ConNic4: Concurrent Bupropion / Varenicline for Smoking Cessation

• Sponsor: Duke University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01303861
• Collaborator: National Institute on Drug Abuse (NIDA) (NIH), Philip Morris USA, Inc. (Industry)
• Enrollment: 702
• Locations: 4
• Arms: 4
• Duration (Months): 28
• Patients Per Site: 175.5
• Patients Per Site Per Month: 6.3

Study Details

Study Description

Brief Summary

This study focuses on the first step in developing an algorithm for maximizing quit-smoking success based on an adaptive approach, which changes treatment from the initial nicotine replacement therapy (NRT) when that treatment alone may not be sufficient. These NRT "non-responders" are switched (in double-blind fashion) before the quit date to receive either varenicline alone or varenicline paired with bupropion. Some participants who would otherwise have failed at their quit smoking attempt could be "rescued" by switching to alternative pharmacotherapies. The proposed study will evaluate the combination treatment against varenicline alone in an adaptive trial design

Condition or Disease	Intervention/Treatment	Phase
Nicotine Dependence	Drug: Varenicline; Drug: Bupropion; Drug: Nicotine patches; Drug: Nicotine Inhaler	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 702 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Official Title: Concurrent Bupropion / Varenicline for Smoking Cessation
• Study Start Date: Mar 1, 2011
• Actual Primary Completion Date: Mar 1, 2013
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: varenicline This group will consist of smokers who, based on smoking behavior, DO NOT respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will receive varenicline.	Drug: Varenicline; For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive varenicline at a dose of 0.5 mg once per day followed by 0.5 mg twice a day for the remaining 4 days of that week. Subsequently, the dose will be 1 mg twice per day, and will remain at that dose for the remainder of the 12 weeks.; Other Names: Chantix
Active Comparator: Nicotine Patches only This group will consist of smokers who, based on smoking behavior, respond favorably to pre-cessation nicotine patches(assessed at Session P2). They will continue to receive only nicotine patches.	Drug: Nicotine patches; Nicotine Replacement Therapy Groups: For smokers with high baseline carbon monoxide (CO): 42 mg/24 h for 2 weeks before the quit date and 3 weeks after the quit date, 21 mg/24 h for 4 weeks, 14 mg/24 h for 2 weeks, and 7 mg/24 h for 2 weeks; or For smokers with low baseline CO: 21 mg/24 h for 2 weeks before the quit date and 7 weeks after the quit date, 14 mg/24 h for 2 weeks, and 7 mg/ 24 h for 2 weeks. Varenicline and varenicline in combination with bupropion groups: For smokers with high baseline CO: 42 mg/24 h for 1 week For smokers with low baseline CO: 21 mg/24 h for 1 week; Other Names: Nicoderm
Active Comparator: Nicotine Patches with Nicotine Inhaler This group will consist of smokers who, based on smoking behavior, respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will continue to receive nicotine patches and will receive a nicotine inhaler to use as needed after their quit date.	Drug: Nicotine patches; Nicotine Replacement Therapy Groups: For smokers with high baseline carbon monoxide (CO): 42 mg/24 h for 2 weeks before the quit date and 3 weeks after the quit date, 21 mg/24 h for 4 weeks, 14 mg/24 h for 2 weeks, and 7 mg/24 h for 2 weeks; or For smokers with low baseline CO: 21 mg/24 h for 2 weeks before the quit date and 7 weeks after the quit date, 14 mg/24 h for 2 weeks, and 7 mg/ 24 h for 2 weeks. Varenicline and varenicline in combination with bupropion groups: For smokers with high baseline CO: 42 mg/24 h for 1 week For smokers with low baseline CO: 21 mg/24 h for 1 week; Other Names: Nicoderm ; Drug: Nicotine Inhaler; Nicotine inhaler to use as needed after quit date; Other Names: Nicotrol Inhaler
Active Comparator: varenicline with bupropion This group will consist of smokers who, based on smoking behavior, DO NOT respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will receive varenicline in combination with bupropion.	Drug: Varenicline; For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive varenicline at a dose of 0.5 mg once per day followed by 0.5 mg twice a day for the remaining 4 days of that week. Subsequently, the dose will be 1 mg twice per day, and will remain at that dose for the remainder of the 12 weeks.; Other Names: Chantix ; Drug: Bupropion; For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive bupropion at a dose of 150mg once per day. Subsequently, the dose will be 150mg twice per day, and will remain at that dose for the remainder of the 12 weeks.; Other Names: Zyban

Outcome Measures

Primary Outcome Measures

1. Four-week Continuous Abstinence From Cigarette Smoking [Study week 8 thru week 11]

   The primary dependent measures will be continuous four-week abstinence from weeks 8-11 post target quit date, defined as a self-report of no smoking confirmed by expired air carbon monoxide.

