Trial Outcomes & Findings for An Efficacy and Safety Study of Vortioxetine (Lu AA21004) in Treating Generalized Anxiety Disorder (NCT NCT00734071)

NCT ID: NCT00734071

Last Updated: 2013-12-18

Results Overview

The HAM-A is an anxiety rating scale consisting of 14 items that assess anxious mood, tension, fear, insomnia, intellectual (cognitive) symptoms, depressed mood, behavior at interview, somatic (sensory), cardiovascular, respiratory, gastrointestinal, genitourinary, autonomic and somatic (muscular) symptoms. Each symptom is rated from 0 (absent) to 4 (maximum severity). Total scores range from 0 to 56 where \<17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. Total scores above 30 are rare, but indicate very severe anxiety. Least Squares (LS) means were from a mixed model for repeated measurements (MMRM).

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 304 participants
• Primary outcome timeframe: Baseline to Week 8
• Results posted on: 2013-12-18

Participant Flow

Participants took part in the study at 33 investigative sites in the United States from 25 June 2008 to 06 March 2009.

Participants with a diagnosis of generalized anxiety disorder were enrolled equally in one of two treatment groups, once a day placebo or 5 mg vortioxetine.

Participant milestones

Measure	Placebo Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Overall Study STARTED	152	152
Overall Study Treated	151	148
Overall Study COMPLETED	114	125
Overall Study NOT COMPLETED	38	27

Reasons for withdrawal

Measure	Placebo Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Overall Study Adverse Event	4	3
Overall Study Lack of Efficacy	3	1
Overall Study Noncompliance	2	2
Overall Study Protocol Deviations	3	4
Overall Study Voluntary Withdrawal	9	7
Overall Study Lost to Follow-up	16	8
Overall Study Other	1	2

Baseline Characteristics

An Efficacy and Safety Study of Vortioxetine (Lu AA21004) in Treating Generalized Anxiety Disorder

Baseline characteristics by cohort

Measure	Placebo n=152 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=152 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.	Total n=304 Participants Total of all reporting groups
Age Continuous	41.4 years STANDARD_DEVIATION 12.81 • n=5 Participants	41.0 years STANDARD_DEVIATION 14.05 • n=7 Participants	41.2 years STANDARD_DEVIATION 13.42 • n=5 Participants
Age, Customized ≤55 years	128 participants n=5 Participants	129 participants n=7 Participants	257 participants n=5 Participants
Age, Customized >55 years	24 participants n=5 Participants	23 participants n=7 Participants	47 participants n=5 Participants
Sex: Female, Male Female	97 Participants n=5 Participants	103 Participants n=7 Participants	200 Participants n=5 Participants
Sex: Female, Male Male	55 Participants n=5 Participants	49 Participants n=7 Participants	104 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian (White, including Hispanic)	131 participants n=5 Participants	123 participants n=7 Participants	254 participants n=5 Participants
Race/Ethnicity, Customized Black	17 participants n=5 Participants	24 participants n=7 Participants	41 participants n=5 Participants
Race/Ethnicity, Customized Asian	2 participants n=5 Participants	3 participants n=7 Participants	5 participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 participants n=5 Participants	2 participants n=7 Participants	2 participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian/ Other Pacific Islander	2 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants
Race/Ethnicity, Customized Hispanic/Latino	24 participants n=5 Participants	26 participants n=7 Participants	50 participants n=5 Participants
Race/Ethnicity, Customized Non-Hispanic/Non-Latino	128 participants n=5 Participants	126 participants n=7 Participants	254 participants n=5 Participants
Region of Enrollment United States	152 participants n=5 Participants	152 participants n=7 Participants	304 participants n=5 Participants
Weight	83.68 kg STANDARD_DEVIATION 20.916 • n=5 Participants	80.10 kg STANDARD_DEVIATION 20.296 • n=7 Participants	81.89 kg STANDARD_DEVIATION 20.652 • n=5 Participants
Height	167.73 cm STANDARD_DEVIATION 8.765 • n=5 Participants	167.72 cm STANDARD_DEVIATION 9.158 • n=7 Participants	167.73 cm STANDARD_DEVIATION 8.949 • n=5 Participants
Body Mass Index (BMI)	29.66 kg/m^2 STANDARD_DEVIATION 6.861 • n=5 Participants	28.42 kg/m^2 STANDARD_DEVIATION 6.680 • n=7 Participants	29.04 kg/m^2 STANDARD_DEVIATION 6.789 • n=5 Participants
Smoking Classification Never Smoked	78 participants n=5 Participants	76 participants n=7 Participants	154 participants n=5 Participants
Smoking Classification Current Smoker	38 participants n=5 Participants	43 participants n=7 Participants	81 participants n=5 Participants
Smoking Classification Ex-smoker	36 participants n=5 Participants	33 participants n=7 Participants	69 participants n=5 Participants
Alcohol Consumption Never	48 participants n=5 Participants	39 participants n=7 Participants	87 participants n=5 Participants
Alcohol Consumption Once monthly or less often	57 participants n=5 Participants	55 participants n=7 Participants	112 participants n=5 Participants
Alcohol Consumption Once a week	17 participants n=5 Participants	28 participants n=7 Participants	45 participants n=5 Participants
Alcohol Consumption 2 to 6 times per week	27 participants n=5 Participants	27 participants n=7 Participants	54 participants n=5 Participants
Alcohol Consumption Daily	3 participants n=5 Participants	3 participants n=7 Participants	6 participants n=5 Participants
Hamilton Anxiety Scale Total Score	24.6 scores on a scale STANDARD_DEVIATION 3.60 • n=5 Participants	24.7 scores on a scale STANDARD_DEVIATION 3.79 • n=7 Participants	24.7 scores on a scale STANDARD_DEVIATION 3.69 • n=5 Participants
Clinical Global Impression - Severity scale score	4.3 scores on a scale STANDARD_DEVIATION 0.49 • n=5 Participants	4.3 scores on a scale STANDARD_DEVIATION 0.53 • n=7 Participants	4.3 scores on a scale STANDARD_DEVIATION 0.51 • n=5 Participants
Hospital Anxiety and Depression - Anxiety subscale	13.5 scores on a scale STANDARD_DEVIATION 3.14 • n=5 Participants	13.8 scores on a scale STANDARD_DEVIATION 3.39 • n=7 Participants	13.7 scores on a scale STANDARD_DEVIATION 3.26 • n=5 Participants
Hospital Anxiety and Depression - Depression subscale	8.5 scores on a scale STANDARD_DEVIATION 3.79 • n=5 Participants	8.1 scores on a scale STANDARD_DEVIATION 3.91 • n=7 Participants	8.3 scores on a scale STANDARD_DEVIATION 3.85 • n=5 Participants
Montgomery Åsberg Depression Rating Scale (MADRS) total score	11.83 scores on a scale STANDARD_DEVIATION 3.007 • n=5 Participants	12.09 scores on a scale STANDARD_DEVIATION 2.902 • n=7 Participants	11.96 scores on a scale STANDARD_DEVIATION 2.953 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline to Week 8

