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Trial registered on ANZCTR


Registration number
ACTRN12616000481471
Ethics application status
Approved
Date submitted
7/04/2016
Date registered
13/04/2016
Date last updated
30/08/2019
Date data sharing statement initially provided
30/08/2019
Date results information initially provided
30/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Proton Pump Inhibitors vs. Histamine-2 REceptor Blockers for Ulcer Prophylaxis Therapy in the Intensive Care Unit
Scientific title
A multi-centre, cluster randomised, crossover, registry trial comparing the safety and efficacy of proton pump inhibitors with histamine-2 receptor blockers for ulcer prophylaxis in intensive care patients requiring invasive mechanical intervention.
Secondary ID [1] 288888 0
None
Universal Trial Number (UTN)
U1111-1151-5142
Trial acronym
PEPTIC
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Critical illness 298190 0
Mechanical ventilation 298191 0
Ulcer prophylaxis 298192 0
Condition category
Condition code
Oral and Gastrointestinal 298352 298352 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Study treatment is open label Proton Pump Inhibitors (PPIs) vs. Histamine-2 Receptor Blockers (H2RBs) as the default routine therapy for ulcer prophylaxis. Each study ICU will use PPIs or H2RBs as routine therapy for a period of six months. At the end of this six month period, the ICU will then swap to the opposite routine ulcer prophylaxis strategy which will then be used for the next six months. The specific PPI or H2RB, dose, mode of administration and duration of study treatment will be the individual ICU clinician’s decision or until the patient is discharged from ICU (whichever is shorter). The PPI and H2RBs will be given as per routine medication (usually by the ICU nurse). Study treatment will only be administered in situations where the treating clinician believes ulcer prophylaxis is in the patient’s best interests and, irrespective of the treatment assigned to the ICU, either a PPI or an H2RB can be used for an individual patient, if the treating clinician believes that a particular treatment is indicated. Intervention adherence will not be checked for individual patients; however once a month, at a set time, stress ulcer prophylaxis use will be recorded for all mechanically ventilated patients.
Intervention code [1] 294345 0
Prevention
Intervention code [2] 294450 0
Treatment: Drugs
Comparator / control treatment
We are comparing PPIs with H2RBs. Both medications are considered standard treatment for ulcer prophylaxis in mechanically ventilated ICU patients, so neither is considered to be the control.
Control group
Active

Outcomes
Primary outcome [1] 297828 0
In-hospital mortality
Timepoint [1] 297828 0
Censoring of all study end points will apply at the time of hospital discharge following the index ICU admission or at 90 days (whichever is earlier).
Secondary outcome [1] 322349 0
Upper gastrointestinal bleeding (new clinically significant upper GI bleeding developing as a complication in ICU).
Clinically significant upper GI bleeding is defined as: overt GI bleeding (eg. haematemesis, malaena or frank blood in the nasogastric tube or upper GI endoscopy)
AND 1 or more of the following features within 24 hours of GI bleeding: 1) spontaneous drop of systolic, mean arterial pressure or diastolic blood pressure of 20 mmHg or more, 2) start of vasopressor or a 20% increase in vasopressor dose 3) decrease in haemoglobin of at least 20 g/L or 4) transfusion of 2 units of packed red blood cells or more).
Timepoint [1] 322349 0
Censored at 90 days
Secondary outcome [2] 322350 0
Clostridium difficile infection rates.
Clostridium difficile infections are defined as toxin-positive or culture-positive stool samples collected during an ICU admission (excluding any patients who had positive tests from specimens collected prior to ICU admission).
Timepoint [2] 322350 0
Censored at 90 days
Secondary outcome [3] 322351 0
Hours of mechanical ventilation (where available)
Timepoint [3] 322351 0
Index ICU admission
Secondary outcome [4] 322352 0
ICU length of stay, which will be obtained from the ANZICS APD.
Timepoint [4] 322352 0
Index ICU admission
Secondary outcome [5] 322353 0
Hospital length of stay, which will be obtained from the ANZICS APD.
Timepoint [5] 322353 0
Hospital length of stay for index ICU admission

