United States Pre-Market Tobacco Application Pharmacokinetics (US-PMTA-PK)

• ClinicalTrials.gov Identifier: NCT03719391
• Recruitment Status: Completed
• First Posted: October 25, 2018
• Last Update Posted: June 14, 2021
• Sponsor: Juul Labs, Inc.
• Information provided by (Responsible Party): Juul Labs, Inc.

Study Description

Brief Summary:

A Randomized, Open-Label, Cross-Over Study to Assess Nicotine Uptake and Subjective Measures with Use of JUUL 5% Electronic Nicotine Delivery Systems (ENDS) Compared to Usual Brand Combustible Cigarettes, a Comparator E-Cigarette, and Nicotine Gum in Healthy Adult Smokers

Condition or disease	Intervention/treatment	Phase
Nicotine Dependence; Nicotine Dependence, Cigarettes; Tobacco Use; Tobacco Smoking	Other: Virginia Tobacco flavored JUUL 5% ENDS; Other: Cool Mint flavored JUUL 5% ENDS; Other: Mango flavored JUUL 5% ENDS; Other: Creme Brulee flavored JUUL 5% ENDS; Other: VUSE Solo e-cigarette; Other: Nicorette White Ice Mint 4mg nicotine polacrilex gum; Other: Usual Brand combustible cigarette	Not Applicable

Detailed Description:

E-cigarettes may be an acceptable alternative to traditional cigarette smoking. In utilizing vaporization rather than combustion, the generation and inhaltion of smoke and carbon monoxide (CO) may be reduced or avoided. JUUL has developed several nicotine based liquid blends for use in e-cigarettes. This study will assess nicotine uptake during a 10-puff controlled and a 5-minute ad libitum use of four JUUL 5% electronic nicotine delivery systems (ENDS) relative to usual brand (UB) combustible cigarettes, a comparator electronic cigarette (e-cigarette), and nicotine gum.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 67 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Randomized, Open-Label, Cross-Over
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Randomized, Open-Label, Cross-Over Study to Assess Nicotine Uptake and Subjective Measures With Use of JUUL 5% Electronic Nicotine Delivery Systems (ENDS) Compared to Usual Brand Combustible Cigarettes, a Comparator E-Cigarette, and Nicotine Gum in Healthy Adult Smokers
• Actual Study Start Date: October 19, 2018
• Actual Primary Completion Date: November 21, 2018
• Actual Study Completion Date: November 28, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: JUUL 5% Virginia Tobacco ENDS; Treatment with JUUL Virginia Tobacco flavored 5.0% ENDS product.	Other: Virginia Tobacco flavored JUUL 5% ENDS; Treatment with Virginia Tobacco flavored JUUL 5% ENDS (10 puffs).; Other Name: JUUL
Experimental: JUUL 5% Cool Mint ENDS; Treatment with JUUL Cool Mint flavored 5.0% ENDS product.	Other: Cool Mint flavored JUUL 5% ENDS; Treatment with Cool Mint flavored JUUL 5% ENDS (10 puffs).; Other Name: JUUL
Experimental: JUUL 5% Mango ENDS; Treatment with JUUL Mango flavored 5.0% ENDS product.	Other: Mango flavored JUUL 5% ENDS; Treatment with Mango flavored JUUL 5% ENDS (10 puffs).; Other Name: JUUL
Experimental: JUUL 5% Creme Brulee ENDS; Treatment with JUUL Creme Brulee flavored 5.0% ENDS product.	Other: Creme Brulee flavored JUUL 5% ENDS; Treatment with Creme Brulee flavored JUUL 5% ENDS (10 puffs).; Other Name: JUUL
Active Comparator: VUSE Solo e-cigarette; Treatment with VUSE Solo Original with 4.8% nicotine product.	Other: VUSE Solo e-cigarette; Treatment with VUSE Solo Original with 4.8% nicotine e-cigarette (10 puffs).; Other Name: VUSE
Active Comparator: Nicotine Gum; Treatment with nicorette white ice mint 4mg nicotine polacrilex gum product.	Other: Nicorette White Ice Mint 4mg nicotine polacrilex gum; Treatment with Nicorette White Ice Mint 4mg Nicotine polacrilex gum (30 minutes Chew and Park method); Other Name: Nicotine Gum
Active Comparator: Usual Brand Combustible Cigarette; Treatment with usual brand combustible cigarette.	Other: Usual Brand combustible cigarette; Treatment with usual brand cigarette (10 puffs).

Outcome Measures

Primary Outcome Measures :

1. To assess nicotine uptake during a 10-puff controlled use of four JUUL 5% electronic nicotine delivery systems (ENDS) relative to usual brand (UB) combustible cigarettes, a comparator electronic cigarette (e-cigarette), and nicotine gum. [ Time Frame: 7 days ]
   Nicotine PK parameters will be calculated from the individual plasma concentrations per details provided in the SAP. Baseline adjustments to the (non-adjusted) PK endpoints will also be presented.

