Conditions: Gastrointestinal Bleeding Stress Ulcers
Keywords: Stress ulcer prophylaxis Proton pump inhibitor Pneumonia Clostridium difficile infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3350
Healthy volunteers: no

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.

Arms:
arm 1: Pantoprazole 40 mg arm 2: Saline (0.9%)

Interventions: intervention 1: Pantoprazole intervention 2: Saline (0.9%)
Intervention descriptions: intervention 1: 40 mg x 1 daily intravenously from ICU admission to ICU discharge intervention 2: 10 ml of isotonic saline x 1 daily intravenously from ICU admission to ICU discharge

Protocol document:
Prot_SAP_000.pdf: 
Protocol
This trial protocol has been provided by the authors to give readers additional information about their work.
Protocol for: Krag M, Marker S, Perner A, et al. Pantoprazole in patients at risk for gastrointestinal bleeding in 
the ICU. N Engl J Med. DOI: 10.1056/NEJMoa1714919


 
2 
 
This supplement contains the following items 
 
 
1. Original protocol (October 2015), page 3-93 
2. Final protocol (August 2017), page 94-195 
3. Summary of changes to protocol, page 196 
4. Original/final statistical analysis plan (no amendments to original version)    
(May 2017), page 197-209 
 


 
3 
 
 
 
 
 
Stress ulcer prophylaxis with proton pump inhibitor (pantoprazole) 
in adult critically ill patients in the intensive care unit: 
A randomised, blinded, placebo-controlled trial 
 
Original protocol, version 3.0, October 20th, 2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Applicable protocol registration numbers: 
EudraCT number: 2015-000318-24 
ClinicalTrials.gov Identifier: NCT02467621  
 
 
 
 
In drafting of present protocol Copenhagen Trial Unit’s Standard Operating Procedures were used


 
4 
 
 
Table of contents 
 
Table of contents .................................................................. Fejl! Bogmærke er ikke defineret. 
Abstract ................................................................................ Fejl! Bogmærke er ikke defineret. 
Trial flow chart ...................................................................... Fejl! Bogmærke er ikke defineret. 
Administrative information .................................................. Fejl! Bogmærke er ikke defineret. 
Sponsor ..................................................................... Fejl! Bogmærke er ikke defineret. 
Trial sites ................................................................... Fejl! Bogmærke er ikke defineret. 
Steering Committee ................................................... Fejl! Bogmærke er ikke defineret. 
Data Monitoring and Safety Committee ..................... Fejl! Bogmærke er ikke defineret. 
List of abbreviations ............................................................ Fejl! Bogmærke er ikke defineret. 
1.  
Introduction and background ..................................... Fejl! Bogmærke er ikke defineret. 
1.1 
The patient population ...................................... Fejl! Bogmærke er ikke defineret. 
1.2 
Current treatment ............................................. Fejl! Bogmærke er ikke defineret. 
1.3 
Trial interventions ............................................. Fejl! Bogmærke er ikke defineret. 
1.4 
Adverse effects of PPI ...................................... Fejl! Bogmærke er ikke defineret. 
1.5 
Risks and benefits ............................................ Fejl! Bogmærke er ikke defineret. 
1.6 
Ethical justification and trial rationale ................ Fejl! Bogmærke er ikke defineret. 
1.6.1  
Outcome considerations ...................... Fejl! Bogmærke er ikke defineret. 
1.6.2 
Sample size considerations ................. Fejl! Bogmærke er ikke defineret. 
1.7 
Trial conduct .................................................... Fejl! Bogmærke er ikke defineret. 
2. 
Trial objectives and purpose ...................................... Fejl! Bogmærke er ikke defineret. 
3. 
Trial design .................................................................. Fejl! Bogmærke er ikke defineret. 
3.1 
Trial design ...................................................... Fejl! Bogmærke er ikke defineret. 
3.2 
Randomisation ................................................. Fejl! Bogmærke er ikke defineret. 
3.3 
Blinding ............................................................ Fejl! Bogmærke er ikke defineret. 
3.3.1 
Unblinding ........................................... Fejl! Bogmærke er ikke defineret. 
3.3.1.1 An individual ...................................... Fejl! Bogmærke er ikke defineret. 
3.3.1.2 Procedure .......................................... Fejl! Bogmærke er ikke defineret. 
3.5 
Participant timeline ........................................... Fejl! Bogmærke er ikke defineret. 
4. 
Selection of participants ............................................. Fejl! Bogmærke er ikke defineret. 
4.1 
Inclusion criteria ............................................... Fejl! Bogmærke er ikke defineret. 
4.2 
Exclusion criteria .............................................. Fejl! Bogmærke er ikke defineret. 
4.3 
Participant discontinuation and withdrawal ....... Fejl! Bogmærke er ikke defineret. 
4.3.1 
Discontinuation and withdrawal at the choice of the participant ........... Fejl! 
Bogmærke er ikke defineret. 
4.3.2 
Discontinuation and withdrawal at the choice of the investigator .......... Fejl! 
Bogmærke er ikke defineret. 
5. 
Selection and trial sites and personnel ..................... Fejl! Bogmærke er ikke defineret. 


 
5 
 
5.1 
Trial sites and setting ....................................... Fejl! Bogmærke er ikke defineret. 
5.2 
Trial personnel ................................................. Fejl! Bogmærke er ikke defineret. 
6. 
Trial interventions ....................................................... Fejl! Bogmærke er ikke defineret. 
6.1 
Experimental intervention ................................. Fejl! Bogmærke er ikke defineret. 
6.2 
Control intervention .......................................... Fejl! Bogmærke er ikke defineret. 
6.3 
Co-interventions ............................................... Fejl! Bogmærke er ikke defineret. 
6.4 
Concomitant interventions ................................ Fejl! Bogmærke er ikke defineret. 
6.5 
Intervention accountability ................................ Fejl! Bogmærke er ikke defineret. 
7. 
Outcomes .................................................................... Fejl! Bogmærke er ikke defineret. 
7.1 
Primary outcome .............................................. Fejl! Bogmærke er ikke defineret. 
7.2 
Secondary outcomes........................................ Fejl! Bogmærke er ikke defineret. 
7.3 
Exploratory outcomes....................................... Fejl! Bogmærke er ikke defineret. 
8. 
Safety ........................................................................... Fejl! Bogmærke er ikke defineret. 
8.1 
Definitions ........................................................ Fejl! Bogmærke er ikke defineret. 
8.2 
Risk and safety issues in the current trial ......... Fejl! Bogmærke er ikke defineret. 
8.3 
Serious adverse reactions and events .............. Fejl! Bogmærke er ikke defineret. 
8.3.1 
Recording of serious adverse reactions and events ...... Fejl! Bogmærke er 
ikke defineret. 
8.4 
Reporting ......................................................... Fejl! Bogmærke er ikke defineret. 
9. 
Procedures, assessments and data collection ......... Fejl! Bogmærke er ikke defineret. 
9.1 
Inclusion procedure .......................................... Fejl! Bogmærke er ikke defineret. 
9.1.1 
Screening ............................................ Fejl! Bogmærke er ikke defineret. 
9.1.2 
Procedures for informed consent ......... Fejl! Bogmærke er ikke defineret. 
9.2 
Data collection.................................................. Fejl! Bogmærke er ikke defineret. 
9.2.1 
Method ................................................ Fejl! Bogmærke er ikke defineret. 
9.2.2 
Timing ................................................. Fejl! Bogmærke er ikke defineret. 
10.  
Data handling and record keeping .................... Fejl! Bogmærke er ikke defineret. 
10.1 
Data management ....................................... Fejl! Bogmærke er ikke defineret. 
10.2 
Confidentiality .............................................. Fejl! Bogmærke er ikke defineret. 
10.3 
Biobanking .................................................. Fejl! Bogmærke er ikke defineret. 
10.4 
Access to data ............................................. Fejl! Bogmærke er ikke defineret. 
11.  
Statistical analysis ............................................. Fejl! Bogmærke er ikke defineret. 
11.1  
Sample size estimation and power calculations ............ Fejl! Bogmærke er ikke 
defineret. 
11.1.1 Sample size estimation for the primary outcome .... Fejl! Bogmærke er ikke 
defineret. 
11.1.2 Power estimations for secondary outcomes ......... Fejl! Bogmærke er ikke 
defineret. 
11.2  
Statistical methods ...................................... Fejl! Bogmærke er ikke defineret. 
11.2.1 Pre-planned subgroup analyses ......... Fejl! Bogmærke er ikke defineret. 
11.2.2  Significance ....................................... Fejl! Bogmærke er ikke defineret. 


 
6 
 
11.2.3 Interim analysis ................................... Fejl! Bogmærke er ikke defineret. 
11.2.4  Early stopping criteria ........................ Fejl! Bogmærke er ikke defineret. 
11.2.5  Accountability procedure for missing data/population for analysis ...... Fejl! 
Bogmærke er ikke defineret. 
12. 
Quality control and quality assurance ....................... Fejl! Bogmærke er ikke defineret. 
12.1 
Monitoring of the intervention groups .......... Fejl! Bogmærke er ikke defineret. 
13. 
Legal and organisational aspects .............................. Fejl! Bogmærke er ikke defineret. 
13.1  
Finance ....................................................... Fejl! Bogmærke er ikke defineret. 
13.1.1 Trial funding ........................................ Fejl! Bogmærke er ikke defineret. 
13.1.2 Compensation ..................................... Fejl! Bogmærke er ikke defineret. 
13.2 
Insurance .................................................... Fejl! Bogmærke er ikke defineret. 
13.3 
Plan for publication, authorship and dissemination ....... Fejl! Bogmærke er ikke 
defineret. 
13.3.1 Publication and authorship .................. Fejl! Bogmærke er ikke defineret. 
13.4  
Spin-off projects .......................................... Fejl! Bogmærke er ikke defineret. 
13.5  
Intellectual property rights ........................... Fejl! Bogmærke er ikke defineret. 
13.6 
Organisational framework............................ Fejl! Bogmærke er ikke defineret. 
13.7 
Trial timeline ................................................ Fejl! Bogmærke er ikke defineret. 
14.  
Appendix ............................................................. Fejl! Bogmærke er ikke defineret. 
15.  
References .......................................................... Fejl! Bogmærke er ikke defineret. 
Appendix 1. Trial organisation ............................................ Fejl! Bogmærke er ikke defineret. 
Appendix 2. Undesirable effects of pantoprazole .............. Fejl! Bogmærke er ikke defineret. 
Appendix 3. Charter for the independent Data Monitoring and Safety Committee (DMSC)
 ............................................................................................... Fejl! Bogmærke er ikke defineret. 
Appendix 4. Definitions ........................................................ Fejl! Bogmærke er ikke defineret. 
Appendix 5. Translation of the Danish summary of product characteristics ................ Fejl! 
Bogmærke er ikke defineret. 
Appendix 6. Adverse reactions not registered ................... Fejl! Bogmærke er ikke defineret. 
Appendix 7. Informed consent, Denmark ........................... Fejl! Bogmærke er ikke defineret. 
Appendix 8. Timeline............................................................ Fejl! Bogmærke er ikke defineret. 
Appendix 9. SAPS II scoring sheet [74] .............................. Fejl! Bogmærke er ikke defineret. 
Appendix 10. SOFA score [75] ............................................ Fejl! Bogmærke er ikke defineret. 
Appendix 11. Power estimation ........................................... Fejl! Bogmærke er ikke defineret. 
Appendix 12. Trial sequential analysis of all-cause ........... Fejl! Bogmærke er ikke defineret. 
Appendix 13. International Committee of Medical Journal Editors (ICMJE) form for 
potential conflicts of interest. .............................................. Fejl! Bogmærke er ikke defineret. 
 
 
 


 
7 
 
Abstract  
Background: Critically ill patients in the intensive care unit (ICU) are at risk of stress related 
gastrointestinal (GI) bleeding, and stress ulcer prophylaxis (SUP) is recommended. However, 
the evidence on SUP is of low quantity and quality, and studies have shown that proton pump 
inhibitors (PPI) may increase the risk of a number of serious adverse events.   
Objectives: To assess the benefits and harms of SUP with PPI in adult, critically ill patients in 
the ICU.  
Design: An investigator-initiated, pragmatic, international, multicentre, randomised, blinded, 
parallel-group trial of SUP with PPI versus placebo. 
Inclusion and exclusion criteria: Inclusion criteria: Adult patients admitted to the ICU with 
one or more of the following acute conditions: shock, renal replacement therapy, mechanical 
ventilation expected to last > 24 hours, any kind of coagulopathy, treatment with anticoagulant 
drugs or liver disease. Exclusion criteria: contraindications to PPI, daily treatment with PPI 
and/or histamine-2-receptor antagonist, GI bleeding of any origin or known peptic ulcer during 
current hospital admission, organ transplant, withdrawal from active therapy or brain death, 
positive urine human chorionic gonadotropin (hCG) or plasma hCG or consent according to 
national regulations not obtainable. 
Intervention: Experimental intervention is intravenous pantoprazole 40 mg daily. Control 
intervention is matching placebo (saline).   
Outcomes: Primary outcome: Mortality 90 days after randomisation. Secondary outcomes: 
proportion of patients with clinically important GI bleeding, pneumonia, Clostridium difficile 
infection and myocardial ischemia, proportion of patients with clinically important GI bleeding, 
proportion of patients with pneumonia or clostridium difficile infections, 1 year mortality post-
randomisation, days alive without organ support in the 90-day period, serious adverse 
reactions and a health economic analysis  
Trial size: 2 x 1675 patients are required to show a 20% relative risk reduction or increase 
(5% absolute risk reduction or increase) in the primary outcome measure, assuming a 
baseline 90-day mortality of 25% (α=0.05 (two-sided), and β=0.1) 
Time schedule:    
2014 – November 2015: Governance approval applications, education of trial sites, other 
preparations 
December 2015: First Danish patient enrolled 
February 2015: Commencement of inclusion in other countries 


 
8 
 
November 2017: Last patient enrolled 
January 2018: Follow-up completed 
May 2018: Data analysis and submission for publication 
 
 


 
9 
 
Trial flow chart 
The flowchart (n=  ) will be filled in during or at the end of the trial. 
 
 
Excluded  (n=   ) 
   Not meeting inclusion criteria (n=  ) 
   Declined to participate (n=  ) 
Analysed  (n=  ) 
 Excluded from analysis (give reasons) (n=  ) 
 Lost to follow-up (give reasons) (n=  ) 
 Discontinued intervention (give reasons) (n=  ) 
Allocated to intervention (n=  ) 
 Received allocated intervention (n=  ) 
 Did not receive allocated intervention (give 
 Lost to follow-up (give reasons) (n=  ) 
 Discontinued intervention (give reasons) (n=  ) 
Allocated to intervention (n=  ) 
 Received allocated intervention (n=  ) 
 Did not receive allocated intervention (give 
Analysed  (n=  ) 
 Excluded from analysis (give reasons) (n=  ) 
Allocation 
Analysis 
Follow-Up 
Randomised (n=  ) 
Assessed for eligibility (n=  ) 
Enrollment 


 
10 
 
Administrative information  
 
The research programme organisation is attached in appendix 1 
 
Sponsor  
Morten Hylander Møller 
Department of Intensive Care 4131 
University hospital of Copenhagen Rigshospitalet 
Blegdamsvej 9, 2100 Copenhagen 
E-mail: mortenhylander@gmail.com 
 
Telephone: +45 3545 8685 
 
Trial sites  
Clinical sites: 
 
ICUs in: 
• 
Denmark 
• 
Finland  
• 
Iceland 
• 
Italy 
• 
Norway 
• 
Switzerland 
• 
The Netherlands 
• 
United Kingdom  
 
Methodological and statistical site: 
Copenhagen Trial Unit (CTU), Rigshospitalet, Copenhagen, Denmark 
Department of Biostatistics, Copenhagen University, Denmark 
 
 
 


 
11 
 
Steering Committee 
The Steering Committee consists of the Management Committee and the National Principal 
Investigators (appendix 1) 
 
Management Committee: 
Sponsor:  
Morten Hylander Møller, MD PhD 
Department of Intensive Care 4131 
Copenhagen University hospital Rigshospitalet 
Denmark 
 
Coordinating investigator: 
Mette Krag, MD 
Department of Intensive Care 4131 
Copenhagen University hospital Rigshospitalet 
Denmark 
 
Anders Perner, professor, MD, PhD 
Department of Intensive Care 4131 
Copenhagen University Hospital Rigshospitalet 
Denmark 
 
Jørn Wetterslev, MD, PhD 
Copenhagen Trial Unit (CTU) 
Copenhagen University Hospital Rigshospitalet 
Denmark 
 
National principal investigators: 
Alma Möller, MD, PhD 
Department of Anaesthesia and Intensive Care 
Landspitali University Hospital, Reykjavik 
Iceland 
 
Anne Berit Guttormsen, professor, MD  


 
12 
 
Department of Anaesthesia and Intensive Care, Haukeland University Hospital, Bergen  
Clinical Institute 1 UiB, Bergen University Hospital 
Norway 
 
Frederik Keus, MD, PhD  
Department of Critical Care 
University of Groningen, University Medical Centre of Groningen 
The Netherlands 
 
Joerg C. Schefold,  MD  
Department of Intensive Care 
University Hospital Bern 
Switzerland  
 
Matthew Wise, MD, PhD 
Department of Adult Critical Care 
University Hospital of Wales, Cardiff 
United Kingdom  
 
Paolo Pelosi, MD, FERS  
Anaesthesia and Intensive Care, IRCCS San Martino IST 
Department of Surgical Sciences and Integrated Diagnostics, University of Genoa 
Italy  
 
Stepani Bendel, MD, PhD  
Department of Intensive Care Medicine  
Kuopio University Hospital, Kuopio 
Finland 
 
Danish sites and locale investigators: 
Hospital 
Locale investigator 
Bispebjerg Hospital 
Bispebjerg Bakke 23 
2400 København NV 
 
Anne Lindhardt 
Tlf: 35316359 
Anne.lindhardt.01@regionh.dk 
Dorthe Fris Palmquist 
dorte.fris.palmqvist.01@regionh.dk 


 
13 
 
Herlev Hospital 
Herlev Ringvej 75  
2730 Herlev 
Henrik Christensen 
Tlf: 38683868 
Henrik.christensen@regionh.dk 
Tina Waldau 
Tina.waldau@regionh.dk 
Herning Sygehus 
Gl Landevej 61 
7400 Herning 
Robert Winding 
Tlf: 78432753 
robewind@rm.dk 
Hillerød Hospital 
Dyrehavevej 29 
3400 Hillerød 
Morten Bestle 
Tlf: 48292017 
morten.bestle@regionh.dk 
Hjørring Sygehus 
Bispensgade 37  
9800 Hjørring 
1. Mary Kruse 
Tlf: 97641075 
mary.kruse@rn.dk 
2. René Christian Bleeg 
r.bleeg@rn.dk 
3. Malgorzata Beata Pawlowicz 
mabep@rn.dk 
4. Andrei Ciubotariu 
anci@rn.dk 
Holbæk Sygehus 
Smedelundsgade 60 
4300 Holbæk 
Jeanie Elkjær 
Tlf: 24920716 
jmel@regionsjaelland.dk 
Hans Henrik Bülow 
hhbu@regionsjaelland.dk 
Holstebro Sygehus 
Lægårdvej 12 
7500 Holstebro 
David Lodahl 
Tlf: 78430000 
davlod@rm.dk 
Hvidovre Hospital 
Kettegård Alle 30 
2650 Hvidovre 
Lene Russel 
Tlf: 38623862 
lene.russell@mail.dk 
Køge Sygehus 
Lykkebækvej 1 
4600 Køge 
Lone Poulsen 
Tlf: 47326450 
lmp@regionsjaelland.dk 
Nykøbing Falster Sygehus 
Fjordvej 15 
4800 Nykøbing F 
Henrik Guldager 
Tlf: 56516355 
hegu@regionsjaelland.dk 
Randers Sygehus 
Skovlyvej 1 
8930 Randers 
Helle Bundgaard 
Tlf: 78420505 
helle.bundgaard@randers.rm.dk 
Regionhospital Viborg  
Heibergs Alle 4 
8800 Viborg 
Lisbeth Liboriussen 
Tlf: 78445213 
Lisbeth.Liboriussen@Viborg.rm.dk 
Rigshospitalet, Intensiv Terapiklinik 4131 
Blegdamsvej 9 
2100 København 
Mette Krag 
Tlf: 35457450 
Mette.krag.01@regionh.dk 
 
Rigshospitalet, Neurointensiv 2093 
Blegdamsvej 9 
2100 København 
Marianne Berntsen 
Tlf: 30253395 
mariannejorgensen2000@yahoo.dk 
Rune Damgaard Nielsen 
Rune.damgaard.nielsen@regionh.dk 
Rigshospitalet, Thoraxintensiv 4141 
Blegdamsvej 9 
2100 København 
Hanne Ravn 
Tlf: 35451710 
hanne.berg.ravn@regionh.dk 


 
14 
 
Roskilde Sygehus 
Køgevej 7-13 
4000 Roskilde 
 
Akil Walli 
aqil@regionsjaelland.dk 
Henrik Planck Pedersen 
Tlf: 47325005 
hppd@regionsjaelland.dk 
Slagelse Sygehus 
Ingemannsvej 18 
4200 Slagelse  
Susanne Andi Iversen 
Tlf: 58559000 
saiv@regionsjaelland.dk 
Vejle Sygehus 
Kabbeltoft 25 
7100 Vejle 
Pawel Berezowicz 
Tlf 79406275 
pawel.berezowicz@rsyd.dk 
Lone Buus 
lonebuus@dadlnet.dk 
Aalborg Universitets Hospital  
Hobrovej 18-22 
9000 Aalborg 
Bodil Steen Rasmussen 
97661864 
bodil.steen.rasmussen@rn.dk 
Søren Ågaard (afdelingslæge) 
soaa@rn.dk 
Århus Universitetshospital  
Nørrebrogade 44 
8000 Århus  
Helle Nibro 
Tlf: 78450000 
hellnibr@rm.dk 
Århus Universitetshospital (Skejby) 
Palle Juul-Jensens Boulevard  
8200 Århus N 
 
Jakob Gjedsted 
Tlf: 78451030 
Jakob.gjedsted@auh.rm.dk 
Steffen Christensen 
Steffen.christensen@auh.rm.dk 
Århus Universitetshospital, Neuro Intensiv Afsnit  
Nørrebrogade 44 
8000 Aarhus C 
Stig Dyrskog  
Tlf: 78463515 
Stig.dyrskog@rm.dk 
 
Finnish sites and locale investigators: 
Hospital 
Locale investigator 
Kuopio University Hospital 
Department of intensive care medicine 
Stepani Bendel 
Email: stepani.bendel@kuh.fi 
Helsinki University Hospital  
Department of anaesthesiology and intensive 
care medicine 
Minna Backlund 
Email: Minna.Backlund@Hus.fi 
Oulu University Hospital  
Department of intensive care medicine 
Janne Liisanantti   
janne.liisanantti@ppshp.fi 
Tampere University Hospital 
Department of intensive care medicine 
Sari Karlsson 
Email: Sari.Karlsson@pshp.fi 
Turku University Hospital  
Department of intensive care medicine 
Juha Grönlund  
juha.gronlund@tyks.fi 
 
Swiss sites and locale investigators (more to be added) 
 
Joerg C. Schefold  MD, PhD, DMSci  
Department of Intensive Care 
University Hospital Bern 
Switzerland  
 


 
15 
 
Netherland, sites and locale investigators (more to be added) 
 
Frederik Keus, MD, PhD  
Department of Critical Care 
University of Groningen, University Medical Centre of Groningen 
The Netherlands 
 
Italian sites and locale investigators (more to be added) 
 
Paolo Pelosi, MD, FERS  
Anaesthesia and Intensive Care, IRCCS San Martino IST 
Department of Surgical Sciences and Integrated Diagnostics, University of Genoa 
Italy  
 
Norwegian sites and locale investigators (more to be added) 
 
Anne Berit Guttormsen, professor, MD  
Department of Anaesthesia and Intensive Care, Haukeland University Hospital, Bergen  
Clinical Institute 1 UiB, Bergen University Hospital 
Norway  
 
Iceland, sites and locale investigators (more to be added) 
 
Alma Möller, MD, PhD 
Department of Anaesthesia and Intensive Care 
Landspitali University Hospital, Reykjavik 
Iceland 
 
 


 
16 
 
Data Monitoring and Safety Committee 
Tim Walsh, professor, MD, PhD 
MRC Centre for Inflammation Research, University of Edinburgh 
The Queens Medical Research Institute 
Edinburgh 
United Kingdom 
 
Anders Åneman, MD, PhD 
Intensive Care Unit  
Liverpool Hospital 
South Western Sydney 
Australia 
 
Aksel Jensen, Biostatistician, PhD  
Department of public health, Section of Biostatistics  
University of Copenhagen  
Denmark 
 
 
 


 
17 
 
List of abbreviations  
 
AE 
Adverse events 
AIDS 
Acquired Immune Deficiency Syndrome 
AR 
Adverse reactions 
ARR 
Absolute risk reduction 
CDI  
Clostridium difficile infection 
CI 
Confidence interval 
CRIC 
Centre for Research in Intensive Care 
CRO 
Contract research organisation 
CT 
Computed Tomography 
CTSM 
Clinical Trial Supply Management 
DMSC 
Data Monitoring and Safety Committee 
eCRF 
Electronic case report form 
FiO2 
Fractional inspired oxygen 
GCP 
Good Clinical Practice 
GDP 
Good Distribution Practice 
GMP 
Good Manufacturing Practice 
GI 
Gastrointestinal 
H2RA 
Histamine-2-receptor antagonist 
hCG 
Human Chorionic Gonadotropin  
ICU 
Intensive care unit 
INR 
International normalized ratio 
MAR 
Missing at random 
MCAR 
Missing completely at random 
MNAR 
Missing not at random 
MR 
Magnetic Resonance 
NSAID 
Non-steroidal anti-inflammatory drugs 
NYHA 
New York Heart Association 
PaO2 
Partial pressure of oxygen in arterial blood 
PPI 
Proton pump inhibitor 
PT 
Prothrombin time 
RCT 
Randomised clinical trial 


 
18 
 
RRI 
Relative risk increase 
RRR 
Relative risk reduction 
SAE 
Serious adverse event 
SAPS 
Simplified Acute Physiology Score 
SAR 
Serious adverse reaction 
SC 
Steering Committee 
SD 
Standard deviation 
SOFA 
Sequential Organ Failure Assessment  
SUP 
Stress ulcer prophylaxis  
SUSAR 
Severe unexpected serious adverse reaction 
TSA 
Trial sequential analysis 
 
 


 
19 
 
1.  
Introduction and background 
1.1 
The patient population 
Critically ill patients are at risk of stress-related gastrointestinal (GI) mucosal damage, which 
can progress to ulceration and GI bleeding [1]. Endoscopic studies have shown that gastric 
erosions are present in up to 90% of patients by the third day in the intensive care unit (ICU) 
[2, 3]. These lesions are in the vast majority of patients superficial and asymptomatic, but can 
progress and result in overt and clinically important bleeding [4]. Clinical important bleeding in 
the ICU is a serious condition, with an estimated 1-4 times increased risk of mortality and is 
associated with an excess length of ICU stay of 4-8 days [1].  
Determining the incidence of GI bleeding in critically ill patients in the ICU is complicated by 
varying definitions of the outcome, difficulties in measuring the outcome, and different case 
mix. In randomised clinical trials (RCTs) and observational studies, the reported incidence of 
stress related GI bleeding among ICU patients ranges from 0.6-6.0% [1, 5–9]. Studies may 
have incorrectly included bleedings not related to stress ulcers e.g. oesophageal varices and 
ulcers already present upon ICU admission, e.g. undiagnosed peptic ulcers. In a prospective 
study by Cook at al. causes of haemorrhage were identified by endoscopy. Stress ulceration 
was defined as the sole source of bleeding in 14 of 30 patients [10]. Accordingly, sources of GI 
bleeding not prevented by stress ulcer prophylaxis (SUP) are frequent and the incidence of 
stress related ulcers may be lower than reported. Furthermore, diagnostics and treatment of 
critically ill patients in the ICU have improved considerably during the last decades [11, 12] 
and the incidence of stress ulcerations in critically ill patients may have changed. 
   
1.2 
Current treatment  
Clinical trials have suggested a reduction in frequency of GI bleeding among ICU patients 
receiving SUP compared with patients receiving placebo or no prophylaxis [3, 13–19]. Based 
on this research conducted 20 years ago, SUP is recommended in international guidelines [20–
23] and regarded as standard of care in the ICU. In a recent international unit evaluation 96 out 
of 97 units used SUP on a regular basis [24] and proton pump inhibitor (PPI) was used as first-
line therapy in 66% of the participating ICUs [24].  
 
The available PPIs are considered equally effective in the following comparative doses [25–29]: 
 
Esomeprazole 10 mg 


 
20 
 
Lanzoprazole 
15 mg 
Omeprazole 
10 mg 
Pantoprazole 
20 mg 
Rabeprazole 
10 mg 
 
 
In 2014 Maclaren et al. published a retrospective cohort study with data from the Premier 
Perspective Database [30]. Patients aged 18 years or older requiring invasive mechanical 
ventilation and receiving either Histamine-2-receptor antagonist (H2RA) or PPI were 
scrutinized. Some 35,312 patients were included and among other findings the authors found 
that pantoprazole was the most frequently used PPI. This finding was confirmed in a cohort 
study from 2014, where pantoprazole was prescribed to 32% of patients treated with acid 
suppressants in the ICU [9].  
 
1.3 
Trial interventions 
 
Because of the increased mortality and morbidity of ICU patients with clinically important GI 
bleeding, it is theoretically possible that PPIs reduce the risk of GI bleeding and hence the risk 
of death. However, research has not been able to confirm this and a 2014 observational study 
comprising more than 1,000 patients concludes that part of the increased mortality is 
explained by confounding [9]. A recent systematic review with meta-analysis and trial 
sequential analysis (TSA) assessed randomised trials comparing PPI or H2RA to placebo or 
no prophylaxis [31]. The review was conducted according to the Cochrane Handbook for 
Systematic Reviews [32] and included 20 trials with high risk of bias. The review results 
showed no significant difference between SUP and placebo/no prophylaxis on mortality and 
the TSA could exclude a 20% relative risk reduction or increase in mortality by using PPI or 
H2RA. Another meta-analysis from 2010 came to the same conclusion. Mortality was reported 
in 14 of the analysed trials and no significant reduction in mortality was found (OR 1.03, 95% 
CI 0.78-1.37; p=0.82). 
 
Three RCTs have been conducted comparing PPI to placebo [33–35], but all had low sample 
size (n=169 [33], n=287 [34], and n=41 [35]) and neither of them were powered to show 
statistically significant differences in clinically relevant outcomes. The 2014 meta-analysis 


 
21 
 
comprised two of the trials (one was published after the meta-analysis) and concluded that the 
trials had a high risk of bias, and there were no differences in GI bleeding, pneumonia and 
mortality when comparing PPI to placebo.    
 
PPI may reduce the risk of GI bleeding, but studies have indicated that they may also increase 
the risk of pneumonia, Clostridium difficile infection (CDI), acute myocardial ischemia, 
rhabdomyolysis, hypomagnesaemia and hypocalcaemia, and all of these conditions may 
increase the risk of death [36–39].  
 
PPI versus H2RA 
In recent years PPI has been considered the drug of choice in the management of most acid-
related GI disorders [40]. The superior efficacy of PPIs over H2RAs has been demonstrated in 
various GI disorders, including peptic ulcer disease, gastroesophageal reflux disease and GI 
damage caused by non-steroidal anti-inflammatory drugs (NSAIDs) [40]. Randomised trials and 
meta-analyses have aimed to evaluate PPI compared to H2RA as SUP in the ICU. A recent 
published meta-analysis by Alhazzani et al. (14 trials, 1720 patients) compared PPI and H2RA 
[41]. The authors found that PPI was more efficient in reducing clinically important and overt GI 
bleeding, but no differences were shown regarding mortality, length of stay or pneumonia [41]. 
According to the authors the results were limited by sparse data, a difference between lower 
and higher quality trials, trial methodology and possible publication bias. Another systematic 
review and meta-analysis conducted in 2010 compared PPI and H2RA [42]. The study 
comprised seven RCTs and 936 ICU patients. The analysis did not find differences in rates of 
clinically important GI bleeding, pneumonia or death. Limitations of the review include limited 
number of patients, significant statistical heterogeneity, and risk of publication bias. 
 
Clinical data on the control intervention 
As described in previous section, studies have indicated that PPI is superior to H2RA to prevent 
clinically important and overt GI bleeding, but there is still a lack of quantitative and qualitative 
evidence for PPI being superior to placebo. Before comparing different SUP agents we need 
firm evidence of SUP being superior to placebo. 
1.4 
Adverse effects of PPI 
Nosocomial pneumonia 
Nosocomial infections are a significant in-hospital burden, and pneumonia is the most 
common nosocomial infection in the ICU, affecting 10–20% of patients receiving mechanical 


 
22 
 
ventilation for more than 48 hours [43]. It has been suggested that SUP agents may increase 
the frequency of nosocomial pneumonia and trials have investigated the incidence of 
pneumonia in patients treated with SUP compared to placebo/no prophylaxis [6, 17, 33, 34, 
37, 44–46]. In 2004 Kantorova et al. found an insignificant difference in the incidence of 
pneumonia in patients treated with PPI/H2RA compared to placebo (n=287, 10%/9% vs. 7%). 
No meta-analysis of randomised trials have shown a statistically significant increased risk of 
nosocomial pneumonia when using SUP compared to placebo/no prophylaxis [31, 47].  
 
Clostridium difficile infection 
In recent years, concern has been raised that PPI increases the risk of CDI because host 
immunity is compromised by higher gastric pH [38, 48]. No randomised trials of SUP have 
reported the incidence of CDI in an ICU setting, but a recently published cohort study in adult 
critically ill patients requiring mechanical ventilation (n=35,312) found a 2-4 times increased 
risk of CDI in patients receiving PPIs compared to H2RAs [30]. Studies conducted outside the 
ICU demonstrate similar findings. In 2007 Leonard et al. found a significantly increased risk of 
CDI in non-ICU patients receiving H2RA or PPI, as compared to placebo [49] and a meta-
analysis pooling 39 observational studies showed a significant association between PPI users 
and risk of developing CDI (OR 1.74, 95% CI 1.16-5.44) compared with non-users [50].  
 
Acute myocardial ischemia 
An association between use of PPIs and increased risk of cardiovascular events in patients 
receiving clopidogrel have been suggested [47, 51]. It may be that PPIs reduce the anti-
platelet effects of clopidogrel, by interaction with the Cytochrome P450 enzyme complex in the 
liver [51].  In a case-control study of 18,130 clopidogrel users, use of co-existing PPI was 
associated with an increased risk of cardiovascular complications [51]. However, in the only 
RCT published, no cardiovascular interaction between clopidogrel and PPI was observed in 
non-ICU patients [42]. A cohort-study including 56,406 patients hospitalized for myocardial 
infarction or stroke, found an association between treatment with PPI and adverse 
cardiovascular outcomes after discharge regardless of treatment with clopidogrel [52].  
 
In conclusion, valid evidence on the use of SUP in the ICU is lacking. Moreover, there is 
increasing concern about side-effects of SUP, in particular PPIs, but the data on side-effects 
are of very low quality.  
 


 
23 
 
1.5 
Risks and benefits 
Since PPI is a well-established drug and thousands of patients are treated with it every day, 
there will be no additional risk to patients receiving PPI. The risk will be limited to the known 
adverse reactions, including intolerance, abdominal pain and headache (appendix 2) 
From the available evidence we do not know whether there will be a higher risk of GI bleeding, 
pneumonia, CDI, cardiovascular events or mortality in the PPI or placebo groups [31].  
 
1.6 
Ethical justification and trial rationale 
As described in former sections, there is no firm evidence from systematic reviews of RCTs or 
single RCTs on the potential benefit or harm of PPIs in adult patients in the ICU. On the other 
hand, SUP is recommended in international guidelines [20–22], is regarded as standard of 
care and surveys have confirmed that PPI is already part of the treatment in ICUs worldwide. 
Since it is a widespread and currently used intervention [24], the patients assigned to the PPI 
group, will not be exposed to additional risk when enrolled in the trial. Any patient with known 
peptic ulcer or GI bleeding will be excluded and treated according to usual care. If a 
randomised patient develops upper GI bleeding and the clinician finds indication for treatment 
with PPI or H2RA, the trial intervention will be discontinued and the patient will be treated 
according to usual care. Therefore, patients in the control group will, presumably, also not be 
exposed to any additional risks.     
Stress ulceration is a condition often seen in critically ill patients in the ICU. The majority of 
patients will be temporarily incompetent because of severe illness or as a consequence of the 
treatment (sedation). We cannot perform the trial randomising competent patients, because 
less sick (and thus competent) patients do not suffer from stress ulcers. Patients requiring 
acute treatment in the ICU e.g. mechanical ventilation are in an acute life-threatening condition 
and it would expose the patient to great risk not to initiate the necessary treatment in order to 
get informed consent. To make clinical trials with the goal of improving the outcome for ICU 
patients at risk of stress related GI bleeding, it is necessary to randomise and enrol patients 
before obtaining informed consent from the patient. Consent will be obtained according to 
national law, which in Denmark is by proxy (consent before randomisation by 2 doctors 
followed by next-of-kin and general practitioner/regional medical officer by health as soon as 
possible). The consenting party will be provided with written and oral information about the 
trial, so he/she is able to make an informed decision about participation in the trial. Written 
information and the consent form will be subjected to review and approval by the ethical 


 
24 
 
committee system according to national law in all participating countries. The consenting party 
can at any time, without further explanation, withdraw consent and data will be deleted if 
demanded.  
The process leading to the achievement of consent may differ in the participating countries, 
but will be described and be in compliance with all applicable regulations in the country. 
No biological material will be collected for the trial, thus no bio-bank will be formed.  
 
