Biomarker of Exposure Reductions Upon Switching for 5 Days from Cigarettes to a Carbon Heated Tobacco Product (CHTP 1.0)

Transcription

1 Biomarker of Exposure Reductions Upon Switching for Days from to a Carbon Heated Tobacco Product () A. Donelli, C. Tran, C. Haziza, J. Ancerewicz, G. de La Bourdonnaye, R. Weitkunat, and F. Lüdicke 8 healthy adult smokers (age of 21+) were randomly assigned to two groups and asked to: (1) switch from cigarettes to (41 participants) or (2) continue to use their own non-menthol cigarettes (39 participants). Participants were eligible if they smoked 1 commercially available non-menthol cigarettes per day for the last 6 weeks prior admission and had smoked cigarettes for 3 consecutive years before enrollment and were not planning to quit smoking in coming 3 months. Intro PMI R&D, Philip Morris Products S.A. Quai Jeanrenaud, 2 Neuchâtel, Switzerland (part of Philip Morris International group of companies) The Carbon Heated Tobacco Product () is designed to heat tobacco without burning it in order to reduce formation of, and consequently exposure to, harmful and potentially harmful constituents (HPHC) as compared to cigarettes while replicating the ritual, taste, sensory characteristics and nicotine uptake of cigarette smoking. The main objective of this study was to demonstrate the reduction of biomarkers of exposure (BoExp) to selected HPHCs in smokers switching from cigarettes to CHTP 1. as compared to smokers continuing to smoke cigarettes for consecutive days. Among other assessments the nicotine uptake and subjective effects of use were evaluated in this study. 1. is a heat-not-burn product that does not involve tobacco combustion 2. The product generates a nicotine-containing aerosol which has significantly lower levels of HPHCs than cigarettes 3. has been designed to resemble a cigarette as closely as possible Selected Harmful or Potentially Harmful Constituents (HPHC) of tobacco smoke 1 HPHCs IN SMOKE Carbon Monoxide Acrolein 1,3-Butadiene Benzene Nicotine Exposure to HPHCs was assessed by measuring the level of corresponding BoExp in urine and plasma. BoExp can be described as substances measured in human body as a result of ingestion of another substance Results REDUCTION IN HPHCs EXPOSURE: VS CIGARETTES (DAY ) NICOTINE UPTAKE Day levels were reduced, relative to cigarettes, by 8.8% to 88.1% in primary biomarkers COHb, MHBMA, 3-HPMA and SPMA. Other biomarkers were reduced by.6% to 97.1%. For more information see the brochure. Neq (mg/g creat) 1 SUBJECTIVE EFFECTS Nicotine (ng/ml) 2 Cotinine (mg/ml) % % Constituent: Acrolein % 1 Constituent: 1,3-Butadiene S-PMA 3 1 Constituent: Carbon Monoxide MHBMA 1 % 3-HPMA Total score 1 COHb Reward (Factor 2) 6 4 CIGARETTES Level of Biomarkers in the group smoking cigarettes Relief (Factor 1) % Constituent: Benzene Total 1-OHP -.6 % Constituent: Pyrene 4-ABP % Constituent: 4-aminobiphenyl 1-NA % 1. NEQ level was 3.% lower for the group compared to the cigarette group over all time points. 2. On day, plasma nicotine and cotinine levels were respectively 3.% lower and 2.6% higher in group than in the cigarette group. 1. Cigarette and users scored the products similarly in the urge-to-smoke assessment questionnaire of relief, reward and total scores. 2. The scoring scales of were close to those of cigarettes over the whole study period. Constituent: 1-aminonaphtalene 2-NA -9.1 % Constituent: 2-aminonaphthalene o-toluidine % Conclusions Constituent: o-toluidine CEMA -8.8 % Constituent: Acrylonitrile HEMA -6.1 % Constituent: Ethylene Oxide 3-HMPMA -7. % At the end of the day exposure period biomarkers of exposure to HPHCs were markedly reduced upon switching to use, whereas nicotine levels were similar to cigarette smoking. Constituent: Crotonaldehyde Total 3-OH-B[a]P % Constituent: Benzo[a]pyrene Total NNAL -7.7 % Smoking urge questionnaire scores indicate similar responses for as for CC, which is encouraging for CHTP adoption as an alternative to CC. NNK Total NNN -7.2 % Constituent: NNN The study was registered at ClinicalTrials.gov (ID: NCT2324) For the competing financial interest see the supplementary brochure Global Forum on Nicotine June 1 17, Warsaw, Poland