Eligibility
Key inclusion criteria
All patients aged 18 years or older who are mechanically ventilated within 24 hours of ICU admission.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients who are admitted to ICU with upper GI bleeding (APACHE III admission diagnostic codes 303, 305, and 1403)

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
The primary data repository for this study is the ANZICS APD. This established registry identifies each individual patient by a unique number. This linkage between each number in the database and a particular patient is maintained by each participating hospital (i.e. data are classified as partially deidentified).
Phase
Phase 3 / Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Analyses will be conducted on an intention-to-treat basis. Analyses of the primary composite endpoint will involve cluster (ICU) summary measures obtained by aggregating the composite endpoint to a rate per ICU per time period and calculating the difference in event rates between the first and second periods for each ICU. These differences will then be entered as the dependent variable into an unweighted linear regression with randomised sequence as the independent variable, from which the coefficient of the randomised sequence is then the estimated PPI versus H2RB difference. Such analyses appropriately control for all clustering effects within ICU and common secular time trends across ICUs. Uncertainty concerning treatment effects will be estimated using standard 95% confidence intervals. For secondary outcomes on a binary scale the same methods will apply, and for outcomes on a continuous scale the linear mixed model methods of Turner et al will be applied. Sensitivity analyses will be performed for the impact of patients with missing outcome data using multiple imputation methods. Analyses will be performed using the Stata software package (StataCorp, Texas, USA).

With 50 ICUs and assuming a baseline mortality of 15% our study will have 80% power to detect a 2.4% absolute difference in in-hospital mortality at a 5%significance. This sample size is based on input parameters estimated from the ANZICS APD administrative data, with an average of 310 admissions per site in each 6 month study period with a variation of admissions of 0.50, and incorporates a within-cluster-within-period correlation of 0.035 and within-cluster-between-period correlation of 0.025.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,TAS,WA,VIC
Recruitment outside Australia
Country [1] 7759 0
New Zealand
State/province [1] 7759 0
Country [2] 7760 0
Ireland
State/province [2] 7760 0
Country [3] 9555 0
Canada
State/province [3] 9555 0
Alberta, Edmonton
Country [4] 9556 0
United Kingdom
State/province [4] 9556 0
England

