Study Protocol P2 - C1 -00 3 23 /06/2023 Version 1 . 0 Table of c ontents TOC \o "1-3" \h \z \u Table of contents PAGEREF _Toc407584080 \h 2 Document History PAGEREF _Toc1490042731 \h 3 LIST OF ABBREVIATIONS PAGEREF _Toc1901959534 \h 6 1. Title PAGEREF _Toc451454118 \h 7 2. Responsible parties – study team PAGEREF _Toc42670985 \h 7 3. ABSTRACT (Stand alone summary of the study protocol) PAGEREF _Toc997627504 \h 8 4. AMENDMENTS AND UPDATES PAGEREF _Toc1410183727 \h 11 5. MILESTONES PAGEREF _Toc1762422145 \h 11 6. RATIONALE AND BACKGROUND PAGEREF _Toc217915439 \h 12 7. RESEARCH QUESTION AND OBJECTIVES PAGEREF _Toc31378405 \h 13 8. RESEARCH METHODS PAGEREF _Toc1157296256 \h 15 8.1 Study Design PAGEREF _Toc1202588871 \h 15 8.2 Study Setting and data sources PAGEREF _Toc431903375 \h 15 8.3 Study Period PAGEREF _Toc965004114 \h 18 8.4 Follow-up PAGEREF _Toc281397987 \h 18 8.5 Study population with inclusion and exclusion criteria PAGEREF _Toc1054263680 \h 20 8.6 Variables PAGEREF _Toc147817710 \h 23 8.6.1 Exposure PAGEREF _Toc1186716251 \h 23 8.6.2 Outcome/s PAGEREF _Toc1678612250 \h 25 8.6.3 Other covariates, including confounders, effect modifiers and other variables (where relevant) PAGEREF _Toc990896236 \h 27 8.7 Study size PAGEREF _Toc1840819492 \h 29 8.8 Analysis PAGEREF _Toc1530996955 \h 29 8.8.1 Federated Network Analyses PAGEREF _Toc568793499 \h 29 8.8.2 Patient privacy protection PAGEREF _Toc30319053 \h 29 8.8.3 Statistical model specification and assumptions of the analytical approach considered PAGEREF _Toc1737365258 \h 29 8.9 Evidence synthesis PAGEREF _Toc1209853795 \h 30 9 DATA MANAGEMENT PAGEREF _Toc879438674 \h 30 9.1 Data management PAGEREF _Toc862306667 \h 30 9.2 Data storage and protection PAGEREF _Toc545460639 \h 32 10. QUALITY CONTROL PAGEREF _Toc41269428 \h 32 11. LIMITATIONS OF THE RESEARCH METHODS PAGEREF _Toc1645804069 \h 33 12. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS PAGEREF _Toc1232847817 \h 33 13. GOVERNANCE BOARD ASPECTS PAGEREF _Toc952613048 \h 33 14. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS PAGEREF _Toc984887294 \h 33 14.1 Study Report PAGEREF _Toc161408808 \h 33 15. OTHER RESULTS PAGEREF _Toc369778037 \h 34 16. REFERENCES PAGEREF _Toc192759253 \h 35 17. ANNEXES PAGEREF _Toc1209398043 \h 36 Appendix I – Table 1: Lists with concept definitions for exposure PAGEREF _Toc1125014451 \h 37 Appendix I – Table 2: Feasibility counts PAGEREF _Toc1922376850 \h 38 Appendix I – Table 3 Characteristics PAGEREF _Toc1595926755 \h 39 Appendix I – Table 4: Preliminary code lists for baseline characterization PAGEREF _Toc180485817 \h 41 Appendix II – ENCePP checklist PAGEREF _Toc1694075486 \h 42 Document History Version Date Description V1.0 23 rd June 2023 S ubmission to EMA Study Title DARWIN EU® - Co-prescribing of endothelin receptor antagonists (ERAs) and phosphodiesterate-5 inhibitors (PDE-5is) in pulmonary arterial hypertension (PAH) Protocol version identifier V 1 .0 Date of last version of protocol 23 rd June 2023 EU PAS register number To be completed after study approval by the EMA Active substance Drugs Class ATC code Ambrisentan Endothelin receptor antagonist C02KX02 B osentan Endothelin receptor antagonist C02KX01 M acitentan Endothelin receptor antagonist C02KX04 S ildenafil Phosphodiesterate-5 inhibitors G04BE03 S itaxentan Endothelin receptor antagonist C02KX03 T adalafil Phosphodiesterate-5 inhibitors G04BE08 Medicinal product N/A Research question and objectives Research question What is the utilization pattern of endothelin receptor antagonists (ERAs) and phosphodiesterase-5 inhibitors (PDE-5is) in pulmonary arterial hypertension (PAH) ? Study objectives Objective 1: To estimate propo rtions of individuals with pulmonary arterial hypertension (PAH) who initiate treatment with endothelin receptor antagonists (ERAs) or phosphodiesterase-5 inhibitors (PDE-5is), either as monotherapy or in combination, during the period from January 1, 2012, to December 31, 2022. Objective 2 : To estimate the duration of prescription for ERAs and PDE-5is in patients with PAH between January 1, 2012, and December 31, 2022 . Object ive 3 : To describe the prescription patterns of ERAs PDE-5is in patients newly diagnosed with PAH between January 1, 2012, and December 31, 2022. Objective 4 : To estimate the proportion of patients with the following events of interest : cardiovascular hospitalization, all-cause hospitalization and death among individuals newly diagnosed with PAH between January 1, 2012, and December 31, 2022. Countries of study Estonia, France, Germany, and t he United Kingdom. Author Johnmary Arinze (
[email protected]) Katia Verhamme (
[email protected] ) LIST OF ABBREVIATIONS Acronyms/terms Description CDM Common Data Model CHUBX Bordeaux University Hospital CPRD GOLD Clinical Practice Research Datalink GOLD DA Disease Analyzer DARWIN EU® Data Analysis and Real World Interrogation Network DUS Drug Utilization Study EBB Estonian Biobank EGCUT Estonian Genome Center at the University of Tartu EHR Electronic Health care Records EMA European Medicines Agency ERAs E ndothelin receptor antagonists GP General Practitioner ID Index date OHDSI Observational Health Data Sciences and Informatics OMOP Observational Medical Outcomes Partnership PAH P ulmonary arterial hypertension PDE-5is P hosphodiesterase-5 inhibitors Title DARWIN EU® - Co-prescribing of endothelin receptor antagonists (ERAs) and phosphodiesterate-5 inhibitors (PDE-5is) in pulmonary arterial hypertension (PAH) Responsible parties – study team Table 1 shows a description of the Study team by role, name and organization . Table SEQ Table \* ARABIC 1 : Description of Study Team Study team Role Names Organisation Principal Investigator (s) / Clinical Epidemiologists Johnmary Arinze Katia Verhamme Erasmus MC Erasmus MC Data Partner* Names Organization L ocal Study Coordinator/Data Analyst Antonella Delmestri James Brash Vianney Jouhet Raivo Kolde University of Oxford – CPRD data IQVIA DA Germany CHUBX France University of Tartu - Estonian Biobank *Data partners’ role is only to execute code at their data source. These people do not have an investigator role . ABSTRACT ( Stand alone summary of the study protocol) Title DARWIN EU® - Co-prescribing of endothelin receptor antagonists (ERAs) and phosphodiesterate-5 inhibitors (PDE-5is) in pulmonary arterial hypertension (PAH) Rationale and Background Pulmonary Arterial Hypertension ( PAH ) is a rare type of pulmonary hypertension characterized by increased mean pulmonary arterial pressure . PAH can be idiopathic, heritable, drug-induced, or secondary to other chronic diseases such as HIV infection, congenital heart diseases, portal hypertension. Median survival is about 7 years from the time of diagnostic catheterisation. The therapeutic management differs based on type and severity and usually involves a mono or combination therapy from the following agents: ERAs ( Endothelin receptor antagonists) , and PDE5-is ( Phosphodiesterase-5 inhibitors) . There is interest in understanding how these therapies are used in clinical practice t o contextualise assessments of potential future development programs in this indication . M acitentan and tadalafil are of particular interest . Research question and Objectives Research question : To understand how PAH is treated in clinical practice. Specific objectives of this study are listed below . Study objectives : ( 1 ) To estimate proportions of individuals with pulmonary arterial hypertension (PAH) who initiate treatment with endothelin receptor antagonists (ERAs) or phosphodiesterase-5 inhibitors (PDE-5is), either as monotherapy or in combination, during the period from January 1, 2012, to December 31, 2022. ( 2 ) To estimate the duration of prescription for ERAs and PDE-5is in patients with PAH between January 1, 2012, and December 31, 2022. (3) To describe the prescription patterns of ERAs PDE-5is in patients newly diagnosed with PAH between January 1, 2012, and December 31, 2022. (4) To estimate the proportion of patients with the following events of interest: cardiovascular hospitalization, all-cause hospitalization and death among individuals newly diagnosed with PAH between January 1, 2012, and December 31, 2022. Research Methods Study design Retrospective cohort study in individuals newly diagnosed with PAH . Cohort study ( Objectives 1, 3 and 4, Disease epidemiology – Patient level characterization ) New drug user cohort study (Objective 2 , Patient level drug utilization ) . Population Patient-level characteri zation – Disease epidemiology study : The patient-level characterization will involve individuals new ly diagnosed with PAH between January 1, 2012, and December 31, 2022 (or the latest available date), with at le ast 1 year of data availability prior to their diagnosis , and no record of being diagnosed with PAH in the previous year . To investigate treatment patterns, a minimum follow-up time of 30 days will be applied to capture PAH treatment (objective 1) , treatment sequences (objective 3) and proportion of outcomes of interest (objective 4). Patient-level drug utilization: New users of ERAs/PDE-5is in patients newly diagnosed with PA H in the period between January 1, 2012, and December 31, 2022 (or latest date available), with at least 1 year of data visibility prior to index date , and no use of the respective ERAs/PDE-5is in the previous 1 year , will be included for patient-level drug utilisation analyses. Therefore, children aged <1year will be excluded. Variables Drug of interest: Ambrisentan , Bosentan , Macitentan , Sildenafil, Sitaxentan , Tadalafil which will be identified through RxNorm drug codes. Condition of interest: PAH which will be identified through SNOMED disease codes. Outcomes of interest : Study outcomes will be identified based on the presence of events of cardiovascular hospitalisation, all-cause hospitalisation , and death . Data sources Clinical Data Warehouse of Bordeaux University Hospital (CHUBX), France Clinical Practice Research Datalink GOLD (CPRD GOLD), United Kingdom Estonian Biobank (EBB), Estonia IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany Sample size No sample size has been calculated as this is a Disease Epidemiology and Drug Utilization Study where we are interested in the characteristics and treatment of all incident PAH patients , regardless of sample size. Feasibility counts have been generated in the general population in each database and are described i n Appendix – Table 2 . Data analyses The number and % of patients receiving each of a pre-specified list of PAH treatments (objective 1) and treatment combinations (objective 3) will be described at index date, 1 to 30, 1 to 90, and 1 to 365 days post index date. A treatment pattern analysis will be conducted to describe the sequence of prescribing of the specific ERAs/PDE-5is following diagnosis. Index date will be the date of diagnosis of PAH. S unburst plots and Sankey diagrams will be used to describe treatment patterns and sequences over time (objective 3). Large-scale patient-level characterisation will be conducted to describe age and sex at time of PAH diagnosis. In addition, medical history will be assessed for anytime –and up to 36 6 days before index date and for 365 to index date. The medical history will include clinical symptoms and signs (chest pain, dyspnea, fatigue, syncope), comorbidities (obesity, congenital heart disease, heart failure, pulmonary embolism, chronic obstructive pulmonary disease, pulmonary fibrosis, obstructive sleep apnea and chronic kidney disease), and important factors possibly related to PAH diagnosis (idiopathic, heritable, connective tissue disease, corrected congenital shunts, drug or toxin induced PAH, and others). See Appendix 1 - Table 3 . We will also report the proportion of patients with outcomes of interest ( objective 4 ) for 1 to 30, 1 to 90, and 1 to 365 days post index date. Patient-level ERAs/ PDE-5is u se: P atient-level features ( See Appendix 1 - Table 3) will be characterized , and the treatment duratio n of prescriptions of the respective drugs of interest will be estimated . Index date will be the date of the first prescription of the specific ERAs / PDE-5is for each person. T reatment duration will be estimated for the first treatment era and the minimum, p25, median, p75, and maximum will be provided. For all analyses a minimum cell count of 5 will be used when reporting results, with any smaller counts obscured. AMENDMENTS AND UPDATES Number Date Section of study protocol Amendment or update Reason MILESTONES STUDY SPECIFIC DELIVERABLE TIMELINE Draft Study Protocol 23th June 2023 Final Study Protocol To be confirmed Creation of Analytical code To be confirmed Execution of Analytical Code on the data To be confirmed I nterim Study Report (if applicable) To be confirmed Draft Study Report To be confirmed Final Study Report To be confirmed RATIONALE AND BACKGROUND Pulmonary arterial hypertension (PAH) is a rare, chronic, and severe medical condition characterized by elevated pulmonary arterial pressure and vascular resistance ADDIN EN.CITE <EndNote><Cite><Author>Marc</Author><Year>2019</Year><RecNum>362</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>362</rec-number><foreign-keys><key app="EN" db-id="tsa2tzw5aarvs7ewdwvvwf9mdwvr90p9vs9r" timestamp="1686209854">362</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Marc, Humbert</author><author>Christophe, Guignabert</author><author>Sébastien, Bonnet</author><author>Peter, Dorfmüller</author><author>James, R. Klinger</author><author>Mark, R. Nicolls</author><author>Andrea , J. Olschewski</author><author>Soni, S. Pullamsetti</author><author>Ralph, T. Schermuly</author><author>Kurt , R. Stenmark</author><author>Marlene, Rabinovitch</author></authors></contributors><titles><title>Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives</title><secondary-title>European Respiratory Journal</secondary-title></titles><periodical><full-title>European Respiratory Journal</full-title></periodical><pages>1801887</pages><volume>53</volume><number>1</number><dates><year>2019</year></dates><urls><related-urls><url>http://erj.ersjournals.com/content/53/1/1801887.abstract</url></related-urls></urls><electronic-resource-num>10.1183/13993003.01887-2018</electronic-resource-num></record></Cite></EndNote> 1 . Its global prevalence ranges from 0.4 to 1.4 cases per 100,000 persons , with significant regional variations. ADDIN EN.CITE <EndNote><Cite><Author>Emmons-Bell</Author><Year>2022</Year><RecNum>360</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>360</rec-number><foreign-keys><key app="EN" db-id="tsa2tzw5aarvs7ewdwvvwf9mdwvr90p9vs9r" timestamp="1686209218">360</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Emmons-Bell, Sophia</author><author>Johnson, Catherine</author><author>Boon-Dooley, Alexandra</author><author>Corris, Paul A.</author><author>Leary, Peter J.</author><author>Rich, Stuart</author><author>Yacoub, Magdi</author><author>Roth, Gregory A.</author></authors></contributors><titles><title>Prevalence, incidence, and survival of pulmonary arterial hypertension: A systematic review for the global burden of disease 2020 study</title><secondary-title>Pulmonary Circulation</secondary-title></titles><periodical><full-title>Pulmonary Circulation</full-title></periodical><pages>e12020</pages><volume>12</volume><number>1</number><dates><year>2022</year></dates><isbn>2045-8940</isbn><urls><related-urls><url>https://onlinelibrary.wiley.com/doi/abs/10.1002/pul2.12020</url></related-urls></urls><electronic-resource-num>https://doi.org/10.1002/pul2.12020</electronic-resource-num></record></Cite></EndNote> 2 Idiopathic PAH is more common in North America and Europe, while acquired PAH is prevalent in Africa and Asia. PAH primarily affects females, especially in idiopathic and heritable cases, and can occur across all age groups ADDIN EN.CITE <EndNote><Cite><Author>Emmons-Bell</Author><Year>2022</Year><RecNum>360</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>360</rec-number><foreign-keys><key app="EN" db-id="tsa2tzw5aarvs7ewdwvvwf9mdwvr90p9vs9r" timestamp="1686209218">360</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Emmons-Bell, Sophia</author><author>Johnson, Catherine</author><author>Boon-Dooley, Alexandra</author><author>Corris, Paul A.</author><author>Leary, Peter J.</author><author>Rich, Stuart</author><author>Yacoub, Magdi</author><author>Roth, Gregory A.