Does Acetylsalicylic Acid Reduce the Mortality of Patients Admitted to an Intensive Care Unit
Phase: PHASE3
Conditions: Critical Illness
Sponsor: Medical University of Vienna

ASA-MORT 
Protocol Version 2.0, 26.06.2012 
 
 
Does acetylsalicylic acid reduce the mortality of patients 
 
admitted to an Intensive Care Unit 
 
EUDRA-CT#: 2012-002235-29 
NCT02285153 
 
A randomized, double-blind, placebo-controlled, parallel group trial 
 
in the Intensive Care Unit 
 
 
 
 
Prinicipal Investigator: 
Bernd Jilma, Ao. Univ. Prof. Dr. med. 
 
Email: bernd.jilma@meduniwien.ac.at 
 
Währinger Gürtel 18-20 
 
1090 Vienna 
Austria 
 
Tel: +43 1 40400 29810 
 
Fax: +43 1 40400 29980 
 
 
 
 
 
 
 
 
Participating Departments 
Department of Internal Medicine I, II, III 
 
Department of Clinical Pharmacology 
 
Department of Pathology 
 
Sponsor: 
Medical University of Vienna 
 
Währinger Gürtel 18-20, 1090 Vienna, Austria 
 
Development Phase: 
Phase III 
 
Version and date: 
Version 2.0, 26.06. 2012 
 
. 
 
 
 
 
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Study Synopsis 
 
Title 
Does acetylsalicylic acid (ASA) reduce the mortality of 
patients admitted to an intensive care unit (ICU) 
 
Clinical Study Phase 
Phase III 
 
Project Number 
ASA-MORT, EUDRA-CT#: 2012-002235-29 
 
 
 
 
Study objective(s) 
To investigate whether ASA-treatment reduces the 
mortality of a mixed medical ICU patient population; 
 
Primary objective: To investigate the 28-/90-day 
mortality of patients treated with ASA vs. placebo; 
 
Secondary objectives: To examine the ICU mortality of 
patients admitted to an ICU treated with ASA or 
placebo; 
 
To examine whether ASA treatment reduces the 
incidence of thromboembolic events; 
 
To evaluate the pharmacokinetics (PK) and the 
pharmacodynamics (PD) of ASA in the intensive care 
unit; 
 
To evaluate safety of ASA treatment assessed by 
post-mortem examinations (PME) with special 
regards to bleeding incidences; 
 
Test drugs 
intravenous ASA 
 
Name of active ingredients 
Acetylsalicylic Acid 
 
Dose(s) 
100mg 
 
Duration of treatment 
once daily for entire ICU stay 
 
Background treatment 
any concomitant treatment is allowed, the study will 
not interfere with standard care of patients 
 
 
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Rationale for the study 
In a retrospective study ASA use was associated with 
a substantial reduction in mortality in a medical ICU 
population (Winning et al., 2010). A stepwise logistic 
regression model suggested an odds ratio of 0.26 
(confidence interval (CI): 0.13-0.53) in ASA treated 
patients (Losche et al., 2012). Also animal models of 
sepsis demonstrated that ASA reduces mortality 
(Halushka et al., 1981). Further ASA in certain 
populations reduces the risk for thromboembolic 
complications (Landolfi et al., 2004; Thomas, 2000). 
 
Main criteria for inclusion 
-patients admitted to an ICU 
 
-patients naïve to ASA 
 
Study design 
randomized, placebo-controlled, double-blind 
interventional trial 
 
 
 
 
METHODOLOGY 
 
Primary variable 
28-day, 90-day mortality 
 
Secondary variables 
 
 
ICU mortality 
 
Thromboembolic events 
 
Bleeding incidences 
 
PK/PD evaluation 
 
Post-mortem examination 
 
Plan for statistical analysis 
Demographic and baseline data: 
 
 
Quantitative descriptive statistics 
 
Primary variables: 
 
 
Kaplan Meier estimates will be plotted 
 
Chi²-Test for primary variable 
 
 
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Secondary variables: 
 
 
Comparative (treatment vs. placebo) 
 
Cox-Regression Model including major 
prognostic factors 
 
Safety assessment 
Standard monitoring at the ICU 
 
Benefit/risk assessment 
Patients included in the trial will receive placebo or 
100mg intravenous (i.v.) ASA. Any concomitant 
treatment is allowed and the trial activities will not 
interfere with standard care of the patients. The main 
side effects of ASA treatment are gastrointestinal 
bleeding incidences. ASA will be infused to lower 
adverse effects in the gastrointestinal system. 
Moreover, routine treatment of patients with proton 
pump inhibitors should reduce this risk. Patients will 
be closely monitored and checked for bleeding and 
will be withdrawn from the trial if major bleeding 
occurs. Winning et al. did not observe increased risk 
for ICU patients treated with ASA (Winning et al., 
2010). We hypothesize that ASA may reduce 
mortality of critically ill patients. Therefore, we 
consider the benefits to outweigh the potential risks 
of the trial. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table of Contents 
1. 
Background ............................................................................................................................. 8 
2. 
Study objectives...................................................................................................................... 9 
2.1. 
Primary end-point............................................................................................................... 9 
2.2. 
Secondary end-points ......................................................................................................... 9 
3. 
Treatments.............................................................................................................................. 9 
4. 
Methods ................................................................................................................................ 10 
4.1. 
Study design...................................................................................................................... 10 
4.1.1. 
Flow-chart ..................................................................................................................... 11 
4.1.2. 
Rationale for the trial design........................................................................................ 11 
4.1.3. 
Benefit/Risk Assessment .............................................................................................. 11 
4.2. 
Study population .............................................................................................................. 12 
4.2.1. 
Inclusion criteria ........................................................................................................... 12 
4.2.2. 
Exclusion criteria........................................................................................................... 12 
4.2.3. 
Premature discontinuation .......................................................................................... 12 
4.3. 
Randomization.................................................................................................................. 13 
4.4. 
Medication ........................................................................................................................ 13 
4.4.1. 
Packaging and labeling of trial medication.................................................................. 13 
4.4.2. 
Drug dispensing and accountability ............................................................................. 14 
4.4.3. 
Blinding of medication.................................................................................................. 14 
4.5. 
Trial procedures ................................................................................................................ 14 
4.5.1. 
Pharmacodynamic analysis .......................................................................................... 15 
4.5.2. 
Pharmacokinetics.......................................................................................................... 15 
4.6. 
Trial schedule .................................................................................................................... 15 
4.6.1. 
Screening....................................................................................................................... 15 
4.6.2. 
Interventional phase..................................................................................................... 16 
4.6.3. 
PK/PD assessment ........................................................................................................ 16 
4.6.4. 
Follow-up visit............................................................................................................... 16 
4.6.5. 
Post-mortem examination ........................................................................................... 16 
4.6.6. 
Safety assessment......................................................................................................... 16 
4.6.6.1. 
Major bleeding.......................................................................................................... 16 
4.6.7. 
Blood sampling and preparation for PK/PD analysis .................................................. 17 
4.6.7.1. 
Labeling of samples .................................................................................................. 17 
4.7. 
Evaluation Parameters ..................................................................................................... 17 
4.7.1. 
Study outcome parameters.......................................................................................... 17 
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4.7.1.1. 
Primary variable........................................................................................................ 17 
4.7.1.2. 
Secondary variables.................................................................................................. 18 
4.7.1.3. 
Tertiary variables ...................................................................................................... 18 
4.8. 
Statistical methods ........................................................................................................... 18 
4.8.1. 
Sample size calculation and statistical power considerations .................................... 18 
4.8.2. 
Stopping rules ............................................................................................................... 19 
4.8.3. 
Feasibility of the trial.................................................................................................... 19 
4.8.4. 
Statistics of the outcome.............................................................................................. 19 
4.8.5. 
Analysis of demographic characteristics...................................................................... 19 
4.8.6. 
Analysis of PK/PD outcome parameters ...................................................................... 19 
4.8.7. 
Analysis of occurrence of major bleeding and thromboembolic events .................... 19 
4.9. 
Adverse events.................................................................................................................. 20 
4.9.1. 
Definitions..................................................................................................................... 20 
4.9.1.1. 
Adverse Event (AE) ................................................................................................... 20 
4.9.1.2. 
Serious Adverse Event (SAE)..................................................................................... 20 
4.9.1.3. 
Non-Serious Adverse Event ...................................................................................... 20 
4.9.1.4. 
Definition of Adverse Reaction (AR) ........................................................................ 20 
4.9.1.5. 
Severity Assessment Definition................................................................................ 21 
4.9.1.6. 
Relationship to Trial Drug Assessment Definitions ................................................. 21 
4.9.1.7. 
Outcome Categories and Definitions ....................................................................... 21 
4.9.2. 
Collection, Recording and Reporting of Adverse Events ............................................. 21 
4.9.3. 
Follow-up of Adverse Events ........................................................................................ 22 
4.9.4. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ........................................ 22 
4.9.5. 
Reporting of SUSARs..................................................................................................... 22 
4.10. 
Monitoring Procedure and Audits................................................................................ 23 
4.11. 
Data Management ........................................................................................................ 23 
4.12. 
Ethics ............................................................................................................................. 23 
4.12.1. 
Informed Consent Form of Trial Subjects (AMG §38).................................................. 24 
4.12.2. 
Independent Ethics Committees (AMG §§40, 41) ....................................................... 24 
4.12.3. 
Regulatory Authorities ................................................................................................. 25 
4.12.4. 
Insurance (AMG § 32(2))............................................................................................... 25 
4.12.5. 
Confidentiality .............................................................................................................. 25 
4.12.6. 
Premature Termination of the Trial ............................................................................. 25 
4.12.7. 
Retention of Clinical Trial Documentation................................................................... 25 
5. 
List of abbreviations ............................................................................................................. 26 
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6. 
References............................................................................................................................. 27 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1. Background 
 
Platelets play a central part in homeostasis and thrombosis as the primary effector cells, but they are 
also key cells in the regulation of the immunological response to various stressors. After activation, 
platelets release their granules which store different inflammatory mediators that induce 
coagulation, recruit further platelets, activate complement, attract neutrophils and leukocytes and 
regulate the vascular tone (Katz et al., 2011; Peerschke et al., 2008). Platelets activated by systemic 
inflammation and infection, may also contribute to the development of multiple organ failure (Gawaz 
et al., 1995; Losche et al., 2012). Thus, various platelet parameters have been established as clinical 
predictors of cardiovascular events and mortality, even in healthy volunteers (Sharma et al., 2011). In 
critical illness a drop in platelet counts predicts a higher mortality (Arevalo-Lorido et al., 2011; 
Baughman et al., 1993; Tekbas et al., 2011; Vanderschueren et al., 2000). 
 
