A Phase III Double-blind Placebo-controlled Randomised Trial of Aspirin on Recurrence and Survival in Colon Cancer Patients
Phase: PHASE3
Conditions: Colon Cancer
Sponsor: University Hospital, Antwerp

 
 
 
 
A Phase III double-blind placebo-controlled 
Randomised Trial of Aspirin on Recurrence and 
Survival in Colon Cancer Patients 
 
 
 
BE 2017-001397-41. 
Version 5.0 - Belgium (26 March 2020) 
 
Coordinating Investigator Belgium: 
Prof. Dr. M. Peeters, Oncology Dept., University Hospital Antwerp, UZA, Edegem, Belgium 
 
Coordinating Investigator The Netherlands: 
Dr. G.J. Liefers, Dept. Surgical Oncology, LUMC, Leiden, The Netherlands 
 
Central Data- and Trial Management: 
M. De Roose & S. Raats, Multidisciplinair Oncology Centre Antwerp, Antwerp University Hospital, 
UZA, Edegem, Belgiumaspirin@uza.be, Tel: +32 3 8214082, Tel.: +32 3 8214215 
Backup: G. Vanhoutte, L. De Backer & S. De Keersmaecker, Multidisciplinair Oncology Centre 
Antwerp, Antwerp University Hospital, UZA, Edegem, Belgium, aspirin@uza.be, Tel: +32 3 8214215, 
Tel: + 32 3 8215274, Tel: + 32 3 8215275, Tel.; +32 3 8214279 
Ir. W.M. Meershoek-Klein Kranenbarg, Clinical Research Center Dept. of Surgery, LUMC, Leiden, The 
Netherlands 
Ing. J.P.B.M. Braak, Clinical Research Center Dept. of Surgery, LUMC, Leiden, The Netherlands 
clinicalresearchcenter@lumc.nl, Tel: +31-71-5263500 
 
Study Sponsor (Belgium):  
Antwerp University Hospital (Universitair Ziekenhuis Antwerpen)  
 
Statistics:  
Dr. E. Bastiaannet, Dept. Surgical Oncology, LUMC, Leiden, The Netherlands 
 
Data Safety Monitoring Committee: 
Chair: Prof. Dr. A.J. Gelderblom, Dept of Oncology, LUMC, Leiden, The Netherlands 
 
FAGG approval: 11 July 2017 
Ethical Committee approval: 31 July 2017     

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PROTOCOL SIGNATURE SHEET 
 
 
A Phase III double-blind placebo-controlled 
Randomised Trial of Aspirin on Recurrence and 
Survival in Colon Cancer Patients 
 
ASPIRIN trial 
 
 
BE 2017-001397-41 
Version: v5.0- Belgium (26 March 2020) 
 
I have read this protocol and agree that it contains all necessary details for carrying out this study. I 
agree to conduct this trial in accordance with all stipulations of the protocol and in accordance with 
the principles outlined in the Declaration of Helsinki. 
 
Name + function 
Site 
Signature 
Date 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS ................................................... 6 
2. 
SUMMARY .................................................................................................................... 9 
3. 
FLOW CHART ASPIRIN TRIAL ........................................................................................ 11 
4. 
INTRODUCTION AND RATIONALE ................................................................................. 12 
5. 
OBJECTIVES ................................................................................................................. 17 
6. 
STUDY DESIGN ............................................................................................................. 18 
7. 
STUDY POPULATION .................................................................................................... 20 
7.1  
Population .......................................................................................................................... 20 
7.2   Inclusion criteria .................................................................................................................... 20 
7.3 
Exclusion criteria ................................................................................................................. 20 
7.4    Sample size calculation .......................................................................................................... 21 
7.5     International Collaboration ................................................................................................... 21 
7.5.1   Collaboration between LUMC and UZA ...................................................................................... 21 
7.5.2   Collaboration with the Add-Aspirin trial ..................................................................................... 22 
8. 
TREATMENT OF SUBJECTS ............................................................................................ 23 
8.1    Investigational product/treatment ......................................................................................... 23 
8.2    Concomitant medication ....................................................................................................... 23 
8.2.1   Gastroprotection ......................................................................................................................... 23 
8.2.2   Chemotherapy ........................................................................................................................... 23 
9. 
INVESTIGATIONAL MEDICINAL PRODUCT ..................................................................... 24 
9.1    Aspirin .................................................................................................................................. 24 
9.2    Summary of findings from non-clinical studies ....................................................................... 24 
9.3    Summary of findings from clinical studies ............................................................................... 25 
9.4    Summary of known and potential risks and benefits ............................................................... 25 
9.4.1   Gastrointestinal ......................................................................................................................... 25 
9.4.2   Central effects ............................................................................................................................. 26 
9.4.3  Hives and swelling ........................................................................................................................ 26 
9.4.4   Other effects .............................................................................................................................. 26 
9.4.5   Precautions ................................................................................................................................ 26 
9.4.6   Pregnancy .................................................................................................................................. 26 
9.4.7   Overdose .................................................................................................................................... 27 

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9.5    Description and justification of route of administration and dosage ............................... 27 
9.6    Dosages, dosage modifications and method of administration ................................................ 27 
9.7    Preparation and labelling of Investigational Medicinal Product ............................................... 28 
9.8    Drug accountability ............................................................................................................... 28 
10. 
METHODS ................................................................................................................ 29 
10.1  Study parameters/endpoints ................................................................................................. 29 
10.1.1 Main study parameter/endpoint ................................................................................................ 29 
10.1.2 Secondary study parameters/endpoints ................................................................................... 29 
10.1.3 Tertiary parameters .................................................................................................................... 29 
10.1.4 Other study parameters ............................................................................................................ 30 
10.2  Randomisation and treatment allocation ............................................................................... 30 
10.2.1 Patient randomisation procedure ............................................................................................. 30 
10.2.2 Unblinding ................................................................................................................................. 31 
10.3  Study procedures .................................................................................................................. 32 
10.3.1 Before treatment starts ............................................................................................................. 32 
10.3.2 During adjuvant therapy (years 1-5) .......................................................................................... 32 
10.4  Withdrawal of individual subjects .......................................................................................... 33 
10.4.1 Specific criteria for withdrawal .................................................................................................. 33 
10.4.2 Replacement of individual subjects after withdrawal ................................................................ 34 
10.4.3 Follow-up of subjects withdrawn from treatment ..................................................................... 34 
10.5 Premature termination of the study ....................................................................................... 35 
10.6 Data collection and data storage ............................................................................................ 35 
11. 
SAFETY REPORTING .................................................................................................. 36 
11.1  Ethical Committee ................................................................................................................. 36 
11.2  Adverse and serious adverse events ....................................................................................... 36 
11.2.1 Suspected unexpected serious adverse reactions (SUSAR) ........................................................ 37 
11.2.2 Recording of adverse events ...................................................................................................... 37 
11.2.3 Annual safety report .................................................................................................................. 38 
11.3  Follow-up of adverse events .................................................................................................. 38 
11.4  Data Safety Monitoring Board (DSMB) ................................................................................... 38 
11.5  Monitoring ........................................................................................................................... 38 
12. 
STATISTICAL ANALYSIS .............................................................................................. 40 
12.1  Descriptive statistics ............................................................................................................. 40 
12.2  Univariate analysis ................................................................................................................ 40 

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12.3  Multivariate analysis ............................................................................................................. 41 
12.4  Interim analysis..................................................................................................................... 41 
13. 
ETHICAL CONSIDERATIONS ....................................................................................... 42 
13.1  Regulation statement ............................................................................................................ 42 
13.2  Recruitment and consent ...................................................................................................... 42 
13.3  Objection by minors or incapacitated subjects ........................................................................ 42 
13.4  Benefits and risks assessment, group relatedness ................................................................... 42 
13.5 Compensation for injury ......................................................................................................... 43 
14. 
DATA COLLECTION AND REPORTING DOCUMENTS ...................................................... 44 
14.1  Guidelines completion of Case Report Forms (CRFs) ............................................................... 44 
14.2  Amendments ........................................................................................................................ 44 
14.3  Annual progress report .......................................................................................................... 44 
14.4  End of study report ............................................................................................................... 45 
14.5  Public disclosure and publication policy ................................................................................. 45 
15. 
FINANCES ................................................................................................................. 46 
16. 
REFERENCES ............................................................................................................. 47 
17. 
APPENDICES ............................................................................................................. 51 
APPENDIX 1: EORTC QLQ-C30 (version 5) ........................................................................................ 51 
APPENDIX 2: Modified ADL and IADL .............................................................................................. 53 
APPENDIX 3: PRO-CTCAE items ...................................................................................................... 54 
APPENDIX 4: G8 ............................................................................................................................ 57 
APPENDIX 5: ACE-27 ...................................................................................................................... 58 
APPENDIX 6: Social Situation ......................................................................................................... 60 
APPENDIX 7: CTCAE v4.0 ................................................................................................................ 61 
APPENDIX 8: ASPIRIN protocol scheme .......................................................................................... 62 
APPENDIX 9: Guidelines for monitoring .......................................................................................... 63 
9.1. NFU guideline for monitoring ......................................................................................................... 63 
9.2. Monitoring guidelines for CRF completion ..................................................................................... 63 
APPENDIX 10: Safety Manual ......................................................................................................... 73 
 
 

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1. 
 LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS 
 
ADL 
Activities of Daily Life Questionnaire 
AE  
 
Adverse Event 
 
AFAP 
Attenuated Familial Adenomatous Polyposis 
APC 
Adenomatous Polyposis Coli 
ASA 
American Society of Anesthesiologists 
BCC 
Basal-cell carcinoma 
CAP 
Capecitabine (Xeloda) OX- oxaliplatin (Eloxatin) 
CAPOX 
Chemotherapy regimen consisting of capecitabine combined with  
oxaliplatin 
CBPL 
Commissie voor de Bescherming van de Persoonlijke Levenssfeer 
(Privacy Commission) 
CEA  
Carcinoembryonic antigen, tumour marker 
 
CIN 
Cervical intraepithelial neoplasia 
CRC 
Colorectal Cancer 
CSCs 
Colon cancer stem cells 
CTCAE 
Common Terminology Criteria for Adverse Events 
CXCL1 
Chemokine Ligand 1 
 
DOAC 
Direct Oral AntiCoagulants 
DFS 
Disease Free Survival 
DSCA 
Dutch Surgical Colorectal Audit 
DSMB EORTC 
Data Safety Monitoring Board 
European Organisation for Research and Treatment of Cancer 
(e)CRF 
(electronic) Case Report Form 
EudraCT  
European drug regulatory affairs Clinical Trials 
 
FAGG 
Federaal agentschap voor geneesmiddelen en gezondheidsproducten 
FAP 
Familial Adenomatous Polyposis 
 
FOLFOX 
A chemotherapy regimen for treatment of colorectal cancer, made up of 
the drugs folinic acid-fluorouracil-oxaliplatin 
O
l
d (l
)
l
l (5
)

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GCP  
Good Clinical Practice 
 
GI 
Gastro-Intestinal 
 
GMP 
Good Manufacturing Practice 
HLA 
Human leukocyte antigen 
 
IADL 
Instrumental Activities of Daily Living 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IFN 
Interferon 
iFOBT 
Immunochemical fecal occult blood test 
IL 
Interleukin 
IMP 
Investigational Medicinal Product 
IMPD  
 
Investigational Medicinal Product Dossier 
 
LMWH 
Low molecular weight heparin 
LUMC 
Leiden University Medical Center 
MAP 
MYH-Associated Polyposis 
MIC 
Macrophage Inhibitory Cytokin 
NFU 
Netherlands Federation of University Medical Centres; in Dutch: 
Nederlandse Federatie van Universitair Medische Centra 
NSAID 
Nonsteroidal anti-inflammatory drug 
OS 
Overall Survival 
PIK3CA 
Phosphatidylinositol 3-kinase catalytic 110-KD alpha 
Po 
 
Per os 
 
PPI  
 
Proton-pump inhibitor, medication for reduction of gastric acid 
production 
PROs 
Patient Reported Outcomes 
PTGS 
Prostaglandin-G Synthase 
 
SAE  
Serious Adverse Event 
SCC 
Squamous Cell Carcinoma 

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SPC 
Summary of Product Characteristics 
Sponsor 
The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical company, 
academic hospital, scientific organisation or investigator. A party that 
provides funding for a study but does not commission it is not regarded 
as the sponsor, but referred to as a subsidising party. 
SSRI 
Selective serotonin reuptake inhibitor 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TNM 
Tumour Node Metastasis 
TTF 
Time to Treatment Failure 
UICC 
Union for International Cancer Control 
UZA 
Antwerp 
University 
Hospital 
(Dutch: 
Universitair 
Ziekenhuis 
Antwerpen) 
QLQ 
Quality-of-Life Questionnaire 
 
 

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2. 
SUMMARY 
 
Rationale: Preclinical, epidemiologic and clinical evidence suggest that acetylsalicylic acid use may 
reduce overall cancer risk and mortality in colon cancer patients. 
 
Objective: To investigate acetylsalicylic acid 80 mg po daily for 5 years as an adjuvant therapy in 
curatively operated, stage II and III colon cancer patients. 
 
Study design: A phase III double-blind placebo-controlled randomised trial of adjuvant low- dose 
acetylsalicylic acid in colon cancer patients. The question will be addressed by means of two 
parallel studies in patients treated with or without adjuvant chemotherapy. 
 
