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

• ClinicalTrials.gov Identifier: NCT05259904
• Recruitment Status: Recruiting
• First Posted: March 2, 2022
• Last Update Posted: April 6, 2023
• Sponsor: University of Colorado, Denver
• Collaborators: National Jewish Health; United States Department of Defense
• Information provided by (Responsible Party): University of Colorado, Denver

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Post Deployment Related Asthma; Asthma	Drug: L-citrulline; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 75 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Study to Improve dEployment Related Asthma by Using L-citrulline Supplementation (SEALS)
• Actual Study Start Date: March 8, 2023
• Estimated Primary Completion Date: October 2028
• Estimated Study Completion Date: October 2028

Arms and Interventions

Arm	Intervention/treatment
Experimental: L-citrulline; 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; 7 weeks of treatment with 15 g/day of orally administered (powder form mixed with water) L-citrulline
Placebo Comparator: Matching Placebo; 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; 7 weeks of treatment with orally administered matching placebo (to 15 g/day of L-citrulline)

Outcome Measures

Primary Outcome Measures :

1. Change in Asthma Control Questionnaire [ Time Frame: Through study completion, up to 22 weeks ]
   To determine L-citrulline efficacy, reduction in questionnaire scores determined
2. Change in FeNO values [ Time Frame: Through study completion, up to 22 weeks ]
   To determine L-citrulline efficacy, increase in FeNO values determined

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: University of Colorado Asthma and Research Education Team; 1-844-365-0852; asthmaresearh@ucdenver.edu

Locations

United States, Colorado

National Jewish Health; Recruiting

Denver, Colorado, United States, 80206

Contact: NJH SEALS Team 303-398-1748 DeploymentLungRes@njhealth.org

Principal Investigator: Cecile Rose, MD, MPH

Sponsors and Collaborators

University of Colorado, Denver

National Jewish Health

United States Department of Defense

Investigators

• Principal Investigator: Fernando Holguin, MD, MPH; University of Colorado Denver- Anschutz Medical Campus

More Information

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT05259904
• Other Study ID Numbers: 21-2804; W81XWH2110677 ( Other Grant/Funding Number: Department of Defense/USAMRAA ); 21-2804 ( Other Identifier: COMIRB ); E02466 ( Other Identifier: USAMRDC ORP HRPO )
• First Posted: March 2, 2022
• Last Update Posted: April 6, 2023
• Last Verified: April 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Asthma; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases