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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests an experimental treatment with L-citrulline, an amino acid, to determine if it can improve breathing in individuals with deployment-related asthma. The trial targets those whose asthma began after exposure to conditions such as diesel fumes or sandstorms during military deployments. Participants will receive either L-citrulline or a placebo (a substance with no active ingredient) to compare effectiveness. Ideal candidates for the trial are those with asthma symptoms, like frequent coughing or wheezing, that do not improve with standard medications. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that L-citrulline is likely to be safe for humans?

Research has shown that L-citrulline is safe and well-tolerated by people with asthma. This amino acid has demonstrated promising results in earlier studies. For instance, one study found that L-citrulline improved asthma control and lung function. It also increased nitric oxide levels in the airways, helping to keep them open. Notably, L-citrulline has been used in much higher doses without causing significant side effects, suggesting it could be a safe option for treating asthma. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

L-citrulline is unique because it offers a new approach for managing asthma by potentially improving nitric oxide production, which can help relax and widen airways, enhancing breathing. Unlike standard asthma treatments like inhaled corticosteroids and bronchodilators that mainly focus on reducing inflammation and opening airways, L-citrulline targets a biochemical pathway that could support respiratory health from a different angle. Researchers are excited about L-citrulline's potential to complement existing therapies, offering a novel and natural alternative that could benefit those who don't find sufficient relief with current options.

What evidence suggests that L-citrulline might be an effective treatment for asthma?

Research has shown that L-citrulline can help people with asthma breathe better by increasing nitric oxide in the airways. Some people with asthma have low levels of this gas, making it hard to breathe. Studies have found that taking L-citrulline improved lung function and asthma control, especially in those who are overweight. L-citrulline converts into L-arginine, which helps increase nitric oxide. In this trial, participants will receive either L-citrulline or a matching placebo to evaluate its effectiveness for those whose asthma doesn't improve with standard medications. ^{1 3 4 6 7}

Who Is on the Research Team?

Fernando Holguin, MD, MPH

Principal Investigator

University of Colorado Denver- Anschutz Medical Campus

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6975256/

L-Citrulline increases nitric oxide and improves control in ... Short-term L-citrulline treatment improved asthma control and FeNO levels in obese asthmatics with low or normal FeNO. Larger FEV1 increments were observed in ...

2. insight.jci.org insight.jci.org/articles/view/137777

l-Arginine supplementation in severe asthma A recent clinical trial of l-citrulline supplementation in individuals with asthma found that l-citrulline increased FeNO and modestly improved forced ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02943161

NCT02943161 | Asthma L-Citrulline Pilot Study In this pilot study subjects with asthma that have an increased body mass index compatible with being obese, will be invited to participate in a short open- ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0014299906007795

Role of the l-citrulline/l-arginine cycle in iNANC nerve ... Remarkably, the impaired iNANC relaxation after the early asthmatic reaction was restored by l-citrulline.

5. researchstudies.cuanschutz.edu researchstudies.cuanschutz.edu/Study/19-0219

Find a Research Study 1. Determine if L-citrulline supplementation improves asthma control and increases FeNO (co-primary outcomes). Secondary outcomes will include changes in plasma ...

6. bmjopenrespres.bmj.com bmjopenrespres.bmj.com/content/10/1/e001683

Phenotypic characteristics of asthma and morbidity are ... L-citrulline supplementation can improve asthma control and lung function while augmenting exhaled nitric oxide (NO). From these and other ...

7. respiratory-research.biomedcentral.com respiratory-research.biomedcentral.com/articles/10.1186/1465-9921-13-68

L-citrulline supplementation reverses the impaired airway ... L-citrulline has been shown to restore impaired relaxation of airways after early asthmatic reaction [27].