Condition category
Not Applicable
Date applied
09/01/2018
Date assigned
31/01/2018
Last edited
01/02/2018
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Cigarette smoking contributes to numerous illnesses including lung cancer, chronic obstructive lung disease and heart disease. The health risks of cigarette smoking are due to chemical toxicants in cigarette smoke which can lead to changes in the body, causing disease. Nicotine is mainly responsible for the addictive properties of cigarette smoking. The sponsor of this study is British American Tobacco (Investments) Limited, a manufacturer of tobacco products. The sponsor is developing an alternative approach to conventional (normal) cigarettes by developing new products which may reduce some of the risks of tobacco-related diseases. This study is designed for research purposes to collect data on newly developed tobacco heating products (THPs) in adult smokers. The main aim of this study is to find out whether the body is exposed to a lower amount of certain chemical toxicants from THPs as compared to smoke from regular cigarettes.

Who can participate?
Healthy volunteers aged 23 to 55, including regular smokers and people who have never smoked (smoked less than 100 cigarettes in their lifetime)

What does the study involve?
Regular smokers are randomly allocated to one of three groups (Arms A-C) to either continue to smoke their own brand cigarettes, or to switch to smoking a THP 1.1 (RT), or THD 2.4T20 for 360 days. The fourth (Arm D) group is made up of participants who are regular smokers and who intend to quit. This group is provided with assisted smoking cessation (NRT/varenicline/counselling). The last group is made up of participants who have never smoked (Arm E). Levels of exposure to chemical toxicants are measured by testing blood and urine collected over a 24-hour period.

What are the possible benefits and risks of participating?
Participants should not expect to receive any health benefits from using the products in this study. Participants in the cessation group may expect the benefits associated with stopping smoking. The tests provided may help participants learn about their general health. They may also help participants discover an unknown medical condition. This study may help doctors, scientists or manufacturers learn things about tobacco and nicotine products that could help others to quit smoking. Nicotine and tobacco use can have side effects but as the participants are already using tobacco products the risks related to the side effects of nicotine are low. Participants are not likely to be exposed to nicotine levels higher than the ones they are usually exposed to when smoking. The following side effects have been reported for e-cigarettes and THPs, and participants are monitored for these: headache, dizziness, palpitations, mouth and throat irritation, skin irritation, and stomach disturbances. Inhalation of too much nicotine has been reported to lead to side effects such as feeling faint, nausea or headache. Common observed side effects also include cough, irritation of the mouth or throat, dizziness, nasal congestion, stomach discomfort, hiccups and sickness (vomiting).

Where is the study run from?
1. Covance Clinical Research Unit Ltd (UK)
2. SIMBEC Research Ltd (UK)
3. Celerion (GB) Ltd (UK)
4. Richmond Pharmacology Ltd (UK)

When is the study starting and how long is it expected to run for?
February 2018 to July 2019

Who is funding the study?
British American Tobacco (UK)

Who is the main contact?
Nik Newland
nik_newland@bat.com

Trial website

Contact information

Type

Public

Primary contact

Mr Nik Newland

ORCID ID

Contact details

British American Tobacco (Investments) Ltd.
R&D Centre
Regents Park Road
Southampton
SO15 8TL
United Kingdom
+44 (0)23807973966
nik_newland@bat.com

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

BAT3117011

Study information

Scientific title

A randomised, controlled study to evaluate the effects of switching from cigarette smoking to using tobacco heating products next generation products on health effect indicators in healthy subjects

Acronym

Study hypothesis

It is hypothesised that there will be a reduction in exposure to toxicants which will cause changes in health effect indicators when smokers switch to using tobacco heating products (THPs) compared with smokers who continue to smoke, and that these changes will be directionally similar to changes seen in smokers who cease smoking (assisted with NRT) over a period of 12 months in an ambulatory setting. Furthermore, it is hypothesised that reductions in toxicant levels in THP emissions will translate to sustained reductions in human exposure to cigarette smoke toxicants, as assessed by measuring biomarker of exposure (BoE) in an ambulatory setting.

