Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU)

• ClinicalTrials.gov Identifier: NCT02467621
• Recruitment Status: Completed
• First Posted: June 10, 2015
• Results First Posted: June 7, 2019
• Last Update Posted: November 15, 2022
• Sponsor: Dr. Morten Hylander Møller
• Collaborators: Rigshospitalet, Denmark; Copenhagen Trial Unit, Center for Clinical Intervention Research
• Information provided by (Responsible Party): Dr. Morten Hylander Møller, Scandinavian Critical Care Trials Group

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention
• Conditions: Gastrointestinal Bleeding; Stress Ulcers
• Interventions: Drug: Pantoprazole; Other: Saline (0.9%)
• Enrollment: 3350

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Proton Pump Inhibitor (PPI)	Normal Saline
Arm/Group Description	Pantoprazole 40 mg Pantoprazole: 40 mg x 1 daily intravenously from ICU admission to ICU discharge	Saline (0.9%) Saline (0.9%): 10 ml of isotonic saline x 1 daily intravenously from ICU admission to ICU discharge
Period Title: Overall Study
Started [1]	1645	1653
Completed [2]	1644	1647
Not Completed	1	6
[1] 52 patients were randomised in error BEFORE receiving the first dose of IMP/placebo. 3350-52=3298; [2] 1644/1647 in the secondary outcome analyses 1642/1640 in the primary outcome analysis

Baseline Characteristics

Arm/Group Title		Proton Pump Inhibitor (PPI)	Normal Saline	Total
Arm/Group Description		Pantoprazole 40 mg Pantoprazole: 40 mg x 1 daily intravenously from ICU admission to ICU discharge	Saline (0.9%) Saline (0.9%): 10 ml of isotonic saline x 1 daily intravenously from ICU admission to ICU discharge	Total of all reporting groups
Overall Number of Baseline Participants		1644	1647	3291
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Median (Inter-Quartile Range); Unit of measure: Years
	Number Analyzed	1644 participants	1647 participants	3291 participants
		67; (56 to 75)	67; (55 to 75)	67; (55 to 75)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1644 participants	1647 participants	3291 participants
	Female	605 36.8%	580 35.2%	1185 36.0%
	Male	1039 63.2%	1067 64.8%	2106 64.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1644 participants	1647 participants	3291 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	0 0.0%	0 0.0%
	White	0 0.0%	0 0.0%	0 0.0%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	1644 100.0%	1647 100.0%	3291 100.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	1644 participants	1647 participants	3291 participants
Netherlands		88	84	172
Norway		96	101	197
Finland		128	130	258
Denmark		1061	1064	2125
United Kingdom		34	33	67
Switzerland		237	235	472

Outcome Measures

1. Primary Outcome

Title	Mortality
Description	Landmark mortality 90-days after randomization
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

Intention-to-treat

Arm/Group Title	Proton Pump Inhibitor (PPI)	Normal Saline
Arm/Group Description:	Pantoprazole 40 mg Pantoprazole: 40 mg x 1 daily intravenously from ICU admission to ICU discharge	Saline (0.9%) Saline (0.9%): 10 ml of isotonic saline x 1 daily intravenously from ICU admission to ICU discharge
Overall Number of Participants Analyzed	1642	1640
Measure Type: Count of Participants; Unit of Measure: Participants
	510 31.1%	499 30.4%

2. Secondary Outcome

Title	Number of Participants With Clinically Important GI Bleeding, Pneumonia, Clostridium Difficile Infection or Acute Myocardial Ischemia
Description	Composite outcome of the number of participants with one or more of the mentioned conditions in the ICU
Time Frame	Until ICU discharge, maximum 90 days

Outcome Measure Data

Analysis Population Description

Intention-to-treat

Arm/Group Title	Proton Pump Inhibitor (PPI)	Normal Saline
Arm/Group Description:	Pantoprazole 40 mg Pantoprazole: 40 mg x 1 daily intravenously from ICU admission to ICU discharge	Saline (0.9%) Saline (0.9%): 10 ml of isotonic saline x 1 daily intravenously from ICU admission to ICU discharge
Overall Number of Participants Analyzed	1644	1647
Measure Type: Count of Participants; Unit of Measure: Participants
	360 21.9%	372 22.6%

