Efficacy and Mechanisms of GLN Dipeptide in the SICU (GLND)
|ClinicalTrials.gov Identifier: NCT00248638|
Recruitment Status : Completed
First Posted : November 4, 2005
Results First Posted : February 13, 2014
Last Update Posted : January 23, 2018
Relative glutamine (GLN) deficiency may contribute to morbidity and mortality in surgical intensive care unit (SICU) patients. During critical illness, GLN utilization by the immune system, gut mucosa and other tissues exceeds endogenous production and plasma GLN concentrations decrease, which may contribute to cellular dysfunction and increase nosocomial infection risk and mortality. Conventional GLN-free parenteral nutrition (PN) has a limited impact on SICU outcomes and does not repair the GLN deficit. Recent pilot data show that GLN dipeptide-supplemented PN decreases nosocomial infections and improves clinical outcomes in SICU patients. The process of benefit is poorly understood, but animal and human data suggest that GLN treatment correlates with a) up-regulation of cytoprotective molecules in blood and tissues [e.g, GSH, specific heat shock proteins (HSPs) and GLN]; and b) improved epithelial barrier defenses and immune cell number and function. Properties of L-GLN limit provision in solution, but the GLN dipeptide alanyl-GLN (AG) confers stability and solubility in PN (AG-PN). Investigators propose a multicenter, double-blind, randomized, controlled phase III trial based on our pilot data to test the hypothesis that AG-PN improves clinical outcomes in SICU patients requiring PN after cardiac, vascular or colonic operations. Subjects will receive either standard GLN-free PN or isocaloric, isonitrogenous, AG-PN until enteral feeds are established. Specific Aim 1 is to determine whether AG-PN decreases hospital mortality, nosocomial infection and other important indices of morbidity. Specific Aim 2 is to obtain novel, mechanistically relevant observational data in the Aim 1 subjects on whether AG-PN a) increases serial blood levels of GSH, HSP-70 and -27, and GLN; b) decreases the presence in serum of the bacterial products flagellin and LPS and the adaptive immune response to these mediators; and c) improves key indices of innate/adaptive immunity. This study is designed to delineate the clinical benefit of a major new nutrition support strategy in high-risk SICU patients.
|Condition or disease||Intervention/treatment||Phase|
|Critical Illness||Drug: Glutamine dipeptide with 15% Clinisol Drug: 15% Clinisol||Phase 3|
Overview: Relative deficiency of glutamine (GLN) appears to contribute to morbidity and mortality in surgical intensive care unit (SICU) patients, but conventional nutrition support does not repair this deficit. GLN requirements increase during critical illness when utilization by the immune system, gut mucosa and other tissues exceeds endogenous production. GLN depletion under these conditions may contribute to hospital morbidity and mortality. Conventional parenteral nutrition (PN) does not contain GLN and thus does not prevent GLN depletion in catabolic patients. However, a pilot study and other reports strongly suggest that GLN-supplemented PN improves metabolic and clinical outcomes in critically ill patients. Underlying mechanisms for GLN action are poorly understood, but may involve systemic upregulation of the cytoprotective molecules glutathione (GSH), specific heat shock proteins (HSP) and GLN itself, improved gut barrier defenses, and improved innate and/or adaptive immune function. Properties of L-GLN limit provision in PN, but the dipeptide alanyl-glutamine (AG) confers stability and solubility in PN solutions. The pilot study demonstrated a marked decrease in nosocomial infection, improved indices of organ function, and a possible decrease in hospital mortality in SICU patients receiving AG-supplemented PN (AG-PN) versus standard, GLN-free PN (STD-PN). Investigators propose a multi-center, double-blind, controlled, Phase III trial, based on a pilot study, that will determine the effect of parenteral GLN on important clinical outcomes in patients requiring SICU care and PN after cardiac, vascular or colonic surgery. Investigators also propose to obtain needed hypothesis-generating, descriptive data from the Aim 1 study subjects to inform subsequent, truly mechanistic studies of GLN action in animal and human models of surgical critical illness. Study subjects will be randomized on an intent-to-treat basis to receive AG-PN or isonitrogenous, isocaloric STD-PN until enteral feeding is established.
- SICU patients receiving PN supplemented with GLN dipeptide (AG-PN) will demonstrate improved clinical outcomes compared to patients receiving STD-PN.