Secondary Outcome Measures :

1. To assess exhaled carbon monoxide [CO] following controlled use of four JUUL 5% ENDS relative to UB combustible cigarettes, a comparator e-cigarette, and nicotine gum [ Time Frame: 7 Days ]
   Exhaled CO levels will be measured using a Bedfont Micro+ Smokerlyzer or similar device and levels at Screening and after product use will be assessed.
2. To assess measures of subjective effects with controlled use of four JUUL 5% ENDS relative to UB combustible cigarettes, a comparator e-cigarette, and nicotine gum using the "modified Product Evaluation Scale (mPES)" [ Time Frame: 7 Days ]

   Change in Evaluation; Scale: 1 = not at all, 2 = very little, 3 = a little, 4 = moderately, 5 = a lot, 6 = quite a lot, 7 = extremely

   Four multi-item subscales will be derived from "Satisfaction" (items 1, 2, 3, and 12); "Psychological Reward" (items 4 through 8); "Aversion" (items 9, 10, 16, and 18); and "Relief" (item 11, 13, 14, 15, and reversed for item 19) and single items 17 and 20 will be summarized.

3. To assess blood pressure following controlled use of four JUUL 5% ENDS relative to UB combustible cigarettes, a comparator e-cigarette, and nicotine gum. [ Time Frame: 7 Days ]
4. To assess heart rate following controlled use of four JUUL 5% ENDS relative to UB combustible cigarettes, a comparator e-cigarette, and nicotine gum. [ Time Frame: 7 Days ]
5. To assess the safety and tolerability of short-term use of four JUUL 5% ENDS. [ Time Frame: 7 Days ]
   Number of participants with Adverse Events associated with use of JUUL 5% Device will be described by individual listings and frequency tables.
6. To characterize product use of four JUUL 5% ENDS during controlled use sessions. [ Time Frame: 7 Days ]
   All product use data will be summarized using descriptive statistics. The difference in weight pre- and post- product use of each JUUL product and comparator e-cigarettes will be summarized.
7. To assess measures of subjective effects with controlled use of four JUUL 5% ENDS relative to UB combustible cigarettes, a comparator e-cigarette, and nicotine gum using Intent to Use Again Questionnaire. [ Time Frame: 7 Days ]
   The Intent to Use Again questionnaire will be assessed using a 100 mm bipolar VAS
8. To assess measures of subjective effects with controlled use of four JUUL 5% ENDS relative to UB combustible cigarettes, a comparator e-cigarette, and nicotine gum using Nicotine Withdrawal Questionnaire. [ Time Frame: 7 Days ]
   The nicotine withdrawal will be assessed using a 100mm visual analog scale (VAS)
9. To assess measures of subjective effects with controlled use of four JUUL 5% ENDS relative to UB combustible cigarettes, a comparator e-cigarette, and nicotine gum using Product Direct Effect Questionnaire. [ Time Frame: 7 Days ]
   Product direct effect will be assessed using a 100 mm VAS
10. To assess measures of subjective effects with controlled use of four JUUL 5% ENDS relative to UB combustible cigarettes, a comparator e-cigarette, and nicotine gum using Product Liking Questionnaire. [ Time Frame: 7 Days ]
    Product liking will be assessed using a 100 mm VAS

Eligibility Criteria

• Ages Eligible for Study: 21 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Healthy, adult, male or female smoker, 21 to 65 years of age, inclusive
• Has been a smoker for at least 12 months prior to Screening. Brief periods of non-smoking (e.g., up to ~7 consecutive days due to illness, trying to quit, participation in a study where smoking was prohibited) during that time will be permitted at the discretion of the PI.
• Currently smokes an average of 10 or more king size or 100s manufactured combustible CPD, as reported at Screening.
• Has a positive urine cotinine (≥ 500 ng/mL) at Screening
• Has an exhaled CO > 12 ppm at Screening.
• Is willing to comply with the requirements of the study, including a willingness to use the study products during the study.

Exclusion Criteria:

