Arm/Group Title	Duloxetine 60 mg With Food	Duloxetine 60 mg Without Food	Duloxetine 30 mg With Food	Duloxetine 30 mg Without Food
Arm/Group Description	Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks	Duloxetine 60 mg capsule po QD without food for 8 weeks	Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks	Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks
Measure Participants	56	59	59	61
Number [percentage of participants]	51.8 87.8%	49.2 78.1%	47.5 75.4%	47.5 74.2%

16. Secondary Outcome

Title	Percentage of Patients Achieving Remission
Description	Remission was defined as 17-item Hamilton Depression Rating Scale (HAMD-17) total score ≤7. HAMD-17 total scores ranged from 0 (not at all depressed)-52 (severely depressed).
Time Frame	Baseline up to 8 weeks

Outcome Measure Data

Analysis Population Description

The efficacy population included the number of participants with baseline and at least 1 post-baseline value analysed under the intent-to-treat (ITT) principle according to the drug dose they were assigned.

Arm/Group Title	Duloxetine 60 mg With Food	Duloxetine 60 mg Without Food	Duloxetine 30 mg With Food	Duloxetine 30 mg Without Food
Arm/Group Description	Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks	Duloxetine 60 mg capsule po QD without food for 8 weeks	Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks	Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks
Measure Participants	56	59	59	61
Number [percentage of participants]	42.9 72.7%	37.3 59.2%	35.6 56.5%	32.8 51.3%

Adverse Events

Arm/Group Title	Duloxetine 30 mg With Food		Duloxetine 60 mg With Food		Duloxetine 30 mg Without Food		Duloxetine 60 mg Without Food
Arm/Group Description	Duloxetine 30 mg capsule po QD with food for 1 week, then 60 mg with food for 7 weeks		Duloxetine 60 milligram (mg) capsule oral (po), once daily (QD) with food for 8 weeks		Duloxetine 30 mg capsule po QD without food for 1 week, then 60 mg without food for 7 weeks		Duloxetine 60 mg capsule po QD without food for 8 weeks
All Cause Mortality
	Duloxetine 30 mg With Food		Duloxetine 60 mg With Food		Duloxetine 30 mg Without Food		Duloxetine 60 mg Without Food
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Duloxetine 30 mg With Food		Duloxetine 60 mg With Food		Duloxetine 30 mg Without Food		Duloxetine 60 mg Without Food
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/63 (1.6%)		1/59 (1.7%)		2/64 (3.1%)		0/63 (0%)
Gastrointestinal disorders
Diarrhoea	0/63 (0%)	0	1/59 (1.7%)	1	0/64 (0%)	0	0/63 (0%)	0
Infections and infestations
Pelvic inflammatory disease	0/63 (0%)	0	1/59 (1.7%)	1	0/64 (0%)	0	0/63 (0%)	0
Injury, poisoning and procedural complications
Muscle injury	0/63 (0%)	0	0/59 (0%)	0	1/64 (1.6%)	1	0/63 (0%)	0
Road traffic accident	0/63 (0%)	0	0/59 (0%)	0	1/64 (1.6%)	1	0/63 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lipoma	0/63 (0%)	0	0/59 (0%)	0	1/64 (1.6%)	1	0/63 (0%)	0
Psychiatric disorders
Completed suicide	1/63 (1.6%)	1	0/59 (0%)	0	0/64 (0%)	0	0/63 (0%)	0
Reproductive system and breast disorders
Ovarian cyst	0/63 (0%)	0	1/59 (1.7%)	1	0/64 (0%)	0	0/63 (0%)	0
Other (Not Including Serious) Adverse Events
	Duloxetine 30 mg With Food		Duloxetine 60 mg With Food		Duloxetine 30 mg Without Food		Duloxetine 60 mg Without Food
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	52/63 (82.5%)		55/59 (93.2%)		57/64 (89.1%)		58/63 (92.1%)
Cardiac disorders
Palpitations	0/63 (0%)	0	4/59 (6.8%)	4	2/64 (3.1%)	2	3/63 (4.8%)	3
Eye disorders
Vision blurred	5/63 (7.9%)	5	1/59 (1.7%)	1	0/64 (0%)	0	2/63 (3.2%)	2
Gastrointestinal disorders
Abdominal discomfort	3/63 (4.8%)	3	6/59 (10.2%)	6	7/64 (10.9%)	7	4/63 (6.3%)	5
Constipation	12/63 (19%)	12	9/59 (15.3%)	10	9/64 (14.1%)	10	10/63 (15.9%)	11
Diarrhoea	4/63 (6.3%)	4	3/59 (5.1%)	3	4/64 (6.3%)	5	3/63 (4.8%)	4
Dry mouth	10/63 (15.9%)	10	10/59 (16.9%)	11	10/64 (15.6%)	10	12/63 (19%)	12
Dyspepsia	4/63 (6.3%)	5	4/59 (6.8%)	5	4/64 (6.3%)	4	2/63 (3.2%)	3
Nausea	39/63 (61.9%)	42	41/59 (69.5%)	49	38/64 (59.4%)	43	39/63 (61.9%)	43
Vomiting	2/63 (3.2%)	2	8/59 (13.6%)	8	8/64 (12.5%)	9	10/63 (15.9%)	10
General disorders
Asthenia	4/63 (6.3%)	4	1/59 (1.7%)	1	5/64 (7.8%)	5	5/63 (7.9%)	6
Metabolism and nutrition disorders
Decreased appetite	11/63 (17.5%)	12	11/59 (18.6%)	11	13/64 (20.3%)	13	11/63 (17.5%)	11
Nervous system disorders
Dizziness	11/63 (17.5%)	11	8/59 (13.6%)	8	10/64 (15.6%)	10	7/63 (11.1%)	7
Headache	11/63 (17.5%)	11	10/59 (16.9%)	10	14/64 (21.9%)	16	8/63 (12.7%)	8
Sedation	5/63 (7.9%)	5	6/59 (10.2%)	6	5/64 (7.8%)	5	6/63 (9.5%)	6
Somnolence	0/63 (0%)	0	4/59 (6.8%)	4	5/64 (7.8%)	5	9/63 (14.3%)	10
Tremor	1/63 (1.6%)	1	4/59 (6.8%)	4	2/64 (3.1%)	2	2/63 (3.2%)	2
Psychiatric disorders
Anxiety	6/63 (9.5%)	7	4/59 (6.8%)	4	3/64 (4.7%)	3	6/63 (9.5%)	6
Insomnia	8/63 (12.7%)	8	8/59 (13.6%)	9	6/64 (9.4%)	6	5/63 (7.9%)	6
Skin and subcutaneous tissue disorders
Hyperhidrosis	5/63 (7.9%)	5	5/59 (8.5%)	5	1/64 (1.6%)	1	5/63 (7.9%)	5

Limitations/Caveats

Large number of protocol violations; bias due to unblinded, open-label design (participants were predisposed to expect an outcome of nausea as the primary endpoint); use of emetogenic medications; incorrect reporting and intake of food and drug.

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.