A Phase 2 interventional study of Gamma Tocopherol and Placebo in Airway Inflammation and Asthma, sponsored by University of North Carolina, Chapel Hill. Completed at 1 site in United States. Open to participants aged 18 Years to 45 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2024-02-05.
Sponsored by University of North Carolina, Chapel Hill · Phase 2, Interventional, and Treatment
Purpose: To determine the efficacy of 1400 mg gamma tocopherol-enriched supplement for mitigating inhaled wood smoke particle-induced airway inflammation in healthy adults with no more than mild asthma.
Particulate matter (PM) is a leading cause of respiratory tract and cardiovascular disease in the United States and world-wide. Wood smoke particles (WSP) derived from wildland and other fires account for a significant fraction of ambient air PM. Health effects associated with WSP include acute bronchitis, asthma exacerbation, pneumonia, cough and systemic inflammation. While these effects are seen in both healthy and asthmatic individuals, many studies indicate that asthmatics have increased susceptibility to the effects of WSP. The investigators have developed a 500 μg/m3 WSP exposure protocol (levels similar to those encountered by firefighters and residents in close proximity to wildland burn sites) that induces airway and systemic inflammation in healthy volunteers. As with other pollutants, these inflammatory responses modulate non-specific bronchial reactivity (NSBR), inflammatory cell recruitment to the airways (primarily neutrophils), and potentially cardiovascular function.
The investigators have focused on gamma tocopherol (γT) as a nutritional intervention to prevent inflammatory responses to air pollutants such as WSP. Building on animal and in vitro preclinical studies, the investigators have established that 1400 mg/day of oral γT-enriched supplement for 7 and 14 days in healthy volunteers and mild asthmatics, respectively, inhibited neutrophil influx into the airways, reduced production of sputum mucins, and improved mucociliary clearance following challenge with inhaled endotoxin, another common component of PM. The findings occurred in the context of significantly increased plasma concentrations of γT and its active metabolite 2,7,8-trimethyl-2-(β-Carboxy-Ethyl)-6-Hydroxychroman (γ-CEHC). Given the findings in these early phase clinical trials, γT supplementation is an attractive approach to prevent WSP-induced adverse health effects. The investigators propose to use γT supplementation in a human model of WSP inhalation to mitigate key features of airway inflammation: inflammatory cell recruitment, production of inflammatory cytokines and mucous, and changes in airway physiology.
Gamma tocopherol will be administered in softgel form, with each softgel containing 700 mg of tocopherols, 89.5% of which is d-gamma tocopherol. Subjects will consume two softgels by mouth once daily for 7 days. This dosing regimen was chosen based on the results of the investigators' previous early phase clinical trials examining the impact of gamma tocopherol on lipopolysaccharide (LPS) -induced airway inflammation in healthy adults and adults with asthma. These studies tested a 7 and 14 day course of treatment, respectively, and found similar plasma concentrations of γT and active metabolites in both studies. Furthermore, the investigators showed in both studies that γT significantly reduced LPS-induced sputum neutrophilia compared to placebo. Based on the previous findings, the investigators will now study the efficacy of γT for mitigating WSP-induced airway inflammation.
January 2022 update: The existing, custom source of gamma tocopherol expired during the protocol paused period during Covid. The Gamma t is replaced by Gamma E Gems, manufactured by Carlson Labs, each capsule with 577mg of gamma tocopherol, based on Certificate of Analysis. Subjects will continue to ingest 2 capsules at each dosing, for a total dose of 1154mg. The safflower oil placebo is replaced with a neutral oil capsule.
Exclusion Criteria
Patients who meet any of these criteria are not eligible for enrollment as study participants:
Clinical contraindications:
Participants that are randomized to placebo treatment will take a short treatment course of Neutral Oil followed by chamber exposure with wood smoke particulate. After a 4-week washout period, participants will cross over to the gamma Tocopherol (active) treatment group.
Drug: Gamma Tocopherol · Drug: Placebo
Participants that are randomized γT treatment will take a short treatment course of gamma Tocopherol followed by chamber exposure with WSP. After a 4-week washout period, participants will cross over to the placebo treatment group.
Drug: Gamma Tocopherol · Drug: Placebo
Each dose consists of two (700 mg) capsules by mouth once daily for a total of 7 days.
Also known as: Vitamin E
Each dose consists of two capsules by mouth once daily for a total of 7 days.
Also known as: Neutral oil
Change in Sputum % Polymorphonuclear Neutrophils (PMN) With Wood Smoke Particulate (WSP) Exposure
A comparison of the WSP-induced change in sputum % PMNs (Post-WSP sputum - Pre-WSP sputum) during gamma tocopherol treatment with the WSP-induced change in sputum % PMNs during placebo treatment.