Secondary Outcome Measures

1. Seven Day Point Abstinence From Cigarette Smoking [Six months post quit date]

   Secondary outcome will include point abstinence (no smoking in the previous 7-day) at 6 months post-quit.

2. Continuous Cigarette Abstinence From Quit Date [From Quit date to end of treatment (week 11)]

   Secondary outcome will include continuous abstinence from quit date to end of treatment (week 11).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 18-65 years old;

• smoked an average of at least 10 cigarettes per day for three cumulative years;

• have an expired air CO reading assessed at screening of at least 10ppm;

• express a desire to quit smoking within the next 30 days.

Exclusion Criteria:

• Hypertension (systolic >140 mm Hg, diastolic >100 mm Hg, coupled with a history of hypertension); subjects with no previous diagnosis of hypertension may have a screening blood pressure up to 160/100.

• Hypotension with symptoms (systolic <90 mm Hg, diastolic <60 mm Hg).

• Coronary heart disease;

• Lifetime history of heart attack;

• Cardiac rhythm disorder (irregular heart rhythm);

• Chest pains (unless history, exam, and ECG clearly indicate a non-cardiac source);

• Cardiac (heart) disorder (including but not limited to valvular heart disease, heart murmur, heart failure);

• History of skin allergy;

• Active skin disorder (e.g., psoriasis) within the last five years, except minor skin conditions (including but not limited to facial acne, minor localized infections, and superficial minor wounds);

• Liver or kidney disorder (except kidney stones, gallstones);

• Gastrointestinal problems or disease other than gastroesophageal reflux or heartburn;

• Active ulcers in the past 30 days;

• Currently symptomatic lung disorder/disease (including but not limited to chronic obstructive pulmonary disease (COPD), emphysema, and asthma);

• Brain abnormality (including but not limited to stroke, brain tumor, and seizure disorder);

• Migraine headaches that occur more frequently than once per week;

• Recent, unexplained fainting spells;

• Problems giving blood samples;

• Diabetes treated with insulin; non-insulin treated diabetes (unless glucose is less than 180mg/dcl and HbA1c is less than 7%);

• Current cancer or treatment for cancer in the past six months (except basal or squamous cell skin cancer);

• Other major medical condition;

• Current psychiatric disease (with the exception of anxiety disorders, obsessive compulsive disorder (OCD) and ADHD);

• Suicidal ideation (within the past 10 years) or lifetime occurrence of attempted suicide;

• Current depression;

• Bulimia or anorexia;

• Pregnant or nursing mothers;

• Alcohol abuse;

• Use of Opiate medications for pain or sleep in the past 14 days;

• Significant adverse reaction to nicotine patches, nicotine inhalers, bupropion / Wellbutrin / Zyban or Chantix / Varenicline in the past.

• Use (within the past 30 days) of:

• Illegal drugs (or if the urine drug screen is positive),

• Experimental (investigational) drugs;

• Psychiatric medications including antidepressants, anti-psychotics or any other medications that are known to affect smoking cessation (e.g. clonidine);

• Smokeless tobacco (chewing tobacco, snuff), cigars, pipes or e-cigarettes;

• Wellbutrin, bupropion, Zyban, Chantix, nicotine replacement therapy or any other smoking cessation aid.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke Center for Nicotine and Smoking Cessation Research	Charlotte	North Carolina	United States	28210
2	Duke Center for Nicotine and Smoking Cessation Research	Durham	North Carolina	United States	27705
3	Duke Center for Nicotine and Smoking Cessation Research	Raleigh	North Carolina	United States	27609
4	Duke Center for Nicotine and Smoking Cessation Research	Winston-Salem	North Carolina	United States	27103

Sponsors and Collaborators

• Duke University
• National Institute on Drug Abuse (NIDA)
• Philip Morris USA, Inc.

