Clinical trial NCT03444298: A Study of Gamma Tocopherol-enriched Supplement on Lower Airway Responses to Inhaled Wood Smoke in Healthy Adults
Official title: A Phase II Randomized, Double Blinded, Placebo-controlled Study of Gamma Tocopherol-enriched Supplement on Lower Airway Responses to Inhaled Wood Smoke in Healthy Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Airway Inflammation
Asthma
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: National Institute of Environmental Health Sciences (NIEHS)
First posted: 2018-02-23
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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).
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: Inclusion Criteria:

1. Age 18-45 years, inclusive, of both genders
2. Negative pregnancy test for females who are not s/p hysterectomy with oophorectomy
3. Forced expiratory volume at one second (FEV1) of at least 75% of predicted (without use of bronchodilating medications for 12 hours), consistent with lung function of persons with no more than mild intermittent or mild persistent asthma.
4. Oxygen saturation of \<93% and blood pressure within the following limits: (Systolic between 150-85 mmHg, Diastolic between 90-50 mmHg).
5. Ability to provide an induced sputum sample.
6. Subject must demonstrate a ≥10% increase in sputum neutrophils following inhaled WSP exposure, when compared to baseline sputum (to be completed in a separate protocol).
7. Ability/willingness to discontinue inhaled corticosteroids, montelukast, and cromolyn for 2 weeks without increased symptoms or increased need for beta agonist rescue medication prior to screening and through the course of the study.

Exclusion Criteria

Patients who meet any of these criteria are not eligible for enrollment as study participants:

1. Clinical contraindications:

   1. Any chronic medical condition considered by the PI as a contraindication to the exposure study including significant cardiovascular disease, diabetes, chronic renal disease, chronic thyroid disease, history of chronic infections/immunodeficiency.
   2. Viral upper respiratory tract infection within 4 weeks of challenge.
   3. Any acute infection requiring antibiotics within 4 weeks of exposure or fever of unknown origin within 4 weeks of challenge.
   4. Abnormal physical findings at the baseline visit, including but not limited to abnormalities on auscultation, temperature of 37.8° C, Systolic BP \> 150mm Hg or \< 85 mm Hg; or Diastolic BP \> 90 mm Hg or \< 50 mm Hg, or pulse oximetry saturation reading less than 93%.
   5. Physician directed emergency treatment for an asthma exacerbation within the preceding 12 months.
   6. Moderate or severe asthma
   7. Exacerbation of asthma more than 2x/weeks which would be characteristic of a person with moderate or severe persistent asthma as outlined in the current National Asthma Education and Prevention Program (NAEPP) guidelines for diagnosis and management of asthma
   8. Daily requirement for albuterol due to asthma symptoms (cough, wheeze, chest tightness) which would be characteristic of a person with moderate or severe persistent asthma as outlined in the current NHLBI guidelines for diagnosis and management of asthma (not to include prophylactic use of albuterol prior to exercise).
   9. Nighttime symptoms of cough or wheeze greater than 1x/week at baseline (not during a clearly recognized viral induced asthma exacerbation) which would be characteristic of a person of moderate or severe persistent asthma as outlined in the current NHLBI guidelines for the diagnosis and management of asthma.
   10. History of intubation for asthma
   11. If there is a history of allergic rhinitis, subjects must be asymptomatic of allergic rhinitis at the time of study enrollment.
   12. Mental illness or history of drug or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements.
   13. Cigarette smoking \> 1 pack per month
   14. Unwillingness to use reliable contraception if sexually active (IUD, birth control pills/patch, condoms).
   15. Abnormal prothrombin time (PT) or activated partial thromboplastin time (aPTT) values at screening or during the treatment period. Normal values will be those published by the clinical lab (Labcorp, INC).
   16. Use of immunosuppressive or anticoagulant medications including routine use of NSAIDS. Oral contraceptives are acceptable, as are Antidepressants and other medications may be permitted if, in the opinion of the investigator, the medication will not interfere with the study procedures or compromise safety and if the dosage has been stable for 1 month.
   17. Orthopedic injuries or impediments that would preclude bicycle or treadmill exercise.
   18. Inability to avoid NSAIDS, Multivitamins, Vitamin C or E or herbal supplements.
   19. Allergy/sensitivity to study drugs or their formulations
   20. Known hypersensitivity to methacholine or to other parasympathomimetic agents
   21. Unwillingness to avoid coffee, tea, cola drinks, chocolate, or other foods containing caffeine after midnight on the days that methacholine challenge testing is to be performed.
2. Pregnant/nursing women and children (\< 18 years as this is age of majority in North Carolina) will also be excluded since the risks associated with woodsmoke exposure to the fetus or child, respectively, are unknown and cannot be justified for this non-therapeutic protocol. Individuals over 45 years of age will not be included due to the increased possibility of co-morbidities and need for prohibited medications.
3. Inability or unwillingness of a participant to give written informed consent.

