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Study Protocol P3-C3-005 DARWIN EU® – Incidence rates of venous thromboembolic events in cancer patients 30/10/2024 Version 1.0 DARWIN EU® Coordination Centre 1/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential Table of Contents LIST OF ABBREVIATIONS ......................................................................................................................... 4 1. TITLE .............................................................................................................................................. 5 2. RESPONSIBLE PARTIES – STUDY TEAM ............................................................................................. 5 3. ABSTRACT ...................................................................................................................................... 7 4. AMENDMENTS AND UPDATES......................................................................................................... 8 5. MILESTONES ................................................................................................................................... 9 6. RATIONALE AND BACKGROUND ...................................................................................................... 9 7. RESEARCH QUESTION AND OBJECTIVES ......................................................................................... 10 8. RESEARCH METHODS .................................................................................................................... 13 8.1 Study type and study design .......................................................................................................... 13 8.2 Study setting and data sources ...................................................................................................... 14 8.3 Study period ................................................................................................................................... 21 8.4 Follow-up ....................................................................................................................................... 21 8.5 Study population with inclusion and exclusion criteria ................................................................. 22 8.6 Variables ......................................................................................................................................... 25 8.7 Study size........................................................................................................................................ 28 8.8 Analysis........................................................................................................................................... 28 8.9 Evidence synthesis ......................................................................................................................... 30 9. DATA MANAGEMENT ................................................................................................................... 30 9.1 Data management................................................................................................................................. 30 9.2 Data storage and protection ................................................................................................................. 30 10. QUALITY CONTROL ................................................................................................................... 31 11. LIMITATIONS OF THE RESEARCH METHODS............................................................................... 31 12. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS ........................... 32 13. GOVERNANCE BOARD ASPECTS ................................................................................................ 32 14. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS ....................................... 32 15. OTHER ASPECTS ....................................................................................................................... 32 16. REFERENCES............................................................................................................................. 33 17. ANNEXES ................................................................................................................................. 34 DARWIN EU® Coordination Centre 2/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential Study Title DARWIN EU® – Incidence rates of venous thromboembolic events in cancer patients Protocol version 1.0 Date 30/10/2024 EU PAS number Study not yet registered Active substance None Medicinal product None Research question This study aims to estimate incidence rates of venous thromboembolic and objectives events (deep vein thrombosis (DVT), pulmonary embolisms (PE), venous thromboembolism (VTE, composite of DVT and PE), pelvic venous thrombosis (PVT), splanchic vein thrombosis (SVT), including hepatic and extra-hepatic vein thrombosis, retinal vein thrombosis (RVT), including retinal central vein thrombosis, and disseminated intravascular coagulation (DIC) in adult patients (aged 18 and above) newly diagnosed with selected cancers in 2016-2023 (lung, breast, ovary, corpus uteri, prostate, pancreas, colorectal, stomach, oesophageal, liver, brain, bone, kidney, melanoma, lymphoma and leukaemia) and to describe their characteristics at the time of cancer diagnosis. The specific objectives of the study are: 1. To estimate the incidence rates of thromboembolic events in patients newly diagnosed with each type of selected cancers stratified by country/database, age group, sex, study sub-period, and cancer stage (when available) one and two years after cancer diagnosis. 2. To characterise cancer patients at the time of cancer diagnosis in terms of demographics, comorbidities, concomitant medications, as well as treatments received in the first 90 days after cancer diagnosis. Country(ies) of study Belgium, Denmark, Estonia, Finland, Germany, The Netherlands, Spain, United Kingdom Author Anton Barchuk ([email protected]) Talita Duarte-Salles ([email protected]) DARWIN EU® Coordination Centre 3/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential LIST OF ABBREVIATIONS Abbreviation Name ATC Anatomical Therapeutic Chemical CDM Common Data Model CPRD Clinical Practice Research Datalink DARWIN EU® Data Analysis and Real World Interrogation Network DK-DHR Danish Data Health Registries DOI Declaration Of Interests DQD Data Quality Dashboard DRE Digital Research Environment DVT Deep Venous Thrombosis DIC Disseminated Intravascular Coagulation GP General Practitioner EHR Electronic Health Record EMA European Medicines Agency EBB Estonian Biobank ECOG Eastern Cooperative Oncology Group EGCUT Estonian Genome Center at the University of Tartu ENCePP European Network of Centres for Pharmacoepidemiology and Pharmacovigilance ICD-O-3 International Classification of Diseases for Oncology, 3rd Edition ICD-10 International Classification of Diseases, 10th revision ICPC-1 International Classification of Primary Care IPCI Integrated Primary Care Information Project LPD Longitudinal Patient Database OHDSI Observational Health Data Sciences and Informatics OMOP Observational Medical Outcomes Partnership PE Pulmonary Embolism PVT Pelvic Venous Thrombosis RVT Retinal vein thrombosis SNOMED Systematized Nomenclature of Medicine SVT Splanchic Vein Thrombosis UKBB UK Biobank VTE Venous Thromboembolism DARWIN EU® Coordination Centre 4/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential 1. TITLE DARWIN EU® – Incidence rates of venous thromboembolic events in cancer patients 2. RESPONSIBLE PARTIES – STUDY TEAM Study team role Names Organisation Study Project Manager / Talita Duarte-Salles Erasmus MC Principal Investigator Anton Barchuk Data Scientist Cesar Barboza Erasmus MC Ger Inberg Maarten van Kessel Adam Black Ross Williams Epidemiologist Berta Raventós Erasmus MC Julieta Politi Clinical Domain Expert Anton Barchuk Erasmus MC DARWIN EU® Coordination Centre 5/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential Data Partner* Names Organisation CPRD GOLD and UKBB Antonella Delmestri University of Oxford DK-DHR Claus Møldrup Elvira Bräuner Susanne Bruun Danish Medicines Agency Tine Iskov Kopp Cæcilie Brinth Christiansen EBB Marek Oja Estonian Biobank, Estonia Raivo Kolde FinOMOP-HILMO Anna Hammais Finnish Care Register for Health Gustav Klingstedt Care, Finland FinOMOP-HUS Eric Fey Hospital District of Helsinki and Kimmo Porkka Uusimaa, Finland Tiina Wahlfors IQVIA DA Germany and IQVIA LPD Gargi Jadhav Belgium Isabella Kacmarczyl Akram Mendez IQVIA Hanne van Ballegooijen Dina Vojinovic IPCI Katia Verhamme Integrated Primary Care Information, Netherlands SIDIAP Anna Palomar-Cros Irene López-Sánchez IDIAPJGol Agustina Giuliodori *Data partners’ role is only to execute code at their data source, review and approve their results. These people do not have an investigator role. DARWIN EU® Coordination Centre 6/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential 3. ABSTRACT Title DARWIN EU® – Incidence rates of venous thromboembolic events in cancer patients Rationale Cancer-associated venous thrombosis is relatively common: from 20% to 30% of all primary venous thromboembolic events are cancer-associated. While cancer patients have an increased risk of developing venous thromboembolism (VTE) compared to individuals without underlying malignancies, it is also recognised as one of the major causes of death in cancer patients. Still, the reported incidence varies across different populations and cancer types and can also be attributed to variations in patient characteristics, management options, and the cancer stage at diagnosis. The incidence of VTE was found to be higher in cases of renal cell, ovarian, pancreatic, stomach, and lung cancers, as well as acute myelogenous leukaemia and non-Hodgkin lymphoma during the four months immediately preceding the cancer diagnosis. When investigating a safety signal, reliable information on background risk is crucial to assess potential associations with oncological treatments. Research Objectives This study aims to estimate incidence rates of venous thromboembolic events (deep vein thrombosis (DVT), pulmonary embolisms (PE), venous thromboembolism (VTE, composite of DVT and PE), pelvic venous thrombosis (PVT), splanchic vein thrombosis (SVT), including hepatic and extra-hepatic vein thrombosis, retinal vein thrombosis (RVT), including retinal central vein thrombosis, and disseminated intravascular coagulation (DIC) in adult patients (aged 18 and above) newly diagnosed with selected cancers in 2016- 2023 (lung, breast, ovary, corpus uteri, prostate, pancreas, colorectal, stomach, oesophageal, liver, brain, bone, kidney, melanoma, lymphoma and leukaemia) and to describe their characteristics at the time of cancer diagnosis. The specific objectives of the study are: 1. To estimate the incidence rates of thromboembolic events in patients newly diagnosed with each type of selected cancers stratified by country/database, age group, sex, study sub-period, and cancer stage (when available) one and two years after cancer diagnosis. 2. To characterise cancer patients at the time of cancer diagnosis in terms of demographics, comorbidities, concomitant medications, as well as treatments received in the first 90 days after cancer diagnosis. Research Methods Study design Population-based cohort study. Population The study population will include all individuals aged 18 years and above with a primary diagnosis of one of the selected cancers (lung, breast, ovary, corpus uteri, prostate, pancreas, colorectal, stomach, oesophageal, liver, brain, bone, kidney, melanoma, lymphoma and leukaemia) in the study period from 01/01/2016 to 31/12/2023. Only patients with the first and one cancer diagnosis (except non-melanoma skin cancer) will be included. Cancer cases and thromboembolic events will be identified based on appropriate computable phenotyping algorithms. Conditions in the OMOP CDM use the Systematised DARWIN EU® Coordination Centre 7/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential Nomenclature of Medicine (SNOMED) as the standard vocabulary for diagnosis codes. The International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) will also be considered for cancer diagnoses. Additional eligibility of a minimum of 1 year of potential follow-up time will be imposed to ensure sufficient time to capture potential outcomes of interest. Variables Outcomes will include thromboembolic events, in particular, DVT, PE, VTE (composite of DVT and PE), PVT, SVT, RVT, DIC. Data sources 1. Clinical Practice Research Datalink GOLD (CPRD GOLD), United Kingdom 2. Danish Data Health Registries (DK-DHR), Denmark 3. Estonian Biobank (EBB), Estonia 4. Finnish Care Register for Health Care (FinOMOP-HILMO) Finland 5. Hospital District of Helsinki and Uusimaa (FinOMOP-HUS), Finland 6. IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany 7. IQVIA Longitudinal Patient Database Belgium (IQVIA LPD Belgium), Belgium 8. Integrated Primary Care Information (IPCI), Netherlands 9. The Information System for Research in Primary Care (SIDIAP), Spain. 