Reduction in Exposure to Selected Harmful and Potentially Harmful Constituents Approaching Those Observed Upon Smoking Abstinence in Smokers Switching to the Menthol Tobacco Heating System 2.2 for 3 Months (Part 1).

INTRODUCTION: The Tobacco Heating System (THS) is a "heat-not-burn" tobacco product designed to generate significantly lower levels of harmful and potentially harmful constituents (HPHCs) and present lower risk of harm than cigarettes. This study assessed the exposure reduction to selected HPHCs in smokers switching to menthol Tobacco Heating System (mTHS) 2.2 compared with smokers continuing smoking menthol cigarettes (mCCs) and smoking abstinence (SA) for 5 days in a confined setting, followed by an 86-day ambulatory period. METHODS: A total of 160 healthy adult US smokers participated in this randomized, three-arm parallel group, controlled clinical study. Biomarkers of exposure to 16 HPHCs were measured in blood and 24-hour urine. Safety was monitored throughout the study. Information was also gathered on product evaluation, product use, subjective effects, and clinical risk markers (co-publication Part 2). RESULTS: Nicotine uptake was comparable in both exposure groups (mTHS:mCC ratio of 96% on day 90). On day 5, biomarker of exposure levels to other HPHCs were reduced by 51%-96% in the mTHS group compared with the mCC group, and these reductions were sustained for most biomarkers of exposure over ambulatory period. After 90 days of use, the level of satisfaction with mTHS and suppression of urge to smoke were comparable to mCC. CONCLUSION: Switching from mCCs to mTHS significantly reduced the exposure to HPHCs to levels approaching those observed in subjects who abstained from smoking for the duration of the study. IMPLICATIONS: This study compared the impact of switching to mTHS on biomarkers of exposure, relative to continued smoking or SA. TRIAL REGISTRATION: NCT01989156 (ClinicalTrials.gov).

Favorable Changes in Biomarkers of Potential Harm to Reduce the Adverse Health Effects of Smoking in Smokers Switching to the Menthol Tobacco Heating System 2.2 for 3 Months (Part 2).

INTRODUCTION: Tobacco Heating System (THS) 2.2, a candidate modified-risk tobacco product, aims at offering an alternative to cigarettes for smokers while substantially reducing the exposure to harmful and potentially harmful constituents found in cigarette smoke. METHODS: One hundred and sixty healthy adult US smokers participated in this randomized, three-arm parallel group, controlled clinical study. Subjects were randomized in a 2:1:1 ratio to menthol Tobacco Heating System 2.2 (mTHS), menthol cigarette, or smoking abstinence for 5 days in confinement and 86 subsequent ambulatory days. Endpoints included biomarkers of exposure to harmful and potentially harmful constituents (reported in our co-publication, Part 1) and biomarkers of potential harm (BOPH). RESULTS: Compliance (protocol and allocated product exposure) was 51% and 18% in the mTHS and smoking abstinence arms, respectively, on day 90. Nonetheless, favorable changes in BOPHs of lipid metabolism (total cholesterol and high- and low-density cholesterol), endothelial dysfunction (soluble intercellular adhesion molecule-1), oxidative stress (8-epi-prostaglandin F2α), and cardiovascular risk factors (eg, high-sensitivity C-reactive protein) were observed in the mTHS group. Favorable effects in other BOPHs, including ones related to platelet activation (11-dehydrothromboxane B2) and metabolic syndrome (glucose), were more pronounced in normal weight subjects. CONCLUSIONS: The results suggest that the reduced exposure demonstrated when switching to mTHS is associated with overall improvements in BOPHs, which are indicative of pathomechanistic pathways underlying the development of smoking-related diseases, with some stronger effects in normal weight subjects. IMPLICATIONS: Switching to mTHS was associated with favorable changes for some BOPHs indicative of biological pathway alterations (eg, oxidative stress and endothelial dysfunction). The results suggest that switching to mTHS has the potential to reduce the adverse health effects of smoking and ultimately the risk of smoking-related diseases. Switching to mTHS for 90 days led to reductions in a number of biomarkers of exposure in smokers, relative to those who continued smoking cigarettes, which were close to those observed when stopping smoking (reported in our co-publication, Part 1). Initial findings suggest reduced levels of 8-epi-prostaglandin F2α and intercellular adhesion molecule 1, when switching to mTHS for 90 days. These changes are comparable to what is observed upon smoking cessation. In normal weight subjects, additional favorable changes were seen in 11-dehydrothromboxane B2, fibrinogen, homocysteine, hs-CRP, percentage of predicted forced expiratory volume in 1 second, systolic blood pressure, diastolic blood pressure, glucose, high-density lipoprotein, apolipoprotein A1, and triglycerides. TRIAL REGISTRATION: NCT01989156.

