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Trial record 76 of 134 for:    "Depressive Disorder" [DISEASE] | ( Map: Arkansas, United States )

A Study in Adult Patients With Major Depressive Disorder

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00795821
Recruitment Status : Completed
First Posted : November 21, 2008
Results First Posted : March 20, 2018
Last Update Posted : March 20, 2018
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Depressive Disorder, Major
Interventions Drug: LY2216684
Drug: Placebo
Enrollment 495
Recruitment Details  
Pre-assignment Details The Screening Phase (Week -1 through Week 0) assessed participant eligibility for not less than 3 days and not more than 30 days. At Week 0, those participants who met entry criteria were randomized in a 1:1 ratio to either LY2216684 (dose range 6 milligram [mg] to 18 mg once daily [QD]) or placebo.
Arm/Group Title LY2216684 Placebo
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10-week Acute Treatment Phase: Day after Week 0=start of 6 milligram (mg) once daily (QD) dosing; Week 1=all participants titrated to 9 mg QD; After Week 1=dose increased, maintained, or decreased to a minimum of 6 mg QD and maximum of 18 mg QD, depending on participant's tolerance of study drug.

1-year Long-term Extension Phase: Day after Week 10=start of same LY2216684 dose participant was taking at the end of Acute Treatment Phase; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).

10-week Acute Treatment Phase: 3 tablets QD for 10 weeks

1-year Long-term Extension Phase: Day after Week 10=6 mg LY2216684; After 1 week=dose escalated to 9 mg QD; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).

Period Title: Acute Treatment Phase
Started 250 245
Completed 194 [1] 214 [2]
Not Completed 56 31
Reason Not Completed
Adverse Event             23             4
Death             1             0
Lack of Efficacy             5             2
Lost to Follow-up             9             12
Physician Decision             1             1
Protocol Violation             1             2
Withdrawal by Subject             16             10
[1]
4 LY-treated participants in the Acute Phase chose not to enter the Long-term Extension Phase.
[2]
7 placebo-treated participants in the Acute Phase chose not to enter the Long-term Extension Phase.
Period Title: Long-term Extension Phase
Started 190 207 [1]
Completed 100 115
Not Completed 90 92
Reason Not Completed
Adverse Event             25             32
Lack of Efficacy             16             12
Lost to Follow-up             20             16
Physician Decision             1             2
Protocol Violation             3             5
Withdrawal by Subject             25             25
[1]
All placebo-treated participants received LY2216684 in the Long-term Extension Phase.
Period Title: Taper Phase
Started 240 [1] 6 [2]
Completed 231 [3] 6 [4]
Not Completed 9 0
Reason Not Completed
Adverse Event             2             0
Lost to Follow-up             1             0
Physician Decision             2             0
Withdrawal by Subject             4             0
[1]
N=240 participants entered Taper Phases: N=4 from Acute Phase; N=236 from Extension Phase.
[2]
N=6 participants entered only Acute Taper Phase.
[3]
N=231 participants completed Taper Phases: N=3 from Acute Phase; N=228 from Extension Phase.
[4]
N=6 participants completed only Acute Taper Phase; N=0 participants entered Extension Taper Phase.
Arm/Group Title LY2216684 Placebo Total
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10-week Acute Treatment Phase: Day after Week 0=start of 6 milligram (mg) once daily (QD) dosing; Week 1=all participants titrated to 9 mg QD; After Week 1=dose increased, maintained, or decreased to a minimum of 6 mg QD and maximum of 18 mg QD, depending on participant's tolerance of study drug.

1-year Long-term Extension Phase: Day after Week 10=start of same LY2216684 dose participant was taking at the end of Acute Treatment Phase; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).

10-week Acute Treatment Phase: 3 tablets QD for 10 weeks

1-year Long-term Extension Phase: Day after Week 10=6 mg LY2216684; After 1 week=dose escalated to 9 mg QD; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).

Total of all reporting groups
Overall Number of Baseline Participants 250 245 495
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 250 participants 245 participants 495 participants
44.2  (11.32) 45.5  (11.61) 44.8  (11.47)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 250 participants 245 participants 495 participants
Female 160 143 303
Male 90 102 192
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 250 participants 245 participants 495 participants
Hispanic or Latino 31 25 56
Not Hispanic or Latino 200 200 400
Unknown or Not Reported 19 20 39
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 250 participants 245 participants 495 participants
American Indian or Alaska Native 0 3 3
Asian 2 2 4
Native Hawaiian or Other Pacific Islander 0 1 1
Black or African American 45 44 89
White 191 187 378
More than one race 9 7 16
Unknown or Not Reported 3 1 4
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 250 participants 245 participants 495 participants
United States 140 135 275
Finland 42 43 85
Argentina 13 13 26
Poland 44 45 89
Russia 11 9 20
1.Primary Outcome
Title Mean Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) at Week 10
Hide Description The MADRS measured severity of depressive mood symptoms. The 10-item checklist rating scale was 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Least Squares (LS) Means were adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
Time Frame Baseline, Week 10
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all randomized participants with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684 Placebo
Hide Arm/Group Description:
10-week Acute Treatment Phase: Day after Week 0=start of 6 mg QD dosing; Week 1=all participants were titrated to 9 mg QD; After Week 1=dose was increased, maintained, or decreased to a minimum of 6 mg QD and maximum of 18 mg QD, depending on participant's tolerance of study drug.
10-week Acute Treatment Phase: 3 tablets QD for 10 weeks
Overall Number of Participants Analyzed 247 242
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-13.30  (0.563) -9.82  (0.544)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LY2216684, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Models Analysis
Comments Model terms included treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
2.Secondary Outcome
Title Mean Change From Baseline (Week 10) in Montgomery-Asberg Depression Rating Scale (MADRS) at Week 62
Hide Description The MADRS measured severity of depressive mood symptoms. The 10-item checklist rating scale was 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit.
Time Frame Baseline (Week 10), Week 62
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all participants in the Long-term Extension Phase with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684/LY2216684 Placebo/LY2216684
Hide Arm/Group Description:
1-year Long-term Extension Phase: Day after Week 10=start of same LY2216684 dose participant was taking at the end of Acute Treatment Phase; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
1-year Long-term Extension Phase: Day after Week 10=6 mg LY2216684; After 1 week=dose escalated to 9 mg QD; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
Overall Number of Participants Analyzed 202 185
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-7.44  (0.674) -9.43  (0.666)
3.Secondary Outcome
Title Mean Change From Baseline in Sheehan Disability Scale (SDS) Global Functional Impairment at Week 10
Hide Description The SDS was completed by the participant and used to assess the effect of the participant's symptoms on their work/social/family life. Total of these 3 items=Global Functional Impairment score; scores ranged from 0 to 30, with higher values indicating greater disruption in the participant's work/social/family life. Least Squares (LS) Means were adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
Time Frame Baseline, Week 10
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all randomized participants with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684 Placebo
Hide Arm/Group Description:
10-week Acute Treatment Phase: Day after Week 0=start of 6 mg QD dosing; Week 1=all participants were titrated to 9 mg QD; After Week 1=dose was increased, maintained, or decreased to a minimum of 6 mg QD and maximum of 18 mg QD, depending on participant's tolerance of study drug.
10-week Acute Treatment Phase: 3 tablets QD for 10 weeks
Overall Number of Participants Analyzed 241 237
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-8.21  (0.499) -5.79  (0.484)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LY2216684, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments To control for multiple comparisons, the analysis of this secondary outcome measure was pre-specified as a gated secondary objective. As the primary hypothesis was statistically significant, this hypothesis was tested at the 0.05 significance level.