10. UK Biobank (UKBB), United Kingdom Sample size No sample size will be calculated as this is a descriptive study. However, analysis by strata will be limited to databases with enough cases (5 or more) to provide meaningful results. Summary measures of occurrence will not be calculated for strata with counts less than 5. Data analyses Analyses will be conducted separately for each database and carried out in a federated manner, allowing analyses to be run locally without sharing patient-level data. The incidence of thromboembolic events (Objective 1) will be estimated over one and two years after the selected cancer diagnosis. Each cancer type and outcome will be assessed separately. Large-scale patient- level characterisation (Objective 2) will be conducted at the index date. Age and sex will be described at the time of diagnosis. The medical history and medication will be assessed at the index date. For all analyses, absolute and relative frequencies will be reported. A minimum cell count of 5 will be used when reporting results, with any smaller counts reported as “<5” and zero counts as “0”. Overall analyses will be done separately for each database. Further stratification by age category (18-29; 30-39; 40-49; 50- 59; 60-69; 70-79; 80-89; 90 and over), sex, study sub-period, cancer stage will be conducted when possible (minimum cell count reached and data available). The following sub-periods will be also used: 2016-2019, 2020-2023. 4. AMENDMENTS AND UPDATES None. DARWIN EU® Coordination Centre 8/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential 5. MILESTONES Study deliverables Timeline Draft Study Protocol October 2024 Final Study Protocol October/November 2024 (or upon EMA acceptance) Creation of Analytical code and Phenotyping November/December 2024 Execution of Analytical Code on the data January 2024 (depending on IRB approval dates) Draft Study Report February 2024 Final Study Report February 2024 6. RATIONALE AND BACKGROUND Cancer-associated venous thrombosis is relatively common: from 20% to 30% of all primary venous thromboembolic events are cancer-associated (Timp, 2013). While cancer patients have an increased risk of developing venous thromboembolism (VTE) compared to individuals without underlying malignancies (Blom, 2005), it is also recognised as one of the major causes of death in cancer patients (Wang, 2017). Still, the reported incidence varies across different populations and cancer types and can also be attributed to variations in patient characteristics, management options, and the cancer stage at diagnosis (Timp, 2013). The association between cancer and thromboembolic events was assessed in various studies. In a large cohort of cancer patients, the incidence of thromboembolic events was found to be higher in cases of renal cell, ovarian, pancreatic, stomach, and lung cancers, as well as acute myelogenous leukaemia and non- Hodgkin lymphoma during the four months immediately preceding the cancer diagnosis (White, 2005). The prevalence of thromboembolic events at the time of diagnosis was highest for pancreatic cancer and lowest for breast cancer in another registry-based study (Ohashi, 2020). All cancer sites showed an increased prevalence in the thromboembolic events incidence cohort (Petterson, 2015). The incidence of thromboembolic events was notably high during the first few months of chemotherapy in a cohort of cancer patients followed for up to 12 months, with higher odds observed in pancreatic, gastric, and lung cancers (Khorana, 2013). Certain cancer medications have also been associated with higher risks of thromboembolic events (Nalluri, 2008; Khorana, 2013). Additionally, major surgery is known to be associated with thromboembolic events, with an increased risk that persists for 90 to 120 days post-surgery (Björklund, 2024). A high rate of recurrent thromboembolic events is observed over time following the discontinuation of anticoagulant therapy in patients with cancer-associated thrombosis (van Hylckama Vlieg, 2023). When a safety signal of this nature appears in cancer populations, it can be challenging to assess a potential association with new treatment options without reliable information on background risk. This study DARWIN EU® Coordination Centre 9/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential addresses this knowledge gap by generating background incidence rates of thromboembolic events events among patients with selected cancer types. 7. RESEARCH QUESTION AND OBJECTIVES This study aims to estimate incidence rates of venous thromboembolic events (deep vein thrombosis (DVT), pulmonary embolisms (PE), venous thromboembolism (VTE, composite of DVT and PE), pelvic venous thrombosis (PVT), splanchic vein thrombosis (SVT), including hepatic and extra-hepatic vein thrombosis, retinal vein thrombosis (RVT), including retinal central vein thrombosis, and disseminated intravascular coagulation (DIC) in adult patients (aged 18 and above) newly diagnosed with selected cancers in 2016- 2023 (lung, breast, ovary, corpus uteri, prostate, pancreas, colorectal, stomach, oesophageal, liver, brain, bone, kidney, melanoma, lymphoma and leukaemia) and to describe their characteristics at the time of cancer diagnosis. The specific objectives of the study are: 1. To estimate the incidence rates of thromboembolic events in patients newly diagnosed with each type of selected cancers stratified by country/database, age group, sex, study sub-period, and cancer stage (when available) one and two years after cancer diagnosis. 2. To characterise cancer patients at the time of cancer diagnosis in terms of demographics, comorbidities, concomitant medications, as well as treatments received in the first 90 days after cancer diagnosis. A description of the proposed objectives to be achieved in the study is found in Table 1. Table 1. Primary and secondary research questions and objectives. A. Primary research question and objective. Objective: To estimate the incidence rates of thromboembolic events in patients newly diagnosed with each type of selected cancers stratified by country/database, age group, sex, study sub-period, and cancer stage (when available) one and two years after cancer diagnosis. Hypothesis: N/A Population (mention key inclusion- The study population will include all individuals aged 18 years and above exclusion criteria): with a primary diagnosis of selected cancers in the study period from 01/01/2016 to 31/12/2023. Selected cancer types include: • Malignant neoplasm of oesophagus (specified in the protocol as oesophageal cancer), • Malignant neoplasm of stomach (stomach cancer), • Malignant neoplasm of colon, rectosigmoid junction, rectum, anus and anal canal (colorectal cancer), • Malignant neoplasm of liver and intrahepatic bile ducts (liver cancer), • Malignant neoplasm of pancreas (pancreatic cancer), DARWIN EU® Coordination Centre 10/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential • Malignant neoplasm of trachea, bronchus and lung (lung cancer), • Malignant neoplasms of bone and articular cartilage • (bone cancer) • Malignant melanoma of skin (skin melanoma) • Malignant neoplasm of breast (breast cancer), • Malignant neoplasm of corpus uteri (corpus uteri cancer including endometrial cancer), • Malignant neoplasm of ovary (ovarian cancer), • Malignant neoplasm of prostate (prostate cancer), • Malignant neoplasm of kidney, except renal pelvis (kidney cancer), • Malignant neoplasm of meninges, brain and spinal cord, cranial nerves and other parts of central nervous system (brain cancer), • Malignant neoplasms, stated or presumed to be primary, of lymphoid, haematopoietic and related tissue (lymphoma and leukaemia) Only patients with the first and one cancer diagnosis (except non- melanoma skin cancer) will be included. Additional eligibility of a minimum of 1 year of potential follow-up time will be imposed to ensure sufficient time to capture potential outcomes of interest. Exposure: N/A Comparator: N/A Outcome: Venous thromboembolic events: • deep vein thrombosis (DVT), • pulmonary embolisms (PE), • venous thromboembolism (VTE, composite of DVT and PE), • pelvic venous thrombosis (PVT), • splanchic vein thrombosis (SVT), including hepatic and extra- hepatic vein thrombosis, • retinal vein thrombosis (RVT), including retinal central vein thrombosis • disseminated intravascular coagulation (DIC) Time (when follow up begins and For each outcome, study participants will be followed up from the date of ends): the selected cancer diagnosis (index date) until the earliest of the following events: occurrence of the outcome, end of follow up (1 year for the main analysis or 2 years), loss to follow-up, end of data availability, or date of death. Setting: Routinely collected data from 10 databases in 8 European countries. DARWIN EU® Coordination Centre 11/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential Main measure of effect: Proportions, incidence rates and incidence rate ratios if information on stage is available B. Secondary research question and objective. Objective: To characterise cancer patients at the time of cancer diagnosis in terms of demographics, comorbidities, concomitant medications, as well as treatments received in the first 90 days after cancer diagnosis. Hypothesis: N/A Population (mention key inclusion- The study population will include all individuals aged 18 years and above exclusion criteria): with a primary diagnosis of selected cancers in the study period from 01/01/2016 to 31/12/2023. Selected cancer types include: • Malignant neoplasm of oesophagus (specified in the protocol as oesophageal cancer, corresponding), • Malignant neoplasm of stomach (stomach cancer), • Malignant neoplasm of colon, rectosigmoid junction, rectum, anus and anal canal ( colorectal cancer), • Malignant neoplasm of liver and intrahepatic bile ducts (liver cancer), • Malignant neoplasm of pancreas (pancreatic cancer), • Malignant neoplasm of trachea, bronchus and lung (lung cancer), • Malignant neoplasms of bone and articular cartilage • (bone cancer) • Malignant melanoma of skin (skin melanoma) • Malignant neoplasm of breast (breast cancer), • Malignant neoplasm of corpus uteri (corpus uteri cancer including endometrial cancer), • Malignant neoplasm of ovary (ovarian cancer), • Malignant neoplasm of prostate (prostate cancer), • Malignant neoplasm of kidney, except renal pelvis (kidney cancer), • Malignant neoplasm of meninges, brain and spinal cord, cranial nerves and other parts of central nervous system (brain cancer), • Malignant neoplasms, stated or presumed to be primary, of lymphoid, haematopoietic and related tissue (Lymphoma and leukaemia) Only patients with the first and one cancer diagnosis (except non- melanoma skin cancer) will be included. Additional eligibility of a DARWIN EU® Coordination Centre 12/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential minimum of 1 year of potential follow-up time will be imposed to ensure sufficient time to capture potential outcomes of interest. Exposure: N/A Comparator: N/A Outcome: Medical History: asthma, COPD, chronic liver disease, Crohn’s disease, Diabetes mellitus, gastro-oesophageal reflux disease (GERD), GI-Bleeding, Human Immunodeficiency Virus (HIV), Hyperlipidaemia, Hypertension, Obesity, Osteoarthritis, Pneumonia, Psoriasis, Renal impairment, Ulcerative Colitis, Viral Hepatitis, Visual system disorder [General] -- Schizophrenia, Dementia, Parkinson, Depressive disorder, Anxiety, Attention Deficit Hyperactivity Disorder (ADHS) [Neurology], thromboembolic events outcomes of interest mentioned above --- Any cancer except non-melanoma skin cancer (for quality assessment purposes, this should be 0 in our study population before index date). Medication use: Agents acting on the renin-angiotensin system, Antibacterials for systemic use, Antidepressants, Antiepileptics, Anti- inflammatory and antirheumatic products, Antineoplastic agents, Anti- psoriatic, Antithrombotic agents, Beta blocking agents, Calcium channel blockers, Diuretics, Drugs for acid related disorders, Drugs for obstructive airway diseases, Drugs used in diabetes, Immunosuppressants, Lipid modifying agents, Opioids, Psycholeptics, Psychostimulants, agents used for ADHD and nootropics [General] -- contraceptives [contraceptives]. Time (when follow up begins and Medical History at the index date and medication at the index date and ends): from 1 to 90 days. Setting: Routinely collected data from 10 databases in 8 European countries. Main measure of effect: Proportions 8. RESEARCH METHODS 8.1 Study type and study design This will be a population-level descriptive epidemiology and patient-level characterisation study. As described in the DARWIN EU® Complete Catalogue of Standard Data Analyses (Table 2). A retrospective cohort study of all newly diagnosed adult patients with selected cancers will be conducted. DARWIN EU® Coordination Centre 13/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential Table 2. Description of potential study types and related study designs. Study type Study design Study classification Population-level descriptive Population-level cohort Off the shelf epidemiology Patient-level characterisation Cohort analysis Off the shelf 8.2 Study setting and data sources This study will use routinely collected health data from 10 databases from 8 European countries. All of them have been previously mapped to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). The databases to be included in the study are: 1. Clinical Practice Research Datalink GOLD (CPRD GOLD), United Kingdom 2. Danish Data Health Registries (DK-DHR), Denmark 3. Estonian Biobank (EBB), Estonia 4. Finnish Care Register for Health Care (FinOMOP-HILMO) Finland 5. Hospital District of Helsinki and Uusimaa (FinOMOP-HUS), Finland 6. IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany 7. IQVIA Longitudinal Patient Database Belgium (IQVIA - LPD Belgium), Belgium 8. Integrated Primary Care Information (IPCI),Netherlands 9. The Information System for Research in Primary Care (SIDIAP), Spain. 