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

NCT ID: NCT01841281

Last Updated: 2020-04-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 54 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-08-31
• Study Completion Date: 2019-12-31

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.

Conditions

Asthma; Inflammation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

L-Arginine

Intervention Type: DRUG

L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles.

Placebo

Intervention Type: DRUG

Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.

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.

Group Type: ACTIVE_COMPARATOR

L-Arginine

Intervention Type: DRUG

L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles.

Placebo

Intervention Type: DRUG

Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.

Interventions

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.

Intervention Type: DRUG

Placebo

Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.

Intervention Type: DRUG

Other Intervention Names

Arginine 1000 (Jarrow Formulas, Los Angeles, CA)

Eligibility Criteria

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

• Minimum Eligible Age: 19 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Nicholas Kenyon

OTHER

Sponsor Role: lead

Responsible Party

Nicholas Kenyon

Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Nicholas Kenyon, MD,MS

Role: PRINCIPAL_INVESTIGATOR

Univ. of California, Davis

Locations

UC Davis CTSC Clinical Research Center

Sacramento, California, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 32497023 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

R01HL105573

Identifier Type: NIH

Identifier Source: secondary_id

View Link

UCD105573

Identifier Type: OTHER

Identifier Source: secondary_id

271515

Identifier Type: -

Identifier Source: org_study_id