Ethics approval

Wales Research Ethics Committee 2, 29/01/2018, REC ref: 17/WA/0212

Study design

Multi-centre randomised controlled interventional study

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Other

Trial type

Other

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

Cigarette smoking

Intervention

Three separate populations:
1. Continue to smoke / THP population
Arm A – conventional cigarettes
Arm B – THP1.1(RT)
Arm C – THD2.4T20

2. Intend-to-quit population
Arm D – assisted smoking cessation

3. Never-smoked population
Arm E – never-smoked

A total of 505 healthy male or female subjects aged 23-55 will be enrolled on the study across 5 study arms. 265 subjects will be enrolled in to study arms 1-3 and randomised using blocks of computer generated random number sequences in PROC PLAN by SAS®. 65 subjects will be randomised to study arm 1, where subjects will continue to smoke their own brand cigarettes for the duration of the study. 100 subjects will be randomised to each study arm 2 and 3, and will switch on study day 1 from smoking conventional cigarettes to exclusive use of a test IP (THP 1 or 2) for 360 days. 50 subjects are required to complete the study to 360 days.

200 subjects who intend to quit tobacco and nicotine product use will be enrolled to the cessation arm. Cessation may be assisted with the use of NRT/varenicline/counselling at the discretion of the PI. 50 subjects are required to complete the study to 360 days.

40 subjects who have smoked less than 100 cigarettes in their lifetime will be recruited to the never smoker arm. 30 subjects are required to complete the study to 360 days.

Follow up for all study arms will be 28 days following discharge from the clinic.

Visit 1: 0 (baseline)
Visit 2: 30 days
Visit 3: 60 days
Visit 4: 90 days
Visit 7: 180 days
Visit 10: 270 days
Visit 13: 360 days

Intervention type

Other

Phase

Drug names

Primary outcome measure

Measured using 24-hour urine ambulatory collection at visits 1, 2 ,3, 4, 7, 10, 13:
1. Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL)
2. 8-epi-prostaglandin F2α Type III (8-Epi-PGF2α Type III)

Physiological measures, measured at visits 1, 2 ,3, 4, 7, 10, 13:
1. Augmentation Index (AIx)

Secondary outcome measures

Measured from 24-hour urine ambulatory collection:
1. Total nicotine equivalents (nicotine, cotinine, 3-hydroxycotinine and their glucuronide conjugates) (TNeq) measured at visits 1, 2 ,3, 4, 7, 10, 13
2. Total N-nitrosonornicotine (Total NNN) measured at visits 1, 2 ,3, 4
3. 3-hydroxypropylmercapturic acid (3-HPMA) measured at visits 1, 2 ,3, 4
4. 3-hydroxy-1-methylpropylmercapturic acid (HMPMA) measured at visits 1, 2 ,3, 4
5. S-phenylmercapturic acid (S-PMA) measured at visits 1, 2 ,3, 4
6. Monohydroxybutenyl-mercapturic acid (MHBMA) measured at visits 1, 2 ,3, 4, 7, 10, 13
7. 2-cyanoethylmercapturic acid (CEMA) measured at visits 1, 2 ,3, 4
8. 1-hydroxypyrene (1-OHP) measured at visits 1, 2 ,3, 4
9. 2-hydroxyethylmercapturic acid (HEMA) measured at visits 1, 2 ,3, 4
10. 11-dehydrothromboxane B2 (11-dTX B2) measured at visits 1, 2 ,3, 4, 7, 10, 13
11. 4-hydroxy-nonenal + metabolites (4-HNE) measured at visits 1, 2 ,3, 4, 7, 10, 13
12. Creatinine measured at visits 1, 2 ,3, 4, 7, 10, 13

