Trial Outcomes & Findings for L-citrulline and Pulmonary Hypertension Associated With Bronchopulmonary Dysplasia (NCT NCT03542812)

Last Updated: 2024-06-10

Results Overview

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.

Recruitment status

TERMINATED

Study phase

EARLY_PHASE1

Target enrollment

16 participants

Primary outcome timeframe

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

Results posted on

2024-06-10

Participant Flow

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	10	6
Overall Study COMPLETED	10	6
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

L-citrulline and Pulmonary Hypertension Associated With Bronchopulmonary Dysplasia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Single-dose n=10 Participants 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.	Steady-state n=6 Participants 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.	Total n=16 Participants Total of all reporting groups
Age, Categorical <=18 years	10 Participants n=5 Participants	6 Participants n=7 Participants	16 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	31.4 Post-menstrual age in weeks at study n=5 Participants	32.0 Post-menstrual age in weeks at study n=7 Participants	31.7 Post-menstrual age in weeks at study n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	2 Participants n=7 Participants	7 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	4 Participants n=7 Participants	9 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	8 Participants n=5 Participants	4 Participants n=7 Participants	12 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	8 Participants n=5 Participants	4 Participants n=7 Participants	12 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Region of Enrollment United States	10 participants n=5 Participants	6 participants n=7 Participants	16 participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Single-dose Group, Baseline L-citrulline Levels n=10 Participants Blood was sampled from all subjects 24-48 hours prior to the first study drug dose of L-citrulline and measured for baseline L-citrulline levels.	Single-dose Group, L-citrulline Level 15 Min After Study Drug n=5 Participants Blood was sampled from 5 subjects at 15 min after study drug L-citrulline was given +/- 10 minutes.	Single-dose Group, L-citrulline Level at 1 Hour After Study Drug n=5 Participants Blood was sampled from 5 subjects at 1 hour after study drug L-citrulline was given +/- 10 minutes.	Single-dose Group, L-citrulline Level at 2.5 Hours After Study Drug n=5 Participants Blood was sampled from 5 subjects at 2.5 hours after study drug L-citrulline was given +/- 10 minutes.	Single-dose Group, L-citrulline Level at 3 Hours After Study Drug n=5 Participants Blood was sampled from 5 subjects at 3 hours after study drug L-citrulline was given +/- 10 minutes.
Plasma L-citrulline Levels Following Administration of a Single Dose of L-citrulline- Arm 1	31 micromol/L Interval 9.0 to 36.0	470 micromol/L Interval 340.0 to 554.0	651 micromol/L Interval 388.0 to 799.0	232 micromol/L Interval 189.0 to 507.0	197 micromol/L Interval 97.0 to 224.0

PRIMARY outcome

Timeframe: 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)

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.

Outcome measures

Outcome measures
Measure	Single-dose Group, Baseline L-citrulline Levels n=6 Participants Blood was sampled from all subjects 24-48 hours prior to the first study drug dose of L-citrulline and measured for baseline L-citrulline levels.	Single-dose Group, L-citrulline Level 15 Min After Study Drug n=6 Participants Blood was sampled from 5 subjects at 15 min after study drug L-citrulline was given +/- 10 minutes.	Single-dose Group, L-citrulline Level at 1 Hour After Study Drug Blood was sampled from 5 subjects at 1 hour after study drug L-citrulline was given +/- 10 minutes.	Single-dose Group, L-citrulline Level at 2.5 Hours After Study Drug Blood was sampled from 5 subjects at 2.5 hours after study drug L-citrulline was given +/- 10 minutes.	Single-dose Group, L-citrulline Level at 3 Hours After Study Drug Blood was sampled from 5 subjects at 3 hours after study drug L-citrulline was given +/- 10 minutes.
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 Interval 20.0 to 45.0	38 micromol/L Interval 30.5 to 53.0	—	—	—

