L-arginine in Severe Asthma Patients Grouped by Exhaled Nitric Oxide Levels

Phase II Study of L-arginine in Severe Asthma Patients Grouped by Exhaled Nitric Oxide Level

The major impact of this study will be to identify the adult severe asthma cohort that will benefit from supplemental L-arginine therapy. The investigators hypothesize that a subset of adult severe asthma patients will respond to supplemental L-arginine and derive clinical benefit from the addition of this therapy to standard-of-care asthma medications. The investigators hypothesize that the patients that benefit most will have low exhaled nitric oxide concentrations (< 20 ppb) at baseline.

We hypothesize that a subset of adult severe asthma patients will respond to supplemental L-arginine and derive clinical benefit from the addition of this therapy to standard-of-care medications. We hypothesize that these patients will have lower exhaled NO concentrations (<20 ppb) and lower nitric oxide synthase 2 (NOS2)/ arginase I (Arg1) mRNA ratios in their airway epithelial cells than "non-responders." The aim is to test the hypothesis that adult severe asthma subjects with exhaled breath NO concentrations < 20 ppb will have fewer American Thoracic Society (ATS)-defined asthma exacerbations over 3 months when treated with L-arginine compared to subjects with exhaled nitric oxide concentration (FeNO) > 25 ppb. The major impact of this study will be to identify the adult severe asthma cohort that will benefit from supplemental L-arginine therapy to define the underlying mechanisms of arginine benefit in asthma. This follows our initial 20 subject trial of L-arginine in asthma subjects (Kenyon et al., Pharmaceuticals 2011) that was designed to determine how L-arginine was metabolized (by testing serum markers) and whether certain participants had clinical benefit.

To do this, we will recruit a total of 50 ATS-defined severe asthmatic subjects with ongoing asthma exacerbations in past two months and enroll them in a randomized, blinded, placebo-controlled, cross-over designed trial of L-arginine and placebo. We will compare 25 subjects with "low" FeNO < 20 with 25 subjects that have "high" FeNO > 25 ppb.

Inclusion Criteria:

• Adults >18 yrs of age
• Diagnosis of severe asthma based on American Thoracic Society Workshop definition (Am J Respir Crit Care Med 2000; 162:2341)
• Active asthma medications of high dose inhaled corticosteroids plus long-acting beta agonist
• History of recent asthma exacerbations or Asthma control test score < 20/25

Exclusion Criteria:

• <19 yrs of age
• Forced expiratory volume 1sec <30% predicted
• Pregnant or nursing women
• Current smokers or smoking history > 15 pack years
• Actively taking or known intolerance to L-arginine