The Effects of NOx and Conjugated Linoleic Acid on Asthmatics

Study Overview
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Brief Summary
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This study will examine the hypothesis that in obese asthmatics; treatment with NOx + CLA is well tolerated, safe and will increase eNO while reducing airway oxidative stress. Allied with this, the investigators will define whether supplementing with this bioactive mediator modifies the airway microbiome, and reduces airway inflammation.

Detailed Description
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Obesity is an asthma comorbidity associated with increased severity, poor control, reduced steroid responsiveness and greater exacerbation and healthcare utilization rates. These associations are not explained by having a greater degree of Th-2 inflammation. Rather, the obese asthma phenotype defined in several cluster studies, has paradoxically reduced levels of Th-2 biomarkers, including sputum eosinophils and exhaled nitric oxide (NO). The investigators previous research has shown that the inverse relation between increased body mass index (BMI) and reduced exhaled NO, may be explained by a metabolic imbalance characterized by lower L-arginine and greater asymmetric di-methyl arginine (ADMA) levels. Having a low L-arginine/ADMA ratio has been shown to inhibit and uncouple all isoforms of nitric oxidase synthase (NOS), thereby reducing NO bioavailability and promoting oxidative stress through enhanced superoxide production. In obese asthmatics, this imbalance not only correlates with exhaled NO, but also with lower FEV1% and poorer asthma-related quality of life. Yet the effect of obesity in asthma is unlikely to be solely dependent on a single mechanism. Other factors, such as increased Th1 and Th-17-mediated inflammation have been shown to occur in human and animal models. Given all of these potential avenues, it is imperative that an intervention is sufficiently pleiotropic that can, in addition to restoring airway NO levels, also reduce other obesity-related non-Th2 mechanism of inflammation. The investigators hypothesize that treatment with conjugated linolenic acid (CLA) + nitrate and nitrite (together known as NOx), will restore NO airway bioavailability, reduce oxidative stress and improve airway inflammation in obese asthmatics. To test this hypothesis, the investigators propose a phase II pilot study in which obese asthmatics with metabolic syndrome, will be treated orally with CLA+NOx for 8 weeks, in an open label study design to assess pre to post-intervention changes in airway and systemic biomarkers, and to determine the effects on lung function and bronchial hyperresponsiveness. Participants will undergo a pre and post intervention bronchoscopy. The results obtained from this project will be greatly informative to our understanding of the obese - asthma pathophysiology and for the development of clinical trials to determine the potential benefit of this intervention in improving health outcomes.

Official Title
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A Proof of Concept Study to Determine the Effects of NOX and Conjugated Linoleic Acid on Asthmatics

