Ignite Creation Date:
2024-10-26 @ 3:35 PM
Last Modification Date:
2024-10-26 @ 3:35 PM
Study NCT ID:
NCT06506162
Status:
RECRUITING
Last Update Posted:
None
First Post:
2024-07-03
Brief Title:
Abuse Liability and Appeal of Oral Nicotine Products
Sponsor:
None
Organization:
None
Study Overview
Official Title:
The Effect of Flavor and Nicotine Strength on the Abuse Liability and Appeal of Oral Nicotine Products
Status:
RECRUITING
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
There has been a recent proliferation of novel oral nicotine products ONPs brought to market including new nicotine gums and pouches Unlike electronic cigarettes ECs ONPs have no impending regulatory barriers with regard to flavoring or nicotine dose and manufacturers have capitalized on this by introducing an extensive slate of characterizing flavors and nicotine concentrations Both sales trajectory and the surge in marketing suggest ONP use is likely to increase in the coming years Work by the investigators and others indicates that interest in these products is high among current EC users and among specific demographic groups including those who identify as sexual and gender minority SGM ONP use is discrete and so can function as a secondary source of nicotine encouraging dual use patterns and more severe nicotine dependence Depending on the use patterns of ONPs that emerge regulation of ONPs may serve the public health interest However very little is known about factors relevant to the actual appeal and abuse liability of these products The investigators propose to address this important gap by assessing the appeal and abuse liability of gum and pouch ONPs as a function of flavor mint vs fruit and nicotine concentration 2mg vs 4mg Flavor and nicotine strength along with product type are regulatable attributes and so it is essential to understand their impact on appeal and abuse liability Evidence from EC use suggests a potential interaction between flavor and nicotine strength with flavorants in the mint category desensitizing receptors integral to the aversive sensory experience of nicotine leading to greater tolerability of high nicotine concentration Because of current ONP marketing emphasis on youth the investigators will recruit young adult exclusive EC users N 320 ages 21 - 25 The investigators will target recruitment of a sufficient number of SGM participants N 64 20 of sample to allow assessment of potential differentiation of this group Participants will complete one virtual session focused on assessment of the sensory appeal of ONPs Based on individual participant ratings the preferred fruit and the preferred mint ONP will be selected from their randomized product type and nicotine strength to each be assessed in a single-product session examining factors known to predict abuse liability relief of withdrawal liking behavioral economic indices of demand and follow-up naturalistic product use The investigators will pay particular attention to evidence suggesting dual use potential of ONPs given its association with greater severity of nicotine dependence The proposed work will inform efforts to mitigate ONPs potential to promote dual-use and more severe nicotine dependence among young adult EC users by isolating the impact of potential regulatory targets
Detailed Description:
E-cigarettes ECs have been the predominant flavored non-combustible tobacco product used by young adults since 2014Ali et al 2022 and are disproportionately used by sexualgender minorities SGM Buchting et al 2017Wheldon et al 2019 However patterns are likely to change due to 1 increasing regulatory restrictions on non-tobacco flavored ECs and 2 the emergence new nonmedicinal oral nicotine products ONPs eg pouches and gums with enhanced palatability eg improved flavoring Lunell et al 2022 Preliminary data shows that many young adult e-cigarette users with no intention to quit vaping perceive ONPs as secondary means of nicotine consumption when vaping is prohibited Because ECONP dual use could exacerbate nicotine dependence by increasing daily nicotine intake it is important to identify drivers of ONP appeal and abuse liability in young adult EC users to inform regulations that prevent adverse dual use in young people Nicotine concentration and flavors are two putative drivers of ONP appeal and abuse liability given that ONPs deliver substantial buccal nicotine absorptionLunell et al 2022 and like ECs their flavors elicit pleasant sensory effects Goldenson et al 2019 Leventhal et al 2020 Certain ONP flavors may offset nicotines oral irritating effects via anesthetizing cooling effects mint flavored ONPs with menthol allowing tolerability of higher doses of nicotine ONP type may also be important to ONP appeal Initial evidence primarily product interest survey data suggests young adult EC users and adolescents may have higher affinity for nicotine gum than pouches and interest in using ONPs was greater within certain vulnerable populations especially SGMs
The investigators will determine the appeal and abuse including dual use liability of gum and pouch ONPs as a function of flavor mint vs fruit and nicotine concentration gum 2mg vs 6mg pouch 2mg vs 6mg among young adult exclusive EC users N 320 ages 21 - 25 Data will be collected via virtual study sessions in which participants residences become remote laboratories allowing nationwide quota sampling Following an orientation participants will be randomized to one of two ONP types gum or pouch and nicotine concentrations low vs high resulting in four study groups The randomized nicotine-ONP combination will then be tested in i a single-visit appealsensory attribute testing involving controlled self-administration of mint and fruit flavored ONPs and ii two abuse liability evaluations one for fruit one for mint each involving a single-visit controlled ONP self-administration session and 1-week post-visit naturalistic use of the respective ONP