Population: The Full Analysis Set included all patients who were randomized, received at least 1 dose of study drug, and had at least 1 post-baseline value for assessment of primary efficacy. A mixed model for repeated measurements (MMRM) based on observed cases was used.

The HAM-A is an anxiety rating scale consisting of 14 items that assess anxious mood, tension, fear, insomnia, intellectual (cognitive) symptoms, depressed mood, behavior at interview, somatic (sensory), cardiovascular, respiratory, gastrointestinal, genitourinary, autonomic and somatic (muscular) symptoms. Each symptom is rated from 0 (absent) to 4 (maximum severity). Total scores range from 0 to 56 where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. Total scores above 30 are rare, but indicate very severe anxiety. Least Squares (LS) means were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=113 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=124 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Change From Baseline in the Hamilton Anxiety Scale (HAM-A) Total Score at Week 8	-13.16 scores on a scale Standard Error 0.655	-12.57 scores on a scale Standard Error 0.646

SECONDARY outcome

Timeframe: Baseline to Week 8

Population: The Full Analysis Set. A mixed model for repeated measurements (MMRM) based on observed cases was used.

The Hospital Anxiety and Depression (HAD) Anxiety sub-scale consists of 7 items that are assessed by a scale from 0 (no anxiety) to 3 (severe feeling of anxiety). The anxiety subscale determines a state of generalized anxiety including anxious mood, restlessness, anxious thoughts and panic attacks. Scores are summed and range from 0 to 21 (maximal severity). LS means were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=111 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=124 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Change From Baseline in the Hospital Anxiety and Depression (HAD) Anxiety Subscale at Week 8	-4.84 scores on a scale Standard Error 0.392	-5.06 scores on a scale Standard Error 0.384

SECONDARY outcome

Timeframe: Baseline to Week 8

Population: Full analysis set. A mixed model for repeated measurements (MMRM) based on observed cases was used.

The Clinical Global Impression - Global Improvement scale assesses the participant's improvement (or worsening) as assessed by the clinician relative to Baseline on 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. LS means were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=113 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=124 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Clinical Global Impression Scale-Global Improvement at Week 8	2.25 scores on a scale Standard Error 0.101	2.25 scores on a scale Standard Error 0.099

SECONDARY outcome

Timeframe: Baseline to Week 8

Population: Full analysis set. A mixed model for repeated measurements (MMRM) based on observed cases was used.