Method Mixed Models Analysis
Comments Model terms included treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
4.Secondary Outcome
Title Mean Change From Baseline (Week 10) in Sheehan Disability Scale (SDS) Global Functional Impairment at Week 62
Hide Description The SDS was completed by the participant and used to assess the effect of the participant's symptoms on their work/social/family life. Total of these 3 items=Global Functional Impairment score; scores ranged from 0 to 30, with higher values indicating greater disruption in the participant's work/social/family life. Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit.
Time Frame Baseline (Week 10), Week 62
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all participants in the Long-term Extension Phase with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684/LY2216684 Placebo/LY2216684
Hide Arm/Group Description:
1-year Long-term Extension Phase: Day after Week 10=start of same LY2216684 dose participant was taking at the end of Acute Treatment Phase; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
1-year Long-term Extension Phase: Day after Week 10=6 mg LY2216684; After 1 week=dose escalated to 9 mg QD; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
Overall Number of Participants Analyzed 179 185
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-3.06  (0.654) -4.56  (0.591)
5.Secondary Outcome
Title Mean Change From Baseline in Clinical Global Impressions of Severity (CGI-Severity) Scale at Week 10
Hide Description CGI-S measured severity of depression at the time of assessment. Scores ranged from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). Least Squares (LS) Means were adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
Time Frame Baseline, Week 10
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all randomized participants with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684 Placebo
Hide Arm/Group Description:
10-week Acute Treatment Phase: Day after Week 0=start of 6 mg QD dosing; Week 1=all participants were titrated to 9 mg QD; After Week 1=dose was increased, maintained, or decreased to a minimum of 6 mg QD and maximum of 18 mg QD, depending on participant's tolerance of study drug.
10-week Acute Treatment Phase: 3 tablets QD for 10 weeks
Overall Number of Participants Analyzed 247 242
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-1.48  (0.075) -1.08  (0.072)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LY2216684, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Models Analysis
Comments Model terms included treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
6.Secondary Outcome
Title Mean Change From Baseline (Week 10) in Clinical Global Impressions of Severity (CGI-Severity) Scale at Week 62
Hide Description CGI-S measured severity of depression at the time of assessment. Scores ranged from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). Least Squares (LS) Means were adjusted for investigator, baseline score, and baseline-by-visit.
Time Frame Baseline (Week 10), Week 62
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all participants in the Long-term Extension Phase with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684/LY2216684 Placebo/LY2216684
Hide Arm/Group Description:
1-year Long-term Extension Phase: Day after Week 10=start of same LY2216684 dose participant was taking at the end of Acute Treatment Phase; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
1-year Long-term Extension Phase: Day after Week 10=6 mg LY2216684; After 1 week=dose escalated to 9 mg QD; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
Overall Number of Participants Analyzed 188 207
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-1.03  (0.087) -1.24  (0.085)
7.Secondary Outcome
Title Mean Change From Baseline in the 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) at Week 10
Hide Description The QIDS-SR16 was a 16-item participant-rated measure of depressive symptomatology. The total score ranged from 0 to 27, with higher scores indicative of greater severity. Least Squares (LS) Means were adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
Time Frame Baseline, Week 10
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all participants with a baseline and at least 1 post-baseline value in the Per Protocol population, defined as the subset of randomized participants who had baseline and post-baseline data collected using the correct version of the QIDS-SR16 worksheet.
Arm/Group Title LY2216684 Placebo
Hide Arm/Group Description:
10-week Acute Treatment Phase: Day after Week 0=start of 6 mg QD dosing; Week 1=all participants were titrated to 9 mg QD; After Week 1=dose was increased, maintained, or decreased to a minimum of 6 mg QD and maximum of 18 mg QD, depending on participant's tolerance of study drug.
10-week Acute Treatment Phase: 3 tablets QD for 10 weeks
Overall Number of Participants Analyzed 193 185
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-6.50  (0.366) -4.93  (0.360)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LY2216684, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.002
Comments [Not Specified]
Method Mixed Models Analysis
Comments Model terms included treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
8.Secondary Outcome
Title Mean Change From Baseline (Week 10) in the 16-Item Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) at Week 62
Hide Description The QIDS-SR16 was a 16-item participant-rated measure of depressive symptomatology. The total score ranged from 0 to 27, with higher scores indicative of greater severity. Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit.
Time Frame Baseline (Week 10), Week 62
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all participants in the Long-term Extension Phase with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684/LY2216684 Placebo/LY2216684
Hide Arm/Group Description:
1-year Long-term Extension Phase: Day after Week 10=start of same LY2216684 dose participant was taking at the end of Acute Treatment Phase; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
1-year Long-term Extension Phase: Day after Week 10=6 mg LY2216684 dose; After 1 week=dose escalated to 9 mg QD; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
Overall Number of Participants Analyzed 183 203
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-2.64  (0.422) -3.33  (0.399)
9.Secondary Outcome
Title Mean Change From Baseline in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) at Week 10
Hide Description The CPFQ was a 7-item participant-rated questionnaire pertaining to a participant's cognitive and physical well-being. It assessed motivation, wakefulness, energy, focus, recall, word-finding difficulty, and mental acuity. Each item was scored on a 6-point scale ranging from 1 (greater than normal) to 6 (totally absent); total score ranged from 7 to 42. Least Squares (LS) Means were adjusted for treatment, investigator, and baseline score.
Time Frame Baseline, Week 10
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all randomized participants with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684 Placebo
Hide Arm/Group Description:
10-week Acute Treatment Phase: Day after Week 0=start of 6 mg QD dosing; Week 1=all participants were titrated to 9 mg QD; After Week 1=dose was increased, maintained, or decreased to a minimum of 6 mg QD and maximum of 18 mg QD, depending on participant's tolerance of study drug.
10-week Acute Treatment Phase: 3 tablets QD for 10 weeks
Overall Number of Participants Analyzed 241 238
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-6.61  (0.435) -5.04  (0.437)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LY2216684, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.007
Comments [Not Specified]
Method ANCOVA
Comments Model terms included treatment, investigator, and baseline score.
10.Secondary Outcome
Title Mean Change From Baseline (Week 10) in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) at Week 62
Hide Description The CPFQ was a 7-item participant-rated questionnaire pertaining to a participant's cognitive and physical well-being. It assessed motivation, wakefulness, energy, focus, recall, word-finding difficulty, and mental acuity. Each item was scored on a 6-point scale ranging from 1 (greater than normal) to 6 (totally absent); total score ranged from 7 to 42. Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit.
Time Frame Baseline (Week 10), Week 62
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all participants in the Long-term Extension Phase with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684/LY2216684 Placebo/LY2216684
Hide Arm/Group Description:
1-year Long-term Extension Phase: Day after Week 10=start of same LY2216684 dose participant was taking at the end of Acute Treatment Phase; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
1-year Long-term Extension Phase: Day after Week 10=6 mg LY2216684; After 1 week=dose escalated to 9 mg QD; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
Overall Number of Participants Analyzed 180 188
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-2.79  (0.534) -3.72  (0.480)
11.Secondary Outcome
Title Mean Change From Baseline in the EuroQol Questionnaire-5 Dimension (EQ-5D) United States (US) Index Score at Week 10
Hide Description EQ-5D was a generic, multidimensional, health-related, quality of life (Qol) instrument allowing participants to rate their health state in 5 domains: mobility, self-care, usual activities, pain/discomfort, and mood. A single score between 1 and 3 was generated for each domain. For each participant, the outcome rating on the 5 domains was mapped to a single index through an algorithm. The index ranged between 0 and 1, with the higher score indicating a better health state perceived by the participant. Least Squares (LS) Means were adjusted for treatment, investigator, and baseline score.
