Ignite Creation Date:
2025-12-24 @ 9:34 PM
Ignite Modification Date:
2026-02-20 @ 6:27 AM
Study NCT ID:
NCT03649932
Status:
COMPLETED
Last Update Posted:
2021-10-25
First Post:
2018-08-24
Is NOT Gene Therapy:
True
Has Adverse Events:
True
Brief Title:
Enteral L Citrulline Supplementation in Preterm Infants - Safety, Efficacy and Dosing
Sponsor:
Organization:
Raw JSON
{'hasResults': True, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24'}, 'conditionBrowseModule': {'meshes': [{'id': 'D001997', 'term': 'Bronchopulmonary Dysplasia'}, {'id': 'D006976', 'term': 'Hypertension, Pulmonary'}, {'id': 'D047928', 'term': 'Premature Birth'}], 'ancestors': [{'id': 'D055397', 'term': 'Ventilator-Induced Lung Injury'}, {'id': 'D055370', 'term': 'Lung Injury'}, {'id': 'D008171', 'term': 'Lung Diseases'}, {'id': 'D012140', 'term': 'Respiratory Tract Diseases'}, {'id': 'D007235', 'term': 'Infant, Premature, Diseases'}, {'id': 'D007232', 'term': 'Infant, Newborn, Diseases'}, {'id': 'D009358', 'term': 'Congenital, Hereditary, and Neonatal Diseases and Abnormalities'}, {'id': 'D006973', 'term': 'Hypertension'}, {'id': 'D014652', 'term': 'Vascular Diseases'}, {'id': 'D002318', 'term': 'Cardiovascular Diseases'}, {'id': 'D007752', 'term': 'Obstetric Labor, Premature'}, {'id': 'D007744', 'term': 'Obstetric Labor Complications'}, {'id': 'D011248', 'term': 'Pregnancy Complications'}, {'id': 'D005261', 'term': 'Female Urogenital Diseases and Pregnancy Complications'}, {'id': 'D000091642', 'term': 'Urogenital Diseases'}]}}, 'resultsSection': {'moreInfoModule': {'pointOfContact': {'email': 'amnahqasim@gmail.com', 'phone': '4097722815', 'title': 'Dr. Sunil Jain', 'organization': 'University of Texas Medical Branch'}, 'certainAgreement': {'piSponsorEmployee': False, 'restrictiveAgreement': False}}, 'adverseEventsModule': {'timeFrame': 'Adverse event data collected for the week during which study drug was administered.', 'eventGroups': [{'id': 'EG000', 'title': 'Low Dose', 'description': '50 mg/kg given two times a day (100 mg/kg/day) for total 7 days.\n\nEnteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.\n\nAdministration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.\n\nStudy drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.', 'otherNumAtRisk': 14, 'deathsNumAtRisk': 14, 'otherNumAffected': 0, 'seriousNumAtRisk': 14, 'deathsNumAffected': 0, 'seriousNumAffected': 0}, {'id': 'EG001', 'title': 'Medium Dose', 'description': '100 mg/kg given two times a day (200 mg/kg/day) for total 7 days\n\nEnteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.\n\nAdministration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.\n\nStudy drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.', 'otherNumAtRisk': 13, 'deathsNumAtRisk': 13, 'otherNumAffected': 0, 'seriousNumAtRisk': 13, 'deathsNumAffected': 0, 'seriousNumAffected': 0}, {'id': 'EG002', 'title': 'High Dose', 'description': '150 mg/kg given two times a day (300 mg/kg/day) for total 7 days.\n\nEnteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.\n\nAdministration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.\n\nStudy drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.', 'otherNumAtRisk': 13, 'deathsNumAtRisk': 13, 'otherNumAffected': 0, 'seriousNumAtRisk': 13, 'deathsNumAffected': 0, 'seriousNumAffected': 0}], 'frequencyThreshold': '0'}, 'outcomeMeasuresModule': {'outcomeMeasures': [{'type': 'PRIMARY', 'title': 'Change in Plasma Levels of L-arginine and L-citrulline as Measured by LCMS Approach', 'denoms': [{'units': 'Participants', 'counts': [{'value': '14', 'groupId': 'OG000'}, {'value': '13', 'groupId': 'OG001'}, {'value': '13', 'groupId': 'OG002'}]}], 'groups': [{'id': 'OG000', 'title': 'Low Dose', 'description': '50 mg/kg given two times a day (100 mg/kg/day) for total 7 days.\n\nEnteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.\n\nAdministration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.\n\nStudy drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.'