Review of biomarkers to assess the effects of switching from cigarettes to modified risk tobacco products.

Context: One approach to reducing the harm caused by cigarette smoking, at both individual and population level, is to develop, assess and commercialize modified risk alternatives that adult smokers can switch to. Studies to demonstrate the exposure and risk reduction potential of such products generally involve the measuring of biomarkers, of both exposure and effect, sampled in various biological matrices.Objective: In this review, we detail the pros and cons for using several biomarkers as indicators of effects of changing from conventional cigarettes to modified risk products.Materials and methods: English language publications between 2008 and 2017 were retrieved from PubMed using the same search criteria for each of the 25 assessed biomarkers. Nine exclusion criteria were applied to exclude non-relevant publications.Results: A total of 8876 articles were retrieved (of which 7476 were excluded according to the exclusion criteria). The literature indicates that not all assessed biomarkers return to baseline levels following smoking cessation during the study periods but that nine had potential for use in medium to long-term studies.Discussion and conclusion: In clinical studies, it is important to choose biomarkers that show the biological effect of cessation within the duration of the study.

Effects of Switching to the Tobacco Heating System 2.2 Menthol, Smoking Abstinence, or Continued Cigarette Smoking on Biomarkers of Exposure: A Randomized, Controlled, Open-Label, Multicenter Study in Sequential Confinement and Ambulatory Settings (Part 1).

Introduction: The menthol Tobacco Heating System 2.2 (mTHS) is a newly developed candidate modified-risk tobacco product intended to reduce exposure to the harmful and potentially harmful constituents (HPHCs) of conventional cigarette (CC) smoke. This study examined the impact of switching to mTHS on biomarkers of exposure to HPHCs relative to menthol CCs (mCCs) and smoking abstinence (SA). Methods: In this three-arm, parallel-group study, 160 Japanese adult smokers (23-65 years; smoking ≥10 mCCs per day) were randomized to mTHS (n = 78), mCC (n = 42), or SA (n = 40) for 5 days in confinement and 85 days in ambulatory settings. Endpoints included biomarkers of exposure to HPHCs, human puffing topography, safety, and subjective effects of smoking measures. Results: After 5 days of product use, the concentrations of carboxyhemoglobin, 3-hydroxypropylmercapturic acid, monohydroxybutenyl mercapturic acid, and S-phenylmercapturic acid were 55%, 49%, 87%, and 89% lower (p < .001), respectively, in the mTHS group than in the mCC group. Other biomarkers of exposure (measured as secondary endpoints) were 50%-94% lower in the mTHS group than in the mCC group on day 5. These reductions in the mTHS group were maintained at day 90, similar to the SA group. Switching to mTHS was associated with changes in human puffing topography (shorter puff intervals and more frequent puffs). The urge-to-smoke and smoking satisfaction levels on day 90 were similar in the mTHS and the mCC groups. Conclusion: Switching from mCCs to mTHS significantly reduced exposure to HPHCs relative to continuing smoking mCCs with concentrations similar to those observed following SA in Japanese adult smokers. Implications: This randomized study compared the impact of switching to a modified-risk tobacco product candidate mTHS on biomarkers of exposure to HPHCs of cigarette smoke relative to continuing smoking cigarettes or abstaining from smoking in sequential confinement and ambulatory settings. The study showed that switching to mTHS was associated with significant biomarker reductions within 5 days in confinement, these reductions being maintained throughout the ambulatory setting up to day 90. The results provide evidence that switching to mTHS reduces real-life exposure to HPHCs in adult smokers.

Effects of Switching to the Menthol Tobacco Heating System 2.2, Smoking Abstinence, or Continued Cigarette Smoking on Clinically Relevant Risk Markers: A Randomized, Controlled, Open-Label, Multicenter Study in Sequential Confinement and Ambulatory Settings (Part 2).

