Bronchopulmonary Dysplasia, Infant,Premature, Pulmonary Hypertension
Conditions
Keywords
L-citrulline, Nitric oxide
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.
Interventions
DRUGL-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.
Sponsors
University of Utah
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Intervention model description
Single dose pharmacokinetic studies using population PKs Steady-state pharmacokinetic studies using population PKs
Eligibility
Sex/Gender
ALL
Age
14 Days to 3 Months
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma L-citrulline Levels Following Administration of a Single Dose of L-citrulline- Arm 1 | Group 1- Baseline, 1 hr post-study drug dose, and 2.5 hours post-study drug dose, Group 2- Baseline, 15 minutes post-study drug dose and 3 hours post-study drug dose | Plasma L-citrulline levels will be measured using population pharmacokinetics (PK) 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. This arm will be split into two groups of 5 subjects each. Group 1 will have PKs done at baseline (24-48 hours prior to first dose), 1 hour (+/- 10 minutes) after dose given and 2.5 hours (+/- 10 minutes) after dose given. Group 2 will have PKs done at baseline (24-48 hours prior to first dose), 15 minutes (+/- 10 minutes) after dose given and 3 hours (+/- 10 minutes) after dose given. |
| Evaluate L-citrulline Plasma Levels at Baseline and Prior to the Last Dose of Study Drug Dose (Dose #12)- Arm 2 | 10 min to 1 hour prior to first study drug dose and 10-30 minutes prior to last dose (approx 65.5 hours after the first dose given). | Evaluate the ability to achieve the target trough L-citrulline plasma level of approx.50-80 µM in patients at high risk of developing BPD-PH treated for 72 hours with oral L-citrulline by measuring baseline L-citrulline levels and L-citrulline plasma levels drawn prior to last dose of L-citrulline study drug. Study drug is given orally every 6 hours over 72 hours for a total of 12 doses. A PK will be done on all subjects at baseline (10 minutes to 6 hours prior to first dose) and again 10-30 minutes prior to last dose. If all 12 doses of study drug are given, this will be at approximately 65.5 hours after the first study drug dose is given. |
| Number of Participants With Feedings Being Stopped Following L-citrulline Administration | 48 hours after last study drug dose | The safety outcome of the tolerability of L-citrulline will be measured by whether a subject has feedings held within 48 hours of receiving oral L-citrulline administration for reasons not attributable to underlying condition. For the stead state arm, feeding tolerance was monitored during the 72 hour period in which study was given and then for another 48 hours after the last study drug was given. |
| Number of Participants With Hypotension Developing Following L-citrulline Administration | 12 hours after last study drug dose | 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
| Measure | Time frame | Description |
|---|---|---|
| Urinary Nitrite and Nitrate Levels Will be Measured in Subjects Enrolled Into the Steady State (Second Arm) of the Study. | Baseline (within 24 hours prior to first study drug dose) and 4-8 hours after last study drug dose given (approximately 70 to 78 hours after first study drug dose) | Urine samples will be obtained to assess baseline levels of nitric oxide metabolites (nitrite/nitrate) in the urine within 24 hours prior to first dose and again 4-8 hours after the last dose of study drug given. The purpose is to assess whether there is an increase in levels of nitric oxide metabolites in the urine in response to 72 hours of L-citrulline dosing. Urine samples are only being obtained in infants enrolled in the steady state (second arm) of the study. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
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. | 10 |
| 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.
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. | 6 |
| Total | 16 |
Baseline characteristics
| Characteristic | Single-dose | Steady-state | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 10 Participants | 6 Participants | 16 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 31.4 Post-menstrual age in weeks at study | 32.0 Post-menstrual age in weeks at study | 31.7 Post-menstrual age in weeks at study |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 4 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) White | 8 Participants | 4 Participants | 12 Participants |
| Region of Enrollment United States | 10 participants | 6 participants | 16 participants |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 6 |
| other Total, other adverse events | 0 / 10 | 1 / 6 |
| serious Total, serious adverse events | 0 / 10 | 0 / 6 |
Outcome results
Primary
Evaluate L-citrulline Plasma Levels at Baseline and Prior to the Last Dose of Study Drug Dose (Dose #12)- Arm 2
Evaluate the ability to achieve the target trough L-citrulline plasma level of approx.50-80 µM in patients at high risk of developing BPD-PH treated for 72 hours with oral L-citrulline by measuring baseline L-citrulline levels and L-citrulline plasma levels drawn prior to last dose of L-citrulline study drug. Study drug is given orally every 6 hours over 72 hours for a total of 12 doses. A PK will be done on all subjects at baseline (10 minutes to 6 hours prior to first dose) and again 10-30 minutes prior to last dose. If all 12 doses of study drug are given, this will be at approximately 65.5 hours after the first study drug dose is given.
Time frame: 10 min to 1 hour prior to first study drug dose and 10-30 minutes prior to last dose (approx 65.5 hours after the first dose given).