The Sheehan Disability Scale assesses functional impairment in 3 domains: work/school, social life or leisure activities, and home life or family responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment. LS means were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=91 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=97 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 8	-6.68 scores on a scale Standard Error 0.618	-6.35 scores on a scale Standard Error 0.616

SECONDARY outcome

Timeframe: Baseline and Week 8

Population: Full analysis set; Last observation carried forward was used.

Response was defined as participants with a ≥50% decrease from Baseline in the Hamilton Anxiety Scale (HAM-A) total score. The HAM-A is an anxiety rating scale consisting of 14 items that assess anxious mood, tension, fear, insomnia, intellectual (cognitive) symptoms, depressed mood, behavior at interview, somatic (sensory), cardiovascular, respiratory, gastrointestinal, genitourinary, autonomic and somatic (muscular) symptoms. Each symptom is rated from 0 (absent) to 4 (maximum severity). Total scores range from 0 (symptoms absent) to 56 (maximum severity).

Outcome measures

Measure	Placebo n=144 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=145 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Percentage of Responders in HAM-A Total Score at Week 8	50.0 percentage of participants	53.1 percentage of participants

SECONDARY outcome

Timeframe: Baseline to Week 8

Population: Full analysis set patients with a HAM-A Baseline score ≥25. A mixed model for repeated measurements (MMRM) based on observed cases was used.

The HAM-A is an anxiety rating scale consisting of 14 items that assess anxious mood, tension, fear, insomnia, intellectual (cognitive) symptoms, depressed mood, behavior at interview, somatic (sensory), cardiovascular, respiratory, gastrointestinal, genitourinary, autonomic and somatic (muscular) symptoms. Each symptom is rated from 0 (absent) to 4 (maximum severity). Total scores range from 0 to 56 where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. Total scores above 30 are rare, but indicate very severe anxiety. Least Squares (LS) means were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=59 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=63 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Change From Baseline in the Hamilton Anxiety Scale (HAM-A) Total Score at Week 8 in Participants With Baseline HAM-A ≥25	-14.04 scores on a scale Standard Error 1.104	-14.05 scores on a scale Standard Error 1.080

SECONDARY outcome

Timeframe: Baseline to Week 8

Population: The Full Analysis Set. A mixed model for repeated measurements (MMRM) based on observed cases was used.

The Medical Outcomes Study SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. The social functioning subscale assesses limitations in social activities because of physical or emotional problems. The sub-score scale ranges from 0 (best) - 100 (worst). LS means were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=113 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=125 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Social Functioning Subscore at Week 8	17.43 scores on a scale Standard Error 2.133	18.44 scores on a scale Standard Error 2.091

SECONDARY outcome

Timeframe: Baseline to Weeks 1, 2, 4 and 6.

Population: The Full Analysis Set. A mixed model for repeated measurements (MMRM) based on observed cases was used. "n" indicates the number of patients included in the analysis at each time point.

The HAM-A is an anxiety rating scale consisting of 14 items that assess anxious mood, tension, fear, insomnia, intellectual (cognitive) symptoms, depressed mood, behavior at interview, somatic (sensory), cardiovascular, respiratory, gastrointestinal, genitourinary, autonomic and somatic (muscular) symptoms. Each symptom is rated from 0 (absent) to 4 (maximum severity). Total scores range from 0 to 56 where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. Total scores above 30 are rare, but indicate very severe anxiety. Least Squares (LS) means were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=144 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=145 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Change From Baseline in Hamilton Anxiety Scale (HAM-A) Total Score at Other Weeks Assessed Week 1 (n=141, 144)	-4.84 scores on a scale Standard Error 0.415	-4.59 scores on a scale Standard Error 0.422
Change From Baseline in Hamilton Anxiety Scale (HAM-A) Total Score at Other Weeks Assessed Week 2 (n=134, 142)	-7.78 scores on a scale Standard Error 0.542	-8.22 scores on a scale Standard Error 0.541
Change From Baseline in Hamilton Anxiety Scale (HAM-A) Total Score at Other Weeks Assessed Week 4 (n=131, 135)	-10.13 scores on a scale Standard Error 0.590	-9.82 scores on a scale Standard Error 0.590
Change From Baseline in Hamilton Anxiety Scale (HAM-A) Total Score at Other Weeks Assessed Week 6 (n=124, 129)	-12.39 scores on a scale Standard Error 0.632	-11.61 scores on a scale Standard Error 0.630

SECONDARY outcome

Timeframe: Baseline to Weeks 1 and 4

Population: The Full Analysis Set with available data at Baseline. A mixed model for repeated measurements (MMRM) based on observed cases was used; "n" indicates the number of patients included in the analysis at each time point.