</author></authors></contributors><titles><title>Prevalence, incidence, and survival of pulmonary arterial hypertension: A systematic review for the global burden of disease 2020 study</title><secondary-title>Pulmonary Circulation</secondary-title></titles><periodical><full-title>Pulmonary Circulation</full-title></periodical><pages>e12020</pages><volume>12</volume><number>1</number><dates><year>2022</year></dates><isbn>2045-8940</isbn><urls><related-urls><url>https://onlinelibrary.wiley.com/doi/abs/10.1002/pul2.12020</url></related-urls></urls><electronic-resource-num>https://doi.org/10.1002/pul2.12020</electronic-resource-num></record></Cite></EndNote> 2 . Individuals with PAH experience progressive dyspnea , fatigue, exercise intolerance, impaired functional capacity, and reduced quality of life, imposing a substantial clinical burden. 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ADDIN EN.CITE <EndNote><Cite><Author>Mak</Author><Year>2017</Year><RecNum>368</RecNum><DisplayText><style face="superscript">4</style></DisplayText><record><rec-number>368</rec-number><foreign-keys><key app="EN" db-id="tsa2tzw5aarvs7ewdwvvwf9mdwvr90p9vs9r" timestamp="1686211119">368</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mak, S. M.</author><author>Strickland, N.</author><author>Gopalan, D.</author></authors></contributors><auth-address>Radiology Department, Hammersmith Hospital, London, UK.</auth-address><titles><title>Complications of pulmonary hypertension: a pictorial review</title><secondary-title>Br J Radiol</secondary-title></titles><periodical><full-title>Br J Radiol</full-title></periodical><pages>20160745</pages><volume>90</volume><number>1070</number><keywords><keyword>Diagnostic Imaging/ methods</keyword><keyword>Heart Diseases/diagnostic imaging/ etiology</keyword><keyword>Humans</keyword><keyword>Hypertension, Pulmonary/ complications/ diagnostic imaging</keyword><keyword>Lung Diseases/diagnostic imaging/etiology</keyword><keyword>Vascular Diseases/diagnostic imaging/ etiology</keyword></keywords><dates><year>2017</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1748-880X (Electronic)&#xD;0007-1285 (Print)&#xD;0007-1285 (Linking)</isbn><accession-num>27925469</accession-num><urls></urls></record></Cite></EndNote> 4 The median survival time from the time of diagnosis is approximately 6 – 9 years . 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defects, HIV infection, portal hypertension, and chronic liver disease. 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This study aim s to provide valuable insights into the prescription patterns of ERAs / PDE-5Is , user characteristics, and clinical outcomes among patients with pulmonary arterial hypertension in Europe. It will offer crucial context for effective post-marketing surveillance and evaluation of the real-world benefit-risk profiles of these medications in managing pulmonary arterial hypertension. RESEARCH QUESTION AND OBJECTIVES Research question: To understand how PAH is treated in clinical practice. Specific objectives of this study are listed below . Study objectives : (1) To estimate proportions of individuals with PAH who initiate treatment with ERAs or pPDE-5is, either as monotherapy or in combination, during the period from January 1, 2012, to December 31, 2022. (2) To estimate the duration of prescription for ERAs and PDE-5is in patients with PAH between January 1, 2012, and December 31, 2022. (3) To describe the prescription patterns of ERAs PDE-5is in patients newly diagnosed with PAH between January 1, 2012, and December 31, 2022. (4) To estimate the proportion of patients with the following events of interest: cardiovascular hospitalization, all-cause hospitalization and death among individuals newly diagnosed with PAH between January 1, 2012, and December 31, 2022. Table 1: Primary and secondary research questions and objective Objective: To describe the patient characteristics, treatment patterns of ERAs/PDE-5is, and the proportion of individuals with outcomes of interest ( cardiovascular hospitalization, all-cause hospitalization, and mortality) among individuals newly diagnosed with PAH, stratified by country/database. Hypothesis: N ot ap plicable Population (mention key inclusion-exclusion criteria): All Individuals newly diagnosed with PAH between January 1, 2012, and December 31, 2022 (or the latest available date), with at le ast 1 year of data availability prior to their diagnosis , and no record of being diagnosed with PAH in the previous year . Therefore, children aged <1year will be excluded. Exposure: Ambrisentan , Bosentan , Macitentan , Sildenafil, Sitaxentan , Tadalafil Comparator: None Outcome: C ardiovascular hospitalisation, all-cause hospitalisation, and death Time (when follow up begins and ends): Follow-up will start on the date of new diagnosis (index date) until the earliest of loss to follow-up, end of data availability or death, or end of study period (31st December 2022). Setting: Inpatient and outpatient setting using data from the following data sources: CPRD GOLD (UK), IQVIA DA (Germany), CHUBX (France), and Estonian Biobank (Estonia). Main measure of effect: P roportions, patient level drug utilisation to assess duration of use of the first exposure episode of the respective drugs of interest. RESEARCH METHODS S tudy Design This will be a patient-level characterisation study classified as “off-the-shelf” (C1) and as described in the DARWIN EU ® Complete Catalogue of Standard Data Analyses. A retrospective cohort study of all incident PAH will be conducted. A new drug user cohort will be used (Patient Level DUS) to characterise patient-level ERAs/ PDE-5is utilisation (treatment duration and patient characteristics of individuals exposed to the drug of interest) . Table 2. D escription of Potential Study Types and Related Study Designs STUDY TYPE STUDY DESIGN STUDY CLASSIFICATION Disease epidemiology - Patient-level characterisation Cohort analysis Off-the-shelf (C1) Patient Level DUS New drug/s user cohort Off the shelf (C1) Study Setting and data sources This study will be conducted using routinely collected data from 4 databases in 4 European countries ( 3 EU countries and United Kingdom). All databases were previously mapped to the OMOP CDM . Clinical Data Warehouse of Bordeaux University Hospital (CHUBX), France Clinical Practice Research Datalink GOLD (CPRD GOLD), United Kingdom Estonian Biobank (EBB), Estonia IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany Information on the data source(s) with a justification for their choice in terms of ability to capture the relevant data is described in a Table 3 . Table 3: Description of data sources Country Name of Database Justification for Inclusion Health Care setting Type of Data Number of active subjects Feasibility count of PAH Data lock for the last update France CHUBX Database covers hospital care setting where PAH treatment may be initiated Secondary care (in and outpatients) EHR 2.1 million 10,900 05/05/2023 UK CPRD GOLD Database covers primary care setting where ERAs/ PDE-5is prescriptions are issued. Also research on PAH has already been conducted using CPRD data . 1 Primary care EHR 3 million 6,459 20/03/2023 Estonia EBB Database covers information from primary care and secondary care setting ( insurance claims , digital prescriptions) where ERAs/ PDE-5is prescriptions are issued. Biobank Claims data 0.2 million 1,100 20/03/2023 Germany IQVIA DA Germany Database covers primary care and secondary care setting (outpatient specialist care) where ERAs/ PDE-5is prescriptions are issued. Research on PH (including PAH) has been conducted using IQVIA DA Germany data . Primary care and outpatient specialist care EHR 8.5 million 16,600 13/03/2023 PAH = Pulmonary arterial hypertension , CHUBX= Bordeaux University Hospital , UK = United Kingdom, , CPRD GOLD = Clinical Practice Research Datalink GOLD, EBB = Estonian Biobank, DA = Disease Analyzer , EHR = Electronic Heath record. Exposure is based on prescription data . Bordeaux University Hospital (CHUBX), France The clinical data warehouse of the Bordeaux University Hospital comprises electronic health records on more than 2 million patients with data collection starting in 2005. The hospital complex is made up of three main sites and comprises a total of 3,041 beds (2021 figures). 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). 