REDOXS: Trial of Glutamine and Antioxidant Supplementation in Critically Ill Patients

• Sponsor: Daren K. Heyland (Other)
• Overall Status: Completed
• CT.gov ID: NCT00133978
• Collaborator: Fresenius Kabi (Industry)
• Enrollment: 1,223
• Locations: 34
• Arms: 4
• Duration (Months): 85
• Patients Per Site: 36
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Critical Illness; Sepsis; Multiple Organ Failure	Other: Glutamine; Other: Antioxidants; Other: Glutamine + Antioxidants; Other: Placebo	N/A

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 Design

• Study Type: Interventional
• Actual Enrollment: 1223 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: REducing Deaths Due to OXidative Stress The REDOXS© Study
• Study Start Date: Apr 1, 2005
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: May 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Glutamine Glutamine supplementation	Other: Glutamine; 0.35 gm/kg/day parenterally and 30 gms/day enterally
Experimental: Antioxidants Antioxidant supplementation	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
Experimental: Glutamine + Antioxidants Glutamine and antioxidant supplementation	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 Names: Dipeptiven, Microselenium/Selenium injection/selenase, EN REDOX formula (from Fresenius Kabi, Germany)
Placebo Comparator: Placebo Non-isonitrogenic, iso-caloric placebo solution	Other: Placebo; Normal saline intravenously and EN placebo formula (from Fresenius Kabi, Germany)

Outcome Measures

Primary Outcome Measures

1. 28-day Mortality [Day 28]

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

Secondary Outcome Measures

1. ICU Length of Stay [Day 28]

   Measure of the duration of participant stay in the ICU

2. ICU Acquired Infection [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.

3. Hospital Length of Stay [6 months (from ICU admission)]

   Measure of the duration of the participant's hospital stay

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Univ. of Colorado at Denver and Health Sciences Center	Aurora	Colorado	United States	80045
2	University of Louisville	Louisville	Kentucky	United States	40202
3	Miami Valley Hospital	Dayton	Ohio	United States	45409
4	University of Texas	Houston	Texas	United States	6431
5	Fletcher Allan Centre	Burlington	Vermont	United States	05401
6	UZ Brussels	Brussels		Belgium
7	University Hospital	Liege		Belgium	B-4000
8	Royal Alexandra Hospital	Edmonton	Alberta	Canada	T5H 3V9
9	Grey Nun's Hospital, Edmonton	Edmonton	Alberta	Canada	T6L 5X8
10	Vancouver Hospital	Vancouver	British Columbia	Canada	V5Z 1C6
11	St Paul's Hospital	Vancouver	British Columbia	Canada	V6Z 1Y6
12	Royal Jubilee Hospital	Victoria	British Columbia	Canada	V8R 1J8
13	Victoria General Hospital	Victoria	British Columbia	Canada	V8Z 6R5
14	St. Boniface General Hospital	Winnipeg	Manitoba	Canada	R2H 2A6
15	Health Science Centre	Winnipeg	Manitoba	Canada	R3A 1R9
16	Capital Health Queen Elizabeth II HSC	Halifax	Nova Scotia	Canada	B3H 2Y9
17	St Joseph's Healthcare	Hamilton	Ontario	Canada	L8N 4A6
18	Kingston General Hospital	Kingston	Ontario	Canada	K7L 2V7
19	London HSC Victoria Campus, ON	London	Ontario	Canada	N6A 5W9
20	Ottawa Hospital	Ottawa	Ontario	Canada	K1H 8H6
21	Ottawa Hospital Civic Hospital	Ottawa	Ontario	Canada	K1Y 4E9
22	Sunnybrook & Women's College, Toronto	Toronto	Ontario	Canada	M4N 3M5
23	Mt Sinai Hospital	Toronto	Ontario	Canada	M5G 1X5
24	Hopital Maisonneuve-Rosemount	Montreal	Quebec	Canada	H1T 2M4
25	Royal Victoria Hospital	Montreal	Quebec	Canada	H3A 1A1
26	Montreal General	Montreal	Quebec	Canada	H3G 1A4
27	Hopital de Sacre-Coeur	Montreal	Quebec	Canada	H4J 1C5
28	Enfant-Jesus	Quebec		Canada	G1J 1Z4
29	Universitatsklinikum der Ernst-Moritz-Arndt-Universitat	Greifswald		Germany
30	Asklepios Kliniken Hamburg Altona	Hamburg		Germany
31	University Medical Center Schleswig-Holstein	Kiel		Germany	24105
32	Universitatsklinikum Schleswig-Holstein Campus Luebeck	Lubeck		Germany
33	CHUV	Lausanne		Switzerland	Ch-1011
34	University of Zurich	Zurich		Switzerland

Sponsors and Collaborators

• Daren K. Heyland
• Fresenius Kabi

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here for more information about this study: A Randomized Trial of Glutamine and Antioxidant Supplementation in Critically Ill Patients

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.

