The Effects of NOx and Conjugated Linoleic Acid on Asthmatics

Phase 2

Completed

Conditions: Asthma

Interventions: Dietary Supplement: Conjugated Linolenic Acid
Drug: Sodium Nitrite
Drug: Sodium Nitrate

Registration Number: NCT02433977

Lead Sponsor: Gladwin, Mark, MD

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 6

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Conjugated Linolenic Acid + NOx	Sodium Nitrate	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)
Conjugated Linolenic Acid + NOx	Conjugated Linolenic Acid	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)
Conjugated Linolenic Acid + NOx	Sodium Nitrite	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)

Primary Outcome Measures

Name	Time	Method
Change in Exhaled NO Before and After Treatment	Before treatment at baseline and after treatment at 8 weeks	Determine how CLA and NOx affect airway NO bioavailability (exhaled NO)

Secondary Outcome Measures

Name	Time	Method
Biomarkers of Inflammation- Concentration of NO2-CLA in Urine	Before treatment at baseline and after treatment at 8 weeks	To determine whether, compared to baseline, treatment with NOx + CLA can quantify the concentrations of NO2-cLA in urine
Biomarkers of Inflammation-bronchial Hyperresponsiveness Using PC20	Before treatment at baseline and after treatment at 8 weeks	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
Biomarkers of Inflammation- Concentration of Free CLA in Plasma	Before treatment at baseline and after treatment at 8 weeks	To determine whether, compared to baseline, treatment with NOx + CLA can quantify the concentrations of free CLA in plasma
Number of Participants With a Decrease of Inflammation Using Mitochondrial ROS Production	Before treatment at baseline and after treatment at 8 weeks	To determine whether, compared to baseline, treatment with NOx + CLA can decrease inflammation using mitochondrial ROS production in fresh and cultured airway epithelial cells.
Biomarkers of Inflammation-airway XO Activity	Before treatment at baseline and after treatment at 8 weeks	To determine whether, compared to baseline, treatment with NOx + CLA can effect airway XO activity determined in endobronchial biopsies
Biomarkers of Inflammation-15NO2-cLA	Before treatment at baseline and after treatment at 8 weeks	To determine whether, compared to baseline, treatment with NOx + CLA can effect measurement of 15NO2-cLA in urine.
Biomarkers of Inflammation-anion Superoxide	Before treatment at baseline and after treatment at 8 weeks	To determine whether, compared to baseline, treatment with NOx + CLA can decrease production of anion superoxide in fresh airway epithelial cells
Biomarkers of Inflammation- Concentration of NO2-CLA in Plasma	Before treatment at baseline and after treatment at 8 weeks	To determine whether, compared to baseline, treatment with NOx + CLA can quantify the concentrations of NO2-cLA in plasma
Number of Participants With an Increase in IL-6 and IL-1b Expression	Before treatment at baseline and after treatment at 8 weeks	To determine whether, compared to baseline, treatment with NOx + CLA will increase a participant's IL-6 and IL-1b expression.