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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Asthma, Inflammation

Intervention / Treatment
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* Drug: L-Arginine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 19 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
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low Exhaled Nitric Oxide (NO)<br>Subjects with a baseline exhaled NO level less than or equal to 20 ppb will be enrolled in the Low Exhaled Nitric Oxide arm. All subjects will receive L-arginine and placebo in this cross-over design study. | Drug: L-Arginine<br>* L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles.<br>* Other names: Arginine 1000 (Jarrow Formulas, Los Angeles, CA);Drug: Placebo<br>* Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.<br>|
| Active Comparator: High Exhaled Nitric Oxide (NO)<br>Subjects with a baseline exhaled NO level greater than or equal to 25 ppb will be enrolled in the High Exhaled Nitric Oxide arm. All subjects will receive L-arginine and placebo in this cross-over design study. | Drug: L-Arginine<br>* L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles.<br>* Other names: Arginine 1000 (Jarrow Formulas, Los Angeles, CA);Drug: Placebo<br>* Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 3 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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%. | 3 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Severe Asthma