Study population: 
• Patients 45 years and older with histologically confirmed adenocarcinoma of the colon 
• Patients must have TNM stage that is one of the following: pT3-4; N0-2 and M0, or pT1-2 
and  N1-2 (Union for International Cancer Control (UICC) stage II and III) (in case of >1 tumour: 
more advanced tumour is stage II or III) 
• Patients must have completed surgical resection (R0) (both laparoscopic and open surgery) 
within 12 weeks of randomisation 
 
Exclusion: 
•   Patients with rectal cancer (defined as tumour within 15 cm from the anal verge) 
•   Patients currently taking oral anti-coagulants or use of low molecular weight heparin   
       (LMWH) or use of DOACs 
•   Patients currently taking (low-dose) acetylsalicylic acid or other anti-aggregantia for any reason 
•   Patients with a history of bleeding disorders or active gastric or duodenal ulcers 
• Patients currently taking high dose systemic glucocorticoids (≥ 30 mg predniso(lo)n or 
equivalent) 
• Patients with (suspected) (non-) polyposis  syndrome (Familial Adenomatous Polyposis 
(FAP)/ Attenuated Familial Adenomatous Polyposis (AFAP), MYH-Associated Polyposis (MAP), 
Lynch syndrome) 
• Patients with >100 polyps of the colon or a known hereditary syndrome of the colon 
in a first degree family member 
• Allergy or intolerance to salicylates 
• Patients with local or distant recurrent disease 
• Previous malignancies other than cervical intraepithelial neoplasia (CIN) or squamous cell 
carcinoma (SCC) with a disease free survival less than 5 years 
• Presence of any psychological, familial, sociological or geographical condition potentially 
hampering compliance with the study protocol and follow-up schedule; those conditions 
should be discussed with the patient before registration in the trial 
 
Intervention: Patients will be randomised for acetylsalicylic acid 80 mg po daily for 5 years versus 
placebo.     
 
 
 

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Main study parameters/endpoints: The primary endpoint of the trial is 5year Overall Survival 
(5-yr OS). Secondary endpoints are Time to Treatment Failure (TTF; time elapsed between 
randomisation until treatment discontinuation due to disease recurrence, unacceptable toxicity, 
death or any other event of interest) and 3-year Disease Free Survival (DFS); time to recurrence or 
death due to any cause. The trial is powered to identify a hazard ratio of 0.75 in the acetylsalicylic 
acid arm, with 80 percent power and a type 1 error of 0.05 (2-sided). In order for the trial to be 
successful, 1588 patients need to be randomised. 
 
Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness: Unexpected adverse events may occur. Given the widespread use of low-dose 
acetylsalicylic acid in cardiovascular risk management, it is unlikely that new toxicities will be 
identified. However, adverse anti-cancer effects may be identified. An independent data safety 
monitoring board will oversee trial conduct. A planned interim futility analysis allows early 
termination of the study if it appears that acetylsalicylic acid will not favourably impact colon 
cancer outcome. 
 
International Collaboration 
This trial is part of a collaboration with the Dutch ASPIRIN trial (NL 38132.058.14). The rationale 
for this collaboration is to accelerate accrual. Both protocols are similar in such a way that allows 
data to be pooled for analysis. One database will be used to collect all data for both countries, central 
data management will be performed by the Datacenter Department of Surgery of the Leiden 
University Medical Center (LUMC) in Leiden, The Netherlands. The total number of required 
patients will be 1588 of which 400 patients will be randomised in the Belgium trial. 
 

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3. 
FLOW CHART ASPIRIN TRIAL 
 
 
 
Primary endpoint: 5 year OS, assuming HR 0.75 with 80% power and type 1 error of 0.05 (2-
sided), 1588 patients need to be randomised.  
 
The Belgian ASPIRIN trial is part of a collaboration with the Dutch ASPIRIN trial. In total 1588 
patients need to be randomised. Four hundred of these patients will be part of the Belgium trial. 
See 7.5 for more information about the collaboration. 
 

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4. 
INTRODUCTION AND RATIONALE 
 
Epidemiology 
Colorectal cancer is one of the most common cancers in developed countries, with about one 
million new cases each year and a mortality rate of nearly 33% (Cunningham et al., 2010). For 
both men and women, in Europe colorectal cancer is the second cause of cancer death. In Europe, 
in 2012 there were 447.000 new colorectal cancer patients and 215.000 patients died of colorectal 
cancer (Ferlay et al., 2014).  
In Belgium colorectal cancer is the 2nd and 3rd cause of cancer-related death in males and females 
respectively. In 2013 there were 8406 new patients diagnosed with colorectal cancer and the 
incidence rate increased with almost 30% from 2004 till 2013 (Belgian Cancer Registry, 2013). The 
5-year overall survival is approximately 66-67% and the incidence is expected to increase in the 
near future. The cornerstone of treatment for CRC is surgical resection. Adjuvant chemotherapy is 
recommended for TNM classified stage III and IV patients and for high risk stage II patients. Despite 
encouraging advances in surgical techniques and improved therapeutic protocols, studies have 
reported that on estimate 20%-35% of stage II-III patients eventually relapse and die from 
metastatic disease. 
Initial therapy after diagnosis usually comprises primary surgical resection. When there is 
evidence of nodal involvement patients often receive adjuvant chemotherapy following initial 
surgery in an attempt to prevent metastatic spread (Cunningham et al., 2010). 50-60% of patients 
diagnosed with colorectal cancer eventually develop metastasis (National Comprehensive Cancer 
Network, 2014). Approximately 35% of patients presenting with stage III, 20% of patients with 
stage II, and 5 to 10% of patients with stage I cancer eventually relapse and subsequently die from 
metastatic disease (Goodwin & Asmis, 2009). 
 
Adjuvant therapy in colon cancer 
Surgical resection remains the corner stone of colon cancer treatment. For patients with an 
indication for adjuvant treatment, the combination of 5-fluorouracil and leucovorin or 
capecitabine and oxaliplatin (FOLFOX or CAPOX) is the current standard of care (College of 
Oncology, 2014; Goodwin & Asmis, 2009). The MOSAIC trial randomised 2246 patients with stage 
II or III colon carcinoma between 5FU/LV or 5-FU/LV+oxaliplatin. Results of this trial showed an 
increase in disease-free survival at 3 years from 72.9 to 78.2% (p = 0.002) for the addition of 
oxaliplatin to FU/LV. Five-year disease-free survival remained significant (HR: 0.80; p = 0.003) 
and at 6 years there was an overall survival benefit for stage III patients (68.3% versus 72.9%). 
The addition of oxaliplatin to LV5FU2 was associated with an increase in neutropenia, febrile 
neutropenia and neuropathy (Marshall et al., 2007). 
 
In the current guidelines for Belgium (Alberts et al., 2012; Het Federaal kenniscentrum voor 
Gezondheidszorg, 2014; Van Cutsem et al., 2009), adjuvant chemotherapy is recommended for 
stage III colon cancer. In fit patients, fluoropyrimidine and oxaliplatin is the combination of choice 
(Alberts et al., 2012; Het Federaal kenniscentrum voor Gezondheidszorg, 2014). In October 2013 
the screening program for colorectal cancer in Belgium started. According to the guidelines of the 
European Union the first phase of this program is for both men and women in the age group 56-
74 years. In a next phase, the decision will be made to include also the age group 50-55 years.  The 
results of the first phase of the screening program state that there are about 6 persons on 1000 

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participants who developed a colorectal cancer in situ and 7 persons out of 1000 participants 
developed invasive colorectal cancer (Bevolkingsonderzoek dikkedarmkanker, 2015). This 
detection limit is between 1.8% and 9.5% in accordance with the European Guidelines for 
population screening using immunochemical fecal occult blood test (iFOBT) (EU Guidelines & 
Crotta et al. 2004; Grazzini et al. 2004; Fenocchi et al. 2006; Saito). 
 
   Acetylsalicylic acid and cancer 
Acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs (NSAIDs) have shown to be 
effective in the prevention of colorectal cancer. Evidence for the role of acetylsalicylic acid as an 
anti-cancer agent comes from large trials primarily assessing the cardiovascular benefits of daily 
acetylsalicylic acid. In a pooled analysis of 5 large trials it was recently shown that 
acetylsalicylic acid taken for several years at doses of at least 75 mg daily reduced long-term 
incidence and mortality due to colorectal cancer (Rothwell et al., 2010). 
In another meta-analysis acetylsalicylic acid was shown to significantly reduce adenoma formation 
in patients with a history of colorectal cancer (Cole et al., 2009). 
Indirect evidence for acetylsalicylic acid as an adjuvant therapy comes from a report from Chan et 
al. In a non-randomised study they found that regular users of acetylsalicylic acid after the 
diagnosis of colorectal cancer had a reduced colorectal cancer-specific mortality (HR 0.71, 95% 
CI: 0.53-0.95) (Chan, Ogino, & Fuchs, 2009). 
These data are very similar with data from our own study. In a large retrospective series of 
4481 patients with colon cancer we found that acetylsalicylic acid use initiated after the diagnosis 
colon cancer was associated with a significantly increased overall survival (adjusted RR 0.61 
(95%CI 0.46-0.81; p=0.001) (Bastiaannet et al., 2012). 
In a third population based study from Scotland, the same conclusion was reached. In 2990 
patients, acetylsalicylic acid use post-diagnosis was associated with a lower risk of all-cause 
mortality (HR 0.67, 95% CI: 0.57-0.79) (McCowan, Munro, Donnan, & Steele, 2013). Increasing age 
at diagnosis was also associated with increased risk reduction. 
In contrast a fourth study by Walker et al. showed a more modest risk reduction of 9 percent (HR 
0.91. 95% CI: 0.84-0.98). Subgroup analysis showed that the benefit was confined to those patients 
who also used acetylsalicylic acid before the diagnosis (Walker, Grainge, & Card, 2012). Again, 
in the report by Walker et al. the effect of acetylsalicylic acid seemed stronger in older patients 
and in colon cancer patients. 
In recent publications from Chan et al. and Liao and co-workers, using the same cohort, 
acetylsalicylic acid use was associated with longer survival in PTGS2 expressing tumours and 
PIK3CA mutated tumours only. In that study, the hazard ratio for cancer related death was even 
0.18 (95% CI 0.06-0.61), but only in tumours harboring a PIK3CA mutation (Liao et al., 2012). These 
results were validated by Domingo et al. where PIK3CA mutations were predictive for 
acetylsalicylic  acid  benefit (Domingo et al., 2013). Interestingly, this study was not able to validate 
the predictive value of PTGS2 expression. 
The magnitude of the clinical benefits seen with acetylsalicylic acid in colorectal cancer seem to be 
larger, for example in Peter Rothwell’s data, than could be explained by an effect on the 
approximately 15% of colorectal tumours with mutated PIK3CA. It is therefore unlikely that all 
effects of acetylsalicylic acid can be explained by this one mutation. 
Acetylsalicylic acid use has also been associated with a decreased risk of developing a colorectal 
tumour with an intact BRAF gene but no association between post-diagnosis acetylsalicylic acid 
use, BRAF mutation status and clinical outcome has been found (Nishihara et al., 2013) 

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Recently, our group was not able to validate the predictive value of PIK3CA mutations and PTGS2 
expression with low-dose acetylsalicylic acid, but did find a survival benefit with acetylsalicylic 
acid in tumours expressing HLA class I antigen only (Reimers et al., 2014). Altogether, these data 
indicate that in subgroups of patients the effect may be larger than in others, however, the findings 
remain inconsistent. A trend towards multifactorial approach of the etiology and treatment of 
colorectal cancer is ongoing. Not just isolated biomarkers seem to determine prognosis but 
molecular subtyping of tumours will be the future. This can also be helpful in developing new 
agents for the treatment of colorectal cancer (Linnekamp, Wang, Medema, & Vermeulen, 2015). 
Currently three other trials are studying the effect of acetylsalicylic acid as adjuvant treatment in 
colorectal cancer. The ASCOLT trial in Singapore is a randomised, placebo-controlled trial studying 
the effect of acetylsalicylic acid 200 mg in patients with Dukes B and C colorectal tumour. The 
ALASCCA trial, currently under development, will be carried out in Sweden, and studies the effect 
of 80 mg acetylsalicylic acid in patients with PIK3CA mutated colorectal tumours. 
In the near future the Add-Aspirin trial, carried out in India and the United Kingdom, will start 
including patients. This trial will randomise patients with different types of cancer for 
acetylsalicylic acid vs placebo treatment. Patients with upper gastro intestinal tumours, breast 
cancer, prostate cancer and colorectal cancer are eligible for inclusion. 
Very recent new retrospective data again report that in parallel to the chemo preventive 
action of acetylsalicylic acid, this cheap and well tolerated drug is also implicated in prevention of 
distant metastases (Algra & Rothwell, 2012; Rothwell et al., 2012a; Rothwell et al., 2012b). These 
data from Rothwell indicate that acetylsalicylic acid might help in treatment of some cancers and 
provides proof of principle for pharmacological intervention specifically to prevent distant 
metastasis. Nevertheless, there is an urgent need for more randomised trials to prove the role of 
acetylsalicylic acid in the adjuvant treatment of cancer. 
 
The mechanism by which acetylsalicylic acid exerts its activity is not completely understood. The 
protective activity of acetylsalicylic acid has been attributed to direct inhibition of the 
prostaglandin-endoperoxide synthase (PTGS), also known as cyclooxygenase (COX), family of 
enzymes involved in prostaglandin synthesis. The PTGS2 enzyme is strongly and rapidly induced 
in response to mediators of inflammation, growth factors, cytokines, and endotoxins; and its 
expression correlates with increased cell proliferation and tumour promotion (Herschman, 1996). 
Acetylsalicylic acid can decrease the production of potentially neoplastic prostaglandins arising 
from PTGS2-mediated catalysis of arachidonic acid (Vane, 1971). However, acetylsalicylic acid has 
a much broader range of downstream effectors, such as NF-KB, insulin-like growth factor I 
(IGF-I) and many others, as well as the inhibition of Wnt signaling and stem cell growth 
possibly as the result of enhanced beta-catenin (Dihlmann, Klein, & Doeberitz, 2003; Dihlmann, 
Siermann, & von Knebel, 2001; Wang et al., 2006). 
Cancer is a heterogeneous disease encompassing differentiated cell types but also less committed 
stem-like cells. Recent evidence suggests that a subpopulation of tumour cells with distinct 
features such as self-renewal and the ability to differentiate into multiple lineages is responsible 
for tumour initiation, invasive growth and possibly dissemination to distant organ sites. The 
acquired ability of a cell to resist to apoptosis is a hallmark of almost all types of cancer. 
Recently, it has been shown that IL-4 expression is essential for the resistance to DNA damage-
induced apoptosis of colon cancer stem cells (CSCs) (Todaro et al., 2007). CSCs are also resistant 
to the cytotoxic effect of chemotherapy. It has been shown that IL-4 confers colon CSCs with 
resistance to apoptosis (Todaro et al., 2007). Consistently, treatment with IL-4Ra antagonist or 

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anti-IL-4 neutralizing antibody strongly enhances the anti-tumour efficacy of standard 
chemotherapeutic drugs through selective CSCs sensitization. Notably, acetylsalicylic acid inhibits 
IL-4 gene expression (Cianferoni et al., 2001). 
Based on the above observations, it is plausible that acetylsalicylic acid may both act as a 
preventive agent in CRC onset by modulating the Wnt pathway in CSCs, but also as adjuvant 
treatment by increasing CSCs' sensitivity to conventional chemotherapy regimens. 
 
