A Study of Gamma Tocopherol-enriched Supplement on Lower Airway Responses to Inhaled Wood Smoke in Healthy Adults
Condition: Airway Inflammation; Asthma
MeSH terms: Inflammation
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Gamma Tocopherol; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Each dose consists of two (700 mg) capsules by mouth once daily for a total of 7 days.; Each dose consists of two capsules by mouth once daily for a total of 7 days.
Other intervention name(s): Vitamin E; Neutral oil
Intervention MeSH terms: Vitamin E; Tocopherols; Tocotrienols; alpha-Tocopherol; gamma-Tocopherol
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Subjects will be allocated to begin the first period of the crossover study with placebo or gamma tocopherol treatment using permuted block randomization with a block size of 4 (2 placebo, 2 gamma tocopherol for the first treatment period of the protocol).
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment