Study of Vascular Function Before vs After Smoking an E-cigarette as Compared to a Normal Cigarette (ECIG-8)

Comparative Investigation of the One-time Use of an Electronic Cigarette (E-cigarette) Versus a Normal Tobacco Cigarette on Vascular Function in Healthy Male Smokers

Investigation of the effect of one-time use of an electronic e-cigarette in comparison to smoking a conventional cigarette on in vivo conduit endothelial function in healthy long-term smokers

Study Overview

• Status: Terminated
• Conditions: Endothelial Function
• Intervention / Treatment: Device: electronic cigarette (e-cigarette); Device: conventional tobacco cigarette

Detailed Description

The overall aim of this study is to compare the short-term vascular effects of smoking an e-cigarette versus smoking a conventional tobacco cigarette in vivo and in vitro.

The specific objectives are as follows:

i. To evaluate the effects of e-cigarette and conventional combustible cigarette (CCC) use on microvascular and macrovascular endothelial function and stiffness in healthy smokers.

ii. To assess circulating markers of endothelial function in response to e-cigarette and CCC smoking.

iii. To investigate the vascular effects of e-cigarette and CCC use on a molecular level by exposing endothelial cells with stimulated serum from the intervention study.

Primary Objective and Outcome Parameter:

The primary objective of this investigator initiated trial (IIT) is to evaluate the short-term effect of e-cigarette puffing on conduit artery function in comparison to smoking a CCC in healthy male long-term smokers.

The relative change in brachial artery diameter in response to reactive hyperemia (flow-mediated vasodilation), a validated surrogate marker of conduit endothelial function, will be used as primary endpoint. FMD [%] is defined as (brachial diameter 60 s after cuff deflation [mm] - baseline brachial diameter [mm]) x 100 / baseline brachial diameter [mm].

The primary outcome measure is the absolute difference of FMD after e-cigarette and CCC.

Secondary Objective and Outcome Parameter:

The secondary objectives are to evaluate in vivo endothelial function in other vascular beds, especially in the microcirculation and the systemic circulation, as well as other aspects of vascular function like stiffness of the arterial tree. Endothelial dysfunction, a key event of atherosclerosis development, is characterized by a respective increase or decrease of endothelium-derived molecules and changes in upstream signaling pathways that control the synthesis and bioavailability of these endothelium-derived molecules. Analysis of circulating biomarkers of endothelial function and expression studies of enzymes involved in endothelial activation will help to closely characterize possible effects of e-cigarette exposure on in vivo endothelial function.

Secondary endpoints are:

• Augmentation index in response to salbutamol (%) as surrogate of global endothelial function in relation to its response to glyceryl trinitrate (%)
• Augmentation index (%) as marker of pulse wave reflection and stiffness
• Retinal arterial and venous diameter in response to flicker-light stimulation (%) as surrogate of microvascular endothelial function
• Central retinal arterial and venous equivalent and arteriolar-to-venular ratio as indicators of generalized arterial narrowing
• Circulating biomarkers of endothelial function and activation (Endothelin-1; BH4/BH2) Secondary outcome measures are the absolute differences of secondary endpoints between e-cigarette and CCC (refer to section 13.4.2).

Functional in vitro assays and molecular analyses:

• mRNA and protein expression of endothelial nitric oxide synthase (eNOS), NRF2 target genes HMOX1, NQO1 and adhesion molecules (ICAM1, VCAM1, SELE, CCL2).
• Primary cultures of human umbilical vein endothelial cells will be stimulated with serum of human subjects (sampled before or after smoking of one cigarette or e-cigarette) and potential of wound healing will be determined.

Tertiary Objective and Outcome Parameter:

The tertiary objective is to assess differences in vascular function between smokers and never smokers. Tertiary endpoints are baseline values of primary and secondary endpoints.

• Study Type: Observational
• Enrollment (Actual): 64

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 33 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

• Sampling Method: Non-Probability Sample

Study Population

80 smokers 25 never smokers will be additionally recruited as a control group who will undergo the same measurements and analyses without smoking intervention.

Description

Inclusion Criteria:

• • Subjects must be males between 22 and 35 years of age, inclusive.

  • Subjects must be able to comprehend, sign and date a written informed consent prior to entering the study.
  • Subjects must be willing and able to comply with the protocol requirements for the duration of the study.

  • Subjects must have experienced one of the following:

    • Smoked for at least the last 4 years and at least 5 cigarettes a day or 1 pack-years,
    • Never having regularly smoked, i.e. < 20 cigarettes in their lifetime and not in last 5 years.

Exclusion Criteria:

• Consumption of cigars, other tobacco and nicotine products and light-cigarettes (less than 8 mg ISO tar).