Overview of Project The investigators will utilize an experimental design to determine the acute appeal and abuse liability of gum and pouch ONPs among young adult current EC users Data will be collected via three online sessions with participants from across the US in which their own residences become a remote lab Following an orientation session participants will be randomized to one of four groups varied by product type a gum or pouch and nicotine concentration low 2mg or high 6mg and receive that type and nicotine level throughout the entire protocol Experimental session 1 Sensory Appeal session collect ratings appeal and sensory attributes directly after self-administering 2 fruit eg citrus pomegranate and 2 mint eg spearmint wintergreen flavored variants of their ONP typenicotine condition in in a single visit Order of the 4 flavors will be in one of 24 possible sequences randomly assigned for each participant The highest rated fruit variant and highest rated mint variant will be selected for the subsequent two sessions Experimental sessions 2 3 Abuse Liability sessions involve 30-min self-administration of one ONP fruit ONP in one session mint ONP in another session order counterbalanced in separate sessions after 18-hours of abstinence Dependent variables will include withdrawalurge suppression subjective effects and behavioral economic indicators of reward value In addition for the 7 days after each abuse liability session visit participants will report on naturalistic use of the same product a free provision of 30 pieces of each product that was administered in the previous Abuse Liability session will be provided to participants to use ad lib
Rationale for Methods Overall design rationale Rationale for the two-part appeal abuse liability protocol Based on the integration of paradigms that the investigators developed to assess abuse liability and appeal of ECs a two-part protocol will be used The first experimental session Sensory Appeal session in the proposed design provides information about the sensory attributes of the user experience that drives appeal of different flavors Given that multiple products four are tested within a single visit and appeal ratings are collected immediately during use differences across flavors are driven by sensory experience and cannot be attributed to differences driven by the neuropharmacological effects of nicotine By contrast the Abuse Liability experimental sessions Sessions 2 - 3 test a single flavored product within a session which will provide a richer source of information about the use and valuation of ONPs due to the combination of the sensory and neuropharmacological effects
Justification of mixed factorial design While a fully within-participant design would provide the greatest power to detect divergence between product conditions an 8 multi-hour abuse liability study sessions would be too burdensome and monotonous to maintain consistent participant engagement A mixed-factorial design allows sufficient statistical power to estimate the impact of study variables without overburdening participants
Justification of 7-day monitoring period Given the limited surveillance ie only nicotine pouches assessed in NYTS no measures of new ONPs in PATH or NSDUH of these new nonmedicinal ONPs and to better understand how young adults may use these products in conjunction with their EC the investigators include brief approximately 2 minutes daily surveys assessing ONP use and use in situations when vaping is constrained This will provide much needed data on the dual use liability of ONPs and ECs in the natural ecology and allow assessment of whether use varies by ONP type flavor and nicotine strength The investigators are well versed in utilizing remote monitoring periods to examine naturalistic use patterns of EC and polytobacco product use behaviors among young adults
Rationale for product type and characteristics Justification of flavors The investigators could have focused on a particular flavoring constituent eg menthol vanillin and designed a study around manipulating the presence or concentration of that constituent to isolate their effect However more than 120 different flavoring constituents have been identified in ONPs including up to 25 flavoring constituents within a single characterizing flavor eg berry that combine to create the sensory profile Hence disaggregating particular constituents would not be representative of the ONP characterizing flavors sold on the market and FDA has historically regulated according to the characterizing flavor rather than particular constituents The TCORS methods core will do a flavoring constituent analysis which will provide contextual data on this issue Among the characterizing flavors the investigators focus on fruit and mint because they are the preferred EC flavor categories among AYAs and tobacco naïve individualsKing et al 2018 and survey data suggesting interest in ONPs of these flavors is high see above
Justification of nicotine concentrations The investigators include 2mg vs 6mg nicotine because of the prominence of these concentrations on the ONP market However there are ONPs currently available with substantially higher nicotine concentration 20mg While many ONP users report titrating up their ONP dose after they become accustomed to the sensations of ONP use most find nicotines irritating oral effects as uncomfortable at first Because study participants are ONP-naïve starting with these two doses which are low and moderate range is indicated The investigators also considered the inclusion of matched products without nicotine However the absence of any such marketed products would require imperfectly matched alternatives eg confectionery gums and would not usefully advance the primary aim of providing information directly relevant to FDA decision-making because FDA-CTP does not regulate such products