Conditions
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Asthma

Intervention / Treatment
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* Dietary Supplement: Conjugated Linolenic Acid
* Drug: Sodium Nitrite
* Drug: Sodium Nitrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adequate completion of informed consent process with written documentation Male and female patients, ≥ 18 - 65 yrs old Diagnosis of asthma: based on previous physician diagnosis and either baseline pre-bronchodilator FEV1 50% or greater predicted with a 12% or greater bronchodilator response to 4 puffs of albuterol or PC20 methacholine (16 mg) if no BD response.If the subject is not currently on an ICS/ ICS LABA, PC20 should be < 8 mg, if no BD response. Spirometry results within the prior 24 months located in the subject's medical records can be used to determine eligibility, if available. All racial/ethnic backgrounds with a diagnosis of asthma for ≥6 months Smoking history ≤10 pack years and no smoking in the last year BMI ≥ 30 If subject is on ICS or ICS/LABA therapy- 30 days on a stable dose (up to 1,000 mcg daily fluticasone equivalent) Asthma diagnosed at age 9 or later Exclusion Criteria: Respiratory tract infection within the last 4 weeks Oral or systemic CS burst within the last 4 weeks Asthma-related hospitalization within the last 2 months Asthma-related ER visit within the previous 4 weeks Significant or uncontrolled concomitant medical illness including (but not limited to) heart disease, cancer, diabetes Chronic renal failure (creatinine > 2.0) at screening (Associated with higher ADMA levels) Current statins use (statins lower ADMA levels), patients may stop and re-enroll after 2 weeks of stopping statins Positive pregnancy test Intolerance or allergy to the intervention drugs Current or recent (within 30 days) in an investigational treatment study. Unable or unlikely to complete study assessments or the study intervention (i.e. bronchoscopy) poses undue risk to patient in the opinion of the Investigator. Any kind of oral nitrates such as nitroglycerin or already taking supplements History of ICU admission/intubation due to asthma in the past year; More than three systemic corticosteroid requiring asthma exacerbations in the past year Systemic steroid dependent asthma (no daily oral steroids- short term therapy for asthma exacerbation is permitted) Use of mouthwash containing chlorhexidine (lowers NO) within 1 week prior to screening and throughout the study Untreated sleep apnea Hgb A1C ≥7 Daily use of PPI's (Proton Pump Inhibitor) or H2 Blockers for GERD (it is permitted to take on an occasional basis- no more than 1x per week. If participants wash out of these meds for 1 week, they can enroll) Use of biologics for asthma/allergies unless there is a 4 month washout prior to enrollment (the washout for biologics is done for clinical reasons and not specifically for inclusion for the study). Drug and/or alcohol abuse for ≥1 year Breastfeeding Any other condition and/or situation that causes the investigator to deem a subject unsuitable for the study (e.g. due to expected study medication non-compliance, inability to medically tolerate the study procedures, or a subject's unwillingness to comply with study-related procedures.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Conjugated Linolenic Acid + NOx<br>This is a single arm study Conjugated Linolenic Acid (CLA)- daily oral dose 3 g/day Sodium Nitrate- Capsules for daily oral administration at the dose of 1 g (2 x 500 mg) Sodium Nitrite- Capsules for daily oral administration at the dose of 20 mg (2 x 10 mg) | Dietary Supplement: Conjugated Linolenic Acid<br>* CLA is a polyunsaturated fatty acid Subjects will receive capsules for daily oral administration at the dose of 3 g/day<br>* Other names: conjugated linolenic acid (CLA);Drug: Sodium Nitrite<br>* Subjects will receive capsules for daily oral administration at the dose of 20 mg (2 x 10 mg)<br>Drug: Sodium Nitrate<br>* Subjects will receive capsules for daily oral administration at the dose of 1g (2 x 500 mg)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Exhaled NO Before and After Treatment | Determine how CLA and NOx affect airway NO bioavailability (exhaled NO) | Before treatment at baseline and after treatment at 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biomarkers of Inflammation-bronchial Hyperresponsiveness Using PC20 | To determine whether, compared to baseline, treatment with NOx + CLA can reduce bronchial hyperresponsiveness. PC20 was measured by methacholine challenge (mg/mL) in three participants pre and post supplementation with Nitrate/Nitrite and cLA | Before treatment at baseline and after treatment at 8 weeks | 
| Biomarkers of Inflammation- Concentration of Free CLA in Plasma | To determine whether, compared to baseline, treatment with NOx + CLA can quantify the concentrations of free CLA in plasma | Before treatment at baseline and after treatment at 8 weeks | 
| Number of Participants With an Increase in IL-6 and IL-1b Expression | To determine whether, compared to baseline, treatment with NOx + CLA will increase a participant's IL-6 and IL-1b expression. | Before treatment at baseline and after treatment at 8 weeks | 
| Biomarkers of Inflammation-airway XO Activity | To determine whether, compared to baseline, treatment with NOx + CLA can effect airway XO activity determined in endobronchial biopsies | Before treatment at baseline and after treatment at 8 weeks | 
| Biomarkers of Inflammation-15NO2-cLA | To determine whether, compared to baseline, treatment with NOx + CLA can effect measurement of 15NO2-cLA in urine. | Before treatment at baseline and after treatment at 8 weeks | 
| Biomarkers of Inflammation-anion Superoxide | To determine whether, compared to baseline, treatment with NOx + CLA can decrease production of anion superoxide in fresh airway epithelial cells | Before treatment at baseline and after treatment at 8 weeks | 
| Number of Participants With a Decrease of Inflammation Using Mitochondrial ROS Production | To determine whether, compared to baseline, treatment with NOx + CLA can decrease inflammation using mitochondrial ROS production in fresh and cultured airway epithelial cells. | Before treatment at baseline and after treatment at 8 weeks | 
| Biomarkers of Inflammation- Concentration of NO2-CLA in Plasma | To determine whether, compared to baseline, treatment with NOx + CLA can quantify the concentrations of NO2-cLA in plasma | Before treatment at baseline and after treatment at 8 weeks | 
| Biomarkers of Inflammation- Concentration of NO2-CLA in Urine | To determine whether, compared to baseline, treatment with NOx + CLA can quantify the concentrations of NO2-cLA in urine | Before treatment at baseline and after treatment at 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Obesity, conjugated linolenic acid, nitrate, nitrite, nutritional supplements