}, {'id': 'OG001', 'title': 'Medium Dose', 'description': '100 mg/kg given two times a day (200 mg/kg/day) for total 7 days\n\nEnteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.\n\nAdministration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.\n\nStudy drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.'}, {'id': 'OG002', 'title': 'High Dose', 'description': '150 mg/kg given two times a day (300 mg/kg/day) for total 7 days.\n\nEnteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.\n\nAdministration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.\n\nStudy drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.'}], 'classes': [{'title': 'Citrulline level (day 0)', 'categories': [{'measurements': [{'value': '24', 'spread': '9.5', 'groupId': 'OG000'}, {'value': '33', 'spread': '17', 'groupId': 'OG001'}, {'value': '26', 'spread': '11', 'groupId': 'OG002'}]}]}, {'title': 'Citrulline level (day 7)', 'categories': [{'measurements': [{'value': '112', 'spread': '85', 'groupId': 'OG000'}, {'value': '150', 'spread': '89', 'groupId': 'OG001'}, {'value': '171', 'spread': '139', 'groupId': 'OG002'}]}]}, {'title': 'Arginine level (day 0)', 'categories': [{'measurements': [{'value': '56', 'spread': '63', 'groupId': 'OG000'}, {'value': '56', 'spread': '62', 'groupId': 'OG001'}, {'value': '59', 'spread': '30', 'groupId': 'OG002'}]}]}, {'title': 'Arginine level (day 7)', 'categories': [{'measurements': [{'value': '91', 'spread': '63', 'groupId': 'OG000'}, {'value': '134', 'spread': '62', 'groupId': 'OG001'}, {'value': '162', 'spread': '67', 'groupId': 'OG002'}]}]}], 'paramType': 'MEAN', 'timeFrame': 'During the week of intervention (day 0 - day 7)', 'description': 'L-arginine and citrulline levels in the plasma will be measured via liquid chromatography-mass spectroscopy (LCMS) and a change (increase) in plasma levels of 20% on day 7 from baseline on day 0 will be considered significant.', 'unitOfMeasure': 'micromol/L', 'dispersionType': 'Standard Deviation', 'reportingStatus': 'POSTED'}, {'type': 'PRIMARY', 'title': 'Safety of L-citrulline in Preterm Infants: Measured by at Least One Adverse Event', 'denoms': [{'units': 'Participants', 'counts': [{'value': '14', 'groupId': 'OG000'}, {'value': '13', 'groupId': 'OG001'}, {'value': '13', 'groupId': 'OG002'}]}], 'groups': [{'id': 'OG000', 'title': 'Low Dose', 'description': '50 mg/kg given two times a day (100 mg/kg/day) for total 7 days.\n\nEnteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.\n\nAdministration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.\n\nStudy drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.'}, {'id': 'OG001', 'title': 'Medium Dose', 'description': '100 mg/kg given two times a day (200 mg/kg/day) for total 7 days\n\nEnteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.\n\nAdministration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.\n\nStudy drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.'}, {'id': 'OG002', 'title': 'High Dose', 'description': '150 mg/kg given two times a day (300 mg/kg/day) for total 7 days.\n\nEnteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.\n\nAdministration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.\n\nStudy drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.'}], 'classes': [{'categories': [{'measurements': [{'value': '0', 'groupId': 'OG000'}, {'value': '0', 'groupId': 'OG001'}, {'value': '0', 'groupId': 'OG002'}]}]}], 'paramType': 'NUMBER', 'timeFrame': 'During the week of intervention (day 0 - day 7)', 'description': 'Measured by at least one adverse event that are determined to be related to the study drug.', 'unitOfMeasure': 'Number of Adverse Events', 'reportingStatus': 'POSTED'}, {'type': 'PRIMARY', 'title': 'Number of Participants With an Increase Plasma Level of L-citrulline > 37 Micromol/L', 'denoms': [{'units': 'Participants', 'counts': [{'value': '10', 'groupId': 'OG000'}, {'value': '11', 'groupId': 'OG001'}, {'value': '13', 'groupId': 'OG002'}]}], 'groups': [{'id': 'OG000', 'title': 'Low Dose', 'description': '50 mg/kg given two times a day (100 mg/kg/day) for total 7 days.