Justification of ONP types The investigators selected nicotine gum and pouch because extensive industry marketing is currently being directed at both products The Center includes monitoring of additional nicotine products including lozenges and if they emerge as highly popular the investigators will add lab assessments through the Centers CECRRP mechanism
Eligibility see inclusionexclusion section
Procedures
Initial screening Advertisements will phone numbers for Research Assistants RAs a QR code and a direct link to an online study screener Potentially eligible participants are contacted by RAs to conduct a detailed phone screen to confirm all self-report eligibility criteria Eligible participants will be scheduled orientation session to be conducted over Zoom to provide informed consent
Orientation Consent Session Before the orientation participants will be mailed supplies including for collecting a baseline urine test of recent nicotine use involving a test strips that provide semi-quantitative total nicotine equivalents TNEs estimates of nicotine and nicotine metabolites 0-14 levels 1 required for eligibility At the outset of the orientation presence of a computer laptop tablet or similar device with working camera microphone and audio and Internet to complete REDCap surveys will be confirmed After confirming age and obtaining digital informed consent the urine nicotine test will be collected and if positive participants will be asked to assure that the study products shipped to participants will be kept in a safe place away from children animals and minors and used only for the research study Next self-report measures of demographics and tobacco product use history will be completed Finally participants will be scheduled for their next experimental visits and remined that 18-hour nicotine abstinence is required and will be confirmed by urine for each visit To provide some control over daily fluctuations in nicotine craving and withdrawal and to facilitate adherence to the abstinence requirement efforts will be made to complete those study visits for which abstinence is required in the morning hours 800-1100 AM near waking time
Randomization to ONP type and nicotine Participants will be randomized into one product condition gum or pouch and one nicotine level high or low stratified by region South West Midwest Northeast and SGM status which will determine the products used for the next 3 visits
Provision of Appeal Session Study Materials The investigators will mail participants a package that will include ONP products blinded ie randomized products will be placed in labeled baggies with numbers indicating each product remote exhaled carbon monoxide eCO Covita device for biochemical verification of no combustible tobacco use urine nicotine sample and test strip and pregnancy test as appropriate product disposal bag with tamper seal tape cleaning supplies and materials for returning salivary samples The eCo device is a remote device that connects to the participants cell phone device both android and iOS and allows for remote bioverification of smoking status see D5e for cut off eCO values The investigators will follow all safety hazard protections for product transport guidelines by shipping and courier agencies Because this study does not involve sales of tobacco products and the products are provided for research use only it is exempt from FDA regulations that apply to transporting tobacco products for business purposes Study RAs will track package during shipping and inform the participant of any updates ie delays estimated arrival etc via phonetext As in prior research all sample products will be clearly labeled CONTAINS TOBACCO PRODUCTS TO BE RECEIVED AND USED BY PERSON 21 YEARS OF AGE OR OLDER FOR RESEARCH USE ONLY NOT FOR PERSONAL USE Upon receipt of study materials the study team will contact the participant within 48 hours to schedule the first experimental session In the investigators prior research providing various EC products N 439 experimental sessions no study packages were opened prior to experimental sessions
ONP Appeal Session After confirming nicotine deprivation semi quantitative reduction by 1 level of TNE and breath eCO of 4ppm participants will be administered the appeal test procedure with 4 different ONPs 2 mint 2 fruit in random order as in prior work eg Leventhal et al 2020 Each ONP trial involves 5-minute administration period in which the product is put into the mouth chewed gum only and parked between the lip and gum per package instructions followed by a 2-minute rating period rate appeal and sensory attributes see outcome measures below and then a 2-minute water mouth rinse inter-trial interval All products will be labeled with a letter and no identifying information about the flavor of the product will be provided to participants ie participant is blinded Prior to administration of the first product participants will be shown a video demonstrating administration procedures This study design has been piloted by the investigators with ONPs and was successfully implemented with ECs over 20 ECs solutions provided and rated for appealsensory characteristics in over 400 remote sessions with no adverse events
Provision of Abuse Liability Session Study Materials Each package will include 31 piecespouches of participants top-rated fruit or mint ONPs ie flavor variant with the highest appeal composite score see below New salivary nicotine collection kits urine cups and pregnancy test as appropriate and other study materials eg product disposal bag with tamper seal tape cleaning supplies return materials for salivary samples
Experimental Sessions Study Visits 2 - 3 Participants will complete two separate single-product abuse liability sessions one fruit one mint order counterbalanced across participants After confirmand nicotine deprivation by urine TNE and eCO Next pre-ONP administration withdrawal and urges will be assessed Participants will then use the sessions ONP for 30-minutes according to a structured protocol adapted from Houtsmuller et al 2001 for therapeutic nicotine In this the participant is informed to keep the ONP in their mouth for the entire 30 min As in the previous sessions following the chew gum only and park procedures while being encouraged to move the ONP around in their mouth to where it is most comfortable Next post-administration phase participants will complete withdrawal and urge follow-up measures and other questionnaires to assess specific domains relevant to abuse liability see description below Naturalistic 7-Day Monitoring Period Finally at the end of the session participants will be instructed that they may use as few or as many of the provided pieces of the session ONP over the next 7 days 30 pieces max provided to participants Participants will report on any use through daily electronic surveys assessing frequency eg number of pieces per dayquantity eg total pieces used during the monitoring periodlocation of use eg vape free locations when EC is unavailable One specific question will ask How many times did you use the ONP in places where you normally couldnt or wouldnt vape such as at work indoor or in other smokevape free locations
Measures Orientation measures Participant characteristics demographics vaping history Leventhal et al 2019 smoking history Leventhal et al 2019 vaping dependence Tackett et al 2021 flavors preferred etc per PhenX Toolkit will be assessed during orientation session Measure updates needed due to market changes eg new types of flavors will be added and developed per the MMC
Appeal and Sensory Ratings The investigators will use the Appeal and Sensory Quality Measures as used in Drs Leventhal and Monterossos current paradigms assessing appeal and sensory attributes of ECs Participants will rate the product on visual analog scales range 0-100 with answers to the following 3 questions for appeal and 4 questions for sensory attributes 1 How much did you like the ONP 2 How much did you dislike the ONP 3 Would you use this product again 4 How sweet was the ONP 5 How bitter was the ONP 6 How much did you like the mouth feel of the ONP 7 How irritating or painful was the ONP in your mouth Rating anchors include not at all and extremely for each measure except use again not at all and definitely The ratings of liking disliking reverse-scored and willingness to use again represent related but nonredundant measures of appeal Thus an appeal composite score will be based on the mean of these 3 ratings per prior work eg Leventhal et al 2019 Sensory ratings will be analyze separately per previous factor analyses of ratings from EC appeal studies indicating that appeal items shared a common factor whereas sensory attributes loaded onto distinct item-specific factors
Abuse and Dual Use Liability All items will be adapted for ONP language ie replace vapingsmoking with ONP descriptors Withdrawalurge suppression pre and post admin Nicotine Withdrawal Scale NWS Nicotine withdrawal will using a validated 8-item version of the Nicotine Withdrawal Scale assessing angerirritability anxiety depressed mood restlessnessdifficulty concentrating increased appetite rated experienced right now on a scale of 0 nonenot at all - 4 severeextremely and summed Brief Questionnaire of Vaping Urges QVU-Brief Cox et al 2001 The QVU-brief is a 10-item self-report measure with items rated from 1 strongly disagree to 7 strongly agree right now which is administered pre and post administration and yields a sum composite score Subjective effects post admin Drug Effects Questionnaire DEQ Morean et al 2019 A modified version of the DEQ will be used to rate acute responses to the ONP on visual analog scales range 0 not at all - 100 extremely Items assess likingwanting the average of I feel good effects from the ONP I want more of that ONP I received I feel the ONP strength and I like the ONP effect
The ONP Purchase Task Cassidy et al 2020 will assess self-reported economic demand in ONP units gum pieces or pouches Following a previously validated protocol used in the investigators pilot study purchase tasks will be completed for the ONP provided during that visit Participants will indicate the amount of the product they would purchase for consumption for a typical day with no opportunity to save anything not consumed at a series of per-unit price points Following Mackillop et al 2008113 the following unit price points will be included 0 01 05 13 25 1 2 3 4 5 6 11 35 70 140 280 560 and 1120 They will complete this task under two scenarios complete two hypothetical scenarios 1 Other nicotine constrained when they are involved with no other accessible nicotine products and 2 Vaping unconstrained the alternative specification that they have free 0 ie no cost to use access to their preferred vape Participants will be instructed to imagine a typical day which may or may not include periods in which vaping is prohibited or uncomfortable Outcomes Four measures will be derived from each task condition Omax the maximum total expenditure on the substance Pmax the price at which expenditure was highest intensity consumption at 0 and demand elasticity a derived measure indicating the steepness with which demand drops as a function of price Elasticity will be estimated following Hursh and Silberberg 2008114 by fitting the demand function logQ logQ0 ke-aPs - 1 where Q0 is the quantity purchased at 0 Ps is price if demand did not change from Q0 k is a constant across participants based on best fit to average consumption and a is an individualized fit-parameter capturing sensitivity to price elasticity Since intensity Omax and elasticity were observed to be most predictive of nicotine use and dependence in a recent meta-analysis González-Roz et al 2019 these will be considered the primary three indices of demand Dual use liability Dual Use Liability Questionnaire DULQ Participants are instructed to consider times in which they want to vape but are somewhere that they dont feel they can To what degree is the ONP you used today an appealing alternative to use during those periods and How willing would you be to try the ONP in a situation when you couldnt vape a mean score of 0-7 not at all to frequently is computed The ONP purchase task unconstrained vs constrained difference Omax Pmax intensity and demand elasticity will be subtracted from the respective values of the constrained variant to provide an index of dual use reward value
