SUP-ICU: Stress Ulcer Prophylaxis in the Intensive Care Unit

• Sponsor: Dr. Morten Hylander Møller (Other)
• Overall Status: Completed
• CT.gov ID: NCT02467621
• Collaborator: Rigshospitalet, Denmark (Other), Copenhagen Trial Unit, Center for Clinical Intervention Research (Other)
• Enrollment: 3,350
• Locations: 33
• Arms: 2
• Actual Duration (Months): 24.7
• Patients Per Site: 101.5
• Patients Per Site Per Month: 4.1

Study Details

Study Description

Brief Summary

Stress ulcer prophylaxis (SUP) is standard of care in the intensive care unit (ICU), however the quantity and quality of evidence is low and potential harm has been reported.

The aim of the SUP-ICU trial is to asses the overall benefits and harms of SUP with proton pump inhibitor in adult critically ill patients in the ICU.

Condition or Disease	Intervention/Treatment	Phase
Gastrointestinal Bleeding; Stress Ulcers	Drug: Pantoprazole; Other: Saline (0.9%)	Phase 4

Detailed Description

Critically ill patients in the ICU are at risk of stress related gastrointestinal (GI) bleeding, and SUP is recommended. However, the quantity and quality of evidence supporting SUP is low and has been questioned. Furthermore studies have shown that proton pump inhibitors (PPIs) may increase the risk of pneumonia, clostridium difficile infection and acute myocardial ischemia. The aim of the SUP-ICU trial is to assess the benefits and harms of SUP with PPI in adult critically ill patients in the ICU.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3350 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU)
• Actual Study Start Date: Jan 1, 2016
• Actual Primary Completion Date: Oct 22, 2017
• Actual Study Completion Date: Jan 21, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Proton pump inhibitor (PPI) Pantoprazole 40 mg	Drug: Pantoprazole; 40 mg x 1 daily intravenously from ICU admission to ICU discharge; Other Names: Pantoloc
Placebo Comparator: Normal saline Saline (0.9%)	Other: Saline (0.9%); 10 ml of isotonic saline x 1 daily intravenously from ICU admission to ICU discharge

Outcome Measures

Primary Outcome Measures

1. Mortality [90 days]

   Landmark mortality 90-days after randomization

Secondary Outcome Measures

1. Number of Participants With Clinically Important GI Bleeding, Pneumonia, Clostridium Difficile Infection or Acute Myocardial Ischemia [Until ICU discharge, maximum 90 days]

   Composite outcome of the number of participants with one or more of the mentioned conditions in the ICU

2. Number of Participants With Clinically Important GI Bleeding [Until ICU discharge, maximum 90 days]

   Number of participants with one or more episodes of clinically important GI bleeding in the ICU

3. Number of Participants With One or More Infectious Adverse Events [Until ICU discharge, maximum 90 days]

   Number of participants with one or more episodes of pneumonia or clostridium difficile infection in the ICU

4. Mortality [1 year]

   Data for landmark mortality 1 year after randomization.

5. Percentage of Days Alive Without Organ Support [Within 90 days]

   Percentage of days alive and free from mechanical ventilation, circulatory support and renal replacement therapy

6. Number of Serious Adverse Reactions [Until ICU discharge, maximum 90 days]

   Serious adverse reactions are: anaphylactic reactions, agranulocytosis, pancytopenia, acute hepatic failure, Steven Johnsons Syndrome and toxic epidermal necrolysis, interstitial nephritis and angioedema.

7. A Health Economic Analysis [90 days]

   This has not been completed yet.

Eligibility Criteria

Criteria

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

INCLUSION CRITERIA:

• Acute admission to the ICU

• Age ≥ 18 years

• One or more of the following risk factors:

• Shock (continuous infusion with vasopressors or inotropes, systolic blood pressure < 90 mmHg, mean arterial blood pressure < 70 mmHg or lactate > 4 mmol/l)

• Acute or chronic intermittent or continuous renal replacement therapy

• Invasive mechanical ventilation which is expected to last > 24 hours

• Coagulopathy (platelets < 50 x 109/l or international normalized ratio (INR) > 1.5 or prothrombin time (PT) > 20 seconds) documented within the last 24 hours

• Ongoing treatment with anticoagulant drugs (prophylaxis doses excluded)

• History of coagulopathy (platelets < 50 x 109/l or INR > 1.5 or PT > 20 seconds) within 6 months prior to hospital admission

• History of chronic liver disease (portal hypertension, cirrhosis proven by biopsy, computed tomography (CT) scan or ultrasound, history of variceal bleeding or hepatic encephalopathy in the past medical history)

EXCLUSION CRITERIA:

• Contraindications to PPI

• Ongoing treatment with PPI and/or H2RA on a daily basis

• GI bleeding of any origin during current hospital admission

• Diagnosed with peptic ulcer during current hospital admission

• Organ transplant during current hospital admission

• Withdrawal from active therapy or brain death

• Fertile woman with positive urine human chorionic gonadotropin (hCG) or plasma-hCG

• Consent according to national regulations not obtainable

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dept. of Intensive Care, Aalborg University Hospital	Aalborg		Denmark	9000
2	Dept. of Intensive Care, Århus University Hospital Nørrebrogade	Aarhus		Denmark	8000
3	Dept. of Intensive Care, Århus University Hospital Skejby	Arhus		Denmark	8000
4	Dept. of Intensive Care 4131, Copenhagen University Hospital Rigshospitalet	Copenhagen		Denmark	2100
5	Dept. of Neurointensive Care, Copenhagen University Hospital Rigshospitalet	Copenhagen		Denmark	2100
6	Dept. of Intensive Care, Bispebjerg Hospital	Copenhagen		Denmark	2400
7	Dept. of Intensive Care, Copenhagen University Hospital Herlev	Herlev		Denmark	2730
8	Dept. of Intensive Care, Herning Hospital	Herning		Denmark	7400
9	Dept. of Intensive Care, Hillerød Hospital	Hillerød		Denmark	3400
10	Dept. of Intensive Care, Hjørring Hospital	Hjørring		Denmark	9800
11	Dept. of Intensive Care, Holbæk Hospital	Holbæk		Denmark	4300
12	Dept. of Intensive Care, Holstebro Hospital	Holstebro		Denmark	7500
13	Dept. of Intensive Care, Køge University Hospital	Køge		Denmark	4600
14	Dept. of Intensive Care, Nykøbing Falster Sygehus	Nykøbing Falster		Denmark	4800
15	Dept. of Intensive Care, Randers Hospital	Randers		Denmark	8930
16	Dept. of Intensive Care, Roskilde Hospital	Roskilde		Denmark	4000
17	Dept. of Intensive Care, Slagelse Hospital	Slagelse		Denmark	4200
18	Dept. of Intensive Care, Vejle Hospital	Vejle		Denmark	7100
19	Dept. of Intensive Care, Viborg Hospital	Viborg		Denmark	8800
20	Dept. of Intensive Care, Helsinki University Hospital	Helsinki		Finland	00120
21	Dept. of Intensive Care, Kuopio University Hospital	Kuopio		Finland	70029
22	Dept. of Intensive Care, Oulu University Hospital	Oulu		Finland	90210
23	Dept. of Intensive Care, Tampere University Hospital	Tampere		Finland	33520
24	Dept. of Intensive Care, Turku University Hospital	Turku		Finland	20521
25	Dept. of Intensive Care, University Medical Center Groningen	Groningen		Netherlands	9713
26	Dept. of Intensive Care, Heerlen Hospital	Heerlen		Netherlands	6419
27	Dept. of Intensive Care, Bergen University Hospital	Bergen		Norway	5021
28	Dept. of Intensive Care, Akershus University Hospital	Lørenskog		Norway	1478
29	Dept. of Intensive Care, Oslo University Hospital	Oslo		Norway	0450
30	Dept. of Intensive Care, Stavanger University Hospital	Stavanger		Norway	4011
31	Dept. of Intensive Care, Basel University Hospital	Basel		Switzerland	4056
32	Dept. of Intensive Care, Bern University Hospital	Bern		Switzerland	3010
33	Dept. of Intensive Care, University Hospital of Wales	Cardiff		United Kingdom

Sponsors and Collaborators

• Dr. Morten Hylander Møller
• Rigshospitalet, Denmark
• Copenhagen Trial Unit, Center for Clinical Intervention Research

Investigators

• Principal Investigator: Morten Hylander Møller, MD, PhD, Rigshospitalet, Denmark
• Study Chair: Anders Perner, MD, PhD, Rigshospitalet, Denmark

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 1, 2017

More Information

Publications

• 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, Møller 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.
• Krag M, Perner A, Wetterslev J, Wise MP, Hylander Møller 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. Review.

• Responsible Party: Dr. Morten Hylander Møller, Principal investigator, Scandinavian Critical Care Trials Group
• ClinicalTrials.gov Identifier: NCT02467621
• Other Study ID Numbers: RH-ITA-006
• First Posted: Jun 10, 2015
• Last Update Posted: Nov 10, 2020
• Last Verified: Oct 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Dr. Morten Hylander Møller, Principal investigator, Scandinavian Critical Care Trials Group: Stress ulcer prophylaxis; Proton pump inhibitor; Pneumonia; Clostridium difficile infection
• Additional relevant MeSH terms: Gastrointestinal Hemorrhage; Ulcer; Pantoprazole

Study Results

Participant Flow

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	1645	1653
COMPLETED	1644	1647
NOT COMPLETED	1	6

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 Participants	1644	1647	3291
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	67	67	67
Sex: Female, Male (Count of Participants)
Female	605 36.8%	580 35.2%	1185 36%
Male	1039 63.2%	1067 64.8%	2106 64%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1644 100%	1647 100%	3291 100%
Region of Enrollment (participants) [Number]
Netherlands	88 5.4%	84 5.1%	172 5.2%
Norway	96 5.8%	101 6.1%	197 6%
Finland	128 7.8%	130 7.9%	258 7.8%
Denmark	1061 64.5%	1064 64.6%	2125 64.6%
United Kingdom	34 2.1%	33 2%	67 2%
Switzerland	237 14.4%	235 14.3%	472 14.3%

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
Measure Participants	1642	1640
Count of Participants [Participants]	510 31%	499 30.3%

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
Measure Participants	1644	1647
Count of Participants [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
Measure Participants	1644	1647
Count of Participants [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
Measure Participants	1644	1647
Count of Participants [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
Measure Participants	1635	1626
Count of Participants [Participants]	610 37.1%	601 36.5%

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
Measure Participants	1644	1647
Number [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
Measure Participants	1644	1647
Count of Participants [Participants]	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

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	90 days (for mortality 1 year)
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	610/1635 (37.3%)		601/1626 (37%)
Serious Adverse Events
	Proton Pump Inhibitor (PPI)		Normal Saline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1644 (0%)		0/1647 (0%)
Other (Not Including Serious) Adverse Events
	Proton Pump Inhibitor (PPI)		Normal Saline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	360/1644 (21.9%)		372/1647 (22.6%)
General disorders
Clinically important events	360/1644 (21.9%)		372/1647 (22.6%)

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.