\n\nEnteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.\n\nAdministration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.\n\nStudy drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.'}, {'id': 'OG001', 'title': 'Medium Dose', 'description': '100 mg/kg given two times a day (200 mg/kg/day) for total 7 days\n\nEnteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.\n\nAdministration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.\n\nStudy drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.'}, {'id': 'OG002', 'title': 'High Dose', 'description': '150 mg/kg given two times a day (300 mg/kg/day) for total 7 days.\n\nEnteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.\n\nAdministration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.\n\nStudy drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.'}], 'classes': [{'categories': [{'measurements': [{'value': '8', 'groupId': 'OG000'}, {'value': '10', 'groupId': 'OG001'}, {'value': '10', 'groupId': 'OG002'}]}]}], 'paramType': 'COUNT_OF_PARTICIPANTS', 'timeFrame': 'During the week of intervention (day 0 - day 7)', 'description': 'Previous studies have shown that a plasma level of \\> 37 micromol/L was effective in preventing pulmonary hypertension. This study sought to identify the dosing group of L-citrulline required to increase the plasma level of L-citrulline \\> 37 micromol/L.', 'unitOfMeasure': 'Participants', 'reportingStatus': 'POSTED'}]}, 'participantFlowModule': {'groups': [{'id': 'FG000', 'title': 'Low Dose', 'description': '50 mg/kg given two times a day (100 mg/kg/day) for total 7 days.\n\nEnteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.\n\nAdministration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.\n\nStudy drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.'}, {'id': 'FG001', 'title': 'Medium Dose', 'description': '100 mg/kg given two times a day (200 mg/kg/day) for total 7 days\n\nEnteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.\n\nAdministration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.\n\nStudy drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.'}, {'id': 'FG002', 'title': 'High Dose', 'description': '150 mg/kg given two times a day (300 mg/kg/day) for total 7 days.\n\nEnteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.\n\nAdministration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.\n\nStudy drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.'}], 'periods': [{'title': 'Overall Study', 'milestones': [{'type': 'STARTED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '14'}, {'groupId': 'FG001', 'numSubjects': '14'}, {'groupId': 'FG002', 'numSubjects': '14'}]}, {'type': 'COMPLETED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '14'}, {'groupId': 'FG001', 'numSubjects': '13'}, {'groupId': 'FG002', 'numSubjects': '13'}]}, {'type': 'NOT COMPLETED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '0'}, {'groupId': 'FG001', 'numSubjects': '1'}, {'groupId': 'FG002', 'numSubjects': '1'}]}]}]}, 'baselineCharacteristicsModule': {'denoms': [{'units': 'Participants', 'counts': [{'value': '14', 'groupId': 'BG000'}, {'value': '13', 'groupId': 'BG001'}, {'value': '13', 'groupId': 'BG002'}, {'value': '40', 'groupId': 'BG003'}]}], 'groups': [{'id': 'BG000', 'title': 'Low Dose', 'description': '50 mg/kg given two times a day (100 mg/kg/day) for total 7 days.\n\nEnteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.\n\nAdministration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.\n\nStudy drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.'}, {'id': 'BG001', 'title': 'Medium Dose', 'description': '100 mg/kg given two times a day (200 mg/kg/day) for total 7 days\n\nEnteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.\n\nAdministration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.\n\nStudy drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.'}, {'id': 'BG002', 'title': 'High Dose', 'description': '150 mg/kg given two times a day (300 mg/kg/day) for total 7 days.