Please select the eligibility criteria that correspond to the clinical trial below.
Title: Varenicline for Long-term Nicotine Replacement Therapy (NRT) Users. A Double Blind, Placebo Controlled Trial
Brief Summary: Primary aim: Will varenicline be better than placebo to get long-term users of NRT to stop?

Secondary aim: To assess in details some side effects of varenicline i.e. nausea and abnormal dreams.


Options:
A: 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.
B: Inclusion Criteria:

1. Smokers smoking at least 10 cigarettes/day (factory made or roll-your-own) in the past year
2. Aged 18 to 70 years
3. Motivated to quit defined as a score \> 5 on a visual rating scale ranging from 0 (not motivated at all) to 10 (extremely motivated)
4. Signed written informed consent
5. Understanding and speaking French
6. Women of childbearing age can be included if they use an effective contraceptive method: either hormonal contraception or an intrauterine device started at least one month before the first research visit
7. Individual affiliated to a health insurance system as defined by the sponsor (except Aide Médicale d'État =AME)
8. Previous failure of nicotine replacement therapy for smoking cessation

Exclusion Criteria:

1. any unstable disease condition within the last 3 months defined by the investigator as major change in symptoms or treatments such as 1.1.recent myocardial infarction, 1.2.unstable or worsening angina 1.3.severe cardiac arrhythmia 1.4.unstable or uncontrolled arterial hypertension 1.5.recent stroke 1.6.cerebrovascular disease 1.7.obliterative peripheral arterial disease 1.8.cardiac insufficiency 1.9.diabetes 1.10.hyperthyroidism 1.11.pheochromocytoma 1.12.severe hepatic insufficiency 1.13.history of seizures 1.14.severe depression 1.15.chronic obstructive pulmonary disease (COPD)
2. any life threatening condition with life-expectancy of less than 3 months
3. alcohol use disorder defined as a score ≥ 10 on the AUDIT-C questionnaire
4. abuse of or dependence on illegal drugs in the last 6 months revealed by the medical history
5. regular use of tobacco products other than cigarettes
6. current or previous (last 6 months) use of electronic cigarette
7. pregnant women
8. breastfeeding women
9. protected adults
10. current or past 3 months participation in another interventional research
11. current or past (last 3 months) use of smoking cessation medication such as varenicline, bupropion, nicotine replacement therapies
12. known lactose intolerance (placebo tablets contain lactose)
13. hypersensitivity to the active substance or to any of the excipients
14. known severe renal failure
C: Inclusion Criteria:

* Long-term, daily NRT users (except nicotine patch) (\>11 months) ex-smokers that are willing to try to stop the use of NRT and adhere to this protocol.
* More than 4 pieces of nicotine gum/ sublingual tablets/ lozenges/ per day, OR more than 3 inhaler cylinders per day, OR
* more than 10 puffs of nasal spray per day.

Exclusion Criteria:

* Age \< 18 years,
* CO Smokers,
* Pregnant and lactating women,
* Used varenicline before,
* Not able to cooperate,
* Other significant diseases that might influence the trial (such as moderate -severe cardiac disease, lung cancer,) in expired air \> 7 ppm.
D: Inclusion Criteria:

Eligible participants will be males and females

1. Between the ages of 18-65.
2. Smoke at least 10 cigarettes/day for the past 6 months.
3. Provide a baseline Carbon Monoxide (CO) reading greater than 10ppm at the Intake Session.
4. Are seeking smoking cessation treatment.
5. Plan to live in the area for the next 12 months.
6. Fluent English speaker.
7. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the combined consent and Health Insurance Portability and Accountability Act (HIPAA) form. All subjects must consent to use a medically accepted method of birth control (e.g., condoms and spermicide, oral contraceptive, Depo-Provera injection, contraceptive patch, tubal ligation) or abstain from sexual intercourse during the time they are taking study medication (pills and patches) and for at least one month after the medication period ends. All female subjects of child-bearing potential should not be pregnant for the duration of the study.