Population: All subjects had a baseline PK and trough PK done prior to 12th dose (approx 65.5 hours after first dose of study drug)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single-dose Group, Baseline L-citrulline Levels | Evaluate L-citrulline Plasma Levels at Baseline and Prior to the Last Dose of Study Drug Dose (Dose #12)- Arm 2 | 37.5 micromol/L |
| Single-dose Group, L-citrulline Level 15 Min After Study Drug | Evaluate L-citrulline Plasma Levels at Baseline and Prior to the Last Dose of Study Drug Dose (Dose #12)- Arm 2 | 38 micromol/L |
Primary
Number of Participants With Feedings Being Stopped Following L-citrulline Administration
The safety outcome of the tolerability of L-citrulline will be measured by whether a subject has feedings held within 48 hours of receiving oral L-citrulline administration for reasons not attributable to underlying condition. For the stead state arm, feeding tolerance was monitored during the 72 hour period in which study was given and then for another 48 hours after the last study drug was given.
Time frame: 48 hours after last study drug dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single-dose Group, Baseline L-citrulline Levels | Number of Participants With Feedings Being Stopped Following L-citrulline Administration | 0 Participants |
| Single-dose Group, L-citrulline Level 15 Min After Study Drug | Number of Participants With Feedings Being Stopped Following L-citrulline Administration | 0 Participants |
Primary
Number of Participants With Hypotension Developing Following L-citrulline Administration
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
Time frame: 12 hours after last study drug dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single-dose Group, Baseline L-citrulline Levels | Number of Participants With Hypotension Developing Following L-citrulline Administration | 0 Participants |
| Single-dose Group, L-citrulline Level 15 Min After Study Drug | Number of Participants With Hypotension Developing Following L-citrulline Administration | 1 Participants |
Primary
Plasma L-citrulline Levels Following Administration of a Single Dose of L-citrulline- Arm 1
Plasma L-citrulline levels will be measured using population pharmacokinetics (PK) 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. This arm will be split into two groups of 5 subjects each. Group 1 will have PKs done at baseline (24-48 hours prior to first dose), 1 hour (+/- 10 minutes) after dose given and 2.5 hours (+/- 10 minutes) after dose given. Group 2 will have PKs done at baseline (24-48 hours prior to first dose), 15 minutes (+/- 10 minutes) after dose given and 3 hours (+/- 10 minutes) after dose given.
Time frame: Group 1- Baseline, 1 hr post-study drug dose, and 2.5 hours post-study drug dose, Group 2- Baseline, 15 minutes post-study drug dose and 3 hours post-study drug dose
Population: All babies in this arm had a baseline level PK. Group 1 (5 subjects) had a PK done at 1 hour (+/- 10 minutes) after dose given and 2.5 hours (+/- 10 minutes) after dose given. Group 2 (5 subjects) had a PK done at 15 minutes (+/- 10 minutes) after dose given and 3 hours (+/- 10 minutes) after dose given.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single-dose Group, Baseline L-citrulline Levels | Plasma L-citrulline Levels Following Administration of a Single Dose of L-citrulline- Arm 1 | 31 micromol/L |
| Single-dose Group, L-citrulline Level 15 Min After Study Drug | Plasma L-citrulline Levels Following Administration of a Single Dose of L-citrulline- Arm 1 | 470 micromol/L |
| Single-dose Group, L-citrulline Level at 1 Hour After Study Drug | Plasma L-citrulline Levels Following Administration of a Single Dose of L-citrulline- Arm 1 | 651 micromol/L |
| Single-dose Group, L-citrulline Level at 2.5 Hours After Study Drug | Plasma L-citrulline Levels Following Administration of a Single Dose of L-citrulline- Arm 1 | 232 micromol/L |
| Single-dose Group, L-citrulline Level at 3 Hours After Study Drug | Plasma L-citrulline Levels Following Administration of a Single Dose of L-citrulline- Arm 1 | 197 micromol/L |
Secondary
Urinary Nitrite and Nitrate Levels Will be Measured in Subjects Enrolled Into the Steady State (Second Arm) of the Study.
Urine samples will be obtained to assess baseline levels of nitric oxide metabolites (nitrite/nitrate) in the urine within 24 hours prior to first dose and again 4-8 hours after the last dose of study drug given. The purpose is to assess whether there is an increase in levels of nitric oxide metabolites in the urine in response to 72 hours of L-citrulline dosing. Urine samples are only being obtained in infants enrolled in the steady state (second arm) of the study.
Time frame: Baseline (within 24 hours prior to first study drug dose) and 4-8 hours after last study drug dose given (approximately 70 to 78 hours after first study drug dose)
Population: Only subjects in the steady state arm (second arm) of the study had urine analyzed. 1 subject only had post-study urine available for analysis so this subject was not included in the overall analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single-dose Group, Baseline L-citrulline Levels | Urinary Nitrite and Nitrate Levels Will be Measured in Subjects Enrolled Into the Steady State (Second Arm) of the Study. | 25.8 micromol/g Cr |
| Single-dose Group, L-citrulline Level 15 Min After Study Drug | Urinary Nitrite and Nitrate Levels Will be Measured in Subjects Enrolled Into the Steady State (Second Arm) of the Study. | 36 micromol/g Cr |