\n\nEnteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.\n\nAdministration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.\n\nStudy drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.'}, {'id': 'BG003', 'title': 'Total', 'description': 'Total of all reporting groups'}], 'measures': [{'title': 'Age, Continuous', 'classes': [{'categories': [{'measurements': [{'value': '30', 'spread': '2.1', 'groupId': 'BG000'}, {'value': '29.6', 'spread': '2.5', 'groupId': 'BG001'}, {'value': '29', 'spread': '1.5', 'groupId': 'BG002'}, {'value': '29.4', 'spread': '2.1', 'groupId': 'BG003'}]}]}], 'paramType': 'MEDIAN', 'unitOfMeasure': 'Weeks', 'dispersionType': 'STANDARD_DEVIATION'}, {'title': 'Sex: Female, Male', 'classes': [{'categories': [{'title': 'Female', 'measurements': [{'value': '8', 'groupId': 'BG000'}, {'value': '8', 'groupId': 'BG001'}, {'value': '10', 'groupId': 'BG002'}, {'value': '26', 'groupId': 'BG003'}]}, {'title': 'Male', 'measurements': [{'value': '6', 'groupId': 'BG000'}, {'value': '5', 'groupId': 'BG001'}, {'value': '3', 'groupId': 'BG002'}, {'value': '14', 'groupId': 'BG003'}]}]}], 'paramType': 'COUNT_OF_PARTICIPANTS', 'unitOfMeasure': 'Participants'}, {'title': 'Race/Ethnicity, Customized', 'classes': [{'title': 'Caucasian', 'categories': [{'measurements': [{'value': '6', 'groupId': 'BG000'}, {'value': '6', 'groupId': 'BG001'}, {'value': '8', 'groupId': 'BG002'}, {'value': '20', 'groupId': 'BG003'}]}]}, {'title': 'African American', 'categories': [{'measurements': [{'value': '0', 'groupId': 'BG000'}, {'value': '2', 'groupId': 'BG001'}, {'value': '0', 'groupId': 'BG002'}, {'value': '2', 'groupId': 'BG003'}]}]}, {'title': 'Hispanic', 'categories': [{'measurements': [{'value': '8', 'groupId': 'BG000'}, {'value': '5', 'groupId': 'BG001'}, {'value': '5', 'groupId': 'BG002'}, {'value': '18', 'groupId': 'BG003'}]}]}], 'paramType': 'COUNT_OF_PARTICIPANTS', 'unitOfMeasure': 'Participants'}, {'title': 'Birth Weight', 'classes': [{'categories': [{'measurements': [{'value': '1125', 'spread': '383.5', 'groupId': 'BG000'}, {'value': '1272', 'spread': '460', 'groupId': 'BG001'}, {'value': '1250', 'spread': '350', 'groupId': 'BG002'}, {'value': '1250', 'spread': '393', 'groupId': 'BG003'}]}]}], 'paramType': 'MEDIAN', 'unitOfMeasure': 'grams', 'dispersionType': 'STANDARD_DEVIATION'}]}}, 'documentSection': {'largeDocumentModule': {'largeDocs': [{'date': '2019-06-02', 'size': 933307, 'label': 'Study Protocol and Statistical Analysis Plan', 'hasIcf': False, 'hasSap': True, 'filename': 'Prot_SAP_000.pdf', 'typeAbbrev': 'Prot_SAP', 'uploadDate': '2021-09-26T19:18', 'hasProtocol': True}]}}, 'protocolSection': {'designModule': {'phases': ['PHASE1'], 'studyType': 'INTERVENTIONAL', 'designInfo': {'allocation': 'RANDOMIZED', 'maskingInfo': {'masking': 'NONE'}, 'primaryPurpose': 'TREATMENT', 'interventionModel': 'PARALLEL', 'interventionModelDescription': 'Previous studies in patients undergoing cardiac surgery have shown that post-operative pulmonary hypertension did not develop in patients with citrulline level \\> 37 micromol/L. A cross-sectional study reported that citrulline levels \\< 29 micromol/L was associated with BPD\\_PH (100% sensitivity and 75% specificity) hence this may be used as a screening tool for BPD\\_PH2. The investigators will use the higher levels of citrulline of the reported levels as our goal (\\>37µmol/L). The investigators will supplement infants with 3 different dosages and check serum levels to see what dose is required to achieve the optimal plasma level of citrulline (\\>37µmol/L).'}, 'enrollmentInfo': {'type': 'ACTUAL', 'count': 42}}, 'statusModule': {'overallStatus': 'COMPLETED', 'startDateStruct': {'date': '2018-09-25', 'type': 'ACTUAL'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2021-09', 'completionDateStruct': {'date': '2021-06-21', 'type': 'ACTUAL'}, 'lastUpdateSubmitDate': '2021-09-27', 'studyFirstSubmitDate': '2018-08-24', 'resultsFirstSubmitDate': '2021-08-03', 'studyFirstSubmitQcDate': '2018-08-27', 'lastUpdatePostDateStruct': {'date': '2021-10-25', 'type': 'ACTUAL'}, 'resultsFirstSubmitQcDate': '2021-09-27', 'studyFirstPostDateStruct': {'date': '2018-08-28', 'type': 'ACTUAL'}, 'resultsFirstPostDateStruct': {'date': '2021-10-25', 'type': 'ACTUAL'}, 'primaryCompletionDateStruct': {'date': '2021-06-21', 'type': 'ACTUAL'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': 'Change in Plasma Levels of L-arginine and L-citrulline as Measured by LCMS Approach', 'timeFrame': 'During the week of intervention (day 0 - day 7)', 'description': 'L-arginine and citrulline levels in the plasma will be measured via liquid chromatography-mass spectroscopy (LCMS) and a change (increase) in plasma levels of 20% on day 7 from baseline on day 0 will be considered significant.'}, {'measure': 'Safety of L-citrulline in Preterm Infants: Measured by at Least One Adverse Event', 'timeFrame': 'During the week of intervention (day 0 - day 7)', 'description': 'Measured by at least one adverse event that are determined to be related to the study drug.'}, {'measure': 'Number of Participants With an Increase Plasma Level of L-citrulline > 37 Micromol/L', 'timeFrame': 'During the week of intervention (day 0 - day 7)', 'description': 'Previous studies have shown that a plasma level of \\> 37 micromol/L was effective in preventing pulmonary hypertension. This study sought to identify the dosing group of L-citrulline required to increase the plasma level of L-citrulline \\> 37 micromol/L.'}]}, 'oversightModule': {'oversightHasDmc': True, 'isFdaRegulatedDrug': False, 'isFdaRegulatedDevice': False}, 'conditionsModule': {'keywords': ['Bronchopulmonary dysplasia', 'Pulmonary hypertension', 'Citrulline'], 'conditions': ['Bronchopulmonary Dysplasia', 'Bronchopulmonary Dysplasia Associated Pulmonary Hypertension', 'Pulmonary Hypertension', 'Premature Birth', 'Chronic Lung Disease of Prematurity']}, 'referencesModule': {'references': [{'pmid': '24862864', 'type': 'BACKGROUND', 'citation': 'Fike CD, Summar M, Aschner JL. L-citrulline provides a novel strategy for treating chronic pulmonary hypertension in newborn infants. Acta Paediatr. 2014 Oct;103(10):1019-26. doi: 10.1111/apa.12707. Epub 2014 Jun 20.'}, {'pmid': '26780635', 'type': 'BACKGROUND', 'citation': 'Montgomery AM, Bazzy-Asaad A, Asnes JD, Bizzarro MJ, Ehrenkranz RA, Weismann CG. Biochemical Screening for Pulmonary Hypertension in Preterm Infants with Bronchopulmonary Dysplasia. Neonatology. 2016;109(3):190-4. doi: 10.1159/000442043. Epub 2016 Jan 19.'}, {'pmid': '25536367', 'type': 'BACKGROUND', 'citation': 'Fike CD, Dikalova A, Kaplowitz MR, Cunningham G, Summar M, Aschner JL. Rescue Treatment with L-Citrulline Inhibits Hypoxia-Induced Pulmonary Hypertension in Newborn Pigs. Am J Respir Cell Mol Biol. 2015 Aug;53(2):255-64. doi: 10.1165/rcmb.2014-0351OC.'}, {'pmid': '20805789', 'type': 'BACKGROUND', 'citation': 'Vadivel A, Aschner JL, Rey-Parra GJ, Magarik J, Zeng H, Summar M, Eaton F, Thebaud B. L-citrulline attenuates arrested alveolar growth and pulmonary hypertension in oxygen-induced lung injury in newborn rats. Pediatr Res. 2010 Dec;68(6):519-25. doi: 10.1203/PDR.0b013e3181f90278.'}, {'pmid': '11688916', 'type': 'BACKGROUND', 'citation': 'Waugh WH, Daeschner CW 3rd, Files BA, McConnell ME, Strandjord SE. Oral citrulline as arginine precursor may be beneficial in sickle cell disease: early phase two results. J Natl Med Assoc. 2001 Oct;93(10):363-71.'}, {'pmid': '16798303', 'type': 'BACKGROUND', 'citation': 'Smith HA, Canter JA, Christian KG, Drinkwater DC, Scholl FG, Christman BW, Rice GD, Barr FE, Summar ML. Nitric oxide precursors and congenital heart surgery: a randomized controlled trial of oral citrulline. J Thorac Cardiovasc Surg. 2006 Jul;132(1):58-65. doi: 10.1016/j.jtcvs.2006.02.012.'}, {'pmid': '26534956', 'type': 'BACKGROUND', 'citation': 'Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, Hanna BD, Rosenzweig EB, Raj JU, Cornfield D, Stenmark KR, Steinhorn R, Thebaud B, Fineman JR, Kuehne T, Feinstein JA, Friedberg MK, Earing M, Barst RJ, Keller RL, Kinsella JP, Mullen M, Deterding R, Kulik T, Mallory G, Humpl T, Wessel DL; American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Surgery and Anesthesia; and the American Thoracic Society. Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation. 2015 Nov 24;132(21):2037-99. doi: 10.1161/CIR.0000000000000329. Epub 2015 Nov 3.'}, {'pmid': '17662768', 'type': 'BACKGROUND', 'citation': 'Barr FE, Tirona RG, Taylor MB, Rice G, Arnold J, Cunningham G, Smith HA, Campbell A, Canter JA, Christian KG, Drinkwater DC, Scholl F, Kavanaugh-McHugh A, Summar ML. Pharmacokinetics and safety of intravenously administered citrulline in children undergoing congenital heart surgery: potential therapy for postoperative pulmonary hypertension. J Thorac Cardiovasc Surg. 2007 Aug;134(2):319-26. doi: 10.1016/j.jtcvs.2007.02.043.'}, {'pmid': '17662090', 'type': 'BACKGROUND', 'citation': 'Schwedhelm E, Maas R, Freese R, Jung D, Lukacs Z, Jambrecina A, Spickler W, Schulze F, Boger RH. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. Br J Clin Pharmacol. 2008 Jan;65(1):51-9. doi: 10.1111/j.1365-2125.2007.02990.x. Epub 2007 Jul 27.'}, {'pmid': '37640809', 'type': 'DERIVED', 'citation': 'Qasim A, Mehdi MQ, Bhatia S, Franco-Fuenmayor ME, Jain SK. Enteral L-citrulline supplementation in preterm infants is safe and effective in increasing plasma arginine and citrulline levels-a pilot randomized trial. J Perinatol. 2024 May;44(5):702-708. doi: 10.1038/s41372-023-01761-x. Epub 2023 Aug 28.'}]}, 'descriptionModule': {'briefSummary': 'Oral L-citrulline supplementation may prevent and/or decrease the severity of chronic lung disease associated with pulmonary hypertension in preterm infants. Since oral L-citrulline supplementation has never been studied in preterm infants before, the side effect profile and appropriate dosing are still unknown. In this pilot study, the investigators will determine the safety profile, efficacy and appropriate dosing of oral L-citrulline in preterm infants. In the future, information from this study will be utilized to conduct a randomized placebo-controlled trial to evaluate the role of L-citrulline supplementation in treating BPD\\_PH.', 'detailedDescription': "Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in preterm infants (PI). Preterm birth causes disruption in pulmonary vascular growth that leads to decreased vascular surface area that increases pulmonary vascular resistance (PVR). Increased PVR leads to altered vasoreactivity and structural remodeling with intimal hyperplasia and increased muscularization of the small pulmonary arteries. There is no definite treatment for BPD\\_PH.\n\nNitric Oxide: Nitric Oxide (NO) is a potent pulmonary vasodilator. Endothelial Nitric oxide synthase (eNOS) mediates production of NO from L-Arginine. L-citrulline is a precursor for L-arginine. L-Arginine is a precursor of nitric oxide (NO). In infants with BPD\\_PH, there are decreased levels of L-arginine \\& L-citrulline with decreased production of NO (measured by urinary nitrates \\& nitrites) leading to increased PVR. Several studies have shown the benefit of oral L-citrulline supplementation in increasing serum citrulline levels, increasing NO production and reducing pulmonary hypertension. Oral L-arginine was not effective in increasing NO production in previous studies and it was due to increased break down of oral L-arginine by intestinal arginases.\n\nSource of L-arginine in preterm infants: Routinely, extremely premature infants receive nutrition as total parental nutrition (TPN i.e. infants get infusion of protein, fat and carbohydrate via central venous line) that contains L-arginine (approximately 1mg/1mL) to metabolize ammonia via urea cycle. PIs receive adequate amount of intra venous arginine from TPN. Routinely, PIs are started with small volumes of enteral feeds which are increased slowly overtime. TPN is slowly decreased as enteral feeds are increasing. As the TPN is going down, intra venous L-arginine intake also drops down and ultimately when the PI are off TPN, they don't get any IV supplemental L-arginine.