Oral L-Citrulline for Bronchopulmonary Dysplasia and Necrotizing Enterocolitis

Overseen By Rachana Patel, MSc, CCRP

Age: < 18

Sex: Any

Trial Phase: Academic

Sponsor: The Hospital for Sick Children

Disqualifiers: Congenital heart disease, Sepsis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 5 years

60 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether participants need to stop taking their current medications. It's best to discuss this with the study team or your doctor.

What data supports the effectiveness of the drug L-Citrulline for treating bronchopulmonary dysplasia and necrotizing enterocolitis?

Research shows that L-Citrulline can reduce lung inflammation and improve lung development in newborn rats with conditions similar to bronchopulmonary dysplasia. Additionally, a case report suggests that L-Citrulline may help reduce chronic pulmonary hypertension in infants with severe bronchopulmonary dysplasia. ^{1 2 3 4 5}

How is the drug L-Citrulline unique in treating bronchopulmonary dysplasia and necrotizing enterocolitis?

L-Citrulline is unique because it helps reduce inflammation and oxidative stress in the lungs, promoting better lung and blood vessel development in conditions like bronchopulmonary dysplasia. It also increases levels of important molecules like L-arginine, which are crucial for lung health, making it a novel alternative to inhaled nitric oxide (iNO) for preventing lung injury in newborns. ^{1 2 3 4 6}

What is the purpose of this trial?

The purpose of this study is to evaluate the safety and explore the PK/PD of L-CIT supplementation in preterm infants to prevent the development of inflammatory pathways initiated by low levels of plasma CIT, specifically in preterm infants with post surgical NEC and BPD±PH.

Research Team

Estelle Gauda, MD

Principal Investigator

Division Head, Division of Neonatology

Eligibility Criteria

This trial is for preterm infants born at or before 30 weeks, currently older than 34 weeks post-menstrual age. It's specifically for those with Bronchopulmonary Dysplasia (BPD) and/or Pulmonary Hypertension (PH), who need breathing support. Infants must have a Respiratory Severity Score (RSS) over 2 and be on ventilation more than half the day.

Inclusion Criteria

My baby is at least 34 weeks in adjusted age since conception.

My baby has heart issues related to lung problems.

You need to give written permission (or have a guardian do it for you).

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral L-Citrulline supplementation at varying dose levels to evaluate safety and pharmacokinetics/pharmacodynamics

5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of BPD severity, postnatal steroid use, and other secondary outcomes

5 years

Treatment Details

Interventions

• L-Citrulline

Trial Overview The study tests L-Citrulline supplementation in these infants to prevent inflammation that can lead to severe lung conditions like BPD±PH and intestinal issues like Necrotizing Enterocolitis (NEC). The safety of this treatment and how it affects the body will be closely monitored.

Participant Groups

Group I: Surgical NEC Experimental Treatment 1 Intervention

Arm 2: sNEC A total of 18-36 infants with Stage III NEC; 6-12 at each dose level of oral dosage form of L-Citrulline. (75, 150 or 225 mg/kg/day divided q6 hours) Dose Level 1 = 75 mg/kg/day Dose Level 2 = 150 mg/kg/day Dose Level 3 = 225 mg/kg/day

Group II: BPD±PH Experimental Treatment 1 Intervention

Arm 1: BPD±PH Total of 12-24 infants; 6-12 at each dose level of oral dosage form of L-Citrulline. (300 or 500 mg/kg/day divided q6 hours). Dose Level 1 = 300 mg/kg/day Dose Level 2 = 500 mg/kg/day

L-Citrulline is already approved in United States, European Union for the following indications:

Approved in United States as L-citrulline for:

• Nutritional supplement

Approved in European Union as L-citrulline for:

• Nutritional supplement

Who Is Running the Clinical Trial?

The Hospital for Sick Children

Lead Sponsor

Trials

724

Recruited

6,969,000+

Findings from Research

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]

An infant diagnosed with neonatal citrullinaemia received early intervention starting on day 1 of life, which included a low-protein diet and oral supplements.

At 3 years of age, the infant showed normal growth and satisfactory psychomotor development, suggesting that the combination of dietary management and supplements, particularly carnitine, contributed to this positive outcome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neonatal citrullinaemia with satisfactory mental development. Sanjurjo, P., Rodríguez-Soriano, J., Vallo, A., et al.[2019]

Oral L-citrulline supplementation (150 mg/kg/day) in a premature infant with severe bronchopulmonary dysplasia and chronic pulmonary hypertension led to significant improvements, including successful weaning from mechanical ventilation within three weeks.

The treatment resulted in a notable decrease in plasma brain natriuretic peptide levels, indicating reduced right ventricle dysfunction, and allowed the patient to maintain lower oxygen requirements at discharge.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

L-citrulline supplementation in the treatment of pulmonary hypertension associated with bronchopulmonary dysplasia in preterm infant: A case report. Lauterbach, R., Pawlik, D., Lauterbach, JP.[2022]

L-citrulline supplementation in newborn rats exposed to high oxygen levels significantly improved lung health by preserving alveolar and vascular growth, suggesting it could prevent bronchopulmonary dysplasia (BPD).

The treatment increased levels of L-arginine and L-citrulline, reduced pulmonary hypertension markers, and reversed harmful changes in lung structure, indicating that L-citrulline may be a promising alternative to inhaled nitric oxide (iNO) for BPD prevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

L-citrulline attenuates arrested alveolar growth and pulmonary hypertension in oxygen-induced lung injury in newborn rats. Vadivel, A., Aschner, JL., Rey-Parra, GJ., et al.[2022]

In a retrospective study of 23 patients with citrullinemia, the majority of neonatal-onset patients required intensive treatments like exchange transfusions and peritoneal dialysis, highlighting the severity of this form of the disease.

Despite the high mortality rate (14 out of 23 patients), the study suggests that early diagnosis and appropriate treatment could improve the prognosis and quality of life for patients with citrullinemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Citrullinemia. Clinical experience with 23 cases. Tokatli, A., Coşkun, T., Ozalp, I.[2015]

In a study involving six premature infants, a multi-dose regimen of L-citrulline (60 mg/kg every 6 hours for 72 hours) was well tolerated, with no serious adverse events reported.

The plasma concentrations of L-citrulline achieved in the infants matched predicted levels from previous single-dose studies, indicating that simulations can effectively guide dosing strategies for future randomized controlled trials evaluating L-citrulline for treating pulmonary hypertension associated with bronchopulmonary dysplasia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-dose enteral L-citrulline administration in premature infants at risk of developing pulmonary hypertension associated with bronchopulmonary dysplasia. Aschner, J., Avachat, C., Birnbaum, A., et al.[2023]

References

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

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

2. Germany pubmed.ncbi.nlm.nih.gov

Neonatal citrullinaemia with satisfactory mental development. [2019]

3. England pubmed.ncbi.nlm.nih.gov

L-citrulline supplementation in the treatment of pulmonary hypertension associated with bronchopulmonary dysplasia in preterm infant: A case report. [2022]

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

L-citrulline attenuates arrested alveolar growth and pulmonary hypertension in oxygen-induced lung injury in newborn rats. [2022]

5. Turkey pubmed.ncbi.nlm.nih.gov

Citrullinemia. Clinical experience with 23 cases. [2015]

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

Multi-dose enteral L-citrulline administration in premature infants at risk of developing pulmonary hypertension associated with bronchopulmonary dysplasia. [2023]