Naturalistic monitoring period Naturalistic use of provided ONPs 30 piecesparticipant 4 pieces availableday over the 7 days will be conducted following each Abuse Liability Session with a brief daily survey asking how many pieces they used that day and how many pieces they have left by counting and whether or not they used at a vape free location indoors or because they wanted to conceal nicotine use due to social concerns Overall self-administration is assessed by the total number of piecespouches used range 0-30 Dual use self-administration the number of days out of the week in which they reported using the ONP in a time that they felt vaping was constrained due to social concerns or indoor restrictions 0-7
Data Analysis Plan Data analyses will be carried out by the Centers Data Processing and Analysis Core DPAC The main research questions from the three Aims in the proposed study have the same structure for data analysis Prior to primary analyses the investigators will examine whether baseline characteristics eg nicotine dependence severity demographics differ between the four study groups Any sample characteristics that do differ significantly between randomized groups will be included in statistical models of study outcomes All relevant outcome variables will be first examined with exploratorydescriptive statistical analyses that focus on describing and understanding patterns and distributions for all relevant measures eg appeal ratings desire to use again
The investigators will determine the appeal and abuse including dual use liability of gum and pouch ONPs as a function of flavor mint vs fruit and nicotine concentration gum 2mg vs 6mg pouch 2mg vs 6mg among young adult exclusive EC users N 320 ages 21 - 25 Data will be collected via virtual study sessions in which participants residences become remote laboratories allowing nationwide quota sampling Following an orientation participants will be randomized to one of two ONP types gum or pouch and nicotine concentrations low vs high resulting in four study groups The randomized nicotine-ONP combination will then be tested in i a single-visit appealsensory attribute testing involving controlled self-administration of mint and fruit flavored ONPs and ii two abuse liability evaluations one for fruit one for mint each involving a single-visit controlled ONP self-administration session and 1-week post-visit naturalistic use of the respective ONP
Overview of Project The investigators will utilize an experimental design to determine the acute appeal and abuse liability of gum and pouch ONPs among young adult current EC users Data will be collected via three online sessions with participants from across the US in which their own residences become a remote lab Following an orientation session participants will be randomized to one of four groups varied by product type a gum or pouch and nicotine concentration low 2mg or high 6mg and receive that type and nicotine level throughout the entire protocol Experimental session 1 Sensory Appeal session collect ratings appeal and sensory attributes directly after self-administering 2 fruit eg citrus pomegranate and 2 mint eg spearmint wintergreen flavored variants of their ONP typenicotine condition in in a single visit Order of the 4 flavors will be in one of 24 possible sequences randomly assigned for each participant The highest rated fruit variant and highest rated mint variant will be selected for the subsequent two sessions Experimental sessions 2 3 Abuse Liability sessions involve 30-min self-administration of one ONP fruit ONP in one session mint ONP in another session order counterbalanced in separate sessions after 18-hours of abstinence Dependent variables will include withdrawalurge suppression subjective effects and behavioral economic indicators of reward value In addition for the 7 days after each abuse liability session visit participants will report on naturalistic use of the same product a free provision of 30 pieces of each product that was administered in the previous Abuse Liability session will be provided to participants to use ad lib
Rationale for Methods Overall design rationale Rationale for the two-part appeal abuse liability protocol Based on the integration of paradigms that the investigators developed to assess abuse liability and appeal of ECs a two-part protocol will be used The first experimental session Sensory Appeal session in the proposed design provides information about the sensory attributes of the user experience that drives appeal of different flavors Given that multiple products four are tested within a single visit and appeal ratings are collected immediately during use differences across flavors are driven by sensory experience and cannot be attributed to differences driven by the neuropharmacological effects of nicotine By contrast the Abuse Liability experimental sessions Sessions 2 - 3 test a single flavored product within a session which will provide a richer source of information about the use and valuation of ONPs due to the combination of the sensory and neuropharmacological effects