Introduction: Modified-risk tobacco products are expected to reduce exposure to harmful and potentially harmful constituents of cigarette smoke, and ultimately reduce the health burden of smoking-related diseases. Clinically relevant risk markers of smoking-related diseases inform about the risk profile of new tobacco products in the absence of in-market epidemiological data. The menthol Tobacco Heating System 2.2 (mTHS) is a modified-risk tobacco product in development as an alternative to cigarettes (conventional cigarettes [CCs]). Methods: In this parallel-group study, Japanese adult smokers (23-65 years; ≥10 mCCs/day) were randomized to mTHS, menthol CCs (mCC), or smoking abstinence (SA) for 5 days in confinement and 85 days in ambulatory settings. Endpoints included biomarkers of exposure to harmful and potentially harmful constituents and clinically relevant risk markers of smoking-related diseases. Results: One-hundred and sixty participants were randomized to the mTHS (n = 78), mCC (n = 42), and SA (n = 40) groups. Switching to the mTHS was associated with reductions in biomarkers of exposure compared with continuing mCCs. Reductions in 8-epi-prostaglandin F2α (biomarker of oxidative stress), 11-dehydro-thromboxane B2 (biomarker of platelet activation), soluble intracellular adhesion molecule-1 (biomarker of endothelial function), and an increase in high-density lipoprotein cholesterol (biomarker of lipid metabolism) and forced expiratory volume in 1 second (biomarker of lung function) occurred in the mTHS group compared with the mCC group. The changes in the mTHS group approached those in the SA group. Conclusions: Switching from mCCs to mTHS was associated with improvements in clinically relevant risk markers linked to mechanistic pathways involved in smoking-related diseases. Implications: In this three-way randomized study, switching from menthol cigarettes to mTHS for 5 days in confinement and 85 days in ambulatory settings was associated with reductions in biomarkers of exposure to cigarette smoke, and changes were observed in clinically relevant biomarkers of oxidative stress (8-epi-prostaglandin F2α), platelet activity (11-dehydro-thromboxane B2), endothelial function (soluble intracellular adhesion molecule-1), lipid metabolism (high-density lipoprotein cholesterol) and lung function (forced expiratory volume in 1 second), similar to the SA group. The results suggest that switching to the mTHS has the potential to reduce the adverse health effects of conventional cigarettes.

Evaluation of Nicotine Pharmacokinetics and Subjective Effects following Use of a Novel Nicotine Delivery System.

Introduction: Novel nicotine delivery systems represent an evolving part of the tobacco harm reduction strategy. The pharmacokinetic (PK) profile of nicotine delivered by P3L, a pulmonary nicotine delivery system, and its effects on smoking urges and craving relief in relation to Nicorette inhalator were evaluated. Methods: This open-label, ascending nicotine levels study was conducted in 16 healthy smokers. Three different nicotine delivery levels, 50, 80, and 150 µg/puff, delivered by the P3L system were evaluated consecutively on different days after the use of the Nicorette inhalator. Venous nicotine PK, subjective effects, and tolerability were assessed. Results: Geometric least-squares means for maximum plasma nicotine concentration (Cmax), generated by the mixed-effect model for exposure comparison, were 9.7, 11.2, and 9.8 ng/mL for the 50, 80, and 150 µg/puff P3L variants, respectively, compared to 6.1 ng/mL after Nicorette inhalator use. Median time from product use start to Cmax was 7.0 minutes for all P3L, compared to 30.0 minutes for the Nicorette inhalator. Craving reduction was slightly faster than with the Nicorette inhalator as assessed with the visual analog scale craving score. The mean Questionnaire of Smoking Urges -brief total scores did not differ for both products. P3L was well tolerated. Conclusions: At all three nicotine levels tested, the inhalation of the nicotine lactate aerosol delivered with the P3L provided plasma nicotine concentrations higher and faster compared to the Nicorette inhalator. The plasma nicotine concentration-time profile supports a pulmonary route of absorption for P3L compared to the oromucosal absorption of the Nicorette inhalator. Implications: The combination of nicotine and lactic acid with the P3L device shows potential over existing nicotine delivery systems by delivering nicotine with kinetics close to published data on conventional cigarettes and without exogenous carrier substances as used in current electronic nicotine delivery systems. Altogether, the PK profile, subjective effects, and safety profile obtained in this study suggest P3L is an innovative nicotine delivery product that will be acceptable to adult smokers as an alternative to cigarettes.

Development and validation of a new instrument to measure perceived risks associated with the use of tobacco and nicotine-containing products.

