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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effectiveness of L-Citrulline, an amino acid supplement, for preterm infants facing serious conditions. It focuses on two groups: infants recovering from severe necrotizing enterocolitis (NEC), a dangerous gut problem, and those with bronchopulmonary dysplasia (BPD), a lung condition that may include pulmonary hypertension. The researchers aim to determine if L-Citrulline can prevent harmful inflammation in these infants. Infants born very early (at 30 weeks or less) who are stable after NEC surgery or have breathing issues related to BPD may qualify for this study. As an unphased trial, this study offers a unique opportunity to contribute to groundbreaking research that could improve care for vulnerable infants.

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.

Is there any evidence suggesting that this trial's treatment is likely to be safe for preterm infants?

Research has shown that L-Citrulline is usually safe for infants. Studies have suggested it might help with conditions like bronchopulmonary dysplasia (BPD) and necrotizing enterocolitis (NEC). In these studies, most infants did not experience serious side effects from L-Citrulline.

One study focused on preterm infants with conditions similar to those in this trial and found that L-Citrulline could be given safely without causing major problems. Another study tested different doses in preterm babies and found it was well-tolerated, with no major safety issues.

These findings offer some reassurance about the safety of L-Citrulline for preterm infants. However, as with any treatment, individual reactions can differ. This trial aims to gather more specific information on its safety for infants with BPD and NEC. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about L-Citrulline as a treatment for bronchopulmonary dysplasia (BPD) and necrotizing enterocolitis (NEC) because it offers a potentially novel approach compared to current treatments. Unlike conventional therapies that primarily focus on managing symptoms and complications, L-Citrulline is an amino acid that might enhance nitric oxide production, improving blood flow and reducing inflammation. This unique mechanism could address the underlying physiological issues in these conditions, rather than just alleviating symptoms. Additionally, oral administration makes it potentially easier and less invasive for infants, which is a significant advantage over other treatment methods.

What evidence suggests that L-Citrulline might be an effective treatment for bronchopulmonary dysplasia and necrotizing enterocolitis?

This trial will study the effects of L-Citrulline on infants with bronchopulmonary dysplasia (BPD) and necrotizing enterocolitis (NEC). Research has shown that L-Citrulline can reduce lung inflammation and improve lung development in newborn rats with conditions like bronchopulmonary dysplasia. In premature babies, L-Citrulline supplements might help prevent or lessen the severity of chronic lung disease related to high blood pressure in the lungs by protecting blood vessels and reducing inflammation. Although these results are promising, further studies are needed to confirm its effectiveness in humans. ^{1 2 3 4 5}

Who Is on the Research Team?

Estelle Gauda, MD

Principal Investigator

Division Head, Division of Neonatology

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 (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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11763423/

L-Citrulline in Neonates: From Bench to Bed Side - PMC While L-CIT shows promise in the treatment of various neonatal conditions, adequately powered studies to evaluate the safety and efficacy of L- ...

2. withpower.com withpower.com/trial/phase-bronchopulmonary-dysplasia-1-2023-6a3b4

Oral L-Citrulline for Bronchopulmonary Dysplasia and ... Research shows that L-Citrulline can reduce lung inflammation and improve lung development in newborn rats with conditions similar to bronchopulmonary dysplasia ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10844094/

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

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03649932?term=CITRULLINE&rank=10

Enteral L Citrulline Supplementation in Preterm Infants Oral L-citrulline supplementation may prevent and/or decrease the severity of chronic lung disease associated with pulmonary hypertension in preterm infants.

5. aging.networkofcare.org aging.networkofcare.org/sanmateo/CommunityResources/ClinicalTrials/Detail/NCT05636397?keyword=%22NEC%22

Safety and PK-PD Study of Oral L-CIT in Preterm Infants With ... It is made in the intestine and has been shown to exert vasoprotective and anti-inflammatory effects. BPD-PH and NEC are two specific inflammatory diseases of ...