1.6.1  
Outcome considerations 
It has been estimated that 39% of the patients receiving SUP in the ICU are discharged from 
the hospital with SUP without an obvious indication for continuation of therapy [53]. Besides 
the side effects described in former sections, long-term treatment with PPI is associated with 
several side effects e.g. an increased risk of fractures, hypomagnesaemia and rhabdomyolysis 
[36, 39], which may all have the potential to increase mortality. Assessing mortality as the 
primary outcome would give the opportunity to weigh the totality of benefits and harms of PPI. 
Furthermore the rationale for choice of outcomes is: 
 
1. Mortality has not been the primary outcome of previous trials and we are sceptical that 
they got reliable information on mortality other than short term mortality (ICU/hospital) 
[31] 
2. Nearly all previous trials assessing PPI or H2RA as SUP have had high risk of bias 
[31]. We know that high risk of bias trials tend to overestimate benefit and 
underestimate harm [54]. Accordingly, previous trial results might be biased and even 
though they seem to find a neutral effect on mortality this may be a biased estimate 
actually concealing excess mortality in the SUP groups 
3. A meta-analysis of the previous trials did not reach a realistic information size so even 
neutral estimates may be misleading [31]. 
4. As a consequence of the 6S trial [55], where we found that bleeding was associated 
with death and that death where partly mediated by bleeding (and renal insufficiency), 
it appears odd that there should be a clinically significant reduction on GI bleeding (if 
PPI do prevent GI bleeding) without any effect on mortality [56]. 
5. A composite outcome of GI bleeding, pneumonia, CDI and acute myocardial ischemia 
seems valid to assess as well and will be a secondary outcome. The recommendation 
for using composite outcomes is reporting of the individual components as well, which 
will be done in a supplement to the primary publication. 


 
25 
 
 
Because of this and the potential to improve treatment of critically ill patients, the research 
question is in the public’s interest. The design of the trial will minimise the risk of systematic 
errors and the trial will provide information on beneficial and/or harmful effects of using PPI as 
SUP.    
 
1.6.2 
Sample size considerations 
It is difficult to produce reliable sample size estimations according to anticipated effects on GI 
bleeding because we have no reliable control groups due to the widespread use of PPI [57] 
and previous trials are in fact very old. As a consequence it has been necessary to calculate 
sample size estimations given that something may change if we stop/avoid PPI until GI 
bleeding actually happens (see appendix 11). The addressed intervention effect of 20% RRR 
or RRI on the primary outcome may seem high, but in a population with septic shock or in e.g. 
patients after cardiac arrest a 20% hazard ratio reduction corresponds to 1 months of extra 
median survival in patients with a median survival of approximately 5 months. So after all, a 
20% RRR or RRI may not be as huge as could be anticipated, when it only results in a 
modestly longer survival in these patients. The power for even major effects on each of the 
possible side effects (pneumonia, CDI and acute myocardial ischemia) are small, but it will still 
be a large contribution to our knowledge on these outcomes that may seriously question, 
overthrow or confirm what we know so far. Furthermore, 3,350 patients included in one trial 
would be a huge contribution to the evidence, more than doubling the number of randomised 
patients and providing trial results with low risk of bias on mortality and serious adverse 
events.  
No single trial, however big or well done, gives the final answer, and the SUP-ICU trial will not 
be an exception. However, the results will inform clinicians, guideline committee members and 
policy-makers on the use of PPI in the ICUs, as well as establish more (reliable) trust in PPI. 
Should we find 10-20% relative risk increase in mortality this will certainly trigger a new wave 
of trials on PPI or SUP in general and even though our trial may not be conclusive it may 
eventually lead to conclusions. 
  
1.7 
Trial conduct 
The trial will be conducted in compliance with a published trial protocol, the Helsinki 
Declaration in its latest version [58], the good clinical practice (GCP) guidelines [59], and 
national laws in the participating countries. The protocol will be registered on 


 
26 
 
www.clinicaltrials.gov and at the European Union Drug Regulating Authorities Clinical Trials 
(EudraCT) before trial start. No substantial deviation from the protocol will be implemented 
without prior review and approval of the regulatory authorities except where it may be 
necessary to eliminate an immediate hazard to the trial participants. In such case, the 
deviation will be reported to the authorities as soon as possible. Enrolment will start after 
approval by the ethical committees, medicines agencies, data protection agencies and health 
authorities in the participating countries. A manuscript with main points of the protocol 
including description of design, rationale and analysis plan will be submitted to a journal in 
English language. 
 
2. 
Trial objectives and purpose 
To assess the benefits and harms of PPI (pantoprazole) in adult, critically ill patients in the 
ICU.  
 
3. 
Trial design 
3.1 
Trial design 
An investigator-initiated, pragmatic, international, multicentre, randomised, blinded, parallel-
group trial of pantoprazole versus placebo. 
 
3.2 
Randomisation 
Patients will be screened for enrolment at admission to the ICU (see section 3.5). This will be 
ensured through implementation of trial methodology at trial sites. 
1:1 randomisation will be centralised and web-based randomisation according to the 
computer-generated allocation sequence list, stratification variables (site and active 
hematologic cancer), and varying block size. The allocation sequence list will be unknown to 
the investigators to allow immediate and concealed allocation to intervention with pantoprazole 
or placebo. Each patient will be allocated a unique patient-screening number. 
 
3.3 
Blinding 
Pantoprazole is preserved as a powder in a glass vial and needs to be dissolved in 10 ml of 
isotonic saline. The powder is momentarily dissolved with no need of shaking the vial. The 
solution is colourless and cannot be distinguished from saline. When the glass vial is masked, 


 
27 
 
it is not possible to determine whether the vial contains powder or is empty. The placebo will 
be an empty vial. Saline (10 ml) will be added to the empty vial in the same way as for the 
experimental intervention.  
The blinding of the trial medication will be a white label covering the whole vial including the 
bottom and the neck. The label will contain the required information of the trial drugs. The top 
of the placebo vial will be identical with the vial of the active drug. 
The allocated trial medication will be blinded to the clinical staff caring for the patient, to the 
patient, investigators, outcome assessors, and the data manager. The statistical analysis of 
the trial will be blinded with the intervention groups coded as, e.g., X and Y. Based on this 
blinded analysis two conclusions will be drawn: one assuming X is the experimental group and 
Y is the control group, and one conclusion assuming the opposite. Two abstracts will be 
written and accepted by the author group. After this, the blinding will be broken. 
 
The members of the Data Monitoring and Safety Committee (DMSC) will remain blinded 
unless 1) they request otherwise or 2) one of the two interim analyses has provided strong 
indications of one intervention being beneficial or harmful (a charter for the independent 
DMSC is attached in appendix 3). 
 
3.3.1 
Unblinding 
 
3.3.1.1 An individual 
The intervention may be unblinded for individual patients if deemed necessary by the clinician 
or investigator for the treatment and safety of the patient.  
In case of a suspected unexpected serious adverse reaction (SUSAR) the sponsor (or 
delegated party) shall break the blinding in order to judge the ‘expectedness’ and therefore the 
occurrence of a SUSAR (according to the summary of product characteristics), and report it to 
the authorities accordingly. See section 8 for more information. 
 
3.3.1.2 Procedure 
If the intervention for an individual patient needs to be unblinded during the trial, the treating 
physician shall contact Copenhagen Trial Unit (CTU), who will reveal the allocated trial 
intervention (pantoprazole or placebo). This can be done by telephone at all hours, any day of 
the week. If the investigator needs immediate unblinding of the trial medication, this can be 
done by removing the white label covering the glass vial. 


 
28 
 
 
3.5 
Participant timeline  
We will strive to enrol patients as soon as they fulfil the inclusion criteria. Patients will be 
allocated to either intravenous pantoprazole or placebo once daily and will continue the 
allocated intervention until death in the ICU or discharge from the ICU with a maximum of 90 
days after randomisation. 
If the patient is readmitted to the ICU within 90 days after randomisation the patient should 
continue the allocated treatment. 
 
4. 
Selection of participants 
All patients referred to a participating clinical trial site will be considered for participation. 
Patients will be eligible, if they fulfil all of the inclusion criteria and none of the exclusion criteria 
listed below (see also appendix 4) 
 
4.1 
Inclusion criteria 
 
• 
Acute admission to the ICU AND 
• 
Aged ≥ 18 years AND  
• 
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 mechanically ventilation which is expected to last > 24 hours. When in 
doubt of the forecast, the patient should be enrolled 
• 
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) 


 
29 
 
 
4.2 
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 
 
4.3 
Participant discontinuation and withdrawal 
4.3.1 
Discontinuation and withdrawal at the choice of the participant 
The procedure of handling withdrawal of consent from a patient will follow national regulations 
and will be described by each participating country.  
 
The Danish procedure: 
A patient, who no longer wishes to participate in the trial, can withdraw his/her consent at any 
time without need of further explanation, and without consequences for further treatment. 
Patients may be withdrawn from the trial at any time if consent is withdrawn by the person(s), 
who has given proxy-consent. 
In order to limit the amount of missing data we plan to collect as much data from each patient 
as possible. Therefore, if possible, the investigator will ask the patient which aspects of the 
trial, he/she wishes to withdraw from: 
  
• 
receiving the trial intervention only (allowing for all data registration and follow-up) 
OR 
• 
receiving the trial intervention AND further registration of daily data and/or follow-up 
 
Only the patient can demand deletion of already registered data and only if the patient did not 
consent previously. If so, data will be deleted and a new patient will be randomised to obtain 
the full sample size. 


 
30 
 
 
4.3.2 
Discontinuation and withdrawal at the choice of the investigator 
A patient can be discontinued from the trial intervention by the investigator at any time, if: 
• 
the patient experiences intolerable adverse reactions suspected to be related to the 
trial intervention 
AND/OR 
• 
the patient develops upper GI bleeding or another condition where the clinician finds 
indication for treatment with PPI or H2RA. The intervention will be stopped and the 
patient will receive relevant treatment. 
In these cases, the collection of data will continue and the follow-up will be conducted. The 
patient will remain in the intention-to-treat population if the allocated trial intervention has been 
given.  
If an ineligible patient is randomised by mistake and the trial intervention has not been given, 
data will be deleted (logged as a flawed randomisation) and a new patient will be randomised 
[60]. If the intervention has been given, the patient will continue in the trial and in the intention-
to-treat population.  
If the patient experiences a serious adverse reaction (SAR) or a suspected unexpected 
serious adverse reaction (SUSAR) the trial intervention will be stopped; data registration will 
continue (see section 8). 
 
Patients who are transferred to another ICU will be regarded as discharged from the ICU 
unless the new ICU is an active SUP-ICU trial site. In any case, patients transferred to another 
ICU will be followed up for the primary outcome measure and as many of the secondary 
outcome measures as possible. 
 
5. 
Selection and trial sites and personnel 
5.1 
Trial sites and setting 
Trial sites will be ICUs [61] in Europe. Trial sites are listed in the section ‘Administrative 
information’. This section will be updated during the trial.  
 
5.2 
Trial personnel 
All clinicians caring for patients in participating ICUs will be eligible to screen patients and 
perform the interventions.  


 
31 
 
All participating ICUs will receive written and oral instructions about the trial procedures. A 24-
hour hotline will be available for questions. 
 
6. 
Trial interventions 
6.1 
Experimental intervention 
To ensure systemic uptake of pantoprazole all patients randomised to the experimental group 
will be given intravenous pantoprazole 40 mg upon randomisation and hereafter once daily. 
The intervention period will be from randomisation until discharge from the ICU or death in the 
ICU. If the patient is readmitted, the allocated intervention should be continued until final 
discharge from the ICU or the end of the 90-day trial period.  
  
6.2 
Control intervention 
The control intervention will be placebo as described in section 3.3. 
The intervention period will be identical to the intervention period of the experimental 
intervention.  
 
6.3 
Co-interventions 
All patients in this trial will be offered co-interventions if indicated. Evidence regarding the use 
of sucralfate and antacids are weak [62] and we do not recommend the use of these drugs.  
 
The registered co-interventions will be: 
• 
any kind of mechanical ventilation (y/n) (daily) 
• 
continuous treatment with vasopressor/inotropes (y/n) (daily) 
• 
renal replacement therapy (y/n) (daily) 
• 
number of units of red blood cells (daily) 
• 
enteral nutrition (y/n) (daily) 
 
ICU treatment and management in general will be at the discretion of the treating clinicians.  
 
6.4 
Concomitant interventions 
PPI or H2RA cannot be prescribed as prophylaxis in the ICU during the intervention period. If 
the patient develops GI bleeding or another condition where treatment with one of the drugs is 


 
32 
 
indicted, the patient will be withdrawn from trial intervention and receive relevant treatment. 
Data collection will continue. If an included patient receives open-label PPI/H2RA (e.g. 
prescribed as prophylaxis) it will be considered a major protocol violation. This will be 
registered and the allocated trial intervention and data collection will be continued.   
 
Previously randomised patients readmitted to the ICU: 
• 
If the clinician finds indication to continue the PPI or H2RA prescribed in the ward, the 
trial medication will not be resumed, but data collection will continue  
• 
If the clinician does not find indication to continue the PPI or H2RA prescribed in the 
ward, the drug will be discontinued and the allocated trial medication will be resumed 
 
All other interventions will be allowed since they are expected to be distributed evenly in the 
two groups.  
 
6.5 
Intervention accountability 
Pantoprazole for intravenous injection will be bought and delivered from Actavis to the 
Hospital Pharmacy of the Capital Region of Denmark. The pantoprazole will be part of the 
regular production and hence not made especially for the SUP-ICU trial. The Hospital 
Pharmacy will send it directly to Nomeco. Pharma-Skan ApS will produce the sterile empty 
vials used for placebo. The production will follow all regulations and according to Good 
Manufacturing Practice (GMP) and Good Distribution Practice (GDP). The vials will be 
delivered to Nomeco CTSM who will be responsible for storage, blinding, packaging and 
distribution of vials with pantoprazole 40 mg and empty vials (placebo) to national and 
international trial sites. All services will be performed by qualified and trained personnel and 
according to GMP and GDP 
A computer program (from CTU) will generate a coding list with numbers for the vials. At 
randomisation, the computer program will allocate vials from the specific trial site to the 
patient. Nomeco CTSM will be responsible for having a sufficient number of vials to be 
allocated to patients enrolled at each trial site. At each trial site, trial products will be stored in 
a secure place. Combined with the unique packaging and labelling number this will ensure that 
trial medications will not be mixed up with other medications. Used and unused products will 
be registered.  
 


 
33 
 
7. 
Outcomes 
All outcomes are defined in appendix 4. 
 
7.1 
Primary outcome 
90-day mortality post-randomisation 
 
7.2 
Secondary outcomes 
• 
Proportion of patients with one or more of the following adverse events: clinically 
important GI bleeding, pneumonia, CDI, or acute myocardial ischemia in the ICU 
• 
Proportion of patients with clinically important GI bleeding in the ICU 
• 
Proportion of patients with one or more infectious adverse events (pneumonia or CDI) 
in the ICU 
• 
1-year “landmark” mortality post-randomisation 
• 
Days alive without the use of mechanical ventilation, renal replacement therapy or 
circulatory support in the 90-day period  
• 
Number of  SARs as defined in appendix 4  
• 
A health economic analysis will be performed. The analytic details will be based on the 
result of the trial and specified (cost-benefit vs cost-minimisation analyses) 
 
The specific elements of the composite outcomes will be reported in supplementary material to 
the primary publication. 
7.3 
Exploratory outcomes 
No exploratory outcomes or sub-studies are planned. However, sub-studies will be 
encouraged as long as they don’t hamper the completion of the main protocol and can be 
conducted after approval of the protocol by the Steering Committee (SC).  
 
8. 
Safety 
8.1 
Definitions  
Adverse event (AE): any undesirable medical event occurring to a patient during a clinical 
trial, which does not necessarily have a causal relationship with the intervention.  
 


 
34 
 
Adverse reaction (AR): any undesirable and unintended medical response related to the 
intervention occurring to a patient during a clinical trial. Adverse reactions are specified in the 
product characteristics of pantoprazole (see appendix 2 and 5) 
 
Serious adverse event (SAE): any adverse event that results in death, is life-threatening, 
requires hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability or incapacity. 
 
Serious adverse reaction (SAR): any adverse reaction (as defined above) that results in 
death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, 
results in persistent or significant disability or incapacity.  
 
Suspected unexpected serious adverse reaction (SUSAR): any suspected adverse 
reaction which is both serious and unexpected. SUSARs will be defined as serious reactions 
not described in the summaries of product characteristics for pantoprazole.  
 
8.2 
Risk and safety issues in the current trial 
Pantoprazole is well tolerated and most adverse reactions have been mild and transient 
showing no consistent relationship with treatment. Approximately 5% of patients can be 
expected to experience adverse drug reactions. The most commonly reported are diarrhoea 
and headache, both occurring in approximately 1% of patients. Because of intravenous 
administration, there will be a risk of phlebitis in both groups. 
In appendix 2 all adverse reactions for pantoprazole are listed.  
Apart from the risk of phlebitis, there is no risk of adverse reactions to the placebo (10 ml of 
isotonic saline).  
See Summary of Product Characteristics in appendix 5. 
 
8.3 
Serious adverse reactions and events 
SARs to pantoprazole: 
Registered SARs are defined in appendix 4 and ARs not registered are discussed in appendix 
6. 
 
SARs to 10 ml of isotonic saline: 


 
35 
 
No SARs are associated with such small amount of intravenous isotonic saline.  
 
8.3.1 
Recording of serious adverse reactions and events  
SARs will be recorded daily in the eCRF from the time of the first administration of trial 
medication and until 24 hours after last administration of trial medication or the patient is 
discharged from the ICU. If the patient is readmitted to the ICU and trial medication is re-
introduced, SARs will be recorded. When a SAR is registered in the eCRF the coordinating 
investigator will be informed directly which will secure fast reporting of SAR. SARs in the two 
groups will be compared in the interim analyses and as an outcome measure. If a patient 
experiences a SAR he or she will be withdrawn from the trial. Daily registration will be 
continued and the follow-up will be conducted.  
 
If a patient experiences SUSAR, the local investigator must report this without undue delay to 
the Sponsor (or delegated party). The patient will be withdrawn from the trial and the trial 
medication will be demasked. If a SUSAR is still reasonable after demasking, a report will be 
conducted describing onset and end of event, severity, the relation to the intervention, the 
actions taken and the outcome.  
 
SAEs will not be recorded as an entity, because the majority of ICU patients will experience 
several SAEs during their critical illness. The most important SAEs will be captured in the 
secondary outcome measures (days alive without life-support). Patient charts, notes and lab 
reports will contain daily registrations of clinical data, which can be obtained on request from 
the medical authorities.  
 
8.4 
Reporting 
Trial investigators are to report SUSARs without any delay to the sponsor, which in turn will 
report these to the Danish Health and Medicine Authorities 7 days at the latest after the report 
has been received. 
 


 
36 
 
9. 
Procedures, assessments and data collection 
9.1 
Inclusion procedure 
9.1.1 
Screening 
All patients admitted to participating ICUs will be eligible for screening. In fertile women a 
negative urine-hCG or plasma-hCG must be present before enrolment. 
 
9.1.2 
Procedures for informed consent 
Patients will be enrolled after consent is obtained according to national regulations. This 
procedure will be described by each participating country. The procedure for Danish patients 
is described in appendix 7. 
 
9.2 
Data collection 
9.2.1 
Method 
Data will be obtained in eCRFs from a combination of patient files and national registers. For 
patients transferred from a trial ICU to a non-trial ICU, data related to the outcomes of interest 
will be collected after transferral e.g. by national registers, phone calls, and patient charts.   
 
9.2.2 
Timing 
Appendix 8 shows an overview of the timing and all variables are defined in appendix 4. 
 
Baseline variables (not collected in the screening procedure) 
• 
Sex 
• 
Age at randomisation/date of birth 
• 
Date of admission to hospital and date and time to ICU 
• 
Elective or emergency surgery during current hospitalization (y/n) 
• 
Treatment of suspected or confirmed CDI during current hospital admission (y/n)  
• 
Treatment with NSAID or acetylsalicylic acid at hospital admission (y/n) 
• 
Treatment with anticoagulants at hospital admission (y/n) 
• 
Intravenous thrombolysis within the previous 3 days (y/n) 
• 
Co-morbidities (see definitions in appendix 4): 
• 
history of chronic lung disease  
• 
history of myocardial ischemia 
• 
history of severe chronic heart failure (NYHA 3-4) 


 
37 
 
• 
history of chronic renal failure in the last year prior to hospital admission 
• 
treatment with at least 0.3 mg/kg/day of prednisolone equivalent for at least one 
month in the 6 month prior to ICU admission 
• 
active hematologic cancer 
• 
metastatic carcinoma 
• 
AIDS 
• 
Values for simplified acute physiology score (SAPS) II 24 hours prior to randomisation 
(not covered above): heart rate, systolic blood pressure, core temperature, PaO2/ FiO2 
ratio, urinary output, urea, white blood cell count, potassium, sodium, bicarbonate, 
bilirubin, Glasgow Coma Scale (GCS) score (appendix 9) 
• 
Variables for severity organ failure assessment (SOFA) scoring 24 hours prior to 
randomisation not covered in SAPS II scoring: blood platelets, MAP, dose of 
noradrenalin, adrenalin and dopamine, use of inotropes, plasma creatinine (appendix 
10) 
 
Daily during ICU admission: 
• 
Delivery of trial medication (y/n) 
• 
Open label treatment with PPI/H2RA (y/n) 
• 
Invasive or non-invasive mechanical ventilation (y/n) 
• 
Circulatory support (infusion of vasopressor/inotropes) (y/n) 
• 
Any form of renal replacement therapy (y/n) 
• 
Onset of pneumonia (as defined in appendix 4) on this day (y/n) 
• 
Treatment with antibiotics (enteral vancomycin, intravenous or enteral metronidazole, 
or enteral fidaxomicin) for suspected or proven CDI on this day (y/n) 
• 
Acute myocardial ischemia (as defined in appendix 4) on this day (y/n) 
• 
Enteral feeding on this day (y/n) 
• 
Number of units of RBCs 
• 
Overt bleeding episodes (hematemesis, coffee ground emesis, melena, hematochezia 
or bloody nasogastric aspirate) (y/n) 
• 
SARs (y/n) (appendix 4) 
 
Bleeding form (only for patients with overt bleeding) 


 
38 
 
• 
Data on clinically important bleeding (overt GI bleeding as defined above and at least 
one of the following four features within 24 hours of GI bleeding (in the absence of other 
causes)  in the ICU: 
• 
a spontaneous drop of systolic blood pressure, mean arterial pressure or 
diastolic blood pressure of 20 mmHg or more 
• 
start of vasopressor or a 20% increase in vasopressor dose 
• 
decrease in haemoglobin of at least 2 g/dl (1.24 mmol/l)  
• 
transfusion of 2 units of packed red blood cells or more 
• 
Origin of GI bleeding confirmed (y/n) 
• 
Verification of ulcer/gastritis/esophageal varices (y/n) 
• 
Haemostasis achieved/attempted by endoscopy/open surgery/coiling (y/n) 
 
Follow-up 90 days after randomisation 
• 
Death (y/n, if yes, date of death) 
 
Follow-up 1 year after randomisation  
• 
Death (y/n, if yes, date of death) 
 
10.  
Data handling and record keeping 
10.1 
Data management 
Data will be entered into an electronically, web-based eCRF from medical files and national 
registers by trial personnel.  
 
10.2 
Confidentiality 
Each patient will receive a unique trial identification number. Trial investigators will receive 
personal username and passwords to access the randomisation system and the eCRF. Each 
site will only have access to site specific data. 
Data will be handled according to the National Data Protection Agency, and is protected by the 
Danish national laws ‘Loven om behandling af personoplysninger’ and ‘Sundhedsloven’. 
 
10.3 
Biobanking 
No biobank will be formed. 


 
39 
 
 
10.4 
Access to data 
All original records (incl. consent forms, eCRFs, and relevant correspondences) will be 
archived at trial sites for 15 years. The clean electronic trial database file will be delivered to 
the Danish Data Archive and maintained for 15 years and anonymised if requested by the 
authorities. 
 
11.  
Statistical analysis 
90-day mortality and 1-year mortality have been chosen as outcomes for all-cause mortality. 
Besides landmark mortality, mortality 90 days and 1 year after last randomised patient have 
been considered, but due to practical and organisational matters, and lack of centralised 
registration, it will be difficult and for some countries impossible to get mortality data up to 3 
years after enrolment of a patient.  
 
11.1  Sample size estimation and power calculations 
 
11.1.1 Sample size estimation for the primary outcome 
Primary outcome measure 
Assuming a baseline 90-day mortality of 25% [9] (see appendix 11) α=0.05 (two-sided), and 
β=0.1, 3350 patients (2 x 1675) will be needed to show a 20% relative risk reduction (RRR)  or 
increase (RRI) corresponding to a 5% absolute risk reduction or risk increase in the primary 
outcome measure.  
Trial Sequential Analysis [63, 64] of existing trials (n=16) has showed that 35% (1584 patients) 
of the required information size to detect or reject a 20% RRR corresponding to 4,575 patients 
has been accrued [31]. Consequently, there is an information gap of around 3000 patients 
assuming a 20% RRR in mortality (appendix 12). With the inclusion of an additional 3350 
patients it is expected that the pooled effect will cross the boundary for benefit/harm or the 
boundary for futility. 
 
11.1.2 
Power estimations for secondary outcomes 
Power estimations are based on 3350 included patients, a risk of type 1 error of 5%, and a 
minimal clinically relevant difference as stated: 


 
40 
 
Clinically important GI bleeding: 46% power (baseline 3% -> 2% = 33% RRR) for showing or 
discarding a numbers-needed-to-treat (NNT) of 100. 
Pneumonia: 85% power (baseline 20% -> 16% = 20% RRR) for showing or discarding a NNT 
of 25. 
CDI: 53% power (baseline 10% -> 8% = 20% RRR) for showing or discarding a NNT of 50. 
Myocardial ischemia: 29% power (baseline 5% -> 4% = 20% RRR) for showing or discarding a 
NNT of 100 
 
11.2  Statistical methods 
The primary analysis will be conducted including the intention-to-treat population [65–67]. A 
sensitivity analysis will be conducted including the per-protocol population, excluding patients 
with a major protocol violation (patients who did not receive the allocated trial intervention at 
all, patients who did not receive the trial intervention for at least two days in a row, treatment 
with PPI or H2RA without clinically indication and withdrawal from trial intervention). Patients 
transferred to another ICU will be considered discharged from the ICU.  
The primary analysis of all dichotomous outcomes will compare the outcome at 90 days after 
randomisation in the two groups by binary logistic regression analysis with adjustment for 
stratification variables [68]: site and active haematological cancer  
A secondary analysis will be performed adjusting for stratification variables together with other 
known major prognostic co-variates: age, baseline SOFA score, and type of admission 
(medical, elective surgery or emergency surgery).  
Further details will be provided in a statistical analysis plan.  
 
11.2.1 
Pre-planned subgroup analyses 
We will compare the primary outcome measure in pre-specified subgroups defined according 
to 1) shock at randomisation (y/n), 2) mechanical ventilation at randomisation (y/n), 3) 
coagulopathy at randomisation or history of coagulopathy (y/n), 4) history of liver disease (y/n) 
5) type of ICU admission (medical/surgery) and 6) SAPS II > 53 points (y/n). 
 
11.2.2  Significance 
A two-sided P value of less than 0.05 will be considered statistically significant.  
 


 
41 
 
11.2.3 
Interim analysis 
Interim analyses will be conducted after patient no. 1650 and 2500 has been followed for 90 
days. 
The DMSC will constitute its own plan of monitoring and meetings. The charter for the 
independent Data Monitoring and Safety Committee (DMSC) (appendix 3) defines the 
minimum of obligations and primary responsibilities of the DMSC as perceived by the SC, its 
relationship with other trial components, its membership, and the purpose and timing of its 
meetings. 
The DMSC may recommend pausing or stopping the trial if group-difference in the primary 
outcome measure, SARs or SUSARs are found at the interim analyses with statistical 
significance levels adjusted according to the LanDeMets group sequential monitoring 
boundaries based on O’Brien Fleming alfa-spending function [69]. If an analysis of the interim 
data from 1650/2500 patients fulfils the LanDeMets stopping criterion the inclusion of further 
patients will be paused and an analysis including patients randomised during the analysis 
period will be performed. If this second analysis also fulfils the LanDeMets stopping criterion 
according to the group sequential monitoring boundaries the SC may stop the trial [67]. 
Furthermore, the DMSC can recommend pausing or stopping the trial if continued conduct of 
the trial clearly compromises patient safety. However, stopping for futility to show an 
intervention effect of 15% RRR will not be an option as intervention effects less than 15% 
RRR of all-cause mortality may be clinically relevant as well.    
 
11.2.4  Early stopping criteria 
See previous section 
 
11.2.5  Accountability procedure for missing data/population for analysis 
If less than 5% of data are missing on any primary or secondary outcome, a complete case 
analysis without input of missing values will be performed. If missing data are more than 5%, a 
blinded statistician will assess whether data are ‘missing completely at random’ (MCAR 
criterion) based on a rational assessment of the pattern of missing data [70]. Little’s test will be 
used if there remains doubt [71]. If it is concluded that data are not ‘missing completely at 
random’, multiple imputation using chained equations will be performed by creating ten input 
data sets under the assumption that the data are missing data at random (MAR criterion) [72, 
73]. We will use outcomes and the most important baseline characteristics in the multiple 
imputation. The exact variables to be used to estimate the missing values will be outlined in 


 
42 
 
the detailed statistical analysis plan: If multiple imputation is used, then the primary result of 
the trial will be based on these data. The unadjusted, non-imputed analysis will also be made 
available. If multiple imputation is used, we use a best-worst worst-best case scenario as a 
sensitivity analysis to assess the potential impact of any pattern of missingness including that 
the data are missing not at random (MNAR criterion) for the trial results. In the ‘best-worst-
case’ scenario it is assumed that all patients lost to follow-up in the experimental group have 
had a beneficial outcome (e.g. have survived, had no serious adverse reactions etc.); and all 
those with missing outcomes in the control group have had a harmful outcome (e.g. have not 
survived; have had a serious adverse reaction etc.). Conversely, in the ‘worst-best-case’ 
scenario, it is assumed that all patients who were lost to follow up in the experimental group 
have had a harmful outcome; and that all those lost to follow-up in the control group have had 
a beneficial outcome. When continuous outcomes are used, a ‘beneficial outcome’ will be 
defined as the group mean plus two standard deviations (SD) of the group mean, and a 
‘harmful outcome’ will be defined as the group mean minus two SD of the group mean.   
 
 
12. 
Quality control and quality assurance 
The coordinating investigator will be responsible for organizing the trial sites including 
education of local investigators, research nurses, and other trial site personnel before the 
initiation of the trial. This education will be continuously documented and two annual 
investigator meetings will be planned.  
After initiation, trial site investigators will be responsible for all trial-related procedures at their 
site, including education of staff in trial-related procedures, recruitment and follow-up of 
patients and entry of data. Clinical staff at the trial sites will be responsible for the treatment of 
trial patients. 
 
12.1 
Monitoring of the intervention groups 
The trial will be externally monitored following a monitoring plan developed in collaboration 
with the GCP Unit in Copenhagen, which will coordinate the monitoring done by local GCP 
units and/or monitors in all countries. A centralised day-to-day monitoring of the eCRF will be 
done by the coordinating investigator or her delegates. 
 


 
43 
 
13. 
Legal and organisational aspects 
13.1  Finance 
13.1.1 
Trial funding 
The SUP-ICU trial is funded by the Innovation Fund Denmark (4108-00011A). The funding 
sources will have no influence on trial design, trial conduct, data handling, data analysis or 
publication.  
 
13.1.2 
Compensation 
Trial sites will be given DKR 1500 (200 EUR) in case money for each patient with 90-day 
follow-up to compensate for the increased workload participation infers.  
 
13.2 
Insurance 
In Denmark, all trial participants are insured by the Patient Insurance Association. Patient 
insurance will be ensured before initiating the trial in each participating countries. Costs for 
insurance will be sought financed by funding.       
 
13.3 
Plan for publication, authorship and dissemination  
13.3.1 
Publication and authorship 
The trial will be registered on www.clinicaltrials.gov. The final protocol will be published as a 
design and rationale paper including the plan for analyses. Upon trial completion the main 
manuscript with trial results whether positive, negative or neutral will be submitted for a peer-
reviewed publication, to one of the major clinical journals. Furthermore the results will be 
published at the SUP-ICU home page (www.sup-icu.com).  
 
The listing of authors will be as follows: M Krag will be the first author, A Perner the second, J 
Wetterslev the third, M Wise will be the fourth author and the next authors will be the national 
investigators according to the number of included patients per country, then the trial 
statistician and trial site investigators dependent on the number of included patients per site. 
MH Møller will be the last and corresponding author, and ‘the SUP-ICU trial co-authors’ will be 
written.  
The SC will grant authorship depending on personal input according to the Vancouver 
definitions. If a trial site investigator is to gain authorship, the site has to include 50 patients or 


 
44 
 
more. If the site includes 100 patients or more, two authorships will be granted per trial site, 
150 patients will give 3 authorships per trial site and so on.  
The DMSC and investigators not qualifying for authorship will be acknowledged with their 
names under the “SUP-ICU Trial investigators’ in an appendix to the final manuscript. 
Funding sources will have no influence on data handling or analyses or writing of the 
manuscript. 
 
13.4  Spin-off projects 
Spin-off projects will be encouraged and conducted when approved by the SC. Presently no 
spin-off projects have been developed. 
 
13.5  Intellectual property rights 
Sponsor and primary investigator is MH Møller. Therefore no contract on intellectual property 
rights is indicated. The initiative for the SUP-ICU trial has been taken by MH Møller and A 
Perner and by doctors at multiple ICUs, none of whom have affiliations to institutions that may 
have economic interests in the trial results. Contracts between national investigators and 
Sponsor and between site investigators and Sponsor will be signed before conduct of the trial.  
 
13.6 
Organisational framework  
The trial is part of the SUP-ICU research programme (www.sup-icu.com) and Centre for 
Research in Intensive Care (CRIC). 
 
13.7 
Trial timeline  
2014 – November 2015: Governance approval applications, education of trial sites, other 
preparations 
December 2015: First Danish patient enrolled 
February 2015: Commencement of inclusion in other countries 
November 2017: Last patient enrolled 
January 2018: Follow-up completed 
May 2018: Data analysis and submission for publication 
 
 
14.  
Appendix 
Appendix 1: Research Programme Organisation 


 
45 
 
Appendix 2: Undesirable effects of pantoprazole  
Appendix 3: Charter for the independent Data Monitoring and Safety Committee 
Appendix 4: Definitions 
Appendix 5: Summary of product characteristics 
Appendix 6: Adverse reactions not registered 
Appendix 7: Informed consent in Denmark 
Appendix 8: Timeline 
Appendix 9: SAPS II Score 
Appendix 10: SOFA score 
Appendix 11: Power estimations 
Appendix 12: Trial sequential analysis 
Appendix 13: International Committee of Medical Journal Editors (ICMJE) form for potential 
conflicts of interest


 
46 
 
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Visitation. Copenhagen: Danish National Board of Health; 2006.  
62.  
Krag M, Perner A, Wetterslev J, Moller MH (2013) Stress ulcer prophylaxis in the 
intensive care unit: is it indicated? A topical systematic review. Acta Anaesthesiol Scand 
57:835–847. 
63.  
TSA. Trial Sequential Analysis (TSA). The Copenhagen Trial Unit, Center for Clinical 
Intervention Research, Rigshospitalet, Copenhagen, Denmark (2011) Software and 
manual available at www.ctu.dk/tsa.  
64.  
Wetterslev J, Thorlund K, Brok J, Gluud C (2008) Trial sequential analysis may 
establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol 
61:64–75. 
65.  
Gabriel SE, Normand S-LT (2012) Getting the methods right--the foundation of patient-
centered outcomes research. N Engl J Med 367:787–90. 


 
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66.  
Schmiemann G (2012) The preliminary draft of the methodology report by the Patient-
Centered Outcomes Research Institute. Z Evid Fortbild Qual Gesundhwes 106:496–9. 
67.  
(1998) International conference on harmonisation; guidance on statistical principles for 
clinical trials; availability--FDA. Notice. Fed Regist 63:49583–98. 
68.  
Kahan BC, Morris TP (2012) Improper analysis of trials randomised using stratified 
blocks or minimisation. Stat Med 31:328–40. 
69.  
Lan K, Demets D (1983) Discrete sequential boundaries for clinical trials. Biometrika. 
Biometrika 70:659–63. 
70.  
Mallinckrodt CH, Lin Q, Molenberghs M (2013) A structured framework for assessing 
sensitivity to missing data assumptions in longitudinal clinical trials. Pharm Stat 12:1–6. 
71.  
Little RJA (1988) A Test of Missing Completely at Random for Multivariate Data with 
Missing Values. J Am Stat Assoc 83:1198. 
72.  
Schafer JL (1999) Multiple imputation: a primer. Stat Methods Med Res 8:3–15. 
73.  
Vickers AJ, Altman DG (2013) Statistics notes: missing outcomes in randomised trials. 
BMJ 346:f3438. 
74.  
Le Gall J-R (1993) A New Simplified Acute Physiology Score (SAPS II) Based on a 
European/North American Multicenter Study. JAMA J Am Med Assoc 270:2957. 
75.  
Vincent JL, Moreno R, Takala J, et al. (1996) The SOFA (Sepsis-related Organ Failure 
Assessment) score to describe organ dysfunction/failure. On behalf of the Working 
Group on Sepsis-Related Problems of the European Society of Intensive Care 
Medicine. Intensive Care Med 22:707–10. 
76.  
Horan TC, Andrus M, Dudeck MA (2008) CDC/NHSN surveillance definition of health 
care-associated infection and criteria for specific types of infections in the acute care 
setting. Am J Infect Control 36:309–32.  


 
52 
 
Appendix 1. Trial organisation 
 
 


 
53 
 
Appendix 2. Undesirable effects of pantoprazole 
 
 
Approximately 5% of patients can be expected to experience adverse drug reactions. The most 
commonly reported adverse drug reactions are diarrhoea and headache, both occurring in 
approximately 1% of patients. 
For all adverse reactions reported from post-marketing experience, it is not possible to apply any 
adverse reaction frequency and therefore they are mentioned with a “not known” frequency. 
Within each frequency grouping, adverse reactions are presented in order of decreasing 
seriousness. 
 
