Concurrent Bupropion / Varenicline for Smoking Cessation (ConNic4)

• Seven day point abstinence from cigarette smoking [ Time Frame: Six months post quit date ] [ Designated as safety issue: No ]
  Secondary outcome will include point (7-day) abstinence at 6 months post-quit.
• Continuous cigarette abstinence from quit date [ Time Frame: From Quit date to end of treatment (week 11) ] [ Designated as safety issue: No ]
  Secondary outcome will include continuous abstinence from quit date to end of treatment (week 11).
• Smoking withdrawal symptoms [ Time Frame: From quit date to end of study participation ] [ Designated as safety issue: No ]

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 NRT (nicotine replacement therapy) 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

• 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 Name: 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 Name: Zyban
• Drug: Nicotine patches

  Nicotine Replacement Therapy Groups:

  1. 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
  2. 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:

  1. For smokers with high baseline CO: 42 mg/24 h for 1 week
  2. For smokers with low baseline CO: 21 mg/24 h for 1 week
  Other Name: Nicoderm
• Drug: Nicotine Inhaler
  Nicotine inhaler to use as needed after quit date
  Other Name: Nicotrol Inhaler

• 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.
  Intervention: Drug: Varenicline
• 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.
  Intervention: Drug: Nicotine patches
• 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.
  Interventions:

  • Drug: Nicotine patches
  • Drug: Nicotine 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.
  Interventions:

  • Drug: Varenicline
  • Drug: Bupropion

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 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, 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.

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