Time Frame Baseline, Week 10
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all randomized participants with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684 Placebo
Hide Arm/Group Description:
10-week Acute Treatment Phase: Day after Week 0=start of 6 mg QD dosing; Week 1=all participants were titrated to 9 mg QD; After Week 1=dose was increased, maintained, or decreased to a minimum of 6 mg QD and maximum of 18 mg QD, depending on participant's tolerance of study drug.
10-week Acute Treatment Phase: 3 tablets QD for 10 weeks
Overall Number of Participants Analyzed 233 234
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
0.12  (0.011) 0.09  (0.011)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LY2216684, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.056
Comments [Not Specified]
Method ANCOVA
Comments Model terms included treatment, investigator, and baseline score.
12.Secondary Outcome
Title Mean Change From Baseline (Week 10) in the EuroQol Questionnaire-5 Dimension (EQ-5D) United States (US) Index Score at Week 62
Hide Description EQ-5D was a generic, multidimensional, health-related, quality of life (Qol) instrument allowing participants to rate their health state in 5 domains: mobility, self-care, usual activities, pain/discomfort, mood. Single score between 1 and 3 was generated for each domain. For each participant, outcome rating on the 5 domains was mapped to a single index through an algorithm. The index ranged between 0 and 1, with higher score indicating a better health state perceived by the participant. Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit.
Time Frame Baseline (Week 10), Week 62
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all participants in the Long-term Extension Phase with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684/LY2216684 Placebo/LY2216684
Hide Arm/Group Description:
1-year Long-term Extension Phase: Day after Week 10=start of same LY2216684 dose participant was taking at the end of Acute Treatment Phase; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
1-year Long-term Extension Phase: Day after Week 10=6 mg LY2216684; After 1 week=dose escalated to 9 mg QD; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
Overall Number of Participants Analyzed 176 187
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
0.08  (0.015) 0.06  (0.014)
13.Secondary Outcome
Title Mean Change From Baseline in the Fatigue Associated With Depression (FAsD) Patient Reported Outcome (PRO): Average Score at Week 10
Hide Description The FAsD was a participant-rated scale with 7 items that asked how often they experience different aspects of fatigue: responses from 1 (Never) to 5 (Always); 9 items that asked how often fatigue impacts various aspects of their lives: responses from 1 (Not at all) to 5 (Very much). Average Score=mean of Items 1-5, 7-12, 14, and 16. Scores ranged from 1 to 5. Least Squares (LS) Means were adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
Time Frame Baseline, Week 10
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all randomized participants with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684 Placebo
Hide Arm/Group Description:
10-week Acute Treatment Phase: Day after Week 0=start of 6 mg QD dosing; Week 1=all participants were titrated to 9 mg QD; After Week 1=dose was increased, maintained, or decreased to a minimum of 6 mg QD and maximum of 18 mg QD, depending on participant's tolerance of study drug.
10-week Acute Treatment Phase: 3 tablets QD for 10 weeks
Overall Number of Participants Analyzed 244 236
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-0.99  (0.059) -0.74  (0.057)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LY2216684, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.002
Comments [Not Specified]
Method Mixed Models Analysis
Comments Model terms included treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
14.Secondary Outcome
Title Mean Change From Baseline (Week 10) in Fatigue Associated With Depression (FAsD) Patient Reported Outcome (PRO): Average Score at Week 62
Hide Description The FAsD was a participant-rated scale with 7 items that asked how often they experience different aspects of fatigue: responses from 1 (Never) to 5 (Always); 9 items that asked how often fatigue impacts various aspects of their lives: responses from 1 (Not at all) to 5 (Very much). Average Score=mean of Items 1-5, 7-12, 14, and 16. Scores ranged from 1 to 5. Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit.
Time Frame Baseline (Week 10), Week 62
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all participants in the Long-term Extension Phase with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684/LY2216684 Placebo/LY2216684
Hide Arm/Group Description:
1-year Long-term Extension Phase: Day after Week 10=start of same LY2216684 dose participant was taking at the end of Acute Treatment Phase; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
1-year Long-term Extension Phase: Day after Week 10=6 mg LY2216684; After 1 week=dose escalated to 9 mg QD; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
Overall Number of Participants Analyzed 184 207
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-0.51  (0.076) -0.65  (0.073)
15.Secondary Outcome
Title Mean Change From Baseline in the Fatigue Associated With Depression (FAsD) Patient Reported Outcome (PRO): Fatigue Experience Average Score at Week 10
Hide Description The FAsD was a participant-rated scale with 7 items that asked how often they experience different aspects of fatigue: responses from 1 (Never) to 5 (Always); 9 items that asked how often fatigue impacts various aspects of their lives: responses from 1 (Not at all) to 5 (Very much). Fatigue Experience Average Score=mean of Items 1 to 5, and 7. Scores ranged from 1 to 5. Least Squares (LS) Means were adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
Time Frame Baseline, Week 10
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all randomized participants with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684 Placebo
Hide Arm/Group Description:
10-week Acute Treatment Phase: Day after Week 0=start of 6 mg QD dosing; Week 1=all participants were titrated to 9 mg QD; After Week 1=dose was increased, maintained, or decreased to a minimum of 6 mg QD and maximum of 18 mg QD, depending on participant's tolerance of study drug.
10-week Acute Treatment Phase: 3 tablets QD for 10 weeks
Overall Number of Participants Analyzed 247 238
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-0.96  (0.060) -0.69  (0.058)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LY2216684, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Models Analysis
Comments Model terms included treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
16.Secondary Outcome
Title Mean Change From Baseline (Week 10) in Fatigue Associated With Depression (FAsD) Patient Reported Outcome (PRO): Fatigue Experience Average Score at Week 62
Hide Description The FAsD was a participant-rated scale with 7 items that asked how often they experience different aspects of fatigue: responses from 1 (Never) to 5 (Always); 9 items that asked how often fatigue impacts various aspects of their lives: responses from 1 (Not at all) to 5 (Very much). Fatigue Experience Average Score=mean of Items 1-5, and 7. Scores ranged from 1 to 5. Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit.
Time Frame Baseline (Week 10), Week 62
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all participants in the Long-term Extension Phase with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684/LY2216684 Placebo/LY2216684
Hide Arm/Group Description:
1-year Long-term Extension Phase: Day after Week 10=start of same LY2216684 dose participant was taking at the end of Acute Treatment Phase; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
1-year Long-term Extension Phase: Day after Week 10=6 mg LY2216684; After 1 week=dose escalated to 9 mg QD; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
Overall Number of Participants Analyzed 186 207
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-0.50  (0.080) -0.70  (0.078)
17.Secondary Outcome
Title Mean Change From Baseline in the Fatigue Associated With Depression (FAsD) Patient Reported Outcome (PRO): Fatigue Impact Average Score at Week 10
Hide Description The FAsD was a participant-rated scale with 7 items that asked how often they experience different aspects of fatigue: responses from 1 (Never) to 5 (Always); 9 items that asked how often fatigue impacts various aspects of their lives: responses from 1 (Not at all) to 5 (Very much). Fatigue Impact Average Score=mean of Items 8-12, 14, and 16. Scores ranged from 1 to 5. Least Squares (LS) Means were adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
Time Frame Baseline, Week 10
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all randomized participants with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684 Placebo
Hide Arm/Group Description:
10-week Acute Treatment Phase: Day after Week 0=start of 6 mg QD dosing; Week 1=all participants were titrated to 9 mg QD; After Week 1=dose was increased, maintained, or decreased to a minimum of 6 mg QD and maximum of 18 mg QD, depending on participant's tolerance of study drug.
