Efficacy And Safety Of Smoking Cessation With Varenicline Tartrate In Diabetic Smokers: (DIASMOKE)
Efficacy And Safety Of Smoking Cessation With Varenicline Tartrate In Diabetic Smokers: (DIASMOKE)
Objectives

 This protocol is intended to provide information regarding the efficacy and safety of the
 nicotine partial agonist varenicline tartrate, at a dose of 1 mg twice daily, for smoking
 cessation in diabetic subjects who smoke. Given that a better understanding of predictors of
 smoking cessation can be useful in identifying potential quitters and likely relapsers and
 that little is known about these predictors in diabetics, the role of different predictors of
 abstinence at the end of the study will also be examined Study Population The study will
 enroll 150 type 2 diabetic patients (≤ 75 years) who are regular smokers (≥10 cigs/day) and
 motivated to stop smoking in each of 2 treatment arms (active drug and placebo) Study Design
 The study is a double-blind, placebo-controlled, randomized clinical trial designed to assess
 the efficacy and safety of varenicline 1 mg BID in comparison to placebo for smoking
 cessation. The duration of active treatment will be 12 weeks and subjects will be followed in
 the nontreatment phase for an additional 12 weeks. This clinical study has an optional
 research component to prolong the follow up in the nontreatment phase for a full year.
 Predictors of abstinence at the end of the study will also be examined Study Endpoints
 Primary Endpoint: Success rates at week 24 in the varenicline vs placebo group. Success rates
 will be defined as the Continuous Quit Rate since last visit. Subjects will be classified as
 responders if they are able to maintain abstinence from cigarette smoking during this period
 of time with end-expiratory exhaled CO measurements ≤ 10 ppm. This measure will be obtained
 through reports of cigarette use by means of the Nicotine Use Inventory confirmed by a
 measurement of an end-expiratory exhaled carbon monoxide concentration that is ≤ 10 ppm on
 the study visit at week 24 Co-primary endpoint: Success rates at week 12 in the varenicline
 vs placebo group. Success rates will be defined as Continuous Quit Rate for Weeks 8 to 12 of
 treatment. Subjects will be classified as responders if they are able to maintain complete
 abstinence from cigarette smoking in each of the last four study visits (week 9, week 10,
 week 11, and week 12) with end-expiratory exhaled CO measurements ≤ 10 ppm. This measure will
 be obtained through reports of cigarette use by means of the Nicotine Use Inventory during
 the last four study visits (week 9, week 10, week 11, and week 12) confirmed by a measurement
 of an end-expiratory exhaled carbon monoxide concentration that is ≤ 10 ppm on each study
 visit Secondary Endpoint: Success rates at week 52 in the varenicline vs placebo group.
 Success rates will be defined as the Continuous Quit Rate throughout the last three visits
 (week 24, week 36, and week 44). Subjects will be classified as responders if they are able
 to maintain abstinence from cigarette smoking during this period of time with end-expiratory
 exhaled CO measurements ≤ 10 ppm. This measure will be obtained through reports of cigarette
 use by means of the Nicotine Use Inventory during the last three study visits (week 24, week
 36 and week 44) confirmed by a measurement of an end-expiratory exhaled carbon monoxide
 concentration that is ≤ 10 ppm on each study visit Additional Measures: Given that a better
 understanding of predictors of smoking cessation can be useful in identifying potential
 quitters and likely relapsers and that little is known about these predictors in diabetics,
 the role of different predictors of abstinence at week 24 and at week 52 will also be
 examined
INTRODUCTION

 Cigarette smoking harms nearly every system of the human body, thus causing a broad range of
 diseases, many of which are fatal. In particular, cardiovascular disease (CVD) is the most
 important cause of death in those who smoke (1). Both diabetes mellitus and cigarette smoking
 are well-known risk factors for the development of CVD and atherothrombosis (2,3). It is now
 acknowledged that endothelial cell dysfunction and clotting activation are not exclusive of
 diabetes. Cigarette smoking is also associated with functional changes of the endothelium and
 with an hypercoagulability state (4). It is likely that the combined injurious effects of
 high blood glucose together with cigarette smoke may be responsible for the observed
 accelerated course of vascular complications in diabetic patients who smoke.

