Assess the Influence of Nicotine Flux and Nicotine Form on Subjective Effects Related to Dependency

• ClinicalTrials.gov Identifier: NCT05430334
• Recruitment Status: Recruiting
• First Posted: June 24, 2022
• Last Update Posted: December 8, 2023
• Sponsor: American University of Beirut Medical Center
• Collaborators: National Institutes of Health (NIH); National Institute on Drug Abuse (NIDA)
• Information provided by (Responsible Party): American University of Beirut Medical Center

Tracking Information

• First Submitted Date: June 8, 2022
• First Posted Date: June 24, 2022
• Last Update Posted Date: December 8, 2023
• Actual Study Start Date: July 13, 2022
• Estimated Primary Completion Date: September 13, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 27, 2022)

• Subjective Measures of Nicotine Abstinence Symptoms - PROMIS-10 Global Health measures [ Time Frame: Visit 1 - Before starting the first session ]
  The PROMIS-10 Global Health measures five domains: physical function, fatigue, pain, emotional distress, and social health. 10 Items are rated on a five-point scale (Poor=1, Fair=2, Good=3, Very good=4, Excellent=5) with higher scores indicating higher activity.
• Subjective Measures of Nicotine Abstinence Symptoms - The corresponding 4-item E-Cigarette Dependence [ Time Frame: Visit 1 - Before starting the first session ]
  The corresponding 4-item E-Cigarette Dependence Scale that assesses dependence on ENDS. 4 Items are rated on a five-point scale (Never=1, Rarely=2, Sometimes=3, Often=4, Almost Always=5) with higher scores indicating higher activity.
• Subjective Measures of Nicotine Abstinence Symptoms - The corresponding 4-item Combustible cigarette Dependence [ Time Frame: Visit 1 - Before starting the first session ]
  The corresponding 4-item Combustible cigarette Dependence Scale that assesses nicotine dependence for daily and nondaily smokers. 4 Items are rated on a five-point scale (Never=1, Rarely=2, Sometimes=3, Often=4, Always=5) with higher scores indicating higher activity.
• Nicotine Dependence questionnaires - The Fagerstrom Test of Nicotine Dependence [ Time Frame: Visit 1 - Before starting the first session ]
  The Fagerstrom Test of Nicotine Dependence questionnaires that assesses nicotine dependence on ENDS. General questions not based on a scale.
• Subjective Measures of Nicotine Abstinence Symptoms - Product liking magnitude scale [ Time Frame: Up to 180 minutes ]
  Product liking will be assessed by the Electronic Cigarette Specific Effects questionnaire, general labeled magnitude scale (gLMS) on a subjective scale (0-100, not at all - extremely), with higher scores indicating higher effects.
• Subjective Measures of Nicotine Abstinence Symptoms - Product liking hedonic scale [ Time Frame: Up to 180 minutes ]
  Product liking will be assessed by the Electronic Cigarette Specific Effects questionnaire, general labeled hedonic scale (LHS) (0-100, most disliked sensation imaginable - most liked sensation imaginable), with higher scores indicating higher effects.
• Subjective Measures of Nicotine Abstinence Symptoms - Drug Effect [ Time Frame: Up to 180 minutes ]
  The Drug Effect Questionnaire (DEQ) will measure acute effects consisting of seven items: drug strength, high, feeling stimulated, good effects, bad effects, wanting more drugs, and drug liking and this will be assessed on a subjective scale (0-100, not at all-extremely), with higher scores indicating higher effects.
• Subjective Measures of Nicotine Abstinence Symptoms - Smoking urges [ Time Frame: Up to 180 minutes ]
  Smoking urges will be assessed by the smoking urges questionnaire on a subjective scale (0-100, Strongly disagree - strongly agree) with higher scores indicating higher urges.
• Subjective Measures of Nicotine Abstinence Symptoms - Hughes and Hatsukami [ Time Frame: Up to 180 minutes ]
  The Hughes-Hatsukami Withdrawal Questionnaire (HHWQ) will be assessed by the Hughes and Hatsukami 1986 questionnaire on a subjective scale (0-100, Not at all - extremely).

Original Primary Outcome Measures (submitted: June 20, 2022)

• Subjective Measures of Nicotine Abstinence Symptoms - PROMIS-10 Global Health measures [ Time Frame: Visit 1 - Before starting the first session ]
  The PROMIS-10 Global Health measures five domains: physical function, fatigue, pain, emotional distress, and social health. 10 Items are rated on a five-point scale (Poor=1, Fair=2, Good=3, Very good=4, Excellent=5) with higher scores indicating higher activity.
• Subjective Measures of Nicotine Abstinence Symptoms - The corresponding 4-item E-Cigarette Dependence [ Time Frame: Visit 1 - Before starting the first session ]
  The corresponding 4-item E-Cigarette Dependence Scale that assesses dependence on ENDS. 4 Items are rated on a five-point scale (Never=1, Rarely=2, Sometimes=3, Often=4, Almost Always=5) with higher scores indicating higher activity.
• Subjective Measures of Nicotine Abstinence Symptoms - The corresponding 4-item Combustible cigarette Dependence [ Time Frame: Visit 1 - Before starting the first session ]
  The corresponding 4-item Combustible cigarette Dependence Scale that assesses nicotine dependence for daily and nondaily smokers. 4 Items are rated on a five-point scale (Never=1, Rarely=2, Sometimes=3, Often=4, Always=5) with higher scores indicating higher activity.
• Nicotine Dependence questionnaires - The Fagerstrom Test of Nicotine Dependence [ Time Frame: Visit 1 - Before starting the first session ]
  The Fagerstrom Test of Nicotine Dependence questionnaires that assesses nicotine dependence on ENDS. General questions not based on a scale.
• Subjective Measures of Nicotine Abstinence Symptoms - Product liking [ Time Frame: Up to 180 minutes ]
  Product liking will be assessed by the Electronic Cigarette Specific Effects questionnaire, general labeled magnitude scale (gLMS) on a subjective scale (0-100, not at all - extremely), and labeled hedonic scale (LHS) (0-100, most disliked sensation imaginable - most liked sensation imaginable) immediately following product use, with higher scores indicating higher liking.
• Subjective Measures of Nicotine Abstinence Symptoms - Drug Effect [ Time Frame: Up to 180 minutes ]
  The Drug Effect Questionnaire (DEQ) will measure acute effects consisting of seven items: drug strength, high, feeling stimulated, good effects, bad effects, wanting more drugs, and drug liking and this will be assessed on a subjective scale (0-100, not at all-extremely), with higher scores indicating higher effects.
• Subjective Measures of Nicotine Abstinence Symptoms - Smoking urges [ Time Frame: Up to 180 minutes ]
  Smoking urges will be assessed by the smoking urges questionnaire on a subjective scale (0-100, Strongly disagree - strongly agree) with higher scores indicating higher urges.
• Subjective Measures of Nicotine Abstinence Symptoms - Hughes and Hatsukami [ Time Frame: Up to 180 minutes ]
  The Hughes-Hatsukami Withdrawal Questionnaire (HHWQ) will be assessed by the Hughes and Hatsukami 1986 questionnaire on a subjective scale (0-100, Not at all - extremely).

Current Secondary Outcome Measures (submitted: June 20, 2022)

• Puff Duration [ Time Frame: Will be measured during the approximately 5-minute, 10-puff use bout and 60-minute, ad lib use bout ]
  Measured topography Average Puff Duration (sec).
• Flow rate [ Time Frame: Will be measured during the approximately 5-minute, 10-puff use bout and 60-minute, ad lib use bout ]
  Measured topography Average Flow rate (LPM).
• Puff Interval [ Time Frame: Will be measured during the approximately 5-minute, 10-puff use bout and 60-minute, ad lib use bout ]
  Measured topography Average Inter Puff Interval (sec).
• Number of Puffs [ Time Frame: Will be measured during the approximately 60-minute, ad lib use bout ]
  Measured topography Total Number of Puffs (puffs).
• Liquid consumed [ Time Frame: Will be measured after the approximately 5-minute, 10-puff use bout and 60-minute, ad lib use bout ]
  Liquid consumption for each participant use session will be determined by pre- and post-weighing the ENDS device tank (g/session).
• Carbonyl compound yield [ Time Frame: Will be measured after the 60-minute, ad lib use bout ]
  Total Carbonyls Compounds will be quantified (microg/session).
• Nicotine flux [ Time Frame: Will be measured after the approximately 5-minute, 10-puff use bout and 60-minute, ad lib use bout ]
  Nicotine flux will be quantified (mg/sec).