Primary outcomes:
measure: Change in Sputum % Polymorphonuclear Neutrophils (PMN) With Wood Smoke Particulate (WSP) Exposure
timeFrame: baseline, and 4 hours post exposure
measure: Change in Sputum % PMNs With WSP Exposure
timeFrame: baseline, and 24 hours post exposure
Secondary outcomes:
measure: Change in Absolute PMN Count (ANC) in Sputum With WSP Exposure
timeFrame: baseline, and 4 hours post exposure
measure: Change in Absolute PMN Count (ANC) in Sputum With WSP Exposure
timeFrame: baseline, and 24 hours post exposure
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: UNC Center for Environmental Medicine, Asthma and Lung Biology
state: North Carolina
Study officials:
affiliation: UNC
name: David Peden, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Burbank AJ, Duran CG, Almond M, Wells H, Jenkins S, Jiang Q, Yang C, Wang T, Zhou H, Hernandez ML, Peden DB. A short course of gamma-tocopherol mitigates LPS-induced inflammatory responses in humans ex vivo. J Allergy Clin Immunol. 2017 Oct;140(4):1179-1181.e4. doi: 10.1016/j.jaci.2017.04.030. Epub 2017 May 12. No abstract available.
citation: Hernandez ML, Wagner JG, Kala A, Mills K, Wells HB, Alexis NE, Lay JC, Jiang Q, Zhang H, Zhou H, Peden DB. Vitamin E, gamma-tocopherol, reduces airway neutrophil recruitment after inhaled endotoxin challenge in rats and in healthy volunteers. Free Radic Biol Med. 2013 Jul;60:56-62. doi: 10.1016/j.freeradbiomed.2013.02.001. Epub 2013 Feb 9.
citation: Wiser J, Alexis NE, Jiang Q, Wu W, Robinette C, Roubey R, Peden DB. In vivo gamma-tocopherol supplementation decreases systemic oxidative stress and cytokine responses of human monocytes in normal and asthmatic subjects. Free Radic Biol Med. 2008 Jul 1;45(1):40-9. doi: 10.1016/j.freeradbiomed.2008.03.002. Epub 2008 Mar 12.
citation: Burbank AJ, Duran CG, Pan Y, Burns P, Jones S, Jiang Q, Yang C, Jenkins S, Wells H, Alexis N, Kesimer M, Bennett WD, Zhou H, Peden DB, Hernandez ML. Gamma tocopherol-enriched supplement reduces sputum eosinophilia and endotoxin-induced sputum neutrophilia in volunteers with asthma. J Allergy Clin Immunol. 2018 Apr;141(4):1231-1238.e1. doi: 10.1016/j.jaci.2017.06.029. Epub 2017 Jul 20.
citation: Peden DB, Almond M, Brooks C, Robinette C, Wells H, Burbank A, Hernandez M, Hinderliter A, Caughey M, Jiang Q, Wang Q, Li H, Zhou H, Alexis N. A pilot randomized clinical trial of gamma-tocopherol supplementation on wood smoke-induced neutrophilic and eosinophilic airway inflammation. J Allergy Clin Immunol Glob. 2023 Oct 5;2(4):100177. doi: 10.1016/j.jacig.2023.100177. eCollection 2023 Nov.