Condition category
Not Applicable
Date applied
14/11/2017
Date assigned
21/11/2017
Last edited
23/11/2017
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Sweden displays the lowest prevalence of smoking in Europe, particularly among males. One explanation for the record-low low smoking prevalence is that snus has replaced cigarettes as the tobacco product of choice. Snus is a smokeless tobacco capable of rapidly delivering nicotine to the bloodstream and therefore may be more satisfactory among smokers than currently available pharmaceutical nicotine products. Snus remains a controversial product as it contains tobacco and is intended for recreational use. The tobacco in snus contains carcinogenic ingredients (that could cause cancer), but at very low amounts. Recently, a novel, non-tobacco-based nicotine product (ZYN®) has been developed. It is similar to snus however it contains no nitrosamines or polycyclic hydrocarbons (PAHs) which may potentially be carcinogenic. The overall safety of ZYN® is better than snus, however it only has a little bit less nicotine than snus. When comparing the nicotine content of different nicotine-containing products, it is important to consider that the nicotine extraction and uptake varies considerably depending on product type and formulation. Commercially available snus products have a nicotine content ranging between 1-2%. Previous studies have shown that on average about 15-20% of the total nicotine content is extracted and absorbed. Extraction is generally not linear with pouch size: it is larger with small compared to larger pouches, which suggests that surface area, saliva penetration and diffusion factors may be more important determinants of nicotine uptake than pouch weight. The nicotine delivery profile of a product is probably a main determinant of its efficacy to function as an alternative to cigarettes among current smokers. The aim of this study is to measure the nicotine delivery profile of ZYN® in comparison with commercially available snus products (which have a documented ability to replace cigarettes as a source of recreational nicotine among current tobacco consumers).

Who can participate?
Healthy volunteers aged over 19 who have used tobacco-based snus for over 1 year

What does the study involve?
The study compares the estimated in-vivo extracted dose of nicotine from a novel, non-tobacco-based nicotine pouch containing 3 or 6 mg of nicotine, with that from a 1 g Swedish snus pouch containing 8 mg of nicotine. The study includes 14 doses of either ZYN® or snus. Participants report to the laboratory on separate days for 14 experimental interventions. All participants receive the same treatment in a randomised order. The amount of nicotine that is extracted from each dose is assessed.

What are the possible benefits and risks of participating?
There are no possible benefits of participating. The tested products are commercially available and only participants who are well acquainted with and used to the effects of nicotine will participate. The only side effects are the effects likely to be related to the nicotine exposure (such as salivation, nausea, and dyspepsia).

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?
June 2017 to November 2017

Who is funding the study?
Swedish Match North Europe (Sweden)

Who is the main contact?
Mikael Staaf
mikael.staaf@swedishmatch.com

Trial website

Contact information

Type

Scientific

Primary contact

Dr Mikael Staaf

ORCID ID

Contact details

Swedish Match North Europe
Maria Skolgata 83
Stockholm
SE-118 53
Sweden

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

SM 17-01

Study information

Scientific title

The in-vivo extraction of nicotine and flavor compounds from a single dose of a non-tobacco-based nicotine pouch (ZYN®) compared with conventional, tobacco-based Swedish snus among current, daily snus users

Acronym

Study hypothesis

The aim of this study is to compare the estimated in-vivo extracted dose of nicotine from a novel, non-tobacco-based nicotine pouch containing 3 or 6 mg of nicotine, with that from a 1 g Swedish snus pouch containing 8 mg of nicotine. Nicotine extraction may serve as a proxy for the in vivo uptake of nicotine.

Ethics approval

EPN Uppsala, 13/09/2017, ref: Dnr 2017/318

Study design

Single-centre open randomized fourteen-way cross-over single dose administration

Primary study design

Interventional

Secondary study design

Randomised cross over trial

Trial setting

Other

Trial type

Prevention

Patient information sheet

Not available in web format, only available in Swedish

Condition

Tobacco use not otherwise specified (NOS)

Intervention

The treatments are administered as single doses in a pre-determined computer-generated randomized order according to a four-sequence list. Participants are randomly allocated as to what order they receive the following doses:

