L-Citrulline for Asthma

(SEALS Trial)

Overseen By University of Colorado Asthma and Research Education Team

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Colorado, Denver

Must not be taking: PDE5 drugs, Oral mononitrates

Disqualifiers: Heart disease, Cancer, Uncontrolled diabetes, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 14 weeks

75 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial aims to help service members with asthma that doesn't respond to usual treatments by using L-citrulline. L-citrulline can boost substances in the body that help keep airways open, potentially improving breathing and asthma symptoms. The goal is to find a safe and affordable treatment to enhance the quality of life for these patients.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it mentions that you cannot use certain drugs like PDE5 inhibitors or oral mononitrates. If you have taken oral or systemic corticosteroids recently, you may need a washout period (time without taking these medications) before starting the trial.

How does the drug L-Citrulline differ from other asthma treatments?

L-Citrulline is unique because it helps increase nitric oxide (NO) levels, which are often low in obese asthmatics, improving asthma control and lung function. Unlike other treatments, it works by being converted into L-arginine, which then boosts NO production without being broken down in the liver or intestines, making it more effective in raising NO levels. ^{1 2 3 4 5}

Research Team

Fernando Holguin, MD, MPH

Principal Investigator

University of Colorado Denver- Anschutz Medical Campus

Eligibility Criteria

This trial is for military personnel aged 18-70 who developed asthma after deployment post-9/11. Participants must have a history of smoking less than or equal to 15 pack years, no recent smoking, and show signs of suboptimal asthma control. Pregnant individuals, those on recent corticosteroids or with significant illnesses like heart disease or uncontrolled diabetes are excluded.

Inclusion Criteria

My asthma is not well-controlled.

You can do the breathing test in a consistent way as per the guidelines.

I have smoked 15 or fewer pack-years and haven't smoked in the last 3 months.

Exclusion Criteria

I do not have any major health issues like heart disease, uncontrolled diabetes, or other serious conditions.

I have not had a respiratory infection in the last 4 weeks.

I am currently taking medication for erectile dysfunction or heart conditions.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive L-citrulline or placebo for 7 weeks, followed by a washout period and crossover phase for another 7 weeks

14 weeks

Visits at 0a/1 and 4

Washout

Participants undergo a washout period before entering the crossover phase

4-6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• L-citrulline

Trial Overview The study tests if L-citrulline supplementation can improve lung function in patients with deployment-related asthma by increasing airway nitric oxide levels. It's compared against a placebo in a controlled setting to see if it offers an effective add-on therapy for better asthma management.

Participant Groups

Group I: L-citrulline Experimental Treatment 1 Intervention

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.

Group II: Matching Placebo Placebo Group 1 Intervention

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.

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

National Jewish Health

Collaborator

Trials

145

Recruited

318,000+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Findings from Research

In a study of 43 patients with urea cycle disorders, l-citrulline treatment significantly reduced ammonia levels by an average of 44.3 μmol/L, indicating its efficacy in managing this condition.

The treatment also led to improved weight gain and increased protein intake among patients, suggesting that l-citrulline should be considered a standard therapy for conditions like ornithine transcarbamylase deficiency and carbamoyl phosphate synthetase I deficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Citrulline for urea cycle disorders in Japan. Tanaka, K., Nakamura, K., Matsumoto, S., et al.[2017]

L-citrulline is a more effective supplement than L-arginine for increasing nitric oxide (NO) production because it bypasses intestinal and liver metabolism, allowing for better conversion to L-arginine in the body.

Unlike L-arginine, L-citrulline does not increase arginase activity, which can limit the effectiveness of L-arginine therapy, making L-citrulline a promising option for improving cardiovascular function in diseases related to L-arginine deficiencies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic use of citrulline in cardiovascular disease. Romero, MJ., Platt, DH., Caldwell, RB., et al.[2022]

In a pilot study involving 41 obese asthmatics, a 2-week treatment with 15 g/d L-citrulline significantly increased fractional excretion of nitric oxide (FeNO) and improved asthma control, indicating potential benefits for airway function.

The treatment led to notable improvements in lung function, particularly in patients with late-onset asthma and females, suggesting that L-citrulline may be a promising intervention for specific subgroups of asthmatics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

L-Citrulline increases nitric oxide and improves control in obese asthmatics. Holguin, F., Grasemann, H., Sharma, S., et al.[2020]

In children with well-controlled asthma, L-arginine levels were significantly lower compared to healthy children, while levels of its metabolic products, L-citrulline and L-ornithine, were increased, indicating altered metabolism of L-arginine in these patients.

The study suggests that understanding L-arginine metabolism could be crucial for managing asthma in children and may lead to new therapeutic strategies, as L-arginine is essential for their growth and development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Altered L-arginine metabolism in children with controlled asthma. Kraj, L., Krawiec, M., Koter, M., et al.[2016]

L-citrulline (L-CIT) effectively reduced lung inflammation and oxidative stress in a rat model of neonatal lung injury, suggesting its potential to protect against bronchopulmonary dysplasia (BPD).

The study demonstrated that L-CIT improved mitochondrial health and modulated key signaling pathways involved in inflammation and oxidative stress, indicating its mechanism of action may help mitigate the progression of BPD in premature infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

L-citrulline attenuates lipopolysaccharide-induced inflammatory lung injury in neonatal rats. Ivanovski, N., Wang, H., Tran, H., et al.[2023]

References

1. Australia pubmed.ncbi.nlm.nih.gov

Citrulline for urea cycle disorders in Japan. [2017]

2. United States pubmed.ncbi.nlm.nih.gov

Therapeutic use of citrulline in cardiovascular disease. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

L-Citrulline increases nitric oxide and improves control in obese asthmatics. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Altered L-arginine metabolism in children with controlled asthma. [2016]

5. United States pubmed.ncbi.nlm.nih.gov

L-citrulline attenuates lipopolysaccharide-induced inflammatory lung injury in neonatal rats. [2023]