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L-citrulline and Pulmonary Hypertension Associated With Bronchopulmonary Dysplasia

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ClinicalTrials.gov Identifier: NCT03542812
Recruitment Status : Recruiting
First Posted : May 31, 2018
Last Update Posted : April 22, 2019
Sponsor:
Information provided by (Responsible Party):
Candice Fike, University of Utah

Brief 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.


Condition or disease Intervention/treatment Phase
Infant,Premature Bronchopulmonary Dysplasia Pulmonary Hypertension Drug: L-Citrulline Early Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Single dose pharmacokinetic studies using population PKs Steady-state pharmacokinetic studies using population PKs
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Pharmacokinetics of L-citrulline in Infants at High Risk of Developing Pulmonary Hypertension Associated With Bronchopulmonary Dysplasia
Estimated Study Start Date : May 1, 2019
Estimated Primary Completion Date : June 30, 2020
Estimated Study Completion Date : June 30, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Single-dose

Participants will be enrolled into the two groups, Group 1 (which will consist of 10 participants) and Group 2 (which will consist of 8 participants) in an alternating basis. Both Group 1 and Group 2 participants will receive a single, 150 mg/kg dose of oral L-citrulline. Population PKs will be done for both groups, at up to 3 time points.

Multiple interim time points and following completion of enrollment into Groups 1 and 2, data analysis will be done and results reviewed by the data safety monitoring board (DSMB). After the DSMB review is complete, enrollment into Group 3 will begin.

Drug: L-Citrulline
The L-citrulline will be procured in powder form and will be solubilized in sterile water to achieve a concentration of 50 mg/ml. Therefore, 3 ml/kg of the solubilized L-citrulline (50 mg/ml) will be administered per dose for the single-dose groups and the dose administered to the steady-state group will be determined from results from the single-dose studies.

Experimental: Steady-state
To evaluate the tolerability and ability to achieve target trough L-citrulline levels of 100-150 µM, an additional group of 18 infants (group 3) will be given oral L-citrulline doses at intervals over a total of 72 hours. If the participant is not nipple feeding, the dose will be delivered via the participant's indwelling gavage feeding tube. The dose and interval of L-citrulline will be based on results from the studies that assess pharmacokinetic parameters using a maximum daily dose of 3 g/kg/d. Blood draws for PKs will be done at baseline and prior to last dose of L-citrulline. Urine will be collected to measure nitric oxide metabolites.
Drug: L-Citrulline
The L-citrulline will be procured in powder form and will be solubilized in sterile water to achieve a concentration of 50 mg/ml. Therefore, 3 ml/kg of the solubilized L-citrulline (50 mg/ml) will be administered per dose for the single-dose groups and the dose administered to the steady-state group will be determined from results from the single-dose studies.




Primary Outcome Measures :
  1. Plasma L-citrulline levels following administration of a single dose of L-citrulline [ Time Frame: 48 hours ]
    Plasma L-citrulline levels will be measured before and at intervals following administration of a single dose of oral L-citrulline and used to generate a population pharmacokinetic model in patients at high risk of developing BPD-PH

  2. Evaluate ability to achieve target trough L-citrulline plasma level [ Time Frame: 72 hours ]
    Evaluate the ability to achieve the target trough L-citrulline plasma level of approx.100-150 µM in patients at high risk of developing BPD-PH treated for 72 hours with oral L-citrulline

  3. Evaluate incidence of feedings being stopped following L-citrulline administration [ Time Frame: 72 hours ]
    The safety outcome of the tolerability of L-citrulline will be measured by whether a subject has feedings held within 72 hours of receiving oral L-citrulline administration for reasons not attributable to underlying condition

  4. Evaluate incidence of hypotension developing following L-citrulline administration [ Time Frame: 12 hours ]
    The safety outcome of tolerability of L-citrulline will be measured by whether a subject develops a decrease in blood pressure more than 25% below baseline within 12 hours of receiving a dose of oral L-citrulline for reasons not attributable to underlying condition


Secondary Outcome Measures :
  1. Urinary nitrite and nitrate levels will be measured in subjects enrolled into Group 3. [ Time Frame: 72 hours ]
    Urine samples will be obtained to assess baseline levels of nitric oxide metabolites (nitrite/nitrate) in the urine and assess whether there is an increase in levels of nitric oxide metabolites in the urine in response to 72 hours of L-citrulline dosing.



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Ages Eligible for Study:   up to 3 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03542812


Contacts
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Contact: Candice Fike, MD 801-587-7804 candice.fike@hsc.utah.edu
Contact: Carrie Rau, RN 801-213-3360 carrie.rau@hsc.utah.edu

Locations
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United States, Utah
University of Utah Health Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Carrie Rau, RN    801-213-3360    carrie.rau@hsc.utah.edu   
Principal Investigator: Candice Fike, MD         
Sponsors and Collaborators
University of Utah
Investigators
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Principal Investigator: Candice Fike, MD University of Utah

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Responsible Party: Candice Fike, Principal Investigator, University of Utah
ClinicalTrials.gov Identifier: NCT03542812     History of Changes
Other Study ID Numbers: 97293
First Posted: May 31, 2018    Key Record Dates
Last Update Posted: April 22, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Candice Fike, University of Utah:
L-citrulline
Nitric oxide
Additional relevant MeSH terms:
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Hypertension, Pulmonary
Bronchopulmonary Dysplasia
Hypertension
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Ventilator-Induced Lung Injury
Lung Injury
Infant, Premature, Diseases
Infant, Newborn, Diseases
Nitric Oxide
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Endothelium-Dependent Relaxing Factors
Vasodilator Agents
Gasotransmitters
Protective Agents