Adverse reactions with pantoprazole in clinical trials and post-marketing experience 
Frequency 
Common* 
 
Uncommon* Rare* 
Very rare* 
Not known 
System Organ 
Class 
Blood and 
lymphatic system 
disorders  
  
  
Agranulocytosis  
Thrombo-
cytopenia; 
Leukopenia 
Pancytopenia  
  
Immune system 
disorders  
  
  
Hypersensitivity 
(including 
anaphylactic 
reactions and 
anaphylactic 
shock)  
  
  
Metabolism and 
nutrition disorders  
  
  
Hyperlipidaemi as 
and lipid increases 
(triglycerides, 
cholesterol); 
Weight changes  
  
Hyponatraemia  
Hypomagnesaemia 
(see section 4.4)  
Hypocalcaemia in 
association with 
hypomagnesemia; 
Hypokalaemia  
Psychiatric 
disorders  
  
Sleep 
disorders  
Depression (and all 
aggravations)  
Disorien-
tation (and all 
aggravations)  
Hallucination; 
Confusion 
(especially in pre-
disposed patients, 
as well as the 
aggravation of 
these symptoms in 
case of pre-
existence)  


 
54 
 
 
Nervous system 
disorders  
  
Headache 
Dizziness  
Taste disorders  
  
Paraesthesia  
Eye disorders  
  
  
Disturbances in 
vision / blurred 
vision  
  
  
Gastrointestinal 
disorders  
  
Diarrhoea; 
Nausea / 
vomiting; 
Abdominal 
distension 
and bloating; 
Constipation; 
Dry mouth; 
Abdominal 
pain and 
discomfort  
  
  
  
Hepatobiliary 
disorders  
  
Liver 
enzymes 
increased 
(transaminas-
es, γ-GT)  
Bilirubin increased    
Hepatocellular 
injury; Jaundice; 
Hepatocellular 
failure  
Skin and 
subcutaneous 
tissue disorders  
  
Rash / 
exanthema / 
eruption; 
Pruritus  
Urticaria; 
Angioedema  
  
Stevens-Johnson 
syndrome; Lyell 
syndrome; Ery-
thema multiforme; 
Photosensitivity  
Musculoskeletal 
and connective 
tissue disorders  
  
Fracture of 
the hip, wrist 
or spine (see 
section 4.4)  
Arthralgia; Myalgia    
Muscle spasm as a 
consequence of 
electrolyte 
disturbances  
Renal and urinary 
disorders  
  
  
  
  
Interstitial nephritis 
(with possible 
progression to 
renal failure)  
Reproductive 
system and breast 
disorders  
  
  
Gynaecomastia  
  
  
General disorders 
and administration 
site conditions  
Injection site 
thrombo-
phlebitis  
Asthenia, 
fatigue and 
malaise  
Body temperature 
increased; 
Oedema peripheral 
  
  
*Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare 
(≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available 
data).


 
55 
 
Appendix 3. Charter for the independent Data Monitoring and Safety Committee (DMSC) 
 
ClinicalTrials.gov Identifier: NCT02467621 
Research ethical committee no: H-15003141 
 
Introduction 
The DMSC will constitute its own plan of monitoring and meetings. However, this charter will define 
the minimum of obligations and primary responsibilities of the DMSC as perceived of the steering 
committee (SC), its relationship with other trial components, its membership, and the purpose and 
timing of its meetings. The charter will also outline the procedures for ensuring confidentiality and 
proper communication, the statistical monitoring guidelines to be implemented by the DMSC, and 
an outline of the content of the open and closed reports which will be provided to the DMSC. 
    
Primary responsibilities of the DMSC 
The DMSC will be responsible for safeguarding the interests of trial patients, assessing the safety 
and efficacy of the interventions during the trial, and for monitoring the overall conduct of the 
clinical trial. The DMSC will provide recommendations about stopping or continuing the trial to the 
SC of the SUP-ICU trial. To contribute to enhancing the integrity of the trial, the DMSC may also 
formulate recommendations relating to the selection/recruitment/retention of patients, their 
management, improving adherence to protocol-specified regimens and retention of patients, and 
the procedures for data management and quality control. 
 
The DMSC will be advisory to the SC. The SC will be responsible for promptly reviewing the DMSC 
recommendations, to decide whether to continue or terminate the trial, and to determine whether 
amendments to the protocol or changes in trial conduct are required. 
 
The DMSC is planned by protocol to meet physically in order to evaluate the planned interim 
analyses of the SUP-ICU trial. The interim analyses will be performed by an independent 
statistician selected by the members of the DMSC (to be announced). The DMSC may additionally 
meet whenever they decide or contact each other by telephone or e-mail in order to discuss the 
safety for trial participants. The sponsor has the responsibility to report the overall number of 
Serious Adverse Reactions (SARs) yearly to the DMSC. The DMSC can, at any time during the 
trial, request the distribution of events, including outcome measures and SARs according to 
intervention groups. Further, the DMSC can request unblinding of the interventions if suggested by 
the data, see section on ‘closed sessions’. The recommendations of the DMSC regarding stopping, 


 
56 
 
continuing or changing the design of the trial should be communicated without delay to the SC of 
the SUP-ICU trial. As fast as possible, and no later than 48 hours, the SC has the responsibility to 
inform all investigators of the trial and all the sites including patients in the trial, about the 
recommendation of the DMSC and the SC decision hereof.   
 
Members of the DMSC 
The DMSC is an independent multidisciplinary group consisting of clinicians and a biostatistician 
that, collectively, has experience in the management of ICU patients and in the conduct, monitoring 
and analysis of randomised clinical trials. 
 
DMSC Members 
Anders Åneman, MD PhD 
Tim Walsh, professor, MD, PhD 
 
DMSC Biostatistician 
Aksel Karl Georg Jensen, Section of Biostatistics, University of Copenhagen 
 
Conflicts of interest 
DMSC members will fill in and sign a declaration of conflicts of interests see appendix 13. DMSC 
membership has been restricted to individuals free of conflicts of interest. The source of these 
conflicts may be financial, scientific, or regulatory in nature. Thus, neither trial investigators nor 
individuals employed by the sponsor, nor individuals who might have regulatory responsibilities for 
the trial products, are members of the DMSC. The DMSC members do not own stock in the 
companies having products being evaluated by the SUP-ICU trial.  
The DMSC members will disclose to fellow members any consulting agreements or financial 
interests they have with the sponsor of the trial, with the contract research organisation (CRO) for 
the trial (if any), or with other sponsors having products that are being evaluated or having 
products that are competitive with those being evaluated in the trial.  
The DMSC will be responsible for deciding whether these consulting agreements or financial 
interests materially impact their objectivity. 
The DMSC members will be responsible for advising fellow members of any changes in these 
consulting agreements and financial interests that occur during the course of the trial. Any DMSC 
members who develop significant conflicts of interest during the course of the trial should resign 
from the DMSC.  


 
57 
 
DMSC membership is to be for the duration of the clinical trial. If any members leave the DMSC 
during the course of the trial, the SC will appoint the replacement(s). 
 
Formal interim analyses meeting 
Two formal interim analysis meetings will be held to review data relating to treatment efficacy, 
patient safety, and quality of trial conduct. The three members of the DMSC will meet when 90-day 
follow-up data of 1650 (approximately 50% of sample size estimation) and 2500 (approximately 
75% of sample size estimation) patients have been obtained. 
 
Proper communication 
To enhance the integrity and credibility of the trial, procedures will be implemented to ensure the 
DMSC has sole access to evolving information from the clinical trial regarding comparative results 
of efficacy and safety data, aggregated by treatment group. An exception will be made to permit 
access to an independent statistician who will be responsible for serving as a liaison between the 
database and the DMSC.  
At the same time, procedures will be implemented to ensure that proper communication is 
achieved between the DMSC and the trial investigators. To provide a forum for exchange of 
information among various parties who share responsibility for the successful conduct of the trial, a 
format for open sessions and closed sessions will be implemented. The intent of this format is to 
enable the DMSC to preserve confidentiality of the comparative efficacy results while at the same 
time providing opportunities for interaction between the DMSC and others who have valuable 
insights into trial-related issues. 
 
Closed sessions 
Sessions involving only DMSC membership who generates the closed reports (called closed 
sessions) will be held to allow discussion of confidential data from the clinical trial, including 
information about the relative efficacy and safety of interventions. In order to ensure that the DMSC 
will be fully informed in its primary mission of safeguarding the interest of participating patients, the 
DMSC will be blinded in its assessment of safety and efficacy data. However, the DMSC can 
request unblinding from the SC. 
 
Closed reports will include analysis of the primary outcome measure. In addition, analyses of the 
secondary outcome measures and SARs will also be reported. These closed reports will be 
prepared by independent biostatistician being a member of the DMSC, with assistance from the 
trial data manager, in a manner that allow them to remain blinded. 


 
58 
 
 
The closed reports should provide information that is accurate, with follow-up on mortality that is 
complete to within two months of the date of the DMSC meeting. 
 
Open reports 
For each DMSC meeting, open reports will be provided available to all who attend the DMSC 
meeting. The reports will include data on recruitment and baseline characteristics, and pooled data 
on eligibility violations, completeness of follow-up, and compliance. The independent statistician 
being a member of the DMSC will prepare these open reports in co-operation with the trial data 
manager. 
 
The reports should be provided to DMSC members approximately three days prior to the date of 
the meeting. 
 
Minutes of the DMSC Meetings 
The DMSC will prepare minutes of their meetings. The closed minutes will describe the 
proceedings from all sessions of the DMSC meeting, including the listing of recommendations by 
the committee. Because it is possible that these minutes may contain unblinded information, it is 
important that they are not made available to anyone outside the DMSC.  
 
Recommendations to the Steering Committee  
After the interim analysis meetings, the DMSC will make a recommendation to the SC to continue, 
hold or terminate the trial. 
 
Interim analyses will be conducted after patient no. 1650 and 2500 has been followed for 90 days. 
The DMSC will recommend pausing or stopping the trial if group-difference in the primary outcome 
measure, SARs or SUSARs are found at the interim analyses with statistical significance levels 
adjusted according to the LanDeMets group sequential monitoring boundaries based on O’Brien 
Fleming alfa-spending function [69]. If an analysis of the interim data from 1650/2500 patients 
fulfils the LanDeMets stopping criterion the inclusion of further patients will be paused and an 
analysis including patients randomised during the analysis period will be performed. If this second 
analysis also fulfils the LanDeMets stopping criterion according to the group sequential monitoring 
boundaries the DMSC will recommend stopping the trial [67]. Furthermore, the DMSC can 
recommend pausing or stopping the trial if continued conduct of the trial clearly compromises 
patient safety. However, stopping for futility to show an intervention effect of 15% RRR will not be 


 
59 
 
an option as intervention effects less than 15% RRR of all-cause mortality may be clinically 
relevant as well.    
 
This recommendation will be based primarily on safety and efficacy considerations and will be 
guided by statistical monitoring guidelines defined in this charter and the trial protocol. 
 
The SC is jointly responsible with the DMSC for safeguarding the interests of participating patients 
and for the conduct of the trial. Recommendations to amend the protocol or conduct of the trial 
made by the DMSC will be considered and accepted or rejected by the SC. The SC will be 
responsible for deciding whether to continue, hold or stop the trial based on the DMSC 
recommendations.  
 
The DMSC will be notified of all changes to the trial protocol or conduct. The DMSC concurrence 
will be sought on all substantive recommendations or changes to the protocol or trial conduct prior 
to their implementation. 
 
Statistical monitoring guidelines 
The outcome parameters are defined in the statistical analyses plan in the protocol. For the two 
intervention groups, the DMSC will evaluate data on: 
 
The primary outcome measure 
Mortality 90 days after randomisation of each patient (“landmark mortality”). 
 
The secondary outcome measures 
• 
Proportion of patients with one or more of the following adverse events: clinically important 
gastrointestinal (GI)  bleeding, pneumoni, clostridium difficile infection (CDI), and acute 
myocardial ischemia 
• 
Proportion of patients with clinically important GI bleeding 
• 
1 year mortality post-randomisation 
• 
The occurrence of SARs in the ICU 
 
The DMSC will be provided with these data from the coordinating centre as: 
Number of patients randomised 
Number of patients randomised per intervention group 
Number of patients stratified pr. stratification variable per intervention group 


 
60 
 
Number of events, according to the outcomes, in the two groups 
 
Based on evaluations of these outcomes, the DMSC will decide if they want further data from the 
coordinating centre and when to perform the next analysis of the data. 
 
For analyses, the data will be provided in one file as described below. 
 
DMSC should yearly be informed about SARs occurring in the two groups of the trial. 
 
The DMSC may also be asked to ensure that procedures are properly implemented to adjust trial 
sample size or duration of follow-up to restore power, if protocol specified event rates are 
inaccurate. If so, the algorithm for doing this should be clearly specified. 
 
 
Conditions for transfer of data from the Coordinating Centre to the DMSC  
The DMSC will be provided with a file containing the data defined as follows: 
 
Row 1 contains the names of the variables (to be defined below). 
 
Row 2 to N (where N-1 is the number of patients having entered the trial) each contains the data of 
one patient. 
 
Column 1 to p (where p is the number of variables to be defined below) each contains in row 1 the 
name of a variable and in the next N rows the values of this variable. 
 
The values of the following variables should be included in the database: 
 
1. screening_id: a number that uniquely identifies the patient 
 
2. rand_code: The randomisation code (group 0 or 1). The DMSC is not to be informed on 
what intervention the groups received 
 
3. clin_imp_bleed: clinically important GI bleeding (1 if the patient had one or more episodes 
and 0 if the patient did not) 
 


 
61 
 
4. pneumonia: onset of pneumonia in the ICU after randomisation (1 = one or more episodes, 
0= no episodes) 
 
5. clostridium: clostridium difficile infection (1 = one or more episodes, 0= no episodes) 
 
6. ami: acute myocardial ischemia in the ICU (1 = one or more episodes, 0= no episodes) 
 
7. SAR_indic: SAR indicator (1 = one or more SARs, 0 = no SARs) 
 
 
 


 
62 
 
Appendix 4. Definitions 
 
Definition of stratification variables  
Site: all participating intensive care units (ICUs) will be assigned a number identifying the 
department.  
 
Haematological malignancy includes any of the following: 
• 
leukemia: Acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), 
chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL). 
• 
lymphoma: Hodgkin's disease, Non-Hodgkin lymphoma (e.g. small lymphocytic lymphoma 
(SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell 
lymphoma (MCL), hairy cell leukemia (HCL), marginal zone lymphoma (MZL), Burkitt's 
lymphoma (BL), post-transplant lymphoproliferative disorder (PTLD), T-cell prolymphocytic 
leukemia (T-PLL), B-cell prolymphocytic leukemia (B-PLL), Waldenström's 
macroglobulinemia, other NK- or T-cell lymphomas 
• 
Multiple myeloma/plasma cell myeloma  
 
Definition of inclusion criteria 
Acute admission to the ICU: a non-planned admission. It does not include planned recovery after 
surgery or similar planned admissions. ICU admission does not include admissions to semi 
intensive care, intermediate intensive care or similar beds. 
 
Age: the age of the patient in whole years at the time of randomisation. The age will be calculated 
from date of birth 
 
Shock: at least one of the following: 
• 
systolic pressure < 90 mmHg 
• 
mean arterial pressure < 70 mmHg  
• 
use of vasopressors or inotropes (norepinephrine, epinephrine, phenylephrine, vasopressin 
or dopamine, dobutamine, milirinone or levosimendan) 
• 
lactate > 4 mmol/l 
Renal replacement therapy: acute or chronic intermittent or continuous renal replacement therapy  
 


 
63 
 
Patients with expected duration of invasive mechanically ventilation > 24 hours: the treating 
clinician estimates that the patient will be invasively mechanically ventilated for more than 24 
hours. When in doubt of this forecast the patient should be enrolled 
 
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  
 
Treatment with anticoagulant drugs: ongoing treatment with: Dipyridamole, vitamin K antagonists, 
ADP-receptor inhibitors, therapeutic doses of low molecular weight heparin, new oral 
anticoagulant drugs, intravenous direct thrombin (II) inhibitors and similar drugs.   
Acetylsalicylic acid (all doses) and low molecular weight heparin in prophylactic doses are NOT 
included 
 
History of coagulopathy: coagulopathy defined as platelets < 50 x 109/l AND/OR INR > 1.5 
AND/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 
 
Definition of exclusion criteria 
Contraindications to proton pump inhibitors (PPI): any history of intolerance to PPI or additives or 
treatment with atazanavir (HIV medication) 
 
Ongoing treatment with PPI and/or histamine-2-receptor antagonists (H2RA): ongoing is defined as 
treatment not being discontinued at ICU admission. If clinicians do not find indication for 
continuation of treatment with PPI/H2RA during ICU stay, the patient will be eligible for inclusion.   
 
GI bleeding during current hospital admission: GI bleeding of any origin (both upper and lower) 
documented in the patient charts 
 
Peptic ulcer: peptic ulcer confirmed by endoscopy or other method during current hospital 
admission  
 
Organ transplant: any kind of organ transplant during current hospital admission.   


 
64 
 
 
Withdrawal from active therapy or brain death: patients where withdrawal or brain death is 
documented in the patient charts 
 
Known pregnancy: fertile woman with positive urine human chorionic gonadotropin (hCG) or 
plasma-hCG  
 
Consent not obtainable according to national regulations: patients where the clinician or 
investigator is unable to obtain necessary consent before inclusion of the patient according to the 
national regulations  
 
Definition of baseline variables 
Sex: the genotypic sex of the patient 
 
Age: defined in inclusion criteria 
 
Date of admission to hospital: the date of admission to the first hospital the patient was admitted to 
during the current hospital admission 
 
Elective surgery: surgery during current hospital admission scheduled 24 hours or latter in advance 
 
Emergency surgery: surgery during current hospital admission that was added to the operating 
room schedule 24 hours or less prior to surgery  
 
Medical admission: when no surgery has been performed during current hospital admission OR 
surgery has been performed more than 1 week prior to ICU admission 
 
Treatment with anticoagulants at hospital admission and at ICU admission: anticoagulants are 
defined in inclusion criteria 
 
Treatment with non-steroidal anti-inflammatory drugs (NSAID) and acetylsalicylic acid at hospital 
admission: treatment with all doses of these drugs at hospital admission 
 
Treatment with intravenous thrombolysis: treatment with all kinds of intravenous thrombolysis 
within 3 days prior to randomisation  


 
65 
 
 
Coagulopathy: defined in inclusion criteria  
 
Treatment of suspected or confirmed Clostridium difficile infection (CDI) during current hospital 
admission 
 
Coexisting illness must have been present in the past medical history prior to ICU admission and 
are defined as follows: 
• 
Chronic lung disease: chronic obstructive pulmonary disease (COPD), asthma or other 
chronic lung disease or treatment with any relevant drug indicating this at admission to 
hospital 
• 
Previous myocardial infarction: history of myocardial infarction 
• 
Chronic heart failure: New York Heart Association Functional Class (NYHA) III-IV. NYHA III: 
The patient has marked limitations in physical activity due to symptoms (fatigue, palpitation 
or dyspnoea) even during less than ordinary activity (walking short distances 20-100 m. or 
walking up stairs to 1st floor). The patient is only comfortable at rest. NYHA class 4: The 
patient is not able to carry out any physical activity (without discomfort (fatigue, palpitation 
or dyspnoea). Symptoms are present even at rest and the patient is mostly bedbound 
• 
History of  chronic renal failure: need of any form of chronic renal replacement therapy 
within the last year 
• 
Liver disease: defined in baseline variables 
• 
History of coagulopathy: defined in baseline variables 
• 
Immunosuppression: patients treated with at least 0,3 mg/kg/day of prednisolone equivalent 
for at least 1 month in the 6 months prior to ICU admission 
• 
Metastatic cancer: proven metastasis by surgery, CT scan or any other method 
• 
Hematologic malignancy: defined as stratification variable 
• 
AIDS: HIV positive patients with one or more HIV defining diseases such as pneumocystis 
jerovechii pneumonia, Kaposi's sarcoma, Lymphoma, tuberculosis or toxoplasma infection 
The Simplified Acute Physiology Score (SAPS II) [74] (appendix 9) is based on the most extreme 
(highest or lowest) values from 24 hours prior to randomisation. The score consists of 17 variables: 
12 physiologic variables, age, type of admission and 3 variables related to underlying disease to 
give a total score ranging from 0 to 163, with higher scores indicating greater severity of illness. 
The score will be calculated from data from the 24 hours prior to randomisation 
 


 
66 
 
The Sequential Organ Failure Assessment (SOFA) Score [75] (appendix 10) will be calculated 
from raw physiology and treatment data from the 24 hours prior to randomisation. The SOFA Score 
consists of weightings for six organ systems to give a total score ranging from 0 to 24, with higher 
scores indicating a greater degree of organ failure. 
 
Definition of daily collected variables: 
Delivery of trial medication: confirmation of administration of the trial drug 
 
Treatment with PPI or H2RA: prescription of any of these drugs in any dose (major protocol 
violation if the treatment is initiated (e.g. as prophylaxis) without clinical indication (e.g. 
gastrointestinal bleeding)  
 
Mechanical ventilation: invasive and non-invasive mechanical ventilation including continuous 
mask CPAP or CPAP via a tracheotomy. Intermittent CPAP is NOT mechanical ventilation. 
 
Circulatory support: continuous infusion of vasopressor or inotrope (norepinephrine, epinephrine, 
phenylephrine, vasopressin or dopamine, dobutamine, milirinone or levosimendan) 
 
Renal replacement therapy: any form of renal replacement therapy on this day. In patients 
receiving intermittent renal replacement therapy days between treatments are included 
 
Clinically important GI bleeding, onset of pneumonia, CDI, and acute myocardial ischemia in the 
ICU are defined as outcomes 
 
Treatment with enteral feeding: any dose of enteral feeding (including oral nutritional intake) during 
the day 
 
Units of red blood cells: cumulated number of units of red blood cells transfused during the day 
 
Serious adverse reactions (SARs) are defined below 
 
Definition of bleeding variables: 
Confirmed diagnosis: diagnosis/origin of bleeding confirmed by endoscopy or other method 
 


 
67 
 
Verification of ulcer/gastritis/bleeding oesophageal varices: confirmation of one of the three specific 
diagnoses by endoscopy or other method 
 
Haemostasis achieved or attempted: documentation in patient charts of haemostasis achieved or 
attempted by endoscopy, open surgery or coiling   
 
Definitions of outcome measures 
Primary outcome:  
90-day mortality: death from any cause within 90 days following the day of randomisation 
 
Secondary outcomes: 
Proportion of patients with one or more of the following adverse events: clinically important GI 
bleeding, pneumonia, CDI, and acute myocardial ischemia. The events are defined as follows: 
 
Clinically important GI bleeding: overt GI bleeding* and at least one of the following four features 
within 24 hours of GI bleeding (in the absence of other causes) in the ICU 
a) spontaneous drop of systolic blood pressure, mean arterial pressure or diastolic blood 
pressure of 20 mmHg or more 
b) start of vasopressor or a 20% increase in vasopressor dose 
c) decrease in haemoglobin of at least 2 g/dl (1.24 mmol/l)  
d) transfusion of 2 units of packed red blood cells or more 
*Overt GI bleeding: hematemesis, coffee ground emesis, melena, haematochezia or bloody 
nasogastric aspirate  
 
Pneumonia: episodes of newly confirmed pneumonia according to the modified CDC criteria [76] 
• 
Two or more serial chest radiographs with at least one of the following (one radiograph is 
sufficient for patients with no underlying pulmonary or cardiac disease): 
1. new or progressive and persistent infiltrate 
2. consolidation 
3. cavitation 
 
• 
AND at least one of the following: 
1. fever (>38°C) with no other recognised cause  
2. leukopenia (white cell count < 4 x 109/l) or leucocytosis (white cell count >12 x 109/l)  
• 
AND at least two of the following 


 
68 
 
 
1. new onset of purulent sputum or change in character of sputum, or increased 
respiratory secretions or increased suctioning requirements 
2. new onset or worsening cough, or dyspnoea, or tachypnoea 
3. rales or bronchial breath sounds 
4. worsening gas exchange (hypoxaemia, increased oxygen requirement, increased 
ventilator demand) 
 
CDI: Treatment with antibiotics (enteral vancomycin, intravenous or enteral metronidazole, enteral 
fidaxomicin) for suspected or proven CDI  
 
Acute myocardial ischemia: ST-elevation myocardial infarction, non-ST elevation myocardial 
infarction or unstable angina pectoris according to the criteria in the clinical setting in question (e.g. 
elevated biomarkers, ischemic signs on ECG and clinical presentation) AND receiving treatment as 
a consequence of this (reperfusion strategies (PCI/thrombolysis) or initiation/increased 
antithrombotic treatment) 
 
Proportions of patients with clinically important GI bleeding: proportion of patients with one or more 
episodes of clinically important GI bleeding as defined above  
 
Proportion of patients with one or more infectious adverse events: proportion of patients with one 
or more episodes of pneumonia or CDI 
 
1-year mortality: landmark mortality 1 year post-randomisation 
 
Duration of life support in the ICU: the number of days alive and free from respiratory or circulatory 
support and of renal replacement therapy as defined below. The outcome will be days alive without 
use of mechanical ventilation, circulatory support or renal replacement therapy in the 90-day 
period, and will be defined as the percentage of days without mechanical ventilation, circulatory 
support and renal replacement therapy (as defined in daily collected variables) in the 90 days after 
randomisation 
 
Serious adverse reactions: number of serious adverse reactions as defined below 
 
The elements of all composite outcomes will be reported in the supplementary material 


 
69 
 
 
A health economic analysis will be performed. The analytic details will be based on the result of the 
trial and specified (cost-benefit vs cost-minimisation analyses). 
 
Definitions of serious adverse reactions 
 
A serious adverse reaction (SAR) is defined as any adverse reaction that results in death, is life-
threatening, requires hospitalization or prolongation of existing hospitalization, or results in 
persistent or significant disability or incapacity.  
 
Patients will be monitored for onset of SARs occurring between the first dose of trial medication 
and until discharge from the ICU. If a patient is withdrawn from the trial intervention, SARs will be 
recorded for 24 hours after the last dose of trial medication or discharge from ICU. If the patient is 
readmitted to the ICU and trial intervention is reintroduced, data collection for SARs will be 
resumed. If a patient experiences a SAR the patient will be withdrawn from the trial intervention but 
data collection and follow-up will be continued (see section 4.3.2)  
 
SARs will be defined as follows:  
 
Anaphylactic reactions defined as urticaria and at least one of the following 
• 
Worsened circulation (>20% decrease in blood pressure or >20% increase in vasopressor 
dose) 
• 
Increased airway resistance (>20% increase in the peak pressure on the ventilation) 
• 
Clinical stridor or bronchospasm 
• 
Subsequent treatment with bronchodilators 
Agranulocytosis is defined as any new, acute and severe drop in granulocytes to < 0.5 x 109/l 
requiring active monitoring or treatment 
 
Pancytopenia is defined as any new, severe drop in red blood cells, white blood cells and platelets 
requiring active monitoring or treatment 
 
Acute hepatic failure is defined as severe and progressing hepatic failure as judged by the treating 
doctor or the investigator 
 


 
70 
 
Steven-Johnson syndrome and toxic epidermal necrolysis are defined as severe dermatological 
reactions with a skin biopsy confirming the diagnosis 
 
Interstitial nephritis is defined as a nephritis affecting the interstitium of the kidneys surrounding the 
tubules with a kidney biopsy confirming the diagnosis  
 
Angioedema (Quincke’s oedema) is defined as a vascular reaction involving the deep dermis, 
subcutaneous or submucosal tissues, resulting in a characteristic localized oedema. 
 
Adverse reactions not registered will be discussed in appendix 6. 
 


 
71 
 
Appendix 5. Translation of the Danish summary of product characteristics  
 
 
SUMMARY OF PRODUCT CHARACTERISTICS 
 
for 
 
Pantoprazol “Actavis”, powder for solution for injection 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
 
 
Pantoprazol “Actavis” 40 mg powder for solution for injection 
 
 
2. 
QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains 40 mg of pantoprazole (as sodium sesquihydrate) 
 
Excipients with known effect: 
Each vial contains 5.0 mg of sodium citrate dihydrate and sodium hydroxide q.s. 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. is essentially “sodium free”. 
 
For the full list of excipients, see section 6.1 
 
3. 
PHARMACEUTICAL FORM 
 
Powder for solution for injection. 
 
White or almost white, uniform porous cake. 
 
For the solution reconstituted with 10 ml of 0.9% NaCl solution the pH is approximately 10 and the osmolality 
is approximately 382 mOsm/Kg 
 
For the solution reconstituted with a further 100 ml of 0.9% NaCl solution or 5% glucose solution the pH is 
approximately 9 and 8.5, respectively 
 
 
4. 
CLINICAL PARTICULARS 
 
4.1 
Therapeutic indications 
 
- 
Reflux oesophagitis 
- 
Gastric and duodenal ulcer 
- 
Zollinger – Ellison Syndrome and other pathological hypersecretory conditions. 
 
4.2 
Posology and method of administration 
 
This medicine should be administered by a healthcare professional and under appropriate medical 
supervision. 
 
The intravenous administration of pantoprazole is recommended only if oral application is not appropriate. 
Data are available on intravenous use for up to 7 days. Therefore as soon as oral therapy is possible, 
treatment with pantoprazole i.v. should be discontinued and 40 mg pantoprazole p.o. should be administered 
instead. 
 


 
72 
 
Posology 
 
Gastric and duodenal ulcer, reflux oesophagitis 
The recommended intravenous dose is one vial of pantoprazole (40 mg) per day. 
 
Zollinger-Ellison Syndrome and other pathological hypersecretory conditions 
For the long-term management of Zollinger-Ellison Syndrome and other pathological hypersecretory 
conditions patients should start their treatment with a daily dose of 80 mg of pantoprazole i.v. Thereafter, the 
dosage can be titrated up or down as needed using measurements of gastric acid secretion to guide. With 
doses above 80 mg daily, the dose should be divided and given twice daily. A temporary increase of the 
dosage above 160 mg pantoprazole is possible but should not be applied longer than required for adequate 
acid control.  
 
In case a rapid acid control is required, a starting dose of 2 x 80 mg of pantoprazole i.v. is sufficient to 
manage a decrease of acid output into the target range (<10 mEq/h) within one hour in the majority of 
patients. 
 
Special populations 
Paediatric population 
The experience in children is limited. Therefore, pantoprazole i.v. is not recommended for use in patients 
below 18 years of age until further data become available.  
 
Hepatic impairment: 
A daily dose of 20 mg pantoprazole (half a vial of 40 mg pantoprazole) should not be exceeded in patients 
with severe liver impairment (see section 4.4).  
 
Renal impairment: 
No dose adjustment is necessary in patients with impaired renal function. 
 
Elderly 
No dose adjustment is necessary in elderly patients. 
 
Method of administration 
A ready-to-use solution is prepared in 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection. For 
instructions for preparation see section 6.6.  The prepared solution may be administered directly or may be 
administered after mixing it with 100 ml of 9 mg/ml (0.9%) sodium chloride injection, or 50 mg/ml glucose 
(5%) solution for injection. 
 
After preparation the solution must be used within 12 hours (see section 6.3). 
 
The medicinal product should be administered intravenously over 2 – 15 minutes. 
 
4.3 
Contraindications 
 
Hypersensitivity to the active substance, substituted benzimidazoles, or to any of the excipients listed in 
section 6.1. 
 
4.4 
Special warnings and precautions for use 
 
In presence of alarm symptoms 
In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, 
dysphagia, haematemesis, anaemia or melaena) and when gastric ulcer is suspected or present, malignancy 
should be excluded, as treatment with pantoprazole may alleviate symptoms and delay diagnosis. 
 
Further investigation is to be considered if symptoms persist despite adequate treatment. 
 
Hepatic impairment 


 
73 
 
In patients with severe liver impairment, the liver enzymes should be monitored during therapy. In the case 
of a rise in the liver enzymes, the treatment should be discontinued (see section 4.2). 
 
Co-administration with atazanavir 
Co-administration of atazanavir with proton pump inhibitors is not recommended (see section 4.5). If the 
combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g. 
virus load) is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg 
of ritonavir.  A pantoprazole dose of 20 mg per day should not be exceeded. 
 
Gastrointestinal infections caused by bacteria 
Pantoprazole, like all proton pump inhibitors (PPIs), might be expected to increase the counts of bacteria 
normally present in the upper gastrointestinal tract. Treatment with pantoprazole may lead to a slightly 
increased risk of gastrointestinal infections caused by bacteria (e.g. Salmonella and Campylobacter and 
C.difficile). 
 
Sodium 
This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially “sodium-free”.  
 
4.5 
Interaction with other medicinal products and other forms of interaction 
 
Effect of pantoprazole on the absorption of other medicinal products 
Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may reduce the 
absorption of drugs with a gastric pH dependant bioavailability, e.g. some azole antifungals such as 
ketoconazole, itraconazole, posaconazole and other medicines such as erlotinib.  
  
HIV medications (atazanavir) 
Co-administration of atazanavir and other HIV medications whose absorption is pH-dependent with proton 
pump inhibitors might result in a substantial reduction in the bioavailability of these HIV medications and 
might impact the efficacy of these medicines. Therefore, the co-administration of proton pump inhibitors with 
atazanavir is not recommended (see section 4.4). 
 
Coumarin anticoagulants (phenprocoumon or warfarin) 
Although no interaction during concomitant administration of phenprocoumon or warfarin has been observed 
in clinical pharmacokinetic studies, a few isolated cases of changes in International Normalised Ratio (INR) 
have been reported during concomitant treatment in the post-marketing period. Therefore, in patients treated 
with coumarin anticoagulants (e.g. phenprocoumon or warfarin), monitoring of prothrombin time/INR is 
recommended after initiation, termination or during irregular use of pantoprazole. 
 
Other interactions studies 
Pantoprazole is extensively metabolised in the liver via the cytochrome P450 enzyme system. The main 
metabolic pathway is demethylation by CYP2C19 and other metabolic pathways include oxidation by 
CYP3A4. 
 
Interaction studies with drugs also metabolised with these pathways, like carbamazepine, diazepam, 
glibenclamide, nifedipine and an oral contraceptive containing levonorgestrel and ethinyl oestradiol did not 
reveal clinically significant interactions.  
 
Results from a range of interaction studies demonstrate that pantoprazole does not effect the metabolism of 
active substances metabolised by CYP1A2 (such as caffeine, theophylline), CYP2C9 (such as piroxicam, 
diclofenac, naproxen), CYP2D6 (such as metoprolol), CYP2E1 (such as ethanol) or does not interfere with p-
glycoprotein related absorption of digoxin.  
 
Methotrexate 
Concomitant use of high dose methotrexate (e.g. 300 mg) and proton-pump inhibitors has been reported to 
increase methotrexate levels in some patients. Therefore in settings where high-dose methotrexate is used, 
for example cancer and psoriasis, a temporary withdrawal of pantoprazole may need to be considered.  
 
There were no interactions with concomitantly administered antacids. 


 
74 
 
 
Interaction studies have also been performed administering pantoprazole concomitantly with the respective 
antibiotics (clarithromycin, metronidazole, amoxicillin).  No clinically relevant interactions were found.  
 
4.6 
Fertility, pregnancy and lactation 
 
Pregnancy 
There are no adequate data from the use of pantoprazole in pregnant women.  Studies in animals have 
shown reproductive toxicity (see section 5.3).  The potential risk for humans is unknown.  Pantoprazole 
should not be used during pregnancy unless clearly necessary.  
 
Breast-feeding 
Animal studies have shown excretion of pantoprazole in breast milk.  Excretion into human milk has been 
reported.  Therefore a decision on whether to continue/discontinue breast-feeding or to continue/discontinue 
therapy with pantoprazole should be made taking into account the benefit of breast-feeding to the child and 
the benefit of pantoprazole therapy to women. 
 
4.7 
Effects on ability to drive and use machines 
 
Adverse drug reactions such as dizziness and visual disturbances may occur (see section 4.8).  If affected, 
patients should not drive or operate machines. 
 
4.8 
Undesirable effects 
 
Approximately 5% of patients can be expected to experience adverse drug reactions (ADRs).  The most 
commonly reported ADRs are diarrhoea and headache, both occurring in approximately 1% of patients. 
 
The table below lists adverse reactions reported with pantoprazole, ranked under the following frequency 
classification: 
Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (<1/10,000 to 
<1/1,000), very rare (1/10,000) not known (cannot be estimated from the available data).  For all adverse 
reactions reported from post-marketing experience, it is not possible to apply any Adverse Reaction 
frequency and therefore they are mentioned with a “not known” frequency. 
 
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 
Table 1. Adverse reactions with pantoprazole in clinical trials and post-marketing experience 
 
     Frequency 
 
System  
organ class 
Common 
Uncommon 
Rare 
Very rare 
Not known 
Blood and 
lymphatic 
system 
disorders 
 
 
Agranulocytosis 
Thrombo- 
Cytopenia; 
Leukopenia; 
Pancytopenia 
 
Immune 
system 
disorders 
 
 
Hypersensitivity 
(including 
anaphylactic 
reactions and 
anaphylactic 
shock) 
 
 
Metabolism 
and nutrition 
disorders 
 
 
Hyperlipidaemia 
and lipid 
increases 
(triglycerides, 
cholesterol); 
Weight changes 
 
Hyponatraemia 
Hypomagnesaemia; 
Hypocalcaemia in 
association with 
hypomagnesaemia; 
Hypokalaemia 


 
75 
 
     Frequency 
 
System  
organ class 
Common 
Uncommon 
Rare 
Very rare 
Not known 
Psychiatric 
disorders 
 
Sleep disorders 
Depression 
(and all 
aggravations) 
Disorientation 
(and all 
aggravations) 
Hallucination: 
Confusion 
(especially in pre-
disposed patients, 
as well as the 
aggravation of 
these symptoms in 
case of pre-
existence) 
Nervous 
system 
disorders 
 
Headache; 
Dizziness 
 
Taste disorders 
 
Paraesthesia 
Eye disorders 
 
 
Disturbances in 
vision/blurred 
vision 
 
 
Gastrointestinal 
disorders 
 
Diarrhoea; 
Nausea/ 
vomiting; 
Abdominal 
distension and 
bloating; 
Constipation; 
Dry mouth; 
Abdominal pain 
and discomfort. 
 