Exclusion Criteria:

Smoking Behavior

1. Regular (daily) use of chewing tobacco, snuff or snus.
2. Current enrollment or plans to enroll in another smoking cessation or research program in the next 12 months.
3. Plan to use other nicotine substitutes or smoking cessation treatments in the next 12 months.
4. Provide a baseline CO reading less than or equal to 10ppm at the Intake Session.

Alcohol/Drug Exclusion Criteria

1. History (within the last year) or currently receiving treatment for substance abuse (e.g., alcohol, opioids, cocaine, marijuana, or stimulants), excluding nicotine.
2. Current use of cocaine and/or methamphetamines (urine drug screen at the Intake Session).
3. Current alcohol consumption that exceeds greater than 25 standard drinks/week.
4. Current alcohol abuse or dependence.
5. Current non-alcoholic psychoactive substance abuse or dependence.

Medical Exclusion Criteria

1. Women who are pregnant, planning a pregnancy, or lactating.
2. History of epilepsy or a seizure disorder.
3. Current medical problems for which transdermal nicotine is contraindicated including:

   * Allergy to latex.
   * History of kidney and/or liver disease, including transplant (self-report).
   * Uncontrolled hypertension (determined as a Systolic Blood pressure (SBP) reading greater than 160 and/or a Diastolic Blood Pressure (DBP) greater than 100).
4. Serious or unstable disease within the past 6 months.
5. History (last 6 months) of abnormal heart rhythms, tachycardia and cardiovascular disease (stroke, angina, heart attack) may result in ineligibility. These conditions will be evaluated on a case by case basis by the Study Physician.
6. Inability to provide a blood sample to be used to assess nicotine metabolite ratio.

Psychiatric Exclusion Criteria (as determined by self report \& MINI)

1. Current diagnosis of major depression. Persons with a history of major depression, if stable for 6 months or longer, are eligible, provided they are not excluded based on medications (below).
2. Any suicide risk score on MINI or self-reported suicide attempt on telephone screen.
3. Current or past hypomanic/manic episode.
4. History or current diagnosis of Post Traumatic Stress Disorder (PTSD).
5. History or current diagnosis of psychotic disorder, bipolar disorder, schizophrenia.

Medication Exclusion Criteria

1. Current use or recent discontinuation (within the last 14-days) of:

   * Smoking cessation medication (e.g. Zyban, Wellbutrin, Wellbutrin SR, Chantix); NOTE: Once participants are found eligible for the study, they are instructed to use the smoking cessation medication provided to them by the study staff. If a subject reports an isolated (non-daily) instance of using a non-study smoking cessation medication, the study physician and PI will evaluate the situation and determine if it is safe for the subject to continue participation.
   * Anti-psychotic medications.
   * Certain medications used to treat depression, including Wellbutrin, Monoamine Oxidase Inhibitors (MAOIs), and tricyclic antidepressants.
   * Prescription stimulants (e.g. Provigil, Ritalin, Adderall).
2. Current use of:

   * Nicotine replacement therapy (NRT); NOTE: Once participants are found eligible for the study, they are told they should only use the NRT provided to them by the study staff. If a subject reports an isolated (non-daily) instance of NRT use during the study, they may be permitted to continue.
   * Tagamet (cimetidine).
   * Heart medications such as digoxin, quinidine, nitroglycerin; use of these medications may result in ineligibility and will therefore be evaluated on a case-by-case basis by the Study Physician.
   * Anti-coagulants (e.g., Coumadin, Warfarin).
3. Daily use of:

   * Opiate-containing medications for chronic pain; if a participant reports taking an opiate-containing medication every day for the 14 days prior to the telephone screen and/or Intake Session, the participant will be ineligible.
   * Rescue Inhalers (e.g. albuterol, proventil, ventolin, or maxair)

General Exclusion

1. Any medical condition, illness, disorder or concomitant medication that could compromise participant safety or treatment, as determined by the Principal Investigator and/or Study Physician.
2. Inability to provide informed consent or complete any of the study tasks as determined by the Principal Investigator and/or Study Physician.

Answer: C