Acetylsalicylic acid is a commonly used drug to reduce platelet activation by irreversibly inhibiting the 
enzyme cyclooxygenase (Paez Espinosa et al., 2012). It has been demonstrated that the effects of 
ASA are dose dependent (Mitchell et al., 1993). ASA is relatively selective for the inhibition of the 
enzyme cyclooxygenase-1 (COX-1). At higher doses ASA will also inhibit the inducible isoform 
cyclooxygenase-2 (COX-2) (Mitchell et al., 1993). COX-1 is mainly found in platelets and metabolizes 
arachidonic acid to Thromboxane A2 (TXA2), which is a potent vasoconstrictor and has 
proaggregatory effects. On the other hand, COX-2 is an enzyme mainly found in the endothelium that 
metabolizes AA to prostacyclin (PGI2), which has anti-aggregatory and vasodilatory effects (Moncada 
et al., 1978). The aim of low-dose therapy with ASA is to inhibit the effects of TXA2 but to maintain 
the effects of PGI2. The American Heart Association recommends the daily use of aspirin for all 
patients with cardiovascular disease for secondary prevention, unless contraindicated, at doses 
ranging from 71-326mg (Smith et al., 2006). However, there are considerable interindividual 
differences in the PK/PD response to ASA treatment. “ASA resistance” or “high on treatment platelet 
reactivity” are at least partly explained by a worse PK profile, occur less frequently at higher doses 
and can be overcome by using higher doses (Neubauer et al., 2011; Zimmermann et al., 2008). 
 
Rationale for the trial: Intake of anti-platelet drugs before hospitalization was associated with a 
substantial decrease in mortality in a mixed intensive care unit patient population. In non-surgical 
patients an odds ratio of 0.26 (CI 0.13-0.53) was found (Winning et al., 2010). A stepwise logistic 
regression model suggested an odds ratio of 0.2 (CI 0.12-0.35) for critically ill patients, and an odds 
ratio of 0.55 (CI 0.38-0.81) for patients suffering from severe sepsis or septic shock (Losche et al., 
2012). Patients with community acquired pneumonia who took ASA before hospitalization were less 
likely to be admitted to the ICU, although they were significantly older than patients without ASA (9% 
vs. 26%). Additionally hospital stay was significantly shorter in the group of patients taking ASA 
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(Winning et al., 2009). Animal studies also demonstrate that ASA reduces the mortality of mice in 
experimentally induced septic shock (Halushka et al., 1981; Losche et al., 2012). 
 
Hypothesis: We hypothesize that ASA reduces mortality in a mixed medical ICU population. 
 
We furthermore hypothesize that ASA leads to a reduction of the risk of suffering thromboembolic 
complications. 
 
2. Study objectives 
 
The aim of the study is to investigate potential beneficial effects of ASA on mortality of a mixed 
medical ICU patient population. Moreover, potential beneficial effects of ASA on the risk of suffering 
thromboembolic complications will be examined. Therefore patients will be randomized to receive 
either 100mg i.v. ASA or a placebo. 
 
2.1.Primary end-point 
 
Evaluation of 28- and 90-day-mortality of patients treated with ASA and patients in the control group 
receiving 0.9% sodium-chloride as a placebo. 
 
2.2.Secondary end-points 
 
Evaluation of the ICU- mortality 
 
Evaluation of the PK/PD of ASA 
 
Incidence of thromboembolic events (symptomatic deep venous thrombosis (DVT), 
pulmonary embolism (PE), myocardial infarction (MCI), stroke) 
 
Incidence of major bleeding 
 
PMEs investigating the occurrence of major bleeding and thromboembolic events 
 
 
3. Treatments 
 
Commercially available products will be stored according to their product information. The doses 
used in this trial are commonly used. 
 
 
Acetylsalicylic acid 100mg i.v. 
 
0.9% sodium-chloride i.v. 
 
 
 
 
 
 
 
 
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4. Methods 
4.1.Study design 
 
A randomized, double-blind, placebo controlled trial will be conducted in ASA naïve patients to 
investigate potential beneficial effects of ASA on the mortality of medical patients admitted to an 
ICU. 
 
Patients will be randomized to receive 100mg ASA i.v. or 0.9% sodium-chloride i.v. as a placebo once 
daily. Patients will be included in the study as soon as possible but at least within 60 hours after their 
admittance to the ICU. 
 
A total of 460 patients will be included in the trial (2 groups, n=230). This sample size is based on the 
results of a study conducted by Winning et al. examining the effects of ASA in a mixed medical ICU 
patient population (Winning et al., 2010). As explained below (4.8.1), we performed some adaptions. 
 
The primary variable is 28/90-day-mortality which is objectively measurable. 28-day and 90-day 
mortality are commonly used end-points in ICU trials and recommended by the specific guidelines of 
EMEA for sepsis (EMEA, 2006). 28-day and 90-day mortality will be assessed by chart review and/or 
telephone survey and/or review of the register of deaths. Moreover, ICU-mortality will be assessed. 
 
PK/PD analyses will be performed to assess the efficacy of ASA treatment. We will furthermore 
compare data from this study with another study conducted in patients pretreated with ASA 
admitted to an ICU. PK/PD will be assessed on the first day of ASA treatment and analyses may be 
repeated during the ICU stay. 
 
Daily physical examinations are part of the standard care of patients in ICUs. All patients included in 
the study will be checked daily for possible thromboembolic events or bleeding incidences. PME will 
be carried out for all patients included in the study who die in the course of the ICU stay. Special 
interest will be paid to thromboembolic events and bleeding incidences during these examinations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.1.1. 
Flow-chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.1.2. 
Rationale for the trial design 
 
We chose to perform this trial as a randomized, double-blind, placebo-controlled trial. Winning et al. 
has shown potential beneficial effects of ASA treatment on mixed medical ICU patients. Although, 
this study was a retrospective, observational study (Winning et al., 2010), this hypothesis is also 
supported by animal studies (Halushka et al., 1981; Losche et al., 2012). To our knowledge no 
prospective, randomized trial exists to test this hypothesis in humans. 
 
