Efficacy and Mechanisms of GLN Dipeptide in the SICU

NCT00248638 | Completed Phase 3 Results DMC

• 3 other identifiers: IRB00024944U01DK069322DK69322
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 5

Brief Summary

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. .

Conditions

Critical Illness

Outcome Measures

Primary Outcomes (2)

• Hospital Mortality Rate

  Number of participants who died during hospitalization.

  Current Hospitalization (Up to 6 Months)

• Percentage of Patients Who do Not Develop Hospital Infections

  Subjects remaining infection-free during the hospitalization.

  Current Hospitalization (Up to 6 Months)

Secondary Outcomes (3)

• Mean Glutathione Level

  Baseline, Day 3, Day 7, Day 14, Day 21, Day 28

• Mean Heat Shock Proteins Level, HSP70

  Baseline, Day 3, Day 7, Day 14, Day 21, Day 28

• Mean Heat Shock Proteins Level, HSP27

  Baseline, Day 3, Day 7, Day 14, Day 21, Day 28

Study Arms (2)

Glutamine dipeptide

ACTIVE COMPARATOR

Glutamine dipeptide supplemented nutrition to be given to participants.

Drug: Glutamine dipeptide with 15% Clinisol

standard

PLACEBO COMPARATOR

Participants given standard nutrition without glutamine dipeptide

Drug: 15% Clinisol

Interventions

Glutamine dipeptide with 15% Clinisol DRUG

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.

Also known as: Alanyl-glutamine Dipeptide, Dipeptiven

Glutamine dipeptide

15% Clinisol DRUG

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.

standard

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• \*Encephalopathy for GLND can be diagnosed only in non-chemically sedated patients by the primary critical care physicians or neurologist consultants and is defined as either a comatose state OR severe abnormalities diagnosed by electroencephalogram (EEG), OR if all of the following criteria are met: a) patient goes to sleep but is arousable to verbal and painful stimuli; does not open eyes spontaneously (decreased level of consciousness); b) patient exhibits severe confusion or complete disorientation when aroused (disorientation); c) patient exhibits severe lethargy or bizarre behavior (behavioral dysfunction); and d) patient exhibits inability to cooperate, asterixis, ataxia, clonus, decortication, decerebration, seizures, or rigidity (severe neuromuscular dysfunction).
• † Patients with malignant metastasis and terminal untreatable carcinoma will be excluded as per the operational definition agreed upon by the Data Safety and Monitoring Board (DSMB).
• ≠ Please note that the patient should be in the SICU at the initial PN hang time.

Sponsors & Collaborators

• Emory University: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (5)

University of Colorado Health Sciences Center

Denver, Colorado, 80262, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

The Miriam Hospital/Brown University

Providence, Rhode Island, 02906, United States

Location

Vanderbilt University

Nashville, Tennessee, 37212-2713, United States

Location

University Of Wisconsin Hospital

Madison, Wisconsin, 53792, United States

Location

Related Publications (1)

• Ziegler TR, May AK, Hebbar G, Easley KA, Griffith DP, Dave N, Collier BR, Cotsonis GA, Hao L, Leong T, Manatunga AK, Rosenberg ES, Jones DP, Martin GS, Jensen GL, Sax HC, Kudsk KA, Galloway JR, Blumberg HM, Evans ME, Wischmeyer PE. Efficacy and Safety of Glutamine-supplemented Parenteral Nutrition in Surgical ICU Patients: An American Multicenter Randomized Controlled Trial. Ann Surg. 2016 Apr;263(4):646-55. doi: 10.1097/SLA.0000000000001487.

  PMID: 26501700 DERIVED

MeSH Terms

Conditions

Critical Illness

Interventions

alanylglutamine

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Thomas R. Ziegler M.D.
• Organization: Emory University

Tzieg01@emory.edu

4047277354

Study Officials

• Thomas R Ziegler, MD

  Emory University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: November 3, 2005
• First Posted: November 4, 2005
• Study Start: September 1, 2006
• Primary Completion: December 1, 2012
• Study Completion: December 1, 2012
• Last Updated: January 23, 2018
• Results First Posted: February 13, 2014

Record last verified: 2018-01

Locations

US (5)