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Assess the Influence of Nicotine Flux and Nicotine Form on Subjective Effects Related to Dependency
• Official Title: Nicotine Flux, a Potentially Powerful Tool for Regulating Nicotine Delivery From Electronic Cigarettes: Significance of Nicotine Flux to the Rate of Nicotine Delivery and Subjective Effect
• Brief Summary: Electronic nicotine delivery systems (ENDS) heat and vaporize a nicotine-containing liquid to produce an aerosol that can deliver nicotine to the blood and the brain. ENDS use has increased rapidly in the last decade, especially among youth: over 20% of US high school students are current ENDS users, and there is evidence of nicotine dependence in this population. Federal legislation has been proposed that would restrict ENDS liquid nicotine concentration to make ENDS "significantly less addictive and appealing to youth." However, these and other efforts to curb addiction by limiting nicotine liquid concentration are unlikely to succeed because nicotine emissions from ENDS depend on multiple variables. To achieve the intended public health aims, regulations targeting addiction must focus on nicotine delivery, not nicotine concentration. While nicotine delivery cannot be regulated directly, the rate at which an ENDS emits nicotine, the "nicotine flux", can be regulated and, importantly, predicted based on a few device design and operating variables. However, to date there is no empirical evidence demonstrating the relationship between flux and delivery, nor between flux and the subjective effects that support nicotine dependence. Closing this gap is essential for providing an effective framework for regulating ENDS. At the American University of Beirut, the investigators will assess the relationship between nicotine flux, form, and subjective effects. Participants will use ENDS devices with varying nicotine fluxes and forms. Dependency measures, such as urge to smoke, craving, and abstinence, will be assessed. The outcome will indicate the degree to which nicotine flux/form influence subjective effects related to dependency, puffing intensity, and exposure to toxicants. In summary, this project will provide the empirical evidence needed for public health agencies to use nicotine flux as an encompassing and convenient construct to regulate nicotine delivery from ENDS.
• Detailed Description: Assess the influence of nicotine flux and nicotine form on subjective effects. At AUB, the investigators will assess subjective effects (e.g. product liking, nicotine craving) and puffing topography for 130 participants who will undergo 5 ENDS use sessions consisting of 2 bouts (10 puffs + 60min ad libitum) with 2 fluxes (16 and 32μg/s) x 2 forms (protonated, freebase) and a 0 nicotine condition. In addition, the investigators will use a state-of-the-art device to sample in situ a fraction of the aerosol generated during each puff to verify actual nicotine flux and form, and measure exposure to pulmonary toxicants (carbonyls). The investigators hypothesize that increasing nicotine flux and protonated nicotine will result in greater reductions of nicotine craving, and lower puffing intensity and carbonyl exposure.
• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:

Each participant will attend the lab for five different visits that differ by nicotine flux and/or form in random order.

Masking: Double (Participant, Investigator)
Masking Description:

Each participant will attend the lab for five different visits that differ by nicotine flux and/or form in random order. All sessions will be double-blind (Participant / Investigator). The analytical chemist will be providing the investigator with e-liquid in a random order in each session for each participant.

Primary Purpose: Other

Condition

• Nicotine Vaping
• Nicotine Dependence
• Nicotine Addiction

Intervention

• Combination Product: e-liquid 1
  30/70 PG/VG ratio with nicotine concentration 4mg/ml protonated
• Combination Product: e-liquid 2
  30/70 PG/VG ratio with nicotine concentration 10mg/ml protonated
• Combination Product: e-liquid 3
  30/70 PG/VG ratio with nicotine concentration 4mg/ml free base
• Combination Product: e-liquid 4
  30/70 PG/VG ratio with nicotine concentration 10mg/ml freebase
• Combination Product: e-liquid 5
  30/70 PG/VG ratio with nicotine concentration 0mg/ml (placebo)

