Smoking Topography Study 2018
Condition: Cigarette Smoking; Smoking Behavior; Cigarette Smoking Toxicity
Study type: Interventional

Summary: 
      Rationale: The World Health Organization Framework Convention on Tobacco Control (WHO FCTC)
      aims for a regulatory strategy including the regulation of the contents of tobacco products
      (Article 9). Cigarette smoke includes more than 7000 chemicals which are harmful and cause
      tobacco-related diseases. In the future, regulation of these harmful cigarette constituents
      should be based on more chemical classes, as the WHO suggested. However, in order to
      introduce such class-based regulation, a scientific base is needed to define upper limits of
      allowed amounts of chemicals (groups) in cigarette smoke emissions and to ensure decreased
      harmful health effects due to cigarette smoking. To date, the causality between human
      exposure to specific cigarette smoke compounds and the harmful effects is unknown. The first
      step in closing the gap in knowledge between cigarette smoke exposure and developing
      tobacco-related diseases includes a proper determination of human exposure to cigarette smoke
      chemicals. This includes measuring smoking topography and inhalation. Smoking topography is
      how the smoker smokes the cigarette (puff volume, duration, flow etc). The goal is to link
      smoking behavior to smoke exposure, for 2 different cigarette brands. The participants will
      smoke their 'normal' brand Marlboro (experimental day 1) after which they receive the low
      TNCO (tar, nicotine and carbon monoxide) Marlboro Prime to smoke at home. A week later the
      experimental day (day 2) is repeated with this cigarette. On the last experimental day (day
      3), the participants will smoke the Prime cigarette while the ventilation holes of this
      low-TNCO cigarette are taped. Afterwards, the personal smoking profiles of the participants,
      and thus their individual exposures, will be mimicked in the lab using machine smoking. The
      observed smoking topography and inhalation parameters together give information about the
      exposure to smoke toxicants. In addition, this study is also designed to measure biomarkers
      of exposure in body fluids of smokers, such as nicotine and the most abundant cigarette smoke
      chemicals and their metabolites.

      Objective: We want to find out whether the individual habitudinal smoking topography of a
      smoker smoking his usual brand, and the changes between cigarettes over the day, can be
      compared to that of smoking a low-TNCO or high nicotine cigarette (i.e. the Marlboro Prime
      and Red Sun). In addition, differences in inhalation patterns are investigated. Next to that,
      the exposure will be connected to the nicotine and carbon monoxide levels in blood and/or
      urine. Also smoke toxicants (and metabolites) in exhaled air, saliva, urine and blood of
      smokers are determined.

      Study design: This prospective observational study monitors smokers in their habitudinal
      smoking during the day (for 10 hr) while smoking Marlboro, Marlboro Prime and Marlboro Prime
      taped cigarette, while during the day bodily fluids are sampled at several time points.

      Study population: This population consists of 18 Caucasian, healthy, adult males, aged
      between 25-34 years old. Participants should be used to smoke Marlboro (red/regular) for at
      least 3 years with a daily average of 13 to 25 cigarettes (about a package every day).

      Nature and extent of the burden and risks associated with participation, benefit and group
      relatedness: The participating smokers smoke according to their habitudinal smoking pattern,
      and are therefore not increasingly exposed to the harmful health effects of cigarette
      smoking. The invasive part of the study is their stay for 3 days (and 1 night when wanted) in
      a hotel, and the sampling of blood, saliva, urine and exhaled air.
    

Detailed description: 
      In 2005, the World Health Organization Framework Convention on Tobacco Control (WHO FCTC) was
      established with the aim for a regulatory strategy as a response to the globalization of the
      tobacco epidemic. One of their non-price measures to reduce the demand for tobacco includes
      article 9: Regulation of the contents of tobacco products . Cigarette product regulation is
      currently based on tar, nicotine and carbon monoxide (TNCO) levels in cigarette smoke, which
      are indicated on the package. This is not sufficient, since cigarette smoke includes more
      than 7000 chemicals. There are aldehydes, VOCs, PAHs, nitrosamines, metals and so much more
      measured in cigarette, causing tobacco-related diseases .