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Single-dose Group, Baseline L-citrulline Levels n=10 Participants Blood was sampled from all subjects 24-48 hours prior to the first study drug dose of L-citrulline and measured for baseline L-citrulline levels.	Single-dose Group, L-citrulline Level 15 Min After Study Drug n=6 Participants Blood was sampled from 5 subjects at 15 min after study drug L-citrulline was given +/- 10 minutes.	Single-dose Group, L-citrulline Level at 1 Hour After Study Drug Blood was sampled from 5 subjects at 1 hour after study drug L-citrulline was given +/- 10 minutes.	Single-dose Group, L-citrulline Level at 2.5 Hours After Study Drug Blood was sampled from 5 subjects at 2.5 hours after study drug L-citrulline was given +/- 10 minutes.	Single-dose Group, L-citrulline Level at 3 Hours After Study Drug Blood was sampled from 5 subjects at 3 hours after study drug L-citrulline was given +/- 10 minutes.
Number of Participants With Feedings Being Stopped Following L-citrulline Administration	0 Participants	0 Participants	—	—	—

PRIMARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Single-dose Group, Baseline L-citrulline Levels n=10 Participants Blood was sampled from all subjects 24-48 hours prior to the first study drug dose of L-citrulline and measured for baseline L-citrulline levels.	Single-dose Group, L-citrulline Level 15 Min After Study Drug n=6 Participants Blood was sampled from 5 subjects at 15 min after study drug L-citrulline was given +/- 10 minutes.	Single-dose Group, L-citrulline Level at 1 Hour After Study Drug Blood was sampled from 5 subjects at 1 hour after study drug L-citrulline was given +/- 10 minutes.	Single-dose Group, L-citrulline Level at 2.5 Hours After Study Drug Blood was sampled from 5 subjects at 2.5 hours after study drug L-citrulline was given +/- 10 minutes.	Single-dose Group, L-citrulline Level at 3 Hours After Study Drug Blood was sampled from 5 subjects at 3 hours after study drug L-citrulline was given +/- 10 minutes.
Number of Participants With Hypotension Developing Following L-citrulline Administration	0 Participants	1 Participants	—	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Single-dose Group, Baseline L-citrulline Levels n=5 Participants Blood was sampled from all subjects 24-48 hours prior to the first study drug dose of L-citrulline and measured for baseline L-citrulline levels.	Single-dose Group, L-citrulline Level 15 Min After Study Drug n=5 Participants Blood was sampled from 5 subjects at 15 min after study drug L-citrulline was given +/- 10 minutes.	Single-dose Group, L-citrulline Level at 1 Hour After Study Drug Blood was sampled from 5 subjects at 1 hour after study drug L-citrulline was given +/- 10 minutes.	Single-dose Group, L-citrulline Level at 2.5 Hours After Study Drug Blood was sampled from 5 subjects at 2.5 hours after study drug L-citrulline was given +/- 10 minutes.	Single-dose Group, L-citrulline Level at 3 Hours After Study Drug Blood was sampled from 5 subjects at 3 hours after study drug L-citrulline was given +/- 10 minutes.
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 Interval 22.0 to 44.0	36 micromol/g Cr Interval 27.0 to 46.6	—	—	—

Adverse Events

Single-dose

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Steady-state

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Single-dose n=10 participants at risk 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.	Steady-state n=6 participants at risk 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.
Cardiac disorders Hypotension	0.00% 0/10 • Subjects will be monitored for the duration of study drug receipt and for another 48 hours after last study drug dose given for all AEs with the exception of hypotension, which will be followed for 12 hours after the last study drug dose. There were two adverse events of special interest: Feeding tolerance and hypotension. All other AEs were only collected if they met the definition of being serious and/or unexpected for the study population and/or related or probably related to the participation in the study.	16.7% 1/6 • Number of events 1 • Subjects will be monitored for the duration of study drug receipt and for another 48 hours after last study drug dose given for all AEs with the exception of hypotension, which will be followed for 12 hours after the last study drug dose. There were two adverse events of special interest: Feeding tolerance and hypotension. All other AEs were only collected if they met the definition of being serious and/or unexpected for the study population and/or related or probably related to the participation in the study.

Additional Information

Candice Fike

University of Utah

Phone: 801-587-7804

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place