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

Tracking Information

• First Submitted Date: June 5, 2015
• First Posted Date: June 10, 2015
• Results First Submitted Date: October 29, 2018
• Results First Posted Date: June 7, 2019
• Last Update Posted Date: November 15, 2022
• Actual Study Start Date: January 2016
• Actual Primary Completion Date: October 22, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 9, 2015)

Mortality [ Time Frame: 90 days ]

Landmark mortality 90-days after randomization

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 11, 2019)

• Number of Participants With Clinically Important GI Bleeding, Pneumonia, Clostridium Difficile Infection or Acute Myocardial Ischemia [ Time Frame: Until ICU discharge, maximum 90 days ]
  Composite outcome of the number of participants with one or more of the mentioned conditions in the ICU
• Number of Participants With Clinically Important GI Bleeding [ Time Frame: Until ICU discharge, maximum 90 days ]
  Number of participants with one or more episodes of clinically important GI bleeding in the ICU
• Number of Participants With One or More Infectious Adverse Events [ Time Frame: Until ICU discharge, maximum 90 days ]
  Number of participants with one or more episodes of pneumonia or clostridium difficile infection in the ICU
• Mortality [ Time Frame: 1 year ]
  Data for landmark mortality 1 year after randomization.
• Percentage of Days Alive Without Organ Support [ Time Frame: Within 90 days ]
  Percentage of days alive and free from mechanical ventilation, circulatory support and renal replacement therapy
• Number of Serious Adverse Reactions [ Time Frame: 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.
• A Health Economic Analysis [ Time Frame: 90 days ]
  This has not been completed yet.

Original Secondary Outcome Measures (submitted: June 9, 2015)

• Proportion of patients with clinically important GI bleeding, pneumonia, clostridium difficile infection or acute myocardial ischemia [ Time Frame: Until ICU discharge, maximum 90 days ]
  Composite outcome of the proportion of patients with one or more of the mentioned conditions in the ICU
• Proportion of patients with clinically important GI bleeding [ Time Frame: Until ICU discharge, maximum 90 days ]
  Proportion of patients with one or more episodes of clinically important GI bleeding in the ICU
• Proportion of patients with one or more infectious adverse events [ Time Frame: Until ICU discharge, maximum 90 days ]
  Proportion of patients with one or more episodes of pneumonia or clostridium difficile infection in the ICU
• Mortality [ Time Frame: 1 year ]
  Landmark mortality 1 year after randomization
• Days alive without organ support [ Time Frame: Within 90 days ]
  Percentage of days alive and free from mechanical ventilation, circulatory support and renal replacement therapy
• Number of serious adverse reactions [ Time Frame: 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.
• A health economic analysis [ Time Frame: 90 days ]
  The analytic details will be based on the results of the trial and specified (cost-benefit vs cost-minimisation analyses).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Stress Ulcer Prophylaxis in the Intensive Care Unit
• Official Title: Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU)

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.

• 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 Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention

Condition

• Gastrointestinal Bleeding
• Stress Ulcers

Intervention

• Drug: Pantoprazole
  40 mg x 1 daily intravenously from ICU admission to ICU discharge
  Other Name: Pantoloc
• Other: Saline (0.9%)
  10 ml of isotonic saline x 1 daily intravenously from ICU admission to ICU discharge

Study Arms

• Experimental: Proton pump inhibitor (PPI)
  Pantoprazole 40 mg
  Intervention: Drug: Pantoprazole
• Placebo Comparator: Normal saline
  Saline (0.9%)
  Intervention: Other: Saline (0.9%)

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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 9, 2015): 3350
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: January 21, 2018
• Actual Primary Completion Date: October 22, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

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: Denmark, Finland, Netherlands, Norway, Switzerland, United Kingdom

Administrative Information

• NCT Number: NCT02467621
• Other Study ID Numbers: RH-ITA-006
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes

• Current Responsible Party: Dr. Morten Hylander Møller, Scandinavian Critical Care Trials Group
• Original Responsible Party: Same as current
• Current Study Sponsor: Dr. Morten Hylander Møller
• Original Study Sponsor: Same as current

Collaborators

• 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

• PRS Account: Scandinavian Critical Care Trials Group
• Verification Date: October 2022