10-week Acute Treatment Phase: 3 tablets QD for 10 weeks
Overall Number of Participants Analyzed 244 240
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-1.02  (0.062) -0.77  (0.060)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LY2216684, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments [Not Specified]
Method Mixed Models Analysis
Comments Model terms included treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
18.Secondary Outcome
Title Mean Change From Baseline (Week 10) in Fatigue Associated With Depression (FAsD) Patient Reported Outcome (PRO): Fatigue Impact Average Score at Week 62
Hide Description The FAsD was a participant-rated scale with 7 items that asked how often they experience different aspects of fatigue: responses from 1 (Never) to 5 (Always); 9 items that asked how often fatigue impacts various aspects of their lives: responses from 1 (Not at all) to 5 (Very much). Fatigue Impact Average Score=mean of Items 8-12, 14, and 16. Scores ranged from 1 to 5. Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit.
Time Frame Baseline (Week 10), Week 62
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all participants in the Long-term Extension Phase with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684 Placebo
Hide Arm/Group Description:
1-year Long-term Extension Phase: Day after Week 10=start of same LY2216684 dose participant was taking at the end of Acute Treatment Phase; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
1-year Long-term Extension Phase: Day after Week 10=6 mg LY2216684; After 1 week=dose escalated to 9 mg QD; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
Overall Number of Participants Analyzed 185 207
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-0.51  (0.078) -0.58  (0.081)
19.Secondary Outcome
Title Mean Change From Baseline in the Brief Fatigue Inventory (BFI) Global Total Score at Week 10
Hide Description The BFI was a participant-rated scale consisting of 9 items: 3 items assessed severity of fatigue at its “worst,” “usual,” and “now” during normal waking hours: 0=no fatigue to 10=fatigue as bad as you can imagine; 6 items assessed the degree to which fatigue has interfered with different aspects of the participant’s life during the past 24 hours: 0=does not interfere to 10=completely interferes. The BFI Global Total Score was the mean of the 9 item scores and ranged from 0 to 10. Least Squares (LS) Means were adjusted for treatment, investigator, and baseline score.
Time Frame Baseline, Week 10
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all randomized participants with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684 Placebo
Hide Arm/Group Description:
10-week Acute Treatment Phase: Day after Week 0=start of 6 mg QD dosing; Week 1=all participants were titrated to 9 mg QD; After Week 1=dose was increased, maintained, or decreased to a minimum of 6 mg QD and maximum of 18 mg QD, depending on participant's tolerance of study drug.
10-week Acute Treatment Phase: 3 tablets QD for 10 weeks
Overall Number of Participants Analyzed 241 237
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-2.25  (0.147) -1.74  (0.148)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LY2216684, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.009
Comments [Not Specified]
Method ANCOVA
Comments Model terms included treatment, investigator, and baseline score.
20.Secondary Outcome
Title Mean Change From Baseline (Week 10) in Brief Fatigue Inventory (BFI) Global Total Score at Week 62
Hide Description The BFI was a participant-rated scale consisting of 9 items: 3 items assessed severity of fatigue at its “worst,” “usual,” and “now” during normal waking hours: 0=no fatigue to 10=fatigue as bad as you can imagine; 6 items assessed the degree to which fatigue has interfered with different aspects of the participant’s life during the past 24 hours: 0=does not interfere to 10=completely interferes. The BFI Global Total Score was the mean of the 9 item scores and ranged from 0 to 10. Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit.
Time Frame Baseline (Week 10), Week 62
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all participants in the Long-term Extension Phase with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684/LY2216684 Placebo/LY2216684
Hide Arm/Group Description:
1-year Long-term Extension Phase: Day after Week 10=start of same LY2216684 dose participant was taking at the end of Acute Treatment Phase; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
1-year Long-term Extension Phase: Day after Week 10=6 mg LY2216684; After 1 week=dose escalated to 9 mg QD; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
Overall Number of Participants Analyzed 180 188
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-1.28  (0.202) -1.59  (0.187)
21.Secondary Outcome
Title Mean Change From Baseline in the Visual Analogue Scale for Fatigue (VAS-F) Overall Severity and Interference With Daily Activities Scores at Week 10
Hide Description The VAS-F was a self-rated assessment with 2 items. For the Overall Severity of Fatigue item, the participant placed a vertical mark on a 100-millimeter (mm) line between 2 anchors (0=not at all to 100=as severe as I can imagine). For the Interference With Daily Activities Due to Fatigue item, the participant placed a vertical mark on a 100 mm line between 2 anchors (0=not at all to 100=complete disability [unable to do any activities]). Least Squares (LS) Means were adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
Time Frame Baseline, Week 10
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all randomized participants with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684 Placebo
Hide Arm/Group Description:
10-week Acute Treatment Phase: Day after Week 0=start of 6 mg QD dosing; Week 1=all participants were titrated to 9 mg QD; After Week 1=dose was increased, maintained, or decreased to a minimum of 6 mg QD and maximum of 18 mg QD, depending on participant's tolerance of study drug.
10-week Acute Treatment Phase: 3 tablets QD for 10 weeks
Overall Number of Participants Analyzed 247 242
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Severity of Overall Fatigue -23.30  (1.813) -16.69  (1.757)
Fatigue Interference With Daily Activities -24.48  (1.831) -18.62  (1.775)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LY2216684, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.008
Comments P-value for Severity of Overall Fatigue
Method Mixed Models Analysis
Comments Model terms included treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection LY2216684, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.024
Comments P-value for Fatigue Interference with Daily Activities
Method Mixed Models Analysis
Comments Model terms included treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
22.Secondary Outcome
Title Mean Change From Baseline (Week 10) in the Visual Analogue Scale for Fatigue (VAS-F) Overall Severity and Interference With Daily Activities Scores at Week 62
Hide Description The VAS-F was a self-rated assessment with 2 items. For the Overall Severity of Fatigue item, the participant placed a vertical mark on a 100-millimeter (mm) line between 2 anchors (0=not at all to 100=as severe as I can imagine). For the Interference With Daily Activities Due to Fatigue item, the participant placed a vertical mark on a 100 mm line between 2 anchors (0=not at all to 100=complete disability [unable to do any activities]). Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit.
Time Frame Baseline (Week 10), Week 62
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all participants in the Long-term Extension Phase with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684/LY2216684 Placebo/LY2216684
Hide Arm/Group Description:
1-year Long-term Extension Phase: Day after Week 10=start of same LY2216684 dose participant was taking at the end of Acute Treatment Phase; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
1-year Long-term Extension Phase: Day after Week 10=6 mg LY2216684; After 1 week=dose escalated to 9 mg QD; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
Overall Number of Participants Analyzed 187 206
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Overall Severity of Fatigue -12.72  (2.277) -18.69  (1.990)
Fatigue Interference With Daily Activities -13.89  (2.229) -17.47  (1.996)
23.Secondary Outcome
Title Percentage of Participants Reporting Resource Utilization at Week 10
Hide Description The Resource Utilization form assessed the frequency and type of medical services that participants have used within the last year, or since the last visit. Resources reported by at least 5% of participants in either treatment group were provided.
Time Frame Baseline through Week 10
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all randomized participants.
Arm/Group Title LY2216684 Placebo
Hide Arm/Group Description:
10-week Acute Treatment Phase: Day after Week 0=start of 6 mg QD dosing; Week 1=all participants were titrated to 9 mg QD; After Week 1=dose was increased, maintained, or decreased to a minimum of 6 mg QD and maximum of 18 mg QD, depending on participant's tolerance of study drug.