Time frame: baseline, and 4 hours post exposure
Change in Sputum % PMNs With WSP Exposure
A comparison of the WSP-induced change in sputum % PMNs (Post-WSP sputum - Pre-WSP sputum) during gamma tocopherol treatment with the WSP-induced change in sputum % PMNs during placebo treatment.
Time frame: baseline, and 24 hours post exposure
Change in Absolute PMN Count (ANC) in Sputum With WSP Exposure
A comparison of the WSP-induced change in sputum ANC (Post-WSP sputum - Pre-WSP sputum) during gamma tocopherol treatment with the WSP-induced change in sputum ANC during placebo treatment.
Time frame: baseline, and 4 hours post exposure
Change in Absolute PMN Count (ANC) in Sputum With WSP Exposure
A comparison of the WSP-induced change in sputum ANC (Post-WSP sputum - Pre-WSP sputum) during gamma tocopherol treatment with the WSP-induced change in sputum ANC during placebo treatment.
Time frame: baseline, and 24 hours post exposure
| Milestone | Placebo First, Then Gamma Tocopherol | GammaTocopherol First, Then Placebo |
|---|---|---|
| Started | 7 | 9 |
| Completed | 7 | 9 |
| Not completed | 0 | 0 |
| Milestone | Placebo First, Then Gamma Tocopherol | GammaTocopherol First, Then Placebo |
|---|---|---|
| Started | 7 | 9 |
| Completed | 4 | 7 |
| Not completed | 3 | 2 |
| Milestone | Placebo First, Then Gamma Tocopherol | GammaTocopherol First, Then Placebo |
|---|---|---|
| Started | 4 | 7 |
| Completed | 4 | 7 |
| Not completed | 0 | 0 |
A comparison of the WSP-induced change in sputum % PMNs (Post-WSP sputum - Pre-WSP sputum) during gamma tocopherol treatment with the WSP-induced change in sputum % PMNs during placebo treatment.
| percent PMNs | GammaTocopherol | Placebo |
|---|---|---|
| Change in Sputum % Polymorphonuclear Neutrophils (PMN) With Wood Smoke Particulate (WSP) Exposure | 18.00 ± 20.89 | 14.75 ± 17.98 |
A comparison of the WSP-induced change in sputum % PMNs (Post-WSP sputum - Pre-WSP sputum) during gamma tocopherol treatment with the WSP-induced change in sputum % PMNs during placebo treatment.
| percent PMNs | GammaTocopherol | Placebo |
|---|---|---|
| Change in Sputum % PMNs With WSP Exposure | 39.87 ± 20.59 | 29.35 ± 28.30 |
A comparison of the WSP-induced change in sputum ANC (Post-WSP sputum - Pre-WSP sputum) during gamma tocopherol treatment with the WSP-induced change in sputum ANC during placebo treatment.
| PMNs per mg sputum | GammaTocopherol | Placebo |
|---|---|---|
| Change in Absolute PMN Count (ANC) in Sputum With WSP Exposure | 8.58 ± 150.6 | -20.51 ± 160.6 |
A comparison of the WSP-induced change in sputum ANC (Post-WSP sputum - Pre-WSP sputum) during gamma tocopherol treatment with the WSP-induced change in sputum ANC during placebo treatment.
| PMNs per mg sputum | GammaTocopherol | Placebo |
|---|---|---|
| Change in Absolute PMN Count (ANC) in Sputum With WSP Exposure | 104.7 ± 146.5 | 96.7 ± 156.2 |
A comparison of the WSP-induced sputum % eosinophils versus predosing values with gamma tocopherol and placebo treatment.
| percent eosinophils | Pre-Dosing | GammaTocopherol | Placebo |
|---|---|---|---|
| 4 Hours | 0.07 ± 0.04 | 0.04 ± 0.08 | 2.3 ± 1.6 |
| 24 Hours | 0.07 ± 0.04 | 0.26 ± 0.15 | 0.39 ± 0.33 |
A comparison of the WSP-induced sputum eosinophils after gamma tocopherol and placebo pre dosing values.