Investigators

• Principal Investigator: Jed E Rose, Ph.D., Duke University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT01303861
• Other Study ID Numbers: Pro00027351; 1P50DA027840-01A1
• First Posted: Feb 25, 2011
• Last Update Posted: Aug 6, 2014
• Last Verified: May 1, 2014

• Keywords provided by Duke University: Nicotine addiction; Cigarette smoking; Smoking cessation; Zyban; Chantix; Nicotine patches; Nicotrol Inhaler; varenicline; bupropion
• Additional relevant MeSH terms: Tobacco Use Disorder; Bupropion; Nicotine; Varenicline

Study Results

Participant Flow

Recruitment Details	Recruitment began on 3/07/11 and ended on 11/30/12. Of the 702 subjects consented during this period, 218 were in our Charlotte, NC office, 157 were in our Durham, NC office, 151 were in our Raleigh, NC office and 176 were in our Winston-Salem, NC office. Only 349 subjects met all study criteria, and 22 discontinued prior to being assigned.

Arm/Group Title	Varenicline	Nicotine Patches Only	Nicotine Patches With Nicotine Inhaler	Varenicline With Bupropion
Arm/Group Description	This group will consist of smokers who, based on smoking behavior, Do NOT respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will receive varenicline. Varenicline: For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive varenicline at a dose of 0.5 mg once per day followed by 0.5 mg twice a day for the remaining 4 days of that week. Subsequently, the dose will be 1 mg twice per day, and will remain at that dose for the remainder of the 12 weeks.	This group will consist of smokers who, based on smoking behavior, respond favorably to pre-cessation nicotine patches(assessed at Session P2). They will continue to receive only nicotine patches. Nicotine patches: Nicotine Replacement Therapy Groups: For smokers with high baseline CO: 42 mg/24 h for 2 weeks before the quit date and 3 weeks after the quit date, 21 mg/24 h for 4 weeks, 14 mg/24 h for 2 weeks, and 7 mg/24 h for 2 weeks; or For smokers with low baseline CO: 21 mg/24 h for 2 weeks before the quit date and 7 weeks after the quit date, 14 mg/24 h for 2 weeks, and 7 mg/ 24 h for 2 weeks. Varenicline and varenicline in combination with bupropion groups: For smokers with high baseline CO: 42 mg/24 h for 1 week For smokers with low baseline CO: 21 mg/24 h for 1 week	This group will consist of smokers who, based on smoking behavior, respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will continue to receive nicotine patches and will receive a nicotine inhaler to use as needed after their quit date. Nicotine patches: Nicotine Replacement Therapy Groups: For smokers with high baseline CO: 42 mg/24 h for 2 weeks before the quit date and 3 weeks after the quit date, 21 mg/24 h for 4 weeks, 14 mg/24 h for 2 weeks, and 7 mg/24 h for 2 weeks; or For smokers with low baseline CO: 21 mg/24 h for 2 weeks before the quit date and 7 weeks after the quit date, 14 mg/24 h for 2 weeks, and 7 mg/ 24 h for 2 weeks. Varenicline and varenicline in combination with bupropion groups: For smokers with high baseline CO: 42 mg/24 h for 1 week For smokers with low baseline CO: 21 mg/24 h for 1 week Nicotine Inhaler: Nicotine inhaler to use as needed after quit date	This group will consist of smokers who, based on smoking behavior, DO NOT respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will receive varenicline in combination with bupropion. Varenicline: For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive varenicline at a dose of 0.5 mg once per day followed by 0.5 mg twice a day for the remaining 4 days of that week. Subsequently, the dose will be 1 mg twice per day, and will remain at that dose for the remainder of the 12 weeks. Bupropion: For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive bupropion at a dose of 150mg once per day. Subsequently, the dose will be 150mg twice per day, and will remain at that dose for the remainder of the 12 weeks.
Period Title: Overall Study
STARTED	109	50	55	113
Finished Treatment Phase	71	34	39	72
COMPLETED	51	25	19	54
NOT COMPLETED	58	25	36	59

