Aggressive Smoking Cessation Trial (ASAP)

Study Overview
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Brief Summary
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The ASAP Trial is a 5-year, multi-centre, randomized controlled trial that will assess the efficacy, safety, and tolerability of aggressive smoking cessation therapy initiated in-hospital following ACS. It will recruit 798 adult patients smoking on average at least 10 conventional (tobacco) cigarettes per day who are motivated to quit smoking and have been diagnosed with ACS requiring hospitalization. Patients will be randomized (1:1) to one of two treatment arms: (1) combination therapy of varenicline and nicotine e-cigarettes plus counseling or (2) varenicline plus counseling for 12 weeks, with 52-week follow-up.

Detailed Description
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Background and Importance: Patients who continue to smoke after an acute coronary syndrome (ACS), including myocardial infarction and unstable angina, have a 35% increased risk of reinfarction or death compared with those who quit. Previous smoking cessation trials conducted by the investigators have established varenicline (Champix) as the gold standard for patients with ACS. However, more than 50% of patients motivated to quit who receive varenicline for 12 weeks immediately post-ACS will return to smoking within 6 months. Therefore, more effective smoking cessation strategies are needed. Based on newly available data from randomized controlled trials (RCTs), including the investigators' E3 Trial, which suggest that nicotine e-cigarettes are more efficacious for smoking cessation than other nicotine replacement therapies and counselling alone, the investigators propose to combine varenicline and nicotine e-cigarettes. The proposed combination therapy is a novel approach needed now to increase abstinence in patients with ACS. Goal(s)/Research Aims: The Aggressive Smoking Cessation Therapy Post-Acute Coronary Syndrome (ASAP) Trial is a 5-year, multi-centre RCT that will assess the efficacy, safety, and tolerability of aggressive smoking cessation therapy initiated in-hospital following ACS. The specific aims are: To assess the efficacy of combination therapy (varenicline and nicotine e-cigarettes) versus varenicline alone for 12 weeks, in terms of biochemically-validated 7-day point prevalence and continuous smoking abstinence, and ≥50% reduction in daily cigarette consumption at 24 and 52 weeks post-ACS. To describe the safety and tolerability of varenicline combined with nicotine e-cigarettes, in terms of serious adverse events (SAEs), adverse events (AEs), treatment discontinuation due to side effects, and therapy adherence over the 12-week treatment period. Methods/Approaches/Expertise: A total of 798 participants will be randomized 1:1 to: (1) varenicline and nicotine e-cigarettes, or (2) varenicline alone for 12 weeks, with follow-up of 52 weeks. Both arms will receive individual smoking cessation counselling. Participants randomized to combination therapy (varenicline and nicotine e-cigarette) will be given funds to cover the purchase of e-cigarettes and nicotine cartridges. Funds will be provided at discharge for the first 4 weeks of e-cigarette use. Participants who follow the e-cigarette purchasing instructions and provide receipts at subsequent clinic visits will be provided additional funds at week 4 (for weeks 4 to 8) and reimbursed at week 12 (for weeks 8 to 12). Participants will begin varenicline (titrated to 1.0 mg twice daily) and counselling in-hospital, and e-cigarette use (if applicable) upon discharge. Eligible patients will be hospitalized for ACS, self-identify as regular smokers (≥10 cigarettes/day for ≥1 year), and be motivated to quit. Participants will complete telephone follow-ups at weeks 1, 2, 8, and 18, and clinic visits at weeks 4, 12, 24, and 52. The investigators will collect information about self-reported smoking, treatment adherence, and adverse events. Self-reported smoking abstinence will be biochemically-validated at clinic visits using exhaled carbon monoxide (≤10 ppm). The primary endpoint will be biochemically-validated 7-day point prevalence smoking abstinence at 24 weeks. With 399 participants per arm and an alpha of .05, the investigators will have 80% power to detect a ≥ 10% difference in abstinence at 24 weeks. The ASAP trial will be conducted by a highly experienced team of researchers and enrolling centres, who have previously completed three smoking cessation RCTs, including two in patients with ACS. Expected Outcomes: Smoking cessation post-ACS is essential to reduce morbidity and mortality in this high-risk patient population. ASAP will provide regulators, health care professionals, and smokers with important information about the efficacy of combination varenicline and nicotine e-cigarettes for smoking cessation in patients with ACS.

