Trial Outcomes & Findings for Smoking Cessation Study In Healthy Adolescent Smokers (NCT NCT01312909)

Last Updated: 2018-08-09

Results Overview

The percentage of participants who, at each visit from Week 9 through Week 12, reported no smoking and no use of other nicotine-containing products since the last study visit (on the Nicotine Use Inventory) and at each of these visits were confirmed to have quit based on urine cotinine less than 200 nanograms/milliliter (ng/mL).

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

312 participants

Primary outcome timeframe

Week 9 through Week 12

Results posted on

2018-08-09

Participant Flow

This study consisted of 3 phases: Screening (3 weeks before first dose of study drug); treatment (from Week 2 to Week 12 after a 2-week titration) and non-treatment follow-up (Week 13 through Week 52).

Participant milestones

Participant milestones
Measure	Varenicline High Dose Participants received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight less than or equal to (\<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.	Varenicline Low Dose Participants received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight \<= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.	Placebo Participants received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.
Overall Study STARTED	109	103	100
Overall Study Treated	108	100	99
Overall Study COMPLETED	67	67	53
Overall Study NOT COMPLETED	42	36	47

Reasons for withdrawal

Reasons for withdrawal
Measure	Varenicline High Dose Participants received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight less than or equal to (\<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.	Varenicline Low Dose Participants received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight \<= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.	Placebo Participants received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.
Overall Study Randomized but not treated	1	3	1
Overall Study Adverse Event	1	0	3
Overall Study Protocol Violation	2	0	2
Overall Study Other	9	6	11
Overall Study Withdrawal by Subject	8	10	7
Overall Study Lost to Follow-up	21	17	20
Overall Study Insufficient clinical response	0	0	1
Overall Study Entrance criteria not met	0	0	2

Baseline Characteristics

Smoking Cessation Study In Healthy Adolescent Smokers

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Varenicline High Dose n=108 Participants Participants received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight less than or equal to (\<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.	Varenicline Low Dose n=100 Participants Participants received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight \<= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.	Placebo n=99 Participants Participants received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.	Total n=307 Participants Total of all reporting groups
Age, Continuous	16.0 years STANDARD_DEVIATION 2.0 • n=5 Participants	16.0 years STANDARD_DEVIATION 1.7 • n=7 Participants	15.8 years STANDARD_DEVIATION 1.8 • n=5 Participants	15.9 years STANDARD_DEVIATION 1.8 • n=4 Participants
Sex: Female, Male Female	38 Participants n=5 Participants	37 Participants n=7 Participants	36 Participants n=5 Participants	111 Participants n=4 Participants
Sex: Female, Male Male	70 Participants n=5 Participants	63 Participants n=7 Participants	63 Participants n=5 Participants	196 Participants n=4 Participants
Race/Ethnicity, Customized White	81 Participants n=5 Participants	73 Participants n=7 Participants	74 Participants n=5 Participants	228 Participants n=4 Participants
Race/Ethnicity, Customized Black	9 Participants n=5 Participants	9 Participants n=7 Participants	5 Participants n=5 Participants	23 Participants n=4 Participants
Race/Ethnicity, Customized Asian	16 Participants n=5 Participants	18 Participants n=7 Participants	19 Participants n=5 Participants	53 Participants n=4 Participants
Race/Ethnicity, Customized Other	2 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants

PRIMARY outcome

Timeframe: Week 9 through Week 12

Population: The full analysis set included all randomized participants.

Outcome measures

Outcome measures
Measure	Varenicline High Dose n=109 Participants Participants received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight less than or equal to (\<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.	Varenicline Low Dose n=103 Participants Participants received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight \<= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.	Placebo n=100 Participants Participants received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.
4-Week Continuous Abstinence Rate: Percentage of Participants Who Remained Abstinent From Week 9 Through Week 12	20.2 percentage of participants	27.2 percentage of participants	18.0 percentage of participants

SECONDARY outcome

Timeframe: Weeks 12, 24 and 52

Population: The full analysis set included all randomized participants.

The percentage of participants who reported no smoking and no use of other nicotine-containing products (treatment phase) or tobacco products (non-treatment phase) on the Nicotine Use Inventory in the 7 days prior to the study visits or telephone contacts at Week 12,24 and 52.

