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

• ClinicalTrials.gov Identifier: NCT01780714
• Recruitment Status: Completed
• First Posted: January 31, 2013
• Last Update Posted: November 20, 2019
• Sponsor: Philip Morris Products S.A.
• Information provided by (Responsible Party): Philip Morris Products S.A.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Smoking	Other: Conventional cigarettes (CC); Other: THS 2.1	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: 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
• Study Start Date: June 2012
• Actual Primary Completion Date: July 2012
• Actual Study Completion Date: December 2012

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: 5 days ]
   Biomarkers of exposure to carbon monoxide (CO), acrolein, 1,3-butadiene, and benzene

Secondary Outcome Measures :

1. Selected secondary biomarkers of exposure to HPHCs [ Time Frame: 5 days ]
   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.
2. CYP1A2 activity and CYP2A6 activity [ Time Frame: 5 days ]
   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
3. Plasma nicotine [ Time Frame: 5 days ]
   Time course of nicotine plasma concentrations and derived pharmacokinetic parameters
4. 11-dehydro-thromboxane B2 (11-DTX-B2) [ Time Frame: 5 days ]
   To describe the 11-DTX-B2 levels in urine as a marker of platelet function
5. Product use and smoking topography [ Time Frame: Up to 5 days ]
   Monitoring of daily product use and human smoking topography
6. Safety monitoring [ Time Frame: 8 days + 7 days follow-up ]
   Monitoring of adverse events, based on clinical and laboratory evaluation
7. Cough Visual Analog Scale (Cough VAS) [ Time Frame: 7 days ]
   Visual Analog Scale on cough
8. Modified Cigarette Evaluation Questionnaire (MCEQ) [ Time Frame: 5 days ]
   MCEQ measuring subjective effects of smoking
9. Questionnaire on Smoking Urges (brief version) (QSU-brief) [ Time Frame: 5 days ]
   QSU-brief measuring subjective effects of smoking
10. Minnesota Withdrawal Scale-Revised (MNSWS-R) [ Time Frame: 5 days ]
    MNWS-R questionnaire measuring subjective effects of smoking

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

Poland

MTZ Clinical Research Sp. z o.o.

Warsaw, Poland, 02-106

Sponsors and Collaborators

Philip Morris Products S.A.

Investigators

• Principal Investigator: Katarzyna Jarus-Dziedzic, MD PhD; MTZ Clinical Research Sp. z o.o., Warsaw, Poland

More Information

Publications of Results:

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.

• Responsible Party: Philip Morris Products S.A.
• ClinicalTrials.gov Identifier: NCT01780714
• Other Study ID Numbers: ZRHX-EX-01
• First Posted: January 31, 2013
• Last Update Posted: November 20, 2019
• Last Verified: November 2019

Keywords provided by Philip Morris Products S.A.:

smoking; cigarette; exposure; biomarker; human smoking topography (HST); modified risk tobacco product (MRTP); THS 2.1