A single-dose, randomised, crossover study to assess the nicotine pharmacokinetics of oral nicotine products in healthy adult users of smokeless pouch products

ISRCTN	ISRCTN12265853
DOI	https://doi.org/10.1186/ISRCTN12265853
Secondary identifying numbers	BAT51121037

Submission date: 06/04/2022
Registration date: 22/04/2022
Last edited: 12/11/2024

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Other

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English Summary

Background and study aims
As smoking is the leading cause of numerous human disorders, the idea is to enable smokers to switch to modern oral products that have less harmful toxicants. The aim of this study is to assess the uptake of nicotine from modern oral smokeless pouches.

Who can participate?
Healthy volunteers aged 19-55 years who are snus or nicotine pouch users

What does the study involve?
Participants are confined to the clinic for 7 days to use all seven different variants of two nicotine pouches (11 and 20 mg) for 10-minute, 20-minute and 30-minute periods while giving blood and saliva samples and undergoing physiological measures.

What are the possible benefits and risks of participating?
There are no medical benefits but this study will provide suitable alternatives to smoking. The risks are low but the participants' safety and wellbeing are of the utmost importance. Participants will be compensated for their time.

Where is the study run from?
CTC Clinical Trial Consultants AB (Sweden)

When is the study starting and how long is it expected to run for?
April 2022 to October 2022

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

Who is the main contact?
1. Nathan Gale, nathan_gale@bat.com
2. Dr Erik Rein-Hedin

Contact information

Dr Erik Rein-Hedin
Principal Investigator

CTC
Dag Hammarskjolds vag 10B
SE-75237 Uppsala
Uppsala
SE-75237
Sweden

ORCID ID	0000-0002-9462-1785
Phone	+46 (0)70755 2089
Email	erik.rein-hedin@ctc-ab.se

Mr Nathan Gale
Scientific

British American Tobacco (United Kingdom)
Regents Park Road
Southampton
SO15 8TL
United Kingdom

Phone	+44 (0)7720418771
Email	nathan_gale@bat.com

Mr Nathan Gale
Public

British American Tobacco (United Kingdom)
Regents Park Road
Southampton
SO15 8TL
United Kingdom

Phone	+44 (0)7720418771
Email	nathan_gale@bat.com

Study information

Study design	Randomized seven-way cross-over pharmacokinetic study
Primary study design	Interventional
Secondary study design	Randomised cross over trial
Study setting(s)	Other
Study type	Other
Participant information sheet	41515_PIS_V1.0_10Feb22.pdf
Scientific title	Pharmacokinetics study assessing nicotine uptake of nicotine smokeless pouches
Study acronym	Velo
Study hypothesis	Assessing the nicotine uptake of smokeless pouches.
Ethics approval(s)	Approved 28/02/2022, Etikprovningsmyndigheten (Box 2110, 750 02 Uppsala, Sweden; +46 (0)10-475 0800; registrator@etikprovning.se), ref: 2022-00703-01-245809
Condition	Nicotine uptake in harm reduction products
Intervention	7-way cross-over study where subjects will use one of two different nicotine pouches (11 and 20 mg) for 10-minute, 20-minute and 30-minute periods in a confined environment. Subjects will be randomised to one of five randomisation sequences according to a balanced Latin square design. Subjects will be confined for 7 days at the designated clinic and will have a follow up on day 14. Blood samples are taken at designated time periods pre, during and post product use. Physiological measures and questionnaire data will also be collected.
Intervention type	Other
Primary outcome measure	Plasma nicotine maximum plasma concentration (Cmax), time to Cmax (Tmax) and area under the plasma concentration versus time curve 0 to 240 minutes (AUC0-240), analysed after collection of blood samples at pre-use, 5, 7, 10, 15, 20, 25, 30, 35, 40 min, 1 hour, 2 hours and 4 hours.
Secondary outcome measures	1. Overall product liking (OPL) and intent to use again (IUA) assessed with questionnaires using a visual analogue scale (VAS) (0-100 mm) at 4 hour post product use 2. Amount mg/unit and extracted fraction (%) of nicotine, sweeteners and major flavour components measured using saliva samples at 4 hours post product use
Overall study start date	06/04/2022
Overall study end date	06/10/2022

