The Efficacy of Acetium Lozenges in Intervention for Smoking Cessation
Condition: Smoking Cessation
Study type: Interventional

Summary: 
      The purpose of this study is to validate the novel hypothesis that regular use of Acetium
      Lozenge is promising novel method to assist in smoking cessation.

      The aim of this confirmatory study is to affirm the promising results obtained in a previous
      smoking intervention trial with Acetium lozenge. If successful, the trial gives adequate
      power to confirm, that the Acetium lozenge represents a breakthrough in the development of
      smoking intervention methods.
    

Detailed description: 
      Background: Smoking dependence has been traditionally ascribed to nicotine, the major
      psychoactive component of tobacco (nicotine addiction). Dependence on smoking, however, is a
      much more complex issue than just nicotine addiction, and during the past several decades, a
      wide variety of approaches have been used in intervention for smoking cessation, with
      variable success.

      Tobacco smoke contains several classes of carcinogens, including acetaldehyde in high
      concentrations. Acetaldehyde from the tobacco smoke is easily dissolved into the saliva
      during smoking, and thus, toxic aldehydes could mediate the carcinogenic effect of tobacco
      smoke through the saliva. In 2009, IARC proclaimed acetaldehyde as Group I carcinogen,
      equivalent to asbestos, formaldehyde and others.

      Based on observations that in rodents, acetaldehyde induces reinforcing effects acting in
      concert with nicotine, Talhout et al (2007) hypothesized that harmans (condensation products
      of acetaldehyde and biogenic amines) may be responsible for these nicotine-reinforcing
      effects of acetaldehyde. Harmans are formed in cigarette smoke, and blood harman levels among
      smokers appear to be 2-10 times higher than in non-smokers. Harmans inhibit monoamine oxidase
      (MAO), and like other MAO-inhibitors, these might help maintaining the behavioral
      sensitization to nicotine. This led these authors to speculate that acetaldehyde may increase
      the addictive potential of tobacco products via formation of harmans in cigarette smoke.

      It has been known for several decades that L-cysteine (a nonessential amino acid) is able to
      eliminate the toxicity of acetaldehyde by reacting covalently with acetaldehyde to form a
      stable 2-methylthiazolidine-4-carboxylic acid (MTCA). This simple principle was used in the
      recent innovation of Biohit HealthCare's Acetium™ capsule containing 100mg L-cysteine. Oral
      administration of Acetium was confirmed to effectively bind acetaldehyde originated from
      ethanol metabolism in the stomach, raising the idea that L-cysteine could also be used to
      eliminate acetaldehyde dissolved into the saliva during smoking. Indeed, Salaspuro et al.
      (2006) confirmed that orally administered L-cysteine (5mg)-containing sucking tablet
      (lozenge) totally inactivated acetaldehyde in the saliva during smoking.

      Given the above, it is tempting to speculate that elimination of acetaldehyde in the saliva
      during cigarette smoking by L-cysteine sucking tablets, might effectively block (or reduce)
      the formation of harmans, reduce their high blood levels, and thus alleviate the
      acetaldehyde-enhanced nicotine addiction (by reducing MAO-inhibition) among smokers. The
      present study is designed to validate the novel hypothesis that regular use of Acetium
      lozenges in context with smoking is an effective intervention for cessation of cigarette
      smoking.

      Objective: To test the efficacy of Acetium lozenges (used simultaneously with smoking) to
      trigger the quit from cigarette smoking as compared with similarly administered placebo
      preparation.

      Study design: A double-blind, placebo-controlled clinical trial comparing Acetium lozenges
      and placebo as triggers of cigarette smoking cessation during one-year intervention.

      Methods: A cohort of 1.800 current cigarette smokers will be enrolled by public invitation.
      Eligible subjects must be current cigarette smokers (no limitation as to pack years), who are
      well motivated to refrain from smoking, and who give a written consent to participate. The
      subjects will be randomly allocated to two groups (n=900 in each), receiving either Acetium
      lozenges or placebo, in a double-blind setting, where both the examiners and the test
      subjects are blinded to the test substance. All subjects must consent for not using any other
      measures of smoking cessation intervention. All subjects are requested to fill in a
      structured questionnaire recoding their detailed smoking history and assessing their nicotine
      dependence by FTND (Fagerström Test for Nicotine Dependence) and breath CO-monitoring. The
      subjects will be administered a smoking diary, to be filled on daily basis, recording the
      daily numbers of cigarettes, test lozenges and subjective sensations of smoking. These
      diaries are returned to study monitors on three-monthly FU visits, when also subjected to new
      FTND and CO-monitoring.

      The primary study endpoints include PPA (point prevalence of abstinent rate) and PA
      (prolonged abstinence), used for calculating OR (95%CI) between the two study arms by
      logistic regression. Changes in FTND score and CO-levels represent intermediate surrogate
      endpoints of PP and PA. In addition, time to quit (TTQ) and duration of quit (QT=quit time)
      can be used as dependent variables in univariate (Kaplan-Meier) and multivariate (Cox)
      survival analyses. GEE and Poisson models are used to estimate the covariates
      (Acetium/Placebo) of i) persistence of abstinence, and ii) quit events (events/person time at
      risk), respectively, based on multiple records (panel data) in a longitudinal setting.
      Finally, the predictors of the multiple outcomes in this intervention trial can be estimated
      using the novel competing-risks regression model, where i) no effect, ii) permanent quit,
      iii) temporary quit with relapse, and iv) smoking reduction, represent the competing-risks
      events.

      The power of the study can be calculated specifically for each of these statistical
      techniques, most simply by the two-sample proportion test for PP and PA. This study (n=900 in
      both arms) is adequately powered (Type II error 0.80, type I error 0.05) to detect a true
      difference (in PP or PA) of 5% between the two arms, within the range of 10% vs. 20% quit
      rate in the two arms. Within this (10-20%) range, the study power is sensitive to any
      decrease in this difference, but allows less difference (7.5%) if the quit rate falls between
      5% and 15% in the arms.

      Specific aims: The null hypothesis of the study implicates that Acetium lozenges are not
      superior to placebo in the intervention for smoking quit during the 1-year intervention.
      Rejection or not of the null hypothesis is based on comparison of the two arms by the
      different statistical approaches listed above.

      Impact of the study: This double-blind, placebo-controlled intervention trial will test the
      new hypothesis whether or not Acetium lozenges are superior to placebo as triggers of smoking
      quit when regularly used in context of smoking for a prolonged period. If this concept proves
      to be correct, the results will have a major clinical impact while providing an entirely
      novel approach to support regular smokers to withdraw this unhealthy habit.
    

Intervention name(s): Acetium Lozenge; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Slow-release L-Cysteine to block smoke.derived acetaldehyde in saliva thereby inhibiting the formation of harmans; Placebo with no active substance will not have the effect on intervention device.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other
Keywords: smoking; tobacco; smoking cessation