The Hospital Anxiety and Depression (HAD) Anxiety sub-scale consists of 7 items that are assessed by a scale from 0 (no anxiety) to 3 (severe feeling of anxiety). The anxiety subscale determines a state of generalized anxiety including anxious mood, restlessness, anxious thoughts and panic attacks. Scores are summed and range from 0 to 21 (maximal severity). LS means were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=140 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=144 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Change From Baseline in the Hospital Anxiety and Depression (HAD) Anxiety Subscale at Other Weeks Assessed Week 1 (n=139, 142)	-1.81 scores on a scale Standard Error 0.269	-2.07 scores on a scale Standard Error 0.273
Change From Baseline in the Hospital Anxiety and Depression (HAD) Anxiety Subscale at Other Weeks Assessed Week 4 (n=130, 135)	-3.41 scores on a scale Standard Error 0.328	-3.72 scores on a scale Standard Error 0.329

SECONDARY outcome

Timeframe: Baseline to Weeks 1, 2, 4 and 6

Population: Full analysis set. A mixed model for repeated measurements (MMRM) based on observed cases was used; "n" indicates the number of patients included in the analysis at each time point.

The Clinical Global Impression - Global Improvement scale assesses the participant's improvement (or worsening) as assessed by the clinician relative to Baseline on 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. LS means were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=144 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=145 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Clinical Global Impression Scale-Global Improvement at Other Weeks Assessed Week 1 (n=141, 144)	3.32 scores on a scale Standard Error 0.066	3.38 scores on a scale Standard Error 0.066
Clinical Global Impression Scale-Global Improvement at Other Weeks Assessed Week 2 (n=134, 142)	2.92 scores on a scale Standard Error 0.081	2.83 scores on a scale Standard Error 0.081
Clinical Global Impression Scale-Global Improvement at Other Weeks Assessed Week 4 (n=131, 135)	2.57 scores on a scale Standard Error 0.089	2.57 scores on a scale Standard Error 0.089
Clinical Global Impression Scale-Global Improvement at Other Weeks Assessed Week 6 (n=124, 129)	2.42 scores on a scale Standard Error 0.096	2.39 scores on a scale Standard Error 0.095

SECONDARY outcome

Timeframe: Baseline to Weeks 1, 2 and 4

Population: Full analysis set with available data at Baseline. A mixed model for repeated measurements (MMRM) based on observed cases was used; "n" indicates the number of patients included in the analysis at each time point.

The Sheehan Disability Scale assesses functional impairment in 3 domains: work/school, social life or leisure activities, and home life or family responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment. LS means and P-values were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=124 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=121 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Other Weeks Assessed Week 1 (n=117, 116)	-2.13 scores on a scale Standard Error 0.484	-2.46 scores on a scale Standard Error 0.497
Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Other Weeks Assessed Week 2 (n=109, 114)	-4.35 scores on a scale Standard Error 0.566	-4.02 scores on a scale Standard Error 0.572
Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Other Weeks Assessed Week 4 (n=106, 108)	-5.57 scores on a scale Standard Error 0.587	-5.38 scores on a scale Standard Error 0.593

SECONDARY outcome

Timeframe: Baseline and Weeks 1, 2, 4 and 6

Population: Full analysis set; Last observation carried forward was used; "n" indicates the number of patients included in the analysis at each time point.

Response was defined as participants with a ≥50% decrease from Baseline in the Hamilton Anxiety Scale (HAM-A) total score. The HAM-A is an anxiety rating scale consisting of 14 items that assess anxious mood, tension, fear, insomnia, intellectual (cognitive) symptoms, depressed mood, behavior at interview, somatic (sensory), cardiovascular, respiratory, gastrointestinal, genitourinary, autonomic and somatic (muscular) symptoms. Each symptom is rated from 0 (absent) to 4 (maximum severity). Total scores range from 0 (symptoms absent) to 56 (maximum severity).

Outcome measures

Measure	Placebo n=144 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=145 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Percentage of Responders in HAM-A Total Score at Other Weeks Assessed Week 1 (n=141, 144)	9.9 percentage of participants	6.9 percentage of participants
Percentage of Responders in HAM-A Total Score at Other Weeks Assessed Week 2 (n=144, 145)	22.9 percentage of participants	24.1 percentage of participants
Percentage of Responders in HAM-A Total Score at Other Weeks Assessed Week 4 (n=144, 145)	34.7 percentage of participants	37.2 percentage of participants
Percentage of Responders in HAM-A Total Score at Other Weeks Assessed Week 6 (n=144, 145)	47.2 percentage of participants	45.5 percentage of participants

SECONDARY outcome

Timeframe: Baseline to Weeks 1, 2, 4 and 6

Population: Full analysis set patients with a HAM-A Baseline score ≥25. A mixed model for repeated measurements (MMRM) based on observed cases was used; "n" indicates the number of patients included in the analysis at each time point.