BACKGROUND: Making tobacco products associated with lower risks available to smokers who would otherwise continue smoking is recognized as an important strategy towards addressing smoking-related harm. Predicting use behavior is an important major component of product risk assessment. In this context, risk perception is a possible factor driving tobacco product uptake and use. As prior to market launch real-world actual product use cannot be observed, assessing risk perception can provide predictive information. Considering the lack of suitable validated self-report instruments, the development of a new instrument was undertaken to quantify perceived risks of tobacco and nicotine-containing products by adult smokers, former smokers and never-smokers. METHODS: Initial items were constructed based on a literature review, focus groups and expert opinion. Data for scale formation and assessment were obtained through two successive US-based web surveys (n = 2020 and 1640 completers, respectively). Psychometric evaluation was based on Rasch Measurement Theory and Classical Test Theory. RESULTS: Psychometric evaluation supported the formation of an 18-item Perceived Health Risk scale and a 7-item Perceived Addiction Risk scale: item response option thresholds were ordered correctly for all items; item locations in each scale were spread out (coverage range 75-87%); scale reliability was supported by high person separation indices > 0.93, Cronbach's alpha > 0.98 and Corrected Item-Total Correlations > 0.88; and no differential item functioning was present. Construct validity evaluations met expectations through inter-scale correlations and findings from known-group comparisons. CONCLUSIONS: The Perceived Risk Instrument is a psychometrically robust instrument applicable for general and personal risk perception measurement, for use in different types of products (including cigarettes, nicotine replacement therapy, potential Modified Risk Tobacco Products), and for different smoking status groups (i.e., current smokers with and without intention to quit, former smokers, never smokers).

Quantifying the risk-reduction potential of new Modified Risk Tobacco Products.

Quantitative risk assessment of novel Modified Risk Tobacco Products (MRTP) must rest on indirect measurements that are indicative of disease development prior to epidemiological data becoming available. For this purpose, a Population Health Impact Model (PHIM) has been developed to estimate the reduction in the number of deaths from smoking-related diseases following the introduction of an MRTP. One key parameter of the model, the F-factor, describes the effective dose upon switching from cigarette smoking to using an MRTP. Biomarker data, collected in clinical studies, can be analyzed to estimate the effects of switching to an MRTP as compared to quitting smoking. Based on transparent assumptions, a link function is formulated that translates these effects into the F-factor. The concepts of 'lack of sufficiency' and 'necessity' are introduced, allowing for a parametrization of a family of link functions. These can be uniformly sampled, thus providing different 'scenarios' on how biomarker-based evidence can be translated into the F-factor to inform the PHIM.

Reduced Exposure to Harmful and Potentially Harmful Smoke Constituents With the Tobacco Heating System 2.1.

INTRODUCTION: Heating rather than burning tobacco reduces levels of harmful and potentially harmful constituents, and consumer products using this approach aim to reduce exposure to tobacco toxicants. The Tobacco Heating System (THS) version 2.1 has been enhanced from earlier prototypes with an improved heat control and sensorial experience and thereby user acceptance. Exposure measurements are required to determine whether it may be possible to reduce the individual health risk compared to smoking combustible cigarettes (CCs). METHODS: This controlled clinical study randomly assigned 40 smokers to either a group continuing to use of their own CC brand (n = 20) or a group switching to THS 2.1 (n = 20) for 5 days. Biomarkers of exposure were measured at baseline and on day 1 through day 5. Product consumption, Human Puffing Topography, the occurrence of adverse events, and an assessment of subjective effects, such as smoking satisfaction and enjoyment of respiratory tract sensations, were also determined. RESULTS: The group of smokers who switched to THS 2.1 adapted their puffing behavior initially through longer puff duration and more puffs. During the duration of the study, total puff volume returned to baseline levels and the mean daily product consumption increased but with similar nicotine exposure compared to baseline CC use. Biomarkers of exposure to tobacco smoke toxicants which inform product risk assessment were significantly reduced with THS use compared to the CC group. THS 2.1 users experienced less reinforcing effects with THS 2.1 than with their own cigarette brand. CONCLUSIONS: THS 2.1 is a promising alternative to smoking CCs. Notwithstanding possible use adaption through consumption or puffing behavior, the exposure to harmful smoke constituents was markedly reduced with the new heated tobacco platform. IMPLICATIONS: Exposure markers to harmful and potentially harmful smoke constituents were lowered with the THS 2.1. Heating tobacco instead of burning can offer a potentially lower risk of delivering nicotine compared to CCs.

Nicotine pharmacokinetic profiles of the Tobacco Heating System 2.2, cigarettes and nicotine gum in Japanese smokers.

