Exploratory THS 2.1 Biomarkers of Exposure Study (ZRHX-EX-01)

A Single-center, Open-label, Randomized, Controlled, 2-arm Parallel Group Study to Evaluate the Exposure to Selected Smoke Constituents in Smoking, But Otherwise Healthy Subjects Switching From Conventional Cigarettes to the Tobacco Heating System (THS) 2.1

The goal of this exploratory study is to evaluate the effect of a candidate modified risk tobacco product (MRTP), THS 2.1, on selected biomarkers of exposure to harmful and potentially harmful smoke constituents (HPHCs), compared to conventional cigarettes (CC). The subjective effects (urge to smoke and withdrawal symptoms) which are related to the use of this product will be explored. Initial information on safety and on some biological effects when using THS 2.1 will be collected. Human Smoking Topography (HST) will be explored.

Study Overview

• Status: Completed
• Conditions: Smoking
• Intervention / Treatment: Other: Conventional cigarettes (CC); Other: THS 2.1

Detailed Description

This study intends to evaluate the levels of selected biomarkers of exposure to selected HPHC and of cytochrome P450 1A2 (CYP1A2) enzymatic activity, as compared to smokers continuing smoking CC ad libitum, after 5 days of ad libitum use.

Additional parameters will be explored, such as: cytochrome P450 2A6 (CYP2A6) enzymatic activity, nicotine pharmacokinetics, product evaluation and safety, marker of platelet function, and HST.

After screening, subjects will be admitted to the clinic for 9 days, including the Day of Admission, 2 days of baseline during which all subjects will continue to smoke their usual CC for a 5-day exposure after randomization. After leaving the clinic on the Day of Discharge, the subjects will be followed up for safety over a period of 7 days. All subjects will receive smoking cessation advice at screening, at Day of Admission and at Day of Discharge.

This clinical study will be conducted in compliance with International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH Good Clinical Practice), the Declaration of Helsinki as amended in 2008, and the applicable regulatory requirements.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Poland
  • Warsaw, Poland, 02-106
    • MTZ Clinical Research Sp. z o.o.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 23 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subject has signed an informed consent form before commencement of study procedures
• Healthy Caucasian aged between 23 to 65 years
• Subject is a current smoker for at least 3 years (based on self-reporting and biochemically verified), who, for the last 4 weeks, had smoked at least 10 commercially available non-mentholated CC per day, and is not planning to make a quit attempt within the next 3 months

Main Exclusion Criteria:

• As per Investigator judgment, the subject should not participate in the study for any reason (e.g. medical, psychiatric and/or social reason)
• The subject has a medical condition requiring smoking cessation, or has a clinically relevant disease / condition which could interfere with the study participation and/or study results
• The subject has participated in a clinical study within 3 months prior to the Screening Visit
• Pregnant or lactating woman, and for woman of childbearing potential, absence / refusal to use an acceptable method of effective contraception

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Conventional cigarettes (CC); Smokers are continuing to smoke exclusively their usual own brand of CC, for 5 days, ad libitum, under highly controlled conditions	Other: Conventional cigarettes (CC); Subjects are randomized in a 1:1 fashion to be assigned either A) continuing CC, or B) switching to THS 2.1
Experimental: Tobacco Heating System 2.1 (THS 2.1); Smokers are switching to the exclusive and ad-libitum use of THS 2.1 for 5 days, under highly controlled conditions	Other: THS 2.1; Subjects are randomized in a 1:1 fashion to be assigned either A) continuing CC, or B) switching to THS 2.1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of carboxyhemoglobin (COHb) levels in blood, and evaluation of excretion of 3-hydroxypropyl mercapturic acid (3-HPMA), monohydroxybutenyl mercapturic acid (MHBMA), and S-phenyl mercapturic acid (S-PMA) in 24-hour urine on switching to THS 2.1	Biomarkers of exposure to carbon monoxide (CO), acrolein, 1,3-butadiene, and benzene	5 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Selected secondary biomarkers of exposure to HPHCs	Evaluation of the levels of total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (total NNAL),1-hydroxypyrene , total N-nitrosonornicotine (NNN), 4-aminobiphenyl (4-ABP), 2- aminonaphthalene (2-NA), o-toluidine, nicotine equivalents and 2-cyanoethylmercapturic acid, biomarkers of exposure to the HPHCs 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanone, NNN, 4-ABP, 2-NA, o-toluidine, nicotine and acrylonitrile, respectively, as excreted in urine.	5 days
CYP1A2 activity and CYP2A6 activity	Evaluation of the CYP1A2 activity, as measured by the plasma caffeine molar metabolic ratio (paraxanthine / caffeine) and in CYP2A6 activity, as measured by nicotine molar metabolic ratio (3-hydroxy-cotinine / cotinine) in plasma and in urine	5 days
Plasma nicotine	Time course of nicotine plasma concentrations and derived pharmacokinetic parameters	5 days
11-dehydro-thromboxane B2 (11-DTX-B2)	To describe the 11-DTX-B2 levels in urine as a marker of platelet function	5 days
Product use and smoking topography	Monitoring of daily product use and human smoking topography	Up to 5 days
Safety monitoring	Monitoring of adverse events, based on clinical and laboratory evaluation	8 days + 7 days follow-up
Cough Visual Analog Scale (Cough VAS)	Visual Analog Scale on cough	7 days
Modified Cigarette Evaluation Questionnaire (MCEQ)	MCEQ measuring subjective effects of smoking	5 days
Questionnaire on Smoking Urges (brief version) (QSU-brief)	QSU-brief measuring subjective effects of smoking	5 days
Minnesota Withdrawal Scale-Revised (MNSWS-R)	MNWS-R questionnaire measuring subjective effects of smoking	5 days

Collaborators and Investigators

• Sponsor: Philip Morris Products S.A.
• Investigators: Principal Investigator: Katarzyna Jarus-Dziedzic, MD PhD, MTZ Clinical Research Sp. z o.o., Warsaw, Poland

Publications and helpful links

General Publications

• Ludicke F, Baker G, Magnette J, Picavet P, Weitkunat R. Reduced Exposure to Harmful and Potentially Harmful Smoke Constituents With the Tobacco Heating System 2.1. Nicotine Tob Res. 2017 Feb;19(2):168-175. doi: 10.1093/ntr/ntw164. Epub 2016 Jul 1.

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: January 15, 2013
• First Submitted That Met QC Criteria: January 29, 2013
• First Posted (Estimate): January 31, 2013

Study Record Updates

• Last Update Posted (Actual): November 20, 2019
• Last Update Submitted That Met QC Criteria: November 18, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: biomarker; smoking; exposure; cigarette; human smoking topography (HST); modified risk tobacco product (MRTP); THS 2.1
• Other Study ID Numbers: ZRHX-EX-01