The HAM-A is an anxiety rating scale consisting of 14 items that assess anxious mood, tension, fear, insomnia, intellectual (cognitive) symptoms, depressed mood, behavior at interview, somatic (sensory), cardiovascular, respiratory, gastrointestinal, genitourinary, autonomic and somatic (muscular) symptoms. Each symptom is rated from 0 (absent) to 4 (maximum severity). Total scores range from 0 to 56 where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. Total scores above 30 are rare, but indicate very severe anxiety. Least Squares (LS) means were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=73 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=71 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Change From Baseline in the Hamilton Anxiety Scale (HAM-A) Total Score at Other Weeks Assessed in Participants With Baseline HAM-A ≥25 Week 4 (n=67, 67)	-10.90 scores on a scale Standard Error 0.994	-10.74 scores on a scale Standard Error 0.980
Change From Baseline in the Hamilton Anxiety Scale (HAM-A) Total Score at Other Weeks Assessed in Participants With Baseline HAM-A ≥25 Week 1 (n=71, 71)	-5.39 scores on a scale Standard Error 0.675	-4.73 scores on a scale Standard Error 0.648
Change From Baseline in the Hamilton Anxiety Scale (HAM-A) Total Score at Other Weeks Assessed in Participants With Baseline HAM-A ≥25 Week 2 (n=70, 70)	-8.37 scores on a scale Standard Error 0.889	-8.94 scores on a scale Standard Error 0.873
Change From Baseline in the Hamilton Anxiety Scale (HAM-A) Total Score at Other Weeks Assessed in Participants With Baseline HAM-A ≥25 Week 6 (n=63, 65)	-13.60 scores on a scale Standard Error 1.040	-12.82 scores on a scale Standard Error 1.021

SECONDARY outcome

Timeframe: Weeks 1, 2, 4, 6 and 8

Population: Full analysis set; Last observation carried forward was used. "n" indicates the number of patients included in the analysis at each time point.

Remission is defined as a Hamilton Anxiety Scale (HAM-A) total score ≤ 7. The HAM-A is an anxiety rating scale consisting of 14 items that assess anxious mood, tension, fear, insomnia, intellectual (cognitive) symptoms, depressed mood, behavior at interview, somatic (sensory), cardiovascular, respiratory, gastrointestinal, genitourinary, autonomic and somatic (muscular) symptoms. Each symptom is rated from 0 (absent) to 4 (maximum severity). Total scores range from 0 (symptoms absent) to 56 (maximum severity).

Outcome measures

Measure	Placebo n=144 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=145 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Percentage of Participants in HAM-A Remission at Each Week Assessed Week 4 (n=144, 145)	15.3 percentage of participants	12.4 percentage of participants
Percentage of Participants in HAM-A Remission at Each Week Assessed Week 1 (n-141, 144)	2.1 percentage of participants	0.7 percentage of participants
Percentage of Participants in HAM-A Remission at Each Week Assessed Week 2 (n=144, 145)	5.6 percentage of participants	7.6 percentage of participants
Percentage of Participants in HAM-A Remission at Each Week Assessed Week 6 (n=144, 145)	22.2 percentage of participants	22.1 percentage of participants
Percentage of Participants in HAM-A Remission at Each Week Assessed Week 8 (n=144, 145)	22.2 percentage of participants	25.5 percentage of participants

SECONDARY outcome

Timeframe: Baseline to Weeks 1, 2, 4, 6 and 8

Population: Full analysis set. A mixed model for repeated measurements (MMRM) based on observed cases was used. "n" indicates the number of patients included in the analysis at each time point.

The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of mental illness on the following 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. LS means were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=144 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=145 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Change From Baseline in Clinical Global Impression Scale-Severity of Illness at Each Week Assessed Week 1 (n=141, 144)	-0.37 scores on a scale Standard Error 0.057	-0.38 scores on a scale Standard Error 0.058
Change From Baseline in Clinical Global Impression Scale-Severity of Illness at Each Week Assessed Week 2 (n=134, 142)	-0.75 scores on a scale Standard Error 0.081	-0.86 scores on a scale Standard Error 0.081
Change From Baseline in Clinical Global Impression Scale-Severity of Illness at Each Week Assessed Week 4 (n=131, 135)	-1.15 scores on a scale Standard Error 0.093	-1.05 scores on a scale Standard Error 0.092
Change From Baseline in Clinical Global Impression Scale-Severity of Illness at Each Week Assessed Week 6 (n=124, 129)	-1.45 scores on a scale Standard Error 0.098	-1.40 scores on a scale Standard Error 0.097
Change From Baseline in Clinical Global Impression Scale-Severity of Illness at Each Week Assessed Week 8 (n=113, 124)	-1.72 scores on a scale Standard Error 0.104	-1.54 scores on a scale Standard Error 0.102

SECONDARY outcome

Timeframe: Baseline to Weeks 1, 4 and 8

Population: The Full Analysis Set with available data at Baseline. A mixed model for repeated measurements (MMRM) based on observed cases was used. "n" indicates the number of patients included in the analysis at each time point.