  • Exhaled CO levels < 10 ppm (smokers) and ≥ 10 ppm (never smokers).
  • Urinary cotinine < 200 ng/ml for smoker group
  • Treatment for arterial hypertension, or clinic blood pressure ≥140/90 mmHg.
  • Body mass index ≥ 30 kg/m2
  • Ocular diseases, glaucoma.
  • Convulsive disorder/epilepsy or intake of anticonvulsant drugs.
  • Subjects with a clinically significant or unstable medical or surgical condition that would preclude safe and complete study participation, as determined by medical history, physical exams, ECG, abnormal laboratory tests. Such conditions may include hepatic, renal or metabolic diseases, systemic disease, acute infection, current malignancy or recent history (5 years) of malignancy, major psychiatric disorder, history of drug and/or alcohol abuse and allergies that could be detrimental according to the investigator's judgment.
  • Prior participation in a clinical study in last 4 weeks.
  • Intake of drugs with potential impact on the endothelial function resp. autonomic nervous system.
  • Known intolerance against salbutamol, nitroglycerin and/or propylene glycol.
  • Regular intake of vitamins and mineral supplements.
  • Heavy exercisers and trained athletes (> 5 hours physical activity / week).

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Crossover
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Smoker_1; Begins with e-cigarette crosses over to conventional cigarette	Device: electronic cigarette (e-cigarette); Device: conventional tobacco cigarette
Non smoker; never smoking participants as control group
Smoker_2; Begins with conventional cigarette crosses over to e-cigarette	Device: electronic cigarette (e-cigarette); Device: conventional tobacco cigarette

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change in conduit artery function related to the smoking pattern	Conduit artery function is defined as the relative response of brachial artery diameter to reactive hyperemia termed as flow-mediated vasodilation (FMD). The primary outcome measure is the absolute difference of FMD after e-cigarette and conventional cigarette consume	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Retinal arterial and venous diameter in response to flicker-light stimulation (%) as surrogate of microvascular endothelial function	Secondary outcome measures are the absolute differences of secondary endpoints between e-cigarette and CCC	7 days
Change in CRAE (central retinal arteriolar equivalents)	To assess circulating marker of endothelial function in response to e-cigarette and CCC smoking. Central retinal arteriolar as marker of retinal structural microvascular abnormalities esp. generalized arteriolar narrowing and venular widening CRAE [µm]: will be automatically determined	7 days
Change in CRVE (central retinal venular equivalents)	To assess circulating marker of endothelial function in response to e-cigarette and CCC smoking. Central retinal venular equivalents as marker of retinal structural microvascular abnormalities esp. generalized arteriolar narrowing and venular widening CRVE [µm]: will be automatically determined	7 days
Change in AVR (arteriolar-to-venular ratio)	To assess circulating marker of endothelial function in response to e-cigarette and CCC smoking. Arteriolar-to-venular ratio as marker of retinal structural microvascular abnormalities esp. generalized arteriolar narrowing and venular widening AVR: will be automatically determined	7 days
Change in circulating biomarkers of endothelial function and activation - Endothelin-1	To assess circulating marker of endothelial function in response to e-cigarette and CCC smoking. Endothelin-1 [pg/ml]	7 days
Change in circulating biomarkers of endothelial function and activation - BH4/BH2	To assess circulating marker of endothelial function in response to e-cigarette and CCC smoking. BH4/BH2	7 days
Augmentation index in response to salbutamol (%) as surrogate of global endothelial function in relation to its response to glyceryl trinitrate (%)	Secondary outcome measures are the absolute differences of secondary endpoints between e-cigarette and CCC	7 days
Augmentation index (%) as marker of pulse wave reflection and stiffness	Secondary outcome measures are the absolute differences of secondary endpoints between e-cigarette and CCC	7 days

Collaborators and Investigators

• Sponsor: GWT-TUD GmbH
• Investigators: Study Director: Tjalf Ziemssen, PhD, MD, Zentrum für Klinische Neurowissenschaften, TU-Dresden; Study Director: Henning Morawietz, PhD, Bereich Gefäßendothel/Mikrozirkulation, TU-Dresden

Study record dates

Study Major Dates

• Study Start (Actual): January 9, 2017
• Primary Completion (Actual): July 30, 2019
• Study Completion (Actual): July 30, 2019

Study Registration Dates

• First Submitted: August 1, 2019
• First Submitted That Met QC Criteria: October 24, 2022
• First Posted (Actual): October 28, 2022

Study Record Updates

• Last Update Posted (Actual): October 28, 2022
• Last Update Submitted That Met QC Criteria: October 24, 2022
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: e-cigarette; microvascular function; arterial wave reflection
• Other Study ID Numbers: ECIG-8

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No