L-citrulline and Pulmonary Hypertension Associated With Bronchopulmonary Dysplasia

  • STATUS
    Recruiting
  • End date
    Jun 30, 2022
  • participants needed
    36
  • sponsor
    University of Utah
Updated on 26 January 2021
vasodilator
FIO2
pulmonary disease
pressure support
very low birth weight
assisted ventilation
chronic lung disease
citrulline

Summary

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that affects up to 35% of very low birth weight infants (VLBW < 1500 g). Based on the current numbers of VLBW infants born annually in the U.S., between 5,000-10,000 neonates will develop BPD each year. It is estimated that 8-42% of infants with BPD will develop pulmonary hypertension (PH). Moreover, it has been known since the 1980's that echocardiographic evidence of PH in infants with BPD is associated with up to 40% mortality.

Treatment options to ameliorate PH in infants with BPD (BPD-PH) are limited. There have been no randomized clinical trials of any therapy in infants with BPD-PH. The standard care for the management of BPD-PH is to attempt to resolve the underlying lung disorder and the judicious use of oxygen as a potent pulmonary vasodilator. Using this management approach, which has not changed since the 1980's, the survival rates for infants with BPD-PH in the 2000's has been reported to be 64% at 6 months and 53% at 2 years after diagnosis of PH. The lack of improvement in outcomes for the past 3 decades has led to the widespread agreement that novel and effective therapies are desperately needed for infants with BPD-PH.

The goal is to develop oral L-citrulline clinically for the treatment of pediatric pulmonary hypertension associated with bronchopulmonary dysplasia (BPD-PH); before pursuing a large scale treatment trial, pharmacokinetic (PK) dose-finding, tolerability studies in patients at high risk of developing BPD-PH are warranted.

The hypothesis is that oral L-citrulline will be well tolerated, without significant adverse effects in infants at high risk of developing pulmonary hypertension (PH) associated with BPD. The investigators propose to first characterize the PK profile of oral L-citrulline in order to define an appropriate dose range and treatment interval for infants at high risk of developing BPD-PH. Then using the doses and intervals generated by the PK profile, with a maximum dose of 3 g/kg/d, the investigators propose to evaluate the tolerability and ability to achieve the target study drug level (100-150 micromolar) in babies treated for 72 hours with oral L-citrulline. These studies will provide the data needed to design a full-scale randomized multi-center trial to evaluate the efficacy of oral L-citrulline therapy to ameliorate BPD-PH in human infants, a patient population that has a desperate need of new therapies.

Details
Condition Bronchopulmonary Dysplasia, Pulmonary Hypertension, Prematurity, Cancer Prevention, Surviving Abuse, Joint Injuries, Abdominal Surgery, Mental Disability, Pelvic Adhesions, Low Testosterone, Dental Filling, Habit Reversal, Complicated Grief, Chronic Pelvic Pain, Gambling Problems, Myopic Macular Degeneration, Nerve Injury, Severe Premenstrual Symptom, Stasis Dermatitis, Pulmonary Arterial Hypertension, Open Heart Surgery, Recurrent Pregnancy Loss, Effects of Chemotherapy, Renal Anemia, Functional Dyspepsia, Catheter Complications, Serial Evaluation of Ductal Epithelium, Chronic Renal Anemia, Cancer Treatment, Anemic Cancer, Spinocerebellar Disorders, Pseudobulbar Affect, Spine Athroplasty, Indikation: Diabetes - Typ II, Partial Medial Meniscectomy, Primary Insulin Hypersecretion, Testotoxikose, Infantile Fibrosarcoma, Late Infantile Neuronal Ceroid Lipfuscinsosis, Memory Problems, bronchopulmonary dysplasia (bpd)
Treatment L-citrulline
Clinical Study IdentifierNCT03542812
SponsorUniversity of Utah
Last Modified on26 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Infants born prematurely at < or = 28 weeks gestation requiring invasive
(mechanical ventilation) or non-invasive positive pressure support (nasal
continuous positive airway pressure, high flow nasal cannula >1 lpm) and FiO2
of at least 0.30 at 32 +/- 1 weeks postmenstrual age
Tolerating at least one-half of full volume oral/gavage tube feedings (using
ml/kg/d as full volume oral/gavage tube feedings)
The continuous need for some form of respiratory support (supplemental
oxygen, flow) for the prior 14 days
Hemoglobin > 10 mg/dL

Exclusion Criteria

Known major fetal anomaly or chromosomal aneuploidy
Clinical evidence of congenital heart disease (except patent ductus arteriosus (PDA), atrial septal defect (ASD), or ventricular septal defect (VSD)
Urine output < 1 ml/kg/hr
History of or known to have liver failure
History of or known to have necrotizing enterocolitis
History of or known to have significant feeding intolerance beyond the first week of life
Presence of any acute illness defined by fever >100.4 F, vomiting, or diarrhea
Hemoglobin < 10 mg/dL
Neonatal Intensive Care Unit (NICU) cases determined to be futile (anticipated death prior to hospital discharge)
Multiple births
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