10. UK Biobank (UKBB), United Kingdom Information on data sources is available in Table 3. Databases were selected based on the person count of cancer diagnoses under interest and thromboembolic events, and European representativeness. We also considered the lack of major issues and errors during the most recent internal and Darwin EU onboarding quality checks for the selected databases. Preliminary stratification by tumour stage will only be feasible in DK-DHR, EBB and FinOMOP-HUS. The selected databases also fulfil the criteria required to capture outcomes of interest and relevant data to conduct a patient-level characterisation of newly diagnosed cancer patients across different European settings and regions. Not all databases have all outcomes of interest. DVT is not present in IQVIA - LPD Belgium. SVT counts are limited in EBB, IQVIA - LPD Belgium. RVT is present only in CPRD GOLD, SIDIAP and UKBB. DARWIN EU® Coordination Centre 14/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential Table 3. Description of the selected data sources. Country Name of Database Justification for Inclusion Health Care Type of Data Number of Data lock for setting active the last subjects update GB CPRD GOLD Covers primary care setting, data on Primary care, EHRs 17.5 M 2024-04-15 cancer diagnoses, comorbidities, hospital care medications, and date of death. (OP) DK DK-DHR National health data database All settings EHRs, 8.5 M 2024-05-15 which includes information on registries, cancer diagnoses, staging and claims medical history EE EBB Contains health insurance claims, Primary care, EHRs, claims, 0.2 M 2023-03-20 digital prescriptions, discharge hospital care (IP registries, information and causes of death and OP) biobank through linkage with the national death register. Data is linked to cancer registry. FI FinOMOP - HILMO Nation-wide hospital registry data Hospital care (IP EHRs, 7.1 M 2024-06-24 with high-quality information on and OP) registries cancer diagnoses and mortality. FI FinOMOP - HUS Hospital registry which includes Hospital care (IP EHRs 3.5 M 2024-05-03 information on cancer patients and and OP) medical history. DARWIN EU® Coordination Centre 15/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential Country Name of Database Justification for Inclusion Health Care Type of Data Number of Data lock for setting active the last subjects update DE IQVIA DA Germany Covers primary care setting with Primary care EHRs 43.1 M 2024-03-25 information on cancer diagnoses and medical history. BE IQVIA LPD Belgium Covers primary care setting with Primary care EHRs 1.1 M 2024-03-25 information on cancer diagnoses and medical history. NL IPCI Covers primary care setting, data on Primary care EHRs 2.9 M 2024-08-29 cancer diagnoses previously validated, information available on comorbidities, medications, and date of death. ES SIDIAP Covers primary care setting with Primary care EHRs 8.6 M 2023-03-20 information on cancer diagnoses and medical history. GB UKBB Genetic data on biobank Primary care, EHRs, 0.5 M 2024-02-16 participants linked to EHRs from hospital care (IP registries, primary care, hospitalisations, and OP) biobank cancer registrations and mortality. BE = Belgium, DE = Germany, DK=Denmark, EE = Estonia, ES=Spain, EHR=Electronic Health Record, FR = France, GB = United Kingdom of Great Britain and Northern Ireland, FI = Finland, IP = Inpatient, NL = the Netherlands, OP = outpatient DARWIN EU® Coordination Centre 16/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential Clinical Practice Research Datalink GOLD (Oxford) (CPRD GOLD) The CPRD GOLD database collects data in the United Kingdom and is maintained by Clinical Practice Research Datalink. CPRD GOLD contains data from all four UK constituent countries (England, Scotland, and Northern Ireland). A database contains data from 1987 to present. Data are collected from general practitioner (GP) clinics that use the Vision® software system. GP clinics are responsible for non-emergency care and referrals. Data is collected from patient records stored at GP clinics. Over 98% of the UK population is registered with a GP. Covering 4.6% of the current UK population, CPRD GOLD includes 4.9% of contributing GP practices. Compared with the UK Census 2011, CPRD patients are broadly representative of the UK population in terms of age, sex, and ethnicity and comparable to the Health Survey for England for body mass index distribution. The CPRD GOLD may not be representative of all practices in the UK based on geography and size. It obtains data from electronic health records. The database currently holds information about the person (demographics), visits (inpatient and outpatient), conditions and procedures (billing codes), drugs (outpatient prescriptions and inpatient orders and administrations), measurements (laboratory tests and vital signs), and dates of death (in or out- hospital death). CPRD GOLD uses SNOMED medical terms. Transformation-level validation checks for referential integrity between records ensure that no orphan records are included in the database (for example, all event records link to a patient). Duplicate records are identified and removed. In contrast, research-quality-level validation covers the actual content of the data. CPRD provides a patient-level data quality metric as a binary ‘acceptability’ flag. This is based on recording and internal consistency of key variables, including date of birth, practice registration date, and transfer out date. Validation of the CPRD has shown a high positive predictive value for some diagnoses, and where evaluated, comparisons of incidence with other UK data sources are also broadly similar. Research into data quality has shown large variations in the inter-practice recording of data. Established linkages include, but are not limited to, Hospital Episode Statistics (hospitalisation data), Office for National Statistics (mortality data including causes of death), Index of Multiple Deprivation and Townsend scores (deprivation data), and disease registries. Vital status (death date and causes) is obtained from the Office for National Statistics. CPRD GOLD is limited to GP records. General practices receive information about patient contacts with secondary care, which must be manually entered into the patient record. However, the database also combines data from various sources through effective linkages. Primary care data quality is variable because GPs enter data during routine consultations, not for research. The database was described by Herrett et al., 2015. The database description is also available at cprd.com. Danish Data Health Registries (DK-DHR) Danish health data is collected, stored, and managed in national health registers at the Danish Health Data Authority. It covers the entire population, which makes it possible to study the development of diseases and their treatment over time. There are no gaps in terms of gender, age and geography in Danish health data due to mandatory reporting on all patients from cradle to grave in all hospitals and medical clinics. Personal identification numbers link data across registers, so we have data on all Danes throughout their lives, regardless of whether they have moved around the country. High data quality due to standardisation, digitisation and documentation means Danish health data is not based on interpretation. The Danish Health Data Authority is responsible for the national health registers and maintaining and developing standards and classifications in the Danish healthcare system. The legislation ensures a balance between personal data protection and use. In the present database, we have access to the following registries for the entire Danish population of 5.9 million persons from 1.1.1995: The Central Person Registry (CPR), The National Patient Registry (LPR), The Register of Pharmaceutical Sales (LSR), The National Cancer Register (CAR), The Cause of Death registry (DAR), The Clinical Laboratory Information Register (LAB), COVID-19 test and DARWIN EU® Coordination Centre 17/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential vaccination Registries (SSI-OVD, SSI-DDV), The complete Vaccination registry (DDV_all). All data registered from 1.1.1995 will be included. Estonian Biobank (EBB) The EBB collects data in Estonia and is maintained at the Estonian Genome Center, University of Tartu. It is a nationwide database, and the network of recruitment offices for EBB covers all 15 counties of the country. The Estonian Genome Project Foundation initiated the Estonian Biobank Project in 1999, which was transformed into the Estonian Genome Center of the University of Tartu (EGCUT) in 2007. The data is available from 2004 onwards. The Estonian Biobank cohort is a volunteer-based sample of the Estonian resident adult population. EBB represents an Estonian population-based cohort size of 52,000 participants aged 18 years and older recruited at GP offices, private practices, and hospitals or in the recruitment offices of the Estonian Genome Center. The age, sex, and geographical distribution closely reflect those of the Estonian adult population and encompass nearly 5% of the population. Overall, the representation of men in the biobank is 3.4%, and women’s is 5.5%. Older people tend to participate less frequently; however, all age groups are well represented. The database obtains data from the biobank records. All participants have undergone a standardised health assessment, including providing blood samples for purification of DNA, white blood cells, and plasma, and completed a questionnaire covering various health-related topics, such as lifestyle, diet, and clinical diagnoses. Diseases and health problems are recorded as ICD-10 codes and prescribed medicine according to the ATC classification. For all starting data collectors, the first ten questionnaires were monitored for completeness and illogical answers, and after that, 10% were selected randomly for monitoring; 21% were inspected and corrected when necessary. From the monitored questionnaires, 99% were classified as high quality, meaning all the fields were filled in, and the answers appeared logical. Follow‐up data are available via linkage with national health‐related registries and re‐examination of participants. Furthermore, electronic health records are updated every half year for phenotypic outcome information. The EBB database is regularly linked with national registries, hospital databases, and the national health insurance fund database, which holds treatment and service bills. Vital status (death date and causes) is obtained from the Causes of Death Registry. Participation in the EBB cohort is voluntary; therefore, the biobank does not represent a classical random sample and could be subject to recruitment bias. Although recruitment was open to everyone, there is a disproportion of ethnic Estonians and ethnic Russians in the biobank, with Estonians being overrepresented and Russians underrepresented. Also, the limited depth of collected data can sometimes limit the number of projects in which the data can be used. The database was described by Leitsalu et al., 2015, 10.1093/ije/dyt268. The database description is also available at genomics.ut.ee/en/content/estonian-biobank. Finnish Care Register for Health Care (FinOMOP - HILMO) The Finnish Care Register for Health Care (fi: Hoitoilmoitusrekisteri) continues the former Hospital Discharge Register, which originally gathered data on hospital discharge (Sund et al., 2012). The Care Register has comprehensive data on services and service users nationwide, including Finnish public inpatient and outpatient primary and specialised care. Since 1998, the register has covered public outpatient and inpatient specialised care and private inpatient care (TerveysHilmo). Since 2011, the register has covered public primary care (AvoHilmo). Since 2020, the register