• Has a history or presence of clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, urologic, pulmonary, immunologic, psychiatric, or cardiovascular disease, or any other condition that, in the opinion of the PI, would jeopardize the safety of the subject or impact the validity of the study results.
• Has a clinically significant abnormal finding on the physical examination, medical history, vital signs, ECG, or clinical laboratory results, in the opinion of the PI.
• Has a positive test for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) at Screening.
• Has had an acute illness (e.g., upper respiratory infection, viral infection) requiring treatment within 14 days prior to Check-in.
• Has a fever (> 100.5°F) at Screening or Check-in.
• Has a body mass index (BMI) > 40.0 kg/m2 or < 18.0 kg/m2 at Screening.
• Has a history of drug or alcohol abuse within 24 months of Check-in, as determined by the PI.
• Has diabetes mellitus, asthma, or chronic obstructive pulmonary disease.
• Has a systolic blood pressure < 90 mmHg or > 150 mmHg, diastolic blood pressure < 40 mmHg or > 95 mmHg, or heart rate < 40 bpm or > 99 bpm at Screening.
• Has experienced an allergic reaction following previous e-cigarette use or with exposure to any primary components of the e-liquids (benzoic acid, propylene glycol and glycerol).
• Has an estimated creatinine clearance < 80 mL/minute (using the Cockcroft-Gault equation) at Screening.
• Has a positive urine screen for alcohol or drugs of abuse at Screening or Check-in.
• Has used medications known to interact with cytochrome P450 (CYP) 2A6 (including, but not limited to, amiodarone, amlodipine, amobarbital, buprenorphine, clofibrate, clotrimazole, desipramine, disulfiram, entacapone, fenofibrate, isoniazid, ketoconazole, letrozole, methimazole, methoxsalen, metyrapone, miconazole, modafinil, orphenadrine, pentobarbital, phenobarbital, pilocarpine, primidone, propoxyphene, quinidine, rifampicin, rifampin, secobarbital, selegiline, sulconazole, tioconazole, tranylcypromine) within 14 days or 5 half-lives of the drug, whichever is longer, prior to Check-in.
• Has used nicotine-containing products other than manufactured cigarettes (e.g., ENDS, roll-your-own cigarettes, bidis, snuff, nicotine inhaler, pipe, cigar, chewing tobacco, nicotine patch, nicotine spray, nicotine lozenge, or nicotine gum) within 14 days prior to Check-in.
• Has a prior history of JUUL product use prior to Screening
• Has used any prescription smoking cessation treatments, including, but not limited to, varenicline (Chantix®) or buproprion (Zyban®) within 3 months prior to Check-in.
• Is a self-reported puffer (i.e., adult smokers who draw smoke from the cigarette into the mouth and throat but do not inhale).
• Is planning to quit smoking during the study or postponing a quit attempt in order to participate in the study.
• Has donated plasma within 7 days prior to Check-in.
• Has donated blood or blood products (with the exception of plasma as noted above), had significant blood loss, or received whole blood or a blood product transfusion within 56 days prior to Check-in.
• Has participated in a previous clinical study for an investigational drug, device, biologic, or tobacco product within 30 days prior to Check-in.
• Is or has a first-degree relative (i.e., parent, sibling, child) who is a current employee of the study site.
• Is or has a first-degree relative (i.e., parent, sibling, child) who is a current employee, shareholder, or is member of the board of directors of JUUL Labs Inc.
• Has previously been diagnosed with any form of cancer, except for basal cell or squamous epithelial carcinomas of the skin that have been resected at least 1 year prior to Screening.

Contacts and Locations

Locations

United States, Kansas

Vince & Associates Clinical Research

Overland Park, Kansas, United States, 66212

Sponsors and Collaborators

Juul Labs, Inc.

More Information

Publications:

Jensen RP, Luo W, Pankow JF, Strongin RM, Peyton DH. Hidden formaldehyde in e-cigarette aerosols. N Engl J Med. 2015 Jan 22;372(4):392-4. doi: 10.1056/NEJMc1413069.

D'Ruiz CD, Graff DW, Robinson E. Reductions in biomarkers of exposure, impacts on smoking urge and assessment of product use and tolerability in adult smokers following partial or complete substitution of cigarettes with electronic cigarettes. BMC Public Health. 2016 Jul 11;16:543. doi: 10.1186/s12889-016-3236-1.

McNeill A et al. E-cigarettes: An Evidence Update. A report commissioned by Public Health England. Available at: https://www.gov.uk/government/uploads/system/uploads/ attachment_data/file/457102/Ecigarettes_an_evidence_update_A_report_commissioned_by_ Public_Health_England_FINAL.pdf (Aug 2015).

Polosa R, Morjaria J, Caponnetto P, Caruso M, Strano S, Battaglia E, Russo C. Effect of smoking abstinence and reduction in asthmatic smokers switching to electronic cigarettes: evidence for harm reversal. Int J Environ Res Public Health. 2014 May 8;11(5):4965-77. doi: 10.3390/ijerph110504965.

Fagerström K. Determinants of tobacco use and renaming the FTND to the Fagerstrom Test for Cigarette Dependence. Nicotine Tob Res. 2012 Jan;14(1):75-8. doi: 10.1093/ntr/ntr137. Epub 2011 Oct 24.

Hatsukami DK, Zhang Y, O'Connor RJ, Severson HH. Subjective responses to oral tobacco products: scale validation. Nicotine Tob Res. 2013 Jul;15(7):1259-64. doi: 10.1093/ntr/nts265. Epub 2012 Dec 13.

HIPAA Privacy Rule. Information for Researchers. De-identifying Protected Health Information Under the Privacy Rule. U.S. Department of Health and Human Services. NIH (Feb 2007). Available at: http://privacyruleandresearch.nih.gov/pr_08.asp#8a. Last accessed 31-Jul-2017.

• Responsible Party: Juul Labs, Inc.
• ClinicalTrials.gov Identifier: NCT03719391
• Other Study ID Numbers: PROT-00009
• First Posted: October 25, 2018
• Last Update Posted: June 14, 2021
• Last Verified: January 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Juul Labs, Inc.:

Electronic Nicotine Delivery System; Combustible Cigarettes; Nicotine

Additional relevant MeSH terms:

Tobacco Use Disorder; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Nicotine; Ganglionic Stimulants; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Nicotinic Agonists; Cholinergic Agonists; Cholinergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action