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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
54
L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles.
Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.
UC Davis CTSC Clinical Research Center
Sacramento, California, United States
Number of Acute Exacerbation at 3 Months
The primary endpoint of the study is the number of acute moderate exacerbations at 3 months. A moderate asthma exacerbation is defined as any of the following: 1) A drop in morning peak flow rate (PEFR) \>30% from baseline on 2 consecutive days (1 event), 2) Need for initiation of oral steroids or am increased dose of inhaled corticosteroids on any two consecutive days (1 event), 3) Doubling of short-acting β-agonist use (e.g. number of puffs of albuterol) per day for 2 consecutive days (1 event).
Time frame: 3 month
Forced Expiratory Volume in One Second (FEV1)/Forced Vital Capacity (FVC)
The secondary endpoint is the change in FEV1/FVC ratio at 3 months. This calcuation is a ratio between the volume of breath exhaled in the first second divided by the total amount of breath exhaled in a vital capacity maneuver. A normal ratio is usually \> 70%.
Time frame: 3 month
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