Asthma
Conditions
Keywords
Airway Inflammation, Moderate persistent asthma, Severe Persistent Asthma
Brief summary
Nitric oxide is an important marker of airway inflammation in asthma. Nitric oxide may have a protective role in patients with moderate to severe asthma. The investigators believe that a natural amino acid, L-arginine, that augments nitric oxide levels can decrease asthma exacerbations and improve the asthma care of moderate to severe asthma patients. This study is a randomized, placebo controlled trial in which subjects will receive either 3 months of L-arginine supplementation or a placebo. The investigators will monitor subjects' symptoms, the number of asthma exacerbations, and lung function. In addition, we will draw blood, obtain induced sputum samples and measure exhaled breath nitric oxide levels at each monthly visit.
Detailed description
The primary objective of this 3 month clinical study is to determine if supplemental L-arginine can decrease the number of asthma exacerbations in patients with severe asthma. L-arginine, a natural amino acid, produces nitric oxide (NO) when it is converted to L-citrulline in the presence of the nitric oxide synthase enzymes. We and others have found that NO can protect against allergic airway inflammation, airway hyperresponsiveness and airway fibrosis in various animal models. In addition, we have found that arginase I expression correlates strongly with the lymphocyte and eosinophil influx into the lung and this enzyme may regulate the airway inflammatory response. Our central hypothesis is that L-arginine will increase NO levels in the lung and decrease the number of acute exacerbations of asthma. It may do this by either decreasing the number of Th2 lymphocytes or down-regulating arginase I expression or both. Our specific aims are, therefore, 1. To test the hypothesis, in a randomized, double-blinded, placebo controlled trial, that 3 months of L-arginine supplementation will decrease the number of acute asthma exacerbations in severe asthmatic patients, 2. To determine whether L-arginine decreases the ratio of peripheral blood Th2 to Th1 lymphocytes and 3. To determine whether L-arginine will modulate serum arginase I/II levels and their downstream products. Patients will be recruited primarily from the UC Davis Asthma Network (UCAN) clinics, which focus on the care of severe asthmatics, and the study will be performed at the UC Davis/VA General Clinical Research Center.
Interventions
DRUGL-arginine
subjects will take matching 0.01 g/kg/day of L-arginine in divided doses for thre months.
DRUGPlacebo
Placebo tablets that match the L-arginine intervention tablets will be given for three months
Sponsors
National Institutes of Health (NIH)
National Center for Research Resources (NCRR)
University of California, Davis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Moderate to severe persistent asthma * Subject is stable on same asthma medications for at least one month * If the subject is a woman of child-bearing age, a negative pregnancy test
Exclusion criteria
* Less than 18 yrs/ age * Baseline Forced Expiratory Volume in 1 second (FEV1) \<40% predicted * Known or suspected allergy to L-arginine * Pregnant women, nursing women, or women actively trying to achieve pregnancy * Current smokers * Subjects with more than a 15 pack-year history of smoking
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Asthma Exacerbations in Three Months | 3 months | Asthma exacerbation is a composite endpoint. An asthma exacerbation is defined as any of the following: a) a drop in the morning peak expiratory flow rate (PEF) \>30% from baseline on 2 consecutive days, b) a need for initiation of or increased dose of inhaled corticosteroids, or the c) doubling of short-acting rescue β-agonist drug use (e.g.Albuterol) on two consecutive days. Any one of these three counts as one asthma exacerbation. |
Secondary
| Measure | Time frame |
|---|---|
| L-arginine Serum Concentration | 90 days |
Countries
United States
Participant flow
Recruitment details
Between 2006-2008, moderate to severe persistent asthma patients, as defined by the NAEPP Expert Panel Reports, were eligible for enrollment \[10\]. Most subjects were recruited from the UC Davis Asthma Network clinics, which are referral clinics for patients with difficult to control asthma.
Pre-assignment details
The randomization process and disbursement of L-arginine (0.05 g/kg twice daily; 6-10 g/day) and placebo were done by the UC Davis Investigational Drug Service.Eligible subjects had documented moderate to severe persistent asthma, were at least 18 years of age, not pregnant, and able to give consent.
Participants by arm
| Arm | Count |
|---|---|
| Arginine 2.3. L-Arginine Intervention The randomization process and disbursement of L-arginine (0.05 g/kg twice daily; 6-10 g/day) and placebo were done by the UC Davis Investigational Drug Service to ensure that both the physician and participant were blinded. The subjects began the study medication on day 0 and continued for 90 days and were asked to discontinue use of any nutritional supplements prior to the start of the study. | 10 |
| Placebo Placebo intervention | 10 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Arginine | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 9 Participants | 18 Participants |
| Age, Continuous | 53.1 years STANDARD_DEVIATION 15.4 | 50.8 years STANDARD_DEVIATION 15.1 | 52.0 years STANDARD_DEVIATION 15.2 |
| Exhaled Nitric oxide | 28.2 ppb (parts per billion) STANDARD_DEVIATION 16.4 | 24.4 ppb (parts per billion) STANDARD_DEVIATION 17.6 | 26.3 ppb (parts per billion) STANDARD_DEVIATION 17 |
| FEV1 Percent Predicted | 75 Percent STANDARD_DEVIATION 17.5 | 70.8 Percent STANDARD_DEVIATION 18.5 | 72.9 Percent STANDARD_DEVIATION 18 |
| Sex: Female, Male Female | 8 Participants | 8 Participants | 16 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 10 | 1 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
Primary
Number of Asthma Exacerbations in Three Months
Asthma exacerbation is a composite endpoint. An asthma exacerbation is defined as any of the following: a) a drop in the morning peak expiratory flow rate (PEF) \>30% from baseline on 2 consecutive days, b) a need for initiation of or increased dose of inhaled corticosteroids, or the c) doubling of short-acting rescue β-agonist drug use (e.g.Albuterol) on two consecutive days. Any one of these three counts as one asthma exacerbation.
Time frame: 3 months
Population: Our original power analysis was based on an expected minor exacerbation rate of 3-4 per month.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arginine | Number of Asthma Exacerbations in Three Months | 30 exacerbations |
| Placebo | Number of Asthma Exacerbations in Three Months | 31 exacerbations |
Secondary
L-arginine Serum Concentration
Time frame: 90 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arginine | L-arginine Serum Concentration | 0.002 pmol/100ul | Standard Error 0.0006 |
| Placebo | L-arginine Serum Concentration | 0.0011 pmol/100ul | Standard Error 0.0002 |