10-week Acute Treatment Phase: 3 tablets QD for 10 weeks
Overall Number of Participants Analyzed 226 229
Measure Type: Number
Unit of Measure: percentage of participants
Use of Primary Doctor 13.3 10.9
Use of Specialist 5.8 5.7
Other Diagnostic Tests 6.6 5.7
Prescribed Medication 34.1 29.3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LY2216684, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.261
Comments P-value for participants reporting use of primary doctor
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel (CMH) test controlling for investigator.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection LY2216684, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.868
Comments P-value for participants reporting use of specialist
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel (CMH) test controlling for investigator.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection LY2216684, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.495
Comments P-value for participants reporting other diagnostic tests
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel (CMH) test controlling for investigator.
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection LY2216684, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.189
Comments P-value for participants reporting prescribed medication
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel (CMH) test controlling for investigator.
24.Secondary Outcome
Title Percentage of Participants Reporting Resource Utilization at Week 62
Hide Description The Resource Utilization form assessed the frequency and type of medical services that participants have used within the last year, or since the last visit. Resources reported by at least 5% of participants in either treatment group were provided.
Time Frame Baseline (Week 10) through Week 62
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all participants in the Long-term Extension Phase with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684/LY2216684 Placebo/LY2216684
Hide Arm/Group Description:
1-year Long-term Extension Phase: Day after Week 10=start of same LY2216684 dose participant was taking at the end of Acute Treatment Phase; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
1-year Long-term Extension Phase: Day after Week 10=6 mg LY2216684; After 1 week=dose escalated to 9 mg QD; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
Overall Number of Participants Analyzed 172 180
Measure Type: Number
Unit of Measure: percentage of participants
Use of Primary Doctor 27.3 24.4
Use of Specialist 14.0 13.3
Use of ER or Urgent Care: Other Reason 5.8 5.6
Special Scans/Tests 5.2 3.3
Other Diagnostic Tests 19.2 15.6
Prescribed Medications 39.5 35.0
25.Secondary Outcome
Title Percentage of Participants With Suicidal Ideation, Behavior, and Acts Based on The Columbia Suicide Severity Rating Scale (C-SSRS) at Week 10
Hide Description C-SSRS scale captured occurrence, severity, and frequency of suicide-related thoughts and behaviors. Number of participants with suicidal ideation, behavior, and acts were provided. Suicidal ideation=a "yes" answer to any 1 of 5 suicidal ideation questions (including wish to be dead) and 4 different categories of active suicidal ideation. Suicidal behavior=a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal act=a "yes" answer to actual attempt or completed suicide.
Time Frame Baseline through Week 10
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all randomized participants with a baseline and at least 1 post-baseline C-SSRS value.
Arm/Group Title LY2216684 Placebo
Hide Arm/Group Description:
10-week Acute Treatment Phase: Day after Week 0=start of 6 mg QD dosing; Week 1=all participants were titrated to 9 mg QD; After Week 1=dose was increased, maintained, or decreased to a minimum of 6 mg QD and maximum of 18 mg QD, depending on participant's tolerance of study drug.
10-week Acute Treatment Phase: 3 tablets QD for 10 weeks
Overall Number of Participants Analyzed 247 242
Measure Type: Number
Unit of Measure: percentage of participants
Suicidal ideation 7.3 8.3
Suicidal behavior 0.0 0.0
Suicidal acts 0.0 0.0
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LY2216684, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.737
Comments P-value for suicidal ideation
Method Fisher Exact
Comments [Not Specified]
26.Secondary Outcome
Title Percentage of Participants With Suicidal Ideation, Behavior, and Acts Based on The Columbia Suicide Severity Rating Scale (C-SSRS) at Week 62
Hide Description C-SSRS scale captured occurrence, severity, and frequency of suicide-related thoughts and behaviors. Number of participants with suicidal ideation, behavior, and acts were provided. Suicidal ideation=a "yes" answer to any 1 of 5 suicidal ideation questions (including wish to be dead) and 4 different categories of active suicidal ideation. Suicidal behavior=a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal act=a "yes" answer to actual attempt or completed suicide.
Time Frame Baseline (Week 10) through Week 62
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all participants in the Long-term Extension Phase with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684/LY2216684 Placebo/LY2216684
Hide Arm/Group Description:
1-year Long-term Extension Phase: Day after Week 10=start of same LY2216684 dose participant was taking at the end of Acute Treatment Phase; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
1-year Long-term Extension Phase: Day after Week 10=6 mg LY2216684; After 1 week=dose escalated to 9 mg QD; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
Overall Number of Participants Analyzed 188 207
Measure Type: Number
Unit of Measure: percentage of participants
Suicidal ideation 5.9 6.8
Suicidal behavior 1.1 0.5
Suicidal acts 0.0 0.5
27.Secondary Outcome
Title Mean Change From Baseline in Supine Systolic and Diastolic Blood Pressure at Week 10
Hide Description Blood pressure was collected while the participant was in the supine position. Least Squares (LS) Means were adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
Time Frame Baseline, Week 10
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all randomized participants with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684 Placebo
Hide Arm/Group Description:
10-week Acute Treatment Phase: Day after Week 0=start of 6 mg QD dosing; Week 1=all participants were titrated to 9 mg QD; After Week 1=dose was increased, maintained, or decreased to a minimum of 6 mg QD and maximum of 18 mg QD, depending on participant's tolerance of study drug.
10-week Acute Treatment Phase: 3 tablets QD for 10 weeks
Overall Number of Participants Analyzed 246 242
Least Squares Mean (Standard Error)
Unit of Measure: millimeters of mercury (mm Hg)
Supine systolic 1.45  (0.708) -1.57  (0.683)
Supine diastolic 3.54  (0.527) -0.64  (0.510)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LY2216684, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.002
Comments P-value for change in supine systolic blood pressure
Method Mixed Models Analysis
Comments Model terms included treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection LY2216684, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments P-value for change in supine diastolic blood pressure
Method Mixed Models Analysis
Comments Model terms included treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
28.Secondary Outcome
Title Mean Change From Baseline (Week 10) in Supine Systolic and Diastolic Blood Pressure at Week 62
Hide Description Blood pressure was collected while the participant was in the supine position. Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit.
Time Frame Baseline (Week 10), Week 62
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all participants in the Long-term Extension Phase with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684/LY2216684 Placebo/LY2216684
Hide Arm/Group Description:
1-year Long-term Extension Phase: Day after Week 10=start of same LY2216684 dose participant was taking at the end of Acute Treatment Phase; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
1-year Long-term Extension Phase: Day after Week 10=6 mg LY2216684; After 1 week=dose escalated to 9 mg QD; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
Overall Number of Participants Analyzed 188 207
Least Squares Mean (Standard Error)
Unit of Measure: millimeters of mercury (mm Hg)
Supine systolic 0.52  (1.017) 2.55  (1.064)
Supine diastolic -0.68  (0.724) 2.25  (0.710)
29.Secondary Outcome
Title Mean Change From Baseline in Supine Pulse at Week 10
Hide Description Pulse was collected while the participant was in the supine position. Least Squares (LS) Means were adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
Time Frame Baseline, Week 10
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all randomized participants with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684 Placebo
Hide Arm/Group Description:
10-week Acute Treatment Phase: Day after Week 0=start of 6 mg QD dosing; Week 1=all participants were titrated to 9 mg QD; After Week 1=dose was increased, maintained, or decreased to a minimum of 6 mg QD and maximum of 18 mg QD, depending on participant's tolerance of study drug.
10-week Acute Treatment Phase: 3 tablets QD for 10 weeks
Overall Number of Participants Analyzed 246 242
Least Squares Mean (Standard Error)
Unit of Measure: beats per minute (bpm)
9.72  (0.677) -0.11  (0.655)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LY2216684, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Models Analysis
Comments Model terms included treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
30.Secondary Outcome
Title Mean Change From Baseline (Week 10) in Supine Pulse at Week 62
Hide Description Pulse was collected while the participant was in the supine position. Least Squares (LS) Means were adjusted for investigator, visit, baseline score, and baseline-by-visit.
Time Frame Baseline (Week 10), Week 62
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all participants in the Long-term Extension Phase with a baseline and at least 1 post-baseline value.
Arm/Group Title LY2216684/LY2216684 Placebo/LY2216684
Hide Arm/Group Description:
1-year Long-term Extension Phase: Day after Week 10=start of same LY2216684 dose participant was taking at the end of Acute Treatment Phase; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
1-year Long-term Extension Phase: Day after Week 10=6 mg LY2216684; After 1 week=dose escalated to 9 mg QD; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).
Overall Number of Participants Analyzed 188 207
Least Squares Mean (Standard Error)
Unit of Measure: beats per minute (bpm)
-1.15  (0.970) 7.33  (0.875)
31.Secondary Outcome
Title Pharmacokinetic (PK) Parameter: Plasma Concentration of LY2216684
Hide Description Blood samples collected from participants that received LY2216684 were measured to determine the plasma LY2216684 concentrations.
Time Frame Baseline through Week 62
Hide Outcome Measure Data
Hide Analysis Population Description
N=number of participants analyzed (N=365); n=number of plasma LY2216684 concentration observations. The sum of the individual ‘n’ values for each dose group does not equal 365 since the same participant could have received various doses during his/her participation in the study.
Arm/Group Title LY2216684
Hide Arm/Group Description:

10-week Acute Treatment Phase: Day after Week 0=start of 6 mg QD dosing; Week 1=all participants were titrated to 9 mg QD; After Week 1=dose was increased, maintained, or decreased to a minimum of 6 mg QD and maximum of 18 mg QD, depending on participant's tolerance of study drug.

1-year Long-term Extension Phase: Day after Week 10=start of same LY2216684 dose participant was taking at the end of acute treatment phase, or 6 mg LY2216684 dose if participants were taking placebo; After Week 1=dose escalated to 9 mg QD; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62).

Overall Number of Participants Analyzed 365
Mean (Standard Deviation)
Unit of Measure: nanograms per milliliter (ng/mL)
6 mg LY2216684 Number Analyzed 162 participants
12.3  (8.55)
9 mg LY2216684 Number Analyzed 328 participants
18.2  (13.6)
12 mg LY2216684 Number Analyzed 136 participants
26.0  (17.3)
18 mg LY2216684 Number Analyzed 185 participants
40.0  (25.5)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title LY2216684 - Acute Placebo - Acute LY2216684/LY2216684 - Extension Placebo/LY2216684 - Extension LY2216684 - Taper Placebo - Taper
Hide Arm/Group Description 10-week Acute Treatment Phase: Day after Week 0=start of 6 milligram (mg) once daily (QD) dosing; Week 1=all participants titrated to 9 mg QD; After Week 1=dose increased, maintained, or decreased to a minimum of 6 mg QD and maximum of 18 mg QD, depending on participant's tolerance of study drug. 10-week Acute Treatment Phase: 3 tablets QD for 10 weeks 1-year Long-term Extension Phase: Day after Week 10=start of same LY2216684 dose participant was taking at the end of Acute Treatment Phase; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62). 1-year Long-term Extension Phase: Day after Week 10=6 mg LY2216684; After 1 week=dose escalated to 9 mg QD; After Week 11=dose increased, maintained, or decreased to minimum of 6 mg QD and maximum of 18 mg QD based on investigator's judgment of safety and tolerability (up to Week 62). Participants who took 18 mg LY2216684 received 12 mg QD for 1 week followed by 6 mg QD for 1 week. Participants who took 12 mg, 9 mg, or 6 mg LY2216684 received 6 mg QD for 2 weeks. Participants who took placebo remained on placebo for 2 weeks.
All-Cause Mortality
LY2216684 - Acute Placebo - Acute LY2216684/LY2216684 - Extension Placebo/LY2216684 - Extension LY2216684 - Taper Placebo - Taper
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
LY2216684 - Acute Placebo - Acute LY2216684/LY2216684 - Extension Placebo/LY2216684 - Extension LY2216684 - Taper Placebo - Taper
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2/250 (0.80%)      2/245 (0.82%)      6/190 (3.16%)      5/207 (2.42%)      0/240 (0.00%)      0/6 (0.00%)    
Cardiac disorders             
Myocardial infarction  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Tachycardia paroxysmal  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
General disorders             
Non-cardiac chest pain  1  0/250 (0.00%)  0 0/245 (0.00%)  0 2/190 (1.05%)  2 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Infections and infestations             
Gastroenteritis  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Injury, poisoning and procedural complications             
Hip fracture  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Intentional overdose  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Musculoskeletal and connective tissue disorders             
Musculoskeletal chest pain  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Spinal osteoarthritis  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Nervous system disorders             
Lumbar radiculopathy  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Ruptured cerebral aneurysm  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Subarachnoid haemorrhage  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Pregnancy, puerperium and perinatal conditions             
Abortion missed  1  1/160 (0.63%)  1 0/143 (0.00%)  0 0/120 (0.00%)  0 0/120 (0.00%)  0 0/143 (0.00%)  0 0/2 (0.00%)  0
Psychiatric disorders             
Drug abuse  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Major depression  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Schizoaffective disorder  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Suicide attempt  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 2/207 (0.97%)  2 0/240 (0.00%)  0 0/6 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
LY2216684 - Acute Placebo - Acute LY2216684/LY2216684 - Extension Placebo/LY2216684 - Extension LY2216684 - Taper Placebo - Taper
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   171/250 (68.40%)      133/245 (54.29%)      126/190 (66.32%)      155/207 (74.88%)      15/240 (6.25%)      0/6 (0.00%)    
Blood and lymphatic system disorders             
Anaemia  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Macrocytosis  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 2/207 (0.97%)  2 0/240 (0.00%)  0 0/6 (0.00%)  0
Normochromic normocytic anaemia  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Cardiac disorders             
Angina pectoris  1  1/250 (0.40%)  1 1/245 (0.41%)  1 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Aortic valve sclerosis  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Arrhythmia  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Atrioventricular block first degree  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Bundle branch block right  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Cardiac flutter  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Left atrial dilatation  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Palpitations  1  6/250 (2.40%)  7 2/245 (0.82%)  4 2/190 (1.05%)  2 8/207 (3.86%)  10 0/240 (0.00%)  0 0/6 (0.00%)  0
Sinus tachycardia  1  1/250 (0.40%)  1 1/245 (0.41%)  1 2/190 (1.05%)  2 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Tachycardia  1  12/250 (4.80%)  13 2/245 (0.82%)  2 8/190 (4.21%)  9 17/207 (8.21%)  21 1/240 (0.42%)  1 0/6 (0.00%)  0
Ear and labyrinth disorders             
Tinnitus  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Vertigo  1  1/250 (0.40%)  1 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Endocrine disorders             
Hypothyroidism  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Eye disorders             
Conjunctivitis  1  0/250 (0.00%)  0 0/245 (0.00%)  0 2/190 (1.05%)  2 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Dry eye  1  2/250 (0.80%)  2 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Eye pain  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Eye pruritus  1  1/250 (0.40%)  1 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Eye swelling  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Lacrimation increased  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Photophobia  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Retinal tear  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Vision blurred  1  3/250 (1.20%)  3 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Gastrointestinal disorders             
Abdominal discomfort  1  1/250 (0.40%)  1 5/245 (2.04%)  5 1/190 (0.53%)  1 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Abdominal distension  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Abdominal pain  1  0/250 (0.00%)  0 1/245 (0.41%)  1 3/190 (1.58%)  3 6/207 (2.90%)  7 0/240 (0.00%)  0 0/6 (0.00%)  0
Abdominal pain lower  1  1/250 (0.40%)  1 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Abdominal pain upper  1  5/250 (2.00%)  7 4/245 (1.63%)  5 1/190 (0.53%)  1 5/207 (2.42%)  5 0/240 (0.00%)  0 0/6 (0.00%)  0
Bowel movement irregularity  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Constipation  1  18/250 (7.20%)  18 6/245 (2.45%)  6 6/190 (3.16%)  7 12/207 (5.80%)  13 2/240 (0.83%)  2 0/6 (0.00%)  0
Dental caries  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Diarrhoea  1  3/250 (1.20%)  3 10/245 (4.08%)  11 2/190 (1.05%)  2 5/207 (2.42%)  5 0/240 (0.00%)  0 0/6 (0.00%)  0
Dry mouth  1  11/250 (4.40%)  13 9/245 (3.67%)  9 8/190 (4.21%)  9 5/207 (2.42%)  5 0/240 (0.00%)  0 0/6 (0.00%)  0
Dyspepsia  1  4/250 (1.60%)  5 5/245 (2.04%)  5 4/190 (2.11%)  5 3/207 (1.45%)  3 1/240 (0.42%)  1 0/6 (0.00%)  0
Epigastric discomfort  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Flatulence  1  1/250 (0.40%)  1 3/245 (1.22%)  3 0/190 (0.00%)  0 2/207 (0.97%)  2 0/240 (0.00%)  0 0/6 (0.00%)  0
Food poisoning  1  0/250 (0.00%)  0 1/245 (0.41%)  1 1/190 (0.53%)  2 1/207 (0.48%)  2 0/240 (0.00%)  0 0/6 (0.00%)  0
Gastrointestinal pain  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Gastrooesophageal reflux disease  1  1/250 (0.40%)  1 2/245 (0.82%)  2 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Haematochezia  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Nausea  1  39/250 (15.60%)  40 12/245 (4.90%)  14 13/190 (6.84%)  15 23/207 (11.11%)  29 1/240 (0.42%)  1 0/6 (0.00%)  0
Paraesthesia oral  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Toothache  1  1/250 (0.40%)  1 3/245 (1.22%)  3 1/190 (0.53%)  1 3/207 (1.45%)  3 0/240 (0.00%)  0 0/6 (0.00%)  0
Vomiting  1  9/250 (3.60%)  9 1/245 (0.41%)  2 3/190 (1.58%)  3 6/207 (2.90%)  6 0/240 (0.00%)  0 0/6 (0.00%)  0
General disorders             
Asthenia  1  1/250 (0.40%)  1 0/245 (0.00%)  0 2/190 (1.05%)  3 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Chest discomfort  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Chills  1  2/250 (0.80%)  2 0/245 (0.00%)  0 3/190 (1.58%)  3 2/207 (0.97%)  2 0/240 (0.00%)  0 0/6 (0.00%)  0
Device leakage  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Fatigue  1  7/250 (2.80%)  7 5/245 (2.04%)  5 1/190 (0.53%)  1 5/207 (2.42%)  5 1/240 (0.42%)  1 0/6 (0.00%)  0
Feeling abnormal  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Feeling cold  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 3/207 (1.45%)  3 0/240 (0.00%)  0 0/6 (0.00%)  0
Feeling drunk  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Feeling hot  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Feeling jittery  1  3/250 (1.20%)  4 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Feeling of body temperature change  1  2/250 (0.80%)  2 0/245 (0.00%)  0 0/190 (0.00%)  0 2/207 (0.97%)  2 0/240 (0.00%)  0 0/6 (0.00%)  0
Gait disturbance  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
General physical health deterioration  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Hunger  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Irritability  1  9/250 (3.60%)  10 10/245 (4.08%)  10 3/190 (1.58%)  3 2/207 (0.97%)  2 2/240 (0.83%)  2 0/6 (0.00%)  0
Malaise  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 1/240 (0.42%)  1 0/6 (0.00%)  0
Medical device complication  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Non-cardiac chest pain  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Oedema peripheral  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Pain  1  1/250 (0.40%)  1 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Pyrexia  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 1/240 (0.42%)  1 0/6 (0.00%)  0
Sluggishness  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Thirst  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Vessel puncture site haematoma  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Hepatobiliary disorders             
Cholelithiasis  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Gallbladder disorder  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Immune system disorders             
Hypersensitivity  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Seasonal allergy  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 2/207 (0.97%)  2 0/240 (0.00%)  0 0/6 (0.00%)  0
Infections and infestations             
Abscess limb  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Bronchitis  1  0/250 (0.00%)  0 4/245 (1.63%)  4 3/190 (1.58%)  3 6/207 (2.90%)  6 0/240 (0.00%)  0 0/6 (0.00%)  0
Cellulitis  1  0/250 (0.00%)  0 1/245 (0.41%)  2 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Cervicitis  1  0/160 (0.00%)  0 0/143 (0.00%)  0 1/120 (0.83%)  1 0/120 (0.00%)  0 0/143 (0.00%)  0 0/2 (0.00%)  0
Chlamydial infection  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Croup infectious  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Cystitis  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Ear infection  1  0/250 (0.00%)  0 1/245 (0.41%)  1 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Eye infection  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Folliculitis  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Fungal infection  1  0/250 (0.00%)  0 1/245 (0.41%)  1 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Gastroenteritis  1  1/250 (0.40%)  1 1/245 (0.41%)  1 2/190 (1.05%)  2 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Gastroenteritis viral  1  0/250 (0.00%)  0 0/245 (0.00%)  0 2/190 (1.05%)  2 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Groin abscess  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Herpes zoster  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Infected bites  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Infectious mononucleosis  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Influenza  1  1/250 (0.40%)  1 1/245 (0.41%)  1 2/190 (1.05%)  2 3/207 (1.45%)  4 0/240 (0.00%)  0 0/6 (0.00%)  0
Lower respiratory tract infection  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Measles  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 1/240 (0.42%)  1 0/6 (0.00%)  0
Nasopharyngitis  1  11/250 (4.40%)  11 7/245 (2.86%)  7 7/190 (3.68%)  7 18/207 (8.70%)  18 0/240 (0.00%)  0 0/6 (0.00%)  0
Oral fungal infection  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Oral herpes  1  1/250 (0.40%)  1 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Otitis media  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Pharyngitis  1  1/250 (0.40%)  1 1/245 (0.41%)  1 2/190 (1.05%)  2 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Pneumonia  1  0/250 (0.00%)  0 1/245 (0.41%)  1 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Pulpitis dental  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Pyelonephritis  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Respiratory tract infection  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 2/207 (0.97%)  2 0/240 (0.00%)  0 0/6 (0.00%)  0