- Administration of AG-PN in the Aim 1 study subjects: a) increases serial blood levels of specific cytoprotective molecules and improves systemic redox status; b) is associated with decreased serum positivity for the bacterial products flagellin and lipopolysaccharide ( LPS) and the adaptive immune response to these mediators; and c) improves key indices of innate/adaptive immunity.
Aim 1: To perform a Phase III randomized controlled trial (RCT) to determine whether AG-PN decreases hospital mortality, nosocomial infections, and other indices of hospital morbidity versus STD-PN in SICU patients. The study will test whether AG-PN: decreases hospital mortality and the incidence of nosocomial infection (primary endpoints) in SICU patients after cardiac, vascular or colonic surgery. We will also determine whether AG-PN decreases total hospital infections, bloodstream infections (BSI), infections due to Staphylococcus aureus or fungal species, the number of days patients require mechanical ventilation, the SICU and total hospital length of stay and the 6-month mortality rate (secondary endpoints).
Aim 2: To determine in the Aim 1 study subjects whether AG-PN: a) increases systemic blood concentrations of the cytoprotective molecules GSH, HSP-70, HSP-27 and GLN and improves systemic GSH and cysteine redox status; b) is associated with decreased serum positivity for the bacterial products flagellin and LPS and titers of anti-flagellin and anti-LPS immunoglobulin M (IgM), immunoglobulin A (IgA) and immunoglobulin G (IgG); and c) improves key indices of innate/adaptive immune cell function.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||150 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Triple (Participant, Care Provider, Investigator)|
|Official Title:||Phase III Study on the Efficacy of Glutamine Dipeptide-Supplemented Parenteral Nutrition in Surgical ICU Patients|
|Study Start Date :||September 2006|
|Primary Completion Date :||December 2012|
|Study Completion Date :||December 2012|
Active Comparator: Glutamine dipeptide
Glutamine dipeptide supplemented nutrition to be given to participants.
Drug: Glutamine dipeptide with 15% Clinisol
Subjects randomized to AG-PN will receive PN containing 0.5 g/kg/day of L alanyl L GLN (AG) dipeptide (Dipeptiven 20%; Fresenius-Kabi) and 1.0 g/kg/day of 15% Clinisol (Baxter Inc., Deerfield, IL) AA solution (total = 1.5 g/kg/day, with AG replacing 1/3 of Clinisol AA). The amount of GLN dipeptide administered each day will be determined by daily PN volume intake data.
Placebo Comparator: standard
Participants given standard nutrition without glutamine dipeptide
Drug: 15% Clinisol
Subjects randomized to STD-PN will receive 1.5 g/kg/day of 15% Clinisol. The amount of Clinisol administered each day will be determined by daily PN volume intake data.
- Hospital Mortality Rate [ Time Frame: Current Hospitalization (Up to 6 Months) ]Number of participants who died during hospitalization.
- Percentage of Patients Who do Not Develop Hospital Infections [ Time Frame: Current Hospitalization (Up to 6 Months) ]Subjects remaining infection-free during the hospitalization.
- Mean Glutathione Level [ Time Frame: Baseline, Day 3, Day 7, Day 14, Day 21, Day 28 ]Glutathione (GSH) levels will be measured in µM (micro moles) from baseline to day 28. Higher levels indicate a higher GSH presence.
- Mean Heat Shock Proteins Level, HSP70 [ Time Frame: Baseline, Day 3, Day 7, Day 14, Day 21, Day 28 ]Levels of the heat shock protein,HSP70, will be measured in ng/mL from baseline to day 28. Higher levels indicate a higher protein presence.
- Mean Heat Shock Proteins Level, HSP27 [ Time Frame: Baseline, Day 3, Day 7, Day 14, Day 21, Day 28 ]Levels of the heat shock protein, HSP27, will be measured in pg/mL from baseline to day 28. Higher levels indicate a higher protein presence.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00248638
|United States, Colorado|
|University of Colorado Health Sciences Center|
|Denver, Colorado, United States, 80262|
|United States, Georgia|
|Atlanta, Georgia, United States, 30322|
|United States, Rhode Island|
|The Miriam Hospital/Brown University|
|Providence, Rhode Island, United States, 02906|
|United States, Tennessee|
|Nashville, Tennessee, United States, 37212-2713|
|United States, Wisconsin|
|University Of Wisconsin Hospital|
|Madison, Wisconsin, United States, 53792|
|Principal Investigator:||Thomas R Ziegler, MD||Emory University|