Clinical Trial to Evaluate the Efficacy of Smoking Cessation (COMBIVAR)

• Determine the efficacy of combined therapy (VRN+nicotine patches) versus monotherapy (VRN+placebo patches) in smoking cessation assessed as continuous abstinence rate (CAR) from week 2 to week 12. [ Time Frame: Participants will be followed for the duration of treatment, 12 weeks. ] [ Designated as safety issue: No ]
  The primary endpoint will be the continuous abstinence rate (CAR) from week 2 (w2) to week 12 (w12) measured objectively during the treatment phase by the CO exhaled.
  
  

• i) Determine safety of combined therapy (VRN+nicotine patches) versus monotherapy (VRN+placebo patches) [ Time Frame: Every two weeks from week 2 to 12 ] [ Designated as safety issue: Yes ]
  The secondary endpoints will be related to efficacy [continued abstinence rate (CAR) from week 2 to week 52, (CAR) from week 2 to week 6, (CAR) from week 2 to week 24, (CAR) from week 2 to week 36; point abstinence rate (PAR) at week 6, PAR at week 12, PAR at week 24, PAR at week 36, PAR at week 52], safety and cravings appearances.
  
  

Seven first-line pharmacotherapies are currently available and recommended by clinical practice guidelines for treating tobacco dependence, all of them have been proven to be effective for increasing tobacco abstinence rates when used as monotherapy. However, not all smokers are able to quit with monotherapy. Some smokers may benefit from combination therapy that includes the simultaneous use of different nicotine replacement therapies (NRTs) or medications with different mechanisms of action (e.g. NRT and bupropion). Combination therapy with different drugs may provide a therapeutic advantage by increasing serum nicotine concentrations, and may capitalize on synergy obtained from two different mechanisms of action. This is why controversy exists regarding this approach as the cost effectiveness of this approach has not been clearly demonstrated neither if the genetic profile determine different treatment responses.

Data from a varenicline pharmacokinetic study have documented that among smokers not instructed to quit and who continued smoking during treatment , varenicline was associated with a 60-80 % of reduction of number of cigarettes and, on the other hand, with a diminution of plasmatic nicotine and cotinine concentrations. (See some studies and trials in the Background Information).

This , led to hypotheses that : a) varenicline not saturate completely all acetylcholinergic receptors with a incomplete response and ; b) varenicline replace incompletely the dopaminergic effect of smoking, with continuous craving. The investigators considered that some smokers may need NRT in addition to varenicline to reduce withdrawal and cravings to smoke.

Finally, available data suggests that combination therapy may increase abstinence rates compared with monotherapy [OR: 2.4 (2.1- 2.7)] without a significant increase of adverse events. So the periodicity, regimen/dose, and periods of combined treatment may be considered as safe as the monotherapy even in an off-label indication.