      In the future, regulation of these harmful cigarette constituents should be based on more
      chemical classes, as the WHO suggested. However, in order to introduce such class-based
      regulation, a scientific base is needed to define upper limits of allowed amounts of
      chemicals (groups) in cigarette smoke emissions and to ensure decreased harmful effects due
      to cigarette smoking. To date, the causality between human exposure to specific cigarette
      smoke compounds and the harmful effects is unknown. The first step in closing the gap in
      knowledge between cigarette smoke exposure and developing tobacco-related diseases includes a
      proper determination of human exposure to cigarette smoke chemicals.

      Unfortunately, there is a lack of methodology to determine cigarette smoke exposure in humans
      .

      In a prospective observational pilot study in February 2016, natural human smoking behavior
      was characterized: Smoking Topography Study 2016 (NL55676.068.15). The smoking topography of
      every smoked Marlboro cigarette was monitored through the CRESSmicro device, which records
      the puff length, the puff interval, the puff flow and the puff volume. In this study, the
      investigators could model the individual smoking profiles per participant by using data of 4
      random cigarettes. During modelling, puff volume, duration (and thus also flow) and interpuff
      interval were taken into account.

      Since there were no differences in smoking topography of cigarettes smoked observed at
      different times of the day implies that in this new study, the researchers can invite
      participants for a shorter time because only data of 4 cigarettes is needed to adequately
      model their overall smoking profile needed for exposure measurements. These smoking
      topography parameters are needed for the settings of a smoking machine, applied to mimic the
      exact exposure to cigarette smoke toxicants for each individual.

      In our previous study the researchers concluded that smokers have their own individual
      smoking topography. Of course, smoking is also accompanied by the inhalation of harmful
      chemicals, but the smoker is not aware of this during smoking and therefore does not adapt
      his smoking topography with respect to that exposure. However, it is unknown by what means
      the individual smoking topography parameters are related to toxicant exposure in the
      different parts of the lungs. For example, higher puff volumes with a different composition
      of toxicants lead to a different inhalation pattern than small puff volumes, possible
      followed by different exposure in the lungs.

      In this new study the researchers want to include respiratory parameters of breathing and
      inhalation over the day as well. Until now, inhalation risk assessment is based on human
      breathing patterns, while breathing and inhaling smoke are not the same due to the presence
      of harsh compounds in the smoke. The current study aims to measure respiratory parameters to
      identify which lung compartments are exposed to what extent in relation to the observed
      smoking topography. This can be achieved by respiratory inductive plethysmography (RIP), a
      non-invasive device that can be worn throughout the day. In the current study, the Hexoskin
      will be applied for these measurements.

      Literature describes that the process of smoking topography and inhalation differs per
      cigarette and situation . In other words, the smoker doses himself to gain nicotine, with
      additional production of carbon monoxide (CO) and other harmful cigarette smoke-associated
      chemicals.

      As described before, in the future cigarettes will be changed as they are only allowed to
      contain a maximum of certain toxicants. One of the options to make cigarettes less addictive
      is to add less nicotine. It is known that smokers show compensating behavior when smoking
      other cigarettes than their used to, to gain the same amount of nicotine. Our machine smoking
      experiments show that when smoking low-TNCO cigarettes, the composition of the smoke per mg
      nicotine changes under the same smoking conditions. This means that the cigarette
      characteristics are also at least partly responsible for the smoke composition. The
      researchers are interested in how smoking behavior and inhalation, and thus exposure, changes
      when offering a smoker another type of cigarette.

      Therefore, the researchers are interested whether the smoking behavior changes when the
      smoker has to smoke a low TNCO cigarette, i.e. the Marlboro Prime. The low values of nicotine
      in the smoke of the Marlboro Prime are partly achieved by ventilation holes in the cigarette
      filter. By closing these filter vents with tape around the filter, the smoke is no longer
      diluted with side stream air, and the cigarette design is slightly different.