Baseline Characteristics

Arm/Group Title	Varenicline	Nicotine Patches Only	Nicotine Patches With Nicotine Inhaler	Varenicline With Bupropion	Dropped Prior to Condition Assignment	Total
Arm/Group Description	This group will consist of smokers who, based on smoking behavior, DO NOT respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will receive varenicline. Varenicline: For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive varenicline at a dose of 0.5 mg once per day followed by 0.5 mg twice a day for the remaining 4 days of that week. Subsequently, the dose will be 1 mg twice per day, and will remain at that dose for the remainder of the 12 weeks.	This group will consist of smokers who, based on smoking behavior, respond favorably to pre-cessation nicotine patches(assessed at Session P2). They will continue to receive only nicotine patches. Nicotine patches: Nicotine Replacement Therapy Groups: For smokers with high baseline carbon monoxide (CO): 42 mg/24 h for 2 weeks before the quit date and 3 weeks after the quit date, 21 mg/24 h for 4 weeks, 14 mg/24 h for 2 weeks, and 7 mg/24 h for 2 weeks; or For smokers with low baseline CO: 21 mg/24 h for 2 weeks before the quit date and 7 weeks after the quit date, 14 mg/24 h for 2 weeks, and 7 mg/ 24 h for 2 weeks. Varenicline and varenicline in combination with bupropion groups: For smokers with high baseline CO: 42 mg/24 h for 1 week For smokers with low baseline CO: 21 mg/24 h for 1 week	This group will consist of smokers who, based on smoking behavior, respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will continue to receive nicotine patches and will receive a nicotine inhaler to use as needed after their quit date. Nicotine patches: Nicotine Replacement Therapy Groups: For smokers with high baseline CO: 42 mg/24 h for 2 weeks before the quit date and 3 weeks after the quit date, 21 mg/24 h for 4 weeks, 14 mg/24 h for 2 weeks, and 7 mg/24 h for 2 weeks; or For smokers with low baseline CO: 21 mg/24 h for 2 weeks before the quit date and 7 weeks after the quit date, 14 mg/24 h for 2 weeks, and 7 mg/ 24 h for 2 weeks. Varenicline and varenicline in combination with bupropion groups: For smokers with high baseline CO: 42 mg/24 h for 1 week For smokers with low baseline CO: 21 mg/24 h for 1 week Nicotine Inhaler: Nicotine inhaler to use as needed after quit date	This group will consist of smokers who, based on smoking behavior, DO NOT respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will receive varenicline in combination with bupropion. Varenicline: For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive varenicline at a dose of 0.5 mg once per day followed by 0.5 mg twice a day for the remaining 4 days of that week. Subsequently, the dose will be 1 mg twice per day, and will remain at that dose for the remainder of the 12 weeks. Bupropion: For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive bupropion at a dose of 150mg once per day. Subsequently, the dose will be 150mg twice per day, and will remain at that dose for the remainder of the 12 weeks.	These subjects discontinued study participation prior to being assigned to a condition.	Total of all reporting groups
Overall Participants	109	50	55	113	22	349
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	109 100%	49 98%	54 98.2%	113 100%	22 100%	347 99.4%
>=65 years	0 0%	1 2%	1 1.8%	0 0%	0 0%	2 0.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.58 (11.39)	45.20 (10.56)	42.09 (12.22)	44.22 (10.47)	44.77 (11.28)	44.42 (11.20)
Sex: Female, Male (Count of Participants)
Female	63 57.8%	30 60%	34 61.8%	58 51.3%	10 45.5%	195 55.9%
Male	46 42.2%	20 40%	21 38.2%	55 48.7%	12 54.5%	154 44.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 3.7%	1 2%	1 1.8%	2 1.8%	1 4.5%	9 2.6%
Not Hispanic or Latino	105 96.3%	49 98%	54 98.2%	111 98.2%	21 95.5%	340 97.4%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	1 1.8%	0 0%	0 0%	1 0.3%
Asian	2 1.8%	0 0%	0 0%	0 0%	0 0%	2 0.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	1 1.8%	0 0%	0 0%	1 0.3%
Black or African American	32 29.4%	20 40%	19 34.5%	41 36.3%	9 40.9%	121 34.7%
White	71 65.1%	29 58%	31 56.4%	68 60.2%	11 50%	210 60.2%
More than one race	1 0.9%	1 2%	3 5.5%	3 2.7%	2 9.1%	10 2.9%
Unknown or Not Reported	3 2.8%	0 0%	0 0%	1 0.9%	0 0%	4 1.1%
Region of Enrollment (participants) [Number]
United States	109 100%	50 100%	55 100%	113 100%	22 100%	349 100%

Outcome Measures

1. Primary Outcome

Title	Four-week Continuous Abstinence From Cigarette Smoking
Description	The primary dependent measures will be continuous four-week abstinence from weeks 8-11 post target quit date, defined as a self-report of no smoking confirmed by expired air carbon monoxide.
Time Frame	Study week 8 thru week 11

Outcome Measure Data

Analysis Population Description

1 subject from varenicline group excluded from analysis due to pregnancy. 1 subject from Nicotine Patches only group excluded due to meeting an exclusion criteria.

