Effects of L-arginine Supplementation in Adults With Moderate to Severe Asthma

Study Overview
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Brief Summary
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Nitric oxide is an important marker of airway inflammation in asthma. Nitric oxide may have a protective role in patients with moderate to severe asthma. The investigators believe that a natural amino acid, L-arginine, that augments nitric oxide levels can decrease asthma exacerbations and improve the asthma care of moderate to severe asthma patients. This study is a randomized, placebo controlled trial in which subjects will receive either 3 months of L-arginine supplementation or a placebo. The investigators will monitor subjects' symptoms, the number of asthma exacerbations, and lung function. In addition, we will draw blood, obtain induced sputum samples and measure exhaled breath nitric oxide levels at each monthly visit.

Detailed Description
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The primary objective of this 3 month clinical study is to determine if supplemental L-arginine can decrease the number of asthma exacerbations in patients with severe asthma. L-arginine, a natural amino acid, produces nitric oxide (NO) when it is converted to L-citrulline in the presence of the nitric oxide synthase enzymes. We and others have found that NO can protect against allergic airway inflammation, airway hyperresponsiveness and airway fibrosis in various animal models. In addition, we have found that arginase I expression correlates strongly with the lymphocyte and eosinophil influx into the lung and this enzyme may regulate the airway inflammatory response. Our central hypothesis is that L-arginine will increase NO levels in the lung and decrease the number of acute exacerbations of asthma. It may do this by either decreasing the number of Th2 lymphocytes or down-regulating arginase I expression or both. Our specific aims are, therefore, To test the hypothesis, in a randomized, double-blinded, placebo controlled trial, that 3 months of L-arginine supplementation will decrease the number of acute asthma exacerbations in severe asthmatic patients, To determine whether L-arginine decreases the ratio of peripheral blood Th2 to Th1 lymphocytes and To determine whether L-arginine will modulate serum arginase I/II levels and their downstream products. Patients will be recruited primarily from the UC Davis Asthma Network (UCAN) clinics, which focus on the care of severe asthmatics, and the study will be performed at the UC Davis/VA General Clinical Research Center.

Official Title
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Phase 2 Study: GCRC: Effects of L-arginine Supplementation on Exhaled Nitric Oxide and Clinical Exacerbations in Adults With Moderate to Severe Asthma

Conditions
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Asthma

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: Moderate to severe persistent asthma Subject is stable on same asthma medications for at least one month If the subject is a woman of child-bearing age, a negative pregnancy test Exclusion Criteria: Less than 18 yrs/ age Baseline Forced Expiratory Volume in 1 second (FEV1) <40% predicted Known or suspected allergy to L-arginine Pregnant women, nursing women, or women actively trying to achieve pregnancy Current smokers Subjects with more than a 15 pack-year history of smoking

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arginine<br>Enrolled subjects will take L-arginine orally, at 0.1 g/kg/day. Subjects will take three to four 1 g capsules (based on weight) of L-arginine twice daily for three months. L-arginine capsules were obtained from Jarrow Pharmaceuticals. | Drug: L-arginine<br>* subjects will take matching 0.01 g/kg/day of L-arginine in divided doses for thre months.<br>* Other names: Arginine 1000;|
| Placebo Comparator: Placebo<br>Enrolled subjects took three to four placebo capsules that matched color and size of the intervention twice daily for three months. Matching placebo capsules were obtained from Jarrow Pharmaceuticals. | Drug: Placebo<br>* Placebo tablets that match the L-arginine intervention tablets will be given for three months<br>* Other names: Matching placebo tablets;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Asthma Exacerbations in Three Months | Asthma exacerbation is a composite endpoint. An asthma exacerbation is defined as any of the following: a) a drop in the morning peak expiratory flow rate (PEF) >30% from baseline on 2 consecutive days, b) a need for initiation of or increased dose of inhaled corticosteroids, or the c) doubling of short-acting rescue β-agonist drug use (e.g.Albuterol) on two consecutive days. Any one of these three counts as one asthma exacerbation. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| L-arginine Serum Concentration |  | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Airway Inflammation, Moderate persistent asthma, Severe Persistent Asthma