has covered private outpatient care and occupational care. The CDM is currently produced from the data collection on inpatient and outpatient specialised care (TerveysHilmo) and is limited to observation periods commencing after 01/01/2015. The Register of Primary Health Care Visits (AvoHilmo) is currently outside the scope of the CDM and will be added to CDM during the remainder of 2023. The inclusion of data collected before 2015 is also being planned. The National Population Registry is also used as a source for the CDM database. The National DARWIN EU® Coordination Centre 18/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential Population Registry data forms the basis for forming the patient population. This ensures up-to-date location (municipality of residence) of patients and complete death occurrences (although not the cause of death). Using the complete population as a basis for the person table also facilitates calculations on a population level, e.g. incidence rates. The HILMO database has been used to assess the quality of cancer registry data in Finland (Leinonen et al., 2017). Hospital District of Helsinki and Uusimaa (FinOMOP - HUS) The HUS data lake is a comprehensive, integrated data source derived in real-time from all patients who visit the HUS hospitals and receive treatment (Vikkula et al., 2023). HUS is responsible for specialised healthcare in Finlands’ Uusimaa region and the treatment of many rare and severe diseases nationally centralised to HUS. HUS’s catchment area covers about 2.2 million people. In 2023, there were 2.43 million booked appointments and 255,896 emergency department visits for specialist medical care. 691,702 patients received any treatment in HUS specialist medical care and at emergency departments, and 86,849 surgical procedures were performed. All visits, examinations, laboratory tests, procedures, and treatments are recorded in the HUS IT systems and integrated into the data lake. The data lake stores decades of clinical information in digital format, and data from past and current source systems are available. IQVIA Disease Analyzer Germany (IQVIA DA Germany) Germany DA is collected from extracts of patient management software used by GPs and specialists from ambulatory care settings. Patients visiting multiple providers are not cross-identified for data protection reasons and, therefore, recorded as separate in the system. Dates of service include from 1992 through the present. The first and last consultation dates define observation time. Germany has no mandatory GP system, and patients can choose specialists. Drugs are recorded as prescriptions of marketed products. No explicit registration or approval is needed for drug utilisation studies. IQVIA Longitudinal Patient Database Belgium (IQVIA LPD Belgium) Belgium Longitudinal patient data (LPD) is collected from GP prescribing systems and contains patient records on all signs and symptoms, diagnoses and prescribed medications. The information recorded allows patients and doctors to be monitored longitudinally. Data are recorded directly in real-time during patient consultations via a practice management software system. It is used in studies to provide various market insights such as treatment trends, patient pathway analysis and treatment compliance. The panel of contributing physicians (a stable 300 GPs) is maintained as a representative sample of Belgium's primary care physician population according to three criteria known to influence prescribing: age, sex and geographical distribution. Currently, the database covers 1.1 M cumulative patients from 2012 through to the present. The panel consists of a stable 300 GPs that are geographically well-spread. The total number of active GPs in Belgium is 15.602. The regional geographical spread of physicians in the LPD data is also representative of the distribution across the country: 57% GPs in the North (compared to 54% nationally), 31% in the South (33% nationally) and 12% in Brussels (13%). The data provider has more than 2.250 GPs under contract, so a replacement is easily found in case of a dropout. Drugs obtained over the counter by the patient outside the prescription system are not reported. No explicit registration or approval is needed for drug utilisation studies. Integrated Primary Care Information (IPCI) The database collects data in the Netherlands. It was started in 1992 by the Department of Medical Informatics of the Erasmus University Medical Center in Rotterdam, the Netherlands. The current database contains patient records from 2006 onwards when the size of the database started to increase significantly. IPCI is a nationwide Dutch database. However, it mainly covers the central part of the country, including the most densely populated and non-urban areas. The IPCI database contains data from records of general DARWIN EU® Coordination Centre 19/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential practitioners' (GPs) practices. It contains information on all patients registered with GPs responsible for non-emergency care and referrals. More than 99% of the Dutch population has health insurance, and almost all citizens are registered with a general practitioner. Over 12 months, around 78% of the population has at least one contact with their GP. IPCI included around 350 GP practices out of around 5000 in the country (~ 7%). The demographic composition of the IPCI population mirrors that of the general Dutch population in terms of age and sex. IPCI obtains data from computer-based patient records. Patient-level data includes demographic information, complaints and symptoms, diagnoses, laboratory test results, lifestyle factors, and correspondence with secondary care, such as referral and discharge letters. Dutch GPs use the International Classification of Primary Care (ICPC-1) coding for complaints, symptoms, and diagnoses, an international standard developed and updated by the World Organization of Family Doctors (WONCA) International Classification Committee. Extensive quality control steps are performed before each data release. These include comparing patient characteristics between practices and checks to identify abnormal temporal data patterns in practices. Additional checks include over 200 indicators related to population characteristics (e.g., reliability of birth and mortality rates) and medical data (e.g., availability of durations of prescriptions, completeness of laboratory results, availability of hospital letters and prescriptions, the proportion of patients with blood pressure measurement, etc.). IPCI is not linked with other databases. Vital status (death date and cause) is collected based on GP records. The main limitation is that IPCI is limited to GP records, and although it contains information on referrals and discharge letters, it may not capture specific hospital information. The database profile was described by de Ritter et al., 2022. The database description is also available at ipci.nl. The Information System for Research on Primary Care (SIDIAP) The database collects data in Spain and is maintained by the SIDIAP team, supported by the Catalan Health Institute and the Institute for Primary Health Care Research Jordi Gol i Gurina. It contains patient records from 2005 onwards and is updated every six months. It is a regional database covering the region of Catalonia. SIDIAP collects data in the primary care setting. It contains data from the population registered in over 280 primary care practices throughout Catalonia. Approximately 80% of the population registered with primary care is covered by SIDIAP. The demographic composition within SIDIAP closely mirrors that of the broader Catalan population, encompassing a representative spectrum of geographic distribution, age, and sex proportions. SIDIAP obtains data from electronic health records. The dataset covers demographics, all-cause mortality, disease diagnoses, prescription and dispensation records of drugs, results of laboratory tests, socio-economic indicators, vaccination records, lifestyle information, parent-child linkage, and various clinical parameters. Diseases are classified under the International Classification of Diseases 10th revision (ICD-10) Quality checks have been implemented, including central identification of duplicate patient IDs and visual inspection for temporal patterns in the registry of a certain variable. Furthermore, the data undergoes assessment for availability (longitudinally and reliability), plausibility (range checks and unusual values), and visualisation tools. Specifically, for biochemistry data, consistency for measurements taken in different laboratories is assessed, and unit conversion is undertaken when needed. SIDIAP is linked with numerous other databases. It integrates data from external sources, including laboratory biomarker data, drug prescription and dispensation records, hospital discharge records, mental health centres, and other specific disease registries. Vital status (death date and cause) is collected through linkage with the civil registry. The main limitation is that SIDIAP covers only primary health care records. However, it is combined with data DARWIN EU® Coordination Centre 20/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential from various other sources through effective linkages. The database profile was described by de Recalde et al., 2022. The database description is also available at sidiap.org. UK BioBank (UKBB) UK Biobank is a powerful biomedical database that can be accessed globally to enable discoveries to improve public health. UK Biobank contains in-depth genetic, biomarker, imaging and health information from over half a million volunteers living in the UK aged 40–69 years at the time of recruitment (2006– 2010). UK Biobank has collected unprecedented biological and medical data for a large-scale, long-term prospective study. With their consent, they regularly provide blood, urine and saliva samples and detailed information about their lifestyle, which is then linked to their health-related records (e.g. primary care data, hospital data, cancer registry) to provide a deeper understanding of how individuals experience diseases. Since 2012, the UK Biobank database, the largest and richest of its kind, has been open to applications from researchers. The resource is available in anonymised format to scientists from the UK and worldwide, subject to verification that the research is health-related and in the public interest. Researchers are required to publish their results in an open-source publication site or an academic journal and return their findings to the UK Biobank. At the time of writing, nearly 3,600 research applications have been approved for using UK Biobank data, and 3,239 peer-reviewed articles based on them have been published. 8.3 Study period The study period will be from 01/01/2016 to 31/12/2023 or the end of available data in each source if it comes earlier (see Table 3 Data lock for the last update column for more details). 8.4 Follow-up Study participants will be followed up from the date of cancer diagnosis (index date, Table 4) until the first occurrence of any of the following events: occurrence of the outcome, loss to follow-up, end of follow-up (one or two years), end of data availability, or date of death. Table 4. Operational definition of time 0 (index date) and other primary time anchors. Study Time Anchor Number of Type of Washout Care Code Diagnosis Incident Measureme Source population Description entries entry window Settin Type2 position with nt of name(s) (e.g. time 0) g1 respect characteristi algorith to… cs/ m validation Cancer Date of Single Incident [any IP, SNOMED, Any Any N/A N/A patients cancer entry time OP ICD-O-3 cancer diagnosis , -1] , diagnos OT is except non- melano ma skin cancer 1 IP = inpatient, OP = outpatient, OT = other, n/a = not applicable 2 SNOMED = Systematized Nomenclature of Medicine, ICD-O-3: International Classification of Diseases for Oncology, 3rd Edition DARWIN EU® Coordination Centre 21/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential 8.5 Study population with inclusion and exclusion criteria The study population will include all individuals aged 18 years and above with a primary diagnosis of selected cancers in the study period. Cancer types will include lung, breast, ovary, endometrium, prostate, pancreas, colorectal, stomach, oesophageal, liver, brain, bone, kidney, melanoma, lymphoma and leukaemia. Only patients with the first and one cancer diagnosis (except non-melanoma skin cancer) will be included. Cancer cases and thromboembolic events will be identified based an appropriate computable phenotyping algorithms. Conditions in the OMOP CDM use the Systematised Nomenclature of Medicine (SNOMED) as the standard vocabulary for diagnosis codes. For cancer diagnoses, the International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) will also be considered. Algorithms to reproduce cancer phenotypes will be shown along with the study results. Additional