What side effects are associated with this type of intervention?

Common treatments for asthma include inhaled corticosteroids, long-acting beta-agonists (LABAs), leukotriene modifiers, and biologics. Inhaled corticosteroids can cause oral thrush and hoarseness. LABAs may increase the risk of severe asthma symptoms if not used with corticosteroids. Leukotriene modifiers can lead to liver enzyme elevation and neuropsychiatric events. Biologics, such as monoclonal antibodies, may cause injection site reactions and an increased risk of infections. L-citrulline, which increases L-arginine and FeNO, is being studied for its potential to improve airway function, and it has shown to be safe and tolerable in preliminary studies, with no notable side effects reported.

What prior FDA approvals exist?

FDA-approved treatments for asthma primarily include inhaled corticosteroids (ICS), long-acting beta agonists (LABA), and leukotriene modifiers. Combination therapies such as ICS/LABA are also common. While specific treatments that increase L-arginine and FeNO are not widely mentioned, the focus on improving airway function through anti-inflammatory and bronchodilatory effects is a common theme. The L-citrulline trial represents a novel approach by potentially normalizing nitric oxide metabolism to improve asthma control.

What other types of research exist?

Promising novel alternatives to L-citrulline for asthma patients include biologics such as dupilumab, which targets the IL-4 receptor alpha to reduce inflammation, and tezepelumab, which inhibits thymic stromal lymphopoietin (TSLP) to prevent asthma exacerbations. Additionally, bronchial thermoplasty, a procedure that reduces airway smooth muscle mass, and new small molecule drugs like fevipiprant, a CRTh2 antagonist, are also being explored for their potential to improve airway function and control asthma symptoms.

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L-Citrulline for Asthma (SEALS Trial)

Phase 2

Recruiting

Led By Fernando Holguin, MD, MPH

Research Sponsored by University of Colorado, Denver

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Suboptimal asthma control at baseline (ACQ ≥ 0.5 or ACT<19)

Smoking tobacco history ≤15 pack years and no smoking in the last 3 months

Must not have

Chronic renal failure (creatinine > 2.0) at Visit 0 (Associated with higher ADMA levels)

Concomitant use of PDE5 drugs or oral mononitrates

Timeline

Screening 3 weeks

Treatment Varies

Follow Up through study completion, up to 22 weeks

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Potential side effects may include intolerance reactions similar to allergies due to L-citrulline or digestive issues since it's an amino acid supplement. However, the exact side effects will be monitored as part of the study.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My asthma is not well-controlled.

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

Select...

I am between 18 and 70 years old.

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I have asthma symptoms that started after military service in Southwest Asia post-9/11.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

Select...

My kidney function is impaired with high creatinine levels.

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

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ through study completion, up to 22 weeks

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~through study completion, up to 22 weeks

This trial's timeline: 3 weeks for screening, Varies for treatment, and through study completion, up to 22 weeks for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Change in Asthma Control Questionnaire

Apo-Feno-Micro

Side effects data

From 2019 Phase 3 trial • 189 Patients • NCT02891837

18%

Pyrexia

14%

Pain

13%

Hypertension

12%

Tachycardia

12%

Hypokalaemia

11%

Constipation

11%

Restlessness

Haemoglobin decreased

Pleural effusion

Hypocalcaemia

Tachypnoea

Vomiting

Electrolyte imbalance

Cough

Pulmonary congestion

Hypotension

Metabolic acidosis

Hypomagnesaemia

Stridor

Oligurea

Atelectasis

Leukocytosis

Anaemia

Sinus bradycardia

Diarrhoea

Post procedural haemorrhage

Blood pressure decreased

Coagulation time prolonged

Pulmonary oedema

Haematocrit decreased

Arrhythmia

Ventricular tachycardia

Staphylococcal infection

Cardiac tamponade

Ventricular fibrillation

Leukopenia

Thrombocytopenia

Aortic valve incompetence

Atrioventricular block complete

Nausea

Peripheral swelling

Blood lactic acid increased

C-reactive protein increased

Chylothorax

100%

80%

60%

40%

20%

Study treatment Arm

L-citrulline - All Patients on Mechanical Ventilation for ≤48 Hours

L-citrulline - All Patients

L-citrulline - US Patients on Mechanical Ventilation for >48 Hours

Placebo - All Patients

L-citrulline - US Patients on Mechanical Ventilation for ≤48 Hours

L-citrulline - All Patients on Mechanical Ventilation for >48 Hours

Placebo - All Patients on Mechanical Ventilation for ≤48 Hours

Placebo - US Patients on Mechanical Ventilation for ≤48 Hours

Placebo - All Patients on Mechanical Ventilation for >48 Hours

Placebo - US Patients on Mechanical Ventilation for >48 Hours

Trial Design

2Treatment groups

Experimental Treatment

Placebo Group

Group I: L-citrullineExperimental Treatment1 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 PlaceboPlacebo Group1 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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

L-citrulline

2010

Completed Phase 3

~530

0 / 6Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for asthma include bronchodilators, corticosteroids, and leukotriene modifiers. Bronchodilators, such as beta-agonists, work by relaxing the muscles around the airways, making it easier to breathe. Corticosteroids reduce inflammation in the airways, preventing asthma attacks. Leukotriene modifiers block chemicals that cause inflammation and bronchoconstriction. L-citrulline, an emerging treatment, increases levels of L-arginine and FeNO, which helps to keep airways open and reduce oxidative stress. These mechanisms are crucial for asthma patients as they improve lung function, reduce symptoms, and prevent exacerbations, thereby enhancing overall quality of life.

Managing Asthma in Pregnancy (MAP) trial: FENO levels and childhood asthma.