Appendix 1. Definitions used in the SUP-ICU trial
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 below 90 mmHg
-
Mean arterial pressure below 70 mmHg
-
Use of vasopressors or inotropes (norepinephrine, epinephrine, phenylephrine, vasopressin or dopamine, dobutamine, milirinone or levosimendan)
-
Lactate level 4 mmol/l or above
Renal replacement therapy: acute or chronic intermittent or continuous renal replacement therapy.
Patients with expected duration of invasive mechanically ventilation longer than 24 hours: the treating clinician estimates that the patient will be invasively mechanically ventilated for more than 24 hours. When there is doubt about this forecast the patient should be enrolled.
Coagulopathy: platelets below 50 × 109/l or international normalised ratio (INR) above 1.5 or prothrombin time (PT) above 20 s 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 below 50 × 109/l and/or INR above 1.5 and/or PT above 20 s within the 6 months prior to hospital admission.
History of chronic liver disease: portal hypertension, cirrhosis proven by biopsy, 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 (PPIs): any history of intolerance to PPIs or additives or treatment with atazanavir (HIV medication).
Ongoing treatment with PPIs and/or histamine-2-receptor antagonists (H2RAs): ongoing, documented daily treatment with the drugs in the patient charts.
Gastrointestinal (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.
Withdrawal from active therapy or brain death: patients where withdrawal or brain death is documented in the patient charts.
Known pregnancy: fertile woman with a positive test for urinary or plasma human chorionic gonadotropin (hCG).
Consent not obtainable according to national regulations: patients where the clinician or investigator is unable to obtain the 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 the current hospital admission scheduled 24 hours or more in advance.
Emergency surgery: surgery during current hospital admission that was added to the operating room schedule 24 hours or less prior to that surgery.
Medical admission: when no surgery has been performed during the 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 the inclusion criteria.
Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) 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.
Coagulopathy: defined in the inclusion criteria.
Treatment of suspected or confirmed Clostridium difficile infection (CDI) during current hospital admission.
Coexisting illnesses 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 (NYHA) functional class III–IV. NYHA class 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 one flight of stairs). The patient is only comfortable at rest. NYHA class IV: 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
-
Haematological 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) is based on the most extreme (highest or lowest) values from 24 hours prior to randomisation. The score consists of 17 variables: 12 physiological 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 illness severity. The score will be calculated from data from the 24 hours prior to randomisation.
The Sequential Organ Failure Assessment (SOFA) score 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 a PPI or a 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. GI bleeding).
Mechanical ventilation: invasive and non-invasive mechanical ventilation including continuous mask continuous positive airway pressure (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 ischaemia 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.
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 ischaemia. 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:
1.
Spontaneous drop of systolic blood pressure, 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 2 g/dl (1.24 mmol/l)
4.
Transfusion of two units of packed red blood cells or more
*Overt GI bleeding: haematemesis, coffee ground emesis, melaena, haematochezia or bloody nasogastric aspirate.
Pneumonia: episodes of newly confirmed pneumonia according to the modified CDC criteria [
47]:
-
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
-
and at least one of the following:
1.
Fever (above 38 °C) with no other recognised cause
2.
Leucopoenia (white cell count below 4 × 109/l) or leucocytosis (white cell count above 12 × 109/l)
-
and at least two of the following:
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, ischaemic signs on an electrocardiogram (ECG) and clinical presentation) and receiving treatment as a consequence of this (reperfusion strategies (percutaneous coronary intervention(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.
One-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 off renal replacement therapy as defined below. The outcome will be days alive without the 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.
SARs: number of SARs as defined below.
The elements of all composite outcomes will be reported in the supplementary material.
A health economic analysis will be performed. The analytic details will be based on the result of the trial and specified (cost-benefit versus cost-minimisation analyses).
Definitions of serious adverse reactions (SARs)
A SAR is defined as any adverse reaction that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, 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 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 (more than 20 % decrease in blood pressure or more than 20 % increase in vasopressor dose)
-
Increased airway resistance (more than 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 below 0.5 × 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 physician or the investigator.
Stevens-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 localised oedema.
Appendix 2. Charter for the independent Data Monitoring and Safety Committee (DMSC) of the SUP-ICU trial
Research ethical committee number: 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 by 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 of 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 soon as possible, and no longer than 48 hours later, 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. 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 their replacement(s).
Formal interim analysis meetings
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 members who generate 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 an independent biostatistician being a member of the DMSC, with assistance from the trial data manager, in a manner that allows them to remain blinded. The closed reports should provide information that is accurate, with follow-up on mortality that is complete to within 2 months of the date of the DMSC meeting.
Open reports
For each DMSC meeting, open reports will be made available to all who attend the DMSC meeting. The reports will include data on recruitment and baseline characteristics, 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 cooperation with the trial data manager.
The reports should be provided to DMSC members approximately 3 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 number 1650 and patient number 2500 have been followed-up 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 the O’Brien-Fleming alpha-spending function [
48]. 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 [
49]. 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 also be clinically relevant.
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’s 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, pneumonia, Clostridium difficile infection (CDI), and acute myocardial ischaemia
-
Proportion of patients with clinically important GI bleeding
-
One-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.
The DMSC should be informed yearly 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 (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 = the patient had one or more episodes, 0 = the patient did not)
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: SAR indicator (1 = one or more SARs, 0 = no SARs).