Measured from blood samples:
1. N-(2-cyanoethyl)valine (HB [haemoglobin] adduct; CEVal) measured at visits 1, 2 ,3, 4, 7, 10, 13
2. White blood cell count (WBC count) measured at visits 1, 2 ,3, 4, 7, 10, 13
3. Monocyte chemotactic protein 1/C-C motif chemokine ligand 2 (MCP 1/CCL2) measured at visits 1, 4, 7, 10, 13
4. Soluble intercellular adhesion molecule-1 (s-ICAM1) measured at visits 1, 4, 7, 10, 13
5. Fibrinogen (Fib) measured at visits 1, 4, 7, 10, 13
6. High-sensitivity C-reactive protein (hsCRP) measured at visits 1, 4, 7, 10, 13
7. Homocysteine (HMCys) measured at visits 1, 4, 7, 10, 13
8. Glucose (Gluc) measured at visits 1, 4, 7, 10, 13
9. Plasminogen activator inhibitor-1 (PAI-1) measured at visits 1, 4, 7, 10, 13
10. Tissue plasminogen activator (tPA) measured at visits 1, 4, 7, 10, 13
11. E-Selectin (SELE) measured at visits 1, 4, 7, 10, 13
12. Endothelin-1 (ET-1) measured at visits 1, 4, 7, 10, 13
13. 3-nitrotyrosine (3-NTyr) measured at visits 1, 4, 7, 10, 13
14. Serum lipids (high-density lipoprotein [HDL], low-density lipoprotein [LDL], total cholesterol [CholTotal], triglycerides [Trigly]) measured at visits 1, 2 ,3, 4, 7, 10, 13

Measured from exhaled breath:
1. Nitric oxide (NO) measured at visits 1, 2 ,3, 4, 7, 10, 13
2. Carbon monoxide (CO) measured at screening, visits 1, 2 ,3, 4, 7, 10, 13

Physiological measures:
1. Blood pressure at screening, visits 1, 2 ,3, 4, 7, 10, 13
2. Spirometry at screening, visits 1, 2 ,3, 4, 7, 10, 13:
2.1. Peak flow
2.2. Forced vital capacity (FVC)
2.3. Forced expiratory flow (FEF) 25-75%
2.4. Forced expiratory volume in 1 second (FEV1)
3. Body weight/waist circumference at visits 1, 4, 7, 10, 13
4. Carotid/femoral pulse wave velocity at visits 1, 2 ,3, 4, 7, 10, 13
5. 6-minute walking test at visits 1, 2 ,3, 4, 7, 10, 13
6. Finger plethysmography at visits 1, 4, 7, 10, 13

Questionnaires:
1. Fagerström Test for Cigarette Dependence (FTCD) at screening and at visits 1, 4, 7, 10, 13
2. Product satisfaction at visits 1, 4, 7, 10, 13
3. Smoking cessation quality of life at visits 1, 4, 7, 10, 13
4. Self-reported product usage (eDiary/SMS) recorded throughout the study
5. Cough and Shortness of Breath VAS at visits 1, 4, 7, 10, 13

Safety:
1. Physical examination at screening and at visits 1 to 13 and follow-up
2. Vital signs at screening and at visits 1, 4, 7, 10, 13 and follow-up
3. Electrocardiogram (ECG) at screening and at visits 1, 4, 7, 10, 13 and follow-up
4. Clinical laboratory evaluations at screening and at visits 1, 4, 7, 10, 13 and follow-up
5. Lung function tests at screening, visits 1, 2 ,3, 4, 7, 10, 13
6. Adverse events (AE)/serious adverse events (SAE) recorded throughout the study