3. Secondary Outcome

Title	Number of Participants With Clinically Important GI Bleeding
Description	Number of participants with one or more episodes of clinically important GI bleeding in the ICU
Time Frame	Until ICU discharge, maximum 90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Proton Pump Inhibitor (PPI)	Normal Saline
Arm/Group Description:	Pantoprazole 40 mg Pantoprazole: 40 mg x 1 daily intravenously from ICU admission to ICU discharge	Saline (0.9%) Saline (0.9%): 10 ml of isotonic saline x 1 daily intravenously from ICU admission to ICU discharge
Overall Number of Participants Analyzed	1644	1647
Measure Type: Count of Participants; Unit of Measure: Participants
	41 2.5%	69 4.2%

4. Secondary Outcome

Title	Number of Participants With One or More Infectious Adverse Events
Description	Number of participants with one or more episodes of pneumonia or clostridium difficile infection in the ICU
Time Frame	Until ICU discharge, maximum 90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Proton Pump Inhibitor (PPI)	Normal Saline
Arm/Group Description:	Pantoprazole 40 mg Pantoprazole: 40 mg x 1 daily intravenously from ICU admission to ICU discharge	Saline (0.9%) Saline (0.9%): 10 ml of isotonic saline x 1 daily intravenously from ICU admission to ICU discharge
Overall Number of Participants Analyzed	1644	1647
Measure Type: Count of Participants; Unit of Measure: Participants
	276 16.8%	279 16.9%

5. Secondary Outcome

Title	Mortality
Description	Data for landmark mortality 1 year after randomization.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Twenty-one patients were lost to follow-up, as compared to the primary outcome (90-day mortality): 7 patients in the PPI arm and 14 patients in the placebo arm

Arm/Group Title	Proton Pump Inhibitor (PPI)	Normal Saline
Arm/Group Description:	Pantoprazole 40 mg Pantoprazole: 40 mg x 1 daily intravenously from ICU admission to ICU discharge	Saline (0.9%) Saline (0.9%): 10 ml of isotonic saline x 1 daily intravenously from ICU admission to ICU discharge
Overall Number of Participants Analyzed	1635	1626
Measure Type: Count of Participants; Unit of Measure: Participants
	610 37.3%	601 37.0%

6. Secondary Outcome

Title	Percentage of Days Alive Without Organ Support
Description	Percentage of days alive and free from mechanical ventilation, circulatory support and renal replacement therapy
Time Frame	Within 90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Proton Pump Inhibitor (PPI)	Normal Saline
Arm/Group Description:	Pantoprazole 40 mg Pantoprazole: 40 mg x 1 daily intravenously from ICU admission to ICU discharge	Saline (0.9%) Saline (0.9%): 10 ml of isotonic saline x 1 daily intravenously from ICU admission to ICU discharge
Overall Number of Participants Analyzed	1644	1647
Measure Type: Number; Unit of Measure: percentage of days
	92	92

7. Secondary Outcome

Title	Number of Serious Adverse Reactions
Description	Serious adverse reactions are: anaphylactic reactions, agranulocytosis, pancytopenia, acute hepatic failure, Steven Johnsons Syndrome and toxic epidermal necrolysis, interstitial nephritis and angioedema.
Time Frame	Until ICU discharge, maximum 90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Proton Pump Inhibitor (PPI)	Normal Saline
Arm/Group Description:	Pantoprazole 40 mg Pantoprazole: 40 mg x 1 daily intravenously from ICU admission to ICU discharge	Saline (0.9%) Saline (0.9%): 10 ml of isotonic saline x 1 daily intravenously from ICU admission to ICU discharge
Overall Number of Participants Analyzed	1644	1647
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	0 0.0%