Acetylsalicylic acid and (non-) polyposis syndrome 
Patients with (non-) polyposis syndrome are not eligible for inclusion in this trial. These patients 
have a different prognosis and different tumour characteristics (Brixen, Bernstein, Bulow, & 
Ehrnrooth, 2013; Myrhoj et al., 1997; Stigliano et al., 2008). 
Additionally, the CAPP2 trial has examined the effect of 600 mg acetylsalicylic acid vs 
placebo in patients with Lynch syndrome plus previously affected patients within families meeting 
the Amsterdam criteria. This is the first large scale genetically targeted chemoprevention trial, 
which randomly assigned 861 participants to acetylsalicylic acid or placebo. Results showed when 
acetylsalicylic acid is used for at least two years, cancer incidence is reduced by 63% (IRR 0.37, 
95% CI 0·18–0·78, p=0·008) (Burn et al., 2011). At this moment the CAPP3 trial is investigating 
the optimum low-dose acetylsalicylic acid to administer in at least 3000 gene carriers (Burn, 
Mathers, & Bishop, 2012). By excluding patients younger than 45 years, patients with a high a 
priori chance of (non-) polyposis syndrome are excluded. 
 
Risk-benefit 
Acetylsalicylic acid, even at low-doses appropriate for cardiovascular risk management, roughly 
doubles the incidence of gastric bleeding, and one or two people in every thousand are likely to 
have a bleeding every year. This risk rises with age and in people older than 80 years, it might be 
as high as seven per 1000 people every year (Elwood, Gallagher, Duthie, Mur, & Morgan, 2009). 
Age specific changes in the risk-benefit ratio of the preventive role of acetylsalicylic acid remain 
unclear. Data on the risk-benefit ratio for cancer prevention are insufficient and no definitive 
recommendations by a recent international consensus statement could be made regarding the 
preventive use of acetylsalicylic acid (Cuzick et al., 2009). 
However, the demonstration of a significant therapeutic effect of acetylsalicylic acid as adjuvant 
treatment will alter the balance of risk and benefit importantly. The data from Chan et al., our 
own data and many more observational studies show a reduction of all-cause mortality (thereby 
including any fatal bleeds) up to 30 % (Bastiaannet et al., 2012; Chan et al., 2009; Chia, Ali, & Toh, 
2012; Reimers et al., 2014). This potential benefit of acetylsalicylic acid is therefore additional to 
the risk-benefit equation in which the risk of bleeding is already offset by other benefits of 
acetylsalicylic acid i.e. prevention of ischemic stroke, myocardial infarction. 
 
 
 

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Relevance 
The currently limited testing of acetylsalicylic acid as a therapeutic agent in the adjuvant 
setting, is in marked contrast to the numerous studies that were initiated using selective PTGS2 
inhibitors before 2004.  
And, with recent high profile failures of adjuvant bevacizumab and cetuximab in resected CRC, 
findings of a potential adjuvant benefit with acetylsalicylic acid, is not only timely, but highly 
important. Acetylsalicylic acid is an unlikely anti-cancer drug, however if proven beneficial, has 
the potential to change treatment paradigms, with significant global health and socio-economic 
impact. Because acetylsalicylic acid is off-patent and costs a-penny, development of acetylsalicylic 
acid as an anti-cancer therapy will be critically dependent on public funding and collaborative 
support from academia. In an era of escalating cancer treatment costs, providing the evidence for 
cost-competitive solutions must also be a necessary strategy and imperative. In this process, 
acetylsalicylic acid should not be over looked because it is neither new nor expensive. 
 
Finally, there is data indicating that subgroups of patients harboring tumor with specific genetic 
mutations (e.g. PIK3CA, BRAF, RAS) may have a greater benefit than others (Cianferoni et al., 2001; 
Cunningham et al., 2010; Cuzick et al., 2009; Dihlmann, Klein & Doeberitz, 2003; Dihlmann, 
Siermann & von Knebel, 2001; Domingo et al., 2013). The goal of the study is to assess PIK3CA, 
BRAF and RAS prospectively. These analyses will then be correlated with overall survival and 
disease-free survival with appropriate methods (Cox Proportional Hazard Model) and adjustment 
and possible confounding factors.  
 
Key points 
• The number of colon cancer patients is increasing and there is a strong need for 
therapeutic improvement 
 
The colorectal cancer screening in Belgium has raised the incidence 
• Pre-clinical, epidemiological and clinical data demonstrate that acetylsalicylic acid use is 
associated with improved colon cancer outcome 
• Demonstration of a significant therapeutic effect of a well-tolerated drug that costs mere 
pennies per day would be a major clinical advance 
 

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5. 
OBJECTIVES 
 
Primary Objective: 
• To study the effect of 80mg acetylsalicylic acid (given orally once daily for 5 years) on 5 year 
overall survival (OS) for stage II and III colon cancer patients 
 
Secondary Objective(s): 
• To study the effect of acetylsalicylic acid on 3 year disease free survival (DFS) 
• To study the effect of acetylsalicylic acid on time to treatment failure (TTF) 
• To study the effect of acetylsalicylic acid on toxicity, for example the interaction of 
acetylsalicylic acid with chemotherapy 
 
Tertiary Objective (s): 
 
Genetic analysis on surgical specimen from all patients: PIK3CA, BRAF and RAS mutation 
analysis 
 
Evaluation of therapeutic compliance (using a diary on paper and/or via smartphone) and 
patient reported outcomes (using a web-based customized survey with patient access) 
 
Define subpopulations with greater adjuvant benefit using acetylsalicylic acid  
 

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6. 
STUDY DESIGN 
 
A phase III double-blind placebo-controlled randomised trial is proposed. Stage II and III 
colon cancer patients with or without adjuvant chemotherapy will be randomised between 
low-dose acetylsalicylic acid (80 mg) or placebo, within 12 weeks after radical resection. 
Treatment will start at least 10 days after surgery. Study medication will be continued for 5 years. 
The research question will be addressed in patients with and without adjuvant chemotherapy by 
means of two parallel studies. 
 
Trial timelines 
Patient inclusion in Belgium starts from 2017 till 2021. The follow-up period for every patient is 5 
years. Collection point of all data is scheduled in 2026-2027. 
 
Stratification factors: 
• Stage in the ‘no adjuvant chemotherapy’ arm 
• Age <70 years and ≥70 years 
 
Diary 
All patients, with or without adjuvant treatment, get the chance to fill out a diary for the therapy 
compliance.  
 
Biobanking: 
15 slides of the surgical resection specimen of the primary tumour will be requested by the biobank 
of UZA from the hospitals where the patients received surgical treatment. The slides will be stored 
in the biobank of the UZA until needed for downstream analysis of molecular biomarkers as 
described in the tertiary objectives above in this protocol. After DNA isolation and biomarker 
testing the left-over of the DNA will be stored in the biobank until maximum 30 years after the end 
of the study. Furthermore, data will be stored in the IT-platform regarding the surgical specimen. 
The individual results of the genetic analysis will be conserved. The patients give permission for 
the use of their clinical resection specimen and genetic testing by signing the informed consent (IC).  
 
Questionnaire (QLQ-C30, ADL, IADL) 
User-friendly electronic communication has proven feasible for treatment intake (Rasschaert et al., 
2016) and would further allow to prospectively evaluate patient reported outcomes (PROs) such 
as quality of life measures and questionnaires like PRO-CTCAE (Kluetz, Chingos, Basch, & Mitchell, 
2016) who are looking at gastro-intestinal bleeding or risk thereof. The self-reported 
questionnaires used in this study will measure the quality of life (QLQ-C30), activities of daily life 
(ADL), and instrumental activities of daily living (IADL). The questionnaires will be offered to the 
patients electronically (via email) or on paper, and will take approximately 20 minutes to complete.  
The paper questionnaires are processed by the UZA research team. The data from the electronic 
questionnaires are processed by order of UZA, on the instruction of the principal investigator, by 
Remedus BVBA, a service company for home care and home hospitalization (Boomsesteenweg 44, 
2630 Aartselaar). For this, Remedus BVBA has concluded a processing agreement with UZA in 
accordance with the applicable General Data Protection Regulation (GDPR). 

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To be able to process the data from the electronic questionnaires, the study patient must complete 
the "Application form for the Aspirin Trial". By completing this application form the patient agrees 
that Remedus BVBA will process his/her personal data including name, date of birth, national 
register number, home address, telephone number and email address. 
 
Web-based customized system 
Since the beneficial effect of acetylsalicylic acid is due to its chronic use by motivated patients, 
further evaluation of therapeutic compliance is important. The local investigator team is free to 
choose if they want to be engaged in the sub-study ‘AMTRA’ (Ambulant Monitoring of cancer 
Therapy using a smaRtphone Application). In this sub-study, only patients receiving adjuvant 
chemotherapy have the option to complete an additional questionnaire during the first 6 months. 
Patients will be questioned daily for the intake of study medication and symptomatic toxicity scores 
through an interactive email-based communication alongside physician reported CTCAE grades (at 
the follow-up visits) to obtain information about treatment tolerability. The 29 questions are 
adapted to the personal situation of the patient (e.g. type of chemotherapy). In this interactive 
system Remedus provides a mobile application ‘RemeCoach’ that the patients can download for 
free on their own smartphone. If any toxicity occurs, the physician will be informed quickly and 
advice can be given on –for example-  taking analgesic medication or pills for diarrhea and so on. 
After six months the patient can decide whether he/she wants to continue the follow-up via the 
mobile application (free of charge) or not. Continuing the follow-up after six months is only possible 
if the principal investigator agrees. 
If the patient wishes to participate in AMTRA, he/she agrees that Remedus BVBA will process 
his/her personal data (name, date of birth, telephone number, email, address) as well as the 
registrations in the smartphone application. 
 
All registrations will be monitored in an interactive email based communication system (RemeCare 
platform) by the central study coordinator. The RemeCare platform is also one of the services of 
Remedus BVBA. This IT-platform, the storage of personal data and the exchange with the electronic 
patient dossier is approved by the privacy commission of Belgium (CBPL).  
 
The patients will be informed by Remedus about this process. A Remedus nurse will visit the 
patient’s home once to explain the application. Once the procedure has become routine, the local 
investigator will inform the patients about the mobile application. However, the patients are able 
to contact Remedus by phone at any time to report technical problems or to ask questions about 
the use of the mobile application. During the follow-up visits, information about the treatment 
tolerability will be assessed. 
 
Patients without adjuvant chemotherapy, or patients receiving adjuvant chemotherapy who don’t 
want to participate in the sub-study AMTRA, will get a paper patient diary in which side effects and 
the intake of medication can be registered.  If the local investigator doesn’t want to be engaged in 
the sub-study AMTRA,  all study subjects will receive the paper patient diary.  
 
 
 

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7. 
STUDY POPULATION 
 
7.1  Population 
 
 
Patients with stage II or III colon cancer, 45 years of age and older after radical (R0) resection 
will be randomised 
 
Patients will be recruited from different Belgian hospitals (target number: 400)  
 
7.2   Inclusion criteria 
 
• Patients 45 years and older  
• Patients with histologically confirmed adenocarcinoma of the colon 
• Patients must have TNM stage that is one of the following: pT3-4; N0-2 and M0, or pT1-2 
and  N1-2 (UICC stage II and III) (in case of >1 tumour: more advanced tumour is stage II or III) 
• Patients who have undergone curative radical resection (R0 resection) within 12 weeks 
prior to study entry 
• Written informed consent according to national and local regulation 
 
7.3 Exclusion criteria 
 
• Patients with rectal cancer (defined as tumour within 15 cm from the anal verge) 
• Patients currently taking (low-dose) acetylsalicylic acid or other anti-aggregantia for any 
reason 
• Patients currently taking oral anti-coagulants or use of LMWH or use of DOACs 
• Patients with a history of bleeding disorders or active gastric or duodenal ulcers 
• Patients currently taking high dose systemic glucocorticoids. (≥ 30 mg predniso(lo)n or 
equivalent) 
• Patients with (suspected) (non-) polyposis syndrome (FAP/AFAP, MAP, Lynch syndrome) 
• Patients with >100 polyps of the colon or a known hereditary syndrome of the colon in a first 
degree family member (father/mother/brother/sister/son/daughter) 
• Allergy or intolerance to salicylates 
• Patients with local or distant recurrent disease 
• Previous malignancies other than CIN, BCC or SCC with a disease free survival less than 5 years 
• Presence of any psychological, familial, sociological or geographical condition potentially 
hampering compliance with the study protocol and follow-up schedule; those conditions 
should be discussed with the patient before registration in the trial 
 
 

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7.4    Sample size calculation 
 
Overall Survival 
The sample size calculation was performed on Overall Survival with the assumption that 
acetylsalicylic acid will increase Overall Survival with a hazard ratio of 0.75 in the acetylsalicylic 
acid group versus placebo (in our retrospective study the upper limit of the confidence interval 
in older patients was 0.78 (Bastiaannet et al., 2012). The study will consist of two parallel 
studies in patients who do and do not receive adjuvant chemotherapy (see flow chart Aspirin trial, 
chapter 3 ). These two arms will be powered separately as we aim to achieve significant 
results in both trials. The calculations relate to the trial in Belgium and the one in The Netherlands.  
 
•  Sample size in patients who receive no chemotherapy. 
The number of events needed in this population was calculated used the next formula: 
d = (1.96 + zβ)2 (δ+1 / δ-1)2where β=0.8 and δ=0.75. 
Overall, the calculation showed that 384 events are needed; so in the control group 219 events are 
needed. In the life tables of patients who received no chemotherapy 912 events were observed in 
1809 patients in 6.5 years. To observe the 219 events in 6.5 years we need to include 
219/(912/1809) = 434 patients per arm with a total of 868 patients. 
 