      The participants will smoke their 'normal' brand Marlboro (day 1). After the experimental
      day, they receive the Marlboro Prime for smoking at home, so they get used to smoking a 'new'
      cigarette. A week later the experimental day (day 2) is repeated with this cigarette. The
      participants can stay overnight, or come back the next day (day 3) to smoke the Prime
      cigarette while the ventilation holes of this low-TNCO cigarette are taped. See the scheme in
      Table 1.

      As in the STS2016, this study again is aimed at measuring smoking in a habitual rhythm
      without imposing it as has been done thus far , , . With this, the natural smoking topography
      per cigarette can be measured, in combination with the respiratory parameters by wearing a
      non-invasive RIP device. By providing the participants with the Marlboro Prime cigarettes
      prior to the experimental days 2 and 3, they can get used to smoking them at home in order to
      develop 'natural' smoking behavior.

      As during the last study, the sampling is following a sampling scheme (Figure 1). In summary,
      during the day, blood, exhaled air, urine and saliva will be sampled to measure nicotine,
      carbon monoxide, but also other cigarette smoke compounds, such as aldehydes and their
      metabolites.

      In the future, the personal smoking regimes of the participants, and thus their personal
      exposures, will be mimicked with machine smoking experiments. This will be linked to the RIP
      parameters.

      Points of attention that came out of the STS 2016, include that smokers smoked less
      cigarettes than expected. Reason for that is, as they mentioned, that they cannot smoke in
      the apartment, while they smoke inside at home. Another reason was that they have to smoke
      alone, while at home or work there often is a co-smoker. The participants didn't experience
      difficulties or changes in smoking behavior due to the use of CRESS. They all 'practiced'
      smoking with the CRESS the evening before the experimental day. In the present study 2
      smokers will be invited at the same time. Again, smokers have to go outside for a smoke to
      protect the researchers to secondhand smoke exposure. This is kept as attainable as possible.

      Primary Objective:

      Is there a difference in natural smoking topography between Marlboro, Marlboro Prime and
      Marlboro Prime taped leading to a different exposure for the smoker?

      Secondary Objective(s):

      Is it possible to map personal smoking profiles with only 4 random cigarettes, as showed in
      the previous Smoking Topography Study 2016?

      Is a different smoking topography profile per smoker related to deviating exposure of
      mainstream smoke in the respiratory tract compartments, for the different cigarettes?

      Can exhaled air of smokers be used as biomarker for exposure to VOCs/aldehydes?

      Are nicotine and toxicant (metabolite) levels in blood/urine changing over the day and
      connected to the smoking behavior of the different cigarettes?

      Study Design The Smoking Topography Study 2018 is a not-randomized cross-over study with a
      single group, with the duration of 3 months. Participants will visit our research apartment
      at Apart Hotel Randwyck, for 1 day in the first week and 2 days in the second week (Table 1).

      An experimental day starts at 08.00hr and ends at 19.00hr (Figure 1). The different study
      days have exactly the same set-up with the cigarette brand smoked during the day being the
      only difference. In this study it is important that the participants are able to smoke
      cigarettes 'ad libitum'. Because it is impossible to monitor this smoking topography at home,
      The smoking topography is measured at a research location. Therefore, this study takes place
      in an apartment at Hotel Randwyck in a homelike atmosphere where standardized meals are
      served and cigarettes can be smoked when and how the participant desires. The smoking
      topography of every smoked cigarette will be monitored through the CRESSmicro device, which
      records the puff length, the puff interval, the puff flow and the puff volume . Furthermore,
      the exact time point of smoking (i.e. the moment the cigarette is lit) is noted in the
      experiment time table.