Arm/Group Title	Varenicline	Nicotine Patches Only	Nicotine Patches With Nicotine Inhaler	Varenicline With Bupropion
Arm/Group Description	This group will consist of smokers who, based on smoking behavior, DO NOT respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will receive varenicline. Varenicline: For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive varenicline at a dose of 0.5 mg once per day followed by 0.5 mg twice a day for the remaining 4 days of that week. Subsequently, the dose will be 1 mg twice per day, and will remain at that dose for the remainder of the 12 weeks.	This group will consist of smokers who, based on smoking behavior, respond favorably to pre-cessation nicotine patches(assessed at Session P2). They will continue to receive only nicotine patches. Nicotine patches: Nicotine Replacement Therapy Groups: For smokers with high baseline CO: 42 mg/24 h for 2 weeks before the quit date and 3 weeks after the quit date, 21 mg/24 h for 4 weeks, 14 mg/24 h for 2 weeks, and 7 mg/24 h for 2 weeks; or For smokers with low baseline CO: 21 mg/24 h for 2 weeks before the quit date and 7 weeks after the quit date, 14 mg/24 h for 2 weeks, and 7 mg/ 24 h for 2 weeks. Varenicline and varenicline in combination with bupropion groups: For smokers with high baseline CO: 42 mg/24 h for 1 week For smokers with low baseline CO: 21 mg/24 h for 1 week	This group will consist of smokers who, based on smoking behavior, respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will continue to receive nicotine patches and will receive a nicotine inhaler to use as needed after their quit date. Nicotine patches: Nicotine Replacement Therapy Groups: For smokers with high baseline CO: 42 mg/24 h for 2 weeks before the quit date and 3 weeks after the quit date, 21 mg/24 h for 4 weeks, 14 mg/24 h for 2 weeks, and 7 mg/24 h for 2 weeks; or For smokers with low baseline CO: 21 mg/24 h for 2 weeks before the quit date and 7 weeks after the quit date, 14 mg/24 h for 2 weeks, and 7 mg/ 24 h for 2 weeks. Varenicline and varenicline in combination with bupropion groups: For smokers with high baseline CO: 42 mg/24 h for 1 week For smokers with low baseline CO: 21 mg/24 h for 1 week Nicotine Inhaler: Nicotine inhaler to use as needed after quit date	This group will consist of smokers who, based on smoking behavior, DO NOT respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will receive varenicline in combination with bupropion. Varenicline: For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive varenicline at a dose of 0.5 mg once per day followed by 0.5 mg twice a day for the remaining 4 days of that week. Subsequently, the dose will be 1 mg twice per day, and will remain at that dose for the remainder of the 12 weeks. Bupropion: For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive bupropion at a dose of 150mg once per day. Subsequently, the dose will be 150mg twice per day, and will remain at that dose for the remainder of the 12 weeks.
Measure Participants	108	49	55	113
Number (95% Confidence Interval) [percentage of participants]	25.93 23.8%	46.94 93.9%	43.64 79.3%	39.82 35.2%

2. Secondary Outcome

Title	Seven Day Point Abstinence From Cigarette Smoking
Description	Secondary outcome will include point abstinence (no smoking in the previous 7-day) at 6 months post-quit.
Time Frame	Six months post quit date

Outcome Measure Data

Analysis Population Description

1 subject from varenicline group excluded from analysis due to pregnancy. 1 subject from Nicotine Patches only group excluded due to meeting an exclusion criteria.