| Cells per mg (eosinophils) | Pre-Dosing | GammaTocopherol | Placebo |
|---|---|---|---|
| 4 Hours | 0.17 ± 0.33 | 0.20 ± 0.52 | 7.10 ± 12.33 |
| 24 Hours | 0.17 ± 0.33 | 1.15 ± 2.11 | 1.02 ± 2.70 |
The IL-1β concentration will be determined in each sputum sample by immunoassay
| pg/mL | Pre-Dosing | GammaTocopherol | Placebo |
|---|---|---|---|
| 4 Hours | 798.3 ± 497.1 | 674.2 ± 494.9 | 654.4 ± 438.3 |
| 24 Hours | 798.3 ± 497.1 | 469.6 ± 237.4 | 675.2 ± 630.6 |
The IL-6 concentration will be determined in each sputum sample by immunoassay
| pg/mL | Pre-Dosing | GammaTocopherol | Placebo |
|---|---|---|---|
| 4 Hours | 458.0 ± 492.3 | 384.8 ± 440.2 | 277.5 ± 255.5 |
| 24 Hours | 458.0 ± 492.3 | 207.0 ± 171.6 | 281.3 ± 338.0 |
The IL-8 concentration will be determined in each sputum sample by immunoassay
| pg/mL | Pre-Dosing | GammaTocopherol | Placebo |
|---|---|---|---|
| 4 Hours | 30850 ± 28306 | 31724 ± 37505 | 25432 ± 23198 |
| 24 Hours | 30850 ± 28306 | 17180 ± 13083 | 36739 ± 60134 |
The TNF-a concentration will be determined in each sputum sample by immunoassay
| pg/mL | Pre-Dosing | GammaTocopherol | Placebo |
|---|---|---|---|
| 4 Hours | 35.67 ± 25.88 | 127.7 ± 342.7 | 25.18 ± 20.84 |
| 24 Hours | 35.67 ± 25.88 | 13.77 ± 12.63 | 29.23 ± 26.18 |
The alpha tocopherol concentration will be determined in blood samples by high-performance liquid chromatography (HPLC).
| microM | GammaTocopherol | Placebo |
|---|---|---|
| Alpha Tocopherol in Blood | 22.54 ± 10.17 | 24.58 ± 3.40 |
The 2, 7,8-trimethyl-2S-(g-carboxyethyl)-6-hydroxychromane (g-CEHC) concentration will be determined in blood samples by high-performance liquid chromatography (HPLC).
| microM | GammaTocopherol | Placebo |
|---|---|---|
| 2, 7,8-trimethyl-2S-(G-carboxyethyl)-6-hydroxychromane (g-CEHC) in Blood | 1.912 ± 2.021 | 0.084 ± 0.08 |
The gamma tocopherol concentration will be determined in blood samples by high-performance liquid chromatography (HPLC).
| microM | GammaTocopherol | Placebo |
|---|---|---|
| GammaTocopherol in Blood | 32.60 ± 7.45 | 4.64 ± 1.71 |
Collected over From the time a participant signed consent through completion of the second intervention, a total of up to 5 months.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| GammaTocopherol | 0/13 (0%) | 0/13 (0%) | 8/13 (61.5%) |
| Placebo | 0/14 (0%) | 0/14 (0%) | 7/14 (50%) |
| Event | GammaTocopherol | Placebo |
|---|---|---|
| Gastrointestinal DistressGastrointestinal disorders | 7/13 | 2/14 |
| HeadacheGeneral disorders | 2/13 | 3/14 |
| Viral Upper Respiratory InfectionRespiratory, thoracic and mediastinal disorders | 1/13 | 1/14 |
| Eye IrritationEye disorders | 1/13 | 0/14 |
| NosebleedVascular disorders | 1/13 | 0/14 |
| Unusual Fatigue or TirednessGeneral disorders | 1/13 | 1/14 |
| Premature Ventricular ContractionCardiac disorders | 1/13 | 0/14 |
| Menstrual CrampsGeneral disorders | 1/13 | 0/14 |
| SweatingSkin and subcutaneous tissue disorders | 1/13 | 1/14 |
| Throat IrritationRespiratory, thoracic and mediastinal disorders | 1/13 | 0/14 |
| Age, Categorical(Participants) | Placebo First, Then Gamma Tocopherol | GammaTocopherol First, Then Placebo | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 7 | 9 | 16 |
| >=65 years | 00 | 0 | 0 |
| Sex: Female, Male(Participants) | Placebo First, Then Gamma Tocopherol | GammaTocopherol First, Then Placebo | Total |
|---|---|---|---|
| Female | 6 | 5 | 11 |
| Male | 1 | 4 | 5 |
| Ethnicity (NIH/OMB)(Participants) | Placebo First, Then Gamma Tocopherol | GammaTocopherol First, Then Placebo | Total |
|---|---|---|---|
| Hispanic or Latino | 2 | 2 | 4 |
| Not Hispanic or Latino | 5 | 7 | 12 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Placebo First, Then Gamma Tocopherol | GammaTocopherol First, Then Placebo | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 1 | 0 | 1 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 3 | 1 | 4 |
| White | 3 | 8 | 11 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(Participants) | Placebo First, Then Gamma Tocopherol | GammaTocopherol First, Then Placebo | Total |
|---|---|---|---|
| United States | 7 | 9 | 16 |
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University of North Carolina, Chapel Hill