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

Nicholas Kenyon

Status and phase: Completed; Phase 2

Conditions: Inflammation; Asthma

Treatments: Drug: L-Arginine; Drug: Placebo

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT01841281

R01HL105573 (U.S. NIH Grant/Contract)

UCD105573 (Other Identifier)

271515

Details and patient eligibility

About

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.

Full 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.

Enrollment: 54 patients

Sex: All

Ages: 19+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Double Blind

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54 participants in 2 patient groups

Low Exhaled Nitric Oxide (NO)

Active Comparator group

Description:

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.

Treatment:

Drug: Placebo

Drug: L-Arginine

High Exhaled Nitric Oxide (NO)

Active Comparator group

Description:

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.

Treatment:

Drug: Placebo

Drug: L-Arginine