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

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

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.

Study Overview

• Status: Completed
• Conditions: Inflammation; Asthma
• Intervention / Treatment: Drug: L-Arginine; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Sacramento, California, United States, 95817
      • UC Davis CTSC Clinical Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Low Exhaled Nitric Oxide (NO); 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; L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles.; Other Names: Arginine 1000 (Jarrow Formulas, Los Angeles, CA); Drug: Placebo; Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.
Active Comparator: High Exhaled Nitric Oxide (NO); 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; L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles.; Other Names: Arginine 1000 (Jarrow Formulas, Los Angeles, CA); Drug: Placebo; Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Nicholas Kenyon
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Nicholas Kenyon, MD,MS, Univ. of California, Davis

Publications and helpful links

General Publications

• Liao SY, Showalter MR, Linderholm AL, Franzi L, Kivler C, Li Y, Sa MR, Kons ZA, Fiehn O, Qi L, Zeki AA, Kenyon NJ. l-Arginine supplementation in severe asthma. JCI Insight. 2020 Jul 9;5(13):e137777. doi: 10.1172/jci.insight.137777.

Study record dates

Study Major Dates

• Study Start: August 1, 2013
• Primary Completion (Actual): August 1, 2018
• Study Completion (Actual): December 1, 2019

Study Registration Dates

• First Submitted: April 23, 2013
• First Submitted That Met QC Criteria: April 25, 2013
• First Posted (Estimate): April 26, 2013

Study Record Updates

• Last Update Posted (Actual): April 21, 2020
• Last Update Submitted That Met QC Criteria: April 20, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Asthma; Severe Asthma
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Inflammation; Asthma
• Other Study ID Numbers: 271515; R01HL105573 (U.S. NIH Grant/Contract); UCD105573 (Other Identifier: UC Davis)