 Findings from both cross-sectional and prospective studies appear to support this notion by
 consistently showing a heightened risk of morbidity and premature death associated with the
 development of micro- and macro-vascular disease from the combination of smoking and
 diabetes. There is evidence that smoking increases the risk of coronary artery disease in
 type 2 diabetes (5,6). For example, in a prospective cohort of 7,401 female nurses with type
 2 diabetes, cigarette smoking was found to be strongly associated with the risk of coronary
 heart disease (CHD) and this risk increased with the number of cigarettes smoked per day (7).
 Based on data from 4,540 patients with type 2 diabetes followed in the UK Prospective
 Diabetes Study (UKPDS), smoking was shown to increase the risk of coronary heart disease in
 both males and females with type 2 diabetes. The estimated Risk Rate (RR) occurrence of a
 fatal or non-fatal MI or sudden death attributable to smoking was 1.35 (8). Smoking also
 increases the risk of stroke (9). Based on patients with type 2 diabetes enrolled in the
 UKPDS, mathematical models including major confounding variables (including age, sex, atrial
 fibrillation, etc) estimated that a non-smoking male with a current age of 67 years would
 have a 6.9% probability of a stroke within 5 years compared with a 10.5% probability for a
 smoking male of the same age (10). Moreover, several studies have shown that smoking promotes
 the onset and progression of nephropathy in type 2 diabetes (11-13). In a logistic regression
 analysis examining associations between gender, age, stage of nephropathy, smoking status,
 cigarette pack-years, hypertension, total cholesterol, triglycerides, Glycated hemoglobin
 (HbA1c), and Blood pressure (BP), current and former smoking (P = 0.0012) and number of
 pack-years (P = 0.011) were shown to be the greatest predictors of the progression of
 nephropathy (12). Smoking has also been shown to exacerbate markers of kidney failure in this
 population, such as microalbuminuria (14). In addition, stopping smoking has been shown to
 reduce the progressive damage to the kidneys in comparison with continued smoking in type 2
 diabetes (14).

 Because the prevalence of smoking among people with diabetes remains elevated (15),
 decreasing the exposure to tobacco products is a public health imperative also for subjects
 with diabetes. Moreover, the most recent US Clinical Guidelines for Treatment of Tobacco
 Dependence (2008) list diabetes, along with other comorbid medical conditions, as a target
 group for smoking cessation treatment, due to the increased health risks associated with this
 disease and smoking (16). It must be also noted that along all known modifiable
 cardiovascular risk factor (e.g. raised glycemic levels, elevated cholesterol levels, high
 Body Mass Index) smoking appears to be the most relevant for the reduction of morbidity and
 mortality in this patient population. Risk management parameters of CVD that include smoking
 cessation may reduce morbidity and mortality more than tightening glycemic control (17,18).

 Surprisingly, there are little data available in the literature on smoking cessation
 intervention for this specific disease group. Also, no specific information on the efficacy
 and safety of new pharmacological support for smokers with diabetes can be found. Varenicline
 is a partial agonist of the α4β2 nicotinic acetylcholine receptor that causes partial
 stimulation while it competitively inhibits nicotine binding. Recently, randomized,
 controlled clinical trials have shown that varenicline at a dose of 1 mg twice a day is
 superior to placebo for smoking cessation (19-21). Varenicline appears to be also more
 effective than sustained-release bupropion (19). Data from these trials indicate that the
 most common adverse event attributed to varenicline at a dose of 1 mg twice daily is nausea
 (19,20). However, the efficacy and safety of varenicline has never been tested in diabetic
 smokers.

 Therefore, the investigators designed a randomized controlled study to test the efficacy and
 safety of a smoking cessation programme with varenicline tartrate 1 mg BID in diabetic
 subjects who smoke. The investigators hypothesized that smoking cessation with varenicline
 could be associated with similar smoking abstinence rates compared to the results obtained in
 the general population. Given that a better understanding of predictors of smoking cessation
 (e.g. gender, age at smoking initiation, previous quit attempts, Fagerstrom Test Nicotine
 Dependence (FTND), motivation, depression, anxiety, social/familial environment, etc.) can be
 useful in identifying potential quitters and likely relapsers (22) and that little is known
 about these predictors in diabetics, the role of different predictors of abstinence at the
 end of the study will also be examined.