Outcome measures

Outcome measures
Measure	Varenicline High Dose n=109 Participants Participants received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight less than or equal to (\<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.	Varenicline Low Dose n=103 Participants Participants received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight \<= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.	Placebo n=100 Participants Participants received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.
Percentage of Participants With 7-Day Point Prevalence of Smoking Abstinence at Weeks 12, 24 and 52 Week 12	31.2 percentage of participants	37.9 percentage of participants	23.0 percentage of participants
Percentage of Participants With 7-Day Point Prevalence of Smoking Abstinence at Weeks 12, 24 and 52 Week 24	31.2 percentage of participants	35.9 percentage of participants	23.0 percentage of participants
Percentage of Participants With 7-Day Point Prevalence of Smoking Abstinence at Weeks 12, 24 and 52 Week 52	28.4 percentage of participants	35.0 percentage of participants	20.0 percentage of participants

SECONDARY outcome

Timeframe: Baseline

Population: The full analysis set included all randomized participants.

The average number of cigarettes smoked per day in the past 7 days reported at the baseline visit.

Outcome measures

Outcome measures
Measure	Varenicline High Dose n=109 Participants Participants received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight less than or equal to (\<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.	Varenicline Low Dose n=103 Participants Participants received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight \<= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.	Placebo n=100 Participants Participants received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.
Daily Number of Cigarettes Smoked at Baseline	10.68 cigarettes smoked per day Standard Error 0.624	9.56 cigarettes smoked per day Standard Error 0.530	9.57 cigarettes smoked per day Standard Error 0.531

SECONDARY outcome

Timeframe: Baseline, Weeks 12, 24, and 52

Population: The full analysis set included all randomized participants. The longitudinal model included all participants regardless of observed visits.

The reduction in the number of the cigarettes smoked was calculated by subtracting the reported average number of cigarettes smoked per day in the past 7 days at Weeks 12, 24 and 52 from the average number of cigarettes smoked per day in the past 7 days reported at the baseline visit.

Outcome measures

Outcome measures
Measure	Varenicline High Dose n=109 Participants Participants received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight less than or equal to (\<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.	Varenicline Low Dose n=103 Participants Participants received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight \<= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.	Placebo n=100 Participants Participants received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.
Change From Baseline in Daily Number of Cigarettes Smoked at Weeks 12, 24, and 52 Change at Week 12	-8.56 cigarettes smoked per day Standard Error 0.43	-8.20 cigarettes smoked per day Standard Error 0.44	-8.01 cigarettes smoked per day Standard Error 0.46
Change From Baseline in Daily Number of Cigarettes Smoked at Weeks 12, 24, and 52 Change at Week 24	-6.93 cigarettes smoked per day Standard Error 0.44	-7.31 cigarettes smoked per day Standard Error 0.45	-6.59 cigarettes smoked per day Standard Error 0.48
Change From Baseline in Daily Number of Cigarettes Smoked at Weeks 12, 24, and 52 Change at Week 52	-6.80 cigarettes smoked per day Standard Error 0.45	-7.74 cigarettes smoked per day Standard Error 0.46	-6.98 cigarettes smoked per day Standard Error 0.48

SECONDARY outcome

Timeframe: Week 9 through Week 24; Week 9 through Week 52

Population: The full analysis set included all randomized participants.

The percentage of participants who, at each visit from Week 9 to 52 (inclusive), reported no smoking and no use of other nicotine-containing products (Weeks 9-12) or tobacco products (Weeks 13-52) since the last study visit/last contact (on the Nicotine Use Inventory) and at any of the study visits were confirmed to have quit based on urine cotinine less than 200 ng/mL.

Outcome measures

Outcome measures
Measure	Varenicline High Dose n=109 Participants Participants received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight less than or equal to (\<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.	Varenicline Low Dose n=103 Participants Participants received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight \<= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.	Placebo n=100 Participants Participants received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.
Continuous Abstinence Rate: Percentage of Participants Who Remained Abstinent From Week 9 Through Week 24 and Week 52 Week 9 through Week 24	10.1 percentage of participants	24.3 percentage of participants	13.0 percentage of participants
Continuous Abstinence Rate: Percentage of Participants Who Remained Abstinent From Week 9 Through Week 24 and Week 52 Week 9 through Week 52	8.3 percentage of participants	20.4 percentage of participants	9.0 percentage of participants

OTHER_PRE_SPECIFIED outcome

Timeframe: First dose up to last dose (up-to Week 12) plus 30 days

Population: The safety analysis set included all participants who took at least one dose of randomized study medication, including partial doses.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both non-serious AEs and SAEs.

Outcome measures

Outcome measures
Measure	Varenicline High Dose n=108 Participants Participants received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight less than or equal to (\<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.	Varenicline Low Dose n=100 Participants Participants received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight \<= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.	Placebo n=99 Participants Participants received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.
Number of Participants With Treatment-Emergent Adverse Events (AEs)	65 Participants	53 Participants	52 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: First dose up to last dose (up-to Week 12) plus 30 days

Population: The safety analysis set included all participants who took at least one dose of randomized study medication, including partial doses.

Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-emergent were events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Relatedness to drug Varenicline was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category. An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. A serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both non-serious AEs and SAEs.

Outcome measures

Outcome measures
Measure	Varenicline High Dose n=108 Participants Participants received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight less than or equal to (\<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.	Varenicline Low Dose n=100 Participants Participants received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight \<= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.	Placebo n=99 Participants Participants received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.
Number of Participants With Treatment Emergent Treatment-Related Adverse Events (AEs)	46 Participants	28 Participants	27 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: First dose up to last dose (up-to Week 12) plus 30 days

Population: The safety analysis set included all participants who took at least one dose of randomized study medication, including partial doses.

An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. SAE: AE causing: death; initial/prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent/significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Solicited AEs collected by semi-structured NAEI inquiring about AEs: depression, anxiety, delusions, hallucinations, paranoia, psychosis, mania, panic, agitation, dissociative states, feeling abnormal, hostility, aggression and homicidal ideation. If a participant had a positive response to any item on the NAEI, investigator determined if it met criteria AE criteria.

Outcome measures

Outcome measures
Measure	Varenicline High Dose n=108 Participants Participants received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight less than or equal to (\<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.	Varenicline Low Dose n=100 Participants Participants received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight \<= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.	Placebo n=99 Participants Participants received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.
Number of Participants With Treatment-Emergent Neuropsychiatric Adverse Event Elicited by Neuropsychiatric Adverse Event Interview (NAEI) Neuropsychiatric AEs	18 Participants	11 Participants	12 Participants
Number of Participants With Treatment-Emergent Neuropsychiatric Adverse Event Elicited by Neuropsychiatric Adverse Event Interview (NAEI) Neuropsychiatric SAEs	0 Participants	0 Participants	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Screening, Baseline, Week 1 up to Week 12 (treatment-emergent [TE]), thereafter up to Week 52 (last follow-up [FU])

Population: The safety analysis set included all participants who took at least one dose of randomized study medication, including partial doses.

The C-SSRS (mapped to Columbia Classification Algorithm of Suicide Assessment (C-CASA) categories);was an interview-based instrument to systematically assess suicidal ideation and suicidal behavior.C-SSRS assessed whether participant experienced any of the following:completed suicide;suicide attempt(response of "Yes" on "actual attempt");preparatory acts toward imminent suicidal behavior ("Yes" on "preparatory acts or behavior","aborted attempt" or "interrupted attempt"),suicidal ideation ("Yes" on "wish to be dead","non-specific active suicidal thoughts","active suicidal ideation with methods without intent to act or some intent to act,without specific plan or with specific plan and intent,any self-injurious behavior with no suicidal intent ("Yes" on "Has participant engaged in non-suicidal self-injurious behavior").Here,number of participants with positive response (response of "yes") to suicidal behavior or/and Ideation,any non-suicidal self-injurious behavior were reported.