•  Sample size in patients who do receive chemotherapy 
In the life tables of the patients who received chemotherapy 204 events were observed in 
335 patients in 6.5 years. To observe the 219 events in 6.5 years in this trial we need to include 
219/(204/335) = 360 patients per arm with a total of 720 patients. 
 
In conclusion, sample size calculation showed that an inclusion of in total 1588 patients will be 
sufficient to detect a hazard ratio of 0.75. Data of the study population in The Netherlands and the 
study population in Belgium will be pooled for analysis. (Target number in Belgium: 400 patients). 
 
7.5     International Collaboration 
 
7.5.1   Collaboration between LUMC and UZA 
Several hospitals in the surroundings of Antwerp will participate in the ASPIRIN trial (NL 
38132.058.14). In the end of 2015 the first meeting between Leiden University Medical Center 
and Antwerp University Hospital was organised to discuss the expansion of the ASPIRIN trial to 
Belgian hospitals. The rationale for this collaboration is to accelerate accrual, because finalising 
the trial within the timeframe is highly important.  For both countries separate protocols are in 
place, since the Belgian trial has several additional side studies implemented which will not take 
place in the Netherlands. Nonetheless, both protocols are similar in a way that allows the data 
to be pooled for analysis. One database will be used to collect all data for both countries, central 
data management will be performed by Datacenter Department of Surgery of the LUMC in 
Leiden, The Netherlands. 
 
 

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7.5.2   Collaboration with the Add-Aspirin trial 
The MRC clinical trial unit in the United Kingdom is ongoing in the development of the ‘Add- 
Aspirin’ trial. In collaboration with this group it was agreed in principle that patients in both trials 
will be shared after both trials are analysed and published separately. The expected accrual in 
the UK is 2300 colorectal cancer patients older than 18 years. These patients will be randomised 
for high-dose acetylsalicylic acid, low-dose acetylsalicylic acid or placebo for 5 years. Assuming 
comparable demographics and incidence of colon cancer, data from approximately 400 patients 
can be shared. 
 

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8. 
TREATMENT OF SUBJECTS 
 
8.1    Investigational product/treatment 
 
Patients will be randomised to either receive orally acetylsalicylic acid 80 mg once daily or placebo. 
 
8.2    Concomitant medication 
 
Patients are allowed to use their concomitant medication in consultation with their treating 
physician. Concomitant medication is defined as (1) any medication that is taken for ≥ 3 months, 
and obtained on prescription, or (2) any medication that is considered relevant by the treating 
physician. Concomitant medication use will be documented with every follow-up visit after the 
start of the treatment. Patients who need to undergo elective surgery or other interventional 
procedures do not have to stop taking the study drug. Evidence suggests that acetylsalicylic acid 
use prior to and after surgery does not increase (post) operative bleeding risk (Sahebally, Healy, 
Coffey, & Walsh, 2014). In case a specific situation (e.g. a procedure at the dentist) requires 
stopping study medication, the patient may stop 7 days prior to the procedure. Recommence of 
study medication is directly after recovery, if clinical condition allows. 
 
8.2.1   Gastroprotection 
Systematic prescription of proton pump inhibitors (PPI’s) for patients taking low-dose aspirin is 
not recommended in the absence of high risk GI-bleeding. On the other hand, PPI’s are 
recommended in patients taking low-dose aspirin in the following 3 cases: history of peptic ulcers 
or GI-bleeding or concomitant NSAID medication or Helicobacter Pylori infection. However, the 
ASPREE study (ASPREE Investigator Group, 2013) (ASPirin in Reducing Events in the Elderly) safely 
enrolled 19.000 patients above 70 years of age in Australia. In this study where patients were 
randomised for low-dose acetylsalicylic acid (100 mg) or placebo, PPI’s were not routinely advised 
as concomitant medication (Prof. Dr. M. Nelson, personal communication). Also in the before 
mentioned 
ASCOLT-study 
(Ali 
R, 
2011) 
(NCT00565708) 
and 
Add-Aspirin 
study 
(ISRCTN74358648) standard PPI use is not recommended. 
If dyspeptic symptoms do occur we recommend to cease the study medication for a period of 14 
days, and then re-challenge. If symptoms recur, the treating physician may add other medication 
(e.g. a PPI). Gastroprotection is advised in patients who chronically use NSAID’s, systemic 
glucocorticoids, SSRI, venlafaxine, duloxetine, trazodon or spironolactone. Also in case of severe 
incapacitating rheumatoid arthritis, heart failure or diabetes, standard PPI’s may be considered. 
 
8.2.2   Chemotherapy 
Concomitant use of chemotherapy and acetylsalicylic acid is allowed. When patients are treated 
with chemotherapy and thrombocytopenia is observed, study treatment may be discontinued 
until thrombocytes reach an acceptable (according to the treating oncologist) level for the re-
administration of the study drug. The study drug may be restarted after the completion of 
chemotherapy, even if chemotherapy duration exceeds the maximum period of study drug 
interruption (see 10.4.1 Specific criteria for withdrawal) 

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9. 
INVESTIGATIONAL MEDICINAL PRODUCT 
 
9.1    Aspirin 
 
Aspirin, also known as acetylsalicylic acid is a salicylate often used as an analgesic to relieve minor 
aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. Salicylic 
acid, the main metabolite of acetylsalicylic acid, is an integral part of human and animal 
metabolism. While much of it is attributable to diet, a substantial part is synthesized endogenously. 
Acetylsalicylic acid also has an antiplatelet effect by inhibiting the production of thromboxane, 
which under normal circumstances binds platelet molecules together to create a patch over 
damaged walls of blood vessels. Because the platelet patch can become too large and also block 
blood flow, locally and downstream, acetylsalicylic acid is also used long-term, at low-doses, to 
help prevent heart attacks, strokes, and blood clot formation in people at high risk for developing 
blood clots (Lewis et al., 1983). It has also been established that low-doses of acetylsalicylic acid 
may be given immediately after a heart attack to reduce the risk of another heart attack or of the 
death of cardiac tissue. Acetylsalicylic acid is part of a group of medication called non-steroidal 
anti-inflammatory drugs (NSAIDs). Though acetylsalicylic acid, and other salicylates have similar 
effects (antipyretic, anti-inflammatory, analgesic) and inhibit the same enzyme cyclooxygenases 
their mechanism of action, acetylsalicylic acid does it in an irreversible manner. For example, 
NSAIDs antiplatelet effects last in the order of hours, whereas acetylsalicylic acid's effect lasts for 
days (until the body replaces the suppressed platelets). 
 
Kinetics: Resorption: orally 80–80%. Tmax  = ½–2 hours.  
Metabolism: in the liver, but also in plasma. 
Elimination: with urine as metabolites and unchanged acetylsalicylic acid (1%). 
 
9.2    Summary of findings from non-clinical studies 
 
Acetylsalicylic acid inhibits prostaglandin-endoperoxide synthase 2 (PTGS2), also known as 
cyclooxygenase-2 (COX-2)(Chan et al., 2009). PTGS2 is an inducible enzyme whose expression and 
activity are up-regulated in response to a variety of cytokines, growth factors, and tumour 
promotors. PTGS2 was shown to be up-regulated in colorectal adenomas and adenocarcinomas 
(Sheng et al., 1997). Approximately, 70% of colorectal tumours express PTGS2, which increases 
with stage (Midgley et al., 2010). PTGS2 plays an important role in colorectal carcinogenesis, 
invasion, angiogenesis and metastasis. The importance of PTGS in tumourigenesis was established 
by knockout of the PTGS2 gene in mice containing a truncating mutation in the adenomatous 
polyposis coli (APC) gene. These mice developed markedly fewer intestinal adenomas than did 
APC-mutated mice with intact PTGS2 (Oshima et al., 1996). Several studies showed that this PTGS2 
effect can be reversed by selective PTGS2 inhibitors (Chen et al., 2001). 
 
 

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9.3    Summary of findings from clinical studies 
 
Acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs (NSAIDs) have shown to be 
effective in the prevention of colorectal cancer. However, results from the Victor trial, a phase III 
randomised trial assessing rofecoxib in the adjuvant setting of colorectal cancer, demonstrated no 
difference in overall survival (McIlhatton et al., 2011; Midgley et al., 2010). 
Previous studies showed that regular use of acetylsalicylic acid was associated with a lower risk of 
colorectal cancer (Chan et al., 2009; McIlhatton et al., 2011). A recent study in patients with stage 
I-III colorectal cancer selected from two nationwide health professional cohorts in the U.S. showed 
that regular acetylsalicylic acid use after the diagnosis of colorectal cancer compared with non-
users is associated with a lower risk of colorectal cancer-specific and overall mortality (adjusted 
Hazard Ratio(HR) 0.71), especially among individuals with tumours that overexpress PTGS2 
(adjusted HR 0.39)(Penning et al.). Another study where pre-diagnosis non-steroidal anti- 
inflammatory drug use and survival after diagnosis of colorectal cancer was evaluated, showed a 
higher reduction in colorectal cancer mortality risk after diagnosis by acetylsalicylic acid use than 
overall NSAID use (Coghill et al., 2011). The magnitude of effect of acetylsalicylic acid in a large 
Scottish cohort (14) (N=2.990) on all-cause mortality (adjusted HR 0.67, 95% CI 0.57–0.79) was 
more marked than that seen in the Dutch study by Bastiaannet et al. (Bastiaannet et al., 2012) 
(HR 0.77, 95% CI 0.63–0.95) and for colorectal cancer mortality (adjusted HR 0.58, 95% CI 0.45–
0.75) than Chan et al. (HR 0.79, 95% CI 0.53–0.95) (Penning et al.). Recently, subgroup analysis in 
a Dutch cohort of elderly patients (75 and older) who received no chemotherapy the survival gain 
was especially large (adjusted RR 0.52 (95% CI 0.35-0.78), p=0.001)(Bastiaannet et al., 2012). 
An important addition to our current understanding of the anticancer effect of acetylsalicylic acid 
is a meta-analysis involving 17.285 persons from 5 randomised trials assessing the effect of 
acetylsalicylic acid to prevent cardiovascular events (Liao et al., 2012). Allocation to acetylsalicylic 
acid reduced the risk of death due to cancer in patients who developed adenocarcinoma, 
particularly in those without metastasis at diagnosis (HR 0.50 95% CI: 0.34-0.74). 
Since all data on the use of acetylsalicylic acid as an adjuvant treatment are retrospective cohort 
studies or from trial designed for cardiovascular risk management, the magnitude of effect on all-
cause and cancer specific mortality remains an open question. But, combining all available data, 
an assumption of 25% risk reduction for all-cause mortality, in patients with colon cancer only 
seems a conservative estimation. 
 
9.4    Summary of known and potential risks and benefits 
 
9.4.1   Gastrointestinal 
Acetylsalicylic acid use has shown to increase the risk of gastrointestinal bleeding. Combining 
acetylsalicylic acid with other NSAIDs has also shown to further increase this risk. Using 
acetylsalicylic acid in combination with clopidogrel or warfarin also increases the risk of upper 
gastrointestinal bleeding. In addition to enteric coating, "buffering" is the other main method 
companies have used to try to mitigate the problem of gastrointestinal bleeding. Buffering agents 
are intended to work by preventing the acetylsalicylic acid from concentrating in the walls of 
the stomach, although the benefits of buffered acetylsalicylic acid are disputed. 
 

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9.4.2   Central effects 
Large doses of salicylate, a metabolite of acetylsalicylic acid, have been hypothesized to cause 
tinnitus based on experiments in rats, via the action on arachidonic acid and N-methyl D- aspartate 
receptors cascade. 
 
9.4.3  Hives and swelling 
For a small number of people, taking acetylsalicylic acid can result in symptoms that resemble an 
allergic reaction, including hives, swelling and headache. The reaction is caused by salicylate 
intolerance and is not a true allergy, but rather an inability to metabolize even small amounts of 
acetylsalicylic acid, resulting in an overdose. 
 
9.4.4   Other effects 
Acetylsalicylic acid can induce angioedema in some people. Acetylsalicylic acid causes an increased 
risk of cerebral microbleeds. Such cerebral microbleeds are important since they often occur prior 
to ischemic stroke or intracerebral hemorrhage, Binswanger disease and Alzheimer's disease. 
Acetylsalicylic acid can cause prolonged bleeding after operations for up to 10 days. 
 
Other cardiovascular complications are also possible. Based on scientific evidence the patients will 
be advised to take the study medication during or after the evening meal. By taking the aspirin in 
the evening, the platelet reactivity will be reduced in the morning, which may be associated with 
less adverse cardiovascular events (Bonten et al., 2015). 
 
9.4.5   Precautions 
Acetylsalicylic acid should not be taken by people who are allergic to ibuprofen or naproxen, or 
who have salicylate intolerance or a more generalized drug intolerance to NSAIDs, and caution 
should be exercised in those with asthma or NSAID-precipitated bronchospasm. Owing to its effect 
on the stomach lining, manufacturers recommend people with mild diabetes seek medical advice 
before using acetylsalicylic acid. Even if none of these conditions is present, there is still an 
increased risk of stomach bleeding when acetylsalicylic acid is taken with alcohol. Acetylsalicylic 
acid is known to cause hemolytic anemia in people who have a genetic disease glucose-6-phosphate 
dehydrogenase deficiency (G6PD), particularly in large doses and depending on the severity of the 
disease. Use of acetylsalicylic acid during dengue fever is not recommended owing to increased 
bleeding tendency. In people with kidney disease, hyperuricemia, or gout caution must be taken 
because acetylsalicylic acid inhibits the kidneys' ability to excrete uric acid, and thus may 
exacerbate these conditions. Acetylsalicylic acid can increase of the activity of several drugs, such 
as sulfonylureumderivates, insulin, and acetazolamide, and the side effects of methotrexate. 
 
9.4.6   Pregnancy 
Regular use of aspirin may adversely affect a pregnancy and/or foetal development. Regular 
aspirin use whilst breast feeding can also cause complications in the neonate/infant and should be 
avoided. Therefore, participants joining the ASPIRIN trial should not be pregnant or breast feeding 
at registration and will be advised against becoming pregnant during the treatment period of 
the trial. If a participant becomes pregnant during the trial, the study drug should be stopped and 
the pregnancy should be reported on the ‘Comment form’. This must also be discussed directly 
with the trial coordinator. Follow-up within the trial will continue. 