The HAD-Depression subscale is completed by the participant and measures depression, focusing on the state of lost interest and diminished pleasure response. The subscale is made up of 7 items that are assessed on a scale from 0 (no depression) to 3 (severe feeling of depression). Participants are required to indicate the response which most accurately reflects the way they have felt over the last few days. The item scores are summed and the total subscore ranges from 0 to 21 (maximal severity). LS means were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=140 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=144 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Change From Baseline in the Hospital Anxiety and Depression (HAD) Depression Subscale at Each Week Assessed Week 1 (n=139, 142)	-1.02 scores on a scale Standard Error 0.226	-1.09 scores on a scale Standard Error 0.228
Change From Baseline in the Hospital Anxiety and Depression (HAD) Depression Subscale at Each Week Assessed Week 4 (n=130, 135)	-1.84 scores on a scale Standard Error 0.273	-2.28 scores on a scale Standard Error 0.273
Change From Baseline in the Hospital Anxiety and Depression (HAD) Depression Subscale at Each Week Assessed Week 8 (n=111, 124)	-2.55 scores on a scale Standard Error 0.316	-2.62 scores on a scale Standard Error 0.308

SECONDARY outcome

Timeframe: Baseline to Weeks 2 and 4

Population: The Full Analysis Set with available data at Baseline. A mixed model for repeated measurements (MMRM) based on observed cases was used. "n" indicates the number of patients included in the analysis at each time point.

The Medical Outcomes Study SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. The social functioning subscale assesses limitations in social activities because of physical or emotional problems. The sub-score scale ranges from 0 (best) - 100 (worst). LS means were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=139 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=143 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Social Functioning Subscore at Other Weeks Assessed Week 2 (n=137, 143)	11.96 scores on a scale Standard Error 1.803	14.06 scores on a scale Standard Error 1.820
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Social Functioning Subscore at Other Weeks Assessed Week 4 (n=129, 134)	17.12 scores on a scale Standard Error 1.993	16.22 scores on a scale Standard Error 1.999

SECONDARY outcome

Timeframe: Baseline to Weeks 2, 4 and 8

Population: The Full Analysis Set with available data at Baseline. A mixed model for repeated measurements (MMRM) based on observed cases was used. "n" indicates the number of patients included in the analysis at each time point.

The Medical Outcomes Study SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. The physical functioning subscale assesses limitations in physical activities because of health problems. The sub-score scale ranges from 0 (best) - 100 (worst). LS means were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=139 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=143 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Physical Functioning Subscore at Each Week Assessed Week 2 (n=137, 143)	1.54 scores on a scale Standard Error 1.322	3.69 scores on a scale Standard Error 1.336
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Physical Functioning Subscore at Each Week Assessed Week 4 (n=129, 134)	4.76 scores on a scale Standard Error 1.424	4.22 scores on a scale Standard Error 1.432
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Physical Functioning Subscore at Each Week Assessed Week 8 (n=113, 125)	3.50 scores on a scale Standard Error 1.640	4.18 scores on a scale Standard Error 1.609

SECONDARY outcome

Timeframe: Baseline to Weeks 2, 4 and 8

Population: The Full Analysis Set with available data at Baseline. A mixed model for repeated measurements (MMRM) based on observed cases was used. "n" indicates the number of patients included in the analysis at each time point.

The Medical Outcomes Study SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. The role-physical subscale assesses limitations in usual role activities because of physical health problems. The sub-score scale ranges from 0 (best) - 100 (worst). LS means were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=139 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=143 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Role-Physical Subscore at Each Week Assessed Week 2 (n=137, 143)	5.03 scores on a scale Standard Error 1.901	4.90 scores on a scale Standard Error 1.906
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Role-Physical Subscore at Each Week Assessed Week 4 (n=129, 134)	8.65 scores on a scale Standard Error 1.966	5.19 scores on a scale Standard Error 1.967
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Role-Physical Subscore at Each Week Assessed Week 8 (n=113, 125)	10.02 scores on a scale Standard Error 1.998	7.74 scores on a scale Standard Error 1.953

SECONDARY outcome

Timeframe: Baseline to Weeks 2, 4 and 8

Population: The Full Analysis Set with available data at Baseline. A mixed model for repeated measurements (MMRM) based on observed cases was used. "n" indicates the number of patients included in the analysis at each time point.