Outcome measures

Outcome measures
Measure	Varenicline High Dose n=108 Participants Participants received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight less than or equal to (\<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.	Varenicline Low Dose n=100 Participants Participants received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight \<= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.	Placebo n=99 Participants Participants received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.
Number of Participants With Categorical Scores on the Columbia Suicide Severity Rating Scale (C-SSRS) Screening:Suicidal Behavior or/and Ideation	2 Participants	3 Participants	2 Participants
Number of Participants With Categorical Scores on the Columbia Suicide Severity Rating Scale (C-SSRS) Screening:Suicidal Ideation	2 Participants	3 Participants	2 Participants
Number of Participants With Categorical Scores on the Columbia Suicide Severity Rating Scale (C-SSRS) Screening: Wish to be Dead	2 Participants	2 Participants	2 Participants
Number of Participants With Categorical Scores on the Columbia Suicide Severity Rating Scale (C-SSRS) Screening: Non-Specific Active Suicidal Thoughts	1 Participants	1 Participants	2 Participants
Number of Participants With Categorical Scores on the Columbia Suicide Severity Rating Scale (C-SSRS) Screen:Self Injurious Behavior, no Suicidal Intent	3 Participants	3 Participants	2 Participants
Number of Participants With Categorical Scores on the Columbia Suicide Severity Rating Scale (C-SSRS) TE:Suicidal Behavior or/and Ideation	1 Participants	0 Participants	1 Participants
Number of Participants With Categorical Scores on the Columbia Suicide Severity Rating Scale (C-SSRS) TE:Suicidal Ideation	1 Participants	0 Participants	1 Participants
Number of Participants With Categorical Scores on the Columbia Suicide Severity Rating Scale (C-SSRS) TE: Wish to be Dead	1 Participants	0 Participants	1 Participants
Number of Participants With Categorical Scores on the Columbia Suicide Severity Rating Scale (C-SSRS) TE: Non-Specific Active Suicidal Thoughts	0 Participants	0 Participants	1 Participants
Number of Participants With Categorical Scores on the Columbia Suicide Severity Rating Scale (C-SSRS) TE:Self Injurious Behavior, no Suicidal Intent	0 Participants	0 Participants	1 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 20, 28, 36, 44, and 52

Population: The safety analysis set included all participants who took at least one dose of randomized study medication, including partial doses. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints.

The HADS is a self-administered questionnaire measuring anxiety. Hospital Anxiety and Depression Scale Anxiety subscale (HADS-A) consisted of 7 items that were assessed on a scale of 0 = no anxiety to 3 = severe feeling of anxiety. Total HADS-A subscale score range from 0 = no anxiety to 21 = severe anxiety; higher scores indicated more severe anxiety.

Outcome measures

Outcome measures
Measure	Varenicline High Dose n=108 Participants Participants received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight less than or equal to (\<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.	Varenicline Low Dose n=100 Participants Participants received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight \<= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.	Placebo n=99 Participants Participants received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Baseline	2.4 units on a scale Standard Deviation 2.05	1.9 units on a scale Standard Deviation 2.06	2.3 units on a scale Standard Deviation 2.26
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 1	-0.6 units on a scale Standard Deviation 1.86	-0.5 units on a scale Standard Deviation 1.53	-0.3 units on a scale Standard Deviation 1.91
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 2	-1.1 units on a scale Standard Deviation 1.95	-0.7 units on a scale Standard Deviation 1.90	-0.5 units on a scale Standard Deviation 2.18
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 3	-1.2 units on a scale Standard Deviation 1.85	-0.8 units on a scale Standard Deviation 1.96	-1.0 units on a scale Standard Deviation 2.09
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 4	-1.5 units on a scale Standard Deviation 1.83	-0.9 units on a scale Standard Deviation 2.31	-0.9 units on a scale Standard Deviation 2.21
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 5	-1.3 units on a scale Standard Deviation 2.03	-1.0 units on a scale Standard Deviation 2.12	-1.2 units on a scale Standard Deviation 2.19
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 6	-1.5 units on a scale Standard Deviation 1.91	-1.0 units on a scale Standard Deviation 2.25	-1.2 units on a scale Standard Deviation 2.31
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 7	-1.6 units on a scale Standard Deviation 2.13	-1.1 units on a scale Standard Deviation 2.41	-1.2 units on a scale Standard Deviation 2.39
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 8	-1.5 units on a scale Standard Deviation 2.11	-1.1 units on a scale Standard Deviation 2.20	-1.3 units on a scale Standard Deviation 1.99
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 9	-1.4 units on a scale Standard Deviation 2.17	-1.2 units on a scale Standard Deviation 2.35	-1.1 units on a scale Standard Deviation 2.13
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 10	-1.4 units on a scale Standard Deviation 2.07	-1.2 units on a scale Standard Deviation 2.44	-1.1 units on a scale Standard Deviation 2.34
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 11	-1.4 units on a scale Standard Deviation 2.00	-1.2 units on a scale Standard Deviation 2.23	-1.3 units on a scale Standard Deviation 2.12
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 12	-1.4 units on a scale Standard Deviation 2.07	-1.3 units on a scale Standard Deviation 2.31	-1.2 units on a scale Standard Deviation 2.15
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 13	-1.5 units on a scale Standard Deviation 2.13	-1.2 units on a scale Standard Deviation 2.17	-1.2 units on a scale Standard Deviation 2.33
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 14	-1.4 units on a scale Standard Deviation 2.33	-1.2 units on a scale Standard Deviation 2.53	-1.2 units on a scale Standard Deviation 2.19
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 15	-1.7 units on a scale Standard Deviation 2.09	-1.3 units on a scale Standard Deviation 2.43	-1.0 units on a scale Standard Deviation 3.35
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 16	-1.6 units on a scale Standard Deviation 2.16	-1.2 units on a scale Standard Deviation 2.44	-1.1 units on a scale Standard Deviation 2.54
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 20	-1.5 units on a scale Standard Deviation 2.28	-1.2 units on a scale Standard Deviation 2.31	-1.3 units on a scale Standard Deviation 2.21
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 28	-1.5 units on a scale Standard Deviation 2.54	-1.2 units on a scale Standard Deviation 2.46	-1.2 units on a scale Standard Deviation 2.38
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 36	-1.4 units on a scale Standard Deviation 2.42	-1.2 units on a scale Standard Deviation 2.51	-1.3 units on a scale Standard Deviation 2.03
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 44	-1.8 units on a scale Standard Deviation 2.21	-1.2 units on a scale Standard Deviation 2.34	-1.0 units on a scale Standard Deviation 1.90
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) - Anxiety (HADS-A) Total Scores at Specified Time-points Change at Week 52	-1.6 units on a scale Standard Deviation 2.20	-1.1 units on a scale Standard Deviation 2.39	-1.5 units on a scale Standard Deviation 2.06

