Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 44 of 68 for:    tpn

Enteral L Citrulline Supplementation in Preterm Infants - Safety, Efficacy and Dosing

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03649932
Recruitment Status : Recruiting
First Posted : August 28, 2018
Last Update Posted : October 23, 2018
Sponsor:
Information provided by (Responsible Party):
Amna Qasim, The University of Texas Medical Branch, Galveston

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Bronchopulmonary Dysplasia Bronchopulmonary Dysplasia Associated Pulmonary Hypertension Pulmonary Hypertension Premature Birth Chronic Lung Disease of Prematurity Dietary Supplement: Enteral L-citrulline Phase 1

Detailed Description:

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.

Nitric 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.

Source 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.

Why 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.

Safety 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.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 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).
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Enteral L Citrulline Supplementation in Preterm Infants - Safety, Efficacy and Dosing
Actual Study Start Date : September 25, 2018
Estimated Primary Completion Date : September 10, 2019
Estimated Study Completion Date : December 31, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Low Dose
50 mg/kg given two times a day (100 mg/kg/day) for total 7 days.
Dietary Supplement: Enteral 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.

Administration 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.

Study 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.


Experimental: Medium Dose
100 mg/kg given two times a day (200 mg/kg/day) for total 7 days
Dietary Supplement: Enteral 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.

Administration 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.

Study 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.


Experimental: High Dose
150 mg/kg given two times a day (300 mg/kg/day) for total 7 days.
Dietary Supplement: Enteral 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.

Administration 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.

Study 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.





Primary Outcome Measures :
  1. Change in plasma levels of L-arginine and L-citrulline as measured by LCMS approach [ Time Frame: During the week of intervention (day 0 - day 7) ]
    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.

  2. Safety of L-citrulline in preterm infants: Measured by at least one adverse event [ Time Frame: During the week of intervention (day 0 - day 7) ]
    Measured by at least one adverse event that are determined to be related to the study drug.

  3. Dose of enteral L-citrulline required to increase plasma level of > 37 micromol/L [ Time Frame: During the week of intervention (day 0 - day 7) ]
    Previous studies have shown that a plasma level of > 37 micromol/L was effective in preventing pulmonary hypertension.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   up to 30 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Infants less than or equal to 30 weeks' gestational age born at UTMB, Galveston.
  • Parents have provided informed consent/assent in a manner that is approved by the IRB

Exclusion Criteria:

  • Known congenital or chromosomal anomalies.
  • Congenital heart disease affecting cardio-respiratory system (other than PDA, PFO or ASD)
  • Necrotizing enterocolitis, sepsis, or any condition requiring surgery prior to recruitment

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): NCT03649932


Contacts
Layout table for location contacts
Contact: Sunil K Professor of Neonatology, MD 7133059772 skjain@utmb.edu
Contact: Amna Resident Physician, MD 2816277508 amnahqasim@gmail.com

Locations
Layout table for location information
United States, Texas
University of Texas Medical Branch Recruiting
Galveston, Texas, United States, 77550
Contact: Amna Qasim    281-627-7508    amqasim@utmb.edu   
Sub-Investigator: Sunil K Jain, MD         
Sub-Investigator: Varun Modi, MD         
Sponsors and Collaborators
The University of Texas Medical Branch, Galveston
Investigators
Layout table for investigator information
Principal Investigator: Amna Investigator, MD University of Texas

Publications:
Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, Hanna BD, Rosenzweig EB, Raj JU, Cornfield D, Stenmark KR, Steinhorn R, Thébaud 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. Erratum in: Circulation. 2016 Jan 26;133(4):e368.

Layout table for additonal information
Responsible Party: Amna Qasim, Principal Investigator, The University of Texas Medical Branch, Galveston
ClinicalTrials.gov Identifier: NCT03649932     History of Changes
Other Study ID Numbers: 17-0194
First Posted: August 28, 2018    Key Record Dates
Last Update Posted: October 23, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Amna Qasim, The University of Texas Medical Branch, Galveston:
Bronchopulmonary dysplasia
Pulmonary hypertension
Citrulline
Additional relevant MeSH terms:
Layout table for MeSH terms
Lung Diseases
Hypertension, Pulmonary
Bronchopulmonary Dysplasia
Premature Birth
Hypertension
Hyperplasia
Vascular Diseases
Cardiovascular Diseases
Respiratory Tract Diseases
Pathologic Processes
Obstetric Labor, Premature
Obstetric Labor Complications
Pregnancy Complications
Ventilator-Induced Lung Injury
Lung Injury
Infant, Premature, Diseases
Infant, Newborn, Diseases