Efficacy of the Use of Genetic Markers in the Choice of the Pharmacological Treatment of Smoking (GENTSMOKING)

Study Overview
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Brief Summary
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Smoking is the leading cause of avoidable death in the world. Smoking is associated with the development of cardiovascular and respiratory diseases, as well as being considered a leading cause of cancer death. Data show that smokers have increased cardiovascular risk in relation to former smokers, even in comparison with individuals who have had a long and intense history tobacco use. Considering this scenario, some drugs are used in tobacco cessation therapy. The first-line anti-smoking treatments approved by the Food and drug administration ( FDA ) are nicotinic reuptake therapy, bupropion ( norepinephrine and dopamine reuptake inhibitor) and varenicline ( partial agonist of nicotinic receptors composed of subunits alpha4Beta2 ). A metanalysis of 16 clinical studies indicated that smokers treated with bupropion had a higher abstinence rate compared to those receiving placebo - Odds ratio (OR ) - of 1,97 for treatment success. Varenicline is more effective compared to others smoking cessation drugs approved by the FDA, with an OR of 2,27 ( IC 95% 2,02-2,55 ) compared to placebo. However, Varenicline is much more expensive than bupropion. Significant advances in genetics have made the variability of the individual response to drugs, as far as efficacy as well as the rate of adverse effects, begin to be specifically investigated through pharmacogenetics studies.

Detailed Description
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The patients will be invited to take part in the study collection genetic´s materials in order to determinate the frequency of CHRNA4 AND CYP2B6. The polymorphisms in genes involved in the coding of metabolized drug enzymes, in the variability of carrier proteins or receptors are at the heart of these investigations. The gene CHRNA4 is an important gene for anti-smoking pharmacogenetics studies because they encode the alpha 4 beta 2 subunits of acetylcholine- nicotinic receptors ( which is important target for an action of varenicline ) and CYP2B6 major isoenzyme that metabolizes the bupropion. Rocha et al found the association of polymorphisms CHRNA4rs1044396 with success in smoking cessation in patients treated with varenicline and Tomaz et al found an association between CYP2B6rs2279343 and efficacy of bupropion. Patients with the CC genotype, for the polymorphism CHRNA4rs1044396, had a lower success rate in treatment with varenicline( 29,5% ), compared to those with CT or TT genotypes (50,9% ) ( P =0,07 , n=167 ). The CT or TT genotypes were associated with a higher risk - Odds ratio ( OR ) - of success ( OR=1,67, IC 95%=1,10-2,53,P=0,02), in a multivariate model. Patients with the genotype AA, for the polymorphism CYP2B6rs2279343, obtained a higher success rate in treatment with bupropion ( 48,0% ), compared to patients with the AG or GG genotypes ( 35,5% ) (P=0,05,n=237). The AA genotype was associated with higher odds ratios for treatment success (OR=1,92,IC 95%=1,08-3,42,P=0,03) ,in a multivariate model. It is suggested that these polymorphisms influence the pharmacological response and may be important for the design of an individualized pharmacotherapy.

Official Title
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Efficacy of Genetic Markers in Choosing Pharmacological Treatment for Smoking Cessation With Bupropion and Varenicline and Its Implications for Combining Drugs: Randomized Control Study.

Conditions
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Smoking Cessation, Genetic Predisposition

Intervention / Treatment
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* Drug: Varenicline Tartrate or bupropion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: smoking who wants to quit smoking, stable clinic diseases, depression or anxiety disorder stable for more than 3 months Exclusion Criteria: contra indication for varenicline and or bupropion unstable psychiatric disorders. In the treatment of neoplastic diseases. Limitation to attend the medical visits

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The Patients will be randomized in two arms. 200 will be treated in the pharmacogenetic arm and 200 in the varenicline arm ( control ).
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Group Varenicline<br>Patients randomized to this group will collect polymorphisms at time zero and will receive varenicline for smoking cessation. The polymorphism result will only be known at the end of the protocol. Varenicline dosage 0,5 mg once a day for 3 days, after this 0,5 mg twice a day until seven day .At day eight 1 mg twice a day until complete week twelve. | |
| Active Comparator: Group Genetic<br>The patients randomized to this arm will collect polymorphisms and could receive varenicline or bupropion or both depending on genetic polymorphisms for each one these drugs. Bupropiona dosage 150 mg once a day seven days, after twice a day until complete week twelve. Varenicline dosage 0,5 mg once a day for 3 days, after this 0,5 mg twice a day until seven day .At day eight 1 mg twice a day until complete week twelve. | Drug: Varenicline Tartrate or bupropion<br>* the drug treatment will be chosen related to the polymorphism. If the polymorphism is favorable to varenicline the patient will receive varenicline, If it is favorable to bupropion the patient will receive bupropion, if not favorable to varenicline and bupropion the patient will receive bupropion + varenicline. If the patient has both favorable polymorphisms he will receive bupropion. Bupropiona dosage 150 mg once a day seven days, after twice a day until complete week twelve. Varenicline dosage 0,5 mg once a day for 3 days, after this 0,5 mg twice a day until seven day .At day eight 1 mg twice a day until complete week twelve.<br>* Other names: Varenicline Tartrate and bupropion;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bupropion favorable genetic marker | Abstinence Rate confirmed througth carbon monoxide concentration in exhalated air in favorable bupropion smokers vs control arm with varenicline | week 4 - | 
| Varenicline favorable genetic marker | abstinence rate confirmed through carbon monoxide concentration in exhalated air in favorable varenicline genetic marker vs unfavorable varenicline genetic marker | week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Abstinence rate at week 12 | Evaluation of add therapy for quitting smoking considering favorable and unfavaroble genetics markers | At week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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varenicline, bupropion