Efficacy of the Use of Genetic Markers in the Choice of the Pharmacological Treatment of Smoking (GENTSMOKING)
Condition: Smoking Cessation; Genetic Predisposition
MeSH terms: Genetic Predisposition to Disease
Study type: Interventional
Phase: Phase 4

Summary: 
      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: 
      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.
    

Intervention name(s): Varenicline Tartrate or bupropion
Intervention type(s): Drug
Intervention description(s): 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.
Other intervention name(s): Varenicline Tartrate and bupropion
Intervention MeSH terms: Bupropion; Varenicline
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention 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 (Participant, Care Provider)
Primary purpose: Treatment
Keywords: varenicline; bupropion