2 Biomarker of Exposure Reductions Upon Switching for Days from to a Carbon Heated Tobacco Product () A. Donelli, C. Tran, C. Haziza, J. Ancerewicz, G. de La Bourdonnaye, R. Weitkunat and F. Lüdicke

3 Introduction and Objectives Methods BACKGROUND DESIGN Carbon Heated Tobacco Product (CHTP 1.) is a heat-not-burn tobacco product designed to heat tobacco without burning it in order to reduce formation of, and consequently exposure to, harmful and potentially harmful constituents (HPHC) as compared to cigarettes, and to replicate the ritual, taste, sensory characteristics and nicotine uptake of cigarette smoking. Randomized, controlled, open-label, 2-arm, parallel group -day confinement study in 8 healthy adult smokers who used ad libitum (n = 41) or continued to smoke their own brand of cigarettes (n = 39). The study was conducted in Poland between July 4th and Aug 2th 21, and measured 1 selected HPHCs assessed in 24-hour urine, or blood. MAIN OBJECTIVES To assess the extent of reduced exposure to a number of HPHCs upon complete switch to use compared to continued cigarette smoking. Nicotine uptake, and subjective effects were also evaluated. Screening n = 124 Unmet criteria n = 39 Enrollment n = 8 Safety population n = 8 Discontinued n = Randomization n = 8 n = 41 n = 39 Completion n = 8 2

4 PARTICIPANTS SAMPLE SIZE ESTIMATION 1 Subject judged healthy at screening by the Investigator years of age Caucasians, smoking 1 commercially available non-menthol cigarettes (maximum ISO nicotine yield of 1 mg per cigarette) per day for the last 6 weeks prior to admission, based on self-reporting 3 Smoking cigarettes during the last 3 years prior to enrollment 4 Not planning to quit smoking in coming 3 months, but ready to switch from cigarettes to use for days Participants willing to quit smoking after enrolment were encouraged to do so and referred to a smoking cessation counselor. PRODUCT 1 is a heat-not-burn product that does not involve the combustion of tobacco 2 The product generates a nicotinecontaining aerosol which has significantly lower levels of harmful and potentially harmful constituents (HPHCs) compared to cigarettes 3 has been designed to resemble a cigarette as closely as possible A total of 8 participants randomized at a ratio of 1:1 to or cigarette groups, were considered sufficient to attain >8 % power to show a reduction of % in the concentrations of COHb, 3-HPMA, MHBMA, and S-PMA in the group relative to the cigarette group, using a onesided test with 2. % type I error probability. STATISTICAL METHODS 1 Inferential analysis was performed on the endpoints observed on Day 2 Analysis of covariance on log-transformed Day values to estimate the ratios between the study groups (one sided type I error of 2. %) 3 Adjustment for sex, cigarette use over the 6 weeks before enrollment, and the baseline value of the biomarker KEY POINTS 1 Completely switching to use reduced exposure, compared to cigarettes 2 use led to nicotine uptake comparable to cigarette smoking 3 use led to urge-to-smoke results similar to cigarette smoking 3

5 Results % REDUCTION VS. CIGARETTES (DAY ) Biomarker abbreviation (Biomarker name: smoke constituent) Level of Biomarkers in the group smoking cigarettes 1 % COHb (Carboxyhemoglobin: Carbon Monoxide) -8.8 % 3-HPMA (3-hydroxypropylmercapturic acid: Acrolein) -63. % MHBMA (Monohydroxybutenyl mercapturic acid: 1,3-Butadiene) % S-PMA (S-phenylmercapturic acid: Benzene) % Total 1-OHP (1-hydroxypyrene: Pyrene) -.6 % 4-ABP (4-aminobiphenyl: 4-aminobiphenyl) % 1-NA (1-aminonaphtalene: 1-aminonaphtalene) % 2-NA (2-aminonaphthalene: 2-aminonaphthalene) -9.1 % O-toluidine (O-toluidine: O-toluidine) % CEMA (2-cyanoethylmercapturic acid: Acrylonitrile) -8.8 % HEMA (2-hydroxyethyl mercapturic acid: Ethylene Oxide) -6.1 % 3-HMPMA (3-hydroxy-1-methylpropylmercapturic acid: Crotonaldehyde) -7. % Total 3-OH-B[a]P (3-hydroxybenzo(a)pyrene: Benzo(a)pyrene) % Total NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone: NNK) -7.7 % Total NNN (N-nitrosonornicotine: NNN) -7.2 % 4