8. Secondary Outcome

Title	A Health Economic Analysis
Description	This has not been completed yet.
Time Frame	90 days

Outcome Measure Data Not Reported

Adverse Events

Time Frame	90 days (for mortality 1 year)
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Proton Pump Inhibitor (PPI)	Normal Saline
Arm/Group Description	Pantoprazole 40 mg Pantoprazole: 40 mg x 1 daily intravenously from ICU admission to ICU discharge	Saline (0.9%) Saline (0.9%): 10 ml of isotonic saline x 1 daily intravenously from ICU admission to ICU discharge
All-Cause Mortality
	Proton Pump Inhibitor (PPI)	Normal Saline
	Affected / at Risk (%)	Affected / at Risk (%)
Total	610/1635 (37.31%)	601/1626 (36.96%)
Serious Adverse Events
	Proton Pump Inhibitor (PPI)	Normal Saline
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/1644 (0.00%)	0/1647 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Proton Pump Inhibitor (PPI)	Normal Saline
	Affected / at Risk (%)	Affected / at Risk (%)
Total	360/1644 (21.90%)	372/1647 (22.59%)
General disorders
Clinically important events †	360/1644 (21.90%)	372/1647 (22.59%)
† Indicates events were collected by systematic assessment

Limitations and 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.

Results Point of Contact

• Name/Title: Dr. Morten Hylander Møller
• Organization: Copenhagen University Hospital Rigshospitalet, Dept. of Intensive Care 4131
• Phone: 22555343 ext +45
• EMail: mortenhylander@gmail.com

Publications:

Krag M, Perner A, Wetterslev J, Wise MP, Hylander Moller M. Stress ulcer prophylaxis versus placebo or no prophylaxis in critically ill patients. A systematic review of randomised clinical trials with meta-analysis and trial sequential analysis. Intensive Care Med. 2014 Jan;40(1):11-22. doi: 10.1007/s00134-013-3125-3. Epub 2013 Oct 19.

Krag M, Perner A, Wetterslev J, Wise MP, Borthwick M, Bendel S, McArthur C, Cook D, Nielsen N, Pelosi P, Keus F, Guttormsen AB, Moller AD, Moller MH; SUP-ICU co-authors. Prevalence and outcome of gastrointestinal bleeding and use of acid suppressants in acutely ill adult intensive care patients. Intensive Care Med. 2015 May;41(5):833-45. doi: 10.1007/s00134-015-3725-1. Epub 2015 Apr 10.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Halling CMB, Moller MH, Marker S, Krag M, Kjellberg J, Perner A, Gyrd-Hansen D. The effects of pantoprazole vs. placebo on 1-year outcomes, resource use and employment status in ICU patients at risk for gastrointestinal bleeding: a secondary analysis of the SUP-ICU trial. Intensive Care Med. 2022 Apr;48(4):426-434. doi: 10.1007/s00134-022-06631-2. Epub 2022 Feb 5.

Granholm A, Marker S, Krag M, Zampieri FG, Thorsen-Meyer HC, Kaas-Hansen BS, van der Horst ICC, Lange T, Wetterslev J, Perner A, Moller MH. Heterogeneity of treatment effect of prophylactic pantoprazole in adult ICU patients: a post hoc analysis of the SUP-ICU trial. Intensive Care Med. 2020 Apr;46(4):717-726. doi: 10.1007/s00134-019-05903-8. Epub 2020 Jan 14.

Granholm A, Lange T, Anthon CT, Marker S, Krag M, Meyhoff TS, Wise MP, Borthwick M, Bendel S, Keus F, Guttormsen AB, Schefold JC, Wetterslev J, Perner A, Moller MH. Time to onset of gastrointestinal bleeding in the SUP-ICU trial: A pre-planned substudy. Acta Anaesthesiol Scand. 2019 Nov;63(10):1346-1356. doi: 10.1111/aas.13459. Epub 2019 Sep 11.