      Due to this setup, the smoking topography measurements do not take place at scheduled time
      points and therefore only 2 participants per day will be measured. Total duration of the
      study will be 3 months, including 18 smoking individuals (Table 1).

      Participants are their own controls by measuring baseline samples (t=baseline). This sampling
      takes place upon arrival, before the first cigarette is smoked. Consequently, participants
      are asked not to smoke when waking up, but to wait upon their arrival at the research
      location. These baseline samplings include the collection of urine, exhaled air, blood, a
      mouth swap and saliva.

      Goal of a study day is to follow the smoker in his personal daily life smoking schedule. They
      can smoke when they want or feel the urge to smoke. Therefore, the sampling time points and
      the amount of cigarettes smoked are unknown per participant (Figure 1). Despite the unknown
      time points on forehand, smoking topography of every single cigarette within their presence
      at the research apartment is measured. During the whole experiment, experimental time is
      used. The start of the experiment (expected to be around 09.00hr) is the start of the
      experimental day, noted as timepoint 0. This is probably shortly after the baseline
      measurements.

      All spent cigarette butts are collected in separate plastic tubes per participant with the
      experimental smoking time noted. Because it is very important not to interfere with the daily
      life smoking schedule, the experiment day is divided into timeslots for urine and a fixed
      time point for saliva sampling.

      Urine will be collected at baseline and during 2 time periods. The first time point includes
      the baseline measurement before the first cigarette is smoked. Next, all urine between t=0
      and t=5 hours is collected in 1 beaker and urine between t=5 and t=10 is collected in another
      beaker. The participant is asked to empty his bladder just before the timeslots end. This
      results in 3 urine samples per participant.

      Saliva and a mouth swap are collected at t=baseline, t=0 (immediately after the first
      cigarette), t=5 and t=10. This results in 4 saliva samples and mouth swaps per participant.

      The exhaled air and blood samples are collected before and immediately after smoking a
      cigarette to have the most accurate measure associated with the cigarette smoking. However,
      the smoking time points are uncertain due to the chosen setup of this study. However, since
      all smokers included smoke around 20 cigarettes a day, they will at least smoke every 2 to
      2.5 hours. Therefore, time periods of 2.5 hours in which the first cigarette smoked is used
      for sampling blood and exhaled air, immediately after finishing smoking.

      At baseline, the participant is asked to exhale via the nosemouth cap of the Owlstone (a
      breathing device) whereby the exhaled air passes the adsorption tubes. The exhaled air just
      before and after finishing smoking the first cigarette is collected (t=0). The same is done
      for cigarettes smoked between t=2.5 and t=5, between t=5 and t=7.5, between t=7.5 and t=10
      and the last sampling at T=10. This results in 7 exhaled air samples per participant.

      To avoid multiple punctures, the participants get a peripheral venous canula at baseline,
      after which the baseline blood sample is withdrawn. The next blood sample is withdrawn just
      before and after finishing smoking the first cigarette (t=0). Then, the sampling points are
      just before and immediately after the first cigarette between t=0 and t=2.5, between t=2.5
      and t=5, between t=5 and t=7.5, between t=7.5 and t=10 and the last sampling is at T=10. For
      analysis of blood aldehydes an extra blood sample will be drawn from the canula at baseline
      and immediately after the first cigarette as well as immediately before and after the first
      cigarette after t=5 and t=7.5. This results in 13 blood sampling points per participant.
    

Intervention name(s): Marlboro; Marlboro Prime; Marlboro Prime (ventilation holes taped)
Intervention type(s): Behavioral; Behavioral; Behavioral
Intervention description(s): Participants smoke Marlboro during the first experimental day, ad libitum.; Participants smoke Marlboro Prime during the second experimental day, ad libitum.; Participants smoke Marlboro Prime (filter ventilation holes taped) during the third experimental day, ad libitum.
Intervention model: Single Group Assignment
Intervention model description: Not-randomized crossover study with a single group
Masking: None (Open Label)
Primary purpose: Other