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Impact of Smoking Cessation and γ-Tocopherol to Restore Vascular Endothelial Function

Cardioprotective Synergy of Smoking Cessation and γ-Tocopherol in Restoring Vascular Endothelial Function

Status
Completed
Phases
Phase 1Phase 2
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT01314443
Enrollment
67
Registered
2011-03-14
Start date
2011-01-31
Completion date
2014-12-31
Last updated
2015-01-21

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Endothelial Dysfunction

Keywords

smoking cessation, gamma-tocopherol, nicotine-replacement therapy, oxidative stress

Brief summary

Cigarette smoking is a significant risk factor for cardiovascular disease (CVD) and is the leading cause of premature mortality in the US. The detrimental effects of smoking on vascular dysfunction are attributed to the effects of smoke itself and the inflammatory responses it induces. Smoking cessation restores vascular function by alleviating these stress responses. However, smoking cessation with nicotine replacement therapy (NRT), the prevailing approach to mitigate tobacco dependence, fails to allow full restoration of vascular function. Thus, a critical public health problem exists to understand how NRT prevents restoration of vascular function and how these NRT-mediated impairments can be overcome by using gamma-tocopherol (g-T) as an innovative co-therapy. The objective of this study is to conduct a clinical intervention trial that aims to reduce CVD risk by defining how smoking cessation and g-T restore vascular function. The hypothesis is that smoking cessation and dietary g-T supplementation will synergistically restore smoking-induced impairments in vascular function by ameliorating oxidative/nitrosative stress responses, and that g-T will facilitate full restoration of vascular function otherwise precluded by NRT. A placebo-controlled, g-T intervention study will be conducted in cigarette smokers undergoing nicotine-free or NRT smoking cessation. Prior to and after 24 h and 7 days of placebo or g-T administration, vascular function will be evaluated using a non-invasive ultrasound technique and an array of antioxidants and biomarkers for vascular inflammation and oxidative/nitrosative stress responses will be assessed. Collectively, these studies will help identify how vascular function is regulated in individuals undergoing smoking cessation, and whether g-T can be used as a strategy to better improve vascular function during smoking cessation.

Detailed description

While it is well known that smoking cessation reduces the risk of cardiovascular disease (CVD), the rate in which CVD risk is normalized is relatively slow. This suggests a need to better define co-therapies that target oxidative stress and inflammatory responses that otherwise impair vascular function. In this randomized placebo-controlled clinical study, smokers undergoing smoking cessation with or without nicotine replacement therapy will receive dietary supplementation of gamma-tocopherol (500 mg/day) or placebo for 7 days. Their vascular function and biomarkers of CVD risk (inflammatory proteins, antioxidants, oxidized lipids) will be assessed prior to, and at 1 day and 7 days during smoking cessation with and without gamma-tocopherol supplementation to define potential mechanisms by which gamma-tocopherol may accelerate the restoration of vascular function and assist in reducing CVD risk.

Interventions

OTHERNicotine Replacement Therapy (NRT)

Participants will quit smoking with nicotine patches

DIETARY_SUPPLEMENTGamma-Tocopherol

Participants will take gamma-tocopherol (500 mg/d) supplements for 7 days

OTHERPlacebo

Participants will take placebo for 7 days

BEHAVIORALSmoking cessation

Participants will quit smoking without any pharmacological aids

Sponsors

University of Connecticut
Lead SponsorOTHER

Study design

Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes

Inclusion criteria

* male or female between 18-60 y, * premenopausal status for women * healthy, verified by serum clinical chemistry * stable body weight (±5 lbs) for 2-mo and BMI 19-30 kg/m2 * non-nutritional supplement user for \>2-mo * free of known diseases including diabetes, CVD, cancer, infections, HIV/AIDS, hepatitis, and bleeding disorders * resting blood pressure \<140/90 mm Hg; * smokers (≥10 cigarettes/d, ≥1 year) * maintaining normal exercise patterns (\<7 h/week) and willingness to avoid exercise 24 h prior to blood sampling and vascular testing * willingness to ingest a dietary vitamin E supplement (gamma-tocopherol; 500 mg/d) or a placebo (composed of tocopherol-free corn oil) daily for 1 week.