Justification of mixed factorial design While a fully within-participant design would provide the greatest power to detect divergence between product conditions an 8 multi-hour abuse liability study sessions would be too burdensome and monotonous to maintain consistent participant engagement A mixed-factorial design allows sufficient statistical power to estimate the impact of study variables without overburdening participants
Justification of 7-day monitoring period Given the limited surveillance ie only nicotine pouches assessed in NYTS no measures of new ONPs in PATH or NSDUH of these new nonmedicinal ONPs and to better understand how young adults may use these products in conjunction with their EC the investigators include brief approximately 2 minutes daily surveys assessing ONP use and use in situations when vaping is constrained This will provide much needed data on the dual use liability of ONPs and ECs in the natural ecology and allow assessment of whether use varies by ONP type flavor and nicotine strength The investigators are well versed in utilizing remote monitoring periods to examine naturalistic use patterns of EC and polytobacco product use behaviors among young adults
Rationale for product type and characteristics Justification of flavors The investigators could have focused on a particular flavoring constituent eg menthol vanillin and designed a study around manipulating the presence or concentration of that constituent to isolate their effect However more than 120 different flavoring constituents have been identified in ONPs including up to 25 flavoring constituents within a single characterizing flavor eg berry that combine to create the sensory profile Hence disaggregating particular constituents would not be representative of the ONP characterizing flavors sold on the market and FDA has historically regulated according to the characterizing flavor rather than particular constituents The TCORS methods core will do a flavoring constituent analysis which will provide contextual data on this issue Among the characterizing flavors the investigators focus on fruit and mint because they are the preferred EC flavor categories among AYAs and tobacco naïve individualsKing et al 2018 and survey data suggesting interest in ONPs of these flavors is high see above
Justification of nicotine concentrations The investigators include 2mg vs 6mg nicotine because of the prominence of these concentrations on the ONP market However there are ONPs currently available with substantially higher nicotine concentration 20mg While many ONP users report titrating up their ONP dose after they become accustomed to the sensations of ONP use most find nicotines irritating oral effects as uncomfortable at first Because study participants are ONP-naïve starting with these two doses which are low and moderate range is indicated The investigators also considered the inclusion of matched products without nicotine However the absence of any such marketed products would require imperfectly matched alternatives eg confectionery gums and would not usefully advance the primary aim of providing information directly relevant to FDA decision-making because FDA-CTP does not regulate such products
Justification of ONP types The investigators selected nicotine gum and pouch because extensive industry marketing is currently being directed at both products The Center includes monitoring of additional nicotine products including lozenges and if they emerge as highly popular the investigators will add lab assessments through the Centers CECRRP mechanism
Eligibility see inclusionexclusion section
Procedures
Initial screening Advertisements will phone numbers for Research Assistants RAs a QR code and a direct link to an online study screener Potentially eligible participants are contacted by RAs to conduct a detailed phone screen to confirm all self-report eligibility criteria Eligible participants will be scheduled orientation session to be conducted over Zoom to provide informed consent
Orientation Consent Session Before the orientation participants will be mailed supplies including for collecting a baseline urine test of recent nicotine use involving a test strips that provide semi-quantitative total nicotine equivalents TNEs estimates of nicotine and nicotine metabolites 0-14 levels 1 required for eligibility At the outset of the orientation presence of a computer laptop tablet or similar device with working camera microphone and audio and Internet to complete REDCap surveys will be confirmed After confirming age and obtaining digital informed consent the urine nicotine test will be collected and if positive participants will be asked to assure that the study products shipped to participants will be kept in a safe place away from children animals and minors and used only for the research study Next self-report measures of demographics and tobacco product use history will be completed Finally participants will be scheduled for their next experimental visits and remined that 18-hour nicotine abstinence is required and will be confirmed by urine for each visit To provide some control over daily fluctuations in nicotine craving and withdrawal and to facilitate adherence to the abstinence requirement efforts will be made to complete those study visits for which abstinence is required in the morning hours 800-1100 AM near waking time
Randomization to ONP type and nicotine Participants will be randomized into one product condition gum or pouch and one nicotine level high or low stratified by region South West Midwest Northeast and SGM status which will determine the products used for the next 3 visits