Overall trial start date

15/02/2018

Overall trial end date

02/07/2019

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Males or non-pregnant, non-lactating females, between 23 and 55 years of age, inclusive
2. Body mass index (BMI) between 17.6 and 32.0 kg/m2, inclusive, body weight exceeding 50 kg (males) or 40 kg (females)
3. Subjects will be in good health, as judged by the Investigator or their appropriately qualified designee based on: medical history, physical examination, vital signs assessment (blood pressure <140 mmHg systolic),12-lead ECG, clinical laboratory evaluations, lung function tests
4. Subjects will have given their written informed consent to participate in the study and will have agreed to abide by the study restrictions
5. Subjects must demonstrate the ability to comprehend the Informed Consent Form (ICF), be able to communicate well with the Investigator or their appropriately qualified designee, understand and comply with the requirements of the study, and be judged suitable for the study in the opinion of the Investigator or their appropriately qualified designee
6. Subjects will be willing to refrain from consuming alcohol within 72 hours prior to Screening and Check-in at each study visit, with the exception of the Follow-up Visit
7. Subjects will be willing to refrain from consuming cruciferous vegetables, and grilled, smoked, fried or barbequed food, and avoid being in the presence of the cooking of cruciferous vegetables, and grilled, smoked, fried or barbequed food for 48 hours prior to Check-in at each study visit. Subjects will also be willing to avoid food containing poppy seeds for 3 days before both Screening and Check-in at each study visit

Arms A to D:
8. Subjects will be regular smokers of commercially manufactured filter cigarettes
9. Subjects will have smoked for at least five consecutive years prior to Screening
10. Subjects will typically smoke at least 10 and a maximum of 30 CPD and must have a urine cotinine level > 200 ng/mL and an exhaled breath CO level > 10 ppm at Screening
11. Subjects in Arm A who continue to smoke will be willing to use factory-manufactured non-mentholated cigarettes
12. Subjects in Arms B and C will be willing to use the study products (THP) provided to them during the study
13. Subjects in Arm D will be willing to abstain from smoking and using NGPs

Arm E
14. Subjects will have never smoked (<100 cigarettes in their life and none within 30 days prior to Screening) and will continue to not smoke or use any form of tobacco or nicotine containing product (including THPs) for the duration of the study

Participant type

Healthy volunteer

Age group

Adult

Gender

Both

Target number of participants

505

Participant exclusion criteria

1. Male subjects who do not agree, or whose partners of childbearing potential do not agree, to use a barrier method of contraception (i.e. a condom with spermicide) in addition to a second highly effective method of contraception used by their female partners or to refrain from donating sperm from Visit 1 until the end of the Follow-up Visit
2. Female subjects of childbearing potential who do not agree to use a highly effective method of birth control in conjunction with male barrier method contraception (i.e. a condom with spermicide) from the time of signing the ICF until the end of the Follow-up Visit
3. Female subjects who are pregnant or breastfeeding. This will be confirmed at Screening and Visit 1. Any female subject who becomes pregnant during this study will be withdrawn
4. Subjects who have donated: ≥400 mL of blood within 12 weeks (male) or 16 weeks (female) prior to Visit 1, plasma in the 2 weeks prior to Visit 1, platelets in the 6 weeks prior to Visit 1
5. Subjects who have an acute illness (e.g. upper respiratory tract infection) requiring treatment within 4 weeks prior to Visit 1 (subjects who had viral infections that resolved ≥2 weeks prior to Visit 1 will be admissible to this study)
6. Subjects who have a significant history of alcoholism or drug/chemical abuse within 24 months prior to Screening, as determined by the Investigator
7. Subjects who have a positive urine drugs of abuse screen (confirmed by repeat) at Screening or Visit 1 and a positive alcohol breath test (confirmed by repeat) at Screening or Visit 1
8. Subjects who are carriers of the hepatitis B surface antigen (HBsAg), hepatitis C antibody and have a positive result for the test for human immunodeficiency virus (HIV) antibodies
9. Subjects who have used prescription or over-the-counter (OTC) bronchodilator medication (e.g. inhaled or oral β-adrenergic agonists) to treat a chronic condition within the 12 months prior to Visit 1
10. Subjects who have received any medications or substances (other than tobacco) which interfere with the cyclooxygenase pathway (e.g. anti-inflammatory drugs including aspirin and ibuprofen) within 14 days prior to Visit 1, are known to be strong inducers or inhibitors of cytochrome P450 (CYP) enzymes within 14 days or 5 half-lives of the drug (whichever is longer) prior to Visit 1
11. Subjects who perform strenuous physical activity (exceeding the subject’s normal activity levels) within 7 days prior to Screening or Visit 1
12. Subjects who are unable to communicate effectively with the Investigator/study staff (i.e. language problem, poor mental development, or impaired cerebral function)
13. Subjects who are unwilling or unable to comply with the study restrictions and requirements
14. Employees and immediate relatives of the tobacco industry and the clinical site
15. Subjects who are still participating in another clinical study (e.g. attending follow-up visits) or who have participated in a clinical study involving administration of an investigational drug (new chemical entity) in the past 3 months prior to first product use
16. Subjects who have any clinically relevant abnormal findings on the physical examination, medical history, ECG, lung function tests (post-bronchodilator FEV1/FVC < 0.7 and FEV1 < 80% predicted value at post-bronchodilator spirometry or have an asthma condition [post-bronchodilator FEV1/FVC < 0.75 and reversibility in FEV1R > 12% and > 200 mL from pre- to post-bronchodilator values at Screening]) or clinical laboratory panel, unless deemed not clinically significant by the Investigator or their appropriately qualified designee
17. Subjects who have, or who have a history of, any clinically significant neurological, gastrointestinal, renal, hepatic, cardiovascular, psychiatric, respiratory, metabolic, endocrine, haematological or other major disorder that, in the opinion of the Investigator or their appropriately qualified designee, would jeopardise the safety of the subject or impact on the validity of the study results
18. Subjects who have previously been diagnosed with any form of malignancy
19. Subjects who have any clinically significant abnormal laboratory safety findings at Screening, as determined by the Investigator or their appropriately qualified designee (1 repeat assessment is acceptable)
20. Subjects who have previously been enrolled in or withdrawn from this study
21. Subjects who, in the opinion of the Investigator, should not participate in this study