 STUDY OBJECTIVES This study is intended to assess the safety and efficacy of 12 weeks
 treatment with varenicline for smoking cessation.

 Primary objective: Compare varenicline to placebo for smoking cessation efficacy 12 weeks
 after treatment (i.e. at week 24) in diabetic smokers

 Co-Primary objective: Compare varenicline to placebo for smoking cessation efficacy and
 safety 1 week after treatment (i.e. at week 13) in diabetic smokers

 Secondary objectives: 1) Compare varenicline to placebo for smoking cessation efficacy after
 treatment at week 52; 2) Compare varenicline to placebo for effects on weight gain in
 participants successfully quitting smoking; 3) Compare diabetic outcomes in quitters vs
 relapsers at week 24 and week 52; 4) Examine predictors of abstinence at week 24 and at week
 52; 5) Summarize safety data for 12 weeks of treatment with either varenicline or placebo.

 METHODS

 Study Design The study is a double-blind, placebo-controlled, randomized, clinical trial
 designed to assess the efficacy and safety of varenicline 1 mg BID in comparison to placebo
 for smoking cessation in diabetic smokers. The duration of active treatment will be 12 weeks
 and participants will be followed in the nontreatment phase for an additional 12 weeks (24
 week time point). This clinical study has an optional research component to prolong the
 follow up in the nontreatment phase for a full year (52 week time point). Predictors of
 abstinence at the end of the study will also be examined.

 Study schedule The subjects will have visits in an outpatient clinic setting. The flowcharts
 in Appendix A and B describe the procedures to be completed at each visit.

 Screening visit Activities to be carried out during the screening visit are detailed in the
 Appendix A. At the screening visit the inclusion/exclusion criteria will be reviewed. The
 baseline visit will be cancelled if the inclusion/exclusion criteria, including laboratory
 results, are not met prior to the baseline visit. The baseline visit will occur no less than
 3 days and no more than 2 weeks after the screen visit, allowing time for laboratory results
 to come back.

 Baseline visit Activities to be carried out during the baseline visit are detailed in the
 Appendix A. Inclusion/exclusion criteria will be reviewed once again. At the baseline visit,
 participants will be instructed on how to prepare to stop smoking and to set a target quit
 date (TQD), which will be planned to coincide with the Week 1 visit. Also at the baseline
 visit, each participant will be randomly assigned to either varenicline 1 mg BID + counseling
 or matched placebo + counseling. Qualified site personnel will dispense the study drug and
 provide dosing instructions. The participants will be provided approximately. 10 minutes of
 counseling, in accordance with Agency for Healthcare Research and Quality (AHRQ) guidelines.
 Diabetic smokers will be subjected to their usual care throughout the study.

 Week 1 to 12 visits Subjects will return for visits to the clinic after the baseline visit
 over the following 12 weeks at Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12. Subsequent to
 Week 1 Target Quit Date (TQD-visit), visits will occur within 3 days of each scheduled visit
 date. The subjects will attempt to quit on the target quit date at the Week 1 visit. The quit
 attempt should occur in the morning prior to the clinic visit that day, so that the subject's
 last cigarette prior to the quit attempt will be before midnight the night prior to the Week
 1 visit. Subjects will be called 3 days after the target quit date (TQD+3) to be reminded of
 study participation and to receive support for the smoking cessation attempt. These contacts
 should be no longer than 5 minutes and counselling will follow AHRQ guidelines. Activities to
 be carried out during these visits are detailed in the Appendix A. At each visit,
 participants will be provided approximately. 10 minutes of counselling. Study drug will be
 dispensed by qualified personnel according to the plan illustrated in the Appendix A. Any
 unused study drug must be returned to the clinic at each visit or upon early termination. All
 subjects will complete the treatment phase after 12 weeks of participation. Following
 completion of the Week 12 visit, subjects will continue in the nontreatment follow-up phase
 of the protocol (see Appendix B). Subjects who do not complete the Week 12 visit will not be
 eligible to continue. If a subject discontinues study drug prior to the Week 12 visit, the
 subject may continue study participation as long as they complete the remaining scheduled
 visits through Week 12. Only subjects completing the week 12 visit will be eligible to
 continue in the nontreatment follow-up phase of the protocol.

