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

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

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.

Study Overview

• Status: Completed
• Conditions: Smoking Cessation; Genetic Predisposition
• Intervention / Treatment: Drug: Varenicline Tartrate or bupropion

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.

• Study Type: Interventional
• Enrollment (Actual): 361
• Phase: Phase 4

Contacts and Locations

Study Locations

• Brazil
  • São Paulo, Brazil, 05403000
    • Ambulatório de Tratamento Tabagismo - Incor HCFMUSP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Group Varenicline; 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; 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; 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 Names: Varenicline Tartrate and bupropion

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety evaluation	Adverse events according to subjects self-reported	week 0 until week 12

Collaborators and Investigators

• Sponsor: University of Sao Paulo General Hospital
• Collaborators: Fundação de Amparo à Pesquisa do Estado de São Paulo
• Investigators: Principal Investigator: Jaqueline R Scholz, MD.Phd, Heart Institute - University of São Paulo - Braziil

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• CYP2B6 rs2279343 polymorphism is associated with smoking cessation success in bupropion therapy
• CHRNA4 rs1044396 is associated with smoking cessation in varenicline therapy

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2016
• Primary Completion (Actual): April 15, 2022
• Study Completion (Actual): April 15, 2022

Study Registration Dates

• First Submitted: November 16, 2017
• First Submitted That Met QC Criteria: December 2, 2017
• First Posted (Actual): December 5, 2017

Study Record Updates

• Last Update Posted (Actual): December 21, 2022
• Last Update Submitted That Met QC Criteria: December 16, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: varenicline; bupropion
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Disease Susceptibility; Genetic Predisposition to Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Enzyme Inhibitors; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Cytochrome P-450 Enzyme Inhibitors; Nicotinic Agonists; Cholinergic Agonists; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Dopamine Uptake Inhibitors; Bupropion; Varenicline
• Other Study ID Numbers: 6013381600000068

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No