Two open-label randomized cross-over studies in Japanese smokers investigated the single-use nicotine pharmacokinetic profile of the Tobacco Heating System (THS) 2.2, cigarettes (CC) and nicotine replacement therapy (Gum). In each study, one on the regular and one on the menthol variants of the THS and CC, both using Gum as reference, 62 subjects were randomized to four sequences: Sequence 1: THS - CC (n = 22); Sequence 2: CC - THS (n = 22); Sequence 3: THS - Gum (n = 9); Sequence 4: Gum - THS (n = 9). Plasma nicotine concentrations were measured in 16 blood samples collected over 24 h after single use. Maximal nicotine concentration (Cmax) and area under the curve from start of product use to time of last quantifiable concentration (AUC0-last) were similar between THS and CC in both studies, with ratios varying from 88 to 104% for Cmax and from 96 to 98% for AUC0-last. Urge-to-smoke total scores were comparable between THS and CC. The THS nicotine pharmacokinetic profile was close to CC, with similar levels of urge-to-smoke. This suggests that THS can satisfy smokers and be a viable alternative to cigarettes for adult smokers who want to continue using tobacco.

Evaluation of Biomarkers of Exposure in Smokers Switching to a Carbon-Heated Tobacco Product: A Controlled, Randomized, Open-Label 5-Day Exposure Study.

INTRODUCTION: Tobacco harm reduction aims to provide reduced risk alternatives to adult smokers who would otherwise continue smoking combustible cigarettes (CCs). This randomized, open-label, three-arm, parallel-group, single-center, short-term confinement study aimed to investigate the effects of exposure to selected harmful and potentially harmful constituents (HPHCs) of cigarette smoke in adult smokers who switched to a carbon-heated tobacco product (CHTP) compared with adult smokers who continued to smoke CCs and those who abstained from smoking for 5 days. METHODS: Biomarkers of exposure to HPHCs, including nicotine and urinary excretion of mutagenic material, were measured in 24-hour urine and blood samples in 112 male and female Caucasian smokers switching from CCs to the CHTP ad libitum use. Puffing topography was assessed during product use. RESULTS: Switching to the CHTP or smoking abstinence (SA) resulted in marked decreases from baseline to Day 5 in all biomarkers of exposure measured, including carboxyhemoglobin (43% and 55% decrease in the CHTP and SA groups, respectively). The urinary excretion of mutagenic material was also markedly decreased on Day 5 compared with baseline (89% and 87% decrease in the CHTP and SA groups, respectively). No changes in biomarkers of exposure to HPHCs or urinary mutagenic material were observed between baseline and Day 5 in the CC group. CONCLUSIONS: Our results provide clear evidence supporting a reduction in the level of exposure to HPHCs of tobacco smoke in smokers who switch to CHTP under controlled conditions, similar to that observed in SA. IMPLICATIONS: The reductions observed in biomarkers of exposure to HPHCs of tobacco smoke in this short-term study could potentially also reduce the incidence of cancer, cardiovascular and respiratory diseases in those smokers who switch to a heated tobacco product.

Comparison of the Pharmacokinetics of Nicotine Following Single and Ad Libitum Use of a Tobacco Heating System or Combustible Cigarettes.

INTRODUCTION: We aimed to compare the pharmacokinetics of nicotine between the heat-not-burn Tobacco Heating System 2.1 (THS 2.1) and combustible cigarettes (CCs). We also examined whether the subjective urge to smoke was associated with the pharmacokinetics of nicotine. METHODS: This open-label, randomized, two-period, two-sequence crossover study conducted in 28 healthy smokers assessed the pharmacokinetics of nicotine after single and ad libitum use of the THS 2.1 or CCs. During the 7-day confinement period, blood samples were drawn for pharmacokinetic analysis. Subjective effects related to THS 2.1 or CC use were assessed using the Questionnaire of Smoking Urges (QSU-Brief). RESULTS: The nicotine delivery rate was similar with the THS 2.1 and CCs after single and ad libitum use. The time to the maximum nicotine concentration was 8 minutes after single use of the THS 2.1 and CCs. The time to the peak concentration following ad libitum use was similar between the THS 2.1 and CCs. The maximum plasma nicotine concentration after single use of the THS 2.1 was 8.4 ng/mL, 70.3% of that obtained with CCs. A transient reduction from baseline in the urge to smoke of 40% was observed 15 minutes after the single use of both the THS 2.1 and CCs. The mean QSU-Brief total scores following single and ad libitum use were similar for the THS 2.1 and CCs. CONCLUSIONS: These results suggest that the THS 2.1 effectively delivers nicotine and achieves similar pharmacokinetic profiles to CCs. The THS 2.1 also reduced the urge to smoke similarly to CCs. IMPLICATIONS: Reducing exposure to toxicants and safer delivery of nicotine are among the strategies that may reduce the harm of smoking-related diseases. In the present study, we investigated the pharmacokinetics of nicotine and their effects on the urge to smoke using the THS 2.1. It was developed to replicate the ritual of smoking as closely as possible by providing nicotine in a way that mimics CC smoking, but limits pyrolysis and combustion by heating tobacco at a much lower temperature than CCs (heat-not-burn).