• Responsible Party: Daren K. Heyland, Director, Clinical Evaluation Research Unit at Kingston General Hospital
• ClinicalTrials.gov Identifier: NCT00133978
• Other Study ID Numbers: REDOXS; EudraCT-No: 2007-001831-73
• First Posted: Aug 24, 2005
• Last Update Posted: Jan 7, 2021
• Last Verified: Dec 1, 2020

• Keywords provided by Daren K. Heyland, Director, Clinical Evaluation Research Unit at Kingston General Hospital: randomized trial; antioxidants; glutamine; organ failure
• Additional relevant MeSH terms: Critical Illness; Multiple Organ Failure; Selenium; Antioxidants

Study Results

Participant Flow

Recruitment Details	This trial was conducted between April 2005 and December 2011 in 40 ICUs in participating countries after local jurisdictional and institutional Research Ethics Board approval.
Pre-assignment Detail	Written informed consent was obtained from patients or their legal representatives before enrollment.

Arm/Group Title	Glutamine	Antioxidants	Glutamine + Antioxidants	Placebo
Arm/Group Description	Glutamine supplementation 0.35 g/kg/day of glutamine intravenously based on ideal body weight, provided as 0.50 g/kg/day of the dipeptide alanyl-glutamine and 30 g/day enterally, provided as alanyl-glutamine and glycine-glutamine dipeptides.	Antioxidant supplementation 500 ug of selenium intravenously, and the following vitamins and minerals enterally-- selenium 300 g, zinc 20 mg, beta carotene 10 mg, vitamin E 500 mg, and vitamin C 1500 mg.	Glutamine and antioxidant supplementation 0.35 g/kg/day of glutamine intravenously based on ideal body weight, provided as 0.50 g/kg/day of the dipeptide alanyl-glutamine and 30 g/day enterally, provided as alanyl-glutamine and glycine-glutamine dipeptides. 500 ug of selenium intravenously , and the following vitamins and minerals enterally-- selenium 300 g, zinc 20 mg, beta carotene 10 mg, vitamin E 500 mg, and vitamin C 1500 mg.	Non-isonitrogenic, iso-caloric placebo solution
Period Title: Overall Study
STARTED	303	308	310	302
COMPLETED	301	307	310	300
NOT COMPLETED	2	1	0	2

Baseline Characteristics

Arm/Group Title	Glutamine	Antioxidants	Glutamine + Antioxidants	Placebo	Total
Arm/Group Description	Glutamine supplementation	Antioxidant supplementation	Glutamine and antioxidant supplementation	Non-isonitrogenic, iso-caloric placebo solution	Total of all reporting groups
Overall Participants	301	307	310	300	1218
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	161 53.5%	156 50.8%	145 46.8%	159 53%	621 51%
>=65 years	140 46.5%	151 49.2%	165 53.2%	141 47%	597 49%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.5 (15.0)	63.6 (14.3)	64.3 (14.0)	62.8 (13.7)	63.3 (14.3)
Sex: Female, Male (Count of Participants)
Female	110 36.5%	130 42.3%	130 41.9%	122 40.7%	492 40.4%
Male	191 63.5%	177 57.7%	180 58.1%	178 59.3%	726 59.6%
Region of Enrollment (participants) [Number]
Canada	259 86%	262 85.3%	263 84.8%	260 86.7%	1044 85.7%
United States	32 10.6%	34 11.1%	34 11%	31 10.3%	131 10.8%
Germany	6 2%	6 2%	5 1.6%	4 1.3%	21 1.7%
Belgium	1 0.3%	2 0.7%	5 1.6%	2 0.7%	10 0.8%
Switzerland	3 1%	3 1%	3 1%	3 1%	12 1%

Outcome Measures

1. Primary Outcome

Title	28-day Mortality
Description	28-day mortality/status: at 28 days after randomization;
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Glutamine	Antioxidants	Glutamine + Antioxidants	Placebo
Arm/Group Description	Glutamine supplementation	Antioxidant supplementation	Glutamine and antioxidant supplementation	Non-isonitrogenic, iso-caloric placebo solution
Measure Participants	301	307	310	300
Number [participants]	97 32.2%	89 29%	101 32.6%	76 25.3%

2. Secondary Outcome

Title	ICU Length of Stay
Description	Measure of the duration of participant stay in the ICU
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Glutamine	Antioxidants	Glutamine + Antioxidants	Placebo
Arm/Group Description	Glutamine supplementation	Antioxidant supplementation	Glutamine and antioxidant supplementation	Non-isonitrogenic, iso-caloric placebo solution
Measure Participants	301	307	310	300
Median (Inter-Quartile Range) [days]	8.9	8.9	8.9	8.3

3. Secondary Outcome

Title	ICU Acquired Infection
Description	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.
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Glutamine	No Glutamine	Antioxidants	No Antioxidants
Arm/Group Description	0.35 g/kg/day of glutamine intravenously based on ideal body weight, provided as 0.50 g/kg/day of the dipeptide alanyl-glutamine and 30 g/day enterally, provided as alanyl-glutamine and glycine-glutamine dipeptides.	Non-isonitrogenic, iso-caloric placebo solution	500 ug of selenium intravenously and the following vitamins and minerals enterally-- selenium 300 ug, zinc 20 mg, beta carotene 10 mg, vitamin E 500 mg, and vitamin C 1500 mg.	Non-isonitrogenic, iso-caloric placebo solution
Measure Participants	611	607	617	601
All Infections	183 60.8%	166 54.1%	168 54.2%	181 60.3%
Infections classified as 'definite' or 'probable'	118 39.2%	120 39.1%	110 35.5%	128 42.7%
Microbiological Confirmed	92 30.6%	87 28.3%	83 26.8%	96 32%

4. Secondary Outcome

Title	Hospital Length of Stay
Description	Measure of the duration of the participant's hospital stay
Time Frame	6 months (from ICU admission)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Glutamine	Antioxidants	Glutamine + Antioxidants	Placebo
Arm/Group Description	Glutamine supplementation	Antioxidant supplementation	Glutamine and antioxidant supplementation	Non-isonitrogenic, iso-caloric placebo solution
Measure Participants	301	307	310	300
Median (Inter-Quartile Range) [days]	17.1	16.0	16.9	16.5

Adverse Events

Time Frame	April 2005 and December 2011
Adverse Event Reporting Description	We collect data related to these hospitalized, critically ill patients' baseline illness in the CRF (e.g. abnormalities in oxygenation or ventilation, hemodynamic measures, etc). We reported changes in patients' baseline condition, events that are inconsistent with the underlying pathophysiology or progression of underlying disease, as SAEs.
Arm/Group Title	Glutamine		Antioxidants		Glutamine + Antioxidants		Placebo
Arm/Group Description	Glutamine supplementation 0.35 g/kg/day of glutamine intravenously based on ideal body weight, provided as 0.50 g/kg/day of the dipeptide alanyl-glutamine and 30 g/day enterally, provided as alanyl-glutamine and glycine-glutamine dipeptides.		Antioxidant supplementation 500 ug of selenium intravenously and the following vitamins and minerals enterally-- selenium 300 ug, zinc 20 mg, beta carotene 10 mg, vitamin E 500 mg, and vitamin C 1500 mg.		Glutamine and antioxidant supplementation 0.35 g/kg/day of glutamine intravenously based on ideal body weight, provided as 0.50 g/kg/day of the dipeptide alanyl-glutamine and 30 g/day enterally, provided as alanyl-glutamine and glycine-glutamine dipeptides. 500 ug of selenium intravenously and the following vitamins and minerals enterally-- selenium 300 ug, zinc 20 mg, beta carotene 10 mg, vitamin E 500 mg, and vitamin C 1500 mg.		Non-isonitrogenic, iso-caloric placebo solution
All Cause Mortality
	Glutamine		Antioxidants		Glutamine + Antioxidants		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Glutamine		Antioxidants		Glutamine + Antioxidants		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/301 (4.7%)		11/307 (3.6%)		11/310 (3.5%)		10/300 (3.3%)
Cardiac disorders
Cardiac Disorders	7/301 (2.3%)	7	2/307 (0.7%)	2	5/310 (1.6%)	5	5/300 (1.7%)	5
Eye disorders
Eye Disorders	0/301 (0%)	0	1/307 (0.3%)	1	0/310 (0%)	0	0/300 (0%)	0
Gastrointestinal disorders
GI Disease	2/301 (0.7%)	2	5/307 (1.6%)	5	3/310 (1%)	3	5/300 (1.7%)	5
Hepatobiliary disorders
Hepatobiliary Disorders	0/301 (0%)	0	0/301 (0%)	0	1/310 (0.3%)	1	0/300 (0%)	0
Nervous system disorders
Nervous System Disorders	4/301 (1.3%)	4	3/307 (1%)	3	2/310 (0.6%)	2	2/300 (0.7%)	2
Respiratory, thoracic and mediastinal disorders
Respiratory Disorders	0/301 (0%)	0	1/307 (0.3%)	1	0/310 (0%)	0	0/300 (0%)	0
Surgical and medical procedures
Procedural Complications	1/301 (0.3%)	1	0/307 (0%)	0	0/310 (0%)	0	2/300 (0.7%)	2
Vascular disorders
Vascular Disorders	0/301 (0%)	0	0/307 (0%)	0	1/310 (0.3%)	1	0/300 (0%)	0
Other (Not Including Serious) Adverse Events
	Glutamine		Antioxidants		Glutamine + Antioxidants		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/301 (0%)		0/307 (0%)		0/310 (0%)		0/300 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.