\n\nWhy oral citrulline: Enteral feeds (formula as well as breast milk) is poor source of arginine. Once PIs are on full enteral feed, an enteral feed is the only source of arginine. Interestingly, 40% of enteral arginine gets metabolized by arginase enzyme present in intestine. We speculate that plasma levels of arginine drop once TPN is discontinued and infants are on full feeds. Oral L-arginine has poor bio-availability that is why oral L-arginine supplementation does not increase blood levels of arginine. Since oral citrulline has high bioavailability, the best way to increase serum arginine levels is by oral citrulline supplementation. Oral supplementation of L-citrulline in preterm infants once they are off TPN will likely to increase arginine levels and NO production.\n\nSafety of oral citrulline: L-citrulline has been safely used for decades in patients with urea cycle defects. It has been used in pediatric patients with sickle cell disease and in infants undergoing cardiac surgery. No side effects were reported in these studies. In a study in newborn rats exposed to hyperoxia, L-citrulline caused a marked increase in arginase-2 expression in the lungs and this could have an impact on lung development and remodeling. However, this is only a theoretical risk."}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['CHILD'], 'maximumAge': '30 Weeks', 'healthyVolunteers': False, 'eligibilityCriteria': "Inclusion Criteria:\n\n* Infants less than or equal to 30 weeks' gestational age born at UTMB, Galveston.\n* Parents have provided informed consent/assent in a manner that is approved by the IRB\n\nExclusion Criteria:\n\n* Known congenital or chromosomal anomalies.\n* Congenital heart disease affecting cardio-respiratory system (other than PDA, PFO or ASD)\n* Necrotizing enterocolitis, sepsis, or any condition requiring surgery prior to recruitment"}, 'identificationModule': {'nctId': 'NCT03649932', 'briefTitle': 'Enteral L Citrulline Supplementation in Preterm Infants - Safety, Efficacy and Dosing', 'organization': {'class': 'OTHER', 'fullName': 'The University of Texas Medical Branch, Galveston'}, 'officialTitle': 'Enteral L Citrulline Supplementation in Preterm Infants - Safety, Efficacy and Dosing', 'orgStudyIdInfo': {'id': '17-0194'}}, 'armsInterventionsModule': {'armGroups': [{'type': 'EXPERIMENTAL', 'label': 'L-citrulline 100 mg/kg/day', 'description': '50 mg/kg given two times a day (100 mg/kg/day) for total 7 days.', 'interventionNames': ['Dietary Supplement: Enteral L-citrulline']}, {'type': 'EXPERIMENTAL', 'label': 'L-citrulline 200 mg/kg/day', 'description': '100 mg/kg given two times a day (200 mg/kg/day) for total 7 days', 'interventionNames': ['Dietary Supplement: Enteral L-citrulline']}, {'type': 'EXPERIMENTAL', 'label': 'L-citrulline 300 mg/kg/day', 'description': '150 mg/kg given two times a day (300 mg/kg/day) for total 7 days.', 'interventionNames': ['Dietary Supplement: Enteral L-citrulline']}], 'interventions': [{'name': 'Enteral L-citrulline', 'type': 'DIETARY_SUPPLEMENT', 'description': 'L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.\n\nAdministration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.\n\nStudy drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.', 'armGroupLabels': ['L-citrulline 100 mg/kg/day', 'L-citrulline 200 mg/kg/day', 'L-citrulline 300 mg/kg/day']}]}, 'contactsLocationsModule': {'locations': [{'zip': '77550', 'city': 'Galveston', 'state': 'Texas', 'country': 'United States', 'facility': 'University of Texas Medical Branch', 'geoPoint': {'lat': 29.30135, 'lon': -94.7977}}], 'overallOfficials': [{'name': 'Amna Investigator, MD', 'role': 'PRINCIPAL_INVESTIGATOR', 'affiliation': 'University of Texas'}]}, 'ipdSharingStatementModule': {'ipdSharing': 'NO'}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'The University of Texas Medical Branch, Galveston', 'class': 'OTHER'}, 'responsibleParty': {'type': 'SPONSOR'}}}}