ASA treatment reduces the incidence of thromboembolic events in patients with polycythemia vera 
and in patients undergoing hip surgery (Landolfi et al., 2004; Thomas, 2000). Therefore we want to 
assess whether ASA reduces the risk of thromboembolic complications in critically ill patients. In 
addition to standard care, which includes a physical examination of each patient every day and 
laboratory control of coagulation parameters, PMEs will be performed to assess the incidence of 
thromboembolic events. 
 
PK/PD analyses will be performed on the first day of treatment and may facultatively be repeated. 
We hypothesize that the responsiveness of patients to ASA treatment varies with the clinical 
condition of patients. We plan to perform another trial investigating the effects of anti-platelet drugs 
in non-naïve patients of ICUs. 
 
4.1.3. 
Benefit/Risk Assessment 
 
The main risk of ASA treatment is the occurrence of bleeding incidences, especially in the 
gastrointestinal system, allergic reactions and asthma. However, we chose to infuse ASA to reduce 
the risk of gastrointestinal bleeding. Moreover, routine treatment with proton pump inhibitors 
should reduce this risk further. Allergic reactions are possible, but generally occur seldom. The first 
dose will therefore be given with great care and special attention will be given to allergic reactions. 
However, patients with known allergies to ASA will be excluded from the trial. The trial will not 
otherwise interfere with standard care of the patient. Concomitant treatment will be recorded, but is 
 
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permitted. All actively bleeding patients and all patients with a planned surgical intervention will not 
be included in the trial. Therefore we consider the risks of the trial to be acceptable. 
 
The studies by Winning et al. suggest a reduction of mortality for ASA treated patients admitted to 
ICU patients and animal studies support this hypothesis (Halushka et al., 1981; Losche et al., 2012; 
Winning et al., 2010; Winning et al., 2009). Moreover, ASA might reduce the risk of thromboembolic 
events in patients admitted to the ICU. Therefore, we consider the potential benefits to outweigh the 
possible risks of this trial. 
 
4.2.Study population 
 
All patients participating in the study are ASA naïve. The trial is conducted to investigate whether 
administration of ASA reduces the mortality in a mixed medical ICU population. Therefore we choose 
open inclusion criteria. 
 
4.2.1. 
Inclusion criteria 
 
≥18 years of age 
 
Admittance to an ICU 
 
 
4.2.2. 
Exclusion criteria 
 
Known allergy or intolerance to ASA 
 
Recent surgery or planned surgery 
 
Active bleeding 
 
Known coagulation disorders 
 
Discretion of the physician 
 
Terminal illness (anticipated life expectancy <3months; e.g. due to cancer) 
 
Platelet count <20000 
 
Recent gastrointestinal bleeding 
 
Recent ulcera 
 
Pregnancy 
 
 
4.2.3. 
Premature discontinuation 
 
Inclusion and exclusion criteria will be checked before the first trial related activity. Patients will be 
withdrawn from the trial in case of a planned surgery, in case of major bleeding or at the discretion 
of the treating physician. All patients who are conscious and able to understand the full nature of the 
study will be informed about their inclusion and informed consent will be sought. Participation of the 
 
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trial is voluntary and patients may discontinue at their free will. Patients, who at the moment of 
study inclusion, are unconscious or unable to understand the nature and purpose of the study will be 
informed about their participation as soon as possible. 
 
4.3.Randomization 
 
A stratified randomization procedure will be used. Age, SAPS III score will be used as stratification 
factors, because they are well known predictors of mortality, and were independently associated 
with mortality in Winning’s study. Furthermore prophylactic and therapeutic anti-coagulation will be 
used as stratification factors. A minimization procedure using software available in the web may be 
used: 
 
https://www.meduniwien.ac.at/randomizer/web/login.php 
 
Allocation concealment will be performed either by using opaque sealed randomization envelopes, 
which are opened only after the patient has been found eligible for the trial, or the randomization 
program. 
 
4.4.Medication 
 
Patients will be randomized to receive either 100mg i.v. ASA or 0.9% sodium-chloride as a placebo. 
 
The most relevant possible side-effects of aspirin include the following: 
 
 
Gastrointestinal bleeding 
 
Asthma 
 
Thrombocytopenia 
 
Renal and hepatic impairment 
 
Dizziness 
 
Tinnitus 
 
Rarely, allergic reactions 
 
No side effects are expected by the infusion of 0.9% sodium-chloride. 
 
4.4.1. 
Packaging and labeling of trial medication 
 
The final packaging size as well as labels will be defined in a note-to-file. 
 
Labels will contain at a minimum the following information: 
 
 
Study number 
 
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 
Product name 
 
Fill volume or dose 
 
Mode of administration 
 
Product will be stored as declared in the product information. Study medication will be prepared by 
trained nurses or pharmacists. 
 
4.4.2. 
Drug dispensing and accountability 
 
An investigational medicinal product (=IMP) log will be kept current by the site, detailing the dates 
and quantities of IMP administered to each subject. This documentation will be available to the CRA 
to verify drug accountability during the study. 
 
4.4.3. 
Blinding of medication 
 
Blinding of medication will be ensured by dissolution of ASA and preparation of identical 
syringes/infusion bottles by a study nurse and/or a pharmacist. 
 
Medication will be labeled as “Placebo (NaCl 0.9%)/ASA 100mg i.v.”. 
 
4.5.Trial procedures 
 
Patients included in the trial will be randomized to ASA treatment or to the control group receiving 
sodium-chloride. They will receive the trial drugs once daily. Inclusion in the trial will be performed as 
soon as possible and latest within 60 hours after their admittance to the ICU. 
 
Beside the administration of the trial drugs we will not interfere with standard care of the patients. 
Any concomitant treatment is allowed. 
 
