Trial Outcomes & Findings for Assessing Neuropsychiatric Symptoms Including Depression, Anxiety, Irritability, and Suicidal Thoughts or Behavior in Subjects Quitting Smoking on Varenicline Tartrate or Placebo (NCT NCT00749944)

Last Updated: 2010-08-31

Results Overview

POMS TMD were responses to 65 items in 6 subscales (Tension-Anxiety, Depression-Dejection, Anger-Hostility, Vigor, Fatigue, and Confusion), on 'How you feel right now?' (scale:0=not at all, 1=a little, 2=moderately, 3=quite a bit, 4=extremely). All items were rated in the same direction except for Relaxed and Efficient in the Tension-Anxiety and Confusion subscales. TMD was the sum of the scores of all 6 subscales but weighting Vigor negatively. Summary results (TMD scores) were presented as transformed T-scores ranging from 30 (less disturbance) to 80 (more disturbance).

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

110 participants

Primary outcome timeframe

Baseline A (Week 0) to Week 2 (Period AB), Week 4 (Period AC), Week 12 or relapse (Period AD), and Week 12 (Period AE). Baseline B (Week 2) to Week 4 (Period BC), Week 12 or relapse (Period BD), and Week 12 (Period BE).

Results posted on

2010-08-31

Participant Flow

857 participants were screened; 110 participants met the criteria for inclusion into the study and were assigned to study treatment

Participant milestones

Participant milestones
Measure	Varenicline Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Overall Study STARTED	55	55
Overall Study COMPLETED	50	54
Overall Study NOT COMPLETED	5	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Varenicline Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Overall Study Lost to Follow-up	2	1
Overall Study Other	1	0
Overall Study Withdrawal by Subject	2	0

Baseline Characteristics

Assessing Neuropsychiatric Symptoms Including Depression, Anxiety, Irritability, and Suicidal Thoughts or Behavior in Subjects Quitting Smoking on Varenicline Tartrate or Placebo

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)	Total n=110 Participants Total of all reporting groups
Age, Customized Between 18 and 44 years	47 Participants n=5 Participants	47 Participants n=7 Participants	94 Participants n=5 Participants
Age, Customized Between 45 and 64 years	7 Participants n=5 Participants	8 Participants n=7 Participants	15 Participants n=5 Participants
Age, Customized >= 65 years	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Sex: Female, Male Female	22 Participants n=5 Participants	15 Participants n=7 Participants	37 Participants n=5 Participants
Sex: Female, Male Male	33 Participants n=5 Participants	40 Participants n=7 Participants	73 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline A (Week 0) to Week 2 (Period AB), Week 4 (Period AC), Week 12 or relapse (Period AD), and Week 12 (Period AE). Baseline B (Week 2) to Week 4 (Period BC), Week 12 or relapse (Period BD), and Week 12 (Period BE).

Population: Full analysis set (FAS): All randomized subjects with at least 1 dose of study drug and at least 1 post-baseline neuropsychiatric evaluation or Minnesota Nicotine Withdrawal Scale (MNWS) obtained; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Change From Baseline in the Profile of Mood States (POMS): Total Mood Disturbance (TMD) Period AB (n=55, 55)	0.06 scores on a scale Standard Error 0.39	-0.66 scores on a scale Standard Error 0.36
Change From Baseline in the Profile of Mood States (POMS): Total Mood Disturbance (TMD) Period AC (n=55, 55)	0.30 scores on a scale Standard Error 0.35	-0.17 scores on a scale Standard Error 0.36
Change From Baseline in the Profile of Mood States (POMS): Total Mood Disturbance (TMD) Period AD (n=55, 55)	0.95 scores on a scale Standard Error 0.43	0.03 scores on a scale Standard Error 0.41
Change From Baseline in the Profile of Mood States (POMS): Total Mood Disturbance (TMD) Period AE (n=55, 55)	0.72 scores on a scale Standard Error 0.36	0.22 scores on a scale Standard Error 0.37
Change From Baseline in the Profile of Mood States (POMS): Total Mood Disturbance (TMD) Period BC (n=53, 54)	0.48 scores on a scale Standard Error 0.35	0.91 scores on a scale Standard Error 0.31
Change From Baseline in the Profile of Mood States (POMS): Total Mood Disturbance (TMD) Period BD (n=53, 54)	1.07 scores on a scale Standard Error 0.47	1.04 scores on a scale Standard Error 0.39
Change From Baseline in the Profile of Mood States (POMS): Total Mood Disturbance (TMD) Period BE (n=54, 54)	0.59 scores on a scale Standard Error 0.37	0.96 scores on a scale Standard Error 0.36

PRIMARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

POMS Tension-Anxiety subscale data were responses to 9 items regarding 'How you feel right now?' on a scale of 0=not at all, 1=a little, 2=moderately, 3=quite a bit, and 4=extremely. All items were rated in the same direction except for Relaxed. Summary results (subscale scores) were presented as transformed T-scores ranging from 30 (less disturbance) to 80 (more disturbance).

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Change From Baseline in the Profile of Mood States (POMS): Tension-Anxiety Subscale Period AB (n=55, 55)	0.30 scores on a scale Standard Error 0.30	-0.31 scores on a scale Standard Error 0.25
Change From Baseline in the Profile of Mood States (POMS): Tension-Anxiety Subscale Period AC (n=55, 55)	0.15 scores on a scale Standard Error 0.25	-0.26 scores on a scale Standard Error 0.21
Change From Baseline in the Profile of Mood States (POMS): Tension-Anxiety Subscale Period AD (n=55, 55)	0.31 scores on a scale Standard Error 0.24	-0.18 scores on a scale Standard Error 0.27
Change From Baseline in the Profile of Mood States (POMS): Tension-Anxiety Subscale Period AE (n=55, 55)	0.01 scores on a scale Standard Error 0.24	-0.43 scores on a scale Standard Error 0.20
Change From Baseline in the Profile of Mood States (POMS): Tension-Anxiety Subscale Period BC (n=53, 54)	-0.01 scores on a scale Standard Error 0.24	-0.10 scores on a scale Standard Error 0.25
Change From Baseline in the Profile of Mood States (POMS): Tension-Anxiety Subscale Period BD (n=53, 54)	0.06 scores on a scale Standard Error 0.23	-0.16 scores on a scale Standard Error 0.29
Change From Baseline in the Profile of Mood States (POMS): Tension-Anxiety Subscale Period BE (n=54, 54)	-0.35 scores on a scale Standard Error 0.19	-0.58 scores on a scale Standard Error 0.21

PRIMARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

POMS Depression-Dejection subscale data responses to 15 items regarding 'How you feel right now?' on a scale of 0=not at all, 1=a little, 2=moderately, 3=quite a bit, and 4=extremely. Summary results (subscale scores) were presented as transformed T-scores ranging from 30 (less disturbance) to 80 (more disturbance).

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Change From Baseline in the Profile of Mood States (POMS): Depression-Dejection Subscale Period AB (n=55, 55)	0.38 scores on a scale Standard Error 0.25	-0.24 scores on a scale Standard Error 0.18
Change From Baseline in the Profile of Mood States (POMS): Depression-Dejection Subscale Period AC (n=55, 55)	0.50 scores on a scale Standard Error 0.24	-0.24 scores on a scale Standard Error 0.13
Change From Baseline in the Profile of Mood States (POMS): Depression-Dejection Subscale Period AD (n=55, 55)	0.56 scores on a scale Standard Error 0.27	-0.10 scores on a scale Standard Error 0.16
Change From Baseline in the Profile of Mood States (POMS): Depression-Dejection Subscale Period AE (n=55, 55)	0.44 scores on a scale Standard Error 0.24	0.00 scores on a scale Standard Error 0.19
Change From Baseline in the Profile of Mood States (POMS): Depression-Dejection Subscale Period BC (n=53, 54)	0.51 scores on a scale Standard Error 0.27	0.03 scores on a scale Standard Error 0.13
Change From Baseline in the Profile of Mood States (POMS): Depression-Dejection Subscale Period BD (n=53, 54)	0.49 scores on a scale Standard Error 0.32	0.10 scores on a scale Standard Error 0.14
Change From Baseline in the Profile of Mood States (POMS): Depression-Dejection Subscale Period BE (n=54, 54)	0.32 scores on a scale Standard Error 0.23	0.23 scores on a scale Standard Error 0.20

PRIMARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

POMS Anger-Hostility subscale data were responses to 12 items regarding 'How you feel right now?' on a scale of 0=not at all, 1=a little, 2=moderately, 3=quite a bit, and 4=extremely. Summary results (subscale scores) were presented as transformed T-scores ranging from 30 (less disturbance) to 80 (more disturbance).

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Change From Baseline in the Profile of Mood States (POMS): Anger-Hostility Subscale Period AB (n=55, 55)	0.16 scores on a scale Standard Error 0.36	-0.69 scores on a scale Standard Error 0.25
Change From Baseline in the Profile of Mood States (POMS): Anger-Hostility Subscale Period AC (n=55, 55)	-0.04 scores on a scale Standard Error 0.31	-0.89 scores on a scale Standard Error 0.16
Change From Baseline in the Profile of Mood States (POMS): Anger-Hostility Subscale Period AD (n=55, 55)	0.24 scores on a scale Standard Error 0.36	-1.00 scores on a scale Standard Error 0.22
Change From Baseline in the Profile of Mood States (POMS): Anger-Hostility Subscale Period AE (n=55, 55)	0.15 scores on a scale Standard Error 0.30	-0.68 scores on a scale Standard Error 0.15
Change From Baseline in the Profile of Mood States (POMS): Anger-Hostility Subscale Period BC (n=53, 54)	-0.00 scores on a scale Standard Error 0.29	-0.52 scores on a scale Standard Error 0.15
Change From Baseline in the Profile of Mood States (POMS): Anger-Hostility Subscale Period BD (n=53, 54)	0.22 scores on a scale Standard Error 0.41	-0.65 scores on a scale Standard Error 0.19
Change From Baseline in the Profile of Mood States (POMS): Anger-Hostility Subscale Period BE (n=54, 54)	-0.05 scores on a scale Standard Error 0.25	-0.43 scores on a scale Standard Error 0.18

PRIMARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

POMS Vigor subscale data were responses to 8 items regarding 'How you feel right now?' on a scale of 0=not at all, 1=a little, 2=moderately, 3=quite a bit, and 4=extremely. Summary results (subscale scores) were presented as transformed T-scores ranging from 30 (less disturbance) to 80 (more disturbance).

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Change From Baseline in the Profile of Mood States (POMS): Vigor Subscale Period AB (n=55, 55)	0.16 scores on a scale Standard Error 0.86	0.98 scores on a scale Standard Error 0.75
Change From Baseline in the Profile of Mood States (POMS): Vigor Subscale Period AC (n=55, 55)	-1.34 scores on a scale Standard Error 0.87	-1.15 scores on a scale Standard Error 0.75
Change From Baseline in the Profile of Mood States (POMS): Vigor Subscale Period AD (n=55, 55)	-3.30 scores on a scale Standard Error 1.18	-1.14 scores on a scale Standard Error 0.97
Change From Baseline in the Profile of Mood States (POMS): Vigor Subscale Period AE (n=55, 55)	-2.80 scores on a scale Standard Error 1.00	-1.82 scores on a scale Standard Error 0.91
Change From Baseline in the Profile of Mood States (POMS): Vigor Subscale Period BC (n=53, 54)	-1.49 scores on a scale Standard Error 0.81	-3.44 scores on a scale Standard Error 0.83
Change From Baseline in the Profile of Mood States (POMS): Vigor Subscale Period BD (n=53, 54)	-3.22 scores on a scale Standard Error 1.25	-3.22 scores on a scale Standard Error 1.11
Change From Baseline in the Profile of Mood States (POMS): Vigor Subscale Period BE (n=54, 54)	-2.28 scores on a scale Standard Error 1.02	-3.37 scores on a scale Standard Error 1.04

PRIMARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

POMS Fatigue subscale data were responses to 7 items regarding 'How you feel right now?' on a scale of 0=not at all, 1=a little, 2=moderately, 3=quite a bit, and 4=extremely. All items were rated in the same direction. Summary results (subscale scores) were presented as transformed T-scores ranging from 30 (less disturbance) to 80 (more disturbance).