Evaluation of the Tobacco Heating System 2.2. Part 1: Description of the system and the scientific assessment program.

This publication introduces a series of eight other publications describing the non-clinical assessment and initial clinical study of a candidate modified risk tobacco product (MRTP) - the Tobacco Heating System 2.2 (THS2.2). This paper presents background information on tobacco harm reduction, to complement the approaches aimed at increasing smoking cessation and reducing smoking initiation to reduce the morbidity and mortality caused by cigarette smoking. THS2.2 heats tobacco without combustion, and the resulting formation of harmful and potentially harmful constituents (HPHC) is greatly reduced compared with cigarette smoke. Assessment of the THS2.2 aerosol in vitro and in vivo reveals reduced toxicity and no new hazards. Additional mechanistic endpoints, measured as part of in vivo studies, confirmed reduced impact on smoking-related disease networks. The clinical study confirmed the reduced exposure to HPHCs in smokers switching to THS2.2, and the associated transcriptomic study confirmed the utility of a gene expression signature, consisting of only 11 genes tested in the blood transcriptome of subjects enrolled in the clinical study, as a complementary measure of exposure response. The potential of THS2.2 as an MRTP is demonstrated by the assessment and additional publications cited in this series.

Evaluation of the Tobacco Heating System 2.2. Part 8: 5-Day randomized reduced exposure clinical study in Poland.

The Tobacco Heating System (THS) 2.2, a candidate Modified Risk Tobacco Product (MRTP), is designed to heat tobacco without burning it. Tobacco is heated in order to reduce the formation of harmful and potentially harmful constituents (HPHC), and reduce the consequent exposure, compared with combustible cigarettes (CC). In this 5-day exposure, controlled, parallel-group, open-label clinical study, 160 smoking, healthy subjects were randomized to three groups and asked to: (1) switch from CCs to THS 2.2 (THS group; 80 participants); (2) continue to use their own non-menthol CC brand (CC group; 41 participants); or (3) to refrain from smoking (smoking abstinence (SA) group; 39 participants). Biomarkers of exposure, except those associated with nicotine exposure, were significantly reduced in the THS group compared with the CC group, and approached the levels observed in the SA group. Increased product consumption and total puff volume were reported in the THS group. However, exposure to nicotine was similar to CC at the end of the confinement period. Reduction in urge-to-smoke was comparable between the THS and CC groups and THS 2.2 product was well tolerated.

Assessment of the reduction in levels of exposure to harmful and potentially harmful constituents in Japanese subjects using a novel tobacco heating system compared with conventional cigarettes and smoking abstinence: A randomized controlled study in confinement.

Smoking conventional cigarettes (CCs) exposes smokers to harmful and potentially harmful constituents (HPHCs). The Tobacco Heating System 2.2 (THS 2.2), a candidate modified risk tobacco product, was developed to reduce or eliminate the formation of HPHCs, while preserving as much as possible the taste, sensory experience, nicotine delivery profile and ritual characteristics of CC. This randomized, controlled, open-label study in confinement for 5 day exposure aimed to demonstrate the reduction in exposure to selected HPHCs, to assess nicotine uptake and subjective effects, in participants switching to THS 2.2 (n = 80) compared to participants continuing smoking CCs (n = 40) and abstaining from smoking (n = 40). The subjects were randomized according to sex and daily CC consumption. The levels of biomarkers of exposure to HPHCs were significantly reduced in participants switching to THS 2.2, compared to CC use. More importantly, the magnitude of exposure reduction observed was close to that which was seen in participants who abstained from smoking for 5 days, while nicotine uptake was maintained. Reduction in urge-to-smoke was comparable between THS and CC groups, however THS 2.2 was slightly less satisfactory than CCs. The new, alternative tobacco product THS 2.2 was well tolerated.

A Japanese cross-sectional multicentre study of biomarkers associated with cardiovascular disease in smokers and non-smokers.