On the first day of treatment PK/PD will be measured and may be repeated once (5-8 days later) 
during the ICU stay. Therefore blood samples will be drawn at the baseline as well as two hours 
thereafter. 
 
The primary end-point is the 28-/90-day mortality which we will assess by chart review, telephone 
survey or the register of deaths. However, ICU- mortality will be assessed by chart review. 
 
Post-mortem examination will be conducted by the department of pathology and special attention 
will be paid to major bleeding incidences and thromboembolic events. 
 
 
 
 
 
 
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4.5.1. 
Pharmacodynamic analysis 
 
The efficacy of ASA will be assessed by whole blood impedance aggregometry (MEA, multiple 
electrode aggregometry) and by thromboxane B2 (TXB2), the stable metabolite of TXA2. A 
commercially available enzyme immune assay will be used to measure TXB2. Whole blood 
impedance aggregometry will be performed using arachidonic acid to induce aggregation. Both tests 
examine ASA specific effects on platelets (Kuliczkowski et al., 2009). Low-dose ASA is thought to 
reduce TXA2 levels by inhibiting COX-1, but not to affect levels of PGI2. PGI2 is unstable and 
therefore the stable metabolite 6-Keto-PGF1-alpha is usually measured. We will use commercially 
available enzyme immune assays for assessment (Gao et al., 2009; Gryglewski, 2008). Platelet 
function under high shear rates will be analyzed by the PFA-100 (platelet function analyzer). Closure 
time of an aperture in a membrane coated with either collagen or epinephrine (CEPI) or collagen and 
adenosine diphosphate (CADP) will be measured in whole blood. The use of the PFA-100 can not 
only identify patients at a high risk for ACS, but help in monitoring therapy with antiplatelet drugs as 
well (Derhaschnig et al., 2009). 
 
 
4.5.2. 
Pharmacokinetics 
 
The population of interest are patients admitted to an ICU. A relatively large amount of blood and 
numerous blood samples would be needed to perform a thorough analysis of PK. In order to keep 
the amount of blood volume small, we will only perform a minimal analysis. Blood samples will be 
drawn at the baseline and 2h after administration. PK will be assessed on the first day and may be 
repeated once during the ICU stay. We will compare the PK profiles of this population with data from 
another study including non-ASA-naïve patients admitted to an ICU. 
 
The PK of aspirin will be determined by plasma ASA and/or salicylate levels in the local central 
laboratory (Hobl et al., manuscript in preparation). 
 
4.6.Trial schedule 
4.6.1. 
Screening 
 
All patients admitted to the ICUs (Dept. of Internal Medicine I-III) will be screened for in- and 
exclusion criteria. All patients who meet the criteria and are ASA naïve will be included in this trial 
and randomized to one of the groups. Patients included to the trial must receive the first dose of the 
trial drugs within 60 hours after their admittance. 
 
 
 
 
 
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4.6.2. 
Interventional phase 
 
All patients randomized will receive the treatment by investigators blinded to the trial drugs. Special 
attention will be paid to the first administration of the trial drug because of possible allergic 
reactions. Patients will receive the trial drug every day in the course of their ICU stay. 
 
4.6.3. 
PK/PD assessment 
 
All patients randomized will be included in the PK/PD assessment. Blood samples will be drawn 
before and 2h after administration of the study drug. We may repeat the analyses once during the 
ICU stay. Analyses will be performed by blinded laboratory personnel. The investigators and the 
treating physicians will remain blinded. 
 
4.6.4. 
Follow-up visit 
 
We plan to assess 28-day and 90-day mortality. Therefore we will perform chart-reviews, telephone 
survey or check the register of deaths. 
 
4.6.5. 
Post-mortem examination 
 
All patients who die during their ICU stay will be examined by the department of pathology. Special 
attention will be paid to major bleeding incidences and to thromboembolic events (PE, MCI, DVT, 
stroke). 
 
4.6.6. 
Safety assessment 
 
Patients admitted to an ICU are closely monitored on a routine basis. 
 
The simplified acute physiology score (SAPS III) will be recorded for each patient (Moreno et al., 
2005). 
 
Concomitant treatment of each patient will be recorded. 
 
4.6.6.1. Major bleeding 
 
To define major bleeding we will use the criteria from the TIMI-Triton-38 study (Wiviott et al., 2007). 
Major bleeding will be defined as bleeding incidences that lead to a decrease in hemoglobin of 
≥5g/dL (each unit of packed red blood cells or whole blood transfused will count as 1g of 
hemoglobin), or a ≥15% absolute decrease in hematocrit (each unit of packed red blood cells or 
whole blood transfused will count as 3% points) or it is intracranial (confirmed by computer 
tomography). 
 
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All bleeding incidences that do not meet these criteria will therefore be identified as minor bleeding. 
 
4.6.7. 
Blood sampling and preparation for PK/PD analysis 
 
Blood samples will be collected from an appropriate forearm vein, an existing central venous 
catheter or an arterial catheter at the baseline and 2 hours after trial drug administration, after 
discarding the first 5 ml. 
 
A total volume of 39 ml blood will be collected for the PK/PD analysis of one trial day. 
 
For PK analysis Sodium-Fluoride/K3EDTA tubes will be used. 
 
For PD assessment hirudin (MEA), buffered sodium-citrate (3.8%) (PFA-100) and serum tubes (TXB 2, 
6-Keto-PGF1-alpha) will be used. 
 
Actual sampling times for each patient will be recorded in the individual CRFs. 
 