Arms A to D:
22. Subjects who regularly use any nicotine or tobacco product other than commercially manufactured filter cigarettes within 14 days of Screening

Arms A to C:
23. Subjects who are self-reported non-inhalers (smokers who draw smoke from the cigarette into the mouth and throat but who do not inhale)
24. Subjects who, prior to randomisation, are planning to quit smoking in the next 12 months. All subjects will be informed that they are free to quit smoking and withdraw from the study at any time. Any subject who decides to quit smoking will be directed to appropriate stop smoking services

Recruitment start date

15/02/2018

Recruitment end date

02/07/2018

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Covance Clinical Research Unit Ltd
Springfield House Hyde Street
Leeds
LS2 9LH
United Kingdom

Trial participating centre

SIMBEC Research Ltd
Simbec House Merthyr Tydfil Industrial Park Pentrebach Merthyr Tydfil
CF48 4DR
United Kingdom

Trial participating centre

Celerion (GB) Ltd
22-24 Lisburn Road
Belfast
BT9 6AD
United Kingdom

Trial participating centre

Richmond Pharmacology Ltd
1a Newcomen Street London Bridge
London
SE1 1YR
United Kingdom

Sponsor information

Organisation

British American Tobacco (Investments) Ltd

Sponsor details

R&D Centre
Regents Park Road
Southampton
SO15 8TL
United Kingdom
+44 (0)2380793966
nik_newland@bat.com

Sponsor type

Industry

Website

Funders

Funder type

Industry

Funder name

British American Tobacco

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

corporate

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Full study protocol, statistical analysis plan, informed consent form, clinical study report will be available. Results from this study will be published in peer-reviewed scientific journals when the study has completed.

IPD sharing statement
Participant level data will be available upon request. Deidentified study data including all data captured using the eCRF, subject diaries and full bioanalytical reports available in SDTM format. Data will be available immediately following publication. Data will be available to anyone who wishes access to the data and for any purpose. Requests for data should be made to clinical_info@bat.com. Data requestors will need to sign a data access agreement. Data will be available for at least 5 years following publication.

Intention to publish date

02/12/2020

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

01/02/2018: Ethics approval details added.