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Y2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG== ADDIN EN.CITE.DATA 13 comprises computerized records of all clinical and referral events in primary care in addition to comprehensive demographic information and medication prescription data in a sample of UK patients (predominantly from Scotland (52% of practices) and Wales (28% of practices). The prescription records include information on the type of product, date of prescription, strength, dosage, quantity, and route of administration. Data from contributing practices are collected and processed into research databases. Quality checks on patient and practice level are applied during the initial processing. Data are available for 20 million patients, including 3.2 million currently registered patients. Access to CPRD GOLD data requires approval via the Research Data Governance Process. CPRD GOLD will be onboarded as Data Partner for DARWIN EU® in 2023 . Estonian Biobank – University of Tartu (Estonia) The Estonian Biobank (EBB) is a population-based biobank of the Estonian Genome Center at the University of Tartu (EGCUT). Its cohort size is currently close to 200,000 participants (“gene donors” >= 18 years of age) which closely reflects the age, sex and geographical distribution of the Estonian adult population. Genomic GWAS analysis have been performed on all gene donors. The database also covers health insurance claims, digital prescriptions, discharge reports, information about incident cancer cases and causes of death from national sources for each donor. IQVIA Disease Analyse r (DA) Germany, Germany DA Germany is collected from extracts of patient management software used by GPs and specialists practicing in ambulatory care settings ADDIN EN.CITE <EndNote><Cite><Author>Rathmann</Author><Year>2018</Year><RecNum>3</RecNum><DisplayText><style face="superscript">14</style></DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="rvs0z9trja0tr6es2zox5r9r9sxww9fz2f59" timestamp="1667165700">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rathmann, W.</author><author>Bongaerts, B.</author><author>Carius, HJ.</author><author>Kruppert, S.</author><author>Kostev, K.</author></authors></contributors><titles><title>Basic characteristics and representativeness of the German Disease Analyzer database</title><secondary-title>Int J Clin Pharmacol Ther</secondary-title></titles><periodical><full-title>Int J Clin Pharmacol Ther</full-title></periodical><pages>459-466</pages><volume>56</volume><number>10</number><dates><year>2018</year></dates><urls></urls></record></Cite></EndNote> 14 . Data coverage includes more than 34M distinct person records out of at total population of 80M (42.5%) in the country and collected from 2,734 providers. Patient visiting more than one provider are not cross identified for data protection reasons and therefore recorded as separate in the system. Dates of service include from 1992 through present. Observation time is defined by the first and last consultation dates. Germany has no mandatory GP system and patient have free choice of specialist. As a result, data are collected from visits to 28.8% General, 13.4% Orthopaedic Surgery, 11.8% Otolaryngology, 11.2% Dermatology, 7.7% Obstetrics/Gynaecology, 6.2% various Neurology and Psychiatry 7.0% Paediatric, 4.6% Urology, 3.7% Cardiology, 3.5% Gastroenterology, 1.5% Pulmonary and 0.7% Rheumatology practices. Drugs are recorded as prescriptions of marketed products. No registration or approval is required for drug utilisation studies. Study Period The study period will be from 01/01/2012 to end of available data in each of the data sources (see Table 3 for more details). Follow-up Study participants will be followed up from their date of first PAH diagnosis (i.e. index date) until the earliest of the following: 1) loss to follow-up, 2) end of data availability, or 3) date of death. For the Patient-level Utilisation of ERAs/ PDE-5is (i.e. to explore duration of use) , p articipants will be followed up from the day of therapy initiation, i.e. the date of the first prescription of the drugs of interest medication (index date), until the earliest of loss to follow-up, end of data availability, death, or end of continuous exposure. Table 4 : Operational Definition of Time 0 (index date) and other primary time anchors Study population name(s) Time Anchor Description (e.g., time 0) Number of entries Type of entry Washout window Care Setting 1 Code Type 2 Diagnosis position Incident with respect to… Measurement characteristics/ validation Source of algorithm All patients from the database eligible for the study and newly diagnosed with PAH Patient present in the database during the study period (2012-2022) and with at least 1 year of valid database history, and no record PAH diagnosis in the previous year Single Incident [-365] IP and OP n/a n/a PAH n/a n/a All patients from the database eligible for the study – Analysis of incident use in patients with newly diagnosed PAH Patient present in the database during the study period (2012-2022) and with at least 1 year of valid database history Multiple Incident [- 365 ] IP and OP n/a n/a Overall, substance n/a n/a 1 IP = inpatient, OP = outpatient, n/a = not applicable , PAH = Pulmonary arterial hypertension Study population with inclusion and exclusion criteria The study cohort will comprise all individuals newly diagnosed with PAH present in the database during the study period (2012-2022) and with at least 365 days of data availability before the day they become eligible for study inclusion. The requirement of at least 365 days of data history will also hold for children. Therefore, children aged <1year will be excluded. Given its complexity, rarity, and multifactorial nature, diagnosing PAH typically requires a comprehensive evaluation involving clinical assessment for signs/symptoms as well as various diagnostic procedures and tests. These may include electrocardiogram, chest radiography, pulmonary function tests, arterial blood gases, echocardiography, ventilation/perfusion lung scan, non-contrast and contrast-enhanced chest computed tomography examinations, digital subtraction angiography, cardiac magnetic resonance imaging, blood tests, immunology, abdominal ultrasound, cardiopulmonary exercise testing, vasoreactivity assessment, fluid challenge, and right heart catheterization. Right heart catheterization is considered the gold standard for diagnosing and classifying PAH. It provides valuable information about pulmonary arterial pressures and hemodynamic parameters. 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The OMOP CDM relies on the SNOMED as the standardized vocabulary for diagnosis codes, ensuring uniform and consistent classification of various conditions. Additional eligibility criteria where patients are required to have at least a minimum follow-up time of 30 days to capture PAH treatment (objective 1), treatment sequences (objective 3) and proportion of outcomes of interest (objective 4 ) . Table 5 . Operational Definitions of Inclusion Criteria Criterion Details Order of application Assessment window Care Settings¹ Code Type Diagnosis position Applied to study populations: Measurement characteristics/validation Source for algorithm Prior database history of 1 year (objective s 1 , 2, 3 and 4 ) Study participants will be required to have a year of prior history observed before contributing observation time After 1 year IP, OP, OT N/A N/A All study participants with incident PAH N/A N/A Minimum follow-up (objectives 1, 3 , and 4 ) Study participants will be required to have at least a minimum follow-up time of 30 days . After 30 days IP, OP, OT N/A N/A All study participants with incident PAH N/A N/A Minimum potential follow-up time (objective 4) Only participants with a diagnosis of PAH (index date) occurring one year prior to end of data availability in the database will be included to allow sufficient follow-up time to capture treatment and outcomes After 1 year IP, OP, OT N/A N/A All study participants with incident PAH N/A N/A 1 IP = inpatient, OP = outpatient, OT = other, n/a = not applicable Variables Exposure For this study, the exposure of interest is prescription (during study period) of Ambrisentan , Bosentan , Macitentan , Sildenafil, Sitaxentan , and Tadalafil . Exposure will be grouped at drug substance level and assessed as monotherapy or combination therapy through the treatment pattern analysis (see 8.8.3) . This list of the drugs of interests (with respective ATC code) is described in Table 6 . Respective RxNorm codes ( at ingredient level) are provided in appendix 1 – table 1. Table 6 : Exposure of interest Drugs Class ATC code Ambrisentan Endothelin receptor antagonist C02KX02 B osentan Endothelin receptor antagonist C02KX01 