1. ZYN® Smooth containing 3 mg nicotine per portion - 15 min single dose administration
2. ZYN® Smooth containing 3 mg nicotine per portion - 60 min single dose administration
3. ZYN® Smooth containing 6 mg nicotine per portion - 15 min single dose administration
4. ZYN® Smooth containing 6 mg nicotine per portion - 60 min single dose administration
5. ZYN® Smooth containing 3 mg nicotine per portion (alternative manufacturing process) - 15 min single dose administration
6. ZYN® Smooth containing 3 mg nicotine per portion (alternative manufacturing process) - 60 min single dose administration
7. ZYN® Smooth containing 6 mg nicotine per portion (alternative manufacturing process) - 15 min single dose administration
8. ZYN® Smooth containing 6 mg nicotine per portion (alternative manufacturing process) - 60 min single dose administration
9. ZYN® Wintergreen containing 3 mg nicotine per portion (Nicotine analysis) - 60 min single dose administration
10. ZYN® Wintergreen containing 3 mg nicotine per portion (Flavor analysis) - 60 min single dose administration
11. ZYN® Peppermint containing 3 mg nicotine per portion (Nicotine and Flavor analysis) - single dose 60 min administration
12. ZYN® Spearmint containing 3 mg nicotine per portion (Nicotine and Flavor analysis) - 60 min single dose administration
13. Swedish portion snus PSWL 1.0 g (8 mg nicotine/g) - 15 min single dose administration
14. Swedish portion snus PSWL 1.0 g (8 mg nicotine/g) - 60 min single dose administration

The treatments are administered as single doses in a pre-determined randomised order. The participant keeps the pouch still between the upper lip and the gum for 15 or 60 minutes.

The total duration of the treatments and follow-up for all study arms is one day followed by 1-14 day(s) of wash-out (repeated for each dose time point) and follow-up seven days after the last dose, i.e. the total duration is different depending on the number of wash-out days.

Intervention type

Other

Phase

Drug names

Primary outcome measure

Extracted dose of nicotine from each portion is measured by using GC-MS analysis and calculated by subtracting the residual amount after use from the mean of 10 unused portions. Used portions are freezed after dosing and analysis using GC-MS is performed at the end of the trial.

Secondary outcome measures

1. Pulse rate is measured using a pulsimeter at baseline, five, ten, 15, 30 and 60 minutes
2. Head buzz (head rush, “hit”, feeling alert, overall “product strength” is measured using a 100-mm visual analogue scale (VAS) at preset time points up to 30 and 60 minutes, respectively, after study product administration (as a proxy for systemic uptake)
3. The extracted dose of flavor components are measured using GC-MS analysis and calculated by subtracting the residual amount after use from the mean of 10 unused portions. Used portions are freezed after dosing and analysis using GC-MS is performed at the end of the trial.
4. Adverse events are measured using patient interviews at predose, five, ten, 15, 30 and 60 minutes

Overall trial start date

02/06/2017

Overall trial end date

14/11/2017

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Snus user, with a minimum weekly consumption of three or more snus cans (brands with nicotine content <1%) or two or more cans (brands with nicotine content >1%) since ≥1 year
2. Consent to participate voluntarily and sign Informed Consent Form prior to any study procedure
3. Healthy male/female, age ≥19. Female subjects should have a negative pregnancy test.
4. Willing and able to comply with study procedures
5. A heart rate increase ≥ 10 beats/min with first use of snus in the morning after overnight abstinence from any nicotine exposure

Participant type

Healthy volunteer

Age group

Adult

Gender

Both

Target number of participants

20

Participant exclusion criteria

1. A history or presence of diagnosed hypertension or any cardiovascular disease
2. Surgery within 6 months of the screening visit that, in the opinion of the investigator, could negatively impact on the subject’s participation in the clinical study
3. Any surgical or medical condition, which, in the judgment of the clinical investigator, might interfere with the absorption, distribution, metabolism or excretion of the drug
4. Subjects who are pregnant

Recruitment start date

14/09/2017

Recruitment end date

22/09/2017

Locations

Countries of recruitment

Sweden

Trial participating centre

CTC Clinical Trial Consultants AB
Akademiska Sjukhuset Ingång 85 Våning 2
Uppsala
SE-752 37
Sweden

Sponsor information

Organisation

Swedish Match North Europe

Sponsor details

Maria Skolgata 83
Stockholm
SE-118 53
Sweden

Sponsor type

Industry

Website

Funders

Funder type

Industry

Funder name

Swedish Match North Europe

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Planned publication in a peer reviewed journal.

IPD sharing statement:
As this is a controlled clinical trial conducted according to GCP-IHC criteria the trialists are obliged and intend to keep all study data stored after completion of the study. However, they have not yet decided where and how this will be done. The data might be shared with relevant authorities. They might potentially also share de-identified data with other researchers on an ad hoc basis. The details and logistics of such data sharing has not yet been decided.

Intention to publish date

14/11/2018

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

23/11/2017: Internal review.