Exclusion criteria

* serum chemistry outside normal limits * alcohol consumption \>3 drinks/d or \>10 drinks per week * nutritional supplement user with past 2 months * \>7 hours/week of exercise * use of any pharmacological therapy to treat high cholesterol or high blood pressure * pregnancy, lactation, or initiation or change in hormonal birth control within the previous 3 mo * use of vasoactive compounds (e.g. erectile dysfunction medication, omega 3-fatty acids, niacin) * suffering from major psychiatric illnesses * currently using non-nicotine aids or drugs to quit smoking; or 10) allergy to adhesive tape.

Design outcomes

Primary

MeasureTime frameDescription
Absolute Change in Brachial Artery Flow-mediated Dilation at Day 7 From Day 0Day 0 and 7 of interventionFlow-mediated dilation (FMD) of the brachial artery is measured to assess vascular endothelial function. FMD is obtained by monitoring change in vessel diameter before and after brachial artery occlusion with a blood pressure cuff. The unit of FMD is % and is calculated using the following equation: FMD = \[(peak dilation at post occlusion - vessel diameter at preocclusion)/vessel diameter at preocclusion\]\*100.

Secondary

MeasureTime frameDescription
Absolute Change From Baseline in Plasma Gamma-tocopherol (Vitamin E) at Day 7 From Day 0.Day 0 and 7 of interventionPlasma measurements of gamma-tocopherol was assessed in response to smoking cessation and in combination with gamma-tocopherol (vitamin E) supplementation.
Absolute Change From Baseline in Plasma Malondialdehyde at Day 7 From Day 0.Day 0 and 7 of interventionPlasma measurements of malondialdehyde, a marker of lipid peroxidation was assessed in response to smoking cessation and in combination with gamma-tocopherol (vitamin E) supplementation

Countries

United States

Participant flow

Recruitment details

Recruitment took place in and around the community surrounding the University of Connecticut. Recruitment occurred from 2010-2011.

Pre-assignment details

Health status of participants was determined from a comprehensive metabolic panel as well as circulating lipid levels. Individuals having serum chemistries outside of acceptable limits were not enrolled.

Participants by arm

ArmCount
Supplement + Smoking Cessation
Individuals will ingest gamma-tocopherol (500 mg/d) for 7 days while undergoing smoking cessation without any aids
14
Placebo + Smoking Cessation
Individuals will ingest placebo for 7 days while undergoing smoking cessation without any aids
16
Supplement + Nicotine Replacement Therapy
Individuals will ingest gamma-tocopherol (500 mg/d) for 7 days while undergoing smoking cessation with the use of NRT
13
Placebo + Nicotine Replacement Therapy
Individuals will ingest placebo for 7 days while undergoing smoking cessation with the use of NRT
13
Total56

Withdrawals & dropouts

PeriodReasonFG000FG001FG002FG003
Overall StudyProtocol Violation2211
Overall StudyWithdrawal by Subject2111

Baseline characteristics

CharacteristicPlacebo + Smoking CessationSupplement + Nicotine Replacement TherapySupplement + Smoking CessationPlacebo + Nicotine Replacement TherapyTotal
Age, Categorical
<=18 years
0 Participants0 Participants0 Participants0 Participants0 Participants
Age, Categorical
>=65 years
0 Participants0 Participants0 Participants0 Participants0 Participants
Age, Categorical
Between 18 and 65 years
16 Participants13 Participants14 Participants13 Participants56 Participants
Age, Continuous22 years
STANDARD_DEVIATION 4
26 years
STANDARD_DEVIATION 8
22 years
STANDARD_DEVIATION 4
25 years
STANDARD_DEVIATION 8
24 years
STANDARD_DEVIATION 6
Region of Enrollment
United States
16 participants13 participants14 participants13 participants56 participants
Sex: Female, Male
Female
5 Participants5 Participants5 Participants4 Participants19 Participants
Sex: Female, Male
Male
11 Participants8 Participants9 Participants9 Participants37 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
EG003
affected / at risk
deaths
Total, all-cause mortality
— / —— / —— / —— / —
other
Total, other adverse events
0 / 140 / 160 / 130 / 13
serious
Total, serious adverse events
0 / 140 / 160 / 130 / 13