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 20, 28, 36, 44, and 52

Hospital Anxiety and Depression Scale Depression subscale (HADS-D) consists of 7 items that were assessed on a scale of 0 = no depression to 3 = severe feeling of depression. Total HADS-D subscale score range from 0 = no depression to 21 = severe feeling of depression; higher scores indicated a greater intensity of depression.

Outcome measures

Outcome measures
Measure	Varenicline High Dose n=108 Participants Participants received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight less than or equal to (\<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.	Varenicline Low Dose n=100 Participants Participants received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight \<= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.	Placebo n=99 Participants Participants received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Baseline	1.5 units on a scale Standard Deviation 1.93	1.4 units on a scale Standard Deviation 1.79	1.4 units on a scale Standard Deviation 1.83
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 1	-0.4 units on a scale Standard Deviation 1.43	-0.2 units on a scale Standard Deviation 1.18	0.1 units on a scale Standard Deviation 1.61
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 2	-0.5 units on a scale Standard Deviation 1.57	-0.2 units on a scale Standard Deviation 1.65	-0.1 units on a scale Standard Deviation 1.80
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 3	-0.5 units on a scale Standard Deviation 1.39	-0.3 units on a scale Standard Deviation 1.55	-0.3 units on a scale Standard Deviation 1.79
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 4	-0.7 units on a scale Standard Deviation 1.39	-0.3 units on a scale Standard Deviation 1.79	-0.4 units on a scale Standard Deviation 2.00
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 5	-0.6 units on a scale Standard Deviation 1.66	-0.3 units on a scale Standard Deviation 1.97	-0.3 units on a scale Standard Deviation 1.88
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 6	-0.6 units on a scale Standard Deviation 1.85	-0.4 units on a scale Standard Deviation 1.60	-0.5 units on a scale Standard Deviation 1.83
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 7	-0.7 units on a scale Standard Deviation 1.52	-0.5 units on a scale Standard Deviation 1.91	-0.4 units on a scale Standard Deviation 2.13
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 8	-0.8 units on a scale Standard Deviation 1.87	-0.5 units on a scale Standard Deviation 1.80	-0.5 units on a scale Standard Deviation 1.80
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 9	-0.8 units on a scale Standard Deviation 1.63	-0.5 units on a scale Standard Deviation 1.85	-0.5 units on a scale Standard Deviation 2.30
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 10	-0.9 units on a scale Standard Deviation 1.67	-0.7 units on a scale Standard Deviation 1.63	-0.4 units on a scale Standard Deviation 2.77
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 11	-0.7 units on a scale Standard Deviation 1.53	-0.9 units on a scale Standard Deviation 1.66	-0.5 units on a scale Standard Deviation 2.11
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 12	-0.7 units on a scale Standard Deviation 1.79	-0.7 units on a scale Standard Deviation 1.72	-0.6 units on a scale Standard Deviation 2.11
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 13	-0.6 units on a scale Standard Deviation 2.16	-0.7 units on a scale Standard Deviation 1.79	-0.7 units on a scale Standard Deviation 1.95
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 14	-0.8 units on a scale Standard Deviation 1.96	-0.6 units on a scale Standard Deviation 1.84	-0.5 units on a scale Standard Deviation 2.22
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 15	-0.8 units on a scale Standard Deviation 1.83	-0.8 units on a scale Standard Deviation 1.84	-0.3 units on a scale Standard Deviation 3.26
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 16	-0.6 units on a scale Standard Deviation 2.09	-0.6 units on a scale Standard Deviation 2.08	-0.2 units on a scale Standard Deviation 2.79
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 20	-0.8 units on a scale Standard Deviation 1.71	-0.8 units on a scale Standard Deviation 1.84	-0.6 units on a scale Standard Deviation 2.24
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 28	-0.9 units on a scale Standard Deviation 1.63	-0.8 units on a scale Standard Deviation 1.90	-0.5 units on a scale Standard Deviation 2.40
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 36	-0.7 units on a scale Standard Deviation 2.19	-0.8 units on a scale Standard Deviation 1.77	-0.4 units on a scale Standard Deviation 2.40
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 44	-0.9 units on a scale Standard Deviation 1.93	-0.9 units on a scale Standard Deviation 1.78	-0.3 units on a scale Standard Deviation 2.44
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Scores - Depression Total Score at Specified Time-Points Change at Week 52	-0.7 units on a scale Standard Deviation 1.81	-0.8 units on a scale Standard Deviation 1.67	-0.6 units on a scale Standard Deviation 2.02