Provision of Appeal Session Study Materials The investigators will mail participants a package that will include ONP products blinded ie randomized products will be placed in labeled baggies with numbers indicating each product remote exhaled carbon monoxide eCO Covita device for biochemical verification of no combustible tobacco use urine nicotine sample and test strip and pregnancy test as appropriate product disposal bag with tamper seal tape cleaning supplies and materials for returning salivary samples The eCo device is a remote device that connects to the participants cell phone device both android and iOS and allows for remote bioverification of smoking status see D5e for cut off eCO values The investigators will follow all safety hazard protections for product transport guidelines by shipping and courier agencies Because this study does not involve sales of tobacco products and the products are provided for research use only it is exempt from FDA regulations that apply to transporting tobacco products for business purposes Study RAs will track package during shipping and inform the participant of any updates ie delays estimated arrival etc via phonetext As in prior research all sample products will be clearly labeled CONTAINS TOBACCO PRODUCTS TO BE RECEIVED AND USED BY PERSON 21 YEARS OF AGE OR OLDER FOR RESEARCH USE ONLY NOT FOR PERSONAL USE Upon receipt of study materials the study team will contact the participant within 48 hours to schedule the first experimental session In the investigators prior research providing various EC products N 439 experimental sessions no study packages were opened prior to experimental sessions
ONP Appeal Session After confirming nicotine deprivation semi quantitative reduction by 1 level of TNE and breath eCO of 4ppm participants will be administered the appeal test procedure with 4 different ONPs 2 mint 2 fruit in random order as in prior work eg Leventhal et al 2020 Each ONP trial involves 5-minute administration period in which the product is put into the mouth chewed gum only and parked between the lip and gum per package instructions followed by a 2-minute rating period rate appeal and sensory attributes see outcome measures below and then a 2-minute water mouth rinse inter-trial interval All products will be labeled with a letter and no identifying information about the flavor of the product will be provided to participants ie participant is blinded Prior to administration of the first product participants will be shown a video demonstrating administration procedures This study design has been piloted by the investigators with ONPs and was successfully implemented with ECs over 20 ECs solutions provided and rated for appealsensory characteristics in over 400 remote sessions with no adverse events
Provision of Abuse Liability Session Study Materials Each package will include 31 piecespouches of participants top-rated fruit or mint ONPs ie flavor variant with the highest appeal composite score see below New salivary nicotine collection kits urine cups and pregnancy test as appropriate and other study materials eg product disposal bag with tamper seal tape cleaning supplies return materials for salivary samples
Experimental Sessions Study Visits 2 - 3 Participants will complete two separate single-product abuse liability sessions one fruit one mint order counterbalanced across participants After confirmand nicotine deprivation by urine TNE and eCO Next pre-ONP administration withdrawal and urges will be assessed Participants will then use the sessions ONP for 30-minutes according to a structured protocol adapted from Houtsmuller et al 2001 for therapeutic nicotine In this the participant is informed to keep the ONP in their mouth for the entire 30 min As in the previous sessions following the chew gum only and park procedures while being encouraged to move the ONP around in their mouth to where it is most comfortable Next post-administration phase participants will complete withdrawal and urge follow-up measures and other questionnaires to assess specific domains relevant to abuse liability see description below Naturalistic 7-Day Monitoring Period Finally at the end of the session participants will be instructed that they may use as few or as many of the provided pieces of the session ONP over the next 7 days 30 pieces max provided to participants Participants will report on any use through daily electronic surveys assessing frequency eg number of pieces per dayquantity eg total pieces used during the monitoring periodlocation of use eg vape free locations when EC is unavailable One specific question will ask How many times did you use the ONP in places where you normally couldnt or wouldnt vape such as at work indoor or in other smokevape free locations
Measures Orientation measures Participant characteristics demographics vaping history Leventhal et al 2019 smoking history Leventhal et al 2019 vaping dependence Tackett et al 2021 flavors preferred etc per PhenX Toolkit will be assessed during orientation session Measure updates needed due to market changes eg new types of flavors will be added and developed per the MMC
Appeal and Sensory Ratings The investigators will use the Appeal and Sensory Quality Measures as used in Drs Leventhal and Monterossos current paradigms assessing appeal and sensory attributes of ECs Participants will rate the product on visual analog scales range 0-100 with answers to the following 3 questions for appeal and 4 questions for sensory attributes 1 How much did you like the ONP 2 How much did you dislike the ONP 3 Would you use this product again 4 How sweet was the ONP 5 How bitter was the ONP 6 How much did you like the mouth feel of the ONP 7 How irritating or painful was the ONP in your mouth Rating anchors include not at all and extremely for each measure except use again not at all and definitely The ratings of liking disliking reverse-scored and willingness to use again represent related but nonredundant measures of appeal Thus an appeal composite score will be based on the mean of these 3 ratings per prior work eg Leventhal et al 2019 Sensory ratings will be analyze separately per previous factor analyses of ratings from EC appeal studies indicating that appeal items shared a common factor whereas sensory attributes loaded onto distinct item-specific factors