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9.4.7   Overdose 
Acetylsalicylic acid overdose can be acute or chronic. In acute poisoning, a single large dose is 
taken; in chronic poisoning, higher than normal doses are taken over a period of time. Acute 
overdose has a mortality rate of 2%. Chronic overdose is more commonly lethal, with a mortality 
rate of 25%. Chronic overdose may be especially severe in children. Toxicity is managed with a 
number of potential treatments, including activated charcoal, intravenous dextrose and normal 
saline, sodium bicarbonate, and dialysis. The diagnosis of poisoning usually involves measurement 
of plasma salicylate, the active metabolite of acetylsalicylic acid, by automated spectrophotometric 
methods. Plasma salicylate levels generally range from 30–80 mg/L after usual therapeutic doses, 
50–300 mg/L in patients taking high doses and 700–1400 mg/L following acute overdose. 
 
9.5    Description and justification of route of administration and 
dosage 
 
Following post-operative randomisation, patients will receive acetylsalicylic acid 80 mg or placebo 
orally for 5 years. Adequate instruction regarding dose and frequency of the study medication will 
be given to the patient. It is very important to emphasise that the patient may not take 
acetylsalicylic acid on their own during participation in the study. Depending on the randomization, 
this could remodel the results or the patient could take a double dose of the acetylsalicylic acid. 
 
9.6    Dosages, dosage modifications and method of administration 
 
Study medication can be taken during any moment of the day. However, to avoid gastric 
complaints, it is advised to take study medication during or just after a meal. In favor of less 
adverse cardiovascular events, the patients will be advised to take the study medication 
during or after the evening meal (Bonten et al., 2015). There will be no dose reduction for 
adverse events related to acetylsalicylic acid. Acetylsalicylic acid should be stopped if the patient 
develops an adverse event that is related to the study drug (toxicity). The drug will not be 
reintroduced in case of anaphylaxis, angioedema or gastrointestinal bleeding. Otherwise, re-
introduction of the drug will be done after complete resolution of the adverse event following a 
rest period without study drugs (maximal duration 6 weeks). If the adverse event subsequently 
recurs, the patient will be taken off treatment with the study drug. 
In case of observed thrombocytopenia when patients receive chemotherapy, it is allowed to 
interrupt study treatment according to the treating medical oncologist. Patients can restart the 
study drug after completion of chemotherapy or when thrombocytes reach an acceptable level 
according to the treating medical oncologist. The study drug may be restarted even if 
chemotherapy duration exceeds the 6 weeks (maximum period of study drug interruption) (see 
10.4.1 Specific criteria for withdrawal). 
 
 

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9.7    Preparation and labelling of Investigational Medicinal Product 
 
Preparation and labeling will be done according to relevant GMP guidelines. The acetylsalicylic 
acid 80 mg tablets and matching placebo tablets are manufactured by Tiofarma Beheer B.V. (Oud-
Beijerland, the Netherlands). The Investigational Medicinal Product Dossier (IMPD) of the 
acetylsalicylic acid and placebo are provided by Tiofarma Beheer B.V. The medication is released 
by the Qualified Person of Tiofarma. 
 
9.8    Drug accountability 
 
Tiofarma is responsible for the manufacturing, packaging, labelling and shipment of the study 
medication, conform GDP. The local hospital pharmacy is responsible for accountability and 
distribution of the investigational product on patient’s level. 
Randomisation codes are kept strictly confidential and are accessible by authorised persons only. 
At the end of the study, all used and unused containers/products must be destroyed on site as 
dictated by the appropriate standard procedures. Under no circumstances should the investigator 
or site personnel supply product to other investigators or clinics or allow the study supplies 
to be used otherwise than as directed by this protocol. 
 

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10. METHODS 
 
10.1  Study parameters/endpoints 
 
10.1.1 Main study parameter/endpoint 
The primary endpoint is 5 year Overall Survival (5y-OS). The time to an event for OS is defined as 
the time interval between the date of randomisation and the date of death. A patient that is still 
alive at the last date of follow-up patient is censored for analysis and the time at risk corresponds 
to the time interval between the date of randomisation and the date of last follow up. 
 
10.1.2 Secondary study parameters/endpoints 
Two secondary endpoints: 
• 
Disease Free Survival (DFS). The time to an event for DFS is defined as the time interval 
between the date of randomisation and the date of disease recurrence or death, whichever comes 
first. Recurrence of a disease can be a loco-regional recurrence, a distant recurrence or a new 
primary colon cancer. The evidence for recurrence must be documented in the patients’ file. The 
date of radiological evidence, e.g. CT, MRI, etc, or colonoscopy will be considered as date of 
recurrence. An elevated carcinoembryonic antigen (CEA) level, as solitary finding, will not be 
considered acceptable evidence of colon cancer recurrence. 
• 
Time to Treatment Failure (TTF). The time elapsed between randomisation until 
treatment discontinuation due to disease progression, unacceptable toxicity, death or any other 
event of interest. 
 
10.1.3 Tertiary parameters 
 
Genetic analysis on surgical specimen from all patients in particular PIK3CA, BRAF and RAS 
mutation analysis 
 
Evaluation of therapeutic compliance and patient reported outcomes using a web-based 
customized survey with patient access 
o Therapeutic compliance information of both aspirin and chemotherapy, treatment 
regimen, medication dose, number of cycles  
o Patient reported outcomes:  
 
Quality of life Questionnaire C30 (European Organisation for Research and 
Treatment of Cancer (EORTC) QLQ-C30; appendix 1) 
 
Activities of Daily Living and Instrumental Activities of Daily Living (Modified 
ADL and IADL; appendix 2) 
 
Patient Reported Outcomes-Common Terminology Criteria for Adverse Events 
(PRO-CTCAE v4.0; appendix 3) (Kluetz et al., 2016)  
 
Comprehensive assessment visits to evaluation of patient’s function, cognition and safety 
o Geriatric Assessment Screening tool (G8; appendix 4) 
o Adult Comorbidity Evaluation comorbidities (ACE-27; appendix 5) 
o Social status (appendix 6) 
o (Serious) Adverse Events ((S)AE according to CTCAE v4.0 (National Institute of Health, 
2010) (appendix 7) 

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 
Define subpopulations with greater adjuvant benefit using acetylsalicylic acid 
 
10.1.4 Other study parameters 
Following patient and tumour characteristics will be documented: 
 
Identification of the patient: unique ASPIRIN study number, Dutch Surgical 
Colorectal Audit (DSCA) registration (see paragraph 14.3) number, sex and date of 
birth 
 
Comorbidities: cardiac, vascular, diabetes, pulmonary, neurological, gastrointestinal, 
urogenital, thrombosis, muscle and joints, endocrine diseases, infectious diseases 
and previous malignancies (also registered by the DSCA, see paragraph 14.3) 
Comorbidities will also be registered by using the Adult Comorbidity Evaluation-27 
(ACE-27)  
 
Previous abdominal surgery 
 
Previous and current medication (registered by case report form (CRF)) 
 
Diagnostics performed preoperative 
 
Treatment: pre-operative treatment, date of surgery, ASA-score, urgency of surgery, 
surgical procedure 
 
Histopathology: Histology, number of resected lymph nodes, number of positive 
lymph nodes, pathological TNM classification 
 
Adjuvant treatment: treatment regimen, dose, no. of cycles, reason no chemotherapy 
 
A total of 15 slides of left-over tissues after surgery will be stored at the biobank of the UZA. After 
the trial this tissue material and/or DNA isolated from the tumour. The tissues will be used for 
biomarker investigation: PIK3CA, RAS and BRAF mutation analyses.  
Therapy compliance and patient reported outcomes will be documented through the web-based 
customized survey with patient access (through email notification) or through paper 
questionnaires.  
 
10.2  Randomisation and treatment allocation 
 
10.2.1 Patient randomisation procedure 
After having properly checked all eligibility criteria and having obtained patients informed 
consent, patients will be randomised online through the ProMISe program or by phone and/or 
email at UZA. 
 
Online randomisation 
Online randomisation will only be performed by the Study Coordinator of UZA during office hours 
after having received a completed randomization CRF (F01) from the local investigator team 
A confirmation email with the patient specifications and the trial number will be automatically 
sent to the central study team, and the local study team (including the primary investigator, the 
local study coordinator, and the local hospital pharmacy). This confirmation email is blinded, i.e. 
the allocated treatment is not mentioned.  

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The result of the randomisation will only be visible in the electronic patient viewer (ProMISe) 
to the local pharmacist. In this way, he or she will be notified about the allocated treatment. In the 
process, only the local pharmacist(s) will be unblinded. 
 
Randomisation by email and/or phone  
Randomisation can also be done by email or phone. The Study Coordinator of UZA can be contacted 
during daytime by email (aspirin@uza.be) or by phone (+32 3 821 40 82). The central Study 
Coordinator can also be approached if there are questions or remarks.    
The local investigator fills out the randomisation CRF (F01) and passes this CRF to the central study 
coordinator. During the randomisation procedure eligibility criteria will be checked/confirmed by 
the central study coordinator. After randomisation, a sequential identification number will be 
applied. This number has to be recorded on the randomisation form, along with the randomisation 
date. The randomisation form must be signed by the investigator and filed with the CRFs. An 
automatic email will be sent to the investigator to confirm the randomisation (see online 
randomisation). 
 
10.2.2 Unblinding 
The treatment will be unblinded in the following cases: 
• End of the study, after the final analysis, prior to writing the publication 
• In case of emergency (SAE to the patient possibly attributed to the study medication) 
• In case of another indication that warrants acetylsalicylic acid treatment (e.g. cardiovascular 
incidents or a (non) polyposis syndrome that was diagnosed after inclusion in the study) 
Because acetylsalicylic acid is prescribed in low dosage and is a drug with only a slight risk of 
causing immediate life threatening events, no 24-hour service is provided for deblinding. When 
deblinding is necessary, the local participating centre can provide deblinding the next work day. In 
case of an SAE which’s treatment requires unblinding of the study treatment, there is a specific 
procedure that needs to be followed (see appendix 11). 
 
 
 

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10.3  Study procedures 
   The timelines of data collection, the tasks involved and the actors performing the tasks are shown   
   in appendix 8. 
 
10.3.1 Before treatment starts 
After surgery, when the histology of the cancer and the disease stage is known, patients will be 
randomised for acetylsalicylic acid use or placebo within 12 weeks after surgery. Within a week 
after randomisation study medication must be started. Treatment with acetylsalicylic acid or 
placebo will start at least 10 days after surgery. In case of treatment with chemotherapy, study 
medication can be used concomitantly with chemotherapy. 
Local investigator fills out baseline CRF (F02), in which the ACE-27, G8 Geriatric Assessment 
Screening tool, Social Situation, chemotherapy, and chronical use of concomitant medication  are 
evaluated. Any medication that is taken for ≥ 3 months, and obtained on prescription, or any 
medication that is considered relevant by the treating physician must be listed in the concomitant 
medication part of the baseline CRF. Also, patients will be asked to fill in the questionnaires: QLQ-
C30, modified ADL and IADL (Laan et al., 2014) on paper or through the web-based customized 
survey (cfr. Chapter 6. Study design).  
 
10.3.2 During adjuvant therapy (years 1-5) 
The follow-up period will be according to the national guidelines, but with a minimum of follow-
up visits every 6 months the first 2 years, and every year in the third to fifth year. These study 
visits must be organized in a time window of 8 weeks before until 8 weeks after the fixed time 
points M6, 12, 18, 24, 36, 48, and 60.  
 
At the time points M0, 6, 36, and 60, the patient will need to complete the QLQ C30, ADL and the 
IADL. These time points also coincide with a study visit. The paper/electronic questionnaires 
must be completed in a time window of 8 weeks before until 8 weeks after the fixed time points 
M0, 6, 36, and 60. 
 
All other visits (≠ fixed study visit time points) that are relevant in the context of the patient’s 
disease and/or the patient’s participation in the study are considered as additional visits. 
Additional visits must be registered in the Follow-Up Form (F03) ‘Additional Visit’.   
 
In case the patient has one of the following events, special forms have to be completed: 
•   Recurrence/new primary form 
•   Concomitant medication form 
•   End of study treatment form 
•   Off study form 
•   Death form 
•   AE form 
•   SAE form 
 

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During the follow-up visits, information about the therapy compliance (grade), treatment tolerability 
(adverse events and grade), and concomitant medication will be assessed. 
 
 
The local investigator team may choose whether or not to fill in the paper CRFs themselves. If not, 
the central study coordinator will perform this task on the condition that the participating center 
gives access to the medical records of the study patients. This is necessary to be able to fill in the 
paper CRFs (with the exception of Randomisation Form (F01),  Baseline Form (F02) and SAE Form 
(F40) that will be completed by the local investigator team). Centers who are not able to permit the 
central study coordinator access to the medical record, have to fill in the paper CRFs themselves (cfr 
Chapter 14 guidelines). 
 
Local investigator teams that complete the paper CRFs themselves, must upload these forms in a 
secure private Cloud.  
The conversion of the paper CRFs into the electronic CRFs in the ProMISe database will be performed 
by the central study coordinator. 
For more information about the study procedure, see study events table (appendix 8). 
 
 
10.4  Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent medical 
reasons.  
 
10.4.1 Specific criteria for withdrawal 
 
Patients who develop anaphylaxis, angioedema or gastrointestinal bleeding 
 
Recurrent disease 
• Patients with diagnosed (non-) polyposis syndrome 
• Intercurrent, cardiovascular disease that warrants acetylsalicylic acid or other anti-
aggregantia treatment 
•   Patients that warrant treatment with oral anti-coagulants or use of LMWH or use of DOACs 
• Greater than 6-week interruption in study drug administration due to toxicities (In case of 
thrombocytopenia when patients are treated with chemotherapy, study drug interruption may 
exceed 6 weeks) 
• Unacceptable study drug toxicity 
• Patient withdrawal of consent to continue treatment 
• Intercurrent, non-cancer related illness that prevents continuation of therapy or regular 
follow-up 
• Changes in a patient’s condition that renders the patient not suitable for further treatment in 
the judgement of the investigator 
• Major protocol violation or discovery of information that, if previously known, would have 
rendered the patient ineligible for study 
 

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10.4.2 Replacement of individual subjects after withdrawal 
After withdrawal subjects will not be replaced. 
 
