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

Phase 2

Completed

Conditions: Asthma
Inflammation

Interventions: Drug: L-Arginine
Drug: Placebo

Registration Number: NCT01841281

Lead Sponsor: Nicholas Kenyon

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 54

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Low Exhaled Nitric Oxide (NO)	Placebo	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.
High Exhaled Nitric Oxide (NO)	Placebo	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.
Low Exhaled Nitric Oxide (NO)	L-Arginine	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.
High Exhaled Nitric Oxide (NO)	L-Arginine	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.

Primary Outcome Measures

Name	Time	Method
Number of Acute Exacerbation at 3 Months	3 month	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).

Secondary Outcome Measures

Name	Time	Method
Forced Expiratory Volume in One Second (FEV1)/Forced Vital Capacity (FVC)	3 month	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%.