Study Arms

• Experimental: Combination One - 16μg/s protonated nicotine flux
  The investigators will test the subjective effects of nicotine flux (16μg/s) coupled with one ratio of nicotine form (100% protonated). Following a one-hour observation period, participants will use Subox Mini C in a 10-puff directed (30sec inter-puff interval) bout. One hour after the first bout, participants will be instructed to puff on the device for 60-min ad libitum. Subjective measures (i.e., nicotine dependence, drug effects, product liking, and craving) will be administered 5 times/session: 5 min before and 5 min after onset of the directed bout and 5 min before, halfway into and 5 min after onset of the ad libitum bout.
  Intervention: Combination Product: e-liquid 1
• Experimental: Combination Two - 32μg/s protonated nicotine flux
  The investigators will test the subjective effects of nicotine flux (32μg/s) coupled with one ratio of nicotine form (100% protonated). Following a one-hour observation period, participants will use Subox Mini C in a 10-puff directed (30sec inter-puff interval) bout. One hour after the first bout, participants will be instructed to puff on the device for 60-min ad libitum. Subjective measures (i.e., nicotine dependence, drug effects, product liking, and craving) will be administered 5 times/session: 5 min before and 5 min after onset of the directed bout and 5 min before, halfway into and 5 min after onset of the ad libitum bout.
  Intervention: Combination Product: e-liquid 2
• Experimental: Combination Three - 16μg/s free base nicotine flux
  The investigators will test the subjective effects of nicotine flux (16μg/s) coupled with one ratio of nicotine form (100% free base). Following a one-hour observation period, participants will use Subox Mini C in a 10-puff directed (30sec inter-puff interval) bout. One hour after the first bout, participants will be instructed to puff on the device for 60-min ad libitum. Subjective measures (i.e., nicotine dependence, drug effects, product liking, and craving) will be administered 5 times/session: 5 min before and 5 min after onset of the directed bout and 5 min before, halfway into and 5 min after onset of the ad libitum bout.
  Intervention: Combination Product: e-liquid 3
• Experimental: Combination Four - 32μg/s free base nicotine flux
  The investigators will test the subjective effects of nicotine flux (32μg/s) coupled with one ratio of nicotine form (100% free base). Following a one-hour observation period, participants will use Subox Mini C in a 10-puff directed (30sec inter-puff interval) bout. One hour after the first bout, participants will be instructed to puff on the device for 60-min ad libitum. Subjective measures (i.e., nicotine dependence, drug effects, product liking, and craving) will be administered 5 times/session: 5 min before and 5 min after onset of the directed bout and 5 min before, halfway into and 5 min after onset of the ad libitum bout.
  Intervention: Combination Product: e-liquid 4
• Placebo Comparator: Placebo - Combination Five - 0μg/s nicotine flux
  The investigators will test the subjective effects of nicotine flux (0μg/s) placebo. Following a one-hour observation period, participants will use Subox Mini C in a 10-puff directed (30sec inter-puff interval) bout. One hour after the first bout, participants will be instructed to puff on the device for 60-min ad libitum. Subjective measures (i.e., nicotine dependence, drug effects, product liking, and craving) will be administered 5 times/session: 5 min before and 5 min after onset of the directed bout and 5 min before, halfway into and 5 min after onset of the ad libitum bout.
  Intervention: Combination Product: e-liquid 5

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 20, 2022): 130
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 31, 2025
• Estimated Primary Completion Date: September 13, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Must be healthy and above 18 years of age
• Must be willing to provide informed consent, attend the lab, and abstain from tobacco/nicotine as required (participants will be instructed to abstain from nicotine/tobacco and/or ENDS use for ≥12h)
• A dual ENDS and tobacco user who reports daily use of ENDS (≥ 3 mg/ml nicotine) or cigarettes (any frequency) AND someday use (≥ 3 days/week) of ENDS (≥ 3 mg/ml nicotine) or cigarettes (any frequency) for the past 3 months or longer

Exclusion Criteria:

• History of chronic disease or an uncontrolled psychiatric condition
• History of or active cardiovascular disease, low/high blood pressure, seizures, regular use of a prescription medication (except vitamins/birth control)
• Past month use of cocaine, opioids, benzodiazepines, or methamphetamines
• Individuals who report using marijuana >15/30 days
• Women will be excluded if they are breast-feeding or pregnant
• Participants intending to quit tobacco/nicotine use in the next 30 days and referred to cessation treatment

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Soha Talih, PhD; +961-1-350000 ext 3627; st38@aub.edu.lb

• Listed Location Countries: Lebanon

Administrative Information

• NCT Number: NCT05430334
• Other Study ID Numbers: American University Of Beirut; 1R01DA052565-01A1 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Participants data will not be available to other researchers

• Current Responsible Party: American University of Beirut Medical Center
• Original Responsible Party: Same as current
• Current Study Sponsor: American University of Beirut Medical Center
• Original Study Sponsor: Same as current

Collaborators

• National Institutes of Health (NIH)
• National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Soha Talih, PhD; American University of Beirut Medical Center

• PRS Account: American University of Beirut Medical Center
• Verification Date: December 2023