NCT05706701

Nicotine Flux, a Potentially Powerful Tool for Regulating Nicotine Delivery From Electronic Cigarettes

Completed NA Results posted Last updated 18 November 2025

What this trial tests

NA trial testing Nicotine vaping visit 1 (free-base nicotine) in Nicotine Vaping in 36 participants. Completed in 17 May 2024.

Timeline

1 February 2023

Primary endpoint
17 May 2024

17 May 2024

Quick facts

Lead sponsor	Yale University
Phase	NA
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	crossover
Masking	double
Primary purpose	other
Enrollment	36
Start date	1 February 2023
Primary completion	17 May 2024
Estimated completion	17 May 2024
Sites	1 location across United States

Drugs / interventions tested

• Nicotine vaping visit 1 (free-base nicotine)
• Nicotine vaping visit 1 (protonated nicotine)
• Nicotine vaping visit 2 (free-base nicotine)
• Nicotine vaping visit 2 (protonated nicotine)

Conditions studied

• Nicotine Vaping — all drugs for Nicotine Vaping →

Sponsor

Yale University

Who can join

21 and older, any sex, with Nicotine Vaping. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change in Maximum Arterial Blood Nicotine Delivery (Cmax) Primary · Day 1 and Week 3

For arterial blood sampling, a radial arterial line will be placed on the non-dominant side to provide access to blood samples during vaping sessions. Blood will be sampled 30sec prior to the initial puff, 5, 15, and 25sec after each puff, and 60sec after the last puff of a bout (3 puffs per bout; 4 bouts per visit day; two visit days, separated by three weeks). The obtained data will be used to calculate pharmacokinetic parameters of nicotine delivery under each condition.

9 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	3.75	± 1.96
Nicotine vaping- freebase	2.48	± 1.11

18 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	8.12	± 4.81
Nicotine vaping- freebase	2.96	± 1.76

27 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	13.23	± 7.7
Nicotine vaping- freebase	5.13	± 3.16

35 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	18.57	± 12.19
Nicotine vaping- freebase	6.11	± 3.55

Change in Area Under the Curve for Nicotine (AUC) Secondary · Day 1 and Week 3

AUC from 0 to 160min for the four 3-puff directed bouts will be estimated using a non-compartmental model and trapezoidal rule. The four 3-puff directed bouts occur on both visit day 1 and 2, separated by 3 weeks. All measures will be corrected for baseline values by subtracting the blood nicotine concentrations by the initial value (at the start of each bout).

9 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	316.06	± 196.91
Nicotine vaping- freebase	225.68	± 133.22

18 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	643.48	± 431.98
Nicotine vaping- freebase	255.38	± 164.15

27 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	1022.42	± 573.32
Nicotine vaping- freebase	443.79	± 231.72

35 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	1499.38	± 1017.08
Nicotine vaping- freebase	571.53	± 317.55

Change in Liquid Consumed Secondary · Day 1 and Week 3

Determined by ENDS gravimetric weight change. Pre- and Post- vaping on both visit day 1 and 2, separated by 3 weeks.

9 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	0.08	± 0.06
Nicotine vaping- freebase	0.08	± 0.13

18 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	0.02	± 0.01
Nicotine vaping- freebase	0.09	± 0.07

27 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	0.03	± 0.01
Nicotine vaping- freebase	0.09	± 0.12

35 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	0.05	± 0.03
Nicotine vaping- freebase	0.08	± 0.10

Mean Change in Puff Topography Secondary · Day 1 and Week 3

Average puff duration in seconds for 3 puffs on both visit day 1 and 2, separated by 3 weeks. Data presented here is the average duration per condition.

9 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	2.81	± 1.18
Nicotine vaping- freebase	2.78	± 1.10

18 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	2.81	± 1.22
Nicotine vaping- freebase	2.66	± 1.16

27 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	2.83	± 1.25
Nicotine vaping- freebase	2.3	± 1.24

35 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	2.8	± 1.23
Nicotine vaping- freebase	2.2	± 1.22

Change in Rate of Nicotine Rise After the Initial Puff (dCi/dt) Secondary · Day 1 and Week 3

Blood will be sampled 30sec prior to the initial puff, 5, 15, and 25sec after each puff, and 60sec after the last puff of a bout. Measurements occur 4 times per visit day, on both visit day 1 and 2, separated by 3 weeks). The obtained data will be used to calculate pharmacokinetic parameters of nicotine delivery under each condition (dCi/dt).

9 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	0.12	± 0.11
Nicotine vaping- freebase	0.09	± 0.07

18 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	0.28	± 0.22
Nicotine vaping- freebase	0.08	± 0.06

27 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	0.44	± 0.34
Nicotine vaping- freebase	0.13	± 0.09

35 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	0.57	± 0.42
Nicotine vaping- freebase	0.18	± 0.13

Change in Time to Maximum Arterial Blood Level Nicotine Concentration (Tmax) Secondary · Day 1 and Week 3

Blood will be sampled 30sec prior to the initial puff, 5, 15, and 25sec after each puff, and 60sec after the last puff of a bout. Measurements occur 4 times per visit day, on both visit day 1 and 2, separated by 3 weeks). The obtained data will be used to calculate pharmacokinetic parameters of nicotine delivery under each condition (Tmax).

9 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	93.83	± 45.33
Nicotine vaping- freebase	102.88	± 42.4

18 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	100.32	± 27.85
Nicotine vaping- freebase	99.81	± 32.44

27 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	99	± 34.56
Nicotine vaping- freebase	106.31	± 23.24

35 μg/s

Group	Value	95% CI
Nicotine vaping- protonated	100	± 28.69
Nicotine vaping- freebase	109.44	± 24.10

Adverse events — posted to ClinicalTrials.gov

Time frame: 3 weeks. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Free-base nicotine

Serious: 0/26 (0%)

Deaths: 0/26

Protonated nicotine

Serious: 0/26 (0%)

Deaths: 0/26

Arterial-line related

Serious: 0/26 (0%)

Deaths: 0/26

Between visits

Serious: 1/26 (4%)

Deaths: 0/26

Serious adverse events (1 terms)

Reaction	System	Free-base nicotine	Protonated nicotine	Arterial-line related	Between visits
Self harm episode	Injury, poisoning and procedural complications	—	—	—	—

Other adverse events (4 terms — click to expand)

Reaction	System	Free-base nicotine	Protonated nicotine	Arterial-line related	Between visits
Wrist discomfort	Musculoskeletal and connective tissue disorders	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—
Pre-syncope	Cardiac disorders	—	—	—	—
Arterial vasospasm	Cardiac disorders	—	—	—	—

Most-reported serious reactions: Self harm episode.

Data from ClinicalTrials.gov NCT05706701 adverse events section.

Sponsor's own description

The investigators will examine the relationship between nicotine flux, nicotine form, and the rate and dose of nicotine delivery. Participants will puff on electronic nicotine delivery system (ENDS) devices under conditions that differ by flux and form, while arterial blood is sampled in high time resolution. The outcome will indicate the degree to which nicotine flux and form determine the speed and dose of ENDS nicotine delivery, and thus, abuse liability.

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

1. Nicotine flux as a powerful tool for regulating nicotine delivery from e-cigarettes: Protocol of two complimentary randomized crossover clinical trials.
   El-Hellani A, Hanna E, Sharma M, Blohowiak R, et al · · 2023 · cited 1× · PMID 37733666 · DOI 10.1371/journal.pone.0291786