M acitentan Endothelin receptor antagonist C02KX04 S ildenafil Phosphodiesterate-5 inhibitors G04BE03 S itaxentan Endothelin receptor antagonist C02KX03 T adalafil Phosphodiesterate-5 inhibitors G04BE08 Table 7 : Exposure details Exposure group name(s) Details Washout window Assessment Window Care Setting Code Type Diagnosis position Applied to study populations: Incident with respect to… Measurement characteristics/ validation Source of algorithm Overall ERAs/ PDE-5is , substance, strength, route Preliminary code lists provided in Table 6 (and table 1 of Appendix 1) – 1 year Calendar year Biobank, primary and secondary care RxNorm N/A All individuals newly diagnosed with PAH present in the database during the study period Previous ERAs/ PDE-5is use N/A N/A Outcome / s This study will examine the following four primary outcomes of interest . Initiation of treatment for PAH I nitiation of treatments will be assessed within a window of 30, 90, and/or 365 days following diagnosis . In relation to the first outcome, a predefined list of PAH treatments will be compiled to address Objectives 1, 2, and 3. PAH treatments will include Ambrisentan , Bosentan , Macitentan , Sildenafil, Sitaxentan , and Tadalafil as listed in Table 6. All cause-hospitalisation All-cause hospitalization will be determined by examining medical records with visit codes indicating inpatient visits or hospital admissions following the diagnosis of PAH (i.e. index date). This will be assessed in a window of 365 days following diagnosis of PAH . cardiovascular hospitalization Cardiovascular hospitalisation as an outcome will be identified through a SNOMED code occurring within 7 days prior to admission, during hospitalization, or within 7 days following discharge will be considered as instances of cardiovascular hospitalization. Cardiovascular hospitalisation will be assessed in a window of 365 days following diagnosis of PAH . Mortality Overall mortality in patients with PAH will also be identified based on the registered date of death . Table 8. Operational Definitions of Outcome Outcome name Details Primary outcome ? Type of outcome Washout window Care Settings¹ Code Type Diagnosis Position Applied to study populations : Measurement characteristics / validation Source of algorithm PAH treatments Preliminary code lists provided in Table 6 Yes Counts and % 365 days as incident use only IP and OP care RxNorm N/A All study participants with incident PAH N/A N/A Hospitalization (All-cause/ cardiovascular) Based on visit type within OMOP-CDM Yes % N/A IP and OP care Date of inpatient visit N/A All study participants with incident PAH N/A N/A Mortality Based on date of death Yes % N/A IP and OP care Date of death N/A All study participants with incident PAH N/A N/A 1 IP = inpatient, OP = outpatient, n/a = not applicable Other covariates, including confounders, effect modifiers and other variables (where relevant) Age at PAH diagnosis will be described. The following age grouping will be used: 0-17; 18-44; 45-64; 65 and over. The sex (male/ female) of study participants will also be identified. All co-morbidities and co ncomitant -medications recorded prior ( any time prior to the ID, 365 to 31 days prior to the ID an d -30 to 1 day before ID ) will be used for large-scale patient characterisation, identified as concept/code and descendants. A list of pre-specified co-morbidities and co-medications will also be provided . These will include: Medical History: c hest pain, dyspnoea , fatigue, syncope, obesity, heart failure, pulmonary embolism, asthma, COPD , idiopathic pulmonary fibrosis, obstructive sleep apnoea , chronic kidney disease, connective tissue disorder, Hu man Immunodeficiency Virus (HIV ) infection , diabetes mellitus, and systemic hypertension . Concomitant Medication use: selective serotonin reuptake i nhibitors, aminorex, fenfluramine, benfluorex, phenylpropanolamine, dexfenfluramine, tryptophan, lithium, i nterferon , sofosbuvir, dasatinib , Nilotinib, ponatinib, carfilzomib, ruxolitinib , buprenorphine, tramadol, thalidomide, paclitaxel, b leomycin, cyclophosphamide, mitomycin , phentermine, mazindol. Concept IDs of these drugs and conditions have been added to the appendix I – table 4 . These codes (with descendant codes) will be further reviewed prior to the analysis. Table 9 : Operational Definitions of Covariates Characteristic Details Type of variable Assessment window Care Settings¹ Code Type 2 Diagnosis Position 3 Applied to study populations: Measurement characteristics/ validation Source for algorithm Co-morbidities Large-scale patient-level characterisation with regard to underlying comorbidities Counts At index date (ID), for 30 to 1 day before ID, for 365 to 31 days before ID, at any time before ID OP, IP, OT SNOMED N/A N/A N/A N/A Concomitant medication # Large-scale patient-level characterisation with regard to use of concomitant drugs Counts At index date (ID), for 30 to 1 day before ID, for 365 to 31 days before ID OP, IP, OT RxNorm N/A N/A N/A N/A 1 IP = inpatient, OP = outpatient, OT = other, n/a = not applicable # ERAs/ PDE-5is are the exposures of interest and are not considered as concomitant medication Study size No sample size has been calculated as this is a Disease Epidemiology and Drug Utilization Study where we are interested in the characteristics of all incident PAH cases and their treatments , regardless of sample size. A table with feasibility counts is available in appendix I – table 2. Analysis Table 9. Description of Study Types and Type of analysis STUDY TYPE STUDY CLASSIFICATION TYPE OF ANALYSIS Disease epidemiology - Patient-level characterisation Off- the - shelf (C1) large-scale characterisation patient-level characteristics Standard care description 8.8.1 Federated Network Analyses Analyses will be conducted separately for each database. Before study initiation, test runs of the analytics are performed 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 package 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 by 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 during the study execution for support. 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 R-packages We will use the R packages “ CohortDiagnostics ” for the patient-level characterization of demographics and clinical characteristics, as well as “ TreatmentPatterns ” for the patient-level characterisation of treatments . Patient-level characterisation Large-scale patient-level characterisation will be conducted (objective 1). Age and sex at time of PAH diagnosis will be described. Medical history and concomitant medication (excluding PAH treatments) will be assessed for anytime – and up to 366 days before index date, for 365 to 31 days before index date, for 30 to 1 day before index date, and at index date. These time windows were defined based on the options currently available in the standard analytical tools that will be used in this projec t. Co-variates to be presented in a summary baseline characteristics table will be pre-defined as described in section 8.6.3. To characterise treatment of PAH, t he number and % of patients receiving each of a pre-specified list of PAH treatments (objective 2, as listed in section 8.6.2) will be described at index date, 1 to 30, 1 to 90, and 1 to 365 days post index date . The index date will be the date of the PAH diagnosis for each patient. A treatment pattern analysis will be conducted to describe how use of PAH evolves over time. This analysis will produce sunburst plots and Sankey diagrams to describe treatment p atterns over time (objective 3) . The number and % of patients with all-cause and cardiovascular hospitalization will be estimated from time of PAH diagnosis to the date of first hospital admission or inpatient care due to any cause, and additionally for any cardiovascular condition (objective 4). Overall mortality (objective 4) will be calculated from the time of PAH diagnosis to death due to any cause. Proportion of patients who died will be reported. Individuals who are lost to follow-up will be censored at the time of loss of follow-up. This analysis will be conducted only for databases with complete information on mortality. For all analyses n and % will be reported. A minimum cell count of 5 will be used when reporting results, with any smaller counts reported as “<5”. Al l analyses will be reported by country/database, overall and stratified by age and sex when possible (minimum cell count reached) . Additionally, to capture treatments availability and changes over time, sunburst plots, and Sankey diagrams will be further stratified by study periods (2012-2017 and 2018-2022) . 