Glutamine Supplementation to Prevent Death or Infection in Extremely Premature Infants (Glutamine)

Randomized Controlled Trial of Parenteral Glutamine Supplementation for Extremely-Low-Birth-Weight (ELBW) Infants

This large multicenter double-masked clinical trial tested whether supplementation of standard neonatal parenteral nutrition with glutamine would reduce the risk of death or late-onset sepsis in extremely-low-birth-weight (ELBW, less than or equal to 1000 gm) infants. Neonates with birth weights of 401-1000gm were randomized to standard TrophAmine or TrophAmine supplemented with glutamine before 72 hours and continued until the infants are tolerating full enteral feedings.

Study Overview

• Status: Completed
• Conditions: Sepsis; Infant, Small for Gestational Age; Infant, Premature; Infant, Low Birth Weight; Infant, Newborn
• Intervention / Treatment: Drug: Glutamine; Drug: Placebo

Detailed Description

Meeting the protein and energy requirements of extremely premature infants in early postnatal life requires early hyperalimentation and the gradual introduction of enteral feedings. Glutamine, which is the most abundant amino acid in the human body and taken up in greatest quantity by the fetus from the placenta, is not routinely provided in neonatal parenteral nutrition preparations.

This large multicenter double-masked clinical trial tested whether supplementation of standard neonatal parenteral nutrition with glutamine would reduce the risk of death or late-onset sepsis in extremely-low-birth-weight (ELBW, less than or equal to 1000 gm) infants. Neonates with birth weights of 401-1000gm were randomized to standard TrophAmine or TrophAmine supplemented with glutamine before 72 hours and continued until the infants are tolerating full enteral feedings.

Infants received a neurodevelopmental assessment by masked, certified examiners at 18-22 months postmenstrual age.

• Study Type: Interventional
• Enrollment (Actual): 1433
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University
    • San Diego, California, United States, 92103-8774
      • University of California at San Diego
  • Connecticut
    • New Haven, Connecticut, United States, 06504
      • Yale University
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Emory University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • RTI International
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Cincinnati Children's Medical Center
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University, Rainbow Babies and Children's Hospital
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Brown University, Women & Infants Hospital of Rhode Island
  • Texas
    • Dallas, Texas, United States, 75235
      • University Of Texas Southwestern Medical Center At Dallas
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 days (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 401-1000 gm
• More than 12 hrs and less than 72 hrs after birth; intravenous access
• Parental consent

Exclusion Criteria:

• One or more major congenital anomalies
• Infants meeting criteria for terminal illness
• Congenital nonbacterial infection with overt signs at birth

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Glutamine; TrophAmine (B. Braun/McGaw) with cysteine hydrochloride (40mg/gm amino acids) with L-glutamine added (20% of the total amount of amino acids)	Drug: Glutamine; Infants randomized to glutamine supplementation will receive glutamine any time that parenteral nutrition is required during the first 120 days of hospitalization.; Other Names: L-Glutamine; TrophAmine
Placebo Comparator: Placebo; Standard TrophAmine (B. Braun/McGaw) with cysteine hydrochloride (40mg/gm amino acids)	Drug: Placebo; TrophAmine given any time that parenteral nutrition is required during the first 120 days of hospitalization.; Other Names: TrophAmine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Death or late-onset sepsis	At hospital discharge

Secondary Outcome Measures

Outcome Measure	Time Frame
Tolerance of enteral feeding (number of days to reach full enteral feeds) and decrease number of episodes of feeding intolerance	At hospital discharge
Necrotizing Enterocolitis	At hospital discharge
Episodes of late-onset sepsis	At hospital discharge
Growth (days to reach 1500 grams)	At hospital discharge
Number of days on parenteral nutrition	At hospital discharge
Length of stay in NICU	At hospital discharge
Neurodevelopmental outcome	18-22 months corrrected age
Levels of pro-inflammatory cytokines	In the perinatal period

Collaborators and Investigators

• Sponsor: NICHD Neonatal Research Network
• Collaborators: National Center for Research Resources (NCRR)
• Investigators: Principal Investigator: Jon E. Tyson, MD MPH, The University of Texas Health Science Center, Houston; Principal Investigator: Abbot R. Laptook, MD, University of Texas Southwestern Medical Center; Principal Investigator: William Oh, MD, Women and Infants Hospital, Brown University