We performed a cross-sectional, multicentre study in Japan to detect the differences in biomarkers of exposure and cardiovascular biomarkers between smokers and non-smokers. Several clinically relevant cardiovascular biomarkers differed significantly between smokers and non-smokers, including lipid metabolism (high-density lipoprotein cholesterol concentrations - lower in smokers), inflammation (fibrinogen and white blood cell count - both higher in smokers), oxidative stress (8-epi-prostaglandin F2α - higher in smokers) and platelet activation (11-dehydro-thromboxane B2 - higher in smokers) (p ≤ 0.0001). These results provide further evidence showing that cardiovascular biomarkers can discriminate smokers from non-smokers, and could be used to evaluate the risks associated with tobacco products.

A novel approach to assess the population health impact of introducing a Modified Risk Tobacco Product.

Based on the Food and Drug Administration's Modified Risk Tobacco Product (MRTP) Application draft guideline, Philip Morris International (PMI) has developed a Population Health Impact Model to estimate the reduction in the number of deaths over a period following the introduction of an MRTP. Such a model is necessary to assess the effect that its introduction would have on population health, given the lack of epidemiological data available prior to marketing authorization on any risks from MRTPs. The model is based on publicly available data on smoking prevalence and on the relationships between smoking-related disease-specific mortality and various aspects of the smoking of conventional cigarettes (CCs), together with an estimate of exposure from the MRTP relative to that from CCs, and allows the exploration of possible scenarios regarding the effect of MRTP introduction on the prevalence of CC and MRTP use, individually and in combination. By comparing mortality attributable in a scenario where the MRTP is introduced with one where it is not, the model can estimate the mortality attributable to CCs and the MRTP, as well as the reduction in the deaths attributable to the introduction of the MRTP.

Influence of smoking on levels of urinary 8-iso Prostaglandin F2α.

BACKGROUND: To evaluate the reduced-risk potential of alternative tobacco products, biomarkers that are involved in the biological pathways affected by cigarette smoking and smoking cessation are needed. Isoprostanes, a measure of oxidative stress, appear to be influenced by smoking and reversible upon smoking cessation and therefore could be a good biomarker. This review aims at quantifying the effect of smoking and smoking cessation on levels of urinary 8-iso prostaglandin F2α (8-epi-PGF2α), an isoprostane. METHODS: PubMed and Scopus databases were searched for publications that reported 8-epi-PGF2α levels in smokers and nonsmokers as well as articles reporting the effect of smoking cessation on 8-epi-PGF2α levels. RESULTS: Eighteen studies assessing 8-epi-PGF2α levels by smoking status were identified. Five of the papers reported the results as quantity excreted in 24-hour urine (µg/24 h), and 15 reported creatinine adjusted values. The meta-analyses show increased levels of 8-epi-PGF2α in current smokers compared with nonsmokers (mean difference = 0.16, 95% confidence interval [95%CI]: 0.14-0.19 µg/24 h with inconsistency statistic [I2] = 98%; mean difference = 172.38, 95%CI: 152.75-192.01 pg/mg creatinine with I2 = 89%, respectively). There were too few publications to perform a meta-analysis assessing the effects of smoking cessation on 8-epi-PGF2α levels. CONCLUSIONS: Due to the high heterogeneity among the studies included in these meta-analyses, it is difficult to generalize the results; however, our study indicates increased levels of 8-epi-PGF2α and therefore increased oxidative stress in smokers compared with nonsmokers. More studies are still needed to assess if 8-epi-PGF2α levels are reversible after cessation.

Household Surveys in the General Population and Web-Based Surveys in IQOS Users Registered at the Philip Morris International IQOS User Database: Protocols on the Use of Tobacco- and Nicotine-Containing Products in Germany, Italy, and the United Kingdom (Greater London), 2018-2020.