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. 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 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-identifiab le aggregate summary results. The output files are stored in the DARWIN Digital Research Environment. These output files do not contain any data that allow identification of subjects included in the study. The DRE implements further security measures in order 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 A number of 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, it is expected that data partners will have 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 align with external benchmarks with expectations derived from known true standards, while verification relates to how well data conform to local knowledge, metadata descriptions, and system assumptions. Study specific quality control When defining multiple myeloma, a systematic search of possible codes for inclusion was previously 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 common data model so as to find potentially relevant codes. 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 PAH in each of the databases, and inform decisions around whether multiple definitions are required. The study code will be based on two R packages currently being developed to (1) characterise demographic and clinical characteristics, (2) characterise treatment patterns, and (3) estimate hospitalization and overall survival using the OMOP CDM. These packages will include numerous automated unit tests to ensure the validity of the codes, alongside software peer review and user testing. The R package will be made publicly available via GitHub. 11. LIMITATIONS OF THE RESEARCH METHODS The study will utilize routinely collected healthcare data, and it is important to address any potential data quality issues. One specific concern is the variation in recording comorbidities across different databases. While false positives are expected to be minimal, there may be a higher likelihood of false negatives, especially in databases that lack patient-level linkage to secondary care data. However, it is worth noting that two of the included databases, IQVIA Germany and CPRD, have previously conducted research on pulmonary arterial hypertension. This prior experience reduces the potential for misclassification. Additionally, we have included CHUBX, a hospital database with expertise in the treatment of pulmonary arterial hypertension. This inclusion provides reassurance that PAH cases in this database will be well phenotyped , ensuring accurate characterization of the condition. It is important to mention that the IQVIA DA Germany database does not provide information on the date of death. Consequently, we will not be able to provide data on the proportion of patients who died during the one year following diagnosis specifically for this database. Furthermore, it is worth noting that the recording of events used for patient characterization may vary across the databases, and the documentation of treatment us e may be incomplete. 12. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS In agreement with the guideline on good pharmacovigilance practice (EMA/873138/2011), there will be no requirement for expedited reporting of adverse drug reactions as only secondary data will be used in this study. 13. GOVERNANCE BOARD ASPECTS All data sources require approval from their respective IRB boards, with the exception of IQVIA DA Germany which will not require any further specific approvals to undertake this study. 1 4 . PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS All data sources require approval from their respective IRB boards, with the exception of IQVIA DA Germany which will not require any further specific approvals to undertake this study. this study. 14.1 Study Report 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. The full set of underlying aggregated data used in the dashboard will also be made available if requested. 15. OTHER RESULTS N/A 16. REFERENCES ADDIN EN.REFLIST 1. Marc H, Christophe G, Sébastien B, Peter D, James RK, Mark RN, Andrea JO, Soni SP, Ralph TS, Kurt RS, et al. Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. European Respiratory Journal . 2019;53:1801887. doi: 10.1183/13993003.01887-2018 2. Emmons-Bell S, Johnson C, Boon-Dooley A, Corris PA, Leary PJ, Rich S, Yacoub M, Roth GA. Prevalence, incidence, and survival of pulmonary arterial hypertension: A systematic review for the global burden of disease 2020 study. Pulmonary Circulation . 2022;12:e12020. doi: h HYPERLINK "ttps://doi.org/10.1002/pul2.12020 " ttps://doi.org/10.1002/pul2.12020 3. Tobita K, Goda A, Teruya K, Nishida Y, Takeuchi K, Kikuchi H, Inami T, Kohno T, Tashiro S, Yamada S, et al. Exercise Capacity and Ventilatory Efficiency in Patients With Pulmonary Arterial Hypertension. J Am Heart Assoc . 2023;12:e026890. 4. Mak SM, Strickland N, Gopalan D. Complications of pulmonary hypertension: a pictorial review. Br J Radiol . 2017;90:20160745. 5. Hendriks PM, Staal DP, van de Groep LD, van den Toorn LM, Chandoesing PP, Kauling RM, Mager H-J, van den Bosch AE, Post MC, Boomars KA. The evolution of survival of pulmonary arterial hypertension over 15 years. Pulmonary Circulation . 2022;12:e12137. doi: https://doi.org/10.1002/pul2.12137 6. Quezada Loaiza CA, Velázquez Martín MT, Jiménez López-Guarch C, Ruiz Cano MJ, Navas Tejedor P, Carreira PE, Flox Camacho Á, de Pablo Gafas A, Delgado Jiménez JF, Gómez Sánchez MÁ, et al. Trends in Pulmonary Hypertension Over a Period of 30 Years: Experience From a Single Referral Centre. Revista Española de Cardiología (English Edition) . 2017;70:915-923. doi: 10.1016/j.rec.2016.12.044 7. Dardi F, Guarino D, Cennerazzo F, Ballerini A, Magnani I, Bertozzi R, Donato F, Martini G, Manes A, Galiè N, et al. Pulmonary Arterial Hypertension Associated with Portal Hypertension and HIV Infection: Comparative Characteristics and Prognostic Predictors. J Clin Med . 2023;12. 8. Lan NSH, Massam BD, Kulkarni SS, Lang CC. Pulmonary Arterial Hypertension: Pathophysiology and Treatment. Diseases . 2018;6. 9. McLaughlin VV, Gaine SP, Howard LS, Leuchte HH, Mathier MA, Mehta S, Palazzini M, Park MH, Tapson VF, Sitbon O. Treatment goals of pulmonary hypertension. J Am Coll Cardiol . 2013;62:D73-81. 10. McLaughlin VV, Shah SJ, Souza R, Humbert M. Management of pulmonary arterial hypertension. J Am Coll Cardiol . 2015;65:1976-1997. 11. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation . 2009;119:2250-2294. 12. Brat GA, Weber GM, Gehlenborg N, Avillach P, Palmer NP, Chiovato L, Cimino J, Waitman LR, Omenn GS, Malovini A, et al. International electronic health record-derived COVID-19 clinical course profiles: the 4CE consortium. NPJ Digit Med . 2020;3:109. doi: 10.1038/s41746-020-00308-0 13. Herrett E, Gallagher AM, Bhaskaran K, Forbes H, Mathur R, van Staa T, Smeeth L. Data Resource Profile: Clinical Practice Research Datalink (CPRD). Int J Epidemiol . 2015;44:827-836. doi: 10.1093/ije/dyv098 14. Rathmann W, Bongaerts B, Carius H, Kruppert S, Kostev K. Basic characteristics and representativeness of the German Disease Analyzer database. Int J Clin Pharmacol Ther . 2018;56:459-466. 15. Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, Carlsen J, Coats AJS, Escribano-Subias P, Ferrari P, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J . 2023;61. 