 
 
Hepatobiliary 
disorders 
 
Liver enzymes 
increased 
(transaminases, 
-GT) 
Bilirubin 
increased 
 
Hepatocellular 
injury; Jaundice; 
Hepatocellular 
failure 
Skin and sub-
cutaneous 
tissue 
disorders 
 
Rash/ 
exanthema/ 
eruption; 
Pruritus 
Urticaria; 
Angioedema 
 
Stevens-Johnson 
syndrome; Lyell 
syndrome; 
Erythema 
multiforme; Photo-
sensitivity  
Musculo-
skeletal and 
connective 
tissue 
disorders 
 
 
Arthralgia; 
Myalgia 
 
Muscle spasm as a 
consequence of 
electrolyte 
disturbances 
Renal and 
urinary 
disorders 
 
 
 
 
Interstitial nephritis 
(with possible 
progression to renal 
failure) 
Reproductive 
system and 
breast 
disorders 
 
 
Gynaecomastia 
 
 
General 
disorders and 
administration 
site conditions 
Injection 
site 
thrombo-
phlebitis 
Asthenia, 
fatigue and 
malaise 
Body 
temperature 
increased; 
Oedema 
peripheral 
 
 


 
76 
 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows 
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked 
to report any suspected adverse reactions.  
 
4.9 
Overdose 
 
There are no known symptoms of overdose in man.  
Systemic exposure with up to 240 mg administered intravenously over 2 minutes was well tolerated.  As 
pantoprazole is extensively protein bound, it is not readily dialysable.  
 
In case of overdose with clinical signs of intoxication, apart from symptomatic and supportive treatment, no 
specific therapeutic recommendations can be made. 
 
 
5. 
PHARMACOLOGICAL PROPERTIES 
 
5.1 
Pharmacodynamic properties 
 
Pharmacotherapeutic group: Proton pump inhibitors, ATC code: A02BC02. 
 
Mechanism of action 
Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the stomach 
by specific blockade of the proton pumps of the parietal cells.  
 
Pantoprazole is converted to its active form in the acidic environment in the parietal cells where it inhibits the 
H+/K+-ATPase enzyme i.e. the final stage in the production of hydrochloric acid in the stomach.  The 
inhibition is dose-dependent and affects both basal and stimulated acid secretion.  In most patients, freedom 
from symptoms is achieved within 2 weeks. As with other proton pump inhibitors and H2 receptor inhibitors, 
treatment with pantoprazole reduces acidity in the stomach and thereby increases gastrin in proportion to the 
reduction in acidity.  The increase in gastrin is reversible.  Since pantoprazole binds to the enzyme distal to 
the cell receptor level, it can inhibit hydrochloric acid secretion independently of stimulation by other 
substances (acetylcholine, histamine, gastrin). The effect is the same whether the product is given orally or 
intravenously. 
 
The fasting gastrin values increase under pantoprazole.  On short-term use, in most cases they do not 
exceed the upper limit of normal.  During long-term treatment, gastrin levels double in most cases.  An 
excessive increase, however, occurs only in isolated cases.  As a result, a mild to moderate increase in the 
number of specific endocrine (ECL) cells in the stomach is observed in a minority of cases during long-term 
treatment (simple to adenomatoid hyperplasia).  However, according to the studies conducted so far, the 
formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids as were found in animal 
experiments (see section 5.3) have not been observed in humans.  
 
An influence of a long term treatment with pantoprazole exceeding one year cannot be completely ruled out 
on endocrine parameters of the thyroid according to results in animal studies.  
 
5.2 
Pharmacokinetic properties 
 
General Pharmacokinetics 
Pharmacokinetics do not vary after single or repeated administration. In the dose range of 10 to 80 mg the 
plasma kinetics of pantoprazole are linear after both oral and intravenous administration. 
 
Distribution 
Pantoprazole's plasma protein binding is about 98%. Volume of distribution is about 0.15 l/kg. 
 
Elimination 


 
77 
 
The substance is almost exclusively metabolised in the liver. The main metabolic pathway is demethylation 
by CYP2C19 with subsequent sulphate conjugation, other metabolic pathways include oxidation by CYP3A4.  
Terminal half-life is about 1 hour and clearance is about 0.1 l/h/kg.  There were few cases of subjects with 
delayed elimination.  Because of specific binding of pantoprazole to the proton pumps of the parietal cell the 
elimination half-life does not correlate with the much longer duration of action (inhibition of acid secretion). 
 
Renal elimination represents the major route of excretion (about 80%) for the metabolites of pantoprazole; 
the rest are excreted in the faeces. The main metabolite in both the serum and urine is 
desmethylpantoprazole which is conjugated with sulphate. The half-life of the main metabolite (about 1.5 
hours) is not much longer than that of pantoprazole.  
 
Characteristics in patients/special groups of subjects: 
Approximately 3% of the European population lack a functional CYP2C19 enzyme and are called poor 
metabolisers.  In these individuals the metabolism of pantoprazole is probably mainly catalysed by CYP3A4.  
After a single dose administration of 40 mg pantoprazole, the mean area under the plasma concentration-
time curve was approximately 6 times higher in poor metabolisers than in subjects having a functional 
CYP2C19 enzyme (extensive metabolisers).  Mean peak plasma concentrations were increased by about 
60%.  These findings have no implications for the posology of pantoprazole. 
 
No dose reduction is recommended when pantoprazole is administered to patients with impaired renal 
function (including dialysis patients). As with healthy subjects, pantoprazole's half-life is short. Only very 
small amounts of pantoprazole are dialysed. Although the main metabolite has a moderately delayed half-life 
(2-3 hours), excretion is still rapid and thus accumulation does not occur.  
Although for patients with liver cirrhosis (classes A and B according to Child) the half-life values increased to 
between 7 and 9 hours and the AUC values increased by a factor of 5 to 7, the maximum serum 
concentration only increased slightly by a factor of 1.5 compared with healthy subjects.  
 
A slight increase in AUC and Cmax in elderly volunteers compared with younger counterparts is also not 
clinically relevant. 
 
Paediatric population 
Following administration of single intravenous doses of 0.8 or 1.6 mg/kg pantoprazole to children aged 2 – 
16 years there was no significant association between pantoprazole clearance and age or weight. AUC and 
volume of distribution were in accordance with data from adults. 
 
5.3 
Preclinical safety data 
 
Preclinical data reveal no special hazard to humans based on conventional studies of safety pharmacology, 
repeated dose toxicity and genotoxicity. 
 
In the two-year carcinogenicity studies in rats neuroendocrine neoplasms were found.  In addition, squamous 
cell papillomas were found in the forestomach of rats. The mechanism leading to the formation of gastric 
carcinoids by substituted benzimidazoles has been carefully investigated and allows the conclusion that it is 
a secondary reaction to the massively elevated serum gastrin levels occurring in the rat during chronic high-
dose treatment. In the two-year rodent studies an increased number of liver tumours was observed in rats 
and in female mice and was interpreted as being due to pantoprazole's high metabolic rate in the liver.  
 
A slight increase of neoplastic changes of the thyroid was observed in the group of rats receiving the highest 
dose (200 mg/kg). The occurrence of these neoplasms is associated with the pantoprazole-induced changes 
in the breakdown of thyroxine in the rat liver. As the therapeutic dose in man is low, no harmful effects on the 
thyroid glands are expected.  
 
In animal reproduction studies, signs of slight fetotoxicity were observed at does above 5 mg/kg.  
Investigations revealed no evidence of impaired fertility or teratogenic effects.  
 
Penetration of the placenta was investigated in the rat and was found to increase with advanced gestation. 
As a result, concentration of pantoprazole in the foetus is increased shortly before birth.  
 


 
78 
 
 
6. 
PHARMACEUTICAL PARTICULARS 
 
6.1 
List of excipients 
 
Mannitol  
Sodium citrate dihydrate 
Sodium hydroxide (for pH adjustment) 
 
6.2 
Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in section 
6.6. 
 
6.3 
Shelf life 
 
As packaged for sale: 3 years 
 
After reconstitution, or reconstitution and dilution, chemical and physical in-use stability has been 
demonstrated for 12 hours at 25ºC. The reconstituted, or reconstituted and diluted medicinal product should 
not be refrigerated. 
From a microbiological point of view, the product should be used immediately. If not used immediately, in-
use storage times and conditions prior to use are the responsibility of the user. 
 
6.4 
Special precautions for storage 
 
Do not store above 25ºC. Keep the vial in the outer carton to protect from light.  
For storage conditions of the reconstituted and diluted medicinal product see section 6.3.  
 
6.5 
Nature and contents of container 
 
15 ml, type I, colourless glass vial, sealed with a grey chlorobutyl stopper and an aluminium flip-off cap, 
containing 40 mg pantoprazole powder for solution for injection.  
 
Pack sizes: 1, 5, 10 and 20 vials 
Not all pack sizes may be marketed. 
 
6.6 
Special precautions for disposal and other handling 
 
A ready-to-use intravenous solution is prepared by injecting 10 ml of sodium chloride 9 mg/ml (0.9%) 
solution for injection into the vial containing the lyophilised powder. The reconstituted solution should be 
clear and colourless. This solution may be administered directly or may be administered after mixing it with 
100 ml of sodium chloride 9 mg/ml (0.9%) solution for injection or glucose 50 mg/ml (5%) solution for 
injection. Glass or plastic containers should be used for dilution 
 
Pantoprazol “Actavis” 40 mg powder for solution for injection should not be prepared or mixed with solvents 
other than those stated.  
 
This medicine should be administered intravenously over 2- 15 minutes. 
 
The content of the vial is for single use only. Any product that has remained in the container or the visual 
appearance of which has changed (e.g. if cloudiness or precipitation is observed) should be disposed of in 
accordance with local requirements.


 
79 
 
Appendix 6. Adverse reactions not registered 
 
Thrombocytopenia will not be registered as a serious adverse reaction (SAR) since it is a frequent 
condition among critically ill patients and is a part of the inclusion criteria (coagulopathy).  
 
Increased plasma levels of bilirubin, (jaundice) and liver enzymes (hepatocellular injury) is not 
registered as they in themselves are not considered serious conditions. The potential serious 
consequence hepatic failure will be registered daily as a SAR.  
 
Hyponatremia, hypokalaemia, hypomagnesaemia and hypocalcaemia will not be registered as 
electrolyte disturbances as they are frequent among ICU patients. These conditions are monitored 
and treated daily in all ICU patients. According to the summary of product characteristics, 
hypomagnesaemia will not be relevant until treatment for at least three months and in most cases 
one year.     
   
Leukopenia will not be registered. Reduced white blood cell counts are frequent among ICU 
patients and can be associated with many different systemic or hematological disorders in critically 
ill patients.   
 
Renal and urinary disorders will not be registered as they are not considered serious conditions in 
themselves, but the potential serious consequence will be reflected in the outcome measure days 
alive without use of renal replacement therapy.  
 
The following possible adverse reactions will not be registered as SARs as they are not considered 
serious conditions:  
  
Hyperlipidaemia, lipid increases, weight changes, taste disorders 
Sleep disorders, depression, disorientation, hallucination, confusion, headache, dizziness 
Paraesthesia, blurred vision 
Nausea, vomiting, abdominal distension, constipation, dry mouth, abdominal pain and discomfort 
Rash, exanthema, pruritus, erythema multiforme, photosensitivity, urticarial, hypersensitivity  
Arthralgia, myalgia, asthenia, fatigue and malaise 
Reproductive system, breast disorders, gynecomastia 
Injection site thrombophlebitis 
Body temperature increased 


 
80 
 
Oedema peripheral 
Fracture of the hip, wrist or spine (treatment > 1 year) 
 
 
 


 
81 
 
Appendix 7. Informed consent, Denmark 
 
In Denmark temporarily incompetent patients will be enrolled after informed consent from two 
physicians, who are independent of the trial (trial guardians). As soon as possible after enrolment, 
consent will be obtained from the patient’s next of kin and general practitioner or the Regional 
Medical Officer of Health according to Danish law. Patients, who regain consciousness, will be 
asked for informed consent as soon as possible. The process leading to the achievement of 
informed consent will be in compliance with all applicable regulations. The consenting party will be 
provided with written and oral information about the trial so he/she is able to make an informed 
decision about participation in the trial. The information will be given in a separate room, and the 
consenting party has the right to bring a companion. 
Written information and the consent form will be subjected to review and approval by the relevant 
ethic committees.  
 
Lack of informed consent from the general practitioner 
If the general practitioner does not want to make up his/her mind about the patient’s participation in 
the trial, e.g. if he/she does not have the knowledge to make the decision or for any other reasons 
the patient will continue in the trial until informed consent can be obtained from the patient him-
/herself. If the general practitioner cannot be reached the Regional Medical Officer of Health will be 
contacted for consent. 
 
 
Lack of informed consent from the patient’s next of kin 
If it is not possible (i.e. contact cannot be obtained) - after obtaining informed consent from two 
independent physicians and from the patient’s general practitioner/the Regional Medical Officer of 
Health - to obtain informed consent from the patient’s next of kin, the patient will continue in the 
trial until informed consent can be obtained from the patient him-/herself.  
  
Lack of informed consent from the patient’s next of kin and the patient deceases  
If it is not possible (i.e. contact cannot be obtained) - after obtaining informed consent from two 
independent physicians and from the patient’s general practitioner/the Regional Medical Officer of 
Health - to obtain informed consent from the patient’s next of kin, the patient will continue in the 
trial until informed consent can be obtained from the patient him-/herself. If the patient deceases 
before informed consent is obtained, or remains in a permanent state of incompetence, the 
collected data will be kept and trial outcomes will be collected centrally.  
 


 
82 
 
Deviation from the standard informed consent 
According to the standard informed consent form from the National Ethics Committee regarding 
competent patients, the patient can choose not to receive information about the data collected 
during the trial. However, the purpose of this trial is not to generate new knowledge about the 
specific patient, so we find that this question is redundant, and have omitted the question from the 
consent form to spare the patient from making unnecessary decisions.  
 
 
 


 
83 
 
 
 
 
 
Appendix 8. Timeline 


 
84 
 
Appendix 9. SAPS II scoring sheet [74] 
 
Part 1 
 
Variable 
Points: 
26 
13 
12 
11 
9 
7 
6 
5 
4 
3 
2 
0 
Age 
 
 
 
 
 
 
 
 
 
 
 
 
< 40 
Heart rate 
 
 
 
 
< 40 
 
 
 
 
 
 
40-69 
70-119 
Systolic blood pressure mmHg 
 
 
< 70 
 
 
 
 
 
70-99 
 
 
 
100-199 
Body temperature  
°C 
°F 
 
 
 
 
 
 
 
 
 
 
 
 
 
< 39 
<102.2 
Only if ventilated 
PaO2 mmHg/FiO2 
PaO2 kPa/FiO2 
 
 
 
 
 
< 100 
<13.3 
 
100-199 
13.3-26.5 
 
 
≥200 
≥26.6 
 
 
 
 
 
Urinary output ml/day 
 
 
 
 
<500 
 
 
 
 
500-999 
 
 
> 1000  
Serum urea level 
mmol/l 
(g/dl) 
 
 
 
 
 
 
 
 
 
 
 
 
 
< 10.0  
(< 0.6)  
WBC 
109/l 
 
 
 
<1.0 
 
 
 
 
 
 
 
 
1.0-19.9 
Serum potassium 
mmol/l 
 
 
 
 
 
 
 
 
 
 
<3.0 
 
3.0-4.9 
Serum sodium mmol/l 
 
 
 
 
 
 
 
 
<125 
 
 
 
125-144 
Serum bicarbonate mEq/l 
 
 
 
 
 
 
 
 
<15 
 
15-19 
 
≥20 
Bilirubin  
umol/l  
(mg/dl) 
 
 
 
 
 
 
 
 
 
 
 
 
 
< 68.4 
(<4.0) 
Glascow coma scale score 
<6 
6-8 
 
 
 
 
9-10 
 
11-13 
 
 
 
14-15 
Chronic disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
Type of admission 
 
 
 
 
 
 
 
 
 
 
 
 
Scheduled surgical 
 
 
 
 
 
 


 
85 
 
Part 2 
 
Variable 
1 
2 
3 
4 
6 
7 
8 
9 
10 
12 
15 
16 
17 
18 
Age 
 
 
 
 
 
40-59 
 
 
 
60-
69 
70-
74 
75-
79 
 
≥80 
Heart rate 
 
 
 
120-159 
 
≥160 
 
 
 
 
 
 
 
 
Systolic blood 
pressure mmHg 
 
≥200 
 
 
 
 
 
 
 
 
 
 
 
 
Body temperature  
°C 
°F 
 
 
 
≥39.0 
≥102.2 
 
 
 
 
 
 
 
 
 
 
 
Only if ventilated 
PaO2 mmHg/FiO2 
PaO2 kPa/FiO2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinary output 
ml/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum urea level 
mmol/l 
(g/dl) 
 
 
 
 
 
10.0-29.9 
0.60-1.79 
 
 
 
 
≥30.0 
≥1.80 
 
 
 
 
 
WBC 
109/l 
 
 
≥20.0 
 
 
 
 
 
 
 
 
 
 
 
Serum potassium 
mmol/l 
 
 
≥5.0 
 
 
 
 
 
 
 
 
 
 
 
Serum sodium 
mmol/l 
≥145 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum bicarbonate 
mEq/l 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin  
umol/l  
 
(mg/dl) 
 
 
 
 
68.4-
102.5 
(4.0-
5.9) 
 
 
 
 
≥102.6 
(≥6.0) 
 
 
 
 
 
 
GCS score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chronic disease 
 
 
 
 
 
 
 
Metastatic 
cancer 
Hematologic 
malignancy 
 
 
 
AIDS 
 
Type of admission 
 
 
 
 
Medical 
 
Unsceduled 
surgical  
 
 
 
 
 
 
 
Sum of points 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
86 
 
Appendix 10. SOFA score [75] 
 
 
0 
1 
2 
3 
4 
Respiraiton 
PaO2/FiO2 
   (mmHg) 
     
   (KPa) 
 
 
≥ 400 
 
≥ 53 
 
 
< 400 
 
< 53 
 
 
< 300* 
 
< 40* 
 
 
< 200† 
 
< 27†  
 
 
< 100† 
 
< 13†  
Coagulation 
Platelets  (x 103/mm3) 
 
≥ 150 
 
101-150 
 
51-100 
 
21-50 
  
≤ 20 
Liver 
Bilirubin   
   (mg/dl)  
   (umol/l) 
 
 
< 1.2 
< 20 
 
 
1.2-1.9 
20-32 
 
 
2.0-5.9 
33-101 
 
 
6.0-11.9 
102-204 
 
 
> 12.0 
> 204 
Cardiovascular 
Hypotension* 
   (MAP) 
 
 
 ≥ 70 
 
 
< 70 
 
Dopamine  ≤ 5☼ OR 
Dobutamine (any dose) OR 
Milrirone (any dose) OR 
Levosimendan (any dose) OR  
 
Dopamine ≥ 5☼ OR 
Norepinephrine  ≤ 0.1☼ OR 
Adrenaline ≤ 0.1☼ OR 
Vasopression (any dose) OR 
Phenylephrine (any dose) OR 
 
Dopamine > 15☼ OR 
Norepinephrine > 0.1☼ OR 
Adrenaline > 0.1☼ 
 
CNS 
Glascow coma scale score 
 
15 
 
13-14 
 
10-12 
 
6-9 
 
< 6 
Renal 
Creatinine  
   (mg/dl) 
   (umol/l) 
 OR 
Urine output 
 
 
< 1.2 
< 110 
 
 
 
1.2-1.9 
110-170 
 
 
2.0-5.9 
171-299 
 
 
6.0-11.9 
300-440 
 
<500 ml/day 
 
 
>12.0 
>440 
 
<200 ml/day 
* without respiratory support 
† with respiratory support 
☼Adrenergic agents administered for at least one hour (doses given are in ug/kg/min). 
 
 


 
87 
 
Appendix 11. Power estimation 
 
All power estimations have been calculated on data from the international SUP-ICU 7-day 
inception cohort study[57].  
Since we do not know whether treatment with acid suppressants reduce or increase mortality, a 
number of scenarios have been considered (+/- 20 relative risk reduction):  
 
1) 25.0% mortality 90 days after inclusion among patients with: 
At least one risk factor* 
No acid suppressants at ICU admission 
Treatment with acid suppressants during ICU admission 
No clinically important bleeding** during ICU admission 
 
Power estimations: 
 
 
We do not know whether PPI benefits or harms the patients, and need to include both scenarios.  
With 1671 patients in each group we will be able to show an absolute increase in risk of 5% with 
90% power at the primary outcome, but also an absolute risk reduction of 5% with 90% power. 
The sample size has been calculated on patients fulfilling inclusion and exclusion criteria in the 
SUP-ICU trial and because few patients were not treated with acid suppressants during ICU 
admission, the estimation is based on the group receiving acid suppressants (intervention group) 
 
2) 25.9% mortality 90 days after inclusion among patients with: 
At least one risk factor* 
No acid suppressants at ICU admission 
Treatment with acid suppressants during ICU admission 
Bleeding (overt or clinically important**) or no bleeding during ICU admission 
 
 
 
ARR 
Power Patients per group 
- 5% 
80% 
1091 
90% 
1461 
+ 5% 
80% 
1248 
90% 
1671 


 
88 
 
Power estimations: 
ARR 
Power Patients per group 
- 5,2% 
80% 
1034 
90% 
1384 
+5,2% 
80% 
1180 
90% 
1579 
 
3) 29.2% mortality 90 days after inclusion among patients with: 
At least one risk factor* 
Acid suppressants and no acid suppressants at ICU admission 
Treatment with acid suppressants during ICU admission 
No bleeding (overt or clinically important**) during ICU admission 
 
Power estimations: 
ARR 
Power Patients per group 
- 5,8% 
80% 
901 
90% 
1206 
+5,8% 
80% 
1014 
90% 
1357 
 
4) 30.5% mortality 90 days after inclusion among patients with: 
At least one risk factor* 
Acid suppressants or no acid suppressants at ICU admission 
Treatment with acid suppressants during ICU admission 
Bleeding (overt or clinically important**) or no bleeding during ICU admission 
 
Power estimations: 
ARR 
Power Patients per group 
- 6,1% 
80% 
837 
90% 
1120 
+6,1% 
80% 
937 
90% 
1254 
 
*Risk factors are: shock, renal replacement therapy, coagulopathy and coagulopathy and liver 
disease as comorbidities) 


 
89 
 
 
** Overt bleeding is defined as any episode of hematemesis, coffee ground emesis, melena, 
hematochezia or bloody nasogastric aspirate in the ICU.  
 
Clinically significant bleeding is defined as overt bleeding and at least one of the following four 
features within 24 hours of GI bleeding (in the absence of other causes) [1, 5, 10] in the ICU 
a. spontaneous drop of systolic blood pressure, mean arterial pressure or diastolic 
blood pressure of 20 mmHg or more 
b. start of vasopressor or a 20% increase in vasopressor dose 
c. decrease in haemoglobin of at least 2 g/dl (1.24 mmol/l)  
d. transfusion of 2 units of packed red blood cells or more 
 
 


 
90 
 
Appendix 12. Trial sequential analysis of all-cause mortality (16 trials).  
A diversity adjusted information size of 4,675 patients was calculated using α=0.05 (two sided), β=0.10 (power 90%), an anticipated diversity at the time when conclusive 
evidence has been reached (D2=20%), an anticipated relative risk reduction of 20%, and an event proportion of 21% in the placebo/control arm. The blue cumulative z 
curve was constructed using a random effects model. The pooled effect is a RR=0.98 with a TSA adjusted 95% confidence interval of (0.75 to 1.28) 


Appendix 13. International Committee of Medical Journal Editors (ICMJE) form for 
potential conflicts of interest.  
 
 
  
 
 


 
92 
 
 


 
93 
 
 
 
 


 
94 
 
 
 
 
 
 
Stress ulcer prophylaxis with proton pump inhibitor (pantoprazole) 
in adult critically ill patients in the intensive care unit: 
A randomised, blinded, placebo-controlled trial 
 
Final protocol, version 3.0, incl. the following amendments (please find a 
summary of the changes at page 196): 
 
 
1. August 2016: Appendix 7.1 Informed consent, Denmark  
2. December 2016: Appendix 7.2 Informed consent, Denmark  
3. June 2017: Appendix 3.1 Charter for the independent Data 
Monitoring and Safety Committee (DMSC) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Applicable protocol registration numbers: 
EudraCT number: 2015-000318-24 
ClinicalTrials.gov Identifier: NCT02467621  
 
In drafting of present protocol Copenhagen Trial Unit’s Standard Operating Procedures were used


 
95 
 
 
Table of contents 
 
Table of contents .................................................................................................................. 95 
Abstract ................................................................................................................................ 98 
Trial flow chart .................................................................................................................... 100 
Administrative information ................................................................................................ 101 
Sponsor ....................................................................................................................... 101 
Trial sites ..................................................................................................................... 101 
Steering Committee ..................................................................................................... 102 
Data Monitoring and Safety Committee ....................................................................... 107 
1.  
Introduction and background ................................................................................... 110 
1.1 
The patient population ........................................................................................ 110 
1.2 
Current treatment ............................................................................................... 110 
1.3 
Trial interventions ............................................................................................... 111 
1.4 
Adverse effects of PPI ........................................................................................ 112 
1.5 
Risks and benefits .............................................................................................. 114 
1.6 
Ethical justification and trial rationale .................................................................. 114 
1.6.1  
Outcome considerations ........................................................................ 115 
1.6.2 
Sample size considerations ................................................................... 116 
1.7 
Trial conduct ...................................................................................................... 116 
2. 
Trial objectives and purpose .................................................................................... 117 
3. 
Trial design ................................................................................................................ 117 
3.1 
Trial design ........................................................................................................ 117 
3.2 
Randomisation ................................................................................................... 117 
3.3 
Blinding .............................................................................................................. 117 
3.3.1 
Unblinding ............................................................................................. 118 
3.3.1.1 An individual ........................................................................................ 118 
3.3.1.2 Procedure ............................................................................................ 118 
3.5 
Participant timeline ............................................................................................. 119 
4. 
Selection of participants ........................................................................................... 119 
4.1 
Inclusion criteria ................................................................................................. 119 
4.2 
Exclusion criteria ................................................................................................ 120 
4.3 
Participant discontinuation and withdrawal ......................................................... 120 
4.3.1 
Discontinuation and withdrawal at the choice of the participant ............. 120 
4.3.2 
Discontinuation and withdrawal at the choice of the investigator ............ 121 
5. 
Selection and trial sites and personnel ................................................................... 121 
5.1 
Trial sites and setting ......................................................................................... 121 
5.2 
Trial personnel ................................................................................................... 121 


 
96 
 
6. 
Trial interventions ..................................................................................................... 122 
6.1 
Experimental intervention ................................................................................... 122 
6.2 
Control intervention ............................................................................................ 122 
6.3 
Co-interventions ................................................................................................. 122 
6.4 
Concomitant interventions .................................................................................. 122 
6.5 
Intervention accountability .................................................................................. 123 
7. 
Outcomes .................................................................................................................. 124 
7.1 
Primary outcome ................................................................................................ 124 
7.2 
Secondary outcomes.......................................................................................... 124 
7.3 
Exploratory outcomes......................................................................................... 124 
8. 
Safety ......................................................................................................................... 124 
8.1 
Definitions .......................................................................................................... 124 
8.2 
Risk and safety issues in the current trial ........................................................... 125 
8.3 
Serious adverse reactions and events ................................................................ 125 
8.3.1 
Recording of serious adverse reactions and events ............................... 126 
8.4 
Reporting ........................................................................................................... 126 
9. 
Procedures, assessments and data collection ....................................................... 127 
9.1 
Inclusion procedure ............................................................................................ 127 
9.1.1 
Screening .............................................................................................. 127 
9.1.2 
Procedures for informed consent ........................................................... 127 
9.2 
Data collection.................................................................................................... 127 
9.2.1 
Method .................................................................................................. 127 
9.2.2 
Timing ................................................................................................... 127 
10.  
Data handling and record keeping .................................................................. 129 
10.1 
Data management ......................................................................................... 129 
10.2 
Confidentiality ................................................................................................ 129 
10.3 
Biobanking .................................................................................................... 129 
10.4 
Access to data ............................................................................................... 130 
11.  
Statistical analysis ........................................................................................... 130 
11.1  
Sample size estimation and power calculations ............................................. 130 
11.1.1 Sample size estimation for the primary outcome ..................................... 130 
11.1.2 Power estimations for secondary outcomes .......................................... 130 
11.2  
Statistical methods ........................................................................................ 131 
11.2.1 Pre-planned subgroup analyses ........................................................... 131 
11.2.2  Significance ......................................................................................... 131 
11.2.3 Interim analysis ..................................................................................... 132 
11.2.4  Early stopping criteria .......................................................................... 132 
11.2.5  Accountability procedure for missing data/population for analysis ........ 132 
12. 
Quality control and quality assurance ..................................................................... 133 
12.1 
Monitoring of the intervention groups ............................................................ 133 


 
97 
 
13. 
Legal and organisational aspects ............................................................................ 134 
13.1  
Finance ......................................................................................................... 134 
13.1.1 Trial funding .......................................................................................... 134 
13.1.2 Compensation ....................................................................................... 134 
13.2 
Insurance ...................................................................................................... 134 
13.3 
Plan for publication, authorship and dissemination ........................................ 134 
13.3.1 Publication and authorship .................................................................... 134 
13.4  
Spin-off projects ............................................................................................ 135 
13.5  
Intellectual property rights ............................................................................. 135 
13.6 
Organisational framework.............................................................................. 135 
13.7 
Trial timeline .................................................................................................. 135 
14.  
Appendix ........................................................................................................... 135 
15.  
References ........................................................................................................ 137 
Appendix 1. Trial organisation .......................................................................................... 143 
Appendix 2. Undesirable effects of pantoprazole ............................................................ 144 
Appendix 3. Charter for the independent Data Monitoring and Safety Committee (DMSC)
 ............................................................................................................................................. 146 
Appendix 3.1 Charter for the independent Data Monitoring and Safety Committee 
(DMSC) (Amendment 3, June 2017): ................................................................................. 153 
Appendix 4. Definitions ...................................................................................................... 160 
Appendix 5. Translation of the Danish summary of product characteristics ................. 169 
Appendix 6. Adverse reactions not registered ................................................................. 177 
Appendix 7. Informed consent, Denmark ......................................................................... 179 
Appendix 7.1 Informed consent, Denmark (Amendment 1, August 2016): .................... 181 
Appendix 7.2 Informed consent, Denmark (Amendment 2, December 2016): ................ 183 
Appendix 8. Timeline.......................................................................................................... 185 
Appendix 9. SAPS II scoring sheet [74] ............................................................................ 186 
Appendix 10. SOFA score [75] .......................................................................................... 188 
Appendix 11. Power estimation ......................................................................................... 189 
Appendix 13. International Committee of Medical Journal Editors (ICMJE) form for 
potential conflicts of interest. ............................................................................................ 193 
 
 
 
 


 
98 
 
Abstract  
Background: Critically ill patients in the intensive care unit (ICU) are at risk of stress related 
gastrointestinal (GI) bleeding, and stress ulcer prophylaxis (SUP) is recommended. However, 
the evidence on SUP is of low quantity and quality, and studies have shown that proton pump 
inhibitors (PPI) may increase the risk of a number of serious adverse events.   
Objectives: To assess the benefits and harms of SUP with PPI in adult, critically ill patients in 
the ICU.  
Design: An investigator-initiated, pragmatic, international, multicentre, randomised, blinded, 
parallel-group trial of SUP with PPI versus placebo. 
Inclusion and exclusion criteria: Inclusion criteria: Adult patients admitted to the ICU with 
one or more of the following acute conditions: shock, renal replacement therapy, mechanical 
ventilation expected to last > 24 hours, any kind of coagulopathy, treatment with anticoagulant 
drugs or liver disease. Exclusion criteria: contraindications to PPI, daily treatment with PPI 
and/or histamine-2-receptor antagonist, GI bleeding of any origin or known peptic ulcer during 
current hospital admission, organ transplant, withdrawal from active therapy or brain death, 
positive urine human chorionic gonadotropin (hCG) or plasma hCG or consent according to 
national regulations not obtainable. 
Intervention: Experimental intervention is intravenous pantoprazole 40 mg daily. Control 
intervention is matching placebo (saline).   
Outcomes: Primary outcome: Mortality 90 days after randomisation. Secondary outcomes: 
proportion of patients with clinically important GI bleeding, pneumonia, Clostridium difficile 
infection and myocardial ischemia, proportion of patients with clinically important GI bleeding, 
proportion of patients with pneumonia or clostridium difficile infections, 1 year mortality post-
randomisation, days alive without organ support in the 90-day period, serious adverse 
reactions and a health economic analysis  
Trial size: 2 x 1675 patients are required to show a 20% relative risk reduction or increase 
(5% absolute risk reduction or increase) in the primary outcome measure, assuming a 
baseline 90-day mortality of 25% (α=0.05 (two-sided), and β=0.1) 
Time schedule:    
2014 – November 2015: Governance approval applications, education of trial sites, other 
preparations 
December 2015: First Danish patient enrolled 
February 2015: Commencement of inclusion in other countries 


 
99 
 
November 2017: Last patient enrolled 
January 2018: Follow-up completed 
May 2018: Data analysis and submission for publication 
 
 


 
100 
 
Trial flow chart 
The flowchart (n=  ) will be filled in during or at the end of the trial. 
 