eligibility of a minimum of 1 year of potential follow-up time will be imposed to ensure sufficient time to capture potential outcomes of interest. For instance, in a database with data up to 31/12/2023, cancer cases diagnosed from 01/01/2016 up to 01/01/2023 will be included. A prior history requirement of one year of observation prior to the index date will be imposed. This is especially relevant for primary care databases, where a minimum observation period of one year before a cancer diagnosis is required to detect prevalent cases. Appendix II provides a preliminary code list for each cancer. The code list might be modified after cohort diagnostics The operational definitions of the inclusion and exclusion criteria are presented in Error! Reference source not found. and Table 6, respectively. DARWIN EU® Coordination Centre 22/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential Table 5. Operational definitions of inclusion criteria. Criterion Details Order of Assessment Care Code Diagnosis Applied to Measurement Source for application window Settings¹ Type position study characteristics/ algorithm populations: validation Patients newly Primary selected cancer After - IP, OP, SNOME N/A Cancer N/A N/A diagnosed with selected OT D, ICD- patients cancers O-3 Age Participants aged 18 or After At index IP, OP, N/A N/A Cancer N/A N/A above date OT patients Minimum prior Only participants with a Before 365 days OP, OT N/A N/A Cancer N/A N/A observation period of minimum observation patients 365 days period of 365 days prior to diagnosis of chondrosarcoma (index date) s Minimum potential Only participants with a After [0, 365] IP, OP, N/A N/A Cancer N/A N/A follow-up time cancer diagnosis (index OT patients date) occurring one year prior to end of data availability in the database will be included 1 IP = inpatient, OP = outpatient, OT = other, n/a = not applicable. DARWIN EU® Coordination Centre 23/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential Table 6. Operational definitions of exclusion criteria. Criterion Details Order of Assessment Care Code Diagnosis Applied to Measurement Source application window Settings¹ Type position study characteristics/ for populations: validation algorithm History of cancer Participants with a diagnosis of After Any time OP, IP, SNOMED, Any Cancer N/A N/A diagnosis cancer (any, excluding non- prior to OT ICD-O-3 patients melanoma skin cancer) any cancer time prior index date diagnosis Multiple primary Participants with a two After At index OP, IP, SNOMED, Any Cancer N/A N/A tumors diagnoses of cancer (any, date OT ICD-O-3 patients excluding non-melanoma skin cancer) at index date 1 IP = inpatient, OP = outpatient, OT = other, n/a = not applicable DARWIN EU® Coordination Centre 24/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential 8.6 Variables 8.6.1. Exposures None. 8.6.2. Outcomes Conditions of interest will include thromboembolic events, in particular, (deep vein thrombosis (DVT), pulmonary embolisms (PE), venous thromboembolism (VTE, composite of DVT and PE), pelvic venous thrombosis (PVT), splanchic vein thrombosis (SVT), including hepatic and extra-hepatic vein thrombosis, retinal vein thrombosis (RVT), including retinal central vein thrombosis, and disseminated intravascular coagulation (DIC). The operational definition of the outcomes is presented in the Table . A preliminary list of codes is provided in the Appendix I. DARWIN EU® Coordination Centre 25/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential Table 7. Operational definitions of outcome. Outcome Details Primary Type of Washout Care Code Type Diagnosis Applied to Measurement Source of algorithm name outcome outcome window Settings¹ Position study characteristics/ populations validation DVT See Appendix Yes Binary [-365,-1] IP, OP, OT SNOMED Any Cancer patients N/A N/A I PE See Appendix Yes Binary [-365,-1] IP, OP, OT SNOMED Any Cancer patients N/A N/A I VTE See Appendix Yes Binary [-365,-1] IP, OP, OT SNOMED Any Cancer patients N/A N/A I PVT See Appendix Yes Binary [-365,-1] IP, OP, OT SNOMED Any Cancer patients N/A N/A I SVT See Appendix Yes Binary [-365,-1] IP, OP, OT SNOMED Any Cancer patients N/A N/A I RTV See Appendix Yes Binary [-365,-1] IP, OP, OT SNOMED Any Cancer patients N/A N/A I DIC See Appendix Yes Binary [-365,-1] IP, OP, OT SNOMED Any Cancer patients N/A N/A I 1 IP = inpatient, OP = outpatient, OT = other, n/a = not applicable, DVT = deep vein thrombosis, PE = pulmonary embolisms, VTE = venous thromboembolism, PVT = pelvic venous thrombosis, SVT = splanchic vein thrombosis, RVT = retinal vein thrombosis, DIC = DIC. DARWIN EU® Coordination Centre 26/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential 8.6.3. Other covariates, including confounders, effect modifiers and other variables The age at the index date (primary cancer diagnosis) will be described. The following age grouping will be used: 18-29; 30-39; 40-49; 50-59; 60-69; 70-79; 80-89; 90 and over. The sex (male/female) of study participants will also be identified. Large-scale patient-level characterisation will be conducted at the time of diagnosis. Age and sex at the time of cancer diagnosis will be described for each generated study cohort. Medical history will be assessed at the time of diagnosis. Medication use history will be reported at the time of diagnosis. We will also report medication use for 1 to 90 days post-index date. A list of pre-specified co-morbidities and co-medications will be described. Co-morbidities and co- medications were selected based on definitions that were previously used in other DARWIN EU studies. These will include: • Medical History: asthma, COPD, chronic liver disease, Crohn’s disease, Diabetes mellitus, gastro- oesophageal reflux disease (GERD), GI-Bleeding, Human Immunodeficiency Virus (HIV), Hyperlipidaemia, Hypertension, Obesity, Osteoarthritis, Pneumonia, Psoriasis, Renal impairment, Ulcerative Colitis, Viral Hepatitis, Visual system disorder [General] -- Schizophrenia, Dementia, Parkinson, Depressive disorder, Anxiety, Attention Deficit Hyperactivity Disorder (ADHS) [Neurology], thromboembolic events outcomes of interest mentioned above --- Any cancer except non-melanoma skin cancer (for quality assessment purposes, this should be 0 in our study population before index date). • Medication use: Agents acting on the renin-angiotensin system, Antibacterials for systemic use, Antidepressants, Antiepileptics, Anti-inflammatory and antirheumatic products, Antineoplastic agents, Anti-psoriatic, Antithrombotic agents, Beta blocking agents, Calcium channel blockers, Diuretics, Drugs for acid related disorders, Drugs for obstructive airway diseases, Drugs used in diabetes, Immunosuppressants, Lipid modifying agents, Opioids, Psycholeptics, Psychostimulants, agents used for ADHD and nootropics [General] -- contraceptives [contraceptives]. If available, AJCC\UICC TNM stage groups, and WHO/ECOG performance status will also be described and used for stratification in objective 1. The operational definition of the covariates is described in the Table 8. Operational definitions of covariates. DARWIN EU® Coordination Centre 27/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential Characteristic Details Type of Assessment Care Cod Diag Applied to Meas Sourc variable window Settings e nosis study ureme e for ¹ Typ Posit population nt algorit e ion s charac hm teristi cs/ valida tion Co- Large-scale patient- Binary [0,0] IP, OP, SNO N/A Cancer N/A N/A morbidities level OT ME patients characterisation D with regard to underlying comorbidities Medication Large-scale patient- Binary [0,0], [1,90] IP, OP, RxN N/A Cancer N/A N/A use level OT orm patients characterisation with regard to use of concomitant drugs 1 IP = inpatient, OP = outpatient, OT = other, n/a = not applicable 8. Table 8. Operational definitions of covariates. Characteristic Details Type of Assessment Care Cod Diag Applied to Meas Sourc variable window Settings e nosis study ureme e for ¹ Typ Posit population nt algorit e ion s charac hm teristi cs/ valida tion Co- Large-scale patient- Binary [0,0] IP, OP, SNO N/A Cancer N/A N/A morbidities level OT ME patients characterisation D with regard to underlying comorbidities Medication Large-scale patient- Binary [0,0], [1,90] IP, OP, RxN N/A Cancer N/A N/A use level OT orm patients characterisation with regard to use of concomitant drugs 1 IP = inpatient, OP = outpatient, OT = other, n/a = not applicable DARWIN EU® Coordination Centre 28/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential 8.7 Study size No sample size will be calculated as this is a descriptive study. However, analysis by strata will be limited to databases with enough cases (5 or more) to provide meaningful results. Summary measures of occurrence will not be calculated for strata with counts less than 5. 8.8 Analysis 8.1.1. Federated network analyses Analyses will be conducted separately for each database and will be carried out in a federated manner, allowing analyses to be run locally without sharing patient-level data. Before study initiation, the analytics are tested on a subset of the data sources or on a simulated set of patients, and quality control checks are performed. Once all the tests are passed, the final study code is released in the version-controlled Study Repository for execution against all the participating data sources. The data partners locally execute the analytics against the OMOP CDM in R Studio and review and approve the default aggregated results before returning them to the Coordination Centre. Sometimes, multiple execution iterations are performed, and additional fine-tuning of the code base is needed. A service desk will be available for support during the study execution. The study results of all data sources are checked, after which they are made available to the team in the Digital Research Environment (DRE), and the Study Dissemination Phase can start. All results are locked and timestamped for reproducibility and transparency. 8.8.2 Patient privacy protection Cell suppression will be applied as required by databases to protect people’s privacy. Cell counts < 5 will be masked. 8.8.3 Statistical model specification and assumptions of the analytical approach considered Data analyses This study will involve the analysis described in Table 9. Table 9. Description of study types and type of analysis. Study Study type Type of analyses classification Patient-level Off-the-shelf - Large-scale characterisation characterisation - Patient-level characteristics - Prognosis / progression to a pre-specified outcome - Standard care description Population-level Off-the-shelf - Incidence rates of the condition of interest descriptive - Prevalence rates of the condition of interest epidemiology DARWIN EU® Coordination Centre 29/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential The incidence rates of thromboembolic events (Objective 1) will be estimated over one and two years after the selected cancer diagnosis. The denominator will include the person-time contributed by the cancer patients from the date of diagnosis till the event or end of the respective period (one or two years). The numerator will include the outcomes of interest. Incidence rates will be presented per person-time with 95% confidence intervals derived using the exact method. Additionally, incidence rate ratios will be calculated when information on cancer stage is available with group AJCC/UICC stage as a reference. Each cancer type and outcome will be assessed separately. Large-scale patient-level characterisation (Objective 2) will be conducted at the index date. Age and sex will be described at the time of diagnosis as well as follow-up time after the index date. The medical history and medication will be assessed at the index date. Medication use will be at the index date and from 1 to 90 days after diagnosis. For all analyses, absolute counts and proportions will be reported. A minimum cell count of 5 will be used when reporting results, with any smaller counts reported as “<5” and zero counts as “0”. Overall analyses will be done separately for each database. Further stratification by age category (18-29; 30-39; 40-49; 50-59; 60-69; 70-79; 80-89; 90 and over), sex, study sub-period, and cancer stage will be conducted when possible (minimum cell count reached and data available). The following sub-periods will also be used: 2016-2019 and 2020-2023. R-packages The following R packages will be used: “CohortDiagnostics” (https://github.com/OHDSI/CohortDiagnostics/) to evaluate the phenotype algorithms developed for the study. “IncidencePrevalence” (https://github.com/darwin-eu/IncidencePrevalence) to estimate incidence rates by dividing the number of events by the person-time. Incidence rates will be calculated using function estimateIncidence() with denominator person-time specified by generateDenominatorCohortSet(). “PatientProfiles” (https://github.com/darwin-eu-dev/PatientProfiles) and “CohortCharacteristics” (https://github.com/darwin-eu-dev/CohortCharacteristics) will be used for summarising characteristics of cohorts of patients with cancer. 