 Nontreatment Follow-up (Weeks 13 through 52) Subjects will return for visits to the clinic at
 Week 24, Week 36, Week 44, and Week 52. Activities to be carried out during these visits are
 detailed in the Appendix B.

 Study Population The study will enroll approximately 150 subjects in each of 2 treatment arms
 (active drug and matched placebo), for a total of approximately 300 subjects.

 STUDY TREATMENTS

 Allocation to Study Treatment Diabetic smokers booked for the baseline visit at the smoking
 cessation center (Centro Per la Prevenzione Cura Tabagimso) will obtain their progressive
 identification numbers and study drug assignments. Randomization will be performed in
 permuted blocks of six.

 Formulation and Packaging Supplies of varenicline will be in a strength of 0.5 mg tablets and
 provided in blister cards.

 Administration Treatment will begin on the day after the baseline visit. The subjects will
 take a total of 1 tablet per day for the first 3 days of the dosing period. The dosing will
 then increase for the next 4 days to 2 tablets per day, 1 in the morning (the first blinded
 varenicline tablet) and 1 in the evening (the second blinded varenicline tablet). The dosing
 will then increase to 4 tablets per day, 2 in the morning (the first 2 blinded varenicline
 tablets) and 2 in the evening (the second 2 blinded varenicline tablets) for the remainder of
 the study. All subjects are to dose study medication on the day of the Week 1 visit in the
 morning prior to the visit. DOSING SHOULD OCCUR WITH 240 ML OF WATER AND IT IS RECOMMENDED
 THAT SUBJECTS EAT PRIOR TO DOSING. There must be at least 8 hours between the morning and
 evening dosing.

 Compliance Subjects will return blister cards at each programmed visit and a dosage record
 will be recorded.

 SAFETY REPORTING

 Adverse Events All observed or volunteered adverse events, regardless of treatment group or
 suspected causal relationship to study drug, will be recorded. This includes symptoms thought
 to be related to withdrawal from nicotine. Events involving adverse drug reactions, illnesses
 with onset during the study, or exacerbations of pre-existing illnesses should be recorded.
 Exacerbation of the disease under study (type 2 diabetes), is defined as a manifestation
 (sign or symptom) of the illness that indicates a significant increase in the severity of the
 illness as compared to the severity noted at the start of the trial. It may include worsening
 or increase in severity of signs or symptoms of the illness, increase in frequency of signs
 and symptoms of an intermittent illness, or the appearance of a new
 manifestation/complication. Exacerbation of a pre-existing illness should be considered when
 a subject requires new or additional concomitant therapy for the treatment of that illness
 during the trial. In addition, clinically significant changes in physical examination
 findings and abnormal objective test findings (e.g., laboratory) should also be recorded as
 adverse events. For all adverse events, the investigator must pursue and obtain information
 adequate both to determine the outcome of the adverse event and to assess whether it meets
 the criteria for classification as a serious adverse event. For all adverse events,
 sufficient information should be obtained by the investigator to determine the causality of
 the adverse event (i.e., study drug or other illness). The investigator is required to assess
 causality.

 Serious Adverse Events

 All serious adverse events (as defined below) regardless of treatment group or suspected
 relationship to study drug must be reported immediately. A serious adverse event is any
 adverse drug experience occurring at any dose that:

 1. Results in death;

 2. Is life-threatening;

 3. Results in inpatient hospitalization or prolongation of existing hospitalization;

 4. Results in a persistent or significant disability/incapacity.

 Any serious adverse event or death must be reported immediately independent of the
 circumstances or suspected cause if it occurs or comes to the attention of the investigator
 at any time during the study through 30 days after the last administration of study drug. Any
 serious adverse event occurring beyond 30 days after the last administration of study drug
 must be promptly reported if a causal relationship to study drug is suspected.