 
Excluded  (n=   ) 
   Not meeting inclusion criteria (n=  ) 
   Declined to participate (n=  ) 
Analysed  (n=  ) 
 Excluded from analysis (give reasons) (n=  ) 
 Lost to follow-up (give reasons) (n=  ) 
 Discontinued intervention (give reasons) (n=  ) 
Allocated to intervention (n=  ) 
 Received allocated intervention (n=  ) 
 Did not receive allocated intervention (give 
 Lost to follow-up (give reasons) (n=  ) 
 Discontinued intervention (give reasons) (n=  ) 
Allocated to intervention (n=  ) 
 Received allocated intervention (n=  ) 
 Did not receive allocated intervention (give 
Analysed  (n=  ) 
 Excluded from analysis (give reasons) (n=  ) 
Allocation 
Analysis 
Follow-Up 
Randomised (n=  ) 
Assessed for eligibility (n=  ) 
Enrollment 


 
101 
 
Administrative information  
 
The research programme organisation is attached in appendix 1 
 
Sponsor  
Morten Hylander Møller 
Department of Intensive Care 4131 
University hospital of Copenhagen Rigshospitalet 
Blegdamsvej 9, 2100 Copenhagen 
E-mail: mortenhylander@gmail.com 
 
Telephone: +45 3545 8685 
 
Trial sites  
Clinical sites: 
 
ICUs in: 
• 
Denmark 
• 
Finland  
• 
Iceland 
• 
Italy 
• 
Norway 
• 
Switzerland 
• 
The Netherlands 
• 
United Kingdom  
 
Methodological and statistical site: 
Copenhagen Trial Unit (CTU), Rigshospitalet, Copenhagen, Denmark 
Department of Biostatistics, Copenhagen University, Denmark 
 
 
 


 
102 
 
Steering Committee 
The Steering Committee consists of the Management Committee and the National Principal 
Investigators (appendix 1) 
 
Management Committee: 
Sponsor:  
Morten Hylander Møller, MD PhD 
Department of Intensive Care 4131 
Copenhagen University hospital Rigshospitalet 
Denmark 
 
Coordinating investigator: 
Mette Krag, MD 
Department of Intensive Care 4131 
Copenhagen University hospital Rigshospitalet 
Denmark 
 
Anders Perner, professor, MD, PhD 
Department of Intensive Care 4131 
Copenhagen University Hospital Rigshospitalet 
Denmark 
 
Jørn Wetterslev, MD, PhD 
Copenhagen Trial Unit (CTU) 
Copenhagen University Hospital Rigshospitalet 
Denmark 
 
National principal investigators: 
Alma Möller, MD, PhD 
Department of Anaesthesia and Intensive Care 
Landspitali University Hospital, Reykjavik 
Iceland 
 
Anne Berit Guttormsen, professor, MD  


 
103 
 
Department of Anaesthesia and Intensive Care, Haukeland University Hospital, Bergen  
Clinical Institute 1 UiB, Bergen University Hospital 
Norway 
 
Frederik Keus, MD, PhD  
Department of Critical Care 
University of Groningen, University Medical Centre of Groningen 
The Netherlands 
 
Joerg C. Schefold,  MD  
Department of Intensive Care 
University Hospital Bern 
Switzerland  
 
Matthew Wise, MD, PhD 
Department of Adult Critical Care 
University Hospital of Wales, Cardiff 
United Kingdom  
 
Paolo Pelosi, MD, FERS  
Anaesthesia and Intensive Care, IRCCS San Martino IST 
Department of Surgical Sciences and Integrated Diagnostics, University of Genoa 
Italy  
 
Stepani Bendel, MD, PhD  
Department of Intensive Care Medicine  
Kuopio University Hospital, Kuopio 
Finland 
 
Danish sites and locale investigators: 
Hospital 
Locale investigator 
Bispebjerg Hospital 
Bispebjerg Bakke 23 
2400 København NV 
 
Anne Lindhardt 
Tlf: 35316359 
Anne.lindhardt.01@regionh.dk 
Dorthe Fris Palmquist 
dorte.fris.palmqvist.01@regionh.dk 


 
104 
 
Herlev Hospital 
Herlev Ringvej 75  
2730 Herlev 
Henrik Christensen 
Tlf: 38683868 
Henrik.christensen@regionh.dk 
Tina Waldau 
Tina.waldau@regionh.dk 
Herning Sygehus 
Gl Landevej 61 
7400 Herning 
Robert Winding 
Tlf: 78432753 
robewind@rm.dk 
Hillerød Hospital 
Dyrehavevej 29 
3400 Hillerød 
Morten Bestle 
Tlf: 48292017 
morten.bestle@regionh.dk 
Hjørring Sygehus 
Bispensgade 37  
9800 Hjørring 
1. Mary Kruse 
Tlf: 97641075 
mary.kruse@rn.dk 
2. René Christian Bleeg 
r.bleeg@rn.dk 
3. Malgorzata Beata Pawlowicz 
mabep@rn.dk 
4. Andrei Ciubotariu 
anci@rn.dk 
Holbæk Sygehus 
Smedelundsgade 60 
4300 Holbæk 
Jeanie Elkjær 
Tlf: 24920716 
jmel@regionsjaelland.dk 
Hans Henrik Bülow 
hhbu@regionsjaelland.dk 
Holstebro Sygehus 
Lægårdvej 12 
7500 Holstebro 
David Lodahl 
Tlf: 78430000 
davlod@rm.dk 
Hvidovre Hospital 
Kettegård Alle 30 
2650 Hvidovre 
Lene Russel 
Tlf: 38623862 
lene.russell@mail.dk 
Køge Sygehus 
Lykkebækvej 1 
4600 Køge 
Lone Poulsen 
Tlf: 47326450 
lmp@regionsjaelland.dk 
Nykøbing Falster Sygehus 
Fjordvej 15 
4800 Nykøbing F 
Henrik Guldager 
Tlf: 56516355 
hegu@regionsjaelland.dk 
Randers Sygehus 
Skovlyvej 1 
8930 Randers 
Helle Bundgaard 
Tlf: 78420505 
helle.bundgaard@randers.rm.dk 
Regionhospital Viborg  
Heibergs Alle 4 
8800 Viborg 
Lisbeth Liboriussen 
Tlf: 78445213 
Lisbeth.Liboriussen@Viborg.rm.dk 
Rigshospitalet, Intensiv Terapiklinik 4131 
Blegdamsvej 9 
2100 København 
Mette Krag 
Tlf: 35457450 
Mette.krag.01@regionh.dk 
 
Rigshospitalet, Neurointensiv 2093 
Blegdamsvej 9 
2100 København 
Marianne Berntsen 
Tlf: 30253395 
mariannejorgensen2000@yahoo.dk 
Rune Damgaard Nielsen 
Rune.damgaard.nielsen@regionh.dk 
Rigshospitalet, Thoraxintensiv 4141 
Blegdamsvej 9 
2100 København 
Hanne Ravn 
Tlf: 35451710 
hanne.berg.ravn@regionh.dk 


 
105 
 
Roskilde Sygehus 
Køgevej 7-13 
4000 Roskilde 
 
Akil Walli 
aqil@regionsjaelland.dk 
Henrik Planck Pedersen 
Tlf: 47325005 
hppd@regionsjaelland.dk 
Slagelse Sygehus 
Ingemannsvej 18 
4200 Slagelse  
Susanne Andi Iversen 
Tlf: 58559000 
saiv@regionsjaelland.dk 
Vejle Sygehus 
Kabbeltoft 25 
7100 Vejle 
Pawel Berezowicz 
Tlf 79406275 
pawel.berezowicz@rsyd.dk 
Lone Buus 
lonebuus@dadlnet.dk 
Aalborg Universitets Hospital  
Hobrovej 18-22 
9000 Aalborg 
Bodil Steen Rasmussen 
97661864 
bodil.steen.rasmussen@rn.dk 
Søren Ågaard (afdelingslæge) 
soaa@rn.dk 
Århus Universitetshospital  
Nørrebrogade 44 
8000 Århus  
Helle Nibro 
Tlf: 78450000 
hellnibr@rm.dk 
Århus Universitetshospital (Skejby) 
Palle Juul-Jensens Boulevard  
8200 Århus N 
 
Jakob Gjedsted 
Tlf: 78451030 
Jakob.gjedsted@auh.rm.dk 
Steffen Christensen 
Steffen.christensen@auh.rm.dk 
Århus Universitetshospital, Neuro Intensiv Afsnit  
Nørrebrogade 44 
8000 Aarhus C 
Stig Dyrskog  
Tlf: 78463515 
Stig.dyrskog@rm.dk 
 
Finnish sites and locale investigators: 
Hospital 
Locale investigator 
Kuopio University Hospital 
Department of intensive care medicine 
Stepani Bendel 
Email: stepani.bendel@kuh.fi 
Helsinki University Hospital  
Department of anaesthesiology and intensive 
care medicine 
Minna Backlund 
Email: Minna.Backlund@Hus.fi 
Oulu University Hospital  
Department of intensive care medicine 
Janne Liisanantti   
janne.liisanantti@ppshp.fi 
Tampere University Hospital 
Department of intensive care medicine 
Sari Karlsson 
Email: Sari.Karlsson@pshp.fi 
Turku University Hospital  
Department of intensive care medicine 
Juha Grönlund  
juha.gronlund@tyks.fi 
 
Swiss sites and locale investigators (more to be added) 
 
Joerg C. Schefold  MD, PhD, DMSci  
Department of Intensive Care 
University Hospital Bern 
Switzerland  
 


 
106 
 
Netherland, sites and locale investigators (more to be added) 
 
Frederik Keus, MD, PhD  
Department of Critical Care 
University of Groningen, University Medical Centre of Groningen 
The Netherlands 
 
Italian sites and locale investigators (more to be added) 
 
Paolo Pelosi, MD, FERS  
Anaesthesia and Intensive Care, IRCCS San Martino IST 
Department of Surgical Sciences and Integrated Diagnostics, University of Genoa 
Italy  
 
Norwegian sites and locale investigators (more to be added) 
 
Anne Berit Guttormsen, professor, MD  
Department of Anaesthesia and Intensive Care, Haukeland University Hospital, Bergen  
Clinical Institute 1 UiB, Bergen University Hospital 
Norway  
 
Iceland, sites and locale investigators (more to be added) 
 
Alma Möller, MD, PhD 
Department of Anaesthesia and Intensive Care 
Landspitali University Hospital, Reykjavik 
Iceland 
 
 


 
107 
 
Data Monitoring and Safety Committee 
Tim Walsh, professor, MD, PhD 
MRC Centre for Inflammation Research, University of Edinburgh 
The Queens Medical Research Institute 
Edinburgh 
United Kingdom 
 
Anders Åneman, MD, PhD 
Intensive Care Unit  
Liverpool Hospital 
South Western Sydney 
Australia 
 
Aksel Jensen, Biostatistician, PhD  
Department of public health, Section of Biostatistics  
University of Copenhagen  
Denmark 
 
 
 


 
108 
 
List of abbreviations  
 
AE 
Adverse events 
AIDS 
Acquired Immune Deficiency Syndrome 
AR 
Adverse reactions 
ARR 
Absolute risk reduction 
CDI  
Clostridium difficile infection 
CI 
Confidence interval 
CRIC 
Centre for Research in Intensive Care 
CRO 
Contract research organisation 
CT 
Computed Tomography 
CTSM 
Clinical Trial Supply Management 
DMSC 
Data Monitoring and Safety Committee 
eCRF 
Electronic case report form 
FiO2 
Fractional inspired oxygen 
GCP 
Good Clinical Practice 
GDP 
Good Distribution Practice 
GMP 
Good Manufacturing Practice 
GI 
Gastrointestinal 
H2RA 
Histamine-2-receptor antagonist 
hCG 
Human Chorionic Gonadotropin  
ICU 
Intensive care unit 
INR 
International normalized ratio 
MAR 
Missing at random 
MCAR 
Missing completely at random 
MNAR 
Missing not at random 
MR 
Magnetic Resonance 
NSAID 
Non-steroidal anti-inflammatory drugs 
NYHA 
New York Heart Association 
PaO2 
Partial pressure of oxygen in arterial blood 
PPI 
Proton pump inhibitor 
PT 
Prothrombin time 
RCT 
Randomised clinical trial 


 
109 
 
RRI 
Relative risk increase 
RRR 
Relative risk reduction 
SAE 
Serious adverse event 
SAPS 
Simplified Acute Physiology Score 
SAR 
Serious adverse reaction 
SC 
Steering Committee 
SD 
Standard deviation 
SOFA 
Sequential Organ Failure Assessment  
SUP 
Stress ulcer prophylaxis  
SUSAR 
Severe unexpected serious adverse reaction 
TSA 
Trial sequential analysis 
 
 


 
110 
 
1.  
Introduction and background 
1.1 
The patient population 
Critically ill patients are at risk of stress-related gastrointestinal (GI) mucosal damage, which 
can progress to ulceration and GI bleeding [1]. Endoscopic studies have shown that gastric 
erosions are present in up to 90% of patients by the third day in the intensive care unit (ICU) 
[2, 3]. These lesions are in the vast majority of patients superficial and asymptomatic, but can 
progress and result in overt and clinically important bleeding [4]. Clinical important bleeding in 
the ICU is a serious condition, with an estimated 1-4 times increased risk of mortality and is 
associated with an excess length of ICU stay of 4-8 days [1].  
Determining the incidence of GI bleeding in critically ill patients in the ICU is complicated by 
varying definitions of the outcome, difficulties in measuring the outcome, and different case 
mix. In randomised clinical trials (RCTs) and observational studies, the reported incidence of 
stress related GI bleeding among ICU patients ranges from 0.6-6.0% [1, 5–9]. Studies may 
have incorrectly included bleedings not related to stress ulcers e.g. oesophageal varices and 
ulcers already present upon ICU admission, e.g. undiagnosed peptic ulcers. In a prospective 
study by Cook at al. causes of haemorrhage were identified by endoscopy. Stress ulceration 
was defined as the sole source of bleeding in 14 of 30 patients [10]. Accordingly, sources of GI 
bleeding not prevented by stress ulcer prophylaxis (SUP) are frequent and the incidence of 
stress related ulcers may be lower than reported. Furthermore, diagnostics and treatment of 
critically ill patients in the ICU have improved considerably during the last decades [11, 12] 
and the incidence of stress ulcerations in critically ill patients may have changed. 
   
1.2 
Current treatment  
Clinical trials have suggested a reduction in frequency of GI bleeding among ICU patients 
receiving SUP compared with patients receiving placebo or no prophylaxis [3, 13–19]. Based 
on this research conducted 20 years ago, SUP is recommended in international guidelines [20–
23] and regarded as standard of care in the ICU. In a recent international unit evaluation 96 out 
of 97 units used SUP on a regular basis [24] and proton pump inhibitor (PPI) was used as first-
line therapy in 66% of the participating ICUs [24].  
 
The available PPIs are considered equally effective in the following comparative doses [25–29]: 
 
Esomeprazole 10 mg 


 
111 
 
Lanzoprazole 
15 mg 
Omeprazole 
10 mg 
Pantoprazole 
20 mg 
Rabeprazole 
10 mg 
 
 
In 2014 Maclaren et al. published a retrospective cohort study with data from the Premier 
Perspective Database [30]. Patients aged 18 years or older requiring invasive mechanical 
ventilation and receiving either Histamine-2-receptor antagonist (H2RA) or PPI were 
scrutinized. Some 35,312 patients were included and among other findings the authors found 
that pantoprazole was the most frequently used PPI. This finding was confirmed in a cohort 
study from 2014, where pantoprazole was prescribed to 32% of patients treated with acid 
suppressants in the ICU [9].  
 
1.3 
Trial interventions 
 
Because of the increased mortality and morbidity of ICU patients with clinically important GI 
bleeding, it is theoretically possible that PPIs reduce the risk of GI bleeding and hence the risk 
of death. However, research has not been able to confirm this and a 2014 observational study 
comprising more than 1,000 patients concludes that part of the increased mortality is 
explained by confounding [9]. A recent systematic review with meta-analysis and trial 
sequential analysis (TSA) assessed randomised trials comparing PPI or H2RA to placebo or 
no prophylaxis [31]. The review was conducted according to the Cochrane Handbook for 
Systematic Reviews [32] and included 20 trials with high risk of bias. The review results 
showed no significant difference between SUP and placebo/no prophylaxis on mortality and 
the TSA could exclude a 20% relative risk reduction or increase in mortality by using PPI or 
H2RA. Another meta-analysis from 2010 came to the same conclusion. Mortality was reported 
in 14 of the analysed trials and no significant reduction in mortality was found (OR 1.03, 95% 
CI 0.78-1.37; p=0.82). 
 
Three RCTs have been conducted comparing PPI to placebo [33–35], but all had low sample 
size (n=169 [33], n=287 [34], and n=41 [35]) and neither of them were powered to show 
statistically significant differences in clinically relevant outcomes. The 2014 meta-analysis 


 
112 
 
comprised two of the trials (one was published after the meta-analysis) and concluded that the 
trials had a high risk of bias, and there were no differences in GI bleeding, pneumonia and 
mortality when comparing PPI to placebo.    
 
PPI may reduce the risk of GI bleeding, but studies have indicated that they may also increase 
the risk of pneumonia, Clostridium difficile infection (CDI), acute myocardial ischemia, 
rhabdomyolysis, hypomagnesaemia and hypocalcaemia, and all of these conditions may 
increase the risk of death [36–39].  
 
PPI versus H2RA 
In recent years PPI has been considered the drug of choice in the management of most acid-
related GI disorders [40]. The superior efficacy of PPIs over H2RAs has been demonstrated in 
various GI disorders, including peptic ulcer disease, gastroesophageal reflux disease and GI 
damage caused by non-steroidal anti-inflammatory drugs (NSAIDs) [40]. Randomised trials and 
meta-analyses have aimed to evaluate PPI compared to H2RA as SUP in the ICU. A recent 
published meta-analysis by Alhazzani et al. (14 trials, 1720 patients) compared PPI and H2RA 
[41]. The authors found that PPI was more efficient in reducing clinically important and overt GI 
bleeding, but no differences were shown regarding mortality, length of stay or pneumonia [41]. 
According to the authors the results were limited by sparse data, a difference between lower 
and higher quality trials, trial methodology and possible publication bias. Another systematic 
review and meta-analysis conducted in 2010 compared PPI and H2RA [42]. The study 
comprised seven RCTs and 936 ICU patients. The analysis did not find differences in rates of 
clinically important GI bleeding, pneumonia or death. Limitations of the review include limited 
number of patients, significant statistical heterogeneity, and risk of publication bias. 
 
Clinical data on the control intervention 
As described in previous section, studies have indicated that PPI is superior to H2RA to prevent 
clinically important and overt GI bleeding, but there is still a lack of quantitative and qualitative 
evidence for PPI being superior to placebo. Before comparing different SUP agents we need 
firm evidence of SUP being superior to placebo. 
1.4 
Adverse effects of PPI 
Nosocomial pneumonia 
Nosocomial infections are a significant in-hospital burden, and pneumonia is the most 
common nosocomial infection in the ICU, affecting 10–20% of patients receiving mechanical 


 
113 
 
ventilation for more than 48 hours [43]. It has been suggested that SUP agents may increase 
the frequency of nosocomial pneumonia and trials have investigated the incidence of 
pneumonia in patients treated with SUP compared to placebo/no prophylaxis [6, 17, 33, 34, 
37, 44–46]. In 2004 Kantorova et al. found an insignificant difference in the incidence of 
pneumonia in patients treated with PPI/H2RA compared to placebo (n=287, 10%/9% vs. 7%). 
No meta-analysis of randomised trials have shown a statistically significant increased risk of 
nosocomial pneumonia when using SUP compared to placebo/no prophylaxis [31, 47].  
 
Clostridium difficile infection 
In recent years, concern has been raised that PPI increases the risk of CDI because host 
immunity is compromised by higher gastric pH [38, 48]. No randomised trials of SUP have 
reported the incidence of CDI in an ICU setting, but a recently published cohort study in adult 
critically ill patients requiring mechanical ventilation (n=35,312) found a 2-4 times increased 
risk of CDI in patients receiving PPIs compared to H2RAs [30]. Studies conducted outside the 
ICU demonstrate similar findings. In 2007 Leonard et al. found a significantly increased risk of 
CDI in non-ICU patients receiving H2RA or PPI, as compared to placebo [49] and a meta-
analysis pooling 39 observational studies showed a significant association between PPI users 
and risk of developing CDI (OR 1.74, 95% CI 1.16-5.44) compared with non-users [50].  
 
Acute myocardial ischemia 
An association between use of PPIs and increased risk of cardiovascular events in patients 
receiving clopidogrel have been suggested [47, 51]. It may be that PPIs reduce the anti-
platelet effects of clopidogrel, by interaction with the Cytochrome P450 enzyme complex in the 
liver [51].  In a case-control study of 18,130 clopidogrel users, use of co-existing PPI was 
associated with an increased risk of cardiovascular complications [51]. However, in the only 
RCT published, no cardiovascular interaction between clopidogrel and PPI was observed in 
non-ICU patients [42]. A cohort-study including 56,406 patients hospitalized for myocardial 
infarction or stroke, found an association between treatment with PPI and adverse 
cardiovascular outcomes after discharge regardless of treatment with clopidogrel [52].  
 
In conclusion, valid evidence on the use of SUP in the ICU is lacking. Moreover, there is 
increasing concern about side-effects of SUP, in particular PPIs, but the data on side-effects 
are of very low quality.  
 


 
114 
 
1.5 
Risks and benefits 
Since PPI is a well-established drug and thousands of patients are treated with it every day, 
there will be no additional risk to patients receiving PPI. The risk will be limited to the known 
adverse reactions, including intolerance, abdominal pain and headache (appendix 2) 
From the available evidence we do not know whether there will be a higher risk of GI bleeding, 
pneumonia, CDI, cardiovascular events or mortality in the PPI or placebo groups [31].  
 
1.6 
Ethical justification and trial rationale 
As described in former sections, there is no firm evidence from systematic reviews of RCTs or 
single RCTs on the potential benefit or harm of PPIs in adult patients in the ICU. On the other 
hand, SUP is recommended in international guidelines [20–22], is regarded as standard of 
care and surveys have confirmed that PPI is already part of the treatment in ICUs worldwide. 
Since it is a widespread and currently used intervention [24], the patients assigned to the PPI 
group, will not be exposed to additional risk when enrolled in the trial. Any patient with known 
peptic ulcer or GI bleeding will be excluded and treated according to usual care. If a 
randomised patient develops upper GI bleeding and the clinician finds indication for treatment 
with PPI or H2RA, the trial intervention will be discontinued and the patient will be treated 
according to usual care. Therefore, patients in the control group will, presumably, also not be 
exposed to any additional risks.     
Stress ulceration is a condition often seen in critically ill patients in the ICU. The majority of 
patients will be temporarily incompetent because of severe illness or as a consequence of the 
treatment (sedation). We cannot perform the trial randomising competent patients, because 
less sick (and thus competent) patients do not suffer from stress ulcers. Patients requiring 
acute treatment in the ICU e.g. mechanical ventilation are in an acute life-threatening condition 
and it would expose the patient to great risk not to initiate the necessary treatment in order to 
get informed consent. To make clinical trials with the goal of improving the outcome for ICU 
patients at risk of stress related GI bleeding, it is necessary to randomise and enrol patients 
before obtaining informed consent from the patient. Consent will be obtained according to 
national law, which in Denmark is by proxy (consent before randomisation by 2 doctors 
followed by next-of-kin and general practitioner/regional medical officer by health as soon as 
possible). The consenting party will be provided with written and oral information about the 
trial, so he/she is able to make an informed decision about participation in the trial. Written 
information and the consent form will be subjected to review and approval by the ethical 


 
115 
 
committee system according to national law in all participating countries. The consenting party 
can at any time, without further explanation, withdraw consent and data will be deleted if 
demanded.  
The process leading to the achievement of consent may differ in the participating countries, 
but will be described and be in compliance with all applicable regulations in the country. 
No biological material will be collected for the trial, thus no bio-bank will be formed.  
 
1.6.1  
Outcome considerations 
It has been estimated that 39% of the patients receiving SUP in the ICU are discharged from 
the hospital with SUP without an obvious indication for continuation of therapy [53]. Besides 
the side effects described in former sections, long-term treatment with PPI is associated with 
several side effects e.g. an increased risk of fractures, hypomagnesaemia and rhabdomyolysis 
[36, 39], which may all have the potential to increase mortality. Assessing mortality as the 
primary outcome would give the opportunity to weigh the totality of benefits and harms of PPI. 
Furthermore the rationale for choice of outcomes is: 
 
6. Mortality has not been the primary outcome of previous trials and we are sceptical that 
they got reliable information on mortality other than short term mortality (ICU/hospital) 
[31] 
7. Nearly all previous trials assessing PPI or H2RA as SUP have had high risk of bias 
[31]. We know that high risk of bias trials tend to overestimate benefit and 
underestimate harm [54]. Accordingly, previous trial results might be biased and even 
though they seem to find a neutral effect on mortality this may be a biased estimate 
actually concealing excess mortality in the SUP groups 
8. A meta-analysis of the previous trials did not reach a realistic information size so even 
neutral estimates may be misleading [31]. 
9. As a consequence of the 6S trial [55], where we found that bleeding was associated 
with death and that death where partly mediated by bleeding (and renal insufficiency), 
it appears odd that there should be a clinically significant reduction on GI bleeding (if 
PPI do prevent GI bleeding) without any effect on mortality [56]. 
10. A composite outcome of GI bleeding, pneumonia, CDI and acute myocardial ischemia 
seems valid to assess as well and will be a secondary outcome. The recommendation 
for using composite outcomes is reporting of the individual components as well, which 
will be done in a supplement to the primary publication. 


 
116 
 
 
Because of this and the potential to improve treatment of critically ill patients, the research 
question is in the public’s interest. The design of the trial will minimise the risk of systematic 
errors and the trial will provide information on beneficial and/or harmful effects of using PPI as 
SUP.    
 
1.6.2 
Sample size considerations 
It is difficult to produce reliable sample size estimations according to anticipated effects on GI 
bleeding because we have no reliable control groups due to the widespread use of PPI [57] 
and previous trials are in fact very old. As a consequence it has been necessary to calculate 
sample size estimations given that something may change if we stop/avoid PPI until GI 
bleeding actually happens (see appendix 11). The addressed intervention effect of 20% RRR 
or RRI on the primary outcome may seem high, but in a population with septic shock or in e.g. 
patients after cardiac arrest a 20% hazard ratio reduction corresponds to 1 months of extra 
median survival in patients with a median survival of approximately 5 months. So after all, a 
20% RRR or RRI may not be as huge as could be anticipated, when it only results in a 
modestly longer survival in these patients. The power for even major effects on each of the 
possible side effects (pneumonia, CDI and acute myocardial ischemia) are small, but it will still 
be a large contribution to our knowledge on these outcomes that may seriously question, 
overthrow or confirm what we know so far. Furthermore, 3,350 patients included in one trial 
would be a huge contribution to the evidence, more than doubling the number of randomised 
patients and providing trial results with low risk of bias on mortality and serious adverse 
events.  
No single trial, however big or well done, gives the final answer, and the SUP-ICU trial will not 
be an exception. However, the results will inform clinicians, guideline committee members and 
policy-makers on the use of PPI in the ICUs, as well as establish more (reliable) trust in PPI. 
Should we find 10-20% relative risk increase in mortality this will certainly trigger a new wave 
of trials on PPI or SUP in general and even though our trial may not be conclusive it may 
eventually lead to conclusions. 
  
1.7 
Trial conduct 
The trial will be conducted in compliance with a published trial protocol, the Helsinki 
Declaration in its latest version [58], the good clinical practice (GCP) guidelines [59], and 
national laws in the participating countries. The protocol will be registered on 


 
117 
 
www.clinicaltrials.gov and at the European Union Drug Regulating Authorities Clinical Trials 
(EudraCT) before trial start. No substantial deviation from the protocol will be implemented 
without prior review and approval of the regulatory authorities except where it may be 
necessary to eliminate an immediate hazard to the trial participants. In such case, the 
deviation will be reported to the authorities as soon as possible. Enrolment will start after 
approval by the ethical committees, medicines agencies, data protection agencies and health 
authorities in the participating countries. A manuscript with main points of the protocol 
including description of design, rationale and analysis plan will be submitted to a journal in 
English language. 
 
2. 
Trial objectives and purpose 
To assess the benefits and harms of PPI (pantoprazole) in adult, critically ill patients in the 
ICU.  
 
3. 
Trial design 
3.1 
Trial design 
An investigator-initiated, pragmatic, international, multicentre, randomised, blinded, parallel-
group trial of pantoprazole versus placebo. 
 
3.2 
Randomisation 
Patients will be screened for enrolment at admission to the ICU (see section 3.5). This will be 
ensured through implementation of trial methodology at trial sites. 
1:1 randomisation will be centralised and web-based randomisation according to the 
computer-generated allocation sequence list, stratification variables (site and active 
hematologic cancer), and varying block size. The allocation sequence list will be unknown to 
the investigators to allow immediate and concealed allocation to intervention with pantoprazole 
or placebo. Each patient will be allocated a unique patient-screening number. 
 
3.3 
Blinding 
Pantoprazole is preserved as a powder in a glass vial and needs to be dissolved in 10 ml of 
isotonic saline. The powder is momentarily dissolved with no need of shaking the vial. The 
solution is colourless and cannot be distinguished from saline. When the glass vial is masked, 


 
118 
 
it is not possible to determine whether the vial contains powder or is empty. The placebo will 
be an empty vial. Saline (10 ml) will be added to the empty vial in the same way as for the 
experimental intervention.  
The blinding of the trial medication will be a white label covering the whole vial including the 
bottom and the neck. The label will contain the required information of the trial drugs. The top 
of the placebo vial will be identical with the vial of the active drug. 
The allocated trial medication will be blinded to the clinical staff caring for the patient, to the 
patient, investigators, outcome assessors, and the data manager. The statistical analysis of 
the trial will be blinded with the intervention groups coded as, e.g., X and Y. Based on this 
blinded analysis two conclusions will be drawn: one assuming X is the experimental group and 
Y is the control group, and one conclusion assuming the opposite. Two abstracts will be 
written and accepted by the author group. After this, the blinding will be broken. 
 
The members of the Data Monitoring and Safety Committee (DMSC) will remain blinded 
unless 1) they request otherwise or 2) one of the two interim analyses has provided strong 
indications of one intervention being beneficial or harmful (a charter for the independent 
DMSC is attached in appendix 3). 
 
3.3.1 
Unblinding 
 
3.3.1.1 An individual 
The intervention may be unblinded for individual patients if deemed necessary by the clinician 
or investigator for the treatment and safety of the patient.  
In case of a suspected unexpected serious adverse reaction (SUSAR) the sponsor (or 
delegated party) shall break the blinding in order to judge the ‘expectedness’ and therefore the 
occurrence of a SUSAR (according to the summary of product characteristics), and report it to 
the authorities accordingly. See section 8 for more information. 
 
3.3.1.2 Procedure 
If the intervention for an individual patient needs to be unblinded during the trial, the treating 
physician shall contact Copenhagen Trial Unit (CTU), who will reveal the allocated trial 
intervention (pantoprazole or placebo). This can be done by telephone at all hours, any day of 
the week. If the investigator needs immediate unblinding of the trial medication, this can be 
done by removing the white label covering the glass vial. 


 
119 
 
 
3.5 
Participant timeline  
We will strive to enrol patients as soon as they fulfil the inclusion criteria. Patients will be 
allocated to either intravenous pantoprazole or placebo once daily and will continue the 
allocated intervention until death in the ICU or discharge from the ICU with a maximum of 90 
days after randomisation. 
If the patient is readmitted to the ICU within 90 days after randomisation the patient should 
continue the allocated treatment. 
 
4. 
Selection of participants 
All patients referred to a participating clinical trial site will be considered for participation. 
Patients will be eligible, if they fulfil all of the inclusion criteria and none of the exclusion criteria 
listed below (see also appendix 4) 
 
4.1 
Inclusion criteria 
 
• 
Acute admission to the ICU AND 
• 
Aged ≥ 18 years AND  
• 
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 mechanically ventilation which is expected to last > 24 hours. When in 
doubt of the forecast, the patient should be enrolled 
• 
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) 


 
120 
 
 
4.2 
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 
 
4.3 
Participant discontinuation and withdrawal 
4.3.1 
Discontinuation and withdrawal at the choice of the participant 
The procedure of handling withdrawal of consent from a patient will follow national regulations 
and will be described by each participating country.  
 
The Danish procedure: 
A patient, who no longer wishes to participate in the trial, can withdraw his/her consent at any 
time without need of further explanation, and without consequences for further treatment. 
Patients may be withdrawn from the trial at any time if consent is withdrawn by the person(s), 
who has given proxy-consent. 
In order to limit the amount of missing data we plan to collect as much data from each patient 
as possible. Therefore, if possible, the investigator will ask the patient which aspects of the 
trial, he/she wishes to withdraw from: 
  
• 
receiving the trial intervention only (allowing for all data registration and follow-up) 
OR 
• 
receiving the trial intervention AND further registration of daily data and/or follow-up 
 
Only the patient can demand deletion of already registered data and only if the patient did not 
consent previously. If so, data will be deleted and a new patient will be randomised to obtain 
the full sample size. 


 
121 
 
 
4.3.2 
Discontinuation and withdrawal at the choice of the investigator 
A patient can be discontinued from the trial intervention by the investigator at any time, if: 
• 
the patient experiences intolerable adverse reactions suspected to be related to the 
trial intervention 
AND/OR 
• 
the patient develops upper GI bleeding or another condition where the clinician finds 
indication for treatment with PPI or H2RA. The intervention will be stopped and the 
patient will receive relevant treatment. 
In these cases, the collection of data will continue and the follow-up will be conducted. The 
patient will remain in the intention-to-treat population if the allocated trial intervention has been 
given.  
If an ineligible patient is randomised by mistake and the trial intervention has not been given, 
data will be deleted (logged as a flawed randomisation) and a new patient will be randomised 
[60]. If the intervention has been given, the patient will continue in the trial and in the intention-
to-treat population.  
If the patient experiences a serious adverse reaction (SAR) or a suspected unexpected 
serious adverse reaction (SUSAR) the trial intervention will be stopped; data registration will 
continue (see section 8). 
 
Patients who are transferred to another ICU will be regarded as discharged from the ICU 
unless the new ICU is an active SUP-ICU trial site. In any case, patients transferred to another 
ICU will be followed up for the primary outcome measure and as many of the secondary 
outcome measures as possible. 
 
5. 
Selection and trial sites and personnel 
5.1 
Trial sites and setting 
Trial sites will be ICUs [61] in Europe. Trial sites are listed in the section ‘Administrative 
information’. This section will be updated during the trial.  
 
5.2 
Trial personnel 
All clinicians caring for patients in participating ICUs will be eligible to screen patients and 
perform the interventions.  


 
122 
 
All participating ICUs will receive written and oral instructions about the trial procedures. A 24-
hour hotline will be available for questions. 
 
6. 
Trial interventions 
6.1 
Experimental intervention 
To ensure systemic uptake of pantoprazole all patients randomised to the experimental group 
will be given intravenous pantoprazole 40 mg upon randomisation and hereafter once daily. 
The intervention period will be from randomisation until discharge from the ICU or death in the 
ICU. If the patient is readmitted, the allocated intervention should be continued until final 
discharge from the ICU or the end of the 90-day trial period.  
  
6.2 
Control intervention 
The control intervention will be placebo as described in section 3.3. 
The intervention period will be identical to the intervention period of the experimental 
intervention.  
 
6.3 
Co-interventions 
All patients in this trial will be offered co-interventions if indicated. Evidence regarding the use 
of sucralfate and antacids are weak [62] and we do not recommend the use of these drugs.  
 
The registered co-interventions will be: 
• 
any kind of mechanical ventilation (y/n) (daily) 
• 
continuous treatment with vasopressor/inotropes (y/n) (daily) 
• 
renal replacement therapy (y/n) (daily) 
• 
number of units of red blood cells (daily) 
• 
enteral nutrition (y/n) (daily) 
 
ICU treatment and management in general will be at the discretion of the treating clinicians.  
 
6.4 
Concomitant interventions 
PPI or H2RA cannot be prescribed as prophylaxis in the ICU during the intervention period. If 
the patient develops GI bleeding or another condition where treatment with one of the drugs is 


 
123 
 
indicted, the patient will be withdrawn from trial intervention and receive relevant treatment. 
Data collection will continue. If an included patient receives open-label PPI/H2RA (e.g. 
prescribed as prophylaxis) it will be considered a major protocol violation. This will be 
registered and the allocated trial intervention and data collection will be continued.   
 
Previously randomised patients readmitted to the ICU: 
• 
If the clinician finds indication to continue the PPI or H2RA prescribed in the ward, the 
trial medication will not be resumed, but data collection will continue  
• 
If the clinician does not find indication to continue the PPI or H2RA prescribed in the 
ward, the drug will be discontinued and the allocated trial medication will be resumed 
 
All other interventions will be allowed since they are expected to be distributed evenly in the 
two groups.  
 
6.5 
Intervention accountability 
Pantoprazole for intravenous injection will be bought and delivered from Actavis to the 
Hospital Pharmacy of the Capital Region of Denmark. The pantoprazole will be part of the 
regular production and hence not made especially for the SUP-ICU trial. The Hospital 
Pharmacy will send it directly to Nomeco. Pharma-Skan ApS will produce the sterile empty 
vials used for placebo. The production will follow all regulations and according to Good 
Manufacturing Practice (GMP) and Good Distribution Practice (GDP). The vials will be 
delivered to Nomeco CTSM who will be responsible for storage, blinding, packaging and 
distribution of vials with pantoprazole 40 mg and empty vials (placebo) to national and 
international trial sites. All services will be performed by qualified and trained personnel and 
according to GMP and GDP 
A computer program (from CTU) will generate a coding list with numbers for the vials. At 
randomisation, the computer program will allocate vials from the specific trial site to the 
patient. Nomeco CTSM will be responsible for having a sufficient number of vials to be 
allocated to patients enrolled at each trial site. At each trial site, trial products will be stored in 
a secure place. Combined with the unique packaging and labelling number this will ensure that 
trial medications will not be mixed up with other medications. Used and unused products will 
be registered.  
 


 
124 
 
7. 
Outcomes 
All outcomes are defined in appendix 4. 
 
7.1 
Primary outcome 
90-day mortality post-randomisation 
 
7.2 
Secondary outcomes 
• 
Proportion of patients with one or more of the following adverse events: clinically 
important GI bleeding, pneumonia, CDI, or acute myocardial ischemia in the ICU 
• 
Proportion of patients with clinically important GI bleeding in the ICU 
• 
Proportion of patients with one or more infectious adverse events (pneumonia or CDI) 
in the ICU 
• 
1-year “landmark” mortality post-randomisation 
• 
Days alive without the use of mechanical ventilation, renal replacement therapy or 
circulatory support in the 90-day period  
• 
Number of  SARs as defined in appendix 4  
• 
A health economic analysis will be performed. The analytic details will be based on the 
result of the trial and specified (cost-benefit vs cost-minimisation analyses) 
 
The specific elements of the composite outcomes will be reported in supplementary material to 
the primary publication. 
7.3 
Exploratory outcomes 
No exploratory outcomes or sub-studies are planned. However, sub-studies will be 
encouraged as long as they don’t hamper the completion of the main protocol and can be 
conducted after approval of the protocol by the Steering Committee (SC).  
 
8. 
Safety 
8.1 
Definitions  
Adverse event (AE): any undesirable medical event occurring to a patient during a clinical 
trial, which does not necessarily have a causal relationship with the intervention.  
 


 
125 
 
Adverse reaction (AR): any undesirable and unintended medical response related to the 
intervention occurring to a patient during a clinical trial. Adverse reactions are specified in the 
product characteristics of pantoprazole (see appendix 2 and 5) 
 
Serious adverse event (SAE): any adverse event that results in death, is life-threatening, 
requires hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability or incapacity. 
 
Serious adverse reaction (SAR): any adverse reaction (as defined above) that results in 
death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, 
results in persistent or significant disability or incapacity.  
 
Suspected unexpected serious adverse reaction (SUSAR): any suspected adverse 
reaction which is both serious and unexpected. SUSARs will be defined as serious reactions 
not described in the summaries of product characteristics for pantoprazole.  
 
8.2 
Risk and safety issues in the current trial 
Pantoprazole is well tolerated and most adverse reactions have been mild and transient 
showing no consistent relationship with treatment. Approximately 5% of patients can be 
expected to experience adverse drug reactions. The most commonly reported are diarrhoea 
and headache, both occurring in approximately 1% of patients. Because of intravenous 
administration, there will be a risk of phlebitis in both groups. 
In appendix 2 all adverse reactions for pantoprazole are listed.  
Apart from the risk of phlebitis, there is no risk of adverse reactions to the placebo (10 ml of 
isotonic saline).  
See Summary of Product Characteristics in appendix 5. 
 
8.3 
Serious adverse reactions and events 
SARs to pantoprazole: 
Registered SARs are defined in appendix 4 and ARs not registered are discussed in appendix 
6. 
 
SARs to 10 ml of isotonic saline: 


 
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No SARs are associated with such small amount of intravenous isotonic saline.  
 
8.3.1 
Recording of serious adverse reactions and events  
SARs will be recorded daily in the eCRF from the time of the first administration of trial 
medication and until 24 hours after last administration of trial medication or the patient is 
discharged from the ICU. If the patient is readmitted to the ICU and trial medication is re-
introduced, SARs will be recorded. When a SAR is registered in the eCRF the coordinating 
investigator will be informed directly which will secure fast reporting of SAR. SARs in the two 
groups will be compared in the interim analyses and as an outcome measure. If a patient 
experiences a SAR he or she will be withdrawn from the trial. Daily registration will be 
continued and the follow-up will be conducted.  
 
If a patient experiences SUSAR, the local investigator must report this without undue delay to 
the Sponsor (or delegated party). The patient will be withdrawn from the trial and the trial 
medication will be demasked. If a SUSAR is still reasonable after demasking, a report will be 
conducted describing onset and end of event, severity, the relation to the intervention, the 
actions taken and the outcome.  
 
SAEs will not be recorded as an entity, because the majority of ICU patients will experience 
several SAEs during their critical illness. The most important SAEs will be captured in the 
secondary outcome measures (days alive without life-support). Patient charts, notes and lab 
reports will contain daily registrations of clinical data, which can be obtained on request from 
the medical authorities.  
 
8.4 
Reporting 
Trial investigators are to report SUSARs without any delay to the sponsor, which in turn will 
report these to the Danish Health and Medicine Authorities 7 days at the latest after the report 
has been received. 
 


 
127 
 
9. 
Procedures, assessments and data collection 
9.1 
Inclusion procedure 
9.1.1 
Screening 
All patients admitted to participating ICUs will be eligible for screening. In fertile women a 
negative urine-hCG or plasma-hCG must be present before enrolment. 
 
9.1.2 
Procedures for informed consent 
Patients will be enrolled after consent is obtained according to national regulations. This 
procedure will be described by each participating country. The procedure for Danish patients 
is described in appendix 7. 
 
9.2 
Data collection 
9.2.1 
Method 
Data will be obtained in eCRFs from a combination of patient files and national registers. For 
patients transferred from a trial ICU to a non-trial ICU, data related to the outcomes of interest 
will be collected after transferral e.g. by national registers, phone calls, and patient charts.   
 