Publications and helpful links

General Publications

• Amari S, Shahrook S, Namba F, Ota E, Mori R. Branched-chain amino acid supplementation for improving growth and development in term and preterm neonates. Cochrane Database Syst Rev. 2020 Oct 2;10(10):CD012273. doi: 10.1002/14651858.CD012273.pub2.
• Poindexter BB, Ehrenkranz RA, Stoll BJ, Koch MA, Wright LL, Oh W, Papile LA, Bauer CR, Carlo WA, Donovan EF, Fanaroff AA, Korones SB, Laptook AR, Shankaran S, Stevenson DK, Tyson JE, Lemons JA; National Institute of Child Health and Human Development Neonatal Research Network. Effect of parenteral glutamine supplementation on plasma amino acid concentrations in extremely low-birth-weight infants. Am J Clin Nutr. 2003 Mar;77(3):737-43. doi: 10.1093/ajcn/77.3.737.
• Poindexter BB, Ehrenkranz RA, Stoll BJ, Wright LL, Poole WK, Oh W, Bauer CR, Papile LA, Tyson JE, Carlo WA, Laptook AR, Narendran V, Stevenson DK, Fanaroff AA, Korones SB, Shankaran S, Finer NN, Lemons JA; National Institute of Child Health and Human Development Neonatal Research Network. Parenteral glutamine supplementation does not reduce the risk of mortality or late-onset sepsis in extremely low birth weight infants. Pediatrics. 2004 May;113(5):1209-15. doi: 10.1542/peds.113.5.1209.
• Oh W, Poindexter BB, Perritt R, Lemons JA, Bauer CR, Ehrenkranz RA, Stoll BJ, Poole K, Wright LL; Neonatal Research Network. Association between fluid intake and weight loss during the first ten days of life and risk of bronchopulmonary dysplasia in extremely low birth weight infants. J Pediatr. 2005 Dec;147(6):786-90. doi: 10.1016/j.jpeds.2005.06.039.
• Poindexter BB, Langer JC, Dusick AM, Ehrenkranz RA; National Institute of Child Health and Human Development Neonatal Research Network. Early provision of parenteral amino acids in extremely low birth weight infants: relation to growth and neurodevelopmental outcome. J Pediatr. 2006 Mar;148(3):300-305. doi: 10.1016/j.jpeds.2005.10.038.
• Vohr BR, Poindexter BB, Dusick AM, McKinley LT, Wright LL, Langer JC, Poole WK; NICHD Neonatal Research Network. Beneficial effects of breast milk in the neonatal intensive care unit on the developmental outcome of extremely low birth weight infants at 18 months of age. Pediatrics. 2006 Jul;118(1):e115-23. doi: 10.1542/peds.2005-2382.
• Vohr BR, Poindexter BB, Dusick AM, McKinley LT, Higgins RD, Langer JC, Poole WK; National Institute of Child Health and Human Development National Research Network. Persistent beneficial effects of breast milk ingested in the neonatal intensive care unit on outcomes of extremely low birth weight infants at 30 months of age. Pediatrics. 2007 Oct;120(4):e953-9. doi: 10.1542/peds.2006-3227.
• Meinzen-Derr J, Poindexter B, Wrage L, Morrow AL, Stoll B, Donovan EF. Role of human milk in extremely low birth weight infants' risk of necrotizing enterocolitis or death. J Perinatol. 2009 Jan;29(1):57-62. doi: 10.1038/jp.2008.117. Epub 2008 Aug 21.
• Peralta-Carcelen M, Moses M, Adams-Chapman I, Gantz M, Vohr BR; NICHD Neonatal Research Network; National Institutes of Health. Stability of neuromotor outcomes at 18 and 30 months of age after extremely low birth weight status. Pediatrics. 2009 May;123(5):e887-95. doi: 10.1542/peds.2008-0135.

Helpful Links

• NICHD Neonatal Research Network
• Click here for the Cochrane review "Glutamine supplementation for preventionof morbidity in the preterm infant."
• NICHD Pregnancy & Perinatology Branch

Study record dates

Study Major Dates

• Study Start: July 1, 1999
• Primary Completion (Actual): December 1, 2000
• Study Completion (Actual): August 1, 2001

Study Registration Dates

• First Submitted: June 1, 2000
• First Submitted That Met QC Criteria: June 1, 2000
• First Posted (Estimate): June 2, 2000

Study Record Updates

• Last Update Posted (Estimate): June 8, 2015
• Last Update Submitted That Met QC Criteria: June 3, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: Nutrition; Glutamine; Prematurity; NICHD Neonatal Research Network; Extremely Low Birth Weight (ELBW) infants; Total parenteral nutrition; Very low birth weight (VLBW) infants
• Additional Relevant MeSH Terms: Body Weight; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth; Birth Weight; Pharmaceutical Solutions; Parenteral Nutrition Solutions; Amino-acid, glucose, and electrolyte solution
• Other Study ID Numbers: NICHD-NRN-0020; U10HD021364 (U.S. NIH Grant/Contract); U10HD021373 (U.S. NIH Grant/Contract); U10HD021385 (U.S. NIH Grant/Contract); U10HD027851 (U.S. NIH Grant/Contract); U10HD027853 (U.S. NIH Grant/Contract); U10HD027856 (U.S. NIH Grant/Contract); U10HD027871 (U.S. NIH Grant/Contract); U10HD027880 (U.S. NIH Grant/Contract); U10HD027904 (U.S. NIH Grant/Contract); U10HD034216 (U.S. NIH Grant/Contract); U10HD021415 (U.S. NIH Grant/Contract); U10HD027881 (U.S. NIH Grant/Contract); M01RR008084 (U.S. NIH Grant/Contract); M01RR006022 (U.S. NIH Grant/Contract); M01RR000750 (U.S. NIH Grant/Contract); M01RR000070 (U.S. NIH Grant/Contract); M01RR000997 (U.S. NIH Grant/Contract); U10HD021397 (U.S. NIH Grant/Contract); U10HD034167 (U.S. NIH Grant/Contract); M01RR001032 (U.S. NIH Grant/Contract); U01HD036790 (U.S. NIH Grant/Contract)