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Change From Baseline in the Profile of Mood States (POMS): Fatigue Subscale Period AB (n=55, 55)	-0.14 scores on a scale Standard Error 0.29	-0.65 scores on a scale Standard Error 0.29
Change From Baseline in the Profile of Mood States (POMS): Fatigue Subscale Period AC (n=55, 55)	-0.29 scores on a scale Standard Error 0.28	-0.83 scores on a scale Standard Error 0.24
Change From Baseline in the Profile of Mood States (POMS): Fatigue Subscale Period AD (n=55, 55)	-0.58 scores on a scale Standard Error 0.26	-0.76 scores on a scale Standard Error 0.27
Change From Baseline in the Profile of Mood States (POMS): Fatigue Subscale Period AE (n=55, 55)	-0.32 scores on a scale Standard Error 0.27	-0.59 scores on a scale Standard Error 0.24
Change From Baseline in the Profile of Mood States (POMS): Fatigue Subscale Period BC (n=53, 54)	0.37 scores on a scale Standard Error 0.32	-0.22 scores on a scale Standard Error 0.23
Change From Baseline in the Profile of Mood States (POMS): Fatigue Subscale Period BD (n=53, 54)	-0.20 scores on a scale Standard Error 0.29	-0.13 scores on a scale Standard Error 0.30
Change From Baseline in the Profile of Mood States (POMS): Fatigue Subscale Period BE (n=54, 54)	-0.16 scores on a scale Standard Error 0.29	-0.26 scores on a scale Standard Error 0.25

PRIMARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

POMS Confusion subscale data were responses to 7 items regarding 'How you feel right now?' on a scale of 0=not at all, 1=a little, 2=moderately, 3=quite a bit, and 4=extremely. All items were rated in the same direction except for Efficient. Summary results (subscale scores) were presented as transformed T-scores ranging from 30 (less disturbance) to 80 (more disturbance).

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Change From Baseline in the Profile of Mood States (POMS): Confusion Subscale Period AB (n=55, 55)	0.14 scores on a scale Standard Error 0.19	-0.09 scores on a scale Standard Error 0.12
Change From Baseline in the Profile of Mood States (POMS): Confusion Subscale Period AC (n=55, 55)	0.03 scores on a scale Standard Error 0.17	-0.18 scores on a scale Standard Error 0.10
Change From Baseline in the Profile of Mood States (POMS): Confusion Subscale Period AD (n=55, 55)	0.10 scores on a scale Standard Error 0.18	-0.11 scores on a scale Standard Error 0.13
Change From Baseline in the Profile of Mood States (POMS): Confusion Subscale Period AE (n=55, 55)	-0.01 scores on a scale Standard Error 0.15	-0.03 scores on a scale Standard Error 0.13
Change From Baseline in the Profile of Mood States (POMS): Confusion Subscale Period BC (n=53, 54)	0.02 scores on a scale Standard Error 0.22	-0.07 scores on a scale Standard Error 0.11
Change From Baseline in the Profile of Mood States (POMS): Confusion Subscale Period BD (n=53, 54)	0.07 scores on a scale Standard Error 0.22	-0.02 scores on a scale Standard Error 0.15
Change From Baseline in the Profile of Mood States (POMS): Confusion Subscale Period BE (n=54, 54)	-0.14 scores on a scale Standard Error 0.18	-0.02 scores on a scale Standard Error 0.16

PRIMARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

The MADRS measures the overall severity of depressive symptoms and is a 10-item checklist. Each item was rated on a scale of 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms).

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS): Total Score Period AB (n=54, 54)	1.05 scores on a scale Standard Error 0.37	0.83 scores on a scale Standard Error 0.25
Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS): Total Score Period AC (n=54, 54)	2.28 scores on a scale Standard Error 0.35	1.84 scores on a scale Standard Error 0.30
Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS): Total Score Period AD (n=54, 54)	1.19 scores on a scale Standard Error 0.29	1.41 scores on a scale Standard Error 0.37
Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS): Total Score Period AE (n=55, 54)	1.52 scores on a scale Standard Error 0.21	1.50 scores on a scale Standard Error 0.28
Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS): Total Score Period BC (n=53, 54)	2.27 scores on a scale Standard Error 0.50	1.69 scores on a scale Standard Error 0.48
Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS): Total Score Period BD (n=53, 54)	-0.10 scores on a scale Standard Error 0.35	0.33 scores on a scale Standard Error 0.53
Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS): Total Score Period BE (n=53, 54)	0.40 scores on a scale Standard Error 0.24	0.49 scores on a scale Standard Error 0.30

PRIMARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

HAM-A measures treatment-related changes in generalized anxiety symptoms and is a 14-item questionnaire. Each item was scored from 0 (not present) to 4 (very severe) and a lower score indicated less affected. Total scores ranged from 0 (not affected) to 56 (very severely affected).

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Change From Baseline in the Hamilton Anxiety Scale (HAM-A): Total Score Period AB (n=54, 54)	1.01 scores on a scale Standard Error 0.32	0.75 scores on a scale Standard Error 0.27
Change From Baseline in the Hamilton Anxiety Scale (HAM-A): Total Score Period AC (n=54, 54)	2.69 scores on a scale Standard Error 0.37	2.16 scores on a scale Standard Error 0.28
Change From Baseline in the Hamilton Anxiety Scale (HAM-A): Total Score Period AD (n=54, 54)	1.95 scores on a scale Standard Error 0.41	1.86 scores on a scale Standard Error 0.42
Change From Baseline in the Hamilton Anxiety Scale (HAM-A): Total Score Period AE (n=55, 54)	1.75 scores on a scale Standard Error 0.28	1.61 scores on a scale Standard Error 0.26
Change From Baseline in the Hamilton Anxiety Scale (HAM-A): Total Score Period BC (n=53, 54)	3.15 scores on a scale Standard Error 0.56	2.65 scores on a scale Standard Error 0.47
Change From Baseline in the Hamilton Anxiety Scale (HAM-A): Total Score Period BD (n=53, 54)	0.74 scores on a scale Standard Error 0.47	0.77 scores on a scale Standard Error 0.62
Change From Baseline in the Hamilton Anxiety Scale (HAM-A): Total Score Period BE (n=53, 54)	0.73 scores on a scale Standard Error 0.30	0.81 scores on a scale Standard Error 0.29

PRIMARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

The OAS-m contains 3 scales: Aggression (Questions \[Q\]1 to 4), Irritability (Q5 to 6), and Suicidality (Q7 to 7b). Aggression total score was calculated by summing the weighted scores in Q1 to 4. Scores for each question ranged from 0 (no events) to 5 (very severe events). Total scores ranged from 0 (no aggression) to any number with no upper limit depending on the frequency of agressive behaviour in a week.

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Change From Baseline in the Overt Aggression Scale (Modified) (OAS-m): Aggression Total Score Period BE (n=53, 54)	1.00 scores on a scale Standard Error 0.88	-0.13 scores on a scale Standard Error 0.23
Change From Baseline in the Overt Aggression Scale (Modified) (OAS-m): Aggression Total Score Period AB (n=54, 54)	0.13 scores on a scale Standard Error 0.27	0.48 scores on a scale Standard Error 0.66
Change From Baseline in the Overt Aggression Scale (Modified) (OAS-m): Aggression Total Score Period AC (n=54, 54)	0.82 scores on a scale Standard Error 0.37	0.72 scores on a scale Standard Error 0.39
Change From Baseline in the Overt Aggression Scale (Modified) (OAS-m): Aggression Total Score Period AD (n=54, 54)	2.24 scores on a scale Standard Error 1.75	0.75 scores on a scale Standard Error 0.34
Change From Baseline in the Overt Aggression Scale (Modified) (OAS-m): Aggression Total Score Period AE (n=55, 54)	1.27 scores on a scale Standard Error 0.70	0.77 scores on a scale Standard Error 0.48
Change From Baseline in the Overt Aggression Scale (Modified) (OAS-m): Aggression Total Score Period BC (n=53, 54)	0.83 scores on a scale Standard Error 0.63	0.22 scores on a scale Standard Error 0.38
Change From Baseline in the Overt Aggression Scale (Modified) (OAS-m): Aggression Total Score Period BD (n=53, 54)	1.94 scores on a scale Standard Error 2.27	-0.15 scores on a scale Standard Error 0.44

PRIMARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

The OAS-m contains 3 scales: Aggression (Questions \[Q\]1 to 4), Irritability (Q5 to 6), and Suicidality (Q7 to 7b). Irritability total score was calculated by summing the items in Q5 to 6. Scores for each question ranged from 0 (not at all) to 5 (extreme). Total scores ranged from 0 (no irritability) to 10 (extreme irritability).

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Change From Baseline in the Overt Aggression Scale (Modified) (OAS-m): Irritability Total Score Period AB (n=54, 54)	0.01 scores on a scale Standard Error 0.10	0.01 scores on a scale Standard Error 0.09
Change From Baseline in the Overt Aggression Scale (Modified) (OAS-m): Irritability Total Score Period AC (n=54, 54)	0.43 scores on a scale Standard Error 0.10	0.41 scores on a scale Standard Error 0.09
Change From Baseline in the Overt Aggression Scale (Modified) (OAS-m): Irritability Total Score Period AD (n=54, 54)	0.46 scores on a scale Standard Error 0.17	0.35 scores on a scale Standard Error 0.17
Change From Baseline in the Overt Aggression Scale (Modified) (OAS-m): Irritability Total Score Period AE (n=55, 54)	0.32 scores on a scale Standard Error 0.10	0.24 scores on a scale Standard Error 0.08
Change From Baseline in the Overt Aggression Scale (Modified) (OAS-m): Irritability Total Score Period BC (n=53, 54)	0.82 scores on a scale Standard Error 0.16	0.78 scores on a scale Standard Error 0.16
Change From Baseline in the Overt Aggression Scale (Modified) (OAS-m): Irritability Total Score Period BD (n=53, 54)	0.53 scores on a scale Standard Error 0.19	0.35 scores on a scale Standard Error 0.24
Change From Baseline in the Overt Aggression Scale (Modified) (OAS-m): Irritability Total Score Period BE (n=53, 54)	0.38 scores on a scale Standard Error 0.11	0.25 scores on a scale Standard Error 0.08

PRIMARY outcome

Population: No change from baseline analysis was performed on the OAS-m Suicidality total score as the majority of observations were recorded as 0.

The OAS-m contains 3 scales: Aggression (Questions \[Q\]1 to 4), Irritability (Q5 to 6), and Suicidality (Q7 to 7b). Suicidality total score was calculated by summing the items Q7 to 7b. Scores for Q7 ranged from 0 (none) to 6 (very extreme) and scores for Q7a to 7b ranged from 0 (none) to 5 (extreme). Total scores ranged from 0 (no suicidal tendency) to 16 (extreme/very extreme suicidal tendency).

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Baseline B (Week 2) to Week 4 (Period BC)

Population: No change from baseline analysis was performed on the SDAS total score as the majority of observations were recorded as 0.

The SDAS contains 11 items with 5 possible responses: 0=not present, 1=doubtful or very mild, 2=mild to moderate, 3=severe, and 4=extremely severe. The SDAS was collected 3 times a day during the inpatient abstinence period (BC). Total scores ranged from 0 (not present) to 44 (extremely severe).

Outcome measures

Outcome data not reported

PRIMARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

The BIS-11 is a 30-item self-report questionnaire designed to assess general impulsiveness taking into account the multifactorial nature of the construct. Possible responses to each item were: 1=rarely/never, 2=occasionally, 3=often, and 4=almost always/always. Scores of Items 1, 7, 8, 9, 10, 12, 13, 15, 20, 29 and 30 were reversed when calculating the total score. Total score ranged from 30 (less impulsive) to 120 (more impulsive).

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Change From Baseline in the Barratt Impulsiveness Scale - Version 11 (BIS-11): Total Score Period AB (n=54, 54)	0.34 scores on a scale Standard Error 0.56	-0.07 scores on a scale Standard Error 0.50
Change From Baseline in the Barratt Impulsiveness Scale - Version 11 (BIS-11): Total Score Period AC (n=54, 54)	0.45 scores on a scale Standard Error 0.62	0.37 scores on a scale Standard Error 0.53
Change From Baseline in the Barratt Impulsiveness Scale - Version 11 (BIS-11): Total Score Period AD (n=54, 54)	1.34 scores on a scale Standard Error 0.74	1.28 scores on a scale Standard Error 1.03
Change From Baseline in the Barratt Impulsiveness Scale - Version 11 (BIS-11): Total Score Period AE (n=55, 54)	1.19 scores on a scale Standard Error 0.69	0.90 scores on a scale Standard Error 0.64
Change From Baseline in the Barratt Impulsiveness Scale - Version 11 (BIS-11): Total Score Period BC (n=53, 54)	0.04 scores on a scale Standard Error 0.49	0.97 scores on a scale Standard Error 0.43
Change From Baseline in the Barratt Impulsiveness Scale - Version 11 (BIS-11): Total Score Period BD (n=53, 54)	1.07 scores on a scale Standard Error 0.49	1.81 scores on a scale Standard Error 0.92
Change From Baseline in the Barratt Impulsiveness Scale - Version 11 (BIS-11): Total Score Period BE (n=53, 54)	0.85 scores on a scale Standard Error 0.52	1.28 scores on a scale Standard Error 0.44

SECONDARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

The MNWS total score contains 9 items (urge to smoke; depressed mood; irritability, frustration, or anger; anxiety; difficulty concentrating; restlessness; increased appetite; difficulty going to sleep; difficulty staying asleep). Each item was rated from 0 to 4 where 0=not at all, 1=slight, 2=moderate, 3=quite a bit, and 4=extreme. Total scores were the average score for all 9 items and ranged from 0 (no withdrawal symptoms) to 4 (extreme withdrawal symptoms).