8.9 Evidence synthesis Results from analyses described in section 8.8 will be presented separately for each database and no meta- analysis of results will be conducted. 9. DATA MANAGEMENT 9.1 Data management All databases are mapped to the OMOP common data model. This enables the use of standardised analytics and tools across the network since the structure of the data and the terminology system is harmonised. The OMOP CDM is developed and maintained by the Observational Health Data Sciences and Informatics (OHDSI) initiative and is described in detail on the wiki page of the CDM: https://ohdsi.github.io/CommonDataModel and in The Book of OHDSI: http://book.ohdsi.org DARWIN EU® Coordination Centre 30/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential The analytic code for this study will be written in R. Each data partner will execute the study code against their database containing patient-level data and will then return the results set which will only contain aggregated data. The results from each of the contributing data sites will then be combined in tables and figures for the study report. 9.2 Data storage and protection For this study, participants from various EU member states will process personal data from individuals which is collected in national/regional electronic health record databases. Due to the sensitive nature of this personal medical data, it is important to be fully aware of ethical and regulatory aspects and to strive to take all reasonable measures to ensure compliance with ethical and regulatory issues on privacy. All databases used in this study are already used for pharmaco-epidemiological research and have a well- developed mechanism to ensure that European and local regulations dealing with ethical use of the data and adequate privacy control are adhered to. In agreement with these regulations, rather than combining person level data and performing only a central analysis, local analyses will be run, which generate non- identifiable aggregate summary results. The output files are stored in the DARWIN Digital Research Environment. These output files do not contain any data that allows the identification of subjects included in the study. The DRE implements further security measures to ensure a high level of stored data protection to comply with the local implementation of the General Data Protection Regulation (GDPR) (EU) 679/20161 in the various member states. 10. QUALITY CONTROL General database quality control Several open-source quality control mechanisms for the OMOP CDM have been developed (see Chapter 15 of The Book of OHDSI http://book.ohdsi.org/DataQuality.html). In particular, data partners are expected to run the OHDSI Data Quality Dashboard tool (https://github.com/OHDSI/DataQualityDashboard). This tool provides numerous checks relating to the conformance, completeness and plausibility of the mapped data. Conformance focuses on checks that describe the compliance of the representation of data against internal or external formatting, relational, or computational definitions; completeness in the sense of data quality is solely focused on quantifying missingness or the absence of data, while plausibility seeks to determine the believability or truthfulness of data values. Each of these categories has one or more subcategories and are evaluated in two contexts: validation and verification. Validation relates to how well data aligns with external benchmarks with expectations derived from known true standards. In contrast, verification relates to how well data conforms to local knowledge, metadata descriptions, and system assumptions. Study-specific quality control When defining selected cancers, outcomes and co-morbidities, a systematic search of possible codes for inclusion was identified using CodelistGenerator R package (https://github.com/darwin- eu/CodelistGenerator). This software allows the user to define a search strategy and using this will then query the vocabulary tables of the OMOP CDM to find potentially relevant codes. The codes returned will be then reviewed by two clinical epidemiologists to consider their relevance. In addition, the CohortDiagnostics R package (https://github.com/OHDSI/CohortDiagnostics) will be run to assess the use of different codes across the databases contributing to the study and identify any codes potentially omitted in error. This will allow for a consideration of the validity of the study cohort of patients with the selected DARWIN EU® Coordination Centre 31/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential cancers and co-morbidities in each of the databases and inform decisions around whether multiple definitions are required. The study code will be based on three R packages currently being developed to (1) estimate incidence rates of thromboembolic events (“IncidencePrevalence”), (2) characterise demographic and clinical characteristics ("PatientProfiles” and “CohortCharacteristics”). These packages will include numerous automated unit tests to ensure the validity of the codes, alongside software peer review and user testing. The study code will be made publicly available via GitHub. 11. LIMITATIONS OF THE RESEARCH METHODS The study will be informed by routinely collected health care data, and so data quality issues must be considered. In particular, the identification of cancer patients and thromboembolic events may vary across databases. While relatively few false positives would be expected, false negatives may be more likely, especially for databases without patient-level linkage to secondary care data. Underestimation of thromboembolic events is also possible, particularly for rare events with complex diagnoses. Given the large number and diverse nature of participating data sources, it is important to note that differences in patient representations might arise from disparate coding practices and specifics of data capture. The granularity or detail of concepts representing clinical facts can vary across source terminologies (e.g., ICD-10, Read codes), influencing how information is later transformed into standardised vocabularies (Ostropolets et al., 2021). The preliminary code lists created to identify cancer patients include codes from standard vocabularies used in tumour registries, such as ICD-O-3 codes. However, most databases will only have information on cancer diagnoses using SNOMED codes, which may not be granular enough to cover all the topology and histology details of cancer (Campbell et al., 2014). ICD-O-3 codes are only available at DK-DHR, EBB and UKBB. The large-scale characterisation will provide an overview of the characteristics, comorbidities, and medication use, including anticancer treatment is available, of cancer patients. However, our study will not differentiate the time before and after cancer treatment initiation, and therefore it will not be able to disentangle the risk of thromboembolic events posed by cancer treatments from the risk posed by cancer itself. In addition, for the calculation of incidence rates (Objective 1), we will apply a one-year washout to exclude patients who experienced the thromboembolic events under study prior to index date. Given that acute thromboembolic events can be the first manifestation of an occult malignancy, we will miss patients with thromboembolic events who are subsequently diagnosed with cancer. 12. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS Adverse events/adverse reactions will not be collected or analysed as part of this evaluation. The nature of this non-interventional evaluation, through the use of secondary data, does not fulfil the criteria for reporting adverse events, according to module VI, VI.C.1.2.1.2 of the Good Pharmacovigilance Practices (https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/guideline-good- pharmacovigilance-practices-gvp-module-vi-collection-management-submission-reports_en.pdf). DARWIN EU® Coordination Centre 32/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential 13. GOVERNANCE BOARD ASPECTS All data sources require approval from their respective IRB boards, with the exception of IQVIA DA Germany and IQVIA LPD Belgium which will not require any further specific approvals to undertake this study. 14. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS A PDF report, including an executive summary and the specified tables and/or figures, will be submitted to EMA by the DARWIN EU® CC upon completion of the study. An interactive dashboard incorporating all the results (tables and figures) will be provided alongside the PDF report. If requested, the full set of underlying aggregated data used in the dashboard will also be made available. 15. OTHER ASPECTS None. 16. REFERENCES Timp, J. F., Braekkan, S. K., Versteeg, H. H., & Cannegieter, S. C. (2013). Epidemiology of cancer-associated venous thrombosis. Blood, The Journal of the American Society of Hematology, 122(10), 1712-1723. Blom, J. W., Doggen, C. J., Osanto, S., & Rosendaal, F. R. (2005). Malignancies, prothrombotic mutations, and the risk of venous thrombosis. Jama, 293(6), 715-722. Björklund, J., Rautiola, J., Zelic, R., Edgren, G., Bottai, M., Nilsson, M., ... & Akre, O. (2024). Risk of Venous Thromboembolic Events After Surgery for Cancer. JAMA Network Open, 7(2), e2354352-e2354352. Khorana, A. A., Dalal, M., Lin, J., & Connolly, G. C. (2013). Incidence and predictors of venous thromboembolism (VTE) among ambulatory high‐risk cancer patients undergoing chemotherapy in the United States. Cancer, 119(3), 648-655. Nalluri, S. R., Chu, D., Keresztes, R., Zhu, X., & Wu, S. (2008). Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. Jama, 300(19), 2277-2285. Ohashi, Y., Ikeda, M., Kunitoh, H., Sasako, M., Okusaka, T., Mukai, H., ... & Sakon, M. (2020). Venous thromboembolism in cancer patients: report of baseline data from the multicentre, prospective Cancer-VTE Registry. Japanese journal of clinical oncology, 50(11), 1246-1253. Petterson, T. M., Marks, R. S., Ashrani, A. A., Bailey, K. R., & Heit, J. A. (2015). Risk of site-specific cancer in incident venous thromboembolism: a population-based study. Thrombosis research, 135(3), 472-478. DARWIN EU® Coordination Centre 33/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential van Hylckama Vlieg, M. A., Nasserinejad, K., Visser, C., Bramer, W. M., Ashrani, A. A., Bosson, J. L., ... & Geijteman, E. C. (2023). The risk of recurrent venous thromboembolism after discontinuation of anticoagulant therapy in patients with cancer-associated thrombosis: a systematic review and meta- analysis. EClinicalMedicine, 64. White, R. H., Chew, H. K., Zhou, H., Parikh-Patel, A., Harris, D., Harvey, D., & Wun, T. (2005). Incidence of venous thromboembolism in the year before the diagnosis of cancer in 528 693 adults. Archives of internal medicine, 165(15), 1782-1787. Wang, T. F., Li, A., & Garcia, D. (2018). Managing thrombosis in cancer patients. Research and Practice in Thrombosis and Haemostasis, 2(3), 429-438. Herrett, E., Gallagher, A. M., Bhaskaran, K., Forbes, H., Mathur, R., van Staa, T., & Smeeth, L. (2015). Data Resource Profile: Clinical Practice Research Datalink (CPRD). International journal of epidemiology, 44(3), 827–836. de Ridder, M. A. J., de Wilde, M., de Ben, C., Leyba, A. R., Mosseveld, B. M. T., Verhamme, K. M. C., van der Lei, J., & Rijnbeek, P. R. (2022). Data Resource Profile: The Integrated Primary Care Information (IPCI) database, The Netherlands. International journal of epidemiology, 51(6), e314–e323. Leinonen, M. K., Miettinen, J., Heikkinen, S., Pitkäniemi, J., & Malila, N. (2017). Quality measures of the population-based Finnish Cancer Registry indicate sound data quality for solid malignant tumours. European journal of cancer (Oxford, England: 1990), 77, 31–39. Vikkula, J., Uusi-Rauva, K., Ranki, T., Toppila, I., Aalto-Setälä, M., Pousar, K., Vassilev, L., Porkka, K., Silvennoinen, R., & Brück, O. (2023). Real-world evidence of multiple myeloma treated from 2013 to 2019 in the Hospital District of Helsinki and Uusimaa, Finland. Future oncology (London, England), 19(30), 2029– 2043. Sund R. (2012). Quality of the Finnish Hospital Discharge Register: a systematic review. Scandinavian journal of public health, 40(6), 505–515. Recalde, M., Davila-Batista, V., Díaz, Y., Leitzmann, M., Romieu, I., Freisling, H., & Duarte-Salles, T. (2021). Body mass index and waist circumference concerning the risk of 26 types of cancer: a prospective cohort study of 3.5 million adults in Spain. BMC medicine, 19(1), 10. Ostropolets A, Reich C, Ryan P, et al. Characterizing database granularity using SNOMED-CT hierarchy. AMIA Annu Symp Proc. 2021;2020:983-992. Published 2021 Jan 25. Campbell, W. S., Campbell, J. R., West, W. W., McClay, J. C., & Hinrichs, S. H. (2014). Semantic analysis of SNOMED CT for a post-coordinated database of histopathology findings. Journal of the American Medical Informatics Association : JAMIA, 21(5), 885–892. 