Trial of Glutamine and Antioxidant Supplementation in Critically Ill Patients (REDOXS)

• ClinicalTrials.gov Identifier: NCT00133978
• Recruitment Status: Completed
• First Posted: August 24, 2005
• Results First Posted: September 9, 2014
• Last Update Posted: September 9, 2014
• Sponsor: Daren K. Heyland
• Collaborator: Fresenius Kabi
• Information provided by (Responsible Party): Daren K. Heyland, Clinical Evaluation Research Unit at Kingston General Hospital

Tracking Information

• First Submitted Date: August 22, 2005
• First Posted Date: August 24, 2005
• Results First Submitted Date: April 29, 2013
• Results First Posted Date: September 9, 2014
• Last Update Posted Date: September 9, 2014
• Study Start Date: April 2005
• Actual Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 26, 2014)

28-day Mortality [ Time Frame: Day 28 ]

28-day mortality/status: at 28 days after randomization;

• Original Primary Outcome Measures (submitted: August 22, 2005): The primary outcome for this study is 28-day mortality.

Current Secondary Outcome Measures (submitted: August 26, 2014)

• ICU Length of Stay [ Time Frame: Day 28 ]
  Measure of the duration of participant stay in the ICU
• ICU Acquired Infection [ Time Frame: Day 28 ]
  We have made some modifications the definitions developed by the International Sepsis Forum Consensus Conference (CCM 2005;33:1538-1548) to operationalize the adjudication of infections in this trial. We grade the certainty of the diagnosis of infection using definitions for 'Definite', 'Probable', and 'Possible' for each category of infection. The categories of infection are: Deep surgical wound infection, Incisional (or superficial) surgical wound infection, Skin and soft-tissue infection (non-surgical) (SSTS), Catheter-related blood stream infections (CRI), Primary blood stream infections (BSI), Lower urinary tract infection, Upper urinary tract infection, Intra abdominal infection, Sinusitis, Lower respiratory tract infection (excluding pneumonia), ICU Acquired Pneumonia and Other.
• Hospital Length of Stay [ Time Frame: 6 months (from ICU admission) ]
  Measure of the duration of the participant's hospital stay

• Original Secondary Outcome Measures (submitted: August 22, 2005): The secondary outcomes are duration of stay in ICU, adjudicated diagnosis of infection, multiple organ dysfunction, duration of mechanical ventilation, hospital length of stay, and health-related quality of life at 3 and 6 months.
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Trial of Glutamine and Antioxidant Supplementation in Critically Ill Patients
• Official Title: REducing Deaths Due to OXidative Stress The REDOXS© Study
• Brief Summary: The purpose of this study is to determine whether providing high dose glutamine and antioxidants to critically ill patients will be associated with improved survival.

Detailed Description

Background:

Critically ill patients experience a degree of hyperinflammation, cellular immune dysfunction, and oxidative stress. Supplementation with key nutrients, like glutamine and antioxidants, is most likely to have a favourable effect on these physiological parameters leading to an improvement in clinical outcomes. The results of two separate meta-analyses suggested that glutamine and antioxidants may be associated with improved survival. We have recently completed a dosing study to determine the maximal tolerable dose (MTD) of glutamine dipeptides and antioxidants in critically ill patients with evidence of hypoperfusion. The purpose of this protocol is to evaluate the effect of high dose glutamine and antioxidant supplementation on mortality in a large scale randomized trial.

Study Intervention:

Patients will be randomized to receive glutamine supplementation or antioxidant supplementation (or respective placebo).

