Study to Improve Deployment Related Asthma by Using L-Citrulline Supplementation

Study Overview
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Brief Summary
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Service men and women returning from deployment are significantly more likely to develop asthma and severe respiratory symptoms from airway obstruction. Why this happens is not well known, but exposure to diesel, burn pits, biomass smoke, and sandstorms are thought to play a role. Ultimately, patients with deployment related asthma develop a complex airway disease that does not respond well to standard asthma medications. Therefore, it is imperative that safe and affordable treatments that could improve quality of life and symptoms are studied. It has been previously shown that adult patients with poorly controlled asthma have an abnormal regulation of an amino acid called L-arginine and airway nitric oxide (FeNO), a gaseous molecule normally produced in the airways of healthy people. In healthy people, nitric oxide is present in amounts that help keep the airways open. However, in some patients with asthma, nitric oxide and L-arginine are often low. The investigators' preliminary data in obese asthmatics show that L-citrulline, which is an amino acid that can be metabolized into L-arginine, improved lung function and asthma control, while increasing the levels of FeNO. This is potentially shifting the paradigm in how investigators think of asthma management, as rising FeNO is often thought of being a bad sign. Based on this, the study investigators hypothesize that an L-citrulline-based drug strategy will normalize nitric oxide metabolism, suppress oxidative inflammatory responses and improve airway function in obese patients with asthma. The study proposal presents a clinical trial approach to treat deployment related asthma patients using L-citrulline as an add-on therapy to improve asthma control. If this confirms the investigators' previous study results, the investigators will be in route for developing the only precision-based therapy available to treat this asthma phenotype. These study results will potentially show that L-citrulline is a safe, tolerable medication that can make a significant impact on the respiratory health of a large segment of our active and veteran population at a reasonable cost.

Official Title
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Study to Improve dEployment Related Asthma by Using L-citrulline Supplementation (SEALS)

Conditions
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Post Deployment Related Asthma, Asthma

Intervention / Treatment
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* Drug: L-citrulline
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adequate completion of informed consent process with written documentation Male and female patients, 18 - 70 years old, inclusive Meets criteria for deployment related asthma or DRA (New onset of persistent respiratory symptoms of cough, dyspnea, wheezing and/or chest tightness during or after post-9/11/2001 military deployment to Southwest Asia, accompanied by a post-bronchodilator increase in FEV1 ≥ 12% and an increase in FEV1 ≥ 200 milliliters on pulmonary function testing and/or methacholine challenge showing airways hyperresponsiveness with a 20 percent drop in FEV1 (PC[-20] FEV1) ≤ 16 mg/mL. ) Historical results from previous studies or documented in clinical records within the last 24 months are acceptable alternatives Able to perform reproducible spirometry according to ATS criteria All racial/ethnic backgrounds may participate Smoking tobacco history ≤15 pack years and no smoking in the last 3 months Suboptimal asthma control at baseline (ACQ ≥ 0.5 or ACT<19) Exclusion Criteria: Respiratory tract infection within the 4 weeks prior to Visit 0 Pulmonary-related ER visit within the 4 weeks prior to Visit 0 Oral or systemic corticosteroid burst (for any indication) within the 4 weeks prior to Visit 0. One-time doses, such as intra-articular injections into a shoulder or knee joint, require a 2-week washout prior to Visit 0 Significant concomitant medical illness at the discretion of the PI, including (but not limited to) heart disease, cancer, uncontrolled diabetes, other chronic lung diseases Chronic renal failure (creatinine > 2.0) at Visit 0 (Associated with higher ADMA levels) Positive urine (or serum) pregnancy test at Visit 0 or at any time during the study Intolerance or allergy to L-arginine or L-citrulline Concomitant use of PDE5 drugs or oral mononitrates Unable or unlikely to complete study assessments in the opinion of the Investigator Study intervention poses undue risk to patient in the opinion of the Investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: L-citrulline<br>L-citrulline with a dose of 15 g/day will be administered in powder form that is mixed with water and taken orally, continuously and daily for at least 7 weeks. Dispensed at Visits 0a/1. Washout period of 4 to 6 weeks and then enter crossover phase of an additional 7 weeks. Drug will be dispensed at Visit 4. | Drug: L-citrulline<br>* 7 weeks of treatment with 15 g/day of orally administered (powder form mixed with water) L-citrulline<br>|
| Placebo Comparator: Matching Placebo<br>Administered in powder form that is mixed with water and taken orally, continuously, and daily for at least 7 weeks. Dispensed at Visits 0a/. Washout period of 4 to 6 weeks and then enter crossover phase of an additional 7 weeks. Drug will be dispensed at Visit 4. | Drug: Placebo<br>* 7 weeks of treatment with orally administered matching placebo (to 15 g/day of L-citrulline)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Asthma Control Questionnaire | To determine L-citrulline efficacy, reduction in questionnaire scores determined | Through study completion, up to 22 weeks | 
| Change in FeNO values | To determine L-citrulline efficacy, increase in FeNO values determined | Through study completion, up to 22 weeks |