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Total Score Period AD (n=54, 54)	0.07 scores on a scale Standard Error 0.03	0.05 scores on a scale Standard Error 0.03
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Total Score Period AE (n=55, 54)	-0.01 scores on a scale Standard Error 0.02	0.04 scores on a scale Standard Error 0.03
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Total Score Period BC (n=53, 54)	-0.04 scores on a scale Standard Error 0.04	0.10 scores on a scale Standard Error 0.06
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Total Score Period BD (n=53, 54)	-0.08 scores on a scale Standard Error 0.03	0.02 scores on a scale Standard Error 0.04
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Total Score Period BE (n=53, 54)	-0.15 scores on a scale Standard Error 0.01	-0.05 scores on a scale Standard Error 0.03
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Total Score Period AC (n=54, 54)	0.10 scores on a scale Standard Error 0.03	0.11 scores on a scale Standard Error 0.03
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Total Score Period AB (n=54, 54)	0.13 scores on a scale Standard Error 0.04	0.05 scores on a scale Standard Error 0.04

SECONDARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

The MNWS negative affect domain subscale contains 4 items (depressed mood; irritability, frustration, or anger; anxiety; difficulty concentrating). Each item was rated from 0 to 4 where 0=not at all, 1=slight, 2=moderate, 3=quite a bit, and 4=extreme. Scores were the average from all 4 items and ranged from 0 (no negative affect) to 4 (extreme negative affect).

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Negative Affect Domain Subscale Period AB (n=54, 54)	0.06 scores on a scale Standard Error 0.03	0.01 scores on a scale Standard Error 0.02
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Negative Affect Domain Subscale Period AC (n=54, 54)	0.10 scores on a scale Standard Error 0.03	0.09 scores on a scale Standard Error 0.03
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Negative Affect Domain Subscale Period AD (n=54, 54)	0.07 scores on a scale Standard Error 0.03	0.03 scores on a scale Standard Error 0.03
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Negative Affect Domain Subscale Period AE (n=55, 54)	0.05 scores on a scale Standard Error 0.02	0.07 scores on a scale Standard Error 0.03
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Negative Affect Domain Subscale Period BC (n=53, 54)	0.07 scores on a scale Standard Error 0.05	0.15 scores on a scale Standard Error 0.05
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Negative Affect Domain Subscale Period BD (n=53, 54)	-0.01 scores on a scale Standard Error 0.03	0.02 scores on a scale Standard Error 0.05
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Negative Affect Domain Subscale Period BE (n=53, 54)	-0.02 scores on a scale Standard Error 0.02	0.03 scores on a scale Standard Error 0.03

SECONDARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

The MNWS insomnia domain subscale contains 2 items (difficulty going to sleep; difficulty staying asleep). Each item was rated from 0 to 4 where 0=not at all, 1=slight, 2=moderate, 3=quite a bit, and 4=extreme. Scores were the average of the 2 items and ranged from 0 (no insomnia) to 4 (extreme insomnia).

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Insomnia Domain Subscale Period AB (n=54, 54)	0.07 scores on a scale Standard Error 0.04	0.12 scores on a scale Standard Error 0.06
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Insomnia Domain Subscale Period AC (n=54, 54)	0.15 scores on a scale Standard Error 0.04	0.17 scores on a scale Standard Error 0.05
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Insomnia Domain Subscale Period AD (n=54, 54)	0.04 scores on a scale Standard Error 0.03	0.10 scores on a scale Standard Error 0.04
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Insomnia Domain Subscale Period AE (n=55, 54)	0.06 scores on a scale Standard Error 0.02	0.13 scores on a scale Standard Error 0.06
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Insomnia Domain Subscale Period BC (n=53, 54)	0.14 scores on a scale Standard Error 0.07	0.09 scores on a scale Standard Error 0.08
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Insomnia Domain Subscale Period BD (n=53, 54)	-0.04 scores on a scale Standard Error 0.05	0.01 scores on a scale Standard Error 0.06
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Insomnia Domain Subscale Period BE (n=53, 54)	-0.06 scores on a scale Standard Error 0.02	-0.01 scores on a scale Standard Error 0.06

SECONDARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

The MNWS urge to smoke subscale contains 1 item (urge to smoke) rated from 0 to 4 where 0=not at all, 1=slight, 2=moderate, 3=quite a bit, and 4=extreme. Scores ranged from 0 (no urge to smoke) to 4 (extreme urge to smoke).

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Urge to Smoke Subscale Period AB (n=54, 54)	-0.60 scores on a scale Standard Error 0.10	-0.29 scores on a scale Standard Error 0.09
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Urge to Smoke Subscale Period AC (n=54, 54)	-1.40 scores on a scale Standard Error 0.09	-0.97 scores on a scale Standard Error 0.09
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Urge to Smoke Subscale Period AD (n=54, 54)	-2.17 scores on a scale Standard Error 0.12	-2.03 scores on a scale Standard Error 0.12
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Urge to Smoke Subscale Period AE (n=55, 54)	-1.90 scores on a scale Standard Error 0.09	-1.55 scores on a scale Standard Error 0.09
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Urge to Smoke Subscale Period BC (n=53, 54)	-1.59 scores on a scale Standard Error 0.12	-1.14 scores on a scale Standard Error 0.14
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Urge to Smoke Subscale Period BD (n=53, 54)	-1.66 scores on a scale Standard Error 0.14	-1.58 scores on a scale Standard Error 0.15
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Urge to Smoke Subscale Period BE (n=53, 54)	-1.56 scores on a scale Standard Error 0.10	-1.29 scores on a scale Standard Error 0.11

SECONDARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

The MNWS restlessness subscale contains 1 item (restlessness) rated from 0 to 4 where 0=not at all, 1=slight, 2=moderate, 3=quite a bit, and 4=extreme. Scores ranged from 0 (no restlessness) to 4 (extreme restlessness).

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Restlessness Subscale Period AB (n=54, 54)	0.06 scores on a scale Standard Error 0.04	0.08 scores on a scale Standard Error 0.04
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Restlessness Subscale Period AC (n=54, 54)	0.10 scores on a scale Standard Error 0.04	0.11 scores on a scale Standard Error 0.04
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Restlessness Subscale Period AD (n=54, 54)	0.09 scores on a scale Standard Error 0.04	0.04 scores on a scale Standard Error 0.03
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Restlessness Subscale Period AE (n=55, 54)	0.03 scores on a scale Standard Error 0.02	0.05 scores on a scale Standard Error 0.03
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Restlessness Subscale Period BC (n=53, 54)	0.07 scores on a scale Standard Error 0.05	0.08 scores on a scale Standard Error 0.05
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Restlessness Subscale Period BD (n=53, 54)	0.03 scores on a scale Standard Error 0.02	-0.03 scores on a scale Standard Error 0.01
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Restlessness Subscale Period BE (n=53, 54)	-0.04 scores on a scale Standard Error 0.02	-0.03 scores on a scale Standard Error 0.03

SECONDARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

The MNWS increased appetite subscale contains 1 item (increased appetite) rated from 0 to 4 where 0=not at all, 1=slight, 2=moderate, 3=quite a bit, and 4=extreme. Scores ranged from 0 (no increased appetite) to 4 (extreme increased appetite).

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Increased Appetite Subscale Period BE (n=53, 54)	-0.10 scores on a scale Standard Error 0.04	-0.03 scores on a scale Standard Error 0.06
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Increased Appetite Subscale Period BC (n=53, 54)	-0.03 scores on a scale Standard Error 0.07	0.16 scores on a scale Standard Error 0.08
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Increased Appetite Subscale Period AB (n=54, 54)	0.14 scores on a scale Standard Error 0.07	0.02 scores on a scale Standard Error 0.05
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Increased Appetite Subscale Period AC (n=54, 54)	0.10 scores on a scale Standard Error 0.05	0.12 scores on a scale Standard Error 0.06
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Increased Appetite Subscale Period AD (n=54, 54)	0.11 scores on a scale Standard Error 0.09	0.15 scores on a scale Standard Error 0.09
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Increased Appetite Subscale Period AE (n=55, 54)	-0.00 scores on a scale Standard Error 0.05	0.04 scores on a scale Standard Error 0.06
Change From Baseline in the Minnesota Nicotine Withdrawal Scale (MNWS): Increased Appetite Subscale Period BD (n=53, 54)	-0.01 scores on a scale Standard Error 0.09	0.15 scores on a scale Standard Error 0.10

SECONDARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

POMS total mood disturbance (TMD) summary results were presented as transformed T-scores ranging from 30 (less disturbance) to 80 (more disturbance). Participants exceeding the threshold had an increase from baseline of 1 standard deviation of the TMD baseline T-score plus 1 or more.

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Number of Participants Exceeding Thresholds for the Profile of Mood States (POMS): Total Score Period AB (n=55, 55)	14 participants	11 participants
Number of Participants Exceeding Thresholds for the Profile of Mood States (POMS): Total Score Period AC (n=55, 55)	32 participants	35 participants
Number of Participants Exceeding Thresholds for the Profile of Mood States (POMS): Total Score Period AD (n=55, 55)	37 participants	38 participants
Number of Participants Exceeding Thresholds for the Profile of Mood States (POMS): Total Score Period AE (n=55, 55)	38 participants	38 participants
Number of Participants Exceeding Thresholds for the Profile of Mood States (POMS): Total Score Period BC (n=53, 54)	27 participants	33 participants
Number of Participants Exceeding Thresholds for the Profile of Mood States (POMS): Total Score Period BD (n=53, 54)	30 participants	36 participants
Number of Participants Exceeding Thresholds for the Profile of Mood States (POMS): Total Score Period BE (n=54, 54)	32 participants	38 participants

SECONDARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively. Statistical analyses were not performed for Period AB due to the small number of participants exceeding the threshold.

The MADRS measures the overall severity of depressive symptoms. Total score ranged from 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Participants exceeding the threshold had a MADRS total score of more than 14 out of 60. MADRS total scores exceeding 14 may represent clinically notable effective symptomatology.

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Number of Participants Exceeding Thresholds for the Montgomery-Asberg Depression Rating Scale (MADRS): Total Score Period AB (n=54, 54)	2 participants	0 participants
Number of Participants Exceeding Thresholds for the Montgomery-Asberg Depression Rating Scale (MADRS): Total Score Period AC (n=54, 54)	7 participants	3 participants
Number of Participants Exceeding Thresholds for the Montgomery-Asberg Depression Rating Scale (MADRS): Total Score Period AD (n=54, 54)	8 participants	3 participants
Number of Participants Exceeding Thresholds for the Montgomery-Asberg Depression Rating Scale (MADRS): Total Score Period AE (n=55, 54)	11 participants	8 participants
Number of Participants Exceeding Thresholds for the Montgomery-Asberg Depression Rating Scale (MADRS): Total Score Period BC (n=53, 54)	5 participants	3 participants
Number of Participants Exceeding Thresholds for the Montgomery-Asberg Depression Rating Scale (MADRS): Total Score Period BD (n=53, 54)	6 participants	3 participants
Number of Participants Exceeding Thresholds for the Montgomery-Asberg Depression Rating Scale (MADRS): Total Score Period BE (n=54, 54)	9 participants	8 participants

SECONDARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

HAM-A measures treatment-related changes in generalized anxiety symptoms. Total scores ranged from 0 (not affected) to 56 (very severely affected). Participants exceeding the threshold had a HAM-A total score of more than or equal to 14 out of 56. HAM-A total scores of more than or equal to 14 may reflect clinically noteworthy levels of anxiety.

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Number of Participants Exceeding Thresholds for the Hamilton Anxiety Scale (HAM-A): Total Score Period BE (n=54, 54)	16 participants	9 participants
Number of Participants Exceeding Thresholds for the Hamilton Anxiety Scale (HAM-A): Total Score Period AB (n=54, 54)	0 participants	2 participants
Number of Participants Exceeding Thresholds for the Hamilton Anxiety Scale (HAM-A): Total Score Period AC (n=54, 54)	9 participants	7 participants
Number of Participants Exceeding Thresholds for the Hamilton Anxiety Scale (HAM-A): Total Score Period AD (n=54, 54)	12 participants	7 participants
Number of Participants Exceeding Thresholds for the Hamilton Anxiety Scale (HAM-A): Total Score Period AE (n=55, 54)	16 participants	10 participants
Number of Participants Exceeding Thresholds for the Hamilton Anxiety Scale (HAM-A): Total Score Period BC (n=53, 54)	9 participants	6 participants
Number of Participants Exceeding Thresholds for the Hamilton Anxiety Scale (HAM-A): Total Score Period BD (n=53, 54)	12 participants	6 participants

SECONDARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

The OAS-m contains 3 scales: Aggression, Irritability, and Suicidality. Aggression total score ranged from 0 (no aggression) to any number with no upper limit depending on the frequency of agressive behaviour in a week. Participants exceeding the threshold had an OAS-m Aggression total score of more than or equal to 3 out of any number with no upper limit depending on the frequency of agressive behaviour in a week. OAS-m Aggression total scores of more than or equal to 3 reflect clinically important aggression.

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Number of Participants Exceeding Thresholds for the Overt Aggression Scale (Modified) (OAS-m): Agression Total Score Period AB (n=54, 54)	9 participants	6 participants
Number of Participants Exceeding Thresholds for the Overt Aggression Scale (Modified) (OAS-m): Agression Total Score Period AC (n=54, 54)	20 participants	21 participants
Number of Participants Exceeding Thresholds for the Overt Aggression Scale (Modified) (OAS-m): Agression Total Score Period AD (n=54, 54)	21 participants	23 participants
Number of Participants Exceeding Thresholds for the Overt Aggression Scale (Modified) (OAS-m): Agression Total Score Period AE (n=55, 54)	28 participants	31 participants
Number of Participants Exceeding Thresholds for the Overt Aggression Scale (Modified) (OAS-m): Agression Total Score Period BC (n=53, 54)	15 participants	19 participants
Number of Participants Exceeding Thresholds for the Overt Aggression Scale (Modified) (OAS-m): Agression Total Score Period BD (n=53, 54)	18 participants	21 participants
Number of Participants Exceeding Thresholds for the Overt Aggression Scale (Modified) (OAS-m): Agression Total Score Period BE (n=54, 54)	27 participants	30 participants

SECONDARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

The OAS-m contains 3 scales: Aggression, Irritability, and Suicidality. Irritability total score ranged from 0 (no irritability) to 10 (extreme irritability). Participants exceeding the threshold had an OAS-m Irritability total score of more than or equal to 2 out of 10. OAS-m Irritability total scores of more than or equal to 2 reflect clinically important irritability.

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Number of Participants Exceeding Thresholds for the Overt Aggression Scale (Modified) (OAS-m): Irritability Total Score Period AB (n=54, 54)	10 participants	11 participants
Number of Participants Exceeding Thresholds for the Overt Aggression Scale (Modified) (OAS-m): Irritability Total Score Period AC (n=54, 54)	32 participants	34 participants
Number of Participants Exceeding Thresholds for the Overt Aggression Scale (Modified) (OAS-m): Irritability Total Score Period AD (n=54, 54)	36 participants	36 participants
Number of Participants Exceeding Thresholds for the Overt Aggression Scale (Modified) (OAS-m): Irritability Total Score Period AE (n=55, 54)	41 participants	39 participants
Number of Participants Exceeding Thresholds for the Overt Aggression Scale (Modified) (OAS-m): Irritability Total Score Period BC (n=53, 54)	31 participants	31 participants
Number of Participants Exceeding Thresholds for the Overt Aggression Scale (Modified) (OAS-m): Irritability Total Score Period BD (n=53, 54)	35 participants	33 participants
Number of Participants Exceeding Thresholds for the Overt Aggression Scale (Modified) (OAS-m): Irritability Total Score Period BE (n=54, 54)	40 participants	38 participants

SECONDARY outcome

Population: The number of participants above the threshold for the OAS-m Suicidality total score was not analyzed as the majority of observations were recorded as 0.

The OAS-m contains 3 scales: Aggression, Irritability, and Suicidality. Suicidality total score ranged from 0 (no suicidal tendency) to 16 (extreme/very extreme suicidal tendency). No threshold criterion was determined for OAS-m Suicidality total score.

Outcome measures

Outcome data not reported

SECONDARY outcome

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

The BIS-11 is designed to assess general impulsiveness taking into account the multifactorial nature of the construct. Total score ranged from 30 (less impulsive) to 120 (more impulsive). Participants exceeding the threshold had a BIS-11 total score more than or equal to 70 out of 120. BIS-11 total scores of more than or equal to 70 could reflect clinically important and potentially pathological impulsivity.

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Number of Participants Exceeding Thresholds for the Barratt Impulsiveness Scale - Version 11 (BIS-11): Total Score Period AB (n=54, 54)	1 participants	0 participants
Number of Participants Exceeding Thresholds for the Barratt Impulsiveness Scale - Version 11 (BIS-11): Total Score Period AC (n=54, 54)	1 participants	2 participants
Number of Participants Exceeding Thresholds for the Barratt Impulsiveness Scale - Version 11 (BIS-11): Total Score Period AD (n=54, 54)	1 participants	2 participants
Number of Participants Exceeding Thresholds for the Barratt Impulsiveness Scale - Version 11 (BIS-11): Total Score Period AE (n=55, 54)	5 participants	5 participants
Number of Participants Exceeding Thresholds for the Barratt Impulsiveness Scale - Version 11 (BIS-11): Total Score Period BC (n=53, 54)	1 participants	2 participants
Number of Participants Exceeding Thresholds for the Barratt Impulsiveness Scale - Version 11 (BIS-11): Total Score Period BD (n=53, 54)	1 participants	2 participants
Number of Participants Exceeding Thresholds for the Barratt Impulsiveness Scale - Version 11 (BIS-11): Total Score Period BE (n=54, 54)	5 participants	5 participants

SECONDARY outcome

Timeframe: Baseline B (Week 2) to Week 4 (Period BC)

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

SDAS total scores ranged from 0 (not present) to 44 (extremely severe). Participants exceeding the threshold had a SDAS total score of more than 6 out of 44.

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Number of Participants Exceeding Thresholds for the Social Dysfunction and Aggression Scale (SDAS): Total Score	2 participants	1 participants

SECONDARY outcome

Timeframe: Week 9 to Week 12

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

Participants who reported no smoking and no use of other nicotine-containing products since the last study visit (on the Nicotine Use Inventory, which was used to collect the information of cigarette or other nicotine use during the study) and who did not have carbon monoxide of more than 10 parts per million at any time from Week 9 to Week 12

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Number of Participants With Carbon Monoxide Confirmed Daily Smoking Cessation	16 participants	10 participants

SECONDARY outcome

Timeframe: Week 5 to Week 13

Population: FAS; (n)=number of subjects with data for analysis for varenicline and placebo, respectively.

Participants who reported no smoking and no use of other nicotine-containing products since the last study visit (during treatment) in the previous 7 days and who did not have carbon monoxide of more than 10 parts per million for that observation (if measured).