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Factorial Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Critical Illness
• Sepsis
• Multiple Organ Failure

Intervention

• Other: Glutamine
  0.35 gm/kg/day parenterally and 30 gms/day enterally
• Other: Antioxidants
  500 micrograms of selenium/day parenterally and selenium 300 microgram, zinc 20 mg, beta carotene 10 mg, vitamine E 500 mg and vitamin C 1500 mg per day enterally
• Other: Glutamine + Antioxidants
  0.35 g/kg/day glutamine parenterally and 30 g/day of glutamine enterally. 500 mcg selenium parenterally plus the following administered enterally: selenium 300 mcg, zing 20 mg, beta-carotene 10 mg, vitamin E 500 mg and vitamin C 1500mg
  Other Name: Dipeptiven, Microselenium/Selenium injection/selenase, EN REDOX formula (from Fresenius Kabi, Germany)
• Other: Placebo
  Normal saline intravenously and EN placebo formula (from Fresenius Kabi, Germany)

Study Arms

• Experimental: Glutamine
  Glutamine supplementation
  Intervention: Other: Glutamine
• Experimental: Antioxidants
  Antioxidant supplementation
  Intervention: Other: Antioxidants
• Experimental: Glutamine + Antioxidants
  Glutamine and antioxidant supplementation
  Intervention: Other: Glutamine + Antioxidants
• Placebo Comparator: Placebo
  Non-isonitrogenic, iso-caloric placebo solution
  Intervention: Other: Placebo

Publications *

• Heyland DK, Dhaliwal R, Drover JW, Gramlich L, Dodek P; Canadian Critical Care Clinical Practice Guidelines Committee. Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. JPEN J Parenter Enteral Nutr. 2003 Sep-Oct;27(5):355-73.
• Heyland DK, Dhaliwal R, Suchner U, Berger MM. Antioxidant nutrients: a systematic review of trace elements and vitamins in the critically ill patient. Intensive Care Med. 2005 Mar;31(3):327-37. Epub 2004 Dec 17. Review.
• Novak F, Heyland DK, Avenell A, Drover JW, Su X. Glutamine supplementation in serious illness: a systematic review of the evidence. Crit Care Med. 2002 Sep;30(9):2022-9. Review.
• Heyland D, Muscedere J, Wischmeyer PE, Cook D, Jones G, Albert M, Elke G, Berger MM, Day AG; Canadian Critical Care Trials Group. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013 Apr 18;368(16):1489-97. doi: 10.1056/NEJMoa1212722. Erratum in: N Engl J Med. 2013 May 9;368(19):1853. Dosage error in article text..
• Heyland DK, Elke G, Cook D, Berger MM, Wischmeyer PE, Albert M, Muscedere J, Jones G, Day AG; Canadian Critical Care Trials Group. Glutamine and antioxidants in the critically ill patient: a post hoc analysis of a large-scale randomized trial. JPEN J Parenter Enteral Nutr. 2015 May;39(4):401-9. doi: 10.1177/0148607114529994. Epub 2014 May 5.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 9, 2012): 1223
• Original Enrollment (submitted: August 22, 2005): 1200
• Actual Study Completion Date: May 2012
• Actual Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Mechanically ventilated patients > or = 18 years old
• 2 or more organ failures related to acute illness

Exclusion Criteria:

• > 24 hours from admission to ICU
• Patients who are moribund
• Lack of commitment to aggressive care
• Absolute contraindication to enteral nutrients
• Severe acquired brain injury
• Routine elective cardiac surgery
• Primary admission of burns > 30% body surface area
• Weight < 50 kgms or > 200 kgms
• Pregnant or lactating patients
• Previous randomization in this study
• Enrollment in a related ICU interventional study
• Child's class C liver disease
• Metastatic cancer with life expectancy < 6 months
• Seizure disorder requiring anticonvulsant medication

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Canada, Germany, Switzerland, United States

Administrative Information

• NCT Number: NCT00133978
• Other Study ID Numbers: REDOXS; EudraCT-No: 2007-001831-73
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Daren K. Heyland, Clinical Evaluation Research Unit at Kingston General Hospital
• Study Sponsor: Daren K. Heyland
• Collaborators: Fresenius Kabi

Investigators

• Study Chair: Daren Heyland, MD; Clinical Evaluation Research Unit, Kingston General Hospital

• PRS Account: Clinical Evaluation Research Unit at Kingston General Hospital
• Verification Date: August 2014