 Clinical Laboratory Parameters and Abnormal Laboratory Test Results

 The results of all laboratory tests required by the protocol will be recorded. All clinically
 important abnormal laboratory tests occurring during the study will be repeated at
 appropriate intervals until they return either to baseline or to a level deemed acceptable by
 the investigator or until a diagnosis that explains them is made. The criteria for
 determining whether an abnormal laboratory test result should be reported as an adverse event
 are as follows:

 1. Test result is associated with accompanying symptoms, and/or

 2. Test result requires additional diagnostic testing or medical/surgical intervention,
 and/or

 3. Test result leads to a change in study dosing or discontinuation from the study,
 significant additional concomitant drug treatment or other therapy, and/or

 4. Test result leads to any of the outcomes included in the definition of a serious adverse
 event, and/or

 5. Test result is considered to be an adverse event by the investigator.

 The following tests will be completed at the screening and baseline visits: blood chemistry
 (including sodium, potassium, chloride, BUN, creatinine, glucose, SGOT, SGPT, LDH, alkaline
 phosphatase, total bilirubin, cholesterol, and triglycerides) and complete blood count. In
 the event of clinically significant abnormalities, urine samples will be sent for urinalysis.
 Moreover, the following additional lab tests will be carried out at screening, baseline, week
 13, week 24 and week 52 (HbA1c, fasting glucose, total cholesterol, HDL, LDL, triglycerides,
 insulinemia, albumin to creatinine ratio, and plasma creatinine).

 Abnormal Physical Examination Findings Clinically significant changes, in the judgment of the
 investigator, in physical examination findings (abnormalities) will be recorded as adverse
 events.

 DATA ANALYSIS/STATISTICAL METHODS

 Sample Size Determination The sample size calculation for this Randomized Clinical Trial,
 based on the success quit rates from our previous smoking cessation study (23), indicates
 that 138 subjects will be required to have 80% power with two-sided 0.05 significance level
 test to detect a difference of at least 20% quit rate (24 week CQR) between treatment groups.
 Allowing for a conservative attrition rate of approximately 50%, the target number of
 participants will be increased to a total of 300.

 Methods of Analysis Baseline, demographic and safety data will be listed for all treatment
 groups. Summary statistics will be provided for each treatment group. The student T-test will
 be used to compare between mean values of continuous variables in either intervention groups,
 while the Chi-square test will be used to compare difference between categorical variables.
 The secondary endpoints will be analyzed using procedures similar to that described above for
 the primary endpoint. Multivariate logistic regression will be used to identify independent
 predictors associated with abstinence at week 24 and at week 52.
Inclusion Criteria:

 1. Type 2 diabetic patients (≤ 75 years of age) who are regular smokers (≥10 cigs/day
 during the past year, with no period of abstinence greater than three months in the
 past year) and willing to quit.

 2. Females of non childbearing potential (surgically sterilized or at least 2 years
 postmenopausal) who are not nursing may be included. Females of childbearing potential
 may be included provided that they are not pregnant, not nursing, and are practicing
 effective contraception.

 3. Subjects must be able to be outpatients and be assessed in a clinic setting.

 4. Participating subjects must be able to provide written informed consent.

 Exclusion Criteria:

 1. Subjects currently or within the past 12 months requiring treatment for depression.
 Subjects with a past or present history of panic disorder, psychosis, or bipolar
 disorder;

 2. Subjects with a current or recent (within the past 12 months) history of alcoholism;

 3. Subjects with a requirement to use other medications during the study that might
 interfere with the evaluation of the study drug (e.g., nicotine replacement therapy);

 4. Subjects with a body mass index (BMI) less than 15 or greater than 38, wearing indoor
 clothing without shoes and determined using the Body Mass Index (BMI);

 5. Subjects with evidence or history of clinically significant allergic (except for
 seasonal allergies at time of dosing), endocrine, gastrointestinal, hematological,
 hepatic, neurologic, pulmonary, or renal disease or a history of cancer (excluding
 treated basal cell carcinoma and squamous cell carcinoma). Exceptions to this
 exclusion may include subjects with a history of mild chronic obstructive pulmonary
 disease, and stable thyroid disease.

 6. Subjects with a history of clinically significant cardiovascular disease. In addition,
 subjects with uncontrolled hypertension or a screening or baseline systolic blood
 pressure greater than 160 mm Hg or a diastolic blood pressure greater than 95 mm Hg
 will be excluded.