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline up to Week 12

Population: The safety analysis set included all participants who took at least one dose of randomized study medication, including partial doses. Here, 'Number of Participants Analyzed= participants evaluable for this outcome measure.

Criteria for laboratory abnormalities: Lymphocytes Absolute (Abs), Lymphocytes percentage (%), Total Neutrophils (Abs), Neutrophils %: \<0.8\*LLN or \>1.2\*ULN; Basophils (Abs), Basophils %Eosinophils (Abs), Eosinophils %, Monocytes (Abs), Monocytes %:\> 1.2\*ULN; Total Bilirubin milligram per deciliter (mg/dl) \>1.5\*ULN; alanine aminotransferase: \>3.0\*ULN; Blood urea nitrogen, Creatinine: \>1.3\*ULN; Uric acid :\> 1.2\*ULN.

Outcome measures

Outcome measures
Measure	Varenicline High Dose n=103 Participants Participants received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight less than or equal to (\<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.	Varenicline Low Dose n=93 Participants Participants received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight \<= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.	Placebo n=90 Participants Participants received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.
Number of Participants With Laboratory Abnormalities	35 Participants	33 Participants	26 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Week 12

Population: The safety analysis set included all participants who took at least one dose of randomized study medication, including partial doses. Here, 'Number of participants analyzed' signifies participants evaluable for this outcome measure.

Measurement of BP included supine and sitting systolic BP, standing systolic BP, supine and sitting diastolic BP and standing diastolic BP. Blood pressure was taken after participants rested in a sitting position for 5 minutes. BP was recorded after participants had been supine for approximately 5 minutes, and then orthostatic blood pressure was recorded immediately when the participant stood.

