Asthma, Inflammation
Conditions
Keywords
Asthma, Severe Asthma
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.
Interventions
DRUGL-Arginine
L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles.
DRUGPlacebo
Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Nicholas Kenyon
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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%. |
Countries
United States
Participant flow
Recruitment details
54 subjects consented and enrolled for the trial, but n=50 were randomized as n=4 participants declined to participate.
Pre-assignment details
Participants were assigned to low or high exhaled nitric oxide groups based on their levels at time of Visit 1.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Baseline characteristics at the enrollment | 24 |
| 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.
Baseline characteristics at the enrollment | 26 |
| Total | 50 |
Baseline characteristics
| Characteristic | Low Exhaled Nitric Oxide (NO) | High Exhaled Nitric Oxide (NO) | Total |
|---|---|---|---|
| Age, Continuous | 56.5 years STANDARD_DEVIATION 11.9 | 52.4 years STANDARD_DEVIATION 14.3 | 54.3 years STANDARD_DEVIATION 13.2 |
| Asthma Control Test Score | 16.0 units on a scale STANDARD_DEVIATION 4.6 | 16.1 units on a scale STANDARD_DEVIATION 5.5 | 16.1 units on a scale STANDARD_DEVIATION 5 |
| Race/Ethnicity, Customized Non-White | 5 Participants | 6 Participants | 11 Participants |
| Race/Ethnicity, Customized White | 19 Participants | 20 Participants | 39 Participants |
| Sex: Female, Male Female | 17 Participants | 21 Participants | 38 Participants |
| Sex: Female, Male Male | 7 Participants | 5 Participants | 12 Participants |
| Spirometry FEV1 | 1.8 Litters STANDARD_DEVIATION 0.7 | 2.2 Litters STANDARD_DEVIATION 0.9 | 2 Litters STANDARD_DEVIATION 0.8 |
| Spirometry FVC | 2.6 Litters STANDARD_DEVIATION 0.9 | 2.8 Litters STANDARD_DEVIATION 1.1 | 2.7 Litters STANDARD_DEVIATION 1 |
| Weight | 94.8 Kg STANDARD_DEVIATION 20.5 | 85.6 Kg STANDARD_DEVIATION 27.3 | 90.0 Kg STANDARD_DEVIATION 24.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 13 | 0 / 19 | 0 / 10 | 0 / 9 | 0 / 12 | 0 / 14 | 0 / 22 | 0 / 16 | 0 / 6 |
| other Total, other adverse events | 0 / 11 | 1 / 13 | 0 / 19 | 1 / 10 | 0 / 9 | 1 / 12 | 0 / 14 | 0 / 22 | 0 / 16 | 0 / 6 |
| serious Total, serious adverse events | 0 / 11 | 0 / 13 | 0 / 19 | 0 / 10 | 0 / 9 | 2 / 12 | 1 / 14 | 1 / 22 | 0 / 16 | 0 / 6 |
Outcome results
Primary
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).
Time frame: 3 month
Population: Several patients dropped after the first intervention
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo | Number of Acute Exacerbation at 3 Months | First Intervention | 2.7 Events | Standard Deviation 2 |
| Low Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo | Number of Acute Exacerbation at 3 Months | Second Intervention | 2.1 Events | Standard Deviation 1.4 |
| High Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo | Number of Acute Exacerbation at 3 Months | First Intervention | 2.2 Events | Standard Deviation 2.2 |
| High Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo | Number of Acute Exacerbation at 3 Months | Second Intervention | 2.7 Events | Standard Deviation 4.2 |
| Low Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine | Number of Acute Exacerbation at 3 Months | Second Intervention | 2.2 Events | Standard Deviation 2.2 |
| Low Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine | Number of Acute Exacerbation at 3 Months | First Intervention | 1.6 Events | Standard Deviation 1.8 |
| High Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine | Number of Acute Exacerbation at 3 Months | First Intervention | 2.2 Events | Standard Deviation 3 |
| High Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine | Number of Acute Exacerbation at 3 Months | Second Intervention | 2.2 Events | Standard Deviation 2.8 |
p-value: 0.78testing for interaction term
Secondary
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%.
Time frame: 3 month
Population: Several patients dropped after the first intervention
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo | Forced Expiratory Volume in One Second (FEV1)/Forced Vital Capacity (FVC) | Second Intervention | 0.01 ratio | Standard Deviation 0.04 |
| Low Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo | Forced Expiratory Volume in One Second (FEV1)/Forced Vital Capacity (FVC) | First Intervention | -0.02 ratio | Standard Deviation 0.05 |
| High Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo | Forced Expiratory Volume in One Second (FEV1)/Forced Vital Capacity (FVC) | Second Intervention | 0.13 ratio | Standard Deviation 0.06 |
| High Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo | Forced Expiratory Volume in One Second (FEV1)/Forced Vital Capacity (FVC) | First Intervention | 0.01 ratio | Standard Deviation 0.06 |
| Low Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine | Forced Expiratory Volume in One Second (FEV1)/Forced Vital Capacity (FVC) | First Intervention | 0.03 ratio | Standard Deviation 0.13 |
| Low Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine | Forced Expiratory Volume in One Second (FEV1)/Forced Vital Capacity (FVC) | Second Intervention | 0.003 ratio | Standard Deviation 0.06 |
| High Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine | Forced Expiratory Volume in One Second (FEV1)/Forced Vital Capacity (FVC) | Second Intervention | -0.04 ratio | Standard Deviation 0.1 |
| High Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine | Forced Expiratory Volume in One Second (FEV1)/Forced Vital Capacity (FVC) | First Intervention | -0.03 ratio | Standard Deviation 0.04 |
Comparison: The treatment effect was tested as an interaction term between treatment and FeNO. The null hypothesis is the effect of treatment is stratified by the FeNO status. We used a regression model instead of t-test or Wilcoxon signed-rank test in order to control period and carry-over effect which is common in a cross-over study designp-value: 0.09testing for interaction term