Preparation for PD analysis: 
 
Hirudin (MEA), buffered sodium-citrate (3.8%) (PFA-100) and serum tubes will be used for the PD 
analysis. For the PFA-100, tubes will be gently inverted (3-4 times). Tubes will be stored <4 hours at 
ambivalent temperature (16-26˚C9) until analysis. For the Multiplate system, tubes will be gently 
inverted (3-4 times). Blood will not be frozen, refrigerated or preheated. Analysis of blood samples 
should be performed within the period of 0.5-3 hours after blood collection. Thromboxane and 6- 
Keto-PGF1-alpha measurements will be conducted according to the user manual of the commercially 
purchased TXB2 enzyme immune assay. 
 
4.6.7.1. Labeling of samples 
 
Each sample tube will be clearly and unequivocally identified by a label resistant to the storage 
temperature and reporting: 
 
Trial ID ASA-MORT 
 
Subject ID number XX 
 
Time ID day X / hours XX 
 
4.7.Evaluation Parameters 
4.7.1. 
Study outcome parameters 
4.7.1.1. Primary variable 
 
28-/90-day mortality between the two trial groups, ASA vs. placebo 
 
 
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4.7.1.2. Secondary variables 
 
ICU-mortality 
 
ASA-/salicylate-serum concentrations for PK assessment 
 
Serum TXB2 levels and 6-keto-PGF1-alpha levels 
 
Area under the aggregation curve (AUC) (MEA): arachidonic acid induced aggregation 
 
Thromboembolic events (PE, MCI, DVT, stroke) 
 
Closure time (s) (PFA-100®) CEPI-CT, CADP-CT, or Innovance CT 
 
Major bleeding 
 
PME for major bleeding and thromboembolic events (PE, MCI, DVT, stroke) 
 
 
4.7.1.3. Tertiary variables 
 
Laboratory analyses 
 
4.8.Statistical methods 
4.8.1. 
Sample size calculation and statistical power considerations 
 
We based our considerations for the sample size on the study conducted by Winning et al. (Winning 
et al., 2010). 
 
Winning et al. observed that intake of anti-platelet therapy in ICU patients of internal medicine wards 
was associated with a substantial decrease in mortality: HR of 0.26 (CI 0.13-0.53) in a logistic 
regression model and a HR of 0.36 (95% CI: 0.18-0.75) in a Chi2 test. 
 
The current mortality rate in the placebo group at our ICUs is 20% and will probably be lower than 
the 30% in Winning’s study. 
 
To be more conservative, we will use the upper 95% confidence interval of the logistic regression 
model for the effect size, i.e. a 47% reduction in mortality. A sample size of 230 patients in each 
group will allow us to define the following confidence intervals when the relative risk (RR) is 0.5 (95% 
CI 0.31-0.79) and when the RR is 0.65 (95% CI 0.43-0.99). 
 
Based on these data we plan an interim analysis after half of the patients (n=230). 
 
Purpose of the interim analysis will be a re-examination of the assumptions of the mortality rate in 
the placebo group and re-adjustment of the sample size if the mortality rate is lower than 20% in the 
placebo group. 
 
 
 
 
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4.8.2. 
Stopping rules 
 
The trial will be stopped at the time of the interim analysis if aspirin shows outstanding efficacy 
(>60% reduction) in mortality. 
 
4.8.3. 
Feasibility of the trial 
 
The trial will be mainly conducted in two ICUs. Approximately 500 patients are admitted to these 
ICUs per year. Even if approximately half of the patients will be on prior aspirin therapy before being 
admitted to the ICU, the remaining half will be sufficient to theoretically allow recruitment within the 
time frame of 2 years. However, it is planned to recruit the patient population over a period of 2.5 
years accounting for the possibility that not all remaining patients may be eligible for the trial 
 
4.8.4. 
Statistics of the outcome 
 
Kaplan Meier estimates will be plotted. A Chi² Test will compare treatment and placebo group with 
regards to the primary outcome variable. A 2-tailed p-value of <0.05 in the adjusted model will be 
considered significant. 
 
4.8.5. 
Regression Model calculation 
 
A Cox regression model including major prognostic factors (age, SAPS III score, therapeutic vs. 
prophylactic anticoagulation) will be calculated for mortality data (ICU-mortality, 28-day mortality 
and 90-day mortality). 
 
4.8.6. 
Analysis of demographic characteristics 
 
Quantitative demographic and baseline data will be summarized using quantitative descriptive 
statistics such as mean, standard deviation, median, quartiles and minimum/maximum values. 
 
4.8.7. 
Analysis of PK/PD outcome parameters 
 
Comparisons between treatment groups will be performed by non-parametric tests (given their 
robustness when assumptions of normal distribution do not apply). Comparisons within subject will 
be performed by the Friedmann ANOVA, and Wilcoxon test. A 2-sided p-value of 0.05 will be 
considered significant. 
 
4.8.8. 
Analysis of occurrence of major bleeding and thromboembolic events 
 
Comparisons between groups will be performed by Chi2-test. A two-sided p-value of 0.05 will be 
considered significant. 
 
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4.9.Adverse events 
4.9.1. 
Definitions 
4.9.1.1. Adverse Event (AE) 
An AE is any undesirable medical event occurring to a subject in a clinical trial, whether or not 
considered related to the trial product(s). This includes events not seen at baseline or worsened if 
present at baseline. The following should not be recorded as AEs, if recorded at screening (on 
Screening Form or CRF): 
Pre-planned procedure, unless the condition for which the procedure was planned has worsened 
since baseline. 
Pre-existing conditions found as a result of screening procedures. 
 