Respiratory tract infection viral  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 2/207 (0.97%)  2 0/240 (0.00%)  0 0/6 (0.00%)  0
Rhinitis  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Sinusitis  1  7/250 (2.80%)  7 3/245 (1.22%)  3 2/190 (1.05%)  2 3/207 (1.45%)  3 0/240 (0.00%)  0 0/6 (0.00%)  0
Sinusitis bacterial  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Streptococcal infection  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Subcutaneous abscess  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Tinea pedis  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Tinea versicolour  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Tooth abscess  1  0/250 (0.00%)  0 0/245 (0.00%)  0 3/190 (1.58%)  3 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Tooth infection  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 3/207 (1.45%)  3 0/240 (0.00%)  0 0/6 (0.00%)  0
Upper respiratory tract infection  1  6/250 (2.40%)  6 9/245 (3.67%)  9 10/190 (5.26%)  12 10/207 (4.83%)  11 0/240 (0.00%)  0 0/6 (0.00%)  0
Urinary tract infection  1  0/250 (0.00%)  0 2/245 (0.82%)  2 2/190 (1.05%)  2 4/207 (1.93%)  4 0/240 (0.00%)  0 0/6 (0.00%)  0
Vaginal infection  1  0/160 (0.00%)  0 1/143 (0.70%)  1 1/120 (0.83%)  1 0/120 (0.00%)  0 0/143 (0.00%)  0 0/2 (0.00%)  0
Viral infection  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Vulvovaginal mycotic infection  1  1/160 (0.63%)  1 0/143 (0.00%)  0 0/120 (0.00%)  0 0/120 (0.00%)  0 0/143 (0.00%)  0 0/2 (0.00%)  0
Injury, poisoning and procedural complications             
Arthropod bite  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Arthropod sting  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Contusion  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Drug exposure during pregnancy  1  1/160 (0.63%)  1 0/143 (0.00%)  0 0/120 (0.00%)  0 1/120 (0.83%)  1 0/143 (0.00%)  0 0/2 (0.00%)  0
Excoriation  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 1/207 (0.48%)  2 0/240 (0.00%)  0 0/6 (0.00%)  0
Foot fracture  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Hand fracture  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Joint injury  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Joint sprain  1  0/250 (0.00%)  0 2/245 (0.82%)  2 0/190 (0.00%)  0 2/207 (0.97%)  2 0/240 (0.00%)  0 0/6 (0.00%)  0
Muscle strain  1  0/250 (0.00%)  0 1/245 (0.41%)  1 3/190 (1.58%)  3 2/207 (0.97%)  2 0/240 (0.00%)  0 0/6 (0.00%)  0
Post-traumatic pain  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 2/207 (0.97%)  3 0/240 (0.00%)  0 0/6 (0.00%)  0
Procedural pain  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Scapula fracture  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Skin laceration  1  0/250 (0.00%)  0 2/245 (0.82%)  2 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Spinal cord injury sacral  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Sunburn  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Thermal burn  1  0/250 (0.00%)  0 1/245 (0.41%)  1 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Investigations             
Alanine aminotransferase increased  1  0/250 (0.00%)  0 1/245 (0.41%)  2 1/190 (0.53%)  1 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Aspartate aminotransferase increased  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Bleeding time prolonged  1  0/250 (0.00%)  0 2/245 (0.82%)  2 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Blood alkaline phosphatase increased  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Blood creatine phosphokinase increased  1  3/250 (1.20%)  3 0/245 (0.00%)  0 1/190 (0.53%)  1 3/207 (1.45%)  3 0/240 (0.00%)  0 0/6 (0.00%)  0
Blood creatinine increased  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Blood pressure diastolic decreased  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Blood pressure diastolic increased  1  2/250 (0.80%)  2 0/245 (0.00%)  0 1/190 (0.53%)  1 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Blood pressure increased  1  11/250 (4.40%)  11 7/245 (2.86%)  8 7/190 (3.68%)  7 8/207 (3.86%)  8 0/240 (0.00%)  0 0/6 (0.00%)  0
Blood pressure orthostatic decreased  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 1/240 (0.42%)  1 0/6 (0.00%)  0
Blood pressure orthostatic increased  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Blood pressure systolic increased  1  1/250 (0.40%)  1 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Electrocardiogram QT prolonged  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Heart rate decreased  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Heart rate increased  1  16/250 (6.40%)  16 4/245 (1.63%)  4 9/190 (4.74%)  9 13/207 (6.28%)  14 1/240 (0.42%)  1 0/6 (0.00%)  0
Hepatic enzyme increased  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Transaminases increased  1  1/250 (0.40%)  1 1/245 (0.41%)  1 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Tuberculin test positive  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Weight decreased  1  3/250 (1.20%)  3 1/245 (0.41%)  1 4/190 (2.11%)  4 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Weight increased  1  4/250 (1.60%)  4 0/245 (0.00%)  0 3/190 (1.58%)  3 2/207 (0.97%)  2 0/240 (0.00%)  0 0/6 (0.00%)  0
Metabolism and nutrition disorders             
Decreased appetite  1  11/250 (4.40%)  11 3/245 (1.22%)  3 0/190 (0.00%)  0 4/207 (1.93%)  4 0/240 (0.00%)  0 0/6 (0.00%)  0
Dehydration  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 3/207 (1.45%)  4 0/240 (0.00%)  0 0/6 (0.00%)  0
Diabetes mellitus  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Hypercholesterolaemia  1  0/250 (0.00%)  0 1/245 (0.41%)  1 2/190 (1.05%)  2 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Increased appetite  1  3/250 (1.20%)  3 3/245 (1.22%)  3 1/190 (0.53%)  1 1/207 (0.48%)  1 1/240 (0.42%)  1 0/6 (0.00%)  0
Vitamin B12 deficiency  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Musculoskeletal and connective tissue disorders             
Arthralgia  1  2/250 (0.80%)  2 3/245 (1.22%)  3 5/190 (2.63%)  6 2/207 (0.97%)  2 0/240 (0.00%)  0 0/6 (0.00%)  0
Arthritis  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Back pain  1  4/250 (1.60%)  4 3/245 (1.22%)  3 4/190 (2.11%)  5 3/207 (1.45%)  3 0/240 (0.00%)  0 0/6 (0.00%)  0
Intervertebral disc protrusion  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 1/240 (0.42%)  1 0/6 (0.00%)  0
Joint crepitation  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Joint swelling  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Muscle spasms  1  0/250 (0.00%)  0 1/245 (0.41%)  2 1/190 (0.53%)  1 2/207 (0.97%)  2 0/240 (0.00%)  0 0/6 (0.00%)  0
Musculoskeletal chest pain  1  0/250 (0.00%)  0 2/245 (0.82%)  2 2/190 (1.05%)  2 2/207 (0.97%)  2 0/240 (0.00%)  0 0/6 (0.00%)  0
Musculoskeletal pain  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Musculoskeletal stiffness  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Myalgia  1  2/250 (0.80%)  2 1/245 (0.41%)  1 4/190 (2.11%)  4 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Neck mass  1  0/250 (0.00%)  0 1/245 (0.41%)  1 0/190 (0.00%)  0 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Neck pain  1  0/250 (0.00%)  0 1/245 (0.41%)  1 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Pain in extremity  1  1/250 (0.40%)  1 1/245 (0.41%)  1 3/190 (1.58%)  3 5/207 (2.42%)  5 0/240 (0.00%)  0 0/6 (0.00%)  0
Plantar fasciitis  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Rotator cuff syndrome  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1 0/207 (0.00%)  0 0/240 (0.00%)  0 0/6 (0.00%)  0
Sensation of heaviness  1  1/250 (0.40%)  1 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Spinal osteoarthritis  1  0/250 (0.00%)  0 0/245 (0.00%)  0 0/190 (0.00%)  0 1/207 (0.48%)  1 0/240 (0.00%)  0 0/6 (0.00%)  0
Synovial cyst  1  0/250 (0.00%)  0 0/245 (0.00%)  0 1/190 (0.53%)  1