6 DEMOGRAPHICS CHTP CC Female n (%) 21 (1.2 %) 2 (1.3 %) Age (Mean ± SD) 34.1 ± ± 11. Daily CC Consumption n (%) 1 19 cig/day 21 (1.2 %) 19 (48.7 %) >19 cig/day 2 (48.8 %) 2 (1.3 %) ISO Nicotine n (%).6 mg 32 (78. %) 34 (87.2 %) >.6 1 mg 9 (22. %) (12.8 %) FTND Total Score Mean (SD).4 (1.78).8 (2.) BIOMARKERS OF EXPOSURE SAFETY 1 Day levels were reduced, relative to cigarettes, by 8.8 % to 88.1 % in primary biomarkers COHb, MHBMA, 3-HPMA and SPMA 2 Other biomarkers were reduced by.6 % to 97.1 % NICOTINE UPTAKE 1 NEQ level was 3. % lower in the CHTP 1. compared to the cigarette group over all time points 2 On day plasma nicotine and cotinine levels were respectively 3. % lower and 2.6 % higher in group as compared to the cigarettes group 1 No serious adverse events were reported during the study 2 31/41 CHTP subjects (7.6%) and 2/39 subjects (1.3%) experienced adverse events (AE) % of AEs were mild and 38.8 % were moderate 4 Occurrence of subjects having cough and headache were higher in the CHTP 1. group (32% vs. % for cough and 46 % vs. 23 % for headache)

7 DAY NICOTINE BIOMARKER LEVELS 1 Neq (mg/g creat) 2 Nicotine (ng/ml) 4 Cotinine (mg/ml) QUESTIONNAIRE ON SMOKING URGE (BRIEF) 6 Relief (Factor 1) Reward (Factor 2) Total score SUBJECTIVE EFFECTS 1 and users scored similarly in the urge-to-smoke assessment questionnaire of relief, reward and total scores 2 The scoring scales of were close to those of cigarettes over the whole study period 6

8 SMOKE CONSTITUENT Biomarker Abbreviation Carbon Monoxide Carboxyhemoglobin COHb Acrolein 3-hydroxypropylmercapturic acid 3-HPMA 1,3-Butadiene monohydroxybutenyl mercapturic acid MHBMA Benzene S-phenylmercapturic acid S-PMA Pyrene 1-hydroxypyrene Total 1-OHP 4-aminobiphenyl 4-aminobiphenyl 4-ABP 1-aminonaphtalene 1-aminonaphtalene 1-NA 2-aminonaphthalene 2-aminonaphthalene 2-NA o-toluidine o-toluidine o-toluidine Acrylonitrile 2-cyanoethylmercapturic acid CEMA Ethylene Oxide 2-hydroxyethyl mercapturic acid HEMA Crotonaldehyde 3-hydroxy-1-methylpropylmercapturic acid 3-HMPMA Benzo(a)pyrene 3-hydroxybenzo(a)pyrene Total 3-OH-B[a]P 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanone (NNK) 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol Total NNAL N-nitrosonornicotine (NNN) N-nitrosonornicotine Total NNN Nicotine Nicotine Nicotine Cotinine Cotinine Nicotine equivalents: free nicotine, nicotineglucuronide, free cotinine, cotinine-glucuronide, free trans-3 -hydroxycotinine, trans-3 - hydroxycotinine-glucuronide Neq Conclusions At the end of the day exposure period, biomarkers of exposure to HPHCs were markedly reduced upon switching to CHTP 1. use, whereas nicotine levels were similar to cigarette smoking. Smoking urge questionnaire scores indicate similar responses for as for CC, which is encouraging for CHTP adoption as an alternative to CC. 7

9 MORE INFORMATION The study was registered at ClinicalTrials.gov (ID: NCT2324) COMPETING FINANCIAL INTEREST FOLLOW /PMISCIENCE The research described in this brochure was sponsored by the Philip Morris International group of companies GLOBAL FORUM ON NICOTINE JUNE 1 17, WARSAW, POLAND