Abuse and Dual Use Liability All items will be adapted for ONP language ie replace vapingsmoking with ONP descriptors Withdrawalurge suppression pre and post admin Nicotine Withdrawal Scale NWS Nicotine withdrawal will using a validated 8-item version of the Nicotine Withdrawal Scale assessing angerirritability anxiety depressed mood restlessnessdifficulty concentrating increased appetite rated experienced right now on a scale of 0 nonenot at all - 4 severeextremely and summed Brief Questionnaire of Vaping Urges QVU-Brief Cox et al 2001 The QVU-brief is a 10-item self-report measure with items rated from 1 strongly disagree to 7 strongly agree right now which is administered pre and post administration and yields a sum composite score Subjective effects post admin Drug Effects Questionnaire DEQ Morean et al 2019 A modified version of the DEQ will be used to rate acute responses to the ONP on visual analog scales range 0 not at all - 100 extremely Items assess likingwanting the average of I feel good effects from the ONP I want more of that ONP I received I feel the ONP strength and I like the ONP effect
The ONP Purchase Task Cassidy et al 2020 will assess self-reported economic demand in ONP units gum pieces or pouches Following a previously validated protocol used in the investigators pilot study purchase tasks will be completed for the ONP provided during that visit Participants will indicate the amount of the product they would purchase for consumption for a typical day with no opportunity to save anything not consumed at a series of per-unit price points Following Mackillop et al 2008113 the following unit price points will be included 0 01 05 13 25 1 2 3 4 5 6 11 35 70 140 280 560 and 1120 They will complete this task under two scenarios complete two hypothetical scenarios 1 Other nicotine constrained when they are involved with no other accessible nicotine products and 2 Vaping unconstrained the alternative specification that they have free 0 ie no cost to use access to their preferred vape Participants will be instructed to imagine a typical day which may or may not include periods in which vaping is prohibited or uncomfortable Outcomes Four measures will be derived from each task condition Omax the maximum total expenditure on the substance Pmax the price at which expenditure was highest intensity consumption at 0 and demand elasticity a derived measure indicating the steepness with which demand drops as a function of price Elasticity will be estimated following Hursh and Silberberg 2008114 by fitting the demand function logQ logQ0 ke-aPs - 1 where Q0 is the quantity purchased at 0 Ps is price if demand did not change from Q0 k is a constant across participants based on best fit to average consumption and a is an individualized fit-parameter capturing sensitivity to price elasticity Since intensity Omax and elasticity were observed to be most predictive of nicotine use and dependence in a recent meta-analysis González-Roz et al 2019 these will be considered the primary three indices of demand Dual use liability Dual Use Liability Questionnaire DULQ Participants are instructed to consider times in which they want to vape but are somewhere that they dont feel they can To what degree is the ONP you used today an appealing alternative to use during those periods and How willing would you be to try the ONP in a situation when you couldnt vape a mean score of 0-7 not at all to frequently is computed The ONP purchase task unconstrained vs constrained difference Omax Pmax intensity and demand elasticity will be subtracted from the respective values of the constrained variant to provide an index of dual use reward value
Naturalistic monitoring period Naturalistic use of provided ONPs 30 piecesparticipant 4 pieces availableday over the 7 days will be conducted following each Abuse Liability Session with a brief daily survey asking how many pieces they used that day and how many pieces they have left by counting and whether or not they used at a vape free location indoors or because they wanted to conceal nicotine use due to social concerns Overall self-administration is assessed by the total number of piecespouches used range 0-30 Dual use self-administration the number of days out of the week in which they reported using the ONP in a time that they felt vaping was constrained due to social concerns or indoor restrictions 0-7
Data Analysis Plan Data analyses will be carried out by the Centers Data Processing and Analysis Core DPAC The main research questions from the three Aims in the proposed study have the same structure for data analysis Prior to primary analyses the investigators will examine whether baseline characteristics eg nicotine dependence severity demographics differ between the four study groups Any sample characteristics that do differ significantly between randomized groups will be included in statistical models of study outcomes All relevant outcome variables will be first examined with exploratorydescriptive statistical analyses that focus on describing and understanding patterns and distributions for all relevant measures eg appeal ratings desire to use again
Study Oversight
Has Oversight DMC:
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Is a FDA Regulated Drug?:
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Is a FDA Regulated Device?:
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Is an Unapproved Device?:
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Is a PPSD?:
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Is a US Export?:
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Is an FDA AA801 Violation?:
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