17. ANNEXES Appendix I : List of Stand-Alone documents ( e.g., lists with concept codes (conditions & drugs etc. ) Appendix II : ENCePP checklist for study protocols Appendix I – Table 1 : Lists with concept definitions for exposure Prescriptions will be identified based on the relevant ingredient. Non-systemic products will be excluded from the code list. Drugs Class ATC code Concept id Ambrisentan Endothelin receptor antagonist C02KX02 1337068 B osentan Endothelin receptor antagonist C02KX01 1321636 , 19113007 M acitentan Endothelin receptor antagonist C02KX04 44507580 S ildenafil Phosphodiesterate-5 inhibitors G04BE03 1316262 S itaxentan Endothelin receptor antagonist C02KX03 36878846 , 44012794 T adalafil Phosphodiesterate-5 inhibitors G04BE08 1336926 , 36849344 Appendix I – Table 2 : Feasibility counts CPRD Gold DA_Germany CHUBX Estonian Biobank Country UK Germany France Estonia Type of database GP Outpatient ( GPs and proportion of specialist ) Secondary care (in and outpatients ) Biobank Number of individuals 17.1M 40.9M 2.19M 0.2M Patient counts Condition Era RC Condition Era RC Condition Era RC Counts of PAH 6,459 16,600 10,900 1,100 Patient counts Drug Era RC Drug Era RC Drug Era RC Counts of macitentan 13 300 <5 <5 Counts of tadalafil 111,602 236,900 1,400 10,000 Counts of sildenafil 280,179 440,100 2,000 26,800 Counts of b osentan 124 900 2,700 100 Counts of ambrisentan 31 100 800 100 Counts of sitaxentan <5 100 <5 <5 PAH: Pulmonary arterial hypertension NA= Not available (as no disease code for pulmonary arterial hypertension in source data) , M= million RC= Record counts . Drug Era: Successive periods of Drug Exposures are combined under certain rules to produce continuous Drug Eras Appendix I – Table 3 Characteristics Characteristics CHUBX CPRD GOLD EBB IQVIA DA Germany Number of patients Treated, % Follow up time after index (days), Mean (SD) Age at index (years), Mean (SD) Female sex, % Clinical symptoms & signs Chest pain Dyspnoea Fatigue Syncope Comorbidities (%) Obesity H eart failure Pulmonary embolism Asthma COPD Idiopathic p ulmonary fibrosis Obstructive sleep apnoea Chronic kidney disease Conne ctive tissue disorder Human Immunodeficiency Virus (HIV) infection Diabetes mellitus Systemic hypertension Ischemic heart disease Drugs associated with PAH (%) Selective serotonin reuptake inhibitors Aminorex Fenfluramine Benfluorex Phenylpropanolamine Dexfenfluramine Tryptophan Lithium Interferon Sofosbuvir Dasatinib Nilotinib Ponatinib Carfilzomib Ruxolitinib Buprenorphine Tramadol Thalidomide Paclitaxel Bleomycin Cyclophosphamide Mitomycin Phentermine Mazindol Appendix I – Table 4: Preliminary code lists for baseline characterization C linical observations/ conditions Concept ID Code Chest pain 7 7670 2 9857009 Dyspnea 312437 267036007 Fatigue 4223659 84229001 Syncope 135360 271594007 Obesity 433736 414916001 Heart failure 316139 84114007 Pulmonary embolism 440417 59282003 Asthma 317009 195967001 COPD 255573 13645005 Idiopathic p ulmonary fibrosis 45763750 700250006 Obstructive sleep apnea 442588 78275009 C hronic kidney disease 46271022 709044004 Connective tissue disorder 253549 105969002 Human Immunodeficiency Virus (HIV) infection 439727 86406008 Diabetes mellitus 201820 73211009 Systemic hypertension 320128 59621000 Drugs associated with PAH 4185932 414545008 Selective serotonin reuptake inhibitors 21604709 N06AB Aminorex 36850446 OMOP5168063 Fenfluramine 753860 4328 B enfluorex 19035533 18880 P henylpropanolamine 1139993 8175 D exfenfluramine 719057 3268 T ryptophan 19006186 10898 Lithium 19124477 6448 Interferon 35884376 OMOP5031280 S ofosbuvir 44785094 1484911 D asatinib 1358436 475342 Nilotinib 1394023 662281 P onatinib 43013182 1364347 C arfilzomib 42873638 1302966 R uxolitinib 40244464 1193326 B uprenorphine 1133201 1819 Tramadol 1103314 10689 T halidomide 19137042 10432 P aclitaxel 1378382 56946 B leomycin 1329241 1622 C yclophosphamide 1310317 3002 M itomycin 1389036 632 P hentermine 735340 8152 M azindol 794229 6664 Appendix II – ENCePP checklist ENCePP Checklist for Study Protocols (Revision 4 ) A dopted by the ENCePP Steering Group on 15/10/2018 The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance ( ENCePP ) welcomes innovative designs and new methods of research. This Checklist has been developed by ENCePP to stimulate consideration of important principles when designing and writing a pharmacoepidemiological or pharmacovigilance study protocol. The Checklist is intended to promote the quality of such studies, not their uniformity. The user is also referred to the ENCePP Guide on Methodological Standards in Pharmacoepidemiology , which reviews and gives direct electronic access to guidance for research in pharmacoepidemiology and pharmacovigilance. For each question of the Checklist, the investigator should indicate whether or not it has been addressed in the study protocol. If the answer is “Yes”, the section number of the protocol where this issue has been discussed should be specified. It is possible that some questions do not apply to a particular study (for example , in the case of an innovative study design). In this case, the answer ‘N/A’ (Not Applicable) can be checked and the “Comments” field included for each section should be used to explain why. The “Comments” field can also be used to elaborate on a “No” answer. This Checklist should be included as an Annex by marketing authorisation holders when submitting the protocol of a non-interventional post- authorisation safety study (PASS) to a regulatory authority (see the Guidance on the format and content of the protocol of non-interventional post- authorisation safety studies ). T he Checklist is a supporting document and does not replace the format of the protocol for PASS presented in the Guidance and Module VIII of the Good pharmacovigilance practices (GVP). Study title: DARWIN EU® - Co-prescribing of endothe lin receptor antagonists and phosphodi esterate-5 inhibitors in pulmonary arterial hypertension (PAH) . EU PAS Register ® number: S tudy reference number (if applicable) : Section 1: Milestones Yes No N/A Section Number 1.1 Does the protocol specify timelines for 1.1 .1 Start of data collection FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 6 - milestones 1.1.2 End of data collection FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 1.1.3 Progress report(s) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 1.1.4 Interim report(s) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 1.1.5 Registration in the EU PAS Register ® FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 1.1.6 Final report of study results. FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX Comments: Section 2: Research question Yes No N/A Section Number 2.1 Does the formulation of the research question and objectives clearly explain: FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 6- Background and 8- Research questions and objectives 2.1.1 Why the study is conducted? (e.g. to address an important public health concern, a risk identified in the risk management plan, an emerging safety issue) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 2.1.2 The objective(s) of the study? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 2.1.3 The target population? (i.e. population or subgroup to whom the study results are intended to be generalized) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 2.1.4 Which hypothesis(-es) is (are) to be tested? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 2.1.5 If applicable, that there is no a priori hypothesis? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX Comments: Section 3: Study design Yes No N/A Section Number 3.1 Is the study design described? (e.g., cohort, case-control, cross-sectional, other design) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.1 3.2 Does the protocol specify whether the study is based on primary, secondary or combined data collection? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.4 3.3 Does the protocol specify measures of occurrence? (e.g., rate, risk, prevalence) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.1 and 9.7.5.1 3.4 Does the protocol specify measure(s) of association? (e.g., risk, odds ratio, excess risk, rate ratio, hazard ratio, risk/rate difference, number needed to harm (NNH)) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 3.5 Does the protocol describe the approach for the collection and reporting of adverse events/adverse reactions? (e.g. adverse events that will not be collected in case of primary data collection) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX Comments: Section 4: Source and study populations Yes No N/A Section Number 4.1 Is the source population described? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.4 4.2 Is the planned study population defined in terms of: 9.2.1 4.2.1 Study time period FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 4.2.2 Age and sex FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 4.2.3 Country of origin FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 4.2.4 Disease/indication FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 4.2.5 Duration of follow-up FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 4.3 Does the protocol define how the study population will be sampled from the source population? (e.g., event or inclusion/exclusion criteria) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.2.3 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 categorizing exposure, measurement of dose and duration of drug exposure) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.3.1 5.2 Does the protocol address the validity of the exposure measurement? (e.g., precision, accuracy, use of validation sub-study) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 5.3 Is exposure categorized according to time windows? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.3.1 5.4 Is intensity of exposure addressed? (e.g., dose, duration) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.7.3 5.5 Is exposure categorized based on biological mechanism of action and taking into account the pharmacokinetics and pharmacodynamics of the drug? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 5.6 Is (are) (an) appropriate comparator(s) identified? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX Comments: Section 6: Outcome definition and measurement Yes No N/A Section Number 6.1 Does the protocol specify the primary and secondary (if applicable) outcome(s) to be investigated? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 6.2 Does the protocol describe how the outcomes are defined and measured? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 6.3 Does the protocol address the validity of outcome measurement? (e.g. precision, accuracy, sensitivity, specificity, positive predictive value, use of validation sub-study) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 6.4 Does the protocol describe specific outcomes relevant for Health Technology Assessment? (e.g. HRQoL , QALYs, DALYS, health care services utilization, burden of disease or treatment, compliance, disease management) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX Comments: Section 7: Bias Yes No N/A Section Number 7.1 Does the protocol address ways to measure confounding? (e.g., confounding by indication) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 7.2 Does the protocol address selection bias? (e.g. healthy user/adherer bias) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 7.3 Does the protocol address information bias? (e.g. misclassification of exposure and outcomes, time-related bias) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 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 analyses, anticipated direction of effect) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 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: 9.1.1 Exposure? (e.g., pharmacy dispensing, general practice prescribing, claims data, self-report, face-to-face interview) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.4 9.1.2 Outcomes? (e.g., clinical records, laboratory markers or values, claims data, self-report, patient interview including scales and questionnaires, vital statistics) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.1.3 Covariates and other characteristics? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.4 and 9.3.3 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, number of days of supply prescription, daily dosage, prescriber) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.4 and 9.7.3 9.2.2 Outcomes? (e.g. date of occurrence, multiple event, severity measures related to event ) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.2.3 Covariates and other characteristics? (e.g., age, sex, clinical and drug use history, co-morbidity, co-medications, lifestyle) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.4 and 9.7.3 9.3 Is a coding system described for: 9.3.1 Exposure? (e.g. WHO Drug Dictionary, Anatomical Therapeutic Chemical (ATC) Classification System) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.4 9.3.2 Outcomes? (e.g., International Classification of Diseases (ICD), Medical Dictionary for Regulatory Activities (MedDRA)) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.3.3 Covariates and other characteristics? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.4 9.4 Is a linkage method between data sources described? (e.g. based on a unique identifier or other) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX Comments: Section 10: Analysis plan Yes No N/A Section Number 10.1 Are the statistical methods and the reason for their choice described? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.7 10.2 Is study size and/or statistical precision estimated? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 10.3 Are descriptive analyses included? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.7 10.4 Are stratified analyses included? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.7 10.5 Does the plan describe methods for analytic control of confounding? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 10.6 Does the plan describe methods for analytic control of outcome misclassification? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 10.7 Does the plan describe methods for handling missing data? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 10.8 Are relevant sensitivity analyses described? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.7.6 Comments: Section 11: Data management and quality control Yes No N/A Section Number 11.1 Does the protocol provide information on data storage? (e.g., software and IT environment, database maintenance and anti-fraud protection, archiving) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.8 11.2 Are methods of quality assurance described? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 9.8 11.3 Is there a system in place for independent review of study results? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX Comments: Section 12: Limitations Yes No N/A Section Number 12.1 Does the protocol discuss the impact on the study results of: 9.9 12.1.1 Selection bias? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 12.1.2 Information bias? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 12.1.3 Residual/unmeasured confounding? (e.g., anticipated direction and magnitude of such biases, validation sub-study, use of validation and external data, analytical methods). FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 12.2 Does the protocol discuss study feasibility? (e.g. study size, anticipated exposure uptake, duration of follow-up in a cohort study, patient recruitment, precision of the estimates) FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX Comments: Section 13: Ethical/data protection issues Yes No N/A Section Number 13.1 Have requirements of Ethics Committee/ Institutional Review Board been described? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 10 13.2 Has any outcome of an ethical review procedure been addressed? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 10 13.3 Have data protection requirements been described? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 10 Comments: Section 14: Amendments and deviations Yes No N/A Section Number 14.1 Does the protocol include a section to document amendments and deviations? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 5 Comments: Section 15: Plans for communication of study results Yes No N/A Section Number 15.1 Are plans described for communicating study results (e.g., to regulatory authorities) ? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 12 15.2 Are plans described for disseminating study results externally, including publication? FORMCHECKBOX FORMCHECKBOX FORMCHECKBOX 12 Comments: Name of the main author of the protocol: Johnmary T. Arinze Date: 2 3 /06/2023 Signature: J.T. Arinze
Saatja: Raivo Kolde <
[email protected]>
Saadetud: 05.07.2023 14:42
Adressaat: <"SM Info">
Teema: Taotlus eesti bioeetika ja inimuuringute nõukogule
uurimisprotokolli kooskõlastamiseks
Manused: D2.2.2_DARWIN_EU_Study_Protocol_P2_C1-003_v1.docx
Tere
Euroopa ravimiameti (EMA) DARWIN projektile on EBIN väljastanud raamloa
(otsus nr 1.1-12/1832), kuid iga uuringu jaoks on vaja kooskõlastada
kiirmenetlusega ka uuringu protokoll.
Nüüd soovib EMA uurida erinevate südameravimite kooskasutamist. Vastava
uuringu protokoll on manuses ja me sooviks seda kiirmenetluse korras
kooskõlastada.
Lugupidamisega,
Raivo Kolde