A study investigating the extraction of nicotine and flavors from tobacco-free nicotine pouches
| ISRCTN | ISRCTN30119403 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN30119403 |
| Secondary identifying numbers | SM 20-01 |
- Submission date
- 09/02/2021
- Registration date
- 09/02/2021
- Last edited
- 05/12/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Other
Plain English Summary
Background and study aims
Sweden has the lowest prevalence of smoking in Europe, particularly among males. It is widely accepted that one contributory factor to this trend is that snus has replaced cigarettes as the tobacco product of choice among many male and some female smokers. Nicotine is the substance that is thought to contribute the most to the dependency of using any type of tobacco product, and nicotine exposure may contribute to adverse pregnancy outcomes. In addition, oral tobacco products typically contain low levels of unwanted substances (including nitrosamines and polycyclic hydrocarbons) that have been classified as human carcinogens. So, although the health effects are substantially smaller for oral tobacco compared to cigarette smoking, some adverse effects cannot be ruled out, in particular not effects related to the nicotine exposure.
Traditionally there has been no non-tobacco-based nicotine product intended for recreational use. Despite the vast risk differential between snus and cigarettes in terms of adverse long-term health effects, snus remains a controversial product as it contains tobacco, is intended for recreational use, and causes dependency. The tobacco component of snus explains why it contains measurable amounts of unwanted, potentially carcinogenic constituents, albeit at very low concentrations. Non-tobacco-based nicotine products (e.g. ZYN) have been commercially available for a few years. They have some features that are similar to snus since they come in pouches that are intended to be placed under the upper lip. However, in contrast to snus, these products contain no nitrosamines or polycyclic hydrocarbons, which are the two main classes of unwanted substances in snus. The nicotine content in ZYN is comparable to that in snus and many other oral tobacco products that are currently common on the market in Scandinavia and the US. Addition of flavors to tobacco products and e-cigarettes have been discussed by regulatory agencies during the last years. It has been suggested that some flavors could enhance nicotine uptake, which has not previously have been fully scientifically investigated for this product category. In addition, focusing on inhaled tobacco and ENDS products, WHO have highlighted that the actual levels of flavor compounds and potential metabolites delivered to the consumer is key for health risk assessment. There is a substantial inter-individual variation in uptake with products used orally which is probably related to constitutional differences in saliva production and results in a wide variation in nicotine extraction from the product. It has been postulated that some flavors could enhance nicotine uptake.
This study is a part of the effort by Swedish Match to assess the levels flavor extracted from the products and consumers could be exposed to. The ZYN Moist products included in the current study, utilize utilize a different matrix compared to ZYN Dry products which earlier have been investigated. The nicotine extraction may differ as a consequence of different pouch geometry, water content, particle size etc. Therefore, the current study will investigate the nicotine and/or flavor extraction of ZYN Moist 9 mg products, utilizing different flavor contents, compared to an unflavored ZYN Moist product. The key goals of the study is to show equivalence of the estimated in vivo extracted fraction of nicotine between ZYN Wintergreen (1) and ZYN Smooth and to evaluate the estimated in vivo extracted amount and fraction of flavor compounds from all products after administration of one single dose.
Who can participate?
Healthy male or female volunteers aged 19 or older. All research subjects are required to be daily users of oral tobacco/nicotine products since at least one year (with an average or above snus consumption) so the participants are well acquainted with, and used to, the effects of nicotine.
What does the study involve?
The participating subjects will receive study product on 9 occasions divided into two treatment visits, in a cross-over fashion. The study will include a screening visit, two treatment visits for administration of in total 9 doses of IP, and a follow-up (FU) telephone visit.
Screening (Visit 1) will take place within 28 days prior to Visit 2 and will include an eligibility check including review of health status and evaluation of nicotine/tobacco use.
The subjects are instructed not to eat, drink, chew chewing gum, use nicotine free pouches or brush teeth from 30 minutes before and during application of the IP. Following administration of 3 or 4 doses of IP, according to a predetermined randomized order, with at least 60 minutes between doses (from end of administration to start of administration). The IPs are administered as single doses and the subject keeps the pouch still between the upper lip and the gum for 60 minutes and are instructed not to manipulate the pouch with the tongue or lips. After 60 minutes the pouches are collected and frozen (-20°C) pending analysis of residual nicotine and flavor compound content.
What are the possible benefits and risks of participating?
There are no possible benefits to participating. Only participants who are well acquainted with and used to the effects of nicotine can participate. The only side effects are the effects likely to be related to 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?
May 2020 to June 2021 (updated 01/04/2021, previously: March 2021)
Who is funding the study?
Swedish Match North Europe (Sweden)
Who is the main contact?
Dr Camilla Pramfalk
camilla.pramfalk@swedishmactch.com
(updated 08/04/2021, previously: Dr Sara Moses
sara.moses@swedishmatch.com)
Contact information
Scientific
SE-Box 17037
Stockholm
104 62
Sweden
| Phone | +46 (0)790984758 |
|---|---|
| camilla.pramfalk@swedishmatch.com |
Study information
| Study design | Open randomized nine-way cross-over single dose administration study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised cross over trial |
| Study setting(s) | Other |
| Study type | Other |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet |
| Scientific title | In vivo extraction of nicotine and flavor compounds from a single dose of non-tobaccobased nicotine pouches (ZYN Moist) |
| Study acronym | SM 20-01 |
| Study hypothesis | The overarching aim of the study is to evaluate if the different flavor components have an impact on the nicotine extraction from a ZYN Moist 9 mg product compared to an unflavored ZYN Moist 9 mg product. In addition, the extraction of selected flavor components will be determined. |
| Ethics approval(s) | Approved 18/01/2021, Swedish Ethics Review Appeals Board (Swedish Research Council. Box 1035 101 38 Stockholm, Sweden; no telephone number provided; Kansli@onep.se), ref: Dnr Ö 72-2020/3.1 Application EPN Dnr 2020-03872 |
| Condition | Tobacco/nicotine use |
| Intervention | Investigational Product (IP) and dosage (oral smokeless nicotine pouch) ZYN Moist Wintergreen (1)* containing 9 mg nicotine/pouch ZYN Moist Wintergreen (2)* containing 9 mg nicotine/pouch ZYN Moist Chill containing 9 mg nicotine/pouch ZYN Moist Cool Mint containing 9 mg nicotine/pouch ZYN Moist Citrus containing 9 mg nicotine/pouch ZYN Moist Spearmint containing 9 mg nicotine/pouch ZYN Moist Deep Freeze containing 9 mg nicotine/pouch ZYN Moist Smooth containing 9 mg nicotine/pouch *ZYN Moist Wintergreen product (1) and (2) contains a different amount of the flavor wintergreen The participating subjects will receive the study product on 9 occasions divided into two treatment visits, in a cross-over fashion, with 60 minutes of treatment per occasion. Each subject will participate in the study for a period of approximately 5 weeks (including a screening period of up to 4 weeks). |
| Intervention type | Other |
| 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. 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 study 2. Self-report of potential adverse events (AEs, frequency, intensity and seriousness) measured throughout the study |
| Overall study start date | 24/06/2020 |
| Overall study end date | 15/06/2021 |
Eligibility
| Participant type(s) | Healthy volunteer |
|---|---|
| Age group | Adult |
| Lower age limit | 19 Years |
| Sex | Both |
| Target number of participants | 36 subjects will be included in the study to achieve 33 fully evaluable subjects. It is estimated that approximately 56 subjects will be screened. |
| Total final enrolment | 35 |
| Participant inclusion criteria | 1. Willing and able to give written informed consent for participation in the study 2. Male or female subject aged ≥19 years 3. Subject who has used oral tobacco/nicotine products for ≥1 year, with a minimum daily consumption of five or more snus pouches, and is willing and able to use brands with nicotine content ≥1% 4. Women of child bearing 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], IUD or IUS. Sexual abstinence is allowed when this is the preferred and usual lifestyle of the subject |
| Participant exclusion criteria | 1. Any surgical or medical condition including abnormal salivation (also pharmaceutically induced), or history thereof, which, in the judgment of the Investigator, might interfere with the absorption of the IP or may either put the subject at risk because of participation in the study, influence the results, or the subject’s ability to participate in the study 2. Any clinically significant illness in the 28 days prior to the first IP administration 3. A history or presence of untreated diagnosed hypertension or any cardiovascular disease 4. Female subject currently breast feeding, pregnant or planning to get pregnant during the study 5. Positive screen for drugs of abuse or alcohol at screening or on admission to the unit prior to first administration of the IP 6. Current or history of alcohol abuse and/or use of anabolic steroids or drugs of abuse, as judged by the Investigator 7. Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements |
| Recruitment start date | 27/01/2021 |
| Recruitment end date | 05/02/2021 |
Locations
Countries of recruitment
- Sweden
Study participating centres
Entrance 85, 2nd level
Uppsala
SE-751 85
Sweden
Uppsala
SE-752 37
Sweden
Sponsor information
Industry
Maria Skolgata 83
Stockholm
SE-118 53
Sweden
| Phone | +46 (0)10 13 93 000 |
|---|---|
| mikael.staaf@swedishmatch.com | |
| Website | https://www.swedishmatch.com/ |
Funders
Funder type
Industry
No information available
Results and Publications
| Intention to publish date | 31/12/2025 |
|---|---|
| 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 | Planned publication in a peer reviewed journal. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are available from the corresponding author Dr Erik Lunell (croelab@gmail.com) or the last author Robert Pendrill (robert.pendrill@swedishmatch.com) on reasonable request. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version 1.0 | 24/06/2020 | 30/11/2022 | No | No |
Additional files
Editorial Notes
05/12/2024: The intention to publish date was changed from 31/12/2024 to 31/12/2025.
12/12/2023: The intention to publish date was changed from 31/12/2023 to 31/12/2024.
10/07/2023: The intention to publish date was changed from 30/09/2023 to 31/12/2023.
09/06/2023: The intention to publish date was changed from 30/06/2023 to 30/09/2023.
07/12/2022: The intention to publish date was changed from 31/12/2022 to 31/03/2023.
30/11/2022: Uploaded protocol (not peer reviewed).
24/11/2022: Publication reference and IPD sharing statement added.
12/07/2022: The contact confirmed the record is up to date.
14/06/2022: The intention to publish date was changed from 01/06/2022 to 31/12/2022.
29/06/2021: Internal review.
15/06/2021: The overall end date was changed from 16/06/2021 to 15/06/2021.
08/06/2021: The overall end date was changed from 11/06/2021 to 16/06/2021.
08/04/2021: The following changes were made to the trial record:
1. The contact was changed.
2. The plain English summary was updated to reflect these changes.
01/04/2021: The following changes were made to the trial record:
1. The overall start date was changed from 12/05/2020 to 24/06/2020.
2. The overall end date was changed from 01/03/2021 to 11/06/2021.
3. The total final enrolment was added.
4. The plain English summary was updated to reflect these changes.
09/02/2021: Trial’s existence confirmed by Swedish Ethics Review Appeals Board.