Official Title
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Aggressive Smoking Cessation Therapy Post-Acute Coronary Syndrome (ASAP) Trial

Conditions
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Acute Coronary Syndrome

Intervention / Treatment
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* Combination Product: Combination Therapy Arm (Varenicline and Nicotine E-Cigarettes Plus Counseling)
* Other: Varenicline Plus Counseling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Currently hospitalized (or at time of discharge from current hospitalization) for ACS, defined as follows: i. MI, defined by positive troponin T, troponin I, or CK-MB levels (as defined by institution-specific cut-offs) and ≥ 1 of the following: Ischemic symptoms for ≥ 20 min; Electrocardiogram (ECG) changes indicative of ischemia (ST-segment elevation or depression); Development of pathological Q waves on the ECG ii. Unstable angina with significant coronary artery disease, defined by all of the following: Ischemic symptoms for ≥ 20 min; ECG changes indicative of ischemia (ST-segment changes); At least one lesion ≥ 50% on angiogram performed during the current hospitalization. [Note: patients who undergo cardiac catheterization or percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery will be eligible provided they are able to start varenicline in-hospital and nicotine e-cigarette at discharge.] Smoked on average ≥ conventional cigarettes/day for the past year; Age ≥18 years; Motivated to quit smoking according to the Motivation To Stop Scale (MTSS) (≥ level 5); Able to understand and provide informed consent in English or French; If randomized to the combination arm (varenicline and e-cigarette plus counseling), willing and able to purchase e-cigarettes with the following properties: rechargeable, closed system that uses sealed cartridges or pods, tobacco or no flavor only, and nicotine strength of 20 mg/ml (2%) or less; Likely to be available for 52 weeks of follow-up. Exclusion Criteria: Pregnant or lactating females; Use of any of the following in the 30 days prior to ACS admission: i. Pharmacotherapy (e.g., NRTs, bupropion, or varenicline) for smoking cessation; ii. Nicotine or non-nicotine e-cigarettes; iii. Other anti-craving medication (e.g., naltrexone, acamprosate) with the potential to alter substance-seeking behaviors; Use of varenicline or e-cigarettes (nicotine or non-nicotine) for ≥14 days consecutively in the past year; Previous serious adverse reaction to varenicline and/or e-cigarettes (nicotine or non-nicotine); NYHA or Killip Class III or IV at the time of randomization; Any unstable psychiatric disorder (as per enrolling physician); Renal impairment with creatinine levels ≥2 times upper limit of normal or eGFR ≤15; Use of any illegal drugs in the past year; Planned use of cannabis (smoked) or other tobacco products (smoked or other) during the study period. [Note: use of cannabis which is not smoked is permitted (e.g., edibles, ingested or vaped oils). However, methods which involve combustion could invalidate biochemical validation via exhaled carbon monoxide.]

