Clinical Trial Results:
Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU)
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Summary
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EudraCT number |
2015-000318-24 |
Trial protocol |
DK FI NO NL |
Global end of trial date |
22 Oct 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
02 May 2019
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First version publication date |
02 May 2019
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Other versions |
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Summary report(s) |
main results and paper |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
RH-ITA-006
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02467621 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Dept. of Intensive Care 4131, Copenhagen University Hospital Rigshospitalet
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Sponsor organisation address |
Blegdamsvej 9, Copenhagen, Denmark, DK-2100
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Public contact |
Ass. prof. Morten Hylander Møller, Dept. of Intensive Care 4131, Copenhagen University Hospital Rigshospitalet, 0045 35458685, mortenhylander@gmail.com
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Scientific contact |
Ass. prof. Morten Hylander Møller, Dept. of Intensive Care 4131, Copenhagen University Hospital Rigshospitalet, 0045 35458685, mortenhylander@gmail.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
21 Mar 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
21 Jan 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
22 Oct 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess benefits and harms in the use of pantoprazole as stress ulcer prophylaxis in adult critically ill patients.
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Protection of trial subjects |
All trial subjects received the highest standard of care with high degree of monitoring.
Also, stress ulcer prophylaxis is an intervention abundantly used across the world.
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Background therapy |
All other treatments than the trial drug were at the discretion of the treating clinicians. | ||
Evidence for comparator |
Placebo-controlled trial. | ||
Actual start date of recruitment |
04 Jan 2016
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Efficacy, Safety | ||
Long term follow-up duration |
1 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 172
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Country: Number of subjects enrolled |
Norway: 197
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Country: Number of subjects enrolled |
Denmark: 2125
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Country: Number of subjects enrolled |
Finland: 258
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Country: Number of subjects enrolled |
Switzerland: 472
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Country: Number of subjects enrolled |
United Kingdom: 67
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Worldwide total number of subjects |
3291
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EEA total number of subjects |
2819
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
1389
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From 65 to 84 years |
1742
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85 years and over |
160
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Recruitment
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Recruitment details |
Recruitment was performed on schedule. | |||||||||
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Pre-assignment
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Screening details |
Adults (age ≥ 18 years) that were acutely admitted to the ICU and fulfilled one or more of our predefined risk factors for gastrointestinal bleeding were screened We screened 10.000 patients. 3.350 were randomised. 3291 were analysed (specified in published paper). | |||||||||
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Period 1
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Period 1 title |
Intervention period (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||
Blinding implementation details |
The following persons were blinded: participants, care providers, investigators, outcomes assessors and trial statistician.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Pantoprazole, PR1 | |||||||||
Arm description |
Pantoprazole 40 mg (daily intravenous injection) | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Pantoprazole, PR1
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Pantoprazole 40 mg milligram(s) administered intravenously once daily until ICU discharge (for a maximum of 90 days).
Preceding administration: 10 mL of isotonic sodium chloride 0.9% (normal saline) added to masked study vial containing pantoprazole powder for solution for injection.
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Arm title
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Placebo, PL1 | |||||||||
Arm description |
Placebo (daily intravenous injection) | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Placebo, PL1
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Placebo administered intravenously once daily until ICU discharge (for a maximum of 90 days).
Preceding administration: 10 mL of isotonic sodium chloride 0.9% (normal saline) added to masked empty study vial.
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Baseline characteristics reporting groups
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Reporting group title |
Pantoprazole, PR1
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Reporting group description |
Pantoprazole 40 mg (daily intravenous injection) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo, PL1
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Reporting group description |
Placebo (daily intravenous injection) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Pantoprazole, PR1
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Reporting group description |
Pantoprazole 40 mg (daily intravenous injection) | ||
Reporting group title |
Placebo, PL1
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Reporting group description |
Placebo (daily intravenous injection) | ||
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End point title |
90 days all-cause mortality | |||||||||
End point description |
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End point type |
Primary
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End point timeframe |
90 days from randomisation.
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Statistical analysis title |
Primary analysis | |||||||||
Statistical analysis description |
Analysis adjusted for the stratification variables: trial site and hematological malignancy.
9 patients were lost to 90-day mortality follow-up and were therefore not included in this analysis.
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Comparison groups |
Pantoprazole, PR1 v Placebo, PL1
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Number of subjects included in analysis |
3282
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | |||||||||
P-value |
= 0.76 | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
1.02
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.91 | |||||||||
upper limit |
1.13 | |||||||||
| Notes [1] - RR computed from OR |
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End point title |
Clinically important events | |||||||||
End point description |
Composite outcome consisting of the following elements:
- clinically important gastrointestinal bleeding
- new-onset pneumonia
- clostridium difficile infection
- myocardial ischemia
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End point type |
Secondary
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End point timeframe |
Randomisation until ICU discharge (within a maximum of 90 days from randomisation)
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Statistical analysis title |
primary analysis | |||||||||
Statistical analysis description |
Analysis adjusted for stratification variables: trial site and hematological malignancy
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Comparison groups |
Placebo, PL1 v Pantoprazole, PR1
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Number of subjects included in analysis |
3291
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Analysis specification |
Pre-specified
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Analysis type |
superiority [2] | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
0.96
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Confidence interval |
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95% | |||||||||
sides |
2-sided
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lower limit |
0.83 | |||||||||
upper limit |
1.11 | |||||||||
| Notes [2] - RR computed from OR P-value not presented for secondary outcomes because of the lack of adjustments for multiple comparisons |
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End point title |
Clinically important gastrointestinal bleeding | |||||||||
End point description |
Defined as overt gastrointestinal bleeding and at least one of the following four features within 24 hours of gastrointestinal bleeding, in the absence of other causes, in the ICU:
- a spontaneous decrease in systolic blood pressure, mean arterial pressure, or diastolic blood pressure of 20 mm Hg or more
- initiation of treatment with a vasopressor or a 20% increase in vasopressor dose
- a decrease in hemoglobin of at least 2 g per deciliter [1.24 mmol per liter]
- transfusion of two or more units of packed red cells
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End point type |
Secondary
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End point timeframe |
Randomisation until ICU discharge (within a maximum of 90 days from randomisation)
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Statistical analysis title |
primary analysis | |||||||||
Statistical analysis description |
Analysis adjusted for stratification variables: trial site and hematological malignancy
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Comparison groups |
Pantoprazole, PR1 v Placebo, PL1
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Number of subjects included in analysis |
3291
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
0.58
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.4 | |||||||||
upper limit |
0.86 | |||||||||
| Notes [3] - RR computed from OR P-value not presented for secondary outcomes because of the lack of adjustments for multiple comparisons |
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End point title |
Infectious adverse events | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Randomisation until ICU discharge (within a maximum of 90 days from randomisation)
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Statistical analysis title |
primary analysis | |||||||||
Statistical analysis description |
Analysis adjusted for the stratification variables: trial site and hematological malignancy
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Comparison groups |
Placebo, PL1 v Pantoprazole, PR1
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Number of subjects included in analysis |
3291
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Analysis specification |
Pre-specified
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Analysis type |
superiority [4] | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
0.99
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.84 | |||||||||
upper limit |
1.16 | |||||||||
| Notes [4] - RR computed from OR P-value not presented for secondary outcomes because of the lack of adjustments for multiple comparisons |
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End point title |
Serious adverse reactions | |||||||||
End point description |
Severe adverse reactions were defined as:
- anaphylactic reactions*
- agranulocytosis*
- pancytopenia*
- acute hepatic failure*
- the Stevens–Johnson syndrome*
- toxic epidermal necrolysis*
- interstitial nephritis*
- angioedema*
* related to the intervention (as judged by the treating clinicians and investigators)
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End point type |
Secondary
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End point timeframe |
Randomisation until ICU discharge (within a maximum of 90 days from randomisation)
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| No statistical analyses for this end point | ||||||||||
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End point title |
Days alive without the use of life support | ||||||||||||
End point description |
The percentage of days alive without the use of life support was calculated as the number of days without the use of invasive or noninvasive mechanical ventilation, infusion of vasopressor or inotropic agents, or any form of renal-replacement therapy, divided by the number of days alive within the 90-day follow-up period
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End point type |
Secondary
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End point timeframe |
90 days from randomisation
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Statistical analysis title |
primary analysis | ||||||||||||
Statistical analysis description |
Analysis adjusted for trial site
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Comparison groups |
Pantoprazole, PR1 v Placebo, PL1
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Number of subjects included in analysis |
3291
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Analysis specification |
Pre-specified
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Analysis type |
superiority [5] | ||||||||||||
P-value |
= 0.34 [6] | ||||||||||||
Method |
The van Elteren test | ||||||||||||
Confidence interval |
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| Notes [5] - P-value presented as no parameter estimates can be presented for this test. Please note: the p-value should be interpreted with caution due to lack of adjustments for multiple comparisons [6] - Please note: the p-value should be interpreted with caution due to lack of adjustments for multiple comparisons |
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Adverse events information [1]
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Timeframe for reporting adverse events |
During ICU stay (from randomisation until a maximum of 90 days from randomisation)
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Adverse event reporting additional description |
Serious adverse events were predefined outcome measures in the trial - please see the 'end points'-section of this report.
Full description available in the published paper.
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Assessment type |
Systematic | ||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||
Dictionary version |
1
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| Frequency threshold for reporting non-serious adverse events: 0% | |||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: SAEs were not recorded as one entity, because the majority of ICU patients will experience several SAEs during their critical illness. The most important SAEs were captured in specific trial outcome measures (incl. in this report - 'end points'-section) . Patient charts contain daily registrations of clinical data, which can be obtained on request from medical authorities. |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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01 Jun 2017 |
Cancellation of the second interim analysis (of 2.500/3.350 included patients).
Due to a high patient inclusion rate in the last part of the SUP-ICU trial, the trial Steering Committee, in full agreement with the
the Data Monitoring and Safety Committee (DMSC), decided to cancel the second interim analysis (of 2500/3350 included patients) as the results (incl. 90-day
follow-up of 2500 patients) would be available only after the inclusion of the last trial patient.
A statement paper from the DMSC following the first interim analysis (1675/3350 included patients) supports this decision. The decision was approved by relevant Danish authorities. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/30354950 http://www.ncbi.nlm.nih.gov/pubmed/27093939 http://www.ncbi.nlm.nih.gov/pubmed/28608496 |
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