The Medical Outcomes Study SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. The bodily pain sub-score scale ranges from 0 (best) - 100 (worst). LS means were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=139 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=143 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Bodily Pain Subscore at Each Week Assessed Week 2 (n=137, 143)	7.24 scores on a scale Standard Error 1.743	6.49 scores on a scale Standard Error 1.755
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Bodily Pain Subscore at Each Week Assessed Week 4 (n=129, 134)	9.81 scores on a scale Standard Error 1.756	8.96 scores on a scale Standard Error 1.761
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Bodily Pain Subscore at Each Week Assessed Week 8 (n=113, 125)	10.14 scores on a scale Standard Error 1.965	8.58 scores on a scale Standard Error 1.915

SECONDARY outcome

Timeframe: Baseline to Weeks 2, 4 and 8

Population: The Full Analysis Set with available data at Baseline. A mixed model for repeated measurements (MMRM) based on observed cases was used. "n" indicates the number of patients included in the analysis at each time point.

The Medical Outcomes Study SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. The general health sub-score scale ranges from 0 (best) - 100 (worst). LS means were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=139 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=143 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) General Health Subscore at Each Week Assessed Week 2 (n=137, 143)	2.79 scores on a scale Standard Error 1.095	3.61 scores on a scale Standard Error 1.109
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) General Health Subscore at Each Week Assessed Week 4 (n=129, 134)	4.85 scores on a scale Standard Error 1.204	1.76 scores on a scale Standard Error 1.212
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) General Health Subscore at Each Week Assessed Week 8 (n=113, 125)	6.14 scores on a scale Standard Error 1.391	3.90 scores on a scale Standard Error 1.365

SECONDARY outcome

Timeframe: Baseline to Weeks 2, 4 and 8

Population: The Full Analysis Set with available data at Baseline. A mixed model for repeated measurements (MMRM) based on observed cases was used. "n" indicates the number of patients included in the analysis at each time point.

The Medical Outcomes Study SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. The vitality sub-score assesses energy and fatigue, and ranges from 0 (best) - 100 (worst). LS means were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=139 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=143 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Vitality Subscore at Each Week Assessed Week 2 (n=137, 143)	8.91 scores on a scale Standard Error 1.528	10.46 scores on a scale Standard Error 1.555
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Vitality Subscore at Each Week Assessed Week 4 (n=129, 134)	12.48 scores on a scale Standard Error 1.655	12.67 scores on a scale Standard Error 1.671
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Vitality Subscore at Each Week Assessed Week 8 (n=113, 125)	16.06 scores on a scale Standard Error 1.828	14.65 scores on a scale Standard Error 1.805

SECONDARY outcome

Timeframe: Baseline to Weeks 2, 4 and 8

Population: The Full Analysis Set with available data at Baseline. A mixed model for repeated measurements (MMRM) based on observed cases was used. "n" indicates the number of patients included in the analysis at each time point.

The Medical Outcomes Study SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. The role-emotional subscale assesses limitations in usual role activities because of emotional problems. The sub-score scale ranges from 0 (best) - 100 (worst). LS means were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=139 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=143 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Role-Emotional Subscore at Each Week Assessed Week 2 (n=137, 143)	14.54 scores on a scale Standard Error 2.028	13.25 scores on a scale Standard Error 2.041
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Role-Emotional Subscore at Each Week Assessed Week 4 (n=129, 134)	16.00 scores on a scale Standard Error 2.055	15.00 scores on a scale Standard Error 2.063
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Role-Emotional Subscore at Each Week Assessed Week 8 (n=113, 125)	21.64 scores on a scale Standard Error 2.202	19.01 scores on a scale Standard Error 2.159

SECONDARY outcome

Timeframe: Baseline to Weeks 2, 4 and 8

Population: The Full Analysis Set with available data at Baseline. A mixed model for repeated measurements (MMRM) based on observed cases was used. "n" indicates the number of patients included in the analysis at each time point.

The Medical Outcomes Study SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. The mental health sub-score assesses general mental health (psychological distress and well-being) and ranges from 0 (best) - 100 (worst). LS means were from a mixed model for repeated measurements (MMRM).

Outcome measures

Measure	Placebo n=139 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=143 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Mental Health Subscore at Each Week Assessed Week 2 (n=137, 143)	10.32 scores on a scale Standard Error 1.455	11.72 scores on a scale Standard Error 1.470
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Mental Health Subscore at Each Week Assessed Week 4 (n=129, 134)	12.58 scores on a scale Standard Error 1.610	15.12 scores on a scale Standard Error 1.617
Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Mental Health Subscore at Each Week Assessed Week 8 (n=113, 125)	17.95 scores on a scale Standard Error 1.716	16.91 scores on a scale Standard Error 1.686

SECONDARY outcome

Timeframe: Baseline and Week 8

Population: Full analysis set with available data at Baseline (139 and 136 patients) and at Week 8 (122 and 131 patients).