Funding & Sponsors
Funding source category [1] 293242 0
Government body
Name [1] 293242 0
Health Research Council of NZ
Address [1] 293242 0
Level 3
110 Stanley St
Grafton
Auckland 1010
Country [1] 293242 0
New Zealand
Funding source category [2] 298592 0
Charities/Societies/Foundations
Name [2] 298592 0
Intensive Care Foundation
Address [2] 298592 0
Level 2, 10 Levers Terrace, Carlton, Victoria, Australia 3053
Country [2] 298592 0
Australia
Funding source category [3] 298593 0
Government body
Name [3] 298593 0
Irish Health Research Board
Address [3] 298593 0
Grattan House
67-72 Lower Mount Street
Dublin 2
D02 H638
Country [3] 298593 0
Ireland
Funding source category [4] 298594 0
Government body
Name [4] 298594 0
National Institute of Health Research
Address [4] 298594 0
Room 132
Richmond House
79 Whitehall
London
SW1A 2NS
Country [4] 298594 0
United Kingdom
Funding source category [5] 303690 0
Government body
Name [5] 303690 0
Canadian Institutes of Health Research
Address [5] 303690 0
160 Elgin Street, 9th Floor
Address Locator 4809A
Ottawa ON K1A 0W9
Canada
Country [5] 303690 0
Canada
Primary sponsor type
Other
Name
Medical Research Institute of New Zealand
Address
Private Bag 7902
Wellington 6242
Level 7, CSB Building
Wellington Hospital
Riddiford St, Newtown
Wellington 6021
New Zealand
Country
New Zealand
Secondary sponsor category [1] 292044 0
Hospital
Name [1] 292044 0
Austin Hospital
Address [1] 292044 0
145 Studley Rd,
Heidelberg,
VIC 3084,
Australia
Country [1] 292044 0
Australia
Secondary sponsor category [2] 297747 0
Hospital
Name [2] 297747 0
Alberta Health
Address [2] 297747 0
Seventh Street Plaza
14th Floor, North Tower
10030 – 107 Street NW
Edmonton, Alberta T5J 3E4
Country [2] 297747 0
Canada
Secondary sponsor category [3] 297748 0
Government body
Name [3] 297748 0
Intensive Care National Audit & Research Centre (ICNARC)
Address [3] 297748 0
Napier House
24 High Holborn
London
WC1V 6AZ
Country [3] 297748 0
United Kingdom
Other collaborator category [1] 279926 0
Government body
Name [1] 279926 0
Intensive Care National Audit & Research Centre (ICNARC)
Address [1] 279926 0
Napier House
24 High Holborn
London
WC1V 6AZ
Country [1] 279926 0
United Kingdom
Other collaborator category [2] 279927 0
Hospital
Name [2] 279927 0
Alberta Health Services
Address [2] 279927 0
Seventh Street Plaza
14th Floor, North Tower
10030 – 107 Street NW
Edmonton, Alberta T5J 3E4
Country [2] 279927 0
Canada
Other collaborator category [3] 279928 0
Government body
Name [3] 279928 0
Irish Health Research Board
Address [3] 279928 0
Grattan House
67-72 Lower Mount Street
Dublin 2
D02 H638
Country [3] 279928 0
Ireland
Other collaborator category [4] 279929 0
Hospital
Name [4] 279929 0
Austin Hospital
Address [4] 279929 0
145 Studley Rd, Heidelberg, VIC 3084, Australia
Country [4] 279929 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294720 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 294720 0
c/- Ministry of Health
Freyberg Building
Reception -Ground floor
20 Aitken Street
Wellington 6011
Ethics committee country [1] 294720 0
New Zealand
Date submitted for ethics approval [1] 294720 0
13/03/2015
Approval date [1] 294720 0
14/04/2015
Ethics approval number [1] 294720 0
15/NTB/52
Ethics committee name [2] 299553 0
Austin Health Human Research Ethics Committee
Ethics committee address [2] 299553 0
Austin Hospital
145 Studley Road
PO Box 5555
Heidelberg
Victoria
Australia 3084
Ethics committee country [2] 299553 0
Australia
Date submitted for ethics approval [2] 299553 0
23/04/2015
Approval date [2] 299553 0
19/11/2015
Ethics approval number [2] 299553 0
HREC/15/Austin/144
Ethics committee name [3] 299554 0
The University of Alberta Health Research Ethics Board
Ethics committee address [3] 299554 0
308 Campus Tower, University of Alberta, Edmonton, AB T6G 1K8
Ethics committee country [3] 299554 0
Canada
Date submitted for ethics approval [3] 299554 0
30/05/2017
Approval date [3] 299554 0
10/08/2017
Ethics approval number [3] 299554 0
Pro00074103
Ethics committee name [4] 299555 0
London-Bromley Research Ethics Committee
Ethics committee address [4] 299555 0
Level 3, Block B
Whitefriars
Lewins Mead
Bristol
BS1 2NT
Ethics committee country [4] 299555 0
United Kingdom
Date submitted for ethics approval [4] 299555 0
12/07/2017
Approval date [4] 299555 0
11/10/2017
Ethics approval number [4] 299555 0
17/LO/1313
Ethics committee name [5] 304215 0
St Vincent's Healthcare Group Research Ethics Committee
Ethics committee address [5] 304215 0
St Vincent's Hospital
Elm Park
Dublin 4
D04 T6F4
Ireland
Ethics committee country [5] 304215 0
Ireland
Date submitted for ethics approval [5] 304215 0
11/02/2015
Approval date [5] 304215 0
23/03/2015
Ethics approval number [5] 304215 0
Not stated