Eligibility

Participant type(s)	Healthy volunteer
Age group	Adult
Lower age limit	19 Years
Upper age limit	55 Years
Sex	Both
Target number of participants	35
Total final enrolment	35
Participant inclusion criteria	1. Willing and able to give written informed consent for participation in the study 2. Healthy male and female subjects aged 19-55 years inclusive 3. Body Mass Index (BMI) ≥ 18.5 and ≤ 30.0 kg/m2 and a minimum weight of ≥45 kg (females) or ≥52 kg (males) 4. Clinically normal medical history, physical findings, vital signs, electrocardiogram (ECG) and laboratory values at the time of screening, as judged by the Investigator. No abnormal results judged by the Investigator as clinically significant are allowed. 5. Daily snus and/or nicotine pouch user who must have used pouched products for at least 12 months and who use these pouch products under their upper lip. Subjects who use pouched snus and/or nicotine pouches should typically use at least five pouches per day, with pouch weights of 0.6 g or above. Subjects should be willing and able to use products with nicotine content ≥15 mg/g. 6. Stated willingness to abstain from nicotine and tobacco products (except for the IPs provided) from 12 hours prior to each study product administration until the end of each PK sampling 7. Successful completion of the product familiarisation session for study product use prior to the first study product administration (the subject is able to follow the instructions, can tolerate the product and does not experience any adverse effects different from what is expected from typical smokeless pouch use during the training session). 8. Positive urine cotinine test (≥200 ng/ml) at screening and at Day -1 9. Women of childbearing potential (WOCBP) must be willing to use a sufficient contraceptive method for the duration of the study, this includes mechanical barrier (e.g., a male condom or a female diaphragm), combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal anticonception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD) or intrauterine system (IUS). Sexual abstinence is allowed when this is the preferred and usual lifestyle of the subject. Women of non-childbearing potential are defined as pre-menopausal females who are sterilised (tubal ligation or permanent bilateral occlusion of fallopian tubes); or females who have undergone hysterectomy or bilateral oophorectomy; or post-menopausal defined as 12 months of amenorrhea (in questionable cases a blood sample with detection of follicle-stimulating hormone [FSH] 25-140 IE/l is confirmatory).
Participant exclusion criteria	1. History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject’s ability to participate in the study 2. Any clinically significant illness, medical/surgical procedure or trauma within 2 weeks of the first administration of IP 3. Malignancy within the past 5 years with the exception of in situ removal of basal cell carcinoma 4. Any planned major surgery within the duration of the study 5. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody and Human Immunodeficiency Virus (HIV) 6. After 10 minutes supine rest at the time of screening, any vital signs values outside the following ranges: 6.1. Systolic blood pressure <90 or >140 mmHg, or 6.2. Diastolic blood pressure <50 or >90 mmHg, or 6.3. Pulse <40 or >90 bpm 7. Prolonged QTcF (>450 ms), cardiac arrhythmias or any clinically significant abnormalities in the resting ECG at the time of screening, as judged by the Investigator 8. Presence of braces, partials, dentures or any dental work that could, in the opinion of an Investigator, affect the conduct of the study (including missing molars) 9. Presence or history of significant form of oral and/or pharyngeal inflammation, oral lesions and/or gum disease or temporomandibular joint dysfunction 10. Existing signs of skin irritation or skin damage at the sites where the Equivital LifeMonitor device is to be located, as judged by the Investigator 11. Subjects with implanted defibrillators or pacemakers 12. Female subject who is pregnant or lactating 13. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to nicotine 14. Plan to quit using tobacco- or nicotine-containing products within 3 months of the end of the current study, or previously attempted to quit using tobacco- or nicotine-containing products in the 28 days prior to the first IP use 15. Planned treatment or treatment with an investigational medicinal product or another IP within 3 months prior to Day -1. Subjects consented and screened but not dosed in previous phase I studies are not excluded. 16. Positive screening result for drugs of abuse or alcohol at the time of screening or on admission to the unit prior to first use of IP. Positive results that are expected given the subject’s medical history and prescribed medications can be disregarded as judged by the Investigator. 17. History of alcohol abuse or excessive intake of alcohol, as judged by the Investigator 18. Presence or history of drug abuse, as judged by the Investigator 19. History of, or current use of, anabolic steroids 20. Plasma or platelet donation within one month of the first IP use or blood donation (or corresponding blood loss, ≥450 mL) during the three months prior to the first IP use 21. Employees or immediate relatives of the tobacco industry or the clinical site 22. Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements
Recruitment start date	25/04/2022
Recruitment end date	30/05/2022

Locations

Countries of recruitment

Sweden

Study participating centre

CTC Clinical Trial Consultants AB

Dag Hammarskjölds väg 10B
Uppsala
SE-752 37
Sweden

Sponsor information

British American Tobacco (United Kingdom)
Industry

Regents Park Road
Southampton
SO15 8TL
England
United Kingdom

Phone	+44 (0)7720418771
Email	nathan_gale@bat.com
Website	https://www.bat.com
"ROR"	https://ror.org/01znsh139

Funders

Funder type

Industry

British American Tobacco
Private sector organisation / For-profit companies (industry)

Location: United Kingdom

Results and Publications

Intention to publish date	31/03/2025
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Data sharing statement to be made available at a later date
Publication and dissemination plan	Publication in a high-impact journal
IPD sharing plan	The data-sharing plans for the current study are unknown and will be made available at a later date

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Participant information sheet	version 1.0	10/02/2022	21/04/2022	No	Yes

Additional files

41515_PIS_V1.0_10Feb22.pdf

Editorial Notes

12/11/2024: The target number of participants was changed from 53 to 35. Total final enrolment added.
11/11/2024: The intention to publish date was changed from 28/02/2023 to 31/03/2025.
04/09/2023: Contact details updated.
03/05/2022: The study contact has been updated and the plain English summary has been updated accordingly.
21/04/2022: Trial's existence confirmed by Etikprovningsmyndigheten.