10.4.3 Follow-up of subjects withdrawn from treatment 
Subjects withdrawn from treatment will still be followed-up for 5 years and their data will 
be corrected later in the statistical analysis for the time they used the study drug.  
 
 
 

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10.5 Premature termination of the study 
 
The study will be terminated when there is one of the following criteria: 
• Serious adverse side effects related only to acetylsalicylic acid use in >5 % of the subjects 
• If the results of the interim analysis do not show survival benefit for acetylsalicylic acid use or 
if these results show a survival gain for control group 
 
10.6 Data collection and data storage 
 
Clinical data are collected through the CRFs in a central database and management is performed by 
the Datacenter Department of Surgery of the LUMC in Leiden, The Netherlands. Patient reported 
outcomes are collected through questionnaires on a web-based customized survey meeting the 
requirements of the privacy commission. The results from the analysis of tumor tissues stored at 
the biobank will be collected on the same IT-platform as the web-based customized survey. All 
individual patient documentation is stored encoded and the same code is used in both the central 
database with CRFs and the web-based survey.  
Biobank specimens and the patient associated clinical data will be stored for 30 years.  
The management of intellectual property rights and the ownership of the data is discussed in detail 
in the contract documents. 
 
 

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11. SAFETY REPORTING 
 
11.1  Ethical Committee 
 
The investigator will inform the subjects and the reviewing accredited Ethical Committee if 
anything occurs, on the basis of which it appears that the disadvantages of participation may be 
significantly  greater than was foreseen in the research proposal. The study will be suspended 
pending further review by the accredited Ethical Committee, except insofar as suspension would 
jeopardise the subjects’ health. The investigator will take care that all subjects are kept informed. 
 
11.2  Adverse and serious adverse events 
 
Adverse events are defined as any undesirable experience occurring to a subject during the study, 
whether or not considered related to acetylsalicylic acid.  
 
A serious adverse event is any untoward medical occurrence or effect that at any dose: 
• results in death 
• is life threatening (at the time of the event) 
• requires hospitalisation or prolongation of existing patients’ hospitalization 
• results in persistent or significant disability or incapacity is a new event of the trial likely to 
affect the safety of the subjects, such as an unexpected outcome of an adverse reaction, lack of 
efficacy of an Investigational Medicinal Product (IMP) used for the treatment of a life 
threatening disease, major safety finding from a newly completed animal study, etc. 
 
All SUSARs will be reported through the web portal of the FAGG and to the accredited Ethical 
Committee that approved the protocol, within 15 days after the sponsor has first knowledge of the 
serious adverse reactions. 
SUSARs that result in unexpected admissions, death, or are life threatening qualify for expedited 
reporting. The expedited reporting will occur no later than 7 days after the responsible investigator 
has first knowledge of the adverse reaction. This is for a preliminary report with another 8 days 
for completion of the report. 
All SAEs, irrespective of relationship to the study treatment must be reported to the UZA oncology 
department by mail to aspirin@uza.be as soon as possible but no later than one working day 
from the time the local investigator has first knowledge of the SAE. UZA will inform the trial 
coordinator and the principal investigator. UZA will also inform the Medical Ethics Committee(s) 
and the Competent Authority as described in the previous section (see appendix 11). 
 
NOTE: In this study, the following events are not considered an AE or SAE: 
• Chemotherapy toxicity not resulting in admission 
• Admission for diagnosis or treatment of recurrences. For recurrences, the CRF “new primary 
/ recurrences” has to be filled in 
• Death due to progression of disease 
• Planned admissions. E.g. a knee operation (prosthesis for the knee) due to gonarthrosis. 
However, gonarthrosis is an AE 

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11.2.1 Suspected unexpected serious adverse reactions (SUSAR) 
Adverse reactions are all untoward and unintended responses to an investigational product 
related to any dose administered. 
Suspected unexpected serious side effects. This is the case in the following: 
1.  Serious event 
2.  Suspected is that the administered drug is related to the event 
3.  The side effect has not been written in existing product information e.g. Investigator’s 
Brochure or summary of  product characteristics ( SPC). 
The expedited reporting will occur not later than 7 days (in case life threatening) to 15 days (in 
case not life threatening)- after the investigator has first knowledge of the adverse reactions. For 
fatal or life threatening cases the term will be maximal 7 days for a preliminary report with 
another 8 days for completion of the report. 
 
11.2.2 Recording of adverse events 
Relevant adverse events (i.e. AEs that may be related to the study medication) of any kind and any 
grade (e.g. bruises, gingival bleedings, epistaxis and thrombocytopenia), as well as all AEs grade 3 
or more, reported spontaneously by the subject or observed by the investigator or his staff will be 
recorded  on the AEs form of the CRF with the following information: 
1.  The severity grade according to the NCI-CTCAE version 4.0, published May 28, 2009 (appendix 
7) (1=mild, 2=moderate, 3=severe, 4=life threatening) 
2.  Whether it constitutes a SAE 
 
All AEs should be treated appropriately. Treatment may include one or more of the following: no 
action taken (i.e. further observation only); study drug dosage temporarily interrupted; study drug 
permanently discontinued due to this AE; concomitant medication given; non-drug therapy given; 
patient hospitalized/patient’s hospitalization prolonged. The action taken to treat the AE should 
be recorded on the AE CRF. 
Once an AE is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of any 
changed in severity, the suspected relationship to the study drug, the interventions required to 
treat it, and the outcome. Information about common side effects already known about the 
investigational drug can be found in the SPC. 
 
 

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11.2.3 Annual safety report 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year throughout 
the clinical trial, a safety report to the central ethical committee of the UZA for distribution to all 
ethical advisory boards of participating hospitals.  
This safety report consists of: 
• a list of all suspected (unexpected or expected) serious adverse reactions, along with an 
aggregated summary table of all reported serious adverse reactions, ordered by organ system, per 
study 
•  a report concerning the safety of the subjects, consisting of a complete safety analysis and  
an evaluation of the balance between the efficacy and the harmfulness of the medicine under 
investigation 
 
11.3  Follow-up of adverse events 
 
All adverse events will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
 
11.4  Data Safety Monitoring Board (DSMB) 
 
A DSMB will be established to evaluate the interim analyses on the safety data. This committee is 
independent of the conducted trial. The DSMB will be composed of three independent members, of 
whom at least one is a statistician. The members of the DSMB are independent and have no conflicts 
of interest with the conducted trial, principal investigator or sponsor of the study. Interim analyses 
are performed according to chapter 12.4. Accumulating data is reviewed, including updated figures 
on recruitment, data quality, primary outcome and safety data. The interim analysis will be 
performed deblinded by an independent statistician. The statistician will report to the independent 
DSMB. The DSMB will discuss the results of the interim-analysis and advice the steering committee. 
Discontinuation of the trial is advised by the DSMB according to the predefined stopping guidelines 
stated in paragraph 10.4. 
Both the Dutch and Belgium safety data will be taken into account by the overall DSMB. See chapter 
7.5.1 about the collaboration between LUMC and UZA. 
 
11.5  Monitoring 
Monitoring in Belgium will be done according to table 2 of the Netherlands Federation of University 
Medical Centres (NFU) guideline ‘Kwaliteitsborging mensgebonden onderzoek 2.0’ chapter 6. The 
ASPIRIN Trial is classified as a low-risk trial and therefore minimal monitoring is required (see 
appendix 10). 
 
 
 

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Objective of on-site monitoring: 
To identify procedural errors in the execution of the research 
Central monitoring: 
• Detection of missing, late and inaccurate research 
 
Source Data Verification:Monitoring will be performed according to the data monitoring plan. 
• Randomisation form (F01) all items, including the 
o General information 
o Inclusion criteria 
o Exclusion criteria 
o Informed consent date 
o Specific questions 
• Baseline form (F02) 
o Chemotherapy given according to stratification at randomisation 
• Follow-up forms (F03) 
o Therapy compliance 
o Disease status 
• Recurrence form (F04) (if applicable) all items, including the 
o Type of event 
o Locations 
o Investigations and results 
o Completeness/missed events 
• End of study treatment form (F06) (if applicable) 
o Date of last study medication intake 
o Reason for end of study treatment 
o Study treatment deblinded 
• Off study form (F07) (if applicable) 
o Last date in study 
o Reason off study 
• Death form (F20) (if applicable) 
o Date of death 
o Cause of death 
• Adverse Event forms (F30) (if applicable) 
o Completeness/missed AEs 
• SAE forms (F40) (if applicable) 
o Completeness/missed SAEs

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12. STATISTICAL ANALYSIS 
 
12.1  Descriptive statistics 
 
In both of the parallel trials, the number of patients will be described for acetylsalicylic acid and 
placebo. Rates and reasons for study discontinuation will be presented in contingency table(s). 
Patient characteristics at study entry will be summarised in frequency tables and descriptive 
statistics will be provided for patient and tumour variables. 
The following information about the study treatment administration will be provided: 
 
• The number of patients who have started on treatment, with details regarding the 
identification of the patients who should have started, and the reasons for the non- 
adherence to the protocol 
• The number of patients who stopped the protocol treatment with the reasons for stopping 
treatment, complemented with a description of the cases who stopped for toxicity (detailing 
the patient identification and the type of toxicity) 
• A summary of the duration of treatment. If all patients have finished  treatment, the duration 
will be summarized using median and ranges of the actual treatment duration. If the treatment 
is still ongoing for some patients, the median treatment duration will be estimated using 
Kaplan-Meier curves 
• Data in the web-based customized survey describe the patient reported different grades of 
toxicity based on the Common Terminology Criteria for Adverse Events (PRO-CTCAE) and 
unravel, if any, difference in toxicity levels or frequencies between the 2 patient groups (with 
and without adjuvant chemotherapy) 
• Data in the web-based customized survey describe therapy compliance and the individual 
patient reported outcome scores resulting from the questionnaires: QLQ-C30, modified ADL 
and IADL 
• Data in the web-based customized survey describe the results on genetic analysis of  the tissue 
sample. These data will be correlated with overall survival and disease-free survival with 
appropriate methods (Cox Proportional Hazard Model) to identify subpopulations with 
greater adjuvant benefit using acetylsalicylic acid 
 
The “intention to treat population” will be used for analysis. This population will include the data 
of all patients randomised, regardless of whether patients received the acetylsalicylic acid or not 
or discontinued treatment. This population will be the primary population to evaluate survival. 
Besides this, a “per-protocol” analysis will be made where patients’ data will be analysed according 
to the study medication they actually used. 
 
12.2  Univariate analysis 
 
The two arms will be compared using a 2-sided non-stratified log-rank test at the 0.05 level of 
significance. Survival curves will be estimated using the Kaplan-Meier technique. Analysis will be 
performed for both parallel studies separately, so for patients who do receive chemotherapy and 
patients who did not receive chemotherapy. Univariate Cox proportional hazard models will be 

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used to estimate the Hazard Ratio and confidence interval for OS and DFS in the acetylsalicylic acid 
arm versus placebo. These analyses will be adjusted to the possible confounding factors. 
 
12.3  Multivariate analysis 
 
To adjust for potential confounders, multivariable Cox proportional hazards model will be 
used to estimate an adjusted HR and 95%CI for acetylsalicylic acid versus placebo in which we 
include all factors that were associated with survival (OS, DFS) in univariate analysis. 
 
12.4  Interim analysis 
 
• 
An interim analysis will be performed when half of the required events have been  
 
observed, in both arms 219/2 (=109) 
• 
An alpha-spending function with an O’Brien-Fleming boundary will be used in order to be  
 
flexible with respect to the timing of the analysis 
•     A futility analysis will take place at the same time with two stopping rules:  
1. when>5% of patients experience serious side effects and  
2. when results indicate that it is unlikely that results at the scheduled end of the trial will 
demonstrate a significant effect (differences between acetylsalicylic acid and control group 
are that small that any prospect of a positive result with the planned sample size is very 
unlikely). Probability and conditional power will be calculated; if this probability is too small 
to meet the pre-specified criteria, we will stop the trial for futility 
• 
The final analysis of the trial will be done when the required number of events has been 
recorded for all patients evaluated by the Study Coordinator 
 

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13. ETHICAL CONSIDERATIONS 
 
13.1  Regulation statement 
 
The responsible investigator will ensure that this study is conducted in agreement with either the 
Declaration of Helsinki or the laws and regulations of the country, whichever provides the greatest 
protection of the patient. The protocol will be approved by the local, regional or national ethics 
committees. 
 
13.2  Recruitment and consent 
 
A sequential identification number will be automatically attributed to each patient registered in 
the trial. This number will identify the patient and must be included on all case report forms. 
In order to avoid identification errors, patients date or birth will be reported on the case 
report forms as well. 
All patients will be informed of the aims of the study, the possible adverse events, the procedures 
and possible hazards to which he/she will be exposed, and the mechanism of treatment allocation. 
They will be informed as to the strict confidentiality of their patient data, but that their medical 
records may be reviewed for trial purposes by authorized individuals other than their treating 
physician. 
It will be emphasized that the participation is voluntary and that the patient is allowed to 
refuse further participation in the protocol whenever he/she wants. This will not prejudice the 
patient’s subsequent care. Documented informed consent must be obtained for all patients 
included in the study before they are registered or randomised. This must be done in 
accordance 
with 
the 
national 
and 
local 
regulatory 
requirements.  
A time window of 3 weeks is used between the signing of the informed consent and the day of 
randomization. The informed consent must be kept as hardcopy and preferably also digitally in the 
electronic patient file. 
The informed consent procedure must conform to the ICH guidelines of Good Clinical Practice. 
This implies that the written information must be personally signed and dated by the patient. 
 
13.3  Objection by minors or incapacitated subjects 
 
Patients that are not competent to make decisions on their own are not eligible for this trial. 
 
13.4  Benefits and risks assessment, group relatedness 
 
The potential of the adjuvant use of acetylsalicylic acid is enormous. It involves a common, very 
cheap drug, with a well-known safety and side effect profile utilised in a conventional 
(cardiovascular) and non-conventional (adenocarcinoma, COX-2 inhibition) manner. In addition 
acetylsalicylic acid is not feared by patients in the same way that conventional chemotherapy is. 
 