9.2.2 
Timing 
Appendix 8 shows an overview of the timing and all variables are defined in appendix 4. 
 
Baseline variables (not collected in the screening procedure) 
• 
Sex 
• 
Age at randomisation/date of birth 
• 
Date of admission to hospital and date and time to ICU 
• 
Elective or emergency surgery during current hospitalization (y/n) 
• 
Treatment of suspected or confirmed CDI during current hospital admission (y/n)  
• 
Treatment with NSAID or acetylsalicylic acid at hospital admission (y/n) 
• 
Treatment with anticoagulants at hospital admission (y/n) 
• 
Intravenous thrombolysis within the previous 3 days (y/n) 
• 
Co-morbidities (see definitions in appendix 4): 
• 
history of chronic lung disease  
• 
history of myocardial ischemia 
• 
history of severe chronic heart failure (NYHA 3-4) 


 
128 
 
• 
history of chronic renal failure in the last year prior to hospital admission 
• 
treatment with at least 0.3 mg/kg/day of prednisolone equivalent for at least one 
month in the 6 month prior to ICU admission 
• 
active hematologic cancer 
• 
metastatic carcinoma 
• 
AIDS 
• 
Values for simplified acute physiology score (SAPS) II 24 hours prior to randomisation 
(not covered above): heart rate, systolic blood pressure, core temperature, PaO2/ FiO2 
ratio, urinary output, urea, white blood cell count, potassium, sodium, bicarbonate, 
bilirubin, Glasgow Coma Scale (GCS) score (appendix 9) 
• 
Variables for severity organ failure assessment (SOFA) scoring 24 hours prior to 
randomisation not covered in SAPS II scoring: blood platelets, MAP, dose of 
noradrenalin, adrenalin and dopamine, use of inotropes, plasma creatinine (appendix 
10) 
 
Daily during ICU admission: 
• 
Delivery of trial medication (y/n) 
• 
Open label treatment with PPI/H2RA (y/n) 
• 
Invasive or non-invasive mechanical ventilation (y/n) 
• 
Circulatory support (infusion of vasopressor/inotropes) (y/n) 
• 
Any form of renal replacement therapy (y/n) 
• 
Onset of pneumonia (as defined in appendix 4) on this day (y/n) 
• 
Treatment with antibiotics (enteral vancomycin, intravenous or enteral metronidazole, 
or enteral fidaxomicin) for suspected or proven CDI on this day (y/n) 
• 
Acute myocardial ischemia (as defined in appendix 4) on this day (y/n) 
• 
Enteral feeding on this day (y/n) 
• 
Number of units of RBCs 
• 
Overt bleeding episodes (hematemesis, coffee ground emesis, melena, hematochezia 
or bloody nasogastric aspirate) (y/n) 
• 
SARs (y/n) (appendix 4) 
 
Bleeding form (only for patients with overt bleeding) 


 
129 
 
• 
Data on clinically important bleeding (overt GI bleeding as defined above and at least 
one of the following four features within 24 hours of GI bleeding (in the absence of other 
causes)  in the ICU: 
• 
a spontaneous drop of systolic blood pressure, mean arterial pressure or 
diastolic blood pressure of 20 mmHg or more 
• 
start of vasopressor or a 20% increase in vasopressor dose 
• 
decrease in haemoglobin of at least 2 g/dl (1.24 mmol/l)  
• 
transfusion of 2 units of packed red blood cells or more 
• 
Origin of GI bleeding confirmed (y/n) 
• 
Verification of ulcer/gastritis/esophageal varices (y/n) 
• 
Haemostasis achieved/attempted by endoscopy/open surgery/coiling (y/n) 
 
Follow-up 90 days after randomisation 
• 
Death (y/n, if yes, date of death) 
 
Follow-up 1 year after randomisation  
• 
Death (y/n, if yes, date of death) 
 
10.  
Data handling and record keeping 
10.1 
Data management 
Data will be entered into an electronically, web-based eCRF from medical files and national 
registers by trial personnel.  
 
10.2 
Confidentiality 
Each patient will receive a unique trial identification number. Trial investigators will receive 
personal username and passwords to access the randomisation system and the eCRF. Each 
site will only have access to site specific data. 
Data will be handled according to the National Data Protection Agency, and is protected by the 
Danish national laws ‘Loven om behandling af personoplysninger’ and ‘Sundhedsloven’. 
 
10.3 
Biobanking 
No biobank will be formed. 


 
130 
 
 
10.4 
Access to data 
All original records (incl. consent forms, eCRFs, and relevant correspondences) will be 
archived at trial sites for 15 years. The clean electronic trial database file will be delivered to 
the Danish Data Archive and maintained for 15 years and anonymised if requested by the 
authorities. 
 
11.  
Statistical analysis 
90-day mortality and 1-year mortality have been chosen as outcomes for all-cause mortality. 
Besides landmark mortality, mortality 90 days and 1 year after last randomised patient have 
been considered, but due to practical and organisational matters, and lack of centralised 
registration, it will be difficult and for some countries impossible to get mortality data up to 3 
years after enrolment of a patient.  
 
11.1  Sample size estimation and power calculations 
 
11.1.1 Sample size estimation for the primary outcome 
Primary outcome measure 
Assuming a baseline 90-day mortality of 25% [9] (see appendix 11) α=0.05 (two-sided), and 
β=0.1, 3350 patients (2 x 1675) will be needed to show a 20% relative risk reduction (RRR)  or 
increase (RRI) corresponding to a 5% absolute risk reduction or risk increase in the primary 
outcome measure.  
Trial Sequential Analysis [63, 64] of existing trials (n=16) has showed that 35% (1584 patients) 
of the required information size to detect or reject a 20% RRR corresponding to 4,575 patients 
has been accrued [31]. Consequently, there is an information gap of around 3000 patients 
assuming a 20% RRR in mortality (appendix 12). With the inclusion of an additional 3350 
patients it is expected that the pooled effect will cross the boundary for benefit/harm or the 
boundary for futility. 
 
11.1.2 
Power estimations for secondary outcomes 
Power estimations are based on 3350 included patients, a risk of type 1 error of 5%, and a 
minimal clinically relevant difference as stated: 


 
131 
 
Clinically important GI bleeding: 46% power (baseline 3% -> 2% = 33% RRR) for showing or 
discarding a numbers-needed-to-treat (NNT) of 100. 
Pneumonia: 85% power (baseline 20% -> 16% = 20% RRR) for showing or discarding a NNT 
of 25. 
CDI: 53% power (baseline 10% -> 8% = 20% RRR) for showing or discarding a NNT of 50. 
Myocardial ischemia: 29% power (baseline 5% -> 4% = 20% RRR) for showing or discarding a 
NNT of 100 
 
11.2  Statistical methods 
The primary analysis will be conducted including the intention-to-treat population [65–67]. A 
sensitivity analysis will be conducted including the per-protocol population, excluding patients 
with a major protocol violation (patients who did not receive the allocated trial intervention at 
all, patients who did not receive the trial intervention for at least two days in a row, treatment 
with PPI or H2RA without clinically indication and withdrawal from trial intervention). Patients 
transferred to another ICU will be considered discharged from the ICU.  
The primary analysis of all dichotomous outcomes will compare the outcome at 90 days after 
randomisation in the two groups by binary logistic regression analysis with adjustment for 
stratification variables [68]: site and active haematological cancer  
A secondary analysis will be performed adjusting for stratification variables together with other 
known major prognostic co-variates: age, baseline SOFA score, and type of admission 
(medical, elective surgery or emergency surgery).  
Further details will be provided in a statistical analysis plan.  
 
11.2.1 
Pre-planned subgroup analyses 
We will compare the primary outcome measure in pre-specified subgroups defined according 
to 1) shock at randomisation (y/n), 2) mechanical ventilation at randomisation (y/n), 3) 
coagulopathy at randomisation or history of coagulopathy (y/n), 4) history of liver disease (y/n) 
5) type of ICU admission (medical/surgery) and 6) SAPS II > 53 points (y/n). 
 
11.2.2  Significance 
A two-sided P value of less than 0.05 will be considered statistically significant.  
 


 
132 
 
11.2.3 
Interim analysis 
Interim analyses will be conducted after patient no. 1650 and 2500 has been followed for 90 
days. 
The DMSC will constitute its own plan of monitoring and meetings. The charter for the 
independent Data Monitoring and Safety Committee (DMSC) (appendix 3) defines the 
minimum of obligations and primary responsibilities of the DMSC as perceived by the SC, its 
relationship with other trial components, its membership, and the purpose and timing of its 
meetings. 
The DMSC may recommend pausing or stopping the trial if group-difference in the primary 
outcome measure, SARs or SUSARs are found at the interim analyses with statistical 
significance levels adjusted according to the LanDeMets group sequential monitoring 
boundaries based on O’Brien Fleming alfa-spending function [69]. If an analysis of the interim 
data from 1650/2500 patients fulfils the LanDeMets stopping criterion the inclusion of further 
patients will be paused and an analysis including patients randomised during the analysis 
period will be performed. If this second analysis also fulfils the LanDeMets stopping criterion 
according to the group sequential monitoring boundaries the SC may stop the trial [67]. 
Furthermore, the DMSC can recommend pausing or stopping the trial if continued conduct of 
the trial clearly compromises patient safety. However, stopping for futility to show an 
intervention effect of 15% RRR will not be an option as intervention effects less than 15% 
RRR of all-cause mortality may be clinically relevant as well.    
 
11.2.4  Early stopping criteria 
See previous section 
 
11.2.5  Accountability procedure for missing data/population for analysis 
If less than 5% of data are missing on any primary or secondary outcome, a complete case 
analysis without input of missing values will be performed. If missing data are more than 5%, a 
blinded statistician will assess whether data are ‘missing completely at random’ (MCAR 
criterion) based on a rational assessment of the pattern of missing data [70]. Little’s test will be 
used if there remains doubt [71]. If it is concluded that data are not ‘missing completely at 
random’, multiple imputation using chained equations will be performed by creating ten input 
data sets under the assumption that the data are missing data at random (MAR criterion) [72, 
73]. We will use outcomes and the most important baseline characteristics in the multiple 
imputation. The exact variables to be used to estimate the missing values will be outlined in 


 
133 
 
the detailed statistical analysis plan: If multiple imputation is used, then the primary result of 
the trial will be based on these data. The unadjusted, non-imputed analysis will also be made 
available. If multiple imputation is used, we use a best-worst worst-best case scenario as a 
sensitivity analysis to assess the potential impact of any pattern of missingness including that 
the data are missing not at random (MNAR criterion) for the trial results. In the ‘best-worst-
case’ scenario it is assumed that all patients lost to follow-up in the experimental group have 
had a beneficial outcome (e.g. have survived, had no serious adverse reactions etc.); and all 
those with missing outcomes in the control group have had a harmful outcome (e.g. have not 
survived; have had a serious adverse reaction etc.). Conversely, in the ‘worst-best-case’ 
scenario, it is assumed that all patients who were lost to follow up in the experimental group 
have had a harmful outcome; and that all those lost to follow-up in the control group have had 
a beneficial outcome. When continuous outcomes are used, a ‘beneficial outcome’ will be 
defined as the group mean plus two standard deviations (SD) of the group mean, and a 
‘harmful outcome’ will be defined as the group mean minus two SD of the group mean.   
 
 
12. 
Quality control and quality assurance 
The coordinating investigator will be responsible for organizing the trial sites including 
education of local investigators, research nurses, and other trial site personnel before the 
initiation of the trial. This education will be continuously documented and two annual 
investigator meetings will be planned.  
After initiation, trial site investigators will be responsible for all trial-related procedures at their 
site, including education of staff in trial-related procedures, recruitment and follow-up of 
patients and entry of data. Clinical staff at the trial sites will be responsible for the treatment of 
trial patients. 
 
12.1 
Monitoring of the intervention groups 
The trial will be externally monitored following a monitoring plan developed in collaboration 
with the GCP Unit in Copenhagen, which will coordinate the monitoring done by local GCP 
units and/or monitors in all countries. A centralised day-to-day monitoring of the eCRF will be 
done by the coordinating investigator or her delegates. 
 


 
134 
 
13. 
Legal and organisational aspects 
13.1  Finance 
13.1.1 
Trial funding 
The SUP-ICU trial is funded by the Innovation Fund Denmark (4108-00011A). The funding 
sources will have no influence on trial design, trial conduct, data handling, data analysis or 
publication.  
 
13.1.2 
Compensation 
Trial sites will be given DKR 1500 (200 EUR) in case money for each patient with 90-day 
follow-up to compensate for the increased workload participation infers.  
 
13.2 
Insurance 
In Denmark, all trial participants are insured by the Patient Insurance Association. Patient 
insurance will be ensured before initiating the trial in each participating countries. Costs for 
insurance will be sought financed by funding.       
 
13.3 
Plan for publication, authorship and dissemination  
13.3.1 
Publication and authorship 
The trial will be registered on www.clinicaltrials.gov. The final protocol will be published as a 
design and rationale paper including the plan for analyses. Upon trial completion the main 
manuscript with trial results whether positive, negative or neutral will be submitted for a peer-
reviewed publication, to one of the major clinical journals. Furthermore the results will be 
published at the SUP-ICU home page (www.sup-icu.com).  
 
The listing of authors will be as follows: M Krag will be the first author, A Perner the second, J 
Wetterslev the third, M Wise will be the fourth author and the next authors will be the national 
investigators according to the number of included patients per country, then the trial 
statistician and trial site investigators dependent on the number of included patients per site. 
MH Møller will be the last and corresponding author, and ‘the SUP-ICU trial co-authors’ will be 
written.  
The SC will grant authorship depending on personal input according to the Vancouver 
definitions. If a trial site investigator is to gain authorship, the site has to include 50 patients or 


 
135 
 
more. If the site includes 100 patients or more, two authorships will be granted per trial site, 
150 patients will give 3 authorships per trial site and so on.  
The DMSC and investigators not qualifying for authorship will be acknowledged with their 
names under the “SUP-ICU Trial investigators’ in an appendix to the final manuscript. 
Funding sources will have no influence on data handling or analyses or writing of the 
manuscript. 
 
13.4  Spin-off projects 
Spin-off projects will be encouraged and conducted when approved by the SC. Presently no 
spin-off projects have been developed. 
 
13.5  Intellectual property rights 
Sponsor and primary investigator is MH Møller. Therefore no contract on intellectual property 
rights is indicated. The initiative for the SUP-ICU trial has been taken by MH Møller and A 
Perner and by doctors at multiple ICUs, none of whom have affiliations to institutions that may 
have economic interests in the trial results. Contracts between national investigators and 
Sponsor and between site investigators and Sponsor will be signed before conduct of the trial.  
 
13.6 
Organisational framework  
The trial is part of the SUP-ICU research programme (www.sup-icu.com) and Centre for 
Research in Intensive Care (CRIC). 
 
13.7 
Trial timeline  
2014 – November 2015: Governance approval applications, education of trial sites, other 
preparations 
December 2015: First Danish patient enrolled 
February 2015: Commencement of inclusion in other countries 
November 2017: Last patient enrolled 
January 2018: Follow-up completed 
May 2018: Data analysis and submission for publication 
 
 
14.  
Appendix 
Appendix 1: Research Programme Organisation 


 
136 
 
Appendix 2: Undesirable effects of pantoprazole  
Appendix 3: Charter for the independent Data Monitoring and Safety Committee 
Appendix 4: Definitions 
Appendix 5: Summary of product characteristics 
Appendix 6: Adverse reactions not registered 
Appendix 7: Informed consent in Denmark 
Appendix 8: Timeline 
Appendix 9: SAPS II Score 
Appendix 10: SOFA score 
Appendix 11: Power estimations 
Appendix 12: Trial sequential analysis 
Appendix 13: International Committee of Medical Journal Editors (ICMJE) form for potential 
conflicts of interest


 
137 
 
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Van Boxel OS, van Oijen MG, Hagenaars MP, et al. (2010) Cardiovascular and 
gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a 
large Dutch cohort study. Am J Gastroenterol 105:2430–6; quiz 2437. 


 
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Charlot M, Ahlehoff O, Norgaard ML, et al. (2010) Proton-pump inhibitors are 
associated with increased cardiovascular risk independent of clopidogrel use: a 
nationwide cohort study. Ann Intern Med 153:378–86. 
53.  
Farley KJ, Barned KL, Crozier TM (2013) Inappropriate continuation of stress ulcer 
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54.  
Savović J, Jones H, Altman D, et al. (2012) Influence of reported study design 
characteristics on intervention effect estimates from randomised controlled trials: 
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55.  
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Ringer’s acetate in severe sepsis. N Engl J Med 367:124–134. 
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Haase N, Wetterslev J, Winkel P, Perner A (2013) Bleeding and risk of death with 
hydroxyethyl starch in severe sepsis: post hoc analyses of a randomized clinical trial. 
Intensive Care Med 39:2126–34. 
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Krag M, Perner A, Wetterslev J, et al. International study of the prevalence and 
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Krag M, Perner A, Wetterslev J, Moller MH (2013) Stress ulcer prophylaxis in the 
intensive care unit: is it indicated? A topical systematic review. Acta Anaesthesiol Scand 
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Gabriel SE, Normand S-LT (2012) Getting the methods right--the foundation of patient-
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Schmiemann G (2012) The preliminary draft of the methodology report by the Patient-
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Kahan BC, Morris TP (2012) Improper analysis of trials randomised using stratified 
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69.  
Lan K, Demets D (1983) Discrete sequential boundaries for clinical trials. Biometrika. 
Biometrika 70:659–63. 
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Mallinckrodt CH, Lin Q, Molenberghs M (2013) A structured framework for assessing 
sensitivity to missing data assumptions in longitudinal clinical trials. Pharm Stat 12:1–6. 
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Little RJA (1988) A Test of Missing Completely at Random for Multivariate Data with 
Missing Values. J Am Stat Assoc 83:1198. 
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Schafer JL (1999) Multiple imputation: a primer. Stat Methods Med Res 8:3–15. 
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Vickers AJ, Altman DG (2013) Statistics notes: missing outcomes in randomised trials. 
BMJ 346:f3438. 
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Le Gall J-R (1993) A New Simplified Acute Physiology Score (SAPS II) Based on a 
European/North American Multicenter Study. JAMA J Am Med Assoc 270:2957. 
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Vincent JL, Moreno R, Takala J, et al. (1996) The SOFA (Sepsis-related Organ Failure 
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Appendix 1. Trial organisation 
 
 


 
144 
 
Appendix 2. Undesirable effects of pantoprazole 
 
 
Approximately 5% of patients can be expected to experience adverse drug reactions. The most 
commonly reported adverse drug reactions are diarrhoea and headache, both occurring in 
approximately 1% of patients. 
For all adverse reactions reported from post-marketing experience, it is not possible to apply any 
adverse reaction frequency and therefore they are mentioned with a “not known” frequency. 
Within each frequency grouping, adverse reactions are presented in order of decreasing 
seriousness. 
 
Adverse reactions with pantoprazole in clinical trials and post-marketing experience 
Frequency 
Common* 
 
Uncommon* Rare* 
Very rare* 
Not known 
System Organ 
Class 
Blood and 
lymphatic system 
disorders  
  
  
Agranulocytosis  
Thrombo-
cytopenia; 
Leukopenia 
Pancytopenia  
  
Immune system 
disorders  
  
  
Hypersensitivity 
(including 
anaphylactic 
reactions and 
anaphylactic 
shock)  
  
  
Metabolism and 
nutrition disorders  
  
  
Hyperlipidaemi as 
and lipid increases 
(triglycerides, 
cholesterol); 
Weight changes  
  
Hyponatraemia  
Hypomagnesaemia 
(see section 4.4)  
Hypocalcaemia in 
association with 
hypomagnesemia; 
Hypokalaemia  
Psychiatric 
disorders  
  
Sleep 
disorders  
Depression (and all 
aggravations)  
Disorien-
tation (and all 
aggravations)  
Hallucination; 
Confusion 
(especially in pre-
disposed patients, 
as well as the 
aggravation of 
these symptoms in 
case of pre-
existence)  


 
145 
 
 
Nervous system 
disorders  
  
Headache 
Dizziness  
Taste disorders  
  
Paraesthesia  
Eye disorders  
  
  
Disturbances in 
vision / blurred 
vision  
  
  
Gastrointestinal 
disorders  
  
Diarrhoea; 
Nausea / 
vomiting; 
Abdominal 
distension 
and bloating; 
Constipation; 
Dry mouth; 
Abdominal 
pain and 
discomfort  
  
  
  
Hepatobiliary 
disorders  
  
Liver 
enzymes 
increased 
(transaminas-
es, γ-GT)  
Bilirubin increased    
Hepatocellular 
injury; Jaundice; 
Hepatocellular 
failure  
Skin and 
subcutaneous 
tissue disorders  
  
Rash / 
exanthema / 
eruption; 
Pruritus  
Urticaria; 
Angioedema  
  
Stevens-Johnson 
syndrome; Lyell 
syndrome; Ery-
thema multiforme; 
Photosensitivity  
Musculoskeletal 
and connective 
tissue disorders  
  
Fracture of 
the hip, wrist 
or spine (see 
section 4.4)  
Arthralgia; Myalgia    
Muscle spasm as a 
consequence of 
electrolyte 
disturbances  
Renal and urinary 
disorders  
  
  
  
  
Interstitial nephritis 
(with possible 
progression to 
renal failure)  
Reproductive 
system and breast 
disorders  
  
  
Gynaecomastia  
  
  
General disorders 
and administration 
site conditions  
Injection site 
thrombo-
phlebitis  
Asthenia, 
fatigue and 
malaise  
Body temperature 
increased; 
Oedema peripheral 
  
  
*Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare 
(≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available 
data).


 
146 
 
Appendix 3. Charter for the independent Data Monitoring and Safety Committee (DMSC) 
 
ClinicalTrials.gov Identifier: NCT02467621 
Research ethical committee no: H-15003141 
 
Introduction 
The DMSC will constitute its own plan of monitoring and meetings. However, this charter will define 
the minimum of obligations and primary responsibilities of the DMSC as perceived of the steering 
committee (SC), its relationship with other trial components, its membership, and the purpose and 
timing of its meetings. The charter will also outline the procedures for ensuring confidentiality and 
proper communication, the statistical monitoring guidelines to be implemented by the DMSC, and 
an outline of the content of the open and closed reports which will be provided to the DMSC. 
    
Primary responsibilities of the DMSC 
The DMSC will be responsible for safeguarding the interests of trial patients, assessing the safety 
and efficacy of the interventions during the trial, and for monitoring the overall conduct of the 
clinical trial. The DMSC will provide recommendations about stopping or continuing the trial to the 
SC of the SUP-ICU trial. To contribute to enhancing the integrity of the trial, the DMSC may also 
formulate recommendations relating to the selection/recruitment/retention of patients, their 
management, improving adherence to protocol-specified regimens and retention of patients, and 
the procedures for data management and quality control. 
 
The DMSC will be advisory to the SC. The SC will be responsible for promptly reviewing the DMSC 
recommendations, to decide whether to continue or terminate the trial, and to determine whether 
amendments to the protocol or changes in trial conduct are required. 
 
The DMSC is planned by protocol to meet physically in order to evaluate the planned interim 
analyses of the SUP-ICU trial. The interim analyses will be performed by an independent 
statistician selected by the members of the DMSC (to be announced). The DMSC may additionally 
meet whenever they decide or contact each other by telephone or e-mail in order to discuss the 
safety for trial participants. The sponsor has the responsibility to report the overall number of 
Serious Adverse Reactions (SARs) yearly to the DMSC. The DMSC can, at any time during the 
trial, request the distribution of events, including outcome measures and SARs according to 
intervention groups. Further, the DMSC can request unblinding of the interventions if suggested by 
the data, see section on ‘closed sessions’. The recommendations of the DMSC regarding stopping, 


 
147 
 
continuing or changing the design of the trial should be communicated without delay to the SC of 
the SUP-ICU trial. As fast as possible, and no later than 48 hours, the SC has the responsibility to 
inform all investigators of the trial and all the sites including patients in the trial, about the 
recommendation of the DMSC and the SC decision hereof.   
 
Members of the DMSC 
The DMSC is an independent multidisciplinary group consisting of clinicians and a biostatistician 
that, collectively, has experience in the management of ICU patients and in the conduct, monitoring 
and analysis of randomised clinical trials. 
 
DMSC Members 
Anders Åneman, MD PhD 
Tim Walsh, professor, MD, PhD 
 
DMSC Biostatistician 
Aksel Karl Georg Jensen, Section of Biostatistics, University of Copenhagen 
 
Conflicts of interest 
DMSC members will fill in and sign a declaration of conflicts of interests see appendix 13. DMSC 
membership has been restricted to individuals free of conflicts of interest. The source of these 
conflicts may be financial, scientific, or regulatory in nature. Thus, neither trial investigators nor 
individuals employed by the sponsor, nor individuals who might have regulatory responsibilities for 
the trial products, are members of the DMSC. The DMSC members do not own stock in the 
companies having products being evaluated by the SUP-ICU trial.  
The DMSC members will disclose to fellow members any consulting agreements or financial 
interests they have with the sponsor of the trial, with the contract research organisation (CRO) for 
the trial (if any), or with other sponsors having products that are being evaluated or having 
products that are competitive with those being evaluated in the trial.  
The DMSC will be responsible for deciding whether these consulting agreements or financial 
interests materially impact their objectivity. 
The DMSC members will be responsible for advising fellow members of any changes in these 
consulting agreements and financial interests that occur during the course of the trial. Any DMSC 
members who develop significant conflicts of interest during the course of the trial should resign 
from the DMSC.  


 
148 
 
DMSC membership is to be for the duration of the clinical trial. If any members leave the DMSC 
during the course of the trial, the SC will appoint the replacement(s). 
 
Formal interim analyses meeting 
Two formal interim analysis meetings will be held to review data relating to treatment efficacy, 
patient safety, and quality of trial conduct. The three members of the DMSC will meet when 90-day 
follow-up data of 1650 (approximately 50% of sample size estimation) and 2500 (approximately 
75% of sample size estimation) patients have been obtained. 
 
Proper communication 
To enhance the integrity and credibility of the trial, procedures will be implemented to ensure the 
DMSC has sole access to evolving information from the clinical trial regarding comparative results 
of efficacy and safety data, aggregated by treatment group. An exception will be made to permit 
access to an independent statistician who will be responsible for serving as a liaison between the 
database and the DMSC.  
At the same time, procedures will be implemented to ensure that proper communication is 
achieved between the DMSC and the trial investigators. To provide a forum for exchange of 
information among various parties who share responsibility for the successful conduct of the trial, a 
format for open sessions and closed sessions will be implemented. The intent of this format is to 
enable the DMSC to preserve confidentiality of the comparative efficacy results while at the same 
time providing opportunities for interaction between the DMSC and others who have valuable 
insights into trial-related issues. 
 
Closed sessions 
Sessions involving only DMSC membership who generates the closed reports (called closed 
sessions) will be held to allow discussion of confidential data from the clinical trial, including 
information about the relative efficacy and safety of interventions. In order to ensure that the DMSC 
will be fully informed in its primary mission of safeguarding the interest of participating patients, the 
DMSC will be blinded in its assessment of safety and efficacy data. However, the DMSC can 
request unblinding from the SC. 
 
Closed reports will include analysis of the primary outcome measure. In addition, analyses of the 
secondary outcome measures and SARs will also be reported. These closed reports will be 
prepared by independent biostatistician being a member of the DMSC, with assistance from the 
trial data manager, in a manner that allow them to remain blinded. 


 
149 
 
 
The closed reports should provide information that is accurate, with follow-up on mortality that is 
complete to within two months of the date of the DMSC meeting. 
 
Open reports 
For each DMSC meeting, open reports will be provided available to all who attend the DMSC 
meeting. The reports will include data on recruitment and baseline characteristics, and pooled data 
on eligibility violations, completeness of follow-up, and compliance. The independent statistician 
being a member of the DMSC will prepare these open reports in co-operation with the trial data 
manager. 
 
The reports should be provided to DMSC members approximately three days prior to the date of 
the meeting. 
 
Minutes of the DMSC Meetings 
The DMSC will prepare minutes of their meetings. The closed minutes will describe the 
proceedings from all sessions of the DMSC meeting, including the listing of recommendations by 
the committee. Because it is possible that these minutes may contain unblinded information, it is 
important that they are not made available to anyone outside the DMSC.  
 
Recommendations to the Steering Committee  
After the interim analysis meetings, the DMSC will make a recommendation to the SC to continue, 
hold or terminate the trial. 
 
Interim analyses will be conducted after patient no. 1650 and 2500 has been followed for 90 days. 
The DMSC will recommend pausing or stopping the trial if group-difference in the primary outcome 
measure, SARs or SUSARs are found at the interim analyses with statistical significance levels 
adjusted according to the LanDeMets group sequential monitoring boundaries based on O’Brien 
Fleming alfa-spending function [69]. If an analysis of the interim data from 1650/2500 patients 
fulfils the LanDeMets stopping criterion the inclusion of further patients will be paused and an 
analysis including patients randomised during the analysis period will be performed. If this second 
analysis also fulfils the LanDeMets stopping criterion according to the group sequential monitoring 
boundaries the DMSC will recommend stopping the trial [67]. Furthermore, the DMSC can 
recommend pausing or stopping the trial if continued conduct of the trial clearly compromises 
patient safety. However, stopping for futility to show an intervention effect of 15% RRR will not be 


 
150 
 
an option as intervention effects less than 15% RRR of all-cause mortality may be clinically 
relevant as well.    
 
This recommendation will be based primarily on safety and efficacy considerations and will be 
guided by statistical monitoring guidelines defined in this charter and the trial protocol. 
 
The SC is jointly responsible with the DMSC for safeguarding the interests of participating patients 
and for the conduct of the trial. Recommendations to amend the protocol or conduct of the trial 
made by the DMSC will be considered and accepted or rejected by the SC. The SC will be 
responsible for deciding whether to continue, hold or stop the trial based on the DMSC 
recommendations.  
 
The DMSC will be notified of all changes to the trial protocol or conduct. The DMSC concurrence 
will be sought on all substantive recommendations or changes to the protocol or trial conduct prior 
to their implementation. 
 
Statistical monitoring guidelines 
The outcome parameters are defined in the statistical analyses plan in the protocol. For the two 
intervention groups, the DMSC will evaluate data on: 
 
The primary outcome measure 
Mortality 90 days after randomisation of each patient (“landmark mortality”). 
 
The secondary outcome measures 
• 
Proportion of patients with one or more of the following adverse events: clinically important 
gastrointestinal (GI)  bleeding, pneumoni, clostridium difficile infection (CDI), and acute 
myocardial ischemia 
• 
Proportion of patients with clinically important GI bleeding 
• 
1 year mortality post-randomisation 
• 
The occurrence of SARs in the ICU 
 
The DMSC will be provided with these data from the coordinating centre as: 
Number of patients randomised 
Number of patients randomised per intervention group 
Number of patients stratified pr. stratification variable per intervention group 


 
151 
 
Number of events, according to the outcomes, in the two groups 
 
Based on evaluations of these outcomes, the DMSC will decide if they want further data from the 
coordinating centre and when to perform the next analysis of the data. 
 
For analyses, the data will be provided in one file as described below. 
 
DMSC should yearly be informed about SARs occurring in the two groups of the trial. 
 
The DMSC may also be asked to ensure that procedures are properly implemented to adjust trial 
sample size or duration of follow-up to restore power, if protocol specified event rates are 
inaccurate. If so, the algorithm for doing this should be clearly specified. 
 
 
Conditions for transfer of data from the Coordinating Centre to the DMSC  
The DMSC will be provided with a file containing the data defined as follows: 
 
Row 1 contains the names of the variables (to be defined below). 
 
Row 2 to N (where N-1 is the number of patients having entered the trial) each contains the data of 
one patient. 
 
Column 1 to p (where p is the number of variables to be defined below) each contains in row 1 the 
name of a variable and in the next N rows the values of this variable. 
 
The values of the following variables should be included in the database: 
 
8. screening_id: a number that uniquely identifies the patient 
 
9. rand_code: The randomisation code (group 0 or 1). The DMSC is not to be informed on 
what intervention the groups received 
 
10. clin_imp_bleed: clinically important GI bleeding (1 if the patient had one or more episodes 
and 0 if the patient did not) 
 


 
152 
 
11. pneumonia: onset of pneumonia in the ICU after randomisation (1 = one or more episodes, 
0= no episodes) 
 
12. clostridium: clostridium difficile infection (1 = one or more episodes, 0= no episodes) 
 
13. ami: acute myocardial ischemia in the ICU (1 = one or more episodes, 0= no episodes) 
 
14. SAR_indic: SAR indicator (1 = one or more SARs, 0 = no SARs) 
 
 
 


 
153 
 
Appendix 3.1 Charter for the independent Data Monitoring and Safety Committee (DMSC) 
(Amendment 3): 
 
Amendment to the previously approved protocol entitled ‘Stress ulcer prophylaxis with 
proton pump inhibitor (pantoprazole) in adult critically ill patients in the intensive care unit: 
A randomised, blinded, placebo-controlled trial’, version 3.0, October 20th 2015.  
EudraCT 2015-000318-24. 
 
This amendment replaces Appendix 3 in the above mentioned protocol.  
 
Amendment June 23, 2017  
Cancelation of the second interim analysis (2500/3350 included patients).  
Due to the high inclusion rate, the SUP-ICU trial Steering Committee and Data Monitoring and Safety 
Committee (DMSC) has decided to cancel the second interim analysis as the results (incl. 90-day 
follow-up) will not be available until the trial has been completed. 
The statement paper from the DMSC following the first interim analysis (1675/3350 included 
patients) supports this decision. The wording in the trial protocol, including appendix 3 has not been 
revised. 
 
ClinicalTrials.gov Identifier: NCT02467621 
Research ethical committee no: H-15003141 
 
Introduction 
The DMSC will constitute its own plan of monitoring and meetings. However, this charter will define 
the minimum of obligations and primary responsibilities of the DMSC as perceived of the steering 
committee (SC), its relationship with other trial components, its membership, and the purpose and 
timing of its meetings. The charter will also outline the procedures for ensuring confidentiality and 
proper communication, the statistical monitoring guidelines to be implemented by the DMSC, and 
an outline of the content of the open and closed reports which will be provided to the DMSC. 
    
Primary responsibilities of the DMSC 
The DMSC will be responsible for safeguarding the interests of trial patients, assessing the safety 
and efficacy of the interventions during the trial, and for monitoring the overall conduct of the 
clinical trial. The DMSC will provide recommendations about stopping or continuing the trial to the 
SC of the SUP-ICU trial. To contribute to enhancing the integrity of the trial, the DMSC may also 
formulate recommendations relating to the selection/recruitment/retention of patients, their 


 
154 
 
management, improving adherence to protocol-specified regimens and retention of patients, and 
the procedures for data management and quality control. 
 
The DMSC will be advisory to the SC. The SC will be responsible for promptly reviewing the DMSC 
recommendations, to decide whether to continue or terminate the trial, and to determine whether 
amendments to the protocol or changes in trial conduct are required. 
 
The DMSC is planned by protocol to meet physically in order to evaluate the planned interim 
analyses of the SUP-ICU trial. The interim analyses will be performed by an independent 
statistician selected by the members of the DMSC (to be announced). The DMSC may additionally 
meet whenever they decide or contact each other by telephone or e-mail in order to discuss the 
safety for trial participants. The sponsor has the responsibility to report the overall number of 
Serious Adverse Reactions (SARs) yearly to the DMSC. The DMSC can, at any time during the 
trial, request the distribution of events, including outcome measures and SARs according to 
intervention groups. Further, the DMSC can request unblinding of the interventions if suggested by 
the data, see section on ‘closed sessions’. The recommendations of the DMSC regarding stopping, 
continuing or changing the design of the trial should be communicated without delay to the SC of 
the SUP-ICU trial. As fast as possible, and no later than 48 hours, the SC has the responsibility to 
inform all investigators of the trial and all the sites including patients in the trial, about the 
recommendation of the DMSC and the SC decision hereof.   
 
Members of the DMSC 
The DMSC is an independent multidisciplinary group consisting of clinicians and a biostatistician 
that, collectively, has experience in the management of ICU patients and in the conduct, monitoring 
and analysis of randomised clinical trials. 
 
DMSC Members 
Anders Åneman, MD PhD 
Tim Walsh, professor, MD, PhD 
 
DMSC Biostatistician 
Aksel Karl Georg Jensen, Section of Biostatistics, University of Copenhagen 
 
Conflicts of interest 


 
155 
 
DMSC members will fill in and sign a declaration of conflicts of interests see appendix 13. DMSC 
membership has been restricted to individuals free of conflicts of interest. The source of these 
conflicts may be financial, scientific, or regulatory in nature. Thus, neither trial investigators nor 
individuals employed by the sponsor, nor individuals who might have regulatory responsibilities for 
the trial products, are members of the DMSC. The DMSC members do not own stock in the 
companies having products being evaluated by the SUP-ICU trial.  
The DMSC members will disclose to fellow members any consulting agreements or financial 
interests they have with the sponsor of the trial, with the contract research organisation (CRO) for 
the trial (if any), or with other sponsors having products that are being evaluated or having 
products that are competitive with those being evaluated in the trial.  
The DMSC will be responsible for deciding whether these consulting agreements or financial 
interests materially impact their objectivity. 
The DMSC members will be responsible for advising fellow members of any changes in these 
consulting agreements and financial interests that occur during the course of the trial. Any DMSC 
members who develop significant conflicts of interest during the course of the trial should resign 
from the DMSC.  
DMSC membership is to be for the duration of the clinical trial. If any members leave the DMSC 
during the course of the trial, the SC will appoint the replacement(s). 
 
Formal interim analyses meeting 
Two formal interim analysis meetings will be held to review data relating to treatment efficacy, 
patient safety, and quality of trial conduct. The three members of the DMSC will meet when 90-day 
follow-up data of 1650 (approximately 50% of sample size estimation) and 2500 (approximately 
75% of sample size estimation) patients have been obtained. 
 
Proper communication 
To enhance the integrity and credibility of the trial, procedures will be implemented to ensure the 
DMSC has sole access to evolving information from the clinical trial regarding comparative results 
of efficacy and safety data, aggregated by treatment group. An exception will be made to permit 
access to an independent statistician who will be responsible for serving as a liaison between the 
database and the DMSC.  
At the same time, procedures will be implemented to ensure that proper communication is 
achieved between the DMSC and the trial investigators. To provide a forum for exchange of 
information among various parties who share responsibility for the successful conduct of the trial, a 
format for open sessions and closed sessions will be implemented. The intent of this format is to 


 
156 
 
enable the DMSC to preserve confidentiality of the comparative efficacy results while at the same 
time providing opportunities for interaction between the DMSC and others who have valuable 
insights into trial-related issues. 
 
Closed sessions 
Sessions involving only DMSC membership who generates the closed reports (called closed 
sessions) will be held to allow discussion of confidential data from the clinical trial, including 
information about the relative efficacy and safety of interventions. In order to ensure that the DMSC 
will be fully informed in its primary mission of safeguarding the interest of participating patients, the 
DMSC will be blinded in its assessment of safety and efficacy data. However, the DMSC can 
request unblinding from the SC. 
 
Closed reports will include analysis of the primary outcome measure. In addition, analyses of the 
secondary outcome measures and SARs will also be reported. These closed reports will be 
prepared by independent biostatistician being a member of the DMSC, with assistance from the 
trial data manager, in a manner that allow them to remain blinded. 
 
The closed reports should provide information that is accurate, with follow-up on mortality that is 
complete to within two months of the date of the DMSC meeting. 
 
Open reports 
For each DMSC meeting, open reports will be provided available to all who attend the DMSC 
meeting. The reports will include data on recruitment and baseline characteristics, and pooled data 
on eligibility violations, completeness of follow-up, and compliance. The independent statistician 
being a member of the DMSC will prepare these open reports in co-operation with the trial data 
manager. 
 
The reports should be provided to DMSC members approximately three days prior to the date of 
the meeting. 
 
Minutes of the DMSC Meetings 
The DMSC will prepare minutes of their meetings. The closed minutes will describe the 
proceedings from all sessions of the DMSC meeting, including the listing of recommendations by 
the committee. Because it is possible that these minutes may contain unblinded information, it is 
important that they are not made available to anyone outside the DMSC.  


 
157 
 
 
Recommendations to the Steering Committee  
After the interim analysis meetings, the DMSC will make a recommendation to the SC to continue, 
hold or terminate the trial. 
 
Interim analyses will be conducted after patient no. 1650 and 2500 has been followed for 90 days. 
The DMSC will recommend pausing or stopping the trial if group-difference in the primary outcome 
measure, SARs or SUSARs are found at the interim analyses with statistical significance levels 
adjusted according to the LanDeMets group sequential monitoring boundaries based on O’Brien 
Fleming alfa-spending function [69]. If an analysis of the interim data from 1650/2500 patients 
fulfils the LanDeMets stopping criterion the inclusion of further patients will be paused and an 
analysis including patients randomised during the analysis period will be performed. If this second 
analysis also fulfils the LanDeMets stopping criterion according to the group sequential monitoring 
boundaries the DMSC will recommend stopping the trial [67]. Furthermore, the DMSC can 
recommend pausing or stopping the trial if continued conduct of the trial clearly compromises 
patient safety. However, stopping for futility to show an intervention effect of 15% RRR will not be 
an option as intervention effects less than 15% RRR of all-cause mortality may be clinically 
relevant as well.    
 
This recommendation will be based primarily on safety and efficacy considerations and will be 
guided by statistical monitoring guidelines defined in this charter and the trial protocol. 
 
The SC is jointly responsible with the DMSC for safeguarding the interests of participating patients 
and for the conduct of the trial. Recommendations to amend the protocol or conduct of the trial 
made by the DMSC will be considered and accepted or rejected by the SC. The SC will be 
responsible for deciding whether to continue, hold or stop the trial based on the DMSC 
recommendations.  
 
The DMSC will be notified of all changes to the trial protocol or conduct. The DMSC concurrence 
will be sought on all substantive recommendations or changes to the protocol or trial conduct prior 
to their implementation. 
 
Statistical monitoring guidelines 
The outcome parameters are defined in the statistical analyses plan in the protocol. For the two 
intervention groups, the DMSC will evaluate data on: 


 
158 
 
 
The primary outcome measure 
Mortality 90 days after randomisation of each patient (“landmark mortality”). 
 
The secondary outcome measures 
• 
Proportion of patients with one or more of the following adverse events: clinically important 
gastrointestinal (GI)  bleeding, pneumoni, clostridium difficile infection (CDI), and acute 
myocardial ischemia 
• 
Proportion of patients with clinically important GI bleeding 
• 
1 year mortality post-randomisation 
• 
The occurrence of SARs in the ICU 
 
The DMSC will be provided with these data from the coordinating centre as: 
Number of patients randomised 
Number of patients randomised per intervention group 
Number of patients stratified pr. stratification variable per intervention group 
Number of events, according to the outcomes, in the two groups 
 
Based on evaluations of these outcomes, the DMSC will decide if they want further data from the 
coordinating centre and when to perform the next analysis of the data. 
 
For analyses, the data will be provided in one file as described below. 
 
DMSC should yearly be informed about SARs occurring in the two groups of the trial. 
 
The DMSC may also be asked to ensure that procedures are properly implemented to adjust trial 
sample size or duration of follow-up to restore power, if protocol specified event rates are 
inaccurate. If so, the algorithm for doing this should be clearly specified. 
 
 
Conditions for transfer of data from the Coordinating Centre to the DMSC  
The DMSC will be provided with a file containing the data defined as follows: 
 
Row 1 contains the names of the variables (to be defined below). 
 


 
159 
 
Row 2 to N (where N-1 is the number of patients having entered the trial) each contains the data of 
one patient. 
 
Column 1 to p (where p is the number of variables to be defined below) each contains in row 1 the 
name of a variable and in the next N rows the values of this variable. 
 
The values of the following variables should be included in the database: 
 
15. screening_id: a number that uniquely identifies the patient 
 
16. rand_code: The randomisation code (group 0 or 1). The DMSC is not to be informed on 
what intervention the groups received 
 
17. clin_imp_bleed: clinically important GI bleeding (1 if the patient had one or more episodes 
and 0 if the patient did not) 
 
18. pneumonia: onset of pneumonia in the ICU after randomisation (1 = one or more episodes, 
0= no episodes) 
 
19. clostridium: clostridium difficile infection (1 = one or more episodes, 0= no episodes) 
 
20. ami: acute myocardial ischemia in the ICU (1 = one or more episodes, 0= no episodes) 
 
21. SAR_indic: SAR indicator (1 = one or more SARs, 0 = no SARs) 


 
160 
 
Appendix 4. Definitions 
 
Definition of stratification variables  
Site: all participating intensive care units (ICUs) will be assigned a number identifying the 
department.  
 
Haematological malignancy includes any of the following: 
• 
leukemia: Acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), 
chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL). 
• 
lymphoma: Hodgkin's disease, Non-Hodgkin lymphoma (e.g. small lymphocytic lymphoma 
(SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell 
lymphoma (MCL), hairy cell leukemia (HCL), marginal zone lymphoma (MZL), Burkitt's 
lymphoma (BL), post-transplant lymphoproliferative disorder (PTLD), T-cell prolymphocytic 
leukemia (T-PLL), B-cell prolymphocytic leukemia (B-PLL), Waldenström's 
macroglobulinemia, other NK- or T-cell lymphomas 
• 
Multiple myeloma/plasma cell myeloma  
 
Definition of inclusion criteria 
Acute admission to the ICU: a non-planned admission. It does not include planned recovery after 
surgery or similar planned admissions. ICU admission does not include admissions to semi 
intensive care, intermediate intensive care or similar beds. 
 
Age: the age of the patient in whole years at the time of randomisation. The age will be calculated 
from date of birth 
 
Shock: at least one of the following: 
• 
systolic pressure < 90 mmHg 
• 
mean arterial pressure < 70 mmHg  
• 
use of vasopressors or inotropes (norepinephrine, epinephrine, phenylephrine, vasopressin 
or dopamine, dobutamine, milirinone or levosimendan) 
• 
lactate > 4 mmol/l 
Renal replacement therapy: acute or chronic intermittent or continuous renal replacement therapy  
 


 
161 
 
Patients with expected duration of invasive mechanically ventilation > 24 hours: the treating 
clinician estimates that the patient will be invasively mechanically ventilated for more than 24 
hours. When in doubt of this forecast the patient should be enrolled 
 
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  
 
Treatment with anticoagulant drugs: ongoing treatment with: Dipyridamole, vitamin K antagonists, 
ADP-receptor inhibitors, therapeutic doses of low molecular weight heparin, new oral 
anticoagulant drugs, intravenous direct thrombin (II) inhibitors and similar drugs.   
Acetylsalicylic acid (all doses) and low molecular weight heparin in prophylactic doses are NOT 
included 
 
History of coagulopathy: coagulopathy defined as platelets < 50 x 109/l AND/OR INR > 1.5 
AND/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 
 
Definition of exclusion criteria 
Contraindications to proton pump inhibitors (PPI): any history of intolerance to PPI or additives or 
treatment with atazanavir (HIV medication) 
 
Ongoing treatment with PPI and/or histamine-2-receptor antagonists (H2RA): ongoing is defined as 
treatment not being discontinued at ICU admission. If clinicians do not find indication for 
continuation of treatment with PPI/H2RA during ICU stay, the patient will be eligible for inclusion.   
 
GI bleeding during current hospital admission: GI bleeding of any origin (both upper and lower) 
documented in the patient charts 
 
Peptic ulcer: peptic ulcer confirmed by endoscopy or other method during current hospital 
admission  
 
Organ transplant: any kind of organ transplant during current hospital admission.   


 
162 
 
 
Withdrawal from active therapy or brain death: patients where withdrawal or brain death is 
documented in the patient charts 
 
Known pregnancy: fertile woman with positive urine human chorionic gonadotropin (hCG) or 
plasma-hCG  
 
Consent not obtainable according to national regulations: patients where the clinician or 
investigator is unable to obtain necessary consent before inclusion of the patient according to the 
national regulations  
 
Definition of baseline variables 
Sex: the genotypic sex of the patient 
 
Age: defined in inclusion criteria 
 
Date of admission to hospital: the date of admission to the first hospital the patient was admitted to 
during the current hospital admission 
 
Elective surgery: surgery during current hospital admission scheduled 24 hours or latter in advance 
 
Emergency surgery: surgery during current hospital admission that was added to the operating 
room schedule 24 hours or less prior to surgery  
 
Medical admission: when no surgery has been performed during current hospital admission OR 
surgery has been performed more than 1 week prior to ICU admission 
 
Treatment with anticoagulants at hospital admission and at ICU admission: anticoagulants are 
defined in inclusion criteria 
 
Treatment with non-steroidal anti-inflammatory drugs (NSAID) and acetylsalicylic acid at hospital 
admission: treatment with all doses of these drugs at hospital admission 
 
Treatment with intravenous thrombolysis: treatment with all kinds of intravenous thrombolysis 
within 3 days prior to randomisation  


 
163 
 
 
Coagulopathy: defined in inclusion criteria  
 
Treatment of suspected or confirmed Clostridium difficile infection (CDI) during current hospital 
admission 
 
Coexisting illness must have been present in the past medical history prior to ICU admission and 
are defined as follows: 
• 
Chronic lung disease: chronic obstructive pulmonary disease (COPD), asthma or other 
chronic lung disease or treatment with any relevant drug indicating this at admission to 
hospital 
• 
Previous myocardial infarction: history of myocardial infarction 
• 
Chronic heart failure: New York Heart Association Functional Class (NYHA) III-IV. NYHA III: 
The patient has marked limitations in physical activity due to symptoms (fatigue, palpitation 
or dyspnoea) even during less than ordinary activity (walking short distances 20-100 m. or 
walking up stairs to 1st floor). The patient is only comfortable at rest. NYHA class 4: The 
patient is not able to carry out any physical activity (without discomfort (fatigue, palpitation 
or dyspnoea). Symptoms are present even at rest and the patient is mostly bedbound 
• 
History of  chronic renal failure: need of any form of chronic renal replacement therapy 
within the last year 
• 
Liver disease: defined in baseline variables 
• 
History of coagulopathy: defined in baseline variables 
• 
Immunosuppression: patients treated with at least 0,3 mg/kg/day of prednisolone equivalent 
for at least 1 month in the 6 months prior to ICU admission 
• 
Metastatic cancer: proven metastasis by surgery, CT scan or any other method 
• 
Hematologic malignancy: defined as stratification variable 
• 
AIDS: HIV positive patients with one or more HIV defining diseases such as pneumocystis 
jerovechii pneumonia, Kaposi's sarcoma, Lymphoma, tuberculosis or toxoplasma infection 
The Simplified Acute Physiology Score (SAPS II) [74] (appendix 9) is based on the most extreme 
(highest or lowest) values from 24 hours prior to randomisation. The score consists of 17 variables: 
12 physiologic variables, age, type of admission and 3 variables related to underlying disease to 
give a total score ranging from 0 to 163, with higher scores indicating greater severity of illness. 
The score will be calculated from data from the 24 hours prior to randomisation 
 


 
164 
 
The Sequential Organ Failure Assessment (SOFA) Score [75] (appendix 10) will be calculated 
from raw physiology and treatment data from the 24 hours prior to randomisation. The SOFA Score 
consists of weightings for six organ systems to give a total score ranging from 0 to 24, with higher 
scores indicating a greater degree of organ failure. 
 
Definition of daily collected variables: 
Delivery of trial medication: confirmation of administration of the trial drug 
 
Treatment with PPI or H2RA: prescription of any of these drugs in any dose (major protocol 
violation if the treatment is initiated (e.g. as prophylaxis) without clinical indication (e.g. 
gastrointestinal bleeding)  
 
Mechanical ventilation: invasive and non-invasive mechanical ventilation including continuous 
mask CPAP or CPAP via a tracheotomy. Intermittent CPAP is NOT mechanical ventilation. 
 
Circulatory support: continuous infusion of vasopressor or inotrope (norepinephrine, epinephrine, 
phenylephrine, vasopressin or dopamine, dobutamine, milirinone or levosimendan) 
 
Renal replacement therapy: any form of renal replacement therapy on this day. In patients 
receiving intermittent renal replacement therapy days between treatments are included 
 
Clinically important GI bleeding, onset of pneumonia, CDI, and acute myocardial ischemia in the 
ICU are defined as outcomes 
 
Treatment with enteral feeding: any dose of enteral feeding (including oral nutritional intake) during 
the day 
 
Units of red blood cells: cumulated number of units of red blood cells transfused during the day 
 
Serious adverse reactions (SARs) are defined below 
 
Definition of bleeding variables: 
Confirmed diagnosis: diagnosis/origin of bleeding confirmed by endoscopy or other method 
 


 
165 
 
Verification of ulcer/gastritis/bleeding oesophageal varices: confirmation of one of the three specific 
diagnoses by endoscopy or other method 
 
Haemostasis achieved or attempted: documentation in patient charts of haemostasis achieved or 
attempted by endoscopy, open surgery or coiling   
 
Definitions of outcome measures 
Primary outcome:  
90-day mortality: death from any cause within 90 days following the day of randomisation 
 
Secondary outcomes: 
Proportion of patients with one or more of the following adverse events: clinically important GI 
bleeding, pneumonia, CDI, and acute myocardial ischemia. The events are defined as follows: 
 
Clinically important GI bleeding: overt GI bleeding* and at least one of the following four features 
within 24 hours of GI bleeding (in the absence of other causes) in the ICU 
e) spontaneous drop of systolic blood pressure, mean arterial pressure or diastolic blood 
pressure of 20 mmHg or more 
f) start of vasopressor or a 20% increase in vasopressor dose 
g) decrease in haemoglobin of at least 2 g/dl (1.24 mmol/l)  
h) transfusion of 2 units of packed red blood cells or more 
*Overt GI bleeding: hematemesis, coffee ground emesis, melena, haematochezia or bloody 
nasogastric aspirate  
 
Pneumonia: episodes of newly confirmed pneumonia according to the modified CDC criteria [76] 
• 
Two or more serial chest radiographs with at least one of the following (one radiograph is 
sufficient for patients with no underlying pulmonary or cardiac disease): 
1. new or progressive and persistent infiltrate 
2. consolidation 
3. cavitation 
 
• 
AND at least one of the following: 
1. fever (>38°C) with no other recognised cause  
2. leukopenia (white cell count < 4 x 109/l) or leucocytosis (white cell count >12 x 109/l)  
• 
AND at least two of the following 


 
166 
 
 
5. new onset of purulent sputum or change in character of sputum, or increased 
respiratory secretions or increased suctioning requirements 
6. new onset or worsening cough, or dyspnoea, or tachypnoea 
7. rales or bronchial breath sounds 
8. worsening gas exchange (hypoxaemia, increased oxygen requirement, increased 
ventilator demand) 
 
CDI: Treatment with antibiotics (enteral vancomycin, intravenous or enteral metronidazole, enteral 
fidaxomicin) for suspected or proven CDI  
 
Acute myocardial ischemia: ST-elevation myocardial infarction, non-ST elevation myocardial 
infarction or unstable angina pectoris according to the criteria in the clinical setting in question (e.g. 
elevated biomarkers, ischemic signs on ECG and clinical presentation) AND receiving treatment as 
a consequence of this (reperfusion strategies (PCI/thrombolysis) or initiation/increased 
antithrombotic treatment) 
 
Proportions of patients with clinically important GI bleeding: proportion of patients with one or more 
episodes of clinically important GI bleeding as defined above  
 
Proportion of patients with one or more infectious adverse events: proportion of patients with one 
or more episodes of pneumonia or CDI 
 
1-year mortality: landmark mortality 1 year post-randomisation 
 
Duration of life support in the ICU: the number of days alive and free from respiratory or circulatory 
support and of renal replacement therapy as defined below. The outcome will be days alive without 
use of mechanical ventilation, circulatory support or renal replacement therapy in the 90-day 
period, and will be defined as the percentage of days without mechanical ventilation, circulatory 
support and renal replacement therapy (as defined in daily collected variables) in the 90 days after 
randomisation 
 
Serious adverse reactions: number of serious adverse reactions as defined below 
 
The elements of all composite outcomes will be reported in the supplementary material 


 
167 
 
 
A health economic analysis will be performed. The analytic details will be based on the result of the 
trial and specified (cost-benefit vs cost-minimisation analyses). 
 
Definitions of serious adverse reactions 
 
A serious adverse reaction (SAR) is defined as any adverse reaction that results in death, is life-
threatening, requires hospitalization or prolongation of existing hospitalization, or results in 
persistent or significant disability or incapacity.  
 
Patients will be monitored for onset of SARs occurring between the first dose of trial medication 
and until discharge from the ICU. If a patient is withdrawn from the trial intervention, SARs will be 
recorded for 24 hours after the last dose of trial medication or discharge from ICU. If the patient is 
readmitted to the ICU and trial intervention is reintroduced, data collection for SARs will be 
resumed. If a patient experiences a SAR the patient will be withdrawn from the trial intervention but 
data collection and follow-up will be continued (see section 4.3.2)  
 
SARs will be defined as follows:  
 
Anaphylactic reactions defined as urticaria and at least one of the following 
• 
Worsened circulation (>20% decrease in blood pressure or >20% increase in vasopressor 
dose) 
• 
Increased airway resistance (>20% increase in the peak pressure on the ventilation) 
• 
Clinical stridor or bronchospasm 
• 
Subsequent treatment with bronchodilators 
Agranulocytosis is defined as any new, acute and severe drop in granulocytes to < 0.5 x 109/l 
requiring active monitoring or treatment 
 
Pancytopenia is defined as any new, severe drop in red blood cells, white blood cells and platelets 
requiring active monitoring or treatment 
 
Acute hepatic failure is defined as severe and progressing hepatic failure as judged by the treating 
doctor or the investigator 
 


 
168 
 
Steven-Johnson syndrome and toxic epidermal necrolysis are defined as severe dermatological 
reactions with a skin biopsy confirming the diagnosis 
 
Interstitial nephritis is defined as a nephritis affecting the interstitium of the kidneys surrounding the 
tubules with a kidney biopsy confirming the diagnosis  
 
Angioedema (Quincke’s oedema) is defined as a vascular reaction involving the deep dermis, 
subcutaneous or submucosal tissues, resulting in a characteristic localized oedema. 
 
Adverse reactions not registered will be discussed in appendix 6. 
 


 
169 
 
Appendix 5. Translation of the Danish summary of product characteristics  
 
 
SUMMARY OF PRODUCT CHARACTERISTICS 
 
for 
 
Pantoprazol “Actavis”, powder for solution for injection 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
 
 
Pantoprazol “Actavis” 40 mg powder for solution for injection 
 
 
2. 
QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains 40 mg of pantoprazole (as sodium sesquihydrate) 
 
Excipients with known effect: 
Each vial contains 5.0 mg of sodium citrate dihydrate and sodium hydroxide q.s. 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. is essentially “sodium free”. 
 
For the full list of excipients, see section 6.1 
 
3. 
PHARMACEUTICAL FORM 
 
Powder for solution for injection. 
 
White or almost white, uniform porous cake. 
 
For the solution reconstituted with 10 ml of 0.9% NaCl solution the pH is approximately 10 and the osmolality 
is approximately 382 mOsm/Kg 
 
For the solution reconstituted with a further 100 ml of 0.9% NaCl solution or 5% glucose solution the pH is 
approximately 9 and 8.5, respectively 
 
 
4. 
CLINICAL PARTICULARS 
 
4.1 
Therapeutic indications 
 
- 
Reflux oesophagitis 
- 
Gastric and duodenal ulcer 
- 
Zollinger – Ellison Syndrome and other pathological hypersecretory conditions. 
 
4.2 
Posology and method of administration 
 
This medicine should be administered by a healthcare professional and under appropriate medical 
supervision. 
 
The intravenous administration of pantoprazole is recommended only if oral application is not appropriate. 
Data are available on intravenous use for up to 7 days. Therefore as soon as oral therapy is possible, 
treatment with pantoprazole i.v. should be discontinued and 40 mg pantoprazole p.o. should be administered 
instead. 
 


 
170 
 
Posology 
 
Gastric and duodenal ulcer, reflux oesophagitis 
The recommended intravenous dose is one vial of pantoprazole (40 mg) per day. 
 
Zollinger-Ellison Syndrome and other pathological hypersecretory conditions 
For the long-term management of Zollinger-Ellison Syndrome and other pathological hypersecretory 
conditions patients should start their treatment with a daily dose of 80 mg of pantoprazole i.v. Thereafter, the 
dosage can be titrated up or down as needed using measurements of gastric acid secretion to guide. With 
doses above 80 mg daily, the dose should be divided and given twice daily. A temporary increase of the 
dosage above 160 mg pantoprazole is possible but should not be applied longer than required for adequate 
acid control.  
 
In case a rapid acid control is required, a starting dose of 2 x 80 mg of pantoprazole i.v. is sufficient to 
manage a decrease of acid output into the target range (<10 mEq/h) within one hour in the majority of 
patients. 
 
Special populations 
Paediatric population 
The experience in children is limited. Therefore, pantoprazole i.v. is not recommended for use in patients 
below 18 years of age until further data become available.  
 
Hepatic impairment: 
A daily dose of 20 mg pantoprazole (half a vial of 40 mg pantoprazole) should not be exceeded in patients 
with severe liver impairment (see section 4.4).  
 
Renal impairment: 
No dose adjustment is necessary in patients with impaired renal function. 
 
Elderly 
No dose adjustment is necessary in elderly patients. 
 
Method of administration 
A ready-to-use solution is prepared in 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection. For 
instructions for preparation see section 6.6.  The prepared solution may be administered directly or may be 
administered after mixing it with 100 ml of 9 mg/ml (0.9%) sodium chloride injection, or 50 mg/ml glucose 
(5%) solution for injection. 
 
After preparation the solution must be used within 12 hours (see section 6.3). 
 
The medicinal product should be administered intravenously over 2 – 15 minutes. 
 
4.3 
Contraindications 
 
Hypersensitivity to the active substance, substituted benzimidazoles, or to any of the excipients listed in 
section 6.1. 
 
4.4 
Special warnings and precautions for use 
 
In presence of alarm symptoms 
In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, 
dysphagia, haematemesis, anaemia or melaena) and when gastric ulcer is suspected or present, malignancy 
should be excluded, as treatment with pantoprazole may alleviate symptoms and delay diagnosis. 
 
Further investigation is to be considered if symptoms persist despite adequate treatment. 
 
Hepatic impairment 


 
171 
 
In patients with severe liver impairment, the liver enzymes should be monitored during therapy. In the case 
of a rise in the liver enzymes, the treatment should be discontinued (see section 4.2). 
 
Co-administration with atazanavir 
Co-administration of atazanavir with proton pump inhibitors is not recommended (see section 4.5). If the 
combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g. 
virus load) is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg 
of ritonavir.  A pantoprazole dose of 20 mg per day should not be exceeded. 
 
Gastrointestinal infections caused by bacteria 
Pantoprazole, like all proton pump inhibitors (PPIs), might be expected to increase the counts of bacteria 
normally present in the upper gastrointestinal tract. Treatment with pantoprazole may lead to a slightly 
increased risk of gastrointestinal infections caused by bacteria (e.g. Salmonella and Campylobacter and 
C.difficile). 
 
Sodium 
This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially “sodium-free”.  
 
4.5 
Interaction with other medicinal products and other forms of interaction 
 
Effect of pantoprazole on the absorption of other medicinal products 
Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may reduce the 
absorption of drugs with a gastric pH dependant bioavailability, e.g. some azole antifungals such as 
ketoconazole, itraconazole, posaconazole and other medicines such as erlotinib.  
  
HIV medications (atazanavir) 
Co-administration of atazanavir and other HIV medications whose absorption is pH-dependent with proton 
pump inhibitors might result in a substantial reduction in the bioavailability of these HIV medications and 
might impact the efficacy of these medicines. Therefore, the co-administration of proton pump inhibitors with 
atazanavir is not recommended (see section 4.4). 
 
Coumarin anticoagulants (phenprocoumon or warfarin) 
Although no interaction during concomitant administration of phenprocoumon or warfarin has been observed 
in clinical pharmacokinetic studies, a few isolated cases of changes in International Normalised Ratio (INR) 
have been reported during concomitant treatment in the post-marketing period. Therefore, in patients treated 
with coumarin anticoagulants (e.g. phenprocoumon or warfarin), monitoring of prothrombin time/INR is 
recommended after initiation, termination or during irregular use of pantoprazole. 
 
Other interactions studies 
Pantoprazole is extensively metabolised in the liver via the cytochrome P450 enzyme system. The main 
metabolic pathway is demethylation by CYP2C19 and other metabolic pathways include oxidation by 
CYP3A4. 
 
Interaction studies with drugs also metabolised with these pathways, like carbamazepine, diazepam, 
glibenclamide, nifedipine and an oral contraceptive containing levonorgestrel and ethinyl oestradiol did not 
reveal clinically significant interactions.  
 
Results from a range of interaction studies demonstrate that pantoprazole does not effect the metabolism of 
active substances metabolised by CYP1A2 (such as caffeine, theophylline), CYP2C9 (such as piroxicam, 
diclofenac, naproxen), CYP2D6 (such as metoprolol), CYP2E1 (such as ethanol) or does not interfere with p-
glycoprotein related absorption of digoxin.  
 
Methotrexate 
Concomitant use of high dose methotrexate (e.g. 300 mg) and proton-pump inhibitors has been reported to 
increase methotrexate levels in some patients. Therefore in settings where high-dose methotrexate is used, 
for example cancer and psoriasis, a temporary withdrawal of pantoprazole may need to be considered.  
 
There were no interactions with concomitantly administered antacids. 


 
172 
 
 
Interaction studies have also been performed administering pantoprazole concomitantly with the respective 
antibiotics (clarithromycin, metronidazole, amoxicillin).  No clinically relevant interactions were found.  
 
4.6 
Fertility, pregnancy and lactation 
 
Pregnancy 
There are no adequate data from the use of pantoprazole in pregnant women.  Studies in animals have 
shown reproductive toxicity (see section 5.3).  The potential risk for humans is unknown.  Pantoprazole 
should not be used during pregnancy unless clearly necessary.  
 
Breast-feeding 
Animal studies have shown excretion of pantoprazole in breast milk.  Excretion into human milk has been 
reported.  Therefore a decision on whether to continue/discontinue breast-feeding or to continue/discontinue 
therapy with pantoprazole should be made taking into account the benefit of breast-feeding to the child and 
the benefit of pantoprazole therapy to women. 
 
4.7 
Effects on ability to drive and use machines 
 
Adverse drug reactions such as dizziness and visual disturbances may occur (see section 4.8).  If affected, 
patients should not drive or operate machines. 
 
4.8 
Undesirable effects 
 
Approximately 5% of patients can be expected to experience adverse drug reactions (ADRs).  The most 
commonly reported ADRs are diarrhoea and headache, both occurring in approximately 1% of patients. 
 
The table below lists adverse reactions reported with pantoprazole, ranked under the following frequency 
classification: 
Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (<1/10,000 to 
<1/1,000), very rare (1/10,000) not known (cannot be estimated from the available data).  For all adverse 
reactions reported from post-marketing experience, it is not possible to apply any Adverse Reaction 
frequency and therefore they are mentioned with a “not known” frequency. 
 
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 
Table 1. Adverse reactions with pantoprazole in clinical trials and post-marketing experience 
 
     Frequency 
 
System  
organ class 
Common 
Uncommon 
Rare 
Very rare 
Not known 
Blood and 
lymphatic 
system 
disorders 
 
 
Agranulocytosis 
Thrombo- 
Cytopenia; 
Leukopenia; 
Pancytopenia 
 
Immune 
system 
disorders 
 
 
Hypersensitivity 
(including 
anaphylactic 
reactions and 
anaphylactic 
shock) 
 
 
Metabolism 
and nutrition 
disorders 
 
 
Hyperlipidaemia 
and lipid 
increases 
(triglycerides, 
cholesterol); 
Weight changes 
 
Hyponatraemia 
Hypomagnesaemia; 
Hypocalcaemia in 
association with 
hypomagnesaemia; 
Hypokalaemia 


 
173 
 
     Frequency 
 
System  
organ class 
Common 
Uncommon 
Rare 
Very rare 
Not known 
Psychiatric 
disorders 
 
Sleep disorders 
Depression 
(and all 
aggravations) 
Disorientation 
(and all 
aggravations) 
Hallucination: 
Confusion 
(especially in pre-
disposed patients, 
as well as the 
aggravation of 
these symptoms in 
case of pre-
existence) 
Nervous 
system 
disorders 
 
Headache; 
Dizziness 
 
Taste disorders 
 
Paraesthesia 
Eye disorders 
 
 
Disturbances in 
vision/blurred 
vision 
 
 
Gastrointestinal 
disorders 
 
Diarrhoea; 
Nausea/ 
vomiting; 
Abdominal 
distension and 
bloating; 
Constipation; 
Dry mouth; 
Abdominal pain 
and discomfort. 
 
 
 
Hepatobiliary 
disorders 
 
Liver enzymes 
increased 
(transaminases, 
-GT) 
Bilirubin 
increased 
 
Hepatocellular 
injury; Jaundice; 
Hepatocellular 
failure 
Skin and sub-
cutaneous 
tissue 
disorders 
 
Rash/ 
exanthema/ 
eruption; 
Pruritus 
Urticaria; 
Angioedema 
 
Stevens-Johnson 
syndrome; Lyell 
syndrome; 
Erythema 
multiforme; Photo-
sensitivity  
Musculo-
skeletal and 
connective 
tissue 
disorders 
 
 
Arthralgia; 
Myalgia 
 
Muscle spasm as a 
consequence of 
electrolyte 
disturbances 
Renal and 
urinary 
disorders 
 
 
 
 
Interstitial nephritis 
(with possible 
progression to renal 
failure) 
Reproductive 
system and 
breast 
disorders 
 
 
Gynaecomastia 
 
 
General 
disorders and 
administration 
site conditions 
Injection 
site 
thrombo-
phlebitis 
Asthenia, 
fatigue and 
malaise 
Body 
temperature 
increased; 
Oedema 
peripheral 
 
 


 
174 
 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows 
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked 
to report any suspected adverse reactions.  
 
4.9 
Overdose 
 
There are no known symptoms of overdose in man.  
Systemic exposure with up to 240 mg administered intravenously over 2 minutes was well tolerated.  As 
pantoprazole is extensively protein bound, it is not readily dialysable.  
 
In case of overdose with clinical signs of intoxication, apart from symptomatic and supportive treatment, no 
specific therapeutic recommendations can be made. 
 
 
5. 
PHARMACOLOGICAL PROPERTIES 
 
5.1 
Pharmacodynamic properties 
 
Pharmacotherapeutic group: Proton pump inhibitors, ATC code: A02BC02. 
 
Mechanism of action 
Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the stomach 
by specific blockade of the proton pumps of the parietal cells.  
 
Pantoprazole is converted to its active form in the acidic environment in the parietal cells where it inhibits the 
H+/K+-ATPase enzyme i.e. the final stage in the production of hydrochloric acid in the stomach.  The 
inhibition is dose-dependent and affects both basal and stimulated acid secretion.  In most patients, freedom 
from symptoms is achieved within 2 weeks. As with other proton pump inhibitors and H2 receptor inhibitors, 
treatment with pantoprazole reduces acidity in the stomach and thereby increases gastrin in proportion to the 
reduction in acidity.  The increase in gastrin is reversible.  Since pantoprazole binds to the enzyme distal to 
the cell receptor level, it can inhibit hydrochloric acid secretion independently of stimulation by other 
substances (acetylcholine, histamine, gastrin). The effect is the same whether the product is given orally or 
intravenously. 
 
The fasting gastrin values increase under pantoprazole.  On short-term use, in most cases they do not 
exceed the upper limit of normal.  During long-term treatment, gastrin levels double in most cases.  An 
excessive increase, however, occurs only in isolated cases.  As a result, a mild to moderate increase in the 
number of specific endocrine (ECL) cells in the stomach is observed in a minority of cases during long-term 
treatment (simple to adenomatoid hyperplasia).  However, according to the studies conducted so far, the 
formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids as were found in animal 
experiments (see section 5.3) have not been observed in humans.  
 
An influence of a long term treatment with pantoprazole exceeding one year cannot be completely ruled out 
on endocrine parameters of the thyroid according to results in animal studies.  
 
5.2 
Pharmacokinetic properties 
 
General Pharmacokinetics 
Pharmacokinetics do not vary after single or repeated administration. In the dose range of 10 to 80 mg the 
plasma kinetics of pantoprazole are linear after both oral and intravenous administration. 
 
Distribution 
Pantoprazole's plasma protein binding is about 98%. Volume of distribution is about 0.15 l/kg. 
 
Elimination 


 
175 
 
The substance is almost exclusively metabolised in the liver. The main metabolic pathway is demethylation 
by CYP2C19 with subsequent sulphate conjugation, other metabolic pathways include oxidation by CYP3A4.  
Terminal half-life is about 1 hour and clearance is about 0.1 l/h/kg.  There were few cases of subjects with 
delayed elimination.  Because of specific binding of pantoprazole to the proton pumps of the parietal cell the 
elimination half-life does not correlate with the much longer duration of action (inhibition of acid secretion). 
 
Renal elimination represents the major route of excretion (about 80%) for the metabolites of pantoprazole; 
the rest are excreted in the faeces. The main metabolite in both the serum and urine is 
desmethylpantoprazole which is conjugated with sulphate. The half-life of the main metabolite (about 1.5 
hours) is not much longer than that of pantoprazole.  
 
Characteristics in patients/special groups of subjects: 
Approximately 3% of the European population lack a functional CYP2C19 enzyme and are called poor 
metabolisers.  In these individuals the metabolism of pantoprazole is probably mainly catalysed by CYP3A4.  
After a single dose administration of 40 mg pantoprazole, the mean area under the plasma concentration-
time curve was approximately 6 times higher in poor metabolisers than in subjects having a functional 
CYP2C19 enzyme (extensive metabolisers).  Mean peak plasma concentrations were increased by about 
60%.  These findings have no implications for the posology of pantoprazole. 
 
No dose reduction is recommended when pantoprazole is administered to patients with impaired renal 
function (including dialysis patients). As with healthy subjects, pantoprazole's half-life is short. Only very 
small amounts of pantoprazole are dialysed. Although the main metabolite has a moderately delayed half-life 
(2-3 hours), excretion is still rapid and thus accumulation does not occur.  
Although for patients with liver cirrhosis (classes A and B according to Child) the half-life values increased to 
between 7 and 9 hours and the AUC values increased by a factor of 5 to 7, the maximum serum 
concentration only increased slightly by a factor of 1.5 compared with healthy subjects.  
 
A slight increase in AUC and Cmax in elderly volunteers compared with younger counterparts is also not 
clinically relevant. 
 
Paediatric population 
Following administration of single intravenous doses of 0.8 or 1.6 mg/kg pantoprazole to children aged 2 – 
16 years there was no significant association between pantoprazole clearance and age or weight. AUC and 
volume of distribution were in accordance with data from adults. 
 
5.3 
Preclinical safety data 
 
Preclinical data reveal no special hazard to humans based on conventional studies of safety pharmacology, 
repeated dose toxicity and genotoxicity. 
 
In the two-year carcinogenicity studies in rats neuroendocrine neoplasms were found.  In addition, squamous 
cell papillomas were found in the forestomach of rats. The mechanism leading to the formation of gastric 
carcinoids by substituted benzimidazoles has been carefully investigated and allows the conclusion that it is 
a secondary reaction to the massively elevated serum gastrin levels occurring in the rat during chronic high-
dose treatment. In the two-year rodent studies an increased number of liver tumours was observed in rats 
and in female mice and was interpreted as being due to pantoprazole's high metabolic rate in the liver.  
 
A slight increase of neoplastic changes of the thyroid was observed in the group of rats receiving the highest 
dose (200 mg/kg). The occurrence of these neoplasms is associated with the pantoprazole-induced changes 
in the breakdown of thyroxine in the rat liver. As the therapeutic dose in man is low, no harmful effects on the 
thyroid glands are expected.  
 
In animal reproduction studies, signs of slight fetotoxicity were observed at does above 5 mg/kg.  
Investigations revealed no evidence of impaired fertility or teratogenic effects.  
 
Penetration of the placenta was investigated in the rat and was found to increase with advanced gestation. 
As a result, concentration of pantoprazole in the foetus is increased shortly before birth.  
 


 
176 
 
 
6. 
PHARMACEUTICAL PARTICULARS 
 
6.1 
List of excipients 
 
Mannitol  
Sodium citrate dihydrate 
Sodium hydroxide (for pH adjustment) 
 
6.2 
Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in section 
6.6. 
 
6.3 
Shelf life 
 
As packaged for sale: 3 years 
 
After reconstitution, or reconstitution and dilution, chemical and physical in-use stability has been 
demonstrated for 12 hours at 25ºC. The reconstituted, or reconstituted and diluted medicinal product should 
not be refrigerated. 
From a microbiological point of view, the product should be used immediately. If not used immediately, in-
use storage times and conditions prior to use are the responsibility of the user. 
 
6.4 
Special precautions for storage 
 
Do not store above 25ºC. Keep the vial in the outer carton to protect from light.  
For storage conditions of the reconstituted and diluted medicinal product see section 6.3.  
 
6.5 
Nature and contents of container 
 
15 ml, type I, colourless glass vial, sealed with a grey chlorobutyl stopper and an aluminium flip-off cap, 
containing 40 mg pantoprazole powder for solution for injection.  
 
Pack sizes: 1, 5, 10 and 20 vials 
Not all pack sizes may be marketed. 
 
6.6 
Special precautions for disposal and other handling 
 
A ready-to-use intravenous solution is prepared by injecting 10 ml of sodium chloride 9 mg/ml (0.9%) 
solution for injection into the vial containing the lyophilised powder. The reconstituted solution should be 
clear and colourless. This solution may be administered directly or may be administered after mixing it with 
100 ml of sodium chloride 9 mg/ml (0.9%) solution for injection or glucose 50 mg/ml (5%) solution for 
injection. Glass or plastic containers should be used for dilution 
 
Pantoprazol “Actavis” 40 mg powder for solution for injection should not be prepared or mixed with solvents 
other than those stated.  
 
This medicine should be administered intravenously over 2- 15 minutes. 
 
The content of the vial is for single use only. Any product that has remained in the container or the visual 
appearance of which has changed (e.g. if cloudiness or precipitation is observed) should be disposed of in 
accordance with local requirements.


 
177 
 
Appendix 6. Adverse reactions not registered 
 
Thrombocytopenia will not be registered as a serious adverse reaction (SAR) since it is a frequent 
condition among critically ill patients and is a part of the inclusion criteria (coagulopathy).  
 
Increased plasma levels of bilirubin, (jaundice) and liver enzymes (hepatocellular injury) is not 
registered as they in themselves are not considered serious conditions. The potential serious 
consequence hepatic failure will be registered daily as a SAR.  
 
Hyponatremia, hypokalaemia, hypomagnesaemia and hypocalcaemia will not be registered as 
electrolyte disturbances as they are frequent among ICU patients. These conditions are monitored 
and treated daily in all ICU patients. According to the summary of product characteristics, 
hypomagnesaemia will not be relevant until treatment for at least three months and in most cases 
one year.     
   
Leukopenia will not be registered. Reduced white blood cell counts are frequent among ICU 
patients and can be associated with many different systemic or hematological disorders in critically 
ill patients.   
 
Renal and urinary disorders will not be registered as they are not considered serious conditions in 
themselves, but the potential serious consequence will be reflected in the outcome measure days 
alive without use of renal replacement therapy.  
 
The following possible adverse reactions will not be registered as SARs as they are not considered 
serious conditions:  
  
Hyperlipidaemia, lipid increases, weight changes, taste disorders 
Sleep disorders, depression, disorientation, hallucination, confusion, headache, dizziness 
Paraesthesia, blurred vision 
Nausea, vomiting, abdominal distension, constipation, dry mouth, abdominal pain and discomfort 
Rash, exanthema, pruritus, erythema multiforme, photosensitivity, urticarial, hypersensitivity  
Arthralgia, myalgia, asthenia, fatigue and malaise 
Reproductive system, breast disorders, gynecomastia 
Injection site thrombophlebitis 
Body temperature increased 


 
178 
 
Oedema peripheral 
Fracture of the hip, wrist or spine (treatment > 1 year) 
 
 
 


 
179 
 
Appendix 7. Informed consent, Denmark 
 
In Denmark temporarily incompetent patients will be enrolled after informed consent from two 
physicians, who are independent of the trial (trial guardians). As soon as possible after enrolment, 
consent will be obtained from the patient’s next of kin and general practitioner or the Regional 
Medical Officer of Health according to Danish law. Patients, who regain consciousness, will be 
asked for informed consent as soon as possible. The process leading to the achievement of 
informed consent will be in compliance with all applicable regulations. The consenting party will be 
provided with written and oral information about the trial so he/she is able to make an informed 
decision about participation in the trial. The information will be given in a separate room, and the 
consenting party has the right to bring a companion. 
Written information and the consent form will be subjected to review and approval by the relevant 
ethic committees.  
 
Lack of informed consent from the general practitioner 
If the general practitioner does not want to make up his/her mind about the patient’s participation in 
the trial, e.g. if he/she does not have the knowledge to make the decision or for any other reasons 
the patient will continue in the trial until informed consent can be obtained from the patient him-
/herself. If the general practitioner cannot be reached the Regional Medical Officer of Health will be 
contacted for consent. 
 
 
Lack of informed consent from the patient’s next of kin 
If it is not possible (i.e. contact cannot be obtained) - after obtaining informed consent from two 
independent physicians and from the patient’s general practitioner/the Regional Medical Officer of 
Health - to obtain informed consent from the patient’s next of kin, the patient will continue in the 
trial until informed consent can be obtained from the patient him-/herself.  
  
Lack of informed consent from the patient’s next of kin and the patient deceases  
If it is not possible (i.e. contact cannot be obtained) - after obtaining informed consent from two 
independent physicians and from the patient’s general practitioner/the Regional Medical Officer of 
Health - to obtain informed consent from the patient’s next of kin, the patient will continue in the 
trial until informed consent can be obtained from the patient him-/herself. If the patient deceases 
before informed consent is obtained, or remains in a permanent state of incompetence, the 
collected data will be kept and trial outcomes will be collected centrally.  
 


 
180 
 
Deviation from the standard informed consent 
According to the standard informed consent form from the National Ethics Committee regarding 
competent patients, the patient can choose not to receive information about the data collected 
during the trial. However, the purpose of this trial is not to generate new knowledge about the 
specific patient, so we find that this question is redundant, and have omitted the question from the 
consent form to spare the patient from making unnecessary decisions.  
 
 
 
 


 
181 
 
Appendix 7.1 Informed consent, Denmark (Amendment 1): 
 
Amendment to the previously approved protocol entitled ‘Stress ulcer prophylaxis with 
proton pump inhibitor (pantoprazole) in adult critically ill patients in the intensive care unit: 
A randomised, blinded, placebo-controlled trial’, version 3.0, October 20th 2015 
 
This amendment replaces Appendix 7 in the above mentioned protocol.  
 
In Denmark temporarily incompetent patients will be enrolled after informed consent from one 
physician, who is independent of the trial (trial guardians). As soon as possible after enrolment, 
consent will be obtained from the patient’s next of kin. Patients, who regain consciousness, will be 
asked for informed consent as soon as possible. The process leading to the achievement of 
informed consent will be in compliance with all applicable regulations. The consenting party will be 
provided with written and oral information about the trial so he/she is able to make an informed 
decision about participation in the trial. The information will be given in a separate room, and the 
consenting party has the right to bring a companion. 
Written information and the consent form will be subjected to review and approval by the relevant 
ethic committees.  
 
Lack of informed consent from the patient’s next of kin 
If information about the patient’s next of kin is not available after inclusion the investigator will seek 
information from e.g. the patient’s general practitioner, the police, nursing homes etc. In these 
situations it may take 1-2 weeks to conclude that no next of kin can be identified. If no one is 
identified and the patient remains incompetent the trial intervention will be discontinued. All 
initiatives to identify the patient’s next of kin will be documented in patient files, logs or similar.  
 
Lack of informed consent from the patient’s next of kin and the patient deceases  
If the patient deceases before informed consent has been obtained (due to rapid progression of 
critical illness or because the patient’s next of kin is not yet identified) and the patients has been 
correctly included in the trial, collected data will be kept for analysis.   
 
Deviation from the standard informed consent 
According to the standard informed consent form from the National Ethics Committee regarding 
competent patients, the patient can choose not to receive information about the data collected 
during the trial. However, the purpose of this trial is not to generate new knowledge about the 


 
182 
 
specific patient, so we find that this question is redundant, and have omitted the question from the 
consent form to spare the patient from making unnecessary decisions.  
 
 
 


 
183 
 
Appendix 7.2 Informed consent, Denmark (Amendment 2): 
 
Amendment to the previously approved protocol entitled ‘Stress ulcer prophylaxis with 
proton pump inhibitor (pantoprazole) in adult critically ill patients in the intensive care unit: 
A randomised, blinded, placebo-controlled trial’, version 3.0, October 20th 2015 
 
This amendment replaces amendment 7.1 to the above mentioned protocol.  
 
In Denmark temporarily incompetent patients will be enrolled after informed consent from one 
physician, who is independent of the trial (first trial guardian). As soon as possible after enrolment, 
consent will be obtained from the patient’s next of kin and a second physician (second trial 
guardian). The second trial guardian must be different from the first trial guardian, but also 
independent of the trial. Patients, who regain consciousness, will be asked for informed consent as 
soon as possible. The process leading to the achievement of informed consent will be in 
compliance with all applicable regulations. The consenting party will be provided with written and 
oral information about the trial so he/she is able to make an informed decision about participation 
in the trial. The information will be given in a separate room, and the consenting party has the right 
to bring a companion. 
Written information and the consent form will be subjected to review and approval by the relevant 
ethic committees.  
 
Lack of informed consent from the patient’s next of kin 
If information about the patient’s next of kin is not available after inclusion the investigator will seek 
information from e.g. the patient’s general practitioner, the police, nursing homes etc. In these 
situations it may take 1-2 weeks to conclude that no next of kin can be identified. If no one is 
identified and the patient remains incompetent the trial intervention will be discontinued. All 
initiatives to identify the patient’s next of kin will be documented in patient files, logs or similar.  
 
Lack of informed consent from the patient’s next of kin and the patient deceases  
If the patient deceases before informed consent has been obtained (due to rapid progression of 
critical illness or because the patient’s next of kin is not yet identified) and the patient has been 
correctly included in the trial, collected data will be kept for analysis.   
 
Deviation from the standard informed consent 
According to the standard informed consent form from the National Ethics Committee regarding 
competent patients, the patient can choose not to receive information about the data collected 


 
184 
 
during the trial. However, the purpose of this trial is not to generate new knowledge about the 
specific patient, so we find that this question is redundant, and have omitted the question from the 
consent form to spare the patient from making unnecessary decisions.  
 


 
185 
 
 
 
 
 
Appendix 8. Timeline 


 
186 
 
Appendix 9. SAPS II scoring sheet [74] 
 
Part 1 
 
Variable 
Points: 
26 
13 
12 
11 
9 
7 
6 
5 
4 
3 
2 
0 
Age 
 
 
 
 
 
 
 
 
 
 
 
 
< 40 
Heart rate 
 
 
 
 
< 40 
 
 
 
 
 
 
40-69 
70-119 
Systolic blood pressure mmHg 
 
 
< 70 
 
 
 
 
 
70-99 
 
 
 
100-199 
Body temperature  
°C 
°F 
 
 
 
 
 
 
 
 
 
 
 
 
 
< 39 
<102.2 
Only if ventilated 
PaO2 mmHg/FiO2 
PaO2 kPa/FiO2 
 
 
 
 
 
< 100 
<13.3 
 
100-199 
13.3-26.5 
 
 
≥200 
≥26.6 
 
 
 
 
 
Urinary output ml/day 
 
 
 
 
<500 
 
 
 
 
500-999 
 
 
> 1000  
Serum urea level 
mmol/l 
(g/dl) 
 
 
 
 
 
 
 
 
 
 
 
 
 
< 10.0  
(< 0.6)  
WBC 
109/l 
 
 
 
<1.0 
 
 
 
 
 
 
 
 
1.0-19.9 
Serum potassium 
mmol/l 
 
 
 
 
 
 
 
 
 
 
<3.0 
 
3.0-4.9 
Serum sodium mmol/l 
 
 
 
 
 
 
 
 
<125 
 
 
 
125-144 
Serum bicarbonate mEq/l 
 
 
 
 
 
 
 
 
<15 
 
15-19 
 
≥20 
Bilirubin  
umol/l  
(mg/dl) 
 
 
 
 
 
 
 
 
 
 
 
 
 
< 68.4 
(<4.0) 
Glascow coma scale score 
<6 
6-8 
 
 
 
 
9-10 
 
11-13 
 
 
 
14-15 
Chronic disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
Type of admission 
 
 
 
 
 
 
 
 
 
 
 
 
Scheduled surgical 
 
 
 
 
 
 


 
187 
 
Part 2 
 
Variable 
1 
2 
3 
4 
6 
7 
8 
9 
10 
12 
15 
16 
17 
18 
Age 
 
 
 
 
 
40-59 
 
 
 
60-
69 
70-
74 
75-
79 
 
≥80 
Heart rate 
 
 
 
120-159 
 
≥160 
 
 
 
 
 
 
 
 
Systolic blood 
pressure mmHg 
 
≥200 
 
 
 
 
 
 
 
 
 
 
 
 
Body temperature  
°C 
°F 
 
 
 
≥39.0 
≥102.2 
 
 
 
 
 
 
 
 
 
 
 
Only if ventilated 
PaO2 mmHg/FiO2 
PaO2 kPa/FiO2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinary output 
ml/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum urea level 
mmol/l 
(g/dl) 
 
 
 
 
 
10.0-29.9 
0.60-1.79 
 
 
 
 
≥30.0 
≥1.80 
 
 
 
 
 
WBC 
109/l 
 
 
≥20.0 
 
 
 
 
 
 
 
 
 
 
 
Serum potassium 
mmol/l 
 
 
≥5.0 
 
 
 
 
 
 
 
 
 
 
 
Serum sodium 
mmol/l 
≥145 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum bicarbonate 
mEq/l 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin  
umol/l  
 
(mg/dl) 
 
 
 
 
68.4-
102.5 
(4.0-
5.9) 
 
 
 
 
≥102.6 
(≥6.0) 
 
 
 
 
 
 
GCS score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chronic disease 
 
 
 
 
 
 
 
Metastatic 
cancer 
Hematologic 
malignancy 
 
 
 
AIDS 
 
Type of admission 
 
 
 
 
Medical 
 
Unsceduled 
surgical  
 
 
 
 
 
 
 
Sum of points 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
188 
 
Appendix 10. SOFA score [75] 
 
 
0 
1 
2 
3 
4 
Respiraiton 
PaO2/FiO2 
   (mmHg) 
     
   (KPa) 
 
 
≥ 400 
 
≥ 53 
 
 
< 400 
 
< 53 
 
 
< 300* 
 
< 40* 
 
 
< 200† 
 
< 27†  
 
 
< 100† 
 
< 13†  
Coagulation 
Platelets  (x 103/mm3) 
 
≥ 150 
 
101-150 
 
51-100 
 
21-50 
  
≤ 20 
Liver 
Bilirubin   
   (mg/dl)  
   (umol/l) 
 
 
< 1.2 
< 20 
 
 
1.2-1.9 
20-32 
 
 
2.0-5.9 
33-101 
 
 
6.0-11.9 
102-204 
 
 
> 12.0 
> 204 
Cardiovascular 
Hypotension* 
   (MAP) 
 
 
 ≥ 70 
 
 
< 70 
 
Dopamine  ≤ 5☼ OR 
Dobutamine (any dose) OR 
Milrirone (any dose) OR 
Levosimendan (any dose) OR  
 
Dopamine ≥ 5☼ OR 
Norepinephrine  ≤ 0.1☼ OR 
Adrenaline ≤ 0.1☼ OR 
Vasopression (any dose) OR 
Phenylephrine (any dose) OR 
 
Dopamine > 15☼ OR 
Norepinephrine > 0.1☼ OR 
Adrenaline > 0.1☼ 
 
CNS 
Glascow coma scale score 
 
15 
 
13-14 
 
10-12 
 
6-9 
 
< 6 
Renal 
Creatinine  
   (mg/dl) 
   (umol/l) 
 OR 
Urine output 
 
 
< 1.2 
< 110 
 
 
 
1.2-1.9 
110-170 
 
 
2.0-5.9 
171-299 
 
 
6.0-11.9 
300-440 
 
<500 ml/day 
 
 
>12.0 
>440 
 
<200 ml/day 
* without respiratory support 
† with respiratory support 
☼Adrenergic agents administered for at least one hour (doses given are in ug/kg/min). 
 
 


 
189 
 
Appendix 11. Power estimation 
 
All power estimations have been calculated on data from the international SUP-ICU 7-day 
inception cohort study[57].  
Since we do not know whether treatment with acid suppressants reduce or increase mortality, a 
number of scenarios have been considered (+/- 20 relative risk reduction):  
 
1) 25.0% mortality 90 days after inclusion among patients with: 
At least one risk factor* 
No acid suppressants at ICU admission 
Treatment with acid suppressants during ICU admission 
No clinically important bleeding** during ICU admission 
 
Power estimations: 
 
 
We do not know whether PPI benefits or harms the patients, and need to include both scenarios.  
With 1671 patients in each group we will be able to show an absolute increase in risk of 5% with 
90% power at the primary outcome, but also an absolute risk reduction of 5% with 90% power. 
The sample size has been calculated on patients fulfilling inclusion and exclusion criteria in the 
SUP-ICU trial and because few patients were not treated with acid suppressants during ICU 
admission, the estimation is based on the group receiving acid suppressants (intervention group) 
 
2) 25.9% mortality 90 days after inclusion among patients with: 
At least one risk factor* 
No acid suppressants at ICU admission 
Treatment with acid suppressants during ICU admission 
Bleeding (overt or clinically important**) or no bleeding during ICU admission 
 
 
 
ARR 
Power Patients per group 
- 5% 
80% 
1091 
90% 
1461 
+ 5% 
80% 
1248 
90% 
1671 


 
190 
 
Power estimations: 
ARR 
Power Patients per group 
- 5,2% 
80% 
1034 
90% 
1384 
+5,2% 
80% 
1180 
90% 
1579 
 
3) 29.2% mortality 90 days after inclusion among patients with: 
At least one risk factor* 
Acid suppressants and no acid suppressants at ICU admission 
Treatment with acid suppressants during ICU admission 
No bleeding (overt or clinically important**) during ICU admission 
 
Power estimations: 
ARR 
Power Patients per group 
- 5,8% 
80% 
901 
90% 
1206 
+5,8% 
80% 
1014 
90% 
1357 
 
4) 30.5% mortality 90 days after inclusion among patients with: 
At least one risk factor* 
Acid suppressants or no acid suppressants at ICU admission 
Treatment with acid suppressants during ICU admission 
Bleeding (overt or clinically important**) or no bleeding during ICU admission 
 
Power estimations: 
ARR 
Power Patients per group 
- 6,1% 
80% 
837 
90% 
1120 
+6,1% 
80% 
937 
90% 
1254 
 
*Risk factors are: shock, renal replacement therapy, coagulopathy and coagulopathy and liver 
disease as comorbidities) 


 
191 
 
 
** Overt bleeding is defined as any episode of hematemesis, coffee ground emesis, melena, 
hematochezia or bloody nasogastric aspirate in the ICU.  
 
Clinically significant bleeding is defined as overt bleeding and at least one of the following four 
features within 24 hours of GI bleeding (in the absence of other causes) [1, 5, 10] in the ICU 
e. spontaneous drop of systolic blood pressure, mean arterial pressure or diastolic 
blood pressure of 20 mmHg or more 
f. start of vasopressor or a 20% increase in vasopressor dose 
g. decrease in haemoglobin of at least 2 g/dl (1.24 mmol/l)  
h. transfusion of 2 units of packed red blood cells or more 
 
 


 
192 
 
Appendix 12. Trial sequential analysis of all-cause mortality (16 trials).  
A diversity adjusted information size of 4,675 patients was calculated using α=0.05 (two sided), β=0.10 (power 90%), an anticipated diversity at the time when conclusive 
evidence has been reached (D2=20%), an anticipated relative risk reduction of 20%, and an event proportion of 21% in the placebo/control arm. The blue cumulative z 
curve was constructed using a random effects model. The pooled effect is a RR=0.98 with a TSA adjusted 95% confidence interval of (0.75 to 1.28) 


 
193 
 
Appendix 13. International Committee of Medical Journal Editors (ICMJE) form for potential 
conflicts of interest.  
 
 
  
 
 


 
194 
 
 
 
 


 
195 
 
 
 
 


 
196 
 
Summary of changes to the original protocol  
 
 
Amendments to the previously approved protocol entitled ‘Stress ulcer prophylaxis with 
proton pump inhibitor (pantoprazole) in adult critically ill patients in the intensive care unit: 
A randomised, blinded, placebo-controlled trial’, version 3.0, October 20th, 2015. 
 
Amendment 1 (August 2016) 
Appendix 7.1 Informed consent, Denmark  
This amendment replaces Appendix 7 in the above-mentioned protocol. 
Description: New legislation on informed consent in Denmark.  
 
Amendment 2 (December 2016) 
Appendix 7.2 Informed consent, Denmark  
This amendment replaces Appendix 7.1 in the above-mentioned protocol.  
Description: New legislation on informed consent in Denmark. 
 
Amendment 3 (June 2017) 
Appendix 3.1 Charter for the independent Data Monitoring and Safety Committee (DMSC) 
This amendment replaces Appendix 3 in the above-mentioned protocol.  
Description: Cancelation of the second interim analysis (2500/3350 included patients).  
Due to the inclusion rate the SUP-ICU trial Steering Committee, in full agreement with the 
DMSC, has decided to cancel the second interim analysis as the results (incl. 90-day 
follow-up) would be available only after the inclusion of the last trial patient. 
The statement paper from the DMSC following the first interim analysis (1675/3350 
included patients) supports this decision. The decision has been approved by relevant 
Danish authorities. 
 
 


 
197 
 
Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial: detailed 
statistical analysis plan 
 
Comprehensive details of the SUP-ICU trial has been published elsewhere.1 This statistical 
analysis plan was prepared before randomisation of patients and data collection in the SUP-ICU 
trial was completed. The analysis plan was approved by the SUP-ICU Steering Committee on 
September 22, 2016. Analysis of data for the primary publication will be conducted according to 
this plan.  
 
Randomisation 
Thirty-one sites in Denmark, Finland, the Netherlands, Switzerland and Norway are currently 
screening and randomising patients in the SUP-ICU trial. Some additional, 5-10 ICUs from the 
United Kingdom, Italy and Denmark are expected to participate.  Copenhagen Trial Unit (CTU)21 is 
responsible for centralised and web-based 1:1 randomisation according to a computer-generated 
allocation sequence list, with two stratification variables (site and active hematologic cancer), and 
varying block size.  
 
Blinding 
The allocated trial medication will be masked to clinical staff caring for the patient, to the patient, 
investigators and outcome assessors. The statistical analysis of the trial will be blinded with the 
intervention groups coded as, e.g., X and Y. Based on this blinded analysis two conclusions will be 
drawn: one assuming X is the experimental group and Y is the control group, and another 
assuming the opposite. Two abstracts will be written and accepted by the SUP-ICU Steering 
Committee. After this, the intervention groups will be unmasked. 
 
Sample size 
Because of the widespread use of SUP, no reliable control group for sample size estimation is 
available and producing reliable sample size estimations according to anticipated effects on GI 
bleeding is difficult.1 As a consequence it has been necessary to calculate sample size estimations 
given that something may change if we withhold PPI until GI bleeding actually happens. Assuming 
a baseline 90-day mortality of 25%,2 α=0.05 (two-sided), and β=0.1, 3350 patients (2 x 1675) will 
be needed to show a 20% relative risk reduction (RRR) or increase (RRI) corresponding to a 5% 
absolute risk reduction or increase in the primary outcome measure. Trial Sequential Analysis22,23 
of existing trials (n=16) has showed that 35% (1584 patients) of the required information size to 


 
198 
 
detect or reject a 20% RRR or RRI corresponding to 4575 patients has been accrued.8 
Consequently, there is at least an information gap of around 3000 patients taking a 20% RRR in 
mortality as a clinically relevant effect size.  
 
Outcome measures 
Primary outcome 
The primary outcome measure is all-cause mortality within 90 days after randomisation.  
 
Secondary outcomes  
1. Proportion of patients with one or more episodes of clinically important GI bleeding, 
pneumonia, Clostridium difficile infection or myocardial ischemia. The events are defined in 
appendix 1 
2. Proportion of patients with one or more episodes of clinically important GI bleeding 
3. Proportion of patients with one or more infectious adverse events (pneumonia or 
Clostridium difficile infections) 
4. All-cause mortality within 1 year after randomisation  
5. Percentage of days alive without use of life support (mechanical ventilation, circulatory 
support or renal replacement therapy) in the 90-day period 
6. The number of patients with one or more serious adverse reactions (SARs) (defined in 
appendix 2) 
7. A health economic analysis will be performed. The analytic details will be based on the 
result of the trial and specified prior to the analysis. 
 
Pre-planned subgroup analyses 
The primary outcome measure will be compared in the following pre-specified subgroups 
(definitions provided in appendix 2) 
1. Shock at randomisation (y/n) (a hypothesised increased intervention effect in patients with 
shock at randomisation) 
2. Mechanical ventilation at randomisation (y/n) (a hypothesised increased intervention effect 
in patients mechanically ventilated at randomisation) 
3. Coagulopathy at randomisation or history of coagulopathy (y/n) (a hypothesised increased 
intervention effect in patients with acute coagulopathy/history of coagulopathy at 
randomisation) 
4. History of liver disease (y/n) (a hypothesised increased intervention effect in patients with 
history of liver disease at randomisation) 


 
199 
 
5. Type of ICU admission (medical/surgical) (a hypothesised increased intervention effect in 
surgical patients) 
6. Simplified acute physiology score (SAPS) II > 53 points (y/n) (a hypothesised increased 
intervention effect in the patients with higher SAPS II at randomisation) 
 
Registered variables 
Baseline variables  
• 
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 mechanically 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 (prophylactic 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) 
• 
Sex 
• 
Age at randomisation/date of birth 
• 
Date of admission to hospital and date and time of admission to ICU 
• 
Elective or emergency surgery during current hospitalization (y/n) 
• 
Treatment of suspected or confirmed Clostridium difficile infection during current hospital 
admission (y/n)  
• 
Treatment with nonsteroidal anti-inflammatory drugs (NSAID) or acetylsalicylic acid at 
hospital admission (y/n) 
• 
Treatment with anticoagulants at hospital admission (prophylaxis not included) (y/n) 
• 
Intravenous thrombolysis within the previous 3 days (y/n) 
• 
Co-morbidities (defined in appendix 1): 
• 
history of chronic lung disease  
• 
history of myocardial ischemia 
• 
history of severe chronic heart failure (NYHA 3-4) 
• 
history of chronic renal failure in the last year prior to hospital admission 


 
200 
 
• 
treatment with at least 0.3 mg/kg/day of prednisolone equivalent for at least one 
month in the 6 month prior to ICU admission 
• 
active hematologic cancer: 
• 
metastatic carcinoma 
• 
acquired immune deficiency syndrome (AIDS) 
• 
Values for SAPS II and severity organ failure assessment (SOFA) scoring 24 hours prior to 
randomisation. 
Daily during ICU admission 
• 
Delivery of trial medication (y/n) 
• 
Open label treatment with PPI/histamine-2-receptor antagonists (y/n) 
• 
Invasive or non-invasive mechanical ventilation (y/n) 
• 
Circulatory support (infusion of vasopressor/inotropes) (y/n) 
• 
Any form of renal replacement therapy (y/n) 
• 
Onset of pneumonia on this day (y/n) 
• 
Treatment with antibiotics (enteral vancomycin, intravenous or enteral metronidazole, or 
enteral fidaxomicin) for suspected or proven Clostridium difficile infection on this day (y/n) 
• 
Acute myocardial ischemia on this day (y/n) 
• 
Enteral feeding on this day (y/n) 
• 
Number of units of red blood cells transfused 
• 
Overt GI bleeding episodes (hematemesis, coffee ground emesis, melena, haematochezia 
or bloody nasogastric aspirate) (y/n) 
• 
Serious adverse reactions (SARs) (y/n) (appendix 2) 
Bleeding form (only for patients with overt bleeding) 
• 
Data on clinically important GI bleeding:  
• 
A spontaneous drop of systolic blood pressure, mean arterial pressure or diastolic 
blood pressure of 20 mmHg or more 
• 
start of vasopressor or a 20% increase in vasopressor dose 
• 
decrease in haemoglobin of at least 2 g/dl (1.24 mmol/l)  
• 
transfusion of 2 units of packed red blood cells or more 
• 
Origin of GI bleeding confirmed (y/n) 
• 
Verification of ulcer/gastritis/esophageal varices (y/n) 
• 
Haemostasis achieved/attempted by endoscopy/open surgery/coiling (y/n) 
Follow-up 90 days and 1 year after randomisation 
• 
Death (y/n, if yes, date of death) 
 


 
201 
 
Missing data 
If more than 5% of the observations are missing for any specific analysis that analysis will be 
conducted both as complete-case and using multiple-imputation based on chained equations. All 
variables in the specific analysis will be included in the multiple imputation as well as stratification 
variables (site and presence of haematological cancer), age, SOFA score at baseline, type of 
admission (medical, elective surgery or emergency surgery), SAPS II at baseline, renal 
replacement therapy at baseline, mechanical ventilation at baseline, shock at baseline, proportion 
of patients with clinically important GI bleeding, proportion of patients with one or more episodes of 
serious adverse events (pneumonia, Clostridium difficile infection and myocardial ischemia), and 
90-day mortality.  
 
If multiple imputation is used, the primary result of the trial will be based on these data. A ‘best-
worst, worst-best case’ scenario will be used as a sensitivity analysis to assess the potential 
impact of any pattern of missingness including that the data are missing not at random (MNAR 
criterion) for the trial results. In the ‘best-worst-case’ scenario it is assumed that all patients lost to 
follow-up in the experimental group have had a beneficial outcome (e.g. have survived) and all 
those with missing outcomes in the control group have had a harmful outcome (e.g. have not 
survived). Conversely, in the ‘worst-best-case’ scenario, it is assumed that all patients who were 
lost to follow up in the experimental group have had a harmful outcome; and that all those lost to 
follow-up in the control group have had a beneficial outcome.  
The unadjusted, non-imputed analysis will also be presented. 
 
General analytic principles 
1. All main analyses will compare the two intervention groups in the intention-to-treat (ITT) 
population.24–26  
The ITT population will be all patients randomised except: 
• 
patients withdrawing consent for the use of data 
• 
patients who were  erroneously randomised AND who did not receive the trial 
intervention.27 
 
The conclusion of the trial will be based on the ITT analysis 
2. In all analyses, a maximum level of 5% (two-sided) type 1 error will be regarded as 
statistically significant  
3. Test-of-interaction will be applied for all subgroup analyses (logistic regression) 


 
202 
 
Statistical analyses 
Trial profile 
The flow of trial participants will be displayed in a Consolidated Standards of Reporting Trials 
(CONSORT) diagram. The number of participants fulfilling the inclusion criteria, the number of 
excluded participants and reasons for exclusion, and the number of participants included in the 
final analyses will be presented. 
 
Primary outcome measure 
The primary analysis will be a logistic regression analysis adjusted for stratification variables (site 
and presence of haematological cancer, y/n) of the ITT population. Results will be presented as 
odds ratios and relative risk ratios (relative risk ratios computed from odds ratios with covariates 
set to mean values for numeric covariates and the largest group for categorical).  
The secondary analysis will be a multiple logistic regression analysis of the ITT population adjusted 
for stratification variables and additionally differences in potential confounders: age, SOFA score at 
baseline, and type of admission (medical, elective surgery or emergency surgery). Intervention 
group and the stratification variable haematological cancer are regarded as fixed effects and trial 
site is regarded as random effects in the model. Furthermore, frequencies and percentages per 
group will be reported and an unadjusted Chi-square test for differences in the primary outcome 
will be provided. 
 
Pre-defined subgroup analyses (see former section) of the ITT population will be conducted using 
logistic regression analysis adjusted for stratification variables.  
A sensitivity analysis of the primary outcome measure including the per-protocol population will be 
conducted. The per-protocol population will be all randomised patients except those having one or 
more protocol violations defined as: 
• 
Patients who did not receive the allocated trial intervention at all 
• 
Patients who did not receive the trial intervention for at least two days in a row 
• 
Patients who received treatment (open label) with PPI or histamine-2-receptor 
antagonists except for those receiving it according to the protocol (i.e. occurrence of 
GI bleeding after randomisation). 
• 
Patients who withdrew from trial intervention, but consented to the use of data 
• 
Monitoring revealed that one or more in- or exclusion criteria were violated 
 
Secondary outcome measures  


 
203 
 
The secondary outcomes will only be analysed in the ITT population. The primary analysis of the 
binary secondary outcome measures will be a logistic regression analysis adjusted for the 
stratification variables (site and presence of haematological cancer). Results will be presented as 
odds ratios and relative risk ratios. 
 
Furthermore, frequencies and percentages per group will be reported and an unadjusted Chi-
square test for differences in the primary outcome will be provided. 
  
The primary analysis of rate data (‘Percentage of days alive without life support in the 90-day 
period’) will be a generalized linear model (initially Poisson distribution, alternatively negative 
binomial).28 If the assumptions for Poisson distribution or negative binomial distribution are not met, 
data will be analysed using the non-parametric Van Elteren test adjusted for site, but no other 
variables.29  
 
The secondary analysis of binary secondary outcomes will be a multiple logistic regression 
analysis additionally adjusted for differences in potential confounders: age, SOFA score at 
baseline, and type of admission (medical, elective surgery or emergency surgery).  
 
Interim analysis   
The Data Monitoring and Safety Committee (DMSC) will perform two formal interim analyses when 
90-day follow-up data of 1650 (approximately 50% of sample size estimation) and 2500 
(approximately 75% of sample size estimation) patients have been obtained. For the two 
intervention groups, the DMSC will evaluate data on: 
 
The primary outcome measure 
Mortality 90 days after randomisation of each patient (“landmark mortality”). 
 
The secondary outcome measures 
• 
Proportion of patients with one or more of the following adverse events: clinically important 
GI bleeding, pneumonia, Clostridium difficile infection, or acute myocardial ischemia 
• 
Proportion of patients with clinically important GI bleeding 
• 
The occurrence of SARs in the ICU 
 
The DMSC will be provided with the following masked (as group 0 and 1) data from the 
coordinating centre as: 


 
204 
 
• 
Number of patients randomised 
• 
Number of patients randomised per intervention group 
• 
Number of patients stratified per stratification variable per intervention group 
• 
Number of events, according to the outcomes, in the two groups 
 
Based on evaluation of these outcomes, the DMSC will decide if they want further data from the 
coordinating centre and when to perform the next analysis of the data. Additionally, the DMSC will 
yearly be informed about SARs occurring in the two groups of the trial. The interim analyses will be 
performed by an independent statistician selected by the members of the DMSC. The DMSC can, 
at any time during the trial, request the distribution of events, including outcome measures and 
SARs according to intervention groups. Further, the DMSC can request unblinding of the 
interventions. The DMSC may recommend pausing or stopping the trial if group-difference in the 
primary outcome measure, SARs or Suspected Unexpected Serious Adverse Events (SUSARs) 
are found in the interim analyses with statistical significance levels adjusted according to the 
LanDeMets group sequential monitoring boundaries based on O’Brien Fleming alfa-spending 
function.30 If an analysis of the interim data from 1650 or 2500 patients fulfils the LanDeMets 
stopping criterion the inclusion of further patients will be paused and an analysis including patients 
randomised during the analysis period will be performed. If this second analysis also fulfils the 
LanDeMets stopping criterion according to the group sequential monitoring boundaries the 
Steering Committee may stop the trial.26 Furthermore, the DMSC can recommend pausing or 
stopping the trial if continued conduct of the trial clearly compromises participant safety. However, 
stopping for futility to show an intervention effect of 15% RRR or RRI will not occur, as intervention 
effects less than 15% RRR or RRI in all-cause mortality may be clinically relevant as well.    
 
Ethical approval and Consent to participate 
The SUP-ICU trial has been registered on www.clinicaltrials.gov (NCT02467621), the trial is 
approved by the Danish Health and Medicine Agency (2015030166), the Committees on Health 
Research Ethics in the Capital Region of Denmark (H-15003141) and by the Danish Data 
Protection Agency (RH-2015-3203695). 
Additionally, the trial is approved by the following ethical committees:  
Norway: Regionale Komiteer for Medisinsk og Helsefaglig Forskningsetikk (2015/1490/REK vest) 
Finland:  Tutkimuseettinen toimikunta (372/2015) 
The Netherlands: Medisch Ethische Toetsingscommissie (M15.182376) 
Switzerland: Kantonale Ethikkommission Bern (205/15) 


 
205 
 
Consent will be obtained according to national law. The consenting party will be provided with 
written and oral information about the trial, so he/she is able to make an informed decision about 
participation in the trial. Written information and the consent form will be subjected to review and 
approval by the ethical committee system according to national law in all participating countries. 
The consenting party can at any time, without further explanation, withdraw consent. 
 
Data sharing statement 
The final dataset used for analysis will be shared through an open access data repository 
 
 
 


 
206 
 
LIST OF ABBREVIATIONS 
AIDS 
Acquired immune deficiency syndrome 
CONSORT Consolidated Standards of Reporting Trials 
CTU 
Copenhagen Trial Unit 
DASAIM 
Danish Society of Anaesthesiology and Intensive Care Medicine 
DMSC 
Data Monitoring and Safety Committee 
GI 
Gastrointestinal 
ICU 
Intensive care unit 
INR 
International normalized ratio 
 
ITT 
Intention-to-treat 
NSAID 
Nonsteroidal anti-inflammatory drugs 
PPI 
Proton pump inhibitor 
PT 
Prothrombin time 
RRI 
Relative risk increase 
RRR 
Relative risk reduction 
SAPS 
Simplified acute physiology score 
SAR 
Serious adverse reaction 
SOFA 
Severity organ failure assessment 
SSAI 
Scandinavian Society of Anaesthesia and Intensive Care Medicine 
SUP 
Stress ulcer prophylaxis  
SUSAR 
Severe unexpected serious adverse reaction 
 
 
 
 


 
207 
 
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