Clinical trial NCT03362099: Efficacy of the Use of Genetic Markers in the Choice of the Pharmacological Treatment of Smoking (GENTSMOKING)
Official title: Efficacy of Genetic Markers in Choosing Pharmacological Treatment for Smoking Cessation With Bupropion and Varenicline and Its Implications for Combining Drugs: Randomized Control Study.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Smoking Cessation
Genetic Predisposition
Keywords: varenicline
bupropion
Lead sponsor: University of Sao Paulo General Hospital
Sponsor class: OTHER
Collaborators: name: Fundação de Amparo à Pesquisa do Estado de São Paulo
First posted: 2017-12-05
Enrollment: 361
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
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 ).
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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

Primary outcomes:
measure: Bupropion favorable genetic marker
timeFrame: week 4 -
measure: Varenicline favorable genetic marker
timeFrame: week 4
Secondary outcomes:
measure: Abstinence rate at week 12
timeFrame: At week 12
Other outcomes:
measure: Safety evaluation
timeFrame: week 0 until week 12
Locations:
city: São Paulo
country: Brazil
facility: Ambulatório de Tratamento Tabagismo - Incor HCFMUSP
Study officials:
affiliation: Heart Institute - University of São Paulo - Braziil
name: Jaqueline R Scholz, MD.Phd
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tomaz PR, Santos JR, Issa JS, Abe TO, Gaya PV, Krieger JE, Pereira AC, Santos PC. CYP2B6 rs2279343 polymorphism is associated with smoking cessation success in bupropion therapy. Eur J Clin Pharmacol. 2015 Sep;71(9):1067-73. doi: 10.1007/s00228-015-1896-x. Epub 2015 Jul 8.
citation: Rocha Santos J, Tomaz PR, Issa JS, Abe TO, Krieger JE, Pereira AC, Santos PC. CHRNA4 rs1044396 is associated with smoking cessation in varenicline therapy. Front Genet. 2015 Feb 27;6:46. doi: 10.3389/fgene.2015.00046. eCollection 2015.