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Combination Therapy Arm (Varenicline and Nicotine E-Cigarettes Plus Counseling)<br>Patients in the combination therapy arm will be supplied funds and instructions for the purchase of e-cigarettes and cartridges/pods upon hospital discharge and at the week 4 and 12 clinic visits. As with standard NRTs such as the gum, inhaler, and lozenge, we expect smokers will self-regulate administration according to their withdrawal symptoms. Use will be monitored via self-report for telephone follow-ups. At clinic visits, patients will be asked to bring their e-cigarettes, used and unused cartridges/pods, and purchasing receipts. Patients will be advised regarding the signs and symptoms of nicotine toxicity and of an allergic reaction. | Combination Product: Combination Therapy Arm (Varenicline and Nicotine E-Cigarettes Plus Counseling)<br>* Varenicline and nicotine e-cigarettes plus counseling<br>|
| Other: Varenicline Plus Counseling<br>All patients will begin varenicline in-hospital upon randomization. For the first 3 days, patients will take a 0.5 mg tablet once a day. They will then take a 0.5 mg tablet twice a day for the following 4 days, and one 1 mg tablet twice a day from day 8 onward for the remainder of the 12-week treatment. Use will be monitored via self-report for telephone follow-ups and return of all unused tablets at the end of the treatment period. Should a patient experience severe side effects (such as headache, nausea, vomiting, dizziness, dyspepsia, fatigue, insomnia, abnormal dreams, constipation, or flatulence) on day 8 onward, the varenicline dose should be reduced from 1 mg twice daily to 0.5 mg twice daily prior to study medication discontinuation. | Other: Varenicline Plus Counseling<br>* Varenicline plus counseling<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with 7-day point prevalence smoking abstinence | Biochemically-validated 7-day point prevalence smoking abstinence at 24 weeks, defined as self-reported abstinence in the past 7 days with exhaled carbon monoxide ≤ 10 ppm. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with continuous smoking abstinence | Biochemically-validated continuous abstinence at 4, 12, and 24 weeks, defined as self-reported abstinence since baseline with exhaled carbon monoxide ≤ 10 ppm at all clinic follow-ups, and self-reported 0 cigarette smoked in the past 7 days at telephone follow-ups (1, 2, 8, and 18 weeks). | 1, 2, 8, and 18 weeks | 
| Number of participants with prolonged smoking abstinence | Prolonged abstinence, defined as self-reported abstinence at all clinical and telephone follow-ups after an initial 2-week grace period with exhaled carbon monoxide ≤ 10 ppm at 4, 12, and 24 weeks, and self-reported 0 cigarette smoked in the past 7 days at the 8, and 18 weeks telephone follow-ups | 4, 8, 12, 18, and 24 weeks | 
| Change in daily cigarette consumption | Change in self-reported daily conventional cigarette consumption from baseline compared to 24 weeks. | 24 weeks | 
| Number of participants with ≥50% reduction in daily cigarette consumption | Proportion of participants with ≥50% reduction in self-reported daily cigarette consumption from baseline compared to 24-weeks. | 24 weeks | 
| Number of participants with point prevalent abstinence or ≥50% reduction in daily cigarette consumption at 24 weeks | Composite endpoint of point prevalent abstinence or ≥50% reduction in daily cigarette consumption at 24 weeks | 24 weeks | 
| Frequency of Serious Adverse Events (SAEs) | The number of serious adverse events (SAE) reported over the 12 week treatment period. A SAE is defined as an adverse event which requires in-patient hospitalization or prolongation of existing hospitalization, that causes congenital malformation, that results in persistent or significant disability or incapacity, that is life-threatening, or that results in death. | 12 weeks | 
| Frequency of Adverse Events (AEs) | The number of adverse events reported over the 12 week treatment period. An adverse event is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of the trial drug, whether or not considered related to the e-cigarettes or varenicline. | 12 weeks | 
| Frequency of drop-outs | The number of drop-outs due to side effects of the e-cigarettes or varenicline over the 12 week treatment period. | 12 weeks | 
| Spirometry measurements (subset) | For a sub-set of 100 patients, 50 from each arm, randomized at 4-5 recruiting sites, undergoing spirometry measurements, differences in FVC, FEV1, and FEV1/FVC ratio as well as measures of small airways disease between pre- and post-bronchodilator at week 24 from baseline. | 24 weeks | 
| O2 Cost Diagram and COPD Assessment Test (subset) | For the same sub-set of 100 patients undergoing spirometry measurements randomized at 4-5 recruiting sites, the difference in the O2 Cost Diagram and the CAT at week 24 from baseline. | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute coronary syndrome, smoking cessation, randomized controlled trial, varenicline, e-cigarettes