L-citrulline and Pulmonary Hypertension Associated With Bronchopulmonary Dysplasia
| Status: | Not yet recruiting |
|---|---|
| Conditions: | Bronchitis, High Blood Pressure (Hypertension), High Blood Pressure (Hypertension), Pulmonary |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 1/9/2019 |
| Start Date: | February 1, 2019 |
| End Date: | June 30, 2021 |
| Contact: | Candice Fike, MD |
| Email: | candice.fike@hsc.utah.edu |
| Phone: | 801-587-7804 |
Pharmacokinetics of L-citrulline in Infants at High Risk of Developing Pulmonary Hypertension Associated With Bronchopulmonary Dysplasia
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.
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.
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
2.Tolerating at least one-half of full volume oral/gavage tube feedings (using 120 ml/kg/d
as full volume oral/gavage tube feedings)
3.The continuous need for some form of respiratory support (supplemental oxygen, flow) for
the prior 14 days
4.Hemoglobin > 10 mg/dL
Exclusion Criteria:
1. Known major fetal anomaly or chromosomal aneuploidy
2. Clinical evidence of congenital heart disease (except patent ductus arteriosus (PDA),
atrial septal defect (ASD), or ventricular septal defect (VSD)
3. Urine output < 1 ml/kg/hr
4. History of or known to have liver failure
5. History of or known to have necrotizing enterocolitis
6. History of or known to have significant feeding intolerance beyond the first week of
life
7. Presence of any acute illness defined by fever >100.4 F, vomiting, or diarrhea
8. Hemoglobin < 10 mg/dL
9. Neonatal Intensive Care Unit (NICU) cases determined to be futile (anticipated death
prior to hospital discharge)
10. Multiple births
We found this trial at
1
site
50 North Medical Drive
Salt Lake City, Utah 84132
Salt Lake City, Utah 84132
Principal Investigator: Candice Fike, MD
Phone: 801-213-3360
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