 
4.9.1.2. Serious Adverse Event (SAE) 
An SAE is any adverse experience that results in any of the following outcomes: 
 
death 
 
a life-threatening experience 
 
in-patient hospitalization or prolongation of existing hospitalization 
 
a persistent or significant disability/incapacity 
 
a congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the health of the subject or patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
 
 
*The term life-threatening in the definition of serious adverse event refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death if it was more severe. 
 
 
4.9.1.3. Non-Serious Adverse Event 
A non-serious adverse event is any AE, which doesn’t fulfill the definition of an SAE. 
 
 
4.9.1.4. Definition of Adverse Reaction (AR) 
An AR is a noxious and unintended response to a study drug irrespective of the dose administered. 
All ARs are judged by either the reporting Investigator or the principal investigator as having a 
reasonable causal relationship to the study drug. The expression reasonable causal relationship 
means to convey in general that there is evidence or argument to suggest a causal relationship. An 
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unexpected adverse reaction is an AR, the nature or severity of which is not consistent with the 
information available on the study drug (i.e. the current Investigator’s Brochure). 
 
 
4.9.1.5. Severity Assessment Definition 
 
Mild: Transient symptoms, no interference with the subject’s daily activities 
 
Moderate: Marked symptoms, moderate interference with the subject’s daily activities 
 
Severe: Considerable interference with the subject’s daily activities, unacceptable 
 
 
4.9.1.6. Relationship to Trial Drug Assessment Definitions 
 
Definitely: Temporal relationship to the administration of the study drug and course 
following a known reaction pattern 
 
Probably: Good reasons and sufficient documentation to assume a causal relationship 
 
Possible: A causal relationship is conceivable and cannot be dismissed 
 
Not Related: No temporal relationship to the administration of the drug or other factors 
have caused the event 
 
 
For reporting purposes, the categories “definitely”, “probably” , “possibly” will be summarized as 
“suspected” Adverse Reactions. 
 
 
4.9.1.7. Outcome Categories and Definitions 
 
Recovered 
 
Stabilized: An AE is stabilized when, according to the investigator, the subject is in a clinically 
stable condition. This term should only be used for chronic conditions and for a given subject 
only when he/she has completed the protocol. 
 
Recovered with sequelae: As a result of the SAE, the subject suffered persistent and 
significant disability/incapacity (e.g. became blind, deaf, paralyzed). Any AE recovered with 
sequelae should be rated as an SAE. 
 
Ongoing at final examination 
 
Died 
 
 
4.9.2. 
Collection, Recording and Reporting of Adverse Events 
All events meeting the definition of an adverse event must be collected and reported from the first 
trial-related activity after the subject signs the informed consent until the end of the ICU stay. 
At each contact to the site (visit or telephone, excluding safety visits, where the subject is not seeing 
the investigator or his staff (e.g. visits to the laboratory)), the subject must be asked about adverse 
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events. All adverse events, either observed by the investigator or reported by the subject, must be 
recorded by the investigator and evaluated. 
The subjects will be asked a general question “How are you?” as well as a specific question “Have you 
experienced any problems since the last contact?” 
The investigator should record the diagnosis, if available. If no diagnosis is available the investigator 
should record each sign and symptom as individual Adverse Events. 
The investigator must record all adverse events on the standard Adverse Event Form. One single 
Adverse Event Form/line must be used per adverse event from start to resolution. For serious 
adverse events, the Serious Adverse Event Supplementary pages must also be completed. 
The investigator must report all SAEs in the first place to the sponsor by direct contact, telephone, e- 
mail or fax and receiving suitable confirmation of receipt. 
Reporting time-frame for the Investigator is 24 h or at the latest the following working day. The 
Monitor must be informed accordingly. 
 
 
4.9.3. 
Follow-up of Adverse Events 
During and following a subject’s participation in a clinical trial, the investigator/institution will ensure 
that adequate medical care is provided to the subject for any adverse events, including clinically 
significant laboratory values related to the trial. The investigator/institution will inform the subject 
when medical care is needed for adverse event(s) of which the investigator becomes aware. The 
active post-treatment follow-up period will end with the end of the ICU stay. 
All serious adverse events must be followed until the subject has recovered, stabilized, recovered 
with sequelae or died. 
 
 
4.9.4. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
All suspected adverse reactions related to a study drug which occur in the concerned study, and that 
are both unexpected and serious are classified as suspected unexpected serious aderse reactions 
(SUSARs). 
 
 
4.9.5. 
Reporting of SUSARs 
SUSARs will be expedited by the principal investigator to health authorities and the IRB. SUSARs must 
be reported as soon as possible, but at least within 7 days in case of a life-threatening reaction or in 
case of death. All other SUSARs must be reported within 15 days. 
 
 
 
 
 
 
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4.10. 
Monitoring Procedure and Audits 
The purpose of monitoring visits is to make sure that the CRFs are completed correctly, the protocol 
is adhered to, to monitor drug accountability, and to collect completed pages of the CRFs. The 
Monitor must be available for discussions by telephone. 
The monitor must be given direct access to source documents (original documents, data and 
records). Direct access includes permission to examine, analyze, verify and reproduce any record(s) 
and report(s) that are important to evaluation of the clinical trial. Source data will be available for all 
data in the CRFs, including all laboratory results. 
An audit of the study may be conducted in the course of the study. 
 
 
4.11. 
Data Management 
CRF entries and corrections will only be performed by trained study site staff authorized by the 
investigator. 
All visit data need to be recorded in the database as soon as possible after each visit. The investigator 
or investigator’s authorized staff must ensure that all information derived from source documents 
should be consistent with the source information. 
Deviations from the protocol will be documented. A major protocol violation is defined as a violation 
that may impact subject safety, affect the integrity of study data and/or affect subject’s willingness 
to participate in the study. A minor deviation is a violation that does not impact subject safety, 
compromise the integrity of study data and/or affect subject’s willingness to participate in the study. 
 