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Number of Participants With 7-day Point Prevalence of Abstinence (Smoking Cessation) Week 5 (n=55, 55)	19 participants	16 participants
Number of Participants With 7-day Point Prevalence of Abstinence (Smoking Cessation) Week 6 (n=55, 55)	23 participants	12 participants
Number of Participants With 7-day Point Prevalence of Abstinence (Smoking Cessation) Week 7 (n=55, 55)	20 participants	17 participants
Number of Participants With 7-day Point Prevalence of Abstinence (Smoking Cessation) Week 8 (n=55, 55)	21 participants	15 participants
Number of Participants With 7-day Point Prevalence of Abstinence (Smoking Cessation) Week 9 (n=55, 55)	25 participants	14 participants
Number of Participants With 7-day Point Prevalence of Abstinence (Smoking Cessation) Week 10 (n=55, 55)	17 participants	17 participants
Number of Participants With 7-day Point Prevalence of Abstinence (Smoking Cessation) Week 11 (n=55, 55)	20 participants	18 participants
Number of Participants With 7-day Point Prevalence of Abstinence (Smoking Cessation) Week 12 (n=55, 55)	19 participants	15 participants
Number of Participants With 7-day Point Prevalence of Abstinence (Smoking Cessation) Week 13 (n=55, 55)	23 participants	15 participants

SECONDARY outcome

Timeframe: Baseline (Week 0) to Week 2

Population: FAS; (n)=number of subjects with at least 1 dose of study drug and an observation for a given day.

Outcome measures

Outcome measures
Measure	Varenicline n=55 Participants Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 Participants Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Change From Baseline in the Number of Cigarettes Smoked Per Day Day 2 (n=55, 54)	-0.1 cigarettes smoked per day Standard Deviation 3.6	-0.2 cigarettes smoked per day Standard Deviation 3.7
Change From Baseline in the Number of Cigarettes Smoked Per Day Day 3 (n=55, 54)	-0.6 cigarettes smoked per day Standard Deviation 4.1	0.0 cigarettes smoked per day Standard Deviation 3.9
Change From Baseline in the Number of Cigarettes Smoked Per Day Day 4 (n=55, 54)	-1.8 cigarettes smoked per day Standard Deviation 5.0	-0.3 cigarettes smoked per day Standard Deviation 3.7
Change From Baseline in the Number of Cigarettes Smoked Per Day Day 5 (n=55, 54)	-1.0 cigarettes smoked per day Standard Deviation 5.2	-0.4 cigarettes smoked per day Standard Deviation 4.0
Change From Baseline in the Number of Cigarettes Smoked Per Day Day 6 (n=54, 54)	-1.3 cigarettes smoked per day Standard Deviation 5.9	0.1 cigarettes smoked per day Standard Deviation 4.5
Change From Baseline in the Number of Cigarettes Smoked Per Day Day 7 (n=54, 54)	-1.8 cigarettes smoked per day Standard Deviation 4.9	-0.3 cigarettes smoked per day Standard Deviation 5.0
Change From Baseline in the Number of Cigarettes Smoked Per Day Day 8 (n=54, 54)	-1.7 cigarettes smoked per day Standard Deviation 5.0	0.4 cigarettes smoked per day Standard Deviation 4.3
Change From Baseline in the Number of Cigarettes Smoked Per Day Day 9 (n=52, 54)	-1.0 cigarettes smoked per day Standard Deviation 5.1	0.1 cigarettes smoked per day Standard Deviation 4.2
Change From Baseline in the Number of Cigarettes Smoked Per Day Day 10 (n=52, 54)	-1.7 cigarettes smoked per day Standard Deviation 5.7	-0.4 cigarettes smoked per day Standard Deviation 6.1
Change From Baseline in the Number of Cigarettes Smoked Per Day Day 11 (n=53, 54)	-1.8 cigarettes smoked per day Standard Deviation 5.3	-0.4 cigarettes smoked per day Standard Deviation 6.3
Change From Baseline in the Number of Cigarettes Smoked Per Day Day 12 (n=53, 54)	-0.7 cigarettes smoked per day Standard Deviation 6.6	-0.2 cigarettes smoked per day Standard Deviation 6.3
Change From Baseline in the Number of Cigarettes Smoked Per Day Day 13 (n=53, 54)	-1.4 cigarettes smoked per day Standard Deviation 5.6	-0.1 cigarettes smoked per day Standard Deviation 6.1
Change From Baseline in the Number of Cigarettes Smoked Per Day Day 14 (n=36, 38)	-17.2 cigarettes smoked per day Standard Deviation 8.6	-15.7 cigarettes smoked per day Standard Deviation 6.6

Adverse Events

Varenicline

Serious events: 0 serious events

Other events: 54 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 52 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer, Inc.

Phone: 1-800-718-1021

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Publication restrictions are in place

Restriction type: OTHER

Other adverse events
Measure	Varenicline n=55 participants at risk Varenicline 0.5 milligrams (mg) administered once daily (QD) for the first 3 days followed by 0.5 mg varenicline twice daily (BID) for the next 4 days, then 1 mg varenicline BID for the remaining 11 weeks (starting on Day 8, the first day of Week 2)	Placebo n=55 participants at risk Placebo administered QD for the first 3 days followed by placebo administered BID for the remaining 11 weeks and 4 days (starting on Day 4)
Cardiac disorders Palpitations	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.5% 3/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Ear and labyrinth disorders Ear pain	7.3% 4/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Ear and labyrinth disorders Tinnitus	5.5% 3/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Eye disorders Conjunctival irritation	0.00% 0/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Eye disorders Eye irritation	1.8% 1/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.5% 3/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Eye disorders Vision blurred	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal distension	7.3% 4/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal pain	18.2% 10/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	9.1% 5/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal tenderness	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Aphthous stomatitis	0.00% 0/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Chapped lips	18.2% 10/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	12.7% 7/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Constipation	14.5% 8/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.5% 3/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Diarrhoea	12.7% 7/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	12.7% 7/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Dry mouth	0.00% 0/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	7.3% 4/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Dyspepsia	9.1% 5/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Flatulence	5.5% 3/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gastrooesophageal reflux disease	1.8% 1/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Nausea	32.7% 18/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	29.1% 16/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Toothache	7.3% 4/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Vomiting	12.7% 7/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	9.1% 5/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Asthenia	0.00% 0/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.5% 3/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Chills	1.8% 1/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Energy increased	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.5% 3/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Fatigue	12.7% 7/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	9.1% 5/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Irritability	30.9% 17/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	30.9% 17/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Thirst	1.8% 1/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.5% 3/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Immune system disorders Hypersensitivity	1.8% 1/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Gastroenteritis	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Rash pustular	0.00% 0/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.5% 3/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Tooth abscess	5.5% 3/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Upper respiratory tract infection	21.8% 12/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	30.9% 17/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Urinary tract infection	0.00% 0/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Excoriation	1.8% 1/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	7.3% 4/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Joint injury	0.00% 0/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Joint sprain	1.8% 1/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Skin laceration	7.3% 4/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Thermal burn	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Tooth fracture	0.00% 0/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.6% 2/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Investigations Weight increased	1.8% 1/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	12.7% 7/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Anorexia	7.3% 4/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.5% 3/55 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.