Outcome results

Primary

Absolute Change in Brachial Artery Flow-mediated Dilation at Day 7 From Day 0

Flow-mediated dilation (FMD) of the brachial artery is measured to assess vascular endothelial function. FMD is obtained by monitoring change in vessel diameter before and after brachial artery occlusion with a blood pressure cuff. The unit of FMD is % and is calculated using the following equation: FMD = \[(peak dilation at post occlusion - vessel diameter at preocclusion)/vessel diameter at preocclusion\]\*100.

Time frame: Day 0 and 7 of intervention

Population: Analysis was performed on all participants completing the 7 d intervention

ArmMeasureValue (MEAN)Dispersion
Dietary Supplement + Smoking CessationAbsolute Change in Brachial Artery Flow-mediated Dilation at Day 7 From Day 04.08 % of preocclusion diameterStandard Error 0.61
Placebo + Smoking CessationAbsolute Change in Brachial Artery Flow-mediated Dilation at Day 7 From Day 02.77 % of preocclusion diameterStandard Error 0.35
Dietary Supplement + Nicotine Replacement TherapyAbsolute Change in Brachial Artery Flow-mediated Dilation at Day 7 From Day 02.97 % of preocclusion diameterStandard Error 0.51
Placebo + Nicotine Replacement TherapyAbsolute Change in Brachial Artery Flow-mediated Dilation at Day 7 From Day 02.66 % of preocclusion diameterStandard Error 0.44
Secondary

Absolute Change From Baseline in Plasma Gamma-tocopherol (Vitamin E) at Day 7 From Day 0.

Plasma measurements of gamma-tocopherol was assessed in response to smoking cessation and in combination with gamma-tocopherol (vitamin E) supplementation.

Time frame: Day 0 and 7 of intervention

ArmMeasureValue (MEAN)Dispersion
Dietary Supplement + Smoking CessationAbsolute Change From Baseline in Plasma Gamma-tocopherol (Vitamin E) at Day 7 From Day 0.7.30 microMStandard Error 0.98
Placebo + Smoking CessationAbsolute Change From Baseline in Plasma Gamma-tocopherol (Vitamin E) at Day 7 From Day 0.-0.10 microMStandard Error 0.21
Dietary Supplement + Nicotine Replacement TherapyAbsolute Change From Baseline in Plasma Gamma-tocopherol (Vitamin E) at Day 7 From Day 0.7.28 microMStandard Error 1.57
Placebo + Nicotine Replacement TherapyAbsolute Change From Baseline in Plasma Gamma-tocopherol (Vitamin E) at Day 7 From Day 0.-0.24 microMStandard Error 0.13
Secondary

Absolute Change From Baseline in Plasma Malondialdehyde at Day 7 From Day 0.

Plasma measurements of malondialdehyde, a marker of lipid peroxidation was assessed in response to smoking cessation and in combination with gamma-tocopherol (vitamin E) supplementation

Time frame: Day 0 and 7 of intervention

ArmMeasureValue (MEAN)Dispersion
Dietary Supplement + Smoking CessationAbsolute Change From Baseline in Plasma Malondialdehyde at Day 7 From Day 0.-0.08 microMStandard Error 0.05
Placebo + Smoking CessationAbsolute Change From Baseline in Plasma Malondialdehyde at Day 7 From Day 0.-0.06 microMStandard Error 0.03
Dietary Supplement + Nicotine Replacement TherapyAbsolute Change From Baseline in Plasma Malondialdehyde at Day 7 From Day 0.-0.04 microMStandard Error 0.04
Placebo + Nicotine Replacement TherapyAbsolute Change From Baseline in Plasma Malondialdehyde at Day 7 From Day 0.-0.07 microMStandard Error 0.02

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026