Arm/Group Title	Varenicline	Nicotine Patches Only	Nicotine Patches With Nicotine Inhaler	Varenicline With Bupropion
Arm/Group Description	This group will consist of smokers who, based on smoking behavior, DO NOT respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will receive varenicline. Varenicline: For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive varenicline at a dose of 0.5 mg once per day followed by 0.5 mg twice a day for the remaining 4 days of that week. Subsequently, the dose will be 1 mg twice per day, and will remain at that dose for the remainder of the 12 weeks.	This group will consist of smokers who, based on smoking behavior, respond favorably to pre-cessation nicotine patches(assessed at Session P2). They will continue to receive only nicotine patches. Nicotine patches: Nicotine Replacement Therapy Groups: For smokers with high baseline CO: 42 mg/24 h for 2 weeks before the quit date and 3 weeks after the quit date, 21 mg/24 h for 4 weeks, 14 mg/24 h for 2 weeks, and 7 mg/24 h for 2 weeks; or For smokers with low baseline CO: 21 mg/24 h for 2 weeks before the quit date and 7 weeks after the quit date, 14 mg/24 h for 2 weeks, and 7 mg/ 24 h for 2 weeks. Varenicline and varenicline in combination with bupropion groups: For smokers with high baseline CO: 42 mg/24 h for 1 week For smokers with low baseline CO: 21 mg/24 h for 1 week	This group will consist of smokers who, based on smoking behavior, respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will continue to receive nicotine patches and will receive a nicotine inhaler to use as needed after their quit date. Nicotine patches: Nicotine Replacement Therapy Groups: For smokers with high baseline CO: 42 mg/24 h for 2 weeks before the quit date and 3 weeks after the quit date, 21 mg/24 h for 4 weeks, 14 mg/24 h for 2 weeks, and 7 mg/24 h for 2 weeks; or For smokers with low baseline CO: 21 mg/24 h for 2 weeks before the quit date and 7 weeks after the quit date, 14 mg/24 h for 2 weeks, and 7 mg/ 24 h for 2 weeks. Varenicline and varenicline in combination with bupropion groups: For smokers with high baseline CO: 42 mg/24 h for 1 week For smokers with low baseline CO: 21 mg/24 h for 1 week Nicotine Inhaler: Nicotine inhaler to use as needed after quit date	This group will consist of smokers who, based on smoking behavior, DO NOT respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will receive varenicline in combination with bupropion. Varenicline: For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive varenicline at a dose of 0.5 mg once per day followed by 0.5 mg twice a day for the remaining 4 days of that week. Subsequently, the dose will be 1 mg twice per day, and will remain at that dose for the remainder of the 12 weeks. Bupropion: For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive bupropion at a dose of 150mg once per day. Subsequently, the dose will be 150mg twice per day, and will remain at that dose for the remainder of the 12 weeks.
Measure Participants	108	49	55	113
Number (95% Confidence Interval) [participants]	18 16.5%	12 24%	6 10.9%	29 25.7%

3. Secondary Outcome

Title	Continuous Cigarette Abstinence From Quit Date
Description	Secondary outcome will include continuous abstinence from quit date to end of treatment (week 11).
Time Frame	From Quit date to end of treatment (week 11)

Outcome Measure Data

Analysis Population Description

1 subject from varenicline group excluded from analysis due to pregnancy. 1 subject from Nicotine Patches only group excluded due to meeting an exclusion criteria.

Arm/Group Title	Varenicline	Nicotine Patches Only	Nicotine Patches With Nicotine Inhaler	Varenicline With Bupropion
Arm/Group Description	This group will consist of smokers who, based on smoking behavior, DO NOT respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will receive varenicline. Varenicline: For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive varenicline at a dose of 0.5 mg once per day followed by 0.5 mg twice a day for the remaining 4 days of that week. Subsequently, the dose will be 1 mg twice per day, and will remain at that dose for the remainder of the 12 weeks.	This group will consist of smokers who, based on smoking behavior, respond favorably to pre-cessation nicotine patches(assessed at Session P2). They will continue to receive only nicotine patches. Nicotine patches: Nicotine Replacement Therapy Groups: For smokers with high baseline CO: 42 mg/24 h for 2 weeks before the quit date and 3 weeks after the quit date, 21 mg/24 h for 4 weeks, 14 mg/24 h for 2 weeks, and 7 mg/24 h for 2 weeks; or For smokers with low baseline CO: 21 mg/24 h for 2 weeks before the quit date and 7 weeks after the quit date, 14 mg/24 h for 2 weeks, and 7 mg/ 24 h for 2 weeks. Varenicline and varenicline in combination with bupropion groups: For smokers with high baseline CO: 42 mg/24 h for 1 week For smokers with low baseline CO: 21 mg/24 h for 1 week	This group will consist of smokers who, based on smoking behavior, respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will continue to receive nicotine patches and will receive a nicotine inhaler to use as needed after their quit date. Nicotine patches: Nicotine Replacement Therapy Groups: For smokers with high baseline CO: 42 mg/24 h for 2 weeks before the quit date and 3 weeks after the quit date, 21 mg/24 h for 4 weeks, 14 mg/24 h for 2 weeks, and 7 mg/24 h for 2 weeks; or For smokers with low baseline CO: 21 mg/24 h for 2 weeks before the quit date and 7 weeks after the quit date, 14 mg/24 h for 2 weeks, and 7 mg/ 24 h for 2 weeks. Varenicline and varenicline in combination with bupropion groups: For smokers with high baseline CO: 42 mg/24 h for 1 week For smokers with low baseline CO: 21 mg/24 h for 1 week Nicotine Inhaler: Nicotine inhaler to use as needed after quit date	This group will consist of smokers who, based on smoking behavior, DO NOT respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will receive varenicline in combination with bupropion. Varenicline: For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive varenicline at a dose of 0.5 mg once per day followed by 0.5 mg twice a day for the remaining 4 days of that week. Subsequently, the dose will be 1 mg twice per day, and will remain at that dose for the remainder of the 12 weeks. Bupropion: For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive bupropion at a dose of 150mg once per day. Subsequently, the dose will be 150mg twice per day, and will remain at that dose for the remainder of the 12 weeks.
Measure Participants	108	49	55	113
Number (95% Confidence Interval) [participants]	9 8.3%	13 26%	15 27.3%	17 15%

Adverse Events

Time Frame	Subjects were receiving study drugs for 13 weeks. At each study session during this period subjects completed a questionnaire about side effects. Subjects were also told to contact us between study sessions if side effects were bothersome.
Adverse Event Reporting Description	Twenty-two subjects discontinued study participation prior to being assigned a condition; therefore, no side effects data were collected.
Arm/Group Title	Varenicline		Nicotine Patches Only		Nicotine Patches With Nicotine Inhaler		Varenicline With Bupropion		Dropped Prior to Condition Assignment
Arm/Group Description	This group will consist of smokers who, based on smoking behavior, DO NOT respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will receive varenicline. Varenicline: For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive varenicline at a dose of 0.5 mg once per day followed by 0.5 mg twice a day for the remaining 4 days of that week. Subsequently, the dose will be 1 mg twice per day, and will remain at that dose for the remainder of the 12 weeks.		This group will consist of smokers who, based on smoking behavior, respond favorably to pre-cessation nicotine patches(assessed at Session P2). They will continue to receive only nicotine patches. Nicotine patches: Nicotine Replacement Therapy Groups: For smokers with high baseline CO: 42 mg/24 h for 2 weeks before the quit date and 3 weeks after the quit date, 21 mg/24 h for 4 weeks, 14 mg/24 h for 2 weeks, and 7 mg/24 h for 2 weeks; or For smokers with low baseline CO: 21 mg/24 h for 2 weeks before the quit date and 7 weeks after the quit date, 14 mg/24 h for 2 weeks, and 7 mg/ 24 h for 2 weeks. Varenicline and varenicline in combination with bupropion groups: For smokers with high baseline CO: 42 mg/24 h for 1 week For smokers with low baseline CO: 21 mg/24 h for 1 week		This group will consist of smokers who, based on smoking behavior, respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will continue to receive nicotine patches and will receive a nicotine inhaler to use as needed after their quit date. Nicotine patches: Nicotine Replacement Therapy Groups: For smokers with high baseline CO: 42 mg/24 h for 2 weeks before the quit date and 3 weeks after the quit date, 21 mg/24 h for 4 weeks, 14 mg/24 h for 2 weeks, and 7 mg/24 h for 2 weeks; or For smokers with low baseline CO: 21 mg/24 h for 2 weeks before the quit date and 7 weeks after the quit date, 14 mg/24 h for 2 weeks, and 7 mg/ 24 h for 2 weeks. Varenicline and varenicline in combination with bupropion groups: For smokers with high baseline CO: 42 mg/24 h for 1 week For smokers with low baseline CO: 21 mg/24 h for 1 week Nicotine Inhaler: Nicotine inhaler to use as needed after quit date		This group will consist of smokers who, based on smoking behavior, DO NOT respond favorably to pre-cessation nicotine patches (assessed at Session P2). They will receive varenicline in combination with bupropion. Varenicline: For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive varenicline at a dose of 0.5 mg once per day followed by 0.5 mg twice a day for the remaining 4 days of that week. Subsequently, the dose will be 1 mg twice per day, and will remain at that dose for the remainder of the 12 weeks. Bupropion: For the first 3 days after being switched from nicotine patches (occurring at one week before the target quit date), smokers in this group will receive bupropion at a dose of 150mg once per day. Subsequently, the dose will be 150mg twice per day, and will remain at that dose for the remainder of the 12 weeks.		