BACKGROUND: Philip Morris International (PMI) has developed a novel heat-not-burn tobacco product, Tobacco Heating System (THS), which is marketed under the brand name of IQOS with HEETS (IQOS). The aerosol generated by THS has substantially fewer toxicants than combustible cigarette smoke, although the extent of the reduction of harmful and potentially harmful constituents reported varies between studies. To evaluate the potential harm reduction associated with IQOS use, the assessment of the uptake and continued use of IQOS in the context of all other tobacco- and nicotine-containing products is crucial. In March 2018, PMI launched cross-sectional surveys in Germany, Italy, and the United Kingdom (Greater London) to estimate the prevalence and use patterns of IQOS and other tobacco- and nicotine-containing products use in these 3 markets following the commercialization of IQOS. This study describes the protocol of the surveys. OBJECTIVE: The objectives of these surveys are to estimate the prevalence of tobacco- and nicotine-containing products use; describe past and current patterns of use; and explore their associations with self-reported health, motivation to use, risk perceptions, and perceived aesthetic changes. METHODS: The overall design of the surveys is similar in all 3 countries. Repeated cross-sectional surveys are being conducted annually over 3 consecutive years (2018 to 2020) and in 2 samples: a representative sample of the general population and a sample of IQOS users. A total of 6085 adults per year will be selected from the general population for each survey through multistage stratified sampling, and participants will respond to face-to-face computer-assisted personal interviews. In addition, 1404, 1384, and 1246 IQOS users per year in Germany, Italy, and Greater London, respectively, will be randomly selected from the PMI IQOS user database and will be invited to complete the Web-based survey using computer-assisted self-interviews. The Smoking Questionnaire is used to assess the tobacco use patterns of the participants. RESULTS: The recruitment of the general population sample began in March 2018 and that of the IQOS user sample began in April 2018. The data collection is ongoing, and the results of the first year data analysis are expected to be available by June 2019. CONCLUSIONS: As the design of the 3 surveys is similar, the results will allow for cross-countries comparison of the prevalence of IQOS and other tobacco- and nicotine-containing products use as well as patterns of use and associated factors. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/12061.

Biological and Functional Changes in Healthy Adult Smokers Who Are Continuously Abstinent From Smoking for One Year: Protocol for a Prospective, Observational, Multicenter Cohort Study.

BACKGROUND: The harm of smoking results mainly from long-term exposure to harmful and potentially harmful constituents (HPHCs) generated by tobacco combustion. Smoking cessation (SC) engenders favorable changes of clinical signs, pathomechanisms, and metabolic processes that together could reduce the harm of smoking-related diseases to a relative risk level approximating that of never-smokers over time. In most SC studies, the main focus is on the quitting rate of the SC program being tested. As there is limited information in the literature on short to multiple long-term functional or biological changes following SC, more data on short to mid-term favorable impacts of SC are needed. OBJECTIVE: The overall aim of the study was to assess the reversibility of the harm related to smoking over 1 year of continuous smoking abstinence (SA). This has been verified by assessing a set of biomarkers of exposure to HPHCs and a set of biomarkers of effect indicative of multiple pathophysiological pathways underlying the development of smoking-related diseases. METHODS: This multiregional (United States, Japan, and Europe), multicenter (42 sites) cohort study consisting of a 1-year SA period in an ambulatory setting was conducted from May 2015 to May 2017. A total of 1184 male and female adult healthy smokers, willing to quit smoking, were enrolled in the study. Nicotine replacement therapy (NRT) was provided for up to 3 months upon the subject's request. SC counseling and behavioral support were continuously provided. Biomarkers of exposure to HPHCs and biomarkers of effect were assessed in urine and blood at baseline, Month 3, Month 6, and Month 12. Cardiovascular biomarkers of effect included parameters reflecting inflammation (white blood cell), lipid metabolism (high-density lipoprotein cholesterol), endothelial function (soluble intercellular adhesion molecule-1), platelet function (11-dehydrothromboxane B2), oxidative stress (8-epi-prostaglandin F2 alpha), and carbon monoxide exposure (carboxyhemoglobin). Respiratory biomarkers of effect included lung function parameters and cough symptoms. The biomarkers of effect to evaluate genotoxicity (total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) and xenobiotic metabolism (cytochrome P450 2A6 activity) were also assessed. Continuous SA was verified at each visit following the actual quit date using self-reporting and chemical verification. Safety assessments included adverse events and serious adverse events, body weight, vital signs, spirometry, electrocardiogram, clinical chemistry, hematology and urine analysis safety panel, physical examination, and concomitant medications. RESULTS: In total, 1184 subjects (50.1% male) were enrolled; 30% of them quit smoking successfully for 1 year. Data analyses of the study results are ongoing and will be published after study completion. CONCLUSIONS: This study provides insights into biological and functional changes and health effects, after continuous SA over 1 year. Study results will be instrumental in assessing novel alternative products to cigarettes considered for tobacco harm reduction strategies. TRIAL REGISTRATION: ClinicalTrials.gov NCT02432729; http://clinicaltrials.gov/ct2/show/NCT02432729 (Archived by WebCite at http://www.webcitation.org/78QxovZrr). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/12138.