Healthcare resource utilization was assessed by the Health Economic Assessment (HEA) questionnaire, which monitors the participants absenteeism from work, as well as resource use such as visits to a general practitioner, outpatient and inpatient services, hospitalization, medications, and other relevant services over the past 8 weeks.

Outcome measures

Measure	Placebo n=139 Participants Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=136 Participants Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Health Care Resource Utilization as Assessed by the Health Economic Assessment Questionnaire Baseline: Any resource use	30 participants	30 participants
Health Care Resource Utilization as Assessed by the Health Economic Assessment Questionnaire Baseline: Any hospitalization-related services	1 participants	0 participants
Health Care Resource Utilization as Assessed by the Health Economic Assessment Questionnaire Baseline: Hospitalization related to anxiety	0 participants	0 participants
Health Care Resource Utilization as Assessed by the Health Economic Assessment Questionnaire Baseline: Any sick leave	8 participants	10 participants
Health Care Resource Utilization as Assessed by the Health Economic Assessment Questionnaire Baseline: Sick leave related to anxiety	7 participants	4 participants
Health Care Resource Utilization as Assessed by the Health Economic Assessment Questionnaire Week 8: Any resource use	22 participants	19 participants
Health Care Resource Utilization as Assessed by the Health Economic Assessment Questionnaire Week 8: Any hospitalization-related service	0 participants	1 participants
Health Care Resource Utilization as Assessed by the Health Economic Assessment Questionnaire Week 8: Hospitalization related to anxiety	0 participants	0 participants
Health Care Resource Utilization as Assessed by the Health Economic Assessment Questionnaire Week 8: Any sick leave	4 participants	6 participants
Health Care Resource Utilization as Assessed by the Health Economic Assessment Questionnaire Week 8: Sick leave related to anxiety	2 participants	1 participants

Adverse Events

Placebo

Serious events: 3 serious events

Other events: 65 other events

Deaths: 0 deaths

Vortioxetine 5 mg

Serious events: 1 serious events

Other events: 89 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=151 participants at risk Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=148 participants at risk Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Infections and infestations Prostate infection	0.66% 1/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Therapeutic agent toxicity	0.00% 0/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.68% 1/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Pregnancy, puerperium and perinatal conditions Abortion spontaneous	1.3% 2/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Other adverse events

Measure	Placebo n=151 participants at risk Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks.	Vortioxetine 5 mg n=148 participants at risk Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks.
Gastrointestinal disorders Nausea	4.6% 7/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	25.0% 37/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Dry mouth	3.3% 5/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.1% 12/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Diarrhoea	4.6% 7/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.4% 8/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Constipation	1.3% 2/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.4% 5/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Dyspepsia	1.3% 2/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.0% 3/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Vomiting	0.66% 1/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.0% 3/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
General disorders Irritability	2.6% 4/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.4% 2/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
General disorders Fatigue	2.0% 3/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.0% 3/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Nasopharyngitis	4.0% 6/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.4% 8/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Upper respiratory tract infection	3.3% 5/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.0% 3/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Viral upper respiratory tract infection	3.3% 5/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.7% 4/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Gastroenteritis viral	0.00% 0/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.7% 4/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Overdose	0.66% 1/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.0% 3/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Investigations Blood pressure increased	4.6% 7/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.68% 1/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Metabolism and nutrition disorders Increased appetite	1.3% 2/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.4% 5/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Metabolism and nutrition disorders Decreased appetite	2.0% 3/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.0% 3/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Back pain	0.66% 1/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	4.1% 6/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.0% 3/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Headache	8.6% 13/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	10.1% 15/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Dizziness	3.3% 5/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.1% 12/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Somnolence	2.0% 3/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	6.1% 9/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Sinus headache	2.6% 4/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.68% 1/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Memory impairment	0.00% 0/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.0% 3/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Tremor	0.66% 1/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.0% 3/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Psychiatric disorders Insomnia	4.0% 6/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	4.7% 7/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Psychiatric disorders Abnormal dreams	2.6% 4/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.0% 3/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Respiratory, thoracic and mediastinal disorders Cough	0.66% 1/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.7% 4/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Vascular disorders Hot flush	0.00% 0/151 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.0% 3/148 • Safety was assessed during the 8-week core treatment period and a 4-week follow-up period. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Additional Information

Medical Director, Clinical Science

Takeda

Phone: 800-778-2860

Email: clinicaltrialregistry@tpna.com

Results disclosure agreements

• Principal investigator is a sponsor employee The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.
• Publication restrictions are in place

Restriction type: OTHER