 

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13.5 Compensation for injury 
 
The sponsor has a liability insurance provided by AMMA (1887617) which will be annually 
renewed for the amount of 12.395.000 EUR. 

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14. DATA COLLECTION AND REPORTING DOCUMENTS  
 
14.1  Guidelines completion of Case Report Forms (CRFs) 
 
On the paper CRFs some fields are obligatory, and other fields are optional. If obligatory fields of a CRF-form 
are left open, this will be considered as a protocol deviation. The reason why an obligatory or optional field is 
left open has to be specified on the CRF-form. The person completing the CRF-form can therefore use the 
abbreviations ‘UK’ (unknown) or ‘ND’ (not done) if applicable. ‘UK’ must be used when it is not known if a 
value has been measured or a test has been performed. ‘ND’ must be used when it is certain that a value has 
not been measured or a test has not been performed. This information must be based on the medical record 
of the patient.  
Some CRF-forms contain specific instructions to indicate if an additional CRF-form needs to be completed. 
For example, when a change in chronical concomitant medication is reported in a Follow-up Form, a 
Concomitant Medication Form (CRF F05) needs to be completed. When the additional CRF is not filled in when 
indicated, this is considered as a protocol deviation.  
The obligatory and optional fields of the different CRF-forms are described in Appendix 9 (Guidelines for 
monitoring). 
Investigators and/or authorized staff members should read and apply the guidelines carefully.  
 
14.2  Amendments 
 
Amendments are changes made to the research protocol after a favourable opinion by the accredited Ethical 
Committee has been given. All amendments will be notified to the Ethical Committee that gave an approval. 
Also amendments will be synchronized with the protocol of the Dutch ASPIRIN trial.  
A ‘substantial amendment’ is defined as an amendment to the protocol or any other supporting 
documentation, that is likely to affect to a significant degree: 
• the safety or physical or mental integrity of the subjects of the trial; 
• the scientific value of the trial; 
• the conduct or management of the trial; or 
• the quality or safety of any intervention used in the trial 
All substantial amendments will be submitted to the Ethical Committee for approval, and to the competent 
authority for notification. 
Non-substantial amendments will be notified to the accredited Ethical Committee and the competent 
authority, and will be recorded and filed by the sponsor. 
 
14.3  Annual progress report 
 
The coordinating investigator will submit a summary of the progress of the trial to the accredited Ethical 
Committee once a year. Information will be provided on the date of inclusion of the first subject, numbers of 
subjects included and numbers of subjects that have completed the trial, serious adverse events/ serious 
adverse reactions, other problems, and amendments. 
 
 
 

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14.4  End of study report 
 
The sponsor will notify the accredited Ethical Committee and the competent authority of the end of the study 
within a period of 90 days. The end of the study is defined as the last patient’s last visit. 
In case the study is ended prematurely, the sponsor will notify the accredited Ethical Committee and the 
competent authority within 15 days, including the reasons for the premature termination. 
Within one year after the end of the study, the sponsor will submit a final study report with the results of 
the study, including any publications/abstracts of the study, to the accredited Ethical Committee and the 
competent authority. 
 
14.5  Public disclosure and publication policy 
 
The final publication of the trial results will be written by the Study Chairman on the basis of the final analysis 
performed at the Datacenter Department of Surgery LUMC. A draft manuscript will be submitted by the study 
coordinator to the Datacenter for review no later than six months after receiving the Datacenter Report. 
After revision by the Datacenter and other co-authors the manuscript will be sent to a major scientific journal. 
Authors of the manuscript will include at least the coordinating investigator of Belgium, all Study 
Coordinators, the Project Manager and the members of the Datacenter team who have contributed to 
the trial. Due to the high number of participating centers only Local Investigators from centers both in 
Belgium and the Netherlands who have entered the top 8 of included patients qualify for co- authorship. The 
other Local Investigators qualify for acknowledgements. All publications, abstracts or presentations 
including data from the present trial will be submitted for review to the Datacenter prior to submission. 
All manuscripts will include an appropriate acknowledgement section, mentioning all investigators who have 
contributed to the trial, as well as supporting bodies. The Group Chairman, the Study Coordinators and the 
Datacenter must approve all publications, abstracts and presentations based on patients included in this 
study. This is applicable to any individual patient registered/randomised in the trial, or any subgroup of the 
trial patients. 
 
 
 
 

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15. FINANCES 
The ASPIRIN Trial is funded by ‘Kom Op Tegen Kanker’ and ‘The Anticancerfund’.  

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17. APPENDICES 
 
APPENDIX 1: EORTC QLQ-C30 (version 5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 2: Modified ADL and IADL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 3: PRO-CTCAE items 
AE 
Ernst NL 
Sévérité FR 
Vermoeidheid 
Geen vermoeidheid 
Pas de fatigue 
Fatique  
Vermoeidheid die overgaat door te rusten 
Fatigue qui s'améliore grâce à du 
repos 
  
Gaat niet over door te rusten en stoort de 
dagdagelijkse taken (bv. koken, winkelen) 
Ne passe pas grâce a du repos et 
perturbe les activités quotidiennes 
(ex. cuisiner, faire les courses) 
  
Gaat niet over door te rusten en stoort de 
zelfzorg (wassen, eten, etc.)  
Ne passe pas grâce à du repos et 
perturbe 
la 
prise 
en 
charge 
personnelle (se laver, manger, etc) 
Braken, misselijkheid 
Afwezig 
Absent 
Vomissements/nausées  
Weinig 
Peu 
  
Matig 
Modéré 
  
Ernstig 
Grave 
Huiduitslag 
Afwezig 
Absent 
Réaction de peau  
Minder dan 50% zonder pijn of jeuk  
Moins que 50% de la peau  et sans 
douleur ou démangeaisons 
  
Minder dan 50% met pijn of jeuk 
Moins que 50% de la peau mais 
avec douleur ou démangeaisons 
  
Meer dan 50% (met of zonder symptomen) 
Plus que 50% de la peau (avec ou 
sans symptomes) 
Frequentie stoelgang 
1 
1 
Fréquence de selles  
2 
2 
  
3 
3 
  
4 
4 
  
5 
5 
  
6 
6 
  
7 
7 
  
8 
8 
  
9 
9 
  
9+ 
9+ 
Ontsteking in de mond 
Geen klachten 
Pas de plainte 
Infection buccale  
Lichte pijn maar er is geen interventie 
nodig 
Légère douleur qui ne nécessite 
pas d'intervention 
  
Matige pijn, stoort niet tijdens het eten 
maar een aangepast dieet is aanbevolen 
Douleur modérée, qui ne dérange 
pas pendant les repas mais qui 
requiert un régime adapté 
  
Ernstige pijn, stoort tijdens het eten 
Douleur modérée, qui dérange 
fortement pendant la prise des 
repas 
Huidaandoening 
Ja 
Oui  
Lésion cutanée  
Nee 
Non 
Haarverlies 
Minder dan 50% van het haar verloren 
La perte des cheveux est moins que 
50% 

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Perte des cheveux 
50% of meer van het haar verloren 
La perte des cheveux est plus que 
50% 
Hospitalisatie 
Gehospitaliseerd 
in 
behandelend 
ziekenhuis 
Hospitalisé à l’hôpital habituel 
Hospitalization  
Gehospitaliseerd in ander ziekenhuis 
Hospitalisé à un autre hôpital 
Verminderde eetlust 
Geen verminderde eetlust 
Pas de perte d’appétit 
 
Mijn eetlust is minder, maar eetgewoonten 
worden niet aangepast 
Je perds l’appétit  mais mes 
habitudes alimentaires ne sont pas 
modifiés 
 
 
Ik kan minder eten maar verlies geen 
gewicht 
Je sais moins manger mais je ne 
perds pas de poids 
 
Ik kan niet (voldoende) eten en verlies 
bijgevolg gewicht 
Je  sais moins manger et je perds du 
poids 
Verstopping 
Geen 
Pas de constipation 
 
 
Stoelgang met af en toe hulpmiddel (fruit, 
laxeermiddel,…) 
Symptômes occasionnels 
ou intermittents de constipation ; 
recours 
occasionnels à des laxatifs, 
adaptations 
diététiques 
(fruits,…)ou 
lavements 
 
 
Stoelgang 
met 
dagelijkse 
nood 
aan 
hulpmiddel (fruit, laxeermiddel,..) 
Symptômes persistants avec 
utilisation journalière de laxatifs 
ou 
de lavements  
 
 
Ik heb zo veel last van verstopping dat het 
mijn dagelijkse activiteiten belemmert en 
hulpmiddelen niet helpen 
Constipation opiniâtre avec 
nécessité d'évacuation 
manuelle ou interférant avec 
les activités élémentaires de 
la vie quotidienne 
Tintelingen 
vingers/tenen 
Picotements main/pied 
Geen 
Pas 
de 
picotements 
ou 
fourmillements 
 
Ik heb hier last van, maar verstoort mijn 
functioneren niet 
Je souffre 
de picotements ou 
fourmillements 
mais 
cela 
ne 
perturbe 
pas 
mes 
activités 
quotidiennes  
 
 
Ik heb hier last van en sommige van mijn 
dagelijkse activiteiten lukken daardoor 
moeilijker 
Symptômes modérés ; 
interférant avec les activités 
de la vie quotidienne 
 

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Ik heb hier last van en sommige van mijn 
dagelijkse activiteiten lukken daardoor niet 
Symptômes sévères ; 
empêchant les activités 
élémentaires de la vie 
quotidienne 
 
Regelmatige 
neusbloedingen 
Neen 
Non 
 
Ja 
Oui 
Kortademigheid 
Afwezig 
Absent 
 
Kortademig bij beperkte inspanning 
Essouflement à l’effort modéré 
(monter les esclaiers) 
 
Kortademig bij minimale inspanning 
Essouflement au moindre effort  
 
Kortademig bij rust 
Essouflement même au repos 
Hand- en voet huidreactie 
Geen klachten 
Pas de plainte 
 
Minimale huidveranderingen zonder pijn 
(bv. roodheid) 
Anomalie cutanée minimale, sans 
douleur (ex. rougeur) 
 
Huidveranderingen met pijn (bv.blaren, 
klovenbloeden), stoort de dagdagelijkse 
taken (bv.koken, winkelen) 
Anomalie cutanée avec douleur 
(ex. cloques, crevasses), perturbe 
les activités quotidiennes (ex. 
cuisiner) 
 
Ernstige huidveranderingen met pijn (bv. 
blaren, kloven, bloeden), stoort de zelfzorg 
(bv. wassen, eten) 
Anomalie cutanée grave et douleur 
(ex. 
cloques, 
saignements), 
perturbe 
prise 
en 
charge 
personnelle (ex. se laver) 
Dorstgevoel & frequent 
plassen 
Neen 
Non 
 
Ja  
Oui  
Slapeloosheid 
Afwezig 
Absent 
 
Ik val moeilijk in slaap, wordt vaak wakker 
’s nachts 
Je m’endors difficilement, je me 
réveille souvent la nuit  
 
 
Ik kan nog amper slapen 
Je n’arrive pas à dormir  
 
 
 
 
 
 
 
 
 
 

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APPENDIX 4: G8  
To be completed by: Clinician or trained coder.  
 
Geriatric Assessment Screening tool 
 
Items 
Possible answers 
Score 
A 
Has food intake declined over the 
past 3 months due to loss of appetite,     
digestive      problems, 
chewing or swallowing difficulties? 
0: severe reduction in food intake 
1:   moderate   reduction   in   food 
intake 
2: normal food intake 
 
 
………... 
B 
Weight   loss   during   the   last   3 
months? 
0: weight loss >3kg 
1: does not know 
2: weight loss between 1 and 3 kg 
3: no weight loss 
 
 
………... 
C 
Mobility 
0: bed or chair bound 
1: able to get out of bed/chair but 
does not go out 
2: goes out 
 
 
………... 
E 
Neuropsychological problems 
0: severe dementia or depression 
1: mild dementia or depression 
2: no psychological problems 
 
 
………... 
F 
Body    Mass    Index    (weight    in 
kg/height in m2) 
0: BMI less than 19 
1: BMI 19 to less than 21 
2: BMI 21 to less than 23 
3: BMI 23 or greater 
 
 
………... 
H 
Takes more than 3 medications per 
day 
0: yes 
1: no 
 
………..... 
P 
In comparison with other people of 
the same age, how does the patient 
consider his/her health status? 
0: not as good 
0,5: does not know 
1: as good 
2: better 
 
 
………... 
 
Age 
0: >85 
1: 80-85 
2: <80 
 
 
………... 
 
Total score (0-17) 
 
 
 
Score >14: Absence of geriatric risk profile 
Score ≤14: Presence of geriatric risk profile 

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APPENDIX 5: ACE-27  
To be completed by: Clinician or trained coder.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 6: Social Situation 
 
To be completed by: Clinician or trained coder.  
Question to the patient: 
Which of the following statements best describes where you live? 
•At home by myself 
•At home with someone 
•In institutional care (for example residential home or nursing home) 
 

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APPENDIX 7: CTCAE v4.0 
 
The grading of adverse events and/or adverse drug reactions will be reported according to the NCI Common 
Terminology Criteria for Adverse Events, CTCAE version 4.0, 
The complete document can be reviewed and downloaded from the following 
internet site: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 

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APPENDIX 8: ASPIRIN protocol scheme 
 
 
 

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APPENDIX 9: Guidelines for monitoring  
 
9.1. NFU guideline for monitoring 
The monitoring will be done according to table 2 of the NFU guideline ‘Kwaliteitsborging mensgebonden 
onderzoek’ version 2.0, chapter 6. The complete guideline can be found at the NFU website: 
 
http://www.nfu.nl/img/pdf/NFU-12.6053_Kwaliteitsborging_mensgebonden_onderzoek_2.0.pdf 
 
Minimal monitoring is required because the ASPIRIN Trial is classified as a low-risk trial. In Dutch: 
‘Verwaarloosbaar risico = Minimale monitoring’. 
 
9.2. Monitoring guidelines for CRF completion 
Randomisation Form (CRF F01): 
 
Obligatory fields  
Optional fields  
- 
Center Id 
- 
Subject Id 
- 
Date of Birth: day, month and year 
- 
Name and function of the physician  
- 
Center name  
- 
Inclusion criteria: all answers must 
be ‘yes’ otherwise patient is not 
eligible   
- 
Exclusion criteria: all answers must 
be ‘no’ otherwise patient is not 
eligible  
- 
Date of written informed consent  
- 
Date of surgery  
- 
Adjuvant chemotherapy (no/yes) 
- 
Stage  
- 
Gender  
- 
Date of randomisation  
- 
Signature and name investigator  
- 
Date signed by investigator  
- 
Notes  
 
The person completing the CRF-form can use the abbreviations ‘UK’ (unknown) or ‘ND’ 
(not done) if applicable. ‘UK’ must be used when it is not known if a value has been 
measured or a test has been performed. ‘ND’ must be used when it is certain that a 
value has not been measured or a test has not been performed.  
Notes: 
o The signature and name of the datacenter, as well as the date signed by the datacenter are 
automatically completed by ProMISe when a randomisation has been performed.    
o The physician who included the patient (cfr. page 1 ‘General Information’) must also sign the 
randomisation form.  
 
 

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Baseline Form (CRF F02): 
 
Obligatory fields  
Optional fields  
- 
Center Id 
- 
Subject Id 
- 
Date of Birth: month and year 
- 
CEA at baseline (pre-operative) 
and date of CEA at baseline  
- 
Adult comorbidity evaluation (ACE 
-27): all criteria must be filled in. 
- 
G8 geriatric assessment screening 
tool & social status: all criteria 
must be filled in. 
- 
Chronical 
use 
of 
concomitant 
medication 
(yes/no). 
If 
concomitant medication was used, 
the name has to be specified. 
- 
Adjuvant chemotherapy started 
(no/yes) 
o If the answer is ‘no’: the 
reason chemotherapy was 
not started has to be filled 
in.  
o If the answer is ‘yes’: date 
of first dose, drugs and 
dose, number of courses 
and 
chemotherapy 
completed (no/yes/not yet 
completed) has to be filled 
in. If chemotherapy is not 
completed, the reason has 
to 
be 
specified. 
If 
chemotherapy 
is 
completed, the date of last 
dose has to be specified. 
- 
Signature and name investigator  
- 
Date signed 
- 
Dose of concomitant medication if 
mentioned in the medical record   
- 
Notes 
 
The person completing the CRF-form can use the abbreviations ‘UK’ (unknown) or ‘ND’ 
(not done) if applicable. ‘UK’ must be used when it is not known if a value has been 
measured or a test has been performed. ‘ND’ must be used when it is certain that a 
value has not been measured or a test has not been performed.  
Note: the Carcinoembryonic antigen (CEA) value has to be reported in µg/L.  
 
 
 

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Follow-up Forms (CRF F03): 
 
Obligatory fields  
Optional fields  
- 
Center Id 
- 
Subject Id 
- 
Date of Birth: month and year 
- 
Date of visit  
- 
Randomized 
therapy 
started 
(no/yes). If yes: date of start 
randomized therapy  
- 
Randomized 
therapy 
stopped 
(yes/no) 
- 
Pattern of compliance  
- 
CEA at X months. Provide date if 
done 
- 
US liver/abdomen. Provide date if 
done 
- 
CT liver/abdomen. Provide date if 
done 
- 
Other 
investigations: 
provide 
specification and date if done 
- 
Locoregional recurrence 
- 
Distant metastases  
- 
New primary tumour  
- 
Toxicity/Adverse Events (no/yes) 
- 
Serious Adverse Event (no/yes) 
- 
Changes Chronical Concomitant 
Medication (no/yes) 
- 
Signature and name investigator  
- 
Date signed 
- 
Notes 
The person completing the CRF-form can use the abbreviations ‘UK’ (unknown) or ‘ND’ 
(not done) if applicable. ‘UK’ must be used when it is not known if a value has been 
measured or a test has been performed. ‘ND’ must be used when it is certain that a 
value has not been measured or a test has not been performed.  
Notes:  
o This information is applicable for all follow-up forms used in this study.  
o The Carcinoembryonic antigen (CEA) value has to be reported in µg/L. 
o If applicable, complete an additional CRF-form according to the instructions on this CRF-form.  
 
 
 

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Recurrence/New Primary Form (CRF F04): 
 
Obligatory fields  
Optional fields  
- 
Center Id 
- 
Subject Id 
- 
Date of Birth: month and year 
- 
Locoregional recurrence. If yes: 
provide date of diagnosis  
- 
Distant metastases. If yes: provide 
date of diagnosis  
- 
New primary tumour. If yes: 
provide date of diagnosis 
- 
Location(s): see instructions below 
(*) 
- 
Cytology: provide date if done 
- 
Histology: provide date if done 
- 
Bone Scintigraphy (bone scan): 
provide date if done 
- 
Chest X ray: provide date if done 
- 
CT chest: provide date if done 
- 
US liver/abdomen: provide date if 
done 
- 
CT liver/abdomen: provide date if 
done 
- 
MRI scan: provide date if done 
- 
PET scan: provide date if done 
- 
CEA: provide value and date if done 
- 
Other investigations and results: 
provide date if done 
- 
Signature and name investigator  
- 
Date signed 
- 
Notes  
The person completing the CRF-form can use the abbreviations ‘UK’ (unknown) or ‘ND’ 
(not done) if applicable. ‘UK’ must be used when it is not known if a value has been 
measured or a test has been performed. ‘ND’ must be used when it is certain that a 
value has not been measured or a test has not been performed.  
(*) Instructions for locations: 
o Location of locoregional recurrence (refers to recurrence of colon cancer) 
 
Original tumour location  
 
At anastomosis  
 
Regional lymph node(s) 
 
Skin local area 
 
Other  
 
Unknown  
o Location of distant metastases  (use abbreviation please) 
 
Pulmonary  PUL  
 
Osseous  OSS 
 
Hepatic  HEP 
 
Brain  BRA 
 
Distant lymph nodes  LYM 
 
Bone marrow  MAR 
 
Pleura  PLE  
 
Peritoneum  PER 
 
Adrenals  ADR 

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 
Skin  SKI 
 
Other  OTH 
 
Unknown  
o Location of new primary tumour  
 
Bladder 
 
Breast  
 
Colon 
 
Endometrium  
 
Lung 
 
Prostate 
 
Other 
 
Unknown  
Notes:  
o A new CRF-form recurrence/new primary needs to be filled in for each new recurrence or new 
primary tumour.  
o The Carcinoembryonic antigen (CEA) value has to be reported in µg/L. 
 
Concomitant Medication Form (CRF F05): 
 
Obligatory fields  
Optional fields  
- 
Center Id 
- 
Subject Id 
- 
Date of Birth: month and year 
- 
Chronical 
Medication 
Stopped 
(no/yes) 
o If chronical concomitant 
medication 
is 
stopped: 
provide date of stop and 
name of stopped chronical 
concomitant medication  
o If chronical concomitant 
medication 
is 
started: 
provide date of start and 
name of started chronical 
concomitant medication  
- 
Signature and name investigator  
- 
Date signed 
- 
If 
chronical 
concomitant 
medication is stopped: provide 
dose and reason of stop(ped) 
chronical concomitant medication  
- 
If 
chronical 
concomitant 
medication is started: provide 
dose and reason of start(ed) 
chronical concomitant medication  
- 
Notes 
The person completing the CRF-form can use the abbreviations ‘UK’ (unknown) or ‘ND’ 
(not done) if applicable. ‘UK’ must be used when it is not known if a value has been 
measured or a test has been performed. ‘ND’ must be used when it is certain that a 
value has not been measured or a test has not been performed.  
Notes:  
o Changes in type of concomitant medication as well as dosage need to be registered in the 
Concomitant Medication Form (CRF F05). 
o If the concomitant medication is related to an adverse event grade 1/2 and not considered 
to be relevant, please mention this AE + grade in the Notes field of the Concomitant 
Medication Form (CRF F05).  
 
 
 

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End of Study Treatment Form (CRF F06): 
 
Obligatory fields  
Optional fields  
- 
Center Id 
- 
Subject Id 
- 
Date of Birth: month and year 
- 
Date of last study medication 
intake  
- 
Reason for end of study treatment  
- 
Study 
treatment 
deblinded 
(no/yes) 
- 
Signature and name investigator  
- 
Date signed 
- 
Notes  
The person completing the CRF-form can use the abbreviations ‘UK’ (unknown) or ‘ND’ 
(not done) if applicable. ‘UK’ must be used when it is not known if a value has been 
measured or a test has been performed. ‘ND’ must be used when it is certain that a 
value has not been measured or a test has not been performed.  
Notes:  
o If applicable, complete an additional CRF-form according to the instructions on this CRF-form.  
o An End of Study Treatment Form needs to be completed when a patient stops/must stop his/her 
study medication for any reason, but there is no withdrawal of Informed Consent. The scheduled 
study visits continue, but no questionnaires should be completed anymore. 
 
Off Study Form (CRF F07): 
 
Obligatory fields  
Optional fields  
- 
Center Id 
- 
Subject Id 
- 
Date of Birth: month and year 
- 
Last date in study  
- 
Reason off study 
- 
Signature and name investigator  
- 
Date signed 
- 
Notes  
The person completing the CRF-form can use the abbreviations ‘UK’ (unknown) or ‘ND’ 
(not done) if applicable. ‘UK’ must be used when it is not known if a value has been 
measured or a test has been performed. ‘ND’ must be used when it is certain that a 
value has not been measured or a test has not been performed.  
Notes:  
o If applicable, complete an additional CRF-form according to the instructions on this CRF-form.  
o An Off Study Form needs to be completed in case of end of study treatment and withdrawal of 
Informed Consent. The data collection stops i.e. no questionnaires should be completed anymore, 
and no more study visits will be organized.  
 
 
 

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Death Form (CRF F20): 
 
Obligatory fields  
Optional fields  
- 
Center Id 
- 
Subject Id 
- 
Date of Birth: month and year 
- 
Date of death  
- 
Autopsy (no/yes). If an autopsy is 
performed, the autopsy report 
must be sent to the central 
coordination 
team 
(aspirin@uza.be) 
- 
Cause of death. If ‘second primary 
malignancy’ or ‘other’ is applicable, 
a specification needs to be filled in 
- 
Signature and name investigator  
- 
Date signed 
- 
Notes  
The person completing the CRF-form can use the abbreviations ‘UK’ (unknown) or ‘ND’ 
(not done) if applicable. ‘UK’ must be used when it is not known if a value has been 
measured or a test has been performed. ‘ND’ must be used when it is certain that a 
value has not been measured or a test has not been performed.  
 
 
 

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Adverse Event Form (CRF F30): 
 
Obligatory fields  
Optional fields  
- 
Center Id 
- 
Subject Id 
- 
Date of Birth: month and year 
- 
Description of AE 
- 
Date of visit  
- 
Date of onset AE 
- 
Serious Adverse Event (no/yes) 
- 
Grade AE 
- 
Relation AE to study medication  
- 
Action with study medication  
- 
Treatment of the AE 
- 
Outcome AE 
- 
Date resolved AE if date is known 
in the medical record  
- 
Signature and name investigator  
- 
Date signed  
- 
Date resolved AE if date is 
unknown in the medical record  
 
The person completing the CRF-form can use the abbreviations ‘UK’ (unknown) or ‘ND’ 
(not done) if applicable. ‘UK’ must be used when it is not known if a value has been 
measured or a test has been performed. ‘ND’ must be used when it is certain that a 
value has not been measured or a test has not been performed.  
 
Notes:  
o The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 needs to be used 
for Adverse Event reporting. A grading (severity) scale is provided herein for each Adverse Event 
term. Grade 3-5 adverse events should always be reported. In addition, relevant (possibly related) 
adverse events grade 1-2 (e.g. bruises, gingival bleedings, epistaxis and thrombocytopenia) 
should also be reported. In this study chemotherapy toxicity is not considered an adverse event 
(cfr. Protocol Chapter 11.2). 
o If applicable, complete an additional CRF-form according to the instructions on this CRF-form.  
 
 
 

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Serious Adverse Event Form (CRF F40): 
 
Obligatory fields  
Optional fields  
- 
Center Id 
- 
Subject Id 
- 
Date of Birth: month and year 
- 
Report type  
- 
Country  
- 
Age (years) 
- 
Sex 
- 
Date of onset SAE 
- 
Onset period of SAE 
- 
Description SAE in a single term  
- 
Intensity SAE according to CTCAE 
version 4.03 
- 
Category of SAE. If the category 
‘patient died’ is applicable, the date 
of death and cause of death has to 
be completed 
- 
Outcome 
SAE. 
If 
the 
patient 
recovered, the date of recovery has 
to be completed  
- 
First date of administration of 
Aspirin or Placebo  
- 
Last date of administration of 
Aspirin or Placebo  
o In case of EOT: report date 
of EOT 
o In case of temporarily stop: 
report 
date 
of 
last 
administration  
- 
Causality  
- 
Did reaction abate after stopping 
study medication? 
- 
Did 
reaction 
reappear 
after 
reintroduction study medication?  
- 
Action taken? 
- 
Concomitant medication (yes/no). 
If concomitant medication was 
used, the name has to be specified  
- 
Relevant laboratory values 
- 
Date of initial report or N.A. 
- 
Date of final report or N.A. 
- 
Contact details of the person who 
filled out this form and e-mail 
address  
- 
Signature and name investigator  
- 
Date signed 
- 
Dose of concomitant medication if 
applicable  
- 
Relevant medical history  
- 
Notes  
- 
If applicable, report date of 
reintroduction study medication 
after temporarily stop in Notes 
field of SAE form 
The person completing the CRF-form can use the abbreviations ‘UK’ (unknown) or ‘ND’ 
(not done) if applicable. ‘UK’ must be used when it is not known if a value has been 
measured or a test has been performed. ‘ND’ must be used when it is certain that a 
value has not been measured or a test has not been performed.  
 
 
 

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Questionnaires 
The questionnaires on T0, T6, T36 and T60 are considered as obligatory. When a questionnaire is not 
completed or is missing, this is regarded as a protocol deviation. Please provide the reason why the 
questionnaire has not been completed or is missing.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 10: Safety Manual 
 
 
 

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