Outcome measures

Outcome measures
Measure	Varenicline High Dose n=77 Participants Participants received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight less than or equal to (\<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.	Varenicline Low Dose n=77 Participants Participants received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight \<= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.	Placebo n=59 Participants Participants received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.
Change From Baseline in Blood Pressure (BP) at Week 12 Standing Diastolic BP:Change at Week 12	0.0 millimeters of mercury (mmHg) Interval -28.0 to 22.0	-1.0 millimeters of mercury (mmHg) Interval -43.0 to 23.0	2.0 millimeters of mercury (mmHg) Interval -21.0 to 20.0
Change From Baseline in Blood Pressure (BP) at Week 12 Supine Systolic BP:Baseline	115.0 millimeters of mercury (mmHg) Interval 85.0 to 164.0	114.0 millimeters of mercury (mmHg) Interval 92.0 to 136.0	109.0 millimeters of mercury (mmHg) Interval 95.0 to 142.0
Change From Baseline in Blood Pressure (BP) at Week 12 Supine Systolic BP:Change at Week 12	0.0 millimeters of mercury (mmHg) Interval -33.0 to 25.0	0.0 millimeters of mercury (mmHg) Interval -32.0 to 31.0	0.0 millimeters of mercury (mmHg) Interval -35.0 to 43.0
Change From Baseline in Blood Pressure (BP) at Week 12 Sitting Systolic BP:Baseline	117.0 millimeters of mercury (mmHg) Interval 90.0 to 148.0	115.0 millimeters of mercury (mmHg) Interval 95.0 to 139.0	113.0 millimeters of mercury (mmHg) Interval 95.0 to 135.0
Change From Baseline in Blood Pressure (BP) at Week 12 Sitting Systolic BP:Change at Week 12	-1.0 millimeters of mercury (mmHg) Interval -24.0 to 31.0	0.0 millimeters of mercury (mmHg) Interval -30.0 to 28.0	2.0 millimeters of mercury (mmHg) Interval -28.0 to 28.0
Change From Baseline in Blood Pressure (BP) at Week 12 Standing Systolic BP:Baseline	116.0 millimeters of mercury (mmHg) Interval 88.0 to 157.0	115.0 millimeters of mercury (mmHg) Interval 92.0 to 155.0	112.0 millimeters of mercury (mmHg) Interval 90.0 to 136.0
Change From Baseline in Blood Pressure (BP) at Week 12 Standing Systolic BP:Change at Week 12	0.0 millimeters of mercury (mmHg) Interval -30.0 to 40.0	0.0 millimeters of mercury (mmHg) Interval -21.0 to 53.0	3.0 millimeters of mercury (mmHg) Interval -18.0 to 47.0
Change From Baseline in Blood Pressure (BP) at Week 12 Supine Diastolic BP:Baseline	69.0 millimeters of mercury (mmHg) Interval 45.0 to 99.0	66.0 millimeters of mercury (mmHg) Interval 45.0 to 84.0	65.0 millimeters of mercury (mmHg) Interval 50.0 to 90.0
Change From Baseline in Blood Pressure (BP) at Week 12 Supine Diastolic BP:Change at Week 12	0.0 millimeters of mercury (mmHg) Interval -26.0 to 17.0	0.0 millimeters of mercury (mmHg) Interval -20.0 to 22.0	0.0 millimeters of mercury (mmHg) Interval -35.0 to 21.0
Change From Baseline in Blood Pressure (BP) at Week 12 Sitting Diastolic BP:Baseline	72.0 millimeters of mercury (mmHg) Interval 50.0 to 94.0	70.0 millimeters of mercury (mmHg) Interval 38.0 to 92.0	69.0 millimeters of mercury (mmHg) Interval 47.0 to 87.0
Change From Baseline in Blood Pressure (BP) at Week 12 Sitting Diastolic BP:Change at Week 12	0.0 millimeters of mercury (mmHg) Interval -20.0 to 28.0	-1.0 millimeters of mercury (mmHg) Interval -35.0 to 23.0	1.0 millimeters of mercury (mmHg) Interval -18.0 to 22.0
Change From Baseline in Blood Pressure (BP) at Week 12 Standing Diastolic BP:Baseline	73.0 millimeters of mercury (mmHg) Interval 57.0 to 106.0	72.0 millimeters of mercury (mmHg) Interval 55.0 to 99.0	70.0 millimeters of mercury (mmHg) Interval 50.0 to 92.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Week 12

Measurement of pulse rate included supine, sitting and standing pulse rate. Pulse rate was taken after participants rested in a sitting position for 5 minutes. Pulse rate was recorded after participants had been supine for approximately 5 minutes and then immediately upon standing.