These subjects discontinued study participation prior to being assigned to a condition.
All Cause Mortality
	Varenicline		Nicotine Patches Only		Nicotine Patches With Nicotine Inhaler		Varenicline With Bupropion		Dropped Prior to Condition Assignment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Varenicline		Nicotine Patches Only		Nicotine Patches With Nicotine Inhaler		Varenicline With Bupropion		Dropped Prior to Condition Assignment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/109 (0%)		1/50 (2%)		0/55 (0%)		0/113 (0%)		0/22 (0%)
Cardiac disorders
Tightness in Chest	0/109 (0%)	0	1/50 (2%)	1	0/55 (0%)	0	0/113 (0%)	0	0/22 (0%)	0
Other (Not Including Serious) Adverse Events
	Varenicline		Nicotine Patches Only		Nicotine Patches With Nicotine Inhaler		Varenicline With Bupropion		Dropped Prior to Condition Assignment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	76/109 (69.7%)		33/50 (66%)		38/55 (69.1%)		80/113 (70.8%)		0/22 (0%)
Gastrointestinal disorders
Heartburn	6/109 (5.5%)	9	3/50 (6%)	5	4/55 (7.3%)	4	6/113 (5.3%)	10	0/22 (0%)	0
Nausea	8/109 (7.3%)	10	5/50 (10%)	6	3/55 (5.5%)	4	4/113 (3.5%)	5	0/22 (0%)	0
Constipation	5/109 (4.6%)	9	1/50 (2%)	1	2/55 (3.6%)	2	9/113 (8%)	13	0/22 (0%)	0
General disorders
Change in Taste	7/109 (6.4%)	11	11/50 (22%)	13	10/55 (18.2%)	15	21/113 (18.6%)	34	0/22 (0%)	0
Mouth / Throat Irritation	7/109 (6.4%)	11	4/50 (8%)	4	2/55 (3.6%)	3	3/113 (2.7%)	3	0/22 (0%)	0
Dry Mouth	7/109 (6.4%)	12	6/50 (12%)	8	3/55 (5.5%)	7	15/113 (13.3%)	24	0/22 (0%)	0
Thirst	14/109 (12.8%)	26	6/50 (12%)	13	7/55 (12.7%)	11	18/113 (15.9%)	30	0/22 (0%)	0
Jaw / Neck Pain	4/109 (3.7%)	4	2/50 (4%)	3	3/55 (5.5%)	4	1/113 (0.9%)	1	0/22 (0%)	0
Metabolism and nutrition disorders
Joint / Muscle Pain	9/109 (8.3%)	13	6/50 (12%)	12	3/55 (5.5%)	7	6/113 (5.3%)	8	0/22 (0%)	0
Nervous system disorders
Headache	10/109 (9.2%)	12	5/50 (10%)	5	5/55 (9.1%)	5	9/113 (8%)	11	0/22 (0%)	0
Irritability	13/109 (11.9%)	18	6/50 (12%)	7	5/55 (9.1%)	8	10/113 (8.8%)	15	0/22 (0%)	0
Nightmares	1/109 (0.9%)	1	6/50 (12%)	9	0/55 (0%)	0	3/113 (2.7%)	3	0/22 (0%)	0
Vivid Dreams	13/109 (11.9%)	20	20/50 (40%)	41	12/55 (21.8%)	23	24/113 (21.2%)	56	0/22 (0%)	0
Insomnia	10/109 (9.2%)	15	14/50 (28%)	20	5/55 (9.1%)	6	18/113 (15.9%)	25	0/22 (0%)	0
Nightmares	7/109 (6.4%)	10	3/50 (6%)	4	1/55 (1.8%)	1	11/113 (9.7%)	13	0/22 (0%)	0
Anxiety	0/109 (0%)	0	1/50 (2%)	1	7/55 (12.7%)	9	1/113 (0.9%)	2	0/22 (0%)	0
Respiratory, thoracic and mediastinal disorders
Nasal / Sinus Irritation	5/109 (4.6%)	5	4/50 (8%)	5	3/55 (5.5%)	3	7/113 (6.2%)	7	0/22 (0%)	0
Coughing	12/109 (11%)	18	6/50 (12%)	9	3/55 (5.5%)	3	6/113 (5.3%)	7	0/22 (0%)	0
Skin and subcutaneous tissue disorders
Itching at Patch Site	1/109 (0.9%)	1	12/50 (24%)	19	8/55 (14.5%)	12	2/113 (1.8%)	2	0/22 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.