17. ANNEXES Appendix I DARWIN EU® Coordination Centre 34/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential Table A1 Preliminary code list for deep vein thrombosis (DVT) Concept Id SNOMED Code Concept Name 762047 286411000119108 Acute bilateral thrombosis of subclavian veins 762148 293471000119106 Acute deep vein thrombosis of bilateral iliac veins 761444 15711361000119101 Acute deep vein thrombosis of bilateral lower limbs following coronary artery bypass graft 35616028 293491000119107 Acute deep vein thrombosis of left iliac vein 35615035 15711401000119105 Acute deep vein thrombosis of left lower limb following procedure 761416 15708441000119103 Acute deep vein thrombosis of left upper limb following coronary artery bypass graft 35615031 15708401000119100 Acute deep vein thrombosis of left upper limb following procedure 43531681 651000119108 Acute deep vein thrombosis of lower limb 35616027 293481000119109 Acute deep vein thrombosis of right iliac vein 35615034 15711241000119106 Acute deep vein thrombosis of right lower limb following procedure 761415 15708281000119109 Acute deep vein thrombosis of right upper limb following coronary artery bypass graft 35615030 15708201000119101 Acute deep vein thrombosis of right upper limb following procedure 44782746 132281000119108 Acute deep venous thrombosis 44782751 134961000119104 Acute deep venous thrombosis of axillary vein 762008 285321000119103 Acute deep venous thrombosis of bilateral axillary veins 760875 12237551000119104 Acute deep venous thrombosis of bilateral calves 765155 285441000119102 Acute deep venous thrombosis of bilateral ileofemoral veins 762017 285501000119103 Acute deep venous thrombosis of bilateral internal jugular veins 762417 350291000119100 Acute deep venous thrombosis of bilateral legs 762020 285561000119102 Acute deep venous thrombosis of bilateral popliteal veins 765546 285621000119106 Acute deep venous thrombosis of bilateral tibial veins 762004 285261000119104 Acute deep venous thrombosis of both upper extremities 44782742 132241000119103 Acute deep venous thrombosis of calf 44782747 132291000119106 Acute deep venous thrombosis of femoral vein 762015 285451000119100 Acute deep venous thrombosis of ileofemoral vein of left leg 765541 285461000119103 Acute deep venous thrombosis of ileofemoral vein of right lower extremity 44782748 132301000119107 Acute deep venous thrombosis of iliofemoral vein 44782752 135001000119100 Acute deep venous thrombosis of internal jugular vein 762009 285331000119100 Acute deep venous thrombosis of left axillary vein 760876 12237631000119109 Acute deep venous thrombosis of left calf 765540 285391000119101 Acute deep venous thrombosis of left femoral vein 765922 285511000119100 Acute deep venous thrombosis of left internal jugular vein DARWIN EU® Coordination Centre 35/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential 762418 350301000119104 Acute deep venous thrombosis of left lower extremity 765537 285271000119105 Acute deep venous thrombosis of left upper extremity 44782767 136781000119101 Acute deep venous thrombosis of lower extremity as complication of procedure 46270071 132111000119107 Acute deep venous thrombosis of lower limb due to and following coronary artery bypass grafting 762022 285581000119106 Acute deep venous thrombosis of politeal vein of right leg 44782743 132251000119101 Acute deep venous thrombosis of popliteal vein 762021 285571000119108 Acute deep venous thrombosis of popliteal vein of left leg 762010 285341000119109 Acute deep venous thrombosis of right axillary vein 760877 12237711000119106 Acute deep venous thrombosis of right calf 762013 285401000119104 Acute deep venous thrombosis of right femoral vein 762018 285521000119107 Acute deep venous thrombosis of right internal jugular vein 762419 350311000119101 Acute deep venous thrombosis of right lower extremity 762005 285281000119108 Acute deep venous thrombosis of right upper extremity 44782745 132271000119105 Acute deep venous thrombosis of thigh 44782744 132261000119104 Acute deep venous thrombosis of tibial vein 762026 285631000119109 Acute deep venous thrombosis of tibial vein of left leg 765156 285641000119100 Acute deep venous thrombosis of tibial vein of right leg 44782421 132321000119103 Acute deep venous thrombosis of upper extremity 764016 449691000124103 Acute deep venous thrombosis of upper extremity after coronary artery bypass graft 44782766 136771000119104 Acute deep venous thrombosis of upper extremity as complication of procedure 762048 286421000119101 Acute thrombosis of left subclavian vein 45757410 133421000119101 Acute thrombosis of mesenteric vein 762049 286431000119103 Acute thrombosis of right subclavian vein 36712892 143561000119108 Acute thrombosis of splenic vein 44782762 132611000119104 Acute thrombosis of subclavian vein 435887 49956009 Antepartum deep vein thrombosis 4179911 297156001 Axillary vein thrombosis 37109253 285381000119104 Bilateral acute deep vein thrombosis of femoral veins 40478951 444325005 Bilateral deep vein thrombosis of lower extremities 4042396 16750002 Deep thrombophlebitis 4046884 134399007 Deep vein thrombosis of leg related to air travel 3655221 860699005 Deep vein thrombosis of lower extremity due to intravenous drug use 4133004 128053003 Deep venous thrombosis 4181315 428781001 Deep venous thrombosis associated with coronary artery bypass graft DARWIN EU® Coordination Centre 36/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential 438820 56272000 Deep venous thrombosis in puerperium 45773536 703277001 Deep venous thrombosis of femoropopliteal vein 763942 448841000124100 Deep venous thrombosis of left lower extremity 761980 25820001000004100 Deep venous thrombosis of left upper extremity 443537 404223003 Deep venous thrombosis of lower extremity 4133975 128055005 Deep venous thrombosis of pelvic vein 40480555 443210003 Deep venous thrombosis of peroneal vein 4322565 427775006 Deep venous thrombosis of profunda femoris vein 763941 448831000124105 Deep venous thrombosis of right lower extremity 761928 20850001000004108 Deep venous thrombosis of right upper extremity 4207899 438785004 Deep venous thrombosis of tibial vein 4028057 128054009 Deep venous thrombosis of upper extremity 435565 195437003 Embolism and thrombosis of the vena cava 40481089 444816006 Embolism from thrombosis of vein of lower extremity 4119760 234044007 Iliofemoral deep vein thrombosis 4124856 234041004 Inferior mesenteric vein thrombosis 4096099 25114006 Phlebitis of deep veins of lower extremity 4281689 66923004 Phlegmasia alba dolens 4284538 66877004 Phlegmasia cerulea dolens 4309333 213220000 Postoperative deep vein thrombosis 46285905 978441000000108 Provoked deep vein thrombosis 46271900 710167004 Recurrent deep vein thrombosis 4033521 14534009 Splenic vein thrombosis 4055089 197001004 Superior mesenteric vein thrombosis 4230403 438646004 Thrombophlebitis of axillary vein 4069561 1748006 Thrombophlebitis of deep femoral vein 761831 16014391000119106 Thrombophlebitis of deep vein of bilateral lower limbs 761830 16014351000119101 Thrombophlebitis of deep vein of left lower limb 761808 16006271000119105 Thrombophlebitis of deep vein of left upper limb 761832 16014431000119101 Thrombophlebitis of deep vein of right lower limb 761809 16006311000119105 Thrombophlebitis of deep vein of right upper limb 4221821 40198004 Thrombophlebitis of deep veins of lower extremity 440750 95452006 Thrombophlebitis of deep veins of upper extremities 4176614 42861008 Thrombophlebitis of iliac vein DARWIN EU® Coordination Centre 37/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential 761821 16012151000119109 Thrombophlebitis of left deep femoral vein 761819 16012071000119101 Thrombophlebitis of left femoral vein 761820 16012111000119108 Thrombophlebitis of right deep femoral vein 761818 16011991000119109 Thrombophlebitis of right femoral vein 4110339 195412008 Thrombophlebitis of the anterior tibial vein 4111868 195425000 Thrombophlebitis of the common iliac vein 4110343 195427008 Thrombophlebitis of the external iliac vein 439314 195410000 Thrombophlebitis of the femoral vein 4109877 195426004 Thrombophlebitis of the internal iliac vein 4112171 195411001 Thrombophlebitis of the popliteal vein 4112172 195414009 Thrombophlebitis of the posterior tibial vein 4250765 7387004 Thrombophlebitis of tibial vein 42538533 762256003 Thrombosis of iliac vein 44811347 864191000000104 Thrombosis of internal jugular vein 765049 16730001000004104 Thrombosis of left peroneal vein 4317289 95446005 Thrombosis of mesenteric vein 4203836 438647008 Thrombosis of subclavian vein 4175649 427776007 Thrombosis of the popliteal vein 4149782 309735004 Thrombosis of vein of lower limb 4153353 371051005 Traumatic thrombosis of axillary vein 46285904 978421000000101 Unprovoked deep vein thrombosis 77310 266267005 Deep vein phlebitis and thrombophlebitis of the leg 4189004 413956008 Deep vein thrombosis of leg related to intravenous drug use Table A2 Preliminary code list for pulmonary embolism (PE) Concept Id SNOMED code Concept name 608954 15964661000119102 Acute cor pulmonale due to septic pulmonary embolism 4120091 233936003 Acute massive pulmonary embolism 45768439 706870000 Acute pulmonary embolism 45768888 707414004 Acute pulmonary thromboembolism 44782732 133971000119108 Chronic pulmonary embolism 45768887 707412000 Chronic pulmonary thromboembolism 45771016 707413005 Chronic pulmonary thromboembolism without pulmonary hypertension 4219469 82153002 Miscarriage with pulmonary embolism 4108681 194883006 Postoperative pulmonary embolus DARWIN EU® Coordination Centre 38/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential 4091708 280964006 Pulmonary air embolism 440417 59282003 Pulmonary embolism 37109911 723859005 Pulmonary embolism due to and following acute myocardial infarction 45757145 10759311000119104 Pulmonary embolism in childbirth 37016922 713078005 Pulmonary embolism on long-term anticoagulation therapy 43530605 1001000119102 Pulmonary embolism with pulmonary infarction 4119608 233938002 Pulmonary fat embolism 4253796 74315008 Pulmonary microemboli 45766471 703636009 Pulmonary oil microembolism 4121618 233935004 Pulmonary thromboembolism 4119610 233940007 Pulmonary tumor embolism 4236271 438773007 Recurrent pulmonary embolism 36713113 328511000119109 Saddle embolus of pulmonary artery 35615055 15964701000119109 Saddle embolus of pulmonary artery with acute cor pulmonale 40479606 441557008 Septic pulmonary embolism 4119607 233937007 Subacute massive pulmonary embolism 4119609 233939005 Subacute pulmonary fat embolism Table A3 Preliminary code list for pelvic venous thrombosis (PVT) Concept Id SNOMED Code Concept Name 762148 293471000119106 Acute deep vein thrombosis of bilateral iliac veins 35616028 293491000119107 Acute deep vein thrombosis of left iliac vein 35616027 293481000119109 Acute deep vein thrombosis of right iliac vein 765155 285441000119102 Acute deep venous thrombosis of bilateral ileofemoral veins 761461 15712201000119101 Acute deep venous thrombosis of bilateral pelvic veins 762015 285451000119100 Acute deep venous thrombosis of ileofemoral vein of left leg 765541 285461000119103 Acute deep venous thrombosis of ileofemoral vein of right lower extremity 44782748 132301000119107 Acute deep venous thrombosis of iliofemoral vein 761462 15712241000119104 Acute deep venous thrombosis of left pelvic vein 44782761 132601000119102 Acute deep venous thrombosis of pelvic vein 765229 15712281000119109 Acute deep venous thrombosis of right pelvic vein 608965 15968901000119104 Bilateral iliac vein thrombophlebitis 765152 293441000119104 Chronic deep vein thrombosis of bilateral iliac veins 35616026 293461000119100 Chronic deep vein thrombosis of left iliac vein DARWIN EU® Coordination Centre 39/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential 761439 15711001000119104 Chronic deep vein thrombosis of left pelvic vein 46271548 709687000 Chronic deep vein thrombosis of pelvic vein 35616025 293451000119102 Chronic deep vein thrombosis of right iliac vein 761441 15711081000119107 Chronic deep vein thrombosis of right pelvic vein 765542 285471000119109 Chronic deep venous thrombosis of bilateral ileofemoral veins 761440 15711041000119102 Chronic deep venous thrombosis of bilateral pelvic veins 44782740 132201000119100 Chronic deep venous thrombosis of iliofemoral vein 765543 285481000119107 Chronic deep venous thrombosis of left ileofemoral vein 762016 285491000119105 Chronic deep venous thrombosis of right ileofemoral vein 761013 132541000119101 Deep venous thrombosis of bilateral pelvic veins 4133975 128055005 Deep venous thrombosis of pelvic vein 4119760 234044007 Iliofemoral deep vein thrombosis 608964 15968861000119105 Left iliac vein thrombophlebitis 4158798 361278002 Mondor's phlebitis of the penis 4285751 67486009 Pelvic thrombophlebitis in puerperium 608963 15968821000119100 Right iliac vein thrombophlebitis 4176614 42861008 Thrombophlebitis of iliac vein 4317290 95449003 Thrombophlebitis of pelvic vein 4111868 195425000 Thrombophlebitis of the common