Outcome measures

Outcome measures
Measure	Varenicline High Dose n=77 Participants Participants received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight less than or equal to (\<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.	Varenicline Low Dose n=77 Participants Participants received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight \<= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.	Placebo n=59 Participants Participants received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.
Change From Baseline in Pulse Rate at Week 12 Supine Pulse Rate:Baseline	75.0 beats per minute (bpm) Interval 50.0 to 111.0	72.0 beats per minute (bpm) Interval 50.0 to 105.0	72.0 beats per minute (bpm) Interval 54.0 to 113.0
Change From Baseline in Pulse Rate at Week 12 Supine Pulse Rate:Change at Week 12	0.0 beats per minute (bpm) Interval -32.0 to 44.0	1.0 beats per minute (bpm) Interval -23.0 to 23.0	3.0 beats per minute (bpm) Interval -30.0 to 29.0
Change From Baseline in Pulse Rate at Week 12 Sitting Pulse Rate:Baseline	75.0 beats per minute (bpm) Interval 58.0 to 118.0	75.0 beats per minute (bpm) Interval 48.0 to 113.0	77.0 beats per minute (bpm) Interval 58.0 to 115.0
Change From Baseline in Pulse Rate at Week 12 Sitting Pulse Rate:Change at Week 12	-1.0 beats per minute (bpm) Interval -22.0 to 25.0	0.0 beats per minute (bpm) Interval -33.0 to 30.0	1.0 beats per minute (bpm) Interval -43.0 to 36.0
Change From Baseline in Pulse Rate at Week 12 Standing Pulse Rate:Baseline	84.0 beats per minute (bpm) Interval 61.0 to 139.0	85.0 beats per minute (bpm) Interval 61.0 to 119.0	85.0 beats per minute (bpm) Interval 63.0 to 122.0
Change From Baseline in Pulse Rate at Week 12 Standing Pulse Rate:Change at Week 12	1.0 beats per minute (bpm) Interval -35.0 to 44.0	-3.0 beats per minute (bpm) Interval -25.0 to 32.0	-3.0 beats per minute (bpm) Interval -53.0 to 44.0

Adverse Events

Varenicline High Dose

Serious events: 3 serious events

Other events: 65 other events

Deaths: 0 deaths

Varenicline Low Dose

Serious events: 1 serious events

Other events: 53 other events

Deaths: 0 deaths

Placebo

Serious events: 1 serious events

Other events: 51 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Varenicline High Dose n=108 participants at risk Participants received 2 tablets of Varenicline 0.5 milligram (mg) (total dose 1 mg) orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight less than or equal to (\<=) 55 kilograms (kg) had Varenicline dose reduced by half, and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration.	Varenicline Low Dose n=100 participants at risk Participants received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, twice daily from Week 2 to Week 12 after a 2-week titration. Participants with a body weight \<= 55 kg had Varenicline dose reduced by half and received one tablet of Varenicline 0.5 mg and one matching placebo tablet orally, in the morning and 2 tablets of matching placebo orally, in the evening from Week 2 to Week 12 after a 2-week titration.	Placebo n=99 participants at risk Participants received 2 tablets of placebo (matched to Varenicline) orally, twice daily from Week 2 to Week 12 after a 2-week titration.
Hepatobiliary disorders Bile duct stone	0.00% 0/108 • First dose up to last dose (up-to Week 12) plus 30 days Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.	1.0% 1/100 • First dose up to last dose (up-to Week 12) plus 30 days Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.	0.00% 0/99 • First dose up to last dose (up-to Week 12) plus 30 days Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.
Hepatobiliary disorders Cholecystitis acute	0.00% 0/108 • First dose up to last dose (up-to Week 12) plus 30 days Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.	1.0% 1/100 • First dose up to last dose (up-to Week 12) plus 30 days Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.	0.00% 0/99 • First dose up to last dose (up-to Week 12) plus 30 days Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.
Infections and infestations Campylobacter gastroenteritis	0.93% 1/108 • First dose up to last dose (up-to Week 12) plus 30 days Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.	0.00% 0/100 • First dose up to last dose (up-to Week 12) plus 30 days Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.	0.00% 0/99 • First dose up to last dose (up-to Week 12) plus 30 days Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.
Infections and infestations Laryngitis	0.93% 1/108 • First dose up to last dose (up-to Week 12) plus 30 days Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.	0.00% 0/100 • First dose up to last dose (up-to Week 12) plus 30 days Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.	0.00% 0/99 • First dose up to last dose (up-to Week 12) plus 30 days Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.
Infections and infestations Salpingitis	0.00% 0/108 • First dose up to last dose (up-to Week 12) plus 30 days Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.	0.00% 0/100 • First dose up to last dose (up-to Week 12) plus 30 days Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.	1.0% 1/99 • First dose up to last dose (up-to Week 12) plus 30 days Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.
Psychiatric disorders Adjustment disorder with mixed disturbance of emotion and conduct	0.93% 1/108 • First dose up to last dose (up-to Week 12) plus 30 days Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.	0.00% 0/100 • First dose up to last dose (up-to Week 12) plus 30 days Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.	0.00% 0/99 • First dose up to last dose (up-to Week 12) plus 30 days Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.

Other adverse events

Additional Information

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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.
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Restriction type: OTHER