The Effects of NOx and Conjugated Linoleic Acid on Asthmatics

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.

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.