iliac vein 4110343 195427008 Thrombophlebitis of the external iliac vein 4109877 195426004 Thrombophlebitis of the internal iliac vein 201045 26373009 Thrombosed external hemorrhoids 195294 75955007 Thrombosed hemorrhoids 608966 15969021000119101 Thrombosed internal hemorrhoid grade IV 201595 52931009 Thrombosed internal hemorrhoids 42538533 762256003 Thrombosis of iliac vein 606527 1145183007 Thrombosis of pampiniform plexus 4319327 95448006 Thrombosis of pelvic vein 4295878 76598006 Thrombosis of penile vein 762443 368351000119106 Thrombosis of superficial vein of penis Table A4 Preliminary code list for splanchic vein thrombosis, including hepatic and extrahepatic (STV) Concept Id SNOMED Code Concept Name 45757410 133421000119101 Acute thrombosis of mesenteric vein DARWIN EU® Coordination Centre 40/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential 36712892 143561000119108 Acute thrombosis of splenic vein 196715 82385007 Budd-Chiari syndrome 45757409 133411000119108 Chronic thrombosis of mesenteric vein 36712891 143551000119106 Chronic thrombosis of splenic vein 4301208 38739001 Hepatic vein thrombosis 4124856 234041004 Inferior mesenteric vein thrombosis 199837 17920008 Portal vein thrombosis 4033521 14534009 Splenic vein thrombosis 4055089 197001004 Superior mesenteric vein thrombosis 4318407 95447001 Thrombophlebitis of mesenteric vein 4317289 95446005 Thrombosis of mesenteric vein Table A5 Preliminary code list for retinal vein thrombosis, including retinal central vein thrombosis (RVT) Concept Id Concept Code Concept Name 4339013 232048009 Branch retinal vein occlusion with macular edema 4334248 232046008 Branch retinal vein occlusion with neovascularization 4199035 314000002 Branch retinal vein occlusion with no neovascularization 313761 68478007 Central retinal vein occlusion 4208221 312997008 Central retinal vein occlusion - ischemic 4339011 232040002 Central retinal vein occlusion - juvenile 4335591 232042005 Central retinal vein occlusion - juvenile with macular edema 4334888 232041003 Central retinal vein occlusion - juvenile with neovascularization 4208222 312998003 Central retinal vein occlusion - non-ischemic 4339010 232039004 Central retinal vein occlusion with macular edema 4334246 232038007 Central retinal vein occlusion with neovascularization 42535735 733325006 Combined occlusion by thrombus of retinal artery and retinal vein 4334247 232043000 Hemispheric retinal vein occlusion 4335592 232045007 Hemispheric retinal vein occlusion with macular edema 4336005 232044006 Hemispheric retinal vein occlusion with neovascularization 4216561 71719003 Thrombophlebitis of retinal vein 4187790 46085004 Thrombosis of retinal vein 312622 24596005 Venous retinal branch occlusion DARWIN EU® Coordination Centre 41/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential Table A6 Preliminary code list for disseminated intravascular coagulation (DIC) Concept Id Concept Code Concept Name 436093 67406007 Disseminated intravascular coagulation 4028488 13507004 Purpura fulminans Appendix II Preliminary code list for selected cancer types is attached as a standalone document DARWIN EU® Coordination Centre 42/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential Appendix III: ENCePP checklist for study protocols ENCePP Checklist for Study Protocols (Revision 4) Study title: DARWIN EU® – Incidence rates of venous thromboembolic events in cancer patients EU PAS Register® number: N/A Study reference number (if applicable): P3-C3-005 Section 1: Milestones Yes No N/A Section Number 1. Does the protocol specify timelines for 1.1.1 Start of data collection 5. Milestones, 1.1.2 End of data collection X 8.2 Data 1.1.3 Progress report(s) Sources 1.1.4 Interim report(s) 1.1.5 Registration in the EU PAS Register ® 1.1.6 Final report of study results. Comments: Section 2: Research question Yes No N/A Section Number 2.1 Does the formulation of the research question and objectives clearly explain: 2.1.1 Why the study is conducted? (e.g. to address an important public health concern, a risk identified in the X 7. Research risk management plan, an emerging safety issue) question and 2.1.2 The objective(s) of the study? objectives 2.1.3 The target population? (i.e. population or subgroup 8. Research to whom the study results are intended to be methods generalised) 2.1.4 Which hypothesis(-es) is (are) to be tested? 2.1.5 If applicable, that there is no a priori hypothesis? Comments: Section 3: Study design Yes No N/A Section Number 3.1 Is the study design described? (e.g. cohort, case-control, 8.1 Study type cross-sectional, other design) X and Study Design DARWIN EU® Coordination Centre 43/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential 3.2 Does the protocol specify whether the study is based on 8.2 Study primary, secondary or combined data collection? X Setting and Data Sources 3.3 Does the protocol specify measures of occurrence? X 8.8 Analysis (e.g., rate, risk, prevalence) 3.4 Does the protocol specify measure(s) of association? (e.g. risk, odds ratio, excess risk, rate ratio, hazard ratio, X 8.8 Analysis risk/rate difference, number needed to harm (NNH)) 3.5 Does the protocol describe the approach for the collection and reporting of adverse events/adverse reactions? X (e.g. adverse events that will not be collected in case of primary data collection) Comments: Section 4: Source and study populations Yes No N/A Section Number 4.1 Is the source population described? 8.5 Study X Population 4.2 Is the planned study population defined in terms of: 4.2.1 Study time period 8.3 Study Period 4.2.2 Age and sex 8.6.3. Other X covariates 4.2.3 Country of origin 8.2 Study Setting and Data Sources 4.2.4 Disease/indication 8.6.1. Exposures 4.2.5 Duration of follow-up 8.4 Follow-up 4.3 Does the protocol define how the study 8.5 Study population will be sampled from the source Population with X population? (e.g. event or inclusion/exclusion inclusion and criteria) exclusion criteria Comments: Section 5: Exposure definition and measurement Yes No N/A Section Number 5.1 Does the protocol describe how the study exposure is defined and measured? (e.g. operational details for defining and X categorising exposure, measurement of dose and duration of drug exposure) 5.2 Does the protocol address the validity of the exposure measurement? (e.g. precision, accuracy, use of validation sub- X study) 5.3 Is exposure categorised according to time windows? X 5.4 Is intensity of exposure addressed? X (e.g. dose, duration) DARWIN EU® Coordination Centre 44/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential 5.5 Is exposure categorised based on biological mechanism of action and taking into account the pharmacokinetics and X pharmacodynamics of the drug? 5.6 Is (are) (an) appropriate comparator(s) identified? X Comments: Section 6: Outcome definition and measurement Yes No N/A Section Number 6.1 Does the protocol specify the primary and secondary (if 8.6.2. X applicable) outcome(s) to be investigated? Outcomes 6.2 Does the protocol describe how the outcomes are defined 8.6.2. X and measured? Outcomes 6.3 Does the protocol address the validity of outcome measurement? (e.g. precision, accuracy, sensitivity, specificity, X positive predictive value, use of validation sub-study) 6.4 Does the protocol describe specific outcomes relevant for Health Technology Assessment? (e.g. HRQoL, QALYs, DALYS, X health care services utilisation, burden of disease or treatment, compliance, disease management) Comments: Section 7: Bias Yes No N/A Section Number 7.1 Does the protocol address ways to measure confounding? X (e.g. confounding by indication) 7.2 Does the protocol address selection bias? (e.g. healthy X user/adherer bias) 7.3 Does the protocol address information bias? (e.g. misclassification of exposure and outcomes, time-related X bias) Comments: Section 8: Effect measure modification Yes No N/A Section Number 8.1 Does the protocol address effect modifiers? (e.g. collection of data on known effect modifiers, sub-group X analyses, anticipated direction of effect) Comments: Section 9: Data sources Yes No N/A Section Number 9.1 Does the protocol describe the data source(s) used in the study for the ascertainment of: DARWIN EU® Coordination Centre 45/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential 9.1.1 Exposure? (e.g. pharmacy dispensing, general practice X prescribing, claims data, self-report, face-to-face interview) 9.1.2 Outcomes? (e.g. clinical records, laboratory markers or 8.2 Study values, claims data, self-report, patient interview including scales X Setting and and questionnaires, vital statistics) Data Sources 9.1.3 Covariates and other characteristics? 8.6.3. Other X covariates 9.2 Does the protocol describe the information available from the data source(s) on: 9.2.1 Exposure? (e.g. date of dispensing, drug quantity, dose, X number of days of supply prescription, daily dosage, prescriber) 9.2.2 Outcomes? (e.g. date of occurrence, multiple event, X severity measures related to event) 9.2.3 Covariates and other characteristics? (e.g. age, sex, clinical 8.2 Study and drug use history, co-morbidity, co-medications, lifestyle) X Setting and Data Sources 9.3 Is a coding system described for: 9.3.1 Exposure? (e.g. WHO Drug Dictionary, Anatomical X Therapeutic Chemical (ATC) Classification System) 9.3.2 Outcomes? (e.g. International Classification of Diseases 8.6.2. X (ICD), Medical Dictionary for Regulatory Activities (MedDRA)) Outcomes 9.3.3 Covariates and other characteristics? 8.6.3. Other X covariates 9.4 Is a linkage method between data sources described? X (e.g. based on a unique identifier or other) Comments: Section 10: Analysis plan Yes No N/A Section Number 10.1 Are the statistical methods and the reason for their choice X 8.8 Analysis described? 10.2 Is study size and/or statistical precision estimated? X 10.3 Are descriptive analyses included? 8.8.2 X Descriptive statistics 10.4 Are stratified analyses included? X 8.8 Analysis 10.5 Does the plan describe methods for analytic control of X confounding? 10.6 Does the plan describe methods for analytic control of X outcome misclassification? 10.7 Does the plan describe methods for handling missing X data? 10.8 Are relevant sensitivity analyses described? X Comments: DARWIN EU® Coordination Centre 46/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential Section 11: Data management and quality control Yes No N/A Section Number 11.1 Does the protocol provide information on data storage? 9. Data (e.g. software and IT environment, database maintenance and X management anti-fraud protection, archiving) 11.2 Are methods of quality assurance described? 10. Quality X Control 11.3 Is there a system in place for independent review of X study results? Comments: Section 12: Limitations Yes No N/A Section Number 12.1 Does the protocol discuss the impact on the study results of: 12.1.1 Selection bias? 11. Limitations of 12.1.2 Information bias? X the research 12.1.3 Residual/unmeasured confounding? methods (e.g. anticipated direction and magnitude of such biases, validation sub-study, use of validation and external data, analytical methods). 12.2 Does the protocol discuss study feasibility? (e.g. study Table size, anticipated exposure uptake, duration of follow-up in a 8.2. Description of X cohort study, patient recruitment, precision of the estimates) the selected Data Sources. Comments: Section 13: Ethical/data protection issues Yes No N/A Section Number 13.1 Have requirements of Ethics Committee/ Institutional 13. Governance X Review Board been described? board aspects 13.2 Has any outcome of an ethical review procedure been X addressed? 13.3 Have data protection requirements been described? 9.2 Data storage X and protection Comments: Section 14: Amendments and deviations Yes No N/A Section Number 14.1 Does the protocol include a section to document 4. amendments and deviations? X Amendments and updates Comments: DARWIN EU® Coordination Centre 47/48  D2.2.2 - Study Protocol for P3-C3-005 Author(s): A. Barchuk, T. Duarte-Salles Version: 1.0 Dissemination level: Confidential Section 15: Plans for communication of study results Yes No N/A Section Number 15.1 Are plans described for communicating study results 14. Plans for (e.g. to regulatory authorities)? disseminating X and communicating study results 15.2 Are plans described for disseminating study results 14. Plans for externally, including publication? disseminating X and communicating study results Comments: Name of the main author of the protocol: Talita Duarte-Salles & Anton Barchuk Date: 30/10/2024 Signature: DARWIN EU® Coordination Centre 48/48 Saatja: "Raivo Kolde" <[email protected]> Saaja: [email protected] Teema: Taotlus Eesti bioeetika ja inimuuringute nõukogule (EBIN-le) uurimisprotokolli kooskõlastamiseks Kuupäev: 2024-11-01 13:03 Tere Sooviksime EMA DARWIN projekti raames (raamtaotluse otsus nr 1.1-12/1832), kiirkooskõlastada järgmise uuringu protokolli. Täpsemalt on eesmärgiks kirjeldada tromboembolismi levikut vähipatsientidel. Lugupidamisega, Raivo Kolde