Granholm A, Marker S, Krag M, Zampieri FG, Thorsen-Meyer HC, Kaas-Hansen BS, van der Horst ICC, Lange T, Wetterslev J, Perner A, Moller MH. Heterogeneity of treatment effect of stress ulcer prophylaxis in ICU patients: A secondary analysis protocol. Acta Anaesthesiol Scand. 2019 Oct;63(9):1251-1256. doi: 10.1111/aas.13432. Epub 2019 Jul 18.

Marker S, Krag M, Perner A, Wetterslev J, Lange T, Wise MP, Borthwick M, Bendel S, Keus F, Guttormsen AB, Schefold JC, Rasmussen BS, Elkmann T, Bestle M, Arenkiel B, Laake JH, Kamper MK, Lang M, Pawlowicz-Dworzanska MB, Karlsson S, Liisanantti J, Dey N, Knudsen H, Granholm A, Moller MH; SUP-ICU trial investigators. Pantoprazole in ICU patients at risk for gastrointestinal bleeding-1-year mortality in the SUP-ICU trial. Acta Anaesthesiol Scand. 2019 Oct;63(9):1184-1190. doi: 10.1111/aas.13436. Epub 2019 Jul 19.

Marker S, Perner A, Wetterslev J, Krag M, Lange T, Wise MP, Borthwick M, Bendel S, Keus F, Guttormsen AB, Schefold JC, Moller MH; SUP-ICU investigators. Pantoprazole prophylaxis in ICU patients with high severity of disease: a post hoc analysis of the placebo-controlled SUP-ICU trial. Intensive Care Med. 2019 May;45(5):609-618. doi: 10.1007/s00134-019-05589-y. Epub 2019 Mar 12.

Krag M, Marker S, Perner A, Wetterslev J, Wise MP, Schefold JC, Keus F, Guttormsen AB, Bendel S, Borthwick M, Lange T, Rasmussen BS, Siegemund M, Bundgaard H, Elkmann T, Jensen JV, Nielsen RD, Liboriussen L, Bestle MH, Elkjaer JM, Palmqvist DF, Backlund M, Laake JH, Badstolokken PM, Gronlund J, Breum O, Walli A, Winding R, Iversen S, Jarnvig IL, White JO, Brand B, Madsen MB, Quist L, Thornberg KJ, Moller A, Wiis J, Granholm A, Anthon CT, Meyhoff TS, Hjortrup PB, Aagaard SR, Andreasen JB, Sorensen CA, Haure P, Hauge J, Hollinger A, Scheuzger J, Tuchscherer D, Vuilliomenet T, Takala J, Jakob SM, Vang ML, Paelestik KB, Andersen KLD, van der Horst ICC, Dieperink W, Fjolner J, Kjer CKW, Solling C, Solling CG, Karttunen J, Morgan MPG, Sjobo B, Engstrom J, Agerholm-Larsen B, Moller MH; SUP-ICU trial group. Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU. N Engl J Med. 2018 Dec 6;379(23):2199-2208. doi: 10.1056/NEJMoa1714919. Epub 2018 Oct 24.

Krag M, Perner A, Wetterslev J, Wise MP, Borthwick M, Bendel S, Pelosi P, Keus F, Guttormsen AB, Schefold JC, Moller MH; SUP-ICU investigators. Stress ulcer prophylaxis with a proton pump inhibitor versus placebo in critically ill patients (SUP-ICU trial): study protocol for a randomised controlled trial. Trials. 2016 Apr 19;17(1):205. doi: 10.1186/s13063-016-1331-3.

• Responsible Party: Dr. Morten Hylander Møller, Scandinavian Critical Care Trials Group
• ClinicalTrials.gov Identifier: NCT02467621
• Other Study ID Numbers: RH-ITA-006
• First Submitted: June 5, 2015
• First Posted: June 10, 2015
• Results First Submitted: October 29, 2018
• Results First Posted: June 7, 2019
• Last Update Posted: November 15, 2022