 
Corrections may be requested as follows: 
Investigators’ responses are checked as they are entered and are rejected if they do not fulfill quality 
criteria. A message will specify the type of error or syntax error and assist in its correction. 
If required, the monitor can ask for information to be corrected during study-site visits. Manual 
checks will identify clinical data discrepancies for resolution. Corresponding queries will be sent and 
the site will be informed about new issues to be resolved online. 
All discrepancies will be solved on-line directly by the investigator or authorized staff. Once all the 
Data Quality Control steps have been performed, the database will be locked and the records will be 
released for reporting and statistical evaluation. 
 
 
4.12. 
Ethics 
The trial will be conducted in accordance with the protocol, ICH-GCP guidelines and the Declaration 
of Helsinki for biomedical research involving human subjects. 
 
 
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4.12.1. Informed Consent Form of Trial Subjects (AMG §38) 
 
 
In obtaining and documenting informed consent, the investigator must comply with the applicable 
regulatory requirement(s) and adhere to ICH guideline for GCP and the requirements in the 
Declaration of Helsinki. 
Prior to any trial-related activity, the investigator or an authorized physician must give the subject 
oral and written information about the trial in a form that the subject can read and understand. 
A voluntary, signed and dated Informed Consent Form will be obtained from the subject prior to any 
trial-related activity. The subject must have consented to participate after the nature, scope and 
possible consequences of the clinical trial have been explained in a form understandable to him. 
The written informed consent must be signed by the person who conducted the informed consent. 
Since this trial is conducted in the ICU, at least part of the patients will be unconscious or 
compromised in their ability to understand the purpose and nature of the trial. As soon as patients 
recover and are able to understand the purpose and nature of the trial, they will be informed about 
their inclusion and informed consent will be sought. 
If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner, and a revised 
written informed consent must be obtained. 
 
 
4.12.2. Independent Ethics Committees (AMG §§40, 41) 
Prior to commencement of the trial, the protocol, any amendments, Subject Information/Informed 
Consent Form, any other written information to be provided to the subject, subject recruitment 
procedures (e.g. advertisements), if any, investigator’s Brochure (IB), package insert (if marketed 
product), information about payments and compensation available to subjects if not mentioned in 
the subject information, the investigator’s current CV and/or other documentation evidencing 
qualifications, and other documents as required by the local Independent Ethics Committee (IEC) 
should be submitted. The submission letter should clearly identify (by including version no. and/or 
date of the document) which documents have been submitted to the IRB/IEC. Written 
approval/favorable opinion must be obtained from the IEC prior to commencement of the trial. 
During the trial, the investigator must promptly report the following to the IEC: Updates to IB, 
unexpected SAEs where a causal relationship cannot be ruled out, amendments to the protocol, 
notes of administrative changes, deviations to the protocol implemented to eliminate immediate 
hazards to the trial subjects, new information that may affect adversely the safety of the subjects or 
the conduct of the trial, annually written summaries of the trial status, and other documents as 
required by the local IEC. 
 
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Amendments must not be implemented before approval/favorable opinion, unless necessary to 
eliminate immediate hazards to the subjects. 
 
 
4.12.3. Regulatory Authorities 
The Regulatory Authorities will receive the protocol, amendments, reports on SAEs, and the Final 
Report according to EU Directive and national regulations. 
 
 
4.12.4. Insurance (AMG § 32(2)) 
All subjects participating in this interventional trial will be insured through the Department of Clinical 
Pharmacology, Vienna University Hospital. The insurance is contracted with the ZÜRICH 
Versicherungs-AG, 1010 Wien, Schwarzenbergplatz 15, Policy number 07229622-2. 
 
 
4.12.5. Confidentiality 
All subject names will be kept secret in the investigator’s files. 
 
 
4.12.6. Premature Termination of the Trial 
The investigator may decide to stop the trial or part of the trial at any time, but agreement on 
procedures to be followed must be obtained. If a trial is prematurely terminated or suspended, the 
investigator should promptly inform the subjects and assure appropriate therapy and follow-up. 
Furthermore, the investigator should promptly inform the IRB/IEC and provide a detailed written 
explanation. The pertinent regulatory authorities should be informed according to national 
regulations. 
 
 
4.12.7. Retention of Clinical Trial Documentation 
Subject notes must be kept for the maximum time period as permitted by the hospital, institution or 
private practice. Other source documents and the investigator’s trial file must be retained for at least 
15 years or longer in accordance with local regulation. 
The investigator must agree to archive the documentation pertaining to the trial in an archive after 
completion or discontinuation of the trial, if not otherwise notified. If any modifications become 
necessary or desirable, these will be documented in writing; major changes require the approval of 
all investigators and the ethics 
 
 
 
 
 
 
 
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5. List of abbreviations 
 
AA = Arachidonic Acid 
 
ASA = Acetylsalicylic Acid 
 
AUC = Area Under the Curve 
 
CI = Confidence Interval 
 
COX-1/-2 = Cyclooxygenase -1/-2 
 
DVT = Deep Venous Thrombosis 
 
ICU = Intensive Care Unit 
 
IMP = Investigational Medicinal Product 
 
i.v. = intravenous 
 
MCI = Myocardial Infarction 
 
MEA = Multiple Electrode Aggregometry 
 
PD = Pharmacodynamic 
 
PE = Pulmonary Embolism 
 
PGI-2 = Prostacyclin 
 
PK = Pharmacokinetic 
 
PME = Post-Mortem Examination 
 
TXA-2 = Thromboxane A2 
 
TXB-2 = Thromboxane B2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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