Summary
Brief summary
Patients who require treatment in the Intensive Care Unit (ICU) can develop stomach ulcers or duodenal (small intestine) ulcers. This occurs most commonly when life support (a breathing machine) is required or when the patient develops a bleeding tendency as a result of their illness. These kinds of ulcers are known as ‘stress ulcers’ and may cause life-threatening bleeding. Patients who require life support in the ICU are typically given one of two types of medicine to try and prevent the development of stress ulcers. The two types of medicines are called ‘proton pump inhibitors’ (PPIs) and ‘histamine-2 receptor blockers’ (H2RBs). While the prevention of stress ulcers is very important, the medicines used to prevent ulcers may have important side effects including an increased risk of developing certain kinds of infections. The risk of side effects may depend on the medication used. This study will establish which of the two types of medicines that are commonly used for stress ulcer prophylaxis in ICU patients who require life support leads to the lowest risk of upper gastrointestinal bleeding, prolonged mechanical ventilation, and Clostridium difficile infection. The study will use a design known as a ‘cluster crossover registry design’. In this type of study, data are collected primarily from existing data sources rather than the medical records of individual patients. There will be two study treatment periods. During the first treatment period, half of the participating ICUs will be randomly (like the toss of a coin) instructed to use PPIs for stress ulcer prophylaxis in patients who require life-support while the other half will use H2RBs. During the second treatment period each ICU will swap to using the opposite treatment. This means that, in situations where PPIs and H2RBs are regarded as being equivalent by the treating clinician, the treatment administered to the patients will be determined based on the treatment assigned to the patient’s ICU. However, if there is a specific indication for either PPI treatment or H2RB treatment (for example, an allergy), the treatment indicated for the particular patient concerned will be administered irrespective of the treatment assigned to the ICU.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64810 0
Dr Paul Young
Address 64810 0
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021
Country 64810 0
New Zealand
Phone 64810 0
+6443855999
Fax 64810 0
Email 64810 0
paul.young@ccdhb.org.nz
Contact person for public queries
Name 64811 0
Dr Paul Young
Address 64811 0
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021
Country 64811 0
New Zealand
Phone 64811 0
+6443855999
Fax 64811 0
Email 64811 0
paul.young@ccdhb.org.nz
Contact person for scientific queries
Name 64812 0
Dr Paul Young
Address 64812 0
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021
Country 64812 0
New Zealand
Phone 64812 0
+6443855999
Fax 64812 0
Email 64812 0
paul.young@ccdhb.org.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Where approved by an ethics committee and allowable in individual participating jurisdictions by law, deidentified individual participant data collected during the PEPTIC trial (and the data dictionary) will be shared.
When will data be available (start and end dates)?
Two years after article publication with no end date
Available to whom?
These data will be available to researchers to who provide a methodologically sound proposal for the purposes of achieving specific aims outlined in that proposal.
Available for what types of analyses?
Only analysis which are part of an approved proposal (outlined below) will be permitted.
How or where can data be obtained?
Proposals should be directed to the corresponding author via email: paul.young@ccdhb.org.nz and will be reviewed by the PEPTIC study management committee. Requests to access data to undertake hypothesis-driven research will not be unreasonably withheld. To gain access, data requesters will need to sign a data access agreement and to confirm that data will only be used for the agreed purpose for which access was granted.
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
Clinical study report
Ethical approval
How or where can supporting documents be obtained?
Type [1] 4432 0
Study protocol
Citation [1] 4432 0
Link [1] 4432 0
Email [1] 4432 0
paul.young@ccdhb.org.nz
Other [1] 4432 0
Attachment [1] 4432 0
Type [2] 4433 0
Statistical analysis plan
Citation [2] 4433 0
Link [2] 4433 0
Email [2] 4433 0
paul.young@ccdhb.org.nz
Other [2] 4433 0
Attachment [2] 4433 0
Type [3] 4444 0
Informed consent form
Citation [3] 4444 0
Link [3] 4444 0
Email [3] 4444 0
paul.young@ccdhb.org.nz
Other [3] 4444 0
Attachment [3] 4444 0
Type [4] 4445 0
Clinical study report
Citation [4] 4445 0
Link [4] 4445 0
Email [4] 4445 0
paul.young@ccdhb.org.nz
Other [4] 4445 0
Attachment [4] 4445 0
Type [5] 4446 0
Ethical approval
Citation [5] 4446 0
Link [5] 4446 0
Email [5] 4446 0
paul.young@ccdhb.org.nz
Other [5] 4446 0
Attachment [5] 4446 0
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary